RU2347784C2 - Macrocyclic compounds, medicinal agents based on them and their use - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I):

(where R³, R⁶, R⁷ and R²¹ can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

Description

FIELD OF THE INVENTION

The present invention relates to a 12-membered cyclic macrolide compound, which can be used as a medicine, its preparation and its use.

BACKGROUND OF THE INVENTION

Compounds with cytotoxicity have already been used as antitumor agents, and many studies have already been conducted by screening using cytotoxicity as an indicator. The results showed that most of the existing antitumor agents affect cancer cells and, at the same time, normal tissues in which cell proliferation is active, for example, bone marrow, intestinal epithelium and the like. Thus, the improvement in QOL of patients is not yet sufficiently ensured.

In addition, although it is hoped that treatment with anticancer agents will be quite effective in leukemia, it cannot always be said that it will be effective for a malignant tumor. Therefore, there was a great need for the creation of antitumor agents effective against a solid tumor and highly safe.

Studies have already been conducted by screening the fermentation products of microorganisms using in vitro cytotoxicity as an indicator in the hope that they can also be used as antitumor agents. Many compounds with cytotoxicity were found, but most of them show cytotoxic activity only in vitro , a small part of them shows antitumor activity in vivo, and among them there are very few compounds that are effective against a malignant tumor.

SUMMARY OF THE INVENTION

The aim of the present invention is to obtain compounds exhibiting antitumor activity not only in vitro , but also in vivo and having antitumor activity against a malignant tumor, from the fermentation products of the microorganism or their derivatives.

It is believed that oncogenesis of a normal cell causes gene mutation in the cell and expression of the abnormal gene. Therefore, the authors of the present invention conducted intensive studies based on the conclusion that the growth of a tumor cell can be suppressed by changing the expression of the tumor cell gene, that is, the growth of the tumor cell can be regulated by changing the expression of the oncogen or tumor suppressor gene or by changing the expression of the gene involved in the cell cycle . The inventors believed that a compound that alters gene expression, in particular a compound that inhibits the production of VEGF (vascular endothelial growth factor) under hypoxic conditions, could suppress tumor-induced angiogenesis and have antitumor activity against a malignant tumor. Then they screened the fermentation products of the microorganism and their derivatives, using VEGF production by U251 cell under conditions of hypoxic stimulation as an indicator. As a result, new physiologically active compounds were found, 12-membered cyclic macrolide compounds, called 11107 and their analogues, which suppress VEGF production under hypoxic conditions in vitro and, in addition, inhibit the growth of solid tumor cells in vivo .

It was also found that 11107D among the 11107 analogues is stable even in aqueous solution and that compounds obtained by chemical modifications of 11107D (hereinafter referred to as derivatives 11107D) inherit the stability property in aqueous solution from 11107D and inhibit the growth of solid tumor cells in in vivo experiments to a much greater extent. Based on these findings, the present invention was created.

As a related 12-membered cyclic macrolide compound, the most structurally similar to the compounds of the present invention, the 12-membered cyclic macrolide compound FD-895 (JP-A 4-352783) represented by the formula (XIV) is known:

The publication discloses that FD-895 has cell growth inhibitory activity in vitro against murine leukemia cell P388, murine leukemia cell L-1210 and human leukemia cell HL-60 in RPM-1640 medium (column 6, table 2). However, it has already been reported that FD-895 does not exhibit antitumor activity in an in vivo experiment using mouse leukemia P388 cells (Seki-Asano M. et al., J. Antibiotics, 47, 1395-1401, 1994).

In addition, FD-895 is unstable in aqueous solution, as described later, and is expected to be unsuitable for mixing with the infusion solution upon administration. Thus, it cannot be said that FD-895 has sufficient properties for an antitumor agent.

Therefore, in accordance with the present invention proposed:

(1) the compound represented by formula (I):

(in the formula R ³ , R ⁶ , R ⁷ and R ²¹ are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ³ , R ⁶ , R ⁷ and R ²¹ is attached, provided that R ^{6 is} limited to a hydroxyl group,

2) an optionally substituted C _1-22 alkoxy group,

3) an optionally substituted unsaturated C _2-22 alkoxy group,

4) an optionally substituted C _7-22 aralkyloxy group,

5) an optionally substituted 5-14 membered heteroaralkyloxy group,

6) RCO-O- (where R represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted 5-14 membered heteroaryl group,

f) an optionally substituted C _7-22 aralkyl group,

g) an optionally substituted 5-14 membered heteroalkyl group,

h) an optionally substituted C _1-22 alkoxy group,

i) an optionally substituted unsaturated C _2-22 alkoxy group,

j) an optionally substituted C _6-14 aryloxy group or

k) an optionally substituted 5-14 membered heteroaryloxy group),

7) R ^S1 R ^S2 R ^S3 SiO- (where R ^S1 , R ^S2 and R ^S3 are the same or different from each other and each of them represents

a) a C _1-6 alkyl group or

b) C _6-14 aryl group),

8) a halogen atom,

9) R ^N1 R ^N2 NR ^M - (where R ^M represents

a) a single bond,

b) —CO — O—,

c) -SO ₂ -O-,

d) -CS-O- or

e) —CO — NR ^N3 - (where R ^N3 represents a hydrogen atom or an optionally substituted C _1-6 alkyl group), provided that each leftmost bond in b) -e) is attached to a nitrogen atom; and

R ^N1 and R ^N2 are the same or different from each other and each of them represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted aliphatic C _2-22 acyl group,

e) an optionally substituted aromatic C _7-15 acyl group,

f) an optionally substituted C _6-14 aryl group,

g) an optionally substituted 5-14 membered heteroaryl group,

h) an optionally substituted C _7-22 aralkyl group,

i) an optionally substituted C _1-22 alkylsulfonyl group,

j) an optionally substituted C _6-14 arylsulfonyl group,

k) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^N1 and R ^N2 together with a nitrogen atom to which R ^N1 and R ^{N2 are} attached, wherein the non-aromatic heterocyclic group may have substituents,

l) an optionally substituted 5-14 membered heteroalkyl group,

m) an optionally substituted C _3-14 cycloalkyl group or

n) an optionally substituted 3-14 membered non-aromatic heterocyclic group),

10) R ^N4 SO ₂ —O— (where R ^N4 represents

a) an optionally substituted C _1-22 alkyl group,

b) an optionally substituted C _6-14 aryl group,

c) an optionally substituted C _1-22 alkoxy group,

d) an optionally substituted unsaturated C _2-22 alkoxy group,

e) an optionally substituted C _6-14 aryloxy group,

f) an optionally substituted 5-14 membered heteroaryloxy group,

g) an optionally substituted C _7-22 aralkyloxy group or

h) an optionally substituted 5-14 membered heteroaralkyloxy group),

11) (R ^N5 O) ₂ PO-O- (where R ^N5 represents

a) an optionally substituted C _1-22 alkyl group,

b) an optionally substituted unsaturated C _2-22 alkyl group,

c) an optionally substituted C _6-14 aryl group,

d) an optionally substituted 5-14 membered heteroaryl group,

e) an optionally substituted C _7-22 aralkyl group or

f) an optionally substituted 5-14 membered heteroaralkyl group),

12) (R ^N1 R ^N2 N) ₂ PO-O- (where R ^N1 and R ^N2 have the same meanings as defined above) or

13) (R ^N1 R ^N2 N) (R ^N5 O) PO-O- (where R ^N1 , R ^N2 and R ^N5 have the same meanings as defined above), provided that the compound in which R ^{3 is} excluded R ⁶ , R ⁷ and R ²¹ all represent hydroxyl groups, and a compound in which R ³ , R ⁶ and R ²¹ all represent hydroxyl groups and R ⁷ represents an acetoxy group), a pharmacologically acceptable salt thereof, or a hydrate thereof;

(2) the compound according to paragraph (1), represented by formula (Ia):

(in the formula R ^3a , R ^6a , R ^7a and R ^21a are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3a , R ^6a , R ^7a and R ^21a is attached, provided that R ^{6a is} limited to a hydroxyl group,

2) an optionally substituted C _1-22 alkoxy group,

3) R ^a CO-O- (where R ^a represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted 5-14 membered heteroaryl group,

f) an optionally substituted C _7-22 aralkyl group,

g) an optionally substituted 5-14 membered heteroalkyl group,

h) an optionally substituted C _1-22 alkoxy group,

i) an optionally substituted unsaturated C _2-22 alkoxy group,

j) an optionally substituted C _6-14 aryloxy group or

k) an optionally substituted 5-14 membered heteroaryloxy group),

^{4) R aS1 R aS2 R aS3 SiO-} ( wherein R ^aS1, R ^aS2 and R ^aS3 are the same or different from each other and each represents

a) a C _1-6 alkyl group or

b) C _6-14 aryl group),

5) a halogen atom or

6) R ^aN1 R ^aN2 NR ^aM - (where R ^aM represents

a) a single bond,

b) —CO — O—,

c) -SO ₂ -O-,

d) -CS-O- or

e) —CO — NR ^aN3 - (where R ^aN3 represents a hydrogen atom or an optionally substituted C _1-6 alkyl group), provided that each leftmost bond in b) -e) is attached to a nitrogen atom; and

R ^aN1 and R ^aN2 are the same or different from each other and each of them represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted aliphatic C _2-22 acyl group,

e) an optionally substituted aromatic C _7-15 acyl group,

f) an optionally substituted C _6-14 aryl group,

g) an optionally substituted 5-14 membered heteroaryl group,

h) an optionally substituted C _7-22 aralkyl group,

i) an optionally substituted C _1-22 alkylsulfonyl group,

j) an optionally substituted C _6-14 arylsulfonyl group,

k) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^aN1 and R ^aN2 together with a nitrogen atom to which R ^aN1 and R ^{aN2 are attached} , and the non-aromatic heterocyclic group may have substituents,

l) an optionally substituted 5-14 membered heteroalkyl group,

m) an optionally substituted C _3-14 cycloalkyl group or

n) an optionally substituted 3-14 membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate thereof;

(3) the compound according to paragraph (1), represented by formula (I-b):

(in the formula R ^3b , R ^6b , R ^7b and R ^21b are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3b , R ^6b , R ^7b and R ^21b is attached, provided that R ^{6b is} limited to a hydroxyl group,

2) an optionally substituted C _1-22 alkoxy group,

3) R ^b CO-O- (where R ^b represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted 5-14 membered heteroaryl group,

f) an optionally substituted C _7-22 aralkyl group,

g) an optionally substituted 5-14 membered heteroalkyl group,

h) an optionally substituted C _1-22 alkoxy group,

i) an optionally substituted unsaturated C _2-22 alkoxy group,

j) an optionally substituted C _6-14 aryloxy group or

k) an optionally substituted 5-14 membered heteroaryloxy group),

4) R ^bS1 R ^bS2 R ^bS3 SiO- (where R ^bS1 , R ^bS2 and R ^bS3 are the same or different from each other and each of them represents

a) a C _1-6 alkyl group or

b) a C _6-14 aryl group) or

5) R ^bN1 R ^bN2 NR ^bM - (where R ^bM represents

a) -CO-O- or

b) -CS-O-, provided that each leftmost bond in a) and b) is attached to a nitrogen atom; and

R ^bN1 and R ^bN2 are the same or different from each other and each of them represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted aliphatic C _2-22 acyl group,

e) an optionally substituted aromatic C _7-15 acyl group,

f) an optionally substituted C _6-14 aryl group,

g) an optionally substituted 5-14 membered heteroaryl group,

h) an optionally substituted C _7-22 aralkyl group,

i) an optionally substituted C _1-22 alkylsulfonyl group,

j) an optionally substituted C _6-14 arylsulfonyl group,

k) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^bN1 and R ^bN2 together with a nitrogen atom to which R ^bN1 and R ^{bN2 are attached} , and the non-aromatic heterocyclic group may have substituents,

l) an optionally substituted 5-14 membered heteroalkyl group,

m) an optionally substituted C _3-14 cycloalkyl group or

n) an optionally substituted 3-14 membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate thereof;

(4) the compound according to paragraph (1), represented by formula (I-c):

(in the formula R ^3c , R ^6c , R ^7c and R ^21c are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3c , R ^6c , R ^7c and R ^{21c is attached} , provided that R ^{6c is} limited to a hydroxyl group,

2) an optionally substituted C _1-22 alkoxy group,

3) R ^c CO-O- (where R ^c represents

a) an optionally substituted C _1-22 alkyl group,

b) an optionally substituted C _6-14 aryl group,

c) an optionally substituted C _7-22 aralkyl group or

d) optionally substituted C _6-14 aryloxy group),

4) R ^сS1 R ^сS2 R ^сS3 SiO- (where R ^сS1 , R ^сS2 and R ^сS3 are the same or different from each other and each of them represents

a) a C _1-6 alkyl group or

b) a C _6-14 aryl group) or

5) R ^cN1 R ^cN2 NR ^cM - (where R ^cM represents

a) -CO-O- or

b) -CS-O-, provided that each leftmost bond in a) and b) is attached to a nitrogen atom; and

R ^cN1 and R ^cN2 are the same or different from each other and each of them represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^cN1 and R ^cN2 together with a nitrogen atom to which R ^cN1 and R ^{cN2 are attached} , wherein the non-aromatic heterocyclic group may have substituents,

d) an optionally substituted 5-14 membered heteroalkyl group,

e) an optionally substituted C _3-14 cycloalkyl group or

f) an optionally substituted 3-14 membered non-aromatic heterocyclic group, wherein the non-aromatic heterocyclic group may have substituents)), a pharmacologically acceptable salt thereof, or a hydrate thereof;

(5) the compound according to paragraph (1), represented by formula (I-d):

(in the formula R ^3d represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which R ^3d is attached,

2) an optionally substituted C _1-22 alkoxy group,

3) an optionally substituted unsaturated C _2-22 alkoxy group,

4) an optionally substituted C _7-22 aralkyloxy group,

5) R ^d CO-O- (where R ^d represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted 5-14 membered heteroaryl group,

f) an optionally substituted C _7-22 aralkyl group,

g) an optionally substituted 5-14 membered heteroalkyl group,

h) an optionally substituted C _1-22 alkoxy group,

i) an optionally substituted unsaturated C _2-22 alkoxy group,

j) an optionally substituted C _6-14 aryloxy group or

k) an optionally substituted 5-14 membered heteroaryloxy group) or

6) R ^dN1 R ^dN2 N-CO-O- (where R ^dN1 and R ^dN2 are the same or different from each other and each of them represents

a) a hydrogen atom,

b) an optionally substituted C _1-22 alkyl group,

c) an optionally substituted unsaturated C _2-22 alkyl group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted 5-14 membered heteroaryl group,

f) an optionally substituted C _7-22 aralkyl group,

g) an optionally substituted 5-14 membered heteroalkyl group,

h) an optionally substituted C _3-14 cycloalkyl group,

i) an optionally substituted 3-14 membered non-aromatic heterocyclic group or

j) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^dN1 and R ^dN2 together with a nitrogen atom to which R ^dN1 and R ^{dN2 are attached} , and the non-aromatic heterocyclic group may have substituents),

and

R ^6d , R ^7d and R ^21d are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^6d , R ^7d and R ^21d is attached, provided that R ^{6d is} limited to a hydroxyl group,

2) an optionally substituted C _1-22 alkoxy group,

3) an optionally substituted unsaturated C _2-22 alkoxy group,

4) an optionally substituted C _7-22 aralkyloxy group,

5) R ^d CO-O- (where R ^d has the same meaning as defined above),

6) R ^dN1 R ^dN2 N-CO-O- (where R ^dN1 and R ^dN2 have the same meanings as defined above),

7) R ^dN1 R ^dN2 N-SO ₂ -O- (where R ^dN1 and R ^dN2 have the same meanings as defined above),

8) R ^dN1 R ^dN2 N-CS-O- (where R ^dN1 and R ^dN2 have the same meanings as defined above),

9) R ^dN3 —SO ₂ —O— (where R ^dN3 is

a) an optionally substituted C _1-22 alkyl group,

b) an optionally substituted C _1-22 alkoxy group,

c) an optionally substituted unsaturated C _2-22 alkoxy group,

d) an optionally substituted C _6-14 aryl group,

e) an optionally substituted C _6-14 aryloxy group,

f) an optionally substituted 5-14 membered heteroaryloxy group,

g) an optionally substituted C _7-22 aralkyloxy group or

h) an optionally substituted 5-14 membered heteroaralkyloxy group,

10) (R ^dN5 O) ₂ PO- (where R ^dN5 is

a) an optionally substituted C _1-22 alkyl group,

b) an optionally substituted unsaturated C _2-22 alkyl group,

c) an optionally substituted C _6-14 aryl group,

d) an optionally substituted 5-14 membered heteroaryl group,

e) an optionally substituted C _7-22 aralkyl group or

f) an optionally substituted 5-14 membered heteroaralkyl group),

11) (R ^dN1 R ^dN2 N) ₂ PO- (where R ^dN1 and R ^dN2 have the same meanings as defined above) or

12) (R ^dN1 R ^dN2 N) (R ^dN5 O) PO— (where R ^dN1 , R ^dN2 and R ^dN5 have the same meanings as defined above), provided that the compound in which R ^3d , R ^{6d is} excluded , R ^7d and R ^21d all represent hydroxyl groups, and a compound in which R ^3d , R ^6d and R ^21d all represent hydroxyl groups and R ^7d represents an acetoxy group), a pharmacologically acceptable salt thereof or a hydrate thereof;

(6) the compound according to paragraph (1), wherein R ⁶ and / or R ⁷ are (is) R ^N1 R ^N2 NR ^M - (where R ^M is

a) -CO-O- or

b) -CS-O-; and

R ^N1 and R ^N2 have the same meanings as defined above, provided that each leftmost bond in a) and b) is attached to a nitrogen atom), a pharmacologically acceptable salt thereof, or a hydrate thereof;

(7) the compound according to paragraph (1), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein R ²¹ is an oxo group formed together with the carbon atom to which R ²¹ is attached;

(8) the compound according to paragraph (5), represented by formula (Ie):

(in the formula, R ^3e and R ^21e are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3e and R ^{21e is attached} ,

2) an optionally substituted C _1-6 alkoxy group,

3) an optionally substituted unsaturated C _2-10 alkoxy group,

4) an optionally substituted C _7-10 aralkyloxy group,

5) an optionally substituted aliphatic C _2-6 acyloxy group or

6) R ^eN1 R ^eN2 N-CO-O- (where R ^eN1 and R ^eN2 are the same or different from each other and each of them represents

A) a hydrogen atom or

B) an optionally substituted C _1-6 alkyl group); and

R ^6e and R ^7e are the same or different from each other and each of them represents

1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^6e and R ^7e is attached, provided that R ^{6e is} limited to a hydroxyl group,

2) an optionally substituted C _1-6 alkoxy group,

3) an optionally substituted unsaturated C _2-10 alkoxy group,

4) an optionally substituted C _7-10 aralkyloxy group,

5) an optionally substituted aliphatic C _2-6 acyloxy group or

6) R ^e C (= Y ^e ) -O- (where Y ^e represents an oxygen atom or a sulfur atom and R ^e represents

a) a hydrogen atom,

b) an optionally substituted C _1-6 alkyl group,

c) an optionally substituted C _7-10 aralkyl group,

d) an optionally substituted 5-14 membered heteroalkyl group,

e) a group of formula (III):

(in the formula

A) n is an integer from 0 to 4;

X _e represents

i) —CHR ^eN4 -,

ii) -NR ^eN5 -,

iii) -O-,

iv) -S-,

v) -SO- or

vi) —SO ₂ -;

R ^eN1 represents

i) a hydrogen atom or

ii) a C _1-6 alkyl group;

R ^eN2 represents

i) a hydrogen atom or

ii) a C _1-6 alkyl group;

R ^eN3 and R ^eN4 are the same or different from each other and each of them represents

i) a hydrogen atom,

ii) an optionally substituted C _1-6 alkyl group,

iii) an optionally substituted unsaturated C _2-10 alkyl group,

iv) an optionally substituted C _6-14 aryl group,

v) an optionally substituted 5-14 membered heteroaryl group,

vi) an optionally substituted C _7-10 aralkyl group,

vii) an optionally substituted C _3-8 cycloalkyl group,

viii) an optionally substituted C _4-9 cycloalkylalkyl group,

ix) an optionally substituted 5-14 membered heteroaralkyl group,

x) an optionally substituted 5-14 membered non-aromatic heterocyclic group,

xi) —NR ^eN6 R ^eN7 (where R ^eN6 and R ^eN7 are the same or different from each other and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group) or

xii) an optionally substituted 5-14 membered non-aromatic heterocyclic group formed by R ^eN3 and R ^eN4 together with a carbon atom to which R ^eN3 and R ^{eN4 are attached} , wherein the non-aromatic heterocyclic group may have substituents; and

R ^eN5 is

i) a hydrogen atom,

ii) an optionally substituted C _1-6 alkyl group,

iii) an optionally substituted unsaturated C _2-10 alkyl group,

iv) an optionally substituted C _6-14 aryl group,

v) an optionally substituted 5-14 membered heteroaryl group,

vi) an optionally substituted C _7-10 aralkyl group,

vii) an optionally substituted C _3-8 cycloalkyl group,

viii) an optionally substituted C _4-9 cycloalkylalkyl group,

ix) an optionally substituted 5-14 membered heteroaralkyl group,

x) an optionally substituted 5-14 membered non-aromatic heterocyclic group, or

xi) an optionally substituted 5-14 membered non-aromatic heterocyclic group formed by R ^eN3 and R ^eN4 together with a nitrogen atom to which R ^eN3 and R ^{eN4 are attached} , and the non-aromatic heterocyclic group may have substituents,

B) X _e , n, R ^eN3 , R ^eN4 and R ^eN5 represent each group as defined above, and R ^eN1 and R ^eN2 together form an optionally substituted 5-14 membered non-aromatic heterocyclic group,

C) X _e , n, R ^eN2 , R ^eN4 and R ^eN5 represent each group as defined above, and R ^eN1 and R ^eN3 together form an optionally substituted 5-14 membered non-aromatic heterocyclic group, or

D) X _e , n, R ^eN1 , R ^eN4 and R ^eN5 represent each group as defined above, and R ^eN2 and R ^eN3 together form an optionally substituted 5-14 membered non-aromatic heterocyclic group) or

f) a group of formula (IV):

(in the formula, R ^eN8 and R ^eN9 are the same or different from each other and each of them represents

i) a hydrogen atom,

ii) an optionally substituted C _1-6 alkyl group,

iii) an optionally substituted C _6-14 aryl group,

iv) an optionally substituted 5-14 membered heteroaryl group,

v) an optionally substituted C _7-10 aralkyl group or

vi) an optionally substituted 5-14 membered heteroaralkyl group))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(9) the compound according to paragraph (5), wherein R ^6d and / or R ^7d are (is) R ^d1 C (= Y ^d1 ) -O- (where Y ^d1 is an oxygen atom or a sulfur atom and R ^d1 is

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted C _7-10 aralkyl group or

4) an optionally substituted 5-14 membered heteroaralkyl group), a pharmacologically acceptable salt thereof or a hydrate thereof;

(10) the compound according to (5), wherein R ^6d and / or R ^7d are (is) R ^d2 C (= Y ^d2 ) -O- (where Y ^d2 is an oxygen atom or a sulfur atom and R ^d2 is a group of formula (III '):

(in the formula, n represents an integer from 0 to 4, X ₁ represents

1) -CHR ^dN7 -,

2) -NR ^dN8 -,

3) -O-,

4) -S-,

5) -SO- or

6) -SO ₂ -;

R ^dN4 and R ^dN5 are the same or different from each other and each of them represents

1) a hydrogen atom or

2) a C _1-6 alkyl group;

R ^dN6 and R ^dN7 are the same or different from each other and each of them represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroalkyl group,

10) an optionally substituted 5-14 membered non-aromatic heterocyclic group,

11) —NR ^dN9 R ^dN10 (where R ^dN9 and R ^dN10 are the same or different from each other and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group) or

12) an optionally substituted 5-14 membered non-aromatic heterocyclic group formed together with R ^dN6 and R ^dN7 , wherein the non-aromatic heterocyclic group may have substituents; and

R ^dN8 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroalkyl group,

10) an optionally substituted 5-14 membered non-aromatic heterocyclic group,

11) an optionally substituted 5-14 membered non-aromatic heterocyclic group formed by R ^dN4 , R ^dN5 or R ^dN6 together with a nitrogen atom to which each of R ^dN4 , R ^dN5 and R ^{dN6 is attached} , and the non-aromatic heterocyclic group may have substituents, or

12) an optionally substituted 5-14 membered non-aromatic heterocyclic group formed by two substituents selected from the group consisting of R ^dN4 , R ^dN5 and R ^dN6 , together with the nitrogen atom to which they are attached, and the non-aromatic heterocyclic group may have substituents) ), its pharmacologically acceptable salt or hydrate thereof;

(11) the compound of (10), a pharmacologically acceptable salt thereof or a hydrate thereof, wherein X ₁ is —NR ^dN8 - (where NR ^dN8 has the same meanings as defined above);

(12) the compound according to paragraph (5), represented by formula (I-f):

(in the formula, R ^7f represents R ^f C (= Y ^f ) -O- (where Y ^f represents an oxygen atom or a sulfur atom and R ^f represents a group of the formula (V):

(where n is an integer from 0 to 4,

R ^fN1 represents

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group and

R ^fN2 represents

1) a hydrogen atom,

2) methylamino group,

3) dimethylamino group,

4) an ethylamino group,

5) diethylamino group,

6) ethylmethylamino group,

7) a pyridinyl group,

8) pyrrolidin-1-ilen group,

9) piperidin-1-ilen group,

10) a morpholin-4-yl group or

11) a 4-methylpiperazin-1-yl group))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(13) the compound according to paragraph (5), wherein R ^6d and / or R ^7d are (is) R ^d3 CO-O- (where R ^d3 is a group of formula (VI):

(where n ₁ and n ₂ are the same or different from each other and each of them is an integer from 0 to 4,

X ₂ represents

1) -CHR ^dN13 -,

2) -NR ^dN14 -,

3) -O-,

4) -S-,

5) -SO- or

6) -SO ₂ -;

R ^dN11 represents

1) a hydrogen atom or

2) an optionally substituted C _1-6 alkyl group;

R ^dN12 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted C _6-14 aryl group or

4) an optionally substituted C _7-10 aralkyl group;

R ^dN13 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroalkyl group,

10) —NR ^dN15 R ^dN16 (where R ^dN15 and R ^dN16 are the same or different from each other and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group) or

11) an optionally substituted 5-14 membered non-aromatic heterocyclic group; and

R ^dN14 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroaralkyl group or

10) an optionally substituted 5-14 membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate thereof;

(14) the compound according to paragraph (5), represented by formula (I-g):

(in the formula R ^7g represents R ^g CO-O- (where R ^g represents a group of formula (VII):

(where n ₃ is 1 or 2,

R ^dN17 represents

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group and

R ^dN18 is

1) a hydrogen atom,

2) a methyl group or

3) an ethyl group))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(15) the compound according to paragraph (5), wherein R ^6d and / or R ^7d are (is) R ^d4 CO-O- (where R ^d4 is a group of formula (VIII):

(where n ₁ and n ₂ are the same or different from each other and each of them is an integer from 0 to 4,

X ₃ represents

1) -CHR ^dN21 -,

2) -NR ^dN22 -,

3) -O-,

4) -S-,

5) -SO- or

6) -SO ₂ -;

R ^dN19 is

1) a hydrogen atom or

2) a C _1-6 alkyl group;

R ^dN20 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted C _6-14 aryl group or

4) an optionally substituted C _7-10 aralkyl group;

R ^dN21 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _1-6 alkoxy group,

5) an optionally substituted C _6-14 aryl group,

6) an optionally substituted 5-14 membered heteroaryl group,

7) an optionally substituted C _7-10 aralkyl group,

8) an optionally substituted C _3-8 cycloalkyl group,

9) an optionally substituted C _4-9 cycloalkylalkyl group,

10) an optionally substituted 5-14 membered heteroaralkyl group,

11) —NR ^dN23 R ^dN24 (where R ^dN23 and R ^dN24 are the same or different from each other and each represents a hydrogen atom or an optionally substituted C _1-6 alkyl group) or

12) an optionally substituted 5-14 membered non-aromatic heterocyclic group; and

R ^dN22 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroaralkyl group or

10) an optionally substituted 5-14 membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate thereof;

(16) the compound according to paragraph (5), represented by formula (I-h):

(in the formula, R ^7h represents R ^h CO — O— (where R ^h represents a group of formula (IX):

(where n ₄ is an integer from 1 to 3 and

R ^dN25 represents

1) an amino group,

2) methylamino group,

3) dimethylamino group,

4) a pyrrolidin-1-ilen group,

5) piperidin-1-ilen group or

6) morpholin-4-yl group))), its pharmacologically acceptable salt or their hydrate;

(17) the compound according to paragraph (5), represented by formula (I-i):

(in the formula R ⁷ⁱ represents R ⁱ CO-O- (where R ⁱ represents a group of formula (X):

(where n ₄ is an integer from 1 to 3,

R ^dN26 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted C _6-14 aryl group or

4) an optionally substituted C _7-10 aralkyl group;

R ^dN27 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted C _3-8 cycloalkyl group,

4) an optionally substituted 3-8 membered non-aromatic heterocyclic group,

5) an optionally substituted C _6-14 aryl group,

6) an optionally substituted 5-14 membered heteroaryl group,

7) an optionally substituted C _7-10 aralkyl group,

8) an optionally substituted 5-14 membered heteroaralkyl group or

9) an optionally substituted C _4-9 cycloalkylalkyl group))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(18) the compound according to paragraph (5), represented by formula (I-j):

(in the formula R ^7j represents R ^j CO-O- (where R ^j represents a group of the formula (XI):

(where n ₄ is an integer from 1 to 3 and

R ^dN28 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) C _3-8 cycloalkyl group,

4) C _4-9 cycloalkylalkyl group,

5) C _7-10 aralkyl group,

6) a pyridinyl group or

7) a tetrahydropyranyl group))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(19) the compound according to paragraph (5), represented by formula (I-k):

(in the formula, R ^7k represents R ^k CO-O- (where R ^k represents a group of formula (XII):

(where m ₁ , m ₂ , m ₃ and m ₄ are the same or different from each other and each of them is 0 or 1,

n ₄ is an integer from 1 to 3 and

R ^dN29 represents

1) a hydrogen atom,

2) an optionally substituted C _1-6 alkyl group,

3) an optionally substituted unsaturated C _2-10 alkyl group,

4) an optionally substituted C _6-14 aryl group,

5) an optionally substituted 5-14 membered heteroaryl group,

6) an optionally substituted C _7-10 aralkyl group,

7) an optionally substituted C _3-8 cycloalkyl group,

8) an optionally substituted C _4-9 cycloalkylalkyl group,

9) an optionally substituted 5-14 membered heteroaralkyl group or

10) an optionally substituted 5-14 membered non-aromatic heterocyclic group))), a pharmacologically acceptable salt thereof, or a hydrate thereof;

(20) the compound according to paragraph (5), represented by formula (I-m):

(in the formula R ^7m represents R ^m CO-O- (where R ^m represents a group of formula (XIII):

(where m ₅ is an integer from 1 to 3 and n ₅ is 2 or 3))), a pharmacologically acceptable salt thereof or a hydrate thereof;

(21) the compound according to paragraph (5), represented by formula (I-n):

(in the formula R ⁷ⁿ represents R ⁿ CO-O- (where R ⁿ represents a group of formula (XIV):

a pharmacologically acceptable salt thereof or a hydrate thereof;

(22) the compound according to paragraph (1), which is selected from:

(8E, 12E, 14E) -7- (N- (2- (N ', N'-dimethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 6);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 9);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 12);

(8E, 12E, 14E) -7 - ((4-butylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 16);

(8E, 12E, 14E) -7 - ((4-ethylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide (compound 21);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 25);

(8E, 12E, 14E) -7 - ((4-cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 26);

(8E, 12E, 14E) -7 - ((4- (cyclopropylmethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 27);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 31);

(8E, 12E, 14E) -7 - ((4- (cyclopropylmethyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 19-epoxytricose-8,12,14-trien-11-olide (compound 36);

(8E, 12E, 14E) -7 - ((4-cyclopentylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 38);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide (compound 44);

(8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 45);

(8E, 12E, 14E) -7- (N- (2- (N ', N'-diethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 75);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isobutylhomopiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide (compound 54);

(8E, 12E, 14E) -7 - ((4-ethylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 63);

(8E, 12E, 14E) -7 - ((4-butylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 64);

(8E, 12E, 14E) -3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-triene-11-olide (compound 85);

(8E, 12E, 14E) -3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (piperidinin-1-yl) piperidin-1-yl ) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 109);

(8E, 12E, 14E) -7 - ((4- (2,2-dimethylpropyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20 pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 69); and

(8E, 12E, 14E) -3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-triene-11-olide (compound 131);

(23) the compound according to paragraph (1), which is selected from:

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 9);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 12);

(8E, 12E, 14E) -7 - ((4-cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 26);

(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide (compound 44);

(8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 45); and

(8E, 12E, 14E) -7- (N- (2- (N ', N'-diethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 75);

(24) a medicament containing a compound according to any one of paragraphs (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof as an active component;

(25) a pharmaceutical composition comprising a compound according to any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof as an active component;

(26) the medicament according to (24), which is an agent for the prophylaxis or treatment of a disease against which regulation of gene expression is effective;

(27) the medicament according to (24), which is an agent for the prophylaxis or treatment of a disease against which inhibition of VEGF production is effective;

(28) the medicament according to (24), which is an agent for the prophylaxis or treatment of a disease against which the antiangiogenic effect is effective;

(29) the medicament according to (24), which is an angiogenesis inhibitor;

(30) the medicament according to (24), which is an antitumor agent;

(31) the medicament according to (24) as a therapeutic agent for the treatment of angioma;

(32) the medicament according to (24), which is an inhibitor of cancer metastasis;

(33) the medicament according to (24), which is a therapeutic agent for the treatment of retinal revascularization or diabetic retinopathy;

(34) the medicament according to (24), which is a therapeutic agent for treating an inflammatory disease;

(35) the medicament according to (24), which is a therapeutic agent for the treatment of inflammatory diseases consisting of deforming arthritis, rheumatoid arthritis, psoriasis and delayed-type hypersensitivity;

(36) the medicament according to (24), which is a therapeutic agent for the treatment of atherosclerosis;

(37) the medicament according to (24), which is a therapeutic agent for treating a malignant tumor;

(38) the medicament according to (37), wherein the malignant malignant tumor is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, colon cancer or melanoma;

(39) the medicament according to (24), which is a therapeutic agent for treating leukemia;

(40) the medicament according to (24), which is an antitumor agent based on regulation of gene expression;

(41) the medicament according to (24), which is an antitumor agent based on inhibition of VEGF production;

(42) the medicament according to (24), which is an antitumor agent based on the effect of inhibiting angiogenesis;

(43) a method for preventing or treating a disease against which regulation of gene expression is effective, comprising administering to a patient a pharmacologically effective dose of a medicament according to (24);

(44) a method for preventing or treating a disease against which the inhibition of VEGF production is effective, comprising administering to a patient a pharmacologically effective dose of a medicament according to paragraph (24);

(45) a method for preventing or treating a disease against which angiogenesis inhibition is effective, comprising administering to a patient a pharmacologically effective dose of a medicament according to (24);

(46) the use of a compound according to any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which regulation of gene expression is effective;

(47) the use of a compound according to any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which the inhibition of VEGF production is effective;

(48) the use of a compound according to any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which angiogenesis inhibition is effective; and

(49) the use of a compound according to any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of malignant malignant tumors.

The following illustrates the terms, symbols and the like used in this description.

In this description, the chemical formula of the compound of the present invention is shown for convenience in the form of a planimetric formula, but the compound may include some isomers derived from this chemical formula. The present invention can encompass all isomers and mixtures of isomers, such as the geometric isomer generated by the configuration of the compound, the asymmetric carbon atom optical isomer, rotamer, stereoisomer and tautomer. The present invention is not limited to a suitable description of the chemical formula for this case, and may include any isomers or mixtures thereof. Thus, when the compound of the present invention contains an asymmetric carbon atom in the formula and its optically active substance and racemate exist, the invention covers them. In addition, when polymorphic crystals exist, the crystalline form of the present invention is not particularly limited to one form, and any of the crystalline forms can exist individually or in a mixture of crystalline forms. The compound represented by formula (I) in accordance with the present invention, or its salt may be an anhydrate or hydrate, and both are included in the present invention. Metabolites formed in vivo by decomposition of a compound of formula (I) of the present invention and a prodrug of a compound of formula (I) of the present invention or its salts are also included in the present invention.

The term “halogen atom” as used herein means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. Among them, it is preferable, for example, a fluorine atom, a chlorine atom or a bromine atom, of which a fluorine atom or a chlorine atom is usually preferred.

The “C _1-22 alkyl group” used in this description of the present invention is an unbranched or branched alkyl group containing 1-22 carbon atoms, such as a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group , 1-ethyl-2-methylpropyl group a, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3 a dimethylbutyl group, a 2,3-dimethylbutyl group, a 2-ethylbutyl group, a 2-methylpentyl group, a 3-methylpentyl group, an n-heptyl group, an n-octyl group, an n-nonyl group or an n-decyl group; preferably a straight or branched alkyl group containing 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group or n- pentyl group; more preferably, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, or a tert-butyl group.

The “unsaturated C _2-22 alkyl group” used in this description of the present invention is an unbranched or branched alkenyl group containing 2-22 carbon atoms, or an unbranched or branched alkynyl group containing 2-22 carbon atoms, such as vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group , 1-hexene ln group, 1,3-hexadienyl group, 1,5-hexadienyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-ethynyl-2 a propynyl group, a 2-methyl-3-butynyl group, a 1-pentinyl group, a 1-hexynyl group, a 1,3-hexanediinyl group or a 1,5-hexanediinyl group. Preferably, it is a straight or branched alkenyl group containing 2-10 carbon atoms, or a straight or branched alkynyl group containing 2-10 carbon atoms, such as a vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group or 3-methyl-1-propine Ordering group.

“C _6-14 aryl group” used in the description of this application means an aromatic cyclic hydrocarbon group containing 6-14 carbon atoms and including a monocyclic group and fused rings, such as a bicyclic group and a tricyclic group. Examples thereof are a phenyl group, an indenyl group, a 1-naphthyl group, a 2-naphthyl group, an azulenyl group, a heptalenyl group, an indacenyl group, an acenaphthyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group, and an anthracenyl group, of which a phenyl group is a preferred example. , 1-naphthyl group or 2-naphthyl group.

The “5-14 membered heteroaryl group” used in the description of this application means a monocyclic, bicyclic or tricyclic 5-14 membered aromatic heterocyclic group containing one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and oxygen atom. Preferred examples of the group are a nitrogen-containing aromatic heterocyclic group, such as a pyrrolyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazolyl group, a tetrazolyl group, a benzotriazolyl group, a pyrazolyl group, an imidazolyl group, a benzimidazolyl group, an indimidazolyl group, an indimidazolyl group, an indimidazolyl group, an indimidazolyl group, an indiminozolyl group, indolysinyl group, purinyl group, indazolyl group, quinolinyl group, isoquinolinyl group, quinolisini th group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, phenazyridinyl group, phenazyridinyl group, phenazyridinyl group, phenazyridinyl group, phenazinyl group , an imidazopyrimidinyl group or a pyrazolopyridinyl group; a sulfur-containing aromatic heterocyclic group such as a thienyl group or a benzothienyl group; and an oxygen-containing aromatic heterocyclic group such as a furyl group, a pyranyl group, a cyclopentapyranyl group, a benzofuryl group or an isobenzofuryl group; an aromatic heterocyclic group containing two or more different heteroatoms, such as a thiazolyl group, an isothiazolyl group, a benzothiazolyl group, a benzothiadiazolyl group, a phenothiazinyl group, an isoxazolyl group, a furazanyl group, a phenoxazinyl group, an oxazolyl group, an isoxazolyl group, a benzoxazolyl group, a pyrazadiene group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group or pyridoxazinyl group, from oryh preferred example is thienyl group, furyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group.

"3-14-membered non-aromatic heterocyclic group" used in the description of this application means a monocyclic, bicyclic or tricyclic 3-14-membered non-aromatic heterocyclic group, which may contain one or more heteroatoms selected from the group consisting of a nitrogen atom, sulfur atom and oxygen atom. Preferred examples thereof are the aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, homopiperidinyl group, homopiperazinyl group, imidazolyl group, pyrazolidinyl group, imidazolidinyl group, morpholinyl iminyl group, thiolorphinyl group, thiolinyl azinol group, thiolinyl azinol group, thiolinyl azinol group, thiolinyl azinol group, thiolinyl iminyl group, thiolinyl azin group , 5-diazabicyclo [2.2.1] heptyl group, 2,5-diazabicyclo [2.2.2] octyl group, 3,8-diazabicyclo [3.2.1] octyl group, 1,4-diazabicy clo [4.3.0] nonyl group, quinuclidinyl group, tetrahydrofuranyl group and tetrahydrothiophenyl group. A non-aromatic heterocyclic group also includes a group derived from the pyridone ring and a non-aromatic fused ring (e.g., a group derived from a phthalimide ring or succinimide ring).

“C _7-22 aralkyl group” used in this description means a group corresponding to the above defined “C _1-22 alkyl group”, the replaced part of which is replaced by the above defined “C _6-14 aryl group”. Specific examples thereof are a benzyl group, a phenethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 1-naphthylmethyl group and a 2-naphthylmethyl group, of which aralkyl group containing 7-10 carbon atoms, such as a benzyl group or phenethyl, is preferred Group.

“5-14-membered heteroalkyl group” used in this description means a group corresponding to the above defined “C _1-22 alkyl group”, the substituted part of which is replaced by the above defined “5-14-membered heteroaryl group”. Specific examples thereof are a thienyl methyl group, a furyl methyl group, a pyridinyl methyl group, a pyridazinyl methyl group, a pyrimidinyl methyl group and a pyrazinyl methyl group, of which a thienyl methyl group, furyl methyl group or pyridinyl methyl group is a preferred example.

“C _3-14 cycloalkyl group” as used herein means a cycloalkyl group containing 3-14 carbon atoms, and suitable examples thereof are a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group, of which a preferred example is a cyclopentyl group, a cyclohexyl group, a cycloheptyl group or a cyclooctyl group.

“C _4-9 cycloalkylalkyl group” as used herein means a group as defined above.

“C _1-22 alkyl group”, the replaced part of which is substituted by the above “C _3-14 cycloalkyl group”. Specific examples thereof are a cyclopropyl methyl group, a cyclobutyl methyl group, a cyclopentyl methyl group, a cyclohexyl methyl group, a cycloheptyl methyl group and a cyclooctyl methyl group, of which a preferred example is a cyclopropyl methyl group, cyclobutyl methyl group or cyclopentyl methyl group.

“C _1-22 alkoxy group” used in this description means a group corresponding to the above defined “C _1-22 alkyl group”, to the end of which an oxygen atom is attached. Suitable examples thereof are methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentyloxy group, 1,1-pentyloxy group, n-pentyloxy group, n-pentyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethyl butoxy group, 2,2-dimethyl butoxy group, 2,3-dimethyl-butoxy group, 1,3-dimethylbutoxy group, 2-ethylbutoxy group, 2-methylpentyloxy group, 3-methylpentyloxy group and hexyloxy group, of which a methoxy group, ethoxy group, n-propoxy group, isopropyl or isoprop -dimethylpropoxy group.

“Unsaturated C _2-22 alkoxy group”, as used herein, means a group corresponding to the above defined “unsaturated C _2-22 alkyl group”, to the end of which an oxygen atom is attached. Suitable examples are vinyloxy, allyloxy, 1-propenyloxy, 2-propenyloxy, isopropenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2-propenyloxy, 1-butenyloxy, 3-butenyloxy, 3-butenyloxy, 3-butenyloxy 1-hexenyloxy group, 1,3-hexadienyloxy group, 1,5-hexadienyloxy group, propargyloxy group and 2-butynyloxy group, of which the allyloxy group, propargyloxy group or 2-butynyloxy group are preferred.

“C _6-14 aryloxy group” as used herein means a group corresponding to the above defined “C _6-14 aryl group”, to the end of which an oxygen atom is attached. Specific examples thereof are phenyloxy group, indenyloxy group, 1-naphthyloxy, 2-naphthyloxy group, azuleniloksigruppa, geptaleniloksigruppa, indatseniloksigruppa, atsenaftiloksigruppa, fluoreniloksigruppa, fenaleniloksigruppa, and fenantreniloksigruppa antratseniloksigruppa, of which a preferred example is phenyloxy group, 1-naphthyloxy or 2-naphthyloxy.

“C _7-22 aralkyloxy group” used in this description means a group corresponding to the above defined “C _7-22 aralkyl group”, to the end of which an oxygen atom is attached. Specific examples are benzyloxy, phenethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 1-naphthylmethyloxy and 2-naphthylmethyloxy, of which benzyloxy is a preferred example.

The “5-14 membered heteroalkyloxy group” as used herein means a group corresponding to the above defined “5-14 membered heteroaralkyl group” to the end of which an oxygen atom is attached. Specific examples thereof are thienylmethyloxy group, furylmethyloxy group, pyridinylmethyloxy group, pyridazinylmethyloxy group, and pyrimidinylmethyloxy group, of which thienylmethyloxymethyloxy or phenylmethyloxy group is a preferred example.

The “5-14 membered heteroaryloxy group” as used herein means a group corresponding to the above defined “5-14 membered heteroaryl group”, to the end of which an oxygen atom is attached. Specific examples thereof are pirroliloksigruppa, pyridinyloxy piridaziniloksigruppa, pyrimidinyloxy, piraziniloksigruppa, triazoliloksigruppa, tetrazoliloksigruppa, benzotriazoliloksigruppa, pirazoliloksigruppa, imidazolyloxy, benzimidazoliloksigruppa, indoliloksigruppa, izoindoliloksigruppa, indoliziniloksigruppa, puriniloksigruppa, indazoliloksigruppa, hinoliniloksigruppa, izohinoliniloksigruppa, hinoliziniloksigruppa, ftalaziniloksigruppa, naftiridiniloksigruppa, hinoksaliniloksigruppa, hee nazoliniloksigruppa, tsinnoliniloksigruppa, pteridiniloksigruppa, imidazotriaziniloksigruppa, pirazinopiridaziniloksigruppa, akridiniloksigruppa, fenantridiniloksigruppa, karbazoliloksigruppa, karbazoliniloksigruppa, perimidiniloksigruppa, fenantroliniloksigruppa, fenaziniloksigruppa, imidazopiridiniloksigruppa, imidazopirimidiniloksigruppa, pirazolopiridiniloksigruppa, thienyloxy, benzotienilgruppa, furyloxy group, pyranyloxy group, tsiklopentapiraniloksigruppa, benzofuriloksigruppa, izobenzofuriloksigruppa, t iazoliloksigruppa, izotiazoliloksigruppa, benzothiazolyloxy, benztiadiazoliloksigruppa, fenotiaziniloksigruppa, izoksazoliloksigruppa, furazaniloksigruppa, fenoksaziniloksigruppa, oksazoliloksigruppa, izoksazoliloksigruppa, benzoksazoliloksigruppa, oksadiazoliloksigruppa, pirazolooksazoliloksigruppa, imidazotiazoliloksigruppa, tienofuraniloksigruppa, and furopirroliloksigruppa piridooksaziniloksigruppa, of which a preferred example is thienyloxy, pyridinyloxy or pyrimidinyloxy iraziniloksigruppa.

An “aliphatic C _2-22 acyl group” as used herein means a group corresponding to the above defined “C _1-22 alkyl group” or “unsaturated C _2-22 alkyl group” to the end of which a carbonyl group is attached. Examples thereof are an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a valeryl group, an isovalery group, a pivaloyl group, a caproyl group, a decanoyl group, a lauroyl group, a myristoyl group, a palmitoyl group, a stearoyl group, an arachidoyl group, an acryloyl group, a propioloyl group , crotonoyl group, isocrotonoyl group, oleoyl group and linolenoyl group, of which acyl group containing 2-6 carbon is a preferred example atoms such as an acetyl group, a propionyl group, a butyryl group, an isobutyryl group or an acryloyl group.

An “aromatic C _7-15 acyl group” as used herein means a group corresponding to the above defined “C _6-14 aryl group” or a “5-14 membered heteroaryl group” to which a carbonyl group is attached. Examples thereof are a benzoyl group, a 1-naphthoyl group, a 2-naphthoyl group, a picolinoyl group, a nicotinoyl group, an isonicotinoyl group, a furoyl group and a thiophenecarbonyl group, of which a benzoyl group, a picolinoyl group, a nicotinoyl group or an isonicotinoyl group are a preferred example.

“C _1-22 alkylsulfonyl group” as used herein means a sulfonyl group to which the above defined “C _1-22 alkyl group” is attached. Specific examples thereof are a methanesulfonyl group, an ethanesulfonyl group, an n-propanesulfonyl group and an isopropanesulfonyl group, of which a methanesulfonyl group is a preferred example.

“C _6-14 arylsulfonyl group” as used herein means a sulfonyl group to which the above defined “C _6-14 aryl group” is attached. Specific examples thereof are a benzenesulfonyl group, a 1-naphthalenesulfonyl group and a 2-naphthalenesulfonyl group, of which a benzenesulfonyl group is a preferred example.

“Aliphatic C _2-22 acyloxy group” as used herein means a group corresponding to the above defined “aliphatic C _2-22 acyl group”, to the end of which an oxygen atom is attached. Specific examples thereof are the acetoxy group, propionyloxy group and acryloxy group, of which the acetoxy group or propionyloxy group is a preferred example.

“C _2-22 alkoxycarbonyl group” as used herein means a group as defined above

“C _1-22 alkoxy group”, to the end of which a carbonyl group is attached. Examples thereof are a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group and a tert-butoxycarbonyl group, of which a preferred example is an ethoxycarbonyl group, an isopropoxycarbonyl group or tert-butylcarbonyl group .

“Unsaturated C _3-22 alkoxycarbonyl group” as used herein means a group corresponding to the above-defined “unsaturated C _2-22 alkoxy group” to which a carbonyl group is attached. Examples thereof are a vinyloxycarbonyl group, an allyloxycarbonyl group, a 1-propenyloxycarbonyl group, an isopropenyloxycarbonyl group, a propargyloxycarbonyl group and a 2-butynyloxycarbonyl group, of which the allyloxycarbonyl group is a preferred example.

“C _1-22 alkylthio group”, as used herein, means a group corresponding to the above defined “C _1-22 alkyl group”, to the end of which a sulfur atom is attached. Examples thereof are methylthio group, ethylthio group, n-propylthio group and isopropylthio group, of which methylthio group or ethylthio group is a preferred example.

“C _1-22 alkylsulfinyl group” used in this description means a group corresponding to the above defined “C _1-22 alkyl group”, to the end of which is attached a sulfinyl group. Examples thereof are a methanesulfinyl group, an ethanesulfinyl group, an n-propanesulfinyl group and an isopropanesulfinyl group, of which a methanesulfinyl group or an ethanesulfinyl group is a preferred example.

“C _1-22 alkylsulfonyloxy group” as used herein means a group corresponding to the above defined “C _1-22 alkylsulfonyl group”, to the end of which an oxygen atom is attached. Examples thereof are a methanesulfonyloxy group, an ethanesulfonyloxy group, an n-propanesulfonyloxy group and an isopropanesulfonyloxy group, of which a methanesulfonyloxy group is a preferred example.

The substituent of the term “optionally substituted” as used herein may be one or more groups selected from:

(1) a halogen atom,

(2) a hydroxyl group,

(3) a thiol group,

(4) nitro groups,

(5) nitroso groups,

(6) cyano groups,

(7) a carboxyl group,

(8) a hydroxysulfonyl group,

(9) amino groups,

(10) a _1-22 alkyl group (e.g., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-butyl group),

(11) an unsaturated C _2-22 alkyl group (e.g., a vinyl group, an allyl group, a 1-propenyl group, a 2-propenyl group, an isopropenyl group, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, 2-butynyl group and 3-butynyl group),

(12) a _6-14 aryl group (e.g., phenyl group, 1-naphthyl group and 2-naphthyl group),

(13) a 5-14 membered heteroaryl group (e.g., a thienyl group, a furyl group, a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, and a pyrazinyl group),

(14) a 3-14 membered non-aromatic heterocyclic group, (e.g., an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a pyrrolyl group, a piperidinyl group, a piperazinyl group, a homopiperidinyl group, a homopiperazinyl group, an imidazolyl group, a pyrazolidinyl group, pyrazolidinyl group, thiomorpholinyl group, imidazolinyl group, oxazolinyl group and quinuclidinyl group),

(15) With a _3-14 cycloalkyl group (e.g., cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and cyclooctyl group),

(16) C _1-22 alkoxy groups (e.g., methoxy groups, ethoxy groups, n-propoxy groups, isopropoxy groups, sec-propoxy groups, n-butoxy groups, isobutoxy groups, and tert-butoxy groups),

(17) an unsaturated C _2-22 alkoxy group (e.g., vinyloxy groups, allyloxy groups, 1-propenyloxy groups, 2-propenyloxy groups, isopropenyloxy groups, ethynyloxy groups, 1-propynyloxy groups, 2-propynyloxy groups, 1-butynyloxy groups and 2-butynyloxy groups)

(18) C _6-14 aryloxy groups (e.g., phenyloxy groups, 1-naphthyloxy groups and 2-naphthyloxy groups),

(19) C _7-22 aralkyloxy groups (e.g., benzyloxy groups, phenethyloxy groups, 3-phenylpropyloxy groups, 4-phenylbutyloxy groups, 1-naphthylmethyloxy groups and 2-naphthylmethyloxy groups),

(20) a 5-14 membered heteroaralkyloxy group (e.g., thienylmethyloxy group, furylmethyloxy group, pyridinylmethyloxy group, pyridazinylmethyloxy group, pyrimidinylmethyloxy group and pyrazinylmethyloxy group),

(21) a 5-14 membered heteroaryloxy group (e.g., thienyloxy group, furyloxy group, pyridinyloxy group, pyridazinyloxy group, pyrimidinyloxy group and pyrazinyloxy group),

(22) an aliphatic C _2-22 acyl group (e.g., acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovalery group, pivaloyl group, caproyl group, decanoyl group, lauroyl group, myristoyl group, palmitoyl group, stearoyl group group, arachidoyl group, acryloyl group, propioloyl group, crotonoyl group, isocrotonoyl group, oleoyl group and linolenoyl group),

(23) an aromatic C _7-15 acyl group (e.g., a benzoyl group, a 1-naphthoyl group and a 2-naphthoyl group),

(24) an aliphatic C _2-22 acyloxy group (e.g., acetoxy group, propionyloxy group and acryloxy group),

(25) C _2-22 alkoxycarbonyl group (e.g., methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group and tert-butoxycarbonyl group),

(26) an unsaturated C _3-22 alkoxycarbonyl group (e.g., a vinyloxycarbonyl group, an allyloxycarbonyl group, a 1-propenyloxycarbonyl group, a 2-propenyloxycarbonyl group, an isopropenyloxycarbonyl group, a propargyloxycarbonyl group, and a 2-butynyloxycarbonyl group),

(27) C _1-22 alkylthio groups (e.g. methylthio groups, ethylthio groups, n-propylthio groups and isopropylthio groups),

(28) C _1-22 alkylsulfinyl group (e.g., methanesulfinyl group, ethanesulfinyl group, n-propanesulfinyl group and isopropanesulfinyl group),

(29) C _1-22 alkylsulfonyl groups (e.g., methanesulfonyl groups, ethanesulfonyl groups, n-propanesulfonyl groups and isopropanesulfonyl groups),

(30) a _6-14 arylsulfonyl group (e.g., a benzenesulfonyl group, a 1-naphthalenesulfonyl group and a 2-naphthalenesulfonyl group),

(31) C _1-22 alkylsulfonyloxy groups (e.g. methanesulfonyloxy groups, ethanesulfonyloxy groups, n-propanesulfonyloxy groups and isopropanesulfonyloxy groups),

(32) carbamoyl group and

(33) formyl group.

Of these, a preferred example is an amino group, a C _1-22 alkyl group, an unsaturated C _2-22 alkyl group, a C _6-14 aryl group, a 5-14 membered heteroaryl group, a 3-14 membered non-aromatic heterocyclic group, and a C _3-14 a cycloalkyl group, and a more preferred example is an amino group, a C _1-22 alkyl group, a 3-14 membered non-aromatic heterocyclic group, and a C _3-14 cycloalkyl group. Each of the above (9) amino groups and (31) carbamoyl groups as a substituent in the “optionally substituted” group may be further substituted with one or two of a C _1-22 alkyl group, an unsaturated C _2-22 alkyl group, or C _6-14 aryl group.

The compounds of formula (I) of the present invention are explained below.

The compounds of formula (I) inhibit the production of VEGF under hypoxic conditions and have inhibitory activity against growth of cells of a solid tumor in vivo . Among them, compounds of formula (Ia) are preferred, of which compounds of formula (Ib) are more preferred, and compounds of formula (Ic) are typical beneficial compounds.

Compounds of formula (I) are structurally characterized by a side chain at position 6 and / or a side chain at position 7, and a group of more preferred compounds can be defined as compounds of formula (Id). In addition to compounds of formula (Id), a group of compounds having good activity include compounds of formula (I) in which R ²¹ forms an oxo group together with the carbon atom to which R ²¹ is attached. As examples of specific variants of more preferred compounds among the compounds of formula (Id), the compounds according to paragraphs (5) to (19) of the present invention can be mentioned.

Preferred examples of the compounds of formula (I) are presented below. A group of preferred compounds, including the compounds described in the examples below, includes, for example, compound 6, compound 9, compound 12, compound 15, compound 16, compound 20, compound 21, compound 22, compound 25, compound 26, compound 27, compound 31, connection 34, connection 36, connection 38, connection 39, connection 40, connection 41, connection 43, connection 44, connection 45, connection 48, connection 51, connection 53, connection 54, connection 55, connection 57, connection 58, Compound 62, Compound 63, Compound 64, Compound 65, Compound compound 69, compound 70, compound 72, compound 74, compound 75, compound 77, compound 79, compound 85, compound 88, compound 105, compound 106, compound 108, compound 109 and compound 131. Among these, examples of more preferred compounds are compound 6, connection 9, connection 12, connection 16, connection 21, connection 25, connection 26, connection 27, connection 31, connection 36, connection 38, connection 44, connection 45, connection 54, connection 63, connection 64, connection 69, compound 75, compound 85, compound 109 and compound 131, from to which, for example, compound 9, compound 12, compound 26, compound 44, compound 45 and compound 75 are typical preferred compounds.

The following explains the preparation of a compound of formula (I) of the present invention.

The compound of formula (I) can be obtained by culturing a strain belonging to the genus Streptomyces, which is capable of producing bioactive substance 11107D [compound of formula (I) in which R ³ , R ⁶ and R ²¹ are hydroxyl groups and R ⁷ is an acetoxy group ] under aerobic conditions, by collecting the compound from the cells of the microorganism and culture and chemically modifying the compound obtained by the traditional method.

The following is first described a method of obtaining 11107D.

Instead of the microorganism, the following deposit strain of the microorganism can be used to produce 11107D. The strain was deposited internationally at the International Patent Organism Depositary (IPOD) of the National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan). In particular, Streptomyces sp. Mer-11107 was deposited as FERM P-18144 at the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology (1-3, Higashi 1-chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan). He was then transferred to the International Deposit FERM BP-7812 at the International Patent Organism Depositary (IPOD) of the National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan).

The strain for the production of 11107D is not particularly limited and also includes variants of such strains, as long as it belongs to the genus Streptomyces and has the ability to produce 11107D. Examples of the strain are Streptomyces sp. A-1532, Streptomyces sp. A-1533 and Streptomyces sp. A-1534 in addition to the above strain. These strains were also deposited internationally with the International Patent Organism Depositary (IPOD) of the National Institute of Advanced Industrial Science and Technology (Tsukuba Central 6, 1-1, Higashi 1-Chome Tsukuba-shi, Ibaraki-ken 305-8566 Japan) as FERM BP-7849, FERM BP-7850 and FERM BP-7851, respectively.

The following is a detailed description: 1. the properties of the isolated microorganism, 2. the method of fermentation of the microorganism, and 3. the method of purification of the active substance when receiving 11107D.

1. Property of an isolated microorganism

As for the strain for use in the present invention, it is expected that any of the strains belonging to the genus Streptomyces and having the ability to produce 11107D can be used. However, as a typical strain used in the present invention, the authors propose, for example, a strain called “strain Mer-11107". The specified strain has the following taxonomic properties.

(1) Morphological characteristics

In this strain, aboveground hyphae in the form of helical spirals depart from the vegetative hyphae. At the end of mature aerial hyphae, a spore chain is formed consisting of approximately 10-20 columnar spores. The spore size is approximately 0.7 x 1.0 μm, the surface of the spores is smooth, and specific organs such as sporangia, sclerotia and flagella are not observed.

(2) Cultural characteristics in various environments

The culture characteristics of the strain after incubation at 28 ° C. for two weeks on various media are shown below. The color tone is described by the color name and codes that are shown in parentheses in the Color Harmony Manual (Container Corporation of America).

1) Agar medium with yeast and malt extracts

A well-grown strain, aerial hyphae that grew on the surface, and light gray spores (Light gray; d) were observed. The opposite side of the colony was Light melon yellow (3еа). Soluble pigment has not been developed.

2) Agar medium with oatmeal

We observed a strain that grew at an average level, aerial hyphae, slightly sprouted on the surface, and gray spores (Gray; g). The opposite side of the colony was tan Nude (4gc) or Putty color (1 1/2 s). Soluble pigment has not been developed.

3) Agar medium with inorganic salt and starch

A well-grown strain, aerial hyphae that grew on the surface, and gray spores (Gray; e) were observed. The opposite side of the colony was Fawn (4ig) or Gray (g). Soluble pigment has not been developed.

4) Agar medium with glycerin and asparagine

A well-grown strain, aerial hyphae that grew on the surface, and white spores (White; a) were observed. The opposite side of the colony was Pearl pink (3ca). Soluble pigment has not been developed.

5) Agar medium with peptone, yeast extract and iron

The strain growth was poor, and aboveground hyphae on the surface did not grow. The opposite side of the colony was Light melon yellow (3еа). Soluble pigment has not been developed.

6) Tyrosine agar medium

A well-grown strain, aerial hyphae that grew on the surface, and white spores (White; a) were observed. The opposite side of the colony was Pearl pink (3ca). Soluble pigment has not been developed.

(3) Use of various carbon sources

Various carbon sources are added to Pridham-Gottlieb agar medium, the strain growth after incubation at 28 ° C. for two weeks is shown below.

1) L-arabinose ± 2) D-xylose ± 3) D-glucose + 4) D-fructose + 5) sucrose + 6) inositol + 7) L-ramnose - 8) D-mannitol + 9) D-raffinose +

(+: positive, ±: slightly positive, -: negative)

(4) Physiological properties

The physiological properties of the strain are as shown below.

(a) Cultivation temperature range (agar medium with yeast and malt extracts, incubation for 2 weeks): 12 ° C-37 ° C

(b) Optimum temperature range (agar medium with yeast and malt extracts, incubation for 2 weeks): 21 ° C-33 ° C

(c) Gelatin liquefaction (agar medium with glucose, peptone and gelatin): negative

(d) Coagulation of milk (agar medium with separated milk): negative

(e) Peptonization of milk (agar medium with separated milk): negative

(f) Hydrolysis of starch (agar medium with inorganic salt and starch): positive

(g) Formation of a melanoid pigment (agar medium with peptone, yeast extract and iron): negative,

(tyrosine medium): negative

(h) Production of hydrogen sulfide (agar medium with peptone, yeast extract and iron): negative

(i) Decrease in nitrate content (broth containing 0.1% potassium nitrate): negative

(j) Sodium chloride tolerance (agar medium with yeast and malt extracts, incubation for 2 weeks): increased at a salt content of 4% or lower

(5) Chemotaxonomy

LL-diaminopimelic acid and glycine were detected from the cell walls of this strain.

Based on the characteristics of the microorganism described above, it is believed that this strain is a strain of the genus Streptomyces. Therefore, the authors of the present invention named this strain of the microorganism as Streptomyces sp. Mer-11107 and deposited it as FERM P-18144 at the National Institute of Bioscience and Human-Technology Agency of Industrial Science and Technology.

2. The method of fermentation of the producer microorganism

Physiologically active substance 11107D of the present invention can be obtained by inoculation of the strain on a nutrient medium and the implementation of aerobic fermentation. The strain for producing the physiologically active substance 11107D is not limited to the strain indicated above, and any strain belonging to the genus Streptomyces and having the ability to produce substance 11107D can be used in the present invention.

The fermentation method of the above microorganism corresponds to the conventional method of fermentation of the microorganism, but preferably it is carried out under aerobic conditions, such as shaking cultivation or aeration and agitation fermentation using a liquid medium. The medium used for cultivation may be a medium containing a food source, which can be used by a microorganism belonging to the genus Streptomyces, therefore, any of the media synthetic, semi-synthetic, organic and the like can be used. As the carbon source in the composition of the medium, glucose, sucrose, fructose, glycerin, dextrin, starch, molasses, soybean oil and the like can be used separately or in combination. Organic nitrogen sources such as pharmaceutical media, peptone, meat extract, soya powder, casein, amino acid, yeast extract and urea, and inorganic nitrogen sources such as sodium nitrate and ammonium sulfate can be used alone or in combination as a nitrogen source. In addition, for example, salts such as sodium chloride, potassium chloride, calcium carbonate, magnesium sulfate, sodium phosphate, potassium phosphate and cobalt chloride, heavy metal salts, vitamins such as vitamin B or biotin can be added and used, if necessary. And yet, when foaming becomes noticeable during cultivation, then various defoamers can be added to the medium if necessary. When adding antifoam, it is necessary to prescribe a concentration that does not adversely affect the production of the target substance, preferably, for example, a concentration of 0.05% or lower.

Culturing conditions can be suitably selected in the range in which the microbial strain grows well and can produce the above substance. For example, the pH of the medium is about 5-9 and is preferably close, as a rule, to neutral. The fermentation temperature is usually kept in the range of 20 ° C-40 ° C, preferably 28 ° C-35 ° C. The fermentation time is about 2-8 days, usually about 3-5 days. These fermentation conditions can be appropriately changed in accordance with the type and properties of the microorganism used, external conditions and the like, not to mention the fact that the optimal mode can be selected. The physiologically active substance 11107D that has accumulated in the liquid nutrient medium can be collected by conventional separation methods using its properties, such as solvent extraction method and resin absorption method.

Physiologically active substance 11107D can also be obtained, for example, by using a microorganism belonging to the genus Streptomyces (for example, a strain of Streptomyces sp. AB-1704 (FERM P-18999) and using substance 11107B (the compound described in example A4 in WO 02 / 060890), as shown in Reference Examples 6-10.

3. The method of purification of biologically active substances

To collect 11107D from the culture medium after fermentation, general separation and purification methods used to isolate microbial metabolites from the liquid culture medium can be used. For example, all appropriate methods are suitable for this, such as extraction with an organic solvent, usually using methanol, ethanol, butanol, ethyl acetate or chloroform; various types of ion exchange chromatography; gel filtration chromatography using Sephadex LH-20; processing by adsorption and desorption using absorption chromatography, usually using activated carbon or silica gel, or thin layer chromatography; or high performance liquid chromatography, usually using a reverse phase column. In addition, methods for purifying 11107D are not particularly limited to the above methods.

Compound 11107D can be isolated and purified using the indicated methods individually or in combination or by their repeated use.

The following explains the preparation of compounds of formula (I) other than 11107D.

The compounds of formula (I) can be synthesized from isolated and purified compounds 11107D as starting material by conversion of the hydroxyl group and / or acetoxy group of the specified compound according to general methods of organic synthesis. Typical examples of synthesis methods are: A. preparation of a urethane derivative, B. preparation of a thiourethane derivative, C. preparation of an ether derivative, D. preparation of an ester derivative, E. preparation of a phosphoric acid ester derivative or amidophosphoric acid ester, F. preparation of a derivative sulfuric acid ester or amidosulfuric acid ester, G. preparation of a halogen-containing derivative, N. preparation of a sulfonic acid ester derivative, I. preparation of an amine derivative and J. Preparation of an oxo derivative by oxidation of a hydroxyl group. The introduction or removal of the protective group for the hydroxy group can be carried out, if necessary, by the method described in the material (Protective Groups in Organic Synthesis, TW Greene, John Wiley & Sons, Inc. 3rd Edition), or by a similar method depending on the type of protective group and stability a compound involved in a particular preparation. Compounds of formula (I) can be prepared by using the reactions of introducing and removing a hydroxyl protecting group and the preparation described above in a suitable combination. In particular, compounds of formula (I) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraph 9 above) can be prepared by the method of preparing a urethane derivative, a thiourethane derivative, an amidosulfuric acid ester derivative or an amine derivative; the compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraphs 2) -5) above can be obtained by the method of obtaining an ether derivative; the compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraph 6 above) can be obtained by the method of obtaining an ester derivative; a compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed above in paragraphs 11) -13) can be obtained by the method of obtaining a derivative of a phosphoric acid ester or amidophosphoric acid ester; the compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraph 10 above) can be obtained by the method of obtaining a derivative of sulfuric acid ester or sulfonic acid ester; the compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraph 8 above) can be obtained by the method of obtaining a halogen-containing derivative; a compound of formula (1) in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed in paragraph 7 above) can be prepared using reactions to introduce or remove a hydroxyl protecting group; and an oxo derivative in which R ³ , R ⁶ , R ⁷ and R ²¹ are the substituents listed above in paragraph 1), can be obtained by the method of producing an oxo derivative by oxidizing a hydroxyl group.

The synthesis methods used to prepare the compounds of formula (I) are explained below.

A. Preparation of the urethane derivative

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents a hydrogen atom or a protective group, provided that R ^3A , R ^6A , R ^16A and R ^{21A are} not all hydrogen atoms at the same time; each of R ^3B , R ^6B , R ^16B and R ^21B represents a hydrogen atom, a protecting group or a group represented by the formula R ^F O —CO— (where R ^F is an optionally substituted C _6-14 aryl group), provided that that R ^3B , R ^6B , R ^16B and R ^21B do not represent hydrogen atoms all at the same time; each of R ^3C , R ^6C , R ^16C and R ^21C represents a hydrogen atom, a protective group or a group represented by the formula R ^N1 R ^N2 N — CO— (where each of R ^N1 and R ^N2 represents a group as previously defined), and each of R ^3D , R ^6D , R ^16D and R ^21D represents a hydrogen atom or a group represented by the formula R ^N1 R ^N2 N — CO— (where each of R ^N1 and R ^N2 represents a group as previously defined).

Step A1 is a step for preparing a compound of formula (IA). This step is carried out protecting the hydroxyl group (s) of compound 11107D.

The protection reaction of the hydroxyl group or groups is carried out according to the method well known in the chemistry of organic synthesis, choosing it depending on the type of protective group.

Examples of the protecting group are 1-ethoxyethyl, tetrahydropyranyl, 1-methyl-l-methoxyethyl, l- (2-chloroethoxy) ethyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, S, S-methoxide 4-methoxytetrahydrothiopyranyl, methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl, trimethylsilylethyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl, trimethylsilyl, triisopropylsilylmethylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylbenylmethyl l, p-chlorobenzyl and triphenylmethyl. All or part of the hydroxyl groups may be suitably protected by said protecting groups.

For example, derivatives with hydroxyl groups protected by 1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or 4-methoxytetrahydrothiopyranyl S, S-dioxide can be synthesized by treatment of ethyl ether with ethyl ether such as 11107D and the corresponding one. or dihydropyran, in the presence of an acid. Examples of acids are conventional acids, including organic acids, such as pyridinium p-toluene sulfonate (PPTS), p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, trifluoroacetic acid or methanesulfonic acid, and inorganic acids such as hydrogen chloride, nitric acid, chlorine acid or sulfuric acid. Of these, a preferred example is p-toluene pyridinium sulfonate (PPTS), p-toluenesulfonic acid or camphorsulfonic acid. The solvent used in the reaction is not particularly limited, but an inert solvent which cannot easily interact with the starting material is desirable. Examples of such solvents are ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, dioxane and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; hydrocarbons such as hexane, benzene and toluene; ketones such as acetone and methyl ethyl ketone; nitriles such as acetonitrile; amides, such as N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyridone and hexamethylphosphoramide; and sulfoxides, such as dimethyl sulfoxide, of which dichloromethane, chloroform or tetrahydrofuran are a preferred example. The reaction time is from 10 minutes to 5 days, preferably 1-2 days. The reaction temperature is in the range of −78 ° C. to the reflux temperature and is preferably equal to room temperature. The amount of vinyl ester and acid used in the reaction is, with respect to compound 11107D, 1-200 equivalents and 0.05-2 equivalents, and preferably 30-50 equivalents and 0.1-0.3 equivalents, respectively.

Examples of other protective groups are methoxymethyl, methylthiomethyl, methoxyethoxymethyl, trichloroethoxymethyl, trimethylsilylethyl, trimethylsilylethoxymethyl, tert-butyldimethylsilyl, triethylsilyl, trimethylsilyl-phenyl-methyl-phenyl-phenyl-methyl-phenyl-phenyl-methyl-phenyl-phenyl-methyl-phenyl-methyl-phenyl-methyl-phenyl-methyl-phenyl-methyl) -benzyl-methyl-phenyl-methyl-phenyl-methyl) , p-chlorobenzyl and triphenylmethyl. Such derivatives with protected hydroxyl groups can be synthesized by reacting the starting material with a chloride, bromide or trifluoromethanesulfonate of the corresponding protective groups in the presence of a base. The base is a conventional organic base or inorganic base. Examples of an organic base are an aromatic base such as imidazole, 4- (N, N-dimethylamino) pyridine (4-dimethylaminopyridine, N, N-dimethylaminopyridine and dimethylaminopyridine mean the same), pyridine, 2,6-lutidine or collidine; a tertiary amine such as N-methylpiperidine, N-methylpyrrolidine, triethylamine, trimethylamine, diisopropylethylamine, cyclohexyl dimethylamine, N-methylmorpholine or 1,8-bis (dimethylamino) naphthalene; a secondary amine such as diisobutylamine or dicyclohexylamine; alkyl lithium, such as methyl lithium or butyl lithium; a metal alkoxide such as sodium methoxide or sodium ethoxide. Examples of the inorganic base are alkali metal hydride, such as sodium hydride or potassium hydride; alkaline earth metal hydride such as calcium hydride; alkali metal hydroxide such as sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as sodium carbonate, potassium carbonate or cesium carbonate, and an alkali metal hydrogen carbonate such as sodium bicarbonate. Preferred examples of a base for protecting a hydroxyl group with a silyl protecting group are an aromatic base such as imidazole or 4-dimethylaminopyridine and a tertiary amine such as triethylamine. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples of such solvents are the inert solvents described above, of which tetrahydrofuran, dichloromethane or N, N-dimethylformamide is a preferred example. The reaction time is from 10 minutes to 3 days, preferably 1-2 days. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C. The amount of chloride, bromide or trifluoromethanesulfate and base used in the reaction is equal to 1-20 equivalents and 0.5-30 equivalents, preferably 1-15 equivalents and 0.5-20 equivalents, respectively, to compound 11107D.

The hydroxyl groups of compound 11107D can be selectively protected by selecting the reagent and its equivalence, used to protect the hydroxyl groups. For example, a compound in which the hydroxyl groups at position 3 and position 21 are selectively protected can be prepared by reacting at room temperature using chlorotriethylsilane, triethylamine and 4-dimethylaminopyridine in dichloromethane or tert-butylchlorodimethylsilane and imidazole in N, N-dimethylformamide. By this technique, for example, the hydroxyl group at position 3 can be selectively protected by adjusting the equivalence of chlorotriethylsilane or tert-butylchlorodimethylsilane. Furthermore, two or three of the four hydroxyl groups can be protected with a silyl group, and then the other two or one hydroxyl group can be protected with the aforementioned ethoxyethyl or the like.

Step A2 is a step for preparing a compound of formula (IIA). This step is carried out by converting the acetoxy group of the compound of formula (IA) to the hydroxyl group by treating the base with an inert solvent.

Examples of the base used in this step are inorganic bases including an alkali metal hydride such as sodium hydride or potassium hydride; alkaline earth metal hydride such as calcium hydride; alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide; an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate, an alkali metal hydrogen carbonate such as sodium bicarbonate, and a metal alkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide or potassium tert-butoxide, as well as bases such as guanidine or ammonia. Preferred examples of the base are potassium carbonate and guanidine.

Examples of the inert solvent used in the reaction include, in addition to the above solvents, an alcohol solvent such as methanol, ethanol, isopropanol or tert-butanol, and water. These solvents can be used in combination as a mixture. A preferred solvent is an alcohol solvent or a mixture of an alcohol and a halogen-containing solvent. The reaction time is from 10 minutes to 5 days, preferably from 30 minutes to 1 day. The reaction temperature is in the range of −78 ° C. to the reflux temperature and is preferably equal to room temperature. The amount of base used in the reaction with respect to the compound of formula (IA) is 1-10 equivalents and preferably 2-5 equivalents.

Step A3 is a step for preparing a compound of formula (IIIA). This step is carried out by treating the hydroxyl group of the compound of formula (IIA) with a chloroformate derivative or carbonyldiimidazole in the presence of a base. Examples of a chloroformate derivative are 4-nitrophenyl chloroformate, phenyl chloroformate, 4-chlorophenyl chloroformate, 4-bromophenyl chloroformate and 2,4-dinitrophenyl chloroformate. Examples of the base are the above organic bases and inorganic bases, of which, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples of such solvents are the inert solvents described above, of which, for example, tetrahydrofuran, dichloromethane or N, N-dimethylformamide are preferably used. The amount of chloroformate derivative and base used in the reaction with respect to the compound of formula (IIA) is 1-10 equivalents and 1-20 equivalents, preferably 1-5 equivalents and 1-10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-4 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

As for the hydroxyl compound (IA), in which one or three of the groups OR ^3A , OR ^6A , OR ^16A and OR ^21A were not protected in step A1, the hydroxyl groups can be converted to carbonic ester groups in step A3. In particular, hydroxyl groups of compound (IA) other than the hydroxyl group at position 7 can be converted to carbonic ester groups in the same way as hydroxyl groups at position 7 by treatment with a base and a chloroformate derivative with equivalents corresponding to the number of hydroxyl groups converted into the ester groups of carbonic acid.

Step A4 is a step for preparing a compound of formula (IVA). This step is carried out by treating a carbonic ester of formula (IIIA) with an amine (R ^N1 R ^N2 H), which can form the desired compound of formula (I) in an inert solvent in the presence of a base or with an amine alone.

Examples of the amine used in this step are methylamine, ethylamine, propylamine, butylamine, octylamine, decylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, dimethylamine, diethylamine, ethylmethylamine, ethylenediamine, 1,3-propanediamine, 1,4-butanediamine, N, N, N -dimethylethylenediamine, N, N-dimethyl-1,3-propanediamine, N, N-dimethyl-1,4-butanediamine, N, N-diethylethylenediamine, N, N-diethyl-1,3-propanediamine, N, N-diethyl -1,4-butanediamine, N, N, N'-trimethylethylenediamine, N, N, N'-trimethyl-1,3-propanediamine, N, N, N'-trimethyl-1,4-butanediamine, N-ethyl N ', N'-dimethylethylenediamine, N-ethyl-N', N'-dimethyl-1 , 3-propanediamine, N-ethyl-N ', N'-dimethyl-1,4-butanediamine, N, N, N'-triethylethylenediamine, N, N, N'-triethyl-1,3-propanediamine, N, N , N'-triethyl-1,4-butanediamine, N, N-diethyl-N'-methylethylenediamine, N, N-diethyl-N'-methyl-1,3-propanediamine, N, N-diethyl-N'-methyl -1,4-butanediamine, N, N'-dimethyl-N-phenylethylenediamine, N, N'-dimethyl-N-phenyl-1,3-propanediamine, N-benzyl-N, N'-dimethylethylenediamine, N-benzyl- N, N'-dimethyl-1,3-propanediamine, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-dioxide, pyrrolidine, piperidine, piperazine, homopiperazine, 4-hydroxypiperidine, 4-methoxypiperidine, 1-methylpiperaz , 1-ethylpiper zine, 1-propylpiperazine, 1-butylpiperazine, 1-isopropylpiperazine, 1-cyclobutylpiperazine, 1-cyclopentylpiperazine, 1-cyclohexylpiperazine, 1-cycloheptylpiperazine-1-cyclooctylpiperazine-1-cyclooctylpiperazine-1 -ethyl homopiperazine, 1- (2-aminoethyl) pyrrolidine, 1- (2- (N-methylamino) ethyl) pyrrolidine), 1- (3-aminopropyl) pyrrolidine, 1- (3- (N-methylamino) propyl) pyrrolidine) , 1- (2-aminoethyl) piperidine, 1- (2- (N-methylamino) ethyl) piperidine), 1- (3-aminopropyl) piperidine, 1- (3- (N-methylamino) propyl) piperidine), 4 - (2-aminoethyl) morpholine, 4- (2- (methylamine) o) ethyl) morpholine), 4- (3-aminopropyl) morpholine, 4- (3- (N-methylamino) propyl) morpholine), 1- (2-aminoethyl) -4-methylpiperazine, 1- (3-aminopropyl) -4-methylpiperazine, 1- (3- (N-methylamino) propyl) -4-methylpiperazine, 1-amino-4-methylpiperidine, 1-methylamino-4-methylpiperidine, 1-ethyl-4- (N-methylamino) piperidine , 1-methylamino-4-propylpiperidine, 1-butyl-4- (N-methylamino) piperidine, 1- (N, N-dimethylamino) piperidine, 1- (N, N-diethylamino) piperidine, 4- (pyrrolidin-1 -yl) piperidine, 4- (piperidin-1-yl) piperidine, 3-aminoquinuclidine, 3- (N-methylamino) quinuclidine, aniline, N-methylaniline, N, N-dimethyl-p-phenylenediamine, N, N-dimethyl -m- phenylenediamine, N, N, N'-trimethyl-p-phenylenediamine, N, N, N'-trimethyl-m-phenylenediamine, 1-naphthylamine, 2-naphthylamine, benzylamine, N-methylbenzylamine, phenethylamine, N-methylphenethylamine, 2- picolylamine, 3-picolylamine, 4-picolylamine, N-methyl-2-picolylamine, N-methyl-3-picolylamine, N-methyl-4-picolylamine, 2,5-diazabicyclo [2.2.1] heptane, 2-methyl- 2,5-diazabicyclo [2.2.1] heptane, 3,8-diazabicyclo [3.2.1] octane and 1,4-diazabicyclo [4.3.0] nonane.

Examples of the base are the above organic bases and inorganic bases, of which, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples of such solvents are the inert solvents described above, of which, for example, tetrahydrofuran, dichloromethane or N, N-dimethylformamide are preferably used. The amount of amine and base used in the reaction with respect to the compound of formula (IIIA) is 1-10 equivalents and 2-20 equivalents, preferably 1.5-5 equivalents and 2-10 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

A compound of formula (IVA) can also be obtained by treating a compound of formula (IIA) with an isocyanate in an inert solvent in the presence of a base and / or copper chloride (1). The isocyanate is not particularly limited, and it includes, for example, ethyl isocyanate, methyl isocyanate and phenyl isocyanate. Examples of the base are the above organic bases and inorganic bases, of which diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples of such solvents are the inert solvents described above, of which, for example, tetrahydrofuran, dichloromethane or N, N-dimethylformamide are preferably used. The amount of base and isocyanate used in the reaction with respect to the compound of formula (IIIA) is 3-100 equivalents and 1-20 equivalents, preferably 5-20 equivalents and 3-10 equivalents, respectively. When using copper chloride (1), its amount is 1-10 equivalents, preferably 2-6 equivalents. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

A hydroxyl compound in which one or three of the groups OR ^3A , OR ^6A , OR ^16A and OR ^21A were not protected in step A1 can be converted to a derivative containing several urethane structures by converting the indicated hydroxyl groups to carbonic ester groups on stage A3 and then converting them into carbamoyloxy groups in stage A4.

Step A5 is a step for preparing a compound of formula (VA). This step is carried out by subjecting a urethane derivative of formula (IVA) to a deprotection process described below in an inert solvent. The reaction for removing the protective groups of hydroxyl groups varies depending on the type of protective group, but is carried out by a method well known in the chemistry of organic synthesis.

With respect to the corresponding hydroxyl group protected, for example, with 1-ethoxyethyl, tetrahydropyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl or 4-methoxytetrahydrothiopyranyl-S, S-dioxide, the deprotection reaction can easily be carried out with an acid in acid solvent. Examples of acids are the above organic acids and inorganic acids, of which, for example, pyridinium p-toluenesulfonate, p-toluenesulfonic acid or camphorsulfonic acid are preferred. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Preferred examples thereof are an alcoholic solvent, such as methanol, ethanol, isopropanol or tert-butanol, or a mixture of alcohol and the above inert solvent. The amount of acid used in the reaction with respect to the compound of formula (IVA) is 0.5-5 equivalents and preferably 1-3 equivalents. The reaction time is from 10 minutes to 10 days, preferably 1-4 days. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

When the hydroxyl group is protected by another protecting group, such as tert-butyldimethylsilyl, triethylsilyl, diethylisopropylsilyl, trimethylsilyl, triisopropylsilyl, di-tert-butylmethylsilyl or diphenylmethylsilyl, it can be deprotected by treatment with fluoridanion or acid. Examples of fluoridanion are tetrabutylammonium fluoride, hydrogen fluoride, potassium fluoride and hydrogen fluoride pyridine. Examples of acids are the above organic acids and inorganic acids, of which the preferred example is acetic acid, formic acid, trifluoroacetic acid, pyridinium p-toluenesulfonate or camphorsulfonic acid. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the above inert solvents, of which, for example, tetrahydrofuran, diethyl ether or water are preferably used. The amount of fluoride anion and acid used in the reaction with respect to the compound of formula (IVA) is 1-5 equivalents and 0.5-5 equivalents, preferably 1-4 equivalents and 0.5-3 equivalents, respectively. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

The combination of various methods of protecting the hydroxyl groups described in step A1 and the various methods of protecting described in step A5, the corresponding hydroxyl groups in position 3, position 6 and position 21 can be selectively converted to urethane derivatives. For example, a urethane derivative containing a hydroxyl group at position 6 can be synthesized by exposing a hydroxyl group at position 6 of compound (IA) in which R ^3A , R ^16A and R ^21A are triethylsilyl groups, the reactions in stage A3, stage A4 and stage A5, respectively.

The selective modification of the hydroxyl group at position 3, position 6, or position 21 by a combination of protection and deprotection techniques can also be applied to other modification methods described below.

B. Preparation of Thiourethane Derivative

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined; each of R ^3E , R ^6E , R ^16E and R ^21E represents a hydrogen atom, a protective group or a group represented by the formula R ^N1 R ^N2 N-CS- (where each of R ^N1 and R ^N2 represents the same group as defined previously), provided that R ^3E , R ^6E , R ^16E and R ^21E do not represent hydrogen atoms all at the same time; and each of R ^3F , R ^6F , R ^16F and R ^21F represents a hydrogen atom or a group represented by the formula R ^N1 R ^N2 N-CS- (where each of R ^N1 and R ^N2 represents the same group as previously defined) .

Step B1 is a step for preparing a compound of formula (IB) using a thioisocyanate or thiocarbamoyl chloride instead of isocyanate. This step is carried out by treating the compound of formula (IIA) with isothiocyanate or thiocarbamoyl chloride in an inert solvent in the presence of a base or bis (tributyltin) oxide. The isothiocyanate used in this reaction is not particularly limited, and it includes, for example, ethyl isothiocyanate, methyl isothiocyanate, phenyl isothiocyanate, benzyl isothiocyanate, allyl isothiocyanate, 2- (N, N-dimethylamino) ethyl isothiocyanate, 2- (N, ethano-3-diethylamino) - (N, N-dimethylamino) propylisothiocyanate, 3- (N, N-diethylamino) propylisothiocyanate, 2- (morpholin-4-yl) ethyl isothiocyanate, 2- (piperidin-1-yl) ethylisothiocyanate and 2- (pyrrolidin-1- 1- il) ethyl isothiocyanate. The thiocarbamoyl chloride used in this reaction is not particularly limited, and it includes, for example, N, N-dimethylthiocarbamoyl chloride, N-phenyl-N-methylthiocarbamoyl chloride, (morpholin-4-yl) thiocarbamoyl chloride, (4-methylpiperazoyl-1-thiamo-chloro-1-azylamino) and (4-methylhomopiperazin-1-yl) thiocarbamoyl chloride. Examples of the base are the above organic bases and inorganic bases, of which, for example, diisopropylethylamine, 4-dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples of such solvents are the inert solvents described above, of which, for example, tetrahydrofuran, dichloromethane, N, N-dimethylformamide or toluene are preferably used. The amount of base or bis (tributyltin) oxide and isothiocyanate or thiocarbamoyl chloride with respect to the compound of formula (IIA) is 1-5 equivalents and 1-10 equivalents, preferably 1-3 equivalents and 2-5 equivalents, respectively. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 70 ° C.

A compound of formula (IB) containing several thiocarbamoyl groups can be synthesized by converting a hydroxyl group or groups of a compound represented by formula (IIA), wherein one to three of OR ^3A , OR ^6A , OR ^16A and OR ^{21A are} not protected, into a thiocarbamoyloxy group (s ) at stage B1.

The thiourethane derivative of the formula (IIB) can be synthesized by removing the protecting group of the hydroxyl group in accordance with step A5.

C. Obtaining an ether derivative

In the formulas, each of R ^3G , R ^6G , R ^16G and R ^21G represents a hydrogen atom or a protective group, provided that R ^3G , R ^6G , R ^16G and R ^{21G are} not all hydrogen atoms at the same time and at least one of which represents a hydrogen atom and each of R ^3H , R ^6H , R ^16H and R ^21H represents a protective group or an optionally substituted C _1-22 alkyl group.

Step C1 is a step for synthesizing a compound of formula (IC). This step is carried out in the same manner as the reaction of Step A1 of Preparation A, except that one to three hydroxyl groups need to be protected.

According to another embodiment, at this stage, a compound in which a hydroxyl group is located in position 3, position 6 or position 21 and the other hydroxyl groups are protected can be synthesized by a combination of various hydroxyl group protection methods corresponding to stage A1 and deprotection methods a protected hydroxyl group corresponding to production step A5.

Step C2 is a step for synthesizing a compound of formula (IIC). This step is carried out by alkylation of an unprotected hydroxyl group or groups of a compound (IC).

Alkylation can be carried out by treatment with an alkylating agent of the formula R ^m —X in the presence of a base. The substituent R ^m represents a C _1-22 alkyl group which may have substituents, and includes, for example, a methyl group, an ethyl group and a benzyl group. X represents a leaving group. Examples of the leaving group are chromium, bromine, iodine and trifluoromethanesulfonyl group. Examples of the base are the above organic and inorganic bases, of which preferred examples are sodium hydride, lithium bis (trimethylsilyl) amide, lithium diisopropylamide, lithium dicyclohexylamide, potassium carbonate, cesium carbonate and 1,8-bis (N, N-dimethylamino) naphthalene . The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the inert solvents described above, of which, for example, diethyl ether, tetrahydrofuran, dimethoxyethane or toluene are preferably used. The amount of alkylating agent and base used in the reaction with respect to the compound of formula (IC) is 3-20 equivalents and 5-30 equivalents, preferably 3-5 equivalents and 5-10 equivalents, respectively. The reaction time is from 10 minutes to 48 hours, preferably 1-24 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 70 ° C.

In the formulas, each of R ^3J , R ^6J , R ^16J and R ^21J represents an alkyl group or a protective group, each of R ^3K , R ^6K , R ^16K and R ^21K represents an alkyl group or a hydrogen atom and R ^7K represents a carbamoyl group or a thiocarbamoyl group, each of which may contain substituents on the nitrogen atom.

If desired, a derivative containing a carbamoyl group introduced into the hydroxyl group at position 7 and an alkyl group introduced into one or two hydroxyl groups at position 3, position 6 and position 21 can be obtained by further exposing the compound of formula (IIC) to the reactions of the steps A2, A3, A4 and A5.

In another embodiment, a derivative containing a thiocarbamoyl group introduced into the hydroxyl group at position 7 and an alkyl group introduced into one or two hydroxyl groups at position 3, position 6 and position 21 can be obtained by subjecting the compound of formula (IIIC) to reaction stage B1 and then the reaction of stage A5.

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, and each of R ^3L , R ^6L , R ^7L R ^16L and R ^21L represents a hydrogen atom or an alkyl group.

An ether derivative represented by the formula (IIC '), wherein the hydroxyl group at position 7 is alkylated, can be obtained by subjecting the compound of formula (IIA) to the reaction of step C2 and then the reaction of step A5 in a manner similar to that described above.

In addition, the corresponding ether derivative can be obtained using an alkylating agent with unsaturated alkyl, an aralkylating agent or a heteroalkylating agent instead of an alkylating agent, which will give the desired compound of formula (I).

D. Preparation of ester derivative

In the formulas, each of R ^3G , R ^6G , R ^16G and R ^21G represents the same group as previously defined, and each of R ^3M , R ^6M , R ^16M and R ^21M represents a hydrogen atom, a protective group or a group represented by the formula R ^CO WITH- (where R ^CO represents a hydrogen atom, an optionally substituted C _1-22 alkyl group, an optionally substituted unsaturated C _2-22 alkyl group, an optionally substituted C _6-14 aryl group, optionally substituted 5-14 membered heteroaryl a group optionally substituted with a C _7-22 aralkyl group or an optional a 5-14 membered heteroalkyl group), provided that R ^3M , R ^6M , R ^16M and R ^{21M are} not all hydrogen atoms at the same time.

Step D1 is the step of converting an unprotected hydroxyl group to an ester group using the compound of formula (IC) synthesized in step CI as a starting material.

The esterification is carried out, for example, using an acid anhydride with a base, a halide with a base, a carboxylic acid with a condensing agent, or by carrying out a Mitsunobu reaction. As the acid anhydride, various carboxylic acid anhydrides are used. Examples thereof are mixed anhydride containing, for example, acetic acid, propionic acid, butyric acid, valerianic acid and benzoic acid; symmetric anhydride; cyclic anhydride such as succinic anhydride, glutaric anhydride or adipic anhydride. Preferred examples are acetic anhydride, propionic anhydride, butyric anhydride and benzoic anhydride. As the acid halide, for example, various acid chlorides and bromides are used, of which the preferred example is acetyl chloride, propionyl chloride, benzoyl chloride or benzoyl bromide. Examples of the base are the above organic and inorganic bases, of which imidazole, 4-dimethylaminopyridine, pyridine or sodium hydride are the preferred examples. Various carboxylic acids are used as the carboxylic acid, of which acetic acid or propionic acid is a preferred example. Preferred examples of the condensing agent are, for example, dicyclohexylcarbodiimide, trifluoroacetic anhydride, carbonyldiimidazole, N, N-diisopropylcarbodiimide and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide. In the Mitsunobu reaction, various carboxylic acids can be substituted in the presence of triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate. The solvent used in each of the reactions is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the inert solvents described above, of which, for example, dichloromethane, chloroform or tetrahydrofuran are preferably used. The amount of acid anhydride with a base, a halide with a base and a carboxylic acid with a condensing agent with respect to a compound of formula (IC) is 1-10 equivalents with 3-20 equivalents, 1-10 equivalents with 3-20 equivalents and 1-20 equivalents with 1 -20 equivalents, preferably 1-5 equivalents with 2-10 equivalents, 1-5 equivalents with 2-10 equivalents and 1-5 equivalents with 1-5 equivalents, respectively. The reaction can be accelerated, when necessary, by the addition of 0.2-2 equivalents of 4-dimethylaminopyridine. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

The compound of formula (ID) can be obtained by subjecting the ester derivative to the reaction synthesized as described above, similar to that carried out in step A5, to remove the protecting group of the hydroxyl group.

One to four hydroxyl groups can also be esterified by esterification in a manner similar to that carried out in step D1 using compound 11107D as the starting material.

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as defined previously, and each of R ^3N , R ^6N , R ^7N R ^16N and R ^21N represents a hydrogen atom or a group represented by the formula R ^CO CO— (where R ^CO represents the same group as previously defined).

The ester derivative represented by the formula (ID '), wherein the hydroxyl group at position 7 is esterified, can be synthesized by subjecting the compound of formula (IIA) to the reaction of step D1 and then the reaction of step A5 in a manner similar to that described above.

E. Preparation of a Derived Phosphoric Acid Ester or Amidophosphoric Acid Ester

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, each of R ^3P , R ^6P , R ^7P R ^16P and R ^21P represents a hydrogen atom, a group represented by the formula ( R ^N3 O) ₂ PO-, formula (R ^N1 R ^N2 N) ₂ PO- or formula (R ^N1 R ^N2 N) (R ^N3 O) PO- (where each of R ^N1 , R ^N2 and R ^N3 represents such same group as defined above).

Step E1 is the step of converting the hydroxyl group of the compound of formula (IIA) as a starting material into an ester of phosphoric acid or an ester of amidophosphoric acid.

The esterification of phosphoric acid is carried out, for example, using phosphoryl halide and a base. Various phosphoryl halides can be used, examples of which are dialkoxyphosphoryl chloride, diphenyloxyphosphoryl chloride, alkoxy (N, N-disubstituted amino) phosphoryl chloride, allyloxy (N, N-disubstituted amino) phosphoryl chloride, alkoxy (N-substituted amino-amino-amino) phosphoryl chloride phosphoryl chloride. Examples of the base are the above organic and inorganic bases, of which the preferred examples are pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodium hydride, n-butyllithium, potassium carbonate or sodium carbonate. The solvent used in each of the reactions is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the inert solvents described above, of which, for example, dichloromethane, chloroform, tetrahydrofuran or N, N-dimethylformamide are preferably used. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The amount of phosphoryl halide and base used in the reaction with respect to the compound of formula (IIA) is 1-10 equivalents and 2-20 equivalents, preferably 1-5 equivalents and 2-10 equivalents, respectively. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

The compound of formula (IE) can be obtained by subjecting the phosphoric acid ester derivative synthesized in the manner described above to a reaction similar to that carried out in step A5 to remove the hydroxyl protecting group.

You can also convert one to four hydroxyl groups into phosphoric acid esters by esterifying the phosphoric acid of compound 11107D as a starting material in a manner similar to that carried out in step E1.

F. Preparation of Derivative of Sulfuric Acid Ester or Amidosulfuric Acid Ester

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, and each of R ^3Q , R ^7Q , R ^6Q , R ^16Q and R ^21Q represents a hydrogen atom or a group represented by the formula R ^N1 R ^N2 N-SO ₂ - or the formula R ^N3 O-SO ₂ - (where each of R ^N1 , R ^N2 and R ^N3 represents the same group as defined above).

Step F1 is the step of converting the hydroxyl group of the compound of formula (IIA) as a starting material into a sulfuric acid ester.

The sulfuric acid esterification is carried out, for example, using a sulfonyl halide and a base. Various sulfonyl halides can be used, examples of which are alkoxysulfonyl chloride and N, N-disubstituted sulfamoyl chloride. Examples of the base are the above organic and inorganic bases, of which the preferred examples are pyridine, 4-dimethylaminopyridine, triethylamine, ethyldiisopropylamine, sodium hydride, n-butyllithium, potassium carbonate or sodium carbonate. The solvent used in each of the reactions is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the inert solvents described above, of which, for example, dichloromethane, chloroform, tetrahydrofuran or N, N-dimethylformamide are preferably used. The amount of sulfonyl halide and base used in the reaction with respect to the compound of formula (IIA) is 1-10 equivalents and 2-20 equivalents, preferably 1-5 equivalents and 2-10 equivalents, respectively. The reaction time is from 10 minutes to 72 hours, preferably 1-24 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, and preferably from −10 ° C. to 50 ° C.

The compound of formula (IF) can be synthesized by subjecting the sulfuric acid ester derivative synthesized in the manner described above to a reaction similar to that carried out in step A5 to remove the hydroxyl protecting group.

One to four hydroxyl groups can also be converted to sulfuric acid esters by subjecting compound 11107D as a starting material to the esterification of sulfuric acid to give a sulfuric acid ester in a manner similar to that carried out in step F1.

G. Obtaining a halogenated derivative

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, each of R ^3R , R ^6R , R ^16R and R ^21R represents a hydroxyl group or a halogen atom.

Step G1 is the step of converting the hydroxyl group of a compound of formula (IA) as a starting material into halogen.

Halogenation is carried out, for example, by treating diethylamino seratrifluoride (DAST) or triphenylphosphine with carbon tetrabromide, bromine, phosphorus tribromide, iodine or carbon tetrachloride in the presence of a base. The base used in this reaction includes, for example, conventional organic and inorganic bases such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in each of the reactions is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are tetrahydrofuran, dichloromethane and N, N-dimethylformamide. Fluorination with diethylamino seratrifluoride is preferred. The amount of diethylamino seratrifluoride (DAST) with respect to the compound of formula (IIA) is 1-5 equivalents and preferably 1-3 equivalents. The reaction time is from 10 minutes to 10 hours. The reaction temperature is in the range of −78 ° C. to room temperature.

The compound of formula (IG) can be synthesized by subjecting the halogen-containing derivative of Step A5 to the synthesized synthesized as described above to thereby remove the hydroxyl protecting group.

H. Preparation of sulfonic acid ester derivative

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, and each of R ^3S , R ^6S , R ^7S , R ^16S and R ^21S represents a hydrogen atom or a group represented the formula R ^N3 SO ₂ - (where R ^N3 represents the same group as previously defined).

Step H1 is a step for sulfonylating a hydroxyl group of a compound of formula (IIA) as a starting material.

Sulfonylation can be carried out, for example, by treatment with a sulfonyl chloride, such as p-toluenesulfonyl chloride, methanesulfonyl chloride or benzenesulfonyl chloride, in the presence of a base. Examples of the base are, for example, conventional organic and inorganic bases, such as diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine and sodium hydride. The solvent used in each of the reactions is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are tetrahydrofuran, dichloromethane and N, N-dimethylformamide. The amount of sulfonyl chloride and base used in the reaction with respect to the compound of formula (IIA) is 1-5 equivalents and 2-10 equivalents, preferably 1-3 equivalents and 2-6 equivalents, respectively. The reaction time is from 10 minutes to 30 hours. The reaction temperature is in the range from -78 ° C to the boiling temperature under reflux.

The derivative represented by the formula (IH) in which the hydroxyl group is sulfonylated at position 7 can be synthesized by subjecting the sulfonic acid ester derivative synthesized in the manner described above to the reaction of Step A5 to remove the hydroxyl protecting group.

You can also sulfonylate compound 11107D as starting material in a manner similar to that described in stage H1, to sulfonylate one to four hydroxyl groups.

I. Obtaining an Amine Derivative

In the formulas, each of R ^3A , R ^6A , R ^16A and R ^21A represents the same group as previously defined, and each of R ^3T , R ^6T , R ^7T , R ^16T and R ^21T represents a hydroxyl group or a group of formula R ^N1 R ^N2 N- (where each of R ^N1 and R ^N2 represents the same group as defined above).

Step I1 is the step of converting the hydroxyl group of a compound of formula (IIA) directly to an amine or to a suitable leaving group, then to an azide and then to an amine by reduction.

In the case where the hydroxyl group is converted to azide, examples of reagents used in the reaction are 1) diphenylphosphoryl azide (DPPA), diethyl azodicarboxylate and triphenylphosphine, 2) DPPA and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU ), 3) hydrogen azide, diethyl azodicarboxylate and triphenylphosphine; 4) DPPA, tetramethylazodicarboxamide (TMAD) and tributylphosphine; and 5) sodium azide in the presence of a base. Examples of the base are the above organic and inorganic bases, of which, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. Said hydroxyl group can also be converted to azide by treatment with sodium azide in the presence of a palladium catalyst. An example of a catalyst is Pd (PPh ₃ ) ₄ . The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are tetrahydrofuran, dichloromethane, N, N-dimethylformamide, toluene and benzene. The reaction time is from 10 minutes to 30 hours. The reaction temperature is in the range from -78 ° C to the boiling temperature under reflux.

The reduction of azide to amine can be carried out using, for example, triphenylphosphine or lithium aluminum hydride. An azide can also be reduced to an amine, for example, by using a catalyst, such as palladium on carbon or a Lindlar catalyst, in an atmosphere of hydrogen. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are tetrahydrofuran, diethyl ether and ethanol. The reaction time is from 10 minutes to 30 hours. The reaction temperature is in the range from -78 ° C to the boiling temperature under reflux.

The conversion of the hydroxyl group to a suitable leaving group can be carried out by a procedure similar to that described in stage G1 (halogenation) or in stage H1 (sulfonylation). Examples of a suitable leaving group are chromium, bromine, iodine, a menthan sulfonyl group and a p-toluenesulfonyl group. In addition, by treating the converted compound containing the leaving group with an amine in an inert solvent in the presence of a base, a compound can be synthesized in which the hydroxyl group is converted to an amino group or a substituted amino group.

Examples of the amine used in this reaction are methylamine, ethylamine, dimethylamine and diethylamine. Examples of the base are the above organic and inorganic bases, of which, for example, diisopropylethylamine, dimethylaminopyridine, triethylamine, pyridine, 2,6-lutidine or sodium hydride are preferably used. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are the above inert solvents, of which, for example, tetrahydrofuran, dichloromethane or N, N-dimethylformamide is preferably used. The reaction time is from 10 minutes to 30 hours, preferably 1-2 hours. The reaction temperature is in the range from −78 ° C. to the reflux temperature, preferably from −10 ° C. to 50 ° C.

The compound of formula (I I ) can be obtained by subjecting the amine derivative synthesized as described above to a deprotection reaction of a hydroxyl group similar to that described in Step A5. You can also convert one or two hydroxyl groups of compound 11107D as starting material into amino groups in a manner similar to that described in stage I1.

The compound of formula (I) can also be obtained by alkylation, acylation, carbamoylation or sulfonylation of the amino group of the compounds of formula (I I ) according to methods well known in chemistry of organic synthesis and the methods described above.

J. Preparation of an oxo compound (oxidation of a hydroxyl group)

In the formulas, either one of R ^3Ja and R ^3Jb represents a hydroxyl group and the other represents a hydrogen atom or R ^3Ja and R ^3Jb together with the carbon atom to which R ^3Ja and R ^{3Jb are} attached, represent an oxo group, or one of R ^21Ja and R ^21Jb represents a hydroxyl group, and the other represents a hydrogen atom or R ^21Ja and R ^21Jb together with the carbon atom to which R ^21Ja and R ^{21Jb are} attached, represent an oxo group.

Step J1 is a step for synthesizing the oxo compound represented by formula (IIJ) by oxidizing the hydroxyl group of compound 11107D as a starting material.

Examples of the oxidizing agent used in this step are manganese dioxide, pyridinium chlorochromate, pyridinium dichromate, Dess-Martin reagent and reagents used in Swern oxidation. The solvent used in the reaction is not particularly limited, but a solvent that cannot easily interact with the starting material is desirable. Examples thereof are tetrahydrofuran, dichloromethane, chloroform and toluene. The reaction temperature is in the range from -78 ° C to the boiling temperature under reflux. The reaction time is from 10 minutes to 78 hours. Among these reactions, a reaction using Dess-Martin reagent, manganese dioxide or reagents used in Swern oxidation is preferred, for example, a reaction using Dess-Martin reagent is more preferable. As a solvent for oxidation using a Dess-Martin reagent, dichloromethane or chloroform is usually preferred. The amount of oxidizing agent used in the reaction relative to said compound (11107D) is 1-20 equivalents, preferably 1-5 equivalents. The reaction temperature is in the range from 0 ° C to room temperature. The reaction time is from 30 minutes to 24 hours, preferably 1-8 hours.

A compound in which the hydroxyl group at position 3 or position 21 of these derivatives is converted to an oxo moiety can be synthesized by exposure instead of 11107D, for example, a urethane derivative, a thiourethane derivative, an ester derivative or an alkyl derivative prepared previously by the above methods to the procedure of step J1. In addition, by oxidizing the hydroxyl group at position 7 of the compound represented by formula (IIA), the 7-oxo compound can be obtained.

And yet, the hydroxyl group at position 3, position 7 and / or position 21 can be selectively converted to an oxo fragment by various combinations of the conditions of the protection and deprotection reactions in step A1 and step A5 with the procedure of step J1. In addition, a compound that contains both an oxo moiety and a urethane, thiourethane, ester or alkyl moiety can be respectively prepared by synthesizing a compound previously converted to an oxo moiety by the methods described above in connection with the preparation of a urethane derivative, a thiourethane derivative, an ester derivative or an alkyl derivative .

The compounds represented by formula (I) can be synthesized by a suitable combination of reactions A to J and protection and deprotection reactions of the hydroxyl group.

At the end of the reaction, the target product of the corresponding reaction is isolated from the reaction mixture by a traditional method. For example, the target compound can be isolated by filtration, if there is insoluble material, and by evaporation of the solvent or by diluting the reaction mixture with an organic solvent such as ethyl acetate, washing the organic layer with water, drying over anhydrous magnesium sulfate and evaporating the solvent. The compound, if necessary, can then be purified by a conventional method such as column chromatography, thin layer chromatography or high performance liquid chromatography.

To illustrate the usefulness of the present invention, in particular, inhibitory activity against VEGF transcription, inhibitory activity against the growth of human colon cancer WiDr cells, inhibitory activity against growth of a malignant tumor, weight loss (acute toxicity) and resistance to aqueous solution were determined. representative compounds of the compounds of formula (I) of the present invention.

Test Example 1 Construction of a reporter system for the selection of compounds that inhibit transcription of VEGF

To obtain a reporter system reflecting transcription from the VEGF promoter, the sequence of the VEGF promoter was cloned and inserted into a secretory alkaline phosphatase (PLAR) vector to construct a reporter vector.

To obtain the promoter region of human VEGF, genomic DNA was cloned from the VEGF phage library. Based on VEGF cDNA (GenBank accession number: X62568), PCR primers containing the sequences described in Sequence Numbers 1 and 2 were determined, and a fragment containing approximately 340 bp was obtained by PCR. A human genomic phage library (Human genomic library, Clontech Co.) was selected and used as a probe to obtain VEGF genomic DNA. Using EcoRI, DNA was digested and the resulting fragments inserted into the pUC18 EcoRI site. Finally, pUC18-VEGFA was obtained containing approximately 5.4 kb. 5'-flanking region of VEGF. Using KpnI / NheI, pUC18-VEGFA and the resulting VEGF promoter region were digested with about 2.3 kb. inserted into the multiclone KpnI / NheI site of the secretory alkaline phosphatase (PLAP) vector (Goto et al, Mol. Pharmacol., 49, 860-873, 1996), and thus the VEGF-PLAP vector was constructed.

The resulting VEGF-PLAP vector was transfected in U251 cell cultured in Dulbecco's modified Eagle medium (DMEM; SIGMA Co. Ltd.) containing 10% fetal calf serum, and the cells were cultured in the presence of 1 mg / ml G418 (Merck Co. ) to create a stable clone resistant to G418 (cell U251 / 1-8).

It was confirmed that U251 / 1-8 cell secreted by PLAP under hypoxic conditions (2% O ₂ incubator) as already described (Cell. Mol. Biol. Res. 40, 35-39, 1994) and was a reporter system reflecting transcription from the VEGF promoter. Using the clone, a compound was further selected to inhibit the production of VEGF caused by hypoxic stimulation.

Test Example 2 VEGF transcription inhibitory activity of various analogs and derivatives 11107

To eliminate the effect of alkaline phosphatase in serum, U251 / 1-8 cells were washed twice with a sufficient amount of PBS (phosphate buffer solution), diluted in DMEM medium containing 10% serum, in which alkaline phosphatase was inactivated by treatment at 65 ° C for 20 min , and distributed in 96-well plates 4 x 10 ⁴ cells / 180 μl.

After culturing at 37 ° C. overnight in a CO ₂ incubator (5% CO ₂ ), 20 μl of the above-described incubation solution containing the test compound diluted with 3-fold dilution was added, and then the cells were incubated in a hypoxic (2% CO ₂ ) incubator within 18 hours. Regarding PLAP activity in culture supernatants, 10 μl supernatants were added to 50 μl 0.28 M Na ₂ CO ₃ -NaHCO ₃ buffer solution (pH 10.0, 8.0 mm MgSO ₄ ) and then 50 μl alkaline phosphatase substrate (LUMISTEIN , Genomescience Co.). After interaction was performed for one hour, alkaline phosphatase PLAP activity was measured by detecting chemical luminescence using a microplate reader (Perkin Elmer Co.). PLAP activity under normoxia was set at 0%, PLAP activity of the cell treated under hypoxia was set at 100%, and the concentration inhibiting PLAP activity at 50% was set at the IC ₅₀ value of PLAP. Measured IC ₅₀ values of the derivatives 11107D shown in the examples, presenting in table 1 IC ₅₀ values of representative derivatives 11107D. Derivatives 11107D showed high inhibitory activity against transcription of VEGF.

Table 1 Compound VEGF transcription inhibitory activity (IC ₅₀ : nM) 6 32,0 9 12.9 12 10.2 16 3,1 17 3.9 21 6.1 22 25.6 24 5.5 25 2.9 26 2,8 27 3,7 44 3.9 45 1.9 75 9.1 95 1,2 109 3.3 122 4.4 127 2,4 131 1.7 136 1,2 142 11,2

Test Example 3 Inhibitory activity against the growth of human colon cancer WiDr cells

Human colon cancer WiDr cells cultured in Dulbecco's modified Eagle medium (DMEM; manufacturer SIGMA Co. Ltd.) containing 10% fetal bovine serum, penicillin (100 units / ml) and streptomycin (100 μg / ml) were distributed in 96-well plates, 2x30 ³ cells / well. After overnight cultivation in a CO ₂ incubator, 20 μl of the above-described incubation solution containing the test compound diluted in 3-fold dilution was added, and then the cells were incubated. After three days, 50 μl of a solution of 3.3 mg / ml MTT was added, and then cultured for another hour. Then formazan, formed by reduction under the action of living cells, was extracted with 100 μl DMSO, the optical density was determined (A540 / A660) and set as an indicator of the number of living cells.

The concentration of compounds of formula (I) was determined in which the growth of human colon cancer WiDr cells was inhibited by 50%. IC ₅₀ values for representative compounds are shown in Table 2. The compounds of formula (I) showed high inhibitory activity against the growth of human colon cancer WiDr cells.

table 2 Compound Inhibitory activity of human colon cancer WiDr cell growth
(IC ₅₀ : nM) 6 12.5 9 5.5 16 2.0 17 2.6 21 3.2 22 14.6 24 5.3 25 1,2 26 1,6 27 1,2 44 2.1 45 0.7 75 4.1 95 0.5 109 1,5 122 1,1 127 0.7 131 0.7 136 0.8 142 4.9

Test Example 4 Inhibitory activity against growth of a solid tumor

In vivo , human WiDr colon cancer cells were implanted subcutaneously in the flanks of exposed mice to examine the inhibitory activity against growth of a solid tumor of the compounds of formula (I). The animals were divided into groups, so that the average volume in the respective groups became the same when it reached about 100 mm ³ . Control groups consisted of 10 mice, and groups administered with 11107D compounds consisted of 5 mice. Derivatives were administered to mice in groups for administration over 5 consecutive days by intravenous injection with any of the doses of 0.625 mg, 1.25 mg, 2.5 mg, 5 mg and 10 mg / kg / day, and a vehicle was administered to the control group. Tumor volumes were measured on day 15 and relative tumor volume ratios (T / C%) were determined by taking the tumor volume of the control group as 100%. T / C% of representative compounds of formula (I) are shown in Table 3. Body weight was measured on day 1, day 5, day 8, day 12, and day 15 (or 16) and relative changes in body weight were determined by taking body weight on day 1 for 100%. The relative body mass coefficients were determined on the day when the body mass reached a minimum, as the minimum body mass coefficients, which are shown in Table 3.

Table 3 Compound Dose (mg / kg) Growth inhibitory activity against a model of a human solid tumor
(T / C%) Minimum Relative Mass Coefficients 6 1.25 35 0.81 9 5,0 10 0.86 12 2.5 21 0.85 fifteen 2.5 36 0.82 16 2.5 28 0.90 21 2.5 28 0.80 22 5,0 39 0.74 26 2.5 42 0.93 44 5,0 19 0.89 45 5,0 twenty 0.90 75 5,0 17 0.82 109 0.625 36 0.89 131 2.5 28 0.83

The compounds of formula (I) showed similar growth inhibitory activity against a human colon colon WiDr tumor model without noticeable weight loss also in vivo .

Test Example 5 Stability in aqueous solution

The compounds of formula (I) were dissolved in DMSO at concentrations of 10-20 mM, and the resulting solution was diluted approximately 500-fold with a Britton-Robinson buffer solution with pH 7. Each of the solutions serving as sample solutions was incubated at 25 ° C for 24 hours.

Sample solutions were analyzed by high performance liquid chromatography before and after incubation, and the residues of the test substances in the sample solutions after incubation were determined from the peak areas of the obtained chromatograms.

Example Peak Area (mAV x sec) The balance indicator (%) Initial After 24 hours Fd895 1197 993 83.0 11107D 3994 3817 95.6 Compound 9 5690 5476 96.2 Compound 12 5450 5169 94.9 Compound 22 4713 4514 95.8 Compound 44 4031 3820 94.8 Compound 45 5291 5024 95.0 Compound 75 2594 2478 95.5 Compound 109 2224 2111 94.9 Compound 122 4872 4620 94.8 Compound 130 4819 4583 95.1 Compound 131 168 157 93.2 Compound 136 3750 3579 95.4 Compound 142 3916 3705 64.6

The results show that the content of FD895 decreased to 83% after 24 hours, and the contents of compounds 9, 12 and 22 as representative compounds of the compounds of formula (I) remained at the level of 95-96%, indicating that derivatives 11107D are stable in aqueous solution.

As can be seen from the examples of pharmacological tests, the compounds of formula (I) of the present invention, in particular, inhibit the production of VEGF by altering gene expression, and are expected to be used as an antitumor agent, in particular a medicine for treating a malignant tumor, suppressor of carcinoma metastasis, as well as drugs for the treatment of diabetic retinopathy, rheumatoid arthritis and angina. In addition, from Example 4 of the toxicity test, it can be seen that the compounds of formula (I) exhibit growth inhibitory activity in the human colon colon WiDr tumor model to such an extent that they do not cause noticeable weight loss of the test mouse, and are safe compounds. Therefore, they are effective as a means of preventing or treating a disease against which regulation of gene expression is effective, a disease against which inhibitory activity against VEGF production is effective, and a disease against which angiogenesis inhibitory activity is effective. “Prevention or treatment” means either prevention, or treatment, or both. In particular, the compounds of formula (I) of the present invention are effective as an antitumor agent and especially as an antitumor agent and a suppressor of carcinoma metastasis for a malignant tumor. As a malignant malignant tumor, for example, pancreatic cancer, stomach cancer, colon cancer, breast cancer, prostate cancer, lung cancer, kidney cancer, brain tumor, head and neck cancer, esophageal cancer, skin cancer, liver cancer, uterine cancer, cervical cancer, bladder cancer, thyroid cancer, testicular cancer, choriocarcinoma, osteosarcoma, soft tissue sarcoma and ovarian cancer, of which cancer of the colon, colon cancer, breast cancer, prostate cancer is preferred glands lung cancer, head and neck cancer, or ovarian cancer. In addition, they are also effective as an antitumor agent for treating leukemia. They are also effective as a treatment for hematoma. And they are also effective as a treatment for diabetic retinopathy, rheumatoid arthritis and hematoma, which is based on the inhibitory effect on VEGF production. In addition, they are also effective as a treatment for inflammatory diseases, including osteoarthritis, psoriasis and a delayed-type allergic reaction, and atherosclerosis.

When the compounds are prepared in the form of an injection solution, then, if necessary, a pH regulator, a buffer, a stabilizer, a solubilizer and the like are added to the main drug to obtain, according to the traditional method, a solution for subcutaneous, intramuscular, intraarticular or intravenous injection.

When a compound is used as a prophylactic or therapeutic agent against various diseases, it can be administered orally in the form of tablets, powders, granules, capsules, syrups and the like, or parenterally in the form of an aerosol, suppository, injection, topical preparation or drops. The dose varies markedly in accordance with the severity of the symptom, age, type of liver disease, etc. and is generally from about 1 mg to 100 mg per day for an adult with a single or multiple administration.

For the manufacture of medicines using traditional inert excipients and traditional methods of manufacture. That is, when a solid oral dosage form is made, an excipient and, if necessary, a binder, a disintegrant, a lubricant, a dye, a corrective substance and the like are added to the main drug substance and then tablets, coated tablets, granules, powders are made capsules and the like. Needless to say, if necessary, tablets and granules may be coated with a sugar coating, gelatin coating or other suitable coating.

In accordance with the present invention, the compounds of formula (I) of the present invention inhibit, in particular, VEGF production by altering gene expression and exhibit high antitumor activity in in vivo models of solid tumors. In addition, the compounds of formula (I) of the present invention are stable in aqueous solution and can provide, for example, an agent for treating cancer, in particular an agent for treating cancer of cancer, a suppressor of carcinoma metastasis, an agent for treating diabetic retinopathy, rheumatoid arthritis and angioma.

Examples

The present invention is described below in more detail with examples and reference examples, which should not be considered limiting the scope of the present invention.

The meanings of the symbols used in the chemical structural formulas in the examples are shown below.

DEIPS: diethylisopropylsilyl group

Et: ethyl group

EE: 1-ethoxyethyl group

Me: methyl group

TES: triethylsilyl group.

Example 1. Fermentation of strain Mer-11107 and purification 11107D

One full loop of the culture cultured on a beveled culture medium (ISP-2) of strain Mer-11107 was introduced into a 500 ml Erlenmeyer flask containing 50 ml of culture medium (2% glycerol, 2% glucose, 2% soy flour (ESUSAN-MEAT manufactured by Ajinomoto Co. Ltd.), 0.5% yeast extract, 0.25% sodium chloride, 0.32% calcium carbonate, 0.0005% copper sulfate, 0.0005% manganese chloride, 0.0005% zinc sulfate, pH 7 , 4), and cultivated at 28 ° C for three days on a shaker, which gave the first seed culture. A seed culture (0.6 ml) was added to a 500 ml Erlenmeyer flask containing 60 ml of producing medium (5% soluble starch, 0.5% liquid corn extract, 0.5% dry yeast, 0.5% gluten flour, 0 , 1% calcium carbonate), and fermented at 28 ° C for four days on a rotary shaker, resulting in a fermented cultured broth.

The cultured broth (10 L) was extracted with 1-butanol (10 L), then the resulting butanol layer was evaporated to dryness to give 100 g of a crude active fraction. The crude active fraction was applied to Sephadex LH-20 (1500 ml; manufactured by Pharmacia Co. Ltd.) and eluted with tetrahydrofuran-methanol (1: 1) as a solvent. The eluted fraction from 540 ml to 660 ml was concentrated to dryness to give a residue (660 mg). The resulting residue was dissolved in a mixture of ethyl acetate and methanol (9: 1, v / v) and subjected to silica gel column chromatography (WAKO GEL C-200, 50 g). The column was eluted with a mixture (2 L) consisting of n-hexane and ethyl acetate (1: 9, v / v), the eluted fractions from 1440 ml to 1566 ml were collected and evaporated to obtain 15 mg of a crude active fraction.

The resulting crude active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the following conditions (A) by preparative HPLC and fractions eluted at a retention time of 17 minutes were collected. After removal of acetonitrile, the appropriate fractions were desalted by HPLC under the following conditions (B) by preparative HPLC to give 11107D (retention time: 36 minutes, 1.8 mg).

Preparative HPLC conditions (A):

Column: YMC-PACK ODS-AM F20 mm x 250 mm (manufacturer YMC Co.)

Flow rate: 10 ml / min.

Detection: 240 nm.

Eluent: acetonitrile / 0.15% aqueous potassium dihydrogen phosphate (pH 3.5) (2: 8-8: 2, v / v, 0-50 min, linear gradient).

Preparative HPLC conditions (B):

Column: YMC-PACK ODS-AM F20 mm x 250 mm (manufacturer YMC Co.).

Flow rate: 10 ml / min.

Detection: 240 nm.

Eluent: methanol / water (2: 8-10: 0, v / v, 0-40 min, linear gradient).

Example 2. Physico-chemical properties of 11107D

The physicochemical properties of 11107D are shown below. The 11107D structure shown below was determined.

1. Appearance: colorless powder.

2. Molecular mass: 552, ESI-MC m / z 551 (MH) ^- , 575 (M + Na) ⁺ .

3. Molecular formula: C ₃₀ H ₄₈ O ₉ .

4. Solubility: soluble in dimethyl sulfoxide, pyridine, methanol and acetone and slightly soluble in water.

5. Color reaction: positive for iodine and sulfuric acid.

6. Ultraviolet absorption spectrum (methanol, maximum value) nm: 239 (ε 33100).

7. Infrared absorption spectrum (KBr) cm ^-1 : 3417, 2967, 1732, 1714, 1455, 1372, 1248, 1176.

8. ¹ H-NMR (CD ₃ OD, 500 MHz): δ ppm: (integral intensity, multiplicity, binding constant J (Hz)): 0.93 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 6.8 Hz), 0.98 ( 3H, t, J = 8.0 Hz), 1.23 (3H, s), 1.30 (1H, m), 1.36-1.66 (9H, m), 1.70 (1H, dd , J = 6.4, 14.2 Hz), 1.82 (3H, d, J = 1.0 Hz), 1.90 (1H, dd, J = 6.4, 14.2 Hz), 2 10 (3H, s), 2.52 (2H, m), 2.62 (1H, m), 2.72 (1H, dd, J = 2.4, 8.3 Hz), 2.94 ( 1H, dt, J = 2.4, 5.7 Hz), 3.55 (1H, dt, J = 8.3, 4.4 Hz), 3.82 (1H, m), 5.10 (1H d, J = 9.8 Hz), 5.11 (1H, d, J = 10.8 Hz), 5.60 (1H, dd, J = 9.8, 15.2 Hz), 5.74 (1H, dd, J = 8.3, 15.2 Hz), 5.92 (1H, d, J = 15.2 Hz), 6.18 (1H, d, J = 10.8 Hz), 6 57 (1H, dd, J = 10.8, 15.2 Hz).

9. ¹³ H-NMR (CD ₃ OD, 125 MHz): δ ppm: (multiplicity): 10.52 (q), 10.82 (q), 11.98 (q), 16.84 (q), 21.07 (q), 24.21 (q), 28.62 ( t), 28.79 (q), 30.46 (t), 37.53 (t), 40.10 (t), 41.80 (d), 42.58 (d), 45.97 (t) ), 55.99 (d), 62.53 (d), 70.41 (d), 73.09 (s), 74.11 (s), 75.30 (d), 80.31 (d) 84.19 (d), 123.64 (d), 127.10 (d), 131.76 (d), 133.81 (s), 141.61 (d), 143.22 (d), 171.75 (s), 172.18 (s).

Example 3. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (pyrrolidin-1-yl) piperidin-1- sludge) carbonyl) oxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 3)

Example 3-1 (8E, 12E, 14E) -7-Acetoxy-3,6,16,21-tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14 -trien-11-olide (formula XV) and (8E, 12E, 14E) -7-acetoxy-3,16,21-tris (1-ethoxyethoxy) -6-hydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (formula XVI)

To a solution of (8E, 12E, 14E) -7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien- 11-olide (50 mg, 0.09 mmol) in dichloromethane (2.5 ml) was added ethyl vinyl ether (326 mg, 4.5 mmol) and pyridinium p-toluenesulfonate (6.8 mg, 27 μmol) at room temperature followed by stirring at the same temperature for 19 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 30: 70) to obtain (8E, 12E, 14E) -7-acetoxy-3,6,16,21-tetrakis ( 1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (60 mg, 79%) as a colorless oil (formula XV).

ESI-MC m / z 863 (M + Na) ⁺ .

Then, (8E, 12E, 14E) -7-acetoxy-3,16,21-tris (1-ethoxyethoxy) -6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8 was obtained , 12,14-trien-11-olide (6 mg, 9%) as a colorless oil (formula XVI) from the eluted fraction of a mixture of ethyl acetate: hexane = 50:50.

ESI-MC m / z 791 (M + Na) ⁺ .

Example 3-2 (8E, 12E, 14E) -3,6,16,21-Tetrakis (1-ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14 -trien-11-olide

To a solution of (8E, 12E, 14E) -7-acetoxy-3,6,16,21-tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (145 mg, 0.17 mmol) in methanol (2.5 ml) was added potassium carbonate (95 mg, 0.69 mmol) at room temperature, followed by stirring at the same temperature for two hours and 30 minutes. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 40: 60) to obtain the title compound (128 mg, 93%) as a colorless oil.

ESI-MC m / z 821 (M + Na) ⁺ .

Example 3-3 (8E, 12E, 14E) -3,6,16,21-Tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-18,19-epoxytricose- 8,12,14-trien-11-olide

To a solution of (8E, 12E, 14E) -3,6,16,21-tetrakis (1-ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (139 mg, 0.17 mmol) in dichloromethane (2.5 ml) was added triethylamine (88 mg, 0.87 mmol), N, N-dimethylaminopyridine (64 mg, 0.52 mmol ) and 4-nitrophenyl chloroformate (105 mg, 0.52 mmol) under ice-cooling, followed by stirring at room temperature in a nitrogen atmosphere for one hour. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 20: 80) to obtain the title compound (134 mg, 80%) as a colorless oil.

ESI-MC m / z 986 (M + Na) ⁺ .

Example 3-4. (8E, 12E, 14E) -3,6,16,21-Tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7 - ((4- (pyrrolidin-1-yl) piperidine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide

K (8E, 12E, 14E) -3,6,16,21-tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-18,19-epoxytricose A solution of 4- (pyrrolidin-1-yl) piperidine (2.4 mg, 16 μmol) in tetrahydrofuran (0.5 ml) at room temperature. Triethylamine (2.3 mg, 24 μmol) was added to the mixture at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was evaporated to give compound (11 mg) as a crude product (pale yellow oil).

Example 3-5. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (pyrrolidin-1-yl) piperidin-1-yl) carbonyl ) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 3)

To the crude product (8E, 12E, 14E) -3,6,16,21-tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7 - ((4- (pyrrolidin-1-yl ) piperidin-1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (11 mg, 11 μmol) was added a solution of pyridinium p-toluenesulfonate (11.4 mg, 45 μmol) in a mixture of tetrahydrofuran: 2-methyl-2-propanol = 1: 1 (1 ml) at room temperature. 4Å molecular sieves (10 mg) were added to the mixture, followed by stirring at room temperature for 18.5 hours. Pyridinium p-toluenesulfonate (11.4 mg, 45 μmol) was added, followed by stirring at room temperature for 72 hours. The reaction mixture was evaporated and the resulting residue was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate, methanol: dichloromethane = 1: 19) to obtain the title compound (2.88 mg, 35%, two steps) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.92 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.22-1.68 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.78-2.00 (9H, m), 2.48-2.62 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.68-2.92 (9H, m), 3.46-3.54 (1H, m), 3.72-3.82 (1H, m), 4.24-4 40 (1H, m), 4.92 (1H, d, J = 10.8 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 14.8 Hz), 5.72 (1H, dd, J = 9.2, 14.8 Hz), 5.86 (1H, d, J = 14.8 Hz), 6.13 ( 1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MC m / z 691 (M + H) ⁺ .

Example 4. (8E, 12E, 14E) -7- (N-Ethylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (compound 4)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.10 (3H, t, J = 7.6 Hz), 1.20 (3H, s), 1.22-1 , 62 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J = 6.6, 13.7 Hz), 1.77 (3H, s), 1.86 ( 1H, dd, J = 5.7, 13.7 Hz), 2.50-2.53 (2H, m), 2.53-2.60 (1H, m), 2.67 (1H, dd, J = 2.4, 7.6 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.12 (2H, q, J = 7.2 Hz), 3, 49-3.54 (1H, m), 3.74-3.81 (1H, m), 4.82-4.98 (1H, overlapped by H ₂ O peak), 5.06 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 9.6, 15.2 Hz), 5.69 (1H, dd, J = 9.2, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 604 (M + Na) ⁺ .

Example 5. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N- (3-morpholin-4-yl) propyl) carbamoyloxy ) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 5)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.20 (3H, s), 1.26-1.73 (10H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.4, 14.1 Hz), 2.35-2.60 (9H, m), 2.67 (1H, dd , J = 2.4, 7.6 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.15 (2H, t, J = 7.2 Hz), 3 , 48-3.54 (1H, m), 3.68 (4H, t, J = 4.8 Hz), 3.74-3.82 (1H, m), 4.82-4.98 (1H covered by the peak of H ₂ O), 5.06 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 10.0, 15.2 Hz), 5.69 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.4 Hz), 6.52 ( 1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 681 (M + H) ⁺ .

Example 6. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Dimethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 6)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.22 (3H, s), 1.24-1.68 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.28 (6H, s), 2.45-2.62 (7H, m ), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.86-2.99 (4H, m), 3.49-3.56 (1H, m), 3, 75-3.82 (1H, m), 4.92 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd , J = 10.0, 15.6 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 14.8 Hz), 6 14 (1H, d, J = 10.8 Hz); 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 639 (M + H) ⁺ .

Example 7. (8E, 12E, 14E) - (7-N- (3- (N ', N'-Dimethylamino) propyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 7)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.24-1.75 (10H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.9, 13.7 Hz), 2.28 (6H, s), 2.37 (2H, t, J = 7 , 6 Hz), 2.48-2.62 (5H, m), 2.67 (1H, dd, J = 2.4, 7.6 Hz), 2.86-2.99 (4H, m) 3.48-3.58 (1H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 10.4 Hz), 5.06 (1H, d , J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5 87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz) ; ESI-MS m / z 653 (M + H) ⁺ .

Example 8. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Dimethylamino) ethyl) carbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 8)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.22-1.68 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.7, 14.3 Hz), 2.29 (6H, s), 2.44-2.62 (7H, m ), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.49-3.56 ( 1H, m), 3.74-3.82 (1H, m), 4.82-4.98 (1H, blocked by a peak of H ₂ O), 5.06 (1H, d, J = 10.8 Hz) 5.55 (1H, dd, J = 10.4, 15.2 Hz), 5.69 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 625 (M + H) ⁺ .

Example 9. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 9)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.887 (3H, d, J = 6.6 Hz), 0.894 (3H, d, J = 7.0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.23-1.27 (4H, m), 1.33 (3H, s), 1.33-1.68 (7H, m) 1.77 (3H, d, J = 0.7 Hz), 1.82-1.91 (3H, m), 2.35 (3H, s), 2.50-2.66 (7H, m ), 2.66 (1H, dd, J = 2.2, 7.7 Hz), 2.89 (1H, dt, J = 2.2, 5.5 Hz), 3.49-3.56 ( 3H, m), 3.58-3.67 (2H, m), 3.75-3.81 (1H, m), 4.94 (1H, d, J = 9.5 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.57 (1H, dd, J = 9.9, 15.0 Hz), 5.72 (1H, dd, J = 9.5, 15.0 Hz), 5.86 (1H, d, J = 15.0 Hz), 6.13 (1H, d, J = 9.9 Hz), 6.52 (1H, dd, J = 11.0, 15 , 0 Hz); ESI-MS m / z 651 (M + H) ⁺ .

Example 10. (8E, 12E, 14E) -7- (N- (3- (N ', N'-Dimethylamino) propyl) carbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 10)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.20 (3H, s), 1.20-1.26 (1H, m), 1.33 (3H, s) 1.33-1.71 (9H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.5, 14.3 Hz), 2.25 (6H, s ), 2.36 (2H, t, J = 7.3 Hz), 2.49-2.61 (3H, m), 2.66 (1H, dd, J = 2.2, 8.1 Hz) 2.89 (1H, dt, J = 2.2, 5.5 Hz), 3.13 (2H, t, J = 6.6 Hz), 3.52 (1H, dt, J = 4.4 8.1 Hz), 3.75-3.81 (1H, m), 4.89 (1H, d, J = 9.5 Hz), 5.05 (1H, d, J = 10.6 Hz ), 5.55 (1H, dd, J = 9.5, 15.4 Hz), 5.69 (1H, dd, J = 9.5, 15.4 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 10.6 Hz), 6.52 (1H, dd, J = 10.6, 15.4 Hz); ESI-MS m / z 639 (M + H) ⁺ .

Example 11. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N - (((pyridin-4-yl) methyl) carbamoyloxy) -18.19-epoxytricose-8,12,14-trien-11-olide (compound 11)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 5.1 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.94 (3H, t, J = 7.3 Hz), 1.23 (3H, s), 1.23-1.27 (1H, m), 1.33 (3H, s) 1.33-1.62 (6H, m), 1.65 (1H, dd, J = 6.2, 14.3 Hz), 1.77 (3H, s), 1.86 (1H, dd , J = 6.2, 14.3 Hz), 2.48-2.65 (3H, m), 2.66 (1H, dd, J = 2.2, 8.1 Hz), 2.89 ( 1H, dt, J = 2.2, 6.2 Hz), 3.52 (1H, dt, J = 4.4, 8.1 Hz), 3.74-3.80 (1H, m), 4 35 (2H, s), 4.93 (1H, d, J = 9.5 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.56 (1H, dd, J = 9.5, 15.4 Hz), 5.73 (1H, dd, J = 9.5, 15.4 Hz), 5.86 (1H, d, J = 15.0 Hz), 6.13 ( 1H, d, J = 11.0 Hz), 6.52 (1H, d, J = 11.0, 15.0 Hz), 7.33 (2H, d, J = 5.9 Hz), 8, 45 (2H, dd, J = 1.5, 4.4 Hz); ESI-MS m / z 645 (M + H) ⁺ .

Example 12. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 12)

First stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-3,6,21- tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 12-1)

A solution of compound 46-4 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,6,21-tris ( triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (628 mg, 0.575 mmol) obtained in the fourth step of Example 46 in tetrahydrofuran (7 ml) was cooled to 5 ° C and was added to it dropwise a solution of 1-methylpiperazine (118 mg, 1.152 mmol) in tetrahydrofuran (1.5 ml) and a solution of triethylamine (236 mg, 2.305 mmol) in tetrahydrofuran (1.5 ml). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate: hexane: methanol, 1: 1: 0 4: 1: 0 9: 1: 0 1: 0: 0 39: 0: 1 19 : 0: 1) to obtain the title compound (514 mg, 85%) as a colorless oil.

Second stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 12-2)

A solution of compound 12-1 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-3 , 6,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (514 mg, 0.489 mmol) obtained in the first stage in tetrahydrofuran (10 ml) was cooled to 5 ° C and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 1.62 ml, 1.62 mmol) was added dropwise. The reaction mixture was stirred at room temperature for two hours. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.3 ml, 0.3 mmol) was added dropwise and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH silica gel, 200-350 mesh; ethyl acetate: hexane: methanol, 1: 1: 0 4: 1: 0 1: 0: 0 49: 0: 1 19: 0: 1) to obtain the title compound (364 mg, 99%) as a colorless oil.

ESI-MC m / z 709 (M + Na) ⁺ .

Third stage

(8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide (compound 12)

To a solution of compound 12-2 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (364 mg, 0.489 mmol) obtained in the second stage, in a mixture of tetrahydrofuran: 2-methyl-2-propanol = Pyridinium p-toluenesulfonate (184 mg, 0.734 mmol) was added 1: 1 (10 ml) and the reaction mixture was stirred at room temperature for 19 hours. Then, triethylamine (75 mg, 0.374 mmol) was added dropwise to the reaction mixture, and the mixture was evaporated. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The obtained residue was purified by silica gel column chromatography (Fuji Silysia, NH silica gel, 200-350 mesh; ethyl acetate: hexane: methanol, 1: 1: 0> 2: 1: 0> 4: 1: 0> 1: 0: 0> 39: 0: 1> 29: 0: 1> 19: 0: 1). The crude fraction was evaporated and the residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate, methanol: dichloromethane = 1: 29) to obtain the title compound (286 mg, 92%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.28 (4H, m), 1.32-1.68 (10H, m), 1.77 ( 3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.6, 14.4 Hz), 2.30 (3H, s), 2.36-2.44 (4H , m), 2.50-2.64 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4 , 6.0 Hz), 3.38-3.70 (5H, m), 3.75-3.81 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5 06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15 , 2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2 15.2 Hz); ESI-MS m / z 637 (M + H) ⁺ .

Example 13. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((piperazin-1-yl) carbonyl) hydroxy-18,19 -epoxytricose-8,12,14-triene-11-olide (compound 13)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.20-1.30 (4H, m), 1.32-1.68 (10H, m), 1.77 ( 3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.6, 14.4 Hz), 2.50-2.64 (3H, m), 2.67 (1H , dd, J = 2.4, 8.0 Hz), 2.76 (4H, t, J = 5.2 Hz), 2.89 (1H, dt, J = 2.4, 5.6 Hz) 3.34-3.68 (5H, m), 3.75-3.81 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.06 (1H, d , J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5 87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz) ; ESI-MS m / z 623 (M + H) ⁺ .

Example 14. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (pyridin-4-yl) piperazin-1- sludge) carbonyl) oxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 14)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.20-1.30 (4H, m), 1.32-1.69 (10H, m), 1.77 ( 3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.6, 14.4 Hz), 2.50-2.64 (3H, m), 2.66 (1H dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.38-3.46 (4H, m), 3, 49-3.84 (6H, m), 4.97 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.59 (1H, dd , J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6 13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz), 6.86 (2H, d, J = 6.8 Hz) 8.13 (2H, d, J = 6.8 Hz); ESI-MS m / z 700 (M + H) ⁺ .

Example 15. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (1- (methylpiperidin-4- il) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 15)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (12H, m), 1.72- 1.90 (6H, m), 2.06-2.22 (2H, m), 2.28 (3H, s), 2.50-2.64 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.7 6-2.98 (6H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3, 75-3.82 (1H, m), 3.85-4.14 (1H, m), 4.95 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 ( 1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 16. (8E, 12E, 14E) -7 - ((4-Butylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 16)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.69 (18H, m), 1 77 (3H, d, J = 1.2 Hz), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.34-2.64 (9H, m), 2, 67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.4 Hz), 3.38-3.72 (5H, m) 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 ( 1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz ), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 17. (8E, 12E, 14E) -7 - ((4-Benzylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 17)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.85-0.92 (6H, m), 0.94 (3H, t, J = 7.6 Hz) , 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.78 (3H, s), 1.79-1.90 (3H, m), 2 50-2.72 (8H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.4 2-3.68 (7H, m), 3.75- 3.82 (1H, m), 4.91-4.97 (1H, m), 5.06 (1H, d, J = 10.8 Hz), 5.53-5.62 (1H, m) 5.67-5.77 (1H, m), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 ( 1H, dd, J = 11.2, 15.2 Hz), 7.21-7.35 (5H, m); ESI-MS m / z 727 (M + H) ⁺ .

Example 18. (8E, 12E, 14E) -7 - ((4- (3-Chloropropyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16, 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 18)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.77 ( 3H, d, J = 0.8 Hz), 1.80-1.96 (5H, m), 2.49-2.74 (10H, m), 2.89 (1H, dt, J = 2, 4, 6.4 Hz), 3.41-3.69 (7H, m), 3.75-3.81 (1H, m), 4.92-4.97 (1H, m), 5.07 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15 , 2 Hz); ESI-MS m / z 713 (M) ⁺ .

Example 19. (8E, 12E, 14E) -7 - ((4- (N, N-Dimethylamino) piperidin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12, 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 19)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.68 (16H, m), 1.77 (3H, d, J = 0.8 Hz), 1 , 83-1.93 (3H, m), 2.28 (6H, s), 2.38 (1H, t, J = 3.6, 11.6 Hz), 2.49-2.62 (3H , m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.71-2.88 (2H, m), 2.89 (1H, dt, J = 2.4 , 6.0 Hz), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3.75-3.82 (1H, m), 4.08-4.45 (2H, m), 4.92 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15 , 2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 20. (8E, 12E, 14E) -7 - ((1,4-Diazabicyclo [4.3.0] nonan-4-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10 , 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 20)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.7 3 -2.02 (6H, m), 2.09-2.22 (2H, m), 2.49-2.71 (6H, m), 2.87-3.12 (6H, m), 3 52 (1H, dt, J = 4.4, 8.0 Hz), 3.75-3.82 (1H, m), 4.01-4.51 (2H, m), 4.88-4 , 99 (1H, m), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 14.8 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 ( 1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 663 (M + H) ⁺ .

Example 21. (8E, 12E, 14E) -7 - ((4-Ethylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 21)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.11 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.22-1 64 (7H, m), 1-34 (3H, s), 1.65 (1H, dd, J = 6.2, 14.2 Hz), 1.77 (3H, s), 1.86 ( 1H, dd, J = 5.2, 14.0 Hz), 2.39-2.49 (6H, m), 2.50-2.53 (2H, m), 2.53-2.62 ( 1H, m), 2.66 (1H, dd, J = 2.4, 7.6 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.34-3 72 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.05 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d , J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 651 (M + H) ⁺ .

Example 22. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (piperidin-1-yl) piperidin-1- sludge) carbonyl) oxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 22)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.20-1.69 (16H, m), 1.34 (3H, s) 1.77 (3H, s), 1.83-1.93 (3H, m), 2.45-2.65 (8H, m), 2.66 (1H, dd, J = 2.4, 7.6 Hz), 2.70-2.85 (2H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.51 (1H, td, J = 4 4, 8.0 Hz), 3.74-3.82 (1H, m), 4.12-4.25 (1H, m), 4.30-4.45 (1H, m), 4, 92 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 10.0, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz ), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 23. (8E, 12E, 14E) -7 - ((Homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18.19 -epoxytricose-8,12,14-triene-11-olide (compound 23)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.4 Hz), 1.23 (3H, s), 1.24-1.69 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.78-1.90 (3H, m), 2.48-2.62 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.72-2.93 (5H, m), 3.43-3.67 (5H, m), 3.74-3.82 (1H, m), 4.94 (1H d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.4, 15.2 Hz), 5.72 (1H, dd, J = 9.8, 15.4 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6 53 (1H, dd, J = 11.0, 15.4 Hz); ESI-MS m / z 637 (M + H) ⁺ .

Example 24. (8E, 12E, 14E) -7 - ((4-Benzylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 24)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.89 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.20 (3H, s), 1.22-1.65 (7H, m), 1.34 (3H, s) 1.65 (1H, dd, J = 6.2, 14.2 Hz), 1.77 (3H, s), 1.87 (1H, dd, J = 5.4, 14.2 Hz), 2.39-2.49 (4H, m), 2.50-2.64 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 ( 1H, dt, J = 2.0, 5.6 Hz), 3.36-3.72 (7H, m), 3.74-3.83 (1H, m), 4.92 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 ( 1H, dd, J = 11.2, 15.2 Hz), 7.22-7.37 (5H, m); ESI-MS m / z 713 (M + H) ⁺ .

Example 25. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylpiperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 25)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.86-0.97 (12H, m), 1.21 (3H, s), 1.21-1, 68 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.87 (1H, dd, J = 5.2, 14.0 Hz), 2.30-2 36 (2H, m), 2.38-2.47 (4H, m), 2.49-2, 63 (3H, m), 2.66 (1H, dd, J = 2.4, 7, 6 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.35-3.72 (5H, m), 3.74-3.83 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz ), 5.71 (1H, dd, J = 1.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10, 0 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 26. (8E, 12E, 14E) -7 - ((4-Cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 26)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.10-1.69 (15H, m), 1.21 (3H, s), 1.34 (3H, s) 1.78 (3H, s), 1.78-1.93 (4H, m), 2.26-2.35 (1H, m), 2.47-2.64 (7H, m), 2 67 (1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.36-3.70 (5H, m ), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 27. (8E, 12E, 14E) -7 - ((4- (Cyclopropylmethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 27)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.12-0.17 (2H, m), 0.52-0.58 (2H, m), 0, 89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.90-0.97 (4H, m), 1.21 (3H, s ), 1.21-1.69 (8H, m), 1.34 (3H, s), 1.78 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.29 (2H, d, J = 6.8 Hz), 2.47-2.64 (7H, m), 2.67 (1H, dd, J = 2.0, 8.0 Hz ), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.40-3.72 (5H, m), 3.74-3.82 (1H, m), 4, 93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz ), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 28. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-morpholin-4-yl) piperidin-1-yl ) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 28)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.68 (12H, m), 1.77 ( 3H, d, J = 1.2 Hz), 1.83-1.95 (3H, m), 2.34-2.43 (1H, m), 2.50-2.64 (7H, m) 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.73-2.89 (2H, m), 2.89 (1H, dt, J = 2.4, 6, 0 Hz), 3.52 (1H, td, J = 4.4, 8.0 Hz), 3.66-3.72 (4H, m), 3.75-3.81 (1H, m), 4.07-4.44 (2H, m), 4.92 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz) 6.13 (1H, d, J = 11.2 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 29. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (3,3,3-trifluoropropyl) piperazine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 29)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.69 (10H, m), 1.77 ( 3H, d, J = 1.2 Hz), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.35-2.66 (11H, m), 2.67 (1H , dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.38-3.71 (5H, m), 3, 75-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd , J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6 13 (1H, d, J = 11.2 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ , 741 (M + Na) ⁺ .

Example 30. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (4,4,4-trifluorobutyl) piperazine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 30)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.70- 1.81 (5H, m), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.14-2.28 (2H, m), 2.38-2.49 ( 6H, m), 2.50-2.64 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2, 4, 6.0 Hz), 3.39-3.72 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 10, 8.15.2 Hz); ESI-MS m / z 733 (M + H) ⁺ , 755 (M + Na) ⁺ .

Example 31. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylhomopiperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 31)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87-0.92 (9H, m), 0.94 (3H, t, J = 7.6 Hz) , 1.20-1.30 (4H, m), 1.32-1.69 (12H, m), 1.77 (3H, d, J = 0.8 Hz), 1.82-1.91 (3H, m), 2.41-2.49 (2H, m), 2.50-2.77 (8H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz ), 3.42-3.67 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz ); ESI-MS m / z 679 (M + H) ⁺ .

Example 32. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - ((4- (2-methoxyethyl) piperazin-1-yl) carbonyl) hydroxy-6,10,12,16, 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 32)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.31-1.69 (10H, m), 1.77 ( 3H, d, J = 1.2 Hz), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.44-2.64 (9H, m), 2.67 (1H dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.33 (3H, s), 3.39-3, 71 (7H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz ), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 681 (M + H) ⁺ .

Example 33. (8E, 12E, 14E) -7 - ((4-Cyclobutylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 33)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.32-1.69 (10H, m), 1.70- 1.81 (5H, m), 1.83-1.95 (3H, m), 2.02-2.11 (2H, m), 2.27-2.37 (4H, m), 2, 49-2.64 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.72-2.81 (1H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.37-3.71 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 34. (8E, 12E, 14E) -7 - ((4- (1-Ethylpropyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16, 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 34)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87-0.97 (15H, m), 1.19-1.69 (18H, m), 1, 77 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.15-2.23 (1H, m), 2.45 -2.64 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.34-3.65 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5, 87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 35. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (tetrahydropyran-4-yl) piperazin-1- sludge) carbonyl) oxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 35)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.21-1.69 (10H, m), 1.34 (3H, s) 1.77 (3H, s), 1.77-1.90 (3H, m), 2.42-2.62 (8H, m), 2.66 (1H, dd, J = 2.0, 7.6 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.34-3.71 (7H, m), 3.74-3.82 (1H, m ), 3.94-4.02 (2H, m), 4.93 (1H, d, J = 9.6 Hz), 5.05 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.4 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 36. (8E, 12E, 14E) -7 - ((4- (Cyclopropylmethyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 36)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.08-0.14 (2H, m), 0.48-0.54 (2H, m), 0, 83 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J = 7.2 Hz), 0.89-0.94 (4H, m), 1.20-1.67 (8H, m), 1.21 (3H, s), 1.31 (3H, s), 1.75 (3H, s), 1.80-1.90 (3H, m), 2.37 ( 2H, d, J = 6.4), 2.47-2.61 (3H, m), 2.62-2.82 (5H, m), 2.87 (1H, dt, J = 2.4 , 6.0 Hz), 3.43-3.69 (5H, m), 3.73-3.80 (1H, m), 4.92 (1H, d, J = 9.6 Hz), 5 04 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 10.0, 15.2 Hz), 5.70 (1H, dd, J = 9.6, 15 , 2 Hz), 5.84 (1H, d, J = 15.2 Hz), 6.11 (1H, d, J = 11.2 Hz), 6.50 (1H, dd, J = 10.8 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 37. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (2,2,2-trifluoroethyl) piperazine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 37)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.20-1.69 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.4 Hz), 2.50-2.69 (8H, m), 2.86-2.92 (1H, m), 3.38-3.72 (2H, m), 3.04-3.14 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H , d, J = 10.0 Hz), 5.05 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6 52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 727 (M + Na) ⁺ .

Example 38. (8E, 12E, 14E) -7 - ((4-Cyclopentylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 38)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.21-1.76 (14H, m), 1.34 (3H, s) 1.77 (3H, s), 1.83-1.95 (3H, m), 2.46-2.62 (8H, m), 2.66 (1H, dd, J = 2.4, 7.6 Hz), 2.88 (1H, dt, J = 2.4, 6.4 Hz), 3.34-3.72 (5H, m), 3.74-3.82 (1H, m ), 4.93 (1H, d, J = 10.0 Hz), 5.05 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15, 2 Hz), 5.71 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 39. (8E, 12E, 14E) -7 - ((4-Isobutylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 39)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87-0.97 (15H, m), 1.21 (3H, s), 1.21-1, 69 (8H, m), 1.34 (3H, s), 1.77 (3H, s), 1.78-1.90 (2H, m), 2.11 (2H, d, J = 7, 2 Hz), 2.32-2.41 (4H, m), 2.50-2.63 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0.6.0 Hz), 3.38-3.70 (5H, m), 3.74-3.82 (1H, m), 4.93 ( 1H, d, J = 9.6 Hz), 5.05 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5, 71 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 40. (8E, 12E, 14E) -7 - (((1S, 4S) -5-Benzyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) carbonyl) oxy-3,6,16 , 21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 40)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.84 (3H, d, J = 7.0 Hz), 0.85 (3H, d, J = 7, 0 Hz), 0.89 (3H, t, J = 7.3 Hz), 1.14-1.27 (4H, m), 1.27-1.65 (7H, m), 1.30 ( 3H, s), 1.65-1.92 (6H, m), 2.44-2.66 (5H, m), 2.79-2.88 (2H, m), 3.16 (0, 6H, dd, J = 1.8, 10.3 Hz), 3.25-3.31 (0.4H, m), 3.45-3.78 (6H, m), 4.29 (0, 4H, br s), 4.52 (0.6H, br s), 4.8 9 (1H, d, J = 9.9 Hz), 5.02 (1H, d, J = 10.6 Hz), 5.54 (1H, dd, J = 9.9, 15.0 Hz), 5.68 (0.6H, dd, J = 9.9, 15.0 Hz), 5.73 (0 , 4H, dd, J = 9.9, 15.0 Hz), 5.82 (1H, d, J = 15.4 Hz), 6.09 (1H, d, J = 11.0 Hz), 6 48 (1H, d, J = 11.0, 15.4 Hz); 7.16-7.32 (5H, m); ESI-MS m / z 725 (M + H) ⁺ .

Example 41. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Dimethylamino) ethyl) -N-ethylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 41)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.0 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.08-1.14 (3H, m), 1.20-1.29 (1H, m), 1.22 ( 3H, s), 1.31-1.68 (7H, m), 1.33 (3H, s), 1.77 (3H, d, J = 0.7 Hz), 1.86 (1H, dd , J = 5.5, 14.3 Hz), 2.28 (6H, s), 2.43-2.62 (5H, m), 2.66 (1H, dd, J = 2.2, 8 , 1 Hz), 2.89 (1H, dt, J = 2.2, 5.5 Hz), 3.23-3.52 (4H, m), 3.52 (1H, dt, J = 4, 4, 8.4 Hz), 3.74-3.82 (1H, m), 4.92 (1H, d, J = 9.9 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.56 (1H, dd, J = 9.9, 15.0 Hz), 5.73 (1H, dd, J = 9.9, 15.0 Hz), 5.86 (1H, d , J = 15.0 Hz), 6.13 (1H, dd, J = 1.1, 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.0 Hz); ESI-MS m / z 653 (M + H) ⁺ .

Example 42. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Diethylamino) ethyl) -N-ethylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 42)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.06 (6H, t, J = 7.0 Hz), 1.06-1.15 (3H, m), 1 , 20-1.29 (1H, m), 1.22 (3H, s), 1.31-1.68 (7H, m), 1.33 (3H, s), 1.77 (3H, d , J = 1.1 Hz), 1.86 (1H, dd, J = 5, 5.14, 3 Hz), 2.48-2.66 (5H, m), 2.59 (4H, q, J = 7.0 Hz), 2.66 (1H, dd, J = 2.2, 8.1 Hz), 2.89 (1H, dt, J = 2.2, 5.5 Hz), 3, 21-3.60 (4H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3.74-3.81 (1H, m), 4.93 (1H, d, J = 9.9 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.57 (1H, dd, J = 9.9, 15.0 Hz), 5.73 ( 1H, dd, J = 9.9, 15.0 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 11.0 Hz), 6, 52 (1H, dd, J = 11.0, 15.4 Hz); ESI-MS m / z 681 (M + H) ⁺ .

Example 43. (8E, 12E, 14E) -7-Acetoxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14 -trien-11-olide (compound 43)

(8E, 12E, 14E) -7-Acetoxy-3,16,21-tris (1-ethoxyethoxy) -6-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 The 14-trien-11-olide (34 mg, 44 μmol) obtained in Example 3, and 1,8-bis (N, N-dimethylamino) naphthalene (57 mg, 266 μmol) were dissolved in toluene (2 ml). Methyl trifluoromethanesulfonate (22 mg, 133 μmol) was added to the resulting solution, and the reaction mixture was stirred at 65 ° C. for 11 hours. After removing the precipitate by filtration, the reaction mixture was diluted with ethyl acetate and an aqueous solution of ammonium chloride was added, followed by vigorous stirring for 5 minutes. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, neutral, 40-100 μm; hexane: ethyl acetate = 1: 1) to obtain (8E, 12E, 14E) -7-acetoxy-3,16,21-tris ( 1-ethoxyethoxy) -6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (14 mg) as a colorless oil.

The resulting compound was subjected to an ethoxyethyl protecting group removal procedure similar to that described in Example 3 to give the title compound (5.7 mg, 22.9%, two steps) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.5 Hz), 0.91 (3H, d, J = 7, 5 Hz), 0.94 (3H, t, J = 7.5 Hz), 1.21 (3H, s), 1.22-1.32 (1H, m), 1.34 (3H, s) , 1.40-1.70 (7H, m), 1.78 (3H, s), 1.86 (1H, dd, J = 5.5, 14.0 Hz), 2.06 (3H, s ), 2.46-2.63 (3H, m), 2.67 (1H, d, J = 8.5 Hz), 2.99 (1H, br s), 3.33 (3H, s) 3.50-3.56 (1H, m), 3.78-3.86 (1H, m), 5.06 (1H, d, J = 10.5 Hz), 5.12 (1H, d) , J = 10.0 Hz), 5.56 (1H, dd, J = 10.0, 15.5 Hz), 5.72 (1H, dd, J = 10.5, 15.5 Hz), 5 87 (1H, d, J = 15.5 Hz), 6.14 (1H, d, J = 10.5 Hz), 6.53 (1H, dd, J = 10.5, 15.5 Hz) ; ESI-MS m / z 589 (M + Na) ⁺ .

Example 44. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 44)

First stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-3,16,21- tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (compound 44-1)

To a solution of compound 46-4 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (1.27 g, 1.16 mmol) obtained in the fourth step of Example 46, triethylamine (470) was added in tetrahydrofuran (25 ml) mg, 4.64 mmol) and isopropylpiperazine (298 mg, 2.32 mmol) at room temperature and the reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; hexane: ethyl acetate = 1: 1 ethyl acetate ethyl acetate: methanol = 97: 3) to obtain the title compound (1.12 g, 89%) in colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.58-0.70 (27H, m), 0.80-1.72 (53H, m), 1, 76 (3H, s), 1.88-1.98 (1H, m), 2.33-2.64 (8H, m), 2.64-2.76 (1H, m), 2.80- 2.90 (1H, m), 3.38-3.66 (6H, m), 3.68-3.7 8 (1H, m), 3.85-3.98 (1H, m), 4 88-4.99 (2H, m), 5.05 (0.4H, q, J = 5.2 Hz), 5.13 (0.6H, q, J = 5.2 Hz), 5, 57 (1H, dd, J = 10.0, 15.2 Hz), 5.72-5.80 (1H, m), 5.82 (1H, d, J = 14.8 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.50 (1H, dd, J = 10.8, 15.2 Hz).

Second stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -3,16,21-trihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 44-2)

To a solution of compound 44-1 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl- 3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (1.12 g, 1.03 mmol) obtained in the first stage in tetrahydrofuran (20 ml ) tetrabutylammonium fluoride (4.1 ml, 1.0 M tetrahydrofuran solution) was added at room temperature and the reaction mixture was stirred at the same temperature for 4 hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel, 200-350 mesh; ethyl acetate> ethyl acetate: methanol = 95: 5) to obtain the title compound (0.76 g, 99%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0, 90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.0 6 (6H, d, J = 6.4 Hz), 1.12-1.70 (20H, m), 1.78 (3H, s), 1.86 (1H, dd, J = 2.4, 7.6 Hz), 2.42-2.62 (7H, m), 2.64-2.76 ( 2H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.38-3.66 (7H, m), 3.75-3.84 (1H, m) 4.98 (1H, d, J = 9.6 Hz), 5.02-5.16 (2H, m), 5.56 (1H, dd, J = 10.0, 15.6 Hz), 5.72-5.80 (1H, m), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H dd, J = 10.8, 15.2 Hz); ESI-MS m / z 737 (M + H) ⁺ .

Third stage

(8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide (compound 44)

To a solution of compound 44-2 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -3,16,21-trihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) oxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (0.76 g, 1.03 mmol) obtained in the second stage, in a mixture of tetrahydrofuran: 2-methyl- Pyridinium p-toluenesulfonate (0.39 g, 1.55 mmol) was added at room temperature and the reaction mixture was stirred at the same temperature for 16 hours. Triethylamine (0.25 g, 3.10 mmol) was added to the reaction mixture at room temperature, and the organic solvent was evaporated. The resulting residue was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel, 200-350 mesh; ethyl acetate> ethyl acetate: methanol = 95: 5) to obtain the title compound (0.76 g, 85%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.6 Hz), 0.90 (3H, d, J = 6, 9 Hz), 0.94 (3H, t, J = 7.4 Hz), 1.07 (6H, d, J = 6.4 Hz), 1.14-1.67 (14H, m), 1 77 (3H, br s), 1.86 (1H, dd, J = 5.4, 14.2 Hz), 2.46-2.63 (7H, m), 2.66 (1H, dd , J = 2.4, 8.0 Hz), 2.64-2.79 (1H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.36- 3.67 (5H, m), 3.72-3.81 (1H, m), 4.93 (1H, d, J = 9.7 Hz), 5.06 (1H, d, J = 10, 8 Hz), 5.57 (1H, dd, J = 9.7, 15.1 Hz), 5.71 (1H, dd, J = 9.7, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 45. (8E, 12E, 14E) -7 - ((4-Cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 45)

First stage

(8E, 12E, 14E) -7 - ((4-Cycloheptylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,16,21- tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (compound 45-1)

To a solution of compound 46-4 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (1.388 g, 1.254 mmol) obtained in the fourth step of Example 46 in tetrahydrofuran (20 ml) was added dropwise 1-cycloheptylpiperazine ( 462 mg, 2.51 mmol) and triethylamine (513 mg, 5.02 mmol). Then tetrahydrofuran (8 ml) was added to the resulting mixture, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane 1: 9 1: 4 1: 3) to obtain the title compound (1.455 g, 99%) as a colorless oil .

Second stage

(8E, 12E, 14E) -7 - ((4-Cycloheptylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 45-2)

A solution of compound 45-1 (8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3 , 16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (1.454 g, 1.254 mmol) obtained in the first stage, in tetrahydrofuran (30 ml) was cooled to 5 ° C, tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 4.5 ml, 4.5 mmol) was added dropwise to it, and the reaction mixture was stirred at room temperature for 1.5 hours. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 0.52 ml, 0.52 mmol) was added dropwise and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel, 200-350 mesh; ethyl acetate-hexane, 1: 1 4: 1 9: 1 1: 0) to obtain the title compound (965 mg, 97% ) as a colorless oil.

ESI-MC m / z 791 (M + H) ⁺ .

Third stage

(8E, 12E, 14E) -7 - ((4-Cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide (compound 45)

To a solution of compound 45-2 (8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (964 mg, 1.218 mmol) obtained in the second stage, in a mixture of tetrahydrofuran: 2-methyl-2-propanol = Pyridinium p-toluenesulfonate (459 mg, 1.827 mmol) was added 1: 1 (22 ml) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel, 200-350 mesh; ethyl acetate-hexane-methanol mixture, 2: 1: 0 4: 1: 0 99: 0: 1 98: 0: 1 97: 0 : 1) and the crude fraction was concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; methanol-dichloromethane mixture, 1:29 1:19 1:17 1:14 1: 9) to obtain the title compound (866 mg, 99 %) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.10-1.77 (24H, m), 1.77 (3H, br s), 1.79-1, 90 (3H, m), 2.42-2.74 (9H, m), 2.85-2.92 (1H, m), 3.36-3.70 (5H, m), 3.72- 3.84 (1H, m), 4.92 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz); 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ .

Example 46. (8E, 12E, 14E) -7 - ((4-Allylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 46)

First stage

(8E, 12E, 14E) -7-Acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14 trien-11-olide (compound 46-1)

To a solution of (8E, 12E, 14E) -7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien- 11-olide (100 mg, 0.18 mmol) in dichloromethane (6 ml) was added N, N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room temperature and the reaction mixture stirred at the same temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 20: 80) to obtain the title compound (159 mg, 98%) as a colorless oil.

ESI-MC m / z 918 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -7-Acetoxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 46-2)

To a solution of compound 46-1 (8E, 12E, 14E) -7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose Of the -8,12,14-trien-11-olide (1.6 g, 1.8 mmol) obtained in the first step, ethyl vinyl ether (2.6 g, 36 mmol) and d was added in dichloromethane (35 ml) and pyridinium toluenesulfonate (22 mg, 89 μmol) at room temperature and the resulting mixture was stirred at the same temperature for 19 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (1.6 g, 93%) as a colorless oil.

ESI-MC m / z 990 (M + Na) ⁺ .

Third stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 46-3)

To compound 46-2 (8E, 12E, 14E) -7-acetoxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18, The 19-epoxytricose-8,12,14-triene-11-olide (1.6 g, 1.7 mmol) obtained in the second stage was added guanidine / guanidine nitrate (41 ml, 0.2 M solution in a mixture of dichloromethane: methanol = 10: 90) at room temperature, followed by stirring at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 20: 80) to obtain the title compound (1.3 g, 84%) as a colorless oil.

ESI-MC m / z 948 (M + Na) ⁺ .

Fourth stage

(8E, 12E, 14E) -6- (1-Ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18, 19-epoxytricose-8,12,14-triene-11-olide (compound 46-4)

To a solution of compound 46-3 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18 , 19-epoxytricose-8,12,14-trien-11-olide (1.3 g, 1.4 mmol) obtained in the third stage, triethylamine (826 mg, 8.2 mmol) was added in dichloromethane (30 ml) , N, N-dimethylaminopyridine (831 mg, 6.8 mmol) and 4-nitrophenyl chloroformate (823 mg, 4.1 mmol) at room temperature and the resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with dichloromethane and washed with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (1.4 g, 97%) as a colorless oil.

ESI-MC m / z 1114 (M + Na) ⁺ .

Fifth stage

(8E, 12E, 14E) -7 - ((Allylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,16,21-tris ( triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (compound 46-5)

To a solution of compound 46-4 (8E, 12E, 14E) -6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (37 mg, 34 μmol) obtained in the fourth stage, triethylamine (14 mg, 0.14 mmol) was added in tetrahydrofuran (2 ml) ) and allyl piperazine (8.5 mg, 68 μmol) at room temperature and the resulting mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 30: 70) to obtain the title compound (28 mg, 77%) as a colorless oil.

ESI-MC m / z 1078 (M + H) ⁺ .

Sixth stage

(8E, 12E, 14E) -7 - ((4-Allylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 46)

To a solution of compound 46-5 (8E, 12E, 14E) -7 - ((allyl piperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3, 16.21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (26 mg, 24 μmol) obtained in the fifth stage, tetrabutylammonium fluoride (2.5 ml) was added 79 μl, 1 M tetrahydrofuran solution) at room temperature and the resulting mixture was stirred at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate; methanol: dichloromethane = 5: 95) to obtain the title compound (13 mg, 72%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.85-0.90 (6H, m), 0.94 (3H, t, J = 7.6 Hz) , 1.12-1.68 (20H, m), 1.78 (3H, s), 1.86 (1H, dd, J = 2.4, 7.6 Hz), 2.38-2.62 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.03 ( 2H, d, J = 6.4 Hz), 3.44-3.62 (7H, m), 3.76-3.84 (1H, m), 4.94-5.14 (3H, m) 5.16-5.26 (2H, m), 5.56 (1H, dd, J = 10.0, 15.6 Hz), 5.70-5.82 (3H, m), 6.13 (1H, d, J = 10.8 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 735 (M + H) ⁺ .

Example 47. (8E, 12E, 14E) -7 - ((4-Allylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 47)

To compound 46 (8E, 12E, 14E) -7 - ((allylpiperazin-1-yl) carbonyl) hydroxy-6- (1-ethoxyethoxy) -3,16,21-trihydroxy-6,10,12,16,20 pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (8.7 mg, 12 μmol) obtained in Example 46, a solution of pyridinium p-toluenesulfonate (3.3 mg, 13 μmol) was added in a mixture of tetrahydrofuran: 2-methyl-2-propanol = 1: 1 (1 ml) at room temperature and the reaction mixture was stirred at the same temperature for 17 hours. The reaction mixture was concentrated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate; methanol: dichloromethane = 5: 95) to obtain the title compound (5.5 mg, 70%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.22-1.68 (8H, m) 1.78 (3H, s), 1.86 (1H, dd, J = 2.4, 7.6 Hz), 2.38-2.46 (4H, m), 2.48-2.60 (3H, m), 2.67 (1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 5.6 Hz), 3.04 ( 2H, d, J = 6.8 Hz), 3.42-3.64 (5H, m), 3.74-3.82 (1H, m), 4.92 (1H, d, J = 9, 6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.16-5.2 6 (2H, m), 5.57 (1H, dd, J = 10.0, 15, 6 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.82-5.92 (2H, m), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 663 (M + H) ⁺ .

Example 48. (8E, 12E, 14E) -7 - ((4- (3,7-Dimethyl-2,6-octadiene-1-yl) piperazin-1-yl) carbonyl) hydroxy-3,6,16, 21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 48)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.24-1.68 (8H, m) , 1.60 (3H, s), 1.66 (6H, s), 1.77 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2, 04-2.16 (4H, m), 2.40-2.46 (4H, m), 2.48-2.62 (3H, m), 2.67 (1H, dd, J = 2.4 8.0 Hz), 2.89 (1H, dt, J = 2.0, 5.2 Hz), 3.02 (2H, d, J = 6.8 Hz), 3.42-3.64 (5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.02-5.12 (2H, m), 5, 24 (1H, t, J = 7.2 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15, 2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 760 (M + H) ⁺ .

Example 49. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-pentylpiperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 49)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 7.2 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.22-1.68 (20H, m), 1.77 (3H, s) 1.86 (1H, dd, J = 5.6, 13.7 Hz), 2.32-2.60 (9H, m), 2.67 (1H, dd, J = 2.4, 8, 0 Hz), 2.89 (1H, dt, J = 1.6, 5.6 Hz), 3.40-3.70 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.8, 15.2 Hz ), 5.72 (1H, dd, J = 10.8, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 9, 2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 50. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - (((1S, 4S) -5-isopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl ) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 50)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.06-1.12 (6H, m), 1.18-1.68 (16H, m), 1.78 ( 3H, s), 1.86 (1H, dd, J = 5.7, 13.7 Hz), 2.47-2.62 (7H, m), 2.67 (1H, dd, J = 2, 4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.4 Hz), 3.05 (1H, t, J = 10.0 Hz), 3.19 (1H, dd, J = 2.4, 10.8 Hz), 3.48-3.68 (2H, m), 3.78 (1H, br s), 4.92 (1H, d, J = 9, 6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.58 (1H, dd, J = 9.6, 15.2 Hz), 5.68-5.78 (1H, m), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15 , 2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 51. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (3-methyl-2-butene-1- il) piperazin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-triene-11-olide (compound 51)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.24-1.64 (8H, m) , 1.67 (3H, s), 1-75 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2, 38-2.48 (4H, m), 2.50-2.53 (2H, m), 2.54-2.62 (1H, m), 2.67 (1H, dd, J = 2.4 , 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.00 (2H, d, J = 6.8 Hz), 3.42-3.66 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz) , 5.25 (1H, t, J = 6.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6 , 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.4 Hz), 6.53 (1H, dd, J = 10 8, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 52. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((morpholin-4-yl) carbonyl) oxy-18.19 -epoxytricose-8,12,14-triene-11-olide (compound 52)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.93 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.24-1.70 (8H, m) 1.78 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.50-2.62 (3H, m), 2.67 (1H, dd , J = 2.4, 8.0 Hz), 2.86-2.92 (1H, m), 3.42-3.56 (5H, m), 3.58-3.68 (4H, m ), 3.76-3.82 (1H, m), 4.95 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.58 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 646 (M + Na) ⁺ .

Example 53. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - ((4-isopropyl homopiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 53)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.04 (6H, d, J = 6.4 Hz), 1.23 (3H, s), 1.23-1 69 (9H, m), 1.34 (3H, s), 1.77 (3H, s), 1.77-1.90 (2H, m), 2.47-2.76 (8H, m ), 2.84-2.98 (2H, m), 3.42-3.68 (5H, m), 3.74-3.82 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.05 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.6 Hz), 5.73 (1H, dd , J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H , dd, J = 11.2, 15.6 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 54. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7 - ((4-isobutylhomopiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 54)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87-0.97 (15H, m), 1.23 (3H, s), 1.23-1, 69 (10H, m), 1.34 (3H, s), 1.77 (3H, s), 1.69-1.90 (2H, m), 2.23 (2H, d, J = 6, 8 Hz), 2.50-2.70 (8H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.43-3.66 (5H, m), 3.74-3.82 (1H, m), 4.94 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H dd, J = 9.6, 15.6 Hz), 5.73 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.6 Hz) 6.13 (1H, d, J = 11.2 Hz); 6.52 (1H, dd, J = 11.2, 15.6 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 55. (8E, 12E, 14E) -7 - ((4-Cyclopentylmethyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 55)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.15-2.20 (20H, m), 1.23 (3H, s), 1.34 (3H, s) 1.77 (3H, s), 2.42 (2H, d, J = 7.2 Hz), 2.46-2.74 (8H, m), 2.86-2.92 (1H, m ), 3.40-3.68 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.6 Hz ); ESI-MS m / z 719 (M + H) ⁺ .

Example 56. (8E, 12E, 14E) -7- (N - ((3S) -1-Ethylpyrrolidin-3-yl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12 , 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 56)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.12 (3H, t, J = 7.6 Hz), 1.23 (3H, s), 1.23-1 70 (9H, m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.08- 2.22 (1H, m), 2.38-2.90 (11H, m), 2.90 (3H, s), 3.28-3.33 (1H, covered CD ₃ OD), 3.49 -3.56 (1H, m), 3.75-3.82 (1H, m), 4.87-4.93 (1H, overlapped H ₂ O), 5.06 (1H, d, J = 10 4 Hz), 5.58 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.6 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 57. (8E, 12E, 14E) -7 - ((4-Cyclobutylmethyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 57)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (6H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7, 2 Hz), 1.23 (3H, s), 1.23-1.96 (16H, m), 1.34 (3H, s), 1.77 (3H, s), 2.02-2, 12 (2H, m), 2.50-2.64 (8H, m), 2.64-2.70 (2H, m), 2.86-2.92 (1H, m), 3.40- 3.68 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10, 8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 58. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - (((2S) -2 - ((pyrrolidin-1-yl ) methyl) pyrrolidin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 58)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.20-2.03 (17H, m), 1.23 (3H, s), 1.34 (3H, s) 1.77 (3H, s), 2.38-2.70 (10H, m), 2.85-2.92 (1H, m), 3.33-3.44 (1H, m), 3 , 49-3.56 (1H, m), 3.75-3.82 (1H, m), 3.93-4.08 (2H, m), 4.93 (1H, d, J = 9, 6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 59. (8E, 12E, 14E) -7 - (((3S) -3,4-Dimethylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 59)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.08 (3H, d, J = 6.4 Hz), 1.21 (3H, s), 1.221-1.69 (8H, m), 1.34 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.02-2, 23 (2H, m), 2.30 (3H, s), 2.46-2.84 (6H, m), 2.89 (1H, dt, J = 2.0, 5.6 Hz), 2 , 94-3.12 (1H, m), 3.48-3.55 (1H, m), 3.75-3.82 (1H, m), 3.82-4.20 (2H, m) 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10 8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 651 (M + H) ⁺ .

Example 60. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (prop-2-yn-1-yl) piperazin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 60)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.22-1.69 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.50-2.64 (7H, m), 2.64-2.70 (2H, m), 2.89 (1H, dt, J = 2.0, 5.6 Hz), 3.30 (2H, d, J = 2.4 Hz), 3.40-3.74 ( 5H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.58 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 661 (M + H) ⁺ .

Example 61. (8E, 12E, 14E) -7 - ((4- (But-2-yn-1-yl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 61)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.22-1.69 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.80 (3H, t, J = 2.4 Hz), 1.86 (1H, dd, J = 14.0, 5.6 Hz), 2.45- 2.64 (7H, m), 2.66 (1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3 25 (2H, q, J = 2.4 Hz), 3.40-3.72 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd , J = 10.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H dd, J = 11.2, 15.2 Hz); ESI-MS m / z 675 (M + H) ⁺ .

Example 62. (8E, 12E, 14E) -7 - ((4-Cyclobutylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 62)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.23 (3H, s), 1.25-1.29 (1H, m), 1.34 (3H, s) 1.34-1.71 (9H, m), 1.77 (3H, br s), 1.80-1.90 (5H, m), 2.01-2.12 (2H, m) 2.38-2.62 (7H, m), 2.66 (1H, dd, J = 2.0, 7.6 Hz), 2.86-2.97 (2H, m), 3.42 -3.67 (5H, m), 3.75-3.82 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10 8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 63. (8E, 12E, 14E) -7 - ((4-Ethyl homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 63)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.09 (3H, t, J = 7.2 Hz), 1.23 (3H, s), 1.23-1 30 (1H, m), 1.34 (3H, s), 1.34-1.69 (7H, m), 1.77 (3H, s), 1.83-1.92 (3H, m ), 2.47-2.78 (10H, m), 2.89 (1H, dt, J = 2.4, 6.4 Hz), 3.44-3.68 (5H, m), 3, 75-3.83 (1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.58 (1H, dd , J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6 13 (1H, d, J = 10.8 Hz); 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 64. (8E, 12E, 14E) -7 - ((4-Butylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 64)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 0.95 (3H, t, J = 7.2 Hz), 1.23 (3H, s), 1.23-1 30 (1H, m), 1-34 (3H, s), 1.30-1.69 (11H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5 6, 14.0 Hz), 1.90-1.98 (2H, m), 2.47-2.62 (3H, m), 2.62-2.73 (3H, m), 2, 78-2.98 (5H, m), 3.44-3.73 (5H, m), 3.76-3.82 (1H, m), 4.95 (1H, d, J = 10.4 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.58 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9 6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 65. (8E, 12E, 14E) -7 - ((4-Cyclohexyl homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 65)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.06-1.69 (20H, m), 1.74-1.90 (10H, m), 2.44- 2.85 (9H, m), 2.89 (1H, dt, J = 2.0, 5.6 Hz), 3.40-3.67 (5H, m), 3.74-3.83 ( 1H, m), 4.94 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6 , 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d , J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ .

Example 66. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (3-methyl-2-butene-1- il) homopiperazin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 66)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.16-1.67 (14H, m), 1.67 (3H, s), 1.76 (3H, s) 1.77 (3H, s), 1.82-1.93 (3H, m), 2.44-2.80 (8H, m), 2.89 (1H, dd, J = 2.4, 5.6 Hz), 3.17 (2H, d, J = 7.2 Hz), 3.43-3.70 (5H, m), 3.72-3.83 (1H, m), 4, 95 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.20-5.30 (1H, m), 5.57 (1H, dd , J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6 13 (1H, d, J = 11.2 Hz); 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 67. (8E, 12E, 14E) -7 - ((4- (2- (N, N-Dimethylamino) ethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6 , 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 67)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.98-1.69 (14H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 6.0, 15.2 Hz), 2.33 (6H, s), 2.40-2.62 (11H, m), 2.66 (1H, dd, J = 2.4, 8, 0 Hz), 2.89 (1H, dt, J = 2.4, 6.4 Hz), 3.38-3.70 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz ), 5.71 (1H, dd, J = 10.0, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10, 8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 694 (M + H) ⁺ .

Example 68. (8E, 12E, 14E) -7 - ((4- (2- (N, N-Diethylamino) ethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 68)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.08 (6H, t, J = 7.2 Hz), 1.21 (3H, s), 1.22-1 30 (1H, m), 1.34 (3H, s), 1.34-1.68 (7H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5 , 2, 14.0 Hz), 2.40-2.72 (16H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.38-3.70 ( 5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 722 (M + H) ⁺ .

Example 69. (8E, 12E, 14E) -7 - ((4- (2,2-Dimethylpropyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12, 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 69)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.85 (6H, s), 0.86 (3H, s), 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.18-1.68 (14H, m) 1.72-1.82 (5H, m), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.28 (2H, s), 2.46-2.62 (3H, m), 2.66 (1H, dd, J = 2.48, O Hz), 2.68-2.75 (2H, m), 2.81 (2H, dd, J = 5 , 2, 10.4 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.36-3.68 (5H, m), 3.72-3.82 ( 1H, m), 4.94 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6 , 14.8 Hz), 5.73 (1H, dd, J = 9.6, 14.8 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d , J = 10.8 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 70. (8E, 12E, 14E) -7 - ((4-Cyclopentyl homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 70)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.18-1.68 (18H, m), 1.70-1.77 (2H, m), 1.77 ( 3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 1.88-2.02 (4H, m), 2.46-2.62 (3H, m) 2.66 (1H, dd, J = 2.0, 8.0 Hz), 2.82-3.02 (5H, m), 3.08-3.22 (1H, m), 3.42 -3.73 (5H, m), 3.73-3.84 (1H, m), 4.95 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10 4 Hz), 5.58 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 71. (8E, 12E, 14E) -7 - ((4-Cyclopropylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 71)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.34-0.52 (4H, m), 0.89 (3H, d, J = 6.8 Hz) , 0.90 (3H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.13-1.70 (15H, m), 1.77 ( 3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.35-2.72 (8H, m), 2.80-2.92 (1H, m) , 3.30-3.68 (5H, m), 3.70-3.82 (1H, m), 4.92 (1H, d, J = 10.0 Hz), 5.05 (1H, d , J = 10.4 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.70 (1H, dd, J = 9.6, 15.2 Hz), 5 86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz) ; ESI-MS m / z 663 (M + H) ⁺ , 685 (M + Na) ⁺ .

Example 72. (8E, 12E, 14E) -7 - ((4- (1,1-Dimethylethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12, 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 72)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.10 (9H, s), 1.22 (3H, s), 1.22-1.30 (1H, m) , 1.34 (3H, s), 1.35-1.69 (7H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz ), 2.50-2.64 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6 , 0 Hz), 3.38-3.68 (5H, m), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15 , 2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 73. (8E, 12E, 14E) -7 - ((4-Cyclopropyl homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 73)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.32-0.54 (4H, m), 0.89 (3H, d, J = 6.8 Hz) , 0.90 (3H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.14-1.68 (15H, m), 1.69- 1.93 (6H, m), 2.42-2.62 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.70-2.92 ( 5H, m), 3.38-3.68 (5H, m), 3.68-3.82 (1H, m), 4.94 (1H, d, J = 10.4 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15 , 2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 74. (8E, 12E, 14E) -7 - ((4- (2,2-Dimethylpropyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12, 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 74)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87-0.92 (15H, m), 0.94 (3H, t, J = 7.6 Hz) , 1.20-1.29 (4H, m), 1.31-1.69 (10H, m), 1.77 (3H, d, J = 1.2 Hz), 1.86 (1H, dd , J = 5.2, 14.0 Hz), 2.09 (2H, s), 2.45-2.64 (7H, m), 2.67 (1H, dd, J = 2.4, 8 , 0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.36-3.67 (5H, m), 3.75-3.83 (1H, m) 4.92 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1 6, 10.8 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 75. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Diethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 75)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.06 (6H, br.t, J = 7.0 Hz), 1.15-1.65 (7H, m) , 1.22 (3H, br s), 1.33 (3H, s), 1.65 (1H, dd, J = 6.2, 14.3H), 1.77 (3H, s), 1 86 (1H, dd, J = 6.2, 14.3 Hz), 2.46-2.65 (5H, m), 2.59 (4H, q, J = 7.0 Hz), 2, 66 (1H, dd, J = 2.2, 8.1 Hz), 2.89 (1H, dt, J = 2.2, 6.2 Hz), 2.92 (1.6H, s), 2 99 (1.4H, s), 3.28-3.40 (1H, m), 3.52 (1H, dt, J = 4.0, 8.4 Hz), 3.52-3.62 (1H, m), 3.74-3.81 (1H, m), 4.92 (1H, d, J = 9.5 Hz), 5.06 (1H, d, J = 10.6 Hz) 5.56 (1H, dd, J = 9.9, 15.0 Hz), 5.72 (1H, dd, J = 9.5, 15.0 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.4 Hz); ESI-MS m / z 667 (M + H) ⁺ .

Example 76. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (2- (morpholin-4- il) ethyl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 76)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.888 (3H, d, J = 6.6 Hz), 0.894 (3H, d, J = 7.0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.19-1.65 (7H, m), 1.22 (3H, s), 1.33 (3H, s), 1.65 (1H, dd, J = 6.6, 13.9 Hz), 1.77 (3H, d, J = 0.7 Hz), 1.86 (1H, dd, J = 6.2, 13.9 Hz), 2.45-2.61 (9H, m), 2.66 (1H, dd, J = 2.6, 7.7 Hz), 2.89 (1H, dt, J = 2.6, 6.2 Hz), 2.91 (1.6H, s), 2.98 (1.4H, s), 3.30-3.45 (1H, m), 3.52 (1H, dt, J = 4.4, 8.1 Hz), 3.60-3.71 (5H, m), 3.74-3.81 (1H, m), 4.92 (1H, d, J = 9.9 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.51-5.60 (1H, m), 5.67-5.77 (1H, m), 5.86 (1H d, J = 15.0 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.0 Hz); ESI-MS m / z 681 (M + H) ⁺ .

Example 77. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (2- (piperidin-1- il) ethyl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 77)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.0 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.19-1.68 (17H, m), 1.33 (3H, s), 1.77 (3H, d, J = 0.7 Hz), 1.86 (1H, dd, J = 5.5, 13.9 Hz), 2.41-2.62 (9H, m), 2.66 (1H, dd, J = 2.6, 7.7 Hz), 2.87-2.92 (1H, m), 2.90 (1.6H, s), 2.98 (1.4H, s), 3.36- 3.45 (1H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3.55-3.62 (1H, m), 3.74-3.81 ( 1H, m), 4.86-4.93 (1H, m), 5.05 (1H, d, J = 10.6 Hz), 5.56 (1H, dd, J = 9.9, 15, 0 Hz), 5.71 (1H, dd, J = 10.6, 15.0 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.4 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 78. (8E, 12E, 14E) -7- (N-Ethyl-N- (2- (morpholin-4-yl) ethyl) carbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12 , 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 78)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.886 (3H, d, J = 6.6 Hz), 0.893 (3H, d, J = 7.0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.08-1.17 (3H, m), 1.18-1.65 (7H, m), 1.22 (3H, s) 1.33 (3H, s), 1.65 (1H, dd, J = 5.5, 13.9 Hz), 1.77 (3H, d, J = 1.1 Hz), 1.86 ( 1H, dd, J = 5.5, 13.9 Hz), 2.44-2.62 (9H, m), 2.66 (1H, dd, J = 2.2, 8.1 Hz), 2 89 (1H, dt, J = 2.2, 5.5 Hz), 3.30-3.54 (3H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz ), 3.54-3.71 (5H, m), 3.73-3.81 (1H, m), 4.92 (1H, brd, J = 9.5 Hz), 5.06 ( 1H, d, J = 10.6 Hz), 5.57 (1H, dd, J = 9.9, 15.0 Hz), 5.67-5.78 (1H, m), 5.86 (1H d, J = 15.0 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.0 Hz); ESI-MS m / z 695 (M + H) ⁺ .

Example 79. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (2- (pyrrolidin-1- il) ethyl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 79)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.19-1.65 (10H, m), 1.33 (3H, s), 1.65 (1H, dd, J = 5.5, 14.3 Hz), 1.74-1.85 (4H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.5, 14, 3 Hz), 2.49-2.68 (10H, m), 2.86-2.92 (1H, m), 2.91 (1.6H, s), 2.99 (1.4H, s ), 3.39-3.60 (2H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3.73-3.81 (1H, m), 4, 91 (1H, d, J = 9.5 Hz), 5.05 (1H, d, J = 10.6 Hz), 5.56 (1H, dd, J = 9.9, 15.4 Hz), 5.72 (1H, dd, J = 9.5, 15.4 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 11.0 Hz ), 6.52 (1H, dd, J = 11.0, 15.4 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 80. (8E, 12E, 14E) -7- (N- (3- (N ', N'-Diethylamino) propyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 80)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.05 (6H, t, J = 7.3 Hz), 1.21-1.81 (10H, m), 1 21 (3H, s), 1.33 (3H, s), 1.77 (3H, s), 1.86 (1H, dd, J = 5.5, 13.6 Hz), 2.46- 2.62 (5H, m), 2.58 (4H, q, J = 7.3 Hz), 2.66 (1H, dd, J = 2.2, 8.1 Hz), 2.87-2 95 (1H, m), 2.89 (1.6H, s), 2.97 (1.4H, s), 3.20-3.32 (1H, m), 3.50-3.59 (1H, m), 3.52 (1H, dt, J = 4.4, 8.4 Hz), 3.74-3.82 (1H, m), 4.93 (1H, d, J = 9 , 9 Hz), 5.06 (1H, d, J = 10.6 Hz), 5.56 (1H, dd, J = 9.9, 15.0 Hz), 5.73 (1H, dd, J = 9.9, 15.0 Hz), 5.86 (1H, d, J = 15.4 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd , J = 11.0, 15.4 Hz); ESI-MS m / z 681 (M + H) ⁺ .

Example 81. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7 - (((1S, 4S) -5-methyl-2,5 diazabicyclo [2.2.1] heptan-2-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 81)

The title compound (colorless oil) was synthesized by a method similar to that described in example 3.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.6 Hz), 0.89 (3H, d, J = 7, 0 Hz), 0.93 (3H, t, J = 7.3 Hz), 1.19-1.70 (7H, m), 1.20 (1.2H, s), 1.22 (1, 8H, s), 1.33 (3H, s), 1.65 (1H, dd, J = 6.2, 14.3 Hz), 1.72-1.77 (1H, m), 1.77 (3H, d, J = 0.7 Hz), 1.86 (1H, dd, J = 6.2, 14.3 Hz), 1.86-1.92 (1H, m), 2.38 ( 1.2H, s), 2.40 (1.8H, s), 2.50-2.62 (3H, m), 2.63-2.7 0 (2H, m), 2.74-2 83 (1H, m), 2.89 (1H, dt, J = 2.2, 6.2 Hz), 3.21 (0.6H, dd, J = 1.8, 10.6 Hz), 3.36 (0.4H, dd, J = 1.8, 10.6 Hz), 3.47-3.59 (3H, m), 3.75-3.82 (1H, m), 4, 32 (0.4H, s), 4.55 (0.6H, s), 4.91 (1H, d, J = 9.9 Hz), 5.06 (1H, d, J = 10.6 Hz ), 5.68-5.77 (1H, m), 5.51-5.61 (1H, m), 5.86 (1H, d, J = 15.0 Hz), 6.13 (1H, d, J = 11.0 Hz), 6.52 (1H, dd, J = 11.0, 15.0 Hz); ESI-MS m / z 649 (M + H) ⁺ .

Example 82. (8E, 12E, 14E) -7 - (((1S, 4S) -5-Ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) carbonyl) oxy-3,6,16 , 21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 82)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.93 (3H, d, J = 6.8 Hz), 0.94 (3H, d, J = 6, 8 Hz), 0.98 (3H, t, J = 7.2 Hz), 1.10-1.18 (3H, m), 1.22-1.74 (14H, m), 1.80 ( 1H, br s), 1.82 (3H, s), 1.87-1.95 (2H, m), 2.51-2.77 (7H, m), 2.87-2.97 ( 2H, m), 3.23-3.29 (0.5H, m), 3.37-3.43 (0.5H, m), 3.51-3.63 (2H, m), 3, 63-3.69 (1H, m), 3.79-3.87 (1H, m), 4.37 (0.5H, br s), 4.60 (0.5H, br s), 4.96 (1H, d, J = 9.6 Hz), 5.11 (1H, d, J = 10.4 Hz), 5.57-5.67 (1H, m), 5.72-5 67 (1H, m), 5.91 (1H, d, J = 15.2 Hz), 6.18 (1H, d, J = 11.2 Hz), 6.57 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 663 (M + H) ⁺ .

Example 83. (8E, 12E, 14E) -7 - ((4-Cyclooctylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 83)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.94 (3H, d, J = 6.8 Hz), 0.94 (3H, d, J = 6, 8 Hz), 0.98 (3H, t, J = 7.2 Hz), 1.25 (3H, s), 1.25-1.87 (28H, m), 1.91 (1H, dd, J = 5.6, 14.4 Hz), 2.50-2.76 (9H, m), 2.93 (1H, dt, J = 2.0, 6.0 Hz), 3.42-3 74 (5H, m), 3.78-3.88 (1H, m), 4.97 (1H, d, J = 9.6 Hz), 5.11 (1H, d, J = 10.4 Hz), 5.61 (1H, dd, J = 9.6, 15.2 Hz), 5.76 (1H, dd, J = 9.6, 15.2 Hz), 5.91 (1H, d , J = 15.2 Hz), 6.18 (1H, d, J = 11.2 Hz), 6.57 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 733 (M + H) ⁺ .

Example 84. (8E, 12E, 14E) -7 - ((4- (Ethoxycarbonylmethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 84)

The title compound (colorless oil) was synthesized by a method similar to that described in examples 46 and 47.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.20-1.42 (3H, m), 1.21 (3H, s), 1.26 (3H, t, J = 7.2 Hz), 1.34 (3H, s), 1.44-1.54 (2H, m), 1.56-1.64 (2H, m), 1.65 (1H, dd , J = 6.5, 14.4 Hz), 1.78 (3H, s), 1.86 (1H, dd, J = 5.0, 14.4 Hz), 2.50-2.62 ( 7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.87-2.91 (1H, m), 3.26 (2H, s), 3.40 -3.70 (4H, m), 3.50-3.55 (1H, m), 3.75-3.81 (1H, m), 4.17 (2H, q, J = 7.2 Hz ), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15, 2 Hz), 5.71 (1H, dd, J = 9.8, 15.2 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 10.0 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 731 (M + Na) ⁺ .

Example 85. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 85)

First stage

(8E, 12E, 14E) -7-Acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14 -trien-11-olide (compound 85-1)

To a solution of compound 46-1 (8E, 12E, 14E) -7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose Of the -8,12,14-trien-11-olide (171 mg, 0.19 mmol) obtained in the first step of Example 46, methyl trifluoromethanesulfonate (188 mg, 1.14 mmol) and 1.8 were added in toluene (6 ml) bis (N, N-dimethylamino) naphthalene (368 mg, 1.71 mmol) at room temperature and the reaction mixture was stirred at 65 ° C for 14 hours. Then, methyl trifluoromethanesulfonate (304 mg, 1.9 mmol) and 1,8-bis (N, N-dimethylamino) naphthalene (400 mg, 1.9 mmol) were added to the resulting mixture at room temperature, and the reaction mixture was stirred at 65 ° C. within 6 hours. The reaction mixture was diluted with diethyl ether and filtered through a glass filter. The filtrate was mixed with 28% aqueous ammonia (1 ml) and the reaction mixture was stirred at room temperature for one hour and washed sequentially with saturated brine, 0.1 M aqueous citric acid, saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (141 mg, 84%) as a colorless oil.

ESI-MC m / z 932 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -7-Hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose-8,12,14 trien-11-olide (compound 85-2)

To a solution of compound 85-1 (8E, 12E, 14E) -7-acetoxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose Of the -8,12,14-trien-11-olide (158 mg, 0.17 mmol) obtained in the first stage, potassium carbonate (120 mg, 0.87 mmol) was added in methanol (5 ml) at room temperature, after wherein the reaction mixture was stirred at the same temperature for three hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The crude product was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (91 mg, 61%) as a colorless oil.

ESI-MC m / z 890 (M + Na) ⁺ .

Third stage

(8E, 12E, 14E) -6-Methoxy-6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose- 8,12,14-trien-11-olide (compound 85-3)

To a solution of compound 85-2 (8E, 12E, 14E) -7-hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose -8,12,14-trien-11-olide (91 mg, 0.11 mmol) obtained in the second stage, triethylamine (64 mg, 0.52 mmol), N, N-dimethylaminopyridine was added in dichloromethane (4 ml) (64 mg, 0.52 mmol) and 4-nitrophenylchloroformate (63 mg, 0.31 mmol) at room temperature and the reaction mixture was stirred at the same temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (97 mg, 89%) as a colorless oil.

ESI-MC m / z 1055 (M + Na) ⁺ .

Fourth stage

(8E, 12E, 14E) -6-Methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-tris (triethylsiloxy) -18.19-epoxytricose-8,12,14-trien-11-olide (compound 85-4)

To a solution of compound 85-3 (8E, 12E, 14E) -6-methoxy-6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) - 18.19-epoxytricose-8,12,14-trien-11-olide (30 mg, 29 μmol) obtained in the third stage, triethylamine (11 mg, 0.12 mmol) and 1- were added in tetrahydrofuran (2 ml) methylpiperazine (5.8 mg, 58 μmol) at room temperature and the reaction mixture was stirred at the same temperature for one hour. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; methanol: dichloromethane = 3: 97) to obtain the title compound (26 mg, 89%) as a colorless oil.

ESI-MC m / z 994 (M + H) ⁺ .

Fifth stage

(8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-trien-11-olide (compound 85)

To a solution of compound 85-4 (8E, 12E, 14E) -6-methoxy-6,10,12,16,20-pentamethyl-7- (4-methylpiperazin-1-yl) carbonyl) hydroxy-3,16,21 -tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (25 mg, 25 μmol) obtained in the fourth stage, tetrabutylammonium fluoride (83 μl, 1, was added in tetrahydrofuran (3 ml) 0 M tetrahydrofuran solution) at room temperature, after which the reaction mixture was stirred at the same temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel Plate; methanol: dichloromethane = 5: 95) to obtain the title compound (11 mg, 67%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.22-1.69 (8H, m) 1.78 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.29 (3H, s), 2.36-2.44 (4H, m ), 2.45-2.60 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.86-2.92 (1H, m), 3, 34 (3H, s), 3.44-3.58 (5H, m), 3.78-3.86 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5 06 (1H, d, J = 11.2 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 10.0, 15 , 2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 9.2 Hz), 6.53 (1H, dd, J = 11.2 15.2 Hz); ESI-MS m / z 651 (M + H) ⁺ .

Example 86. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((piperazin-1-yl) carbonyl) oxy-18 , 19-epoxytricose-8,12,14-trien-11-olide (compound 86)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.22-1.82 (8H, m), 1.34 (3H, s) 1.77 (3H, s), 1.86 (1H, dd, J = 6.0, 14.0 Hz), 2.44-2.62 (3H, m), 2.66 (1H, dd , J = 2.0, 8.0 Hz), 2.70-2.82 (4H, m), 2.89 (1H, dt, J = 2.4, 5.6 Hz), 3.25- 3.36 (3H, overlapped CD ₃ OD), 3.38-3.55 (5H, m), 3.78-3.86 (1H, m), 5.02 (1H, d, J = 9, 6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.6 Hz), 5.73 (1H, dd, J = 9.6, 15.6 Hz), 5.86 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11.2, 15.6 Hz); ESI-MS m / z 637 (M + H) ⁺ .

Example 87. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Diethylamino) ethyl) carbamoyloxy) -3,16,21-trihydroxy-6-methoxy-6,10,12 , 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 87)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.06 (6H, t, J = 7.2 Hz), 1.22 (3H, s), 1.22-1 70 (8H, m), 1.34 (3H, s), 1.78 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.44- 2.64 (9H, m), 2.66 (1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3 21 (2H, t, J = 7.2 Hz), 3.25-3.36 (3H, covered CD ₃ OD), 3.48-3.56 (1H, m), 3.77-3, 85 (1H, m), 4.97 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.54 (1H, dd, J = 10 , 0, 15.2 Hz), 5.71 (1H, dd, J = 9.6, 15.6 Hz), 5.86 (1H, d, J = 15.6 Hz), 6.13 (1H d, J = 10.8 Hz), 6.52 (1H, dd, J = 11.2, 15.6 Hz); ESI-MS m / z 667 (M + H) ⁺ .

Example 88. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (1-methylpiperidin-4 -yl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 88)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.17-1.69 (16H, m), 1.72-1.90 (6H, m), 2.10- 2.2 6 (2H, m), 2.33 (3H, s), 2.44-2.62 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz ), 2.82 (3H, s), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 2.95-3.03 (2H, m), 3.35 (3H, s), 3.52 (1H, dt, J = 4.4, 8.0 Hz), 3.78-3.85 (1H, m), 3.92-4.04 (1H, m), 5 03 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz) 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 89. (8E, 12E, 14E) -7 - ((4- (N, N-Dimethylamino) piperidin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10, 12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 89)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.89 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.17-1.68 (16H, m), 1.78 (3H, s), 1.81-1.94 ( 3H, m), 2.29 (6H, s), 2.34-2.63 (4H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.73 -2.89 (2H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.33 (3H, s), 3.52 (1H, dt, J = 4 4, 7.6 Hz), 3.78-3.85 (1H, m), 4.10-4.30 (2H, m), 5.01 (1H, d, J = 9.2 Hz) , 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6 , 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10 8, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 90. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-propylhomopiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 90)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.84-0.92 (9H, m), 0.94 (3H, t, J = 7.2 Hz) , 1.24 (3H, s), 1.34 (3H, s), 1.22-1.69 (10H, m), 1.78 (3H, d, J = 0.8 Hz), 1, 82-1.90 (3H, m), 2.4 0-2.72 (10H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.24-3 36 (3H, overlapped CD ₃ OD), 3.44-3.60 (5H, m), 3.78-3.86 (1H, m), 5.03 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.74 (1H, dd, J = 9 6, 15.2 Hz), 5.87 (1H, d, J = 15.6 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.6 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 91. (8E, 12E, 14E) -7 - ((4-Butylhomopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 91)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.86-0.98 (12H, m), 1.23 (3H, br s), 1.34 ( 3H, s), 1.22-1.70 (12H, m), 1.78 (3H, d, J = 0.8 Hz), 1.82-1.89 (3H, m), 2.44 -2.74 (10H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.30 (3H, s), 3.42-3.58 (5H, m ), 3.79-3.85 (1H, m), 5.03 (1H, d, J = 9.2 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 92. (8E, 12E, 14E) -7 - ((4-Cyclopropyl homopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 92)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.38-0.42 (2H, m), 0.47-0.52 (2H, m), 0, 88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7.2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.23 ( 3H, s), 1.34 (3H, s), 1.22-1.68 (9H, m), 1.78 (3H, d, J = 0.8 Hz), 1.80-1.92 (3H, m), 2.44-2.60 (3H, m), 2.66 (1H, dd, J = 2.0, 7.6 Hz), 2.74-2.87 (4H, m ), 2.89 (1H, dt, J = 1.6, 5.6 Hz), 3.33 (3H, s), 3.44-3.60 (5H, m), 3.78-3, 86 (1H, m), 5.03 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10 , 0, 15.6 Hz), 5.74 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 93. (8E, 12E, 14E) -7 - ((4-Cyclobutylhomopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 93)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.23 (3H, s), 1.34 (3H, s), 1.22-1.72 (10H, m) 1.78 (3H, s), 1.80-1.90 (5H, m), 2.02-2.10 (2H, m), 2.41-2.60 (7H, m), 2 67 (1H, dd, J = 2.4.8, O Hz), 2.86-2.94 (2H, m), 3.24-3.36 (3H, covered CD ₃ OD), 3, 44-3.60 (5H, m), 3.78-3.86 (1H, m), 5.03 (1H, dd, J = 2.0, 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz ); ESI-MS m / z 705 (M + H) ⁺ .

Example 94. (8E, 12E, 14E) -7 - ((4-Cyclopentyl homopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 94)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.23 (3H, s), 1.34 (3H, s), 1.36-1.72 (16H, m) 1.78 (3H, d, J = 0.8 Hz), 1.82-1.90 (3H, m), 2.44-2.60 (3H, m), 2.64-2.70 (3H, m), 2.73-2.82 (2H, m), 2.84-2.94 (2H, m), 3.24-3.36 (3H, covered CD ₃ OD), 3, 44-3.60 (5H, m), 3.78-3.86 (1H, m), 5.04 (1H, d, J = 11.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6, 15.6 Hz), 5.74 (1H, dd, J = 10.0, 15.2 Hz), 5.87 ( 1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ .

Example 95. (8E, 12E, 14E) -7 - ((4-Cyclohexyl homopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 95)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.23 (3H, s), 1.34 (3H, s), 1.12-1.68 (18H, m) 1.78 (3H, d, J = 0.8 Hz), 1.75-1.89 (3H, m), 2.42-2.60 (4H, m), 2.64-2.72 (3H, m), 2.75-2.82 (2H, m), 2.89 (1H, dt, J = 1.2, 5.2 Hz), 3.26-3.36 (3H, closed CD ₃ OD), 3.42-3.56 (5H, m), 3.78-3.86 (1H, m), 5.03 (1H, dd, J = 3.2, 9.6 Hz) , 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 10.0 , 14.8 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11 , 2, 15.2 Hz); ESI-MS m / z 733 (M + H) ⁺ .

Example 96. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - ((4-isopropylhomopiperazin-1-yl) carbonyl) hydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 96)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.03 (6H, d, J = 6.4 Hz), 1.24 (3H, s), 1.34 (3H , s), 1.22-1.69 (8H, m), 1.78 (3H, s), 1.76-1.90 (3H, m), 2.44-2.74 (8H, m ), 2.86-2.94 (2H, m), 3.33 (3H, s), 3.44-3.60 (5H, m), 3.79-3.86 (1H, m), 5.03 (1H, dd, J = 4.4, 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.8, 16.0 Hz), 5.74 (1H, dd, J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.6 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 97. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - ((4-isobutylhomopiperazin-1-yl) carbonyl) hydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 97)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.84-0.95 (15H, m), 1.26 (3H, s), 1.34 (3H, s), 1.22-1.76 (9H, m), 1.78 (3H, s), 1.78-1.90 (3H, m), 2.23 (2H, d, J = 6, 8 Hz), 2.44-2.72 (8H, m), 2.89 (1H, dt, J = 2.0, 5.2 Hz), 3.24-3.38 (3H, covered CD ₃ OD), 3.42-3.58 (5H, m), 3.78-3.86 (1H, m), 5.03 (1H, d, J = 9.6 Hz), 5.07 (1H d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.74 (1H, dd, J = 9.2, 14.8 Hz) 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 98. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (morpholin-4-yl) piperidine - 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 98)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 5.2 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.24-1.68 (10H, m) 1.78 (3H, d, J = 1.2 Hz), 1.82-1.96 (3H, m), 2.32-2.43 (1H, m), 2.44-2.62 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.74-2.92 (3H, m), 3.32 (3H, s), 3, 52 (1H, dt, J = 3.6, 8.0 Hz), 3.64-3.74 (4H, m), 3.78-3.86 (1H, m), 4.08-4, 28 (2H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.54 (1H, dd, J = 9 6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H d, J = 11.2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 721 (M + H) ⁺ .

Example 99. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (pyrrolidin-1-yl) piperidin- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 99)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 5.6 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.34 (3H, s), 1.23-1.70 (10H, m) 1.78 (3H, s), 1.79-1.90 (5H, m), 1.92-2.00 (2H, m), 2.20-2.30 (1H, m), 2 , 44-2.68 (8H, m), 2.76-2.92 (3H, m), 3.24-3.36 (3H, covered CD ₃ OD), 3.52 (1H, dt, J = 4.8, 8.0 Hz), 3.77-3.86 (1H, m), 4.04-4.24 (2H, m), 5.01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9 6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 100. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - ((4- (4-hydroxypiperidin-1-yl) piperidin-1-yl) carbonyl) oxy-6-methoxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 100)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.21 (3H, s), 1.34 (3H, s), 1.22-1.69 (12H, m) 1.78 (3H, s), 1.82-1.93 (5H, m), 2.28-2.38 (2H, m), 2.43-2.58 (4H, m), 2 67 (1H, dd, J = 2.0, 7.6 Hz), 2.72-2.83 (5H, m), 3.24-3.39 (3H, covered CD ₃ OD), 3, 52 (1H, dt, J = 4.8, 8.0 Hz), 3.56-3.64 (1H, m), 3.78-3.86 (1H, m), 4.10-4, 30 (2H, m), 5.00 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 10 4, 15.2 Hz), 5.73 (1H, dd, J = 10.0, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 735 (M + H) ⁺ .

Example 101. (8E, 12E, 14E) -7- (N- (3- (N ', N'-Dimethylamino) propyl) -N-methylcarbamoyloxy) -3,16,21-trihydroxy-6-methoxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 101)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.34 (3H, s), 1.20-1.78 (10H, m) 1.78 (3H, s), 1.86 (1H, dd, J = 6.3, 14.5 Hz), 2.24 (6H, s), 2.31 (2H, t, J = 8 , 8 Hz), 2.44-2.60 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.85-2.96 (4H, m) , 3.22-3.38 (5H, overlapped CD ₃ OD), 3.52 (1H, dd, J = 3.6, 8.0 Hz), 3.78-3.85 (1H, m), 5.01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.55 (1H, dd, J = 9.6, 15.2 Hz ), 5.74 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10, 8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 667 (M + H) ⁺ .

Example 102. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (2- (morpholine- 4-yl) ethyl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 102)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.22 (3H, s), 1.34 (3H, s), 1.23-1.69 (8H, m) 1.78 (3H, s), 1.86 (1H, dd, J = 4.6, 12.7 Hz), 2.44-2.56 (9H, m), 2.66 (1H, dd , J = 2.4, 7.6 Hz), 2.86-2.96 (4H, m), 3.22-3.38 (2H, covered CD ₃ OD), 3.34 (3H, s) 3.52 (1H, dt, J = 4.0, 8.0 Hz), 3.62-3.72 (4H, m), 3.78-3.84 (1H, m), 5.01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 10.0, 15.2 Hz), 5 68-5.79 (1H, m), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.4 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 695 (M + H) ⁺ .

Example 103. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7- (N-methyl-N- (2- (pyrrolidine- 1-yl) ethyl) carbamoyloxy) -18,19-epoxytricose-8,12,14-trien-11-olide (compound 103)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.22 (3H, s), 1.34 (3H, s), 1.23-1.68 (8H, m) 1.78 (3H, d, J = 0.8 Hz), 1.78-1.83 (4H, m), 1.86 (1H, dd, J = 5.4, 13.1 Hz), 2.44-2.68 (10H, m), 2.86-2.97 (4H, m), 3.34 (3H, s), 3.40-3.48 (2H, m), 3, 52 (1H, dt, J = 4.0, 7.6 Hz), 3.78-3.86 (1H, m), 5.00 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.55 (1H, dd, J = 10.0, 14.8 Hz), 5.74 (1H, dd, J = 9.6, 14.8 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15 , 2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 104. (8E, 12E, 14E) -7- (N- (3- (N ', N'-Diethylamino) propyl) -N-methylcarbamoyloxy) -3,16,21-trihydroxy-6-methoxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 104)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.05 (6H, t, J = 7.2 Hz), 1.22 (3H, s), 1.34 (3H , s), 1.20-1.82 (10H, m), 1.78 (3H, s), 1.86 (1H, dd, J = 5.6, 14.4 Hz), 2.42- 2.60 (9H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.84-2.96 (4H, m), 3.22-3.40 ( 5H, overlapped CD ₃ OD), 3.52 (1H, dt, J = 3.6, 8.0 Hz), 3.78-3.86 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.55 (1H, dd, J = 10.0, 15.6 Hz), 5.74 (1H, dd , J = 9.6, 15.6 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.0 Hz), 6.53 (1H dd, J = 11.2, 15.2 Hz); ESI-MS m / z 695 (M + H) ⁺ .

Example 105. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 105)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.69 ( 7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.83-1.93 (3H, m), 2.35 (3H, s), 2.45-2.65 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 ( 1.5H, s), 3.33 (1.5H, s), 3.46-3.62 (5H, m), 3.79-3.86 (1H, m), 5.01-5, 06 (1H, m), 5.07 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.74 (1H, dd , J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 11.2 Hz), 6 53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 106. (8E, 12E, 14E) -7 - ((4-Ethylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 106)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.11 (3H, t, J = 7.6 Hz), 1.20-1.29 (4H, m), 1 34 (3H, s), 1.37-1.69 (7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2 , 14.0 Hz), 2.41-2.63 (9H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.43-3.59 (5H, m), 3.79-3.86 (1H, m), 5.01 (1H d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 107. (8E, 12E, 14E) -7 - ((4-Ethyl homopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 107)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.08 (3H, t, J = 7.2 Hz), 1.19-1.29 (4H, m), 1 34 (3H, s), 1.38-1.70 (7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.82-1.90 (3H, m), 2.45-2.73 (10H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.33 (1.5H, s), 3.33 (1, 5H, s), 3.46-3.62 (5H, m), 3.79-3.85 (1H, m), 5.00-5.06 (1H, m), 5.07 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz ); ESI-MS m / z 679 (M + H) ⁺ .

Example 108. (8E, 12E, 14E) -7- (N- (2- (N ', N'-Dimethylamino) ethyl) -N-methylcarbamoyloxy) -3,16,21-trihydroxy-6-methoxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 108)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.70 ( 7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.27 (6H, s), 2.45-2.63 (5H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.87-2.97 (4H, m), 3.30- 3.36 (3H, m), 3.37-3.46 (2H, m), 3.52 (1H, td, J = 4.4, 8.0 Hz), 3.78-3.85 ( 1H, m), 5.00 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.55 (1H, dd, J = 9.6 , 15.2 Hz), 5.69-5.79 (1H, m), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz ), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 653 (M + H) ⁺ .

Example 109. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (piperidin-1-yl) piperidin- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 109)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.31-1.69 (18H, m), 1.78 ( 3H, s), 1.83-1.93 (3H, m), 2.41-2.61 (8H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz) 2.70-2.88 (2H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.33 (3H, s), 3.52 (1H, td) , J = 4.4, 8.0 Hz), 3.78-3.85 (1H, m), 4.11-4.29 (2H, m), 5.00 (1H, d, J = 9 6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd , J = 10.8, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ .

Example 110. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - ((4- (isopropylpiperazin-1-yl) carbonyl) hydroxy-6-methoxy-6,10,12,16,20- pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 110)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.07 (6H, d, J = 6.8 Hz), 1.20-1.29 (4H, m), 1 32-1.76 (10H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2, 45-2.63 (7H, m), 2.64-2.75 (2H, m), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.42-3.59 (5H, m), 3.78-3.86 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz) 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 111. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-propylpiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 111)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.93 (3H, t, J = 7.2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.20-1.30 (4H, m), 1 34 (3H, s), 1.39-1.69 (9H, m), 1.78 (3H, d, J = 1.2 Hz), 1.87 (1H, dd, J = 5.2 , 14.0 Hz), 2.31-2.37 (2H, m), 2.40-2.63 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.90 (1H, dt, J = 2.0, 6.0 Hz), 3.32 (3H, s), 3.42-3.60 (5H, m), 3.79-3 86 (1H, m), 5.02 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.14 ( 1H, d, J = 11.2 Hz); 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 112. (8E, 12E, 14E) -7 - ((4-Butylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 112)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.19-1.29 (4H, m), 1 , 29-1.69 (14H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2, 34-2.39 (2H, m), 2.40-2.63 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.32 (3H, s), 3.41-3.60 (5H, m), 3.79-3.85 (1H, m), 5 01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz) 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 113. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - ((4-isobutylpiperazin-1-yl) carbonyl) hydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 113)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.91 (6H, d, J = 6.4 Hz), 0.94 (3H, t, J = 7.6 Hz), 1, 19-1.29 (4H, m), 1 34 (3H, s), 1.39-1.69 (7H, m), 1.76-1.90 (5H, m), 2.11 (2H, d, J = 7.2 Hz), 2.33-2.41 (4H, m), 2.45-2.63 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 ( 1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.40-3.58 (5H, m), 3.79-3.86 (1H, m) 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10 8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 693 (M + H) ⁺ .

Example 114. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-7 - ((4- (2-methoxyethyl) piperazin-1-yl) carbonyl) oxy-6,10,12, 16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 114)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.69 ( 7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.44-2.63 (9H , m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.32 (3H, s), 3.33 (3H, s), 3.41-3.59 (7H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J = 9, 6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 695 (M + H) ⁺ .

Example 115. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (tetrahydropyran-4-yl) piperazine- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 115)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.69 ( 9H, m), 1.77-1.85 (5H, m), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.43-2.63 (8H, m) 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.35-3.43 (2H, m), 3.43-3.59 (5H, m), 3.78-3.85 (1H, m), 3.98 (2H, dd, J = 4 4, 11.2 Hz), 5.01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 11.2 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 721 (M + H) ⁺ .

Example 116. (8E, 12E, 14E) -7 - ((4-Cyclopropylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 116)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.40-0.46 (2H, m), 0.46-0.53 (2H, m), 0, 89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19- 1.29 (4H, m), 1.34 (3H, s), 1.38-1.70 (8H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.45-2.63 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.37-3.56 (5H, m), 3.78-3.85 ( 1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6 , 15.2 Hz), 5.73 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd , J = 1.2, 10.8 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 117. (8E, 12E, 14E) -7 - ((4-Cyclobutylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 117)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.39-1.78 ( 9H, m), 1.78 (3H, d, J = 0.8 Hz), 1.83-1.95 (3H, m), 2.02-2.10 (2H, m), 2.31 (4H, t, J = 4.8 Hz), 2.45-2.63 (3H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.72- 2.81 (1H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.31 (3H, s), 3.40-3.58 (5H, m) , 3.78-3.85 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 ( 1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz ), 6.13 (1H, d, J = 11.2 Hz); 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 118. (8E, 12E, 14E) -7 - ((4-Cyclopentylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 118)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.36-1.77 ( 13H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 1.86-1.95 (2H , m), 2.44-2.63 (8H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0 , 6.0 Hz), 3.32 (3H, s), 3.42-3.59 (5H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 705 (M + H) ⁺ .

Example 119. (8E, 12E, 14E) -7 - ((4-Cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 119)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.09-1.33 (10H, m), 1.34 (3H, s), 1.39-1.69 ( 7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.78-1.93 (5H, m), 2.27-2.35 (1H, m), 2.45 -2.65 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4, 6.0 Hz), 3.32 (3H, s), 3.39-3.58 (5H, m), 3.79-3.86 (1H, m), 5.01 (1H, d, J = 9.6 Hz) , 5.07 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.74 (1H, dd, J = 9.6 , 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10 8, 15.2 Hz); ESI-MS m / z 719 (M + H) ⁺ .

Example 120. (8E, 12E, 14E) -7 - ((4-Cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 120)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H, s), 1.38-1.75 ( 17H, m), 1.78 (3H, d, J = 0.8 Hz), 1.79-1.86 (2H, m), 1.86 (1H, dd, J = 5.2, 14, 0 Hz), 2.45-2.64 (8H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.4 , 6.0 Hz), 3.32 (3H, s), 3.39-3.57 (5H, m), 3.78-3.85 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 ( 1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 733 (M + H) ⁺ .

Example 121. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - (((1S, 4S) -5-methyl-2 , 5-diazabicyclo [2.2.1] heptan-2-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 121)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.20-1.29 (4H, m), 1.34 (3H, s), 1.40-1.69 ( 7H, m), 1.74-1.82 (4H, m), 1.83-1.93 (2H, m), 2.38 (1.2H, s), 2.41 (1.8H, s), 2.44-2.63 (3H, m), 2.65-2.71 (2H, m), 2.75-2.85 (1H, m), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.20-3.30 (1H, m), 3.33 (1.8H, s), 3.34 (1.2H, s), 3.46 -3.59 (3H, m), 3.79-3.85 (1H, m), 4.32 (0.4H, s), 4.42 (0.6H, s), 4.98-5 04 (1H, m), 5.06 (1H, d, J = 10.4 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.74 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 ( 1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 663 (M + H) ⁺ .

Example 122. (8E, 12E, 14E) -7 - (((1S, 4S) -5-Ethyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) carbonyl) oxy-3.16.21 -trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 122)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.05-1.13 (3H, m), 1.20-1.30 (4H, m), 1.34 ( 3H, s), 1.38-1.69 (7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.83-1.91 (2H, m), 2.45 -2.72 (8H, m), 2.82-2.93 (2H, m), 3.20-3.31 (1H, m), 3.33 (1.5H, s), 3.34 (1.5H, s), 3.50-3.64 (3H, m), 3.79-3.85 (1H, m), 4.32 (0.5H, s), 4.42 (0 , 5H, s), 4.98-5.04 (1H, m), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15 , 2 Hz), 5.74 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 677 (M + H) ⁺ .

Example 123. (8E, 12E, 14E) -3,16,21-Trihydroxy-7 - (((1S, 4S) -5-isopropyl-2,5-diazabicyclo [2.2.1] heptan-2-yl) carbonyl ) hydroxy-6-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 123)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.05-1.11 (6H, m), 1.19-1.30 (4H, m), 1.34 ( 3H, s), 1.37-1.69 (7H, m), 1.73-1.90 (5H, m), 2.45-2.65 (6H, m), 2.67 (1H, dd, J = 2.4, 8.0), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.01-3.20 (1H, m), 3.18- 3.29 (1H, m), 3.32-3.35 (3H, m), 3.52 (1H, td, J = 4.4, 8.4 Hz), 3.54-3.65 ( 1H, m), 3.76-3.86 (2H, m), 4.30 (0.5H, s), 4.40 (0.5H, s), 4.98-5.09 (2H, m), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.70-5.79 (1H, m), 5.87 (1H, d, J = 15.2 Hz ), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 691 (M + H) ⁺ .

Example 124. (8E, 12E, 14E) -7 - ((4- (2- (N, N-Dimethylamino) ethyl) piperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6-methoxy -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 124)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H, s), 1.37-1.69 ( 7H, m), 1.78 (3H, d, J = 0.8 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.27 (6H, s), 2.43-2.48 (4H, m), 2.48-2.62 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz), 2.89 ( 1H, dt, J = 2.0, 6.0 Hz), 3.32 (3H, s), 3.41-3.59 (5H, m), 3.78-3.85 (1H, m) 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz), 5.73 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10 8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 708 (M + H) ⁺ .

Example 125. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (1-methylpiperidin-4-yl) piperazin-1-yl) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 125)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.30 (4H, m), 1.34 (3H, s), 1.39-1.69 ( 9H, m), 1.78 (3H, d, J = 1.2 Hz), 1.83-1.90 (3H, m), 1.98-2.07 (2H, m), 2.24 -2.33 (1H, m), 2.25 (3H, s), 2.45-2.62 (7H, m), 2.67 (1H, dd, J = 2.4, 8.0 Hz ), 2.87-2.96 (3H, m), 3.32 (3H, s), 3.41-3.58 (5H, m), 3.79-3.86 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 10.0, 15.2 Hz ), 5.73 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1, 2, 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 734 (M + H) ⁺ .

Example 126. (8E, 12E, 14E) -3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (pyridin-4-yl) piperazin- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 126)

The title compound (colorless oil) was synthesized by a method similar to that described in example 85.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.19-1.29 (4H, m), 1.34 (3H, s), 1.38-1.69 ( 7H, m), 1.78 (3H, d, J = 1.2 Hz), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.45-2.63 (3H , m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.34 (3H, s), 3.40-3.47 (4H, m), 3.52 (1H, td, J = 4.4, 8.4 Hz), 3.56-3.72 (4H, m), 3 80-3.87 (1H, m), 5.05 (1H, d, J = 9.2 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.58 (1H, dd, J = 10.0, 15.2 Hz), 5.76 (1H, dd, J = 10.0, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz), 6.86 (2H, d, J = 6.4 Hz), 8.02-8.04 (2H, m); ESI-MS m / z 714 (M + H) ⁺ .

Example 127. (8E, 12E, 14E) -6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 127)

The title compound (colorless oil) was synthesized in a manner similar to that described in Example 85, except for using ethyl trifluoromethanesulfonate in the first step.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.16 (3H, t, J = 7.2 Hz), 1.22 (3H, s), 1.22-1 60 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J = 6.4, 14.0 Hz), 1.78 (3H, s), 1.86 ( 1H, dd, J = 5.6, 13.6 Hz), 2.30 (3H, s), 2.36-2.43 (4H, m), 2.43-2.69 (4H, m) , 2.89 (1H, dt, J = 2.4, 5.6 Hz), 3.43-3.61 (7H, m), 3.77-3.84 (1H, m), 4.98 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.55 (1H, dd, J = 10.0, 15.2 Hz), 5 7 6 (1H, dd, J = 9.6, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz ), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 128. (8E, 12E, 14E) -6-Ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-7 - ((4- (piperidin-1-yl) piperidin- 1-yl) carbonyl) oxy-18,19-epoxytricose-8,12,14-trien-11-olide (compound 128)

The title compound (colorless oil) was synthesized by a method similar to that described in example 127.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.0 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.17 (3H, t, J = 6.8 Hz), 1.22 (3H, s), 1.22-1 69 (16H, m), 1.34 (3H, s), 1.78 (3H, s), 1.83-1.93 (3H, m), 2.42-2.63 (8H, m ), 2.67 (1H, dd, J = 2.4, 7.6 Hz), 2.70-2.92 (3H, m), 3.49-3.62 (3H, m), 3, 77-3.84 (1H, m), 4.13-4.27 (2H, m), 4.98 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.54 (1H, dd, J = 10.0, 15.2 Hz), 5.76 (1H, dd, J = 9.6, 15.6 Hz), 5.86 ( 1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.0 Hz), 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 733 (M + H) ⁺ .

Example 129. (8E, 12E, 14E) -7-Acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis (triethylsiloxy) -18,19-epoxytricose-8, 12,14-trien-11-olide (compound 129)

Solution (8E, 12E, 14E) -7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11 -olide (221 mg, 0.4 mmol), N, N-dimethylaminopyridine (25 mg, 0.2 mmol) and triethylamine (613 mg, 6 mmol) in dichloromethane (7 ml) were cooled to 5 ° C, was added dropwise thereto a solution of chlorotriethylsilane (609 mg, 4 mmol) in dichloromethane (3 ml) and the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1: 9> 1: 4> 1: 3) to obtain the title compound (320 mg, quantitative) as a colorless oil .

ESI-MC m / z 803 (M + Na) ⁺ .

Example 130. (8E, 12E, 14E) -3,6,16-Trihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-21-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 130)

First stage

(8E, 12E, 14E) -7-Acetoxy-6,16-bis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,21-bis (triethylsiloxy) -18,19-epoxytricose- 8,12,14-trien-11-olide (compound 130-1)

To a solution of compound 129 (8E, 12E, 14E) -7-acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis (triethylsiloxy) -18,19-epoxytricose-8 , 12,14-trien-11-olide (320 mg, 0.41 mmol) obtained in Example 129, and ethyl vinyl ether (589 mg, 8 mmol) in dichloromethane (6 ml) were added a solution of pyridinium p-toluenesulfonate (5 mg, 20 μmol) in dichloromethane (1 ml) at room temperature and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1: 9 1: 7) to obtain the title compound (252 mg, 67%) as a colorless oil.

ESI-MC m / z 947 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -7-Acetoxy-6,16-bis (1-ethoxyethoxy) -3,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (compound 130-2)

A solution of compound 130-1 (8E, 12E, 14E) -7-acetoxy-6,16-bis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-3,21-bis (triethylsiloxy) -18 , 19-epoxytricose-8,12,14-trien-11-olide (107 mg, 0.1156 mmol) obtained in the first stage, in tetrahydrofuran (6 ml) was cooled to 5 ° C, tetrabutylammonium fluoride was added dropwise to it ( 1.0 M tetrahydrofuran solution, 0.25 ml, 0.25 mmol) and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1: 1> 2: 1) to obtain the title compound (81 mg, 100%) as a colorless oil.

ESI-MC m / z 719 (M + Na) ⁺ .

Third stage

(8E, 12E, 14E) -7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 130-3)

A solution of compound 130-2 (8E, 12E, 14E) -7-acetoxy-6,16-bis (1-ethoxyethoxy) -3,21-dihydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-trien-11-olide (33.2 mg, 47.6 μmol) obtained in the second stage, N, N-dimethylaminopyridine (3 mg, 23.8 μmol) and triethylamine (49 mg, 0.476 mmol) in dichloromethane (1 ml) was cooled to -20 ° C, diethylisopropylsilyl chloride (10.3 mg, 59.5 μmol) was added dropwise and the reaction mixture was stirred at a temperature of from -20 ° C to 5 ° C for 1.2 hours. Then, diethylisopropylsilyl chloride (31 mg, 179 μmol) was added dropwise to the reaction mixture at the same temperature, followed by stirring for 4.5 hours. Diethylisopropylsilyl chloride (41.2 mg, 238 μmol) was added dropwise to the reaction mixture at the same temperature, followed by stirring for 1.3 hours and then stirring at room temperature for one hour. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by thin layer chromatography (Merck Art 1,05628; ethyl acetate-hexane, 1: 2) to obtain the title compound (19.1 mg, 49%) as a colorless oil.

ESI-MC m / z 847 (M + Na) ⁺ .

Fourth stage

(8E, 12E, 14E) -7-Acetoxy-3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 130-4)

A solution of compound 130-3 (8E, 12E, 14E) -7-acetoxy-3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-hydroxy-6,10,12,16,20-pentamethyl-18, 19-epoxytricose-8,12,14-triene-11-olide (33.2 mg, 40 μmol) obtained in the third stage, and 1,8-bis (N, N-dimethylamino) naphthalene (51.4 mg, 0.24 mmol) in toluene (), 7 ml) was cooled to 5 ° C and methyl trifluoromethanesulfonate (20 mg, 0.12 mmol) was added dropwise to the reaction mixture, followed by 0.5 ml of toluene. The reaction mixture was stirred at 50 ° C for 12.5 hours. The reaction mixture was cooled to room temperature, diluted with toluene, and 0.06 N was added at 5 ° C. aqueous ammonia (5 ml), followed by stirring at room temperature for about 20 minutes. Ethyl acetate, water and a saturated aqueous solution of ammonium chloride were added to the mixture, the mixture was stirred for some time and the organic layer was separated. The organic layer was washed successively with 0.05 M aqueous citric acid and aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1: 9> 1: 7> 1: 4> 1: 3) to obtain the title compound (15.8 mg, 47%) as a colorless oil.

ESI-MC m / z 861 (M + Na) ⁺ .

Fifth stage

(8E, 12E, 14E) -3-Diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 130-5)

To compound 130-4 (8E, 12E, 14E) -7-acetoxy-3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-methoxy-6,10,12,16,20-pentamethyl-18, The 19-epoxytricose-8,12,14-trien-11-olide (21.5 mg, 25.6 μmol) obtained in the fourth step was added a 0.2 M solution of guanidine / guanidine nitrate (methanol-dichloromethane mixture, 9: 1) (0.26 ml, 52 μmol), followed by stirring at room temperature for 12.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of ammonium chloride, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 1: 7> 1: 5> 1: 4) to obtain the title compound (19.3 mg, 95%) in colorless oil.

ESI-MC m / z 819 (M + Na) ⁺ .

Sixth stage

(8E, 12E, 14E) -3-Diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-methoxy-6,10,12,16,20-pentamethyl-7- (4-nitrophenoxy) carboxy-18, 19-epoxytricose-8,12,14-triene-11-olide (compound 130-6)

A solution of compound 130-5 (8E, 12E, 14E) -3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -7-hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18, 19-epoxytricose-8,12,14-triene-11-olide (19.3 g, 24.2 μmol) obtained in the fifth stage, N, N-dimethylaminopyridine (3 mg, 24.2 μmol) and triethylamine (25 mg, 0.242 mmol) in dichloromethane (1.2 ml) was cooled to 5 ° C, a solution of 4-nitrophenylchloroformate (25 mg, 121 μmol) in dichloromethane (0.3 ml) was added dropwise and then the resulting mixture was stirred at room temperature temperature for three hours. The reaction mixture was diluted with ethyl acetate and then washed with aqueous sodium bicarbonate. Then, the organic layer was washed successively with an aqueous solution of ammonium chloride, an aqueous solution of sodium bicarbonate and water in this order. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give the title compound (40.7 mg) as a pale yellow solid.

The resulting solid was subjected to a subsequent reaction without purification.

Seventh stage

(8E, 12E, 14E) -3-Diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-21-methoxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 130-7)

A solution of the crude compound 130-6 (8E, 12E, 14E) -3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -21-methoxy-7- (4-nitrophenoxy) carboxy-6,10,12,16, The 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (20.4 mg, 12.1 μmol) obtained in the sixth stage in tetrahydrofuran (0.9 ml) was cooled to 5 ° C and a solution of 1-isopropylpiperazine (2.4 mg, 18.2 μmol) in tetrahydrofuran (0.1 ml) and triethylamine (3.7 mg, 36.3 μmol) was added dropwise thereto, followed by stirring at room temperature in within 6.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel plate; 1: 3 ethyl acetate-hexane mixture) to give the title compound (10.0 mg, 87%, two steps) as a colorless oil.

ESI-MC m / z 951 (M + H) ⁺ .

Eighth stage

(8E, 12E, 14E) -6.16-Bis (1-ethoxyethoxy) -3-hydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-21-methoxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide (compound 130-8)

A solution of compound 130-7 (8E, 12E, 14E) -3-diethylisopropylsiloxy-6,16-bis (1-ethoxyethoxy) -7 - ((4-isopropylpiperazin-1-yl) carbonyl) oxy-21-methoxy-6, 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (10 mg, 10.5 μmol) obtained in the seventh stage in tetrahydrofuran (1.0 ml) cooled to 5 ° C. and tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 11.6 μl, 11.6 μmol) was added dropwise thereto, followed by stirring at room temperature for 1.5 hours. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by thin layer chromatography (Merck Art 1,05628; methanol-dichloromethane, 1:29) to obtain the title compound (7.4 mg, 86%) as a colorless oil.

ESI-MC m / z 823 (M + H) ⁺ .

Ninth stage

(8E, 12E, 14E) -3,6,16-Trihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-21-methoxy-6,10,12,16,20-pentamethyl-18, 19-epoxytricose-8,12,14-triene-11-olide (compound 130)

To a solution of compound 130-8 (8E, 12E, 14E) -6,16-bis (1-ethoxyethoxy) -3-hydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) oxy-21-methoxy-6 , 10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (7.4 mg, 9 μmol) obtained in the eighth stage, in a mixture of tetrahydrofuran: 2-methyl -2-propanol = 1: 1 (0.7 ml) was added pyridinium p-toluenesulfonate (6.8 mg, 27 μmol), followed by stirring at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by thin layer chromatography (Fuji Silysia, NH Silica gel plate, methanol: dichloromethane = 1: 39) to give the title compound (4.2 mg, 69%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.2 Hz), 0.88 (3H, t, J = 7, 6 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.07 (6H, d, J = 6.4 Hz), 1.21 (3H, s), 1.28-1 70 (11H, m), 1.77 (3H, d, J = 1.2 Hz), 1.85 (1H, dd, J = 5.2, 14.0 Hz), 2.47-2, 62 (7H, m), 2.64 (1H, dd, J = 2.4, 8.0 Hz), 2.67-2.74 (1H, m), 2.88 (1H, dt, J = 2.4, 6.0 Hz), 3.14-3.19 (1H, m), 3.38 (3H, s), 3.42-3.70 (4H, m), 3.75-3 82 (1H, m), 4.93 (1H, d, J = 10.0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 ( 1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 131. (8E, 12E, 14E) -3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 131)

The title compound (colorless oil) was synthesized by a method similar to that described in example 130.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.2 Hz), 0.88 (3H, t, J = 7, 6 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.21 (3H, s), 1.29-1.70 (11H, m), 1.77 (3H, d, J = 1.2 Hz), 1.85 (1H, dd, J = 5.2, 14.0 Hz), 2.30 (3H, s), 2.35-2.63 (7H, m), 2.64 (1H, dd, J = 2.4, 8.0 Hz), 2.88 (1H, dt, J = 2.4, 6.0 Hz), 3.14-3.20 (1H, m), 3.38 (3H, s), 3.39-3.71 (4H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 10, 0 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, dd, J = 1.2, 10.8 Hz), 6.53 ( 1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 651 (M + H) ⁺ .

Example 132. (8E, 12E, 14E) -3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 132)

The title compound (colorless oil) was synthesized by a method similar to that described in example 130.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.2 Hz), 0.88 (3H, t, J = 7, 6 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.22 (1.2H, s), 1.23 (1, 8H, s), 1.28-1.71 ( 11H, m), 1.77 (3H, d, J = 0.8 Hz), 1.81-1.93 (3H, m), 2.34 (1.2H, s), 2.35 (1 , 8H, s), 2.50-2.67 (8H, m), 2.88 (1H, dt, J = 2.0, 6.0 Hz), 3.14-3.20 (1H, m ), 3.38 (3H, s), 3.47-3.56 (2H, m), 3.58-3.67 (2H, m), 3.75-3.82 (1H, m), 4.95 (1H, d, J = 10.0 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz ), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11, 2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 665 (M + H) ⁺ .

Example 133. (8E, 12E, 14E) -7 - ((4-Ethyl homopiperazin-1-yl) carbonyl) hydroxy-3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 133)

The title compound (colorless oil) was synthesized by a method similar to that described in example 130.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 7.2 Hz), 0.88 (3H, t, J = 7, 6 Hz), 0.89 (3H, d, J = 6.8 Hz), 1.08 (1.5H, t, J = 7.2 Hz), 1.09 (1.5H, t, J = 7.2 Hz), 1.22 (1.5H, s), 1.23 (1.5H, s), 1.28-1.70 (11H, m), 1.77 (3H, d, J = 1.2 Hz), 1.82-1.91 (3H, m), 2.47-2.76 (10H, m), 2.88 (1H, dt, J = 2.4, 6.0 Hz), 3.14-3.19 (1H, m), 3.38 (3H, s), 3.45-3.67 (4H, m), 3.75-3.82 (1H, m) 4.95 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.8 Hz), 5.57 (1H, dd, J = 9.6, 15.2 Hz), 5.73 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11 , 2 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 134. (8E, 12E, 14E) -7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy -18.19-epoxytricose-8,12,14-trien-11-olide (compound 134)

First stage

(8E, 12E, 14E) -7-Acetoxy-6,10,12,16,20-pentamethyl-6- (4-nitrophenoxy) carboxy-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose- 8,12,14-trien-11-olide (compound 134-1)

To a solution of compound 46-1 (8E, 12E, 14E) -7-acetoxy-6-hydroxy-6,10,12,16,20-pentamethyl-3,16,21-tris (triethylsiloxy) -18,19-epoxytricose -8,12,14-trien-11-olide (44 mg, 49 μmol) obtained in the first step of Example 46, triethylamine (30 mg, 0.29 mmol), N, N was added in dichloromethane (2.0 ml) -dimethylaminopyridine (90 mg, 0.73 mmol) and 4-nitrophenylchloroformate (90 mg, 0.44 mmol) under ice-cooling, and the reaction mixture was stirred at room temperature under nitrogen for three days. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 10: 90) to obtain the title compound (19 mg, 36%) as a colorless oil.

ESI-MC m / z 1082 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -7-Acetoxy-6,10,12,16,20-pentamethyl-6 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-tris (triethylsiloxy) -18.19-epoxytricose-8,12,14-trien-11-olide (compound 134-2)

To a solution of compound 134-1 (8E, 12E, 14E) -7-acetoxy-6,10,12,16,20-pentamethyl-6- (4-nitrophenyl) carboxy-3,16,21-tris (triethylsiloxy) - 18.19-epoxytricose-8,12,14-trien-11-olide (9 mg, 8.5 μmol) obtained in the first step, triethylamine (8 mg, 85 μmol) and 1- were added in tetrahydrofuran (1 ml) methylpiperazine (1.7 mg, 17 μmol) at room temperature, followed by stirring at the same temperature in a nitrogen atmosphere for 4 hours. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 50:50) to obtain the title compound (8.6 mg, 100%) as a colorless oil.

ESI-MC m / z 1021 (M + H) ⁺ .

Third stage

(8E, 12E, 14E) -7-Acetoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-6 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-triene-11-olide (compound 134)

To a solution of compound 134-2 (8E, 12E, 14E) -7-acetoxy-6,10,12,16,20-pentamethyl-6 - ((4-methylpiperazin-1-yl) carbonyl) oxy-3.16, 21-Tris (triethylsiloxy) -18,19-epoxytricose-8,12,14-triene-11-olide (9 mg, 8.5 μmol) obtained in the second stage, tetrabutylammonium fluoride (1 ml) was added in tetrahydrofuran (1 ml) A 0 M tetrahydrofuran solution, 48 μl, 48 μmol) at room temperature and the reaction mixture was stirred at the same temperature in a nitrogen atmosphere for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; methanol: dichloromethane = 5: 95) to obtain the title compound (4.4 mg, 77%) as a colorless oil.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (6H, d, J = 6.8 Hz), 0.94 (3H, t, J = 7, 2 Hz), 1.20-1.28 (1H, m), 1.34 (3H, s), 1.38-1.70 (10H, m), 1.78 (3H, s), 1, 86 (1H, dd, J = 5.2, 14.0 Hz), 2.04 (3H, s), 2.31 (3H, s), 2.38-2.48 (4H, m), 2 , 48-2.52 (2H, m), 2.56-2.65 (1H, m), 2.66 (1H, dd, J = 2.0, 7.6 Hz), 2.89 (1H , dt, J = 2.0, 6.4 Hz), 3.42-3.62 (5H, m), 3.76-3.84 (1H, m), 5.01 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.8 Hz), 5.63 (1H, dd, J = 9.6, 15.2 Hz), 5.75 (1H, dd , J = 9.2, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 10.8 Hz), 6.52 (1H dd, J = 10.8, 15.2 Hz); ESI-MS m / z 679 (M + H) ⁺ .

Example 135. (8E, 12E, 14E) -7-Acetoxy-6 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 135)

The title compound (colorless oil) was synthesized by a method similar to that described in example 134.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.22-1.32 (1H, m), 1.34 (3H, m), 1.40-1.78 ( 20H, m), 1.79 (3H, s), 1.82-1.93 (3H, m), 2.05 (3H, s), 2.39-2.47 (1H, m), 2 50 (2H, d, J = 3.6 Hz), 2.54-2.66 (6H, m), 2.89 (1H, dt, J = 2.0, 6.4 Hz), 3, 37-3.64 (5H, m), 3.76-3.83 (1H, m), 5.07 (1H, d, J = 10.8 Hz), 5.15 (1H, d, J = 9.2 Hz), 5.63 (1H, dd, J = 9.2, 15.2 Hz), 5.71 (1H, dd, J = 9.2, 15.2 Hz), 5.87 ( 1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 761 (M + H) ⁺ .

Example 136. (8E, 12E, 14E) -7-Acetoxy-6 - ((4-ethylhomopiperazin-1-yl) carbonyl) hydroxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl -18.19-epoxytricose-8,12,14-trien-11-olide (compound 136)

The title compound (colorless oil) was synthesized by a method similar to that described in example 134.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (6H, d, J = 7.2 Hz), 0.94 (3H, t, J = 7, 2 Hz), 1.08 (3H, t, J = 7.2 Hz), 1.20-1.28 (1H, m), 1.34 (3H, s), 1.38-1.70 ( 10H, m), 1.78 (3H, s), 1.83-1.91 (3H, m), 2.03 (3H, s), 2.33-2.42 (1H, m), 2 50 (2H, d, J = 3.9 Hz), 2.58-2.80 (7H, m), 2.89 (1H, dt, J = 2.4, 6.4 Hz), 3, 45-3.65 (5H, m), 3.75-3.84 (1H, m), 5.02 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.63 (1H, dd, J = 9.6, 15.2 Hz), 5.76 (1H, dd, J = 9.6, 15.6 Hz), 5.87 ( 1H, d, J = 15.6 Hz), 6.14 (1H, d, J = 11.2 Hz), 6.53 (1H, dd, J = 11.2, 15.6 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Example 137. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7- (N-isopropylthiocarbamoyloxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (compound 137)

First stage

(8E, 12E, 14E) -3,6,16,21-Tetrakis (1-ethoxyethoxy) -7- (N-isopropylthiocarbamoyloxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8 , 12,14-trien-11-olide (compound 137-1)

To a suspension of sodium hydride (60% oil dispersion, 2 mg, 0.052 mmol) in tetrahydrofuran (0.5 ml) was added dropwise a solution of (8E, 12E, 14E) -3,6,16,21-tetra (1-ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (19 mg, 0.019 mmol) obtained in Example 3- (2) in tetrahydrofuran (0.5 ml) under ice-cooling and stirring, and the reaction mixture was stirred at room temperature for 10 minutes. Then isopropylisothiocyanate (6.6 mg, 0.066 mmol) was added dropwise to the mixture, and the reaction mixture was stirred at room temperature for three hours. Water was added to the reaction mixture under ice-cooling to terminate the reaction, after which the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 25: 75) to obtain the title compound (10 mg, 60%) as a colorless oil.

ESI-MC m / z 922 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-7- (N-isopropylthiocarbamoyloxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14- trien-11-olide (compound 137)

The title compound (colorless oil) was obtained by a method similar to that described in example 3-5.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.89 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.14-1.69 (20H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.48-2.60 (3H, m), 2.66 (1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H , dt, J = 2.0, 6.0 Hz), 3.49-4.08 (1H, m), 3.73-3.83 (1H, m), 4.23-4.34 (1H , m), 4.95 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.60-5.92 (3H, m), 6 13 (1H, d, J = 10.8 Hz); 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 634 (M + Na) ⁺ .

Example 138. (8E, 12E, 14E) -7- (N-Butylthiocarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (compound 138)

The title compound (colorless oil) was obtained by a method similar to that described in example 137.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.937 (3H, t, J = 7.2 Hz), 0.942 (3H, t, J = 7.2 Hz), 1.19 (3H, s), 1.19-1.69 (15H , m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.49-2.62 (3H, m), 2.66 ( 1H, dd, J = 2.0, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.42-3.57 (3H, m), 3 , 73-3.83 (1H, m), 4.95 (1H, d, J = 9.6 Hz), 5.07 (1H, d, J = 10.4 Hz), 5.62-5, 92 (3H, m), 6.14 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 648 (M + Na) ⁺ .

Example 139. (8E, 12E, 14E) -7- (N- (3- (N ', N'-Diethylamino) propyl) thiocarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 139)

The title compound (colorless oil) was obtained by a method similar to that described in example 137.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.14 (6H, t, J = 6.8 Hz), 1.19 (3H, s), 1.21-1 69 (13H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.48-2.61 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 3.70-3.86 (6H, m), 2.89 (1H, dt, J = 2.4, 5.6 Hz), 3.44-3.58 (3H, m), 3.75-3.83 (1H, m), 4.96 (1H, d, J = 8.4 Hz), 5.07 (1H d, J = 10.4 Hz), 5.64-5.92 (3H, m), 6.14 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 683 (M + H) ⁺ .

Example 140. (8E, 12E, 14E) -7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene -11-olide (compound 140)

First stage

(8E, 12E, 14E) -7-Benzoyloxy-3,6,16,21-tetrakis (1-ethoxyethoxy) -6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14 -trien-11-olide (compound 140-1)

To a solution of (8E, 12E, 14E) -3,6,16,21-tetrakis (1-ethoxyethoxy) -7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12 , 14-trien-11-olide (10 mg, 12.5 μmol) obtained in Example 3-2, N, N-dimethylaminopyridine (8 mg, 62.5 μmol) and benzyl chloride were added in pyridine (0.5 ml) (17.6 mg, 125 μmol) at room temperature and the reaction mixture was stirred at the same temperature in a nitrogen atmosphere for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate: hexane = 25: 75) to obtain the title compound (6 mg, 55%) as a colorless oil.

ESI-MC m / z 925 (M + Na) ⁺ .

Second stage

(8E, 12E, 14E) -7-Benzoyloxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11- olide (compound 140)

The title compound (colorless oil) was obtained by a method similar to that described in example 3-5.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.89 (3H, d, J = 7, 2 Hz), 0.93 (3H, t, J = 7.2 Hz), 1.20-1.76 (14H, m), 1.78 (3H, s), 1.86 (1H, dd, J = 5.6, 14.0 Hz), 2.53-2.64 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H , dt, J = 2.4, 5.6 Hz), 3.52 (1H, dt, J = 4.8, 8.0 Hz), 3.78-3.85 (1H, m), 5, 09 (1H, d, J = 10.8 Hz), 5.29 (1H, d, J = 9.6 Hz), 5.69 (1H, dd, J = 9.6, 15.2 Hz), 5.83 (1H, dd, J = 9.6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 10.4 Hz ), 6.53 (1H, dd, J = 10.8, 15.2 Hz), 7.47 (2H, dd, J = 7.6, 7.6 Hz), 7.60 (1H, dd, J = 7.6, 7.6 Hz), 8.12 (2H, d, J = 7.6 Hz); ESI-MS m / z 637 (M + Na) ⁺ .

Example 141. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-propanoyloxy-18,19-epoxytricose-8,12,14-triene -11-olide (compound 141)

The title compound (colorless oil) was obtained by a method similar to that described in example 140.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 0.89 (3H, d, J = 7, 2 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.11 (3H, t, J = 8.0 Hz), 1.18 (3H, s), 1.22-1 68 (11H, m), 1.77 (3H, s), 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.28-2.45 (2H, m), 2.50-2.61 (3H, m), 2.66 (1H, dd, J = 2.4, 8.0 Hz), 2.89 (1H, dt, J = 2.0, 6.0 Hz), 3.52 (1H, dt, J = 4.8, 8.0 Hz), 3.75-3.82 (1H, m), 4.95 (1H, d, J = 9.6 Hz ), 5.05 (1H, d, J = 9.6 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.70 (1H, dd, J = 9, 6, 15.2 Hz), 5.87 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 589 (M + Na) ⁺ .

Example 142. (8E, 12E, 14E) -3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7- (3-phenylpropanoyl) oxy-18,19-epoxytricose-8, 12,14-trien-11-olide (compound 142)

The title compound (colorless oil) was obtained by a method similar to that described in example 140.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.86 (3H, d, J = 6.8 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.2 Hz), 1.09 (3H, s), 1.20-1.69 (11H, m), 1.77 (3H, s) 1.86 (1H, dd, J = 5.2, 14.0 Hz), 2.46-2.59 (3H, m), 2.62-2.70 (3H, m), 2.85 -2.96 (3H, m), 3.48-3.56 (1H, m), 3.72-3.80 (1H, m), 5.03 (1H, d, J = 9.2 Hz ), 5.05 (1H, d, J = 10.8 Hz), 5.54 (1H, dd, J = 9.6, 15.2 Hz), 5.66 (1H, dd, J = 9, 2, 15.2 Hz), 5.87 (1H, d, J = 14.8 Hz), 6.13 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 14.8 Hz), 7.12-7.28 (5H, m); ESI-MS m / z 665 (M + Na) ⁺ .

Example 143. (8E, 12E, 14E) -7- (Hexanoyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12, 14-trien-11-olide (compound 143)

The title compound (colorless oil) was obtained by a method similar to that described in example 140.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.76-0.83 (9H, m), 0.98 (3H, t, J = 7.2 Hz) , 1.23 (3H, s), 1.24-1.74 (17H, m), 1.82 (3H, br s), 1.91 (1H, dd, J = 5.6, 14, 4 Hz), 2.32-2.44 (2H, m), 2.52-2.69 (3H, m), 2.71 (1H, dd, J = 2.4, 8.0 Hz), 2.94 (1H, dt, J = 2.4, 6.0 Hz), 3.53-3.60 (1H, m), 3.78-3.86 (1H, m), 5.10 ( 1H, d, J = 9.6 Hz), 5.11 (1H, d, J = 9.6 Hz), 5.61 (1H, dd, J = 9.6, 15.2 Hz), 5, 74 (1H, dd, J = 9.6, 15.2 Hz), 5.91 (1H, d, J = 15.2 Hz), 6.18 (1H, d, J = 11.2 Hz), 6.57 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 631 (M + Na) ⁺ .

Example 144. (8E, 12E, 14E) -7,21-Diacetoxy-3,6,16-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene -11-olide (compound 144-1) and 8E, 12E, 14E) -3,7,21-triacetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose- 8,12,14-trien-11-olide (compound 144-2)

Compound 144-1

Compound 144-2

Solution (8E, 12E, 14E) -7-acetoxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-triene-11 -olide (276 mg, 0.5 mmol), N, N-dimethylaminopyridine (31 mg, 0.25 mmol) and triethylamine (256 mg, 2.5 mmol) in dichloromethane (15 ml) were cooled to -20 ° C, a solution of acetic anhydride (53 mg, 0.5 mmol) in dichloromethane (2 ml) was added dropwise thereto over 30 minutes, and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1 ml) was added dropwise to the reaction mixture over 30 minutes, after which the reaction mixture was stirred at the same temperature for 2.5 hours. Then again, a solution of acetic anhydride (10.5 mg, 0.1 mmol) in dichloromethane (1 ml) was added dropwise to the reaction mixture over 30 minutes, after which the mixture was stirred at the same temperature for 30 minutes. A solution of acetic anhydride (21 mg, 0.2 mmol) in dichloromethane (1 ml) was added dropwise to the reaction mixture over 5 minutes, followed by stirring at the same temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The obtained residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-50 μm; ethyl acetate-hexane, 2: 1 3: 1 4: 1 9: 1) to give the residue 144-1 as a colorless oil and a compound 144-2 (67.7 mg, 21%) as colorless crystals. The residue of compound 144-1 was then purified by thin layer chromatography (Merck Art 1.13792; ethyl acetate-hexane, 8: 1 9: 1) to give compound 144-1 (214.3 mg, 72%) as a colorless oil.

Compound 144-1

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87 (3H, t, J = 7.6 Hz), 0.88 (3H, d, J = 7, 2 Hz), 0.92 (3H, d, J = 6.8 Hz), 1.18 (3H, s), 1.31-1.68 (11H, m), 1.77 (3H, d, J = 0.8 Hz), 1.82 (1H, dd, J = 5.2, 14.0 Hz), 2.05 (3H, s), 2.06 (3H, s), 2.46- 2.63 (4H, m), 2.88 (1H, dt, J = 2.0, 6.0 Hz), 3.75-3.81 (1H, m), 4.84-4.92 ( 1H, overlapped H ₂ O), 5.04 (1H, d, J = 9.6 Hz), 5.05 (1H, d, J = 10.8 Hz), 5.56 (1H, dd, J = 9.6, 15.2 Hz), 5.70 (1H, dd, J = 9.6, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 ( 1H, d, J = 11.2 Hz); 6.52 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 617 (M + Na) ⁺ .

Compound 144-2

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87 (3H, t, J = 7.6 Hz), 0.89 (3H, d, J = 6, 8 Hz), 0.91 (3H, d, J = 6.8 Hz), 1.18 (3H, s), 1.33 (3H, s), 1.34-1.73 (8H, m) 1.77 (3H, d, J = 0.8 Hz), 1.83 (1H, dd, J = 5.6, 14.0 Hz), 2.04 (3H, s), 2.05 ( 3H, s), 2.06 (3H, s), 2.53-2.68 (4H, m), 2.88 (1H, dt, J = 2.0, 6.0 Hz), 4.78 -4.96 (2H, overlapped H ₂ O), 4.99 (1H, d, J = 10.4 Hz), 5.02 (1H, d, J = 9.6 Hz), 5.57 (1H dd, J = 9.6, 15.2 Hz), 5.72 (1H, dd, J = 9.6, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz) 6.14 (1H, dd, J = 1.2, 10.8 Hz); 6.52 (1H, dd, J = 11.2, 15.2 Hz); ESI-MS m / z 659 (M + Na) ⁺ .

Example 145. (8E, 12E, 14E) -21-Acetoxy-3,6,16-trihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl -18,19-epoxytricose-8,12,14-trien-11-olide (compound 145-1) and (8E, 12E, 14E) -3,21-diacetoxy-6,16-dihydroxy-7 - ((4 isopropylpiperazin-1-yl) carbonyl) oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide (compound 145-2)

Compound 145-1

Compound 145-2

The title compounds (each is a colorless oil) were synthesized by a method similar to that described in example 144, except for using compound 44 obtained in example 44.

Compound 145-1

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.91 (3H, t, J = 7.2 Hz), 0.93 (3H, d, J = 6, 8 Hz), 0.96 (3H, d, J = 7.2 Hz), 1.12 (6H, d, J = 6.4 Hz), 1.26 (3H, s), 1.30-1 56 (6H, m), 1.58-1.76 (5H, m), 1.82 (3H, s), 1.87 (1H, dd, J = 5.6, 14.0 Hz), 2.10 (3H, s), 2.48-2.70 (8H, m), 2.70-2.82 (1H, m) 2.93 (1H, dt, J = 2.0, 5, 6 Hz), 3.44-3.76 (4H, m), 3.78-3.88 (1H, m), 4.86-4.98 (1H, overlapped H ₂ O), 4.97 ( 1H, d, J = 9.6 Hz), 5.10 (1H, d, J = 10.8 Hz), 5.62 (1H, dd, J = 10.0, 15.2 Hz), 5, 76 (1H, dd, J = 9.6, 15.2 Hz), 5.90 (1H, d, J = 15.2 Hz), 6.18 (1H, d, J = 10.8 Hz), 6.57 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 707 (M + H) ⁺ .

Compound 145-2

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.91 (3H, t, J = 7.6 Hz), 0.93 (3H, d, J = 6, 8 Hz), 0.96 (3H, d, J = 7.2 Hz), 1.12 (6H, d, J = 6.4 Hz), 1.25 (3H, s), 1.30-1 92 (15H, m), 2.088 (3H, s), 2.094 (3H, s), 2.50-2.80 (9H, m), 2.93 (1H, dt, J = 2.0, 6 , 0 Hz), 3.40-3.76 (4H, m), 4.80-4.96 (2H, overlapped H ₂ O), 4.96 (1H, d, J = 9.6 Hz), 5.04 (1H, d, J = 10.8 Hz), 5.63 (1H, dd, J = 10.0, 15.2 Hz), 5.78 (1H, dd, J = 9.6, 15.2 Hz), 5.91 (1H, d, J = 15.2 Hz), 6.18 (1H, d, J = 10.8 Hz), 6.56 (1H, dd, J = 10, 8, 15.2 Hz); ESI-MS m / z 749 M ⁺ .

Example 146. (8E, 12E, 14E) -6,16-Dihydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-3,21-dioxo -18,19-epoxytricose-8,12,14-triene-11-olide (compound 146-1) and (8E, 12E, 14E) -3,6,16-trihydroxy-7 - ((4-isopropylpiperazin-1 -yl) carbonyl) oxy-6,10,12,16,20-pentamethyl-21-oxo-18,19-epoxytricose-8,12,14-trien-11-olide (compound 146-2)

Compound 146-1

Compound 146-2

To a solution of compound 44 (20 mg, 30 μmol) obtained in Example 44 in dichloromethane (2.0 ml) was added Dess-Martin reagent (43 mg, 0.101 mmol) under ice-cooling and stirring, and the reaction mixture was stirred at room temperature in nitrogen atmosphere for six hours. The reaction mixture was diluted with ethyl acetate and then washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; dichloromethane: methanol = 95: 5 90:10) to obtain the title compounds: compounds 146-1 (9.6 mg, 48%) and Compounds 146-2 (8.9 mg, 45%) each as a colorless oil.

Compound 146-1

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.91 (3H, d, J = 6.8 Hz), 1.00 (3H, t, J = 7, 2 Hz), 1.07 (3H, d, J = 7.2 Hz), 1.10 (6H, d, J = 6.4 Hz), 1.30 (3H, s), 1.33 (3H , s), 1.63 (1H, dd, J = 6.8, 14.4 Hz), 1.74-1.80 (1H, m), 1.80 (3H, s), 1.89 ( 1H, dd, J = 5.6, 14.4 Hz), 2.00-2.08 (1H, m), 2.28-2.37 (1H, m), 2.46 (2H, d, J = 12.4 Hz), 2.52-2.70 (7H, m), 2.72-2.84 (3H, m), 2.92 (1H, dt, J = 2.0, 6, 4 Hz), 3.31-3.33 (1H, m), 3.42-3.64 (4H, m), 4.94 (1H, d, J = 8.0 Hz), 4.96 ( 1H, d, J = 10.8 Hz), 5.23 (1H, dd, J = 8.8, 15.6 Hz), 5.50 (1H, dd, J = 8.4, 15.6 Hz ), 5.86 (1H, d, J = 15.2 Hz), 6.10 (1H, d, J = 10.8 Hz), 6.54 (1H, dd, J = 10.8, 15, 2 Hz); ESI-MS m / z 661 (M + H) ⁺ , 683 (M + Na) ⁺ .

Compound 146-2

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.88 (3H, d, J = 6.8 Hz), 1.00 (3H, t, J = 7, 2 Hz), 1.07 (3H, d, J = 6.8 Hz), 1.10 (6H, d, J = 7.2 Hz), 1.21 (3H, s), 1.38-1 , 42 (5H, m), 1.54-1.68 (3H, m), 1.77 (3H, s), 1.89 (1H, dd, J = 4.8, 14.0 Hz), 2.28-2.36 (1H, m), 2.50-2.64 (8H, m), 2.75 (1H, dd, J = 2.0, 8.4 Hz), 2.76- 2.84 (1H, m), 2.91 (1H, dt, J = 2.4, 7.6 Hz), 3.31-3.33 (1H, m), 3.42-3.64 ( 4H, m), 3.75-3.82 (1H, m), 4.93 (1H, d, J = 9.6 Hz), 5.06 (1H, d, J = 10.4 Hz), 5.57 (1H, dd, J = 10.0, 15.2 Hz), 5.72 (1H, dd, J = 10.0, 15.2 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.14 (1H, d, J = 10.8 Hz), 6.53 (1H, dd, J = 10.8, 15.2 Hz); ESI-MS m / z 663 (M + H) ⁺ , 685 (M + Na) ⁺ .

Example 147. (8E, 12E, 14E) -7-Acetoxy-6-ethoxy-3,16,21-trihydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricose-8,12,14 -trien-11-olide (compound 147)

The title compound (colorless oil) was synthesized by a method similar to that described in example 43, except for the use of ethyl trifluoromethanesulfonate.

¹ H-NMR spectrum (CD ₃ OD, 400 MHz) δ (ppm): 0.87 (3H, d, J = 6.4 Hz), 0.90 (3H, d, J = 6, 8 Hz), 0.94 (3H, t, J = 7.6 Hz), 1.17 (3H, t, J = 7.2 Hz), 1.20 (3H, s), 1.22-1 60 (7H, m), 1.34 (3H, s), 1.65 (1H, dd, J = 6.4, 14.0 Hz), 1.78 (3H, s), 1.86 ( 1H, dd, J = 5.2, 14.0 Hz), 2.04 (3H, s), 2.44-2.68 (4H, m), 2.89 (1H, dt, J = 2, 4, 5.2 Hz), 3.49-3.66 (3H, m), 3.77-3.84 (1H, m), 5.06 (1H, d, J = 10.4 Hz), 5.10 (1H, d, J = 9.6 Hz), 5.55 (1H, dd, J = 9.6, 15.6 Hz), 5.75 (1H, dd, J = 10.0, 15.6 Hz), 5.86 (1H, d, J = 15.2 Hz), 6.13 (1H, d, J = 11.2 Hz), 6.52 (1H, dd, J = 11, 2, 15.6 Hz); ESI-MS m / z 603 (M + Na) ⁺ .

Formulation Examples

The following are examples of the manufacture of dosage forms from compounds of the present invention, but these examples do not limit the manufacture of dosage forms from compounds of the present invention.

Formulation Example 1

The compound of example 44 45 (parts)

Heavy Magnesium Oxide 15

Lactose 75

were subjected to homogeneous mixing with the formation of a powdered drug in the form of a powder or fine granules with a size of 350 microns or less. The powdered drug was loaded into capsules to provide an encapsulated dosage form.

Formulation Example 2

The compound of example 75 45 (parts)

Starch 15

Lactose 16

Crystalline Cellulose 21

Polyvinyl alcohol 3

Distilled water 30

were subjected to homogeneous mixing, spraying, granulating, drying and then sieving with the formation of granules with a size of 1410-177 microns.

Formulation Example 3

Having obtained the granules in a manner similar to that described in Example 2 for the manufacture of dosage forms, 4 parts of calcium stearate were added to 96 parts of the granules, pressed and molded to obtain tablets with a diameter of 10 mm.

Formulation Example 4

To 90 parts of the granules obtained by the method of Example 2 for the manufacture of dosage forms, 10 parts of crystalline cellulose and 3 parts of calcium stearate were added, pressed and molded to obtain tablets with a diameter of 8 mm. A mixed suspension of syrup, gelatin and precipitated calcium carbonate was then applied to them, resulting in sugar coated tablets.

Formulation Example 5

Compound of Example 45 0.6 (parts)

Nonionic surfactant 2.4

Isotonic Sodium Chloride 97

heated, mixed and loaded into the ampoule, the ampoule was sterilized to obtain an injectable dosage form.

Reference Examples

Compounds were obtained by the following three-step synthesis.

Reference Example 1-1

Benzyl 4- (cyclopropylcarbonyl) piperazine-1-carboxylate

Benzyl 1-piperazinecarboxylate (5.00 g, 22.7 mmol) and cyclopropanecarboxylic acid (2.54 g, 29.5 mmol) were dissolved in 35 ml of N, N-dimethylformamide, and 1-ethyl hydrochloride was added to the resulting solution at room temperature -3- (3- (N, N-dimethylamino) propyl) carbodiimide (6.53 g, 34.1 mmol), 1-hydroxybenzotriazole (4.52 g, 29.5 mmol) and triethylamine (3.60 g, 35.9 mmol) followed by stirring at the same temperature for three hours. The reaction mixture was mixed with water and extracted twice with ethyl acetate. The organic layer was washed successively with water twice, saturated aqueous sodium bicarbonate once, and saturated brine once, and then dried over anhydrous sodium sulfate. The organic layer was passed through a silica gel column (Fuji Silysia, NH Silica gel) and evaporated to give the title compound (6.10 g, 93.1%) as a white amorphous.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 0.75-0.83 (2H, m), 0.95-1.03 (2H, m), 1.65 -1.75 (1H, m), 3.40-3.80 (8H, m), 5.16 (2H, s), 7.30-7.40 (5H, m).

Reference Example 1-2 1- (Cyclopropylcarbonyl) piperazine

Benzyl 4- (cyclopropylcarbonyl) piperazine-1-carboxylate (3.00 g, 10.4 mmol) was dissolved in 100 ml of ethanol, and 1.5 g of 10% palladium on carbon was added to the resulting solution, followed by stirring at room temperature in a hydrogen atmosphere during the night. Palladium-carbon was removed by filtration and the filtrate was evaporated to give the title compound (1.50 g, 97.3%) as a colorless oil.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 0.73-0.80 (2H, m), 0.96-1.03 (2H, m), 1.67 -1.77 (1H, m), 2.82-2.97 (4H, m), 3.60-3.71 (4H, m).

Reference Example 1-3 1- (Cyclopropylmethyl) piperazine

Lithium aluminum hydride (770 mg, 20.3 mmol) was suspended in tetrahydrofuran (150 ml), 1- (cyclopropylcarbonyl) piperazine (1.56 g, 10.1 mmol) was gradually added to the resulting suspension, and the reaction mixture was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and 0.8 ml of water, 0.8 ml of a 15% aqueous sodium hydroxide solution and 2.3 ml of water were gradually added to it. The precipitated insoluble matter was removed by filtration through Celite, and the filtrate was evaporated to obtain the title compound (1.40 g) as a colorless oil. The product was used to synthesize (8E, 12E, 14E) -7 - ((4-cyclopropylmethylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl- 18,19-epoxytricose-8,12,14-trien-11-olide (compound of Example 27) without further purification.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 0.09-0.15 (2H, m), 0.48-0.56 (2H, m), 0.82 -0.93 (1H, m), 2.25 (2H, d, J = 7.2 Hz) 2.48-2.65 (4H, m), 2.90-2.99 (4H, m) .

Reference Example 2. 1-Isobutylpiperazine

Benzyl 1-piperazinecarboxylate (1.1 g, 5.00 mmol) and isobutylaldehyde (0.91 ml, 10.0 mmol) were dissolved in 30 ml of tetrahydrofuran and acetic acid (0.57 ml, 10.0 mmol) was added to the resulting solution. ) and sodium triacetoxyborohydride (2.11 g, 10.0 mmol) and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with 1 N. aqueous sodium hydroxide solution was extracted with ethyl acetate twice and the combined organic layers were washed with brine once. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate: hexane = 50:50) to obtain benzyl 4-isobutylpiperazine-1-carboxylate (1.05 g) as a colorless oil.

The resulting benzyl 4-isobutylpiperazine-1-carboxylate (1.05 g) was dissolved in 35 ml of ethanol, 10% palladium on carbon (750 mg) was added to the solution, and the reaction mixture was stirred at room temperature in a hydrogen atmosphere (1 atm) for 12 hours. Palladium-carbon was removed by filtration and the filtrate was evaporated to give the title compound (610 mg) as a colorless oil.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 0.90 (6H, d, J = 6.8 Hz), 1.71-1.86 (1H, m), 2.07 (2H, d, J = 7.6 Hz), 2.33-2.4 3 (4H, m), 2.86-2.93 (4H, m).

Reference Example 3.1 1- (Tetrahydropyran-4-yl) piperazine

The title compound was synthesized in a manner similar to that described for the compound of Reference Example 2 (1-isobutylpiperazine).

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 1.50-1.64 (2H, m), 1.72-1.80 (2H, m), 2.36 -2.46 (1H, m), 2.54-2.64 (4H, m), 2.91-2.97 (4H, m), 3.37 (2H, dt, J = 2.0, 11.6 Hz), 4.03 (2H, dd, J = 4.4, 11.6 Hz).

Reference Example 4. 1- (Cyclopropylmethyl) homopiperazine

Benzyl 1-homopiperazine carboxylate (1.95 g, 8.32 mmol) and cyclopropanecarboxyaldehyde (700 mg, 10.0 mmol) were dissolved in 40 ml of tetrahydrofuran. Acetic acid (600 mg, 10.0 mmol) and sodium triacetoxyborohydride (2.11 g, 10.0 mmol) were added to the solution, and the reaction mixture was stirred at room temperature for two hours. The reaction mixture was mixed with 1 N. aqueous sodium hydroxide solution was extracted with ethyl acetate twice and the combined organic layers were washed with brine once. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate: hexane = 50:50) to obtain benzyl 4- (cyclopropylmethyl) homopiperazine-1-carboxylate (2.5 g) as a colorless oil.

The resulting benzyl 4- (cyclopropylmethyl) homopiperazine-1-carboxylate (2.5 g) was dissolved in 50 ml of ethanol, 10% palladium on carbon (500 mg) was added to the solution, and the reaction mixture was stirred at room temperature in a hydrogen atmosphere (1 atm) within 12 hours. Palladium-carbon was removed by filtration and the filtrate was evaporated to give the title compound (1.4 g) as a colorless oil.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 0.08-0.15 (2H, m), 0.47-0.56 (2H, m), 0.82 -0.95 (1H, m), 1.80-1.89 (2H, m), 2.44 (2H, d, J = 6.4 Hz) 2.75-2.85 (4H, m) 2.94-3.03 (4H, m).

Reference Example 5. 1- (2,2,2-Trifluoroethyl) piperazine

Benzyl 1-piperazinecarboxylate (2.0 g, 9.08 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.5 g, 10.8 mmol) and triethylamine (1.9 ml, 13.8 mmol) were dissolved in 50 ml of tetrahydrofuran and the reaction mixture was stirred at 60 ° C for two hours. After cooling to room temperature, the reaction mixture was mixed with saturated aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic layers were washed successively with water and brine in this order. The mixture was dried over anhydrous sodium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Fuji Silysia, NH Silica gel; ethyl acetate: hexane = 50:50) to obtain 4- (2,2,2-trifluoroethyl) piperazine-1-carboxylic acid benzyl ester (3.1 g) in the form of a colorless oil.

The resulting benzyl 4- (2,2,2-trifluoroethyl) piperazine-1-carboxylate (3.1 g) was dissolved in 50 ml of ethanol and 10% palladium on carbon (900 mg) was added to the solution, followed by stirring at room temperature in the atmosphere hydrogen (1 atm) overnight. Palladium-carbon was removed by filtration and the filtrate was evaporated to give the title compound (1.4 g) as a colorless oil.

¹ H-NMR spectrum (CDCl ₃ , 400 MHz) δ (ppm): 2.64-2.77 (4H, m), 2.90-3.01 (6H, m).

Reference Example 6

One full loop of a culture grown on a mowed culture medium [0.5% soluble starch, 0.5% glucose, 0.1% fish meat extract (manufacturer Wako Pure Chemical Industries, Ltd.), 0.1% yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.2% NZ-shell (manufacturer Humko Sheffield Chemical Co.), 0.2% sodium chloride, 0.1% calcium carbonate and 1.6% agar (manufacturer Wako Pure Chemical Industries, Ltd.)] strain of Streptomyces sp. AB-1704 (FERM P-18999) isolated from the soil was added to a 65 ml tube containing 7 ml of culture medium [2.0% soluble starch, 1.0% glucose, 0.5% polypeptone (manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% calcium carbonate], and cultured at 28 ° C. for three days in a shaking incubator with getting a seed crop.

Then, 0.5 ml of the seed culture was inoculated into a 65 ml tube containing 7 ml of production medium [2.0% soluble starch, 1.0% glucose, 0.5% polypeptone (manufacturer Nihon Pharmaceutical Co., Ltd.) , 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% calcium carbonate], and cultured at 28 ° C. for three days in a shaking incubator.

Next, a solution (25 mg / ml) of substrate substance 11107B (compound of Example A4 in WO 02/060890) in ethanol was prepared and 0.2 ml of the solution was added to the culture. After addition, the culture was shaken at 28 ° C. for 48 hours to effect a conversion reaction.

At the end of the reaction, the reaction mixture was analyzed by HPLC under the following conditions (a) analysis by HPLC to confirm the formation of 11107D in the reaction mixture.

Conditions (a) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 Ш4.6 mm х 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40 ° C

Flow rate: 1 ml / min

Detection: 240 nm

Eluent: acetonitrile / 0.15% potassium dihydrogen phosphate (pH 3.5) (3: 7-5: 5, v / v, 0-18 min, linear gradient), acetonitrile / 0.15% potassium dihydrogen phosphate (pH 3.5) (5: 5-85: 15, v / v, 18-22 min, linear gradient)

Retention time: substance 11107D - 9.9 minutes, substance 11107B - 19.4 minutes.

Reference Example 7

One full loop of the culture grown on a mowed nutrient medium (agar medium with yeast and malt) of strain A-1545 (FERM P-18944), isolated from the soil, was inoculated into a 250-ml Erlenmeyer flask containing 20 ml of inoculum [2.4 % soluble starch, 0.1% glucose, 0.5% soy flour (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.3% beef extract (manufacturer Difco), 0.5% yeast extract (manufacturer Difco), 0.5% tryptone-peptone (manufacturer Difco) and 0.4% calcium carbonate], and cultured at 28 ° C for three days in a shaking in ubatore to give seed culture.

Then, 0.6 ml of the seed culture was inoculated into a 500 ml Erlenmeyer flask containing 60 ml of production medium [2% soluble starch, 2% glucose, 2% soy flour (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride, 0.32% calcium carbonate, 0.0005% copper sulfate, 0.0005% manganese chloride, 0.0005 % zinc sulfate, pH 7.4 before sterilization], and cultured at 28 ° C for four days in a shaking incubator. Every 2 ml of the resulting culture was added to 15 ml tubes. Then, a solution (20 mg / ml) of the 11107B substrate substance in dimethyl sulfoxide was prepared and 0.05 ml of the resulting solution was added. After addition, the culture was shaken at 28 ° C for 23 hours to effect a conversion reaction. At the end of the reaction, the reaction mixture was analyzed by HPLC under the following conditions (b) analysis by HPLC to confirm the formation of 11107D in the reaction mixture.

Conditions (b) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 Ш4.6 mm х 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40 ° C

Flow rate: 1 ml / min

Detection: 240 nm

Eluent: acetonitrile / water (50:50, v / v), isocratic elution

Retention time: substance 11107B - 7.2 minutes, substance 11107D - 3.6 minutes.

Reference Example 8

One full loop of a culture grown on a mowed culture medium [0.5% soluble starch, 0.5% glucose, 0.1% fish meat extract (manufacturer Wako Pure Chemical Industries, Ltd.), 0.1% yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.2% NZ-shell (manufacturer Humko Sheffield Chemical Co.), 0.2% sodium chloride, 0.1% calcium carbonate and 1.6% agar (manufacturer Wako Pure Chemical Industries, Ltd.)] strain of Streptomyces sp. AB-1704 (FERM P-18999), isolated from soil, was added to a 500 ml Erlenmeyer flask containing 100 ml of culture medium [2.0% soluble starch, 1.0% glucose, 0.5% polypeptone (company manufacturer Nihon Pharmaceutical Co., Ltd.), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% calcium carbonate], and cultured at 28 ° C. for three days in a shaking incubator with the sowing crop. Then, every 2 ml of inoculum was inoculated into 500 ml Erlenmeyer flasks (150 flasks), each containing 100 ml of production medium [2.0% soluble starch, 1.0% glucose, 0.5% polypeptone (manufacturer of Nihon Pharmaceutical Co ., Ltd.), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.) and 0.1% calcium carbonate], and cultured at 28 ° C. for two days in a shaking incubator.

A solution (20 mg / ml) of 11107B substrate substance in ethanol was prepared and every 0.44 ml of the solution was added to the culture (100 ml / 500 ml Erlenmeyer flask, 150 flasks). After addition, the culture was shaken at 28 ° C. for 9 hours to effect a conversion reaction. At the end of the reaction, the cultures were collected and separated on the culture supernatant and the mycelium pellet by centrifugation at 2700 rpm for 10 minutes. The mycelium precipitate was extracted with 5 L of methanol and filtered to obtain a methanol extract. The methanol extract was evaporated to remove methanol, combined with the culture supernatant and extracted with 10 L of ethyl acetate. The resulting ethyl acetate solution was evaporated to give 2090 mg of a crude active fraction. The crude active fraction was dissolved in 4 ml of a mixture of tetrahydrofuran-methanol (1: 1, v / v) and 6 ml of a 50% aqueous solution of acetonitrile, subjected to chromatography on an ODS column (manufacturer YMC Co., ODS-AM 120-S50 W3.6 cm x 43 cm) and was suirable 40% aqueous solution of acetonitrile. The eluted fraction from 336 ml to 408 ml was concentrated to dryness under reduced pressure to obtain 560 mg of a residue. The residue was then dissolved in 10 ml of a 50% aqueous methanol solution, chromatographed on an ODS column (manufacturer YMC Co., ODS-AM 120-S50 Ш3.6 cm x 40 cm) and eluted with a 50% aqueous methanol solution. The eluted fraction from 1344 ml to 1824 ml was concentrated to dryness under reduced pressure to obtain 252 mg of the substance 11107D.

Reference Example 9

One full loop of the culture grown on a mowed nutrient medium (agar medium with yeast and malt) of strain A-1544 (FERM P-18943) isolated from the soil was inoculated into a 250 ml Erlenmeyer flask containing 25 ml of inoculum [2% soluble starch, 2% glucose, 2% soy flour (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% yeast extract (manufacturer Difco), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization], and cultured at 28 ° C for two days in a shaking incubator to obtain a seed culture. Each 0.75 ml of culture was added to 2 ml serum tubes (manufacturer Sumitomo Bakelite Co., Ltd.) and an equal amount of 40% aqueous glycerol solution was added. After stirring, the contents were frozen at -70 ° C to give a frozen seed culture. The frozen seed culture was thawed, 0.25 ml inoculated into a 250 ml Erlenmeyer flask containing 25 ml of culture medium [2% soluble starch, 2% glucose, 2% soy flour (AUSINAN-MEAT, manufacturer Ajinomoto Co., Ltd.), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization], and cultured at 28 ° C for two days in a shaking incubator to obtain a seed culture. The seed culture (0.5 ml) was then inoculated into a 500 ml Erlenmeyer flask containing 100 ml of production medium [2% soluble starch, 2% glucose, 2% soy flour (ESUSAN-MEAT, manufacturer Ajinomoto Co., Ltd. ), 0.5% yeast extract (manufacturer Oriental Yeast Co., Ltd.), 0.25% sodium chloride and 0.32% calcium carbonate, pH 7.4 before sterilization] and cultured at 28 ° C for three days in a shaking incubator.

Each of the resulting cultures (100 ml / 500 ml Erlenmeyer flask, 10 flasks) was centrifuged at 3000 rpm for 10 minutes to collect cells, and the cells were suspended in 100 ml of 50 mM phosphate buffer solution (pH 6.0) . Then, a solution (100 mg / ml) of substrate substance 11107B in dimethyl sulfoxide was prepared and every 0.5 ml of the resulting solution was added. After addition, the culture was shaken at 28 ° C. for 24 hours to effect a conversion reaction. At the end of the reaction, the reaction mixtures were collected and separated into supernatant and mycelium pellet by centrifugation at 5000 rpm for 20 minutes. The supernatant was extracted with 1 L of ethyl acetate. The mycelium precipitate was extracted with 500 ml of methanol and then filtered to obtain a methanol extract. The methanol extract was evaporated to remove methanol and extracted with 1 L of ethyl acetate. Each of the ethyl acetate layers was washed with water, dried over anhydrous sodium sulfate and the combined layers were evaporated to give 937 mg of a crude active fraction. The crude active fraction was subjected to silica gel column chromatography (Kiesel gel 60, 50 g) and 1200 ml of a mixture of ethyl acetate and n-hexane (90:10, v / v) were eluted to obtain 234 mg of the active fraction. The resulting active fraction was subjected to preparative high performance liquid chromatography (HPLC) under the following conditions (C) by preparative HPLC and the obtained eluate was analyzed by HPLC under the following conditions (c) by HPLC analysis. The solvent was removed from the fraction containing the resulting 11107D substance to give 80 mg of the 11107D substance.

Preparative HPLC conditions (C):

Column: CAPCELL PACK C18 UG120 Ш30 х 250 mm (manufacturer SHISEIDO Co.)

Flow rate: 20 ml / min

Detection: 240 nm

Eluent: acetonitrile / water (30:70, v / v), isocratic elution

Conditions (c) analysis by HPLC:

Column: CAPCELL PACK C18 SG120 Ш4.6 mm х 250 mm (manufacturer SHISEIDO Co.)

Temperature: 40 ° C

Flow rate: 1 ml / min

Detection: 240 nm

Eluent: acetonitrile / water (35:65, v / v), isocratic elution

Retention time: substance 11107D - 7.8 minutes

Reference Example 10

Each of the cultures of strain A-1545 (FERM P-18944), (100 ml / 500 ml Erlenmeyer flask, 10 flasks), obtained by a method similar to that described in reference example 9, was subjected to centrifugation at 3000 rpm for 10 minutes, to collect cells, and the cells were suspended in 100 ml of 50 mM phosphate buffer solution (pH 6.0). Then, a solution (100 mg / ml) of substrate 11107B in dimethyl sulfoxide was prepared and each 1 ml of the resulting solution was added. After addition, the culture was shaken at 28 ° C. for 24 hours to effect a conversion reaction. At the end of the reaction, the reaction mixtures were collected and separated into supernatant and mycelium pellet by centrifugation at 5000 rpm for 20 minutes. The supernatant was extracted with 1 L of ethyl acetate. The mycelium precipitate was extracted with 500 ml of acetone and then filtered to obtain an acetone extract. The acetone extract was evaporated to remove acetone and extracted with 1 L of ethyl acetate. Each of the ethyl acetate layers was washed with water, dried and dehydrated over anhydrous sodium sulfate, and the combined layers were evaporated to give 945 mg of a crude active fraction. The crude active fraction was subjected to silica gel column chromatography (Kiesel gel 60, 50 g) and eluted with 100 ml of a mixture of ethyl acetate and n-hexane (50:50, v / v), 200 ml of a mixture of ethyl acetate and n-hexane (75:25 , vol./about.) and 600 ml of a mixture of ethyl acetate and n-hexane (90:10, vol./about.) to obtain 463 mg of the active fraction. The resulting active fraction was subjected to preparative high performance liquid chromatography (HPLC) under preparative HPLC conditions (C) described in Example 4, and the obtained eluate was analyzed by HPLC under the following HPLC analysis conditions described in Example 4. The solvent was removed from the fraction containing this substance 11107D, with the receipt of 304 mg of substance 11107D.

Claims (35)

1. The compound represented by formula (I)

(in the formula R ³ , R ⁶ , R ⁷ and R ²¹ are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ³ , R ⁶ , R ⁷ and R ²¹ is attached, provided that R ^{6 is} limited to a hydroxyl group,
2) an optionally substituted C _1-22 alkoxy group,
3) an optionally substituted unsaturated C _2-22 alkoxy group,
4) RCO-O- (where R represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted C _6-14 aryl group,
d) an optionally substituted 5-14 membered heteroaryl group,
e) an optionally substituted C _7-22 aralkyl group,
f) an optionally substituted 5-14 membered heteroalkyl group,
g) optionally substituted C _6-14 aryloxy group
5) R ^S1 R ^S2 R ^S3 SiO - (where R ^S1 , R ^S2 and R ^S3 are the same or different from each other, and each of them represents
a) a C _1-6 alkyl group or
b) C _6-14 aryl group),
6) R ^N1 R ^N2 NR ^M (where R ^M represents
a) single bond,
b) -CO-O-,
c) -CS-O- or
d) —CO — NR ^N3 - (where R ^N3 represents a hydrogen atom or an optionally substituted C _1-6 alkyl group), provided that each leftmost bond in b) is attached to a nitrogen atom; and
R ^N1 and R ^N2 are the same or different from each other, and each of them represents a) a hydrogen atom, b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted unsaturated C _2-22 alkyl group,
d) an optionally substituted 5-14 membered heteroaryl group,
f) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^N1 and R ^N2 together with a nitrogen atom to which R ^N1 and R ^{N2 are} attached, wherein the non-aromatic heterocyclic group may have substituents, or
g) an optionally substituted 5-14 membered heteroalkyl group,
i) an optionally substituted 3-14 membered non-aromatic heterocyclic group),
with the proviso that a compound is excluded in which R ³ , R ⁶ , R ⁷ and R ^{21 are} all hydroxyl groups; a compound in which R ³ , R ⁶ and R ^{21 are} all hydroxyl groups and R ⁷ is an acetoxy group and a compound in which R ³ , R ⁶ are hydroxyl groups, R ⁷ is an acetoxy group and R ²¹ is an oxo group together with the carbon atom to which R ²¹ ) is attached, its pharmacologically acceptable salt or hydrate thereof. 2. The compound according to claim 1, represented by formula (Ia)

(in the formula R ^3a , R ^6a , R ^7a and R ^21a are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3a , R ^6a , R ^7a and R ^21a is attached, provided that R ^{6a is} limited to a hydroxyl group,
2) an optionally substituted C _1-22 alkoxy group,
3) R ^a CO-O- (where R ^a represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted C _6-14 aryl group,
d) an optionally substituted 5-14 membered heteroaryl group,
e) an optionally substituted C _7-22 aralkyl group,
g) an optionally substituted C _6-14 aryloxy group or
h) an optionally substituted 5-14 membered heteroaryloxy group),
^{4) R aS1 R aS2 R aS3 SiO-} ( wherein R ^aS1, R ^aS2 and R ^aS3 are the same or different from each other and each of them represents
a) a C _1-6 alkyl group or
b) C _6-14 aryl group),
5) R ^aN1 R ^aN2 NR ^aM - (where R ^aM represents
a) single bond,
b) -CO-O-,
c) -CS-O- or
e) —CO — NR ^aN3 - (where R ^aN3 represents a hydrogen atom or an optionally substituted C _1-6 alkyl group, provided that each leftmost bond in b) is attached to a nitrogen atom); and
R ^aN1 and R ^aN2 are the same or different from each other, and each of them represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted unsaturated C _1-22 alkyl group,
d) an optionally substituted 5-14 membered heteroaryl group,
f) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^aN1 and R ^aN2 together with a nitrogen atom to which R ^aN1 and R ^{aN2 are attached} , and the non-aromatic heterocyclic group may have substituents,
g) an optionally substituted 5-14 membered heteroaralkyl group, or
i) an optionally substituted 3-14 membered non-aromatic heterocyclic group, a pharmacologically acceptable salt thereof or a hydrate thereof. 3. The compound according to claim 1, represented by formula (Ib)

(in the formula, R ^3b , R ^6b , R ^7b and R ^21b are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3b , R ^6b , R ^7b and R ^21b is attached, provided that R ^{6b is} limited to a hydroxyl group,
2) an optionally substituted C _1-22 alkoxy group,
3) R ^b CO-O- (where R ^b represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted C _6-14 aryl group,
d) an optionally substituted 5-14 membered heteroaryl group,
e) an optionally substituted C _7-22 aralkyl group,
g) an optionally substituted C _6-14 aryloxy group,
4) R ^bS1 R ^bS2 R ^bS3 SiO- (where R ^bS1 , R ^bS2 and R ^bS3 are the same or different from each other, and each of them represents
a) a C _1-6 alkyl group or
b) a C _6-14 aryl group) or
5) R ^bN1 R ^bN2 NR ^bM - (where R ^bM represents
a) -CO-O- or
b) -CS-O-, provided that each leftmost bond in a) and b) is attached to a nitrogen atom;
and
R ^bN1 and R ^bN2 are the same or different from each other, and each of them represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted unsaturated C _2-22 alkyl group,
d) an optionally substituted 5-14 membered heteroaryl group,
f) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^bN1 and R ^bN2 together with a nitrogen atom to which R ^bN1 and R ^{bN2 are attached} , and the non-aromatic heterocyclic group may have substituents,
g) an optionally substituted 5-14 membered heteroaralkyl group or
i) an optionally substituted 3-14 membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof, or a hydrate thereof. 4. The compound according to claim 1, represented by formula (Ic)

(in the formula R ^3c , R ^6c R ^7c and R ^21c are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3c , R ^6c , R ^7c and R ^{21c is attached} , provided that R ^{6c is} limited to a hydroxyl group,
2) an optionally substituted C _1-22 alkoxy group,
3) R ^c CO-O- (where R ^c represents
a) an optionally substituted C _1-22 alkyl group,
b) an optionally substituted C _6-14 aryl group,
e) optionally substituted C _6-14 aryloxy group),
4) R ^cS1 R ^cS2 R ^cS3 SiO- (where R ^cS1 , R ^cS2 and R ^cS3 are the same or different from each other, and each of them represents
a) a C _1-6 alkyl group or
b) a C _6-14 aryl group) or
5) R ^cN1 R ^cN2 NR ^cM - (where R ^cM represents
a) -CO-O- or
b) -CS-O-, provided that each leftmost bond in a) and b) is attached to a nitrogen atom;
and
R ^cN1 and R ^cN2 are the same or different from each other, and each of them represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^cN1 and R ^cN2 together with a nitrogen atom to which R ^cN1 and R ^{cN2 are attached} , and the non-aromatic heterocyclic group may have substituents,
d) an optionally substituted 5-14 membered heteroalkyl group,
e) an optionally substituted C _3-14 cycloalkyl group or
f) an optionally substituted 3-14 membered non-aromatic heterocyclic group, a pharmacologically acceptable salt thereof or a hydrate thereof. 5. The compound according to claim 1, represented by formula (Id)

(in the formula R ^3d represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which R ^3d is attached,
2) an optionally substituted C _1-22 alkoxy group,
3) an optionally substituted unsaturated C _2-22 alkoxy group,
4) R ^d CO-O- (where R ^d represents
a) a hydrogen atom,
b) an optionally substituted C _1-22 alkyl group,
c) an optionally substituted C _6-14 aryl group,
d) an optionally substituted 5-14 membered heteroaryl group,
e) optionally substituted C _6-14 aryloxy group
or
5) R ^dN1 R ^dN2 N-CO-O- (where R ^dN1 and R ^dN2 are the same or different from each other, and each of them represents
a) a hydrogen atom,
b) an optionally substituted C _7-22 alkyl group,
c) an optionally substituted unsaturated C _2-22 alkyl group,
d) an optionally substituted 5-14 membered heteroaryl group,
f) an optionally substituted 3-14 membered non-aromatic heterocyclic group formed by R ^dN1 and R ^dN2 together with a nitrogen atom to which R ^dN1 and R ^{dN2 are attached} , and the non-aromatic heterocyclic group may have substituents), and
R ^6d , R ^7d and R ^21d are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^6d , R ^7d and R ^21d is attached, provided that R ^{6d is} limited to a hydroxyl group,
2) an optionally substituted C _1-22 alkoxy group,
3) an optionally substituted unsaturated C _2-22 alkoxy group,
5) R ^d CO-O- (where R ^d has the same meaning as defined above),
6) R ^dN1 R ^dN2 N-CO-O- (where R ^dN1 and R ^dN2 have the same meanings as defined above),
8) R ^dN1 R ^dN2 N-CS-O- (where R ^dN1 and R ^dN2 have the same meanings as defined above),
its pharmacologically acceptable salt or hydrate thereof. 6. The compound according to claim 1, where R ⁶ and / or R ⁷ represent (is) represents R ^N1 R ^N2 NR ^M (where R ^M represents
a) -CO-O- or
b) -CS-O-; and
R ^N1 and R ^N2 have the same meanings as defined above, provided that each extreme left bond in a) and b) is attached to a nitrogen atom), its pharmacologically acceptable salt or their hydrate. 7. The compound according to claim 1, its pharmacologically acceptable salt or hydrate thereof, where R ²¹ represents an oxo group formed together with the carbon atom to which R ²¹ is attached. 8. The compound according to claim 5, represented by formula (I-e)

(in the formula, R ^3e and R ^21e are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^3e and R ^21e is attached, provided that R ^{6e is} limited to a hydroxyl group,
2) an optionally substituted C _1-6 alkoxy group,
3) an optionally substituted unsaturated C _2-10 apoxy group,
4) an optionally substituted aliphatic C _2-6 acyloxy group or
5) R ^eN1 R ^eN2 N-CO-O- (where R ^eN1 and R ^eN2 are the same or different from each other, and each of them represents
A) a hydrogen atom or
B) an optionally substituted C _1-6 alkyl group); and
R ^6e and R ^7e are the same or different from each other, and each of them represents
1) a hydroxyl group or an oxo group formed together with a carbon atom to which each of R ^6e and R ^7e is attached, provided that R ^{6e is} limited to a hydroxyl group,
2) an optionally substituted C _1-6 alkoxy group,
3) an optionally substituted unsaturated C _2-10 alkoxy group,
5) an optionally substituted aliphatic C _2-6 acyloxy group,
its pharmacologically acceptable salt or hydrate thereof. 9. The compound according to claim 5, where R ^6d and / or R ^7d represent (is) R ^d1 C (= Y ^d1 ) -O- (where Y ^d1 represents an oxygen atom or a sulfur atom and R ^d1 represents
1) a hydrogen atom,
2) an optionally substituted C _1-6 alkyl group, a pharmacologically acceptable salt thereof or a hydrate thereof. 10. The compound according to claim 5, represented by the formula (If)

(in the formula, R ^7f represents R ^f C (= Y ^f ) -O- (where Y ^f represents an oxygen atom and R represents a group of formula (V)

(where n is an integer 0,
R ^fN1 represents
1) a hydrogen atom,
2) a methyl group or
3) an ethyl group, and R ^fN2 represents 1) a hydrogen atom,
7) a pyridinyl group,
8) pyrrolidin-1-ilen group,
9) piperidin-1-ilen group,
10) a morpholin-4-yl group or
11) 4-methylpiperazin-1-ilen group))), its pharmacologically acceptable salt or their hydrate. 11. The compound according to claim 1, which is selected from:
(8E, 12E, 14E) -7- (N- (2- (N ', N'-dimethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-butylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-ethylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4- (cyclopropylmethyl) piperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 19-epoxytricose-8,12,14-trien-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-propylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4- (cyclopropylmethyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18 19-epoxytricose-8,12,14-trien-11-olide;
(8E, 12E, 14E) -7 - ((4-cyclopentylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7- (N- (2- (N ', N'-diethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isobutylhomopiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-ethylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-butylhomopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,16,21-trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7 - ((4- (piperidinin-1-yl) piperidin-1-yl ) carbonyl) hydroxy-18,19-epoxytricose-8,12,14-trien-11-olide;
(8E, 12E, 14E) -7 - ((4- (2,2-dimethylpropyl) homopiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20 pentamethyl-18,19-epoxytricose-8,12,14-triene-11-olide; and
(8E, 12E, 14E) -3,6,16-trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) oxy-18, 19-epoxytricose-8,12,14-triene-11-olide. 12. The compound according to claim 1, which is selected from
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylhomopiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7 - ((4-methylpiperazin-1-yl) carbonyl) hydroxy-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-cyclohexylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -3,6,16,21-tetrahydroxy-7 - ((4-isopropylpiperazin-1-yl) carbonyl) hydroxy-6,10,12,16,20-pentamethyl-18.19- epoxytricose-8,12,14-triene-11-olide;
(8E, 12E, 14E) -7 - ((4-cycloheptylpiperazin-1-yl) carbonyl) hydroxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19- epoxytricose-8,12,14-triene-11-olide; and
(8E, 12E, 14E) -7- (N- (2- (N ', N'-diethylamino) ethyl) -N-methylcarbamoyloxy) -3,6,16,21-tetrahydroxy-6,10,12,16 , 20-pentamethyl-18,19-epoxytricose-8,12,14-trien-11-olide. 13. A drug having cytotoxic activity, containing the compound according to any one of claims 1 to 12, its pharmacologically acceptable salt or hydrate thereof as an active component. 14. A pharmaceutical composition having cytotoxic activity, containing a compound according to any one of claims 1 to 12, a pharmacologically acceptable salt thereof or a hydrate thereof as an active component. 15. The drug according to item 13, which is a means for the prevention or treatment of a disease against which the regulation of gene expression is effective. 16. The drug according to item 13, which is a means for the prevention or treatment of a disease against which the inhibition of VEGF production is effective. 17. The drug according to item 13, which is a means for the prevention or treatment of a disease against which the antiangiogenic effect is effective. 18. The drug according to item 13, which is an inhibitor of angiogenesis. 19. The drug according to item 13, which is an antitumor agent. 20. The drug according to item 13 as a therapeutic agent for the treatment of angioma. 21. The drug according to item 13, which is an inhibitor of cancer metastasis. 22. The drug according to item 13, which is a therapeutic agent for the treatment of retinal revascularization or diabetic retinopathy. 23. The drug according to item 13, which is a therapeutic agent for the treatment of solid malignant tumors. 24. The drug according to item 23, where the solid malignant tumor is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, colon cancer or melanoma. 25. The drug according to item 13, which is a therapeutic agent for the treatment of leukemia. 26. The drug according to item 13, which is an antitumor agent based on the regulation of gene expression. 27. The drug according to item 13, which is an antitumor agent based on inhibition of VEGF production. 28. The drug according to item 13, which is an antitumor agent based on the effect of inhibiting angiogenesis. 29. A method for the prevention or treatment of a disease against which regulation of gene expression is effective, comprising administering to a patient a pharmacologically effective dose of a drug according to claim 13. 30. A method for the prevention or treatment of a disease against which the inhibition of VEGF production is effective, comprising administering to a patient a pharmacologically effective dose of a drug according to claim 13. 31. A method for the prevention or treatment of a disease against which angiogenesis inhibition is effective, comprising administering to a patient a pharmacologically effective dose of a drug according to claim 13. 32. The use of a compound according to any one of claims 1 to 12, a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which regulation of gene expression is effective. 33. The use of a compound according to any one of claims 1 to 12, a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which the inhibition of VEGF production is effective. 34. The use of a compound according to any one of claims 1 to 12, a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of a disease against which the inhibition of angiogenesis is effective. 35. The use of a compound according to any one of claims 1 to 12, a pharmacologically acceptable salt thereof or a hydrate thereof for the manufacture of an agent for the prophylaxis or treatment of solid malignant tumors.
Priority from 05/23/2002 according to claims 9, 10, 14-36
according to the filing date of 05/29/2003 according to claims 1-8, 11-13.