JPS63295589A - Derivative of physiologically active substance k-252 - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I {R<1> and R<2> are H, bromine or nitro; R<3> is H, lower alkyl, aralkyl or -(CH2)nZ [Z is OH or formula II (R<4> and R<5> are H, lower alkyl, etc.), etc.]; X is carboxyl, lower alkoxycarbonyl, carbamoyl, hydroxymethyl, etc.; Y is OH, lower alkoxy or aralkyloxy, provided that X and Y together represent formula III or IV} and salt thereof. USE:A antiallergic agent, antithrombotic agent, anti-inflammatory agent, antitumor agent, etc., having powerful inhibitory activity against C-kinase. PREPARATION:A raw material compound expressed by formula V, such as a physiologically active substance K-252, is reacted with an oxidizing agent (e.g. Collins' reagent consisting of chromic acid dipyridine complex) in an amount of 5-7 equiv. based on the above-mentioned compound in pyridine solvent at 0 deg.C - room temperature for 1 day.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel compound that inhibits protein kinase C (hereinafter referred to as C-kinase) and has various pharmacological actions.

BACKGROUND OF THE INVENTION C-kinase is a protein kinase that is activated depending on phospholipids and calcium, and is widely distributed in tissues and organs within the body. In recent years, it has become known that this enzyme plays an extremely important role in the cell membrane receptor and transmission mechanisms for many hormones and neurotransmitters. Examples of physiological reactions induced by such information transduction mechanisms involving C-kinase include serotonin release in platelets, lysosomal enzyme release and aggregation reactions, neutrophil superoxide production and sosomal enzyme release, and adrenal medulla. Epinephrine release from
Aldosterone secretion from the renal glomerulus, insulin secretion from the islets of Langerhans, histamine release from mast cells, acetylcholine release from the ileum, contraction of vascular smooth muscle, etc. have been reported. Furthermore, C-kinase is thought to be involved in cell proliferation and carcinogenesis [References: Y, N15hizuka, 5science,
225.1365 (1984): H, Ra5fflu
ssen et al, ^dvance in Cy
clic Nucle-otide and Prot
ein Phosphorylation Re5ea
rch.

Vol, 18. P2S5. edited by P
, Greengard and G, ^.

Robison, Raven Press, New
York, 1984) It has thus become clear that C-kinase is involved in many important physiological reactions and various pathological conditions in the body. If it can be artificially suppressed by using such drugs, it is thought that it will be possible to prevent and treat a wide variety of diseases such as circulatory system diseases, inflammation, allergies, and tumors.

On the other hand, antipsychotic drugs such as trifluoperazine and chloropromacine, dibenamine and tetracaine known as local anesthetics, and the calmodulin inhibitor W-7CN
-(6-aminohexyl) -5-chloro
-1-naphthalenesulfonamide
Although it has been found that drugs such as Y , N15hizuka et at, , J, B
iol, Chem.

255, 8378 (1980); RoClSchat
Zman et al., Biocheffl.

Biophys, Res, Commun, 98.
669 (1981); B, C.

! 1ise et al,,J,Biol,Chem,.
, 257.8489 (1982)).

On the other hand, -252, KT-5556, and -252 derivatives modified at the RA and Rm sites are known (for K-252, JP-A-60-41489.
US Pat. No. 455,402, JP-A-61-176531 for KT-5556, and JP-A-62-155284 for K-252 derivatives. 62-155285)
.

K^ ni-252: RA = C mouth acL, Rm = H.

KT 5556: Ra = CO2 ■, Ra
=H JP-A No. 60-41489 shows that Ni-252 has antihistamine-releasing action and anti-allergy action, as reported in JP-A No. 62-155284. No. 62-155285 describes that Ni-252 derivatives have C-kinase inhibitory activity and antihistamine-releasing activity. Furthermore, JP-A-61-176531 describes that K T -5556 has an antihistamine releasing effect. Additionally, a compound presumed to be the same as K-252 and K T-5556 has been reported as an antibacterial substance [Gou 5en
zaki et al, J, ^nLibiotics
, 38.1437 (1985)].

In this document, in the above formula, RA = C01CHs, Ra
= C mouth C1 (.

Also disclosed are compounds. A compound presumed to be the same compound as ni-252 and its halogen derivative were published in JP-A-62-120388. 62-164626, and a derivative modified with Ra was published in JP-A No. 62-240689.
All of them have been described to have antihypertensive and diuretic effects.

Furthermore, Staurosporine (Staurospor 1ne), which has the following structure and has an antibacterial effect, is known as a compound having a structure relatively similar to the structure of -252.
5 (1977); ^, Furusaki et al.
, ,J,Chem,Sac.

Chem, Commun, 800 (1981); JP 60-1857193゜ ■ New active ingredients such as anti-allergic agents, anti-thrombotic agents, anti-inflammatory agents, or anti-tumor agents with strong C-kinase inhibitory activity are always sought. It is being

According to the present invention, a novel derivative of -252 represented by formula (1) and a pharmacologically acceptable salt thereof are provided.

(wherein R1 and R2 are the same or different and represent hydrogen, bromine or nitro, R3 represents hydrogen, lower xyl, lower alkoxycarbonyl, carbamoyl, lower alkylaminocarbonyl, hydroxymethyl or substituted or unsubstituted aminomethyl, Here, the substituent is
It refers to an acyl group obtained by removing the hydroxyl group from the carboxyl group of an amino acid, and Y is hydroxy, lower alkoxy, or aralkyloxy, or X and Y taken together form -YX- to form 10-C( CHs)! -0-CH,- or -〇-C-
0- CH, i-).

Hereinafter, the compound represented by formula (1) will be referred to as compound (1). The same applies to compounds having other formula numbers. Compound(
In addition to having excellent C-kinase inhibitory activity, it also has excellent antihistamine release inhibitory activity, platelet aggregation inhibitory activity, anti-inflammatory activity, or cell growth inhibitory activity.

In the definition of R', R' and R' in formula (1), lower alkyl is a linear or branched alkyl having 1 to 3 carbon atoms,
That is, it includes methyl, ethyl, n-propyl, and i-propyl. In the definition of R3, aralkyl has an aryl moiety such as phenyl or naphthyl, and an alkyl moiety having a linear or branched alkylene having 1 to 3 carbon atoms, such as methylene,
It means ethylene, etc., and benzyl is a preferred example. Examples of the heterocycle formed by R4 and R5 include pyrrolidine, piperidine, N-methylpiperazine, formoline, and N-methylhomopiperazine.

In the definition of X, lower alkoxycarbonyl has 2 to 7 carbon atoms.
straight-chain or branched alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, n-hexyloxycarbonyl, and the like. In the definition of
Includes i-propylaminocarbonyl. In the definition of butoxycarbonyl, etc.).

In the definition of Y, lower alkoxy includes linear or branched alkoxy having 1 to 3 carbon atoms, ie, methoxy, ethoxy, n-propoxy, and i-propoxy. In the definition of Y, the aralkyl referred to in aralkyloxy has the same meaning as in the definition of R3, and benzyloxy is preferred.

When compound (,1) is a basic compound, an acid addition salt can be formed. Acid addition salts of compound (I) include hydrochloride, hydrobromide, sulfate, nitrate, formate, acetate, benzoate, maleate, fumarate, succinate, tartrate, and citric acid. acid salt, sinuate, methanesulfonate, toluenesulfonate, aspartate,
Examples include glutamate. Non-toxic pharmacologically acceptable salts, such as the acid addition salts listed above, are preferred, but
Other salts are also useful in product isolation and purification.

The compounds according to the invention are those obtained from optically active di-252, usually by steric retention reactions, but all possible stereoisomers and mixtures thereof are also encompassed by the invention.

Next, a method for producing compound (1) will be explained.

However, the method for producing compound (1) is not limited thereto.

Compound (1) is derived from K-252 and the following formula (■, ~.) X' (n,) (X' = C0OH) (L) (X' = CH20H) (nc) (X' =CH20Ha) by various synthetic means. In addition, the compound (■,) is described in JP-A No. 61-176531.
b) The right side and (■C) are disclosed in Japanese Patent Application Laid-Open No. 155285/1985.

In addition, in the production method shown below, if the defined group changes under the conditions of the method or is inappropriate for carrying out the method, methods commonly used in organic synthetic chemistry, such as protection and desorption of functional groups, should be used. Easily by subjecting it to protective measures (see, for example, Protective Groups in Organic Synthesis, Green, John Wiley & Sons, Inc. (1981)).

(See Examples 7 and 16, etc.).

Method 1:! Synthesis (III) of i-form biimide compound 1) (in the formula, R', R", R', )l- and Y have the same meanings as above).

Compound (1) is an oxidizing agent suitable for the lactam compound (III),
For example, it can be obtained by reacting Collins reagent (dipyridine chromate complex) in a pyridine solvent at a temperature ranging from 0° C. to room temperature for one day. The oxidizing agent is used in an amount of 5 to 7 equivalents based on compound (III).

In this reaction, if X, Y, R3, etc. are inappropriate functional groups for the oxidation reaction, the above-mentioned means of protection, oxidation, and deprotection of the functional groups are carried out as appropriate (for example, in Example 7).
reference).

Further, the compound (1) obtained here can be further led to a new -252 derivative by methods 2 to 6 described below using this as a synthetic intermediate.

Method 2: Synthesis of compound (1-2) having a functional group in R' and/or R2 2-1: Synthesis of compound (1-2) in which R' and/or R2 is nitro
-2-1) and/or (I-2-1') (in the formula, x, Y and R3 have the same meanings as in the description) The reaction is carried out with compound (1-1a) (R1 and R3 in compound (1)
2 is hydrogen] and a suitable nitrating agent, such as nitronium tetrafluorobalate, in a solvent inert to the reaction, to obtain the target compound (1-2-1) and/or
Or (T-2-1') can be obtained. The nitrating agent is used in an amount of 1 to 1.1 equivalents. As the inert solvent, sulfolane, acetonitrile, etc. are used. The reaction is carried out at a temperature ranging from room temperature to 80°C and is completed in 1 to 2 hours.

2-2: Compound in which R' and/or R2 is bromine (1-
2-2) and/or (1-2-2') (wherein, The target product (
I-2-2) # and/or (1-2-2') can be obtained.

Method 3: Synthesis of a compound (1-3>) having a functional group in R3 3-1: Compound where R' is alkyl or aralkyl (I-3
-1) ■ (In the formula, X, Y, R1 and R2 have the same meanings as above, R3a means lower alkyl and aralkyl in the definition of R3, and Hai represents halogen) The reaction is carried out with the compound (1-1b) [R3 in compound (1)
is hydrogen] and halide (IV) in an inert solvent such as dimethylformamide (DMF) in the presence of a base to produce compound (1-3-1).
can be obtained. The reaction is usually 03 to 1 to 12 at room temperature.
Finish in time.

The halide is preferably a highly reactive iodide or bromide, and is usually used in an amount of 1 to 2 equivalents relative to compound (I-1b).

The base includes sodium hydride, potassium t-butoxide, etc., and is preferably used in an amount of 1 to 1.5 equivalents relative to compound (I-1b) in order to suppress side reactions.

3-2: Compound where R' is -(CH,) and n=o in Z (I
-3-2) 3-2a: Compound where Z (R') is OH (1-3-2a) ■ C00CJs (V) λ (wherein, X, Y, R' and R2 have the same meanings as above) Compound (V) can be obtained by reacting compound (I-1b) with ethyl chloroformate in the presence of an appropriate base, such as sodium hydride, in a solvent inert to the reaction, such as tetrahydrofuran (THF). . Ethyl chloroformate is used in an amount of 1 to 2 equivalents, and the base is used in an amount of 1 to 1.5 equivalents, relative to compound (I-1b). The reaction is usually completed in 1 hour to 1 day at 0° to room temperature. Compound (1-3-2a) can then be obtained by reacting the compound with hydroxylamine hydrochloride in the presence of an appropriate base, such as triethylamine, in a solvent inert to the reaction, such as DMF. Hydroxylamine hydrochloride and base are used in an amount of 5 to 10 equivalents based on compound (V). The reaction is (in the formula,
(X, Y, R', R", R' and R5 have the same meanings as above) The reaction is carried out between compound (1-1b) and hydrazines (Vl)
0 to 50 equivalents in an inert solvent at 70 to 110°C.
Compound (1-3-2b) is obtained by reacting for 0 hours. If a suitable base such as 1,8-diazabicycloundecene (Bu) is used, the reaction will proceed more quickly.

Inert solvents include dioxane, DMF, and the like.

3-3: Compound (1
-3-3) 3-3a: Compound in which Z is OH (I-3-3a) (I-1b) CH3-H (wherein, X, Y, R'k and R2 are as defined above ) For the reaction, compound (1-1b) and 35% formaldehyde aqueous solution or paraformaldehyde, etc. are mixed in an inert solvent,
For example, the compound (1-3-
3a) can be obtained. Formaldehyde is used in an amount of 3 to 5 equivalents based on compound (1-1b). The reaction is carried out using a mixture of compound (1-1b) and a 35% aqueous formaldehyde solution or paraformaldehyde, etc. (■
) Compound (1-3-3b) can be obtained by reacting in an inert solvent, such as DMF, in the presence of a compound (1-3-3b).

Formaldehydes and compounds (■) are compound (■-
tb> is used in an amount of 3 to 5 equivalents. The reaction is usually 70~
It is carried out at 100°C and is completed in one day to one week.

3-4: Compound (1
-3-4) 3-4a: Compound where Z is OH (1-3-48) ■ CH*CH*H (wherein, X, Y, R', R'' and HaIl have the same meanings as above) Compound (I-3-4a) is obtained by reacting compound (I-1b) and halide (■) under the same alkylation conditions as in Method 3-1 above.

-4b) ■ (1-1b) (X) λ (wherein, X, Y, R', R'', R', R',
15. and Hal have the same meanings as above) First, compound (X) is obtained by reacting compound (1-1b) and halide (IX) under the same alkylation conditions as in Method 3-1 above.

Then, compound (X) is mixed with amine (■) in a DMF solvent in the presence of 15 to 20 equivalents of a suitable base, such as DBU.
Compound (1-3-4
b) can be obtained. The reaction is usually completed in one day at room temperature.

(1-3-5> (CH3) , -Nl2 (wherein, X, Y, R', R'' and n have the same meanings as above) Compound (1-3b) (Compound (1-3-2b ), (1-
3-3b) and (1-3-4b), a compound in which R4 and R5 are hydrogen] and N,N-dimethylformamide dimethyl acetal in an inert solvent, such as DM
Compound (1-3-5) can be obtained by reacting in F. N,,N-dimethylformamide dimethyl acetal is used in an amount of 1 to 10 equivalents based on compound (I-3b). The reaction is usually carried out at 0°C to room temperature and is completed in 1 to 2 weeks.

Method 4: Synthesis of compound (1-4) with modified x 4-1:
Compound (1-4-1) (1-1c) where X is lower alkoxycarbonyl (wherein, Y, R', Rj and R3 have the same meanings as above, and R" represents lower alkyl), where R@ is Carbon number 1~
6 straight or branched alkyl.

Alcohol (XI) and excess thionyl chloride were added to compound (I-1c) [a compound in which X is carboxyl in compound (1)], and the mixture was heated to reflux to form compound (
1-4 to l) can be obtained. Thionyl chloride is usually used in an amount that is about one-tenth (by volume) of the alcohol that is also used as a solvent. The reaction is carried out at a temperature of 80 to 100°C and is almost completed in 1 hour to 1 day.

4-2: Compound (I-4-2) (1-1c) (XI[) (T-4-2) where X is carbamoyl and lower alkylaminocarbonyl (wherein, Y, R', R' and R3 has the same meaning as above, and R7 represents hydrogen or lower alkyl) In the definition of R7, lower alkyl means a straight or branched alkyl having 1 to 3 carbon atoms.

Compound (I-1c) is heated under reflux in thionyl chloride to obtain acid chloride (XI). Then, by reacting compound (Xn) with amine (XIII), compound (1-
4-2) can be obtained. The amine component is usually used in an equivalent to excess amount, usually in an amount of 1 to 5 equivalents, relative to compound (XII),
Anhydrous chloroform, dichloromethane, etc. are used as a reaction solvent. The reaction is usually carried out at room temperature and is completed in 1 to 12 hours.

4-3: Compound where X is substituted aminomethy (1-(1-1d
) (In the formula, Y, R', R" and R' have the same meanings as above, R" represents the part obtained by removing the hydroxy group from the carboxyl group of the amino acid, and the amino group of the amino acid is free or protected. Here, as the N-protecting group for amino acids, groups commonly used in peptide chemistry, such as benzyloxycarbonyl, t
-butoxycarbonyl, etc.

Compound (1-1d) [a compound in which X is aminomethyl in compound (1)] and an N-protected amino acid (XI
Compound (1-4-3) can be obtained by condensing V) with N-oxysuccinimide and dicyclohexylcarbodiimide (DCC) in a THF solvent. Compound (X■) is 1 to 2 equivalents, N-oxysuccinimide is 1 equivalent, DC
C is used in an amount of 1 to 2 equivalents. The reaction is usually carried out at 0° C. to room temperature and is completed in 1 hour to 1 day.

In addition, the compound (1-4-3a) having a free amino group
If desired, it may be deprotected by a conventional method. For example, when the protecting group is benzyloxycarbonyl, the compound (I-4-3a
) can be obtained. The catalyst contains 5 to 10% palladium on carbon, etc., and usually contains 0% to the weight of the compound (1-4-3).
．． Use 1 to 0.5 times the weight. Inert solvent is THFSDM
Includes F etc. The reaction is usually carried out at room temperature and is completed in 1 hour to 1 day (see Example 19, etc.).

Method 5: Synthesis of Y-modified compound (1-5) 5-1
: Compound (1-5-1) (I-1e) λ in which Y is lower alkoxy or araloxy (wherein, X, R', R'', R' and Hal are as defined above, and R'' is Synonymous with R1) Compound (1-1e)C A compound in which Y is hydroxy in compound (1)] and halide (XV) are reacted in the presence of a base in a solvent inert to the reaction to form compound ( 1-
5-1) can be obtained.

The halide is preferably a highly reactive iodide or bromide, and is usually used in an amount of 1 to 2 equivalents based on compound (1-1e). The base includes sodium hydride, potassium t-butoxide, etc., and is preferably used in an amount of 1 equivalent or less, particularly 0.9 to 1 equivalent, relative to compound (1-1e) in order to suppress side reactions.

DMFlTHF or the like is used as the inert solvent.

The reaction is usually carried out at a temperature of θ°C to room temperature and is completed in 1 hour to 1 day.

Method 6: Synthesis of compound (1-6) of -Y-X- R3 has the same meaning as above) Compound (1-1f) [a compound in which X is hydroxymethyl and Y is hydroxy in addition to compound (I)] and 5 equivalents of 2,2-dimethoxypropane in a chloroform solvent. The compound (1-1- 6-1) can be obtained.

(In the formula, R', R" and R3 have the same meanings as above.) Compound (1-1f) and the olulponyldiimidazole are mixed in DMF in the presence of a suitable base such as triethylamine at room temperature for 1 hour to By reacting for one day, the compound (1
-6-2) can be obtained. The base is the compound (1-1
3 equivalents for f), 5 equivalents for thiocarbonyldiimidazole
Equivalent amounts are used.

Compound (1) having a desired functional group at a desired position can be obtained by appropriately combining methods 1-6.

Compound (1) is a lactam (■) [compound ([[
a), (II b) and (Inc)] by first applying the above methods 2 to 6 and then subjecting it to method 1.

In each of the above methods, isolation and purification of the product after completion of the reaction can be carried out by appropriately combining methods used in ordinary organic synthesis, such as extraction, crystallization, chromatography, etc.

Compound (1) has C-kinase inhibitory activity, antihistamine release inhibiting activity, and platelet aggregation inhibiting activity, and is expected to be useful as an active ingredient of antiallergic agents, antihistamine agents, antithrombotic agents, and the like. Such pharmaceutical preparations usually contain an effective amount of compound (1) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The dosage of the pharmaceutical preparation depends on the administration method, treatment period, age,
Although it varies depending on body weight, etc., the dose for humans is 0.5 to 10 per day for oral or parenteral (e.g. injection, application, inhalation, etc.)
mg/kg is appropriate. Pharmaceutical forms include tablets, pills, powders, granules, capsules, halves, injections, and the like.

For formulation, conventional pharmaceutical carriers such as lactose, dextrose, sucrose, sorbitol, mannitol, glucose, cyclodextrin, talc, starch, methylcellulose, gelatin, gum arabic, polyethylene glycol, carboxymethylcellulose, hydroxypropylcellulose, sodium benzoate, sulfite are used. Sodium hydrogen, aluminum stearate, magnesium stearate, vegetable oil, white petrolatum, distilled water for injection, etc. are appropriately selected and used in a conventional manner. This preparation contains compound (T) in the composition.
or 0.01 to 85% by weight of a pharmaceutically acceptable salt thereof.

Furthermore, compound (I) can be used in human cervical cancer cells (He).
J! a) An antitumor compound containing Compound (I) as an active ingredient that exhibits remarkable cell growth inhibitory activity against cells, human breast cancer cells 1ti1McF7, human colon gland cells COLO320DM, human lung differentiated squamous cell carcinoma cells PC-10, etc. agent is provided.

When compound (1) is used as an antitumor agent, each compound is dissolved in physiological saline, glucose, lactose, or mannitol injection solution at a dose of 0.01 to 20 mg/kg, and usually used as an injection. Administer intravenously. It may also be freeze-dried in accordance with the Japanese Pharmacopoeia, or may be prepared as a powder injection containing sodium chloride. It may further contain well-known pharmaceutically acceptable diluents, adjuvants and/or carriers such as pharmaceutically acceptable salts. When used as an injection, it may be preferable to use an auxiliary agent to increase solubility. The dosage can be increased or decreased as appropriate depending on age and symptoms. The administration schedule can also be changed depending on the symptoms and dosage, and includes intermittent administration such as once a day (single administration or daily administration), 1 to 3 times a week, or once every 3 weeks. Oral administration and rectal administration are also possible using the same dosage and administration method.

For oral administration, tablets, powders,
It can be administered as granules, syrup, halved, etc.

Examples Representative examples of compound (1) obtained by the above production method are shown in Table 1, and its intermediates are shown in Table 2.

In addition, the production examples of these compounds are used as Examples, the production examples of their intermediates are used as Reference Examples, the pharmacological activity of Representative Compound (1) is used as Experimental Examples, and the formulation example of Representative Compound (I) is used as Reference Examples. show.

Bzl, M e s E t s in the tables and examples
P r sBu, hex, Ac, and Cbz are benzyl, methyl, ethyl, propyl, butyl, hexyl, acetyl, and penzyloxy, respectively. means.

Table 1 Compound Examples kkR'R'R"xy Salt 1 1HIIHC, Me Ro■2
2 HHHC01Bt OH33HHHC01
nPr 0H 44HHHC port 2nBu 0H 55HHHC port, nhex OH 66HHHCONHMe RoH? 7HHHCH, 口) 1 0H 88HH8zl CO, Me OH98H
HBzj! CO, Me RO B
z110 9 HHMe CO, Me
0H119HH, Me C mouth 2Me
OMe12 10 HHn-P
r C sMe OH Compound Example 11hkR'R"R' XY Salt 13 11 0r Or HC
Mouth 21e 0H1412HHH-C1laOC
(CHs)z low 15 13 HHH-C
H20C(=S)-0-1614NO, HHCO2Me
01117 15 HHOHCLOHO
)! 18 16 HHN=CH-NMe*CH
aOH0H1917HHCH-OHCHJH0H 20t8 HHct+*Q-Me co20
HroH2119HHCHaCHJMei C)IJH
i 0H2220HHHCHJHC口CH,NH,ROH2321HHNH2CHJHCOC1laNH*OH
HCl Table 2 ■ ^^ Compound reference example k R” XA YA
a I HC mouth, HOHb 2 NO, CD, Me
OHc3H-CH20C
(CHa) J-d 4
HCC port 0Ace
5 HCONHMe OHf
6 HCO, Bt 0ilCH5 ■ QC) 13 h 8 ) I CHJHCb
z OHt 9 HCHJHC
OCf12NflCbz OH Example 1 Pyridine 50mJ! Add 3 g (30 mmo) of chromic acid under ice cooling.
1) was added, and then after 10 minutes -252,2,9g (
6.2 mmol) of pyridine solution at 30 mA was added thereto, and the mixture was stirred at room temperature for 1 day. The reaction mixture was filtered through Celite,
THF was added to the filtrate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (chloroform), and recrystallized from chloroform to obtain compound 1, 2.53 g (85%), mp, 288-29
Obtained as a yellow powder at 0°C.

NMR (CDCj! s 10 MS load dS) δ;
2.18 (s, 3H), 2.38 (dd, IH, J
=5.14Hz), 3.37(dd, IH, J=6.
14Hz), 4.00(s, 3H), 6.05(b
r, s, 1) 1), 6.95 (dd, IH, J=5.
6Hz).

7.20-8.04 (m, 6H), 9.08 (d, I
H, J=811z), 9.28(d, LH.

J=8Hz), 10.16(s, IH)MS(m/
e); 481 (M Example 2 Compound f obtained in Reference Example 6 in the same manner as Example 1
(K-252 engineering methyl ester) 50mg (0.1mm
2.30 mg (60.6%) of the compound from mp,
Obtained as a yellow powder at >300°C.

NMR (CDC1s+DMsO-da) δ; 1.
51 (t, 3H, J=8Hz).

2.22 (s, 3H), 2.37 (dd, IH, J
=5.14Hz), 3.35(dd,1)1°J=
7.14Hz), 4.53(q, 2H, J=8)1
z), 5.61 (s, IH).

6.93 (dd, IH, J=5.7Hz), 7.2
8-7.70 (m, 5H), 7.98 (d.

IH, J = 8Hz), 9.16 (d, IH, J = 8
Hz), 9.36 (d, 111.J=8Hz).

9,66 (br, s, IH) MS (m/e); 495 (Ma Example 3 Obtained in the same manner as in Example 1 using n-proper tool and in the same manner as in Reference Example 6. Compound 3 from 70 u (0.14 mmol) of 2520-propyl ester
．． 5 hg (70,2%) mp, 272-274
Obtained as yellow prismatic crystals at ℃.

NMR (CDC1s) δ: 1.12 (t, 3H
, J=8Hz), 1.76-2.08(m, 2H),
2.21 (s, 3H), 2J7 (dd, IH, J=5
．． 14Hz).

3.32 (dd, IH, J=8.14Hz), 3.9
2(s, IH), 4.45(t, 2tl.

J=7Hz), 6.88 (dd, IH, J=5.8)
1z), 7J2-7.68 (m, 6H).

7.80 (d, 1f1.J=8Hz), 9.08 (d
, 1tl, J=8Hz), 9.20 (d.

IH, J = 8 Hz) MS (m/e); 509 (Ma Example 4 N-252 n-butyl ester obtained in the same manner as in Example 1 using n-butanol and in the same manner as in Reference Example 6 From 70+ag (0.13 mmol), compound 4
．． Obtained 50ag (70%) as yellow prismatic crystals with mp of 251-253°C.

NMR (CroC11s+RoMSO-ds) δ:
1,04 (t, 3H, J=7Hz).

1.32-2.04 (m, 4H), 2.20 (s, 3
H), 2.39 (dd, IH, J=5°14)1z)
, 3.35 (dd, IH, J=7.14Hz), 4
．． 46(t, 2H, J=7)1z).

5.34 (s, IH), 6.91 (dd, IH, J=
5.7Hz), 7JO-7,70 (m.

5H), 7.96 (d, IH, J=8Hz), 9.
16 (d, IH, J=8Hz), 9.24 (s, I
H), 9.36 (d, LH1J=8Hz) MS (m
/e) ; 523 (M'') Example 5 N-hexyl ester 70 [(0.14 mmol) obtained in the same manner as in Example 1 using n-hexanol and in the same manner as in Reference Example 6. From, compound 5
．． 48 mg (67%) was obtained as yellow prismatic crystals, mp, 228-229°C.

NMR (CDCjl S) δ; 0.96 (m, 31),
1.16-1.72 (m, 6H).

1.76-2.08 (m, 2H), 2.24 (s, 3
H), 2.41 (dd, IH, J=5°14Hz),
3J5 (dd, IH, J=7.14)1z), 3.
96(s, IH).

4.51(t,2)1. J=7Hz), 6.89(d
d, IH, J=5.7Hz).

7.28-7.92 (m, 7H), 9.10 (d, I
H, J=8Hz), 9°24(d, ill.

J=8Hz) MS (m/e); 551 (M'') Example 6 Compound e obtained in Reference Example 5 in the same manner as Example 1
From 50 ag (0.1 meal), compound 6.
Obtained 33 mg (64%) as a yellow powder, mp, 295-296°C.

NMR (DNS load dS) δ; 2.03-2.2
8 (m, LH), 2.13 (s, 3H).

2.86 (d, 3H, J = 3) 1z), 3.35 (d
d, LH, J=6.13Hz), 7.00-7.20
(m, HI), 7J2-8.52 (m, 7H), 9
．． 04 (d, IH, J=8Hz).

9, 23 (d, IH, J=8Hz) MS (m/e)
: 480 (M'') Example 7 Compound (I[b) (Compound a obtained in Reference Example 1)
176 N (0.4 mmol) was dissolved in 5 ml of DMF, 136 mg (2, Q mmol) of imidazole and 181 μ (1,
2 mmol was added and stirred at room temperature. One day later, 20 all of chloroform was added, and the mixture was washed successively with a 5% aqueous citric acid solution, a saturated aqueous sodium chloride solution, and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain a mono-t-butyldimethylsilyl compound [compound (■);
i(Me)a'Bu)240w (100%) was obtained as a pale yellow amorphous.

NMR (CDC1*) δ; 0.26 (s, 6H),
1.04 (s, 9H).

2.16 (s, 3H), 2.73 (dd, IH, J
=5.14Hz), 3.08(dd.

IH, J=7.14Hz), 4.05(s, 2H)
, 4.44 (d, IH, J=17Hz).

4.86 (d, IH, J2 17Hz), 5.58 (
s, IH), 6.56 (dd, IH, J=5.7H
z), 7.00-7.64 (m, 5H), 7.
88(d,1)1. J=8Hz).

7.96 (d, IH, J=8Hz), 8.00 (s
, IH), 8.90 (d, LH, J = 8 Hz) In the same manner as in Example 1, the imide form [compound (1); R' = R"=R'=H,X=
CH1O5s (Me) *'Bu, Y=O)
i] 140 mg (75%) was obtained as a yellow powder.

NMR (CDCjl, +0 MS load dS) δ; 0
．． 24 (s, 68), 1.06 (s.

9N), 2.24 (s, 38), 2.12-2.4
4 (m, IH), 2.92-3.24 (m, IH),
3.93(d,l)1. J=10tlz), 4.0
8 (d, lH, J=10Hz).

5.38 (s, IH), 6.74 (dd, 1fl, J
=5.7Hz), 7.24-7.68(m, 5)1)
, 7.97 (d, IH, J=8Hz), 9.14 (
d, IH, J=8Hz).

9.32 (d, l)1. J=8)1z)MS(n
+/e) ; 567 (M″)) imide body 80 u
(0.14meal) in THF5mj! To the mixture was added 1 ml of a 1M (11°C) T)IF warm solution of tetra-n-butylammonium fluoride, and the mixture was stirred at room temperature. After 1 hour, the mixture was made acidic by adding 3N aqueous hydrochloric acid solution, washed with saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (
2% methanol/chloroform) to obtain the compound ?
, 75q (100%) was obtained as a yellow powder at m9.278-280°C.

NMR (CDCjl, 100 MS loads) δ;
2.13 (dd, LH, J=5.14Hz).

2.18 (s, 3H), 3. QQ-3, 36 (m, L
H), 3.76-4.04 (m, 2N).

6.76-7.00 (m, LH), 7.20-7.8
4 (m, 5H), 8.01 (d, IH.

J=8Hz), 9.12(d, LH, J=8Hz),
9.30 (d, IH, J=8Hz) MS (m/e)
;453 Example 8 Compound 1. 96+ag (0.2 mmol) in DMF
9.6 lml of 50% sodium hydride under water cooling.
ff1g (0.2 mmol) was added and stirred for 20 minutes.

Then benzyl bromide 0.024 mA (0.2 mm
ol) was added and stirred for 30 minutes under water cooling. 2 ml of saturated aqueous ammonium chloride solution and 101111 chloroform were added, and the organic layer was separated, washed with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (25% ethyl acetate/n-
Hexane) and recrystallized from methanol-chloroform to obtain 8.35 mg (30.6%) of the compound.
Obtained as yellow prism crystals at 300°C. Also, compound 9
, 18 mg (13,6%) mp, 140-147 °C
Obtained as a yellow prism product.

Compound 8: NMR (CDCj! 3) δ: 2.2
3 (s, 3H), 2.43 (dd, 18. J=
5.14Hz), 3.36 (dd, LH, J=7
．． 14Hz), 3.84(s, 1)I), 4.13
(s, 3H), 4.82 (s, 2H), 6.90 (
dd, IH, J=5.7Hz), 7.24-7.76
(m, 5H), 7.88 (d, IH, J=8flz)
.

9, 17 (d, 1M, J=8Hz), 9.46
(d, 1)1. J=8Hz)MS(m/e);
571 (M”) Compound 9: NMR (CDC13
) δ: 2.48 (s, 3N), 2.49 (dd, I
H, J=5.1411z), 3.47(dd, IH
, J=7.14Hz), 4.06(s, 3)1),
4.18(d, LH, J=111(z), 4.5
9 (d, IH, J=11Hz).

5.04 (s, 2H), 6.64-8.00 (m, 1
6H), 9.24 (d, IH, J=8Hz), 9J
6-9.50 (m, IH) MS (III/e); 6
61 (M”) Example 9 In the same manner as in Example 8, 1.96 mg of the compound (0.2
mmol) from compound 10. 60wg (60.6%
) was obtained as yellow prismatic crystals with mp of 267-269°C. Also, compound 11. 25+ag ('24.5
%) was obtained as yellow prismatic crystals with a mp of 288-294°C.

Compound 10: NMR (CDCI13) δ: 2.4
Hs, ]).

2.52 (dd, IH, J=5.14Hz), 2.9
8(s, 3H), 3;40(dd, IH.

J=7.14)1z), 4.12(s, 3H), 6
．． 87 (dd, IH, J=5.7Hz).

7.28-7.68 (m, 5H), 7.84 (d,
IH, J=8Hz), 9.05 (d, lH.

J=8)1z), 9J4(d, LH, J=8Hz)
MS (m/e); 495 (M”) Compound 11:
NMR (CDCJ s) δ: 2.40 (s, 3H)
.

2.49 (dd, LH, J=6.14Hz), 3.
16 (s, 3H), 3.24 (s, 3H).

3.42 (dd, IH, J=7.14Hz), 4.
04 (s, 3H), 6.97 (dd, IH.

J=6.7Hz), 7.32-7.68(m, 5H
), 7.90 (d, IH, J=8Hz).

9, 18 (d, IH, J=8Hz), 9.36
(d, LH, J=8Hz) MS (m/e); 5
09 (Ma Example 10 Compound 12.84 (80.3%) was extracted from compound 1.96 (0,2) by the same method as in Example 8,
Obtained as yellow prism crystals at 204-207°C.

NMR (CDCj 3) δ: 1.0 (t, 3H, J=
811z), 1.60-1.96 (m, 2H), 2
．． 21 (s, 3H), 2.38 (dd, 1)1. J＝
5.14Hz).

3.37 (dd, IH, J=7.14Hz), 3.7
0(t, 2H, J=7)(z), 4.12(s, 3
H), 6.92 (dd, LH, J=5.7Hz),
7.36-7.72 (m, 5H).

7.84 (d, lH, J=8Hz), 9.21 (d,
IH, J=8flz), 9.44 (d.

18, J=8Hz) MS (a+/e); 523 (M”) Example 11 Compound 1.96Q (0,2ma+ol) was dissolved in pyridine 1
11 and bromine 0.02 rnl (0,411I
mol) was added and stirred at room temperature for 3 hours. THF10mj
! The mixture was washed with 10% thiosulfate (10% thiosulfate) and saturated saline solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was recrystallized from pyridine-THF-chloroform to obtain compound 13.100 (78.2%).
was obtained as a yellow powder at >300°C.

NMR (CDCJ-ROMSO-ds) δ: 2.
04-2.32 (m, 18).

2.17 (s, 3H), 3.44 (dd, 1N, J=
7.14Hz), 3.98(s, 3H).

6.48 (s, IH), 7.15 (dd, 111.J
=5.7Hz), 7.59-8.04(m, 4H),
9.20 (s, IH), 9.44 (s, IH) MS
(m/e); 639 (M”) Example 12 Compound c obtained in Reference Example 3 in the same manner as in Example 1
From 550 mg (1.15 mmol), compound 14
．． mp 424+ag (75%), 175-18
Obtained as a yellow powder at 0°C.

NMR (CDCj! 3>δ; 1.26 (s, 3H),
1.47 (s, 3)ri.

2J6 (s, 3H), 2.34 (dd, 1N, J
=5.14Hz), 2.99(dd, IH.

J=7.14)1z), 4J? (d, IH, J=10
Hz), 4.60 (d, l)1. J=10Hz),
6.77 (dd, 1) 1. J=5.7Hz>, 7J2
-7.92 (m, 611).

9, 17 (d, 1N, J=8Hz), 9.36
(d, IH, J=8tlz)MS(m/e); 4
93 (M”) Example 13 Compound 7.58 (0.12 mmol) was added to DMF3mj
! Triethylamine dissolved in 0.6 tall (0,
38ff++nol) and 107 ml (0.6 mmol) of thiocarbonylimidazole were added, and the mixture was stirred at room temperature for 1 day. THF was added to the reaction solution, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The residue was tritinilated with chloroform to give compound 15.20 (33,7
%) was obtained as a yellow powder at -ρ, 260-273°C.

NMR (CDCJ!s+0MSO-ds) δ;
2.43 (s, 3H), 2.77 (dd, IH
, J=5.14Hz), 3.54(dd, 11(,J
=7.14Hz), 5.09(d, LH, J=10H
z), 5.43 (d, IH, J=10Hz), 7.
21 (dd, IH.

J=5.7Hz), 7.30-7.90(m, 68)
, 9.12 (d, IH, J=8Hz).

9, 34 (d, 1) 1. J=8Hz)MS(m/e
); 495 (M+) Example 14 Compound b obtained in Reference Example 2 in the same manner as in Example 1
From 30 mg (0,058 mmo+), compound 16
, 10 mg (32,5%) were obtained as a yellow powder with mp, >300°C.

NMR (CDCJ s+0M5O-ds) δ; 2.2
4 (s, 3H), 2.44 (dd, LH, J=5
．． 13Hz), 3.49(dd, Ift, J=7
．． 13Hz), 4.08(s, 3H), 6.27(
s, 1tl), 7.06 (dd, IH, J=5.7H
z).

7.32-7.88 (m, 3H), 8.06 (d, I
H, J=8flz), 8.40(dd.

IH, J = 2.8 Hz), 9.30 (d, IH, J =
811z), 9.80 (d, IH, J=2Hz),
10.57 (s, IH) MS (m/e); 527
(M+1)” Example 15 Compound 14 1.11 g (2.18 mmol) was added to T
Dissolved in 30 ml of HF and added 130 mL of sodium hydride under water cooling.
111 g (3,27 mmol) was added, and then after 1 q minutes, 0.44 ml (4,36 mmol) of ethyl chloroformate was added.
ol) was added thereto, and the mixture was stirred overnight at room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution, which was then washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was purified by silica gel column chromatography (chloroform) to obtain an N-ethoxycarbonyl compound [compound (
1); R'=R"=H, R'=C0iEt.

X=CHaOAc, Y=OH) 885 .mu.(70%) was obtained.

NMR (DMSO-ds) δ; 1.40 (t,
3H, J=7Hz), 2.18(s, 3H), 2.
21 (s, 3H), 2.00-2.36 (w, LH)
, 3.00-3.44 (m, LH), 4.24-4
．． 60 (m, 4H), 5.90 (s, IH).

7, 10 (m, LH), 7.28-8.16 (m,
6H), 8.98 (d, IH, J=8Hz).

9, 19 (d, IH, J=8Hz) MS (m/e)
; 568 (M+1)" 835 mg (1,44 mmol) of the above N-ethoxycarbonyl compound was added to 50 m of DMF.
Hydroxylamine hydrochloride was dissolved in 1.0 l of hydroxylamine hydrochloride under water cooling.
Og (14,4 mmol and triethylamine 2.
01 ml (144 mmol) was added thereto, and the mixture was stirred at room temperature for 3 days. After the solvent was distilled off under reduced pressure, 50 ml of THF was added to the residue, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the N-hydroxy form [Compound (1);
R'=R"=H, R3=OH, X=CH20Ac, Y=
Obtained OHI.

The N-hydroxy compound was added to 30 ml of THF without purification.
and 10 ml of methanol, and add 2.16 ml of 7 um aqueous solution (2N hydroxide) at room temperature.
Stir for hours. The reaction solution was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (7% methanol-chloroform) to obtain compound 17.112 (
17%).

NMR (MSO-d,) δ; 1.92-
2.22 (a+, LH), 2.16 (s, :jH)
, 3.08-3.40 (m, IH), 3.68-3
．． 96 (m, 2H).

5.16 (br, s, IH), 5.50 (s, LH)
, 7.04 (m, IH), 7.28-8, 12 (
+a, 6H), 9.02 (d, IH, J=8
Hz), 9.20 (d, IH, J=8Hz) (m
/e) ; 47 Q (M+1)” Example 16 Compound g obtained in Reference Example 7, 150
From l), an imide compound (%) was obtained in the same manner as in Example 1.

NMR (CDCI,) δ; 1.46 and 1.58 (
s, 3H).

2, 20-3.20 (m, 2) 1), 2.32 and 2.36 (s, 3H), 3.11 and 3.3
8 (s, 3H), 4.04-4.72 (m, 2H),
6.60-6.84 (m, lH), 7.20-8.
12 (m, 7H), 9.04-9.36 (m, 2H)
MS (m/e); 510 (M+1)” imide body 3
20mg (0.63mmol) in chloroform 20m
1 and methanol 2.51111, 1 ml of 3N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. After washing the reaction solution with saturated sodium bicarbonate solution and saturated saline, 2
1.5 ml of N sodium hydroxide and 10 ml of methanol were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed successively with 5% citric acid water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the dialcohol [compound (
I); R'=R2=R3=H, X=CH20H, Y=O
H] 320 reports were obtained.

NMR (CDIJ, -〇MSO-ds) δ;
2.08-2.12 (m, IH).

2.20 (s, 3H), 3.08-3.36 (m, I
H), 3.80-4.00 (m, 2H).

4.842 (t, IH, J=6Hz), 6.15 (s
, IH), 6.83 (m, LH).

7.20-8.04 (+a, 6M), 9.08 (d,
IH, J=8Hz), 9.26 (d, IH.

J=8Hz), 10.68(br,s,IH)MS(
m/e) ; 454 (M+1)” dialcohol body 7
43q (1.64 mmol) was dissolved in 20 ml of dioxane, 3.97 ml of hydrazine hydrate was added, and the mixture was heated at 100° C. for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform = 10:90) to obtain the N-amino form [compound (
[); R'=R"=H, R"=NH2, X=CH2OH
, Y=OH) 472■ (62%) as lρ, 245-26
Obtained as a yellow powder at 0°C.

NMR (MS load) δ; 2.19 (d
d, IN, J = 5.14 Hz).

2.16 (s, 3H), 3.00-3.40 (m, 3
H), 3.80 (br, s, 2H).

4.96 (br, s, IH), 5.44 (br, s,
LH), 6.88-7.12 (m, IH).

7.24-8.20 (m, 6H), 9.04 (d, L
H, J=8Hz), 9.04(d, LH,.

J=8Hz) MS (m/e); 469 (M"+1) N-amino compound 234 mg (0.5mIIIol) in DMF3
ml, 0.56 ml (4.2 mmol) of N,N-dimethylformamide dimethyl acetal was added thereto, and the mixture was stirred at room temperature for 2 weeks. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform/aqueous ammonia = 3/9710.1) to obtain 179 ml of compound 18 (68%).

NMR (MS load dS) δ; 2.03 (d
d, IH, J = 5.14Hz).

2.16 (s, 3H), 3.04 (s, 6H), 3
．． 00-3.26 (m, IH).

3.72-4.00 (m, 2H), 5.16 (t, I
H, J=6Hz), 5.48 (s, IH).

7.04 (m, IH), 7.28-7.72 (m, 4
H), 7.90 (d, IH, J=8Hz).

8,02 (d, IH, J=8Hz), 8.09
(s, IH), 9.03 (d, IH, J=8)
1z).

9, 22 (d, IH, J=8Hz) MS (m/e)
: 524 (M+1)'' Example 17 Dialcohol compound obtained in Example 16 [Compound (I);
R'=R2=R'=H, X=CHlOH.

Y=OH] 90q (0.2 mmol) in DMF2s
Dissolved in 35% formaldehyde aqueous solution 0.050
11 (0.6 mmol) was added and stirred at 70°C for 2.5 hours.

The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/chloroform 728% ammonia water = 2/9810.2) to obtain compound 193.
0■ (31%) was obtained.

NMR (DNS load dS) δ; 2,07(d
d, IH, J = 5.14Hz).

2.20 (s, 3H), 3.12-3.40 (m, L
H), 3.68-4.04 (n, 2H).

5.00-5.30 (m, 3H), 5.52 (s, E
), 6.40 (t, IH, J=7tlz).

7.07 (dd, IH, J=5.7Hz), 7.30
-7.80 (m, 4H), 7.92 (d.

LH, J=8H2), 8.07 (d, IH, J
=8Hz), 9.08 (d, IH, J=8Hz
).

9, 28 (d, IH, J=8Hz) MS (m/e)
484 (M+1)” Example 18 Dialcohol compound obtained in Example 16 [Compound (1);
R'=R"=R'=H, X=CH20H.

Y=OH] 90mg (0.2mmo+) in DMF2
ml of 35% formaldehyde aqueous solution 0.05
m1 (0,6 mmol) and N-methylpiperazine 0
．． 0.07ml (0.6mmol) was added thereto and stirred at 70°C for 2 days. The solvent was distilled off under reduced pressure, and 10 ml of THF was added to the residue.
was added, washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.

The residue was subjected to silica gel column chromatography (methanol/chloroform/28% aqueous ammonia = 3/9710
．． 1) to obtain compound 2044m2O44%).

NMR (DMS load dS) δ; 1.88-2
．． 80 (m, 91 (), 2.14 (s.

3H), 2.20(s, 3H), 3.08-3
．． 48 (m, 1N), 3.72-4.08 (m, 2
H), 4.64 (s, 2H), 5.18 (+n
, IH), 5.48 (s, IH).

7.06 (m, LH), 7.30-7.76 (m,
4H), 7.92 (d, 1f1.J=8)1z).

8.05 (d, IH, J=8Hz), 9.05 (d
, IH, J=8Hz), 9.24 (d, IH.

J=8)1z) MS(n+/e); 566 (M+1)"Example 1
9 Compound h obtained in Reference Example 8 in the same manner as in Example 1
From 262 mg (0.45 mmol), imide [
Compound (1); R'=R"=R'=H, X=CH2NH
Cbz, Y=OH] 17011g (64.5%
) was obtained as a yellow powder with mp, 281-285°C.

NMR (C mouth Cj7.-〇MSO-ds) δ; 2
．． 00-2.30 (m, IH).

2.18 (s, 3H), 3.05 (dd, IH, J=
7.14Hz), 3.48-3.90 (m, 2H),
5.20 (s, 2N), 5.69 (s, IH),
6.68-7.00 (m, LH).

7.08-7.70 (m, 10H), 8. OHd,
IH, J=7Hz), 9.08 (d.

1)1. J=8Hz), 9.27(d, IH, J=7
Hz) MS (m/e); 587 (M+1)” 260 mg (0.45 mmol) of imide body was added to DMFlo
60% sodium hydride at -20°C.
4 mg (1.08 mmol) was added, and after 10 minutes 1.
4 ml (4.5 mmol) of 2-dibromoethane was added, and the mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution and chloroform were added to the reaction solution, and the organic layer was separated, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (
chloroform) to obtain the N-bromoethyl compound [Compound (1) R'=R2=H.

R'=CH1CHaBr, X=CH2NHCbz.

Y=OH) 230■ (74%) was obtained.

NMR (C mouth Cj!3) δ; 2.08 (
s, 3H), 2.40-2.68 (m.

IH), 3.00-4.00 (+n, 7H), 5.
20 (s, 2H), 5J2-5.60 (m, IH)
, 6.40-6.64 (m, IH), 7.00-
7.64 (m, 10H).

7.84 (d, IH, J=8Hz), 8.66 (d,
IH, J=8Hz), 9.20 (d.

IH, J=8Hz) MS (m/e); 679 (M+1)” 210 mg (0.3 mmo+) of N-bromoethyl compound in DMF 8 m
dimethylamine hydrochloride (3 mmo
1) and 0.45 ml of DBU were added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol/chloroform/28
% ammonia water = 5/9510.1) and purified with N-
Dimethylaminoethyl compound [Compound (1); R'=R'' H1 R3=CH2CH2NMea, X=CHaNHCb z
.

Y=OH] 190■ (96%) was obtained.

NMR (CDCi! s) δ; 2.06 (s,
3H), 2.14(s, 6H).

1.96-3.96 (m, 9H), 5.19 (s,
2H), 5.80 (m, IH).

6.51 (m, IH), 6.84-7.64 (m,
1Ofl), 7.84 (d, IH, J=8Hz).

8.52 (d, IH, J=8Hz), 9.26 (
d, IH, J=8Hz) MS (m/e); 65
B (Mal)”N-dimethylaminoethyl compound 190■
(0.29 mmol) was dissolved in 5 ml of DMF, and 1
200+*g of 0% palladium/carbon was added, and the mixture was stirred at 50 to 60°C for 2 hours under a hydrogen stream. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (methanol/chloroform/28% aqueous ammonia = 10/9010.5) to obtain 122■ (81%) of compound 21.

NMR (original MSO-d6) δ: 1.84-3.
96 (m, IIH), 2.12 (s.

31(), 2.24(s, 3H), 7.03(m,
1N), 7.2B-7,72 (m, 4tl).

7.84 (d, IH, J=8Hz), 8.00 (d,
lH, J=8Hz), 9.00 (d.

IH, J=8Hz), 9.20(d, LH, J=8H
z) MS (m/e); 524 (Mal)” Example 20 Compound 1 obtained in Reference Example 9 in the same manner as Example 1
From 629■ (1 mmol), imide form [compound (1)
; R'=R''=R3=H.

X=CH2NHCOCH, NHCbZ, Y=OH)46
0■ (73%) was obtained.

NMR (original MSO-ds) δ; 1.992-
2J6 (, IH), 2.19 (s.

3H), 2.80-3.16 (m, IH), 3.5
2-4.00 (m, 4H), 5.10 (s.

2) 1), 5.77 (s, 111), 6.96 (m
, IH), 7:12-8.24 (+n, 12H).

8, 98 (d, IH, J=8Hz), 9.18
(d, IH, J=8Hz) MS (m/e); 6
45 (M+2)” imide body 400■ (0,63 chuo1
) was reduced in the same manner as in Example 19 to obtain compound 22.
320■ (100%) was obtained.

NMR (MS load dS) δ; 1.92-
2.28 (m, IH), 2.16 (s.

3H), 2.80-3.90 (m, 7H), 5.8
4 (br, s, IH), 6.96 (m.

IH), 7.24-8.40 (m, 7H), 8.9
7 (d, IH, J=8Hz), 9.16 (d, IH
, J=8Hz) MS (m/e); 510 (Mal)"Example 21 Compound 22 obtained in Example 20 277■ (0,54
mIIIol) was dissolved in 15 ml of dioxane, 1.3 ml of hydrazine hydrate was added, and the mixture was heated under reflux for 3 hours.

After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (methanol/chloroform 728% aqueous ammonia = 5/9510.1), converted to hydrochloride with 1.7 N hydrochloric acid/ethyl acetate, and compound 23 140 ■(
50%).

NMR (MSOds) δ; 2.04-2
．． 32 (m, LH), 2.20 (s.

3H), 2.96-3.96 (m, 7H), 5.8
8 (m, IH), 7.03 (m, IH).

7.28-8.40 (m, 8H), 8.76 (m, I
H), 9.04 (d, IH, J=8Hz).

9, 24 (d, lH, J=8Hz) MS (m/e)
; 525 (Mal)” Reference Example I K-252, 7,01 g (15 mmol) of anhydrous THF
(100 mA) The solution was ice-cooled, 1.14 g (30 mmo+) of lithium aluminum hydride was added thereto, and the mixture was stirred at room temperature for 2 hours. After adding methanol to destroy excess reducing agent, the reaction mixture was filtered through Celite.

The filtrate was washed with IN hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (chloroform-methanol) to obtain 5.34 g of compound a as a pale yellow powder.
(81%).

mp, 266-275°C (recrystallized from methanol) NM
R (DMS load ds + C port C1,) δ; 9.24
(d, IH, J=8Hz).

8.2-7.7 (m, 3H), 7.6-7.0 (m,
411), 6.74. (dd, 111°J=5.7H
z), 4.90 (d, 1) 1. J=1811z),
4.69 (d, IH, J=18Hz).

4, 13 (d, IH, J=11Hz), 3.9
1 (d, IH, J=11Hz), 3.29 (dd
.

IH, J=7.14Hz), 2.38(dd, I
H, J=5.14Hz), 2.19(s, 3H)
MS (m/e); 440 (Mal)" Reference Example 2 -252,467 mmol) was dissolved in 10 ml of acetonitrile, and then 133 mg (1 mmo+) of nitronium tetrafluoroborate was added and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (5% DMF/chloroform), and compound b50■ (10%) was purified by mp, > 3
Obtained as a yellow powder at 00°C.

NMR (MS load d6), δ; 2.12 (dd
, LH, J=5.14Hz), 2.16(s, 3H
), 3.45 (dd, IH, J=7.14Hz),
3.94 (s, 3H).

4.99 (d, IH, 18Hz), 5.06 (d, I
H, 18Hz), 6.44 (s, E).

7, 26 (dd, ltl, J=5.7.4Hz),
? , 39 (t, LH, J=8Hz).

7,53 (t, LH, 7Hz), 7.96 (d
, LH18Hz), 8.08(t, 2H, J=8H
z), 8.31 (dd, LH, J=2.4.7Hz)
, 8.77 (s, IH).

10,09 (d, IH, J=2Hz) MS (m/e
) ; 512 (M”) Reference Example 3 87 mg (0.2 mmol) of compound a was dissolved in chloroform 5II+1, 104 μ (l maol) of 2,2-dimethoxypropane and 10 μ of camphorsulfonic acid were added, and heated for 2 hours. The reaction solution was washed successively with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (1% methanol/chloroform). Compound c68■ (71,5%)
was obtained as a tan powder with a mp of 278-280°C.

NMR (CDCIS) δ: 1.14 (s, 3H), 1
．． 40 (s, 3H).

2.24 (s, 3tl), 2.41 (dd, LH, J
=5.14Hz), 2.82(dd, LH.

J=5.14tlz), 4.05(d, LH, J=1
0Hz), 4.49 (d, IH, J=10Hz),
4.96 (s, 2H), 6゜68 (dd, IH, J=
5.7Hz), 7.24-8.20 (m, 7H),
9.40-9.60 (m, IH) MS (m/e);
479 (Ma Reference Example 4 Compound (Ila) 4.53 g (10 mmol of anhydrous pyridine 50 mJ!) To a solution of acetic anhydride 1.42 mj (1
511IIIol) was added thereto, and the mixture was stirred at room temperature for 1 hour. The solvent in the reaction mixture was distilled off under reduced pressure, and 50 mj of IN hydrochloric acid was added to the residue, followed by stirring. Insoluble materials were collected by filtration and washed with IN hydrochloric acid and then with water. It was dried under reduced pressure to obtain 4.79 g (97%) of compound d as a pale yellow powder.

mp, 267-270°C NMR (mouth MSO-d, +c [llJ s) δ;
9.36 (d, 18.J=8 Hz).

8.2-7.7 (m, 3H), 7.7-7.25 (
m, 4N), 7.27 (dd, IH, J=5.7H
z), 5.07 (s, 2H), 3.98 (dd
, IH, J=7.14Hz) Reference Example 5 Compound d 2.5 g of thionyl chloride 60mj! The solution was heated to reflux for 2 hours. Thionyl chloride in the reaction solution was distilled off under reduced pressure, and 40w+1 ethyl ether was added to the solid residue and stirred. Insoluble matter was filtered, washed with ethyl ether, and dried under reduced pressure to obtain 2.29 g (88%) of O-acetyl-acid chloride as a pale yellow powder.

206sg (0.4mmol) of the above compound in anhydrous solution
.

Add 0.5 mJl of 30% methylamine/methanol to the form (dehydrated with phosphorus pentoxide) 511 solution, stir at room temperature for 3 hours, then add 1 ml of IN aqueous sodium hydroxide solution and 5 sj of methanol, and stir for another 1 hour. did. THF in the reaction mixture? Omj! The resulting solution was washed with IN hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound e109 (58
%) was obtained.

mm, 261-263℃ (methanol) NMR (MS)
Low dS) δ; 9.22 (d, LH, J=7.9
Hz), 8.1-7.8 (m, 3H), 7.55
-7.25 (m, 4) 1), 7.04 (dd, IH,
J = 4.7, 7.5Hz), 5.04 (d, IH, J
=17.5Hz), 4.97(d, IH.

J=17.5Hz), 3.26(dd, LH, J=7
．． 5.13.6Hz), 2.8Hd.

3H, J=4.7Hz), 2.12(s, 3H),
2.04 (dd, LH, J=4.7°13,6Hz) MS (m/e): 466 (M”) Reference Example 6 Compound (II a) 227q (0,5+no+ol
) in 20 + yJ suspension of thionyl chloride.
ml was added and heated to reflux. After 2 and 4 hours, thionyl chloride was further added at 1 mA each, and the mixture was heated under reflux for a total of 8 hours. Volatile substances in the reaction mixture are distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain compound f160 (66%) as a pale yellow powder.

mm, 193-195°C (acetone-methanol) NM
R (mouth MSO-di) δ; 9.22 (d, IH,
J=7.6Hz), 8.1-7.85(m, 3H)
, 7.55-7.25 (m, 4H), 7.11 (d
d, IH1J=4.9.7J)lz), 5.04(d
,1)1. J=17.7Hz), 4.98(d, IN
.

J=17.7Hz), 4.40(m, 2H),
3.38 (dd, IH, J=7.3.13.9Hz),
2.17 (s, 3K), 2.02 (dd, LH
, J=4.9.13.9)1z).

1,43 (t, an, J=7.1Hz) MS(s
/e); 481 (M”) Reference Example 7 Compound (Ilb) 439 (1 mmol) was suspended in 310 ml of chloroform, and 0.25 a of trimethoxyethane was added.
+1 (2IIIal) and 23μ of camphorsulfonic acid were added, and the mixture was heated under reflux for 10 minutes. The reaction solution was washed successively with saturated aqueous sodium bicarbonate and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was powdered with chloroform-ether to give compound g380 (77%
) was obtained.

NMR (COCJ!s) a; 1.40 and 1
．． 52 (s, 3H).

2.12-3.52 (m, 2H), 2.29 and 2
J2(s, 3H), 3.05 and 3.36(s, 3
H), 4.04-4.68 (m, 2H), 5.02
(s, 2H).

6.44 (s, IH), 6.73 (s, IH),
7.20-8.12 (a, 78).

9, 34 (d, IH, J=8Hz) MS (m/e)
: 496 (Mal)" Reference Example 8 Compound (II c) 438 mg (1 mmol) was added to T
Dissolved in 20 ml of HF and 10 ml of water, added 420 μm (5 mmol) of sodium bicarbonate, and then added 0.21 a+1 (1
, 5 ma+ol) was added thereto, and the mixture was stirred at the same temperature for 1 hour.

The reaction solution was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol/chloroform) to obtain compound h282M (49.3%).
Obtained as a pale yellow powder with p, >300°C.

NMR (DMSO-d@) δ; 1.88-2.20 (
m, IH), 2.15 (s, 3H).

3.00 (dd, 1)1. J=7.14Hz), 3.
40-3.72 (m, 2H), 5.00 (br, s,
28), 5.15 (s, 2H), 5.60 (s, I
H), 5.68-6.96 (m, IH), 7.12
-7.72 (m, 10H), 7.90-8.16 (m
, 2H).

8.56 (s, IH), 9.20 (d, IJI, J
=8Hz) MS (m/e); 573 (Mal)" Reference Example 9 Compound (Ilc) 131■ (0.3 mmol), N-
94 ml of benzyloxycarbonylglycine (0.45 ml) and 93 ml of DCC (0.45 a+mol) were added and stirred overnight. After the reaction is complete, the precipitate is suction filtered,
The solvent from the furnace liquid was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (2% methanol/chloroform).
Obtained as a pale yellow powder at 162°C.

NMR (DMS load dS) δ; 1.96-2.3
0 (m, LH), 2.19 (s, 3H).

2.58 (s, IH), 2.72-3.08 (m, I
H), 3.60-3.88 (m, 4H).

5.00 (s, 28), 5.11 (s, 2H), 5
．． 72 (s, IH), 6.86-8.20 (m, 13
H), 8.56 (s, IH), 9.20 (dd, I
H, J=2.8)1z)&Is(m/e); 630
(Mal)” Reference Example 10 A 10% hydroxypropyl cellulose solution was added to compound 7.
It is added to a mixture consisting of 100g of lactose, 40g of lactose, 18g of corn starch, and carboxymethylcellulose calcium Log, and kneaded. Add the mixture to 1. Granulate in an extrusion granulator with an OH screen and dry at 60°C. The dried granules are sieved through a 16-mesh sieve and magnesium stearate is added to the sieve to prepare granules for tablets.

Next, 10 per drug (170 ■) with 8 fin diameters using the usual method.
A tablet containing 0 μ of compound 7 is obtained.

Experimental Example 1 The C-kinase inhibitory activity of the compounds obtained according to the present invention was determined by the method of Hizuka Y., N15 et al.
hem,.

257, 13341 (1982)). The concentration of the test compound was varied, and the compound concentration that inhibited oxygen activity by 50% (IC5o) was determined. The results are shown in Table 3.

Table 3 C-kinase inhibitory activity of synthetic compounds 1
0,0069 6 0,004 7 0.016 14 0.017 17 1.8 19 0.066 20 0.052 23 L 1 Experimental Example 2 The histamine release inhibiting effect of the compound obtained according to the present invention was tested as follows. I looked it up.

Rats weighing 150-180 g were sacrificed by exsanguination under dry ether anesthesia using the method of 5ullivan et al. [J.

Immunol, 114.1473 (1975)]
Mast cell culture medium (mast cell culture medium) prepared according to
l medium) (abbreviated as MCM, composition: 150
+nM NaCj! , 3.7mM KCj! , 3m
M NaJP mouth.

3, 5mM KHiPOn, lmM CaC12
, 5,6mM glucose.

0.1% bovine serum albumin, 10U/mj! heparin)
, 6 ml/ania+al was injected intraperitoneally. 1
[After 2 minutes of IS surgery, the abdomen was opened and intraperitoneal exudate was collected. The exudate collected from 6 animals was heated at 4℃ and 1100X.
After centrifugation for 5 minutes at
Cell suspension (per
itoneal exudate cells, P
(abbreviated as EC) was prepared. In addition, the identification of mast cells is 0.
．． This was done by staining intracellular granules with 0.05% toluidine blue. PEC1mJ obtained in this way! 3
After pre-incubating at 7°C for 10 minutes, add 0.1 mJ of test drug solutions of various concentrations and ink for 10 minutes! 100 μg/ml of phosphatidyl-serine and 100 μg/ml of concanavalin A.
．． 1mM was added and incubated for an additional 15 minutes.

After stopping the reaction by adding 3 ml of ice-cold physiological saline,
The supernatant and precipitate were obtained by centrifugation at 1 l 100X for 10 minutes at °C. The amount of histamine in the supernatant and sediment was measured by fluorescence method according to the method of Komatsu [Allergy 27゜67 (197B)]. Histamine release rate was expressed as a percentage of the amount of histamine in the supernatant relative to the total amount of histamine in the cells. In addition, the histamine release inhibition rate of the test drug solution was calculated using the following formula.

Release inhibition rate (%) The concentration of the test compound was varied, and the compound concentration (IC5°) that inhibited histamine release by 50% was determined.

The results are shown in Table 4.

Table 4 Experimental Example 3 of Synthetic Compounds for Inhibiting Histamine Release The cell growth inhibiting activity of the compounds obtained according to the present invention was tested by the following method, and the results are shown in Table 5.

(1)MCF? Cell growth inhibition test: In a 96-well microtiter plate, add 10% beef tallow serum to a 96-well microtiter plate. Dispense 1 ml of MCF7 cells prepared at 4.5 x 104 cells/ml in RPMl 164G medium containing insulin 10-''M estradiol into each well. Incubate overnight in a carbon dioxide incubator.
After culturing at ℃, the test sample diluted appropriately with culture medium was
．． Add 0.5ml each. In the case of 72-hour contact, culture the cells in a carbon dioxide incubator, remove the culture supernatant, wash - times with PBS (-), and add 0.1 ml of fresh medium to each well. Culture in a carbon dioxide gas incubator at 37°C for 72 hours. After removing the culture supernatant, 0.1 ml of a culture solution containing 0.02% Nibineal Red is added to each well and cultured at 37° C. for 1 hour in a carbon dioxide incubator to stain the cells. After removing the culture supernatant, wash once with physiological saline,
After extracting the dye with N-hydrochloric acid/30% ethanol, the absorption of 550nIII is measured using a microplate reader. By comparing the absorption of untreated cells and cells treated with a drug at a known concentration, the drug concentration that inhibits cell proliferation by 50% is calculated and defined as IC3°.

(2) HeLaSs cell growth inhibition test: In a 96-well microtiter plate, 0.11 HeLaSs cells prepared at 3X10 cells/m1 in MEM medium containing 10% tallow serum and 2mM glutamine were added to each cell. Dispense into wells.

Perform in the same manner as after well dispensing in (1).

(3) COLO320DM cell growth inhibition test = 10% tallow serum 100% in a 96-well microtiter plate.
u/ml penicillin, 100 q/m! RPMI 1640 medium containing streptomycin t'IO' pieces/m
Dispense 0.1 ml of the prepared 1L COLO320DM cells into each well. The following procedure is carried out in the same manner as in (1), and the number of cells is calculated using a microcell counter. By comparing the cell numbers of untreated cells and cells treated with a drug at a known concentration, the drug concentration that inhibits cell proliferation by 50% is calculated, and this is used for ICS. shall be.

7 0.95 0.181
? 0.13 0.1T O,1
3190,260,160,03 200,0,80,150,03 230,1? 0.71 1.00 Effects of the Invention Compound (1) and its pharmacologically acceptable salts exhibit C-kinase inhibitory activity, antihistamine release inhibitory activity, platelet aggregation inhibitory activity, anti-inflammatory activity, cell growth inhibitory activity, etc. It is expected to be useful as an active ingredient in antiallergic agents, antithrombotic agents, antiinflammatory agents, antitumor agents, and the like.

Procedural amendment (voluntary)

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ {In the formula, R^1 and R^2 are the same or different and represent hydrogen, bromine, or nitro, and R^3 is hydrogen, lower alkyl, Aralkyl or -(CH_2)_nZ [wherein,
Z is hydroxy, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (
In the formula, R^4 and R^5 are the same or different and are hydrogen,
(represents lower alkyl or a group forming a heterocycle with the adjacent nitrogen atom) or ▲represents a mathematical formula, chemical formula, table, etc.▼, where n represents 0, 1 or 2], and X is carboxyl, lower alkoxy Represents carbonyl, carbamoyl, lower alkylaminocarbonyl, hydroxymethyl, or substituted or unsubstituted aminomethyl, where the substituent is an acyl group obtained by removing the hydroxy group from the carboxyl group of an amino acid, and Y is hydroxy, lower alkoxy Or it is aralkyloxy, or when X and Y are combined as -Y-X-, -O-C(CH_3)_2-O-CH_2- or ▲There is a mathematical formula, chemical formula, table, etc.▼} K expressed
-252 derivatives and pharmacologically acceptable salts thereof.