JPH09208571A - Alkylidenecyclohexane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent neovascularization inhibiting action, physical stability and low toxicity and useful as an agent for the treatment and prevention of rheumatoid arthritis, psoriasis, diabetic retinopathy, cancer, etc. SOLUTION: The objective compound is expressed by formula I [R<1> is a (substituted)hydrocarbon group; R<2> is H, R<1> or a (substituted)acyl; R<3> and R<4> are each H, R<1> , or together form a (substituted)cyclic hydrocarbon group; X is O, S or group of the formula NR<5> (R<5> is H or R<1> ); R<1> is not 2-methylpropyl when R<2> is acetyl and X is O]or its salt, e.g. (2R,3S,4R)4-acetoxy-3-methoxy-2-[(2 R,3R)-2-methyl-3-(3-methyl-2-butenyl)oxiran-2-yl]-1-methylenecyclohexane. The compound of formula I can be produced e.g. by the elimination reaction of a compound of formula II (W is a protecting group; Y is an eliminable group).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an alkylidenecyclohexane derivative or a salt thereof, a method for producing the same, and a medicine containing the same.

[0002]

BACKGROUND OF THE INVENTION Angiogenesis is deeply involved in the onset or progression of chronic inflammatory diseases such as rheumatoid arthritis and psoriasis, ophthalmic diseases associated with ischemia such as diabetic retinopathy, and solid cancer. . Therefore, inhibition of angiogenesis is thought to lead to treatment of these diseases. Up to now, many compounds having an angiogenesis-inhibiting effect have been reported, but a compound showing excellent effects in clinical trials and having low toxicity has not yet been found. Further, conventional compounds having an angiogenesis-suppressing action still have problems in terms of instability of physical properties, administration method and side effects. On the other hand, as a compound in which the spiroepoxy ring of the fumagillin derivative is substituted with alkylidene, "Journal of American Chemical Society (J. Am. Chem. Soc.), No. 83, 3097-3113, 1961. , The compound

Embedded image Is described as a production intermediate.

[0003]

There is a demand for the development of a drug having excellent angiogenesis-inhibiting activity and exhibiting a sufficient therapeutic effect against various diseases, which is stable in physical properties and low in toxicity.

[0004]

Means for Solving the Problems The inventors of the present invention have made various studies in view of the above problems, and as a result, have found that the spiroepoxy ring of the fumagillin derivative is substituted with alkylidene, which is a novel chemical structure. General formula [I]:

Embedded image [Wherein, R ¹ is a hydrocarbon group which may have a substituent,
R ² is a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³
And R ⁴ may together form a cyclic hydrocarbon which may have a substituent, X is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a substituent Represents a hydrocarbon group which may be present). However, when R ² is an acetyl group and X is an oxygen atom, R ¹ excludes a 2-methylpropyl group. ] For the first time, a compound represented by Based on these findings, it was found to be useful as a therapeutic and prophylactic agent for chronic inflammatory diseases (eg, rheumatoid arthritis, psoriasis, etc.), ophthalmic diseases associated with ischemia (eg, diabetic retinopathy, etc.), cancer and the like. And completed the present invention.

That is, the present invention provides (1) the compound [I] or a salt thereof, (2) the compound according to the above (1), wherein R ¹ is an optionally substituted aliphatic hydrocarbon group, ( 3) R ¹
Is a 2-methylpropyl or 2-methyl-1-propenyl group which may have a substituent, (4) The compound described in (1) above, (4) The compound described in (1) above, wherein R ² is an acyl group. (5) The compound according to (4) above, wherein the acyl group is a carbamoyl group which may have a substituent, (6) the compound according to (1) above, wherein R ³ and R ⁴ are both hydrogen atoms,
(7) The compound described in (1) above, wherein X is an oxygen atom or NH, (8) R ¹ is an alkyl or alkenyl group which may have a substituent, and R ² is an acyl group (1) (9) The compound described in (8) above, wherein R ³ and R ⁴ are both hydrogen atoms, (10) X is an oxygen atom or N
The compound according to the above (9) which is H, (11) R ² has an aliphatic acyl group which may have a substituent, an optionally substituted aroyl group, which has a substituent A heterocyclic carbonyl group, a carbamoyl group which may have a substituent or a thiocarbamoyl group which may have a substituent, (12) wherein R ¹ is 2-methyl The compound according to (11) above, which is a propyl group or a 2-methyl-1-propenyl group, (13) the compound according to (12), wherein X is an oxygen atom, (14) R ¹ is a 2-methylpropyl group, or 2-methyl-1-propenyl group, carbamoyl group in which R ² may have a substituent, R ³ and R ⁴ are both hydrogen atoms, and X is an oxygen atom, (1) The compound described in (15) ) General formula

Embedded image [Wherein, R ¹ is a hydrocarbon group which may have a substituent,
R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³ and R ⁴ together form a cyclic hydrocarbon which may have a substituent. May be. Or a salt thereof. (16) (a) General formula

Embedded image [In the formula, W is a protecting group, Y is a leaving group, and other symbols are as described above.
(1) Shows the same meaning as described. ] The compound represented by or a salt thereof is subjected to an elimination reaction, (b) the general formula

Embedded image [The symbols in the formula are as defined above. Or a salt thereof, with a compound R ² -Z is expressed by] (Z is a leaving group, R ² is. Which as defined above) is reacted with a compound represented by, (c) general formula

Embedded image [The symbols in the formula are as defined above. ] Or a salt thereof is subjected to an alkylideneation reaction, or (d) the general formula

Embedded image [The symbols in the formula are as defined above. A compound represented by] or the preparation of a compound represented by or wherein (1) a compound according reacting a salt thereof with a salt thereof with R ⁵ NH ₂ (R ⁵ is as defined above.) ( 17) General formula

Embedded image [In the formula, R ^1a represents a hydrocarbon group which may have a substituent,
R ² is a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³
And R ⁴ may together form a cyclic hydrocarbon which may have a substituent, X is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a substituent Represents a hydrocarbon group which may be present). ] The drug containing the compound or its salt represented by these, (18) The medicine of the said (17) description which shows an angiogenesis inhibitory action, (19) The therapeutic agent with respect to the disease accompanied with angiogenesis. Related to medicine, etc.

In the above general formula [I], R ¹ , R ^1a , R ² and
The “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)” represented by R ³ , R ⁴ and R ⁵ is, for example, an aliphatic hydrocarbon group having 1 to 20 carbon atoms or a carbon number. 3 to 20 cyclic hydrocarbon groups are used. Specific examples include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a cycloalkenyl group and an aryl group. The “hydrocarbon group” represented by R ¹ and R ^1a is preferably an aliphatic hydrocarbon group (eg, an alkyl group, an alkenyl group, an alkynyl group, etc.). More preferred examples include a 2-methylpropyl group and a 2-methyl-1-propenyl group. As the “hydrocarbon group” represented by R ² , for example, an aliphatic hydrocarbon group (eg, an alkyl group, an alkenyl group, an alkynyl group, etc.) is generally used. The “hydrocarbon group” represented by R ³ and R ⁴ is preferably, for example, an aliphatic hydrocarbon group (eg, an alkyl group, an alkenyl group, an alkynyl group, etc.), and an alkyl group is particularly commonly used. The “hydrocarbon group” represented by R ⁵ is preferably, for example, an aliphatic hydrocarbon group (eg, an alkyl group, an alkenyl group, an alkynyl group, etc.), and an alkyl group is particularly commonly used. The "alkyl group"
Is, for example, methyl, ethyl, propyl, 2-propyl, 1-ethylpropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl,
Preferred are C _1-10 alkyl groups such as 1,1-dimethylbutyl, 2,2-dimethylbutyl, pentyl, 3-methylbutyl, 2,2-dimethylpropyl and hexyl.
The "alkenyl group" is, for example, ethenyl, 2-propenyl, 1-methylethenyl, butenyl, 2-methyl-1-.
Propenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 2-hexenyl, 3-hexenyl, 5
A C _2-10 alkenyl group such as -hexenyl and the like are preferable. The "alkynyl group" is, for example, ethynyl, 2-propynyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyn-3-yl, 3-pentyn-1-yl, 4-pentyn-yl. A C _2-10 alkynyl group such as 2-yl and 3-hexyn-1-yl is preferable. The "cycloalkyl group" is preferably a C _3-10 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The “cycloalkenyl group” is preferably a C _3-10 cycloalkenyl group such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl and the like. The "aryl group"
Is preferably a C _6-14 aryl group such as phenyl, 1-naphthyl, 2-naphthyl and the like. The general formula [I]
In the above, the “cyclic hydrocarbon” of the “cyclic hydrocarbon optionally having substituent (s)” formed by combining R ³ and R ⁴ represents, for example, a 3- to 7-membered cyclic hydrocarbon, For example, C
_3-7 cycloalkylidene (eg, cyclopentylidene, cyclohexylidene, etc.), C _3-7 cycloalkenylidene (eg, cyclopentenylidene, cyclohexenylidene, etc.) and the like may be formed.

In the above general formula [I], the "acyl group" represented by R ² is, for example, a carboxylic acid acyl group which may have a substituent or a sulfonic acid which may have a substituent. Acyl group, a carbamoyl group which may have a substituent, a thiocarbamoyl group which may have a substituent, an acid residue such as a sulfamoyl group which may have a substituent, and the like, For example, an aliphatic acyl group which may have a substituent, an aroyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, and a substituent which may have a substituent. Carbamoyl group, optionally substituted thiocarbamoyl group, optionally substituted aliphatic sulfonyl group, optionally substituted arylsulfonyl group, optionally substituted Having a good sulfamoyl group, a substituent Which may be aliphatic oxycarbonyl group, and an aryloxy group which may have a substituent. Among these, for example, an aliphatic acyl group which may have a substituent, an aroyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, and a substituent which has a substituent. A carbamoyl group which may be substituted, a thiocarbamoyl group which may be substituted and the like are preferable, and a carbamoyl group which may be substituted is most widely used. The "aliphatic" of the "aliphatic acyl group", "aliphatic sulfonyl group" and "aliphatic oxycarbonyl group" means, for example, a saturated or unsaturated aliphatic hydrocarbon having 1 to 10 carbon atoms. Preferred are, for example, C _1-10 alkyl (eg methyl, ethyl,
Propyl, 2-propyl, 1-ethylpropyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1
-Dimethylethyl, 1,1-dimethylbutyl, 2,2-
Dimethylbutyl, pentyl, 3-methylbutyl, 2,2
-Dimethylpropyl, hexyl, etc., C _2-10 alkenyl (eg ethenyl, 2-propenyl, 1-methylethenyl, butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl) ,
2-pentenyl, 3-pentenyl, 4-pentenyl, 2
-Hexenyl, 3-hexenyl, 5-hexenyl, etc.), C _2-10 alkynyl (eg ethynyl, 2-propynyl, 2-butyn-1-yl, 3-butyn-2-yl,
1-pentyn-3-yl, 3-pentyn-1-yl, 4
-Pentin-2-yl, 3-hexyn-1-yl, etc.)
And the like. The “aliphatic acyl group” of the “aliphatic acyl group optionally having substituent (s)” is, for example, C _1-6
Alkanoyl groups (eg formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl,
Hexanoyl etc.), C _2-6 alkenyloxy groups (eg allyloxy, isopropenyloxy etc.), C
_{2-6 represents an} alkynyloxy group (eg, propargyloxy etc.) and the like.

The "aroyl group" of the "aroyl group which may have a substituent (s)" is, for example, a C _7-11 aroyl group (eg benzoyl, 1-naphthoyl, 2-naphthoyl etc.) and the like. The “heterocyclic carbonyl group” of the “heterocyclic carbonyl group which may have a substituent (s)” means 5 or 1 containing 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to carbon atoms. 6-membered heterocyclic carbonyl group (for example, 3-pyrrolylcarbonyl, 2-imidazolylcarbonyl, 1-pyrazolylcarbonyl, 3-isothiazolylcarbonyl, 3-isoxazolylcarbonyl, pyrazinylcarbonyl, 2-pyrimidinylcarbonyl, 3-pyrazinylcarbonyl, 2-indoridinylcarbonyl, 2-isoindolylcarbonyl, 1-indolylcarbonyl, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.) and the like. The “aliphatic sulfonyl group” of the “aliphatic sulfonyl group optionally having substituent (s)” is, for example, C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), C _2-6 alkenyl A sulfonyl group (eg, allylsulfonyl, isopropenylsulfonyl, etc.), a C _2-6 alkynylsulfonyl group (eg, propargylsulfonyl, etc.) are shown. The “arylsulfonyl group” of the “arylsulfonyl group optionally having substituent (s)” is, for example, a C _6-14 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.) and the like. Indicates. The “aliphatic oxycarbonyl group” of the “aliphatic oxycarbonyl group which may have a substituent (s)” means a C _1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl,
Butoxycarbonyl, isobutoxycarbonyl, etc.),
A C _2-6 alkenyloxy-carbonyl group (eg, aryloxycarbonyl, isopropenyloxycarbonyl, etc.), a C _2-6 alkynyloxy-carbonyl group (eg, propargyloxycarbonyl, etc.) and the like are shown. The “aryloxycarbonyl group” of the “aryloxycarbonyl group which may have a substituent (s)” means C
_{6-14 represents an} aryloxy-carbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.) and the like.

In the above general formula [I], R ¹ , R ^1a , R ² and
The substituent which the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” represented by R ³ , R ⁴ and R ⁵ may have, but is not particularly limited to, for example, Amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, etc.), mono- or di-C _6-10 arylamino group ( For example, phenylamino, diphenylamino, etc.), mono-
Or a di-C _7-11 aralkylamino group (eg, benzylamino, dibenzylamino etc.), an azido group, a nitro group, a halogen (eg, fluorine, chlorine, bromine, iodine etc.), a hydroxyl group, C _1-6 alkoxy Groups (eg,
Methoxy, ethoxy, propoxy, isopropoxy, butoxy etc.), C _6-10 aryloxy group (eg phenoxy, 1-naphthyloxy, 2-naphthyloxy etc.), C _7-11 aralkyloxy group (eg benzyloxy etc.) ), Formyloxy group, C _1-6 alkyl-carbonyloxy group (eg, acetoxy, propionyloxy, etc.), C _6-10 aryl-carbonyloxy group (eg, benzoyloxy, etc.), C _7-11 aralkyl-carbonyloxy Group (for example, benzylcarbonyloxy and the like), sulfonyloxy group, C _1-6 alkylsulfonyloxy group (for example, methylsulfonyloxy and the like),
Mercapto group, C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), C _6-10 arylthio group (eg, phenylthio,
1-naphthylthio, 2-naphthylthio etc.), C _7-11 aralkylthio group (eg benzylthio etc.), phosphonooxy group, cyano group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group (eg methylcarbamoyl). , Ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), mono- or di-C
_6-10 arylcarbamoyl group (eg, phenylcarbamoyl, diphenylcarbamoyl, etc.), mono- or di-C _7-11 aralkylcarbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl, etc.), carboxyl group, C _1-6 alkoxy- A carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.),
A C _6-10 aryloxy-carbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-
Naphthyloxycarbonyl etc.), C _7-11 aralkyloxy-carbonyl group (eg benzyloxycarbonyl etc.), formyl group, C _1-6 alkyl-carbonyl group (eg acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl) Etc.), C
_6-10 aryl-carbonyl groups (eg benzoyl, 1
-Naphthoyl, 2-naphthoyl etc.), C _7-11 aralkyl-carbonyl group (eg benzylcarbonyl etc.), sulfo group, C _1-6 alkylsulfinyl group (eg methylsulfinyl, ethylsulfinyl etc.),
C _6-10 arylsulfinyl group (eg, benzenesulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), C
_6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-6 cyclo Alkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), 1 to 3
Cyclic heterocyclic group (for example, a heterocyclic group formed from 1 to 3 5- or 6-membered ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur: pyridyl, pyrazyl, pyrimidyl, quinolyl, Isoquinolyl, indolyl, isoindolyl, indazolyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, furyl, benzofuranyl, thienyl, benzothienyl, benzimidazolyl,
Quinazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indoridyl, isoindolidyl, morpholinyl, etc.) and the like are used. In the above-mentioned “hydrocarbon group”, the cyclic hydrocarbon group may be a C _1-6 alkyl group (eg,
Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl etc.), C _2-6 alkenyl group (eg vinyl, allyl, 2-butenyl etc.), C _2-6 alkynyl group (eg ethynyl, propargyl etc.) ), An oxo group and the like may be present on the ring. These substituents are substituted on the “hydrocarbon group” within a chemically acceptable range, and the number of substituents of this substituent is 1 to 5,
The number is preferably one to three. However, when the number of substituents is two or more, they may be the same or different.

The substituents of the above-mentioned "hydrocarbon group" may, if chemically permitted, further be an amino group, a mono- or di- group.
C _1-6 alkylamino group, mono- or di-C _6-10 arylamino group, mono- or di-C _7-11 aralkylamino group, azido group, nitro group, halogen, hydroxyl group, C _1-6 alkoxy Group, C _6-10 aryloxy group, C
_7-11 aralkyloxy group, formyloxy group, C _1-6 alkyl-carbonyloxy group, C _6-10 aryl-carbonyloxy group, C _7-11 aralkyl-carbonyloxy group, sulfonyloxy group, C _1-6 alkyl Sulfonyloxy group, mercapto group, C _1-6 alkylthio group, C _6-10
Arylthio group, C _7-11 aralkylthio group, phosphonooxy group, cyano group, carbamoyl group, mono- or di-
C _1-6 alkylcarbamoyl group, mono- or di-C
_6-10 arylcarbamoyl group, mono- or di-C _7-11
Aralkylcarbamoyl group, carboxyl group, C _1-6 alkoxy-carbonyl group, C _6-10 aryloxy-carbonyl group, C _7-11 aralkyloxy-carbonyl group, formyl group, C _1-6 alkyl-carbonyl group, C _{6 -10} aryl-carbonyl group, C _7-11 aralkyl-carbonyl group, sulfo group, C _1-6 alkylsulfinyl group, C _6-10
Arylsulfinyl group, C _1-6 alkylsulfonyl group, C _6-10 arylsulfonyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkenyl group, C _6-10 aryl group,
Substitution of 1 to 5 (preferably 1 to 3) selected from 1 to 3 cyclic heterocyclic groups, C _1-6 alkyl groups, C _2-6 alkenyl groups, C _2-6 alkynyl groups, oxo groups and the like. It may have a group. The definitions of these substituents are as defined above. Further, the groups included in the range of the “hydrocarbon group” may also have the same substituents as described above.

The "acyl group" is not particularly limited,
For example, amino group, mono- or di-C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, etc.), mono- or di-C _6-10 arylamino group. (Eg, phenylamino, diphenylamino, etc.), mono- or di-C _7-11 aralkylamino group (eg, benzylamino, dibenzylamino, etc.), azido group, nitro group, halogen (eg, fluorine, chlorine, bromine) , Iodine, etc.), hydroxyl group, C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, etc.), C _6-10 aryloxy group (eg, phenoxy, 1-naphthyloxy, 2-naphthyl). Oxy), C _7-11 aralkyloxy groups (eg benzyloxy), Rucapto group, C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, etc.), C _6-10 arylthio group (eg, phenylthio, 1-naphthylthio, 2-naphthylthio, etc.), C _7-11 aralkylthio group Groups (eg,
Benzylthio), phosphonooxy group, cyano group, carbamoyl group, mono- or di-C _1-6 alkylcarbamoyl group (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, etc.), mono- or di-C _{6- 10} arylcarbamoyl group (eg, phenylcarbamoyl, diphenylcarbamoyl, etc.), mono- or di-C _7-11 aralkylcarbamoyl group (eg, benzylcarbamoyl, dibenzylcarbamoyl, etc.), carboxyl group, C _1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, etc.), C _6-10 aryloxy - carbonyl group (e.g., phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), C _7-11 aralkyl Carboxy - carbonyl group (e.g., benzyloxycarbonyl), formyl groups, C
_1-6 alkyl-carbonyl group (eg, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C _6-10 aryl-carbonyl group (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _{7 -11} aralkyl-carbonyl group (eg benzylcarbonyl etc.), sulfo group, C _1-6 alkylsulfinyl group (eg methylsulfinyl, ethylsulfinyl etc.), C _6-10 arylsulfinyl group (eg benzenesulfinyl, 1- Naphthylsulfinyl, 2-naphthylsulfinyl, etc., C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl,
2-naphthylsulfonyl etc.), C _3-6 cycloalkyl group (eg cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl etc.), C _3-6 cycloalkenyl group (eg cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl etc.) ), A C _6-10 aryl group (eg, phenyl, 1-naphthyl, 2-naphthyl, etc.), a 1 to 3 ring heterocyclic group (eg, nitrogen,
Heterocyclic group formed from 1 to 3 5- or 6-membered ring containing 1 to 4 heteroatoms selected from oxygen and sulfur:
Pyridyl, pyrazyl, pyrimidyl, quinolyl, isoquinolyl, indolyl, isoindolyl, indazolyl,
Pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl,
Furyl, benzofuranyl, thienyl, benzothienyl,
Benzimidazolyl, quinazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, indolizyl, isoindolidyl, morpholinyl, etc.),
1 to 3 cyclic heterocyclic carbonyl group (for example, a group in which a carbonyl group is bonded to the same heterocyclic group as described above, specifically, 3-pyrrolylcarbonyl, 2-imidazolylcarbonyl, 1-pyrazolylcarbonyl, 3- Isothiazolylcarbonyl, 3-isoxazolylcarbonyl, pyrazinylcarbonyl, 2-pyrimidinylcarbonyl, 3-pyrazinylcarbonyl, 2-indolidinylcarbonyl,
2-isoindolylcarbonyl, 1-indolylcarbonyl, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc., 1 to 3 cyclic heterocyclic thio group (for example, a thio group is bonded to the above heterocyclic group) Groups, specifically 4-pyridylthio, 2-pyrimidylthio, 1,3,4
-Thiadiazol-2-ylthio, 5-tetrazolylthio, 2-benzothiazolylthio, 8-quinolylthio, etc.) and the like. In the “acyl group”,
Those containing a cyclic group include, for example, a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, etc.), C _{2-6 in} addition to the above-described substituents. Alkenyl group (for example, vinyl, allyl, 2-butenyl, etc.), C _2-6 alkynyl group (for example,
Ethynyl, propargyl, etc.), oxo group, etc. may be present on the ring. When R ² represents a di-substituted carbamoyl group, a thiocarbamoyl group or a sulfamoyl group, the carbamoyl group, the thiocarbamoyl group or the sulfamoyl group represents a 4- to 7-membered nitrogen-containing heterocycle (for example, pyrrolidine) together with the nitrogen atom. -1-yl,
Piperidino, morpholino, piperazin-1-yl, 4
-Methylpiperazin-1-yl, 4-phenylpiperazin-1-yl, etc.) may be formed. These substituents are included on the “acyl group” within a chemically acceptable range, and the number of the substituents is 1 to 5, preferably 1 to 3. However, when the number of substituents is two or more, they may be the same or different.

[0012] If chemically permitted, these substituents may further have 1 to 5 (preferably 1 to 3) substituents at substitutable positions. Examples of such a substituent include an amino group, mono- or di-
C _1-6 alkylamino group, mono- or di-C _6-10 arylamino group, mono- or di-C _7-11 aralkylamino group, azido group, nitro group, halogen, hydroxyl group, C _1-6 alkoxy Group, C _6-10 aryloxy group, C
_7-11 aralkyloxy group, formyloxy group, C _1-6 alkyl-carbonyloxy group, C _6-10 aryl-carbonyloxy group, C _7-11 aralkyl-carbonyloxy group, sulfonyloxy group, C _1-6 alkyl Sulfonyloxy group, mercapto group, C _1-6 alkylthio group, C _6-10
Arylthio group, C _7-11 aralkylthio group, phosphonooxy group, cyano group, carbamoyl group, mono- or di-
C _1-6 alkylcarbamoyl group, mono- or di-C
_6-10 arylcarbamoyl group, mono- or di-C _7-11
Aralkylcarbamoyl group, carboxyl group, C _1-6 alkoxy-carbonyl group, C _6-10 aryloxy-carbonyl group, C _7-11 aralkyloxy-carbonyl group, formyl group, C _1-6 alkyl-carbonyl group, C _{6 -10} aryl-carbonyl group, C _7-11 aralkyl-carbonyl group, sulfo group, C _1-6 alkylsulfinyl group, C _6-10
Arylsulfinyl group, C _1-6 alkylsulfonyl group, C _6-10 arylsulfonyl group, C _3-6 cycloalkyl group, C _3-6 cycloalkenyl group, C _6-10 aryl group,
1 to 3 ring heterocyclic group, 1 to 3 ring heterocyclic carbonyl group, 1 to 3 ring heterocyclic thio group, C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, Examples thereof include an oxo group. These substituents further include amino group, mono- or di-C _1-6 alkylamino group, nitro group, halogen, hydroxyl group, C _1-6 alkoxy group,
It may have 1 to 3 substituents selected from a cyano group, a carbamoyl group, a carboxyl group, a C _1-6 alkoxy-carbonyl group, a C _1-6 alkyl-carbonyl group and the like. The definitions of these substituents are as defined above. Further, the groups included in the range of the “acyl group” may have the same substituents as described above. The substituent that the “cyclic hydrocarbon” of the “cyclic hydrocarbon that may have a substituent” may have is the same as the substituent that the “hydrocarbon group” may have. The thing etc. are used.

In the above general formula [I], R ¹ and R ^1a each represent a hydrocarbon group which may have a substituent. R
¹ and R ^1a are each preferably an optionally substituted alkyl or alkenyl group, and particularly preferably an optionally substituted 2-methyl-1-propenyl or 2-
It is commonly used when it is a methylpropyl group. R ¹ is preferably, for example, 2-methyl-1-propenyl or 2-methylpropyl group which may be substituted with hydroxyl group, diC _1-6 alkylamino group (eg, dimethylamino etc.), and the like. The commonly used ones are an unsubstituted 2-methyl-1-propenyl group and a 2-methylpropyl group. As used herein, "may have a substituent"
Are the same as those exemplified as the substituent of the above-mentioned "hydrocarbon group". In the above general formula [I], R ² represents a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group. R ² is preferably an acyl group (eg, an acid residue such as a carboxylic acid acyl group which may have a substituent and a carbamoyl group which may have a substituent). In particular, an aliphatic acyl group which may have a substituent, an aroyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, and which may have a substituent. A good carbamoyl group and a thiocarbamoyl group which may have a substituent are preferable, and a carbamoyl group which may have a substituent is generally used. The “which may have a substituent” here has the same meaning as that exemplified as the substituent of the aforementioned “acyl group”. In the general formula [I], R ³ and R ⁴ each represent a hydrogen atom or a hydrocarbon group which may have a substituent. Further, R ³ and R ⁴ may be combined together to form a cyclic hydrocarbon which may have a substituent. The "cyclic hydrocarbon" is preferably unsubstituted. It is preferable that both R ³ and R ⁴ are hydrogen atoms. The “which may have a substituent” here has the same meaning as that exemplified as the substituent of the above-mentioned “hydrocarbon group”. In the general formula [I], X
Represents an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ represents a hydrogen atom or a hydrocarbon group which may have a substituent). X is preferably an oxygen atom or NH. The "which may have a substituent" here means the above-mentioned "hydrocarbon group".
It has the same meaning as that exemplified as the substituent of.

Preferred embodiments of the general formula [I] are, for example, the following (A) to (E). (A) R ¹ is a hydrocarbon group which may have a substituent, R ²
Is a hydrocarbon group which may have a substituent, R ³ and R ⁴
When both are hydrogen atoms and X is an oxygen atom. (B) R ¹ is a hydrocarbon group which may have a substituent, R ²
Is a hydrocarbon group which may have a substituent, R ³ and R ⁴
Are both hydrogen atoms and X is NR ⁵ (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent). (C) R ¹ is a hydrocarbon group which may have a substituent, R ²
Is an acyl group, R ³ and R ⁴ are both hydrogen atoms, and X is an oxygen atom. (D) R ¹ is a hydrocarbon group which may have a substituent, R ²
Is an acyl group, R ³ and R ⁴ are both hydrogen atoms, and X is NR.
⁵ (R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent). (E) R ¹ is a hydrocarbon group which may have a substituent, R ²
Is an acyl group, R ³ and R ⁴ are both hydrogen atoms, and X is a sulfur atom. The definition and preferred range of each symbol are the same as above.

Preferred embodiments of the general formula [I] are, for example, the following (F) to (I). (F) 2-methyl-1 in which R ¹ may have a substituent
-Propenyl or 2-methylpropyl group, R ² is an acyl group, R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, X is an oxygen atom, a sulfur atom or NR ⁵ (R ^{5 5} is a hydrogen atom or a hydrocarbon group which may have a substituent). (G) In the above (F), R ³ and R ⁴ are hydrogen. (H) In the above (G), X is an oxygen atom. (I) In the above (H), R ² is an aliphatic acyl group which may have a substituent, an aroyl group which may have a substituent or a carbamoyl group which may have a substituent. If there is. The definition and preferred range of each symbol are the same as above.

Preferred embodiments of the general formula [I] are, for example, the following (J) to (L). (J) R ¹ is 2-methyl-1-propenyl or 2-methylpropyl group, R ² is optionally substituted aliphatic acyl group, optionally substituted aroyl group or substituted A carbamoyl group which may have a group, R ³ and R ⁴ are hydrogen atoms, X is an oxygen atom, a sulfur atom or NR ⁵
(R ⁵ is a hydrogen atom or a hydrocarbon group which may have a substituent). (K) In the above (J), R ² is a carbamoyl group which may have a substituent. (L) In the above (K), X is an oxygen atom. The definition and preferred range of each symbol are the same as above.
More preferable embodiments in the general formula [I] are, for example, the following (M) to (N). (M) R ¹ is a 2-methyl-1-propenyl or 2-methylpropyl group, R ² is a substituted carbamoyl group, R ³
And R ⁴ are both hydrogen atoms and X is an oxygen atom. (M) In the above (L), R ¹ is a 2-methyl-1-propenyl group and R ² is a carbamoyl group substituted with a monochloroacetyl group. (N) In the above (L), R ² is a 2-methylpropyl group and R ² is a carbamoyl group substituted with a monochloroacetyl group. In the above (A) to (N), R ¹ has the same meaning as R ^1a .

The compound [I] has an asymmetric center in the molecule and has optical activity. Here, the bonding mode of the substituent on the cyclohexane ring in the general formula [I] is

Embedded image Show the case. The absolute configuration of the present invention is the formula

Embedded image Is preferred.

Reaction diagram:

Embedded image In the compound [I] or a salt thereof, R ³ and R ⁴
Is a hydrogen atom and X is an oxygen atom, the compound [Ia] or a salt thereof can be used to protect the 6-position hydroxyl group of the fumagillol derivative [II] or a salt thereof, convert the spiroepoxy group into exo-methylene, and deprotect it to the 6-position. It can be produced by alkylating, acylating, carbamoylating, sulfonylating or carbonating a hydroxyl group. Also, X is N
The compound [Ib] or a salt thereof which is R ⁵ is obtained by oxidizing the above deprotected 6-position hydroxyl group to a carbonyl group.
It can be produced by carrying out reductive amination using a primary amine and alkylating, acylating, carbamoylating, sulfonylating or urethanizing the amino group in the same manner as described above. In the compound [I] or a salt thereof, R ³ and R ⁴
Are not both hydrogen atoms (Ic) and (Id) or salts thereof obtained in the above (Ia) and (Ib) or after oxidative cleavage of exomethylene of these salts into carbonyl compounds, It can be produced by introducing an alkylidene group by the Wittig reaction. Also. Acyl mercapto form [XII] of hydroxyl form [VII] or its salt using Mitsunobu reaction etc.
Alternatively, the compound [Ie] in which X is a sulfur atom or a salt thereof can be produced by converting the salt to a salt thereof and deacylating the resulting mercapto compound [XIII] or a salt thereof and reacting them in the same manner as above.

Step A is a nucleophilic ring-opening reaction of a spiro epoxy group, and Y in the formula is a group capable of leaving together with an oxygen functional group, such as iodine, alkylselenium, arylselenium, alkylthio and arylthio groups. Is mentioned.
The nucleophilic ring-opening reaction of the spiro epoxy group is carried out by reacting the fumagillol derivative [II] or [IV] or a salt thereof with Na-Y. The Na-Y is generally used in an amount of 1 to 5 times, preferably 1 to 2 times, the molar amount of the starting fumagillol derivative [II]. This reaction is usually performed in an organic solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include alcohols such as methanol and ethanol, organic carboxylic acids such as acetic acid and propionic acid, amides such as dimethylformamide and dimethylacetamide, and halogenated hydrocarbons such as dichloromethane and chloroform. , Ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane,
Ketones such as acetone and methyl ethyl ketone, and aromatic hydrocarbons such as benzene and toluene are used.
These may be used alone or in combination of two or more kinds at an appropriate ratio. The reaction temperature is -80 to 100 ° C, preferably -20 to room temperature. The reaction time is about 5 minutes to 2 days. When iodine is used as Y, the reaction proceeds rapidly if sodium acetate or the like is used as an additive.
In that case, the amount of sodium acetate used is usually 1 to 5 times, and preferably 1 to 2 times the amount of the raw material.

Step B is a reaction for protecting the 6-position hydroxyl group of the fumagillol derivative [II] or a salt thereof, wherein W is a protecting group, and the hydroxyl group protecting reaction is carried out by a method known per se. [Reference: Greene, TW,
“Protective Group in Organic Synthesis”, John W
iley & Sons, New York (1991)]. Preferred protective groups W are, for example, acyl groups such as acetyl group and benzoyl group, and silyl compounds such as t-butyldimethylsilyl and triethylsilyl.

Step C is a de-YOH reaction, and when Y is iodine, for example, a method of Comfort et al. In which tin (II) chloride phosphorus oxychloride is reacted in pyridine [Journal of Chemical Society, 112 ( 1959)], an exomethylene compound [VI] or a salt thereof can be produced. Further, when Y is alkyl selenium, aryl selenium, alkylthio, arylthio, etc., by converting the tertiary alcohol into a group having good eliminability under basic conditions, the de-YOH reaction proceeds and the exomethylene compound [V
I] or a salt thereof can be produced. In that case,
As the base, for example, a tertiary amine such as triethylamine, pyridine or dimethylaminopyridine is used, and is used in an amount of 2 to 500 mol, preferably 3 to 50 mol, per 1 mol of the raw material [V]. As the reagent for improving the leaving group of the tertiary alcohol, for example, sulfonyl chlorides such as methanesulfonyl chloride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride, thionyl chloride, phosphorus oxychloride, phosphorus triiodide, etc. are used. 1 to 10 mol per 1 mol of the raw material [V]
0 molar amount is used, and preferably 1 to 30 molar amount. This reaction is usually performed in an organic solvent that does not affect the reaction. Examples of the organic solvent that does not adversely affect the reaction include amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, dioxane and tetrahydrofuran, methyl acetate and ethyl acetate. Ester, acetonitrile, nitriles such as propionitrile, nitro compounds such as nitromethane and nitroethane, ketones such as acetone and methyl ethyl ketone, and aromatic hydrocarbons such as benzene and toluene are used. You may use it in mixture by 1 or more types in an appropriate ratio. A base can also be used as a solvent. The reaction temperature is -50 to 150 ° C, preferably -20 to 50 ° C. The reaction temperature is about 5 minutes to 5 days.

Step D is a deprotection reaction of the 6-position hydroxyl group of the fumagillol derivative, and a method known per se is used (the same reference as step B). Step E is an acylation, alkylation, carbamoylation and sulfonylation reaction of the hydroxyl group of compound [VII] or a salt thereof and the amino group of compound [X] or a salt thereof and the mercapto group of compound [XIII] or a salt thereof. is there. When carrying out an acylation, carbamoylation, alkylation or sulfonylation reaction, if necessary, a hydroxyl group in R ¹ ,
If the amino, alkylamino and nitrogen-containing heterocycle are protected, the reaction can proceed advantageously. A method known per se is used for the protection and deprotection of hydroxyl, amino, alkylamino and nitrogen-containing heterocycle in R ¹ [Reference: Greene, TW, “Protective Group in O.
rganic Synthesis ”, John Wiley & Sons, New York
(1991)]. When substituents such as amino, hydroxyl, and carboxyl are present in acylating agents, carbamoylating agents, alkylating agents, sulfonylating agents, etc., these substituents are preferably protected, and stability of the product A suitable protecting group is selected according to Examples of preferable protecting groups include 4-nitrobenzyloxycarbonyl and 2-trimethylsilylethoxycarbonyl in the case of amino, and 4-nitrobenzyl, t-butyldimethylsilyl and the like in the case of hydroxyl. In the case of carboxyl, for example, 4-nitrobenzyl and the like can be mentioned. As the deprotection method, a catalytic reduction or a usual method of reacting with a fluoride ion can be adopted. In the case of a carbamoylation reaction and an alkylation reaction, a lower alkyl group such as a methyl group or an ethyl group is used as a carboxyl group protecting group,
It is also possible to deprotect by hydrolyzing under mild alkaline conditions after the reaction.

1) Acylation Reaction The acylation reaction is carried out by using, for example, an acid anhydride or an acid halide (eg It is carried out by reacting a reactive derivative of an activated carboxylic acid such as acid chloride and acid bromide. That is, it is usually carried out by the reaction represented by the following formula. R ^2a OH or its reactive derivative + raw material → compound [I] [R ^2a in the formula represents a group derived from a carboxylic acid such as an alkanoyl group, an aroyl group and a heterocyclic carbonyl group. The reactive derivative of the carboxylic acid is usually used in an amount of about 1 to 10 times, preferably 1 to 5 times the molar amount of the starting material.

This reaction is usually carried out in the presence of a base. Examples of the base include tertiary amines such as diisopropylethylamine, triethylamine, pyridine, N, N-dimethylaminopyridine, sodium hydrogencarbonate,
Alkali metal bicarbonates such as potassium hydrogen carbonate, Alkali metal carbonates such as potassium carbonate and sodium carbonate,
Alkali metal hydrides such as sodium hydride and potassium hydride, organometals such as butyllithium and lithium diisopropylamide are used, and the addition amount thereof is usually about 1 to 10 times mol per mol of the raw material. Is the amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. Examples of organic solvents that do not adversely affect the reaction include amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, and dioxane, acetic acid. Esters such as methyl, ethyl acetate, isobutyl acetate and methyl propionate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane, ketones such as acetone and methyl ethyl ketone, aromatic carbonization such as benzene and toluene. Hydrogen or the like is used, and one kind or two or more kinds thereof may be mixed and used at an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature is the amount of carboxylic acid derivative, base, solvent,
The temperature varies depending on the type and the like, but is −80 to 100 ° C., preferably 0 ° C. to room temperature (here, room temperature is about 20 to 35 ° C.
Means degree. Unless otherwise specified, the same applies below).
It is. The reaction time is about 30 minutes to 5 days.

2) Alkylation reaction The alkylation reaction is carried out by using the starting material of the formula R ^2b -Z [R ^2b
Is a hydrocarbon group which may have a substituent, and Z is a leaving group (for example, halogen such as chlorine, bromine or iodine). ] It is carried out by reacting an alkylating agent such as an alkyl halide or a dialkylsulfate (eg, dimethylsulfate, diethylsulfate, etc.) represented by The alkylating agent is usually used in an amount of about 1 to 5 times the molar amount of the starting material. This reaction is usually performed in the presence of a base. As the base, the above-mentioned alkali metal hydrogencarbonates, alkali metal carbonates, alkali metal hydrides, organic metals and the like are used, and the addition amount thereof is usually about 1 to 5 times per mol of the raw material. It is a molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. Examples of the organic solvent that does not adversely affect the reaction include amides, halogenated hydrocarbons, ethers, esters, nitriles,
Nitro compounds, ketones, and aromatic hydrocarbons are used, and these may be used alone or in combination of two or more at an appropriate ratio. The reaction temperature varies depending on the amount and type of the alkylating agent, the base, the solvent, etc., but is −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction time is about 20 minutes to 5 days.

3) Carbamoylation Reaction The carbamoylation reaction for introducing a mono-substituted carbamoyl group is usually carried out by reacting a raw material with an isocyanate. For example, it is produced by the reaction represented by the following formula. R ^2c NCO + Raw material → Compound [I] (R ^2c in the formula represents a carbamoyl substituent or the like.) The isocyanate is usually used in an amount of about 1 to 5 moles per 1 mole of the raw material. This reaction is usually performed in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic metal and the like are used, and the addition amount thereof is usually about 0 relative to 1 mol of the raw material. 0.1 to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitrites, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature will differ depending on the amount and type of isocyanate, base, solvent, but is usually about -80 to 100 ° C, preferably 0 ° C to room temperature. The reaction time is about 1 hour to 5 days. Among the compounds having a mono-substituted carbamoyl group thus obtained, for example, compounds having chloroacetylcarbamoyl, trichloroacetylcarbamoyl and the like can be chloroacetylated by a conventional method (eg, room temperature to warming under basic conditions). It is also possible to convert the compound having a carbamoyl group by removing the group and the trichloroacetyl group. The carbamoylation reaction is also carried out by reacting the raw material with a carbamoyl halide. The carbamoyl halide is based on 1 mol of the raw material.
Usually, about 1 to 5 times the molar amount is used.

This reaction is usually carried out in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic alkali metal, etc. are used, and the addition amount thereof is usually about 1 mol of the raw material. It is 1 to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitrites, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature varies depending on the amount and kind of the carbamoyl halide, the base and the solvent, but the reaction temperature is about 0 ° C. to about the reflux temperature of the reaction medium, preferably about 25 ° C. to the reflux temperature. The carbamoylation reaction is carried out by reacting the raw material with a chloroformate (eg, phenyl chloroformate, ethyl chloroformate, isobutyl chloroformate, 1-chloro-ethyl chloroformate, etc.) or 1,1-carbonyldiimidazole. It is also carried out by converting the compound into an active ester and then reacting it with a primary or secondary amine. The chloroformic acid esters, 1,1-carbonyldiimidazole and amines are usually used in an amount of 1 mol to 5 times mol per mol of the raw material.

In this reaction, the reaction between the raw materials and the chloroformate is usually carried out in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate,
Alkali metal carbonates, alkali metal hydrides, organic alkali metals, etc. are used, and the addition amount is usually 1
The amount is about 1 to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. As the organic solvent that does not adversely affect the reaction, the above-mentioned amides, halogenated hydrocarbons, ethers, esters, nitrites, nitro compounds, ketones, and aromatic hydrocarbons are used. You may use it in mixture by 1 or more types in an appropriate ratio. The reaction temperature is chloroformate,
Depending on the amount and type of base, amines, solvent, etc., it is -20 ° C to the reflux temperature of the reaction medium, preferably 0 ° C.
To 50 ° C. The active esters obtained as intermediates are also included in the target compound [I] of the present invention. Of the compounds having a mono-substituted carbamoyl group,
The compound having a lower alkanoylcarbamoyl group having a substituent can also be produced by reacting a compound having chloroacetylcarbamoyl with a nucleophile. As the nucleophile, lower carboxylic acid, lower thiocarboxylic acid, thiols, amines and the like or metal salts thereof are used.

This reaction is usually carried out in an organic solvent that does not adversely affect the reaction. Examples of the organic solvent that does not adversely affect the reaction include the above-mentioned saturated aliphatic hydrocarbons, alcohols, amides, halogenated hydrocarbons, ethers, esters, nitriles, nitro compounds, ketones and aromatics. Hydrocarbons are used, and these may be used alone or in combination of two or more kinds at an appropriate ratio. In addition, this reaction
It is usually carried out in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic alkali metal and the like are used, and the addition amount thereof is usually about 1 mol based on the raw material. To 5 times the molar amount. The reaction temperature will differ depending on the amount and type of nucleophile, base, solvent, etc., but is usually −80 to 100 ° C., preferably 0 ° C. to room temperature. The reaction temperature is about 20 minutes to 5 days.

4) Sulfonylation Reaction In the sulfonylation reaction, as a raw material, for example, an activated sulfonic acid derivative such as sulfonic anhydride, sulfonic acid halide (eg, sulfonyl chloride, sulfonyl bromide, etc.) or sulfamoyl halide ( For example, it is carried out by reacting an activated sulfamic acid derivative such as sulfamoyl chloride, sulfamoyl bromide). That is, it is performed by reacting as in the following formula. Reactive derivative of R ^2d OH + raw material → compound [I] (R ^2d in the formula represents a group derived from sulfonic acid such as alkylsulfonyl, arylsulfonyl, sulfamoyl group, etc.) Reactivity of the sulfonic acid The derivative is usually used in an amount of about 1 to 5 times the molar amount of the raw material. This reaction is usually performed
It is carried out in the presence of a base. As the base, the above-mentioned tertiary amine, alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydride, organic metal and the like are used, and the addition amount thereof is usually about 1 mol per 1 mol of the raw material. It is a molar amount to 10 times the molar amount. This reaction is usually carried out in an organic solvent that does not adversely influence the reaction. Examples of the organic solvent that does not adversely affect the reaction include the above-mentioned amides, halogenated hydrocarbons,
Ethers, esters, nitriles, nitro compounds,
Ketones and aromatic hydrocarbons are used, and these may be used alone or in combination of two or more kinds at an appropriate ratio. Further, the tertiary amine used as the base may be directly used as the solvent. The reaction temperature varies depending on the amounts and types of the sulfonic acid or sulfamic acid derivative, the base and the solvent, but is -80 to 100 ° C, preferably 0 ° C to room temperature. The reaction time is about 10 minutes to 5 days.

Step F is a reaction for oxidizing the hydroxyl group of compound [VII] or a salt thereof to a carbonyl group,
Examples of the oxidizing agent used include chromic acid-pyridine (Johns reagent), pyridinium chlorochromate (PC
C), chromates such as pyridinium dichromate (PDC), permanganates, manganese dioxide, lead tetraacetate,
Ruthenium tetraoxide, tetrapropylammonium perruthenate, dimethylsulfoxide-oxalyl chloride-triethylamine (Swern's oxidation), cerium (IV)
Examples thereof include salts and vanadate salts. The oxidizing agent is used in an amount of 0.1 to 50 mol, preferably 0.1 to 10 mol, per 1 mol of the raw material [VII]. When it acts catalytically like a ruthenium reagent, it may be used as an oxidative aid such as N-methylmorpholine oxide.
-Oxides and the like are used in about 1.5 to 5 times the molar amount of the raw materials. This reaction is usually performed in a solvent that does not affect the reaction. Examples of the organic solvent that does not adversely affect the reaction include, for example, hexane, saturated hydrocarbons such as pentane, acetic acid,
Aliphatic carboxylic acids such as propionic acid, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as methyl acetate and ethyl acetate. , Nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane, ketones such as acetone and methyl ethyl ketone,
Aromatic hydrocarbons such as benzene and toluene are used, and these may be used alone or in admixture of two or more at an appropriate ratio. In this reaction, if a dehydrating agent such as molecular sieves is added, the reaction may proceed efficiently. The reaction temperature is −50 to 100 ° C., preferably −
20 to 50 ° C. The reaction time is about 5 minutes to 5 days.

Step G is a reductive amination reaction for converting the carbonyl group of compound [IX] or a salt thereof into an amino group, and is carried out in the presence of ammonium acetate, for example, metal hydrides such as sodium cyanoborohydride, palladium. A compound [X] in which R ⁵ is a hydrogen atom can be produced by reduction by a catalytic reduction method using carbon or the like as a catalyst. A primary amine (R ⁵ NH ₂ ) was used instead of ammonium acetate, and the pH of the reaction solution was
Is reduced to neutral to weakly acidic to give a compound [X] or a salt thereof in which R ⁵ is a hydrocarbon group. Ammonium acetate and primary amine are generally used in an amount of 1 to 10 times, preferably about 1 to 5 times the molar amount of the raw material [IX]. The metal hydride is usually used in a molar amount of 1 to 10 times, preferably about 1 to 5 times the molar amount of the raw material. This reaction is usually performed in a solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include hexane, saturated hydrocarbons such as pentane, alcohols such as methanol and ethanol, acetic acid, aliphatic carboxylic acids such as propionic acid, amides such as dimethylformamide and dimethylacetamide, Halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane, Aromatic hydrocarbons such as benzene and toluene are used, and these may be used alone or in admixture of two or more at an appropriate ratio. In this reaction, if a dehydrating agent such as molecular sieves is added to efficiently generate an imine from a carbonyl compound and an amine, the reaction proceeds efficiently. Reaction temperature is -50 to 100
C., preferably 0 to 50.degree. The reaction time is about 5 minutes to 5 days.

Step H is an oxidative cleavage reaction of a double bond, which is carried out, for example, by a cleavage reaction with ozone, a diolation of osmium tetroxide and a subsequent cleavage reaction with sodium metaperiodate, etc. X
I] or salts thereof can be prepared. In the diolation of osmium tetroxide and the subsequent cleavage reaction with sodium metaperiodate, osmium tetroxide is used in about 0.01 to 0.1 times the molar amount of the raw materials [Ia] and [Ib].
N-oxides such as N-methylmorpholine oxide, hydrogen peroxide, etc., are used as auxiliary oxidants for catalytically acting osmium tetroxide as raw materials [Ia], [Ib].
It is used in a molar amount of about 1.5 to 5 times. Sodium metaperiodate is generally used in an amount of 1 to 10 times, preferably about 1.5 to 5 times the molar amount of the raw materials [Ia] and [Ib]. This reaction is usually performed in a solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include hexane, saturated hydrocarbons such as pentane, methanol,
Alcohols such as ethanol, water, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, ethers such as diethyl ether, dioxane and tetrahydrofuran, esters such as methyl acetate and ethyl acetate, Nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane,
Aromatic hydrocarbons such as benzene and toluene are used, and these may be used alone or in admixture of two or more at an appropriate ratio. The reaction temperature is -80 to 100 ° C, preferably 0 to 50 ° C. The reaction time is about 5 minutes to 5 days. Step I is a reaction for forming a carbon-carbon double bond from a ketone of the compounds [VIII] and [XI] or a salt thereof, for example, an alkylidenecyclohexane compound [Ic] by utilizing a Wittig reaction, [Id] or salts thereof can be prepared. As a Wittig type reaction reagent,
For example, phosphonium salts such as triphenylalkylphosphonium salts, dimethoxyphosphorylalkyl, diethoxyphosphorylalkyl, etc.
rner-Emmons) type Wittig reagents and the like are used, and are used in an amount of 1 to 10 times, preferably 1 to 3 times the molar amount of the raw materials [VIII], [XI] or salts thereof. . This reaction is usually performed in an organic solvent that does not affect the reaction. Examples of the organic solvent that does not adversely influence the reaction include saturated hydrocarbons such as hexane and pentane, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane and chloroform, diethyl ether, dioxane, tetrahydrofuran and the like. Ethers, esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane, and aromatic hydrocarbons such as benzene and toluene are used. You may mix and use double or more at an appropriate ratio. This reaction is usually performed in the presence of a base. As the base, alkali metal hydrides, organic alkali metals, alkali metal alkoxides and the like are used, and the addition amount thereof is about 1 to 5 times the molar amount of the raw material. Reaction temperature is -80 to 1
The temperature is 00 ° C, preferably -20 to 50 ° C. The reaction time is about 5 minutes to 5 days.

Step J is a reaction for converting a hydroxyl group into an acylmercapto group, for example, by directly subjecting the hydroxyl group to a Mitsunobu reaction or after converting the hydroxyl group into a leaving group, substitution with potassium thioacetate or the like is performed. By reacting, the acylmercapto compound [XI
I] or a salt thereof (in the formula, R ⁶ represents an optionally substituted hydrocarbon group represented by R ¹ ). The Mitsunobu reaction is carried out by reacting thiocarboxylic acids such as thioacetic acid and thiobenzoic acid in the presence of phosphines such as triphenylphosphene and azodicarboxylic acid derivatives such as azodicarboxylic acid diesters and azodicarboxylic acid diamides. Can be done by. In this case, the phosphine and the azodicarboxylic acid derivative are used in a molar amount of 1 to 10 times, preferably 1 to 3 times, the molar amount of the raw material. The thiocarboxylic acid is used in a molar amount of 1 to 10 times, preferably 1 to 3 times, the molar amount of the raw material. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of the organic solvent that does not influence the reaction include saturated hydrocarbons such as hexane and pentane, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane, ethers such as diethyl ether, dioxane and tetrahydrofuran. , Esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane,
Aromatic hydrocarbons such as benzene and toluene are used, and these may be used alone or as a mixture of two or more kinds at an appropriate ratio. On the other hand, the conversion of a hydroxyl group into a leaving group can be carried out by reacting sulfonyl chlorides such as methanesulfonyl chloride, p-toluenesulfonyl chloride and trifluoromethanesulfonyl chloride. The sulfonyl chlorides are used in a molar amount of 1 to 10 times, preferably 1 to 3 times, the molar amount of the raw material. This reaction is usually performed in the presence of a base. As the base, for example, alkali metal hydrogencarbonates, alkali metal carbonates, alkali metal hydrides, tertiary amines, etc. are used, and the addition amount thereof is 1 with respect to the raw material.
It is a molar amount to 5 times the molar amount. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of the organic solvent that does not influence the reaction include saturated hydrocarbons such as hexane and pentane, amides such as dimethylformamide and dimethylacetamide, halogenated hydrocarbons such as dichloromethane, ethers such as diethyl ether, dioxane and tetrahydrofuran. , Esters such as methyl acetate and ethyl acetate, nitriles such as acetonitrile and propionitrile, nitro compounds such as nitromethane and nitroethane, and aromatic hydrocarbons such as benzene and toluene, which are used alone or in combination. You may use it in mixture by 1 or more types in an appropriate ratio. Reaction temperature is -80 to 1
The temperature is 00 ° C, preferably -20 to 50 ° C. The reaction time is about 5 minutes to 5 days. The resulting leaving group of the hydroxyl group can be subjected to a substitution reaction with potassium thiocarboxylic acid salts such as potassium thioacetate and potassium thiobenzoate to produce an acylmercapto compound [XII] or a salt thereof. . The potassium thiocarboxylic acid salt is used in a molar amount of 1 to 10 times, preferably 1 to 3 times, the molar amount of the raw material. This reaction is usually carried out in an organic solvent that does not affect the reaction. Examples of organic solvents that do not adversely affect the reaction include amides such as dimethylformamide and dimethylacetamide, ethers such as diethyl ether, dioxane, and tetrahydrofuran, nitro compounds such as nitromethane and nitroethane, and aromatic hydrocarbons such as benzene and toluene. Etc. are used, and these may be used alone or in combination of two or more kinds at an appropriate ratio. The reaction temperature is-
The temperature is 80 to 100 ° C, preferably 0 to 50 ° C. The reaction time is about 5 minutes to 5 days. Step K is a deprotection reaction from an acyl mercapto group to a mercapto group, for example, alkyl hydroxide metal such as sodium hydroxide and potassium hydroxide, amines such as ammonia, netylamine and dimethylamine, sodium borohydride,
The mercapto compound [XIII] or a salt thereof can be produced by a method known per se (the same reference as in step B), such as metal hydrides such as lithium aluminum hydride.

The raw material compounds and production intermediates of the present invention are
It may form a salt and is not particularly limited as long as the reaction proceeds. Examples of salts of these compounds include inorganic acid salts (eg, hydrochloride, sulfate, hydrobromide, phosphate, etc.), organic acid salts (eg, acetate, trifluoroacetate, succinate). , Maleate, fumarate, propionate, citrate,
Tartrate, malate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.), alkali metal salt (eg sodium salt, potassium salt etc.), alkaline earth metal salt (eg calcium) Salt, magnesium salt, etc.), organic base salt (eg, trimethylamine salt,
Triethylamine salt, pyridine salt, piperidine salt, ethanolamine salt, etc.), aluminum salt, ammonium salt and the like are used. Further, the starting material compound and the production intermediate of the present invention can be isolated according to a conventional method, but can also be directly used as a starting material for the next reaction step without isolation. In each reaction of the present invention,
When the compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry and the like may be introduced into these groups, and if necessary after the reaction, The target compound can be obtained by removing the protecting group. Examples of the amino-protecting group include formyl group, C _1-6 alkylcarbonyl group (eg, acetyl, propionyl, etc.), benzyl group, tert-butyloxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxy group. Carbonyl group, allyloxycarbonyl group, benzoyl group, C _1-6 alkyloxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-10 aralkylcarbonyl group (eg, benzylcarbonyl, etc.), trityl group, phthaloyl group , N, N-dimethylaminomethylene group and the like are used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro group and the like.

Examples of the protective group for the carboxyl group include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), a phenyl group, a silyl group, a benzyl group, an allyl group and the like. Used. These groups may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), nitro group and the like. Examples of the protective group for the hydroxyl group include methoxymethyl group, allyl group, tert-butyl group, C
_7-10 aralkyl group (eg benzyl etc.), formyl group, C _1-6 alkylcarbonyl group (eg acetyl,
Propionyl etc.), benzoyl group, C _7-10 aralkylcarbonyl group (eg benzylcarbonyl etc.), pyranyl group, furanyl group, trialkylsilyl group etc. are used. These groups include 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, etc.), C _1-6 alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, etc.), phenyl groups. , C _7-10
It may be substituted with an aralkyl group (for example, benzyl and the like), a nitro group and the like. As a method for removing these protecting groups, a method known per se or a method analogous thereto can be used, and examples thereof include acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, A method using palladium acetate or the like is used. When the compound is obtained in a free state by each reaction of the present invention, it may be converted into a salt according to a conventional method, and when obtained as a salt, it is converted into a free form or other salt according to a conventional method. It can also be converted. The compound [I] of the present invention thus obtained or a salt thereof can be isolated and purified from the reaction solvent by known means such as phase transfer, concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography and the like. You can When the compound [I] of the present invention or a salt thereof exists as a diastereomer, a conformer or the like, each can be isolated by a usual separation and purification means, if desired.

When the compound [I] of the present invention contains a basic group, it can be obtained as a pharmaceutically acceptable acid addition salt by a method known per se or a method analogous thereto. Examples of such acids include inorganic acids (for example, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, etc.), organic acids (for example, acetic acid, trifluoroacetic acid, succinic acid, maleic acid, fumaric acid, propionic acid, Citric acid, tartaric acid, malic acid, lactic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) and amino acids (eg, glutamic acid, aspartic acid, etc.) and the like. When the compound [I] of the present invention contains an acidic group, it can be converted into a salt with a pharmaceutically acceptable base by a method known per se or a method analogous thereto. Such bases include, for example, alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), organic bases (eg, trimethylamine, triethylamine, pyridine, piperidine, ethanolamine, etc.), Aluminum, ammonium and the like can be mentioned.

The compound [I] of the present invention or a salt thereof is stable, has low toxicity, and has few side effects, so that it can be used in mammals (eg, humans, cows, horses, dogs, cats, monkeys, mice,
It is effective in ameliorating the condition in which angiogenesis is pathologically enhanced in rats and the like, particularly in humans).

The compound [I] of the present invention or a pharmaceutically acceptable salt thereof may be used as it is, but usually, the following carrier for pharmaceutical preparation is appropriately used in an appropriate amount,
Formulated according to a conventional method. Examples of the carrier for pharmaceutical preparations include excipients (eg, calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, D-mannitol, starches, crystalline cellulose, talc, granulated sugar, porous substances, etc.), binders ( For example, dextrin, rubber,
Pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, etc.), thickeners (eg natural gums, cellulose derivatives, acrylic acid derivatives etc.), disintegrants (eg carboxymethylcellulose calcium, croscarmellose sodium) , Crospovidone, low-substituted hydroxypropyl cellulose, partially pregelatinized starch, etc.), solvent (eg water for injection, alcohol, propylene glycol,
Macrogol, sesame oil, corn oil, etc.), dispersant (eg, Tween 80, HCO60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), solubilizing agent (eg, polyethylene glycol, propylene glycol, D-mannitol, etc.)
Benzyl benzoate, ethanol, trisaminomethane,
Triethanolamine, sodium carbonate, sodium citrate, etc.), suspending agents (eg, stearyltriethanolamine, sodium lauryl sulfate, benzalkonium chloride, polyvinyl alcohol, polyvinylpyrrolidone, hydroxymethylcellulose, etc.), soothing agents (eg, , Benzyl alcohol, etc., isotonicity agents (eg,
Sodium chloride, glycerin, etc.), buffers (eg,
Phosphates, acetates, carbonates, citrates, etc.), lubricants (eg magnesium stearate, calcium stearate, talc, starch, sodium benzoate etc.),
Colorants (eg tar pigments, caramel, iron sesquioxide,
Titanium oxide, riboflavin, etc.), flavoring agents (eg,
Sweeteners, flavors and the like), stabilizers (eg sodium sulfite, ascorbic acid etc.) and preservatives (eg parabens, sorbic acid etc.) and the like. The content of the compound [I] of the present invention or a pharmaceutically acceptable salt thereof in the preparation of the present invention is an effective amount for treating and preventing the following diseases, and it is usually about 0 in the whole preparation. 0.1 to about 100% by weight. In addition, the preparation used in the present invention may contain a pharmaceutical ingredient other than the compound [I] of the present invention or a pharmaceutically acceptable salt thereof (for example, an antitumor agent shown below), These components are not particularly limited as long as the object of the present invention is achieved, and it is possible to mix them in an appropriate mixing ratio to form a mixture. Specific examples of the dosage form include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, eye drops, drip drops,
Syrup, emulsion, suspension, injection, inhalation, ointment,
Suppositories, lozenges, poultices, sustained-release agents and the like are used. These preparations are prepared according to a conventional method (for example, the method described in Japanese Pharmacopoeia 12th Edition).

The production methods of the main preparations in the present invention are shown below, but of course the present invention is not limited thereto. (1) Tablets The compound of the present invention as it is, or an even mixture of an excipient, a binder, a disintegrating agent or other appropriate additives is mixed and granulated by an appropriate method and then lubricated. Add agents etc. and press-mold. Then, if necessary, for purposes such as taste masking, enteric coating or persistence,
The coating may be applied with a suitable coating agent. (2) Injection A certain amount of the compound of the present invention is dissolved, suspended or emulsified in water for injection or the like, if necessary, by adding a stabilizer, a solubilizing agent, a suspending agent, an emulsifier, a buffer, a preservative and the like. To make a fixed dose. (3) Suppository Based on an oily base, water-soluble base or other suitable substance, add an emulsifier, a suspending agent, and the like, if necessary, add the compound of the present invention, mix and equalize. After that, it is made into an appropriate shape. (4) Capsules The compound of the present invention and additives such as suitable excipients are mixed evenly, or granulated by an appropriate method, or the granules are coated with an appropriate coating agent. The capsules are filled as they are or lightly. (5) Eye drops A solvent is heated if necessary, and the compound of the present invention is added and completely dissolved.

The pharmaceutical preparation containing the compound [I] or a salt thereof of the present invention is stable and low toxic, highly safe, and has excellent angiogenesis-inhibiting activity. Therefore, for example, (1) solid malignant neoplasm (for example, Gastric cancer, esophageal cancer, duodenal cancer, tongue cancer, pharyngeal cancer, brain cancer, rectal cancer, colon cancer, non-small cell lung cancer, small cell lung cancer, liver cancer, kidney cancer, breast cancer, biliary tract cancer, pancreatic cancer, prostate cancer, uterus Body cancer, cervical cancer, ovarian cancer, bladder cancer, skin cancer, malignant melanoma, thyroid cancer, bone tumor, hemangiomas, angiofibromas, retinal sarcomas, penile cancer, Kaposi's sarcoma, etc.) and other organs Metastasis, (2) diabetic retinopathy, neovascular glaucoma,
Rubeosis iris, trachoma, central retinal vein occlusion,
Central retinal artery occlusion, retinopathy of prematurity, senile discoid macular degeneration, sickle cell retinopathy, corneal opacities, other ischemic conditions, (3) rheumatoid arthritis, (4) psoriasis, thickening Scar, (5) abnormal capillary network of atherosclerotic adventitia,
(6) It is useful as a therapeutic and prophylactic agent for various diseases such as allergic inflammation, respiratory tract inflammation, nephritis, and other chronic inflammation. The pharmaceutical preparation of the present invention can be used in combination with other pharmaceutical preparations as long as the object of the present invention is achieved. For example, when the pharmaceutical preparation of the present invention is used as an antitumor agent, it exhibits an excellent antitumor effect even when used alone, but is used in combination with another drug having an antitumor activity or an antitumor activity enhancing effect. By (multi-drug combination), the effect can be further enhanced. In addition, as an advantage of combination, it is possible to reduce the amount of each drug used, which reduces side effects,
It can also be said to contribute significantly to improving the quality of life of cancer patients. Examples of the drug having an antitumor activity action or an antitumor activity enhancement action used in the combination treatment include, but are not limited to, the followings. Examples of the alkylating agent include Nitrogen mustard, Nitrogen mustard hydrochloride-N-oxide (Nitorogen).
mustard-N-oxidehydrochloride), chlorambucil (Ch
lorambucil), cyclophosphamide (Cyclophosphamid)
e), Ifosfamide, Thiotepa (Thiot)
epa), Carboquone, Improsulfan tosilate, Busulfan, Nimustine Hydrochlor
ide), Mitobronitol, Melphalan, Dacarbazine, Ranimustine, Estramustine sodium phosphate, Triethylenemelamine, Carmustine, Lomustine Lomustine), Streptozocin, Pipobroman
oman), etoglucid (Ethoglucid), carboplatin (Carboplatin), cisplatin (Cisplatin), Miboplatin (Miboplatin), Nedaplatin (Nedaplatin),
Oxaliplatin, altretamine (A
ltretamine), Ambamustine, Dibrospidium chloride, Fotemustine, Prednimust
ustine), Pumitepa, Ribomustine (Ribo
mustin), Temozolomide, Treosulfan, Trofosfamid (Trofosfa)
mide), Zinostatin stilame
r) and the like.

Examples of antimetabolites include mercaptopurine (6-Mercaptopurine) and thioinosin (Thioinosin).
e), Methotrexate, Enocitabine, Cytarabine, Cytarabine ocfosfate, Ancitabine hydrochloride, Fluorouracil, Tegafu
r), UFT, Doxifluridine, Carmofur, Aminopteri
n), leucovorin calcium (Calcium leucovori
n), Carmofur, FUDR, Tabloid, Butocin, Calcium folinate, Levofolinate Calcium, Cladribine
ribine), emitefur (Emitefur), fludarabine (Fludarabine), gemcitabine (Gemcitabine), hydroxycarbamide (Hydroxycarbamide), pentostatin (Pentostatin) and the like. Examples of plant alkaloids include Etoposide, Etoposide phosphate, Vinblastine sulfate, and Vincristine sulfate.
cristine sulfate, Vindesine sulfate
ate), teniposide (Teniposide), paclitaxel (P
aclitaxel), vinorelbine (Vinorelbine) and the like. Examples of anticancer antibiotics include Actinomycin D (Actinomycin D) and Actinomycin C (Actinom).
ycin C), mitomycin C (Mitomycin C), chromomycin A ₃ (Chromomycin A ₃ ), bleomycin hydrochloride (Bleomycin hydrochloride), bleomycin sulfate (B
leomycin sulfate), Peplomycin sulfate
sulfate), Daunorubicin Hydrochloride
chloride), Doxorubicin hydroc
hloride), Aclarubicin hydroch
loride), pirarubicin hydrochloride, epirubicin hydrochloride, neocarzinostatin, mithramycin, sarkomycin, carzinophilin, mitotan
e), Zorubicin hydrochloride, Mitoxantorone hydrochloride
And the like.

Examples of sex hormone agents include, for example, fosfestrol, diethylstilbestrol, chlorotrianisene.
trianisene), medroxyprogesterone acetate (Medrox)
yprogesterone acetate), Megestrol acetate (Meges
trol acetate), Chlormadinonea acetate
cetate), Cyproterone acetat
e), Tamoxifen citrate,
Mepitiostane, Goserelin acetate (Go
serelin acetate, Testololavton
e), Aminoglutethimido, Buserelin, Droloxifen
e), epithiostanol, ethinylestradiol sulfo
nate), flutamide, and leuprorelin. Immunotherapeutic agent (BR
As M), for example, Picibanil, Krestin, Schizophyllan,
Lentinan, Ubenimex,
Interferon-α, -β, -γ, Interleukin-1, -2, -12, Macrophage colony-stimulating fact
or), Granulocytemacrophag
e colony-stimulating factor), erythropoietin (E
rythropoietin), lymphotoxin, B
CG vaccine (BCG vaccine), Corynebacterium parvum, levamisole (Le
vamisole), Polysaccharide K (Polysaccharide-
K), Procodazol (Procodazol) and the like. In addition, L-Asparaginase (L-Asparaginas
e), Aceglatone, Procarbazine hydrochloride, Doxorubicin, Protoporphyrin-cobalt complex (Cobalt-protoporphyrin), mercury hematoporphyrin-sodium (Hg-Hematoporphyrin-Na), topoisomerase I inhibitor (for example, , Irinotecan
Etc.) can also be used.

From these, 1 to 5 types (preferably 1 to 3 types) can be selected and used in combination with the pharmaceutical preparation of the present invention. In addition, the combination, the administration period, and the administration method can be arbitrarily changed in the course of treatment of cancer. Furthermore, when the pharmaceutical preparation of the present invention is used, a therapeutic method using a drug as described above and, as supportive therapy, for example, antibiotics (for example, β-lactams such as pansporin, macrolides such as clarithromycin, etc.) ), Drug administration for improving nutritional disorders (for example, high calorie infusion, amino acid preparation, multivitamin preparation, etc.), morphine administration, drug administration to reduce side effects,
Combination with administration of cachexia improver and the like may be considered. The amount of the compound of the present invention used in the pharmaceutical preparation varies depending on the selected compound, the animal species selected for administration, the number of times of administration, and the like, but exhibits a wide range of effectiveness. For example, for an adult solid tumor patient (for example, a prostate cancer patient), the daily dose when the pharmaceutical preparation of the present invention is orally administered is usually an effective amount of the compound [I] of the present invention, About 0.001 to about 5
00 mg / kg body weight, preferably about 0.1 to about 4
The dose is 0 mg / kg body weight, more preferably about 0.5 to about 20 mg / kg body weight, but generally lower than these doses when administered parenterally or in combination with other anticancer agents. However, the amount of the compound to be actually administered is determined by the conditions such as the selection of the compound, various preparation forms, the age, weight, sex, degree of the disease, the degree of the disease, the route of administration, the period and interval of the administration. It can be changed at any time according to the judgment of the doctor. The administration route of the pharmaceutical preparation is not particularly limited by various circumstances, and for example, can be administered by an oral or parenteral route. As used herein, "parenteral" includes intravenous, intramuscular, subcutaneous, intranasal, intradermal, instillation, intracerebral, rectal, vaginal, intraperitoneal, etc. administration. The administration period and interval of the above-mentioned pharmaceutical preparation may be changed according to various circumstances and may be determined at any time by the judgment of the doctor, but divided administration, daily administration, intermittent administration, short-term large-dose administration, repeated administration There are methods such as administration. For example, in the case of oral administration,
It is desirable to administer in divided doses once to several times a day (especially 1 to 3 times a day). It is also possible to give an intravenous drip over a long period of time.

[0044]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Preparation Examples, and Test Examples. However, these examples are merely examples and do not limit the present invention, and may be changed without departing from the scope of the present invention. The abbreviations in Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, d
t: double triplet, m: multiplet, br:
Wide range, J: Coupling constant, room temperature: 0-30 ° C

Reference Example 1 (1R, 2R, 3S, 4R) 1,4-dihydroxy-1
-Iodomethyl-3-methoxy-2-[(2R, 3R)
2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] cyclohexane To a solution of ammonium acetate (360 mg) in acetic acid (5 ml) and propionic acid (10 ml) was added sodium iodide (3 .98g), followed by fumagillol (5.0
g) was added and stirred at that temperature for 15 minutes. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate,
Wash with saturated aqueous sodium hydrogen carbonate solution, water, aqueous sodium thiosulfate solution, brine, dry and concentrate, and concentrate on silica gel column chromatography (hexane / ethyl acetate = 2 /
The product was purified in 1) and crystallized from isopropyl ether to give the title compound (7.53 g). NMR (CDCl ₃ ) δ, ppm: 1.51 (3H, s), 1.67 (3H, s),
1.75 (3H, s), 1.39-2.54 (7H, m), 3.01 (1H, t, J = 6.8Hz), 3.27
(1H, dd, J = 10.8,2.2Hz), 3.35 (3H, s), 3.50 (1H, d, J = 10.0H
z), 3.57 (1H, d, J = 10.0Hz), 3.77 (1H, brs), 4.20 (1H, m), 5.1
9 (1H, m).

Reference Example 2 (1R, 2R, 3S, 4R) 4-acetoxy-1-hydroxy-1-iodomethyl-3-methoxy-2-[(2
R, 3R) -2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] cyclohexane (1R, 2R, 3S, 4R) 1,4-dihydroxy-1
-Iodomethyl-3-methoxy-2-[(2R, 3R)
Acetic anhydride (621 mg) was added to a dichloromethane (5 ml) solution of 2-methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] cyclohexane (2.08 g) and dimethylaminopyridine (743 mg) at room temperature. 30
Stirred for minutes. The reaction solution is poured into water and extracted with ethyl acetate,
The extract was washed with water and brine, dried and concentrated, and then purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (2.19 g) as a colorless oil. NMR (CDCl ₃ ) δ, ppm: 1.53 (3H, s), 1.66 (3H, s),
1.74 (3H, s), 1.45-2.24 (5H, m), 2.13 (3H, s), 2.36-2.55 (2
H, m), 2.98 (1H, t, J = 6.6Hz), 3.20-3.35 (1H, m), 3.29 (3H,
s), 3.55 (2H, s), 4.05 (1H, brs), 5.19 (1H, m), 5.45 (1H, m).

Reference Example 3 (1R, 2R, 3S, 4R) 4- (t-butyldimethylsilyloxy) -1-hydroxy-3-methoxy-2-
[(2R, 3R) -2-Methyl-3- (3-methyl-2
-Butenyl) oxiran-2-yl] -1- (phenylselenylmethyl) cyclohexane diphenyl diselenide (1.97 g) in methanol (2
Sodium hydride (1.0 g) was added to the suspension (6 ml) under ice-cooling little by little, and the mixture was stirred for 10 minutes.
Stirred for hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give a colorless oil, which was crystallized in the refrigerator to give the title compound (6.97 g). NMR (CDCl ₃ ) δ, ppm: 0.04 (3H, s), 0.08 (3H, s),
0.92 (9H, s), 1.40-2.55 (7H, m), 1.41 (3H, s), 1.65 (3H, s),
1.73 (3H, s), 2.96 (1H, t, J = 6.4Hz), 3.10 (1H, dd, J = 11.2,2.
2Hz), 3.25 (3H, s), 3.34 (1H, d, J = 11.8Hz), 3.41 (1H, d, J = 1
1.8Hz), 3.93 (1H, brs), 4.19 (1H, m), 5.21 (1H, m), 7.15-7.3
0 (3H, m), 7.47-7.55 (2H, m).

Reference Example 4 (2R, 3S, 4R) 4- (t-Butyldimethylsilyloxy) -3-methoxy-2-[(2R, 3R) -2-
Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane (1R, 2R, 3S, 4R) 4- (t-butyldimethylsilyloxy) -1-hydroxy-3- Methoxy-2-
[(2R, 3R) -2-Methyl-3- (3-methyl-2
-Butenyl) oxiran-2-yl] -1- (phenylselenylmethyl) cyclohexane (6.77 g) in dichloromethane (30 ml) in triethylamine (29.
7 g) was added, followed by methanesulfonyl chloride (20.
2 g) was added dropwise and stirred for 3 hours. The reaction mixture is poured into water, extracted with ethyl acetate, washed with water, 10% aqueous citric acid solution and brine, dried, concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give a colorless oil. The title compound (4.34 g) was obtained. NMR (CDCl ₃ ) δ, ppm: 0.06 (3H, s), 0.10 (3H, s),
0.88 (9H, s), 1.28 (3H, s), 1.40 (1H, m), 1.65 (3H, s), 1.72 (3
H, s), 1.80 (1H, m), 2.02 (1H, m), 2.15-2.52 (4H, m), 2.61 (1
H, t, J = 6.3Hz), 3.07 (1H, dd, J = 10.2,2.2Hz), 3.40 (3H, s),
4.27 (1H, m), 4.60 (1H, d, J = 1.2Hz), 4.82 (1H, d, J = 1.2Hz),
5.23 (1H, m).

Reference Example 5 (1R, SR, 3S, 4R) 1,4-dihydroxy-3
-Methoxy-2-[(2R, 3R) -2-methyl-3-
(3-Methyl-2-butenyl) oxiran-2-yl]
-1- (Phenylselenylmethyl) cyclohexane Diphenyl diselenide (1.16 g) in methanol (4
0 ml) suspension under ice cooling with sodium borohydride (30
1 mg) was added little by little, and after stirring for 10 minutes, fumagillol (2.0 g) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and then purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (1.741 g) as a colorless solid. NMR (CDCl ₃ ) δ, ppm: 1.44 (3H, s), 1.66 (3H, s),
1.72 (3H, s), 1.50-1.87 (4H, m), 2.00-2.54 (3H, m), 2.98 (1
H, t, J = 6.4Hz), 3.27 (1H, d, J = 12.0Hz), 3.35 (3H, s), 3.50 (1
H, d, J = 12.0Hz), 4.21 (1H, brs), 5.22 (1H, t, J = 7.4Hz), 7.18
-7.29 (3H, m), 7.49-7.58 (2H, m).

Reference Example 6 (1R, 2R, 3S, 4R) 4-acetoxy-1-hydroxy-3-methoxy-2-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) ) Oxirane-
2-yl] -1- (phenylselenylmethyl) cyclohexane (1R, 2R, 3S, 4R) 1,4-dihydroxy-3
-Methoxy-2-[(2R, 3R) -2-methyl-3-
(3-Methyl-2-butenyl) oxiran-2-yl]
-1- (phenylselenylmethyl) cyclohexane (1.41 g), dimethylaminopyridine (20 mg) and triethylamine (0.9 ml) in dichloromethane (10
acetic anhydride (0.45 ml) was added to the solution at room temperature for 20
Stirred for hours. The reaction mixture was poured into water, extracted with ethyl acetate, washed with 10% aqueous citric acid solution, water and brine, dried and concentrated to give the title compound (1.537 g) as a colorless oil. NMR (CDCl ₃ ) δ, ppm: 1.45 (3H, s), 1.65 (3H, s),
1.72 (3H, s), 1.50-1.86 (4H, m), 2.00-2.53 (3H, m), 2.13 (3
H, s), 2.96 (1H, d, J = 6.5Hz), 3.20-3.40 (2H, m), 3.29 (3H,
s), 3.51 (1H, d, J = 12.0Hz), 5.18 (1H, t, J = 7.3Hz), 5.46 (1H,
d, J = 2.6Hz), 7.21-7.32 (3H, m), 7.50-7.59 (2H, m).

Example 1 (2R, 3S, 4R) 4-acetoxy-3-methoxy-
2-[(2R, 3R) -2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane

Embedded image To a solution of stannous chloride (1.26 g) in pyridine (4 ml), (1R, 2R, 3S, 4R) 4-acetoxy-1-
Hydroxy-1-iodomethyl-3-methoxy-2-
[(2R, 3R) -2-Methyl-3- (3-methyl-2
-Butenyl) oxiran-2-yl] cyclohexane (1.58 g) was added, followed by phosphorus oxychloride (64
1 mg) was added and the mixture was stirred at room temperature for 3 days. The reaction solution is poured into water, extracted with ethyl acetate, washed with water, 10% citric acid aqueous solution and brine, dried and concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give a colorless oil. The title compound (307 mg) was obtained. NMR (CDCl ₃ ) δ, ppm: 1.30 (3H, s),
1.50 (1H, m), 1.65 (3H, s), 1.7
2 (3H, s), 1.88-2.45 (6H, m),
2.09 (3H, s), 2.66 (1H, t, J = 6.
4 Hz), 3.28 (1H, dd, J = 10.6, 2.
8Hz), 3.41 (3H, s), 4.68 (1H,
d, J = 1.2 Hz), 4.90 (1H, d, J = 1.
2Hz), 5.22 (1H, m), 5.53 (1H,
m).

Example 2 (2R, 3S, 4R) 4-Hydroxy-3-methoxy-
2-[(2R, 3R) -2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane

Embedded image (2R, 3S, 4R) 4- (t-Butyldimethylsilyloxy) -3-methoxy-2-[(2R, 3R) -2-
Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane (4.14
To a solution of g) in tetrahydrofuran (30 ml) was added a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (36 ml), and the mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (hexane / ethyl acetate = 4/1 → 1/1) to give the title compound (2.69 g) as a colorless oil. NMR (CDCl ₃ ) δ, ppm: 1.32 (3H, s), 1.45 (1H, m),
1.65 (3H, s), 1.72 (3H, s), 1.95-2.48 (6H, m), 2.64 (1H, t, J =
6.4Hz), 3.27 (1H, dd, J = 10.6,2.8Hz), 3.47 (3H, s), 4.29 (1
H, m), 4.62 (1H, d, J = 1.3Hz), 4.86 (1H, d, J = 1.3Hz), 5.22 (1
H, m).

Example 3 (2R, 3S, 4R) 4-chloroacetylcarbamoyloxy-3-methoxy-2-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxirane-
2-yl] -1-methylenecyclohexane

[Chemical 21] (2R, 3S, 4R) 4-Hydroxy-3-methoxy-
2-[(2R, 3R) -2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane (500 mg) in dichloromethane (4 m
l) Chloroacetyl isocyanate (337 mg) in the solution
Dichloromethane (1 ml) solution was added and the mixture was stirred at room temperature for 15 minutes. The reaction mixture is poured into water, extracted with ethyl acetate, washed with water and brine, dried and concentrated, purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) and crystallized from hexane to give a colorless solid. Of the title compound (6
40 mg) was obtained. NMR (CDCl ₃ ) δ, ppm: 1.31 (3H, s), 1.56 (1H, m),
1.65 (3H, s), 1.72 (3H, s), 1.98-2.48 (6H, m), 2.65 (1H, t, J =
6.4Hz), 3.33 (1H, dd, J = 10.6,2.8Hz), 3.44 (3H, s), 4.43 (2
H, s), 4.71 (1H, d, J = 1.2Hz), 4.93 (1H, d, J = 1.2Hz), 5.21 (1
H, m), 5.51 (1H, m), 8.03 (1H, brs).

Example 4 (2R, 3S, 4R) 4-carbamoyloxy-3-methoxy-2-[(2R, 3R) -2-methyl-3- (3
-Methyl-2-butenyl) oxiran-2-yl] -1
-Methylenecyclohexane

Embedded image (2R, 3S, 4R) 4-Chloroacetylcarbamoyloxy-3-methoxy-2-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxirane-
To a solution of 2-yl] -1-methylenecyclohexane (45 mg) in methanol (4 ml) was added a 1N aqueous sodium hydroxide solution (0.2 ml), and the mixture was stirred at room temperature for 15 minutes.
The reaction mixture was poured into water, extracted with ethyl acetate, washed with water and brine, dried, concentrated, and crystallized from hexane to give the title compound (33 mg) as a colorless solid. NMR (CDCl ₃ ) δ, ppm: 1.31 (3H, s), 1.50 (1H, m),
1.65 (3H, s), 1.73 (3H, s), 1.98-2.48 (6H, m), 2.65 (1H, t, J =
6.4Hz), 3.30 (1H, dd, J = 10.6,2.8Hz), 3.43 (3H, s), 4.68 (3
H, brs), 4.90 (1H, d, J = 1.2Hz), 5.23 (1H, m), 5.38 (1H, m).

Example 5 (2R, 3S, 4R) 3-Methoxy-2-[(2R, 3
R) -2-Methyl-3- (3-methyl-2-butenyl)
Oxilan-2-yl] -1-methylene-4- (1-naphthylcarbamoyloxy) cyclohexane

Embedded image (2R, 3S, 4R) 4-Hydroxy-3-methoxy-
2-[(2R, 3R) -2-methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane (100 mg), dimethylaminopyridine (46 mg) in dichloromethane (4 ml) 1-naphthyl isocyanate (70 mg) in dichloromethane (1 m
l) The solution was added and stirred at room temperature for 30 minutes. The reaction solution is
Pour into water, extract with ethyl acetate, wash with 10% aqueous citric acid solution, water, brine, dry, and purify by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give a colorless amorphous form. Powder of title compound (1
51 mg) was obtained. NMR (CDCl ₃ ) δ, ppm: 1.35 (3H, s), 1.60 (1H, m),
1.67 (3H, s), 1.73 (3H, s), 2.10-2.50 (6H, m), 2.70 (1H, t, J =
6.4Hz), 3.39 (1H, dd, J = 10.6,2.8Hz), 3.49 (3H, s), 4.71 (1
H, d, J = 1.0Hz), 4.93 (1H, d, J = 1.0Hz), 5.25 (1H, m), 5.55 (1
H, m), 7.12 (1H, brs), 7.42-7.60 (3H, m), 7.66 (1H, d, J = 8.4H
z), 7.80-8.00 (3H, m).

Example 6 (2R, 3S) 3-Methoxy-2-[(2R, 3R)-
2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylene-4-cyclohexanone

Embedded image (2R, 3S, 4R) 4-Hydroxy-3-methoxy-
2-[(2R, 3R) -2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexane (500 mg) in dichloromethane (10
ml) solution with pyridinium chlorochromate (900 mg)
Was added and the mixture was stirred at room temperature for 1 day. The reaction solution was subjected to silica gel column chromatography (hexane / ethyl acetate = 4 /
Purified in 1) to give the title compound as a colorless oil (217mg)
I got NMR (CDCl ₃ ) δ, ppm: 1.34 (3H, s), 1.65 (3H, s),
1.73 (3H, s), 2.10-2.82 (7H, m), 2.10-2.50 (6H, m), 2.70 (1
H, t, J = 6.4Hz), 3.39 (1H, dd, J = 10.6,2.8Hz), 3.49 (3H, s),
3.44 (3H, s), 3.70 (1H, d, J = 8.4Hz), 4.94 (1H, s), 5.11 (1H,
s), 5.18 (1H, m).

Example 7 (2R, 3S, 4R) 4-Amino-3-methoxy-2-
[(2R, 3R) -2-Methyl-3- (3-methyl-2
-Butenyl) oxiran-2-yl] -1-methylenecyclohexane

Embedded image (2R, 3S) 3-Methoxy-2-[(2R, 3R)-
2-Methyl-3- (3-methyl-2-butenyl) oxiran-2-yl] -1-methylenecyclohexanone (2
00 mg) and ammonium acetate (550 mg) in methanol (8 ml) solution, sodium cyanoborohydride (50 mg)
mg) was added and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added, the organic layer was extracted with 10% aqueous citric acid solution, then the pH of the water tank was adjusted to 9 and extracted with ethyl acetate, and washed with brine. , Dried, and concentrated to give the title compound (12
7 mg). NMR (CDCl ₃ ) δ, ppm: 1.31 (3H, s), 1.37 (1H, m),
1.65 (3H, s), 1.72 (3H, s), 1.79 (1H, m), 2.00-2.45 (5H, m),
2.67 (1H, t, J = 6.4Hz), 3.25 (1H, dd, J = 9.2,3.4), 3.42 (3H,
s), 3.48 (1H, m), 4.64 (1H, s), 4.87 (1H, s), 5.21 (1H, m).

Formulation Example 1 (Dose per tablet) (1) Compound of Example 3 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Stearic acid Magnesium 2.0 mg A mixture of 10.0 mg of the compound of Example 3, 60.0 mg of lactose and 35.0 mg of corn starch was added to 0.03 ml of 10% by weight gelatin aqueous solution (3.0 m as gelatin).
g) and then granulated by sieving with a 1 mm mesh,
It was dried at 40 ° C. and sieved again. The obtained granules were mixed with 2.0 mg of magnesium stearate and compression molded. The obtained central tablets were coated with sugar coating of a suspension of sucrose, titanium dioxide, talc and gum arabic to give tablets coated with beeswax to obtain coated tablets. Formulation Example 2 (dose per ampoule) (1) Compound of Example 3 10.0 mg (2) Purified water for injection 2.0 ml Compound of Example 3 was dissolved in purified water for injection, and further purified water for injection. Was added to make 2.0 ml.

Test Example 1 Vascular Endothelial Cell-Specific Growth Inhibitory Activity Human umbilical vein-derived endothelial cells (HUVE cells) were Endothelial SFM culture medium (Gibco BR) containing 2% fetal bovine serum.
96-well microplate (Nunc)
50 seeds were seeded at 1500 cells / well. Human skin capillary-derived endothelial cells (HCE cells) contain 2% fetal calf serum
Suspend in Endothelial SFM culture medium (Gibco BRL) and cultivate it in a 96-well microplate at 3000 / well, 50μ
l Seeded. Human fetal lung diploid normal fibroblasts (WI-
38 cells) were suspended in an F-12K culture solution (Dainippon Pharmaceutical Co., Ltd.) containing 10% fetal bovine serum, and seeded in a 96-well microplate at 4000 cells / well in an amount of 50 μl. The next day, HU
For VE cells, 5ng / ml bFGF (R & D), 20ng
/ Ml EGF (Wako Pure Chemical Industries, Ltd.), 2% fetal bovine serum,
50 μl / well of various concentrations of drug, or 30 ng / ml VEGF (Peprotech), 2% fetal bovine serum, and GIT culture medium (Nippon Pharmaceutical Co., Ltd.) containing various concentrations of drug were added. In HCE cells, 5 ng / ml bFGF, 20 ng /
50 μl / well of GIT culture medium containing ml EGF, 2% fetal bovine serum and various concentrations of the drug was added. In WI-38 cells, GI containing 10% fetal bovine serum, various concentrations of drug
50 μl / well of T culture medium was added. HUVE cells, HC
E cells were cultured for 5 days at 37 ° C. under 5% CO ₂ after drug addition. In WI-38 cells, 37 days after drug addition for 3 days
Culturing was performed at 5 ° C. and 5% CO ₂ . After culturing, 5mg / ml MTT
(4,5 dimethyl 2 thiazolyl-2,5-diphenyl-2
H tetrazolium bromide) was added at 20 μl / well.
After culturing at 37 ° C. under 5% CO _{2 for} 4 hours, 100 μl / well of 10% sodium dodecyl sulfate was added. Next day, 5
The absorbance at 90 nm was measured with a 96-well spectrophotometer (Titer Tech). The measurement result is 5 of the absorbance of the drug-free group.
The amount of drug showing 0% inhibitory activity was interpolated and estimated to obtain IC
_Expressed as ₅₀ values.

IC ₅₀ (ng / ml) HUVE HCE bFGF VEGF bFGF Compound of Example 1 91 34 50 Compound of Example 3 5.5 2.8 6.2 From the results of Table 1, the compound of the present invention [I ] Or a salt thereof selectively inhibits the proliferation of vascular endothelial cells in the presence of vascular growth factor.

The compound [I] of the present invention or a salt thereof comprises
Since it has an excellent angiogenesis inhibitory action, it is useful as a preventive and therapeutic drug for various diseases such as tumors in which angiogenesis is pathologically enhanced.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/335 ADU A61K 31/335 ADU AED AED

Claims (19)

[Claims] 1. A compound of the general formula [Wherein, R ¹ is a hydrocarbon group which may have a substituent,
R ² is a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³
And R ⁴ may together form a cyclic hydrocarbon which may have a substituent, X is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a substituent Represents a hydrocarbon group which may be present). However, when R ² is an acetyl group and X is an oxygen atom, R ¹ excludes a 2-methylpropyl group. Or a salt thereof. 2. The compound according to claim 1, wherein R ¹ is an aliphatic hydrocarbon group which may have a substituent. 3. The compound according to claim 1, wherein R ¹ is a 2-methylpropyl or 2-methyl-1-propenyl group which may have a substituent. 4. The compound according to claim 1, wherein R ² is an acyl group. 5. The compound according to claim 4, wherein the acyl group is a carbamoyl group which may have a substituent. 6. The compound according to claim 1, wherein R ³ and R ⁴ are both hydrogen atoms. 7. The compound according to claim 1, wherein X is an oxygen atom or NH. 8. The compound according to claim 1, wherein R ¹ is an optionally substituted alkyl or alkenyl group and R ² is an acyl group. 9. The compound according to claim 8, wherein R ³ and R ⁴ are both hydrogen atoms. 10. The method according to claim 9, wherein X is an oxygen atom or NH.
A compound as described. 11. R ² is an aliphatic acyl group which may have a substituent, an aroyl group which may have a substituent, a heterocyclic carbonyl group which may have a substituent, a substituent The compound according to claim 10, which is a carbamoyl group optionally having or a thiocarbamoyl group optionally having a substituent. 12. R ¹ is a 2-methylpropyl group or 2-
The compound according to claim 11, which is a methyl-1-propenyl group. 13. The compound according to claim 12, wherein X is an oxygen atom. 14. R ¹ is a 2-methylpropyl group or 2-
The compound according to claim 1, wherein a methyl-1-propenyl group, R ² is a carbamoyl group which may have a substituent, R ³ and R ⁴ are both hydrogen atoms, and X is an oxygen atom. 15. A compound of the general formula [Wherein, R ¹ is a hydrocarbon group which may have a substituent,
R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³ and R ⁴ together form a cyclic hydrocarbon which may have a substituent. May be. Or a salt thereof. 16. (a) General formula: [In the formula, W is a protecting group, Y is a leaving group, and other symbols have the same meanings as in claim 1. ] The compound represented by the formula or a salt thereof is subjected to elimination reaction, (b) the general formula: [The symbols in the formula are as defined in claim 1. Or a salt thereof, with a compound R ² -Z is expressed by] (Z is a leaving group, R ² represents. The same meaning as claim 1) or a salt thereof, or reacting an isocyanate, Let
(C) General formula [The symbols in the formula are as defined in claim 1. ] Or a salt thereof is subjected to an alkylidene reaction, or (d) a compound represented by the general formula: [The symbols in the formula are as defined in claim 1. ] A compound represented by or a salt thereof with R ⁵ NH ₂ (R ⁵ is. Of the same meaning as claim 1) preparation of a compound according to claim 1 is reacted with a compound represented by . 17. A general formula: [In the formula, R ^1a represents a hydrocarbon group which may have a substituent,
R ² is a hydrogen atom, a hydrocarbon group which may have a substituent or an acyl group, R ³ and R ⁴ are each a hydrogen atom or a hydrocarbon group which may have a substituent, or R ³
And R ⁴ may together form a cyclic hydrocarbon which may have a substituent, X is an oxygen atom, a sulfur atom or NR ⁵ (R ⁵ is a hydrogen atom or a substituent Represents a hydrocarbon group which may be present). ] The pharmaceutical containing the compound or its salt represented by these. 18. The medicine according to claim 17, which exhibits an angiogenesis inhibitory action. 19. The medicine according to claim 17, which is a therapeutic drug for diseases associated with angiogenesis.