JPH06234631A - Stable pharmaceutical composition of fumagillol derivative - Google Patents

Abstract

PURPOSE:To obtain a sustained release pharmaceutical composition containing a stabilized fumagillol derivative. CONSTITUTION:The pharmaceutical composition is produced by compounding a fumagillol derivative with a glycerol or polyglycerol fatty acid ester. The fumagillol derivative is stably held in this composition and slowly released to develop the excellent effect as a pharmaceutical preparation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a stable pharmaceutical composition of a fumagillol derivative which is an angiogenesis inhibitor useful as a medicine.

[0002]

BACKGROUND OF THE INVENTION Angiogenesis is the development or growth of blood vessels, and it has been clarified that it is deeply involved in diseases such as cancer, diabetic retinopathy, and rheumatoid arthritis. Since an angiogenesis inhibitor suppresses the development of blood vessels and blood supply to diseased sites, it has a new mechanism of action different from conventional drugs,
It may be a therapeutic agent for these diseases. In particular, since angiogenesis for nutritional supplementation is indispensable for the growth of solid tumors, angiogenesis inhibitors are highly expected as cancer therapeutic agents. Further, as a result of searching for angiogenesis inhibitors, fumagillol derivatives were found, and EP-A-3
59,036 (JP-A-3-7270), EP-A-35.
7,061 (JP-A-3-7222), EP-A-354,7
87, EP-A-386,667 (JP-A-3-1457).
1), EP-A-387,650 (JP-A-3-727)
1), EP-A-415,294 (JP-A-3-27937).
6) etc. EP-A-470,569 (JP-A-5-969) discloses a vascular embolic agent containing both a fumagillol derivative and a vascular embolic substance such as a wax such as a glycerol ester of a fatty acid.

[0003]

The object of the present invention is to enhance the stability of a fumagillol derivative having an angiogenesis-inhibiting action so that the drug is gradually released from the administration site over a long period of time so that the pharmacological action is more effectively exhibited. Especially.

[0004]

In view of the above facts, the present inventors have earnestly studied and, as a result, have surprisingly succeeded in producing a composition which retains this angiogenesis inhibitor extremely stably, The present invention has been completed.

That is, the present invention provides a pharmaceutical composition comprising (1) a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin.
(2) The pharmaceutical composition according to (1) above, wherein the fumagillol derivative is dissolved or dispersed in a fatty acid ester of glycerin or polyglycerin, and (3) the pharmaceutical according to (1) above, wherein the fatty acid ester of glycerin is a fatty acid triglyceride. The composition, (4) the pharmaceutical composition according to (1) above, wherein the fumagillol derivative is dissolved in fatty acid triglyceride, and (5) the ratio of the fumagillol derivative to the fatty acid ester of glycerin or polyglycerin is about 0.00.
The pharmaceutical composition according to (1) above, which is 1 to 50% (w / v), (6) The pharmaceutical composition according to (1) above, wherein the fatty acid esterification degree of glycerin or polyglycerin is about 60% or more. (7) The pharmaceutical composition according to (1) above, wherein the degree of polymerization of polyglycerin is 2 to 10, (8) the pharmaceutical composition according to (1) above which is an injection, and (9) above in the liquid form. (1) The pharmaceutical composition as described above, (10) Particle size of about 10
The pharmaceutical composition according to the above (1), which is a fine particle-shaped solid composition having a particle size of 1 to 1000 μm,

[0006]

[Chemical 2]

[Wherein R ¹ is hydrogen, R ² is halogen, N
^{(O) mR 5 R 6,} N + R 5 R 6 R 7 · X -, S (O) nR 5 or S
⁺ R ⁵ R ⁶ · X ⁻ (In the formula, R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group or a heterocyclic group which may have a substituent,
^- is a counter anion, m is an integer of 0 or 1, n
Represents an integer of 0 to 2. Further, R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or a sulfur atom, and these may be condensed. The nitrogen or sulfur-containing heterocyclic group may have a substituent. ), Or R ¹ and R
² represents a bond, R ³ represents an optionally substituted 2-methyl-1-propenyl group or an isobutyl group, A is O or NR ⁸ (in the formula, R ⁸ is hydrogen or Each represents a lower alkyl group or an aryl group which may have a substituent), and R ⁴ represents hydrogen, a hydrocarbon group which may have a substituent or an acyl group. ] The pharmaceutical composition according to (1) above, which is a fumagillol derivative or a salt thereof, represented by the above (1), wherein R ¹ and R ² represent a bond, or R ¹ is hydrogen and R ² is N (O). mR ⁵ R ⁶ ,
N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ , S (O) nR ⁵ or S ⁺ R ⁵ R ⁶ ·
X ⁻ ; A is O or NH; R ³ is a 2-methyl-1-propenyl or isobutyl group which may have a substituent; and R ⁴ is hydrogen or a carbamoyl group which may have a substituent. A certain pharmaceutical composition according to the above (11),
(13) The pharmaceutical composition according to the above (12), wherein R ¹ and R ² represent a bond, (14) A is O; and R ³ may be substituted with a hydroxyl group or a dialkylamino group, respectively 2- Methyl-1-propenyl or isobutyl group, R
⁴ is a carbamoyl group substituted by C _1-6 alkyl or halogeno C _1-6 alkanoyl group (12) a pharmaceutical composition according, (15) fumagillol derivative is 6-O
The pharmaceutical composition according to (1) above, which is-(N-chloroacetylcarbamoyl) fumagillol, and (16) the fumagillol derivative is 4- (N'-chloroacetylureido) -2-.
(1,2-epoxy-1,5-dimethyl-4-hexenyl)
The pharmaceutical composition according to (1) above, which is -1- (1,3-dihydrobenzo [c] thiophene-2-ylio) methyl-3-methoxycyclohexanol chloride, and (17) the fatty acid constituting the fatty acid ester is carbon. Number 6 to 22 (C ₆
To C ₂₂ ) saturated fatty acid, the pharmaceutical composition according to (1) above, (18) the pharmaceutical composition according to (1) above, wherein the main component of the fatty acid constituting the fatty acid ester is caprylic acid (C ₈ ). (19) The pharmaceutical composition according to (1) above, wherein the main component of the fatty acid constituting the fatty acid ester is capric acid (C ₁₀ ), and (20) the main component of the fatty acid constituting the fatty acid ester is caprylic acid (C _8). ) And capric acid (C ₁₀ ), the pharmaceutical composition according to the above (1), (21) The main component of the fatty acid constituting the fatty acid ester is lauric acid (C ₁₂ ). Pharmaceutical composition, (22)
The pharmaceutical composition according to (1) above, wherein the main component of the fatty acid that constitutes the fatty acid ester is myristic acid (C ₁₄ ).
3) The pharmaceutical composition according to (1) above, wherein the main component of the fatty acid constituting the fatty acid ester is palmitic acid (C ₁₆ ),
(24) The pharmaceutical composition according to (1) above, wherein the main component of the fatty acid constituting the fatty acid ester is stearic acid (C ₁₈ ), (25) The main component of the fatty acid constituting the fatty acid ester is arachidic acid (C ₂₀ ). (26) The pharmaceutical composition according to the above (1), wherein the main component of the fatty acid constituting the fatty acid ester is behenic acid (C ₂₂ ). (28) A method for stabilizing a fumagillol derivative, which comprises dissolving or dispersing the fumagillol derivative in a fatty acid ester of glycerin or polyglycerin (28). ,
A pharmaceutical composition for inhibiting angiogenesis, which is characterized by being blended with glycerin or polyglycerin fatty acid ester, and (30) Blending with fumagillol derivative and glycerin or polyglycerin fatty acid ester And a stable sustained release pharmaceutical composition for inhibiting angiogenesis. The fumagillol derivative used in the present invention has a general formula

[0008]

[Chemical 3]

[Wherein R ¹ is hydrogen, R ² is halogen, N
^{(O) mR 5 R 6,} N + R 5 R 6 R 7 · X -, S (O) nR 5 or S
⁺ R ⁵ R ⁶ · X ⁻ (In the formula, R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group or a heterocyclic group which may have a substituent,
^- is a counter anion, m is an integer of 0 or 1, n
Represents an integer of 0 to 2. Further, R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or a sulfur atom, and these may be condensed. The nitrogen or sulfur-containing heterocyclic group may have a substituent. ), Or R ¹ and R
² represents a bond, R ³ represents an optionally substituted 2-methyl-1-propenyl group or an isobutyl group, A is O or NR ⁸ (in the formula, R ⁸ is hydrogen or Each represents a lower alkyl group or an aryl group which may have a substituent), and R ⁴ represents hydrogen, a hydrocarbon group which may have a substituent or an acyl group. ] The fumagillol derivative represented by or its salt, etc. are mentioned. In the general formula (I), examples of the halogen represented by R ² include fluorine, chlorine, bromine and iodine. When R ¹ and R ² represent a bond, an epoxy ring is formed.

The hydrocarbon group represented by R ⁵ , R ⁶ or R ⁷ which may have a substituent is a straight-chain or branched alkyl group having 1 to 6 carbon atoms ( Example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), an alkenyl group having 2 to 6 carbon atoms (eg, vinyl,
Allyl, 2-butenyl, methylallyl, 3-butenyl,
2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), an alkynyl group having 2 to 6 carbon atoms (eg, ethynyl, propargyl, 2-butyn-1-yl, 3-butyn-2-yl, 1-pentyne-3). -Yl, 3-pentyn-1-yl, 4-pentyn-2-yl, 3-hexyn-1-yl, etc.), a cycloalkyl group having 3 to 6 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. ), A cycloalkenyl group having 3 to 6 carbon atoms (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), an aralkyl group having 7 to 13 carbon atoms (eg, benzyl, 1-phenethyl, 2-phenethyl, etc.) , And an aryl group having 6 to 10 carbon atoms (eg, phenyl, naphthyl, etc.) and the like.

The heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ which may have a substituent has 1 to 4 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.). 5 or 6-membered heterocyclic groups containing (eg, 2-furyl, 2-thienyl, 4-thiazolyl, 4-imidazolyl, 4-pyridyl, 1,3,4
-Thiadiazol-2-yl, tetrazolyl, etc.) and the like. The heterocyclic group includes a 5- or 6-membered ring (eg, benzene, pyridine, cyclohexane, etc.) which may contain 1 to 3 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to carbon atoms. Fused to form a bicyclic fused ring group (eg, 8-
Quinolyl, 8-purinyl, etc.) and the like.

The nitrogen-containing heterocyclic ring which R ⁵ and R ⁶ may form together with the adjacent nitrogen atom includes 1-3 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to the nitrogen atom. And a 4- to 7-membered nitrogen-containing heterocyclic ring (eg, pyrrolidin-1-yl, piperidino, morpholino, piperazin-1-yl, etc.) and the like. Examples of the sulfur-containing heterocyclic ring which R ⁵ and R ⁶ may form together with the adjacent sulfur atom include 1 to 3 hetero atoms (eg,
Examples thereof include a 4- to 7-membered sulfur-containing heterocycle (eg, tetrahydrothiophen-1-yl, 1,4-thioxan-1-yl etc.) which may contain nitrogen, oxygen, sulfur and the like.

The nitrogen-containing or sulfur-containing heterocycle which R ⁵ and R ⁶ may form together with the adjacent nitrogen atom or sulfur atom is a 5- or 6-membered ring (eg, benzene, pyridine, pyrazine, pyrimidine, pyridazine, A condensed bicyclic ring group (eg, isoindoline-
2-yl, 2-isoquinolyl, 1,3-dihydrobenzo
[c] thiophen-2-yl, 2,3-dihydrobenzo [b]
Thiophen-1-yl, 3,4-dihydro-1H-2-
Benzopyran-2-yl, 3,4-dihydro-2H-1
-Benzopyran-1-yl, 1,2,4,5-tetrahydro-3-benzothiepin-3-yl, 1,3-dihydrothieno [3,4-c] pyridin-2-yl, 5,7-dihydrothieno [3 , 4-b] Pyrazin-6-yl, 5,7-dihydrothieno [3,4-d] pyridazin-6-yl) and the like may be formed.

The lower alkyl group of the lower alkyl group which may have a substituent represented by R ⁸ has 1 to 1 carbon atoms.
6 straight chain or branched alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl, pentyl, isopentyl, hexyl etc.)
And so on. The aryl group of the aryl group optionally represented by R ⁸ has 6 to 1 carbon atoms.
Examples thereof include an aryl group of 0 (eg, phenyl, naphthyl, etc.).

The hydrocarbon group which may have a substituent represented by R ⁴ is the hydrocarbon group which may have a substituent represented by R ⁵ , R ⁶ or R ⁷ described above. The ones mentioned are listed. When the hydrocarbon group represented by R ⁴ is an alkenyl group, it is preferably unsubstituted. As the acyl group which may have a substituent represented by R ⁴ ,
Acyl carboxylate, each of which may have a substituent,
Acyl sulfonate, carbamoyl, thiocarbamoyl,
Examples of the residue of an acid such as sulfamoyl (acyl group derived from the corresponding acid) and the like, for example, alkanoyl optionally having a substituent, aroyl, heterocyclic carbonyl, carbamoyl, thiocarbamoyl, arylsulfonyl, Examples include alkylsulfonyl, sulfamoyl, alkoxycarbonyl, aryloxycarbonyl and the like. Carbamoyl which may have a substituent is preferable.

Examples of the alkanoyl group which may have a substituent include alkanoyl groups having 1 to 6 carbon atoms (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.) Is mentioned. The aroyl group of the aroyl group which may have a substituent has 7 to 1 carbon atoms.
1 aroyl group (eg, benzoyl, 1-naphthoyl, 2
-Naphthoyl, etc.) and the like. As the heterocyclic carbonyl group in the heterocyclic carbonyl group which may have a substituent, a hetero atom (eg, nitrogen, oxygen, sulfur, etc.)
A 5- or 6-membered heterocyclic carbonyl group containing 1 to 4 (eg,
2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.) and the like. Examples of the arylsulfonyl group of the arylsulfonyl group which may have a substituent include an arylsulfonyl group having 6 to 10 carbon atoms (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.) and the like.

The alkylsulfonyl group of the alkylsulfonyl group which may have a substituent has 1 to 6 carbon atoms.
Alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, pentylsulfonyl, etc.) and the like. Examples of the alkoxycarbonyl group of the alkoxycarbonyl group which may have a substituent include an alkoxycarbonyl group having 2 to 7 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, isobutoxycarbonyl, etc.) and the like. The aryloxycarbonyl group of the aryloxycarbonyl group which may have a substituent has 7 carbon atoms.
To 11 aryloxycarbonyl groups (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl, etc.) and the like. 2-methyl- each of which may have a substituent, represented by R ^3.
As the substituent of the 1-propenyl or isobutyl group,
For example, hydroxyl group, amino group, lower (C _1-3 ) alkylamino group (eg, methylamino, ethylamino, isopropylamino, etc.), dilower (C _1-3 ) alkylamino group (eg, dimethylamino, diethylamino) Etc.) and the like. Of these, a hydroxyl group and a di-lower (C _1-3 ) alkylamino group, particularly a dimethylamino group is preferable.

An optionally substituted hydrocarbon group or heterocyclic group represented by R ⁵ , R ⁶ or R ⁷ , R
⁵ and R ⁶ are nitrogen-containing or sulfur-containing heterocyclic groups which may be condensed with a nitrogen atom or a sulfur atom adjacent to each other, a lower alkyl group or aryl represented by R ⁸ which may have a substituent, respectively. Group, and a hydrocarbon group or acyl group represented by R ⁴ , each of which may have a substituent
(E.g., alkanoyl group, aroyl group, heterocyclic carbonyl group, carbamoyl group, thiocarbamoyl group, arylsulfonyl group, alkylsulfonyl group, sulfamoyl group, alkoxycarbonyl group, aryloxycarbonyl group, etc.) May have 1 to 3 substituents.

Examples of the substituent include a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, etc.), a C _2-6 alkenyl group ( Examples, vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl, etc.), C _2-6 alkynyl group (eg, ethynyl, propargyl, 2-butyn-1-yl). , 3-butyn-2-yl, 1
-Pentin-3-yl, 3-pentyn-1-yl, 4-
Pentin-2-yl, 3-hexyn-1-yl, etc.),
C _3-6 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), C _3-6 cycloalkenyl group (eg, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, etc.), C _6-10 aryl Group (eg, phenyl, naphthyl, etc.), amino group, mono C _1-6 alkylamino group (eg, methylamino, ethylamino, isopropylamino, etc.),
Di C _1-6 alkylamino group (eg, dimethylamino, diethylamino, etc.), azido group, nitro group, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, C
_1-4 alkoxy group (eg, methoxy, ethoxy, etc.), C
_6-10 aryloxy group (eg, phenoxy, naphthyloxy, etc.), C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, etc.), C _6-10 arylthio group
(Eg, phenylthio, naphthylthio, etc.), cyano group, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, etc.), C _7-11 aryloxycarbonyl group (eg, phenoxycarbonyl, 1-naphthyloxycarbonyl, 2
-Naphthyloxycarbonyl, etc.), carboxy-C _1-4
Alkoxy group (eg, carboxymethoxy, 2-carboxyethoxy, etc.), C _1-6 alkanoyl group (eg, formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl, etc.), C _7-11 aroyl group (eg, Benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, etc.), C _6-10 arylsulfonyl group (eg, benzenesulfonyl, 1-naphthylsulfonyl, 2- Naphthylsulfonyl, etc.), C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, etc.), C _6-10 arylsulfinyl group (eg,
Benzenesulfinyl, 1-naphthylsulfinyl, 2
-Naphthylsulfinyl, etc.), heteroatoms (e.g., nitrogen,
5- or 6-membered heterocyclic group containing 1 to 4 oxygen, sulfur, etc.)
(Eg 2-furyl, 2-thienyl, 4-thiazolyl, 4
-Imidazolyl, 4-pyridyl, 1,3,4-thiadiazol-2-yl, 1-methyl-5-tetrazolyl, etc.), heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) 1 to 4
1 to 4 5- or 6-membered heterocyclic carbonyl groups (eg, 2-furoyl, 2-thenoyl, nicotinyl, isonicotinyl, etc.) and heteroatoms (eg, nitrogen, oxygen, sulfur, etc.)
A 5- or 6-membered heterocyclic thio group (eg, 4-pyridylthio, 2-pyrimidylthio, 1,3,4-thiadiazole-
2-ylthio, 1-methyl-5-tetrazolylthio, etc., and the heterocyclic thio group is further condensed with a benzene ring to form a bicyclic condensed ring thio group (eg, 2-benzothiazolylthio, 8-quinolylthio group). Etc.) may be formed. Among these substituents, C _1-6 alkyl group and C _1-6
Alkanoyl groups are preferred. When R ⁴ represents a di-substituted carbamoyl group, thiocarbamoyl group, or sulfamoyl group, the carbamoyl group, thiocarbamoyl group, or sulfamoyl group is a nitrogen-containing heterocyclic ring together with its nitrogen atom [eg, pyrrolidine-1- Ill,
Piperidino, morpholino, piperazin-1-yl, 4
-Methylpiperazin-1-yl, 4-phenylpiperazin-1-yl and the like, which may contain 1 to 3 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) in addition to the nitrogen atom 4 To 7-membered nitrogen-containing heterocycle, etc.] may be formed.

Further, a substituent in a hydrocarbon group or a heterocyclic group, which may have a substituent, represented by R ⁵ , R ⁶ or R ⁷ , a nitrogen atom in which R ⁵ and R ⁶ are adjacent to each other, or a sulfur atom. A substituent in a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an atom, a substituent in a lower alkyl group or an aryl group which may have a substituent represented by R ⁸ , and R ⁴ A hydrocarbon group or an acyl group each of which may have a substituent (for example,
Alkanoyl group, aroyl group, heterocyclic carbonyl group, carbamoyl group, thiocarbamoyl group, arylsulfonyl group, alkylsulfonyl group, sulfamoyl group, alkoxycarbonyl group or aryloxycarbonyl group, etc. 1-3
May have one substituent.

Examples of the substituent include the above C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group and C
_3-6 cycloalkyl group, C _3-6 cycloalkenyl group, C
_6-10 aryl group, amino group, mono C _1-6 alkylamino group, di C _1-6 alkylamino group, azido group, nitro group,
Halogen, hydroxyl group, C _1-4 alkoxy group, C
_6-10 aryloxy group, C _1-6 alkylthio group, C _6-10
Arylthio group, cyano group, carbamoyl group, carboxyl group, C _1-4 alkoxycarbonyl group, C _7-11 aryloxycarbonyl group, carboxy C _1-4 alkoxy group, C _1-6 alkanoyl group, halogeno C _1-6 alkanoyl Group, C _7-11 aroyl group, C _1-6 alkylsulfonyl group,
C _6-10 arylsulfonyl group, C _1-6 alkylsulfinyl group, C _6-10 arylsulfinyl group, 5 or 6-membered heterocyclic group, 5 or 6-membered heterocyclic carbonyl group, 5 or 6-membered heterocyclic thio group, etc. Is mentioned.

[0022] by X ^- as the counter anion represented, for example, halogen ions (e.g., iodide ion, bromine ion, chloride ion), sulfur ion, phosphate ion, nitrate ion, perchlorate ion, tetrafluoroborate ion, Methane sulfate ion, p-tolyl sulfate ion, benzene sulfate ion, hydroxide ion, carboxylate ion of organic acid (e.g., oxalate ion, maleate ion, fumarate ion,
Succinate ion, citrate ion, lactate ion, trifluoroacetate ion, lactobionate ion, acetate ion, propionate ion,
(Tartrate ion, ethyl succinate ion, etc.)
And so on. Of these, halogen ions are preferred.

The compound (I) has an asymmetric center in the molecule and has optical activity, but its absolute structure is based on the raw material fumagillol. Unless otherwise specified, the compound that matches the absolute structure of fumagillol should be used. means. The bonding mode of the substituents on the cyclohexane ring is

[0024]

[Chemical 4]

A case is shown. In the compound (I), R ¹
Or R ² represents a bond, or R ¹ is hydrogen and R ² is N (O) mR
⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ , S (O) nR ⁵ or S ⁺ R ⁵ R ⁶
· X ^-, more preferably ^{S + R 5 R 6 · X} - in which compounds are preferred. Further, it is preferable that R ⁵ and R ⁶ form a sulfur-containing heterocycle with the adjacent sulfur atom, and the sulfur-containing heterocycle is condensed with a 5- or 6-membered ring to form a bicyclic condensed ring. May be. As the compound (I), a compound having a bond with R ¹ and R ² is more preferable. A is preferably O or NH. O is particularly preferable. R ³ is preferably a 2-methyl-1-propenyl group or an isobutyl group, each of which may be substituted with a hydroxyl group or a dialkylamino group. Especially, a 2-methyl-1-propenyl group is more preferable. R ⁴ is preferably hydrogen or carbamoyl which may have a substituent. Particularly, a C _1-6 alkyl group or a C _1-6 alkanoyl group which may be substituted with a halogen is preferable as the substituent. Compound
Specific preferred examples of (I) include 6-O- (N-chloroacetylcarbamoyl) fumagillol, 6α- (N′-chloroacetylureido) -6-desoxyfumagillol,
4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,
3-dihydrobenzo [c] thiophene-2-ylio) methyl-3-methoxycyclohexanol chloride, 6-
O- (N-methylcarbamoyl) fumagillol and the like can be mentioned.

When the compound (I) has an acidic substituent (eg, carboxyl) or a basic substituent (eg, amino, mono-lower alkylamino, di-lower alkylamino, nitrogen-containing heterocyclic group, etc.) in the molecule. It may form a physiologically acceptable salt. Examples of the salt include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like. Inorganic bases that can form these salts include alkali metals (eg, sodium, potassium, etc.), alkaline earth metals (eg, calcium, magnesium, etc.), and organic bases such as trimethylamine, triethylamine, pyridine, picoline, N, N-dibenzylethylenediamine, ethanolamine, diethanolamine,
Trishydroxymethylaminomethane, dicyclohexylamine and the like, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, organic acids such as formic acid, acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, Fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used, and examples of the basic or acidic amino acid include arginine, lysine, ornithine, aspartic acid and glutamic acid. Of these salts, salts with bases (that is, salts with inorganic bases, salts with organic bases, salts with basic amino acids) are salts with carboxyl groups in the substituents of compound (I) and also with acids.
(That is, a salt with an inorganic acid, a salt with an organic acid, a salt with an acidic amino acid) is an amino group, a mono-lower alkylamino group, a di-lower alkylamino group, a nitrogen-containing heterocyclic group in the substituent of compound (I). Etc. means a salt that can be formed.

When compound (I) has a di-lower alkylamino group, a nitrogen-containing heterocyclic group or a nitrogen-containing aromatic heterocyclic group in the molecule, the nitrogen atom in these groups is further alkylated. May form a quaternary ammonio group (eg, trimethylammonio, N-methylpyridinyl, N-methylpyrrolidin-1-ylium, etc.), and the counter anion is the same as the counter anion represented by X ⁻ . A counter anion is mentioned. The compound represented by the general formula (I) or a salt thereof is a hydrolyzate of fumagillin produced by a microorganism, fumagillol [Tarbell, Tarbell.
D. S. ) Et al., Journal of American Chemical Society (J. Am. Chem. Soc.) 83 , 30.
96 (1961)] as a starting material, and can be produced by the method described in the aforementioned EP publication or a method analogous thereto. The physicochemical and biological properties of the compounds are described in detail in the EP publications mentioned above.

The fatty acid ester of glycerin or polyglycerin used in the present invention is used as a stabilizer of the fumagillol derivative. From the viewpoint of the stabilizing effect or the sustained-release effect of the fumagillol derivative, the fatty acid constituting the ester of the fatty acid ester of glycerin or polyglycerin is preferably a saturated type having 6 to 22 carbon atoms. Specifically, for example, caproic acid (C ₆ ), caprylic acid (C ₈ ), capric acid (C ₁₀ ) lauric acid (C ₁₂ ), myristic acid (C ₁₄ ), palmitic acid (C ₁₆ ), stearic acid (C _18), arachidic acid (C _20), behenic acid (C ₂₂₎
Etc. The degree of esterification, that is, the ratio of esterified hydroxyl groups to all hydroxyl groups in the fatty acid ester of glycerin or polyglycerin is preferably about 60% or more, more preferably about 80% or more. Further, the polymerization degree of polyglycerin is preferably 2-16. The fatty acid ester of glycerin or polyglycerin is used alone or in combination of two or more kinds. Preferably, the degree of esterification is about 60% or more,
More preferably, it is used by appropriately selecting it so as to be about 80% or more.

The glycerin fatty acid ester is preferably a fatty acid triglyceride (triacylglycerol) in which one molecule of glycerol is ester-bonded with three molecules of fatty acid. These ester-bonded fatty acids are of the same type,
Different types may be used, preferably 6 to 22 carbon atoms
Is a saturated fatty acid. More preferably, it has 8 to 8 carbon atoms.
18 saturated fatty acids. Of these, those having 8 to 12 carbon atoms are particularly preferable.

For example, Miglyol 810 (MIGLY
OL810, caprylic / capric triglyceride,
The fatty acid composition is 65-75% caprylic acid, 25-35% capric acid, and Miglyol 812 (MIGLYOL8).
12, caprylic acid / capric acid triglyceride, the fatty acid composition is 50-65% caprylic acid, 30-capric acid
45%), Dynasan 110 (DYNASAN 110, capric acid triglyceride), Dynasan 112 (DYNA
SAN112, lauric acid triglyceride), Dynasan 114 (DYNASAN114, myristic acid triglyceride), Dynasan 116 (DYNASAN116,
Palmitic acid triglyceride), Dynasan 118 (DY
NASAN118, stearic acid triglyceride, etc. are manufactured by Hills (HULS AKTIENGESELLSCH).
(AFT, Germany) and also Triester F-810
(Caprylic acid / capric acid triglyceride) are sold by Nikko Chemicals (Tokyo). You may use these in mixture of 2 or more types.

The polyglycerin fatty acid ester is preferably one of various glycerin polymers having a degree of polymerization of glycerin of 2 to 16 as described above. Particularly, 2 to 10 are preferable. The fatty acid is ester-bonded to at least one of the (polymerization degree + 2) hydroxyl groups, preferably about 60% or more, preferably about 80% or more. The fatty acid is preferably saturated. It is a saturated fatty acid having 6 to 22 carbon atoms, and more preferably 8 to 18 carbon atoms. The fatty acids to be esterified may be of the same type or of different types. The products actually sold are various types of polyglycerin fatty acid ester depending on the combination of the degree of polymerization of glycerin, the type of fatty acid and the degree of esterification thereof, and any of these can be used in the present invention.

For example, PS-310 (tetraglycerin pentastearate), DAS-750 (decaglycerin decasterate) and the like are from Sakamoto Yakuhin (Osaka), and Poem J46B (tetraglycerin hexabehenate) and the like are from RIKEN Vitamin ( Tetraglyn 5-S (tetraglycerin pentastearate), Decaglyn 10-S (decaglycerin decasterate), etc. are sold by Nikko Chemicals (Tokyo). You may use these individually or in mixture of 2 or more types. Further, it can be used in combination with glycerin fatty acid ester.

The pharmaceutical composition of the present invention is a composition in which a fumagillol derivative is blended with a fatty acid ester of glycerin or polyglycerin to stabilize the fumagillol derivative. The pharmaceutical composition may be in liquid form or solid form, but is preferably in liquid form.
The pharmaceutical composition can be produced by a method known per se. For example, the following method may be mentioned.

When a fatty acid ester of glycerin or polyglycerin which is liquid at room temperature is used, a fumagillol derivative is added thereto and dissolved or dispersed by a method such as stirring to obtain a composition. When a fatty acid ester of glycerin or polyglycerin that is solid at room temperature is used, it is made into a liquid state, and then the fumagillol derivative is dissolved or dispersed and solidified. According to a method known per se, for example, an ester of glycerin or polyglycerin fatty acid is heated to a temperature equal to or higher than the melting point, and the fumagillol derivative is dissolved or dispersed in a liquefied state, and then cooled to be solidified. When solidifying, it may be shaped into particles or pellets, if necessary. As the molding method, a method known per se is used. For example, in the case of particles, the particle size is preferably about 10 to about 1.
Spherical fine particles of 000 μm. As a molding method,
A method known per se (see, for example, JP-A-2-223533)
Is adopted. For example, there are a method of dispersing a solution or dispersion of the above fumagillol derivative in an aqueous phase, a spray dry method, or a spray chilling method of forming fine oil droplets and rapidly cooling and solidifying. In order to avoid aggregation of particles, an aqueous solution containing, for example, a dispersant (eg, Tween 80, carboxymethyl cellulose, polyvinyl alcohol, etc.) or the like is used as the aqueous phase. The ratio of the fumagillol derivative in the composition to the fatty acid ester of glycerin or polyglycerin can be appropriately selected depending on the physicochemical properties of these components, such as solubility, dispersibility and the effective dose of the fumagillol derivative. It is preferably about 0.001 to 50% (w / v). More preferably, about 0.01 to 30% (w / v)
Is. The concentration of the fumagillol derivative in the composition can be appropriately selected depending on the physicochemical properties of the composition, and is usually about 0.0005 to 30% (w / v), preferably about 0.005.
~ 25% (w / v). The pharmaceutical composition of the present invention may contain additives which are usually used in formulating as a pharmaceutical. For example, when used for injection, preservatives (eg, benzyl alcohol, ethyl alcohol, benzalkonium chloride, phenol, chlorobutanol, etc.), antioxidants (eg, butylhydroxyanisole, propyl gallate, ascorbic acid) Palmitate, α-tocopherol, etc.), thickeners (eg, lecithin, hydroxypropyl cellulose, aluminum stearate, etc.) and the like may be used.

The pharmaceutical composition of the present invention is preferably obtained by a suitable method known per se in a sterile form so that it can be used for medical purposes. The pharmaceutical composition of the present invention can be prepared according to a method known per se, for example, distilled water for injection, sodium chloride, saccharides (eg, glucose, mannitol, inositol, etc.) or a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co.). ), HCO60 (manufactured by Nikko Chemicals) polyethylene glycol, carboxymethylcellulose, sodium carboxymethylcellulose, sodium alginate, etc.) and the like are dispersed as an emulsion or suspending agent. After dispersion, the fumagillol derivative can be administered as an injectable preparation at an effective concentration for the target disease intravenously, intraarterially, intramuscularly, subcutaneously, in an organ, or in a lesion such as a tumor. When the pharmaceutical composition is in liquid form, it can be directly administered as an injection. In addition, the pharmaceutical composition obtained by the present invention is an administration agent other than injection administration according to a conventional method, for example, an external preparation (eg, nasal preparation, transdermal preparation), suppository (eg, rectal suppository, vaginal suppository). Etc.) is also possible. For example, to prepare an external preparation, the pharmaceutical composition of the present invention can be made into a solid, semi-solid or liquid nasal administration agent according to a method known per se. For example, as the above solid, the pharmaceutical composition of the present invention is used as it is, or an excipient (eg, glucose, mannitol, starch, microcrystalline cellulose, etc.), a thickener (eg, natural gums, cellulose derivative). , Acrylic acid polymer, etc.) and mixed to form a powdery composition. The above-mentioned liquid form is almost the same as the case of the injection, and is an oily or aqueous suspension. In the case of semi-solid form, an aqueous or oily gel or ointment form is preferable. In addition, all of these are pH regulators (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic acid esters, chlorobutanol, benzalkonium chloride, etc.), etc. May be added. For example, in the case of a suppository, the pharmaceutical composition of the present invention can be made into an oily or aqueous solid, semisolid or liquid suppository according to a method known per se. The pharmaceutical composition of the present invention has low toxicity and a strong pharmacological action. For example, treatment, prevention and inhibition of angiogenesis-related diseases such as inflammatory diseases such as rheumatoid arthritis, diabetic retinopathy or tumors (such as breast cancer, liver cancer, colon cancer, and Kaposi's sarcoma cancer) Indicates. Therefore, a drug of a mammal (eg, mouse, rat, monkey, cow, dog, human, etc.) [eg, inflammatory disease such as rheumatoid arthritis, diabetic retinopathy or tumor (eg, breast cancer,
It is useful as a therapeutic and prophylactic drug for liver cancer, colon cancer, and Kaposi's sarcoma). For example, when administered subcutaneously or intramuscularly in the treatment of cancer, a sustained release effect of the fumagillol derivative can be obtained over a long period of time, and the number of administrations can be reduced. Further, it can be directly injected into the tumor-dominant artery and used as a useful chemoembolic agent. When it is used for treating an adult cancer patient, it is appropriately selected depending on the type, site, size, and type of fumagillol derivative of the tumor.
1 mg to about 5.0 g, preferably about 1.0 mg to about 2.0 g, more preferably about 5 mg to about 1.0 g of a fumagillol derivative dissolved or dispersed in a fatty acid ester of glycerin or polyglycerin, It may be administered at regular intervals. The frequency of administration can be appropriately selected depending on the type of disease and the dosage form. For example, a nasal formulation may be given twice or three times daily.
The suppository can usually be administered once a day. For parenteral formulations, subcutaneous or intramuscular depot formulations may be injected 1-3 times per week. If injected into the tumor-dominant artery or the tumor itself, frequent repeated injections are not necessary, and one injection every 1-4 weeks is sufficient to obtain the desired therapeutic effect.

The pharmaceutical composition of the present invention improves the stability of the fumagillol derivative, provides stronger pharmacological activity, and is expected to have a more reliable therapeutic effect.

[0037]

The present invention will be described in detail with reference to the following examples, but the present invention is not limited thereto. Example 1 The concentration of 6-O- (N-chloroacetylcarbamoyl) fumagillol (hereinafter referred to as compound A) was Miglyol 812.
(MIGLYOL 812, caprylic / capric triglyceride, HILLS AKTIENGES
ELLSCHAFT), Germany) 1 mg / ml (0.1
% W / v) and 10 mg / ml (1% w / v) were dissolved to prepare a uniform solution. These solutions were dispensed into vials purged with nitrogen and allowed to stand at 37 ° C. to
The residual rate of was measured. For comparison, the same examination was carried out also for Compound A dissolved in sesame oil, Lipiodol (trade name), the main component being iodized poppy oil ethyl ester) and water. The results are shown in Table 1.
Shown in.

[0038]

[Table 1]

Compound A was hardly decomposed in Miglyol 812, which is a fatty acid triglyceride, even after 14 days, and was extremely stable as compared with an aqueous solution and other oil solutions. Thus, the preparation containing Miglyol 812 showed excellent stability because the base is a triglyceride of saturated fatty acid, which has no double bond, has few polar groups, and has a low water content. It is considered that the decomposition due to hydrolysis and oxidation was prevented.

Example 2 The concentration of compound A was 10 mg / milliol 812.
A uniform solution was prepared by dissolving the solution so that the solution became ml (1% w / v). Dispense this solution into a vial purged with nitrogen and
After leaving still at 5 ° C., 40 ° C. and 60 ° C. respectively, the residual rate of Compound A after 1 month and 2 months was measured. A similar experiment was conducted using Lipiodol, and the results are shown in Table 2.

[0041]

[Table 2]

Compound A was much more stable when Miglyol 812 was used as compared to Lipiodol. Example 3 Example 1 was carried out in order to examine the persistence in blood or body fluid.
5 ml of 1/30 M phosphate buffer (pH 7.0) was added to 1 ml of the solution used in each step, and the mixture was stirred with a rotator at a speed of 10 rpm, and the mixture was aged (37 ° C for 1 day, 2 days).
Day and after 7 days), the content of compound A in the oil phase was established to determine the drug residual rate. The results are shown in Table 3.

[0043]

[Table 3] When fatty acid triglycerides were used compared to other oil solutions, Compound A was shown to be the most stable with sustained drug release over 7 days.

Example 4 5 g of Dynasan 118 (DYNASAN118, triglyceride stearate, manufactured by Hills Co., Ltd.) was heated to about 90 ° C. and melted, and then 2% by weight (about 2% w /
v) and 10% (about 10% w / v) were added and dissolved, respectively. Next, this solution is subjected to a spray chilling method to obtain a particle size of 125 to 250 μm.
Spherical particles (hereinafter TG18-msp 2% charged and 10
%). 3 g was obtained. Similarly, Dynasan 114 (myristic acid triglyceride, Hills Co.) 5
After heating g to about 60 ° C. to melt, 2% (about 2% w / v) and 10% (about 10% w / v) by weight of this
Compound A was added and dissolved to obtain v). Next, by subjecting this solution to the spray chilling method,
Spherical fine particles having a particle diameter of 125 to 250 μm (hereinafter referred to as TG14
-Msp 2% charge and 10% charge).

Example 5 As in Example 1, the TG14-msp obtained in Example 4 was used.
2% preparation, 10% preparation, TG18-msp 2% preparation, 10
The mixture was allowed to stand at 37 ° C. in a vial in which the% charge was replaced with nitrogen, and the residual rate of Compound A was measured. The results are shown in Table 4.

[0046]

[Table 4]

When the fatty acid triglyceride was used, it was more stable than when the solutions of sesame oil, lipiodol and water shown in Table 1 were used. Especially TG14-
The 10% charge of msp and TG18-msp was extremely stable with almost no decomposition of compound A even after 14 days.

Example 6 As in Example 3, the TG18-msp obtained in Example 4 was used.
1 / for each 10 mg of 2% and 10%
5 ml of 30 M phosphate buffer (pH 7.0) was added to each, and the mixture was stirred using a rotator at a speed of 10 rpm. Then, the TG18-msp 2% charge and the 10% charge were separated over time, the content of the compound A in the particles was measured, and the residual rate was determined. The results are shown in Table 5.

[0049]

[Table 5] The release rate was slightly faster in the 10% preparation, but it was revealed that both the 2% preparation and the 10% preparation sustainedly released for 14 days or more.

Example 7 Poem J46B (tetraglycerin hexabehenate,
After heating 3 g of RIKEN vitamin) to about 90 ° C to melt it,
On the other hand, Compound A was added and dissolved so that the weight ratio was 10% (about 10% w / v). Next, this solution was solidified into a cylindrical shape having a diameter of 2 mm to obtain 3 g of a rod-shaped pellet (hereinafter abbreviated as Poem J46B-pellet).
The obtained Poem J46B-pellet was allowed to stand at 37 ° C. in a nitrogen-purged vial in the same manner as in Example 1, and the residual rate of Compound A was measured. The results are shown in Table 6.

[0051]

[Table 6]

When the polyglycerin fatty acid ester was used, the compound A was extremely stable as compared with the case of the aqueous solution shown in Table 1.

Example 8 10 mg / m based on Decaglin 10-O (Decaglyn 10-O, decaglycerin decaoleate, Nikko Chemicals)
Compound A was dissolved to give a uniform solution of l. Poem J obtained in Example 7 as in Example 3
Approximately 10 mg of 46B-pellet and the above decagrine 10-
A 1/30 M phosphate buffer (pH 7.
0) was added in 5 ml portions, and the mixture was stirred using a rotator at a speed of 10 rpm. After that, over time Poem J46B-pe
The content of compound A in the llet and decagrine 10-O solution was measured, and the residual rate was determined. The results are shown in Table 7.

[0054]

[Table 7] When the fatty acid constituting the polyglycerin fatty acid ester is saturated tetraglycerin hexabehenate is used, it is stable and excellent in sustained release property than when the unsaturated decaglucerin decaoleate is used, It was revealed that the drug was sustainedly released for 14 days or longer.

Example 9 A suspension of VX2 carcinoma cell suspension was transplanted subcutaneously under the knee of the right hind leg of a male Kbs: JW rabbit to prepare a cancer-bearing rabbit.
Two weeks after the transplantation, the rabbits were divided into 4 groups, and 1 ml of an aqueous solution containing 1 mg of Compound A, 0.5 ml of Miglyol 812 solution containing 1 mg and 5 mg of Compound A, respectively, were added to the femoral artery on the same side. It was administered from the upstream, and the volume of the tumor was measured 5 days after the administration. V5 / V0 was determined from the volume of the tumor 5 days after administration and the volume value of each group at the start of administration, and the volume ratio (T / C) to the untreated control group was determined. The results are shown in Table 8. V5 / V0 = (volume of tumor 5 days after administration / volume of tumor at the start of administration) × 100 T / C = (volume of tumor in treated group / volume of tumor in untreated control group) × 100

[0056]

[Table 8]

In an aqueous solution administration group containing 1 mg of Compound A,
The tumor volume remained at 74% of the untreated group and increased to 175% of the tumor volume before administration, whereas the tumor volume was increased in the intra-arterial administration group of 1 mg and 5 mg of Compound A Miglyol 812 solution. Was suppressed to 37% and 32% of the untreated group, respectively, and further reduced to 89% and 75% of the tumor volume before administration, respectively.

Example 10 Cancer-bearing rabbits similar to those in Example 9 were divided into 3 groups at 2 weeks after transplantation, and TG18-msp 2% and 10 prepared in Example 4 were used.
% Of TG14-msp 2% and 10% of TG14-msp (1 mg and 5 mg, respectively, as compound A) were administered from the upstream of the femoral artery on the same side, and the volume of the tumor was measured 5 days after the administration. Relative value (V5 / V0) where the volume of each group before administration was 100%, and the volume ratio with the untreated control group
(T / C) was determined. The results are shown in Table 9.

[0059]

[Table 9]

In the TG18-msp 2% -loaded and 10% -loaded intraarterial administration groups, the tumor volume was suppressed to 27% and 21% of the untreated group, respectively, and further, the tumor volume was 65% and the tumor volume before administration, respectively. It was reduced to 49%. TG
In the 14-msp 2% -loaded and 10% -loaded intraarterial administration groups, the tumor volume was 26% and 27% of that of the untreated group, respectively.
% And further reduced to 63% and 65% of the tumor volume before administration, respectively. An extremely strong tumor growth inhibitory effect was observed as compared with the results of the aqueous solution administration group shown in Table 8.

Example 11 50 g of 6-O- (N-chloroacetylcarbamoyl) fumagillol (Compound A) and 30 g of chlorobutanol were dissolved in 1 liter of Miglyol 812 (see Example 1) and filtered (Dimex, 0.2 μm). (Millipore Co., Ltd.) to remove bacteria. Ampoules were filled with 2 ml each of this oil solution, and after purging with nitrogen, the ampoules were sealed and sterilized by an autoclave for 20 minutes at 121 ° C. to give a preparation for injection (containing 0.1 g of compound A).

Example 12 920 g of Dynasan 118 (see Example 4) is heated to about 90 ° C.
After being heated and melted, 50 g of 6-O- (N-chloroacetylcarbamoyl) fumagillol (Compound A) and 30 g of chlorobutanol are dissolved therein. The nozzle temperature of this solution was 90 ° using a spray dryer (Mobile Minor Spray Dryer, manufactured by Nilo Atomizer).
Powder was set at -100 ° C. Particle size of this powder 5
500 g of the 0-200 μm portion is separated by a sieve
After adding 100 g of mannitol to the mixture and mixing well, 6
A vial was filled with 00 mg to prepare a suspension for injection at the time of use. As a dispersion medium for this suspension, 1% carboxymethylcellulose sodium salt and 0.5% Tween 80 aqueous solution are used, and 2 ml per 1 vial is used for dispersion.

Example 13 4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-dimethyl-4-hexenyl) -1- (1,
3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride (hereinafter,
Compound B) was dispersed in Miglyol 812 containing 2% (w / w) Tween 80. The dispersion was carried out by using a sonicator (Sono Cleaner, manufactured by Kaijo Denki Co., Ltd.).
The concentration of Compound B to 2 was adjusted to 1 mg / ml (0.1% w / v) to obtain a uniform suspension.

Example 14 Walker (Wal) was added to the left lobe of the liver of 8-week-old male SD rats.
ker) 256 carcinosarcoma 50% (w / v) cell suspension was injected and transplanted to prepare tumor-bearing rats.
One week after transplantation, the rats were divided into three groups, one group was given 50 μl of Miglyol 812 solution containing 5 mg of Compound A once into the hepatic artery, and another group was given an aqueous solution containing 5 mg of Compound A. It was administered intravenously three times a week in total. The remaining 1 group was an untreated group, and the change in tumor surface area 1 week after administration (△
S ₁ → ₂ ) was measured. The results are shown in Table 10.

[0065]

[Table 10]

Next, in order to examine the effect on the further enlarged tumor, the rats were divided into two groups two weeks after the transplantation, and one group contained 50 μ of Miglyol 812 solution containing 5 mg of Compound A.
1 was administered once into the hepatic artery, and the remaining 1 group was an untreated group. Then, the change in the surface area of the tumor (ΔS ₂ → ₃ ) for one week was measured. The results are shown in Table 11.

[0067]

[Table 11]

Intrahepatic arterial administration of the Miglyol 812 solution of the compound A showed a stronger tumor-reducing effect than the repeated intravenous administration of the aqueous solution of the compound A and the untreated group. In addition, for a further enlarged tumor, a strong tumor-reducing effect was obtained by intrahepatic arterial administration of the Miglyol 812 solution of Compound A, suggesting its usefulness in the treatment of advanced unresectable liver cancer.

[0069]

Industrial Applicability The pharmaceutical composition of the fumagillol derivative of the present invention stabilizes the fumagillol derivative to suppress decomposition of the fumagillol derivative during storage. Furthermore, the pharmaceutical composition is a sustained release composition, which can gradually release the fumagillol derivative, and can be advantageously used as a pharmaceutical preparation and the like.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Reference number within the agency FI Technical indication location A61K 31/38 7431-4C 31/40 7431-4C 31/415 7431-4C 31/425 7431-4C 31/44 7431-4C 47/14 G 7433-4C J 7433-4C C 7433-4C

Claims (30)

[Claims] 1. A pharmaceutical composition comprising a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin. 2. The pharmaceutical composition according to claim 1, wherein the fumagillol derivative is dissolved or dispersed in a fatty acid ester of glycerin or polyglycerin. 3. The pharmaceutical composition according to claim 1, wherein the fatty acid ester of glycerin is fatty acid triglyceride. 4. The pharmaceutical composition according to claim 1, wherein the fumagillol derivative is dissolved in fatty acid triglyceride. 5. The ratio of fumagillol derivative to fatty acid ester of glycerin or polyglycerin is about 0.1.
The pharmaceutical composition according to claim 1, which is 001 to 50% (w / v). 6. The pharmaceutical composition according to claim 1, wherein the fatty acid esterification degree of glycerin or polyglycerin is about 60% or more. 7. The polymerization degree of polyglycerin is 2 to 10.
The pharmaceutical composition according to claim 1, which is 8. The pharmaceutical composition according to claim 1, which is an injection. 9. The pharmaceutical composition according to claim 1, which is in liquid form. 10. The pharmaceutical composition according to claim 1, which is a finely divided solid composition having a particle size of about 10 to 1000 μm. 11. A fumagillol derivative is represented by the general formula (I): [Wherein R ¹ is hydrogen, R ² is halogen, N (O) mR ⁵ R ⁶ ,
N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ , S (O) nR ⁵ or S ⁺ R ⁵ R ⁶ · X
^- (Wherein R ⁵ , R ⁶ and R ⁷ are each a hydrocarbon group or a heterocyclic group which may have a substituent, X ^- is a counter anion, m is an integer of 0 or 1 and n is Represents an integer of 0 to 2. Further, R ⁵ and R ⁶ may form a nitrogen-containing or sulfur-containing heterocyclic group which may be condensed with an adjacent nitrogen atom or a sulfur atom. The optionally condensed nitrogen-containing or sulfur-containing heterocyclic group may have a substituent), or R ¹ and R ² represent a bond, and R ³ is a substituted group. 2 which may have a group
Represents a methyl-1-propenyl group or an isobutyl group, A represents O or NR ⁸ (in the formula, R ⁸ represents hydrogen or a lower alkyl group or an aryl group which may have a substituent). , R ⁴ each represent hydrogen, a hydrocarbon group which may have a substituent or an acyl group. ] The pharmaceutical composition according to claim 1, which is a fumagillol derivative represented by the following formula or a salt thereof. 12. R ¹ and R ² represent a bond, or R ¹ is hydrogen and R ² is N (O) mR ⁵ R ⁶ , N ⁺ R ⁵ R ⁶ R ⁷ · X ⁻ , S.
(O) nR ⁵ or S ⁺ R ⁵ R ⁶ · X ⁻ ; A is O or NH; R
The pharmaceutical composition according to claim 11, wherein ³ is a 2-methyl-1-propenyl or isobutyl group each optionally having a substituent; and R ⁴ is hydrogen or a carbamoyl group optionally having a substituent. 13. A bond is formed by R ¹ and R ^2.
The described pharmaceutical composition. 14. A is O; and R ³ may be substituted with a hydroxyl group or a dialkylamino group, respectively.
The pharmaceutical composition according to claim 12, wherein -methyl-1-propenyl or isobutyl group and R ⁴ is a carbamoyl group substituted with a C _1-6 alkyl or halogeno C _1-6 alkanoyl group. 15. The fumagillol derivative is 6-O- (N-
The pharmaceutical composition according to claim 1, which is chloroacetylcarbamoyl) fumagillol. 16. The fumagillol derivative is 4- (N'-chloroacetylureido) -2- (1,2-epoxy-1,5-).
The pharmaceutical composition according to claim 1, which is dimethyl-4-hexenyl) -1- (1,3-dihydrobenzo [c] thiophen-2-ylio) methyl-3-methoxycyclohexanol chloride. 17. The pharmaceutical composition according to claim 1, wherein the fatty acid constituting the fatty acid ester is a saturated fatty acid having 6 to 22 carbon atoms (C _{6 to} C ₂₂ ). 18. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is caprylic acid (C ₈ ). 19. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is capric acid (C ₁₀ ). 20. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is a mixture of caprylic acid (C ₈ ) and capric acid (C ₁₀ ). 21. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is lauric acid (C ₁₂ ). 22. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is myristic acid (C ₁₄ ). 23. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is palmitic acid (C ₁₆ ). 24. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is stearic acid (C ₁₈ ). 25. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is arachidic acid (C ₂₀ ). 26. The pharmaceutical composition according to claim 1, wherein the main component of the fatty acid constituting the fatty acid ester is behenic acid (C ₂₂ ). 27. The pharmaceutical composition according to claim 1, which is an angiogenesis inhibiting composition. 28. A method for stabilizing a fumagillol derivative, which comprises dissolving or dispersing the fumagillol derivative in a fatty acid ester of glycerin or polyglycerin. 29. A pharmaceutical composition for inhibiting angiogenesis, which comprises a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin. 30. A stable sustained-release pharmaceutical composition for inhibiting angiogenesis, which comprises a fumagillol derivative and a fatty acid ester of glycerin or polyglycerin.