JPH08337523A - Angiogenesis inhibitors - Google Patents

Abstract

PURPOSE: To obtain a compound useful as a treating agent for solid tumor, rheumatism, diabetic retinitis, psoriasis, etc., and capable of exhibiting excellent vascularization inhibiting activity. CONSTITUTION: This is a trans-stilbene derivative of formula I (A is phenyl, 4-isopropylphenyl, etc.), e.g. 1,2,5-trimethoxy-4-[4-(N,N-dimethylamino)-1- naphtho]ethenylbenzene. A derivative of formula I is obtained by reacting a compound of formula II (X is Cl, Br or I), e.g. 2,4,5- trimethoxybenzyltriphenylphosphonium chloride with a base (methyllithium, etc.) of 1-1.5 equivalent to it in a solvent (diethyl ether, etc.) at a temperature from -78 deg.C to room temperature for about 0.1-2hr and optionally in the atmosphere of an inert gas (nitrogen, etc.), and subsequently, reacting the reaction product with a compound expressed by the formula ACHO, e.g. 4-(N,N- dimethylamino)naphtho-1-aldehyde of about 1-1.2 equivalent at a temperature from 0 deg.C to room temperature for about 0.1-2hr.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an angiogenesis inhibitor containing a trans-stilbene derivative or a salt thereof as an active ingredient and useful as a therapeutic drug for solid tumors, rheumatism, diabetic retinopathy, psoriasis and the like.

[0002]

2. Description of the Related Art Conventionally, many compounds are known as trans-stilbene derivatives, and one of the benben ring substituents is 2,4,5-trimethoxy. The compounds mentioned are known.

3,7-Dihydro-7-methyl-1,3-
Dipropyl-8- [2- (2,4,5-trimethoxyphenyl) ethenyl] -1H-purine-2,6-dione and 3,7-dihydro-1,3-dipropyl-8- [2-
(2,4,5-Trimethoxyphenyl) ethenyl] -1
H-purine-2,6-dione is described in WO94 / 01114.
No. 1 as a muscle / nerve depressant, EP 565377 as an anti-Parkinson's disease drug, Journal of Me
dicinal Chemistry, 36 (10),
1333-42 (1993) describes it as an A2-selective adenosine antagonist. 1, 2, 3
-Trimethoxy-5- [2- (2,4,5-trimethoxyphenyl) ethenyl] benzene and 1,2,4-trimethoxy-5- (2-phenylethenyl) benzene are
Known as an anticancer substance (WO93 / 23357)
Issue and Journal of Medicinal
Chemistry, 34 (8), 2579-88 (1
991)), 1-ethyl-2- [2- (2,2, iodide
4,5-Trimethoxyphenyl) ethenyl] quinolinium and iodide 1-methyl-2- [2- (2,4,5-
Trimethoxyphenyl) ethenyl] quinolinium is known as an antibiotic (Doklady Borg.
arskoi Akademii Nauk, 39 (1
2), 63-5 (1986)). In addition, 2- [2-
(2,4,5-Trimethoxyphenyl) ethenyl] quinoline hydrochloride is known as an anticancer substance (Dok).
lady Bolgarskoi Akademii
Nauk, 39 (11), 69-72 (1986)).
2- [2- (2,4,5-trimethoxyphenyl) ethenyl] quinoline is commercially available from Doklady Bolgarsk.
oi Akademii Nauk, 39 (12), 6
3-5 (1986) as an antibiotic, Arzneim.
ittel-Forschung, 31 (3), 404.
-6 (1981) and Doklady Bolgars
koi Akademii Nauk, 39 (11),
69-72 (1986), it is described as an anticancer substance.

Further, 1- [2- (2,4,5-trimethoxyphenyl) ethenyl] isoquinoline and iodide 1-
Methyl-2- [2- (2,4,5-trimethoxyphenyl) ethenyl] quinolinium iodide 1-methyl-4
-[2- (2,4,5-Trimethoxyphenyl) ethenyl] quinolinium, 4- [2- (2,4,5-Trimethoxyphenyl) ethenyl] cinnoline, 2- [2-
(2,4,5-Trimethoxyphenyl) ethenyl] benzoxazole, 2- [2- (2,4,5-trimethoxyphenyl) ethenyl] benzothiazole and 2- [2
-(2,4,5-Trimethoxyphenyl) ethenyl] pyridine is known as an anticancer substance (Arznei).
mitter-Forschung, 31 (3) 404
-6 (1981)). 4-oxo-3-propyl-2-
[2- (2,4,5-Trimethoxyphenyl) ethenyl] -4H-benzopyran-6-carboxylic acid methyl ester is used as an allergic asthma drug (DE302513).
8), 1,8a-dihydro-7-oxo-6-propyl-5- [2- (2,4,5-trimethoxyphenyl) ethenyl] cyclopropa [5,6] pyrido [1,2a] pyrimidine-1a. (7H) -carboxylic acid and 4-oxo-
3-Propyl-2- [2- (2,4,5-trimethoxyphenyl) ethenyl] -4H-pyrido [1,2a] pyrimidine-7-carboxylic acid was used as a skin hypersensitivity drug (DE
3015738), 2- [2- (2,4,5-trimethoxyphenyl) ethenyl] -4H-3,1-benzoxazin-4-one as an anti-allergic drug (Japanese Patent Laid-Open No. Sho 5 (1999) -58242).
No. 2-83429).

However, there are still no reports that many known trans-stilbene derivatives including these compounds have angiogenesis inhibitory activity.

[0006]

Therefore, the object of the present invention is to find a compound having an excellent angiogenesis inhibitory activity,
It is intended to provide an angiogenesis inhibitor effective for treating solid tumors, rheumatism, diabetic retinopathy, psoriasis and the like.

[0007]

Under the circumstances, as a result of intensive studies by the present inventors, the trans-stilbene derivative represented by the general formula (1) described below is an excellent blood vessel satisfying the above object. The present invention was completed by finding out that it has an anti-development activity.

That is, the present invention is based on the general formula (1)

[0009]

Embedded image

(In the formula, A is an aryl group, a substituted aryl group, a 5-membered or 6-membered heteroaromatic monocyclic group containing one oxygen atom or a sulfur atom, an oxygen atom or a sulfur atom, and a nitrogen atom containing one nitrogen atom. Membered heteroaromatic monocyclic group, 1,3-dioxaindane-
5-yl group, 1,2,3,4-tetrahydroquinolyl group in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group, a quinolyl group, a substituted quinolyl group or a 2-benzothiazolyl group is shown) The present invention provides an angiogenesis inhibitor containing a trans-stilbene derivative or a salt thereof as an active ingredient.

The trans-stilbene derivative used in the present invention is represented by the above general formula (1). Among the groups represented by A in the formula, examples of the aryl group include a phenyl group, a 1-naphthyl group, and a 2-naphthyl group.

Further, the substituted aryl group is not particularly limited as long as it has 1 to 3 substituents on the ring of the aryl group, and the substituents include a lower alkyl group, a halogen atom, A hydroxyl group, a lower alkoxy group, an amino group, an amino group in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group or a lower alkanoyl group, a nitro group, or a nitrogen atom is 1
A 5-membered or 6-membered hetero-saturated monocyclic group containing 2 to 3, an imidazolidinyl group or a piperazinyl group in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group or a lower alkanoyl group, and a hydrogen atom on the nitrogen atom is a lower alkyl group. Examples thereof include a substituted amino-lower alkoxy group, lower alkoxycarbonyl-lower alkoxy group, aryl-lower alkoxy group and the like.

Examples of the lower alkyl group include linear or branched alkyl groups having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, n-propyl group, i-propyl group. , N-butyl group, i-butyl group, sec-butyl group, t-butyl group. Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 4 carbon atoms, and specifically,
Methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, sec-
Examples thereof include butoxy group and t-butoxy group.

The amino group in which the hydrogen atom on the nitrogen atom is substituted with a lower alkyl group or a lower alkanoyl group includes
Amino group in which hydrogen atom on nitrogen atom is substituted with the above lower alkyl group; straight chain having 1 to 4 carbon atoms such as formyl group, acetyl group, propionyl group, 2-methylpropanoyl group, butyryl group, isobutyryl group Or an amino group substituted with a branched lower alkanoyl group, specifically, N-methylamino group, N, N-dimethylamino group,
N-ethylamino group, N, N-diethylamino group, N,
N-di (n-propyl) amino group, N, N-di (i-propyl) amino group, N, N-di (n-butyl) amino group, N, N-di (i-butyl) amino group, Examples thereof include N, N-di (sec-butyl) amino group, N, N-di (t-butyl) amino group, acetamide group, and N-methylacetamide group. Examples of the 5- or 6-membered hetero-saturated monocyclic group containing one nitrogen atom include a 1-pyrrolidinyl group and a piperidino group, and a 5-membered or 6-membered heterocyclic group containing two nitrogen atoms.
Membered saturated saturated monocyclic groups include 1-pyrazolidinyl group, 1
—Imidazolidinyl group and 1-piperazinyl group.

The imidazolidinyl group or piperazinyl group in which the hydrogen atom on the nitrogen atom is substituted with a lower alkyl group or a lower alkanoyl group is an imidazolidinyl group in which the hydrogen atom on a nitrogen atom is substituted with the above lower alkyl group or a lower alkanoyl group. Group or piperazinyl group, specifically, 3-methyl-1-imidazolidinyl group, 3-formyl-1-imidazolidinyl group, 4-methyl-1-piperazinyl group, 4-formyl-1-piperazinyl group. To be Examples of the amino-lower alkoxy group in which a hydrogen atom on a nitrogen atom is substituted with a lower alkyl group include the above lower alkoxy group in which a hydrogen atom on a nitrogen atom is substituted with an amino group substituted with the above lower alkyl group. Specifically, N, N-dimethylaminomethoxy group, N, N-diethylaminomethoxy group, 2-
(N, N-dimethylamino) ethoxy group, 2- (N, N
-Diethylamino) ethoxy group.

Examples of the lower alkoxycarbonyl-lower alkoxy group include the above lower alkoxy groups substituted by the carbonyl group to which the above lower alkoxy groups are bonded, and specific examples thereof include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, Examples thereof include a 2- (methoxycarbonyl) ethoxy group and a 2- (ethoxycarbonyl) ethoxy group. Examples of the aryl-lower alkoxy group include the above-mentioned lower alkoxy groups substituted with an aryl group, and specifically, phenylmethoxy group, 2-phenylethoxy group, naphthyl-1-methoxy group, naphthyl- group.
2-methoxy group, 2- (1-naphthyl) ethoxy group, 2
A-(2-naphthyl) ethoxy group may be mentioned.

Preferred examples of the above aryl group and substituted aryl group are phenyl group, 4- (N, N-dimethylamino) -2-methylphenyl group, 4-isopropylphenyl group, 4-chlorophenyl group and 4- Hydroxy-
3-methoxyphenyl group, 4- (N, N-dimethylamino) -2-methoxyphenyl group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 2,3,4
-Trimethoxyphenyl group, 2,4,5-trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group,
3,4,5-trimethoxyphenyl group, 4-aminophenyl group, 4- (N-methylamino) phenyl group, 2-
(N, N-dimethylamino) phenyl group, 3- (N, N)
-Dimethylamino) phenyl group, 4- (N, N-dimethylamino) phenyl group, 4- (N, N-diethylamino) phenyl group, 4- [N, N-di (n-butyl) amino] phenyl group, 4-acetamidophenyl group, 4-
(N-methylacetamido) phenyl group, 4-nitrophenyl group, 2,4-dinitrophenyl group, piperidino-
4-phenyl group, 4- (4-methyl-1-piperazinyl) phenyl group, 4- (4-formyl-1-piperazinyl) phenyl group, 4- [2- (N, N-dimethylamino) ethoxy] phenyl group , 4- (methoxycarbonylmethoxy) phenyl group, 4- (2-phenylethoxy)
Phenyl group, 1-naphthyl group, 2-naphthyl group, 4-
(N, N-dimethylamino) -1-naphthyl group may be mentioned.

Among the groups represented by A, the 5- or 6-membered heteroaromatic monocyclic group containing one oxygen atom or sulfur atom includes 2-furyl group, 2-thienyl group and 2-pyridyl group, Of these, a 2-thienyl group and a 2-pyridyl group are preferable. Further, as the 5-membered heteroaromatic monocyclic group containing an oxygen atom or a sulfur atom and one nitrogen atom, 1,3-
Oxazol-2-yl group, 1,3-thiazol-2-
And the 1,3-thiazol-2-yl group is preferable. The 1,2,3,4-tetrahydroquinolyl group in which the hydrogen atom on the nitrogen atom is substituted with a lower alkyl group is 1-methyl-1,2,3,4-
A tetrahydro-6-quinolyl group is preferred.

The substituted quinolyl group is not particularly limited as long as it has 1 to 2 substituents on the ring of the quinolyl group, and the substituents include a nitro group, an amino group and a nitrogen atom. And an amino group in which the hydrogen atom of is substituted with a lower alkyl group, trimethylammonium iodide, and the like. Preferred examples of the quinolyl group and the substituted quinolyl group include 2-quinolyl group, 8-nitro-2-quinolyl group, 8
-Amino-2-quinolyl group, 8- (N-methylamino)
-2-quinolyl group, 8- (N, N-dimethylamino)-
Examples include 2-quinolyl group and 8-trimethylammonio-2-quinolinium iodide.

The salt of the trans-stilbene derivative (1) used in the present invention is not particularly limited as long as it is a pharmacologically acceptable salt, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. Inorganic acid salts; organic acid salts such as maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid and p-toluenesulfonic acid. In addition, solvates represented by hydrates of trans-stilbene derivative (1) can also be used in the present invention.

Among these trans-stilbene derivatives (1), especially 1,2,5-trimethoxy-4-
(4- (N, N-dimethylamino) -1-naphtho) ethenylbenzene, 1,2,5-trimethoxy-4- (2,2
4,5-trimethoxyphenyl) ethenylbenzene,
1,2,5-trimethoxy-4- (4- (N, N-dimethylamino) phenyl) ethenylbenzene, 1,2,5
-Trimethoxy-4- (8-nitro-2-quinolyl) ethenylbenzene, 1,2,5-trimethoxy-4- (8
-Amino-2-quinolyl) ethenylbenzene, 1,2,
5-trimethoxy-4- (8- (N, N-dimethylamino) -2-quinolyl) ethenylbenzene, 1,2,5-
Trimethoxy-4- (8- (N-methylamino) -2-
(Quinolyl) ethenylbenzene, 8-trimethylammonio-2- (2- (2,4,5-trimethoxyphenyl)
Ethenyl) quinolinium iodide is preferred.

The trans-stilbene derivative (1) can be produced from various compounds as raw materials, for example, according to the following methods AF.

[0023]

Embedded image

(In the formula, A has the same meaning as described above, and X represents a chlorine atom, a bromine atom or an iodine atom.) A compound represented by the general formula (2) is added in a suitable solvent, if necessary. The trans-stilbene derivative (1) can be produced by reacting with a base in an inert gas atmosphere and then reacting with a compound represented by the general formula (3).

The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, ethers such as diethyl ether and tetrahydrofuran; halogenated hydrocarbons such as methylene chloride and chloroform; benzene, toluene and the like. Aromatic hydrocarbons; examples thereof include alcohols such as methanol and ethanol. The inert gas is not limited as long as it does not participate in the reaction, and examples thereof include nitrogen and argon.

Examples of the base include methyllithium and n
-Organolithium compounds such as butyllithium; organomagnesium compounds such as ethylmagnesium bromide and isopropylmagnesium bromide; metal halides such as sodium hydride and potassium hydride; alkali metal compounds such as sodium hydroxide and potassium hydroxide; Can be mentioned. In the reaction of the compound represented by the general formula (2) with the base, it is preferable to use 1 to 10 equivalents, particularly 1 to 1.5 equivalents of the base for the compound of the general formula (2), and the reaction temperature is , -7
8 ° C to room temperature, reaction time is 0.1 to 48 hours,
The reaction proceeds advantageously in about 0.1 to 2 hours.

In the reaction with the compound represented by the general formula (3), the reaction rate is 1 to 1 for the compound of the general formula (3).
It is preferable to use about 2 equivalents, particularly about 1 to 1.2 equivalents, and the reaction temperature is about -40 to 50 ° C, preferably 0 ° C.
To room temperature, the reaction time is about 0.1 to 48 hours, preferably about 0.1 to 2 hours, and the reaction proceeds advantageously.
When A has a hydroxyl group, it can be reacted after being protected by a suitable protecting group. As the protecting group, when removing this group by a deprotection reaction later,
There is no particular limitation as long as it has no other influence, and examples thereof include methoxyethoxymethyl group, methoxymethyl group, tetrahydrofuranyl group, tetrahydropyranyl group, benzyl group, paramethoxybenzyl group, tert-butyldimethylsilyl group, diphenyl. Examples thereof include a methylsilyl group and an ethoxycarbonyl group. As a method for introducing these protecting groups, Protective Groups in Organic Synthesis (Protective Group) can be used.
s in Organic Synthesis), No. 2
Edition, 14-174 (1991).

In place of the compound of the general formula (2), A
A trans-stilbene derivative (1) can also be produced by subjecting CH ₂ P ⁺ Ph ₃ X ⁻ to 2,4,5-trimethoxybenzaldehyde in place of the compound of the general formula (3) to carry out a similar reaction. it can.

[0029]

[Chemical 4]

(In the formula, A has the same meaning as above)

2,4,5-trimethoxybenzaldehyde and the compound represented by the general formula (4) are reacted in the presence of a base or acetic anhydride in a suitable solvent or in the absence of a solvent to give trans. A stilbene derivative (1) can be prepared.

The solvent used here is not particularly limited as long as it does not participate in the reaction, for example, ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as benzene and toluene; methanol, ethanol and the like. Examples include alcohols. Examples of the base include metal halides such as sodium hydride and potassium hydride; hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; organic amines such as pyridine, triethylamine and piperidine; sodium methoxide. , Sodium ethoxide, potassium-ter
Alkoxides such as t-butoxide and sodium isopropoxide; sodium acetate, potassium carbonate, sodium carbonate and the like can be mentioned.

The reaction ratio is such that the compound represented by the general formula (4) is 1 to 2 equivalents, the base is 1 to 1000 equivalents, and preferably 5 to 20 equivalents, relative to 2,4,5-trimethoxybenzaldehyde. Preference is given to using. The reaction temperature is
The reaction proceeds advantageously under ice-cooling-about the boiling point of the solvent, preferably room temperature to 50 ° C, and the reaction time is 1 to 96 hours, preferably 12 to 36 hours. Further, in order to accelerate the reaction, a phase transfer catalyst such as triethylbenzylammonium chloride or tetraethylammonium chloride may be added.

Compounds (2), (3) and (4) used as raw materials in Method A or Method B are known and easily available compounds, or Organic Synthes
ses Collective, 5 , 251 (197)
3) The method of Journal of the A
Merchanic Chemical Society,
112 (20), 7083 (1990),
Chemical Abstract, 16066f
Although it can be produced by a conventionally known synthetic method such as the method described in (1959), the compound represented by the general formula (2) can also be produced by the following method.

[0035]

Embedded image

(In the formula, X has the same meaning as above)

That is, first, 2,4,5-trimethoxybenzaldehyde is reacted with a reducing agent in a suitable solvent under a hydrogen pressure if necessary to give 2,4,5-trimethoxybenzaldehyde.
Trimethoxybenzyl alcohol is obtained, then this 2,
After reacting 4,5-trimethoxybenzyl alcohol with a halogenating agent in a suitable solvent to prepare a compound represented by the general formula (5), the compound represented by the general formula (5) is appropriately prepared. A compound represented by the general formula (2) can be obtained by reacting with triphenylphosphine in a different solvent.

First, in the reaction of 2,4,5-trimethoxybenzaldehyde with a reducing agent, the solvent is not particularly limited as long as it does not participate in the reaction, for example, alcohols such as methanol and ethanol; diethyl ether. , Ethers such as tetrahydrofuran, halogenated hydrocarbons such as methylene chloride and chloroform, aromatic hydrocarbons such as benzene and toluene, aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like; Examples thereof include lower aliphatic carboxylic acids such as formic acid and acetic acid, water, and the like, and these can be used alone or in combination of two or more kinds.

As the reducing agent, sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, Raney nickel, palladium / carbon,
Etc. The hydrogen pressure is preferably about 1 to 200 atm.

The reaction ratio is preferably such that the reducing agent is used in an amount of 0.1 to 100 equivalents, particularly 0.1 to 10 equivalents, relative to 2,4,5-trimethoxybenzaldehyde.
The reaction temperature is preferably under ice-cooling-about the boiling point of the solvent, particularly under ice-cooling-about room temperature, and the reaction time is 0.1-96.
The reaction proceeds advantageously in about time, preferably 0.1 to 1 hour.

Next, in the reaction of 2,4,5-trimethoxybenzyl alcohol and the halogenating agent, the solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include diethyl ether and tetrahydrofuran. Ethers; halogenated hydrocarbons such as methylene chloride and chloroform; aromatic hydrocarbons such as benzene and toluene; aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile; water and the like. These may be used alone or in combination of two or more.

Examples of the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphorus pentabromide, hydrochloric acid,
Examples thereof include hydrobromic acid, dimethyl sulfide / N-chlorosuccinimide, and hydroiodic acid. When these are liquids, a halogenating agent can be directly used as a solvent. Further, pyridine, dimethylformamide or the like can be added to accelerate the reaction.

The reaction ratio is such that the halogenating agent is 1 to 10 relative to 2,4,5-trimethoxybenzyl alcohol.
It is preferable to use 0 equivalent, particularly about 1 to 10 equivalent.
The reaction temperature is preferably under ice-cooling-about the boiling point of the solvent, particularly under ice-cooling-about room temperature, and the reaction time is about 0.1-96 hours, preferably 0.5-12 hours, and the reaction is advantageous. proceed.

Finally, in the reaction of the compound represented by the general formula (5) with triphenylphosphine, the solvent is not particularly limited as long as it does not participate in the reaction,
Examples thereof include aromatic hydrocarbons such as benzene and toluene.

The reaction ratio is 1 to 100 triphenylphosphine based on the compound represented by the general formula (5).
It is preferable to use an equivalent amount, particularly about 1 to 2 equivalents. The reaction temperature is preferably room temperature to about the boiling point of the solvent, and the reaction time is about 1 to 96 hours, preferably 4 to 24 hours, and the reaction proceeds advantageously.

(Method C) In the trans-stilbene derivative (1) obtained by Method A or Method B, when A has a nitro group as a substituent, this is hydrogenated in a suitable solvent, if necessary. It can be converted to an amino group by reduction under pressure.

The solvent used here is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol and ethanol; diethyl ether,
Ethers such as tetrahydrofuran; aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide and acetonitrile; lower aliphatic carboxylic acids such as formic acid and acetic acid; water and the like, which may be used alone or in combination of two or more. It can also be used as a mixture. Examples of the reducing agent include tin chloride and Raney nickel, which are reacted in the presence of iron, tin or hydrogen chloride.

The reaction ratio is preferably such that the reducing agent is used in an amount of 0.1 to 10 equivalents relative to the nitro group in the trans-stilbene derivative (1), and the reaction temperature is 0 ° C. to the boiling point of the solvent. The reaction time is about 0.1 to 48 hours, preferably 1 to 24 hours, and the reaction proceeds advantageously.
The hydrogen pressure is about 1 to 200 atm, preferably 1 atm.
It is -10 atm.

(Method D) Among the trans-stilbene derivatives obtained by Method A or Method B, when A has an amino group as a substituent, it is acylated in a suitable solvent to give an amide group. Can be converted to.

As the acylating agent used here, a desired carboxylic acid or its reactive derivative can be used. When a reactive derivative is used, the reaction is carried out in a suitable solvent, and a suitable base can be added to accelerate the reaction. Examples of such reactive derivatives include acid anhydrides, mixed acid anhydrides, acid halides and the like. The solvent is not particularly limited as long as it does not participate in the reaction, and examples thereof include ethers such as diethyl ether and tetrahydrofuran; aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform; Examples thereof include alcohols such as methanol and ethanol. Further, when the desired carboxylic acid or its reactive derivative is a liquid, it can be directly used as a solvent.

The reaction ratio is preferably about 1 to 5 equivalents of the desired carboxylic acid or its reactive derivative with respect to the amino group in the trans-stilbene derivative. The reaction temperature is 0 to the boiling point of the solvent, and the reaction time is 0.5.
It is preferably about 24 hours, particularly 0.5 to 16 hours.

(Method E) Among the trans-stilbene derivatives obtained by Method A or Method B, when A has an amino group or an amide group as a substituent, this is added in a suitable solvent.
It can be converted into an alkylated amino group or amido group by alkylation in the presence of a base.

The solvent used here is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol and ethanol; diethyl ether,
Ethers such as tetrahydrofuran; halogenated hydrocarbons such as methylene chloride and chloroform; alkyl ketones such as acetone and methyl ethyl ketone; aromatic hydrocarbons such as benzene and toluene; N, N-dimethylformamide, dimethyl sulfoxide, acetonitrile and the like Aprotic polar solvents; water, etc., and these may be used alone or in combination of two or more.

Examples of the base include organic amines such as pyridine, triethylamine and piperidine; organic lithium compounds such as n-butyllithium and methyllithium; metal halides such as sodium hydride and potassium hydride;
Hydroxides of alkali metals such as sodium hydroxide and potassium hydroxide; sodium acetate, potassium carbonate, sodium carbonate and the like. Examples of the alkylating agent include lower alkyl halides such as methyl iodide and bromoethane; sulfuric acid esters such as dimethylsulfate and diethylsulfate.

The reaction rate is such that 1 base is added to the amino group or amide group in the trans-stilbene derivative (1).
It is preferable to use -100 to 100 equivalents, particularly 1 to 20 equivalents, and an alkylating agent of 1 to 10 equivalents. The reaction temperature is
It is preferably under ice cooling to about the boiling point of the solvent, and the reaction time is 0.
The reaction proceeds advantageously in about 1 to 96 hours, preferably in about 1 to 24 hours.

(Method F) When the trans-stilbene derivative (1) has an amino group, an alternative method to the alkylation reaction is to react an aldehyde with a reducing agent in a solvent under pressure of hydrogen if necessary. The compound having the desired alkylated amino group can also be obtained.

The solvent used here is not particularly limited as long as it does not participate in the reaction. For example, alcohols such as methanol and ethanol; diethyl ether,
Ethers such as tetrahydrofuran; halogenated hydrocarbons such as methylene chloride and chloroform; aromatic hydrocarbons such as benzene and toluene; aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, acetonitrile; formic acid , Lower aliphatic carboxylic acids such as acetic acid; water and the like, and these may be used alone or in combination of two or more.

Examples of aldehydes include formaldehyde, acetaldehyde, propyl aldehyde and butyraldehyde. Also, as the reducing agent,
Examples thereof include sodium borohydride, sodium cyanoborohydride, lithium aluminum hydride, Raney nickel, palladium / carbon and the like.

The reaction ratio is such that both the aldehyde and the reducing agent are used in an amount of 0.1 to 100 equivalents, particularly 0.1 to 10 equivalents, relative to the amino group in the trans-stilbene derivative (1). preferable. The reaction temperature is preferably under ice cooling to about the boiling point of the solvent, particularly under ice cooling to room temperature, and the reaction time is about 0.1 to 96 hours, preferably 1 to 24 hours, and the reaction proceeds advantageously. The hydrogen pressure is preferably about 1 to 200 atm, particularly preferably 1 to 10 atm.

The trans-stilbene derivative (1) thus obtained can be used in various pharmaceutical compositions for inhibiting angiogenesis. That is, the angiogenesis inhibitor of the present invention can adopt various pharmaceutically acceptable administration forms according to various modes of treatment of solid tumor, rheumatism, diabetic retinopathy, psoriasis and the like. Examples of such forms include oral preparations such as tablets, capsules, powders, granules, fine granules, solutions, pills, emulsions and suspensions; injections, suppositories, ointments, plasters, patches, Any parenteral agent such as an aerosol may be used, and each of these dosage forms can be manufactured by a conventional manufacturing method known to those skilled in the art.

When preparing a solid oral preparation, a pharmaceutically acceptable pharmaceutical carrier such as an excipient, a binder,
Tablets, capsules, powders, granules, fine granules and the like can be produced by a conventional method using a disintegrating agent, a lubricant, a coloring agent, a flavoring agent, a flavoring agent and the like. Here, as the excipient, for example, lactose, sucrose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate,
Examples thereof include gum arabic, examples of the binder include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, shellac, sucrose, and the like. Examples of the lubricant include magnesium stearate, talc, and the like. As the coloring agent, the disintegrating agent, etc., known ones can be used. The tablets may be coated by a usual method.

In the case of preparing an injection, for example, a pH adjuster, a buffer, a stabilizer, an isotonicity agent, a local anesthetic, etc. are used, and intravenous, intramuscular, subcutaneous, intradermal and It can be an intraperitoneal injection. Here, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate, and the like, and examples of the stabilizer include sodium pyrosulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and the like. To be

When preparing a suppository, a suppository may be produced by a conventional method by adding a base and, if necessary, a surfactant and the like. As the base, for example, an oily base such as macrogol, lanolin, cacao butter, fatty acid triglyceride, Witepsol (manufactured by Dynamite Nobels) can be used.

The dose of the angiogenesis inhibitor of the present invention to be administered is appropriately selected depending on the usage, the age, sex, condition of the patient, the kind of compound to be administered, other conditions, etc. It is preferable to administer an amount as an active ingredient of about 0.1 to 1000 mg / kg / day, particularly about 0.5 to 100 mg / kg / day, once a day or in 2 to 4 divided doses. .

[0065]

EXAMPLES The present invention will be described in more detail below with reference to reference examples and examples, but the present invention is not limited thereto.

Reference Example 1 Synthesis of 2,4,5-trimethoxybenzyl triphenylphosphonium chloride: 44.5 g of 2,4,5-trimethoxybenzaldehyde was suspended in 200 ml of methanol and hydrogenated under ice cooling. Slowly add 8.5 g of sodium boron and stir for 10 minutes. After the reaction, water 20
0 ml was added, and the mixture was extracted twice with 200 ml of methylene chloride. It was extracted with methylene chloride, washed with saturated saline, and dried over anhydrous sodium carbonate. The drying agent was collected by filtration to obtain a methylene chloride solution of 2,4,5-trimethoxybenzyl alcohol. N-chlorosuccinimide 43
g was dissolved in 300 ml of methylene chloride, and 25 ml of dimethyl sulfide was added at -10 ° C. After stirring for 1 hour, the methylene chloride solution of 2,4,5-trimethoxybenzyl alcohol was added dropwise and stirred for 1 hour. After the reaction,
The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ether to obtain 34,5 g (yield 66%) of 2,4,5-trimethoxybenzyl chloride. Melting point: 77-79 ° C. ¹ H-NMR (CDCl ₃ ) δ: 3.81 (3H, s), 3.87 (3H, s), 3.90 (3H,
s), 6.52 (1H, s), 6.65 (2H, s), 6.88 (1H, s).

32.5 g of the above 2,4,5-trimethoxybenzyl chloride and 4 of triphenylphosphine
0 g was added to 200 ml of toluene, and the mixture was heated under reflux for 6 hours. After allowing to cool, the precipitated salt was collected by filtration to obtain the title compound (53.7 g, yield 75%). Melting point: 257-259 ° C (decomposition). ¹ H-NMR (CDCl ₃ ) δ: 3.20 (3H, s), 3.58 (3H, bt), 3.83 (3H,
s), 5.18-5.34 (2H, m), 6.24 (1H, s), 7.06 (1H, bs), 7.57-
7.81 (15H, m).

Reference Example 2 Synthesis of 4- (4-formyl-1-piperidino) benzaldehyde: 21 ml of phosphorus oxychloride was added dropwise to 100 ml of dimethylformamide under ice cooling, and the mixture was stirred for 1 hour. Further, 25 g of N-phenylpiperidine is added dropwise and heated at 80 ° C. for 4 hours. After allowing to cool, 10 ml of 1N hydrochloric acid was added, and the mixture was stirred at room temperature for 1 hour. Add sodium hydroxide solution to pH
It was adjusted to 14 or more, extracted with chloroform, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent: chloroform) to obtain 1.37 g (yield 4%) of the title compound. ¹ H-NMR (CDCl ₃ ) δ: 3.36-3.79 (8H, m), 6.96 (2H, d, J = 8.5H
z), 7.78 (2H, d, J = 8.5Hz), 8.14 (1H, s), 9.81 (1H, s).

Reference Example 3 Synthesis of 4-ethoxycarbonyloxy-3-methoxybenzaldehyde: To 25 g of vanillin, 100 ml of water and 7 g of sodium hydroxide were added, 16 ml of ethyl chlorocarbonate was added dropwise under ice cooling, and the mixture was stirred for 3 hours. After the reaction, the precipitated crystals were collected by filtration and dried to give 31 g of the title compound.
(Yield 84%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t, J = 7.1Hz), 3.94 (3H, s), 4.
34 (2H, q, J = 7.1Hz), 7.28-7.54 (3H, m), 9.96 (1H, s).

Example 1 Synthesis of 1,2,5-trimethoxy-4- (4- (N, N-dimethylamino) -1-naphtho) ethenylbenzene (Compound 1): 2, obtained in Reference Example 1 4,5-Trimethoxybenzyltriphenylphosphonium chloride 15
g in 200 ml of THF, at -78 ° C. under nitrogen atmosphere.
20 ml of 1.6M n-butyllithium was added and the temperature was raised to room temperature. A solution of 6.5 g of 4- (N, N-dimethylamino) naphth-1-aldehyde in 50 ml of methylene chloride was added, and the mixture was stirred at room temperature for 3 hours. After the reaction, add water,
After extraction with chloroform, the extract was washed with saturated saline and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure and recrystallized from methanol to obtain 2.4 g (yield 21%) of the title compound.

Example 2 Synthesis of Compounds 2-30: Compounds 2-30 were prepared in the same manner as in Example 1.

Example 3 Synthesis of 1,2,5-trimethoxy-4- (4- (4-formyl-1-piperidino) phenyl) ethenylbenzene (Compound 31): Starting from the compound obtained in Reference Example 2 And 0.65 g of the title compound in the same manner as in Example 1.
(Yield 37%) was obtained.

Example 4 1,2,5-Trimethoxy-4- (4-hydroxy-3)
-Methoxyphenyl) ethenylbenzene (Compound 32)
Synthesis: First, using the compound obtained in Reference Example 3 as a raw material,
In the same manner as in Example 1, 1,2,5-trimethoxy-4
-(4-Ethoxycarbonyloxy-3-methoxyphenyl) ethenylbenzene was synthesized. ¹ H-NMR (CDCl ₃ ) δ: 1.37 (3H, t, J = 7.3Hz), 3.52 (3H, s),
3.66 (3H, s), 3.81 (3H, s), 3.89 (3H, s), 4.29 (2H, q, J = 7.3
Hz), 6.48-7.04 (7H, m).

Then, 2 g of this compound was added to 50 ml of THF,
50 ml of methanol and 2 g of sodium hydroxide were added, and the mixture was stirred for 30 minutes under ice cooling. After the reaction, neutralized by adding dilute hydrochloric acid, extracted with chloroform, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane) to obtain 0.89 g (yield 52%) of the title compound.

Example 5 Synthesis of 2- (2- (2,4,5-trimethoxyphenyl) ethenyl) benzothiazole (Compound 33): 3 g of 2-methylbenzothiazole, 2 g of 2,4,5-trimethoxybenzaldehyde. And 0.5 g of triethylbenzylammonium chloride were added to 6 ml of 50% sodium hydroxide aqueous solution, and the mixture was stirred at room temperature for 24 hours. After the reaction, a saturated aqueous solution of ammonium chloride was added, extracted with chloroform, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, methanol was added to the residue, and the precipitated crystals were collected by filtration to give the title compound (2.6 g, yield 40%).

Example 6 Synthesis of 1,2,5-trimethoxy-4- (4-aminophenyl) ethenylbenzene (Compound 34): Example 2
1.16 g of 1,2,5-trimethoxy-4- (4-nitrophenyl) ethenylbenzene (Compound 20) obtained in 1. and 1.2 g of iron were added to 30 ml of acetic acid and 30 ml of ethanol and heated at 120 ° C. for 6 hours. It was stirred. After the reaction, the mixture was allowed to cool, the insoluble matter was collected by filtration, and an aqueous sodium hydroxide solution was added to the filtrate.
The pH was adjusted to 14 or higher, the mixture was extracted with ethyl acetate, and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane) to obtain 0.26 g (yield 25%) of the title compound.

Example 7 Synthesis of 1,2,5-trimethoxy-4- (4-acetamidophenyl) ethenylbenzene (Compound 35): 1,2,5-trimethoxy-4- (4) obtained in Example 6 -Aminophenyl) ethenylbenzene (Compound 34) 2.0
g, acetyl chloride 0.55 ml and triethylamine 1.
4 ml was added to 50 ml of methylene chloride, and the mixture was stirred at room temperature for 12 hours. After the reaction, water was added and the mixture was extracted with methylene chloride and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane) to obtain 2.1 g of the title compound (yield 88%).

Example 8 Synthesis of 1,2-5-trimethoxy-4- (4- (N-methylamino) phenyl) ethenylbenzene (Compound 36): 1,2,5-trimethoxy obtained in Example 6 -4-
(4-aminophenyl) ethenylbenzene (compound 3
4) To a solution of 1 g and 0.28 g of 37% aqueous formalin solution in 30 ml of acetonitrile was added 0.22 g of sodium cyanoborohydride under ice cooling, and the mixture was stirred at room temperature for 12 hours.
After the reaction, water was added and the mixture was extracted with chloroform and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane),
0.89 g (yield 16%) of the title compound was obtained.

Example 9 1,2,5-Trimethoxy-4- (4- (N-methylacetamido) phenyl) ethenylbenzene (Compound 3
Synthesis of 7): 2.1 g of 1,2,5-trimethoxy-4- (4-acetylaminophenyl) ethenylbenzene (compound 35) obtained in Example 7 and 0.4 g of 60% sodium hydride in 50 ml of THF. And 0.5 ml of methyl iodide
Was added and the mixture was heated under reflux for 12 hours. After the reaction, water was added and the mixture was extracted with chloroform and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (developing solvent; ethyl acetate:
(n-hexane) to separate and purify, and n-hexane-
The title compound was recrystallized from ethyl acetate to give 1.
23 g (yield 56%) was obtained.

Example 10 1,2,5-Trimethoxy-4- (2- (N, N-dimethylamino) phenyl) ethenylbenzene (Compound 3
Synthesis of 8): First, using 1,2-nitrobenzaldehyde as a raw material and in the same manner as in Example 1, 1,2,5-trimethoxy-4- (2-nitrophenyl) ethenylbenzene was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.88 (3H, s), 3.91 (3H, s), 3.93 (3H,
s), 6.54 (1H, s), 7.12 (1H, s), 7.31-7.62 (4H, m), 7.78-
7.97 (2H, m).

Next, using this compound as a raw material, Example 6
And 1,2,5-trimethoxy-4- (2-
Aminophenyl) ethenylbenzene was obtained. ¹ H-NMR (CDCl ₃ ) δ: 3.86 (3H, s), 3.91 (3H, s), 3.92 (3H,
s), 6.54 (1H, s), 6.69-6.84 (2H, m), 6.98-7.13 (3H, m),
7.27 (1H, d, J = 16.2Hz), 7.40-7.44 (1H, m).

Finally, 1.28 g of the above amino compound, 0.67 ml of methyl iodide and 1.3 g of potassium carbonate were added to 50 ml of acetone, and the mixture was heated under reflux for 24 hours. After the reaction, water was added and the mixture was extracted with chloroform and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane), and further n-
By recrystallizing with hexane-diethyl ether,
0.73 g (yield 52%) of the title compound was obtained.

Example 11 1,2,5-Trimethoxy-4- (3- (N, N-dimethylamino) phenyl) ethenylbenzene (Compound 3
Synthesis of 9): The title compound was synthesized in the same manner as in Example 10 using 3-nitrobenzaldehyde as a starting material.

Example 12 Synthesis of 1,2,5-trimethoxy-4- (8-nitro-2-quinolyl) ethenylbenzene (Compound 40): 2-
Methyl-8-nitroquinoline (5 g) and 2,4,5-trimethoxybenzaldehyde (5.5 g) were added to acetic anhydride (50 ml), and the mixture was heated with stirring at 150 ° C for 12 hours. After allowing to cool, the precipitated crystals were collected by filtration to give 6.3 g of the title compound.
(Yield 59%) was obtained.

Example 13 Synthesis of 1,2,5-trimethoxy-4- (8-amino-2-quinolyl) ethenylbenzene (Compound 41): 1,2,5-trimethoxy-obtained in Example 12 4- (8
-Nitro-2-quinolyl) ethenylbenzene (compound 4
0) To a solution of 15.9 g of dioxane in 100 ml, 5 g of Raney nickel was added, and the reaction was carried out for 14 hours under a pressure of hydrogen of 3 atm using a Parr apparatus. Raney nickel was filtered off, the filtrate was concentrated under reduced pressure, and the crystals precipitated by adding methanol were collected by filtration to give 12.5 of the title compound.
g (yield 86%) was obtained.

Example 14 Synthesis of 1,2,5-trimethoxy-4- (8- (N, N-dimethylamino) -2-quinolyl) ethenylbenzene (Compound 42): 1, obtained in Example 13 6.1 g of 2,5-trimethoxy-4- (8-amino-2-quinolyl) ethenylbenzene (Compound 41) and 5 ml of 37% aqueous formalin were added to a mixed solvent of 70 ml of acetic acid and 20 ml of ethanol, and hydrogen was added under ice cooling. Sodium cyanoborohydride 2.0
g was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure, the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane), and recrystallized from n-hexane-diethyl ether to give the title compound. To 5.5
g (yield 83%) was obtained.

Example 15 1,2,5-Trimethoxy-4- (8- (N-methylamino) -2-quinolyl) ethenylbenzene (Compound 4
Synthesis of 3): 6.0 g of 1,2,5-trimethoxy-4- (8-amino-2-quinolyl) ethenylbenzene (Compound 41) obtained in Example 13 and 1.5 ml of 37% formalin aqueous solution, Add to a mixed solvent of 100 ml of acetic acid and 10 ml of methanol, and add sodium cyanoborohydride under ice cooling.
1 g was added, and the mixture was stirred at room temperature for 12 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, 2N aqueous sodium hydroxide solution was added, and the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate.
The organic layer was concentrated under reduced pressure, the obtained residue was separated and purified by silica gel column chromatography (developing solvent; ethyl acetate: n-hexane), and recrystallized from n-hexane-diethyl ether to give the title compound. 1.
2 g (yield 19%) was obtained.

Example 16 8-Trimethylammonio-2- (2- (2,4,5-
Synthesis of trimethoxyphenyl) ethenyl) quinolinium iodide (Compound 44): 1,2, obtained in Example 13
5-trimethoxy-4- (8-amino-2-quinolyl)
Ethenylbenzene (Compound 41) 14.8 g, methyl iodide 10 ml and potassium carbonate 15 g are added to acetone 100 ml.
In addition, the mixture was heated under reflux for 12 hours. After the reaction, chloroform and water were added and the insoluble material was collected by filtration. The crystals were washed with warm methanol, the filtrate was concentrated, and the precipitated crystals were collected by filtration to give the title compound (6.0 g, yield 27%).

The physical properties of the compounds 1 to 44 obtained in the above examples are shown in Tables 1 to 11.

[0090]

[Table 1]

[0091]

[Table 2]

[0092]

[Table 3]

[0093]

[Table 4]

[0094]

[Table 5]

[0095]

[Table 6]

[0096]

[Table 7]

[0097]

[Table 8]

[0098]

[Table 9]

[0099]

[Table 10]

[0100]

[Table 11]

Example 17 (Angiogenesis Inhibitory Action Test) The inhibitory activity of the angiogenesis inhibitor of the present invention on human umbilical vein endothelial cells was examined by the following method. The compounds used are as shown in Table 12, and the results are also shown in Table 12.

HUVEC (human umbilical vein endothelial cells; manufactured by Kurabo Industries) was added to a 96-well microplate at 3000 cells per well, and 10 μg / ml ECGS (Endot) was added.
hial Cell Growth Supplem
ent; manufactured by Collaborative) 3 ng / ml EGF
(Epithelial growth factor; manufactured by Genzyme)
And in 200 μl of RPMI-164 medium (manufactured by Nissui) containing 2% fetal bovine serum, the cells were cultured for 48 hours at 37 ° C. in 5% CO ₂ . ³ H-Thymidine 0.
After adding 1 μCi (3.7 KBq) and further culturing for 17 hours, the cells were collected on a glass filter, washed with 5% trichloroacetic acid and ethanol, and the incorporated radioactivity was measured with β-plate (Pharmacia). It was measured. The concentration showing 50% growth inhibitory activity (IC ₅₀ ) was calculated with the control group as 100%, and the results are shown in Table 12.

[0103]

[Table 12]

[0104]

INDUSTRIAL APPLICABILITY The angiogenesis inhibitor of the present invention exhibits an excellent angiogenesis inhibitory activity and is useful as a therapeutic agent for solid tumors, rheumatism, diabetic retinopathy, psoriasis and the like.

Continuation of front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical display area A61K 31/425 AED A61K 31/425 AED 31/44 ABL 31/44 ABL 31/445 31/445 31/47 31 / 47 31/495 31/495 // C07D 333/08 C07D 333/08 (72) Inventor Kayo Okazaki 1-2-19, Sugidohara-cho, Ichigaya, Shinjuku-ku, Tokyo No. 2 Ichigaya Royal Corp 108 (72) Inventor Nozaki Kenji 11-9-504 Shinmachi, Hanno City, Saitama Prefecture (72) Inventor Tetsuji Asao 5063-1, Yamaguchi, Tokorozawa City, Saitama Prefecture 48-2504 (72) Shozo Yamada 25-7, Nakamachi, Hanno City, Saitama Prefecture Oyama Dai 2 Month 101

Claims (3)

[Claims] 1. A compound represented by the general formula (1): (In the formula, A is an aryl group, a substituted aryl group, a 5-membered or 6-membered heteroaromatic monocyclic group containing one oxygen atom or a sulfur atom, a 5-membered heteroaromatic group containing an oxygen atom or a sulfur atom and one nitrogen atom. A monocyclic group, a 1,3-dioxaindan-5-yl group, a hydrogen atom on a nitrogen atom substituted with a lower alkyl group 1,
2,3,4-tetrahydroquinolyl group, quinolyl group,
An angiogenesis inhibitor comprising a trans-stilbene derivative represented by a substituted quinolyl group or a 2-benzothiazolyl group) or a salt thereof as an active ingredient. 2. In the general formula (1), the substituent of the substituted aryl group represented by A is a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, an amino group, or a hydrogen atom on the nitrogen atom is a lower alkyl group. Alternatively, an amino group substituted with a lower alkanoyl group, a nitro group, or a nitrogen atom is 1 to 2
A 5-membered or 6-membered heterosaturated monocyclic group, an imidazolidinyl group or a piperazinyl group in which a hydrogen atom on a nitrogen atom is replaced with a lower alkyl group or a lower alkanoyl group, An amino-lower alkoxy group, a lower alkoxycarbonyl-lower alkoxy group or an aryl-lower alkoxy group, wherein the substituent of the substituted quinolyl group is a nitro group, an amino group, or a hydrogen atom on a nitrogen atom is substituted with a lower alkyl. The angiogenesis inhibitor according to claim 1, which is an amino group or trimethylammonium iodide. 3. In the general formula (1), A is a phenyl group, 4- (N, N-dimethylamino) -2-methylphenyl group, 4-isopropylphenyl group, 4-chlorophenyl group, 4-hydroxy-3. -Methoxyphenyl group, 4
-(N, N-dimethylamino) -2-methoxyphenyl group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 2,3,4-trimethoxyphenyl group,
2,4,5-trimethoxyphenyl group, 2,4,6-trimethoxyphenyl group, 3,4,5-trimethoxyphenyl group, 4-aminophenyl group, 4- (N-methylamino) phenyl group, 2- (N, N-dimethylamino) phenyl group, 3- (N, N-dimethylamino) phenyl group,
4- (N, N-dimethylamino) phenyl group, 4-
(N, N-diethylamino) phenyl group, 4- [N, N
-Di (n-butyl) amino] phenyl group, 4-acetamidophenyl group, 4- (N-methylacetamido) phenyl group, 4-nitrophenyl group, 2,4-dinitrophenyl group, piperidino-4-phenyl group, 4- (4-methyl-1-piperazinyl) phenyl group, 4- (4-formyl-1-piperazinyl) phenyl group, 4- [2- (N,
N-dimethylamino) ethoxy] phenyl group, 4- (methoxycarbonylmethoxy) phenyl group, 4- (2-phenylethoxy) phenyl group, 1-naphthyl group, 2-naphthyl group, 4- (N, N-dimethylamino) ) -1-naphthyl group, 2-thienyl group, 2-pyridyl group, 1,3-thiazol-2-yl group, 1,3-dioxaindane-5
-Yl group, 1-methyl-1,2,3,4-tetrahydro-6-quinolyl group, 2-quinolyl group, 8-nitro-2
-Quinolyl group, 8-amino-2-quinolyl group, 8- (N
-Methylamino) -2-quinolyl group, 8- (N, N-dimethylamino) -2-quinolyl group, 8-trimethylammonio-2-quinolinium iodide or 2-benzothiazolyl group. Angiogenesis inhibitor.