WO2002056886A1

WO2002056886A1 - Angiogenesis inhibitors contaiing urea derivative as the active ingredient

Info

Publication number: WO2002056886A1
Application number: PCT/JP2002/000318
Authority: WO
Inventors: Hidehito Matsuoka; Kazuo Nishimura; Hisayuki Seike
Original assignee: Santen Pharmaceutical Co., Ltd.
Priority date: 2001-01-19
Filing date: 2002-01-18
Publication date: 2002-07-25

Abstract

It is intended to provide novel pharmacological effects of a urea derivative. As the results of studies on the angiogenesis inhibitory and tumor proliferation inhibitory effects of the urea derivative by using the hypoxia-induced retinal angiogenesis method, it is revealed that this urea derivative has excellent angiogenesis inhibitory and tumor proliferation inhibitory effects and, therefore, is useful as a preventive and a remedy for diseases in which angiogenesis participates, in particular, diabetic retinopathy, retinopathy of prematurity, macular degeneration, angiogenic glaucoma, retinal vein obstruction, retinal artery obstruction, pterygium, rubeosis, corneal neovascularization, solid tumor, angioma, tumor proliferation/metastasis, etc.

Description

Description 血管 Angiogenesis inhibitor containing a rare derivative as an active ingredient

'The present invention relates to an angiogenesis inhibitor containing a peria derivative as an active ingredient, and particularly to a drug useful for treating ocular diseases and cancer. Background art

Vascular homeostasis is maintained by various functions of endothelial cells. Vascular endothelial cells 1) mediate the transport of necessary components such as nutrients in blood to tissues and prevent the passage of unnecessarily large components.2) Smoothly circulate without coagulation of blood. 3) has the effect of preventing bleeding when a blood vessel is cut off; and 4) has the regulatory effect of keeping blood vessel tension constant.

Basement membrane division by proteases produced by vascular endothelial cells ^: Angiogenesis at the stage of dissolution, migration and proliferation of vascular endothelial cells, formation of vascular endothelial cell lumen, formation of basement membrane and surrounding pericytes Occurs. Angiogenesis is a variety of diseases, especially diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeosis, corneal neovascularization, solid There is a close connection with tumors, hemangiomas, tumor growth and metastasis.

On the other hand, in Japanese Unexamined Patent Publication No. 2000-44533, a urea-induced conductor having a urea structure as a basic structure and having a sulfur atom and an amide bond in a side chain has a TNF-α production inhibitory effect. It is disclosed that the compound is useful as an antirheumatic drug and a therapeutic agent for autoimmune diseases. However, there is no report on the therapeutic effect of a disease based on the angiogenesis inhibitory action of such a perrea derivative. It is a very interesting subject to find new pharmacological actions for this urea derivative useful as a medicine. Disclosure of the invention

The present inventors conducted an angiogenesis inhibition test and a tumor growth inhibition test by a hyperoxic load-induced retinal blood angiogenesis method in order to find a new pharmacological action of a perea derivative. As a result, urea derivatives exert an excellent angiogenesis inhibitory action, so that diseases involving angiogenesis, especially diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, and retinal vein occlusion , Retinal artery occlusion., Pterygium, rubeosis, corneal neovascular disease, solid tumors, hemangiomas, tumor growth and metastasis, and found to be useful as a therapeutic agent.

The present invention relates to an angiogenesis inhibitor comprising a compound represented by the following general formula [E] or a salt thereof (hereinafter, referred to as “the present compound”) as an active ingredient, a therapeutic agent for ocular diseases and cancer involving angiogenesis: It is a fool to provide.

[ 13

[Wherein, R ¹ is a hydrogen atom, a lower alkyl group, an aromatic group, R ^A — CO—

RS— or a group represented by the following formula [II]

[II]

R ² , R ³ and R ⁴ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group. When R ⁴ is a lower alkyl group, the lower alkyl group may form a cycloalkyl ring by linking the terminal carbon atom of the alkyl group to the carbon atom to which the lower alkyl group is bonded.

R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group, and both R ⁵ and R ⁶ are lower When they are alkyl groups, they may be linked to each other to form a non-aromatic heterocyclic ring having a nitrogen atom and / or an oxygen atom in the ring, and the heterocyclic ring is a lower alkyl group.

, A lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aromatic group, or R ^A —CO—.

R ⁷ is hydrogen atom, lower alkyl group, cycloalkyl group, hydroxy group, mercapto group, phenyl group, RB • 0—, -SRDC

^{OS-, R E - OCO-, R} F -N (R u) - or an HONHCO-. R ⁷ may also be linked to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring containing a sulfur atom in the ring, and the ring may further have a carbonyl group in the ring. Good.

A ¹ represents a lower alkylene group. A ² represents a lower alkylene group.

Each of the lower alkyl groups defined above includes a hydroxy group, a non-aromatic heterocyclic ring having a nitrogen atom and / or an oxygen atom in the ring, a cycloalkyl group, a cycloalkenyl group, an adamantyl group, an aromatic group, a phthalimide group, ^A guanidino group optionally substituted with a lower alkylsulfonyl group or an aromatic sulfonyl group, 'R ^A — CO—, R ^B — 0—, R ^C — S-, R ^D -COS-, R ^D -OCO -, R ^F -N (R ^G )-, R ^H -N ( ^J ) CO-, R ^K- CONH- or HONHCO-.

Each lower alkenyl group defined above may be substituted with a hydroxy group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkenyl group, or an aromatic group.

Each cycloalkyl group, lower alkyl group, hydroxy group, oxo group or the group defined above may be substituted with: ^E— OC ——.

Each of the aromatic groups defined above is a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkanoloxy group, a halogen atom, a nitro group, an aromatic group, a lower alkylsulfonyl group, an aromatic sulfonyl group, R ^E — It may be substituted with OCO—, ^F— N (R ^G ) — or R ^K —CONH—.

Non-aromatic heterocyclic group having a nitrogen atom and or an oxygen atom as defined above in the ring is. A lower alkyl group, a cycloalkyl group, an aromatic Motoma other may be substituted by R ^A -CO- And the lower alkyl group is a hydroxy group, a cycloalkyl group, a cycloalkenyl group, an aromatic group, R ^A —CO—, R ^B —O—, R ^E —OCO— or R ^F —N (R) —. It may be substituted.

R ^A is a lower alkyl group, an octogeno lower alkyl group, an aromatic group, a lower alkoxy group, an aromatic lower alkoxy group or R ^F —N (R ^G ) — Show. R ^B represents a lower alkyl group or an aromatic group. R ^C represents a hydrogen atom, a lower alkyl group or an aromatic group. ^RD represents a lower alkyl group or an aromatic group. ^RE represents a hydrogen atom, a lower alkyl group or an aromatic group. R ^F and R ^G are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. R ⁿ and are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. ^RK represents a lower alkyl group, a lower alkoxy group or an aromatic group. same as below. ]

The lower alkyl group is described in detail for each group defined in the above general formula [I]. The lower alkyl group is methyl, ethyl, propyl, butyl, hexyl, isopropyl, isoptyl, isopentyl, isohexyl, t-butyl, 3,3 —Indicates straight or branched alkyl having 1 to 8 carbon atoms such as dimethylbutyl. 'A lower alkenyl group refers to a linear or branched alkenyl having 2 to 8 carbon atoms such as vinyl, aryl, 3-butenyl, 5-hexyl, and isopropyl.

The cycloalkyl group refers to cycloalkyl having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The cycloalkenyl group refers to cycloalkenyl having 3 to 8 carbon atoms such as cycloprobenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.

The lower alkoxy group means a linear or branched alkoxy having 1 to 8 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, t-butoxy and the like.

Halogen atom means fluorine, chlorine, bromine and iodine. Lower alkylene group means 1 to 8 of methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, ethylethylene, dimethylethylene, propylethylene, isopropylethylene, methyltrimethylene, etc. Represents a linear or branched alkylene having a carbon atom of

The aromatic group means a monocyclic or condensed polycyclic hydrocarbon aromatic group such as a phenyl group or a naphthyl group, or a heterocyclic aromatic group such as a pyridyl group, a phenyl group, a thienyl group or an imidazolyl group. '

A non-aromatic heterocyclic ring having a nitrogen atom or an oxygen atom in the ring: One or two nitrogen atoms such as piperidine, piperazine, pyrroline, and homopirazine in the ring And a non-aromatic heterocycle having a nitrogen atom and an oxygen atom in the ring, such as morpholine.

A non-aromatic heterocyclic ring containing a sulfur atom in the ring linked to a sulfur atom is a non-aromatic heterocyclic ring containing one or two sulfur atoms in the ring, such as dithiolane, or a carbohydrate in the ring. It represents a non-aromatic heterocyclic ring such as thiolactone having a bis group.

The salts in the present invention are not particularly limited as long as they are pharmaceutically acceptable salts. Salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, cunic acid, tartaric acid, and ditartaric acid And salts with organic acids such as benzoic acid and substituted benzoic acid, and salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium. In addition, when a geometric isomer or an optical isomer exists in the present compound, those isomers are also included in the scope of the present invention. The present compound may be in the form of an addition salt such as a hydrate or an organic solvate.

Preferable examples of the compound include a compound in which each group defined by the general formula [I] is one selected from the following (1) to (10) or a combination of two or more thereof, or a salt thereof. Can be (1) R ¹ represents an acetyl group, a benzoyl group or a group represented by the following formula [Π];

― S

ヽ A 'ヽ²

(2) R ² is 2-cyclohexylethyl, 2-cyclopentylethyl, 2- (1-adamantyl) ethyl, 2- (cyclohexene-1-yl) ethyl, phenethyl, 2 — Represents [3,5-di (t-butyl) -1-hydroxyphenyl] ethyl group or 3- (4-fluorophenyl) propyl group;

(3) R ³ represents a hydrogen atom;

(4) R ⁴ is a methyl group, an acetylthiomethyl group, a benzyl group, a 2-naphthylmethyl group, a 4-fluorobenzyl group, a 4-fluorobenzyl group,

4-biphenylmethyl group, 4-nitrobenzyl group, 3-nitro-4-phenylphenylmethyl group, 4-methoxybenzyl group or 4-isopropoxybenzyl group;

(5) R ° represents a hydrogen atom;

(6) R ⁰ is a 2- (dimethylamino) ethyl group, a 2- (diethylamino) ethyl group, a 2- (diisopropylamino) ethyl group, an N-methyl-12- (cyclohexylamino) ethyl group, a 2- ( 2-pyridyl) ethyl, 2- (1-piperidyl) ethyl or 2- (4-methylbiperazinyl) ethyl; (7) R ⁵ is linked to R ⁶ to form a 1-piperidyl group, a 4-morpholinyl group or a 4-methyl-1-piperazinyl group;

(8) R ⁷ represents a hydrogen atom;

(9) A ¹ represents an ethylene group;

(10) A ² represents a methylene group.

More preferred specific examples of the present compound include the following compounds and salts thereof.

① 1— [(2 S) — 2— [3-[2- (acetylthio) ethyl] — 3 — [2- (1-adamantyl) ethyl] ureido] propionyl] 1-4-methylpiperazine

② 1 1 [(2 S) — 2— 〖3— [2— (acetylthio) ethyl] 1 3 1 (2-cyclohexylethyl) ureido] Propionyl 1 — 4—

③ 1-[(2S) -2-[3-1- [2- (acetylthio) ethyl]-3-(2-cyclopentylethyl) ureido] propionyl] 1-4-methylbiperazine

④ 1 1 [(2 S) — 2— [3 [2— (acetylthio) ethyl] 1 3 ― [2- [3,5-di (t-butyl) —4-hydroxyphenyl] ethyl] ured] propionyl] —4-methylpiperazine

In order to examine the usefulness of the urea derivative represented by the above general formula [1], the angiogenesis inhibitory effect of the present compound was examined. The details will be shown in the section on pharmacological studies below, but this compound not only has a strong inhibitory effect on retinal neovascularization induced by high oxygen load, which is an in vivo evaluation model of angiogenesis, It has also been found that it also exhibits an anticancer effect due to the effect. Based on these results, this compound is an angiogenesis inhibitor and a disease involving angiogenesis, particularly diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal confusion, and retina It is useful as a prophylactic, therapeutic and suppressive agent for arterial occlusion, pterygium, rubeosis, corneal neovascularization, solid tumors, hemangiomas, tumor growth and metastasis.

The present invention also relates to a method for treating ophthalmic diseases accompanied by angiogenesis, which comprises administering to a patient an effective amount of a perrea derivative represented by the above general formula [I].

Administration of the compounds can be oral or parenteral. Dosage form Examples thereof include tablets, capsules, powders, granules, transdermal absorbents, injections, eye drops, eye ointments, and the like, which can be prepared using commonly used techniques.

The dose of the compound can be appropriately selected depending on the symptom, age, dosage form, etc., but in the case of an oral preparation, it is usually 0.1 to 500 mg / day, preferably 1 to 100 mg / day, once or several times. It may be administered separately.

BEST MODE FOR CARRYING OUT THE INVENTION

The results of the pharmacological tests are shown below, but these are for better understanding of the present invention and do not limit the scope of the present invention.

1. Angiogenesis inhibition test by hyperoxia-induced retinal neovascularization

Arch Ophthalmol, 114.1 210-1217, a model for evaluating retinal neovascularization induced by hyperoxia, which measures the angiogenesis inhibitory effect of a drug induced by hyperoxia loading on neonatal rats ^ as a model for evaluating retinal neovascularization in vivo (1994). Therefore, according to the method described in the above-mentioned literature, the test compound [1-1 [(2S) —2-—3- [2 -— (acetylthio) ethyl] -13- [2- (1-adamantyl) ethyl [Ureide] The effect of propionyl {4-methylbiperazine} on the angiogenesis evaluation model was examined.

(Preparation of test compound solution)

Dissolve the test compound in phosphate buffered saline (PBS) and add 0.1 I SmgZm

One test compound solution was obtained.

(experimental method)

A 0-day-old newborn rat is bred together with the parent rat in a high oxygen loading breeding box maintained at 80% oxygen condition for 1 day, and returned to normal breeding conditions on the 11th day after birth. The animals were returned to normal breeding conditions once a day for 30 minutes during the period of high oxygen load. The test compound (0.3 jti gZ21 / eye) was intravitreally administered under avertin anesthesia on days 1 and 13 after birth.

II Was administered. On the 18th day after birth (P18), the rats were euthanized by Nembutal administration, and the eyes were enucleated. The excised eye was fixed with 4.% paraformaldehyde, and the retina was separated. The separated retina was stained with ADPase, and the degree of angiogenesis was evaluated by the angiogenesis evaluation method described by Byon. As a control model rats were administered with PBS (2 a 1 / eye) intravitreally instead of the test compound, _c (angiogenesis Evaluation method) was carried out the same operation as above

The retina colored in ADPas 6 was divided into four quadrants and observed and evaluated under an optical microscope. The evaluation was scored for each quadrant according to the following evaluation criteria. The angiogenesis inhibition rate (%) was calculated from the total score obtained by adding the scores in each quadrant. The results are shown in Table 1 (the numbers in the table indicate the average values of 10 cases).

(Evaluation criteria)

0: There was no neovascular bud and continuous vascular protuberance

1: There were less than 3 neovascular buds "

2: More than 4 neovascular buds or short vascular bulges

3: Less than half of one quadrant had vascular uplift

: More than half of one quadrant had vascular prominence Table 1

2. Tumor growth inhibition test

To examine the anticancer effect of the test compound, the test compound was administered to tumor-bearing mice, and the tumor growth inhibitory effect was examined.

(experimental method) Under the skin of mice were inoculated with IX 1 0 ⁷ one of Lewis lung carcinoma cells create a tumor-bearing mouse. The test compound · (1 Omg / kg) or 1% methylcellulose (control group) was orally administered to the tumor-bearing mice once a day at a dose of 0.2 ral per 10 g of body weight.

(Tumor growth inhibitory effect)

14. From cell inoculation. On the day, tumors were collected, and the tumor weight was measured to calculate the tumor growth inhibition rate (% ').

The results are shown in Table 2 (the numbers in the table indicate the average values of 9 cases). Table 2

Industrial applicability

As is evident from the results of the above pharmacological tests, this compound has excellent angiogenesis inhibitory activity and tumor growth inhibitory activity, so that diseases involving angiogenesis, especially diabetic retinopathy, retinopathy of prematurity, and macula Preventive agents and treatments for degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, rubeiosis, corneal neovascular disease, solid tumors, hemangiomas, tumor growth and metastasis Useful as an agent.

Claims

The scope of the claims

1. An angiogenesis inhibitor comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. .

R ^A — CO

[Π]

R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group. When R ⁴ is a lower alkyl group, the lower alkyl group may form a cycloalkyl ring by linking the terminal carbon atom of the alkyl group to the carbon atom to which the lower alkyl group is bonded. . R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group, and both R ⁵ and R ⁶ are lower When it is an alkyl group, these may be linked to each other to form a non-aromatic heterocyclic ring having a nitrogen atom and / or an oxygen atom in the ring, wherein the heterocyclic ring is a lower alkyl group, a lower alkenyl group, a cycloalkyl Group, a cycloalkenyl group, an aromatic group, or a group substituted by R ^A —C〇.

R ⁷ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy group, a mercapto group, a phenyl group, R ^B — 0—, R ^C — S—, R ^D -C OS—, R ^E —〇CO—, R ^F — N (R ^G ) Indicates one or one CONHOH. R ⁷ may also be linked to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring containing a sulfur atom in the ring, and the ring may further have a carbonyl group in the ring. Good.

A ¹ represents a lower alkylene group.

A ² represents a lower alkylene group.

Each of the lower alkyl groups defined above is a hydroxy group, a nitrogen atom, a non-aromatic heterocycle having a Z or oxygen atom in the ring, a cycloalkyl group, a cycloalkenyl group, an adamantyl group, or an aromatic group. group, Futaruimi de group, a lower alkylsulfonyl group or an aromatic optionally substituted Guanijino group sulfonyl ^{^{group, R A - CO-, R B}} - 0-, R C - S -, D COS -, R E ^{- OCO-, R F - N (} R G) -, R H -N (R J) CO- R K - CONH- or may be substituted with HONHCO-.

Each cycloalkyl group defined above is a lower alkyl group, It may be substituted by a silo group, an oxo group or R ^E —OCO—.

Each of the aromatic groups defined above is a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, a halogen atom, a nitro group, an aromatic group, a lower alkylsulfonyl group, an aromatic sulfonyl group, ^E — OCO—, R ^F —N ( ^G ) — or R ^K —CONH—.

Non-aromatic heterocyclic group having a nitrogen atom and / or oxygen atoms as defined above in the ring, the lower alkyl group, a cycloalkyl group, an aromatic Motoma other R ^A '- may be substituted by CO- well, further the lower alkyl group 'is hydroxy group, a cycloalkyl group, a cycloalkenyl group, an aromatic ^{^{group, R A - CO-, R B}} - 0-, R E -OCO- or: R ^F - N (R ^G ) — may be substituted.

R ^A represents a lower alkyl group, an octogeno lower alkyl group, an aromatic group, a lower alkoxy group, an aromatic lower alkoxy group, or R ^F —N (R ^G ). : ^B represents a lower alkyl group or an aromatic group. .: ^C represents a hydrogen atom, a lower alkyl group or an aromatic group. ^RD represents a lower alkyl group or an aromatic group. ^RE represents a hydrogen atom, a lower alkyl group or an aromatic group. R ^F and R ^G are the same or different and each represent a hydrogen atom, a lower alkyl group ′, a cycloalkyl group or an aromatic group. R ^H and are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. ^Rκ represents a lower alkyl group, a lower alkoxy group or an aromatic group. ]

2. The compound according to claim 1 or a salt thereof as an active ingredient, wherein each group defined by the general formula [I] is one selected from the following (1) to (10) or a combination of two or more thereof. Angiogenesis inhibitors.

(1) R ¹ ′ represents an acetyl group, a benzoyl group or a group represented by the following formula [Π]; R

ゝ A, ノ

Four

0 R

(2) R ² is 2-cyclohexylethyl, 2-cyclopentylethyl, 2- (1-adamantyl) ethyl, 2- (cyclohexene)

/

1-yl) ethyl group, phenethyl group, 2A-2 [3,5-di (t-butyl) —4-hydroxyphenyl] ethyl group or 3- (4-fluorophenyl) propyl group;

(3) R ³ represents a hydrogen atom;

(4) R ⁴ is a methyl group, an acetylthiomethyl group, a benzyl group, a 2-naphthylmethyl group, a 4-fluorobenzyl group, a 4-chlorobenzyl group, a 4-biphenylylmethyl group, a 4-nitrobenzyl group. Benzyl, 3-nitro-14-biphenylylmethyl, 4-methoxybenzyl or 4-isopropoxybenzyl;

(5) R ⁵ represents a hydrogen atom;

(6) R ⁶ is a 2- (dimethylamino) ethyl group, a 2- (diethylamino) ethyl group, a 2- (diisopropylamino) ethyl group, an N-methyl-12- (cyclohexylamino) ethyl group, a 2- ( Represents a 2-pyridyl) ethyl group, a 2_ (1-piperidinyl) ethyl group or a 2- (4-methylpiperazinyl) ethyl group;

(7) R ⁵ is linked to R ⁶ to form a 1-piperidyl group, a 41-morpholinyl group or a 4-methyl-11-piperazinyl group;

(8) R ⁷ represents a hydrogen atom;

(9) A ¹ represents an ethylene group;

(10) A ² represents a methylene group;

3. 1-[(2S) 1 2— [3— [2— (Acetylthio) ethyl]] — 3— [2— (1—adamantyl) ethyl] ureido] propionyl] —4-methylbiperazine, 1 ― [(2 S)-2-[3-1 [2- (acetylthio) ethyl] 1-3-(2 -cyclohexylethyl) ureido] propionyl] 1-4-methylpiperazine, 1-[(2 S) — 2 — [3— [2— (Acetylthio) ethyl] -1-3- (2-cyclobenzylethyl) ureido] propionyl] _4-Methylbiperazine or 1 — [(2S) —2— [3 '— [ 2-(Acetylthio) Ethil :! —.3— [2- [3,5-di (t-butyl) -1-4-hydroxyphenyl] ethyl] ureido] propionyl] — Angiogenesis inhibitor containing 4-methylpiperazine or a salt thereof as an active ingredient.

4. A therapeutic agent for an ophthalmic disease associated with angiogenesis, comprising the compound according to claim 1 or a quay thereof as an active ingredient.

5. The ophthalmic disease is diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, lubeosis or corneal neovascularization. The therapeutic agent as described above.

6. A therapeutic agent for a cancer disease, comprising the compound according to claim 1 or a salt thereof as an active ingredient.

7. The therapeutic agent according to claim 6, wherein the cancer disease is a solid tumor or a hemangioma.

8. The following general formula [I]

[I]

One

S

/

[Wherein, R ¹ is a hydrogen atom, a lower alkyl group, an aromatic group, R ^A — CO

_C indicating the group represented by R c _ S- or formula [[pi]

ヽ¹

Four

0

[Π]

R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group. When R ⁴ is a lower alkyl group, the lower alkyl group may form a cycloalkyl ring by linking the terminal carbon atom of the alkyl group to the carbon atom to which the lower alkyl group is bonded.

R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group, and R ^{5 and} R ⁶ are both lower When they are alkyl groups, they are linked together to form a nitrogen atom and a Z or oxygen atom into a ring ^! The heterocyclic ring may be substituted with a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aromatic group, or R ^A —CO—.

R ⁷ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy group, a mercapto group, a phenyl group, R ^B —〇, R ^C —S—, R ^D —COS—, R ^E— CO—, R R ⁷ representing ^F —N (R ^G ) — or one CONHOH may also be linked to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring containing a sulfur atom in the ring, wherein the ring is Further, it may have a carbonyl group in the ring.

A ¹ represents a lower alkylene group.

A ² represents a lower alkylene group.

Each of the lower alkyl groups defined above includes a hydroxy group, a non-aromatic heterocycle having a nitrogen atom and / or an oxygen atom in the ring, a cycloalkyl group, a cycloalkenyl group, an adamantyl group, an aromatic group, and phthalimide. group, a lower alkylsulfonyl group or an aromatic sulfonyl group substituted is, which may have been Guanijino group,: ^A - CO-, R ^B one 〇-, ^C - S one, R ^{^D} -COS-, R ^D -OCO -, ^r -N ^(R ^b) ^{^{one, R H -N (R J ·}} ) CO-, R K - CONH- or may be substituted with HONHCO-.

Each cycloalkyl group defined above may be substituted with a lower alkyl group, a hydroxy group, an oxo group, or R ^E —OCO—.

Each aromatic group defined above is a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, a halogen atom, a nitro group, an aromatic group, a lower alkylsulfonyl group, an aromatic sulfonyl group, R ^E — OCO —, R ^F — N. (R ^G ) one or R ^K — CONH— may be substituted.

Non-aromatic heterocyclic group having a nitrogen atom and / or oxygen atoms as defined above in the ring, the lower alkyl group, a cycloalkyl group, the aromatic Motoma other may be substituted by R ^A -CO- And the lower alkyl group is a cycloalkyl group such as a hydroxy group, a cycloalkenyl group, an aromatic group, R ^A —CO—, R ^D —I, R ^E —OCO— or R ^F —N (R ^G ) May be substituted with one.

^RA represents a lower alkyl group, an octogeno lower alkyl group, an aromatic group, a lower alkoxy group, an aromatic lower alkoxy group, or R ^F —N (R ^G ) —. R ^B represents a lower alkyl group or an aromatic group. ^RE represents a hydrogen atom, a lower alkyl group or an aromatic group. ^RD represents a lower alkyl group or an aromatic group. ^RE represents a hydrogen atom, a lower alkyl group or an aromatic group. R ^F and R ^G are the same or different and represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. R ^H and RJ are the same or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. RK represents a lower alkyl group, a lower alkoxy group or an aromatic group. ]

A method for treating a disease associated with angiogenesis, comprising administering to a patient an effective amount of the compound represented by the formula (I) or a salt thereof.

9. The treatment method according to claim 8, wherein each group defined by the general formula [I] is one selected from the following (1) to (10) or a combination of two or more thereof.

(1) R ¹ represents an acetyl group, a benzoyl group or a group represented by the following formula [II]; R ³

― S \ A _A

R ⁷ 0 R

[Π]

(2) R ² is 2-cyclohexylethyl group, 2-cyclopentylethyl group, 2- (1-adamantyl) ethyl group, 2- (cyclohexene-1

1-yl) ethyl group, phenethyl group, 2- [3,5-di (t-butyl) -4-hydroxyphenyl] ethyl group or 3- (4-fluorophenyl) propyl group;

(3) R ³ represents a hydrogen atom;

(4) R ⁴ is methyl, acetylthiomethyl, benzyl, 2-naphthylmethyl, 4-fluorobenzyl, 4-cyclobenzyl, 4-biphenylmethyl, 4-nitrobenzyl Benzyl, 3-nitro-4-biphenylylmethyl, 4-methoxybenzyl or 4-isopropoxybenzyl;

(5) R ⁵ represents a hydrogen atom;

(6) R ⁶ is a 2- (dimethylamino) ethyl group, a 2- (diethylamino) ethyl group, a 2- (diisopropylamino) ethyl group, an N-methyl-1- (cyclohexylamino) ethyl group, a 2- ( 2-pyridyl) ethyl, 2- (1-piperidyl) ethyl or 2- (4-methylbiperazinyl) ethyl;

(7) R ⁵ is linked to R ° to form a .1-piperidyl, 4-morpholinyl or 4-methyl-1-piperazinyl group; (8) R ⁷ represents a hydrogen atom;

(9) A ¹ represents an ethylene group;

(10) A ² represents a methylene group;

1 0.1-[(2 S)-2-[3 — [2-(Acetylthio) ethyl] 1 3 — [2 — (1 -adamantyl) ethyl] ureido] Propionyl] 1 -methylbiperazine, 1 — [(2S) —2— [3— [2- (acetylthio). 'Ethyl] _3— (2-cyclohexylethyl) ureido] propionyl] 1-4 methylbiperazine, 1 — [(2S) — 2— [3— [2— (Acetylthio) ethyl] 1 3— (2—cyclopentylethyl) ureido] propionyl] —4—Methylbiperazine or 1 — [(2S) '— 2— [3— [2 — (Acetylthio) ethyl] — 3 — [2 — [3,5-di (t-butyl) -14-hydroxyphenyl] ethyl] 'ureido] propionyl] _4-methylbiperazine or its salts A method for treating a disease associated with angiogenesis, comprising administering an effective amount to a patient.

1 1. The method according to any one of claims 810, wherein the disease is an ophthalmic disease.

1 2. The ophthalmic disease is diabetic retinopathy, retinopathy of prematurity, macular degeneration, neovascular glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, lubeosis or corneal neovascularization. The treatment method according to 1.

1 3. The treatment method according to any one of claims 810, wherein the disease is a cancer disease.

14. The method according to claim 1.3, wherein the cancer disease is a solid tumor or a hemangioma.

1 5. Use of a compound represented by the following general formula [I] or a salt thereof for production of an angiogenesis inhibitor.

[I I

[Wherein, R ¹ is a hydrogen atom, a lower alkyl group, an aromatic group, R ^A —CO

10—, R ^C- S— or a group represented by the following formula [II].

Fifteen

[I]

R ² , R ³ and R ⁴ are the same or different and represent a hydrogen atom, a lower 20. alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group. If R ⁴ is a lower alkyl group, lower alkyl group may form a Shikuroarugiru ring it are joined to connecting the terminal carbon ratio atoms of the same alkyl group carbon atoms.

R ⁵ and R ⁶ are the same or different and each represent a hydrogen atom, a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group or an aromatic group, wherein R ⁵ and R ⁶ are both When they are lower alkyl groups, they are linked to each other to form a nitrogen atom and / or an oxygen atom in the ring. The heterocyclic ring may be substituted with a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aromatic group, or R ^A —C〇. Good.

R ⁷ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a hydroxy-5 group, a mercapto group, a phenyl group, R ^B — '0—, R ^C — S—, ^D — COS—, R ^E —OCO—, R ^F -N (R ^G ) Indicates one or one CONHOH. R ⁷ may also be connected to a sulfur atom adjacent to A ¹ to form a non-aromatic heterocyclic ring containing a sulfur atom in the ring, and the ring may further have a carbonyl group in the ring. Good.

10 A ¹ represents a lower alkylene group.

A ² represents a lower alkylene group.

Each of the lower alkyl groups defined above includes a hydroxy group, a non-aromatic heterocycle having a nitrogen atom and Z or an oxygen atom in the ring, a cycloalkyl group, a cycloalkenyl group, an adamantyl group, an aromatic group, and a phthalimidium. Do

15 groups, a guanidino group optionally substituted with a lower alkylsulfonyl group or an aromatic sulfonyl group, R ^A — CO—, R ^B —O—, R ^C — S—, R ^D— COS—, R ^E— ^{OCO-, R F - N (R} G) -, R H -N (R J) CO-, optionally substituted with R ^K -CONH- or HONHCO-.

20 Each of the lower argenyl groups defined above may be substituted with a hydroxy group, a lower alkyl group, a lower alkoxy group, a cycloalkyl group, a cycloalkenyl group, or an aromatic group.

Each cycloalkyl group defined above may be substituted with a lower alkyl group, a hydroxy group, an oxo group or —OCO—.

25 Each aromatic group defined above is a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkoxy group, a halogen atom, a nitro group, an aromatic group, a lower alkylsulfonyl group, an aromatic sulfonyl group. Group, R ^E -OCO- R ^F —N (R ^G ) — or R ^K —C〇NH— may be substituted.

Non-aromatic heterocyclic group having a nitrogen atom and / or oxygen atoms as defined above in the ring, the lower alkyl group, a cycloalkyl group, the aromatic Motoma other may be substituted by R ^A -CO- further the lower alkyl group, hydroxy group, a cycloalkyl group, a cycloalkenyl group, an aromatic ^{^{group,; A -CO-, R B -}} O-, R - OCO- or ^{^{R F - N (R u)}} - in It may be substituted.

^RA represents a lower alkyl group, a halogeno lower alkyl group, an aromatic group, a lower alkoxy group, an aromatic lower alkoxy group, or R ^F -N (R ^G ). R ^B represents a lower alkyl group or an aromatic group. ^RC represents a hydrogen atom, a lower alkyl group or an aromatic group; ^RD represents a lower alkyl group or an aromatic group. R ^E is hydrogen廪子, lower alkyl group or an aromatic group. R ^F and R ^G are the same or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. R ^H and R ^J \ are the same or different and each represent a hydrogen atom, a lower alkyl group, a cycloalkyl group or an aromatic group. ^RK represents a lower alkyl group, a lower alkoxy group or an aromatic group. ] ''

16. Use of the compound according to claim 15 or a salt thereof, wherein each group defined by the general formula [I] is one selected from the following (1) to (10) or a combination of two or more thereof. .

(1) R ¹ represents an acetyl group, a benzoyl group or a group represented by the following formula [II]; R

S ヽ '

A '

ヽ²

0 R

cni

(3) R ³ represents a hydrogen atom;

(4) R ⁴ is a methyl group, acetylthiomethyl group, benzyl group, .2-naphthylmethyl group, 4-fluorobenzyl group, 4-cyclobenzyl group, 4-biphenylylmethyl group, 4- Shows nitrobenzyl, 3-nitro-4-biphenylylmethyl, 4-methoxybenzyl or 4-isopropoxybenzyl;

(5) R ⁵ represents a hydrogen atom;

(6) ⁶ is a 2- (dimethylamino) ethyl group, a 2- (diethylamino) ethyl group, a 2- (diisopropylamino) ethyl group, an N-methyl-1- (cyclohexylamino) ethyl group, a 2- (2 —Pyridyl) ethyl group, 2- (1-piperidyl) ethyl group or 2- (4-methylbiperazinyl) ethyl group;

(7) ⁵ is linked to R ⁶ to form a 1-piperidyl, 41-morpholinyl or 4-methyl-1-piperazinyl group; (8) R ⁷ represents a hydrogen atom;

(9) A ¹ represents an ethylene group;

(10) A ² represents a methylene group.

1 7. Use of the following compounds or salts thereof for the manufacture of an angiogenesis inhibitor.

1 1 [(2 S)-2-[3-[2-(Acetylthio) ethyl]-3--[2-(1 -adamantyl) ethyl] ureido] Propionyl] 1 -methylbiperazine, 1 — [ (2 S)-2-[3-[2-(Acetylthio) ethyl]-3-(2 -cyclohexylethyl) ureido] pulpionyl] — 4-methylbiperazine, 1 — [(2 S) — 2 — [3-— [2- (acetylthio) ethyl)] — 3- (2-cyclopentylethyl) ureido] propionyl] —4-methylbiperazine or 1-[(2S) —2— [3— [ 2- (Acetylthio) ethyl]-3-[2- [3,5-di (t-butyl) —4-hydroxyphenyl] ethyl] レイ reid] propionyl] — 4-methylbiperazine

18. The use according to any one of claims 15 to 17, wherein the therapeutic agent for angiogenesis is a therapeutic agent for an ophthalmic disease accompanied by angiogenesis.

1 9. The ophthalmological disease is diabetic retinopathy, retinopathy of prematurity, macular degeneration, vascular firewood glaucoma, retinal vein occlusion, retinal artery occlusion, pterygium, lubeosis or corneal neovascular disease. 18. Use as described in 8.

20. The use according to any one of claims 15 to 17, wherein the therapeutic agent for angiogenesis is a therapeutic agent for a cancer disease.

21. The use according to claim 20, wherein the cancer disease is a solid tumor or a hemangioma.