JP3135616B2 - Angiogenesis inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel angiogenesis inhibitor.

[0002]

2. Description of the Related Art Angiogenesis is a normal physiological condition of humans or animals, such as embryogenesis, ovulation or placenta formation by the female sexual cycle, wound healing, repair processes such as inflammation, and rapid proliferation of capillaries. It is known to occur in many pathological conditions and the like that increase and cause severe damage to tissues. Diseases due to such a pathological increase in capillaries include diabetic retinopathy in the ophthalmology area, posterior lens fibroplasia, angiogenesis associated with corneal transplantation, glaucoma, eye tumors and trachoma, and the like in the dermatology area. Such as psoriatic and suppurative granulomas, such as hemangiomas and fibrous hemangiomas in the pediatric area, hypertrophic scars and granulations in the surgical area, and rheumatoid arthritis and edema sclerosis in the medical area. Atherosclerosis and the like in diseases and various tumors are known. In particular, increased abnormal angiogenesis in diabetic retinopathy and trachoma drives blindness to many people, and in rheumatoid arthritis, abnormal neovascularization in joints causes destruction of cartilage in joints, and Is troubled. Therefore, there is a demand for the development of a compound useful as a therapeutic or preventive drug for such diseases accompanied by abnormal proliferation of angiogenesis. The rapid growth and progression of tumors is thought to be due to neovascularization induced by angiogenic factors produced by tumor cells, and angiogenesis inhibitors are expected to be new therapeutic agents for various tumors. Search studies for inhibitors have been initiated [J. Folkman, Advances in Cancer Research,
43 , 175 (1985), George Klein
e Klein) and Sydney Wine House (Sidney W)
einhouse) edit]. It is already known that angiogenesis is inhibited by a combination of heparin or a heparin fragment and a so-called angiostatic steroid such as cortisone [J. Folkman et al. .), Science
(Science), 221 , 719 (1983); J. Folkman et al., Annals of Surgery, 206 , 37.
4 (1987)]. Furthermore, the synergistic use of α, β and γ-cyclodextrin sulphates, in particular β-cyclodextrin tetradeca sulphate or heparin, in combination with the aforementioned angiogenesis inhibiting steroids, fumagillin or collagen synthesis inhibitors and the like. Have been shown to exhibit angiogenesis inhibitory activity [D. Ingber and J. Volkman (D.
an), Laboratory Investigation
tory Investigation), 59 , 44 (1988)].

On the other hand, US Pat. No. 4,599,331 describes that steroids (ethianic acid derivatives) alone can be used to inhibit angiogenesis. However, these steroids have a strong corticosteroid action at the same time, which poses a major obstacle for their use as medicines. There have been many reports on imidazo [1,2-a] pyridine derivatives, but few reports on the pharmacological action of compounds having an alkylthio group having a functional group bonded to the 5-position. In particular, those having a carbamate as the functional group are disclosed in European Patent Application P
87108189.9 describes 5- [2- (tert-butoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine and 5- [2- (N-chloroacetylcarbamoyloxy) ethylthio] imidazo [1,2- a] Pyridine is only reported as a raw material for synthesizing cephem agents having an excellent antibacterial action, and no description is given of its pharmacological action. The present inventors have synthesized various imidazo [1,2-a] pyridine derivatives having a substituent at the 5-position and studied their pharmacological actions. As a result, they found an excellent angiogenesis inhibitory action among them. Completed the invention.

[0004]

The present invention provides: formula

Embedded image [Where A is the formula (1)

Embedded image (In the formula, k, m and n each represent an integer of 0 to ⁵ , and R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each represent (i) hydrogen, (ii) a lower alkyl group ( This lower alkyl group is halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
(Iv) may have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) phenyl-lower alkyl group (the phenyl moiety is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen, lower alkyl, lower alkenyl, which may have 1 to 4 substituents selected from hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); , Lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl which may have 1 to 4 substituents), (vi) an aryl group having 6 to 14 carbon atoms ( This aryl group is halogen, lower alkyl, lower alkenyl, lower Coxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, may have 1 to 4 substituents selected from lower alkylcarbamoyl) or (vii) selected from sulfur, oxygen and nitrogen A heterocyclic group bonded via a carbon atom with an aromatic monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms (this heterocyclic group may be halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro , Cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl which may have 1 to 4 substituents) or a group represented by the formula (2)

Embedded image (Wherein o and p each represent an integer of 0 to 5), R ¹ and R ² are the same or different, and (i) hydrogen, (ii) a lower alkyl group (the lower alkyl group Is halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
(Iv) may have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) phenyl-lower alkyl group (the phenyl moiety is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen, lower alkyl, lower alkenyl, which may have 1 to 4 substituents selected from hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); , Lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl which may have 1 to 4 substituents), (vi) an aryl group having 6 to 14 carbon atoms ( This aryl group is halogen, lower alkyl, lower alkenyl, lower (Vii) may have 1 to 4 substituents selected from oxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl), (vii) halogen, (viii) nitro group , (Ix) nitroso group, (x)
An amino group which may be protected, (xi) a lower alkoxycarbonyl group or (xii) a lower alkylcarbamoyl group, R ³ is (i) hydrogen, (ii) a lower alkyl group (this lower alkyl group is halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
May have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) a cycloalkyl group having 3 to 8 carbon atoms (this cycloalkyl group is halogen, nitro, amino, lower alkylamino, It has 1 to 5 substituents selected from 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl. (V) a phenyl-lower alkyl group wherein the phenyl moiety is selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl Or may have 4 to 4 substituents) (vi) naphthyl-lower alkyl group (where the naphthyl moiety is one to four substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl) (Vii) an aryl group having 6 to 14 carbon atoms, wherein the aryl group is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino,
Which may have 1 to 4 substituents selected from lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl), or R ³ and R ⁵ or R ⁶ , or R ³ and R ⁷ or R ⁸ , or R ³ and R ⁹ or R
¹⁰ joins expression

Embedded image (Wherein Q and R each represent 2 or 3), and R ⁴ represents (i) a lower alkyl group (the lower alkyl group is a halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (ii) a lower alkenyl group (this lower alkenyl group may be halogen, nitro, amino, lower alkylamino, 4-7
May have 1 to 5 substituents selected from membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl. (Iii) a cycloalkyl group having 3 to 8 carbon atoms (the cycloalkyl group is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy) Carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl which may have 1 to 5 substituents), (iv) phenyl-lower alkyl group (this phenyl moiety is Halogen, lower alkyl, lower alkenyl, lower alcohol (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen) (Vi) having 6 to 4 substituents selected from lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); To 14 aryl groups (where the aryl group is 1 to 4 substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl) May be included) Show. 1. An angiogenesis inhibitor comprising a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof: R ³ is (i) hydrogen, (ii) a lower alkyl group (the lower alkyl group is a halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
May have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) a cycloalkyl group having 3 to 8 carbon atoms (this cycloalkyl group is halogen, nitro, amino, lower alkylamino, It has 1 to 5 substituents selected from 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl. (V) a phenyl-lower alkyl group wherein the phenyl moiety is selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl Or may have 4 to 4 substituents) (vi) naphthyl-lower alkyl group (where the naphthyl moiety is one to four substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl) (Vii) an aryl group having 6 to 14 carbon atoms, wherein the aryl group is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino,
2. the angiogenesis inhibitor according to claim 1, which has 1 to 4 substituents selected from lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl. An amino group which may be protected is an amino group, a lower alkylcarbonylamino group, a C _7-10 aralkyl-carbonylamino group, a C _6-10 aryl-carbonylamino group,
3. The angiogenesis inhibitor according to 1, which is a lower alkyloxycarbonylamino group, a C _7-10 aralkyloxycarbonylamino group or a C _6-10 aryloxycarbonylamino group; 2. An angiogenesis inhibitor according to item 1, which is an antitumor agent, an antiinflammatory agent, an antirheumatic agent for rheumatoid arthritis or an antidiabetic retinopathy agent.

In the formula (I), the group represented by A is, for example,

Embedded image [Wherein, k, m and n each represent an integer of 0 to 5,
R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each represent hydrogen, a lower alkyl group which may have a substituent, a lower alkenyl group, an aralkyl group, an aryl group or a heterocyclic group]
A group represented by

Embedded image [Wherein, o and p each represent an integer of 0 to 5]. R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹
And lower alkyl groups represented by R ¹⁰ include, for example, linear or branched C ¹ -C 1 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. ~
About 6 alkyl groups are exemplified. R ⁵ , R ⁶ , R ⁷ ,
Examples of the lower alkenyl group represented by R ⁸ , R ⁹ and R ¹⁰ include lower alkenyl groups having about 2 to 6 carbon atoms, such as vinyl, allyl, 2-butenyl and 3-butenyl. Examples of the 1 to 5 substituents which the lower alkyl group and lower alkenyl group may have include, for example, halogen, nitro, amino, lower alkylamino group, cyclic amino group, lower alkoxy, aryloxy,
Carbamoyl, cyano, hydroxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl and the like. As the halogen, fluoro, bromo,
Chloro and iodine are mentioned.

The lower alkylamino group as the substituent includes, for example, an N-monoalkylamino group in which the alkyl portion has about 1 to 6 carbon atoms, such as methylamino, ethylamino, propylamino, and butylamino;
For example, N, N-dialkylamino groups in which each alkyl portion has about 1 to 6 carbon atoms, such as dimethylamino, diethylamino, dibutylamino, and methylethylamino. As the cyclic amino group as the substituent,
Examples include 4- to 7-membered cyclic amino groups such as pyrrolidino, piperidino, piperazino, morpholino, and homopiperazino. Examples of the lower alkoxy group as the substituent include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, and pentoxy. Examples of the aryloxy group as the substituent include a phenoxy group, a 1-naphthoxy group,
And a naphthoxy group. Examples of the lower alkoxycarbonyl group as the substituent include an alkoxycarbonyl group having about 1 to 6 carbon atoms in the alkoxy moiety such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl.
The lower alkylcarbamoyl group as the substituent includes, for example, an N-monoalkylcarbamoyl group in which the alkyl portion has about 1 to 6 carbon atoms, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, and butylcarbamoyl; Carbamoyl, diethylcarbamoyl, dibutylcarbamoyl,
N, N-dialkylcarbamoyl groups in which each alkyl moiety has 1 to 6 carbon atoms, such as methylethylcarbamoyl.

The aralkyl group represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ includes, for example, the number of carbon atoms in the alkyl moiety such as benzyl, phenethyl, 3-phenylpropyl and 4-phenylbutyl. Has about 1 to 6 carbon atoms in an alkyl portion such as a phenyl lower alkyl group, (1-naphthyl) methyl, 2- (1-naphthyl) ethyl, and 2- (2-naphthyl) ethyl. And naphthyl lower alkyl. The phenyl part of the phenyl lower alkyl group and the naphthyl part of the naphthyl lower alkyl group include, for example, halogen, lower alkyl group, lower alkenyl group, lower alkoxy group, nitro group, cyano group, hydroxy group,
It may have 1 to 4 substituents such as a lower alkoxycarbonyl group, a carbamoyl group and a lower alkylcarbamoyl group. Examples of the halogen for the substituent include fluoro, bromo, chloro, and iodo. Lower alkyl group,
As the lower alkenyl group, R ⁵ , R ⁶ , R ⁷ ,
Examples thereof include the same groups as the lower alkyl groups and lower alkenyl groups represented by R ⁸ , R ⁹ and R ¹⁰ . Examples of the lower alkoxy group include linear or branched alkoxy groups having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and pentoxy. Examples of the lower alkoxycarbonyl group include alkoxycarbonyl groups having about 1 to 6 carbon atoms in the alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and butoxycarbonyl. Examples of the lower alkylcarbamoyl include N-monoalkylcarbamoyl groups in which the alkyl portion has about 1 to 6 carbon atoms, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, and butylcarbamoyl; and dimethylcarbamoyl, diethylcarbamoyl, dibutyric N, N-dialkylcarbamoyl groups in which each alkyl moiety has about 1 to 6 carbon atoms, such as rucarbamoyl and methylethylcarbamoyl.

The aryl group represented by R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ includes, for example, phenyl, 1-
Naphthyl, 2-naphthyl, phenanthryl, anthryl
An aromatic monocyclic, bicyclic or tricyclic hydrocarbon group which is an aryl group having 6 to 14 carbon atoms such as (anthryl) is used. As the heterocyclic group, for example, thienyl, furyl, benzothienyl, benzofuranyl And an aromatic monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms such as sulfur, oxygen, nitrogen, etc., which are bonded via a carbon atom. The aryl group and heterocyclic group include, for example, halogen, lower alkyl group, lower alkenyl group, lower alkoxy group, nitro group, cyano group, oxo group, hydroxy group, amino group, lower alkoxycarbonyl group, carbamoyl group, lower alkylcarbamoyl It may have 1 to 4, preferably 1 or 2, substituents such as groups. Examples of the halogen in the substituent include fluoro, bromo, chloro, iodo and the like. Examples of the lower alkyl group include the above-mentioned alkyl groups having about 1 to 6 carbon atoms, and examples of the lower alkenyl group include the above-described alkyl group having 2 carbon atoms.
And about 6 lower alkenyl groups. The lower alkoxy group includes an alkoxy group having about 1 to 6 carbon atoms, the lower alkoxycarbonyl group includes an alkoxycarbonyl group having about 1 to 6 carbon atoms in the alkoxy moiety, and the lower alkylcarbamoyl group includes an alkyl group. And N, N-dialkylcarbamoyl groups having 1 to 6 carbon atoms in each alkyl moiety. Specific examples of these groups include the same groups as the lower alkoxy group, lower alkoxycarbonyl group and lower alkylcarbamoyl group as the substituent of the phenyl moiety in the aralkyl group. Examples of the aryl group having an oxo group include benzoquinonyl, naphthoquinonyl, anthraquinonyl and the like. R
⁵ and ring R ^6, R ⁷ and R ⁸ or R ⁹ and R ¹⁰ are formed by bonding is, for example, cyclopropane, cyclobutane, cyclopentane, etc. C _3-8 cycloalkane such as cyclohexane, R ⁵ or R ⁷ is R ⁹ or R ¹⁰ respectively
The ring formed by combining with, for example, C _3-8 cycloalkane such as cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and the like.

The optionally substituted hydrocarbon group in R ¹ and R ² includes, for example, an optionally substituted lower alkyl group, lower alkenyl group, Aralkyl groups and aryl groups. Examples of the halogen include fluoro, chloro, bromo, and iodo. Examples of the amino group which may be protected include, for example, an amino group and an acylamino group. The acyl group of the acylamino group, a group represented by -COR ⁴ or -CO ₂ R ^4, for example, C of lower alkylcarbonyl groups (e.g. acetyl, etc.
_1-6 alkyl-carbonyl group), aralkylcarbonyl group (for example, C _7-10 aralkyl- such as benzylcarbonyl)
Carbonyl group), arylcarbonyl group (for example, C _6-10 aryl-carbonyl group such as benzoyl), lower alkyloxycarbonyl group (for example, C _1-4 alkyloxycarbonyl group such as methoxycarbonyl), aralkyloxycarbonyl group (for example, benzyl group) C _7-10 aralkyloxycarbonyl groups such as oxycarbonyl), aryloxycarbonyl groups (for example,
_6-10 aryloxycarbonyl group).
As the lower alkoxycarbonyl group and the lower alkylcarbamoyl group for R ¹ and R ² , R ⁵ ,
The same groups as the lower alkoxycarbonyl group and the lower alkylcarbamoyl group as substituents of the phenyl moiety in the aralkyl groups represented by R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are used. Examples of the optionally substituted hydrocarbon group for R ³ and R ⁴ include an optionally substituted lower alkyl group, lower alkenyl group, cycloalkyl group, aralkyl group, and aryl group. Examples of the lower alkyl group, lower alkenyl group, aralkyl group and aryl group which may have a substituent include the same groups as those exemplified for the group represented by A. Examples of the cycloalkyl group include cycloalkyl groups having about 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As the substituent of the cycloalkyl group, the same substituents as the lower alkyl group which may have a substituent as described in the above A are used, and the number thereof is 1 to 5. In A, R ³ and R ⁵ or R
⁶ or R ³ and R ⁷ or R ⁸ , or R ³ and R ⁹ or R ¹⁰ bonded to form a ring,

Embedded image [Wherein Q and R each represent 2 or 3].

The salt of the compound of the formula (I) includes an acid addition salt. Examples of the acid used to form the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Acids include organic acids such as acetic acid, oxalic acid, methanesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, lactic acid and the like. The compound (I) or a salt thereof may be a solvate. Examples of the solvent as such a solvate include alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, and tetrahydrofuran. And ethers such as dioxane. Preferred embodiments of the compound of the formula (I) or a salt thereof include, for example,

Embedded image [Wherein R ¹ ′ represents hydrogen or a lower alkyl group, and R ² ′ represents hydrogen or a lower alkyl group which may have a substituent.
⁴ ′ represents a lower alkyl group, a cycloalkyl group or a lower alkenyl group which may have a substituent], or a salt thereof. In the formula (I ′), a lower alkyl group represented by R ¹ ′, a lower alkyl group which may have a substituent represented by R ² ′, and a lower alkyl group represented by R ⁴ ′ Preferred lower alkyl groups and lower alkenyl groups are those described above for R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ ,
And those described for the group represented by R ¹⁰ , and the cycloalkyl group optionally having a substituent represented by R ⁴ ′ include those described for R ⁴ . R ⁴ ′ is preferably a C _1-6 alkyl group or a C _1-6 alkenyl group.
Compound (I) may have an asymmetric carbon in the molecule,
When two kinds of stereoisomers of R-coordination and S-coordination exist, each of them or a mixture thereof is included in the present invention.

The imidazo [1,2-a] pyridine derivative (I) of the present invention or a salt thereof can be synthesized, for example, by the following method. (A) Formula

Embedded image [Wherein, X represents a halogen such as chloro, bromo, iodo, and R ¹ and R ² have the same meanings as described above]

Embedded image Wherein A, R ³ and R ⁴ are as defined above, or a salt thereof. (B) Formula

Embedded image Wherein R ¹ and R ² are as defined above, and a compound represented by the formula

Embedded image Wherein A, R ³ and R ⁴ are as defined above, X ¹ is a halogen such as chloro, bromo or iodo, an arylsulfonyloxy group such as a toluenesulfonyloxy group, or an alkylsulfonyloxy group such as a methanesulfonyloxy group. And a salt thereof.

Equation (C)

Embedded image [Wherein A, R ¹ , R ² and R ³ are as defined above] or a salt thereof, and formula XCO ₂ R ⁴ (VII) [wherein R ⁴ and X are as defined above] With the compound represented by Equation (D)

Embedded image Wherein A, R ¹ , R ² and R ⁴ are as defined above, or a salt thereof, and a compound of the formula X ¹ R ³ ′ (IX) wherein X ¹ is as defined above. R ³ ′ represents a hydrocarbon group which may have a substituent].

Equation (E)

Embedded image Wherein A, R ¹ and R ² are as defined above, and a compound represented by the formula R ⁴ OH (XI), wherein R ⁴ is as defined above. Formula (F)

Embedded image [In the formula, X ² represents a halogen such as chloro, a leaving group such as a phenoxy group or an imidazolyl group, and A, R ¹ , R ² and R ³ have the same meanings as defined above] R ⁴ OH (XI) wherein R ⁴ is as defined above.

Equation (G)

Embedded image Wherein A, R ¹ , R ³ and R ⁴ are as defined above, or a salt thereof with a halogenating agent,

Embedded image [Wherein, A, R ¹ , R ³ and R ⁴ are as defined above, and X represents halogen. Or a salt thereof. (H) A compound of the formula (Ia) or a salt thereof is nitrated,

Embedded image [Wherein A, R ¹ , R ³ and R ⁴ are as defined above] or a salt thereof.

(I) The compound represented by the formula (Ia) or a salt thereof is nitrosated, and

Embedded image [Wherein A, R ¹ , R ³ and R ⁴ are as defined above] or a salt thereof. (J) reducing the compound represented by the formula (Ic) or (Id) or a salt thereof,

Embedded image [Wherein A, R ¹ , R ³ and R ⁴ are as defined above] or a salt thereof. Or further compounds
(Ie) or a salt thereof, compound (VII) or compound XCO
R ⁴ [wherein X and R ⁴ are the same as defined above]

Embedded image [Wherein R ¹¹ represents —CO ₂ R ⁴ or —COR ⁴ , and A, R ¹ , R ³ and R ⁴ are as defined above] or a salt thereof. (K) formula

Embedded image [Wherein R ^2a represents a lower dialkylamino group or a cyclic amino group, and A, R ¹ , R ³ and R ⁴ are as defined above] to give compound (Ig) or a salt thereof.

Compound (II) or a salt thereof in Method A is combined with (I
The reaction of II) is carried out by reacting the compound (II) or a salt thereof with the compound
(III) is used in an amount of 1 equivalent or an excess in a range not interfering with the reaction, in a solvent at −10 to + 200 ° C. in the presence of a basic compound such as sodium hydroxide, potassium hydroxide, sodium hydride or potassium carbonate. It can be carried out. On this occasion,
Examples of the solvent used include water or lower alcohols such as methanol, ethanol, and propanol; ketones such as acetone and methyl ethyl ketone; ethers such as tetrahydrofuran; and non-protons such as N, N-dimethylformamide and dimethyl sulfoxide. Polar solvent and the like. The reaction time is generally 1 hour to 2 days, preferably 1 hour to 8 hours. The reaction of compound (IV) or a salt thereof with (V) in Method B is carried out under the same conditions as the reaction conditions of compound (II) or a salt thereof with (III) in Method A. The reaction of the compound (VI) or a salt thereof with the compound (VII) in the method C is carried out by using 1 equivalent to a large excess of the compound (VII) with respect to the compound (VI) or a salt thereof, and using an inorganic compound such as potassium carbonate or sodium hydrogen carbonate. Base or triethylamine, pyridine, dimethylaniline, 1,4-
The reaction can be carried out at -30 to + 200 ° C in a solvent in the presence of an organic base such as diazabicyclo [2,2,2] octane (DABCO). In this case, examples of the solvent used include halogenated hydrocarbons such as methylene chloride, chloroform, and dichloroethane; ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane; esters such as methyl acetate and ethyl acetate; Aprotic polar solvents such as N-dimethylformamide and dimethylsulfoxide; The reaction time is usually from 10 minutes to
24 hours, preferably 30 minutes to 6 hours.

Compound (VIII) or a salt thereof in Method D
The reaction of (IX) is carried out by using 1 equivalent to a large excess of the compound (IX) relative to the compound (VIII) or a salt thereof, and adding potassium hydride,
The reaction can be carried out at -30 to + 200 ° C in a solvent in the presence of a base such as sodium hydride and sodium amide.
In this case, examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, and aprotic polar solvents such as N, N-dimethylformamide and dimethyl sulfoxide. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 6 hours. Compounds (X) and (X
In the reaction of I), the compound (XI) is used in an amount of 1 equivalent to a large excess with respect to the compound (X).
It can be performed at 0 to + 150 ° C. In this case, examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and non-solvents such as N, N-dimethylformamide and dimethyl sulfoxide. Protic polar solvents and the like can be mentioned. To promote the reaction, tertiary amines such as triethylamine, pyridine, dimethylaminopyridine, N-methylpiperidine, and boron trifluoride ether (BF _3.
Et ₂ O) may be added. The reaction time is usually from 30 minutes to
24 hours, preferably 30 minutes to 6 hours. In the reaction of the compound (XII) or a salt thereof with the compound (XI) in the method F, the compound (XI) is used in an amount of 1 equivalent to a large excess with respect to the compound (XII) or a salt thereof, in the absence or presence of a solvent. 30
To + 200 ° C. In this case, examples of the solvent used include ethers such as diethyl ether, tetrahydrofuran and dimethoxyethane, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and non-solvents such as N, N-dimethylformamide and dimethyl sulfoxide. Protic polar solvents and the like can be mentioned. Tertiary amines such as triethylamine, pyridine, dimethylaminopyridine and N-methylpiperidine may be added to promote the reaction. The reaction time is usually 30
Minutes to 24 hours, preferably 30 minutes to 6 hours.

In the method G, the reaction of the compound (Ia) or a salt thereof with a halogenating agent is carried out by using 1 equivalent to a large excess of the halogenating agent with respect to the compound (Ia) or a salt thereof, in the absence of a solvent or in the presence of a solvent. Below, it can be performed at -20 to + 150 ° C. At this time, as the solvent used, for example,
Examples include halogenated hydrocarbons such as methylene chloride, chloroform, dichloroethane, and carbon tetrachloride, acetic acid, and propionic acid. Examples of the halogenating agent include halogen molecules such as chlorine and bromine or halogenating agents such as N-halogen succinimides such as N-chlorosuccinimide, N-bromosuccinimide and N-iodosuccinimide. No. At the time of the reaction, a radical reaction initiator such as benzoyl peroxide may be added. The reaction time is generally 30 minutes to 12 hours, preferably 1 hour to 12 hours.
Time. In the nitration reaction of compound (Ia) or a salt thereof in method H, the nitrating agent is used in an amount of 1 equivalent to a large excess with respect to compound (Ia) or a salt thereof, and in the absence of a solvent or in the presence of a solvent, -20 to +100. C. can be performed. At this time, examples of the solvent used include acetic acid, acetic anhydride, sulfuric acid and the like. Examples of the nitrating agent include fuming nitric acid, concentrated nitric acid, and mixed acids (sulfuric acid, fuming nitric acid, phosphoric acid, or acetic anhydride and nitric acid). The reaction time is generally 30 minutes to 1 day, preferably 30 minutes to 6 hours. In the nitrosation reaction of compound (Ia) or a salt thereof in method I, the nitrosating agent is used in an amount of 1 equivalent to a large excess with respect to compound (Ia) or a salt thereof, in the absence of a solvent or in the presence of a solvent, at -20 to +100. C. can be performed.
In this case, examples of the solvent used include water, lower fatty acids such as acetic acid and propionic acid, ethers such as tetrahydrofuran and dioxane, and aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide. Is mentioned. Examples of the nitrosating agent include potassium nitrite, sodium nitrite and the like. The reaction is performed in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, and acetic acid. The reaction time is generally 30 minutes to 1 day, preferably 30 minutes to 6 hours.

In the reduction reaction of compound (Ic) or (Id) or a salt thereof in method J, a reducing agent is used in an amount of 1 equivalent to a large excess with respect to compound (Ic) or (Id) or a salt thereof, and the reaction is carried out in the presence of a solvent. It can be performed at -20 to + 200 ° C. In this case, examples of the solvent used include water, methanol, ethanol, propanol, isopropanol, acetic acid and the like. Examples of the reducing agent include a mixture of iron and hydrochloric acid and zinc and acetic acid. In addition, the reaction is carried out using a hydrogenation catalyst such as palladium black, palladium carbon, Raney nickel or the like, in the presence of a solvent, under normal pressure of hydrogen,-
It can be performed at 20 to + 200 ° C. The reaction time is generally 30 minutes to 2 days, preferably 1 hour to 12 hours. Also, the reaction of (Ie) or a salt thereof with (VII), or
The reaction between (Ie) or a salt thereof and XCOR ⁴ is carried out under the same conditions as the reaction conditions of compound (VI) or a salt thereof and (VII) in Method C. In the Method K, the Mannich reaction of the compound (Ia) or a salt thereof with a lower dialkylamine and formalin, or a cyclic amine and formalin is carried out by using a Mannich reagent in an amount of 1 equivalent to a large excess with respect to the compound (Ia) or a salt thereof in the presence of a solvent. , -20 to + 100 ° C. At this time, as the solvent used, for example,
Water, lower alcohols such as methanol, ethanol, propanol and isopropanol, and lower fatty acids such as acetic acid and propionic acid. The reaction time is generally 30 minutes to 1 day, preferably 1 hour to 12 hours. In the above methods A to K, the compound forming a salt may be used in the form of a salt, and examples of such a salt include those described for the salt of compound (I).

In the raw materials used in the methods A to K, the compound (II) can be obtained, for example, by the following method.

Embedded image The reaction of compound (XIII) with compound (XIV) can be carried out at 0 to + 200 ° C. in the absence or presence of a solvent, using 1 equivalent to a large excess of compound (XIV) relative to compound (XIII).
In this case, as a solvent used, for example, water or lower alcohols such as methanol, ethanol, propanol, tetrahydrofuran, dimethoxyethane,
Examples thereof include ethers such as dioxane, nitriles such as acetonitrile and propionitrile, and aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide. In addition, at the time of the reaction, an inorganic base such as potassium carbonate or sodium hydrogen carbonate, or an organic base such as triethylamine, pyridine or dimethylaniline may be added as a deoxidizing agent. The reaction time is generally from 10 minutes to 7 minutes.
Days, preferably 1 hour to 2 days. Compound (IV) can be obtained, for example, by the method shown below.

Embedded image [Wherein, Y represents sodium or potassium, and R ¹ and R ² are as defined above]

Embedded image [Wherein T represents a protecting group such as p-methoxybenzyl and benzyl, and R ¹ and R ² are as defined above]

The reaction of compound (II) with YSH is carried out under the same conditions as in the reaction of compound (II) with compound (III) in Method A. The reaction between compound (XV) and (XIV) is performed by the above-mentioned compound (XI
The reaction is carried out under the same conditions as in the reaction between (II) and (XIV). Compound
The reaction between (XVI) and (XIV) is carried out under the same conditions as in the reaction between the compounds (XIII) and (XIV). Compound (VI) can be obtained, for example, by the method shown below.

Embedded image [Wherein, A, R ¹ , R ² and R ³ are as defined above]

Embedded image [Wherein T ¹ represents a protecting group for an amino group such as benzyloxycarbonyl, tert-butoxycarbonyl, trifluoroacetyl, trityl, benzyl and the like, and A, R ¹ , R ² and R ³ are as defined above]

[0022]

Embedded image [Wherein, A, T ¹ and R ³ have the same meanings as described above, further including the case where —NT ¹ R ³ is phthalimide]

Embedded image [Wherein, A, R ¹ , R ² , R ³ and X ¹ are as defined above]

Embedded image [Wherein X ¹ and R ³ are as defined above]

Embedded image [Wherein, A, R ³ and T ¹ are the same as described above, but further includes the case where —NT ¹ R ³ is phthalimide]

Reaction of compound (II) with (XVIII), compound (I
The reaction between (I) and (XIX), the reaction between compound (IV) and (XXI), the reaction between compound (II) and (XXII), and the reaction between compound (IV) and (XXV) are described in the above A. The reaction is carried out under the same conditions as in the reaction of compounds (II) and (III) in the method. When the hydroxyl group of compound (XXIII) is converted to X ¹ , when X ¹ is halogen, compound (XXI)
The reaction is carried out by reacting II) with a phosphorus halide such as phosphorus trichloride, phosphorus oxychloride, phosphorus pentachloride or phosphorus tribromide, or with red phosphorus and a halogenating agent such as halogen or thionyl chloride. When X ¹ is a toluenesulfonyloxy group or a methanesulfonyloxy group, the compound (XXI
It is obtained by reacting II) with toluenesulfonyl chloride or methanesulfonyl chloride. The subsequent reaction with compound (XXIV) is carried out without a solvent or in a suitable solvent at 0 to 200 ° C. These reactions are all known reactions per se, and can be performed under known conditions.

The reaction between the compounds (XXVI) and (XIV) is carried out under the same conditions as in the reaction between the compounds (XIII) and (XIV). Compound (X) can be obtained, for example, by the following method. (i) After reacting compound (XXVII) with phosgene, the mixture is heated and dehydrochlorinated. (ii) Compound (XXVIII) is reacted with silver cyanate. These reactions are also known reactions per se, and can be carried out under known conditions.

Embedded image Wherein A, R ¹ and R ² are as defined above.

Embedded image [Wherein A, R ¹ and R ² are as defined above] Compound (XII) can be obtained, for example, by the following method. (i) When X ² is Cl, (VI) is reacted with phosgene. (ii) When X ² is phenoxy, (VI) is reacted with phenyl chlorocarbonate. (iii) When X ² is imidazolyl, (VI) is reacted with carbonyldiimidazole. These reactions are all known reactions per se, and can be performed under known conditions.

The reaction for removing the protecting group is a known reaction itself, and can be carried out under known conditions.
For example, a p-methoxybenzyl group as a protecting group for a mercapto group can be removed by treating with mercuric acetate in trifluoroacetic acid, followed by treatment with hydrogen sulfide or 2-mercaptoethanol. The benzyl group can be removed with aqueous ammonia or metallic sodium. For example, a benzyloxycarbonyl group as a protecting group for an amino group,
Benzyl group is a catalyst (palladium carbon, platinum oxide, etc.)
In a solvent (eg, alcohol, acetic acid, water, tetrahydrofuran, a mixed solvent thereof and the like) in the presence of, it can be removed by a catalytic reduction reaction (reaction temperature, 0 to 100 ° C). In the case of a trityl group or a tert-butoxycarbonyl group, a solvent (e.g.,
Water, alcohol, tetrahydrofuran, dioxane, etc.), acid (eg, mineral acid such as hydrochloric acid, phosphoric acid, sulfuric acid, and organic acid such as toluenesulfonic acid, methanesulfonic acid, acetic acid)
Can be removed at 0 to 150 ° C in the presence of The trifluoroacetyl group can be easily removed by treating with an alkali (eg, sodium hydroxide, aqueous sodium hydrogen carbonate solution). The phthalimide group can be removed by reacting with hydrazine hydrate in a solvent (eg, methanol, ethanol). Compound (II) obtained by the above method, (I
V), (VI), (X), and (XII) can be isolated by the following separation and purification means known per se. It may be provided as. In the above compounds, (III), (V), (VI
(I), (XIII), (XIV), (XVIII), (XIX), (XXI), (XXII),
(XXIV) and (XXV) are described, for example, in "New Experimental Chemistry Course Vol. 14,
"Synthesis and Reaction of Organic Compounds IV" (edited by The Chemical Society of Japan, Maruzen, Tokyo); "New Experimental Chemistry Vol.15, Oxidation and Reduction I-
II ”(edited by The Chemical Society of Japan, Maruzen, Tokyo);
Organic Synthesis ”(John Wiley and Sons Incorporated)
and Sons, Inc.), New York);
"Theilheimer's Synthetic Methods of Organic Chemistry (Theilheimer's Synthe
tic Methods of Organic Chemistry) "(Basel
el), New York, Karger) or a method analogous thereto. Separation and purification of compound (I) or a salt thereof from the reaction mixture can be performed by a conventional separation and purification means (eg, extraction, concentration,
Filtration, recrystallization, column chromatography, thin-layer chromatography).

Since the compound (I) of the present invention or a salt thereof has an angiogenesis inhibitory action, angiogenesis inhibitors, specifically antitumor agents, antiinflammatory agents, antirheumatic rheumatoid agents, antidiabetic retinopathy agents, etc. Useful as Since compound (I) or a salt thereof has low toxicity, it may be used as a powder as it is or as a pharmaceutical composition in an appropriate dosage form for mammals (eg, human, rabbit, dog, cat, rat, mouse, guinea pig). Can be administered orally or parenterally. The dose varies depending on the administration subject, target disease, symptoms, administration route, etc., and when the compound (I) or a salt thereof is used as, for example, an antitumor agent, the angiogenesis inhibitor is compound (I)
Alternatively, it may be obtained by mixing a salt thereof with a pharmacologically acceptable carrier. Compound (I) or a salt thereof can also be used in the form of drops, injections, capsules, tablets, suppositories, solutions, emulsions, suspensions and other pharmaceutically suitable forms. When producing parenteral therapeutic agents, for example, injections, isotonic agents (eg, glucose, D-sorbitol, D-mannitol, sodium chloride, etc.), preservatives (eg, benzyl alcohol, chlorobutanol, para Methyl hydroxybenzoate, propyl parahydroxybenzoate, etc.), anticoagulants (eg, dextran sulfate, heparin, etc.) and buffers (eg, phosphate buffer, sodium acetate buffer, etc.) may be used. Oral preparations are compounds
(I) or a salt thereof is mixed with lactose or the like and used as a capsule or a sugar-coated tablet produced by a known method. The method of administration is, for example, parenterally using Compound (I) or a salt thereof as an injection, at a dose of about 0.05 to 50 mg / kg / day, preferably about 0 to 50 mg / kg / day to the affected part, subcutaneously, intravenously or intramuscularly of the mammal. 0.2-20 mg / kg / day, more preferably 0.5
Administer 10 mg / kg / day. As an oral preparation, about 0.1 per day.
1-500 mg / kg / day, preferably about 1-100 mg / kg
kg / day, more preferably 5 to 50 mg / kg / day. Compound (I) or a salt thereof can also be used as an external preparation. For example, as a solution prepared by dissolving Compound (I) or a salt thereof in an isotonic solution at a concentration of about 0.01 to 2 w / v%, or as an ointment containing about 0.1 to 50 mg per gram, By washing or applying to the affected area such as the head, chest, abdomen, and limbs, it can be used for the prevention and treatment of tumors in these areas.

[0027]

Next, the present invention will be described in more detail with reference to Reference Examples, Production Examples, Examples and Test Examples. In addition, the room temperature in an example shows 15-25 degreeC. Reference Example 1 Synthesis of 5- [2- (methylsulfonyloxy) ethylthio] imidazo [1,2-a] pyridine 5- [2- (hydroxy) ethylthio] imidazo [1,2-a]
9.71 g (50 mmol) of pyridine and triethylamine 1
0.5 ml (75.3 mmol) of methylene chloride 3
To the 00 ml solution was added 4.26 ml (55 mmol) of methanesulfonyl chloride under ice-cooling and stirring, followed by stirring for 2 hours under ice-cooling. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off to obtain 13.6 g of the desired product (quantitative, brown oil). NMR (200 MHz, CDCl ₃ ) δ: 2.97 (3H, s),
3.28 (2H, t, J = 6.4 Hz), 4.35 (2H, t, J =
6.4 Hz), 7.08 (1 H, dd, J = 7, 1.2 Hz), 7.1
8 (1H, dd, J = 8.8, 7Hz), 7.64 (1H, m), 7.
73 (1H, d, J = 1.4Hz), 7.91 (1H, m)

Reference Example 2 (1) 5- [2- (methylamino) ethylthio] imidazo [1,
Synthesis of 2-a] pyridine 5.18 g (8 mmol) of 5- [2- (methylsulfonyloxy) ethylthio] imidazo [1,2-a] pyridine, 2.24 ml (16 mmol) of triethylamine and 4
20 ml of a 0% methylamine-methanol solution in 20 ml of chloroform was heated under reflux for 3 hours. The reaction solution was washed with 3N-NaOH and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was subjected to column chromatography (eluent: methanol / chloroform =
1:10) to give 781 mg (47.1%, pale brown oil) of the desired product. NMR (200 MHz, CDCl ₃ ) δ: 2.31 (1H, br),
2.88 (2H, t, J = 6.4 Hz), 3.16 (2H, t, J =
6.4Hz), 6.94 (1H, dd, J = 7,1Hz), 7.15
(1H, dd, J = 9,7Hz), 7.58 (1H, dd, J = 9,
1 Hz), 7.69 (1, d, J = 1.2 Hz), 7.86 (1 H,
s) IR (KBr) cm ^-1 : 3290,3105,2930,285
0,2790,1655,1615,1530,1490 The following compounds were obtained in the same manner as in Reference Example 2 (1).

(2) 5- [2- (ethylamino) ethylthio]
Imidazo [1,2-a] pyridine NMR (200 MHz, CDCl ₃ ) δ: 1.11 (3H, t, J
= 7Hz), 1.88 (1H, br), 2.70 (2H, m), 2.9
0 (2H, t, J = 6.2 Hz), 3.15 (2H, t, J = 6.2 H)
z), 6.94 (1H, dd, J = 7.1Hz), 7.16 (1H, dd,
J = 9, 7 Hz), 7.59 (1 H, dd, J = 9, 1 Hz), 7.
70 (1H, d, J = 1.2Hz), 7.87 (1H, s) IR (KBr) cm ^-1 : 3280,3105,2965,293
0,2890,2820,1655,1620,1530,1
490

Reference Example 3 Synthesis of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine dihydrochloride After washing 13.31 g (50 mmol) of a 200 ml suspension of chloroform with 50 ml of 3N sodium hydroxide, the aqueous layer was extracted with chloroform, and the chloroform layers were combined and dried over anhydrous magnesium sulfate. After evaporating the solvent, 9.63 g of the desired product (99.7%,
A pale yellow oil was obtained. NMR (200 MHz, CDCl ₃ ) δ: 1.67 (2H, br),
2.95 (2H, m), 3.08 (2H, m), 6.95 (1H, d, J
= 7Hz), 7.15 (1H, dd, J = 9.2,7Hz), 7.5
9 (1H, d, J = 9.2 Hz), 7.71 (1H, s), 7.88
(1H, s)

Reference Example 4 Synthesis of 5- [3- (amino) propylthio] imidazo [1,2-a] pyridine Add S- [3- (amino) propyl] isothiourea.
8.85 g (39 mmol) of dihydrobromide were added and stirred at room temperature for 1.5 hours. To the reaction mixture was added 3.05 g (20 mmol) of 5-chloroimidazo [1,2-a] pyridine,
After stirring at room temperature for 1.5 hours, the mixture was stirred at 65 ° C for 20 hours.
Water was added to the reaction solution, extracted with chloroform, washed several times with 1N-sodium hydroxide, and dried over anhydrous magnesium sulfate. After evaporating the solvent, 2.66 g (64.3%, pale yellow oily substance) of the desired product was obtained. NMR (200 MHz, CDCl) δ: 1.29 (2H, br),
1.80 (2H, m), 2.85 (2H, t, J = 6.8Hz), 3.
08 (2H, t, J = 7.2 Hz), 6.91 (1H, dd, J = 7,
1Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.58
(1H, d, J = 9,1Hz), 7.71 (1H, d, J = 1.2H
z), 7.85 (1H, d, J = 1.2Hz)

Production Example 1 (1) 5- [2- (methoxycarbonylamino) ethylthio]
Synthesis of imidazo [1,2-a] pyridine (compound 1) 1.93 g (10 mmol) of 5- [2- (amino) ethylthio] imidazo [1,2-a] pyridine and 1.5 of triethylamine
To a solution of 3 ml (11 mmol) in 30 ml of methylene chloride was added, under ice-cooling and stirring, 0.7 ml of methyl chloroformate.
7 ml (10 mmol) was added and stirred at room temperature for 20 minutes. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethanol / ethyl acetate = 1: 10) to give 1.6 of the desired product.
8 g (66.9%, colorless crystals) were obtained. Melting point: 198.0-20.0 ° C Elemental analysis: Calculated for C ₁₁ H ₁₃ N ₃ O ₂ S: C; 52.57, H; 5.21, N; 16.72. Found: C; 52.68, H; 5.22, N; 16.60 NMR (200 MHz, CDCl ₃ ) δ: 3.12 (2H, m),
3.40 (2H, m), 3.68 (3H, s), 5.10 (1H, b
r), 7.00 (1H, d, J = 7 Hz), 7.16 (1H, dd, J =
9, 7 Hz), 7.61 (1 H, d, J = 9 Hz), 7.72 (1
H, s), 7.87 (1H, s)

The following compounds were obtained in the same manner as in Production Example 1 (1). (2) 5- [2- (ethoxycarbonylamino) ethylthio]
Imidazo [1,2-a] pyridine (Compound 2) mp 68-70 ° C. Elemental analysis as _{C 12 H 15 N 3 O 2} S, Calculated C; 54.32, H; 5.70, N; 15. 84 found C; 54.43, H; 5.75, N; 15.83.

(3) 5- [2- (propyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 3) Melting point 62-64 ° C. Elemental analysis, as C ₁₃ H ₁₇ N ₃ O ₂ S Calculated C; 55.89, H; 6.13, N; 15.04 Found: C; 55.87, H; 6.09, N; 14.96 NMR (200 MHz, CDCl ₃ ) δ: 0. 92 (3H, t, J
= 7.4Hz), 1.62 (2H, m), 3.14 (2H, t, J =
6.6 Hz), 3.42 (1 H, m), 4.01 (1 H, t, J = 6.6)
Hz), 5.07 (1H, br), 7.02 (1H, d, J = 7Hz),
7.17 (1H, dd, J = 9,7Hz), 7.60 (1H, d, J
= 9 Hz), 7.71 (1 H, d, J = 1.2 Hz), 7.86 (1
H, s) IR (KBr) cm ^-1 : 3210,3025,2965,169
5,1620,1545,1490,1275

(4) 5- [2- (butyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 4) Melting point 75-76 ° C. Elemental analysis, as C ₁₄ H ₁₉ N ₃ O ₂ S Calculated C; 57.31, H; 6.53, N; 14.32 Found C; 57.32, H; 6.55, N; 14.23 NMR (200 MHz, CDCl ₃ ) δ: 0. 93 (3H, t, J
= 7Hz), 1.35 (2H, m), 1.58 (2H, m), 3.1
4 (2H, t, J = 6.4 Hz), 3.41 (2H, m), 4.05
(2H, t, J = 6.6Hz), 5.04 (1H, br), 7.16 (1
H, dd, J = 9,7Hz), 7.60 (1H, d, J = 9Hz),
7.71 (1H, d, J = 1.2Hz), 7.85 (1H, s) IR (KBr) cm ^-1 : 3490,3210,2970,169
5,1615,1500,1285

(5) 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine
(Compound 5) Melting point: 80.0-81.0 ° C. Elemental analysis; calculated as C ₁₃ H ₁₇ N ₃ O ₂ S: C; 55.89, H; 6.13, N; 15.04 Found C; 55.85, H; 6.14, N; 14.96 NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J
= 6.2 Hz), 3.14 (2H, t, J = 6.4 Hz), 3.41
(2H, m), 4.94 (1H, br), 7.02 (1H, d, J = 7H
z), 7.17 (1H, dd, J = 9, 7Hz), 7.61 (1H,
d, J = 9, 7 Hz), 7.71 (1 H, d, J = 1.4 Hz), 7.
86 (1H, s) IR (KBr) cm ^-1 : 3220,3025,2970,170
5,1630,1545,1300,1240

(6) 5- [2- (isobutyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 6) Melting point 75-76 ° C. Elemental analysis, as C ₁₄ H ₁₉ N ₃ O ₂ S Calculated C; 57.31, H; 6.53, N; 14.32 Found C; 57.29, H; 6.53, N; 14.41 NMR (200 MHz, CDCl ₃ ) δ: 0. 91 (6H, d, J
= 6.8Hz), 1.89 (1H, m), 3.14 (2H, t, J =
6.4 Hz), 3.42 (2H, m), 3.84 (2H, t, J = 6.6)
Hz), 5.15 (1H, br), 7.01 (1H, d, J = 7Hz),
7.16 (1H, dd, J = 9,7Hz), 7.59 (1H, d, J
= 9 Hz), 7.70 (1 H, d, J = 1.2 Hz), 7.85 (1
H, s)

(7) 5- [2- (allyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 7) Melting point 72.5-73.5 ° C. Elemental analysis, C ₁₃ H ₁₅ N ₃ As O ₂ S, Calculated C; 56.30, H; 5.45, N; 15.15 Found C; 56.34, H; 5.44, N; 15.04 NMR (200 MHz, CDCl ₃ ) δ: 3.15 (2H, t, J
= 6.4 Hz), 3.43 (2H, m), 4.56 (2H, m), 5.
07 (1H, br), 5.18-5.36 (2H, m), 5.90
(1H, m), 7.02 (1H, d, J = 7Hz), 7.17 (1H,
dd, J = 9, 7 Hz), 7.61 (1 H, d, J = 9 Hz), 7.7
2 (1H, d, J = 1.4Hz), 7.86 (1H, m) IR (KBr) cm ^-1 : 3205,3020,1700,162
5,1570,1490,1270

(8) 5- [2- [2,2,2- (trichloro) ethoxycarbonylamino] ethylthio] imidazo [1,2-
a] pyridine (compound 8) melting point 113.0-114.0 ° C. elemental analysis, calculated as C ₁₂ H ₁₂ N ₃ O ₂ SCl ₃ , calculated C; 39.10, H; 3.28, N; 11.4 Found: C; 39.23, H; 3.27, N; 11.25 NMR (200 MHz, CDCl ₃ ) δ: 3.17 (2H, t, J
= 6.4 Hz), 3.48 (2H, m), 4.73 (2H, s), 5.
52 (1H, br), 7.03 (1H, d, J = 7Hz), 7.17
(1H, dd, J = 9,7Hz), 7.62 (1H, d, J = 9H
z), 7.71 (1H, d, J = 1.2 Hz), 7.87 (1 H, m) IR (KBr) cm ^-1 : 3195,2975,1725,161
5,1545,1485,1260,1210

(9) 5- [2- (benzyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 9) Melting point 52.0-53.0 ° C. Elemental analysis, C ₁₇ H ₁₇ N ₃ As O ₂ S, Calculated C; 62.36, H; 5.23, N; 12.83 Found C; 62.34, H; 5.22, N; 12.75 NMR (200 MHz, CDCl ₃ ) δ: 3.14 (2H, t, J
= 6.4 Hz), 3.43 (2H, m), 5.09 (2H, s), 5.
17 (1H, br), 6.99 (1H, d, J = 6.8 Hz), 7.1
3 (1H, dd, J = 9.2,6.8Hz), 7.35 (5H, s),
7.59 (1H, d, J = 9.2 Hz), 7.69 (1H, s), 7.
84 (1H, s)

(10) 5- [2-[(9-fluorenyl) methyloxycarbonylamino] ethylthio] imidazo [1,
2-a] pyridine (compound 10) melting point 105.0-108.0 ° C. elemental analysis, calculated as C ₂₄ H ₂₁ N ₃ O ₂ S.0.4H ₂ O, calculated C; 69.07, H; 05, N; 9.67 found C; 69.14, H; 5.23, N; 9.96 NMR (200 MHz, CDCl ₃ ) δ: 3.13 (2H, t, J
= 6Hz), 3.42 (2H, m), 4.21 (1H, t, J = 6.
6Hz), 4.43 (2H, d, J = 6.6 Hz), 5.17 (1H,
br), 7.01 (1H, d, J = 7.4 Hz), 7.15 (1H, dd,
J = 8.6, 7.4Hz), 7.29-7.46 (4H, m),
7.53-7.65 (3H, m), 7.60-7.87 (4H, m) IR (KBr) cm ^-1 : 3205,3020,1710,162
5,1550,1485,1450,1270

(11) 5- [2- (phenoxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine (compound 11) Melting point 96.0-97.0 ° C. Elemental analysis, C ₁₆ H ₁₅ N ₃ O _{As 2} S, Calculated value C; 61.32, H; 4.82, N; 13.41 Actual value C; 61.35, H; 4.86, N; 13.30 IR (KBr) cm ^-1 : 3200,3005,1725,161
5,1555,1485,1270,1210

(12) 5- [2- (N-methyl-N-isopropyloxycarbonylamino) ethylthio] imidazo
[1,2-a] pyridine (compound 12) NMR (200 MHz, CDCl ₃ ) δ: 1.02-1.35
(6H, m), 2.91 (3H, s), 3.05-3.26 (2H,
m), 3.38-3.60 (2H, m), 4.89 (1H, m), 7.
01 (1H, br), 7.18 (1H, dd, J = 9,7Hz), 7.
60 (1H, d, J = 9Hz), 7.71 (1H, s), 7.84
(1H, s) IR (KBr) cm ^-1 : 3220,3025,2970,170
5,1630,1545

(13) 5- [2- (N-ethyl-N-isopropyloxycarbonylamino) ethylthio] imidazo
[1,2-a] pyridine (compound 13) NMR (200 MHz, CDCl ₃ ) δ: 0.95-1.35
(9H, m), 3.02-3.68 (6H, m), 4.90 (1H,
m), 7.04 (1H, m), 7.19 (1H, dd, J = 9,7H
z), 7.60 (1H, d, J = 9Hz), 7.72 (1H, s),
7.83 (1H, s) IR (KBr) cm ^-1 : 3220,3025,2970,170
5,1630,1545

(14) 5- [3- (methoxycarbonylamino) propylthio] imidazo [1,2-a] pyridine (compound 14) Melting point 69.0-70.0 ° C. Elemental analysis, C ₁₂ H ₁₅ N ₃ O _{As 2} S, Calculated C; 54.32, H; 5.70, N; 15.84 Found C; 54.48, H; 5.74, N; 15.72 NMR (200 MHz, CDCl ₃ ) δ : 1.85 (2H, m),
3.02 (2H, t, J = 7 Hz), 3.32 (2H, m), 3.6
7 (3H, s), 4.85 (1H, br), 6.91 (1H, dd, J =
7, 1.2 Hz), 7.15 (1 H, dd, J = 9, 7 Hz), 7.
58 (1H, d, J = 9Hz), 7.70 (1H, d, J = 1.2H)
z), 7.84 (1H, s)

(15) 5- [3- (isopropyloxycarbonylamino) propylthio] imidazo [1,2-a] pyridine (compound 15) NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J
= 6.2Hz), 1.85 (2H, m), 3.03 (2H, m), 3.
31 (2H, m), 4.82 (1H, br), 4.90 (1H, hepte
t, J = 6.2 Hz), 6.90 (1 H, dd, J = 7, 1 Hz),
7.15 (1H, dd, J = 9,7Hz), 7.57 (1H, m),
7.69 (1 H, d, J = 1.4 Hz), 7.84 (1 H, m) IR (KBr) cm ^-1 : 3210, 3025, 2965, 169
5,1620,1545,1490,1275

(16) 5- [1- (tert-butoxycarbonyl) -4-piperidylthio] imidazo [1,2-a] pyridine
(Compound 16) NMR (200 MHz, CDCl ₃ ) δ: 1.45 (9H, s),
1.50-1.98 (4H, m), 2.90 (2H, m), 3.36
(1H, m), 3.98 (2H, m), 7.03 (1H, dd, J = 7,
1.2Hz), 7.15 (1H, dd, J = 9, 7Hz), 7.6
4 (1H, m), 7.70 (1H, d, J = 1.2Hz), 7.96
(1H, m)

(17) 5- [1- (isopropyloxycarbonyl) -4-piperidylthio] imidazo [1,2-a] pyridine (compound 17) NMR (200 MHz, CDCl ₃ ) δ: 1.23 (6H, d, J
= 6.2Hz), 1.50-1.98 (4H, m), 2.94 (2
H, m), 3.37 (1H, m), 4.03 (2H, m), 4.91 (1
H, heptet, J = 6.2 Hz), 7.03 (1H, dd, J = 7,
1.2Hz), 7.16 (1H, dd, J = 9, 7Hz), 7.65
(1H, d, J = 9Hz), 7.71 (1H, d, J = 1.2Hz),
7.97 (1H, s)

Production Example 2 (1) 3-bromo-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine
Synthesis of (Compound 18) To a solution of 279 mg (1 mmol) of 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine in 5 ml of chloroform was added 187 mg (1.05 mmol) of N-bromosuccinimide. )
Stirred at room temperature for 1 hour. The reaction solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate),
296 mg (82.7%, colorless crystals) of the desired product were obtained. Melting point: 103.0-104.0 ° C. Elemental analysis, calculated as C ₁₃ H ₁₆ N ₃ O ₂ SBr C: 43.58, H; 4.50, N; 11.73 Found C: 43.60, H; 4.53, N; 11.74 NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J
= 6.2 Hz), 3.11 (2H, t, J = 6.6 Hz), 3.42
(2H, m), 4.90 (1H, heptet, J = 6.2Hz), 4.9
6 (1H, br), 7.00 (1H, dd, J = 7,1.2Hz),
7.14 (1H, dd, J = 8.8,7Hz), 7.57 (1H, dd,
J = 8.8, 1.2 Hz), 7.59 (1H, s) The following compounds were obtained in the same manner as in Production Example 2 (1).

(2) 3-chloro-5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-
a] Pyridine (compound 19) Melting point 113.0-114.0 ° C. Elemental analysis, calculated as C ₁₃ H ₁₆ N ₃ O ₂ SCl · 0.2H ₂ O, calculated C: 49.19, H; 5.21, N; 13.24 found C; 49.38, H; 5.26, N; 13.22 NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H, d, J
= 6.4 Hz), 3.12 (2H, t, J = 6.4 Hz), 3.43
(2H, m), 4.90 (1H, heptet, J = 6.4Hz), 4.9
6 (1H, br), 6.99 (1H, dd, J = 7.2,1.2Hz),
7.10 (1H, dd, J = 8.8, 7.2Hz), 7.53 (1
H, dd, J = 8.8,1.2Hz), 7.54 (1H, s)

Production Example 3 Synthesis of 5- [2- (isopropyloxycarbonylamino) ethylthio] -3-morpholinomethylimidazo [1,2-a] pyridine (Compound 20) 210 mg (2.59 mmol) of a 37% aqueous solution of formalin 226 μl (2.59 mmol) of morpholine was added to a solution of acetic acid in 2 ml of acetic acid under ice-cooling, and the mixture was stirred at room temperature for 45 minutes. 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine 651
mg (2.33 mmol) was added and the mixture was stirred at 60 ° C. for 2 hours. After evaporation of the solvent, the residue was diluted with chloroform and
The extract was washed with an aqueous solution of N-NaOH and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to column chromatography (eluent: ethanol / ethyl acetate =
1:10) to give 442 mg (50.1%, light brown solid) of the desired product. NMR (200 MHz, CDCl ₃ ) δ: 0.96 (6H, d, J
= 6.2Hz), 2.56 (4H, m), 3.26 (2H, m), 3.
36 (2H, m), 3.69 (4H, m), 4.10 (2H, s),
4.59 (1 H, heptet, J = 6.2 Hz), 6.85 (1 H, b
r), 7.01 (1H, d, J = 5 Hz), 7.13 (1H, dd, J
= 8.6, 6.6 Hz), 7.51 (1H, s), 7.53 (1H,
d, J = 8.6 Hz)

Production Example 4 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine hydrochloride (compound 2
Synthesis of 1) A solution of 279 mg (1 mmol) of 5- [2- (isopropyloxycarbonylamino) ethylthio] imidazo [1,2-a] pyridine in methanol (10 ml) was treated with hydrogen chloride.
Treated with methanol. After evaporation of the solvent, the residue was crystallized from isopropanol-ethyl acetate-ether. After washing with ether and drying, 290 mg (92.1%, colorless crystals) of the desired product was obtained. Melting point 145-150 ° C elemental analysis, calculated as C ₁₃ H ₁₇ N ₃ O ₂ S.HCl C; 49.44, H; 5.74, N; 13.30 found C; 49.51, H; 5.64, N; 13.14

Production Example 5 Synthesis of 5- [4- (isopropyloxycarbonylamino) butylthio] imidazo [1,2-a] pyridine (Compound 22) 5- [4- (amino) butylthio] imidazo [1,2- a) 0.25 g (2.04 mmol) of isopropyl chloroformate was added to 370 mg (1.67 mmol) of pyridine and 20 ml of methylene chloride of 0.35 ml (2.51 mmol) of triethylamine under ice-cooling and stirring. The mixture was stirred for 1 hour under ice cooling. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline in this order, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to give the desired product 2
15 mg (41.8%, pale tan oil) were obtained. NMR (200 MHz, CDCl ₃ ) δ: 1.22 (6H,
d, J = 6.2 Hz), 1.54-1.72 (4H, m),
3.02 (2H, m), 3.18 (2H, m), 4.66
(1H, br), 4.90 (1H, hept, J = 6.2H)
z), 6.90 (1H, dd, J = 7.1, 1 Hz), 7.15
(1H, dd, J = 9, 7 Hz), 7.58 (1H, d, J
= 9Hz), 7.70 (1H, m), 7.84 (1H, m)

Example 1 (1) Compound 5 50 g (2) Lactose 100 g (3) Corn starch 15 g (4) Carboxymethylcellulose calcium 44 g (5) Magnesium stearate 1 g 1000 tablets 210 g (1), (2), (3) ) And 30 g of (4) were kneaded with water, dried in vacuo, and granulated. 1 to this granulated powder
By mixing 4 g of (4) and 1 g of (5) and making a tablet with a tableting machine, 1000 tablets containing (1) 50 mg per tablet were produced.

Example 2 An ointment was prepared by uniformly kneading the following components. Compound 5 0.5 g Liquid paraffin 1 g White petrolatum qs 100 g

Example 3 (1) Compound 5 1 g (2) Cocoa butter 19 g All of (1) and (2) were kneaded in a water bath at about 60 ° C., put into a suppository mold, cooled, Ten suppositories of 2 g each were produced.

Example 4 (1) 10 g of compound 5 (2) 4.5 g of lactose (3) 4.5 g of corn starch (4) 1 g of magnesium stearate 1 g 1000 capsules 20 g All components were mixed well and mixed into an appropriate gelatin capsule. By filling, (1) 100mg per capsule
Was produced in 100 capsules.

Example 5 The following ingredients were mixed and dissolved to prepare an ampoule injection.

Test Example 1 Effect of Compound of Interest on Endothelial Cell Proliferation In this experiment, human umbilical vein-derived endothelial cells (HUVE cells) were used.
This was performed using GIT of 2 × 10 ³ HUVE cells
The medium (Nihon Pharmaceutical) was suspended in 2.5% FBS (fetal bovine serum) in complete medium, dispensed into a 96-well microtiter plate, and mixed in a 5% carbon dioxide gas-7% oxygen-88% nitrogen mixed atmosphere. At 37 ° C. Twenty-four hours later, human recombinant basic FGF (endothelial cell growth factor) at a final concentration of 2 ng / milliliter was added, and a test compound was added.
Cultured for days. After culturing, the proliferation rate of HUVE cells was determined by MTT.
Law [Cancer Treatment Reports
Treatment Reports), Volume 71, 1141-114
9, 1987]. The test compound inhibited the proliferation of human umbilical cord endothelial cells. IC ₅₀ values of test compounds (concentration of test compound that inhibits 50% of the endothelial cell proliferation) HUV
It was determined from the growth curve of E cells and is shown in the table below (the numbers of test compounds indicate the compound numbers in Production Examples). As shown in this table, the compounds of the present invention have an excellent endothelial cell proliferation inhibitory action.

Test Example 2 Effect of Target Compound on Proliferation of Bovine Arterial Vascular Endothelial Cells This experiment was performed using bovine aortic endothelial cells (BAE cells). 5 × 10 ³ BAE cells were added to Dulbecco's modified Eagle's minimum required medium (D-MEM medium) at 5%
Suspended in complete medium supplemented with FBS (fetal calf serum), 9
The mixture was dispensed into a 6-well microtiter plate and cultured at a temperature of 37 ° C. in a mixed atmosphere of 5% carbon dioxide and 95% air. 2
Four hours later, human recombinant basic FGF (endothelial cell growth factor) at a final concentration of 2 ng / ml.
And a test compound was further added, followed by culturing for 3 days.
After the culture, the proliferation rate of BAE cells was determined by the MTT method [Cancer
Treatment Reports (Cancer Treatment Rep)
orts), Vol. 71, 1141-1149, 1987]. The test compound inhibited the growth of bovine arterial vascular endothelial cells. The IC ₅₀ value of compound 1 (the concentration of the test compound that inhibits endothelial cell proliferation by 50%) was 48 μM.

Test Example 3 Effect of target compound on proliferation of human umbilical vein endothelial cells by phorbol ester In this experiment, human umbilical vein-derived endothelial cells (HUVE cells) were used.
This was performed using GIT of 2 × 10 ³ HUVE cells
The medium (Nihon Pharmaceutical) was suspended in 2.5% FBS (fetal bovine serum) in complete medium, dispensed into a 96-well microtiter plate, and mixed in a 5% carbon dioxide gas-7% oxygen-88% nitrogen mixed atmosphere. At 37 ° C. After 24 hours, 12-O-tetradecanoylphorbol at a final concentration of 1 nM 13
-Acetate (TPA) was added, the test compound was further added, and the cells were cultured for 3 days. After the culture, the proliferation rate of the HUVE cells was determined by the MTT method [Cancer Treatment Reports (C
ancer Treatment Reports), 71 volumes, 1141-1
149, 1987]. The test compound inhibited the proliferation of human umbilical cord endothelial cells by phorbol ester (TPA). IC ₅₀ value of compound 1 (endothelial cell proliferation was
% Inhibitory concentration) was 15 μM.

Test Example 4 Inhibitory effect of target compound on increase in intracellular calcium concentration by phorbol ester Bovine aortic endothelial cells (BAE cells) cultured on cover glass loaded with 4 μM Fuller 2 (Dojindo Laboratories)
Was inserted into a quartz cuvette containing 2.5 milliliters of Hepes buffer (pH 7.5). At this time, the cover glass was fixed so as to come on a diagonal plane at 45 ° to the incident direction of the excitation light. Fluorescence measurement is a spectrofluorometer manufactured by Hitachi, Ltd.
340 nm and 380 n
m and fluorescence at 505 nm was recorded. Fmax is a calcium ionophore ionomycin 2 uM
(Kalvairochen) Fmin is calcium
It was determined with EGTA 8 mM, which is an ion chelating agent.
The intracellular calcium ion concentration [Ca ⁺⁺ ] i is Kd = 2
The equation of Tween et al. As 24 nM, [Ca ⁺⁺ ] i = Kd × (F-Fmin) / (Fmax
F) was calculated by the following equation, which is a corrected equation. ^{[Ca ++] i = Kd ×} (R-Rmin) × Sf 2 / (Rm
ax−R) × Sb ₂ , R = {D (W ₁ ) −AutoF ₁ } / {D (W ₂ ) −Au
TOF _2}, where, D (W _1): measurement value of the excitation wavelength _{W 1, D (W 2)} : measurement of the excitation wavelength W _2, AutoF _2:
Autofluorescence of W _1, AutoF _2: autofluorescence at W _2, Rmin: R at zero Ca ⁺⁺ = Fmin (W
₁ ) / Fmin (W ₂ ), Rmax: R = Fmax (W ₁ ) / Fmax (W ₂ ) at a saturated Ca ⁺⁺ concentration, Sf ₂ :
Fluorescence intensity of W ₂ in Ca ⁺⁺ free state, Sb ₂ : W ₂
5 shows the fluorescence intensity in the Ca ⁺⁺ binding state in FIG. The experiment was performed by adding various concentrations of the test compound to the solution in the cuvette and
After a 2 minute incubation, 12 nM final concentration
-O-Tetradecanoylphorbol 13-acetate (TPA) was added, and the change in fluorescence intensity was observed. The test compound was found to inhibit the increase in intracellular calcium concentration due to this phorbol ester (TPA). The change in the inhibitory activity with respect to the change in the concentration of Compound 1 is shown in the table below. Inhibitory activity of compound 1 on increase of intracellular calcium concentration by phorbol ester

[0063]

The angiogenesis inhibitor containing the compound (I) of the present invention or a salt thereof has an excellent action, and based on this action, an agent for treating or preventing tumors and rheumatoid arthritis in humans and mammals, etc. It is useful as a medicine.

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI A61P 29/00 101 A61P 29/00 101 35/00 35/00 C07D 471/04 108 C07D 471/04 108E (56) -141292 (JP, A) JP-A-55-7287 (JP, A) JP-A-63-152391 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/41- 31/49 C07D 471/04 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] (1) Formula (1) [Wherein A is the formula (1): (In the formula, k, m and n each represent an integer of 0 to ⁵ , and R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ each represent (i) hydrogen, (ii) a lower alkyl group ( This lower alkyl group is halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
(Iv) may have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) phenyl-lower alkyl group (the phenyl moiety is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen, lower alkyl, lower alkenyl, which may have 1 to 4 substituents selected from hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); , Lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl which may have 1 to 4 substituents), (vi) an aryl group having 6 to 14 carbon atoms ( This aryl group is halogen, lower alkyl, lower alkenyl, lower Coxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, may have 1 to 4 substituents selected from lower alkylcarbamoyl) or (vii) selected from sulfur, oxygen and nitrogen A heterocyclic group bonded via a carbon atom with an aromatic monocyclic or bicyclic heterocyclic group containing 1 to 4 heteroatoms (this heterocyclic group may be halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro , Cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl which may have 1 to 4 substituents), or a group represented by the formula (2) 34 (Wherein o and p each represent an integer of 0 to 5), wherein R ¹ and R ² are the same or different, and (i) hydrogen, (ii) a lower alkyl group (the lower alkyl group Is halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
(Iv) may have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) phenyl-lower alkyl group (the phenyl moiety is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen, lower alkyl, lower alkenyl, which may have 1 to 4 substituents selected from hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); , Lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl which may have 1 to 4 substituents), (vi) an aryl group having 6 to 14 carbon atoms ( This aryl group is halogen, lower alkyl, lower alkenyl, lower (Vii) may have 1 to 4 substituents selected from oxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl), (vii) halogen, (viii) nitro group , (Ix) nitroso group, (x)
An optionally protected amino group, (xi) a lower alkoxycarbonyl group or (xii) a lower alkylcarbamoyl group, R ³ is (i) hydrogen, (ii) a lower alkyl group (the lower alkyl group is a halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
May have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) a cycloalkyl group having 3 to 8 carbon atoms (this cycloalkyl group is halogen, nitro, amino, lower alkylamino, It has 1 to 5 substituents selected from 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl. (V) a phenyl-lower alkyl group wherein the phenyl moiety is selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl Or may have 4 to 4 substituents) (vi) naphthyl-lower alkyl group (where the naphthyl moiety is one to four substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl) (Vii) an aryl group having 6 to 14 carbon atoms, wherein the aryl group is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino,
^May have 1 to 4 substituents selected from lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl), or R ³ and R ⁵ or R ⁶ , or R ³ and R ⁷ or R ⁸ , or R ³ and R ⁹ or R ¹⁰ are bonded to form a compound of the formula (Wherein Q and R each represent 2 or 3), and R ⁴ represents (i) a lower alkyl group (the lower alkyl group is a halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (ii) a lower alkenyl group (this lower alkenyl group may be halogen, nitro, amino, lower alkylamino, 4-7
May have 1 to 5 substituents selected from membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxycarbonyl, lower alkylcarbamoyl. (Iii) a cycloalkyl group having 3 to 8 carbon atoms (the cycloalkyl group is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy) Carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl which may have 1 to 5 substituents), (iv) phenyl-lower alkyl group (this phenyl moiety is Halogen, lower alkyl, lower alkenyl, lower alcohol (V) a naphthyl-lower alkyl group (where the naphthyl moiety is halogen) (Vi) having 6 to 4 substituents selected from lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl); To 14 aryl groups (where the aryl group is 1 to 4 substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino, lower alkoxycarbonyl, carbamoyl, and lower alkylcarbamoyl) May be included) Show. Or a pharmaceutically acceptable salt thereof. 2. R ³ is (i) hydrogen, (ii) a lower alkyl group (the lower alkyl group is a halogen,
1 selected from nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl And (iii) a lower alkenyl group, which is halogen, nitro, amino, lower alkylamino, 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-
Naphthoxy, 2-naphthoxy, carbamoyl, cyano,
Hydroxy, carboxy, lower alkoxycarbonyl,
May have 1 to 5 substituents selected from lower alkylcarbamoyl), (iv) a cycloalkyl group having 3 to 8 carbon atoms (this cycloalkyl group is halogen, nitro, amino, lower alkylamino, It has 1 to 5 substituents selected from 4- to 7-membered cyclic amino, lower alkoxy, phenoxy, 1-naphthoxy, 2-naphthoxy, carbamoyl, cyano, hydroxy, carboxy, lower alkoxy-carbonyl, lower alkyl-carbamoyl. (V) a phenyl-lower alkyl group wherein the phenyl moiety is selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl Or may have 4 to 4 substituents) (vi) naphthyl-lower alkyl group (where the naphthyl moiety is one to four substituents selected from halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, hydroxy, lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl) (Vii) an aryl group having 6 to 14 carbon atoms, wherein the aryl group is halogen, lower alkyl, lower alkenyl, lower alkoxy, nitro, cyano, oxo, hydroxy, amino,
The angiogenesis inhibitor according to claim 1, which has 1 to 4 substituents selected from lower alkoxycarbonyl, carbamoyl and lower alkylcarbamoyl. 3. An amino group which may be protected is an amino group, a lower alkylcarbonylamino group, a C _7-10 aralkyl-carbonylamino group, a C _6-10 aryl-carbonylamino group, a lower alkyloxycarbonylamino group, C
_7-10 aralkyloxycarbonylamino group or C _6-10
The angiogenesis inhibitor according to claim 1, which is an aryloxycarbonylamino group. 4. The angiogenesis inhibitor according to claim 1, which is an antitumor agent, an antiinflammatory agent, an antirheumatic agent for rheumatoid arthritis or an antidiabetic retinopathy agent.