# US 2014/0194407 A1 · Novel antiplatelet agent

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- Number: US 2014/0194407 A1
- Document ID: US20140194407A1
- Status: Published application
- Kind: A1
- Application number: 14/189,140
- Filed: 2014-02-25
- Published: 2014-07-10
- Earliest claimed: 2009-12-18
- Assignees: Mitsubishi Tanabe Pharma Corporation
- Applicants: Mitsubishi Tanabe Pharma Corporation
- Inventors: Hiroshi SATO; Kazutoshi YOKOYAMA; Kazushi SATO
- Web page: https://patentgrep.com/patent/US20140194407A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 25/00: Drugs for disorders of the nervous system
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/14: containing three or more hetero rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a novel antiplatelet agent and a novel compound which is an active ingredient for the agent. The present invention provides the antiplatelet agent comprising a compound represented by the formula I: wherein, X is N, or CR1d, Xb1-Xb5 are the same or different, and are nitrogen or carbon, R1a-R1d are the same or different, and are hydrogen, an optionally substituted alkyl, an optionally substituted alkoxy, an optionally substituted alkylthio, an alkenyl, a cycloalkyl, a halogen, cyano, or hydroxyl or optionally substituted by 1 or 2 alkylamino, R2 is an optionally substituted aryl or an optionally substituted heteroaryl, R3 is an optionally substituted aryl or an optionally substituted heteroaryl, or pharmaceutically acceptable salt thereof as an active ingredient.

## Claims

### Claim at position 1

1-2. (canceled)

### Claim 3

A method for preventing or treating ischemic stroke, acute coronary syndrome, microvascular dysfunction, peripheral arterial disease, arteriosclerosis obliterans, ischemic heart disease, thrombotic microangiopathy, or unstable or stable angina, comprising:
administrating an effective amount of a compound of formula IIa:
or a pharmaceutically acceptable salt thereof,
wherein Xa is N, or CH,
R1e is i) an alkyl optionally substituted by an aryl or a halogen, ii) an alkoxy optionally substituted by an aryl, a halogen or a cycloalkyl, iii) an alkylthio optionally substituted by an aryl, a halogen or a cycloalkyl, iv) an alkenyl, v) cyano, vi) a cycloalkyl, vii) a halogen, or viii) an amino optionally substituted by 1 or 2 alkyl,
R1f is hydrogen, an alkyl, an alkoxy, hydroxyl, cyano or a halogen,
R21 is pyrrolyl, imizazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyraziniyl, pyridaziny, pyrimidyl, pyridyl, or quinolyl, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an optionally substituted alkyl; an optionally substituted alkoxy; an optionally substituted alkylthio; an alkenyl; a halogen; cyano; a carbamoyl optionally substituted by 1 or 2 alkyl; an amino optionally substituted by 1 or 2 alkyl; hydroxyl; an alkanoyl; a cycloalkylcarbonyl; an arylcarbonyl; nitro; an optionally substituted aliphatic heteromonocyclic group; an aryl; or a heteroaryl, and
R31 is pyridyl, pyradinyl, pyrimidyl, or pyridaziny, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an optionally substituted alkyl; an optionally substituted alkoxy; an optionally substituted alkylthio; a cycloalkyl; an amino optionally substituted by 1 or 2 alkyl; an aliphatic heteromonocycle; and a halogen.

### Claim 4 (depends on 3)

The method of claim 3, wherein R1e is an alkyl substituted by a halogen or an alkoxy substituted by a halogen.

### Claim 5 (depends on 3)

The method of claim 3, wherein R1e is trifluoromethyl or trifluoromethoxy.

### Claim 6 (depends on 3)

The method of claim 3, wherein R1f is hydrogen.

### Claim 7 (depends on 3)

The method of claim 3, wherein R21 is pyrrolyl, imizazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyraziniyl, pyridazinyl, pyrimidyl, pyridyl, or quinolyl, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an optionally substituted alkyl; an optionally substituted alkoxy; a halogen; cyano; a carbamoyl optionally substituted by 1 or 2 alkyl; an amino optionally substituted by 1 or 2 alkyl; hydroxyl; nitro; and an optionally substituted aliphatic hetero-monocyclic group.

### Claim 8 (depends on 3)

The method of claim 3, wherein R21 is pyrrolyl, imizazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyraziniyl, pyridazinyl, pyrimidyl, pyridyl, or quinolyl each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an alkyl, an alkoxy, a halogen, cyano, a carbamoyl optionally substituted by 1 or 2 alkyl, and nitro.

### Claim 9 (depends on 3)

The method of claim 3, wherein R21 is pyrrolyl, imizazolyl, pyrazolyl, thiazolyl, isoxazolyl, oxazolyl, triazolyl, pyraziniyl, pyridazinyl, pyrimidyl, pyridyl, or quinoly, leach of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an alkyl, a halogen, and cyano.

### Claim 10 (depends on 3)

The method of claim 3, wherein R31 is pyridyl, pyradinyl, pyrimidyl, or pyridazinyl, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an alkyl, an alkoxy, a halogen, and an amino optionally substituted by 1 or 2 alkyl.

### Claim 11 (depends on 3)

The method of claim 3, wherein Xa is N.

### Claim 12 (depends on 3)

The method of claim 3, wherein
R1e is trifluoromethyl or trifluoromethoxy,
R1f is hydrogen,
R21 is pyridyl or pyradiny, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an alkyl, a halogen, and cyano,
R31 is pyridyl or pyrdazinyl, each of which may be substituted with the same or different 1-3 substituents selected from the group consisting of an alkyl, an alkoxy, a halogen, and an amino optionally substituted by 1 or 2 alkyl,
Xa is N.

### Claim 13

A method for preventing or treating ischemic stroke, acute coronary syndrome, microvascular dysfunction, peripheral arterial disease, arteriosclerosis obliterans, ischemic heart disease, thrombotic microangiopathy, or unstable or stable angina, comprising:
administrating an effective amount of a compound selected from the group consisting of:
1-(6-methoxypyridazin-3-yl)-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
2-(6-fluoropyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-pyridin-2-yl-5-(trifluoromethoxy)-1H-benzimidazole;
2-(5-fluoropyridin-2-yl)-3-(6-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
N-methyl-5-[2-pyridin-2-yl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl]pyridin-2-amine;
N,N-dimethyl-5-[2-pyridin-2-yl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl]pyridin-2-amine;
6-[1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]nicotinonitrile;
5-[3-(6-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]pyrazine-2-carbonitrile;
2-(6-methoxypyridazin-3-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
3-(6-methoxypyridin-3-yl)-2-(1H-pyrrol-2-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
2-(1H-imidazol-4-yl)-3-(6-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1,2-dipyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole;
5-ethyl-1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-1H-benzimidazole;
2-(5-bromopyridin-2-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-fluoropyridin-2-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1,2-bis(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
5-cyclopropyl-1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-1H-benzimidazole;
5-(cyclopropylmethoxy)-1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-1H-benzimidazole;
2-(5-bromopyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-chloropyridin-2-yl)-1-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-5-(trifluoromethoxy)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(5-nitropyridin-2-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1,3-thiazol-2-yl)-5-(trifluoromethyl)-1H-benzimidazole;
6-chloro-1-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-ethylpyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(4-methylpyridin-2-yl)-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-fluoropyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-[6-(methylthio)pyridazin-3-yl]-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-fluoropyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
2-(5-methylisoxazol-3-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
3-(6-methoxypyridin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
2-(4-bromopyridin-2-yl)-1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole;
2-[1-(6-methoxypyridazin-3-yl)-5-(trifluoromethyl)-1H-benzimidazole-2-yl]nicotinonitrile;
1-(6-methoxypyridazin-3-yl)-2-(1,3-oxazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1,3-thiazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(5-methylpyrazine-2-yl)-5-(trifluoromethyl)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(2-methyl-1,3-thiazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole;
3-(6-methoxypyridin-3-yl)-2-(1,3-oxazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(5-methylisoxazol-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(1,3-thiazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(2-methyl-1,3-thiazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methylpyridin-3-yl)-2-pyridin-2-yl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(2-methyl-1,3-oxazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-pyridin-2-yl-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(5-methyl-1,3-oxazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
6-[3-(6-methylpyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]nicotinonitrile;
1-(6-methoxypyridazin-3-yl)-2-(2-methyl-1,3-oxazol-4-yl)-5-(trifluoromethyl)-1H-benzimidazole;
2-(5-fluoropyridin-2-yl)-3-(5-methoxypyrazine-2-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
6-isopropoxy-3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
6-(difluoromethoxy)-3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-6-(trifluoromethoxy)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-(1,3-thiazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
5-[2-(5-fluoropyridin-2-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl]-N-methylpyridin-2-amine;
6-{3-[6-(methylamino)pyridin-3-yl]-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]nicotinonitrile;
3-(5-methoxypyrazine-2-yl)-2-(1,3-oxazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-(2-methyl-1,3-oxazol-4-yl)-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-(1-methyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-(5-methylisoxazol-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1-(6-methoxypyridazin-3-yl)-2-(1,3-oxazol-4-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
5-[3-(5-methoxypyridazin-2-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-2-yl]pyrazine-2-carbonitrile;
1-(6-methoxypyridazin-3-yl)-2-(2-methyl-1,3-oxazol-4-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
2-(5-chloropyridin-2-yl)-3-(6-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1-(5-methoxypyrazine-2-yl)-2-pyridin-2-yl-5-(trifluoromethyl)-1H-benzimidazole;
3-(6-methoxypyridin-3-yl)-2-(1-methyl-1H-pyrazol-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(trifluoromethyl)-1 H-benzimidazole;
3-(5-methoxypyrazine-2-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(5-methoxypyrazine-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-pyrazol-4-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(1-methyl-1H-1,2,3-triazol-4-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
1-(6-methoxypyridazin-3-yl)-2-(5-methylisoxazol-3-yl)-5-(trifluoromethoxy)-1H-benzimidazole;
3-(5-methoxypyrazine-2-yl)-2-(1-methyl-1H-imidazol-4-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
6-ethoxy-3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
6-(cyclopropylmethoxy)-3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
2-(2-ethyl-1,3-oxazol-4-yl)-3-(6-methoxypyridin-3-yl)-6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-6-propoxy-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
6-isobuthoxy-3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-6-(2,2,2-trifluoroethoxy)-3H-imidazo[4,5-b]pyridine;
3-(6-methoxypyridin-3-yl)-2-pyridin-2-yl-6-(2,2,2-trifluoro-1-methylethoxy)-3H-imidazo[4,5-b]pyridine;
2-(5-fluoropyridin-2-yl)-3-(6-methoxypyridin-3-yl)-6-(trifluoromethoxy)-3H-imidazo[4,5-b]pyridine; and
6-difluoromethoxy-2-(5-fluoropyridin-2-yl)-3-(6-methoxypyridin-3-yl)-3H-imidazo[4,5-b]pyridine; or
a pharmaceutically acceptable salt thereof.