# US 9,040,536 B2 · Substituted pyrrolo[1,2-a]quinoxalines as PDE9 inhibitors

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- Number: US 9,040,536 B2
- Document ID: US9040536B2
- Status: Granted
- Kind: B2
- Application number: 14/448,335
- Filed: 2014-07-31
- Published: 2014-11-13
- Granted: 2015-05-26
- Earliest claimed: 2006-12-13
- Assignees: Aska Pharmaceutical Co., Ltd.
- Applicants: ASKA Pharmaceutical Co., Ltd.
- Inventors: Makoto Okada; Shuichiro Sato; Kenji Kawade; Kotaro Gotanda; Atsushi Shinbo; Youichi Nakano; Hideo Kobayashi
- Web page: https://patentgrep.com/patent/US9040536B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/10: Laxatives
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/10: Expectorants
- A61P 11/16: Central respiratory analeptics
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/04: for urolithiasis
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/10: for impotence
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 487/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention discloses quinoxaline derivatives or salts thereof having PDE9-inhibiting activity and being useful as treating agent of dysuria and the like, which are represented by the formula (I) in the formula, R1 and R2 each independently stands for hydrogen, halogen, alkyl, alkoxy, acyl, amino and the like, R3 stands for alkyl, aryl, saturated carbocyclic group, saturated heterocyclic group, acyl and the like, R4 stands for hydrogen, hydroxy, alkyl or amino, R5 and R8 each independently stands for hydrogen, halogen, alkyl, alkenyl, alkoxy, cyano or nitro, R6 and R7 each independently stands for hydrogen, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, carbocyclic group, heterocyclic group, COR9 or SO2R9, R9 stands for hydrogen, hydroxy, alkyl, amino, pyrrolidin-1-yl, piperidin-1-yl, pyperazin-1-yl or the like, X stands for S or O, and A1, A2 and A3 each independently stands for N or C.

## Claims

### Claim 1

A compound of the formula (I)
wherein,
R1 and R2 each independently are hydrogen or C1-6 alkyl;
R3 is C1-9 alkyl or C2-9 alkenyl each of which may be substituted with carboxy or C1-6 alkoxycarbonyl;
R4 is hydrogen;
R5 and R8 are hydrogen;
R6 and R7 each independently are hydrogen; C1-6 alkyl or C1-6 alkoxy each of which is optionally substituted with halogen;
X is O; and
A1, A2 and A3 are C,
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1, R2 and R7 are hydrogen, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R3 is C1-6 alkyl or C2-6 alkenyl each of which is substituted with carboxy, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R6 is C1-6 alkyl which is substituted with fluorine, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

The compound of claim 1, wherein said compound is
(E)-3-(4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl)acrylic acid;
3-(4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl) propanoic acid;
3-(2-methyl-4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl) propanoic acid;
2-methyl-3-(4-oxo-7-trifluoromethyl-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl) propanoic acid;
3-(7-butyl-4-oxo-4,5-dihydropyrrolo[1,2-a]quinoxalin-1-yl) propanoic acid, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 1)

A pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 7 (depends on 1)

A method for treating overactive bladder syndrome, pollakiuria, urinary incontinence, dysuria in benign prostatic hyperplasia, neurogenic bladder, interstitial cystitis, urolithiasis, benign prostatic hyperplasia, erectile dysfunction, cognitive impairment, neuropathy, Alzheimer's disease, pulmonary hypertension, chronic obstructive pulmonary disease, ischemic heart disease, hypertension, angina, myocardial infarction, arteriosclerosis, thrombosis, embolism, type 1 diabetes or type 2 diabetes in a mammal, comprising administering to said mammal a compound of the formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 8 (depends on 1)

A method for modulating phosphodiesterase type-9 activity in a mammal, comprising administering to said mammal a compound according to claim 1, or a pharmaceutically acceptable salt thereof.