# US 9,040,693 B2 · Fused heterocyclic derivative, medicinal composition containing the same, and medicinal use thereof

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- Number: US 9,040,693 B2
- Document ID: US9040693B2
- Status: Granted
- Kind: B2
- Application number: 12/089,674
- Filed: 2006-10-17
- Published: 2009-12-31
- Granted: 2015-05-26
- Earliest claimed: 2005-10-19
- Assignees: Kissei Pharmaceutical Co., Ltd.
- Applicants: Kohsuke Ohno; Takashi Miyagi; Tomonaga Ozawa; Nobuhiko Fushimi
- Inventors: Kohsuke Ohno; Takashi Miyagi; Tomonaga Ozawa; Nobuhiko Fushimi
- Web page: https://patentgrep.com/patent/US9040693B2

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 5/04: for decreasing, blocking or antagonising the activity of the hypothalamic hormones
- A61P 5/24: of the sex hormones
- A61P 5/28: Antiandrogens
- A61P 5/32: Antioestrogens
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/18: Feminine contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/10: Anti-acne agents
- A61P 17/14: for baldness or alopecia
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/20: Hypnotics; Sedatives
- 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 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides a compound useful as an agent for the prevention or treatment of a sex hormone-dependent disease or the like. That is, the present invention provides a fused heterocyclic derivative represented by the following general formula (I), a pharmaceutical composition containing the same, a medicinal use thereof and the like. In the formula (I), ring A represents 5-membered cyclic unsaturated hydrocarbon or 5-membered heteroaryl; RA represents halogen, alkyl, alkenyl, alkynyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl or the like ; ring B represents aryl or heteroaryl; RB represents halogen, alkyl, carboxy, alkoxy, carbamoyl, alkylcarbamoyl or the like; E1 and E2 represent an oxygen atom or the like; U represents a single bond or alkylene; X represents a group represented by Y, —SO2—Y, —O—(alkylene)—Y, —O—Z in which Y represents Z, amino or the like; Z represents cycloalkyl, heterocycloalkyl, aryl, heteroaryl or the like; or the like.

## Claims

### Claim 1

A fused heterocyclic derivative of the general formula (I):
wherein ring A is a thiophene ring;
RAis a halogen atom, a cyano group, a nitro group, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, a hydroxyiminomethyl group, an optionally substituted (lower alkyl)sulfonyl group, an optionally substituted (lower alkyl)sulfinyl group, a tetrazolyl group, OW1, SW1, COW1, COOW1, NHCOW1, NHCONW2W3, NW2W3, CONW2W3 or SO2NW2W3 in which W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
m is an integer number of 0 to 3;
ring B is aryl or a monocyclic heteroaryl group;
RB is a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4 or CONW5W6 in which W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and W6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
n is an integer number of 0 to 2;
El is an oxygen atom;
E2 is an oxygen atom;
U is a single bond;
X is a group of —S—L—Y, —O—L—Y, —CO—L—Y, or —SO2—L—Y in which L is an optionally substituted lower alkylene group;
Y is a group of Z or —NW7W8 wherein W7 and W8 independently are a hydrogen atom, an optionally substituted lower alkyl group or Z with the proviso that W7 and W8 are not hydrogen atoms at the same time, or W7 and W8 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
Z is an optionally fused and optionally substituted cycloalkyl group, an optionally fused and optionally substituted heterocycloalkyl group, an optionally fused and optionally substituted aryl group or an optionally fused and optionally substituted heteroaryl group;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein the ring A is a thiophene ring of the formula:
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein RAis a halogen atom, an optionally substituted lower alkyl group, COOW1 or CONW2W3 in which W1 to W3 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W2 and W3 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

A fused heterocyclic derivative as claimed in claim 3, wherein RA is (1) a lower alkyl group substituted by any group selected from the group consisting of a hydroxyl group, a carboxy group and a carbamoyl group; (2) a carboxy group; or (3) a carbamoyl group, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein m is 0 or 1, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

A fused heterocyclic derivative as claimed in claim 5, wherein m is 1 and ring A is a thiophene ring in which RA binds to the position of ring A at the position shown by the following general formula:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein ring B is a benzene ring, a thiophene ring or a pyridine ring, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 7)

A fused heterocyclic derivative as claimed in claim 7, wherein ring B is any of rings of any of the formulae:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

A fused heterocyclic derivative as claimed in claim 8, wherein n is 1 and ring B is any of rings in which RB binds to the position of ring B at the position shown by any of the following formulae:
in the formulae, RB is a halogen atom, a cyano group, an optionally substituted lower alkyl group, OW4, COW4, COOW4 or CONW5W6 in which W4 to W6 independently are a hydrogen atom or an optionally substituted lower alkyl group, or W5 and W6 may bind together with the neighboring nitrogen atom to form an optionally substituted cyclic amino group;
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 8)

A fused heterocyclic derivative as claimed in claim 8, wherein ring B is any of rings of any of the formulae:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein RB is a halogen atom, an optionally substituted lower alkyl group, OW4 in which W4 is a hydrogen atom or an optionally substituted lower alkyl group, or a cyano group, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 11)

A fused heterocyclic derivative as claimed in claim 11, wherein RB is a halogen atom, or a lower alkyl group which may be substituted by a halogen atom, or OW4 in which W4 is a hydrogen atom or an optionally substituted lower alkyl group, or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 12)

A fused heterocyclic derivative as claimed in claim 12, wherein RB is a fluorine atom, a chlorine atom or OW4 in which W4 is a lower alkyl group, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein L is a C1-3 alkylene group, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

A fused heterocyclic derivative as claimed in claim 1, wherein Z is an optionally fused and optionally substituted aryl group, or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising as an active ingredient a fused heterocyclic derivative as claimed in claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 16)

A pharmaceutical composition as claimed in claim 16, which is a gonadotropin releasing hormone antagonist.

### Claim 18 (depends on 16)

A pharmaceutical composition as claimed in claim 16, wherein the composition is an oral formulation.

### Claim 19 (depends on 16)

A pharmaceutical composition as claimed in claim 16, which comprises a combination with at least one drug selected from the group consisting of a gonadotropin releasing hormone agonist, a chemotherapeutic agent, a peptidic gonadotropin releasing hormone antagonist, a 5α-reductase inhibitor, an α-adrenoceptor inhibitor, an aromatase inhibitor, an adrenal androgen production inhibitor and a hormonotherapeutic agent.

### Claim 20 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the gonadotropin releasing hormone agonist is selected from the group consisting of leuprorelin acetate, gonadorelin, buserelin, triptorelin, goserelin, nafarelin, histrelin, deslorelin, meterelin and lecirelin.

### Claim 21 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the chemotherapeutic agent is selected from the group consisting of ifosfamide, adriamycin, peplomycin, cisplatin, cyclophosphamide, 5-FU, UFT, methotrexate, mitomycin C, mitoxantrone, paclitaxel and dotaxel.

### Claim 22 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the peptidic gonadotropin releasing hormone antagonist is selected from the group consisting of cetrorelix, ganirelix, abarelix, ozarelix, iturelix, degarelix and teverelix.

### Claim 23 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the 5α-reductase inhibitor is selected from the group consisting of finasteride and dutasteride.

### Claim 24 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the α-adrenoceptor inhibitor is selected from the group consisting of tamsulosin, silodosin and urapidil.

### Claim 25 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the aromatase inhibitor is selected from the group consisting of fadrozole, letrozole, anastrozole and formestane.

### Claim 26 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the adrenal androgen production inhibitor is liarozole.

### Claim 27 (depends on 19)

A pharmaceutical composition as claimed in claim 19, wherein the hormonotherapeutic agent is selected from the group consisting of an antiestrogenic agent, a progestational agent, an androgenic agent, an estrogeninc agent and an antiandrogenic agent.

### Claim 28 (depends on 8)

A fused heterocyclic derivative as claimed in claim 8, wherein n is 2 and ring B is any of rings in which RB binds to the position of ring B at the position shown by any of the following formulae:
wherein RB can be the same or different from each other; or a pharmaceutically acceptable salt thereof.

### Claim 29

5-Carboxy-3-{2-fluoro-5-[1-(2-fluoro-6-methoxyphenyl)-ethoxy]phenyl}thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

### Claim 30

5-Carboxy-3-[2-fluoro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenyl]thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

### Claim 31

5-Carboxy-3-[2-chloro-5-(1-methyl-1-phenylethoxy)phenyl]-thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.

### Claim 32

5-Carboxy-3-{2-fluoro-5-[2,3-difluoro-6-(2-methoxyethoxy)-benzyloxy]phenyl}thieno[3,4-d]pyrimidine-2,4(1H,3H)-dione, or a pharmaceutically acceptable salt thereof.