# US 2008/0188495 A1 · A2a adenosine receptor antagonists

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- Number: US 2008/0188495 A1
- Document ID: US20080188495A1
- Status: Published application
- Kind: A1
- Application number: 11/947,690
- Filed: 2007-11-29
- Published: 2008-08-07
- Earliest claimed: 2006-12-01
- Assignees: Gilead Palo Alto, Inc.
- Inventors: Tetsuya Kobayashi; Rao Kalla; Elfatih Elzein; Jeff Zablocki; Brent Blackburn
- Web page: https://patentgrep.com/patent/US20080188495A1

## CPC

- C07D 495/04: Ortho-condensed systems
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/04: Anorexiants; Antiobesity agents
- 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
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/24: Antidepressants
- 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 25/30: for treating abuse or dependence
- A61P 25/32: Alcohol-abuse
- A61P 25/36: Opioid-abuse
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- 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 relates to novel compounds that are A2A adenosine receptor antagonists, and to their use in treating mammals for various disease states, such as CNS disorders, including the “movement disorders” (Parkinson's disease, Huntington's Chorea, and catalepsy), and cerebral ischemia, excitotoxicity, cognitive and physiological disorders, depression, ADHD, hepatic fibrosis, cirrhosis of the liver, and drug addiction (alcohol, amphetamine, cannabinoids, cocaine, nicotine, and opioids) and to their use in the enhancement of immune response. The invention also relates to methods for the preparation of such compounds, and to pharmaceutical compositions containing them.

## Claims

### Claim 1

A compound of Formula I:
wherein
R1 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-6 alkynyl;
R2 is hydrogen, optionally substituted C1-4 alkyl, —X—O—P(O)(OR)2, or —X—O—R7, in which X is C1-4 alkylene, R is hydrogen or C1-6 alkyl, and R7 is C1-6 alkyl;
R3 is hydrogen, optionally substituted C1-4 alkyl, or a 5 or 6 membered optionally substituted monocyclic heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur and nitrogen;
R4 and R5 are independently methyl or hydrogen; and
R6 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycle, or optionally substituted cycloalkyl,
or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 is hydrogen.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R1 is optionally substituted C1-6 alkyl.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R3 is optionally substituted C1-4 alkyl.

### Claim 5 (depends on 4)

The compound of claim 4, wherein R6 is optionally substituted phenyl or optionally substituted heteroaryl.

### Claim 6 (depends on 5)

The compound of claim 5, selected from the group consisting of:
6-[(1E)-2-(3,4-dimethoxyphenyl)vinyl]-3-ethyl-1,5-dimethyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(4-fluorophenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(3-fluorophenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(4-chlorophenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(4-phenylphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-{(1E)-2-[4-(trifluoromethyl)phenyl]vinyl}-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(3,4-dimethoxyphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-5-methyl-3-(2-methylpropyl)-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(3,4-dimethoxyphenyl)vinyl]-5-methyl-3-(2-methylpropyl)-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-(3-pyridyl)vinyl)-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(4-methylphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(4-methoxyphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(2-fluorophenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(3-methoxyphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(2-methoxyphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione; and
6-[(1E)-2-(3,5-dimethoxyphenyl)vinyl]-3-ethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R2 is optionally substituted C1-4 alkyl, —X—O—P(O)(OR)2 or —X—O—R7 in which X is C1-4 alkylene, R is hydrogen or C1-6 alkyl and R7 is C1-6 alkyl.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R2 is optionally substituted C1-4 alkyl.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R1 is optionally substituted C1-6 alkyl or optionally substituted C2-6 alkynyl.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R3 is optionally substituted C1-4 alkyl.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R6 is optionally substituted phenyl.

### Claim 12 (depends on 11)

The compound of claim 11, selected from the group consisting of:
6-[(1E)-2-(3,4-dimethoxyphenyl)vinyl]-3-ethyl-1,5-dimethyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-[(1E)-2-(3,4-dimethoxyphenyl)vinyl]-3-ethyl-5-methyl-1-[(phenylmethoxy)methyl]-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-1,5-dimethyl-3-prop-2-ynyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-3-ethyl-1,5-dimethyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-1,3-diethyl-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-3-ethyl-1-(2-hydroxyethyl)-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione;
6-((1E)-2-phenylvinyl)-3-ethyl-1-(3-hydroxypropyl)-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione; and
6-((1Z)-2-phenylvinyl)-3-ethyl-1-(2-hydroxyethyl)-5-methyl-1,3-dihydrothiopheno[2,3-d]pyrimidine-2,4-dione.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

### Claim 14

A method for treating a disease or condition in a mammal that can be treated with an A2A adenosine receptor antagonist compound comprising administering to a mammal in need thereof a therapeutically effective dose of a compound having the structure of Formula I:
wherein
R1 is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-6 alkynyl;
R2 is hydrogen, optionally substituted C1-4 alkyl, —X—O—P(O)(OR)2, or —X—O—R7, in which X is C1-4 alkylene, R is hydrogen or C1-6 alkyl, and R7 is C1-6 alkyl;
R3 is hydrogen, optionally substituted C1-4 alkyl, or a 5 or 6 membered optionally substituted monocyclic heterocycle containing 1, 2, 3, or 4 heteroatoms independently selected from oxygen, sulfur and nitrogen;
R4 and R5 are independently methyl or hydrogen; and
R6 is optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocycle, or optionally substituted cycloalkyl,
or a pharmaceutically acceptable salt, ester, prodrug, or hydrate thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the disease state or condition is selected from the group consisting of obesity, CNS disorders, including the “movement disorders” (Parkinson's disease, Huntington's Chorea, and catalepsy), cerebral ischemia, excitotoxicity, cognitive and physiological disorders, depression, ADHD, hepatic fibrosis, cirrhosis of the liver, and drug addiction (alcohol, amphetamine, cannabinoids, cocaine, nicotine, and opioids) and to their use in the enhancement of immune response.