# US 9,518,015 B2 · EP1 receptor ligands

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- Number: US 9,518,015 B2
- Document ID: US9518015B2
- Status: Granted
- Kind: B2
- Application number: 14/345,136
- Filed: 2012-09-14
- Published: 2014-10-30
- Granted: 2016-12-13
- Earliest claimed: 2011-09-16
- Assignees: Laboratorios Del Dr. Esteve, S.A.
- Applicants: Antoni Torrens Jover; Ramon Mercè Vidal; Francesc Xavier Caldentey Frontera; Antonio David Rodríguez Garrido; Elena Carceller González; Jordi Salas Solana
- Inventors: Antoni Torrens Jover; Ramon Mercè Vidal; Francesc Xavier Caldentey Frontera; Antonio David Rodríguez Garrido; Elena Carceller González; Jordi Salas Solana
- Web page: https://patentgrep.com/patent/US9518015B2

## CPC

- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- 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 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/06: Antiabortive agents; Labour repressants
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- 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 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 209/12: Radicals substituted by oxygen atoms
- C07D 209/34: in position 2
- C07D 215/48: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 231/56: Benzopyrazoles; Hydrogenated benzopyrazoles
- C07D 235/06: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D 241/42: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 265/36: condensed with one six-membered ring
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention belongs to the field of EP1 receptor ligands. More specifically it refers to compounds of general formula (I) having great affinity and selectivity for the EP1 receptor. The invention also refers to the process for their preparation, to their use as medicament for the treatment and/or prophylaxis of diseases or disorders mediated by the EP1 receptor as well as to pharmaceutical compositions comprising them.

## Claims

### Claim 1

A compound of general formula I:
wherein:
W1 is a phenyl ring;
W2 is a 6-membered heterocyclic ring that contains at least 1 N atom and can additionally contain 1 or 2 heteroatoms selected from the group consisting of N, O, and S; wherein said 6-membered heterocyclic ring is aromatic, partially unsaturated or saturated, and which is optionally substituted by one or more R3;
R1 is -R6-R7;
each R2 is independently selected from the group consisting of H, halogen, C1-6-alkyl, C1-6-haloalkyl, —O—C1-6-alkyl, —O—C1-6-haloalkyl, hydroxyC1-6-alkyl, CN, —NR14COR15, —NR14SO2R15 and —SO2R15;
each R3 is independently selected from the group consisting of H, halogen, C1-6-alkyl C1-6-haloalkyl, —O—C1-6-alkyl, —O—C1-6-haloalkyl, hydroxyC1-6-alkyl, —C1-4-alkylene-OR14, —C2-4-alkenylene-COOH, ═O and CN;
each R4 is independently selected from the group consisting of H and C1-6-alkyl, or both R4 together with the C atom to which they are bonded form a C3-6cycloalkyl;
R5 is selected from the group consisting of H, halogen, C1-6-haloalkyl, —O—C1-6-alkyl, —O—C1-6-haloalkyl, -OH, C1-6-alkyl, C3-6cycloalkyl and —SO2R15;
R6 is selected from the group consisting of a direct bond, —C1-4-alkylene-, —O—C1-4-alkylene-and —C2-4-alkenylene-;
R7 is selected from the group consisting of —CO2H, —SO3H, 5-tetrazolyl, —OPO3H2, —PO3H2, —CONR12R12, —CONH—SO2R12, —NR14CONR14—SO2R15 and —SO2—NHCOR15
Y is selected from the group consisting of —C2-4-alkylene-, —O—C1-4-alkylene-, —C2-4-alkenylene-, —C1-4-alkylene-O—, —NR13—C1-4-alkylene- and —C1-4-alkylene-NR13—;
B is selected from the group consisting of C2-6-alkyl, C2-6 alkenyl and Cy, any of them optionally substituted by one or more R8;
each R8 is independently selected from the group consisting of halogen, C1-6-haloalkyl, —O—C1-6-alkyl, —O—C1-6-haloalkyl, C1-6-alkyl, —OH, —CN, —CH2OR14 and —CONR12R12;
each R9 is independently selected from the group consisting of CR10 and N;
each R10 is independently selected from the group consisting of H, halogen, C1-6-alkyl, C1-6-haloalkyl, —O—C1-6-alkyl, —O—C1-6-haloalkyl and hydroxyC1-6-alkyl;
R11 is CR5 or N,
each R12 is independently selected from the group consisting of H, C1-6-alkyl, C1-6-haloalkyl, —NR14R14 and C3-6cycloalkyl;
each R13 is independently selected from the group consisting of H, C1-6-alkyl, C1-6-haloalkyl, and C3-6cycloalkyl;
each R14 is independently selected from the group consisting of H and C1-6-alkyl;
each R15 is independently selected from the group consisting of C1-6-alkyl;
Cy is a 3-6 membered monocyclic or 8-12 membered polycyclic ring which can be carbocyclic or heterocyclic containing 1 to 3 heteroatoms selected from N, O and S and which can be aromatic, partially unsaturated or saturated and wherein one or more C or S atoms in Cy can be oxidized to form CO, SO or SO2;
with the proviso that when W1 and W2 is a benzimidazole, R6 and R7 are not at the same time respectively a —O—C1-4-alkylene- and a —CO2H or that R7 is not —CONH—SO2R12;
and the salts and prodrugs thereof.

### Claim 2 (depends on 1)

The compound according to claim 1 wherein each R9 is CR10 and each R10 is H.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein each R4 is H.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein Y is —O—CH2— or —CH2—O—, preferably —O—CH2—.

### Claim 5 (depends on 1)

The compound according to claim 1, where R11 is CR5 and R5 is selected from the group consisting of H, halogen and —C1-6-haloalkyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein B is phenyl, C3-6-cycloalkyl, C2-6-alkyl, C2-6 alkenyl or is a 5-6 membered monocyclic heterocycle containing 1 or 2 N atom which can be aromatic, partially unsaturated or saturated, any of them optionally substituted by one or more R8.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein B is phenyl optionally substituted by 1 to 5 R8.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein
represents
where E1, E2 and E3 are CR2; or one of E1, E2 or E3 is N and the others are CR2; or two of E1, E2 or E3 are N and the other is CR2.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein
represents
where G is selected from the group consisting of CR3, CR3R3, OCR3R3; OCR3; CR3R3—CR3R3 and N;
D is selected from the group consisting of CR3, CR3R3 and N;
- - - represents a single bond or a double bond.

### Claim 10 (depends on 1)

The compound according to claim 1 wherein
is selected from the group consisting of

### Claim 11 (depends on 10)

The compound according to claim 10 wherein
represents

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R6 is a direct bond and R7 is —CO2H.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein each R2 is independently selected from the group consisting of H and halogen and each R3 is H.

### Claim 14 (depends on 1)

A compound according to claim 1 selected from:
1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
4-(5-chloro-2-cyclobutoxybenzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-bromo-2-(4-chloro-2-fluorobenzyloxy)benzyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(2-(benzyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(2-((2-chloro-4-fluorobenzyl)oxy)-5-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(2-((2,4-difluorobenzyl)oxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
1-(2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-((2,4-difluorobenzyl)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-(cyclobutylmethoxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-isobutoxybenzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-[5-chloro-2-(1,2-dimethylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-[5-chloro-2-(2-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-[5-chloro-2-(cyclobutyloxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-{5-chloro-2-[(2-methylprop-2-enyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-[5-chloro-2-(3-fluoro-2-methylpropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-[5-chloro-2-(2-fluoropropoxy)benzyl]-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-{[2-(fluoromethyl)prop-2-enyl]oxy}benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-sulfonic acid,
1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-sulfonic acid,
1-(2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-sulfonic acid,
N-((1-(5-chloro-2-((2,4-difluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)acetamide,
N-((1-(5-chloro-2-((4-chloro-2-fluorobenzyl)oxy)benzyl)-1,2,3,4-tetrahydroquinolin-5-yl)sulfonyl)acetamide,
1-(5-chloro-2-(cyclopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-(propooxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
1-(5-chloro-2-(neopentyloxy)benzyl)-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
4-(2-(4-chloro-2-fluorobenzyloxy)-5-methylbenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-fluoro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-isobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-cyclobutoxybenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-(cyclopropylmethoxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
4-(5-chloro-2-(neopentyloxy)benzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-2-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylic acid,
8-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8-naphthyridine-4-carboxylic acid,
8-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-5,6,7,8-tetrahydro-1,8-naphthyridine-4-carboxylic acid,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine-5-carboxylic acid,
1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,7-naphthyridine-5-carboxylic acid,
1-{5-chloro-2-[(2,4-difluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carboxylic acid,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydro-1,6-naphthyridine-5-carboxylic acid,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-(methylsulfonyl)-1,2,3,4-tetrahydroquinoline-5-carboxamide,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-[(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide,
1-{5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl}-N-[(dimethylamino)sulfonyl]-1,2,3,4-tetrahydroquinoline-5-carboxamide,
N-({1-(5-chloro-2-[(4-chloro-2-fluorobenzyl)oxy]benzyl})-1,2,3,4-tetrahydroquinolin-5-yl]amino}carbonyl)methanesulfonamide,
4-(2-cyclobutoxy-5-fluorobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-8-carboxylic acid,
and the salts and prodrugs thereof.

### Claim 15 (depends on 1)

A medicament comprising at least a compound according to claim 1.

### Claim 16 (depends on 1)

Pharmaceutical composition comprising at least one compound according to claim 1 and at least one pharmaceutically acceptable carrier, additive, adjuvant or vehicle.