# US 7,410,991 B2 · Pyrazolidinone compounds as ligands of the prostaglandin EP2 and/or EP4 receptors

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- Number: US 7,410,991 B2
- Document ID: US7410991B2
- Status: Granted
- Kind: B2
- Application number: 10/492,910
- Filed: 2002-10-23
- Published: 2004-12-16
- Granted: 2008-08-12
- Earliest claimed: 2001-10-23
- Assignees: Laboratoires Serono SA
- Inventors: Gian Luca Araldi; Yihua Liao; Adulla P. Reddy; Zhong Zhao
- Web page: https://patentgrep.com/patent/US7410991B2

## CPC

- A61K 31/4152: having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 5/24: of the sex hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- 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 11/06: Antiasthmatics
- 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 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 15/10: for impotence
- A61P 17/06: Antipsoriatics
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 19/10: for osteoporosis
- 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 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/12: Antivirals
- A61P 31/18: for HIV
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 231/08: with oxygen or sulfur atoms directly attached to ring carbon atoms
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides substituted pyrazolidinone compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for a variety of therapies, including treating or preventing preterm labor, dysmenorrhea, asthma, hypertension, infertility or fertility disorder, undesired blood clotting, preeclampsia or eclampsia, an eosinophil disorder, sexual dysfunction, osteporosis and other destructive bone disease or disorder, and other diseases and disorders associated with the prostaglandin EP2 and/or EP4 receptors.

## Claims

### Claim 1

A compound of the following Formula VI:
Wherein M is COX with X is OR′ and R′ is H;
D is (CH2)n″ wherein n″ is 2;
Q is (CH2)n′″ wherein n′″ is 0 or 1;
R5 is H or C1-C6 alkyl; and
R6 is —CHR7—W, wherein R7 is H or C1-C6 alkyl; W is phenyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R6 is —CHR7—W, wherein R7 is H or methyl; W is unfused phenyl substituted with a group selected from H, halogen, —OCF3, and —CF3.

### Claim 3 (depends on 1)

The compound as claimed in claim 1, wherein the compound exhibits a Ki of about 50 μM or less in a standard EP2 receptor binding assay.

### Claim 4 (depends on 1)

The compound as claimed in claim 1, wherein the compound exhibits a Ki of about 10 μM or less in a standard EP2 receptor binding assay.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds as claimed in claim 1.

### Claim 6 (depends on 5)

The pharmaceutical composition as claimed in claim 5, wherein the compound is packaged together with instructions for use of the compound to treat preterm labor, dysmenorrhea, asthma, hypertension, infertility or a fertility disorder, sexual dysfunction, undesired blood cloning, a destructive bone disease or disorder, preeclampsia or eclampsia, or an cosinophil disorder.

### Claim 7

A compound selected from the group consisting of:
4-[2-(2-(3-hydroxyoctyl)-5-oxopyrazolidin-1-yl)ethyl]benzoic acid;
4-{2-[2-(4-hydroxynon-2-ynyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-(4-hydroxynonyl)-5-oxopyrazolidin-1-yl]ethyl }benzoic acid;
4-(2-{2-[(2Z)-4-hydroxynon-2-enyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid;
4-(2-{2-[(2E)-4-hydroxynon-2-enyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid;
4-{2-[2-(4-hydroxyoctyl)-5-oxopyrazolidin-1-yl]ethyl) benzoic acid;
4-{2-[2-(4-hydroxy-6-methylheptyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-(4-hydroxy-5-methyloctyl)-5-oxopyrazolidin-1-yl)ethyl}benzoic acid;
4-{2-[2-(4-ethyl-4-hydroxyoctyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-(4-hydroxy-4-methylheptyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-(2-[2-(4-hydroxy-4,7-dimethyloctyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-(3 -hydroxy-5-methylhexyl)-5-oxopyrazolidin-1-yl]ethyl) benzoic acid;
4-{2-[2-(3 -cyclobutyl-3-hydroxypropyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-((4S)-hydroxynonyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-{2-[2-((4R)-hydroxynonyl)-5-oxopyrazolidin-1-yl]ethyl }benzoic acid;
4-[2-(2-{4-[1-(cyclopropylmethyl)cyclobutyl]-4-hydroxybutyl)-5-oxopyrazolidin-1-yl)ethyl]benzoic acid;
4-(2-{2-[4-(1-ethylcyclobutyl)-4-hydroxybutyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid; 4-(2-{2-[3-hydroxy-4-(3-methylphenyl)butyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid; 4-{2-[2-(3-hydroxy-4-phenylbutyl)-5-oxopyrazolidin-1-yl]ethyl}benzoic acid;
4-(2-{2-[4-(3-iodophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl}ethyl) benzoic acid;
4-(2-{2-[4-(3-bromophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid;
4-[2-(2-{3-hydroxy-4-[3-(trifluoromethoxy)phenyl]butyl)-5-oxopyrazolidin-1-yl) ethyl]benzoic acid;
4-(2-{2-[4-(3-fluorophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl }ethyl) benzoic acid;
4-[2-(2-{3-hydroxy-4-[3-(trifluoromethyl)phenyl]butyl}-5-oxopyrazolidin-1-yl) ethyl]benzoicacid;
4-(2-{2-[(3S, 4S)-3-hydroxy-4-phenylpentyl]-5-oxopyrazolidin-1-yl}ethyl) benzoic acid;
4-(2-(2-[4-(1,3-benzodioxol-5-yl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl}ethyl) benzoicacid;
4-(2-{2-[4-(3-chlorophenyl)-3-hydroxybutyl]-5-oxopyrazolidin-1-yl}ethyl) benzoic acid;
4-(2-{2-[(4R)-3-hydroxy-4-phenylpentyl]-5-oxopyrazolidin-1-yl)ethyl)benzoic acid;
and pharmaceutically acceptable salts thereof.

### Claim 8 (depends on 7)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds as claimed in claim 7.

### Claim 9 (depends on 2)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and one or more compounds as claimed in claim 2.