Dibenzo chromene derivatives and their use as ERβ selective ligands

• US 7,157,492 B2
• Filed: 02/23/2005
• Issued: 01/02/2007
• Est. Priority Date: 02/26/2004
• Status: Expired due to Fees

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Mewshaw, Richard Eric, Edsall, Richard James Jr.
• Primary Examiner(s): Seaman; Margaret D.
• Assistant Examiner(s): Rahmani; Niloofar
• Application Number:
  US11/064,397
• Publication Number:
  US 20050234074A1
• Time in Patent Office: 678 Days
• Field of Search: 549/381, 549/356, 549/383, 549/384, 514/453
• US Class Current: 514/453
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/06 Anti-spasmodics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: 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
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 39/06 : Free radical scavengers or antioxidants
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/30 : Oestrogens
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 311/78 : Ring systems having three or more relevant rings
• CPC Class Codes: C07D 311/92 : Naphthopyrans; Hydrogenated naphthopyrans

Abstract

This invention provides estrogen receptor modulators of formula I, having the structure

where R¹, R², R³, R⁴, R⁵, R⁶, R⁷ and R⁸ are as defined in the specification.

Claims

1. A compound of the formula

2. A compound according to claim 1 wherein R⁴ is selected from hydrogen, C₁–

C₆ alkyl, halogen, C₁–

C₆ alkoxy, —

CN, C₂–

C₇ alkenyl, —

CHO, phenyl, furyl, thienyl, pyrimidinyl and pyridinyl.

3. A compound according to claim 1 wherein R⁴ is selected from hydrogen, C₁–

C₆ alkyl, halogen, C₁–

C₆ alkoxy, —

CN, C₂–

C₇ alkenyl, furyl, thienyl, and pyridinyl.

4. A compound according to any one of claim 1 wherein R⁵, R⁷, and R⁸ are each, independently, hydrogen or halogen.

5. A compound according to any one of claim 4 wherein R¹, R², R³, and R⁶ are each, independently, hydrogen, halogen, or hydroxyl.

6. A compound according to any one of claim 5 wherein at least one of R¹, R², R³ and R⁶ is hydroxyl.

7. A compound according to any one of claim 6 wherein R² and R⁶ are each hydroxyl.

8. A compound according to claim 1 which is one of the following:

(a) 5H-Dibenzo[c,g]chromene-3,9-diol;

(b) 8-Chloro-5H-dibenzo[c,g]chromene-3,9-diol;

(c) 7-Chloro-5H-dibenzo[c,g]chromene-3,9-diol;

(d) 7-Bromo-5H-dibenzo[c,g]chromene-3,9-diol;

(e) 3,9-Dihydroxy-5H-dibenzo[c,g]chromene-7-carbonitrile;

(f) 7-Methoxy-5H-dibenzo[c,g]chromene-3,9-diol;

(g) 7-Vinyl-5H-dibenzo[c,g]chromene-3,9-diol;

(h) 12-Bromo-7-methoxy-5H-dibenzo [c,g]chromene-3,9-diol;

(i) 12-Chloro-7-methoxy-5H-dibenzo [c,g]chromene-3,9-diol;

(j) 7-Methyl-5H-dibenzo[c,g]chromene-3,9-diol;

(k) 7-[2-(Hydroxymethyl)phenyl]-5H-dibenzo[c,g]chromene-3,9-diol;

(l) 7-Phenyl-5H-dibenzo[c,g]chromene-3,9-diol;

(m) 7-(2-Tolyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(n) 7-(3-Tolyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(o) 7-(4-Tolyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(p) 7-(4-Methoxyphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(q) 7-(4-Chlorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(r) 7-(4-Fluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(s) 7-Thien-2-yl-5H-dibenzo[c,g]chromene-3,9-diol;

(t) 7-Thien-3-yl-5H-dibenzo[c,g]chromene-3,9-diol;

(u) 7-(3-Fluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(v) 7-(3-Chlorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(w) 7-(3-Methoxyphenyl)-5H-dibenzo[c,g]chromene -3,9-diol;

(x) 7-(2-Chlorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(y) 7-(3,4-Difluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(z) 7-(4-Pyridyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(aa) 7-(2-Fluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(bb) 7-(3,4-Dimethylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(cc) 7-(4-Cyanophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(dd) 7-(3-Fluoro-4-Methylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ee) 7-(3,4-Dimethoxyphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ff) 7-(3-Trifluoromethylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(gg) 7-(3,5-Difluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(hh) 7-(3,5-Dichlorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ii) 7-(3-Methyl-4-Fluorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(jj) 7-(3-Furyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(kk) 7-(2-Furyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ll) 7-Butyl-5H-dibenzo[c,g]chromene-3,9-diol;

(mm) 7-(3-Pyridyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(nn) 7-(4-Methoxy-3-Pyridyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(oo) 7-(Pyrimidyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(pp) 7-(5-Methoxy-3-Pyridyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(qq) 7-(2-Pyridyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(rr) 7-(3,4-Dichlorophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ss) 7-(4-Methylthiophenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(tt) 7-(4-Cyanomethylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(uu) 7-(3-Trifluoromethoxyphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(vv) 7-(4-Trifluoromethoxyphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(ww) 7-(4-tert-Butylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(xx) 7-(Naphthyl)-5H-dibenzo[c,g]chromene-3,9-diol;

(yy) 7-(4-Ethylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol;

or

(zz) 7-(3,5-Dimethylphenyl)-5H-dibenzo[c,g]chromene-3,9-diol.

9. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claim 1 and a pharmaceutical carrier.