Estrogen receptor modulators and uses thereof

• US 9,399,646 B2
• Filed: 09/15/2011
• Issued: 07/26/2016
• Est. Priority Date: 09/16/2010
• Status: Active Grant

• Current Assignee: Seragon Pharmaceuticals, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Smith, Nicholas D., Kahraman, Mehmet, Govek, Steven P., Nagasawa, Johnny Y., Lai, Andiliy G., Julien, Jackaline D., Herbert, Mark R., Bonnefous, Celine, Douglas, Karensa L.
• Primary Examiner(s): Barker, Michael
• Assistant Examiner(s): Cheng, Karen
• Application Number:
  US13/821,190
• Publication Number:
  US 20130231333A1
• Time in Patent Office: 1,776 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/7056 containing five-membered rings with nitrogen as a ring hetero atom
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/708 having oxo groups directly attached to the purine ring system, e.g. guanosine, guanylic acid
• CPC Class Codes: A61K 31/7105 Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
• 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 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• 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 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 21/00 : Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 : Antimigraine agents
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 : Antidepressants
• 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 25/32 : Alcohol-abuse
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/20 : for DNA viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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 9/12 : Antihypertensives
• CPC Class Codes: C07C 215/10 : with one amino group and at least two hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07D 209/08 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 217/24 : Oxygen atoms
• CPC Class Codes: C07D 231/56 : Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 249/18 : Benzotriazoles
• CPC Class Codes: C07D 265/18 : with hetero atoms directly attached in position 2
• CPC Class Codes: C07D 277/68 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 279/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 401/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 409/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 413/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 417/10 : linked by a carbon chain containing aromatic rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

Claims

1. A compound of Formula (XVII), or a pharmaceutically acceptable salt, or N-oxide thereof:

3. The compound of claim 1, wherein:

ring A is

4. The compound of claim 1, or a pharmaceutically acceptable salt, or N-oxide thereof, wherein:

ring A is indolizinyl, azaindolizinyl, indolyl, azaindolyl, indazolyl, azaindazolyl, benzimidazolyl, azabenzimidazolyl, benzotriazolyl, azabenzotriazolyl, benzoxazolyl, azabenzoxazolyl, benzisoxazolyl, azabenzisoxazolyl, benzofuranyl, azabenzofuranyl, benzothienyl, azabenzothienyl, benzothiazolyl, or azabenzothiazolyl;

Z is —

OH, —

OR¹⁰, —

NR⁸R^8′

, or —

NR⁸S(═

O)₂R¹⁰;

R² is C₁-C₆ alkyl, C₁-C₆fluoroalkyl, C₁-C₆ deuteroalkyl, or C₃-C₆ cycloalkyl;

each R³ is independently halogen, —

CN, C₁-C₄ alkyl, or C₁-C₄ fluoroalkyl;

each R⁴ is independently selected from H, halogen, —

CN, —

OH, —

OR⁹, —

SR⁹, —

S(═

O)R¹⁰, —

S(═

O)₂R¹⁰, —

C(═

O)R¹⁰, —

OC(═

O)R¹⁰, —

CO₂R⁹, —

C(═

O)N(R⁹)₂, C₁-C₄alkyl, C₂-C₄alkenyl, C₂-C₄alkynyl, C₁-C₄fluoroalkyl, C₁-C₄heteroalkyl, C₁-C₄fluoroalkoxy, and C₁-C₄alkoxy;

each R⁵ is independently halogen, C₁-C₄alkyl, or C₁-C₄fluoroalkyl;

R⁶ is H;

R⁷ is H;

R⁸ and R^8′

is independently H or C₁-C₆ alkyl;

each R⁹ is independently selected from H and C₁-C₆alkyl;

R¹⁰ is C₁-C₆alkyl;

p is 0 or 1.

5. The compound of claim 4, or a pharmaceutically acceptable salt, or N-oxide thereof, wherein:

ring A is

6. A pharmaceutical composition comprising a compound as claimed in claim 1, or a pharmaceutically acceptable salt, or N-oxide thereof, and at least one pharmaceutically acceptable inactive ingredient.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

2. A compound of Formula (XVI), or a pharmaceutically acceptable salt, or N-oxide thereof:

9. The compound (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of claim 9, or a pharmaceutically acceptable salt, and at least one pharmaceutically acceptable inactive ingredient.

11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is formulated for intravenous injection, subcutaneous injection, oral administration, or topical administration.

12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion.

13. The pharmaceutical composition of claim 10 comprising the N-methylglucamine salt of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid.

14. The pharmaceutical composition of claim 10 comprising the sodium salt of (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-1-(1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid.

15. The pharmaceutical composition of claim 10 comprising at least one pharmaceutically acceptable inactive ingredient selected from microcrystalline cellulose, hydroxypropyl cellulose, carboxymethylcellulose, and magnesium stearate.