Compounds with activity at estrogen receptors

• US 8,822,548 B2
• Filed: 10/29/2010
• Issued: 09/02/2014
• Est. Priority Date: 05/04/2004
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Hyldtoft, Lene, Piu, Fabrice, Gustafsson, Magnus, Sherbukhin, Vladimir, Winther Lund, Birgitte
• Primary Examiner(s): Fetterolf, Brandon
• Assistant Examiner(s): Shiao, Yih-Horng
• Application Number:
  US12/915,354
• Publication Number:
  US 20110046237A1
• Time in Patent Office: 1,404 Days
• Field of Search: 514/719, 514/729
• US Class Current: 514/729
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 17/04 Antipruritics
• 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 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/30 Oestrogens
• 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 17/263 : by condensation reactions
• CPC Class Codes: C07C 17/2632 : involving an organo-magnesium compound, e.g. Grignard synthesis
• CPC Class Codes: C07C 22/08 : containing fluorine
• CPC Class Codes: C07C 25/18 : Polycyclic aromatic halogenated hydrocarbons
• CPC Class Codes: C07C 25/24 : Halogenated aromatic hydrocarbons with unsaturated side chains
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 2602/20 : the ring system containing seven carbon atoms
• CPC Class Codes: C07C 2602/24 : the ring system containing nine carbon atoms, e.g. perhydroindane
• CPC Class Codes: C07C 307/02 : Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids
• CPC Class Codes: C07C 37/055 : the substituted group being bound to oxygen, e.g. ether group
• CPC Class Codes: C07C 37/14 : by addition reactions, i.e. reactions involving at least one carbon-to-carbon unsaturated bond
• CPC Class Codes: C07C 37/62 : by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• CPC Class Codes: C07C 39/17 : containing other rings in addition to the six-membered aromatic rings , e.g. cyclohexylphenol
• CPC Class Codes: C07C 39/42 : containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 43/21 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 43/225 : containing halogen
• CPC Class Codes: C07C 43/23 : containing hydroxy or O-metal groups
• CPC Class Codes: C07C 43/30 : Compounds having groups
• CPC Class Codes: C07C 43/303 : having acetal carbon atoms bound to acyclic carbon atoms
• CPC Class Codes: C07C 45/71 : being hydroxy groups
• CPC Class Codes: C07C 49/517 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/753 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 49/84 : containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/72 : containing six-membered aromatic rings and other rings
• CPC Class Codes: C07C 65/17 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 65/26 : containing rings other than six-membered aromatic rings
• CPC Class Codes: C07C 69/017 : Esters of hydroxy compounds having the esterified hydroxy group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 69/24 : esterified with monohydroxylic compounds
• CPC Class Codes: C07C 69/76 : Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/30 : Oxygen atoms
• CPC Class Codes: C07D 263/32 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 265/06 : not condensed with other rings
• CPC Class Codes: C07D 265/10 : with oxygen atoms directly attached to ring carbon atoms
• CPC Class Codes: C07D 295/096 : with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 309/06 : Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 313/04 : not condensed with other rings
• CPC Class Codes: C07D 319/06 : not condensed with other rings
• CPC Class Codes: C07D 333/06 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
• CPC Class Codes: C07D 333/16 : by oxygen atoms
• CPC Class Codes: C07F 9/12 : with hydroxyaryl compounds

Abstract

Disclosed herein are methods of treatment and prevention of diseases and disorders related to estrogen receptors comprising administering novel di-aromatic compounds to patients in need thereof.

Claims

1. A method of treating a disorder selected from the group consisting of Alzheimer'"'"' s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, stroke;

multiple sclerosis, acute or chronic pain, and symptoms associated therewith, the method comprising;

identifying a subject in need of said treating; and

administering to the subject a pharmaceutically effective amount of a compound of formula I;

2. The method of claim 1, wherein;

n is an integer selected from the group consisting of 3, 4, and 5;

R₁ is selected from the group consisting of hydrogen, C₁-C₄ straight chained or branched alkyl, C₁-C₄ straight chained or branched alkenyl, C₁-C₄ straight chained or branched perhaloalkyl, and substituted or unsubstituted aryl;

each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅ alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —

CN, —

OR₆, —

C(═

O)R₆, —

C(═

O)OR₆, —

C(═

O)NR₆R_6a, —

N(R₆)—

C(═

O)R_6a, —

N(R₆)—

S(═

O)₂R_6a, —

OC(═

O)R₆, and —

SR₆;

R₃, located in one or more sites, is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅ alkenyl, cycloalkyl, cycloalkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —

CN, ═

O, and —

OR₆, or is each separately absent to accommodate a double bond;

each of R₄, R_4a, R_4b, and R_4c is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅ alkenyl, hydroxy, halogen, sulfonyl, perhaloalkyl, —

OR₆, —

CN, —

C(═

O)R₆, —

C(═

O)OR₆, —

C(═

O)NR₆R_6a, —

N(R₆)—

C(═

O)R_6a, —

OC(═

Z)R₆, —

N(R₆)—

S(═

O)₂R_6a, and —

SR₆; and

R₅ is selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, halogen, —

CN, —

SR₆, sulfonyl, —

OCF₃, and perhaloalkyl.

3. The method of claim 2 wherein;

n is 3;

R₁ is selected from the group consisting of hydrogen, C₁-C₄ straight chained or branched alkyl, substituted or unsubstituted aryl;

each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, F, Cl, Br, perhaloalkyl, —

CN,—

OR₆, —

C(═

O), and —

SR₆;

R₃, located in one or more sites, is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, C₁-C₅ alkenyl, cycloalkyl, halogen, perhaloalkyl, —

CN, and —

OR₆, or is each separately absent to accommodate a double bond;

each of R₄, R_4a, R_4b, and R_4c is separately selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, halogen, sulfonyl, perhaloalkyl, —

OR₆, —

CN, —

N(R₆)—

S(═

O)₂R_6a, and —

SR₆; and

R₅ is selected from the group consisting of hydrogen, C₁-C₅ straight chained or branched alkyl, F, Cl, —

CN, —

SR₆, —

OCF₃, and CF₃.

4. The method of claim 2, wherein the compound of formula I is selected from the group consisting of:

5. The method of claim 1, wherein R₁ is selected from the group consisting of hydrogen, C₁-C₈ straight chained or branched alkyl, C₁-C₈ straight chained or branched alkenyl, and C₁-C₈ straight chained or branched perhaloalkyl.

6. The method of claim 1, wherein, R₁ is selected from the group consisting of hydrogen, cycloalkyl, cycloalkenyl, and substituted or unsubstituted aryl.

7. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, alkenyl, hydroxy, halogen, and perhaloalkyl.

8. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, halogen, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heteroalicyclyl.

9. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, and halogen, wherein the halogen is fluoro, chloro, or iodo.

10. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, and halogen, wherein the halogen is fluoro or iodo.

11. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, and halogen, wherein the alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, isobutyl, and tert-butyl.

12. The method of claim 1, wherein each of R₂, R_2a, R_2b, and R_2c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, and halogen, wherein the alkyl is methyl and wherein the halogen is fluoro or iodo.

13. The method of claim 1, wherein R₃, located in one or more sites, is separately selected from the group consisting of hydrogen, alkyl, alkenyl, and perhaloalkyl.

14. The method of claim 1, wherein R₃, located in one or more sites, is separately selected from the group consisting of hydrogen, isopropyl, and trifluoromethyl.

15. The method of claim 1, wherein each of R₄, R_4a, R_4b, R_4c is separately selected from the group consisting of hydrogen, alkyl, hydroxy, halogen, and —

OR₆.

16. The method of claim 1, wherein each of R₄, R_4a, R_4b, and R_4c is separately selected from the group consisting of hydrogen, halogen, and —

OR₆, wherein the halogen is chloro or fluoro, and wherein R₆ is hydrogen.

17. The method of claim 1, wherein R₅ is hydrogen or halogen, wherein the halogen is fluoro.

18. The method claim 1, wherein the compound of formula (I) is:

19. The method of claim 1, wherein the compound of formula I is 2-Fluoro-4-(1-(2-fluorophenyl)cyclohexyl)phenol.

20. A method of hormonal replacement therapy in a subject, the method comprising:

identifying a subject in need thereof; and

administering to the subject a pharmaceutically effective amount of a compound of formula I;

21. The method of claim 20, wherein the compound is selected from the group consisting of: