Therapeutic tetrahydronaphthalene compounds

Patent metadata

Field	Value
Publication number	US-10017458-B2
Application number	US-201514665928-A
Country	US
Kind code	B2
Filing date	Mar 23, 2015
Priority date	May 5, 2009
Publication date	Jul 10, 2018
Grant date	Jul 10, 2018

Abstract

The invention relates to protein binding interacting/binding compounds and methods of identifying and using them. The invention further relates to pharmaceutical compositions and methods for treating 5-HT2C and/or RSK disorders, including diseases and disorders mediated by CPCRs and/or RSKs.

First claim

What is claimed is:

1. A method of treating a GPCR-mediated disorder in a subject comprising administering to the subject identified as in need thereof a compound of formula (I), or salt thereof, wherein the GPCR-mediated disorder is a neuropsychiatric disorder, a neurodegenerative disorder, a neurological disorder, a cardiovascular disorder, a gastrointestinal disorder, or a genito-urinary tract disorder:

wherein,
R 1 is independently H, NH 2 , NH(R′), N(R′) 2 ;
or

wherein ring A is a 3-8 membered heterocyclic or heteroaryl, containing 0-3 additional heteroatoms selected from O, N and S; wherein ring A is optionally substituted;
each R′ is independently alkyl, alkenyl, or alkynyl, each of which may be optionally substituted;
R 2 is independently —(CH 2 )n-;
each n is independently 1 or 2;
R 3 is independently H, OH, or halo;
R 4 is independently H, OH, or halo
each R 5 is independently alkyl, aryl, halo, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy;
R 6 is independently H or alkyl;
R 7 independently H, or N(alkyl) 2 ; and
each R 8 is independently cycloalkyl, heteroaryl, or heterocyclic, each optionally substituted with 1, 2, 3, or 4 independent R 5 ;

or salt, hydrate or solvate thereof;
wherein the neuropsychiatric disorder is obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, anxiety, depression, schizophrenia, or sleep disorders, the neurodegenerative disorder is Parkinson's Disease or Alzheimer's Disease, the neurological disorder is epilepsy, the cardiovascular disorder is hypertension, the gastrointestinal disorder is irritable bowel syndrome, and the genito-urinary tract disorder is bladder control.

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

or salt thereof.

3. The method of claim 1 , wherein in the compound of formula (I), R 1 is —NMe 2 , or

wherein ring A is a 3-8 membered heterocyclic or heteroaryl, containing 0-3 additional heteroatoms selected from O, N and S; wherein ring A is optionally substituted.

4. The method of claim 1 , wherein in the compound of formula (I), R 8 is cycloalkyl optionally substituted with 1, 2, 3, or 4 independent R 5 .

5. The method of claim 1 , wherein the disorder is cocaine addiction or amphetamine or methamphetamine addiction.

6. The method of claim 1 , wherein the disorder is obesity.

7. A method of treating a GPCR-mediated disorder in a subject comprising administering to the subject identified as in need thereof a compound of formula (I), or salt thereof, wherein the GPCR-mediated disorder is a neuropsychiatric disorder, a neurodegenerative disorder, a neurological disorder, a cardiovascular disorder, a gastrointestinal disorder, or a genito-urinary tract disorder:

wherein,
R 1 is independently H, NH 2 , NH(R′), N(R′) 2 ;
or

wherein ring A is a 3-8 membered heterocyclic or heteroaryl, containing 0-3 additional heteroatoms selected from O, N and S; wherein ring A is optionally substituted;
each R′ is independently alkyl, alkenyl, or alkynyl, each of which may be optionally substituted;
R 2 is independently —(CH 2 )n-;
each n is independently 1 or 2;
R 3 is independently H, OH, or halo;
R 4 is independently H, OH, or halo
R 6 is independently H or alkyl;
R 7 independently H, or N(alkyl) 2 ; and
R 8 is aryl substituted with 1, 2, 3, or 4 independent aryl, nitro, amino, heteroaryl, cycloalkyl, heterocyclic, or alkoxy;

or salt, hydrate or solvate thereof;
wherein the neuropsychiatric disorder is obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, anxiety, depression, schizophrenia, or sleep disorders, the neurodegenerative disorder is Parkinson's Disease or Alzheimer's Disease, the neurological disorder is epilepsy, the cardiovascular disorder is hypertension, the gastrointestinal disorder is irritable bowel syndrome, and the genito-urinary tract disorder is bladder control.

8. The method of claim 7 , wherein in the compound of formula (I), R 1 is —NMe 2 , or

wherein ring A is a 3-8 membered heterocyclic or heteroaryl, containing 0-3 additional heteroatoms selected from O, N and S; wherein ring A is optionally substituted.

9. The method of claim 7 , wherein the disorder is cocaine addiction or amphetamine or methamphetamine addiction.

10. The method of claim 7 , wherein the disorder is obesity.

11. A method of treating a GPCR-mediated disorder in a subject comprising administering to the subject identified as in need thereof a compound or salt thereof, wherein the GPCR-mediated disorder is a neuropsychiatric disorder, a neurodegenerative disorder, a neurological disorder, a cardiovascular disorder, a gastrointestinal disorder, or a genito-urinary tract disorder, wherein the compound is:

or salt thereof, wherein the neuropsychiatric disorder is obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, anxiety, depression, schizophrenia, or sleep disorders, the neurodegenerative disorder is Parkinson's Disease or Alzheimer's Disease, the neurological disorder is epilepsy, the cardiovascular disorder is hypertension, the gastrointestinal disorder is irritable bowel syndrome, and the genito-urinary tract disorder is bladder control.

12. A method of treating a GPCR-mediated disorder in a subject comprising administering to the subject identified as in need thereof a compound of formula (I), or salt thereof, wherein the GPCR-mediated disorder is a neuropsychiatric disorder, a neurodegenerative disorder, a neurological disorder, a cardiovascular disorder, a gastrointestinal disorder, or a genito-urinary tract disorder:

wherein,
R 1 is

wherein ring A is a 3-8 membered heterocyclic or heteroaryl, containing 0-3 additional heteroatoms selected from O, N and S; wherein ring A is optionally substituted;
R 2 is independently —(CH 2 )n-;
each n is independently 1 or 2;
R 3 is independently H, OH, or halo;
R 4 is independently H, OH, or halo
R 6 is independently H or alkyl;
R 7 is independently H, or N(alkyl) 2 ; and
R 8 is aryl substituted with 1, 2, 3, or 4 independent alkyl or halo;

or salt, hydrate or solvate thereof;
wherein the neuropsychiatric disorder is obesity, addiction, cocaine addiction, amphetamine/methamphetamine addiction, anxiety, depression, schizophrenia, or sleep disorders, the neurodegenerative disorder is Parkinson's Disease or Alzheimer's Disease, the neurological disorder is epilepsy, the cardiovascular disorder is hypertension, the gastrointest

Assignees

• Univ Florida
• Univ Florida

Inventors

• Booth Raymond G

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/22

  Anxiolytics · CPC title