# US 8,772,296 B2 · Benzamide derivatives and uses related thereto

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- Number: US 8,772,296 B2
- Document ID: US8772296B2
- Status: Granted
- Kind: B2
- Application number: 11/806,461
- Filed: 2007-05-31
- Published: 2007-12-27
- Granted: 2014-07-08
- Earliest claimed: 2006-06-08
- Assignees: Amgen Inc.
- Applicants: Jay P. Powers; Michael Degraffenreid; Lisa Julian; Jacob Kaizerman; Dustin McMinn; Yosup Rew; Daqing Sun; Xuelei Yan; Zhulun Wang; Felix Gonzalez Lopez De Turiso
- Inventors: Jay P. Powers; Michael Degraffenreid; Lisa Julian; Jacob Kaizerman; Dustin McMinn; Yosup Rew; Daqing Sun; Xuelei Yan; Zhulun Wang; Felix Gonzalez Lopez De Turiso
- Web page: https://patentgrep.com/patent/US8772296B2

## CPC

- C07C 235/42: having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/381: having five-membered rings
- A61K 31/42: Oxazoles
- A61K 31/426: 1,3-Thiazoles
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4965: Non-condensed pyrazines
- A61K 31/50: Pyridazines; Hydrogenated pyridazines
- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 237/24: having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
- C07C 237/42: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
- C07C 255/31: having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing rings other than six-membered aromatic rings
- C07C 255/46: to carbon atoms of non-condensed rings
- C07C 255/60: at least one of the singly-bound nitrogen atoms being acylated
- C07C 271/12: to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C 271/20: to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
- C07C 307/06: having nitrogen atoms of the sulfamide groups bound to acyclic carbon atoms
- C07D 213/30: Oxygen atoms
- C07D 213/53: Nitrogen atoms
- C07D 237/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 241/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 277/22: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 277/24: Radicals substituted by oxygen atoms
- C07C 2601/02: with a three-membered ring
- C07C 2601/14: The ring being saturated
- C07C 2603/94: containing "free" spiro atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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

Benzamide derivatives of formula I are described and have therapeutic utility, particularly in the treatment of diabetes, obesity and related conditions and disorders: wherein R1, R2, R3, R4, R5, R6, R7, R8, and n are as defined herein.

## Claims

### Claim 1

A compound having the formula (I):
or pharmaceutically acceptable salts, solvates, stereoisomers or prodrugs thereof,
wherein:
n is 0;
R1 is a member selected from the group consisting of —OH, halogen and (C1-C8)haloalkyl;
R2 and R3 are members independently selected from the group consisting of halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)alkoxy, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl and (C3-C8)cycloalkyl, wherein no more than two of R1, R2 and R3 are halogen;
R4 is a member selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl and (C3-C8)cycloalkyl;
R5 is selected from the group consisting of (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, and (C3-C8)heterocycloalkyl;
R6 is selected from the group consisting of (C2-C8)alkenyl, (C1-C8)haloalkyl, aryl(C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, and aryl;
wherein each aryl and heteroaryl group is optionally substituted by substituents numbering from one to the number of open valences on the aryl or heteroaryl group selected from the group consisting of -halo, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO2, —CO2R′, —C(O)NR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″CO2R′, —NR′″C(O)NR′R″, —NR′″SO2NR′R″, —NHC(NH2)═NH, —NR′C(NH2)═NH, —NH—C(NH2)═NR′, —S(O)R′, —SO2R′, —SO2NR′R″, —NR″SO2R′, —N3, —CH(Ph)2, perfluoroalkoxy and perfluoro(C1-C4)alkyl;
wherein R5 or R6 is optionally substituted with from one to two members selected from the group consisting of halogen, —CN, —NO2, (C1-C4)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C2-C4)hydroxyalkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR′, —OR′, —SR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R′, —SO2R′, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′ and —NR′ SO2R′;
R7 is selected from the group consisting of —CN, (C2-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C8)haloalkyl, (C1-C8)hydroxyalkyl, —C(O)R′, —C(O)OR′, —NR′C(O)OR′, —OR′, —OC(O)R′, —C(O)N(R′)2, —S(O)R′, —SO2R′, —SO2N(R′)2, —N(R′)2, —NR′C(O)R′, —NR′SO2R′, —X—CN, —X—C(O)R′, —X—C(O)OR′, —X—NR′C(O)OR′, —X—OR′, —X—OC(O)R′, —X—C(O)N(R′)2, —X—S(O)R′, —X—SO2R′, —X—SO2N(R′)2, —X—N(R′)2, —X—NR′C(O)R′,
wherein each alkyl, alkenyl, and alkynyl can be substituted by one to three substitutents selected from the group consisting of —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, -halo, —SiR′R″R′″, —OC (O)R′, —C(O)R′, —CO2R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″, —NR′″SO2NR′R″, —NR″CO2R′, —NHC(NH2)═NH, —NR′C(NH2)═NH, —NHC(NH2)═NR′, —S(O)R′, —SO2R′, —SO2NR′R″, —NR″SO2R′, —CN and —NO2;
R6 and R7 may be combined to form a (C3-C8)cycloalkyl or (C3-C8)heterocycloalkyl;
R8 is selected from the group consisting of halogen, —CN, (C1-C6)alkyl, (C1-C6)alkyloxy, and —OH;
X is a branched or straight chain (C1-C8)alkylene group;
each occurrence of R′, R″, and R′″ is independently hydrogen or an unsubstituted member selected from the group consisting of (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C1-C4)alkoxy(C1-C4)alkyl, (C1-C8)haloalkyl, (C2-C8)hydroxyalkyl, (C3-C8)cycloalkyl, (C3-C8)heterocycloalkyl, heteroaryl, aryl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)heterocycloalkyl(C1-C6)alkyl, heteroaryl(C1-C6)alkyl, aryl(C1-C6)alkyl, or two R′ groups, when attached to the same nitrogen atom, can be combined with the nitrogen atom to which they are attached to form a heterocycle or heteroaryl group; and
with the proviso that when R1 is —OH, then R2 and R3 are not both CF3.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, solvate, stereoisomer, or prodrug thereof, wherein:
n is 0;
R1 is —OH; R2 is (C1-C3)alkyl; and R3 is (C1-C3)haloalkyl;
R5 is selected from the group consisting of (C1-C4)alkyl, (C3-C6)cycloalkyl, (C1-C3)haloalkyl; and
R6 is selected from the group consisting of (C3-C8)cycloalkyl, aryl, and heteroaryl.

### Claim 3 (depends on 2)

The compound of claim 2, wherein R6 is optionally substituted phenyl or pyridinyl.

### Claim 4 (depends on 2)

The compound of claim 2, wherein R6 is cyclopropyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R1 is —OH, R2 is methyl, and R3 is trifluoromethyl.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein R1, R2, and R3, together with the carbon atom to which they are attached, are an (S)-trifluoromethyl carbinol group of the formula:

### Claim 7 (depends on 5)

The compound according to claim 5, wherein R1, R2, and R3, together with the carbon atom to which they are attached, are an (R)-trifluoromethyl carbinol group of the formula:

### Claim 8 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and a pharmaceutically acceptable carrier.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1, and an additional therapeutic agent.

### Claim 10 (depends on 9)

A pharmaceutical composition of claim 9, wherein the additional therapeutic agent is useful for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, muscle wasting, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immune disorder.

### Claim 11 (depends on 1)

A method for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, Cushing's syndrome, and atherosclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1.

### Claim 12 (depends on 11)

The method of claim 11, wherein the condition or disorder is diabetes or obesity.

### Claim 13

A compound selected from the group consisting of:
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 14 (depends on 13)

The compound according to claim 13, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 15 (depends on 13)

The compound according to claim 13, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 16 (depends on 13)

The compound according to claim 13, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 17 (depends on 13)

The compound according to claim 13, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 18 (depends on 13)

The compound according to claim 13, which is
or a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug thereof.

### Claim 19 (depends on 13)

A pharmaceutical composition comprising the compound of claim 13, and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 13)

A pharmaceutical composition comprising the compound of claim 13, and an additional therapeutic agent.

### Claim 21 (depends on 20)

A pharmaceutical composition of claim 20, wherein the additional therapeutic agent is useful for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, polycystic ovarian disease, an eating disorder, craniopharyngioma, Prader-Willi syndrome, Frohlich's syndrome, hyperlipidemia, dyslipidemia, hypercholesterolemia, hypertriglyceridemia, low HDL levels, high HDL levels, hyperglycemia, insulin resistance, hyperinsulinemia, Cushing's syndrome, hypertension, atherosclerosis, vascular restenosis, retinopathy, nephropathy, neurodegenerative disease, neuropathy, muscle wasting, cognitive disorders, dementia, depression, psoriasis, glaucoma, osteoporosis, a viral infection, an inflammatory disorder and an immune disorder.

### Claim 22 (depends on 13)

A method for treating a condition or disorder selected from the group consisting of diabetes, syndrome X, obesity, Cushing's syndrome, and atherosclerosis, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 13.

### Claim 23 (depends on 22)

The method of claim 22, wherein the condition or disorder is diabetes or obesity.