US 7,253,168 B2 · Substituted 1-benzyl-4-substituted piperazine analogues

Abstract

Compounds of Formula I are provided, in which variables are as described herein: Such compounds may be used to modulate MCH binding to MCH receptors in vivo or in vitro, and are particularly useful in the treatment of a variety of metabolic, feeding and sexual disorders in humans, domesticated companion animals and livestock animals. Pharmaceutical compositions and methods for treating such disorders are provided, as are methods for using such ligands for detecting MCH receptors (e.g., receptor localization studies).

A compound of the formula

or a pharmaceutically acceptable salt thereof, wherein:
V is absent or —(C═O)—;
W is nitrogen,
Y1 is CH or nitrogen;
Y3 and Y4 are independently CR1 or nitrogen;
and Z is nitrogen or CR2;
such that at least one of Y3, Y4 and Z is nitrogen, and at least one of Y3, Y4 and Z is substituted carbon;
each R1 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl, (C3-C7cycloalkyl)C0-C6alkyl or (4- to 7-membered heterocycloalkyl)C0-C6alkyl;
or
(ii) taken together with R2 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
R2 is halogen, nitro, cyano, amino, acetyl, carboxamide, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C2-C6alkanoyl, C2-C6alkyloxime, C1-C6alkoxy, C1-C6alkoxyC1-C4alkyl, hydroxyC1-C6alkyl, C1-C6alkoxycarbonyl, mono- or di-alkylcarboxamide, C1-C6alkylthio, C1-C6alkylsulfonyl, haloC1-C6alkyl, haloC1-C6alkoxy, aminoC1-C6alkyl, mono- or di-(C1-C6alkyl)aminoC0-C6alkyl or (C3-C7cycloalkyl)C0-C6alkyl;
or
R2 is (4- to 7-membered heterocycloalkyl)C0-C6alkyl, phenylC0-C2alkyl, phenylC1-C2alkoxy or (5 or 6-membered heteroaryl)C0-C2alkyl, each of which is substituted with 0 to 3 substituents independently chosen from halogen, C1-C2alkoxy and C1-C2alkyl;
or
R2 is taken together with a R1 to form a fused 5- or 6-membered carbocycle or heterocycle, each of which is substituted with 0 to 3 substituents independently chosen from halogen, hydroxy, nitro, cyano, amino, C1-C4alkyl, C1-C4alkoxy, haloC1-C4alkyl and haloC1-C4alkoxy;
n is 1 or 2;
R3 is:
taken together with R6 to form a fused heterocycle having one ring, wherein the ring contains 6 ring members and 0 additional heteroatoms;
R4 is hydrogen, C1-C6alkyl or haloC1-C6alkyl;
each R5 is independently:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
R6 is:
taken together with R3 to form a fused heterocycle having one ring, wherein the ring contains 6 ring members and 0 additional heteroatoms;
P is N or CR7;
Q is N or CR8;
U is N or CR9;
T is N or CR10;
X is N or CR11;
R7 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOR or a group of the formula L-M;
or (ii) taken together with R8 to form a fused 5- or 6-membered carbocycle or heterocycle;
R8 is:
(i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or (ii) taken together with R7 to form a fused 5- or 6-membered carbocycle or heterocycle;
R9 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or (ii) taken together with R10 or R11 to form a fused 5- to 10-membered carbocycle or heterocycle;
R10 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
(ii) taken together with R9 to form a fused 5- to 10-membered carbocycle or heterocycle;
R11 is:
(i) halogen, hydroxy, nitro, cyano, —COOH or a group of the formula L-M;
or (ii) taken together with R9 to form a fused carbocycle or heterocycle;
R12 is:
(i) hydrogen, halogen, hydroxy, nitro, cyano, amino, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, haloC1-C6alkyl, haloC1-C6alkoxy, mono- or di-(C1-C6alkyl)amino or aminoC1-C6alkyl;
or
each L is independently a single covalent bond, N(R13), O, C(═O), SO2, SO2NH, C(═))N(R13) or N(R13)C(═O), wherein each R13 is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl or haloC1-C6alkyl;
and
each M is independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, haloC1-C6alkyl, aminoC1-C6alkyl or a 5- to 10-membered cycloalkyl or heterocycloalkyl;
such that if Y1 and Y3 are both nitrogen and R11 is trifluoromethyl, then R2 is not amino.

48 more elements

Description21,707 words

Summary1,917 words

#This invention relates generally to substituted 1-benzyl-4-substituted piperazine analogues. The invention further relates to the use of such compounds for treating a variety of metabolic, eating and sexual disorders, and as probes for the detection and localization of melanin concentrating hormone receptors.

#Melanin concentrating hormone, or MCH, is a cyclic 19 amino acid neuropeptide first identified as a regulator of skin coloration in fish and other vertebrates, and subsequently as a regulator of food intake and energy balance in higher vertebrates. In many species, including humans, MCH is produced in the hypothalamus. MCH is also produced at various peripheral sites, including the gastrointestinal tract and testis.

#The postulated role of MCH in feeding behavior and body weight regulation is confirmed by the finding that i.c.v. injection of MCH increases caloric consumption in rats over similarly treated control animals. Furthermore, rats having the ob/ob genotype exhibit a 50-80% increase in MCH mRNA expression as compared to leaner ob/+ genotype mice, and prepro-MCH knockout mice, as well as MCH receptor knockout mice, are leaner than normal mice, due to hypophagia and an increased metabolic rate.

Detailed description19,790 words

#As noted above, the present invention provides substituted 1-benzyl-4-substituted piperazine analogues of Formula I. Certain such compounds are MCH receptor modulators that may be used in vitro or in vivo, to inhibit MCH binding to MCH receptors, activate MCH receptors, or to otherwise modulate MCH receptor activity in a variety of contexts, as discussed in further detail below.

#Terminology

#Compounds are generally described herein using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise specified) all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention unless otherwise specified. Where a compound exists in various tautomeric forms, a recited compound is not limited to any one specific tautomer, but rather is intended to encompass all tautomeric forms. Compound descriptions are intended to encompass compounds with all possible isotopes of atoms occurring in the compounds. Isotopes are those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C and 14C. Certain compounds are described herein using a general formula that includes variables (e.g., X, V, R3). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than one time in a formula is defined independently at each occurrence. In general, the variables may have any definition described herein that results in a stable compound.

Facts

Application

11/100,355Filed 6 Apr 2005 · us provisional application

Priority

7 Apr 2004

Published

US 2006/0142301 A129 Jun 2006

Granted

7 Aug 2007

Term ended

6 Apr 2025

Estimated · how

20 years from earliest known nonprovisional domestic filing plus recorded patent term adjustment. Maintenance-fee lapses, terminal disclaimers and statutory extensions have not been checked. The continuity chain may be incomplete; this is not an enforceability determination.

Classification9 codes

C07D 213/74
Nitrogen atoms: amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics
C07D 213/82
Amides; Imides: in position 3

Substituted 1-benzyl-4-substituted piperazine analogues

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Substituted 1-benzyl-4-substituted piperazine analogues

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Abstract

Drawings

Drawings

Claims26

Description21,707 words

Drawings

Classification9 codes

Life of this patent

Description21,707 words