US 7,479,493 B2Granted

Substituted benzyl amine compounds

AssigneeJanssen Pharmaceutica NV

InventorsBrett Allison, Michael P. Curtis, Cheryl A. Grice, John M. Keith, Michael A. Letavic, Jennifer M. B. Miller, Emily M. Stocking

Life of this patent

Estimating the term…

Abstract

Certain substituted benzyl amine compounds are histamine H3 receptor and/or serotonin transporter modulators useful in the treatment of histamine H3 receptor- and/or serotonin-mediated diseases.

Claims31

Dependent claims

A compound of Formula (I):

wherein
one of R1a and R1b is
and the other is —H;
R2 and R3 taken together with the nitrogen to which they are attached form a piperazine group unsubstituted or substituted on a carbon ring member with one, two, or three Rd moieties and substituted on a nitrogen ring member with an Re moiety;
where each Rd moiety is independently selected from the group consisting of:
—C1-6alkyl;
—C1-4alkyl-OH;
halo;
—OH;
—OC1-6alkyl;
ipso-substituted —OC2-3alkylO—;
—CN;
—NO2;
—N(Rg)Rh;
—C(O)N(Rg)Rh;
—N(Rg)SO2C1-6alkyl;
—C(O)C1-6alkyl;
—S(O)0-2—C1-6alkyl;
—SO2N(Rg)Rh;
—SCF3;
—CF3;
—OCF3;
—CO2H;
and —CO2C1-6alkyl;
where Rg and Rh are each independently —H or —C1-6alkyl, or Rg and Rh taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
and
where Re is selected from the group consisting of:
—H;
a —C1-6alkyl or —C(O)C1-6alkyl group unsubstituted or substituted with halo, —CN, —OH, —OC1-4alkyl, or —CF3;
—C(O)CF3;
—S(O)0-2—C1-6alkyl;
—CO2C1-6alkyl;
and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with —C1-4alkyl, halo, —CN, —OH, —OC1-4alkyl, or —CF3;
q is 0 or 1;
each R4 is independently —H or methyl, or both R4 substituents taken together form a carbonyl;
Y is —O—, —OCH2—, —S—, —SO—, or —SO2—;
R5 is —H or —C1-6alkyl;
R6 is —H;
or —C1-6alkyl, —C3-6alkenyl, —C3-6alkynyl, monocyclic cycloalkyl, or —C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C1-4alkyl, —OH, —OC1-4alkyl, halo, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CN, —CO2H, or —CO2C1-4alkyl;
R7 is —H;
or —C1-6alkyl, —C3-6alkenyl, —C3-6alkynyl, monocyclic cycloalkyl, or —C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C1-4alkyl, —OH, —OC1-4alkyl, halo, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CN, —CO2H, or —CO2C1-4alkyl;
or R6 and R7 taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with —C1-4alkyl, —OC1-4alkyl, or halo;
and
Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three Rk moieties;
where each Rk moiety is independently selected from the group consisting of:
—C1-6alkyl, —CHF2, —CF3, —C2-6alkenyl, —C2-6alkynyl, —OH, —OC1-6alkyl, —OCHF2, —OCF3, —OC3-6alkenyl, —OC3-6alkynyl, —CN, —NO2, —N(Rl)Rm, —N(Rl)C(O)Rm, —N(Rl)SO2C1-6alkyl, —C(O)C1-6alkyl, —S(O)0-2—C1-6alkyl, —C(O)N(Rl)Rm, —SO2N(Rl)Rm, —SCF3, halo, —CO2H, and —CO2C1-6alkyl;
or two Rk moieties on adjacent carbon atoms of attachment together are —OC1-4alkyleneO— to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
where Rl and Rm are each independently —H or —C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

46 more elements

A compound selected from the group consisting of:

[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone;
(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-methanone;
(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
(4-Isopropyl-piperazin-1-yl)-[4-(3-methoxy-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-phenoxy)-3-cyclopropylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-methanone;
[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-(3-methylaminomethyl-4-phenoxy-phenyl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[4-(3-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-phenoxy)-phenyl]-methanone;
[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(3-methyl-4-methylsulfanyl-phenoxy)-phenyl]-methanone;
[3-Cyclopropylaminomethyl-4-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[4-(4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(6-methyl-pyridin-3-yloxy)-phenyl]-methanone;
[4-(3-Chloro-4-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
[4-(3-Chloro-2-fluoro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-phenylsulfanyl)-3-methylaminomethyl-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(pyridin-2-ylsulfanyl)-phenyl]-methanone;
[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
[4-Cyclopropylaminomethyl-3-(pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[4-piperidin-1-ylmethyl-3-(pyridin-3-yloxy)-phenyl]-methanone;
[3-(4-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
[3-(3,4-Dichloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
[3-(3-Chloro-phenoxy)-4-methylaminomethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[3-(3,4-dichloro-phenoxy)-4-methylaminomethyl-phenyl]-methanone
[5-(4-Isopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;
Methyl-[5-(4-methyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;
[5-(4-Cyclobutyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;
Methyl-[2-(4-methylsulfanyl-phenoxy)-5-(4-pyridin-4-yl-piperazin-1-yl)-benzyl]-amine;
[5-[4-(2-Fluoro-ethyl)-piperazin-1-yl]-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;
[5-(4-Cyclopropyl-piperazin-1-yl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine
[5-(4-Cyclopropyl-piperazin-1-yl)-2-(3,4-dichloro-phenoxy)-benzyl]-methyl-amine;
[2-(3,4-Dichloro-phenoxy)-5-(4-isopropyl-piperazin-1-yl)-benzyl]-methyl-amine;
1-[3-Methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one;
4-Isopropyl-1-[3-methylaminomethyl-4-(4-methylsulfanyl-phenoxy)-phenyl]-piperazin-2-one;
1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-phenyl]-4-isopropyl-piperazin-2-one;
(4-Cyclopropyl-piperazin-1-yl)-[4-(3,4-dichloro-benzyloxy)-3-methylaminomethyl-phenyl]-methanone;
Cyclopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;
[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-methyl-amine;
[5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-dimethyl-amine;
Ethyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;
Isopropyl-[5-(4-isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzyl]-amine;
5-(4-Isopropyl-piperazin-1-ylmethyl)-2-(4-methylsulfanyl-phenoxy)-benzylamine;
4-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-1-isopropyl-piperazin-2-one;
1-[4-(3,4-Dichloro-phenoxy)-3-methylaminomethyl-benzyl]-4-isopropyl-piperazin-2-one;
[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone;
(4-Cyclobutyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
(4-Cyclopentyl-piperazin-1-yl)-[4-(3,4-dichloro-phenoxy)-3-methylaminomethyl-phenyl]-methanone;
[4-(3-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclobutyl-piperazin-1-yl)-methanone;
[4-(4-Chloro-phenoxy)-3-methylaminomethyl-phenyl]-(4-cyclopentyl-piperazin-1-yl)-methanone;
(4-Isopropyl-piperazin-1-yl)-[3-methylaminomethyl-4-(4-trifluoromethyl-pyridin-2-ylsulfanyl)-phenyl]-methanone;
(4-Cyclopropyl-piperazin-1-yl)-[4-dimethylaminomethyl-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-methanone;
(3-Benzyloxy-4-dimethylaminomethyl-phenyl)-(4-cyclopropyl-piperazin-1-yl)-methanone;
[4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-(2,6-dimethyl-pyridin-3-yloxy)-phenyl]-(4-cyclopropyl-piperazin-1-yl)-methanone;
[3-(2,6-Dimethyl-pyridin-3-yloxy)-4-morpholin-4-ylmethyl-phenyl]-(4-isopropyl-piperazin-1-yl)-methanone;
(4-{[Bis-(2-methoxy-ethyl)-amino]-methyl}-3-phenoxy-phenyl)-(4-isopropyl-piperazin-1-yl)-methanone;
[5-(4-Isopropyl-piperazine-1-carbonyl)-2-(3-methoxy-phenoxy)-benzyl]-methyl-carbamic acid tert-butyl ester;
and pharmaceutically acceptable salts thereof.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/766,172Filed 21 Jun 2007 · us provisional application
Priority: 29 Jun 2006
Published: US 2008/0045509 A121 Feb 2008
Granted: 20 Jan 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07C 237/34
Having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the…:…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents

Family

Application60/806,169Us provisional application · filed 29 Jun 2006
US 2008/0045509 A1Pre-grant publication · published 21 Feb 2008
US 7,479,493 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Certain substituted benzyl amine compounds are histamine H3 receptor and/or serotonin transporter modulators useful in the treatment of histamine H3 receptor- and/or serotonin-mediated diseases.

A compound of Formula (I):

wherein
one of R1a and R1b is
and the other is —H;
R2 and R3 taken together with the nitrogen to which they are attached form a piperazine group unsubstituted or substituted on a carbon ring member with one, two, or three Rd moieties and substituted on a nitrogen ring member with an Re moiety;
where each Rd moiety is independently selected from the group consisting of:
—C1-6alkyl;
—C1-4alkyl-OH;
halo;
—OH;
—OC1-6alkyl;
ipso-substituted —OC2-3alkylO—;
—CN;
—NO2;
—N(Rg)Rh;
—C(O)N(Rg)Rh;
—N(Rg)SO2C1-6alkyl;
—C(O)C1-6alkyl;
—S(O)0-2—C1-6alkyl;
—SO2N(Rg)Rh;
—SCF3;
—CF3;
—OCF3;
—CO2H;
and —CO2C1-6alkyl;
where Rg and Rh are each independently —H or —C1-6alkyl, or Rg and Rh taken together with their nitrogen of attachment form a monocyclic heterocycloalkyl group;
and
where Re is selected from the group consisting of:
—H;
a —C1-6alkyl or —C(O)C1-6alkyl group unsubstituted or substituted with halo, —CN, —OH, —OC1-4alkyl, or —CF3;
—C(O)CF3;
—S(O)0-2—C1-6alkyl;
—CO2C1-6alkyl;
and a phenyl, monocyclic carbon-linked heteroaryl, monocyclic cycloalkyl, or monocyclic carbon-linked heterocycloalkyl group, each unsubstituted or substituted with —C1-4alkyl, halo, —CN, —OH, —OC1-4alkyl, or —CF3;
q is 0 or 1;
each R4 is independently —H or methyl, or both R4 substituents taken together form a carbonyl;
Y is —O—, —OCH2—, —S—, —SO—, or —SO2—;
R5 is —H or —C1-6alkyl;
R6 is —H;
or —C1-6alkyl, —C3-6alkenyl, —C3-6alkynyl, monocyclic cycloalkyl, or —C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C1-4alkyl, —OH, —OC1-4alkyl, halo, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CN, —CO2H, or —CO2C1-4alkyl;
R7 is —H;
or —C1-6alkyl, —C3-6alkenyl, —C3-6alkynyl, monocyclic cycloalkyl, or —C1-6alkyl-(monocyclic cycloalkyl), each unsubstituted or substituted with —C1-4alkyl, —OH, —OC1-4alkyl, halo, —NH2, —NH(C1-4alkyl), —N(C1-4alkyl)2, —CN, —CO2H, or —CO2C1-4alkyl;
or R6 and R7 taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group unsubstituted or substituted with —C1-4alkyl, —OC1-4alkyl, or halo;
and
Cyc is a phenyl or monocyclic carbon-linked heteroaryl group, unsubstituted or substituted with one, two, or three Rk moieties;
where each Rk moiety is independently selected from the group consisting of:
—C1-6alkyl, —CHF2, —CF3, —C2-6alkenyl, —C2-6alkynyl, —OH, —OC1-6alkyl, —OCHF2, —OCF3, —OC3-6alkenyl, —OC3-6alkynyl, —CN, —NO2, —N(Rl)Rm, —N(Rl)C(O)Rm, —N(Rl)SO2C1-6alkyl, —C(O)C1-6alkyl, —S(O)0-2—C1-6alkyl, —C(O)N(Rl)Rm, —SO2N(Rl)Rm, —SCF3, halo, —CO2H, and —CO2C1-6alkyl;
or two Rk moieties on adjacent carbon atoms of attachment together are —OC1-4alkyleneO— to form a cyclic ring which is unsubstituted or substituted with one or two fluoro substituents;
where Rl and Rm are each independently —H or —C1-6alkyl;
or a pharmaceutically acceptable salt thereof.

46 more elements

Facts

Application

11/766,172Filed 21 Jun 2007 · us provisional application

Priority

29 Jun 2006

Published

US 2008/0045509 A121 Feb 2008

Granted

20 Jan 2009

Term ends

Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07C 237/34
Having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the…:…
A61P 1/08
Drugs for disorders of the alimentary tract or the digestive system: for nausea, cinetosis or vertigo; Antiemetics
A61P 1/14
Drugs for disorders of the alimentary tract or the digestive system: prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics,…
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents