US 2010/0144852 A1Published application

Bicyclo[2.2.1]hept-7-ylamine Derivatives and Their Uses

AssigneeArgenta Discovery Limited

InventorsHarry Finch, Nicholas Charles Ray, Richard James Bull, Monique Bodil van Niel, Andrew Stephen Robert Jennings

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Abstract

Compounds of formula (I) have muscarinic M3 receptor modulating activity; Formula (I) wherein A is an oxygen atom or group —N(R12)—; (i) R1 is C1-C6-alkyl or a hydrogen atom; and R2 is a hydrogen atom or a group —R5, —Z—Y—R5—Z—NR9R10; —Z—CO—NR9R10; —Z—NR9—CO—R5; or —Z—CO2H; and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or (ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a hydrogen atom; or a group —R5, —Z—Y—R5, —Z—NR9R10, —Z—CO—NR9R10, —Z—NR9—CO—R5, or —Z—CO2H, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; or (iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group —Y—R5, —Z—Y—R5, —Z—NR9R10; —Z—CO—NR9R10; —Z—NR9—CO—R5; or —Z—CO2H and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge; R4 is a group of formula (a), (b), (c) or (d); is an C1-C6-alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group, and the remaining variables are as defined in the specification.

Claims38

Dependent claims

A compound of formula (I);

wherein
A is an oxygen atom or group —N(R12)—;
(i) R1 is C1-C6-alkyl or a hydrogen atom;
and R2 is a hydrogen atom or a group —R5, —Z—Y—R5, —Z—NR9R10;
—Z—CO—NR9R10;
—Z—NR9—CO—R5;
or —Z—CO2H;
and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
or
(ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a hydrogen atom;
or a group —R5, —Z—Y—R5, —Z—NR9R10, —Z—CO—NR9R10, —Z—NR9—CO—R5, or —Z—CO2H, in which cases the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
or
(iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group —Y—R5, —Z—Y—R5, —Z—NR9R10;
—Z—CO—NR9R10;
—Z—NR9—CO—R5;
or —Z—CO2H and R3 is a lone pair, or C1-C6-alkyl in which case the nitrogen atom to which it is attached is a quaternary nitrogen and carries a positive charge;
R4 is a group of formula (a), (b), (c) or (d);
Z is a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group;
Y is a bond or oxygen atom;
R5 is an C1-C8-alkyl, aryl, aryl-fused-cycloalkyl, aryl-fused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group;
R6 is C1-C6-alkyl or a hydrogen atom;
R7a and R7b are a C1-C6-alkyl group or halogen;
n and m are independently 0, 1, 2 or 3;
R8a and R8b are independently selected from the group consisting of aryl, aryl-fused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl;
R8c is —OH, C1-C6-alkyl, hydroxy-C1-C6-alkyl, nitrile, a group CONR8d2 or a hydrogen atom;
R8d is C1-C6-alkyl or a hydrogen atom;
R9 and R16 are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)-group;
or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing a further nitrogen or oxygen atom;
R12 is C1-C6-alkyl or a hydrogen atom;
Ar1 is aryl, heteroaryl or cycloalkyl;
Ar2 are independently aryl, heteroaryl or cycloalkyl;
and
Q is an oxygen atom, —CH2—, —CH2CH2— or a bond;
or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof.

31 more elements

A compound as claimed in any of the preceding claims wherein, in any group —R5, —Y—R5, —Z—Y—R5, —Z—NR9R10, —Z—CO—NR9R10, —Z—NR9—CO—R5, or —Z—CO2H:

Z is —(CH2)1-16—, optionally substituted on up to three carbons in the chain by methyl;
Y is a bond or —O—;
R5 is methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl;
or
phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl;
or
pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl;
or
arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the —(C1-C6-alkyl)-part is —CH2— or —CH2CH2—;
or
heteroarylalkyl wherein the hetroaryl part is pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl, and the —(C1-C6-alkyl)- part is —CH2— or —CH2CH2—;
or
indanyl or 1,2,3,4-tetrahydronaphthalenyl;
or
heterocycloalkyl(C1-C6-alkyl)-, wherein the heterocycloalkyl part is azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl, or tetrahydropyrrolyl and the —(C1-C6-alkyl)- part is —CH2— or —CH2CH2—, or
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
and
R9 and R10 are independently
hydrogen;
methyl, ethyl or n- or isopropyl;
phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl;
pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl;
or
arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the —(C1-C6-alkyl)-part is —CH2— or —CH2CH2—;
or R9 and R10 together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring.

22 more elements

A compound as claimed in any of the preceding claims wherein A is an oxygen atom

Dependencies are inferred from the claim text.

Facts

Application: 12/063,212Filed 8 Aug 2006
Priority: GB 0516314.28 Aug 2005
Published: 10 Jun 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification28 codes

C07C 271/38
Having oxygen atoms of carbamate groups bound to carbon atoms of rings other than six-membered aromatic rings: with the nitrogen atom of at least…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/06
Drugs for disorders of the alimentary tract or the digestive system: anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia