US 8,785,681 B2 · 2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

Abstract

The present invention relates to 2-(substituted sulphur, sulphone or sulphoxide)-3-(substituted phenyl)propionic acid derivatives, 2-(substituted oxygen)-3-(substituted phenyl)propionic acid derivatives, benzoic acid derivatives, and derivatives of 2-methyl-2-(phenoxy or phenylthio)propanoic acid and 2-(methyl or ethyl)-2-(phenoxy or phenylthio)butanoic acid, to processes for preparing such compounds, to their use in the treatment of inflammatory conditions, and to pharmaceutical compositions containing them.

A compound of general formula (I),

wherein:
R1 represents H, F, CH3 or CF3;
X represents S, S(O) or SO2;
R2 represents C1-C3 alkylaryl or C1-C3 alkylheteroaryl, wherein aryl or heteroaryl each optionally is substituted by one or more of the following:
halogen, OH, OSO2Rb, C1-C2 alkoxy, C1-C4 alkyl, which C1-C2 alkoxy or C1-C4 alkyl substituents is each optionally substituted by one or more F;
R3 is situated in the ortho, meta or para position and represents F, C1-C4 alkyl or C1-C2 alkoxy, which C1-C4 alkyl or C1-C2 alkoxy substituents is each optionally substituted by one or more F;
or R3 is CH2Ph, or NHC(O)OC(CH3)3;
p is an integer 0-4;
L is situated in the meta or para position and represents (CH2)nC(O)O(CH2)i, (CH2)nC(O)S(CH2)i, (CH2)nOC(O)(CH2)i, or (CH2)nSC(O)(CH2)i, each optionally substituted on any available carbon atom with one or more of the following substituents independently selected from:
F, C2-C3 alkenyl, C1-C3 alkyl, C1-C2 alkoxy, which C1-C3 alkyl or C1-C2 alkoxy each optionally is substituted with one or more F;
n is an integer 0-3;
i is an integer 0-3;
A represents aryl or heteroaryl, each optionally substituted by one or more of the following independently selected from:
halogen, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, OSO2Rb, NO2, C1-C4alkyl which is optionally substituted by one or more F;
monocyclic heterocyclyl, monocyclic cycloalkyl, wherein said monocyclic heterocyclyl or monocyclic cycloalkyl are each optionally substituted by one or more of the following independently selected from:
F, OH, oxo, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C1-C4alkyl which is optionally substituted by one or more F;
monocyclic aryl, monocyclic heteroaryl, wherein said monocyclic aryl or monocyclic heteroaryl are each optionally substituted by one or more of the following independently selected from:
halogens, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, OSO2Rb, NO2, C(O)Rb, C1-C4alkyl which is optionally substituted by one or more F, or
A is cycloalkyl or heterocyclyl, each optionally substituted by one or more of the following independently selected from:
F, OH, oxo, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C(O)NRaRa, NRaC(O)Rb, C(O)ORa, OC(O)Rb, SO2NRaRa, NRaSO2Rb, NRaC(O)ORb, OC(O)NRaRa, NRaC(O)NRaRa, C1-C4alkyl which is optionally substituted by one or more F;
monocyclic heterocyclyl, monocyclic cycloalkyl, wherein said monocyclic heterocyclyl or monocyclic cycloalkyl are each optionally substituted by one or more of the following independently selected from:
F, OH, oxo, CN, NRaRa, ORb, SRb, SiRbRbRb, S(O)Rb, SO2Rb, C(O)Rb, C1-C4 alkyl which is optionally substituted by one or more F;
monocyclic aryl, monocyclic heteroaryl, wherein said monocyclic aryl or monocyclic heteroaryl are each optionally substituted by one or more of the following independently selected from:
halogens, OH, CN, NRaRa, ORb, SRb, SiRbRbRb, OS(O)Rb, S(O)Rb, SO2Rb, NO2, C(O)Rb, C1-C4alkyl which is optionally substituted by one or more F;
and in the above definitions
C1-C3 alkylaryl binds to X via the alkyl chain;
C1-C3 alkylheteroaryl binds to X via the alkyl chain;
Ra independently represents H or a straight or branched, saturated or unsaturated C1-C4 alkyl chain optionally substituted by one or more F;
and
Rb independently represents a straight or branched, saturated or unsaturated C1-C4 alkyl chain optionally substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

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2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

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2-substituted-3-phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

Life of this patent

Abstract

Claims5