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

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- Number: US 8,785,681 B2
- Document ID: US8785681B2
- Status: Granted
- Kind: B2
- Application number: 13/046,288
- Filed: 2011-03-11
- Published: 2011-07-07
- Granted: 2014-07-22
- Earliest claimed: 2007-03-08
- Assignees: Albireo AB
- Applicants: Anders Broo; Johan Gottfries; Michael Kossenjans; Li Lanna; Eva-Lotte Lindstedt-Alstermark; Kristina A. Nilsson; Bengt Ohlsson; Maria Thorstensson; Per Olof Sjögren
- Inventors: Anders Broo; Johan Gottfries; Michael Kossenjans; Li Lanna; Eva-Lotte Lindstedt-Alstermark; Kristina A. Nilsson; Bengt Ohlsson; Maria Thorstensson; Maria Boije
- Web page: https://patentgrep.com/patent/US8785681B2

## CPC

- C07C 323/56: the carbon skeleton containing six-membered aromatic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07C 271/28: to a carbon atom of a non-condensed six-membered aromatic ring
- C07C 309/66: Methanesulfonates
- C07C 317/44: having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C 323/62: having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C 327/28: having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
- C07D 213/55: Acids; Esters
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D 277/24: Radicals substituted by oxygen atoms
- C07D 277/30: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 295/04: with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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.

## Claims

### Claim 1

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.

### Claim 2

A compound selected from one or more of the following:
4-Methanesulfonyloxy-benzoic acid 4-{2-carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzyl ester;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-methanesulfonyloxy-phenyl)-acetoxymethyl]-phenyl}-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-[4-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenyl]-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-[4-(4-methanesulfonyloxy-benzyloxycarbonylmethyl)-phenyl]-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-(4-{2-[2-(4-methanesulfonyloxy-phenyl)-acetoxy]-ethyl}-phenyl)-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-(4-{3-[2-(4-methanesulfonyloxy-phenyl)-acetoxy]-propyl}-phenyl)-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-[4-(2-phenyl-propionyloxymethyl)-phenyl]-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-methoxylphenylacetoxymethyl]phenyl}-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-isobutyl-phenyl)-propionyloxymethyl]-phenyl}-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-[4-(2-pyridin-2-yl-acetoxymethyl)-phenyl]-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-methyl-piperazin-1-yl)-acetoxymethyl]-phenyl}-propionic acid;
4-{2-Carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzoic acid 2-phenyl-5 trifluoromethyl-oxazol-4-ylmethyl ester;
2-Phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid 4-{2-carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzyl ester;
4-{2-Carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzoic acid 2-(5-methyl-2 phenyl-oxazol-4-yl)-ethyl ester;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)acetoxymethyl]-phenyl}-propionic acid;
4-{2-Carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzoic acid 4-methanesulfonyloxy-benzyl ester;
2-[2-(4-Fluoro-phenyl)-ethanesulfonyl]-3-[4-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenyl]-propionic acid;
2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-methanesulfonyloxy-phenyl)-ethylsulfanylcarbonyl]-phenyl}-propionic acid;
(−)-2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxymethyl]-phenyl}-propionic acid;
4-{(−)-2-Carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzoic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester;
(S)-2-Ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid;
(S)-3-{4-[2-(4-tert-Butoxycarbonylamino-phenyl)-acetoxy]-phenyl}-2-ethoxy-propionic acid;
3-{3-Benzyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-2-ethoxy-propionic acid;
3-{3-Benzyl-4-[2-(4-tert-butoxycarbonylamino-phenyl)-acetoxy]-phenyl}-2-ethoxy-propionic acid;
2-Ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-acetoxy]-phenyl}-propionic acid;
3-{4-[2-(4-tert-Butoxycarbonylamino-phenyl)-acetoxy]-3-methyl-phenyl}-2-ethoxy-propionic acid;
4-(2-Carboxy-2-ethoxy-ethyl)-benzoic acid 4-methanesulfonyloxy-benzyl ester;
2-[3-(4-Trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-{4-[2-(4-Trifluoromethyl-phenyl)-acetoxymethyl]-phenylsulfanylmethyl}-benzoic acid;
2-[4-(4-Trifluoromethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-{3-[1-(4-Trifluoromethyl-phenyl)-ethoxycarbonylmethyl]phenylsulfanylmethyl-benzoic acid;
2-{3-[2-(4-Trifluoromethyl-phenyl)-ethoxycarbonylmethyl]-phenylsulfanylmethyl}-benzoic acid;
2-[4-(2,6-Dimethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-[4-(1-Phenyl-but-3-enyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-[3-(1-Methoxycarbonyl-2-phenyl-ethoxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-{4-[2-(3,4-Dimethoxy-phenyl)-ethoxycarbonylmethyl]-phenylsulfanylmethyl}-benzoic acid;
2-[4-(1-Methoxycarbonyl-2-phenylethoxycarbonylmethyl)phenylsulfanylmethyl]-benzoic acid;
2-{3-[2-(2-Trifluoromethylphenyl)ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid;
2-[4-(Oxazol-2-yl-phenyl-methoxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-{4-[2-(2-Trifluoromethylphenyl)ethoxycarbonylmethyl]phenylsulfanylmethyl}-benzoic acid;
2-[3-(2,6-Dimethyl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-[3-(4-Pyrazol-1-yl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid;
2-[4-(4-Pyrazol-1-yl-benzyloxycarbonylmethyl)-phenylsulfanylmethyl]-benzoic acid; or
2-{3-[2-(3,4-Dimethoxy-phenyl)-ethoxycarbonylmethyl]-phenylsulfanylmethyl}-benzoic acid; and
4-(1-Carboxy-1-methyl-ethoxy)-benzoic acid 4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl ester;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein
R1 represents H;
X represents S or SO2;
R2 represents C2alkylaryl, wherein aryl optionally is substituted by one or more of F;
L is situated in the meta or para position and represents (CH2)nC(O)O(CH2)i, (CH2)nOC(O)(CH2)i, or (CH2)nSC(O)(CH2)i, each optionally substituted on any available carbon atom with one C1alkyl;
n is an integer 0-2;
i is an integer 0-3;
p is 0;
A represents aryl or heteroaryl, each optionally substituted by one or more of the following: ORb, OSO2Rb, C1-C4alkyl (which is optionally substituted by one or more F); monocyclic aryl;
or A is heterocyclyl optionally substituted by C1alkyl, which C1alkyl optionally is substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein
R1 represents H;
X represents S;
R2 represents C2alkylaryl, wherein aryl is substituted by one F;
L is situated in the meta or para position and represents (CH2)nC(O)O(CH2)i or (CH2)nOC(O)(CH2)i;
n is an integer 0-1;
i is an integer 0-1;
p is 0;
A represents aryl or heteroaryl, each optionally substituted by one or more of the following: ORb, OSO2Rb, C1alkyl (which is optionally substituted by one or more F); monocyclic aryl;
or A is heterocyclyl optionally substituted by C1alkyl, which C1alkyl optionally is substituted by one or more F;
or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1, 2)

A pharmaceutical formulation comprising a compound according to any of claims 1 or 2, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.