Substituted amino-furan-2-yl-acetic acid and amino-thien-2-yl-acetic acid derivatives and their use in the treatment of migraine and pain

• US 20040030156A1
• Filed: 05/30/2003
• Published: 02/12/2004
• Est. Priority Date: 11/30/2000
• Status: Active Grant

• Current Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Original Assignee: Grunenthal GMBH (Grünenthal Pharma GmbH & Co. KG)
• Inventors: Englberger, Werner, Maul, Corinna, Przewosny, Michael
• Granted Patent: US 6,797,712 B2
• Time in Patent Office: Days
• US Class Current: 549/4
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 29/02 without antiinflammatory effect
• CPC Class Codes: C07D 307/54 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
• CPC Class Codes: C07D 307/56 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
• CPC Class Codes: C07D 307/68 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/24 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
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of formula I, or a pharmaceutically acceptable salt thereof,

The compounds of the present invention are suitable for the treatment of pain and migraine. Also disclosed are method for preparing the compounds, and pharmaceutical composition comprising the compounds as well as methods for treating pain and migraine using the pharmaceutical compositions.

Claims

1. A compound of formula I, or a pharmaceutically acceptable salt thereof,

2. A compound according to claim 1, or a pharmnaceutically acceptable salt thereof, wherein

R¹ represents aryl or heterocyclyl¹,

R² represents H, C_1-12-alkyl, (C_1-6-alkyl)-C_3-8-cycloalkyl, aryl or (C_1-6-alkyl)-aryl,

R³, R⁴ and R⁵ each independently of the others represents H, OH, SH, Cl, Br, C_1-12-alkyl, C_3-8-cycloalkyl, (C_1-6-alkyl)-C_3-8-cycloalkyl, aryl, (C_1-6-alkyl)-aryl, heterocyclyl¹, (C_1-6-alkyl)-heterocyclyl¹, —

SiR⁶R⁷R⁸, —

(CH₂)_n—

O—

(CH₂)_m—

R⁹ wherein n=1, 2, 3 or 4 and m=0, 1 or 2, —

(CH₂)_o—

S_p—

(CH₂)_q—

R¹⁰ wherein o=1, 2, 3 or 4, p=1 or 2 and q 0, 1 or 2, —

(CH₂)_r—

CO₂R¹¹ wherein r=0, 1, 2 or 3, —

(CH₂)_s—

OC(═

O)R¹² wherein s=0, 1 or 2, or —

C(═

O)R¹³,

R⁶, R⁷ and R⁸ each independently of the others represents C_1-6-alkyl or phenyl,

R⁹ and R¹⁰ each independently of the other represents H, CH₃, aryl, heterocyclyl or —

C(═

O)—

C_1-6-alkyl, —

C(═

O)—

(C_1-6-alkyl)-aryl or —

C(═

O)-aryl,

R¹¹ represents H, C_1-6-alkyl or CH₂-phenyl,

R¹² represents C_1-6-alkyl or aryl,

R¹³ represents C_1-6-alkyl or aryl,

 

wherein aryl represents

heterocyclyl¹ represents a monocyclic or bicyclic organic radical in which at least one ring is 5- or 6-membered and contains one hetero atom or 2 identical or different hetero atoms selected from the group consisting of N, O and S, the radical being saturated or unsaturated and being unsubstituted or monosubstituted or polysubstituted by identical or different substituents,

R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently of the others represents H, OR²⁸, S(O)_tR²⁹ wherein t=0 or 2, SO₂OR³⁰, F, Cl, Br, I, —

CN, NO₂, C_1-12-alkyl, C_3-8-cycloalkyl, (C_1-6-alkyl)-C_3-8-cycloalkyl, phenyl or (C_1-6-alkyl)-phenyl, wherein phenyl is unsubstituted or is monosubstituted or polysubstituted by identical or different substituents, heterocyclyl¹, (C_1-6-alkyl)-heterocyclyl¹, —

CO₂R³¹ or —

NR³²R³³,

R²⁸, R²⁹, R³⁰ and R³¹ each independently of the others represents H, C_1-6-alkyl or phenyl, and

R³² and R³³ each independently of the other represents H, C_1-6-alkyl, (C_1-6-alkyl)-phenyl, or R³² and R³³ together form —

(CH₂)_h—

wherein h=4, 5 or 6.

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

R¹ represents aryl or heterocyclyl²,

R² represents H, methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, n-hexyl,

R³, R⁴ and R⁵ each independently of the others represents H, OH, SH, Br, Cl, C_1-6-alkyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, —

SiR⁶R⁴R⁸, —

CH₂OH, —

CH₂—

O—

(C═

O)—

CH₃, —

(CH₂)—

S_p—

(CH₂)_q—

R¹⁰ wherein p=1 or 2 and q=0 or 1, —

(CH₂)_r—

CO₂R¹¹ wherein r=0 or 1, or —

COR¹³,

R⁶, R⁷ and R⁸ each independently of the others represents methyl, tert-butyl or phenyl,

R¹⁰ represents H, methyl, ethyl, n-propyl, 2-furyl, 2-thienyl or —

C(═

O)—

CH₃,

R¹¹ represents H, methyl, ethyl or tert-butyl,

R¹³ represents methyl,

 

wherein aryl represents

 

heterocyclyl² represents

R¹⁶, R¹⁷, R¹⁸, R¹⁹ and R²⁰ each independently of the others represents H, OR²⁸, S(O)_tR²⁹ wherein t=0, F, Cl, Br, I, —

CN, —

NO₂, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl, CF₃ or —

CO₂R³¹,

R²⁸, R²⁹ and R³¹ each independently of the others represents H, methyl, ethyl, —

CF₃ or phenyl,

X-Y represents CR³⁸—

CR³⁹, CR³⁸—

N or N—

CR³⁹,

R³⁶, R³⁷, R³⁸ and R³⁹ each independently of the others represents H, F, Cl, Br, I, —

CN, —

NO₂, —

OH, —

SH, C_1-6-alkyl or —

CF₃, and

R⁴⁰ and R⁴¹ each independently of the other represents H, F, Cl, Br, I, —

CN, —

OH, —

O-C_1-6-alkyl, —

SH, —

S-C_1-6-alkyl, C_1-6-alkyl, CO₂—

C_1-6-alkyl or —

N═

N-aryl.

4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein

R¹ represents aryl or heterocyclyl²,

R² represents H, methyl, ethyl or tert-butyl,

R³ represents H, Cl, methyl, ethyl, n-propyl, 2-propyl, n-butyl, tert-butyl, —

CH₂OH, —

CH₂SH, —

CH₂—

S—

CH₃, —

CH₂—

S—

CH₂-furan-2-yl, —

CH₂—

O—

(C═

O)—

CH₃, —

CH₂—

S—

(C═

O)—

CH₃, —

CH₂—

S—

S—

CH₃, —

CH₂—

S—

S—

CH₂-furan-2-yl, —

CH₂—

CO₂methyl or —

CH₂—

CO₂ethyl,

R⁴ represents H, Br, methyl, ethyl, —

CH₂OH, —

CO₂methyl, —

CO₂ethyl or C(═

O)methyl,

R⁵ represents H, methyl or ethyl,

 

wherein aryl represents

 

heterocyclyl² represents

R¹⁶ represents H, —

O-phenyl, F, Cl, Br, methyl, ethyl, n-propyl, 2-propyl or tert-butyl,

R¹⁷ represents H, Cl, methyl, ethyl or CF₃,

R¹⁸ represents H, F, Cl, Br, I, —

CN, —

O—

CH₃, —

O—

CF₃, —

O-phenyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl or tert-butyl,

R¹⁹ represents H, Cl, Br, methyl or ethyl,

R²⁰ represents H or methyl,

X-Y represents CR³⁸—

CR³⁹, CR³³—

N or N—

CR³⁹,

R³⁶represents H, methyl or ethyl,

R³⁷ represents H, NO₂, Cl, Br, methyl or CF₃,

R³⁸ represents H,

R³⁹ represents H, Cl or Br,

R⁴⁰ represents H, —

N=N-phenyl, —

CN, CO₂H, CO₂-methyl or CO₂-ethyl, and

R⁴¹ represents H, OH, SH, S-methyl, methyl, ethyl, n-propyl, 2-propyl, n-butyl or tert-butyl.

5. A compound according claim 4, or a pharmaceutically acceptable salt thereof, wherein

R¹ represents 4-trifluoromethoxy-phenyl, 2-phenoxy-phenyl, 4-phenoxy-phenyl, 2-chloro-phenyl, 4-chloro-phenyl, 4-iodo-phenyl, 4-cyano-phenyl, 2-methyl-phenyl, 2-ethyl-phenyl, 4-ethyl-phenyl, 2-(2-propyl)-phenyl, 4-(2-butyl)-phenyl, 4-tert-butyl-phenyl, 2,4-dichlorophenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 2,4-dibromo-phenyl, 4-chloro-2-fluoro-phenyl, 2-chloro-4-fluoro-phenyl, 4-bromo-2-chloro-phenyl, 2-chloro-4-iodo-phenyl, 3-chloro-2-methyl-phenyl, 4-chloro-2-methyl-phenyl, 5-chloro-2-methyl-phenyl, 2-chloro-4-methyl-phenyl, 4-chloro-3-trifluoromethyl-phenyl, 2,4-dibromo-5-methyl-phenyl, 5-nitro-pyridin-2-yl, 3,5-dibromo-pyridin-2-yl, 3,5-dichloro-pyridin-2-yl, 3-chloro-5-trifluoromethyl-pyridin-2-yl, 3,5-dibromo-6-methyl-pyridin-2-yl, pyrazin-2-yl, 5-bromo-pyrimidin-2-yl, 4-carboxyethyl-pyrazol-3-yl, 4-cyano-pyrazol-3-yl, 5-tert-butyl-pyrazol-3-yl, 5-hydroxy-4-(4-phenylazo)-pyrazol-3-yl or 4-cyano-5-methylsulfanyl-pyrazol-3-yl,

R² represents H or ethyl,

R³ represents H, Cl, methyl, ethyl, n-propyl, tert-butyl, —

CH₂OH, —

CH₂SH, —

CH₂S—

CH₃, —

CH₂—

S—

CH₂-furan-2-yl, —

CH₂—

O—

(C═

O)—

CH₃, —

CH₂—

S—

(C═

O)—

CH₃—

, —

CH₂—

S—

S—

CH₃, —

CH₂—

S—

S—

CH₂-furan-2-yl or —

CH₂—

CO₂ethyl,

R⁴ represents H, Br, methyl, —

CH₂OH, —

CO₂methyl, —

CO₂ethyl or —

C(═

O)CH₃,

R⁵ represents H or methyl.

6. A compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein

R¹ represents 3,5-dichlorophenyl and

R² represents H.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of

(5-methylsulfanylmethyl-furan-2-yl)-(5-nitro-pyridin-2-ylamino)-acetic acid,

(5-bromopyrimidin-2-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

5-[carboxy-(3,5-dichloropyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(3,5-dibromopyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(3,5-dibromo-6-methyl-pyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

(3,5-dibromo-6-methyl-pyridin-2-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid,

(3,5-dichloro-pyridin-2-ylamino)-(4-methyl-thiophen-2-yl)-acetic acid,

(2,4-dibromo-5-methyl-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid,

(4-methyl-thiophen-2-yl)-(5-nitro-pyridin-2-ylamino)-acetic acid,

(3,5-dichloro-pyridin-2-ylamino)-furan-2-yl-acetic acid,

(3,5-dibromopyridin-2-ylamino)-furan-2-yl-acetic acid,

(3,5-dibromo-6-methyl-pyridin-2-ylamino)-furan-2-yl-acetic acid,

(3-chloro-5-trifluoromethyl-pyridin-2-ylamino)-furan-2-yl-acetic acid,

(5-bromopyrimidin-2-ylamino)-furan-2-yl-acetic acid,

5-[(3,5-dichloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid ethyl ester,

3-{[ethoxycarbonyl-(4-ethoxycarbonyl-5-methyl-furan-2-yl)-methyl]-amino}-1H-pyrazole-4-carboxylic acid ethyl ester,

5-[(4-cyano-5-methylsulfanyl-1H-pyrazol-3-ylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(4-cyano-1H-pyrazol-3-ylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(4-bromo-2-chloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

(4-hydroxymethyl-furan-2-yl)-(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-acetic acid ethyl ester,

(4-cyano-5-methylsulfanyl-1H-pyrazol-3-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(4-bromo-2-chloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(3,5-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(5-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmcthylsulfanylmethyl)-furan-2-yl]-acetic acid ethyl ester,

(2,4-dibromo-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid,

(5-chloro-2-methyl-phenylamino)-(5-methylsulfanylmethyl-firan-2-yl)-acetic acid,

(2-ethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(4-sec-butyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(5-methylsulfanylmethyl-furan-2-yl)-(4-trifluoromethoxy-phenylamino)-actic acid,

(2-isopropyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2,4-dibromo-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(4-tert-butyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(5-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

(2-ethyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

(4-sec-butyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(2-isopropyl-phenylamino)-acetic acid,

(4-tert-butyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

5-[ethoxycarbonyl-(4-Iodo-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[(4-chloro-2-methyl-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[ethoxycarbonyl-(4-phenoxy-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[ethoxycarbonyl-(4-iodo-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(2-chloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(4-chloro-2-methyl-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(2-chloro-4-fluoro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[ethoxycarbonyl-(4-phenoxy-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[(2,3-dichloro-phenylamino)-ethoxycarbonyl-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

(4-hydroxymethyl-furan-2-yl)-(4-iodo-phenylamino)-acetic acid ethyl ester,

(2,4-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(4-chloro-2-methyl-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(4-hydroxymethyl-furan-2-yl)-(4-phenoxy-phenylamino)-acetic acid ethyl ester,

(2,3-dichloro-phenylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid ethyl ester,

(2,3-dichloro-phenylamino)-furan-2-yl-acetic acid ethyl ester,

5-[carboxy-(3,5-dibromo-6-methyl-pyridin-2-ylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

(5-methylsulfanylmethyl-furan-2-yl)-(pyrazin-2-ylamino)-acetic acid,

(3,5-dibromo-pyridin-2-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(3,5-dibromo-6-methyl-pyridin-2-ylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid methyl ester,

5-[carboxy-(2-phenoxy-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester,

5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(4-cyano-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2,4-dimethyl-furan-3-carboxylic acid ethyl ester,

5-[(4-bromo-2-chloro-phenylamino)-carboxy-methyl]-2-methyl-furan-3-carboxytic acid ethyl ester,

5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(3,5-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

(5-tert-butyl-1H-pyrazol-3-ylamino)-(4-hydroxymethyl-furan-2-yl)-acetic acid,

(4-bromo-2-chloro-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid,

(4-cyano-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(3-methyl-thiophen-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-furan-2-yl-acetic acid,

[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(4-phenoxy-phenylamino)-acetic acid ethyl ester,

(5-ethoxycarbonylmethyl-thiophen-2-yl)-(5-hydroxy-4-phenylazo-1H-pyrazol-3-ylamino)-acetic acid, ethyl ester,

{5-[1-(4-cyano-1H-pyrazol-3-ylamino)-3-methoxy-2-oxo-propyl]-thiophen-2-yl}-acetic acid ethyl ester,

(4-ethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(3-chloro-2-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(4-chloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(5-methylsulfanylmethyl-furan-2-yl)-o-tolylamino-acetic acid,

5-[carboxy-(4-chloro-3-trifluoromethyl-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(2-chloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(2-chloro-4-fluoro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(4-chloro-2-fluoro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

5-[carboxy-(2,3-dichloro-phenylamino)-methyl]-2-methyl-furan-3-carboxylic acid ethyl ester,

(2,4-dichloro-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid,

(4-chloro-3-trifluoromethyl-phenylamino)-(4-methyl-thiophen-2-yl)-acetic acid,

(2,4-dichloro-phenylamino)-furan-2-yl-acetic acid,

(4-chloro-3-trifluoromethyl-phenylamino)-furan-2-yl-acetic acid,

(4-iodo-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2,4-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(4-chloro-3-trifluoromethyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2-chloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(4-chloro-2-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2-chloro-4-fluoro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2-chloro-4-methyl-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(2,3-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-(4-iodo-phenylamino)-acetic acid,

(4-chloro-3-trifluoromethyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

(4-chloro-2-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

(2-chloro-4-methyl-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-y]-acetic acid,

(4-chloro-3-trifluoromethyl-phenylamino)-(5-ethoxycarbonylmethyl-thiophen-2-yl)-acetic acid,

(4-acetyl-3,5-dimethyl-furan-2-yl)-(2-chloro-4-methyl-phenylamino)-acetic acid,

(4-acetyl-3,5-dimethyl-furan-2-yl)-(2,3-dichloro-phenylamino)-acetic acid,

(3,5-dichloro-phenylamino)-(5-methylsulfanylmethyl-furan-2-yl)-acetic acid,

(3-chloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid,

(3,4-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(5-methyl-thiophen-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(5-hydroxymethyl-thiophen-2-yl)-acetic acid,

(5-acetylsulfanylmethyl-furan-2-yl)-(3,5-dichloro-phenylamino)-acetic acid,

(3,5-dichloro-phenylamino)-(5-ethyl-thiophen-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(5-n-propyl-thiophen-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

(3-chloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid,

(3,4-dichloro-phenylamino)-(5-mercaptomethyl-furan-2-yl)-acetic acid,

(3,5-dichloro-phenylamino)-(thiophen-2-yl)-acetic acid ethyl ester,

(4-bromofuran-2-yl)-(3,5-dichloro-phenylamino)-acetic acid ethyl ester,

(3,5-dichloro-phenylamino)-(5-propylthiophen-2-yl)-acetic acid ethyl ester,

(3,5-dichloro-phenylamino)-(3-methylthiophen-2-yl)-acetic acid ethyl ester,

(5-tert-butylfuran-2-yl)-(3,5-dichloro-phenylamino)-acetic acid,

(3,5-dichlorophenylamino)-[5-(furan-2-ylmethyldisulfanylmethyl)-furan-2-yl]-acetic acid,

(3,5-dichlorophenylamino)-(5-methyldisulfanylmethylfuran-2-yl)-acetic acid,

(3,5-dichlorophenylamino)-[5-(furan-2-ylmethylsulfanylmethyl)-furan-2-yl]-acetic acid,

5-acetoxymethylfuran-2-yl-(3,5-dichlorophenylamino)-acetic acid,

(3,5-dichlorophenylamino)-thiophen-3-yl-acetic acid,

(3,5-dichlorophenylamino)-(5-methylthiophen-2-yl)-acetic acid,

(3,5-dichlorophenylamino)-(4-methylthiophen-2-yl)-acetic acid, and

(5-chlorothiophen-2-yl)-(3,5-dichlorophenylamino)-acetic acid.

8. A method for the preparation of a compound according to claim 1, comprising reacting an amine of formula II

R¹—

NH₂ 

 

II

in the presence of an acid, with a glyoxalic acid derivative of formula III

9. A method according to claim 8, which is carried out as a one-pot reaction.

10. A method according to claim 8, wherein the reaction of the compounds (II), (III) and (IV) is carried out under the action of microwave radiation.

11. A method according to claim 9, wherein the reaction of the compounds of formulae II, III and IV is carried out under the action of microwave radiation.

12. A method according to claim 8, wherein the reaction is carried out in an organic solvent at a temperature of from about 0°

C. to 100°

C.

13. A method according to claim 12, wherein the reaction is carried out at a temperature of from about 15°

C. to 50°

C.

14. A pharmaceutical composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof,

15. A method for treating pain, comprising administering a pharmaceutical composition of claim 14 to a patient in need thereof.

16. A method according to claim 15, wherein the patient is a mammal.

17. A method according to claim 16, wherein the mammal is a human.

18. A method for treating migraine, comprising administering a pharmaceutical composition of claim 14 to a patient in need thereof.

19. A method according to claim 18, wherein the patient is a mammal.

20. A method according to claim 19, wherein the mammal is a human.