IP Library › Granted Patent US 9,624,209

Granted Patent B2

US 9,624,209 · App. 14/568,592 · Granted Apr 18, 2017

Substituted phenylureas and phenylamides as vanilloid receptor ligands

Inventors: Robert Frank-Foltyn (Aachen, DE); Gregor Bahrenberg (Monschau-Konzen, DE); Thomas Christoph (Aachen, DE); Klaus Schiene (Juechen, DE); Jean De Vry (Stolberg, DE); Nils Damann (Cologne, DE); Sven Frormann (Aachen, DE); Bernhard Lesch (Aachen, DE); Jeewoo Lee (Seoul, KR); Yong-Soo Kim (Gyengnam, KR); Myeong-Seop Kim (Gangw-do, KR); Derek Saunders (Aachen, DE); Hannelore Stockhausen (Huertgenwald, DE)

Assignee: Gruenenthal GmbH

C07D417/12 A61K31/415 A61K31/4155 A61K31/427 C07D231/12 C07D249/08 C07D403/12 C07D405/12

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Quick Facts

Patent No.: US 9,624,209
App. No.: 14/568,592
Granted: Apr 18, 2017
Kind: B2

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Abstract

Substituted phenylureas and phenylamides, processes for their preparation, pharmaceutical compositions containing these compounds, and the use of these compounds for preparing pharmaceutical compositions.

Claims (284)

1. A compound corresponding to formula (Q)

wherein

R 101 , R 102 and R 103 are each independently selected from the group consisting of H, F, Cl, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 —OH, CH 2 CH 2 —OH, CH 2 —OCH 3 , CH 2 CH 2 —OCH 3 , OCFH 2 , OCF 2 H, OCF 3 , OH, NH 2 , a C 1-4 alkyl, an O—C 1-4 alkyl, a NH—C 1-4 alkyl, and a N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl is in each case unsubstituted;

R 2 represents CF 3 , an unsubstituted C 1-4 alkyl or an unsubstituted C 3-6 cycloalkyl;

R 7 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, CFH 2 , CF 2 H, CF 3 , CN, OH, OCF 3 , a C 1-4 alkyl, and an O—C 1-4 alkyl, wherein the C 1-4 alkyl is in each case unsubstituted;

A denotes N, CH or C(CH 3 );

p denotes 0 or 1;

R 115 represents H or a C 1-6 alkyl, which is unsubstituted or mono-, di- or trisubstituted with 1, 2 or 3 substituents independently selected from the group consisting of OH and OCH 3 ;

B denotes C(R 116a )(R 116b ), wherein

R 116a is selected from the group consisting of H, CH 3 , CH 2 OH and OH, and

R 116b is selected from the group consisting of H, CH 3 and CH 2 OH,

with the proviso that R 116a is not OH, when R 115 represents H; or

R 116a and R 116b together with the carbon atom connecting them form an unsubstituted C 3-6 cycloalkyl or an unsubstituted 3 to 6 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N(C 1-4 alkyl); or

B denotes C(R 116c )(R 116d )—C(R 117a )(R 117b ), wherein

R 116c is selected from the group consisting of H, CH 3 , CH 2 OH and OH, and

R 116d is selected from the group consisting of H, CH 3 and CH 2 OH; or

R 116c and R 116d together with the carbon atom connecting them form an unsubstituted C 3-6 cycloalkyl or an unsubstituted 3 to 6 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N(C 1-4 alkyl);

R 117a is selected from the group consisting of H, CH 3 , CH 2 OH and OH, and

R 117b is selected from the group consisting of H, CH 3 and CH 2 OH,

with the proviso that R 117a is not OH, when R 115 represents H; or

R 117a and R 117b together with the carbon atom connecting them form an unsubstituted C 3-6 cycloalkyl or an unsubstituted 3 to 6 membered heterocyclyl, wherein at least one ring member of the heterocyclyl is selected from the group consisting of O, S, N, NH and N(C 1-4 alkyl);

in the form of a free compound or a physiologically acceptable salt thereof, and if appropriate, in the form of an individual stereoisomer or a mixture of stereoisomers.

2. A compound according to claim 1 , wherein

R 2 represents CF 3 , tert.-butyl or cyclopropyl;

R 101 , R 102 and R 103 are each independently selected from the group consisting of H, F, Cl, Br, CFH 2 , CF 2 H, CF 3 , CN, CH 2 —OH, CH 2 —OCH 3 , OCF 3 , OH, CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , O—CH 3 , O—CH 2 CH 3 , NH 2 , NH(CH 3 ), and N(CH 3 ) 2 ;

R 7 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, CF 3 , CN, OH, OCF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , O—CH 3 , and O—CH 2 CH 3 ; and

A denotes N or C(CH 3 ).

3. A compound according to claim 1 , wherein at least one of R 101 , R 102 and R 103 is not H, and at least one of R 7 and R 9 is not H.

4. A compound according to claim 1 , wherein the partial structure (QS1)

represents

(a) partial structure (PQ1)

wherein

R 115 represents H, CH 2 OH, CH 2 CH 2 OH, CH(OH)CH 2 OH, or CH(OCH 3 )CH 2 OH;

R 116a is selected from the group consisting of H, CH 3 , and OH, and

R 116b is selected from the group consisting of H, and CH 3 ,

with the proviso that R 116a is not OH, when R 115 represents H; or

R 116a and R 116b together with the carbon atom connecting them form an unsubstituted moiety selected from the group consisting of cyclopropyl, cyclobutyl, oxiranyl and oxetanyl; or

(b) partial structure (PQ2)

wherein

R 115 represents H, CH 3 , CH 2 OH, CH 2 OCH 3 , CH 2 CH 3 , CH(OH)CH 3 , CH 2 CH 2 OH, CH(OH)CH 2 OH, CH(OCH 3 )CH 2 OH, CH(OH)CH 2 OCH 3 , or CH 2 CH 2 OCH 3 ;

R 116c is selected from the group consisting of H, CH 3 , and CH 2 OH, and

R 116d is selected from the group consisting of H, CH 3 and CH 2 OH;

R 117a is selected from the group consisting of H, CH 3 , CH 2 OH and OH, and

R 117b is selected from the group consisting of H, CH 3 and CH 2 OH,

with the proviso that R 117a is not OH, when R 115 represents H;

or, if p is 0,

wherein

v denotes 0 or 1;

w denotes 0 or 1;

R 118a is selected from the group consisting of H and OH, and

R 118b is selected from the group consisting of H and CH 3 ;

R 119a is selected from the group consisting of H and OH, and

R 119b is selected from the group consisting of H and CH 3 ;

R 120a is selected from the group consisting of H and OH, and

R 120b is selected from the group consisting of H and CH 3 ;

R 121 represents H or CH 3 ;

with the proviso that R 120a is not OH, when R 121 represents H.

5. A compound according to claim 1 , wherein partial structure (QS1)

represents

(a) partial structure (PQ1)

wherein

R 115 represents H, CH 2 OH, or CH 2 CH 2 OH;

R 116a is selected from the group consisting of H, CH 3 , and OH, and

R 116b is selected from the group consisting of H, and CH 3 ,

with the proviso that R 116a is not OH, when R 115 represents H; or

R 116a and R 116b together with the carbon atom connecting them form an unsubstituted C 3-6 cycloalkyl selected from the group consisting of cyclopropyl and cyclobutyl or an unsubstituted 3 to 6 membered heterocyclyl selected from the group consisting of oxiranyl and oxetanyl; or

(b) partial structure (PQ2)

wherein

R 115 represents H, CH 2 OH, CH 2 CH 2 OH, or CH(OH)CH 2 OH;

R 116c is selected from the group consisting of H, CH 3 , and CH 2 OH, and

R 116d is selected from the group consisting of H, CH 3 and CH 2 OH;

R 117a is selected from the group consisting of H, CH 3 , CH 2 OH and OH, and

R 117b is selected from the group consisting of H, CH 3 and CH 2 OH;

with the proviso that R 117a is not OH, when R 115 represents H;

or, if p is 0,

wherein

v denotes 0 or 1;

w denotes 0 or 1;

R 118a is selected from the group consisting of H and OH, and

R 118b is selected from the group consisting of H and CH 3 ;

R 119a is selected from the group consisting of H and OH, and

R 119b is selected from the group consisting of H and CH 3 ;

R 120a is selected from the group consisting of H and OH, and

R 120b is selected from the group consisting of H and CH 3 ;

R 121 represents H or CH 3 ,

with the proviso that R 120a is not OH, when R 121 represents H.

6. A compound according to claim 1 , wherein partial structure (QS1)

represents

(a) partial structure (PQ1-1)

wherein R 115 represents H, CH 2 OH, or CH 2 CH 2 OH; or

(b) partial structure (PQ2-1)

wherein R 115 represents H, CH 2 OH, or CH 2 CH 2 OH;

or, if p is 0,

wherein

v denotes 0 or 1;

w denotes 0 or 1;

R 119a is selected from the group consisting of H and OH, and

R 119b is selected from the group consisting of H and CH 3 .

7. A compound according to claim 1 , wherein partial structure (QS1)

represents

(a) partial structure (PQ1-2) or partial structure (PQ1-3)

(b) partial structure (PQ2-1)

or, if p is 0,

wherein

w denotes 1, and R 119a represents OH; or

w denotes 0.

8. A compound according to claim 1 , wherein

R 2 represents CF 3 , tert.-butyl or cyclopropyl;

R 7 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, CF 3 , CN, OH, OCF 3 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , O—CH 3 , and O—CH 2 CH 3 ;

A denotes N, CH or C(CH 3 ), and

partial structure (QS1)

represents

(a) CH 2 OH or CH 2 O—CH 2 CH 2 OH,

(b) CH 2 CH 2 OH, or

9. A compound according to claim 1 , selected from the group consisting of:

A1 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-acetamide;

A2 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-acetamide;

A3 N-[[2-(3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-propionamide;

A4 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-propionamide;

A5 N-[[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-propionamide;

A6 N-[[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-acetamide;

A7 N-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-acetamide;

A8 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3,5-difluoro-4-methoxy-phenyl)-urea;

A9 N-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-methoxy-phenyl)-propionamide;

A10 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3,5-difluoro-4-hydroxy-phenyl)-propionamide;

A11 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-(3,5-difluoro-4-hydroxy-phenyl)-urea;

A12 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3,5-difluoro-4-hydroxy-phenyl)-urea;

A13 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-(3,4-dimethoxyphenyl)-urea;

A14 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3,4-dimethoxyphenyl)-urea;

A15 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(4-hydroxy-3-methoxy-phenyl)-urea;

A16 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-(3-hydroxy-4-methoxy-phenyl)-urea;

A17 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-urea;

A18 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methoxy-ethoxy)-phenyl]-urea;

A19 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-urea;

A20 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-urea;

A21 1-[3-Fluoro-4-(2-hydroxy-ethoxy)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A22 1-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-urea;

A23 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(2,3-dihydroxy-propoxy)-phenyl]-urea;

A24 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(2,3-dihydroxy-propoxy)-3-fluoro-phenyl]-urea;

A25 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(2,3-dihydroxy-propoxy)-3-fluoro-phenyl]-urea;

A26 1-[4-(2,3-Dihydroxy-propoxy)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A27 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(hydroxymethyl)-phenyl]-urea;

A28 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(hydroxymethyl)-phenyl]-urea;

A29 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-acetamide;

A30 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-acetamide

A31 N-[[2-(3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A32 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A33 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A34 (2S)—N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A35 (2R)—N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A36 2-[3-Chloro-4-(hydroxymethyl)-phenyl]-N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A37 N-[[5-tert-Butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A38 2-[3-Fluoro-4-(hydroxymethyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A39 N-[[5-tert-Butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A40 N-[[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A41 N-[[5-tert-Butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A42 N-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A43 2-[3-Fluoro-4-(hydroxymethyl)-phenyl]-N-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A44 2-[3-Fluoro-4-(hydroxymethyl)-phenyl]-N-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A45 N-[[5-tert-Butyl-2-(4-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A46 2-[3-Fluoro-4-(hydroxymethyl)-phenyl]-N-[[2-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A47 N-[[5-tert-Butyl-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A48 2-[3-Fluoro-4-(hydroxymethyl)-phenyl]-N-[[5-(trifluoromethyl)-2-[3-(trifluoromethyl)phenyl]-2H-pyrazol-3-yl]-methyl]-propionamide;

A49 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(hydroxymethyl)-3-methoxy-phenyl]-propionamide;

A50 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(hydroxymethyl)-3-methoxy-phenyl]-propionamide;

A51 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-chloro-4-(hydroxymethyl)-phenyl]-propionamide;

A52 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3,5-difluoro-4-(hydroxymethyl)-phenyl]-propionamide;

A53 1-[[2-(3-Chlorophenyl)-5-cyclopropyl-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A54 1-[[5-tert-Butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A55 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A56 1-[[5-tert-Butyl-2-(m-tolyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A57 1-[[5-tert-Butyl-2-(3,4-difluoro-phenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A58 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-phenyl-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A59 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A60 1-[[2-(4-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A61 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(2-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A62 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A63 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A64 1-[[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A65 1-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A66 1-[[2-(3,5-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A67 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A68 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(4-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A69 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(o-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A70 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A71 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(p-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A72 1-[[2-(2,3-Dimethyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A73 1-[[2-(3,5-Dimethyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A74 1-[[2-(2,5-Dimethyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A75 1-[[2-(3,4-Dimethyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A76 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(2-fluoro-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A77 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-fluoro-5-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A78 1-[[2-(4-Chloro-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A79 1-[[2-(4-Ethoxy-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A80 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(4-fluoro-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A81 1-[[2-(4-Cyano-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A82 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A83 1-[[2-[3-(Difluoro-methyl)-phenyl]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A84 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-[3-(methoxymethyl)-phenyl]-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A85 1-[[2-(3-Cyano-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A86 1-[[2-(3-Dimethylamino-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A87 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(4-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A88 1-[[2-(2-Ethoxy-5-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A89 1-[[2-(2,3-Dichloro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A90 1-[[2-(3-Chloro-2-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A91 1-[[2-(5-Chloro-2-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A92 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-methoxy-5-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A93 1-[[2-(3-Ethoxy-5-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(hydroxymethyl)-phenyl]-urea;

A94 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(2-methoxy-3-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A95 1-[3-Fluoro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-fluoro-4-methoxy-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A96 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-chloro-4-(hydroxymethyl)-phenyl]-urea;

A97 1-[3-Chloro-4-(hydroxymethyl)-phenyl]-3-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A98 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-propionamide;

A99 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(1-hydroxy-ethyl)-phenyl]-propionamide;

A100 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-propionamide;

A101 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-propionamide;

A102 2-[3-Fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A103 2-[3-Fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-N-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A104 N-[[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-propionamide;

A105 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-urea;

A106 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(1-hydroxy-cyclopropyl)-phenyl]-urea;

A107 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-urea;

A108 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(3-hydroxy-oxetan-3-yl)-phenyl]-urea;

A109 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3-hydroxy-oxetan-3-yl)-phenyl]-urea;

A110 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(3-hydroxy-oxetan-3-yl)-phenyl]-urea;

A111 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-methoxy-ethoxy-methyl)-phenyl]-propionamide;

A112 N-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-methoxy-ethoxy-methyl)-phenyl]-propionamide;

A113 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-acetamide;

A114 2-[3-Fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-N-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A115 2-[3-Fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-N-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A116 N-[[5-tert-Butyl-2-(3-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A117 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A118 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A119 (2S)—N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A120 (2R)—N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A121 N-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A122 2-[3-Fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A123 2-[3-Fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-N-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A124 N-[[5-tert-Butyl-2-(4-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A125 N-[[5-tert-Butyl-2-[3-(trifluoromethyloxy)-phenyl]-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A126 N-[[2-(3,5-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-propionamide;

A127 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A128 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-methoxy-ethoxy-methyl)-phenyl]-urea;

A129 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A130 1-[[2-(3-Chloro-4-fluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A131 1-[3-Fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A132 1-[[2-(3,4-Difluoro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A133 1-[[2-(2,3-Dichloro-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A134 1-[[5-tert-Butyl-2-(4-fluorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A135 1-[[2-(3-Ethoxy-5-methyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethoxy-methyl)-phenyl]-urea;

A136 2-[3-Fluoro-4-(2-hydroxy-ethyl)-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A137 2-[3-Fluoro-4-(2-hydroxy-ethyl)-phenyl]-N-[[2-(3-isopropyl-phenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A138 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-propionamide;

A139 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-propionamide;

A140 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-urea;

A141 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-(2-hydroxy-ethyl)-phenyl]-urea;

A142 1-[3-Fluoro-4-(2-hydroxy-ethyl)-phenyl]-3-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A143 1-[3-Fluoro-4-(2-hydroxy-ethyl)-phenyl]-3-[[2-(3-methoxyphenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A144 1-[3-Fluoro-4-(2-hydroxy-ethyl)-phenyl]-3-[[2-(m-tolyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-urea;

A145 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,2-dihydroxy-ethyl)-3-fluoro-phenyl]-propionamide;

A146 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,2-dihydroxy-ethyl)-phenyl]-propionamide;

A147 N-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,2-dihydroxy-ethyl)-phenyl]-propionamide;

A148 N-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-[4-(1,2-dihydroxy-ethyl)-3-fluoro-phenyl]-propionamide;

A149 2-[4-(1,2-Dihydroxy-ethyl)-3-fluoro-phenyl]-N-[[2-(3-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-propionamide;

A150 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(1,2-dihydroxy-ethyl)-3-fluoro-phenyl]-urea;

A151 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-(1,2-dihydroxy-ethyl)-3-fluoro-phenyl]-urea;

A152 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[2-hydroxy-1-(hydroxymethyl)-ethyl]-phenyl]-urea;

A153 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[2-hydroxy-1-(hydroxymethyl)-ethyl]-phenyl]-urea;

A154 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]-phenyl]-urea;

A155 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]-phenyl]-urea;

A156 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[3-fluoro-4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]-phenyl]-urea;

A157 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[2-hydroxy-1-(hydroxymethyl)-1-methyl-ethyl]-phenyl]-urea;

A158 1-[[2-(3-Chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[1,2-dihydroxy-1-(hydroxymethyl)-ethyl]-phenyl]-urea; and

A159 1-[[5-tert-Butyl-2-(3-chlorophenyl)-2H-pyrazol-3-yl]-methyl]-3-[4-[1,2-dihydroxy-1-(hydroxymethyl)-ethyl]-phenyl]-urea;

in the form of a free compound or a physiologically acceptable salt thereof, and if applicable, in the form of an individual stereoisomer or a mixture of stereoisomers.

10. A pharmaceutical composition comprising a compound according to claim 1 and at least one pharmaceutically acceptable carrier or auxiliary substance.

11. A method of treating in inhibiting a disease or disorder selected from the group consisting of pain; hyperalgesia; allodynia; causalgia; migraine; depression; nervous affection; axonal injuries; neurodegenerative diseases; cognitive dysfunctions; epilepsy; respiratory diseases; coughs; urinary incontinence; overactive bladder; disorders and injuries of the gastrointestinal tract; duodenal ulcers; gastric ulcers; irritable bowel syndrome; strokes; eye irritations; skin irritations; neurotic skin diseases; allergic skin diseases; psoriasis; vitiligo; herpes simplex; inflammations; diarrhea; pruritus; osteoporosis; arthritis; osteoarthritis; rheumatic diseases; eating disorders; medication dependency; misuse of medication; withdrawal symptoms in medication dependency; development of tolerance to medication; drug dependency; misuse of drugs; withdrawal symptoms in drug dependency; alcohol dependency; misuse of alcohol and withdrawal symptoms in alcohol dependency; or for effecting diuresis; antinatriuresis; influencing the cardiovascular system; increasing vigilance; treatment of wounds or burns; treatment of severed nerves; increasing libido; modulating movement activity; effecting anxiolysis; local anaesthesia or inhibiting undesirable side effects triggered by the administration of a vanilloid receptor 1 agonist, in a subject in need thereof, said method comprising administering to said subject a pharmacologically effective amount of a compound according to claim 1 .

12. A method as claimed in claim 11 , wherein said disease or disorder is pain selected from the group consisting of acute pain, chronic pain, neuropathic pain, visceral pain and joint pain; a neurodegenerative disease selected from the group consisting of multiple sclerosis, Alzheimer's disease, Parkinson's disease and Huntington's disease; a cognitive deficiency state; a respiratory disease selected from the group consisting of asthma, bronchitis and pulmonary inflammation; an inflammation of the intestine, the eyes, the bladder, the skin or the nasal mucous membrane; an eating disorder selected from the group consisting of bulimia, cachexia, anorexia and obesity; or development of tolerance to natural or synthetic opioids; or for inhibiting undesirable side effects selected from the group consisting of hyperthermia, hypertension and bronchoconstriction triggered by administration of a vanilloid receptor 1 agonist selected from the group consisting of capsaicin, resiniferatoxin, olvanil, arvanil, SDZ-249665, SDZ-249482, nuvanil and capsavanil.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 19, 2017

From: GRUENENTHAL GMBH

To: MEDIFRON DBT INC.

Reel/Frame 042439/0076 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 17, 2017

From: FRANK, ROBERT; BAHRENBERG, GREGOR; CHRISTOPH, THOMAS; SCHIENE, KLAUS; DE VRY, JEAN; DAMANN, NILS; FRORMANN, SVEN; LESCH, BERNHARD; SAUNDERS, DEREK; LEE, JEEWOO; KIM, YONG-SOO; KIM, MYEONG-SEOP; STOCKHAUSEN, HANNELORE

To: GRUENENTHAL GMBH

Reel/Frame 041613/0927 →

Priority Claims (1)

EP 09006237 · May 7, 2009 · regional

Continuity (4)

Division 13292563 · Nov 9, 2011

Continuation In Part 12775235 · May 6, 2010

Provisional Application 61176284 · May 7, 2009

Related Publication 20150099728A1 · Apr 9, 2015