US 2003/0125344 A1Published application

Rho-kinase inhibitors

AssigneeBayer Aktiengesellschaft

InventorsDhanaphalan Nagarathnam, Davoud Asgari, Jianxing Shao, Xiao-Gao Liu, Uday Khire, Chunguang Wang, Barry Hart, Stephen Boyer, Olaf Weber, Mark Lynch

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Abstract

Disclosed are compounds and derivatives thereof, their synthesis, and their use as Rho-kinase inhibitors. These compounds of the present invention are useful for inhibiting tumor growth, treating erectile dysfunction, and treating other indications mediated by Rho-kinase, e.g., coronary heart disease.

Claims27

Dependent claims

A compound of Formula I

82
wherein Y is ═N— or ═CR17,
X is —(CH2)x—, —O—(CH2)n—, —S—(CH2)n—, —NR7—CO—(CH2)n—, —NR7—SO2—(CH2)n—, —NR7—(CH2)n—, or —(O)C—NR7—,
each n is an integer which is independently 0, 1, 2 or 3,
x is 0-3
p is 0-3
a and c are each independently —CR5═, —N═, or —NR6—, wherein one of a or c is —NR6—, and b is —CR5═ or —N═;
A is H, halogen, —CO—OR8, —CO—R8, cyano, —OR8, —NR8R9, —CO—NR8R9, —NR8—CO—R9, —NR8—CO—OR9, —NR8—SO2—R9, —SR8, —SO2—R8, —SO2—NR8R9, NR8—CO—NHR9,
or
A is a 3-20 atom, cyclic or polycyclic moiety, containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C1-C10 alkyl or C2-C10-alkenyl, each optionally substituted with halogen up to perhalo;
(ii) C3-C10 cycloalkyl;
(iii) aryl;
(iv) heteroaryl;
(v) halogen;
(vi) —CO—OR8;
(vii) —CO—R8;
(viii) cyano;
(ix) —OR8, (x) (x) —NR8R13;
(xi) nitro;
(xii) —CO—NR8R9;
(xiii) —C1-10-alkyl-NR8R9;
(xiv) —NR8—CO—R12;
(xv) —NR8—CO—OR9;
(xvi) —NR8—SO2—R9;
(xvii) —SR8;
(xviii) —SO2—R8;
(xix) —SO2—NR8R9;
or (xx) NR8—CO—NHR9;
Ring B is optionally independently substituted up to 3 times in any position by R5,
R1, and R6-R11 are each independently hydrogen or C1-6 alkyl,
R2-R5 are each independently (i) hydrogen, (ii) C1-10 alkyl or C2-10-alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR10, —COR14, —OCOR14, —OR10, C5-10-heteroaryl, C5-10-heteroaryloxy, or C5-10-heteroaryl-C1-10-alkoxy, halogen up to perhalo;
(iii) C3-C10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S;
(iv) C3-10-cycloalkenyl;
(v) partially unsaturated C5-10-heterocyclyl;
(vi) aryl;
(vii) heteroaryl;
(viii) halogen;
(ix) —CO—OR10;
(x) —OCOR10;
(xi) —OCO2R10;
(xii) —CHO;
(xiii) cyano;
(xiv) —OR16;
(xv) —NR10R15;
(xvi) nitro;
(xvii) —CO—NR10R11;
(xviii) —NR10—CO—R12;
(xix) —NR10—CO—OR11;
(xx) —NR10—SO2—R12;
(xxi) —SR16;
(xxii) —SOR16;
(xxiii) —SO2—R16;
(xxiv) —SO2—NR10R11;
(xxv) NR10—CO—NHR11;
(xxvi) amidino;
(xxvii) guanidino;
(xxviii) sulfo;
(xxix) —B(OH)2;
(xxx) —OCON(R10)2;
or (xxxi) —NR10CON(R10)2;
R12 is H, C1-6-alkyl or C5-10-aryl,
R13 is H, C1-6-alkyl or C1-6-alkoxy,
R14 is C1-6 alkyl or phenyl;
R15 is C1-6 alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR10, —COR14 or —OCOR14;
R16 is hydrogen, C1-6-alkyl optionally substituted by halogen, up to perhalo, or C5-10-heteroaryl;
and
R17 is H, C1-6 alkyl or CN,
or a pharmaceutically acceptable salt thereof,
with the provisos that A is not hydrogen when x is 0, and that Formula I is not
83

67 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/103,566Filed 22 Mar 2002
Priority: 23 Mar 2001
Published: 3 Jul 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 7/04
Drugs for disorders of the blood or the extracellular fluid: antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
A61P 9/00
Drugs for disorders of the cardiovascular system

Family

Application60/277,974Us provisional application · filed 23 Mar 2001
Application60/315,341Us provisional application · filed 29 Aug 2001
US 2003/0125344 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula I

82
wherein Y is ═N— or ═CR17,
X is —(CH2)x—, —O—(CH2)n—, —S—(CH2)n—, —NR7—CO—(CH2)n—, —NR7—SO2—(CH2)n—, —NR7—(CH2)n—, or —(O)C—NR7—,
each n is an integer which is independently 0, 1, 2 or 3,
x is 0-3
p is 0-3
a and c are each independently —CR5═, —N═, or —NR6—, wherein one of a or c is —NR6—, and b is —CR5═ or —N═;
A is H, halogen, —CO—OR8, —CO—R8, cyano, —OR8, —NR8R9, —CO—NR8R9, —NR8—CO—R9, —NR8—CO—OR9, —NR8—SO2—R9, —SR8, —SO2—R8, —SO2—NR8R9, NR8—CO—NHR9,
or
A is a 3-20 atom, cyclic or polycyclic moiety, containing 1-4 rings, which optionally contain 1-3 N, O or S atoms per ring, and may optionally be aryl or heteroaryl, which cyclic or polycyclic moiety may optionally be substituted up to 3 times by (i) C1-C10 alkyl or C2-C10-alkenyl, each optionally substituted with halogen up to perhalo;
(ii) C3-C10 cycloalkyl;
(iii) aryl;
(iv) heteroaryl;
(v) halogen;
(vi) —CO—OR8;
(vii) —CO—R8;
(viii) cyano;
(ix) —OR8, (x) (x) —NR8R13;
(xi) nitro;
(xii) —CO—NR8R9;
(xiii) —C1-10-alkyl-NR8R9;
(xiv) —NR8—CO—R12;
(xv) —NR8—CO—OR9;
(xvi) —NR8—SO2—R9;
(xvii) —SR8;
(xviii) —SO2—R8;
(xix) —SO2—NR8R9;
or (xx) NR8—CO—NHR9;
Ring B is optionally independently substituted up to 3 times in any position by R5,
R1, and R6-R11 are each independently hydrogen or C1-6 alkyl,
R2-R5 are each independently (i) hydrogen, (ii) C1-10 alkyl or C2-10-alkenyl each optionally substituted by amino, N-lower alkylamino, N,N-dilower alkylamino, N-lower alkanoylamino, hydroxy, cyano, —COOR10, —COR14, —OCOR14, —OR10, C5-10-heteroaryl, C5-10-heteroaryloxy, or C5-10-heteroaryl-C1-10-alkoxy, halogen up to perhalo;
(iii) C3-C10 cycloalkyl, in which 1-3 carbon atoms are optionally independently replaced by O, N or S;
(iv) C3-10-cycloalkenyl;
(v) partially unsaturated C5-10-heterocyclyl;
(vi) aryl;
(vii) heteroaryl;
(viii) halogen;
(ix) —CO—OR10;
(x) —OCOR10;
(xi) —OCO2R10;
(xii) —CHO;
(xiii) cyano;
(xiv) —OR16;
(xv) —NR10R15;
(xvi) nitro;
(xvii) —CO—NR10R11;
(xviii) —NR10—CO—R12;
(xix) —NR10—CO—OR11;
(xx) —NR10—SO2—R12;
(xxi) —SR16;
(xxii) —SOR16;
(xxiii) —SO2—R16;
(xxiv) —SO2—NR10R11;
(xxv) NR10—CO—NHR11;
(xxvi) amidino;
(xxvii) guanidino;
(xxviii) sulfo;
(xxix) —B(OH)2;
(xxx) —OCON(R10)2;
or (xxxi) —NR10CON(R10)2;
R12 is H, C1-6-alkyl or C5-10-aryl,
R13 is H, C1-6-alkyl or C1-6-alkoxy,
R14 is C1-6 alkyl or phenyl;
R15 is C1-6 alkyl, halogen, amino, N-lower alkyl amino, N,N-dilower alkylamino, N-lower alkanoylamino, OH, CN, COOR10, —COR14 or —OCOR14;
R16 is hydrogen, C1-6-alkyl optionally substituted by halogen, up to perhalo, or C5-10-heteroaryl;
and
R17 is H, C1-6 alkyl or CN,
or a pharmaceutically acceptable salt thereof,
with the provisos that A is not hydrogen when x is 0, and that Formula I is not
83

67 more elements

Facts

Application

10/103,566Filed 22 Mar 2002

Priority

23 Mar 2001

Published

3 Jul 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification24 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 7/04
Drugs for disorders of the blood or the extracellular fluid: antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
A61P 9/00
Drugs for disorders of the cardiovascular system