US 8,940,769 B2 · Biaryl benzoimidazole derivatives and pharmaceutical composition comprising the same

Abstract

Disclosed are biaryl benzoimidazole derivatives. They have an inhibitory effect on calcium influx in HEK cells, thereby showing a powerful antagonistic effect on a vanilloid receptor, and further have an analgesic effect, thereby being useful for preventing or treating pain, acute pain, chronic pain, neuropathic pain, postoperative pain, migraine, arthralgia, neuropathies, nerve injury, diabetic neuropathy, neurological illness, neurodermatitis, stroke, bladder hypersensitivity, irritable bowel syndrome, a respiratory disorder such as cough, asthma, and chronic obstructive pulmonary disease, burning, psoriasis, itching, vomiting, irritation of the skin, eyes, and mucous membranes, gastric-duodenal ulcers, inflammatory intestinal diseases, and inflammatory diseases.

A biaryl benzoimidazole represented by the following Formula 1, a pharmaceutically acceptable salt, or an isomer thereof,

wherein,
R1 is hydrogen or (CRaRa′)mRb;
m is an integer of 0, 1 or 2;
Ra and Ra′ are each independently hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
NH(C1-6 alkyl);
N(C1-6 alkyl)2;
alkoxy having 1 to 8 carbon atoms;
alkyl having 1 to 8 carbon atoms substituted or unsubstituted with one or more Rc;
alkenyl having 2 to 8 carbon atoms substituted or unsubstituted with one or more Rc;
phenyl substituted or unsubstituted with one or more Rc;
or benzyl substituted or unsubstituted with one or more Rc;
Rb is hydrogen;
hydroxy;
alkyl having 1 to 6 carbon atoms substituted or unsubstituted with one or more Rc;
phenyl substituted or unsubstituted with one or more Rc;
or benzyl substituted or unsubstituted with one or more Rc;
Rc is halogen;
cyano;
nitro;
azide;
phenyl;
benzyl;
C(═O)Rd;
C(═O)ORd;
C(═O)NRdRd′;
ORd;
OC(═O)Re;
OC(═O)ORe;
OC(═O)NRdRd′;
OC1-6alkylORd;
OC1-6alkylNRdRd′;
SRd;
S(═O)Re;
S(═O)2Re;
S(═O)2NRdRd′;
CRd═NRd;
NRdRd′;
NRdC(═O)Re;
NRdC(═O)ORe;
NRdC(═O)NRd′Rd″;
NRdC(═NRd′)NRd″Rd′″;
NRdS(═O)2Re;
NRdORd′;
NRdC1˜6alkylNRd′Rd″;
or NRdC1-6alkylORd′;
Rd, Rd′, Rd″ and Rd′″ are each independently hydrogen or Re;
Re is phenyl substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl), and N(C1-4 alkyl)2;
benzyl substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl), and N(C1-4 alkyl)2;
alkyl having 1 to 6 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl), and N(C1-4 alkyl)2;
or phosphoric acid;
R2 is hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
alkoxy having 1 to 8 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atoms;
alkyl having 1 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
alkenyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
alkynyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
cycloalkyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
bicycloalkyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rf;
cycloalkenyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
bicycloalkenyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rf;
phenyl substituted or unsubstituted with one or more Rf;
naphthyl substituted or unsubstituted with one or more Rf;
benzyl substituted or unsubstituted with one or more Rf;
C(═O)ORd;
C(═O)NRdRd′;
ORd;
OC(═O)Re;
OC(═O)ORe;
OC(═O)NRdRd′;
OC1-6alkylORd;
OC1-6alkylNRdRd′;
SRd;
S(═O)Re;
S(═O)2Re;
S(═O)2NRdRd′;
CRd═NRd′;
NRdRd′;
NRdC(═O)Re;
NRdC(═O)ORe;
NRdC(═O)NRd′Rd″;
NRdC(═NRd′)NRd″Rd′″;
NRdS(═O)2Re;
NRdORd′;
NRdC1-6alkylNRd′Rd″;
or NRdC1-6alkylORd′;
Rf is alkyl having 1 to 6 carbon atoms;
alkenyl having 2 to 6 carbon atoms;
alkynyl having 2 to 6 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atoms;
halogen;
azide;
nitro;
cyano;
phenyl;
benzyl;
C(═O)Rd;
C(═O)ORd;
C(═O)NRdRd′;
ORd;
OC(═O)Re;
OC(═O)ORe;
OC(═O)NRdRd′;
C1-6alkylORd;
OC1-6alkylNRdRd′;
SRd;
S(═O)Re;
S(═O)2Re;
S(═O)2NRdRd′;
CRd═NRd′;
NRdRd′;
NRdC(═O)Re;
NRdC(═O)ORe;
NRdC(═O)NRd′Rd″;
NRdC(═NRd′)NRd″Rd′″;
NRdS(═O)2Re;
NRdORd′;
NRdC1-6alkylNRd′Rd″;
or NRdC1-6alkylORd′;
A is (CRgRg′)pZ or Z(CRgRg′)p;
p is an integer of 0, 1 or 2;
Z is C(═O);
C(═O)O;
C(═O)NRd;
C(═NRd);
C(═NRd)NRd′;
C(═O)C1-6alkylC(═O);
C(═O)C1-6alkylO;
C(═O)C1-6alkylS;
C(═O)C1-6alkylS(═O)2;
C(═O)C1-6alkylNRd;
O;
OC(═O);
OC(═O)NRd;
OC(═O)NRdS(═O)2;
OC1-6alkylC(═O);
OC1-6alkylO;
OC1-6alkylS;
OC1-6alkylS(═O)2;
OC1-6alkylNRd;
S;
SC1-6alkylC(═O);
SC1-6alkylO;
SC1-6alkylS;
SC1-6alkylS(═O)2;
SC1-6alkylNRd;
S(═O);
S(═O)2;
S(═O)2NRd;
S(═O)2NRdC(═O);
S(═O)2NRdC(═O)O;
S(═O)2NRdC(═O)NRd′;
S(═O)2C1-6alkylC(═O);
S(═O)2C1-6alkylO;
S(═O)2C1-6alkylS;
S(═O)2C1-6alkylS(═O)2;
S(═O)2C1-6alkylNRd;
NRd;
NRdC(═O);
NRdC(═O)O;
NRdC(═O)NRd′;
NRdC(═NRd′)NRd″;
NRdS(═O)2;
NRdS(═O)2NRd′;
NRdC1-6alkylC(═O);
NRdC1-6alkylO;
NRdC1-6alkylS;
NRdC1-6alkylS(═O)2;
or NRdC1-6alkylNRd′;
Rg and Rg′ are each independently hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
NH(C1-6 alkyl);
N(C1-6 alkyl)2;
alkoxy having 1 to 8 carbon atoms;
alkyl having 1 to 8 carbon atoms substituted or unsubstituted with one or more Rc;
alkenyl having 2 to 8 carbon atoms substituted or unsubstituted with one or more Rc;
phenyl substituted or unsubstituted with one or more Rc;
or benzyl substituted or unsubstituted with one or more Rc;
R3 is hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
alkoxy having 1 to 8 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atom;
alkyl having 1 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
alkenyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
alkynyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
cycloalkyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
bicycloalkyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rf;
cycloalkenyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rf;
bicycloalkenyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rf;
phenyl substituted or unsubstituted with one or more Rf;
naphthyl substituted or unsubstituted with one or more Rf;
or benzyl substituted or unsubstituted with one or more Rf;
Q1 is CR4;
Q2 is CR5;
Q3 is CR5′;
Q4 is CR4′;
Q5 is N;
Q6 is CR7;
Q7 is CR6′;
Q8 is CR7′;
W is CR8;
X is CR8′;
R4, R4′, R5, R5′, R6′, R7 and R7′ are the same or different from each other, and each independently hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
alkoxy having 1 to 8 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atoms;
alkyl having 1 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
alkenyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
alkynyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
cycloalkyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
bicycloalkyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rh;
cycloalkenyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
bicycloalkenyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rh;
phenyl substituted or unsubstituted with one or more Rh;
naphthyl substituted or unsubstituted with one or more Rh;
benzyl substituted or unsubstituted with one or more Rh;
C(═O)Ri;
C(═O)ORi;
C(═O)NRiRi′;
ORi;
OC(═O)Rj;
OC(═O)ORj;
OC(═O)NRiRi′;
OC1-6alkylORi;
OC1-6alkylNRiRi′;
SRi;
S(═O)Rj;
S(═O)2Rj;
S(═O)2NRiRi′;
CRi═NRi′;
NRiRi′;
NRiC(═O)Rj;
NRiC(═O)ORj;
NRiC(═O)NRi′Ri″;
NRiC(═NRi′)NRi″Ri′″;
NRiS(═O)2Rj;
NRiRi′;
NRiC1-6alkylNRi′Ri″;
or NRiC1-6alkylORi;
Rh is alkyl having 1 to 6 carbon atoms;
alkenyl having 2 to 6 carbon atoms;
alkynyl having 2 to 6 carbon atoms;
cycloalkyl having 3 to 8 carbon atoms;
cycloalkenyl having 5 to 8 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atoms;
halogen;
azide;
nitro;
cyano;
phenyl;
benzyl;
C(═O)Ri;
C(═O)ORi;
C(═O)NRiRi′;
ORi;
OC(═O)Rj;
OC(═O)ORj;
OC(═O)NRiRi′;
OC1-6alkylORi;
OC1-6alkylNRiRi′;
SRi;
S(═O)Rj;
S(═O)2Rj;
S(═O)2NRiRi′;
CRi═NRi′;
NRiRi′;
NRiC(═O)Rj;
NRiC(═O)ORj;
NRdC(═O)NRiRi′;
NRiC(═NRi′)NRi″Ri′″;
NRiS(═O)2Rj;
NRiORi′;
NRiC1-6alkylNRi′Ri″;
NRiC1-6alkylORi′;
Ri, Ri′, Ri″ and Ri′″ are each independently hydrogen or Rj;
Rj is phenyl substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
benzyl substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
alkyl having 1 to 6 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
alkenyl having 2 to 6 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
alkynyl having 2 to 6 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
cycloalkyl having 3 to 8 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
or
cycloalkenyl having 5 to 8 carbon atoms substituted or unsubstituted with one or more groups selected from the group consisting of hydroxy, halogen, alkyl having 1 to 4 carbon atoms, haloalkyl having 1 to 3 carbon atoms, alkoxy having 1 to 4 carbon atoms, amine, NH(C1-4 alkyl) and N(C1-4 alkyl)2;
R8 and R8′ are the same or different from each other, and each independently hydrogen;
halogen;
nitro;
hydroxy;
cyano;
azide;
amine;
alkoxy having 1 to 8 carbon atoms;
haloalkyl having 1 to 6 carbon atoms;
haloalkoxy having 1 to 6 carbon atoms;
alkyl having 1 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
alkenyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
alkynyl having 2 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
cycloalkyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
bicycloalkyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rh;
cycloalkenyl having 3 to 10 carbon atoms substituted or unsubstituted with one or more Rh;
bicycloalkenyl having 8 to 14 carbon atoms substituted or unsubstituted with one or more Rh;
phenyl substituted or unsubstituted with one or more Rh;
naphthyl substituted or unsubstituted with one or more Rh;
benzyl substituted or unsubstituted with one or more Rh;
C(═O)Ri;
C(═O)ORi;
C(═O)NRiRi′;
ORi;
OC(═O)Rj;
OC(═O)ORj;
OC(═O)NRiRi′;
OC1-6alkylORi;
OC1-6alkylNRiRi′;
SRi;
S(═O)Rj;
S(═O)2Rj;
S(═O)2NRiRi′;
CRi═NRi′;
NRiRi′;
NRiC(═O)Rj;
NRiC(═O)ORj;
NRiC(═O)NRi′Ri″;
NRiC(═NRi′)NRi″Ri′″;
NRiS(═O)2Rj;
NRiORi′;
NRiC1-6alkylNRi′Ri″;
or NRiC1-6alkylORi.

354 more elements

Biaryl benzoimidazole derivatives and pharmaceutical composition comprising the same

Life of this patent

Biaryl benzoimidazole derivatives and pharmaceutical composition comprising the same

Life of this patent

Abstract

Claims6