# US 2014/0155596 A1 · Cysteinyl leukotriene antagonists

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- Number: US 2014/0155596 A1
- Document ID: US20140155596A1
- Status: Published application
- Kind: A1
- Application number: 14/234,961
- Filed: 2012-07-26
- Published: 2014-06-05
- Earliest claimed: 2011-07-26
- Assignees: Sun Pharma Advanced Research Company Ltd.
- Inventors: Rajendrasinh Rathod; Tushar Bhatt; Kritkumar Joshi; Binaka Dole; Kadiyala V.S.N. Murty; Rajamannar Thennati
- Web page: https://patentgrep.com/patent/US20140155596A1

## CPC

- C07D 413/10: linked by a carbon chain containing aromatic rings
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 17/04: Antipruritics
- A61P 25/06: Antimigraine agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 215/18: Halogen atoms or nitro radicals
- C07D 241/42: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 407/10: linked by a carbon chain containing aromatic rings
- C07D 407/12: linked by a chain containing hetero atoms as chain links
- C07D 407/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to novel cysteinyl leukotriene (specifically LTD4) antagonists, mainly to quinolin, quinoxaline or benz[c]thiazole derivatives represented by the general formula (I), or the pharmaceutically acceptable salt thereof, process of preparation thereof, and to the use of the compounds in the preparation of pharmaceutical compositions for the therapeutic treatment of disorders related to cysteinyl leukotriene, in mammals, more specially in humans.

## Claims

### Claim 1

A compound of formula (I), or the pharmaceutically acceptable salt thereof,
wherein,
ring ‘a’, ring ‘b’ and ring ‘c’ are independently an aryl or a heteroaryl ring optionally substituted by one or more identical or different radicals R1 or R2,
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, —OH, —CN, —NO2, —NH2, —C1-10-alkyl, —C3-10 cycloalkyl, —O—C1-8 alkyl (alkoxy), —O—C3-8 cycloalkyl (cycloalkoxy), —S—C1-8 alkyl (thioalkoxy), —C(O)—C1-8 alkyl, —COOH, —C(O)NH2, —C(O)NH—C1-8 alkyl, —C(O)N(C1-8 alkyl)2, —C(O)O—C1-8 alkyl, —C1-8 haloalkyl (haloalkoxy), —C3-8 alkenyl, —C3-8 alkynyl, —OC(O)—NH2, —OC(O)—NH(C1-8 alkyl), —OC(O)—N(C1-8 alkyl)2, —NH2, —NH(C1-8 alkyl), —N(C1-8 alkyl)2, —NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-SO2—C1-8 alkyl, —NH—C(O)—(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—(C1-8 alkyl), —NH—C(O)O—C1-8 alkyl, —N(C1-8 alkyl)-C(O)O—C1-8 alkyl, —NH—C(O)—NH2, —NH—C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)2, —NH—C(O)—NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—NHSO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)-SO2—C1-8 alkyl, —S—C1-8 alkyl, —S(O)—C1-8 alkyl, —SO2—C1-8 alkyl, —S-aryl, —S(O)-aryl, SO2-aryl, —SO2NH2, —SO2NH—(C1-8 alkyl), —SO2N(C1-8 alkyl)2;
W represents a group selected from —CH═ or —N═;
X represents a group selected from —CH═CH—, —S—, or —N═CH—;
Y represents a group selected from —CH═CH— or —C≡C—;
Z represents a bond or group selected from —(CH2)n—, —O—CH2- or —CH═CH—;
A is a group selected from hydrogen, —OH, —OR, —SR, —O(CH2)n aryl, —O(CH2)n heteroaryl, —OCOR, —OCO-aryl, —SCOR, —SCO-aryl, —NRR′, —NRCOR′, —NRCO-aryl, —NRCO-aryl-COOR, —NRCH2ArCOOR, —NHCH2(CR,R′)OH, —NHCOCH2heteroaryl, —NHCOCH2(CR,R′)CH2COOR, —NHCOCH2(P)-aryl-COOR, —NHCOCH2NRR′, —NRSO2R′, —NRSO2-aryl, —NRCONRR′, —NRCONR′-aryl, —NRCOCH2-aryl-COOR′, —NRPO(OR′)(OH);
B is a group selected from hydrogen, —OR′, —SR, —NRR′ and —NRCOR′;
or, A and B together can form a substituted or unsubstituted 5 to 8 membered cyclic ring containing at least two heteroatoms selected from oxygen and sulfur;
or, A and B together represent group consisting of C═O, C═S, C═N(OR) or C═NNRR′;
P is selected from the group consisting of —O—, —S—, —CH2— and —NR—; or P may form a —CH═CH— moiety with the adjacent carbon atom;
J represents a group selected from aryl-Q, heteroaryl-Q or —(CH2)nQ, wherein Q is a group selected from hydrogen, —CH3, —CF3, OR, —COOR, —CONRR′, —CR═CR—COOR′; —OCH2 aryl-COOR, —CH2O-aryl-COOR, —CONHSO2R, —CONHSO2 aryl, —OCH2CONRR′, —NHSO2R, —NHSO2 aryl, —NHSO2NHR, —SO2NHR, —SO2NH aryl, —NHCOR, —NHCO(CRR′)—COOR, —C(R,R′)—COOR, tetrazole, —C(R,R′)OH, —C(R,R′)CONRR′, —CH2NRR′ or —OCH2C(R,R′)OH;
R and R′ are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-6 cycloalkyl, —C1-3 alkyl (cycloalkyl), —C3-6 alkenyl and —C3-6 alkynyl or, R and R′ along with the atom to which they are attached, together can form a substituted or unsubstituted 5 to 8 membered cyclic ring;
‘n’ is an integer selected from 1, 2 or 3;
‘m’ is an integer selected from 0 to 4, both inclusive;
with the proviso that when P is —CH2—, then A and B both represent groups connected to carbon through heteroatom and when B is hydrogen, then A is —NR—.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein rings ‘a’ and ‘b’ comprise a fused hetero-cyclic aromatic ring system, selected from a substituted or unsubstituted quinolin, benzothiazole or a quinoxaline ring.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein the substitution pattern in the ring ‘c’ is (1, 2); (1, 3) or (1, 4) with respect to ‘Y’ and preferably (1, 3) as disclosed in the specification.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein W is —CH═.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein X is —CH═CH—.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein Y is —CH═CH—.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein Z represents a bond.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R1 and R2 are selected from hydrogen and halogen.

### Claim 9

A compound of formula (Ia), or the pharmaceutically acceptable salt thereof,
wherein,
R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, —OH, —CN, —NO2, —NH2, —C1-10 alkyl, —C3-10 cycloalkyl, —O—C1-8 alkyl, —O—C1-8 alkyl (alkoxy), —O—C3-8 cycloalkyl (cycloalkoxy), —S—C1-8 alkyl (thioalkoxy), —C(O)—C1-8 alkyl, —COOH, —C(O)NH2, —C(O)NH—C1-8 alkyl, —C(O)N(C1-8 alkyl)2, —C(O)O—C1-8 alkyl, —C1-8 haloalkyl (haloalkoxy), —C3-8 alkenyl, —C3-8 alkynyl, —OC(O)—NH2, —OC(O)—NH(C1-8 alkyl), —OC(O)—N(C1-8 alkyl)2, —NH(C1-8 alkyl), —N(C1-8 alkyl)2, —NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-SO2—C1-8 alkyl, —NH—C(O)—(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—(C1-8 alkyl), —NH—C(O)O—C1-8 alkyl, —N(C1-8 alkyl)-C(O)O—C1-8 alkyl, —NH—C(O)—NH2, —NH—C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)2, —NH—C(O)—NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—NHSO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)-SO2—C1-8 alkyl, —S—C1-8 alkyl, —S(O)—C1-8 alkyl, —SO2—C1-8 alkyl, —S-aryl, —S(O)-aryl, SO2-aryl, —SO2NH2, —SO2NH—(C1-8 alkyl), —SO2N(C1-8 alkyl)2;
W represents a group selected from —CH═ or —N═;
X represents a group selected from —CH═CH—, —S—, or —N═CH—;
Y represents a group selected from —CH═CH— or —C≡C—;
A is a group selected from hydrogen, —OH, —OR, —SR, —O(CH2)n aryl, —O(CH2)n heteroaryl, —OCOR, —OCO-aryl, —SCOR, —SCO-aryl, —NRR′, —NRCOR′, —NRCO-aryl, —NRCO-aryl-COOR, —NRCH2ArCOOR, —NHCH2(CR,R′)OH, —NHCOCH2 heteroaryl, —NHCOCH2(CR,R′)CH2COOR, —NHCOCH2(P)-aryl-COOR, —NHCOCH2NRR′, —NRSO2R′, —NRSO2-aryl, —NRCONRR′, —NRCONR′-aryl, —NRCOCH2-aryl-COOR′, —NRPO(OR′)(OH); with a proviso that when A is —OR or —SR, then is P is selected from —O—, —S— or —NR— and when A is —NR—, P is selected from —O—, —S—, —NR— or —CH2—;
P is selected from the group consisting of —O—, —S—, —CH2— and —NR—; or P may form a —CH═CH— moiety with the adjacent carbon atom;
Q is a group selected from hydrogen, —CH3, —CF3, OR, —COOR, —CONRR′, —CR═CR—COOR′; —OCH2 aryl-COOR, —CH2O-aryl-COOR, —CONHSO2R, —CONHSO2 aryl, OCH2CONRR′, —NHSO2R, —NHSO2 aryl, —NHSO2NHR, —SO2NHR, —SO2NH aryl, —NHCOR, —NHCO(CRR′)—COOR, —C(R,R′)—COOR, tetrazole, —C(R,R′)OH, —C(R,R′)CONRR′, —CH2NRR′ or —OCH2C(R,R′)OH;
R and R′ are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-6 cycloalkyl, —C1-3 alkyl (cycloalkyl), —C3-6 alkenyl and —C3-6 alkynyl or, R and R′ along with the atom to which they are attached, together can form a substituted or unsubstituted 5 to 8 membered cyclic ring;
‘n’ is an integer selected from 1, 2 or 3;
‘m’ is an integer selected from 0 to 4, both inclusive;
with the proviso that when P is —CH2—, then A is —NR—.

### Claim 10 (depends on 9)

A compound according to claim 9, wherein W is —CH═.

### Claim 11 (depends on 9)

A compound according to claim 9, wherein X is —CH═CH—.

### Claim 12 (depends on 9)

A compound according to claim 9, wherein Y is —CH═CH—.

### Claim 13 (depends on 9)

A compound according to claim 9, wherein Z represents a bond.

### Claim 14 (depends on 9)

A compound according to claim 9, wherein R1 and R2 are selected from hydrogen and halogen.

### Claim 15 (depends on 9)

A compound according to claim 9, wherein A is —OR or —SR and P is selected from —O—, —S— or —NR—.

### Claim 16 (depends on 9)

A compound according to claim 9, wherein A is —NR— and P is selected from —O—, —S—, —NR— or —CH2—.

### Claim 17 (depends on 9)

A compound according to claim 9 wherein Q is a group selected from hydrogen, OR, —COOR, —CONRR′, —CONHSO2R, —NHCO(CRR′)—COOR, —C(R,R′)OH, or —OCH2C(R,R′)OH.

### Claim 18

A compound of formula (Ib), or the pharmaceutically acceptable salt thereof,
wherein,
R1, R2 and R3 are independently selected from the group consisting of hydrogen, halogen, —OH, —CN, —NO2, —NH2, —C1-10-alkyl, —C3-10 cycloalkyl, —O—C1-8 alkyl (alkoxy), —O—C3-8 cycloalkyl (cycloalkoxy), —S—C1-8 alkyl (thioalkoxy), —C(O)—C1-8 alkyl, —COOH, —C(O)NH2, —C(O)NH—C1-8 alkyl, —C(O)N(C1-8 alkyl)2, —C(O)O—C1-8 alkyl, —C1-8 haloalkyl (haloalkoxy), —C3-8 alkenyl, —C3-8 alkynyl, —OC(O)—NH2, —OC(O)—NH(C1-8 alkyl), —OC(O)—N(C1-8 alkyl)2, —NH(C1-8 alkyl), —N(C1-8 alkyl)2, —NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-SO2—C1-8 alkyl, —NH—C(O)—(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—(C1-8 alkyl), —NH—C(O)O—C1-8 alkyl, —N(C1-8 alkyl)-C(O)O—C1-8 alkyl, —NH—C(O)—NH2, —NH—C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)2, —NH—C(O)—NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—NHSO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)-SO2—C1-8 alkyl, —S—C1-8 alkyl, —S(O)—C1-8 alkyl, —SO2—C1-8 alkyl, —S-aryl, —S(O)-aryl, SO2-aryl, —SO2NH2, —SO2NH—(C1-8 alkyl), —SO2N(C1-8 alkyl)2;
W represents a group selected from —CH═ or —N═;
X represents a group selected from —CH═CH—, —S—, or —N═CH—;
Y represents a group selected from —CH═CH— or —C≡C—;
A and B are independently selected from —OR′, —SR, —NRR′ or —NRCOR′;
or, A and B together can form a substituted or unsubstituted 5 to 8 membered cyclic ring containing at least two heteroatoms selected from oxygen and sulfur;
or, A and B together represent group consisting of C═O, C═S, C═N(OR) or C═NNRR′;
P is selected from the group consisting of —O—, —S—, —CH2— and —NR—; or P may form a —CH═CH— moiety with the adjacent carbon atom;
Q is a group selected from hydrogen, —CH3, —CF3, OR, —COOR, —CONRR′, —CR═CR—COOR′; —OCH2 aryl-COOR, —CH2O-aryl-COOR, —CONHSO2R, —CONHSO2 aryl, —OCH2CONRR′, —NHSO2R, —NHSO2 aryl, —NHSO2NHR, —SO2NHR, —SO2NH aryl, —NHCOR, —NHCO(CRR′)—COOR, —C(R,R′)—COOR, tetrazole, —C(R,R′)OH, —C(R,R′)CONRR′, —CH2NRR′ or —OCH2C(R,R′)OH;
R and R′ are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C1-6 cycloalkyl, —C1-3 alkyl (cycloalkyl), —C3-6 alkenyl and —C3-6 alkynyl or, R and R′ along with the atom to which they are attached, together can form a substituted or unsubstituted 5 to 8 membered cyclic ring;
‘n’ is an integer selected from 1, 2 or 3;
‘m’ is an integer selected from 0 to 4, both inclusive;
with the proviso that when P is —CH2—, then A and B both represent groups connected to carbon through heteroatom.

### Claim 19 (depends on 18)

A compound according to claim 18, wherein W is —CH═.

### Claim 20 (depends on 18)

A compound according to claim 18, wherein X is —CH═CH—.

### Claim 21 (depends on 18)

A compound according to claim 18, wherein Y is —CH═CH—.

### Claim 22 (depends on 18)

A compound according to claim 18, wherein Z represents a bond.

### Claim 23 (depends on 18)

A compound according to claim 18, wherein R1 and R2 are selected from hydrogen and halogen.

### Claim 24 (depends on 18)

A compound according to claim 18, wherein A and B is —OR′ and R′ is selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-6 cycloalkyl, —C1-3 alkyl (cycloalkyl), —C2-6 alkenyl or —C2-6 alkynyl.

### Claim 25 (depends on 18)

A compound according to claim 18, wherein A and B together form a substituted or unsubstituted 5 to 8 membered cyclic ring containing at least two heteroatoms selected from oxygen and sulfur.

### Claim 26 (depends on 18)

A compound according to claim 18, wherein A and B together represent group C═N(OR) and R is selected from the group consisting, of hydrogen, —C1-6 alkyl, —C3-6 cycloalkyl, —C3-6 alkenyl or —C3-6 alkynyl.

### Claim 27 (depends on 18)

A compound according to claim 18, wherein Q is a group selected from hydrogen, OR, —COOR, —CONRR′, —CH2O-aryl-COOR, —C(R,R′)—COOR, —CH2NRR′, tetrazole, —C(R,R′)OH, or —OCH2C(R,R′)OH and R and R′ are as defined above;

### Claim 28

A compound of formula (Ic), or the pharmaceutically acceptable salt thereof,
wherein,
R1 and R2 are independently selected from the group consisting of hydrogen, halogen, 20-OH, —CN, —NO2, —NH2, —C1-10-alkyl, —C3-10 cycloalkyl, —O—C1-8 alkyl (alkoxy), —O—C3-8 cycloalkyl (cycloalkoxy), —S—C1-8 alkyl (thioalkoxy), —C(O)—C1-8 alkyl, —COOH, —C(O)NH2, C(O)NH—C1-8 alkyl, —C(O)N(C1-8 alkyl)2, —C(O)O—C1-8 alkyl, —C1-8 haloalkyl (haloalkoxy), —C2-8 alkenyl, —C2-8 alkynyl, —OC(O)—NH2, —OC(O)—NH(C1-8 alkyl), —OC(O)—N(C1-8 alkyl)2, —NH2, —NH(C1-8 alkyl), —N(C1-8 alkyl)2, —NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-SO2—C1-8 alkyl, —NH—C(O)—(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—(C1-8 alkyl), —NH—C(O)O—C1-8 alkyl, —N(C1-8 alkyl)-C(O)O—C1-8 alkyl, —NH—C(O)—NH2, —NH—C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—NH(C1-8 alkyl), —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)2, —NH—C(O)—NH—SO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—NHSO2—C1-8 alkyl, —N(C1-8 alkyl)-C(O)—N(C1-8 alkyl)-SO2—C1-8 alkyl, —S—C1-8 alkyl, —S(O)—C1-8 alkyl, —SO2—C1-8 alkyl, —S-aryl, —S(O)-aryl, SO2-aryl, —SO2NH2, —SO2NH—(C1-8 alkyl), —SO2N(C1-8 alkyl)2;
W represents a group selected from —CH═ or —N═;
X represents a group selected from —CH═CH—, —S—, or —N═CH—;
Y represents a group selected from —CH═CH— or —C≡C—;
A and B are independently selected from hydrogen, —OR′, —SR, —NRR′ and —NRCOR; with a proviso that when B is hydrogen, P is selected from —O—, —S— or —NR—;
or, A and B together can form a substituted or unsubstituted 5 to 8 membered cyclic ring containing at least two heteroatoms selected from oxygen and sulfur;
or, A and B together represent group consisting of C═O, C═S, C═N(OR) or C═NNRR′;
P is selected from the group consisting of —O—, —S—, —CH2— and —NR—; or P may form a —CH═CH— moiety with the adjacent carbon atom; with a proviso that when B is hydrogen then P is selected from the group consisting of —O—, —S— and —NR—.
Q is a group selected from hydrogen, —CH3, —CF3, OR, —COOR, —CONRR′, —CR═CR—COOR′; —OCH2 aryl-COOR, —CH2O-aryl-COOR, —CONHSO2R, —CONHSO2 aryl, —OCH2CONRR′, —NHSO2R, —NHSO2 aryl, —NHSO2NHR, —SO2NHR, —SO2NH aryl, —NHCOR, —NHCO(CRR′)—COOR, —C(R,R′)—COOR, tetrazole, —C(R,R′)OH, —C(R,R′)CONRR′, —CH2NRR′ or —OCH2C(R,R′)OH;
R and R′ are independently selected from the group consisting of hydrogen, —C1-6 alkyl, —C3-6 cycloalkyl, —C1-3 alkyl (cycloalkyl), —C3-6 alkenyl and —C3-6 alkynyl or, R and R′ along with the atom to which they are attached, together can form a substituted or unsubstituted 5 to 8 membered cyclic ring;
‘n’ is an integer selected from 1, 2 or 3;
‘m’ is an integer selected from 0 to 4, both inclusive.

### Claim 29 (depends on 28)

A compound according to claim 28, wherein W is —CH═.

### Claim 30 (depends on 28)

A compound according to claim 28, wherein X is —CH═CH—.

### Claim 31 (depends on 28)

A compound according to claim 28, wherein Y is —CH═CH—.

### Claim 32 (depends on 28)

A compound according to claim 28, wherein Z represents a bond.

### Claim 33 (depends on 28)

A compound according to claim 28, wherein R1 and R2 are selected from hydrogen and halogen.