# US 5,705,504 A · Piperidine derivatives with PAF antagonist activity

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- Number: US 5,705,504 A
- Document ID: US5705504A
- Status: Granted
- Kind: A
- Application number: 08/669,440
- Filed: 1996-10-22
- Granted: 1998-01-06
- Earliest claimed: 1994-11-07
- Assignees: J. Uriach & Cia. S.A.
- Inventors: Elena Carceller; Pere J. Jimenez; Nuria Recasens; Jordi Salas; Carmen Almansa; Javier Bartroli
- Web page: https://patentgrep.com/patent/US5705504A

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/00: Drugs for dermatological disorders
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of general formula I and their salts and solvates are PAF antagonists and as such are useful in the treatment of various diseases or disorders mediated by PAF. Pharmaceutical compositions including these compounds and processes for their preparation are also provided.

## Claims

### Claim 1

A compound of formula I: ##STR12## wherein: m represents 0, 1 or 2;
a, b and c represent CR, wherein each R independently represents hydrogen or C.sub.1-4 alkyl;
R.sup.1 represents C.sub.1-4 alkyl or C.sub.3-7 cycloalkyl;
A represents --CO--, --SO.sub.2 --, --NHCO-- or --OCO--;
B represents a group of formula (i), and when A represents --CO-- or --SO.sub.2 --, then B can also represent a group of formula (ii) or (iii) ##STR13## n represents 0, 1, 2 or 3; one of R.sup.2 or R.sup.3 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl, and the other represents hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl;
Z represents hydrogen, C.sub.1-4 alkyl, --CH.sub.2 --OR.sup.4, --COOR.sup.4 or --CONR.sup.4 R.sup.5, and when A represents --CO-- or --SO.sub.2 --, then Z can also be hydroxy, --NR.sup.4 R.sup.5, --NR.sup.6 C(.dbd.O)OR.sup.4, --NR.sup.6 C(.dbd.O)R.sup.4, --NR.sup.6 C(.dbd.O)NR.sup.4 R.sup.5, --N(OH)C(.dbd.O)NR.sup.4 R.sup.5 or --NR.sup.6 SO.sub.2 R.sup.4 ;
or Z and R.sup.3 together form a C.sub.2-5 polymethylene chain in which case R.sup.2 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;
R.sup.4 represents hydrogen, C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl;
R.sup.5 and R.sup.6 independently represent hydrogen or C.sub.1-4 alkyl;
R.sup.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, aryl, aryl-C.sub.1-4 alkyl or bisaryl-C.sub.1-4 alkyl;
Y represents hydrogen, C.sub.1-4 alkyl, aryl, aryl-C.sub.1-4 alkyl, --C(.dbd.O)OR.sup.4, --C(.dbd.O)R.sup.4, --C(.dbd.O)NR.sup.4 R.sup.5, or --SO.sub.2 R.sup.4 ;
aryl, whenever appearing in the above definitions, represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy, cyano, nitro, amino, C.sub.1-4 alkylamino, C.sub.1-4 dialkylamino, C.sub.1-4 alkylcarbonyl, C.sub.1-4 alkylcarbonyloxy, C.sub.1-4 alkoxycarbonyl, C.sub.1-4 alkylsulfonyl, C.sub.1-4 alkylsulfinyl, C.sub.1-4 alkylthio, C.sub.1-4 alkylcarbonylamino or C.sub.1-4 alkoxycarbonylamino; and the salts and solyates thereof.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein m represents 1 or 2.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein A represents --CO-- or --SO.sub.2 --.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 wherein A represents --NHCO-- or --OCO--.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 wherein B represents a group of formula (i).

### Claim 6 (depends on 1)

A compound as claimed in claim 1 wherein n represents 0, 1 or 2.

### Claim 7 (depends on 1)

A compound as claimed in claim 1 wherein B represents a group of formula (ii).

### Claim 8 (depends on 1)

A compound as claimed in claim 1 wherein B represents a group of formula (iii).

### Claim 9 (depends on 1)

A compound as claimed in claim 1 wherein Z represents hydrogen, C.sub.1-4 alkyl, --CH.sub.2 --OR.sup.4, --COOR.sup.4, or --CONR.sup.4 R.sup.5, and when A represents --CO-- or --SO.sub.2 --, Z can also represent hydroxy, --NR.sup.6 C(.dbd.O)OR.sup.4, --NR.sup.6 C(.dbd.O)R.sup.4 or --NR.sup.6 SO.sub.2 R.sup.4 ; or Z and R.sup.3 together form a C.sub.2-5 polymethylene chain.

### Claim 10 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl.

### Claim 11 (depends on 1)

A compound as claimed in claim 1 wherein aryl represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy or amino.

### Claim 12 (depends on 1)

A compound as claimed in claim 1 wherein:
A represents --CO-- or --SO.sub.2 --;
B represents a group of formula (i), (ii) or (iii);
n represents 1 or 2;
one of R.sup.2 or R.sup.3 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl, and the other represents hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, aryl-C.sub.1-4 or aryl-C.sub.1-4 -alkyl;
Z represents hydrogen, C.sub.1-4 alkyl, --CH.sub.2 --OR.sup.4, --COOR.sup.4, --CONR.sup.4 R.sup.5, hydroxy, --NR.sup.6 C(.dbd.O)OR.sup.4, --NR.sup.6 C(.dbd.O)R.sup.4 or --NR.sup.6 SO.sub.2 R.sup.4 ;
or Z and R.sup.3 together form a C.sub.2-5 polymethylene chain in which case R.sup.2 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;
R.sup.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl; and
aryl represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy or amino.

### Claim 13 (depends on 1)

A compound as claimed in claim 1 wherein:
A represents
NHCO-- or --OCO--;
B represents a group of formula (i);
n represents 0 or 1; and
aryl represents phenyl or phenyl substituted with 1, 2, 3 or 4 groups independently selected from halogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy, hydroxy, C.sub.1-4 haloalkyl, C.sub.1-4 haloalkoxy or amino.

### Claim 14 (depends on 12)

A compound as claimed in claim 12 wherein:
B represents a group of formula (i) or (iii);
one of R.sup.2 or R.sup.3 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl, and the other represents hydrogen, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, C.sub.3-7 cycloalkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl;
Z represents hydrogen, C.sub.1-4 alkyl, --CH.sub.2 --OR.sup.4, --COOR.sup.4 or hydroxy;
or Z and R.sup.3 together form a C.sub.2-5 polymethylene chain in which case R.sup.2 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl or aryl;
R.sup.4 represents hydrogen, C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl;
R.sup.7 represents C.sub.1-4 alkyl, C.sub.3-7 cycloalkyl, or aryl; and
Y represents C.sub.1-4 alkyl, aryl or --SO.sub.2 R.sup.4.

### Claim 15 (depends on 12)

A compound as claimed in claim 12 wherein:
B represents a group of formula (ii); and
one of R.sup.2 or R.sup.3 represents C.sub.1-4 alkyl or aryl, and the other represents hydrogen, C.sub.1-4 alkyl, C.sub.1-4 alkoxy-C.sub.1-4 alkyl, aryl or aryl-C.sub.1-4 alkyl.

### Claim 16 (depends on 1)

A compound according to claim 1 selected from:
1-››1-(3,3-diphenylpropionyl)-4-piperidyl!methyl!-1H-2-methylimidazo›4,5-c! pyridine;
1-››1-›3-›N-(4-aminobenzoyl)amino!-3-phenylpropionyl!-4-piperidyl!methyl!-H -2-methylimidazo›4,5-c!pyridine;
cis-1-››1-›3-(4-aminophenyl)-3-phenylpropenoyl!-4-piperidyl!methyl!-1H-2met hylimidazo›4,5-c!pyridine;
trans-1-››1-›3-(4-aminophenyl)-3-phenylpropenoyl!-4-piperidyl!methyl!-1H-2- methylimidazo›4,5-c!pyridine;
1-››1-(3-hydroxy-3-phenylbutanoyl)-4-piperidyl!methyl!-1H-2-methylimidazo-› 4,5-c!pyridine;
1-››1-›2-(4-aminophenyl)propionyl!-4-piperidyl!methyl!-1H-2-methylimidazo-› 4,5-c!pyridine;
1-››1-(3-phenylhexanoyl)-4-piperidyl!methyl!-1H-2-methylimidazo›4,5-c!pyrid ine;
(S)-1-››1-››N-(1-ethoxycarbonyl-1-phenylmethyl)amino!carbonyl!-4-piperimeth yl!-1H-2-methylimidazo›4,5-c!pyridine;
1-››1-(3-phenylbutanoyl)-4-piperidyl!methyl!-1H-2-methylimidazo›4,5-c!pyrid ine;
1-››1-(3-methyl-3-phenylbutanoyl)-4-piperidyl!methyl!-1H-2-methylimidazo›4, 5-c!pyridine;
1-››1-›3-(4-aminophenyl)-3-methylbutanoyl!-4-piperidyl!methyl!-1H-2-methyl- imidazo›4,5-c!pyridine;
1-››1-(3-hydroxy-3-phenyl-3-trifluoromethylpropionyl)-4-piperidyl!methyl!-1 H-2-methylimidazo›4,5-c!pyridine;
(R)-1-››1-›(1-phenylethylamino)carbonyl!-4-piperidyl!methyl!-1H-2-methylimi dazo›4,5-c!pyridine;
1-››1-›(1-phenyl-1-cyclopropylamino)carbonyl!-4-piperidyl!methyl!-1H-2-meth yl-imidazo ›4,5-c!pyridine;
(S)-1-››1-›(2-ethoxy-1-phenylethylamino)carbonyl!-4-piperidyl!methyl!-1H-2- methylimidazo›4,5-c!pyridine;
1-››1-››N-(2-methoxyphenyl)-N-methylamino!acetyl!-4-piperidyl!methyl!-1H-2- methylimidazo›4,5-c!pyridine;
1-››1-››(1-phenyl-1-cyclopropyl)methoxy!carbonyl!-4-piperidyl!methyl!-1H-2- methylimidazo›4,5-c!pyridine;
1-››1-››N-(4-aminophenylsulfonyl)-N-phenylamino!acetyl!-4-piperidyl!methyl! -1H-2-methylimidazo›4,5-c!pyridine;
1-››1-››N-(4-aminophenylsulfonyl)-N-isobutylamino!acetyl!-4-piperidyl!methy l!-1H-2-methylimidazo›4,5-c!pyridine; or a salt or solvate thereof.

### Claim 17 (depends on 1)

A pharmaceutical composition which comprises an effective amount of a compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.

### Claim 18 (depends on 1)

A process for preparing a compound of formula I as defined in claim 1 which comprises:
(A) reacting a compound of formula II, ##STR14## wherein a, b, c, m and R.sup.1 are as defined in claim 1, with an acid of formula BCOOH (III) or a suitable derivative thereof such as the acid chloride or the anhydride, a sulfonyl chloride of formula BSO.sub.2 C.sub.1 (IV), a compound of formula BOC(.dbd.O)G (V), a compound of formula BNHC(.dbd.O)G (VI) or a compound of formula BN=C.dbd.O (VII), wherein B is as defined in claim 1 and G represents a good leaving group such as chloro or --OPh; or
(B) converting in one or a plurality of steps a compound of formula I into another compound of formula I; and
(C) if desired, after steps A or B, reacting a compound of formula I with an acid to give the corresponding acid addition salt.

### Claim 19 (depends on 1)

A compound of formula II ##STR15## wherein a, b, c, m and R.sup.1 are as defined in claim 1.

### Claim 20 (depends on 19)

A compound according to claim 19 which is 1-›(4-piperidyl)methyl!-1H-2-methylimidazo›4,5-c!pyridine.

### Claim 21 (depends on 1)

A method for the prevention or treatment of diseases mediated by platelet activating factor in a mammal, said method comprising administering an effective amount of the compound according to claim 1 to a mammal in need of such prevention or treatment.