# US 5,350,852 A · Arylalkylamines, process for preparing them and pharmaceutical compositions containing them

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- Number: US 5,350,852 A
- Document ID: US5350852A
- Status: Granted
- Kind: A
- Application number: 08/105,677
- Filed: 1993-08-13
- Granted: 1994-09-27
- Earliest claimed: 1990-09-05
- Assignees: Sanofi
- Inventors: Xavier Emonds-Alt; Pierre Goulaouic; Vincenzo Proietto; Didier Van Broeck
- Web page: https://patentgrep.com/patent/US5350852A

## CPC

- C07D 239/42: One nitrogen atom (nitro radicals C07D239/30)
- A61P 11/08: Bronchodilators
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 211/48: having an acyclic carbon atom attached in position 4
- C07D 211/52: having an aryl radical as the second substituent in position 4
- C07D 211/64: having an aryl radical as the second substituent in position 4
- C07D 295/125: with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D 295/13: to an acyclic saturated chain
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 417/12: 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 invention relates to a process for making compounds of formula: ##STR1##

## Claims

### Claim 1

Process for the preparation of a compound of Formula (I): ##STR124## wherein Y represents either
a group Cy--N in which Cy represents a phenyl, unsubstituted or substituted one or more times with a substituent selected from the group consisting of hydrogen, a halogen atom, a hydroxyl , a C.sub.1 -C.sub.4 alkoxy, a C.sub.1 -C.sub.4 alkyl, a trifluoromethyl, the said substituents being identical or different; a C.sub.3 -C.sub.7 cycloalkyl group, a pyrimidinyl group or a pyridyl group; or
a group ##STR125## in which Ar represents a phenyl, pyridyl or thienyl group, said phenyl group being unsubstituted or substituted one or more times with a substituent selected from the group consisting of hydrogen, a halogen atom, a hydroxyl, a C.sub.1 -C.sub.4 alkoxy, a trifluoromethyl, a C.sub.1 -C.sub.4 alkyl, the said substituents being identical or different;
x is zero or one; and
X represents a hydroxyl, a C.sub.1 -C.sub.4 alkoxy; a hydroxyalkyl in which the alkyl is a C.sub.1 -C.sub.3 group; a C.sub.1 -C.sub.4 acyloxy; a phenacyloxy; a carboxyl; a C.sub.1 -C.sub.4 carbalkoxy; a cyano; an aminoalkylene in which the alkylene is a C.sub.1 -C.sub.3 group; a group --N--(X.sub.1).sub.2 in which the groups X.sub.1 independently represent hydrogen or C.sub.1 -C.sub.4 alkyl; a group ##STR126## in which Alk represents a C.sub.1 -C.sub.6 alkyl; a group ##STR127## in which Alk.sub.1 is a C.sub.1 -C.sub.3 alkylene and Alk'.sub.1 is a C.sub.1 -C.sub.3 alkyl; a C.sub.1 -C.sub.4 acyl; a group --S--X.sub.2 in which X.sub.2 represents hydrogen or C.sub.1 -C.sub.4 alkyl;
or alternatively X is a double bond between the carbon atom to which it is linked and the adjacent carbon in the heterocycle;
m is 2 or 3;
Ar' represents a phenyl, unsubstituted or substituted one or more times with a substituent selected from the group consisting of hydrogen, a halogen atom, a trifluoromethyl, a C.sub.1 -C.sub.4 alkoxy, a C.sub.1 -C.sub.4 alkyl, the said substituents being identical or different; a thienyl; a benzothienyl; a naphthyl; an indolyl; or an indolyl N-substituted with a C.sub.1 -C.sub.3 alkyl;
R represents hydrogen or C.sub.1 -C.sub.4 alkyl;
T represents a group selected from ##STR128## W being an oxygen or sulphur atom, and Z represents either hydrogen, or M or OM when T represents a ##STR129## group, or M when T represents a group ##STR130## M representing a C.sub.1 -C.sub.6 alkyl; a phenylalkyl in which the alkyl is a C.sub.1 -C.sub.3 group, optionally substituted on the aromatic ring with a halogen, a trifluoromethyl, a C.sub.1 -C.sub.4 alkyl, a hydroxyl, a C.sub.1 -C.sub.4 alkoxy; a pyridyl alkyl in which the alkyl is a C.sub.1 -C.sub.3 group; a naphthylalkyl in which the alkyl is a C.sub.1 -C.sub.3 group, optionally substituted on the naphthyl ring-system with a halogen, a trifluoromethyl, a C.sub.1 -C.sub.4 alkyl, a hydroxyl, a C.sub.1 -C.sub.4 alkoxy; a pyridylthioalkyl in which the alkyl is a C.sub.1 -C.sub.3 group; a styryl; or an optionally substituted mono-, di- or tricyclic aromatic or heteroaromatic group;
or a salt of a compound of Formula I with an inorganic or organic acid;
the process comprising the steps of:
(a) reacting a free amine of Formula (II) ##STR131## in which m, Ar' and R are as defined above and E represents an O-protecting group or a group ##STR132## in which Y is defined as above wherein, when Y represents a group ##STR133## in which X is a hydroxyl, this hydroxyl may be protected; or a free amine of Formula (II'") ##STR134## in which m, Ar' and R are as defined above, with either a functional derivative of an acid of formula
HO--CO--Z (III)
in which Z is as defined above when a compound of Formula (I) in which T is --CO-- is to be prepared, or
an iso(thio)cyanate of formula:
W.dbd.C.dbd.N--Z (III')
in which W and Z are as defined above, when a compound of Formula (I) in which T is --C(W)--NH-- is to be prepared,
to form the compound of Formula (IV) ##STR135## (b) then, when E represents tetrahydropyranyloxy as an O-protecting group, removing the tetrahydropyranyl group by the action of an acid, said deprotection optionally being carried out directly on the compound of Formula (II) in order to yield a compound of Formula (II") which is then treated with a compound of Formula (III) or (III');
(c) reacting the N-substituted alkanolamine thereby obtained, of formula: ##STR136## with methanesulphonyl chloride; (d) reacting the mesylate thereby obtained, of formula: ##STR137## with a secondary amine of formula: ##STR138## in which Y is as defined above; and (e) after deprotection, where appropriate, of the hydroxyl represented by X, optionally converting the product thereby obtained to one of its salts.

### Claim 2 (depends on 1)

A process according to claim 1, wherein Y is ##STR139## in which Ar is phenyl, X is --NH--CO--CH.sub.3 and x is zero.

### Claim 3 (depends on 1)

A process according to claim 1, wherein Y is ##STR140## in which Ar is phenyl, x is zero and X is a hydroxyl, an acetyloxy or a group --NH--CO--Alk in which Alk represents a C.sub.1 -C.sub.6 alkyl, or a salt thereof with a pharmaceutically acceptable inorganic or organic acid.

### Claim 4 (depends on 1)

A process according to claim 1, wherein the compound of Formula (I) is N-Methyl-N-[4-(4-phenyl-4-acetylamino piperidyl)-2-(3,4-dichlorophenyl)butyl]benzamide or a salt thereof with a pharmaceutically acceptable organic or mineral acid.

### Claim 5 (depends on 3)

A process according to claim 3, wherein the compound of Formula (I) is the (+) enantiomer of N-Methyl-N-[4-(4-phenyl-4-acetylamino piperidyl)-2-(3,4dichlorophenyl)butyl]benzamide or a salt thereof with a pharmaceutically acceptable organic or mineral acid.

### Claim 6 (depends on 3)

A process according to claim 3, wherein the compound of Formula (I) is the (-) enantiomer of N-Methyl-N-[4-(4-phenyl-4-acetylamino piperidyl)-2-(3,4dichlorophenyl)butyl]benzamide or a salt thereof with a pharmaceutically acceptable organic or mineral acid.

### Claim 7 (depends on 1)

A process according to claim 1, wherein Ar' is a 3,4-dichlorophenyl group.

### Claim 8 (depends on 1)

A process according to claim 1, wherein R is a methyl.

### Claim 9 (depends on 1)

A process according to claim 1, wherein T is a --C.dbd.O group.

### Claim 10 (depends on 9)

A process according to claim 9, wherein Z is a thienyl group.

### Claim 11 (depends on 9)

A process according to claim 9, wherein Z is a phenyl group that optionally is disubstituted with a halogen.