# US 5,708,026 A · Cyclohexane derivatives

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- Number: US 5,708,026 A
- Document ID: US5708026A
- Status: Granted
- Kind: A
- Application number: 08/448,470
- Filed: 1996-07-15
- Granted: 1998-01-13
- Earliest claimed: 1994-02-10
- Assignees: John Wyeth & Brother Limited
- Inventors: Roger Crossley; Albert Opalko
- Web page: https://patentgrep.com/patent/US5708026A

## CPC

- C07C 217/74: with rings other than six-membered aromatic rings being part of the carbon skeleton
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/24: Antidepressants
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07C 229/46: having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C 2601/14: The ring being saturated
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention concerns compounds of generic formula: ##STR1## or a pharmaceutically acceptable salt thereof, where the dotted line represents an optional bond, one of R.sup.1 and R.sup.5 represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.7 -C.sub.16 aralkyl, --(CHR.sup.6).sub.n CHR.sup.7 CN, --(CHR.sup.6).sub.n CHR.sup.7 CONH.sub.2, --(CHR.sup.6).sub.n CHR.sup.7 COOR.sup.8, --(CHR.sup.6).sub.n CHR.sup.7 CH.sub.2 OH wherein n is 0 or 1, R.sup.6 and R.sup.7 independently represent hydrogen, C.sub.1 -C.sub.6 alkyl- or C.sub.7 -C.sub.16 aralkyl-, and R.sup.7 also represents hydroxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.2 -C.sub.7)alkanoyloxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6 alkoxy)carbonyl- and R.sup.8 is hydrogen or C.sub.1 -C.sub.6 alkyl; the other of R.sup.1 and R.sup.5 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl; R.sup.3 is C.sub.6 -C.sub.10 aryl or heteroaryl group optionally substituted by one or more substituents the same or differnet, R.sup.2 and R.sup.4 independently represent hydrogen, or a group of formula --CR.sup.a R.sup.b R.sup.c where R.sup.a, R.sup.b and R.sup.c are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, optionally substituted C.sub.6 -C.sub.10 aryl, optionally substituted heteroaryl, C.sub.1 -C.sub.6 alkyl substituted by optionally substituted C.sub.6 -C.sub.10 aryl or heteroaryl or R.sup.2 also represents COR.sup.11 where R.sup.11 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or an optionally substituted (C.sub.6 -C.sub.10 aryl)alkyl or a heteroaryl alkyl radical; one of Y and Y.sub.1 is ##STR2## where R.sup.13 represents hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl; the other of Y and Y.sub.1 is --CHR.sup.12 -- where R.sup.12 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl, which compounds have pharmaceutical uses conferred by their ability to block voltage gated potassium channels.

## Claims

### Claim 1

A compound of generic formula: ##STR18## or a pharmaceutically acceptable salt thereof, where the dotted line represents an optional bond,
one of R.sup.1 and R.sup.5 represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.7 -C.sub.16 aralkyl, --(CHR.sup.6).sub.n CHR.sup.7 CN, --(CHR.sup.6).sub.n CHR.sup.7 CONH.sub.2, --(CHR.sup.6).sub.n CHR.sup.7 COOR.sup.8, --(CHR.sup.6).sub.n CHR.sup.7 CH.sub.2 OH wherein n is 0 or 1, R.sup.6 and R.sup.7 independently represent hydrogen, C.sub.1 -C.sub.6 alkyl- or C.sub.7 -C.sub.16 aralkyl-, and R.sup.7 also represents hydroxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.2 -C.sub.7)alkanoyloxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6 alkoxy)carbonyl- and R.sup.8 is hydrogen or C.sub.1 -C.sub.6 alkyl;
the other of R.sup.1 and R.sup.5 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl; R.sup.3 is an optionally substituted C.sub.6 -C.sub.10 aryl or heteroaryl group; said heteroaryl group containing 5 to 10 ring atoms of which one or more (e.g up to 3) of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur, the same or different; said aryl or heteroaryl radicals being optionally substituted by one or more substituents the same or different, eg substituents commonly used in pharmaceutical chemistry such as for example: C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkoxy or such groups substituted by C.sub.6 -C.sub.10 aryl or heteroaryl as defined above; halogen; halo C.sub.1 -C.sub.6 alkyl; halo C.sub.1 -C.sub.6 alkoxy; carboxy; hydroxy(C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6 alkoxy)carbonyl; amino including substituted amino, e.g mono- or di- (C.sub.1 -C.sub.6 alkyl)-amino; nitro; hydroxy; mercapto; C.sub.1 -C.sub.6 alkylthio; (C.sub.1 -C.sub.6)alkyl carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyl; (C.sub.2 -C.sub.7)alkanoyloxy; (C.sub.7 -C.sub.11)aroyloxy; (C.sub.1 -C.sub.6)alkylcarbonylamino, (C.sub.6 -C.sub.10 aryl)carbonylamino; (C.sub.2 -C.sub.7) alkoxycarbonylamino; C.sub.6 -C.sub.10 aryl; heteroaryl as defined above; or C.sub.1 -C.sub.2 alkylenedioxy;
R.sup.2 and R.sup.4 independently represent hydrogen, or a group of formula --CR.sup.a R.sup.b R.sup.c where R.sup.a, R.sup.b and R.sup.c are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, optionally substituted C.sub.6 -C.sub.10 aryl, optionally substituted heteroaryl, C.sub.1 -C.sub.6 alkyl substituted by optionally substituted C.sub.6 -C.sub.10 aryl or heteroaryl in which the substituent(s) is/are for example as illustrated above in connection with R.sup.3 ; or R.sup.2 also represents COR.sup.11 where R.sup.11 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or an optionally substituted (C.sub.6 -C.sub.10 aryl)alkyl or a heteroaryl alkyl radical; said heteroaryl group containing 5 to 10 ring atoms of which one or more (e.g up to 3) of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur, the same or different; said aryl or heteroaryl radicals being optionally substituted by one or more substituents the same or different, eg substituents commonly used in pharmaceutical chemistry such as for example: C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or such groups substituted by C.sub.6 -C.sub.10 aryl or hetemaryl as defined above; halogen; halo C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkoxy; carboxy; hydroxy(C.sub.1 -C.sub.6)alkyl C.sub.2 -C.sub.7 alkanoyloxy(C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6 alkoxy)carbonyl; amino including substituted amino, e.g mono- or di-(C.sub.1 -C.sub.6 alkyl)-amino; nitro; hydroxy; mercapto; C.sub.1 -C.sub.6 alkylthio; (C.sub.1 -C.sub.6 alkyl)carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyl; (C.sub.2 -C.sub.7)alkanoyloxy; (C.sub.7 -C.sub.11)aroyloxy; (C.sub.1 -C.sub.6 alkyl)carbonylamino, (C.sub.6 -C.sub.10 aryl)carbonylamino; (C.sub.2 -C.sub.7 alkoxycarbonyl)amino; C.sub.6 -C.sub.10 aryl; heteroaryl as defined above; or C.sub.1 -C.sub.2 alkylenedioxy;
one of Y and Y.sub.1 is ##STR19## where R.sup.13 represents hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl;
the other of Y and Y.sub.1 is --CHR.sup.12 -- where R.sup.12 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl.

### Claim 2 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.4 and R.sup.2 are independently hydrogen or a group of formula --CR.sup.a R.sup.b R.sup.c where R.sup.a and R.sup.b are independently selected from hydrogen, methyl, ethyl, propyl, isopropyl or butyl and R.sup.c is selected from hydrogen, methyl, ethyl, isopropyl, propyl, butyl or a C.sub.6 -C.sub.10 aryl or a heteroaryl group containing 5-10 ring atoms of which one or more of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur in which said aryl and heteroaryl moieties are optionally substituted as defined in claim 1.

### Claim 3 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.3 may be for example phenyl or phenyl substituted by one or more substitutents as illustrated above the same or different selected from: C.sub.1 -C.sub.6 alkoxy, halogen, CF.sub.3, CF.sub.3 O, C.sub.1 -C.sub.6 alkyl, hydroxy, cyano and carboxy.

### Claim 4 (depends on 1)

A compound as claimed in claim 1 wherein Y.sub.1 is CH.sub.2.

### Claim 5 (depends on 1)

A compound as claimed in claim 1 wherein Y is CH.sub.2.

### Claim 6 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.3 is an optionally substituted phenyl or pyridyl group, said substituents being selected from: C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkoxy or such groups substituted by C.sub.6 -C.sub.10 aryl or heteroaryl as defined above; halogen; haloC.sub.1 -C.sub.6 alkyl; haloC.sub.1 -C.sub.6 alkoxy; carboxy; hydroxy(C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6 alkoxy)carbonyl; amino, mono- or di- (C.sub.1 -C.sub.6 alkyl)-amino; nitro; hydroxy; mercapto; C.sub.1 -C.sub.6 alkylthio; (C.sub.1 -C.sub.6)alkyl carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyl; (C.sub.2 -C.sub.7)alkanoyloxy; (C.sub.7 -C.sub.11)aroyloxy; (C.sub.1 -C.sub.6)alkylcarbonylamino, (C.sub.6 -C.sub.10 aryl)-carbonylamino; (C.sub.2 -C.sub.7) alkoxycarbonylamino; C.sub.6 -C.sub.10 aryl; heteroaryl as defined above; or C.sub.1 -C.sub.2 alkylenedioxy.

### Claim 7 (depends on 1)

A compound as claimed in claim 1 wherein R.sup.1, R.sup.5 and R.sup.6 are hydrogen.

### Claim 8 (depends on 1)

A compound of claim 1 which is methyl 5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohexanepropionate or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

A compound of claim 1 which is methyl 5-((4-methoxyphenyl)-2-(1'-phenylethylamino)ethylamino)cyclohexanepropiona te or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

A compound of claim 1 which is methyl 4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

A compound of claim 1 which is methyl 4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

A compound of claim 1 which is
methyl (1'R,1S,2R,5R)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohex anepropionate;
methyl (1'R,1S,2R,5S)-5-((4-methoxyphenyl)methyl-2-(1'-phenylethylamino)-cyclohex anepropionate;
(-)-methyl (1'S,1R,2S,5R)-5-(4-methoxyphenyl)methyl)-2-(1'phenylethylamino)-cyclohexa nepropionate;
methyl (1'R,1S,2R,5R)-5-((4-methoxyphenyl)-2-(1'-phenylethylamino)ethyl-amino)cyc lohexanepropionate;
cis-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine;
trans-(S)-4-(4-methoxyphenylmethyl)-N-(1'-phenylethyl)cyclohexylamine;
trans-(R)-4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine;
cis-(R)-4-(4-methoxyphenylmethyl)-N-(1'phenylethylmethyl)cyclohexylamine;
or
methyl (1'S,1R,2S.5S)-5-(4-methoxyphenyl)methyl)-2-(1-'phenylethylamino)-cyclohex anepropionate
or a pharmaceutically acceptable salt thereof.

### Claim 13

A compound of formula IA: ##STR20## in which formula R.sup.1 is hydrogen, C.sub.1 -C.sub.6 alkyl, --(CHR.sup.6).sub.n CHR.sup.7 CN, --(CHR.sup.6).sub.n CHR.sup.7 CONH.sub.2, --(CHR.sup.6).sub.n CHR.sup.7 COOR.sup.8 or --(CHR.sup.6).sub.n CHR.sup.7 CH.sub.2 OH; R.sup.3 is unsubstituted or substituted phenyl where the substituents is/are selected from C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, hydroxy, halogen and methylene or ethylenedioxy; and R.sup.4' is hydrogen, alkyl or optionally substituted aryl(C.sub.1 -C.sub.6)alkyl in which the alkyl group is itself optionally substituted by C.sub.1 -C.sub.6 alkyl; R.sup.6 and R.sup.7 independently represent hydrogen C.sub.1 -C.sub.6 alkyl- or C.sub.7 -C.sub.16 aralkyl-, and R.sup.7 also represents hydroxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.2 -C.sub.7 alkanoyloxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6 alkoxy)carbonyl- and R.sup.8 is hydrogen or C.sub.1 -C6 alkyl; with the proviso that when R.sup.3 is unsubstituted phenyl, then R.sup.1 and R.sup.4' cannot both be hydrogen.

### Claim 14 (depends on 13)

A compound as claimed in claim 13 wherein R.sup.1 is are hydrogen, Me, Et, .sup.n Pr, benzyl, --(CH.sub.2).sub.2 OH, --CH.sub.2 CH.sub.2 CN, --(CH.sub.2).sub.2 COOMe, and --(CH.sub.2).sub.2 COOEt.

### Claim 15

A pharmaceutical composition comprising a compound of formula ##STR21## or a pharmaceutically acceptable salt thereof, where the dotted line represents an optional bond,
one of R.sup.1 and R.sup.5 represents hydrogen, C.sub.1 -C.sub.6 alkyl, C.sub.7 -C.sub.16 aralkyl, --(CHR.sup.6).sub.n CHR.sup.7 CN, --(CHR.sup.6).sub.n CHR.sup.7 CONH.sub.2, --(CHR.sup.6).sub.n CHR.sup.7 COOR.sup.8, --(CHR.sup.6).sub.n CHR.sup.7 CH.sub.2 OH wherein n is 0 or 1, R.sup.6 and R.sup.7 independently represent hydrogen, C.sub.1 -C.sub.6 alkyl- or C.sub.7 -C.sub.16 aralkyl-, and R.sup.7 also represents hydroxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.2 -C.sub.7)alkanoyloxy(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6 alkoxy)carbonyl- and R.sup.8 is hydrogen or C.sub.1 -C.sub.6 alkyl;
the other of R.sup.1 and R.sup.5 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl; R.sup.3 is an optionally substituted C.sub.6 -C.sub.10 aryl or heteroaryl group; said heteroaryl group containing 5 to 10 ring atoms of which one or more (e.g up to 3) of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur, the same or different; said aryl or heteroaryl radicals being optionally substituted by one or more substituents the same or different, eg substituents commonly used in pharmaceutical chemistry such as for example: C.sub.1 -C.sub.6 alkyl; C.sub.1 -C.sub.6 alkoxy or such groups substituted by C.sub.6 -C.sub.10 aryl or heteroaryl as defined above; halogen; halo C.sub.1 -C.sub.6 alkyl; halo C.sub.1 -C.sub.6 alkoxy; carboxy; hydroxy(C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6 alkoxy)carbonyl; amino including substituted amino, e.g mono- or di- (C.sub.1 -C.sub.6 alkyl)-amino; nitro; hydroxy; mercapto; C.sub.1 -C.sub.6 alkylthio; (C.sub.1 -C.sub.6)alkyl carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyl; (C.sub.2 -C.sub.7)alkanoyloxy; (C.sub.7 -C.sub.11 )aroyloxy; (C.sub.1 -C6)alkylcarbonylamino, (C.sub.6 -C.sub.10 aryl)carbonylamino; (C.sub.2 -C.sub.7) alkoxycarbonylamino; C.sub.6 -C.sub.10 aryl; heteroaryl as defined above; or C.sub.1 -C.sub.2 alkylenedioxy;
R.sup.2 and R.sup.4 independently represent hydrogen, or a group of formula --CR.sup.a R.sup.b R.sup.c where R.sup.a, R.sup.b and R.sup.c are independently selected from hydrogen, C.sub.1 -C.sub.6 alkyl, optionally substituted C.sub.6 -C.sub.10 aryl, optionally substituted heteroaryl, C.sub.1 -C.sub.6 alkyl substituted by optionally substituted C.sub.6 -C.sub.10 aryl or heteroaryl in which the substituent(s) is/are for example as illustrated above in connection with R.sup.3 ; or R.sup.2 also represents COR.sup.11 where R.sup.11 is C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy or an optionally substituted (C.sub.6 -C.sub.10 aryl)alkyl or a heteroaryl alkyl radical; said heteroaryl group containing 5 to 10 ring atoms of which one or more (e.g up to 3) of said atoms are heteroatoms selected from oxygen, nitrogen and sulphur, the same or different; said aryl or heteroaryl radicals being optionally substituted by one or more substituents the same or different, eg substituents commonly used in pharmaceutical chemistry such as for example: C.sub.1 -C.sub.6 alkyl, C.sub.1 -C.sub.6 alkoxy, or such groups substituted by C.sub.6 -C.sub.10 aryl or heteroaryl as defined above; halogen; halo C.sub.1 -C.sub.6 alkyl, halo C.sub.1 -C.sub.6 alkoxy; carboxy; hydroxy(C.sub.1 -C.sub.6)alkyl C.sub.2 -C.sub.7 alkanoyloxy(C.sub.1 -C.sub.6)alkyl; (C.sub.1 -C.sub.6 alkoxy)carbonyl; amino including substituted amino, e.g mono- or di- (C.sub.1 -C.sub.6 alkyl)-amino; nitro; hydroxy; mercapto; C.sub.1 -C.sub.6 alkylthio; (C.sub.1 -C.sub.6 alkyl)carbonyl; (C.sub.6 -C.sub.10 aryl)carbonyl; (C.sub.2 -C.sub.7)alkanoyloxy; (C7-C.sub.11 )aroyloxy; (C.sub.1 -C.sub.6 alkyl)carbonylamino, (C.sub.6 -C.sub.10 aryl)carbonylamino; (C.sub.2 -C.sub.7 alkoxycarbonyl)amino; C.sub.6 -C.sub.10 aryl; heteroaryl as defined above; or C.sub.1 -C.sub.2 alkylenedioxy;
one of Y and Y.sub.1 is ##STR22## where R.sup.13 represents hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl;
the other of Y and Y.sub.1 is --CHR.sup.12 -- where R.sup.12 is hydrogen, C.sub.1 -C.sub.6 alkyl or C.sub.7 -C.sub.16 aralkyl, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.