US 4,593,102 AGranted

N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position

AssigneeA. H. Robins Company, Incorporated

InventorJames R. Shanklin, Jr.

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Abstract

Novel pyrrolidine, piperidine and homopiperidinecarboxamide and thiocarboxamide compounds having the formula: ##STR1## wherein X is --S--, --S(O)-- or --S(O).sub.2 --; A is a loweralkalene chain and A.sup.1 and A.sup.2 are alkalene chains when p and d are one; R, R.sup.1 and R.sup.2 are hydrogen, loweralkyl, phenyl cycloalkyl or phenylalkyl and R.sup.1 and R.sup.2 may form a heterocyclic residue with the adjacent nitrogen atom; Q is a selected aromatic radical, and the pharmaceutically acceptable acid addition salts useful as cardiac antiarrhythmia agents are disclosed. Novel chemical intermediates, unsubstituted on pyrrolidine, piperidine and homopiperidine nitrogen but with --(A.sup.2).sub.p --X--(A.sup.2).sub.d --Q side chain are also disclosed.

Claims38

Dependent claims

A compound selected from the group having the formula:

##STR45## wherein;
n is selected from zero, one or two;
Y is selected from oxygen or sulfur;
A, A.sup.1 and A.sup.2 are selected from straight or branched-chain alkalenes having 1 to 8 carbon atoms and p and d are selected from zero or one with the proviso that when the --(A.sup.1).sub.p --X--(A.sup.2).sub.d --Q radical is in the 2-position, p is at at least one;
X is selected from --S--, --S(O)-- or --S(O).sub.2 --;
R, R.sup.1 and R.sup.2 are selected from hydrogen, loweralkyl (1-8 carbons), phenyl, cycloalkyl (1-9 carbons) or phenylalkyl (7-14 carbons) and may be the same or different and R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of
(a) 1-pyrrolidino,
(b) 1-piperidino,
(c) 4-morpholino,
(d) 1-piperazino,
(e) a heterocycle of (a) to (d) substituted by a methyl, ethyl, phenyl or phenylloweralkyl,
(f) 2,6-(loweralkyl).sub.2 -piperidino,
(g) 4-hydroxy-4-phenylpiperidino,
(h) 4-cyano-4-phenylpiperidino, or,
(i) 4-phenyl-1,2,3,6-tetrahydropyridino,
Q is selected from the group consisting of:
(1) 1 or 2-naphthyl,
(2) 2,3-dihydro-1H-inden-4-yl or 2,3-dihydro-1H-inden-5-yl,
(3) biphenyl,
(4) phenyl, ##STR46## wherein R.sup.3 is selected from fluorine, chlorine, bromine, iodine, loweralkyl (1-8 carbons), loweralkoxy (1-8 carbons), trifluoromethyl, hydroxy, cyano or nitro, R.sup.4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy and nitro and R.sup.5 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio and phenylthio, ##STR47## wherein R.sup.6 is selected from --NR.sup.7 R.sup.8, --C(O)NR.sup.7 R.sup.8, --(CH.sub.2).sub.b NR.sup.7 R.sup.8, --B--(CH.sub.2).sub.b NR.sup.7 R.sup.8 or --B--(CH.sub.2).sub.b OR.sup.7 wherein B is selected from --O--, --S--, --S(O)-- or --S(O).sub.2 --, b is 2 or 3 and R.sup.7 and R.sup.8 are selected from hydrogen, loweralkyl (1-8 carbons), and may be the same or different, ##STR48## wherein R.sup.9 is selected from --SR.sup.10, --S(O)R.sup.10 and --S(O.sub.2)R.sup.10 wherein R.sup.10 is selected from loweralkyl (1-8 carbons) and phenyl with the proviso that X must be --S(O).sub.2 --, or, ##STR49## wherein A.sup.3 is selected from straight or branched-chain alkalenes (2-8 carbons) and G is selected from loweralkoxy (1-8 carbons) or --NR.sup.11 R.sup.12 wherein R.sup.11 and R.sup.12 are selected from hydrogen, loweralkyl (1 to 8 carbons), phenyl and phenyl-loweralkyl (7-14 carbons) and may be the same or different, and the pharmaceutically acceptable acid addition salts and hydrates thereof.

17 more elements

A method for treating cardiac arrhythmia in an animal which comprises administering to said animal an effective amount of a compound having the formula:

##STR50## wherein;
n is selected from zero, one or two;
Y is selected from oxygen or sulfur;
A, A.sup.1 and A.sup.2 are selected from straight or branched-chain alkalenes having 1 to 8 carbon atoms and p and d are selected from zero or one with the proviso that when the --(A.sup.1).sub.p --X--(A.sup.2).sub.d --Q radical is in the 2-position, p is at least one;
X is selected from --S--, --S(O)--, or --S(O).sub.2 --;
R, R.sup.1 and R.sup.2 are selected from hydrogen, loweralkyl (1-8 carbons), phenyl, cycloalkyl (1-9 carbons) or phenylalkyl (7-14 carbons) and may be the same or different and R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of
(a) 1-pyrrolidino,
(b) 1-piperidino,
(c) 4-morpholino,
(d) 1-piperazino,
(e) a heterocycle of (a) to (d) substituted by a methyl, ethyl, phenyl or phenylloweralkyl,
(f) 2,6-(loweralkyl).sub.2 -piperidino,
(g) 4-hydroxy-4-phenylpiperidino,
(h) 4-cyano-4-phenylpiperidino, or,
(i) 4-phenyl-1,2,3,6-tetrahydropyridino,
Q is selected from
(1) 1 or 2-naphthyl,
(2) 2,3-dihydro-1H-inden-4-yl or 2,3-dihydro-1H-inden-5-yl,
(3) biphenyl,
(4) phenyl, ##STR51## wherein R.sup.3 is selected from fluorine, chlorine, bromine, iodine, loweralkyl (1-8 carbons), loweralkoxy (1-8 carbons), trifluoromethyl, hydroxy, cyano or nitro, R.sup.4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy and nitro and R.sup.5 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio and phenylthio, ##STR52## wherein R.sup.6 is selected from --NR.sup.7 R.sup.8, --C(O)NR.sup.7 R.sup.8, --(CH.sub.2).sub.b NR.sup.7 R.sup.8, --B--(CH.sub.2).sub.b NR.sup.7 R.sup.8 or --B--(CH.sub.2).sub.b OR.sup.7 wherein B is selected from --O--, --S--, --S(O)-- or --S(O).sub.2 --, b is 2 or 3 and R.sup.7 and R.sup.8 are selected from hydrogen, loweralkyl (1-8 carbons), and may be the same or different, ##STR53## wherein R.sup.9 is selected from --SR.sup.10, --S(O)R.sup.10 and --S(O.sub.2)R.sup.10 wherein R.sup.10 is selected from loweralkyl (1-8 carbons) and phenyl with the proviso that X must be --S(O).sub.2 --, or, ##STR54## wherein A.sup.3 is selected from straight or branched-chain alkalenes (2-8 carbons) and G is selected from hydrogen, loweralkoxy (1-8 carbons) or --NR.sup.11 R.sup.12 wherein R.sup.11 and R.sup.12 are selected from loweralkoxy (1-8 carbons), phenyl and phenyl-loweralkyl (7-14 carbons) and may be the same or different, and the pharmaceutically acceptable acid addition salts and hydrates thereof.

17 more elements

A therapeutic composition for the treatment of cardiac arrhythmias comprising (a) an effective amount of a compound selected from the group having the formula:

##STR55## wherein;
n is selected from zero, one or two;
Y is selected from oxygen or sulfur,
A, A.sup.1 and A.sup.2 are selected from straight or branched-chain alkalenes having 1 to 8 carbon atoms and p and d are selected from zero or one with the proviso that when the --(A.sup.1).sub.p --X--(A.sup.2).sub.d --Q radical is in the 2-position, p is at least one;
X is selected from --S--, --S(O)-- or --S(O).sub.2 --, R, R.sup.1 and R.sup.2 are selected from hydrogen, loweralkyl (1-8 carbons), phenyl, cycloalkyl (1-9 carbons) or phenylalkyl (7-14 carbons) and may be the same or different and R.sup.1 and R.sup.2 taken together with the adjacent nitrogen atom may form a heterocyclic residue selected from the group consisting of
(a) 1-pyrrolidino,
(b) 1-piperidino,
(c) 4-morpholino,
(d) 1-piperazino,
(e) a heterocyclic of (a) to (d) substituted by a methyl, ethyl, phenyl or phenylloweralkyl,
(f) 2,6-(loweralkyl).sub.2 -piperidino,
(g) 4-hydroxy-4-phenylpiperidino,
(h) cyano-4-phenylpiperidino, or,
(i) 4-phenyl-1,2,3,6-tetrahydropyridino,
Q is selected from
(1) 1 or 2 naphthyl,
(2) 2,3-dihydro-1H-inden-4-yl or 2,3-dihydro-1H-inden-5-yl,
(3) biphenyl,
(4) phenyl, ##STR56## wherein R.sup.3 is selected from fluorine, chlorine, bromine, iodine, loweralkyl (1-8 carbons), loweralkoxy (1-8 carbons), trifluoromethyl, hydroxy, cyano or nitro, R.sup.4 is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, isopropyl, methoxy, ethoxy and nitro and R.sup.5 is selected from hydrogen, methyl, ethyl, methoxy, ethoxy, methylthio and phenylthio, ##STR57## wherein R.sup.6 is selected from --NR.sup.7 R.sup.8, --C(O)NR.sup.7 R.sup.8, --(CH.sub.2).sub.b NR.sup.7 R.sup.8, --B--(CH.sub.2).sub.b NR.sup.7 R.sup.8 or --B--(CH.sub.2).sub.b OR.sup.7 wherein B is selected from --O--, --S--, --S(O)-- or --S(O).sub.2 --, b is 2 or 3 and R.sup.7 and R.sup.8 are selected from hydrogen, loweralkyl (1-8 carbons) and may be the same or different, ##STR58## wherein R.sup.9 is selected from --SR.sup.10, --S(O)R.sup.10, and --S(O.sub.2)R.sup.10 wherein R.sup.10 is selected from loweralkyl (1-8 carbons) and phenyl with the proviso that X must be --S(O).sub.2 --, or, ##STR59## wherein A.sup.3 is selected from straight or branched-chain alkalenes (2-8 carbons) and G is selected from loweralkoxy (1-8 carbons) or --NR.sup.11 R.sup.12 wherein R.sup.11 and R.sup.12 are selected from hydrogen, loweralkyl (1-8 carbons), phenyl and phenyl-loweralkyl (7-14 carbons) and may be the same or different, and the pharmaceutically acceptable acid addition salts and hydrates thereof, and
(b) a pharmaceutically acceptable carrier therefor.

17 more elements

Dependencies are inferred from the claim text.

Facts

Application: 06/750,156Filed 1 Jul 1985 · continuation in part
Priority: 10 Apr 1984
Granted: 3 Jun 1986
Term ends: Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 223/06
Not condensed with other rings: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen,…
C07D 207/34
Having two double bonds between ring members or between ring members and non-ring members: with hetero atoms or with carbon atoms having three…
C07D 207/36
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…
C07D 211/54
With hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals,…:…