US 5,385,908 AGranted

Hindered esters of rapamycin

AssigneeAmerican Home Products Corporation

InventorsFrances C. Nelson, Guy A. Schiehser

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Abstract

A compound of the structure ##STR1## wherein R and R.sup.1 are each, independently, ##STR2## or hydrogen; R.sup.2 and R.sup.3 are each, independently, alkyl, arylalkyl, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring; R.sup.4 is a heterocyclic radical which may be optionally substituted; R.sup.5 is alkyl or arylalkyl; R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring which may be optionally substituted; k=0-1, m=0-1; n=1-6; with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof, which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

Claims26

Dependent claims

A compound of the structure ##STR13## wherein R and R.sup.1 are each, independently, ##STR14## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl which may be optionally mono-, di-, or tri- substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aroyl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof.

6 more elements

A method of inducing immunosuppression in a mammal in need thereof, which comprises administering an immunosuppressive effective amount of a compound of the structure ##STR17## wherein R and R.sup.1 are each, independently, ##STR18## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl, which may be optionally mono-, di-, or tri- substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aroyl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof.

6 more elements

A method of treating transplantation rejection or graft vs, host disease in a mammal in need thereof which comprises administering an antirejection effective amount of a compound of the structure ##STR19## wherein R and R.sup.1 are each, independently, ##STR20## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl, which may be optionally mono-, di-, or tri- substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aryl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof.

6 more elements

A method of treating rheumatoid arthritis in a mammal in need thereof which comprises administering an antiarthritis effective amount of a compound of the structure ##STR21## wherein R and R.sup.1 are each, independently, ##STR22## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aroyl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof.

6 more elements

A pharmaceutical composition which comprises a compound of the structure ##STR23## wherein R and R.sup.1 are each, independently, ##STR24## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathioyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aroyl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.

6 more elements

Dependencies are inferred from the claim text.

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Abstract

A compound of the structure ##STR13## wherein R and R.sup.1 are each, independently, ##STR14## or hydrogen;

R.sup.2 and R.sup.3 are each, independently, alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbons, or R.sup.2 and R.sup.3 may be taken together to form a cycloalkyl ring of 3-8 carbon atoms;
R.sup.4 is a heterocyclic radical selected from the group consisting of furanyl, thiophenyl, pyrrolyl, isopyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 1,2,3-oxathiolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, 1,3,4-dioxazolyl, 1,2,5-oxathiazolyl, 1,3-oxathiolyl, 1,2-pyranyl, 1,4-pyranyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,2,4-oxazinyl, 1,3,2-oxazinyl, 1,2,6-oxazinyl, 1,4-oxazinyl, isoxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-oxathiazinyl, 1,3,5,2-oxadiazinyl, azepinyl, oxepinyl, thiepinyl, 1,2,4-diazepinyl, benzofuranyl, isobenzofuranyl, thionaphthenyl, indolyl, indolenyl, 2-isobenzazolyl, 1,5-pyrindinyl, pyrano[3,4-b]pyrrolyl, benzpyrazolyl, benzisoxazolyl, benzoxazolyl, anthranilyl, 1,2-benzopyranyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, naphthyridinyl, pyrido[3,4-b]pyridinyl, pyrido[4,3-b]pyridinyl, pyrido[2,3-b]pyridinyl, 1,3,2-benzozazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, 3,1,4-benzoxazinyl, 1,2-benzisoxazinyl, 1,4-benzisoxazinyl, carbazolyl, and purinyl which may be optionally mono-, di-, or tri- substituted with a group selected from alkyl of 1-6 carbon atoms, arylalkyl of 7-10 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, --SO.sub.3 H, --PO.sub.3 H, and --CO.sub.2 H;
R.sup.5 is alkyl of 1-6 carbon atoms or arylalkyl of 7-10 carbon atoms;
R.sup.6 and R.sup.7 are taken together to form a saturated heterocyclic ring selected from the group consisting of piperidine, morpholine, thiomorpholine, piperazine, pyrazolidine, imidazolidine, and pyrrolidine, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, aroyl of 3-11 carbon atoms, and perfluoroalkyl of 1-6 carbon atoms;
wherein the aryl moiety of the arylalkyl group of R.sup.2, R.sup.3, R.sup.4, and R.sup.5 and the aryl moiety of the aroyl group of R.sup.6 and R.sup.7 is a phenyl, naphthyl, pyridinyl, quinolinyl, isoquinolinyl, thienyl, thionaphthyl, furanyl, benzofuranyl, benzodioxyl, benzoxazolyl, benzoisoxazolyl, indolyl, thiazolyl, isoxazolyl, pyrimidinyl, pyrazinyl, benzopyranyl, or benzimidazolyl group;
k=0-1,
m=0-1;
n=1-6;
with the proviso that R and R.sup.1 are not both hydrogen, or a pharmaceutically acceptable salt thereof.

6 more elements