US 5,366,997 AGranted

Oxygen substituted derivatives of nucleophile-nitric oxide adducts as nitric oxide donor prodrugs

AssigneeThe United States of America, as represented by the Secretary, Department of Health and Human Services

InventorsLarry K. Keefer, Tambra M. Dunams, Joseph E. Saavedra

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Abstract

There are disclosed cardiovascularly active compounds possessing antihypertensive properties, and pharmaceutical compositions containing these agents and a method of treating cardiovascular disorders with the compounds. The active components of the pharmaceutical compositions are compounds of formula I ##STR1## wherein R.sub.1 and R.sub.2 are independently chosen from straight chain and branched chain alkyl and olefinic groups, which may be unsubstituted or substituted; or R.sub.1 and R.sub.2 together with the nitrogen atom they are bonded to form a heterocyclic group; and R.sub.3 is a pharmaceutically acceptable organic group selected from alkyl and olefinic groups which may be unsubstituted or substituted, acyl, a sulfonyl, sulfinyl, sulfenyl, carbonate, or carbamate derivative; or R.sub.3 is a group of the formula--(CH.sub.2).sub.n ONN(O)NR.sub.1 R.sub.2, wherein n is 2-8, and R.sub.1 and R.sub.2 are as described above. Novel compounds are disclosed wherein at least one of R.sub.1, R.sub.2 and R.sub.3 is an olefinic group or heteroatom-substituted straight or branched chain alkyl or olefinic group. Novel methods of synthesizing the compounds are also disclosed.

Claims25

Dependent claims

A pharmaceutical composition, comprising:

an effective amount of a compound of the formula:
##STR25## wherein:
R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of:
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by alkoxy or acyloxy,
C.sub.2-12 straight chain alkyl substituted by hydroxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl;
substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 straight chain olefinic,
C.sub.3-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl,
C.sub.3-12 branched chain olefinic, and
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl;
or
R.sub.1 and R.sub.2 join together with the nitrogen atom to which they are bonded to form a heterocyclic ring selected from the group consisting of:
##STR26## wherein w is 1 to 12, y is 1 or 2, z is 1 to 5, X is NH or O, R.sub.4 is hydrogen, C.sub.1-8 straight chain alkyl, C.sub.3-8 branched chain alkyl, C.sub.3-8 cycloalkyl, or unsubstituted or substituted aryl, and R.sub.5 is hydrogen, C.sub.1-6 straight chain alkyl or C.sub.3-6 branched chain alkyl;
and
R.sub.3 is selected from the group consisting of
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.2-12 straight chain olefinic,
C.sub.2-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain olefinic,
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.1-12 acyl, a sulfonyl derivative, a sulfinyl derivative, and a sulfenyl derivative;
or
R.sub.3 is a group of the formula --(CH.sub.2).sub.n --ONN(O)NR.sub.1 R.sub.2, wherein n is an integer of 2-8, and R.sub.1 and R.sub.2 are as defined above;
with the proviso that at least one of R.sub.1, R.sub.2 and R.sub.3 is an olefinic group or heteroatom-substituted straight or branched chain alkyl group or olefinic group as recited above;
and with the further proviso that R.sub.1, R.sub.2 and R.sub.3 do not contain a halo or a hydroxy substituent .alpha. to an oxygen or a nitrogen atom;
and a pharmaceutically acceptable carrier therefor.

29 more elements

A method for treating cardiovascular disorders in a patient in need thereof, wherein said disorders may be treated by lowering the patient's blood pressure, the method comprising:

administering to the patient in need thereof, a blood pressure lowering effective amount of a compound of the formula:
##STR27## wherein:
R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of:
C.sub.2-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by alkoxy or acyloxy,
C.sub.2-12 straight chain alkyl substituted by hydroxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 straight chain olefinic,
C.sub.3-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl,
C.sub.3-12 branched chain olefinic, and
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl;
or
R.sub.1 and R.sub.2 join together with the nitrogen atom to which they are bonded to form a heterocyclic ring selected from the group consisting of:
##STR28## wherein w is 1 to 12, y is 1 or 2, z is 1 to 5, X is NH or O, R.sub.4 is hydrogen, C.sub.1-8 straight chain alkyl, C.sub.3-8 branched chain alkyl, C.sub.3-8 cycloalkyl, or unsubstituted or substituted aryl, and R.sub.5 is hydrogen, C straight chain alkyl or C.sub.3-6 branched chain alkyl;
and
R.sub.3 is selected from the group consisting of
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.2-12 straight chain olefinic,
C.sub.2-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain olefinic,
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.1-12 acyl, a sulfonyl derivative, sulfinyl derivative, and a sulfenyl derivative;
or
R.sub.3 is a group of the formula --(CH.sub.2).sub.n ONN(O)NR.sub.1 R.sub.2, wherein n is an integer of 2-8, and R.sub.1 and R.sub.2 are as defined above;
with the proviso that R.sub.1, R.sub.2 and R.sub.3 do not contain a halo or a hydroxy substituent .alpha. to an oxygen or a nitrogen atom;
and a pharmaceutically acceptable carrier therefore.

27 more elements

A method of treating hypertension in a patient in need thereof, said method comprising:

administering to the patient a blood pressure lowering effective amount of a compound of the formula:
##STR29## wherein:
R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of:
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain substituted by alkoxy or acyloxy,
C.sub.2-12 straight chain alkyl substituted by hydroxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, or alkoxy, acyloxy or halo,
C.sub.3-12 straight chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 straight chain olefinic,
C.sub.3-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl,
C.sub.3-12 branched chain olefinic, and
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl;
or
R.sub.1 and R.sub.2 join together with the nitrogen atom to which they are bonded to form a heterocyclic ring selected from the group consisting of:
##STR30## wherein w is 1 to 12, y is 1 or 2, z is 1 to 5, X is NH or 0, R.sub.4 is hydrogen, C.sub.1-8 straight chain alkyl, C.sub.3-8 branched chain alkyl, C.sub.3-8 cycloalkyl, or unsubstituted or substituted aryl, and R.sub.5 is hydrogen, C.sub.1-6 straight chain alkyl or C.sub.3-6 branched chain alkyl;
and
R.sub.3 is selected from the group consisting of
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.2-12 straight chain olefinic,
C.sub.2-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain olefinic,
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.1-12 acyl, a sulfonyl derivative, sulfinyl derivative, and a sulfenyl derivative;
or
R.sub.3 is a group of the formula --(CH.sub.2).sub.n ONN(O)NR.sub.1 R.sub.2, wherein n is an integer of 2-8, and R.sub.1 and R.sub.2 are as defined above;
with the proviso that R.sub.1, R.sub.2 and R.sub.3 do not contain a halo or a hydroxy substituent .alpha. to an oxygen or a nitrogen atom;
and
a pharmaceutically acceptable carrier therefor.

29 more elements

A compound having the formula:

##STR31## wherein:
R.sub.l and R.sub.2 are the same or different and are selected from the group consisting of:
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by alkoxy or acyloxy,
C.sub.2-12 straight chain alkyl substituted by hydroxy or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 straight chain olefinic,
C.sub.3-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy, halo or benzyl,
C.sub.3-12 branched chain olefinic and
C.sub.3-12 branched chain olefinic substituted by, hydroxy, alkoxy, acyloxy, halo or benzyl;
or
R.sub.1 and R.sub.2 join together with the nitrogen atom to which they are bonded to form a heterocyclic ring selected from the group consisting of:
##STR32## wherein w is 1 to 12, y is 1 or 2, z is 1 to 5, X is NH or O, R.sub.4 is hydrogen, C.sub.1-8 straight chain alkyl, C.sub.3-8 branched chain alkyl, C.sub.3-8 cycloalkyl, or unsubstituted or substituted aryl, and R.sub.5 is hydrogen, C.sub.1-6 straight chain alkyl or C.sub.3-6 branched chain alkyl;
and
R.sub.3 is selected from the group consisting of
C.sub.1-12 straight chain alkyl,
C.sub.1-12 straight chain alkyl substituted by hydroxy, alkoxy, acyloxy. or halo,
C.sub.3-12 branched chain alkyl,
C.sub.3-12 branched chain alkyl substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.2-12 straight chain olefinic,
C.sub.2-12 straight chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo,
C.sub.3-12 branched chain olefinic,
C.sub.3-12 branched chain olefinic substituted by hydroxy, alkoxy, acyloxy or halo, a sulfonyl derivative, a sulfinyl derivative, and
a sulfenyl derivative;
or
R.sub.3 is a group of the formula --(CH.sub.2).sub.n ONN(O)NR.sub.1 R.sub.2 wherein n is an integer of 2-8, and R.sub.1 and R.sub.2 are as defined above;
with the proviso that at least one of R.sub.1, R2 and R.sub.3 is an olefinic group or heteroatom-substituted straight or branched chain alkyl group or olefinic group, as recited above;
and with the further proviso that R.sub.1, R.sub.2 and R.sub.3 do not contain a halo or hydroxy substituent .alpha. to an oxygen or a nitrogen atom.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 07/950,637Filed 23 Sep 1992 · continuation in part
Priority: 24 Sep 1991
Granted: 22 Nov 1994
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 295/30
Nitrogen atoms: non-acylated
A61K 31/13
Medicinal preparations containing organic active ingredients: amines
A61K 31/135
Amines: having aromatic rings , e.g. ketamine, nortriptyline
A61K 31/40
Having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins: having five-membered rings with one nitrogen as the only ring hetero atom,…