Back to results
US 6,143,790 AGranted
L-N.sup.6 -(1-iminoethyl)lysine derivatives useful as nitric oxide synthase inhibitors
AssigneeG.D. Searle & Co.
InventorsE. Ann Hallinan, Foe S. Tjoeng, Kam F. Fok, Timothy J. Hagen, Mihaly V. Toth, Sofya Tsymbalov, Barnett S. Pitzele
Life of this patent
Estimating the term…
Abstract
There is disclosed a novel amino glycol derivatives of L-N.sup.6 -(1-iminoethyl)lysine, pharmaceutical compositions containing these novel compounds, and to their use in therapy, in particular their use as nitric oxide synthase inhibitors.
Claims28
A compound or a pharmaceutically acceptable salt, prodrug or ester thereof having the formula:
- ##STR97## Y is hydrogen, lower alkyl radical, lower alkenyl radical, lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical, wherein all said radicals may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene radical, lower alkenylene radical, lower alkynylene radical, aromatic hydrocarbon radical, (CH.sub.2).sub.m Q(CH.sub.2).sub.n, where m=1-3, n =1-3, and Q is sulfur, sulfinyl, sulfonyl, oxygen, carbonyl, lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical wherein all said radicals are optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkyl radical, lower alkenyl radical,lower alkynyl radical, alicyclic hydrocarbon radical, carbonyl, or aromatic hydrocarbon radical, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, alkoxycarbonyl, alkylaryloxy, thiol, lower thioalkoxy, thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, halogen, aromatic hydrocarbon radicals, or alicyclic hydrocarbon radicals;
- B is hydrogen, lower alkyl radical, lower alkenyl radical, lower alkynyl radical, lower alkoxy radical, hydroxy, alkylaryloxy, thiol, lower thioalkoxy, lower thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, aromatic hydrocarbon radical, alicyclic hydrocarbon radical, or NHOH, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, halogen, aromatic hydrocarbon radicals,or alicyclic hydrocarbon radical;
- with the proviso that when A is CHOR, B cannot be OR and Y cannot be amino wherein R is alkyl;
- with the proviso that when A is carbonyl, B is not hydroxy, aryloxy, thioalkoxy, alkoxy, or NHOH.
4 more elements
A compound or a pharmaceutically acceptable salt, prodrug or ester thereof having the formula:
- ##STR98## wherein;
- Y is hydrogen or lower alkyl which may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene from 3-5 carbons which may optionally be substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkylene from 2-4 carbons optionally substituted with hydroxyl B is hydroxyl.
2 more elements
A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR99## wherein:
- Y is hydrogen, lower alkyl radical, lower alkenyl radical,lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical, wherein all said radicals may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene radical, lower alkenylene radical, lower alkynylene radical, aromatic hydrocarbon radical, (CH.sub.2).sub.m Q(CH.sub.2).sub.n, where m=1-3, n=1-3, and Q is sulfur, sulfinyl, sulfonyl, oxygen, carbonyl, lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical wherein all said radicals are optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkyl radical, lower alkenyl radical,lower alkynyl radical, alicyclic hydrocarbon radical, carbonyl, or aromatic hydrocarbon radical, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, alkoxycarbonyl, alkylaryloxy, thiol, lower thioalkoxy, thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, halogen, aromatic hydrocarbon radicals, or alicyclic hydrocarbon radicals;
- B is hydrogen, lower alkyl radical, lower alkenyl radical, lower alkynyl radical, lower alkoxy radical, hydroxy, alkylaryloxy, thiol, lower thioalkoxy, lower thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, aromatic hydrocarbon radical, alicyclic hydrocarbon radical, or NHOH, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, halogen, aromatic hydrocarbon radicals,or alicyclic hydrocarbon radical;
- with the proviso that when A is CHOR, B cannot be OR and Y cannot be amino wherein R is alkyl;
- with the proviso that when A is carbonyl, B is not hydroxy, aryloxy, thioalkoxy, alkoxy, or NHOH.
5 more elements
A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR100## wherein:
- Y is hydrogen or lower alkyl which may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene from 3-5 carbons which may optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkylene from 2-4 carbons optionally substituted with hydroxyl B is hydroxyl.
2 more elements
A method of selectively inhibiting nitric oxide synthesis produced by inducible NO synthase over nitric oxide produced by the constitutive forms of NO synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR101## wherein:
- Y is hydrogen, lower alkyl radical, lower alkenyl radical,lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical, wherein all said radicals may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene radical, lower alkenylene radical, lower alkynylene radical, aromatic hydrocarbon radical, (CH.sub.2).sub.m Q(CH.sub.2).sub.n, where m=1-3, n=1-3, and Q is sulfur, sulfinyl, sulfonyl, oxygen, carbonyl, lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical wherein all said radicals are optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkyl radical, lower alkenyl radical,lower alkynyl radical, alicyclic hydrocarbon radical, carbonyl, or aromatic hydrocarbon radical, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, alkoxycarbonyl, alkylaryloxy, thiol, lower thioalkoxy, thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, halogen, aromatic hydrocarbon radicals, or alicyclic hydrocarbon radicals;
- B is hydrogen, lower alkyl radical, lower alkenyl radical, lower alkynyl radical, lower alkoxy radical, hydroxy, alkylaryloxy, thiol, lower thioalkoxy, lower thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, aromatic hydrocarbon radical, alicyclic hydrocarbon radical, or NHOH, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, halogen, aromatic hydrocarbon radicals,or alicyclic hydrocarbon radical;
- with the proviso that when A is CHOR, B cannot be OR and Y cannot be amino wherein R is alkyl;
- with the proviso that when A is carbonyl, B is not hydroxy, aryloxy, thioalkoxy, alkoxy, or NHOH.
5 more elements
A method of selectively inhibiting nitric oxide synthesis produced by inducible NO synthase over nitric oxide produced by the constitutive forms of NO synthase in a subject in need of such selective inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR102## wherein:
- Y is hydrogen or lower alkyl which may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene from 3-5 carbons which may optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkylene from 2-4 carbons optionally substituted with hydroxyl B is hydroxyl.
2 more elements
A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR103## wherein:
- Y is hydrogen, lower alkyl radical, lower alkenyl radical,lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical, wherein all said radicals may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene radical, lower alkenylene radical, lower alkynylene radical, aromatic hydrocarbon radical, (CH.sub.2).sub.m Q(CH.sub.2).sub.n, where m=1-3, n=1-3, and Q is sulfur, sulfinyl, sulfonyl, oxygen, carbonyl, lower alkynyl radical, aromatic hydrocarbon radical, or alicyclic hydrocarbon radical wherein all said radicals are optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkyl radical, lower alkenyl radical,lower alkynyl radical, alicyclic hydrocarbon radical, carbonyl, or aromatic hydrocarbon radical, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, alkoxycarbonyl, alkylaryloxy, thiol, lower thioalkoxy, thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, halogen, aromatic hydrocarbon radicals, or alicyclic hydrocarbon radicals;
- B is hydrogen, lower alkyl radical, lower alkenyl radical, lower alkynyl radical, lower alkoxy radical, hydroxy, alkylaryloxy, thiol, lower thioalkoxy, lower thioalkylaryloxy, thioaryloxy, sulfinylalkyl, sulfinylalkylaryl, sulfinylaryl, sulfonylalkyl, sulfonylalkylaryl, sulfonylaryl, aromatic hydrocarbon radical, alicyclic hydrocarbon radical, or NHOH, wherein all said radicals are optionally substituted with hydrogen, lower alkyl, hydroxyl, lower alkoxy, halogen, aromatic hydrocarbon radicals,or alicyclic hydrocarbon radical;
- with the proviso that when A is CHOR, B cannot be OR and Y cannot be amino wherein R is alkyl;
- with the proviso that when A is carbonyl, B is not hydroxy, aryloxy, thioalkoxy, alkoxy, or NHOH.
5 more elements
A method of inhibiting nitric oxide synthesis in a subject in need of such inhibition by administering a therapeutically effective amount of a compound having the formula:
- ##STR104## wherein:
- Y is hydrogen or lower alkyl which may optionally be substituted with hydrogen, lower alkyl, nitro, amino, alicyclic hydrocarbon radicals, or aromatic hydrocarbon radicals which may be optionally substituted with lower alkyl;
- X is lower alkylene from 3-5 carbons which may optionally substituted with hydrogen, halogen and lower alkyl;
- R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen and lower alkyl;
- A is lower alkylene from 2-4 carbons optionally substituted with hydroxyl B is hydroxyl.
2 more elements
Dependencies are inferred from the claim text.