Diester prodrugs of a decahydroisoquinoline-3-carboxylic acid

Details Diester prodrugs of a decahydroisoquinoline-3-carboxylic acid Diester prodrugs of a decahydroisoquinoline-3-carboxylic acid

2001-12-11

2002-11-26

Davis, Zinna Northington (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S147000

Reexamination Certificate

active

06486175

ABSTRACT:

The present invention relates to novel prodrug forms of 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, to pharmaceutical compositions containing the prodrug forms, and to methods of using the prodrug forms.
European Patent Application Publication No. 590789A1 and U.S. Pat. No. 5,446,051 disclose that certain decahydroisoquinoline derivatives are AMPA receptor antagonists, and as such are useful in the treatment of many different conditions, including pain. In addition, WO 98/45270, published Oct. 15, 1998, discloses that certain selective GluR
5
antagonists are useful for treating pain.
It is an object of the present invention to provide diesters of 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid which provide substantially improved bioavailability of the parent diacid in a patient. In addition, it is an object of the present invention to provide diesters of 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid which are substantially converted to the parent diacid in the patient.
It has now been found that novel diesters of the diacid, 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, possess substantially improved bioavailability as compared to the diacid. In addition, the diesters are substantially converted to the diacid in the patient. The diacid is generically disclosed in U.S. Pat. No. 5,446,051, issued Aug. 29, 1995, and specifically disclosed in, WO 98/45270, published Oct. 15, 1998, as a selective GluR
5
antagonist for treatment of pain.
Thus, the present invention provides compounds of formula I:
wherein R
1
and R
2
are each independently C
1
-C
20
alkyl, C
2
-C
6
alkenyl, C
1
-C
6
alkylaryl, C
1
-C
6
alkyl(C
3
-C
10
) cycloalkyl, C
1
-C
6
alkyl-N, N—C
1
-C
6
dialkylamine, C
1
-C
6
alkyl-pyrrolidine, C
1
-C
6
alkyl-piperidine, or C
1
-C
6
alkyl-morpholine; or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of antagonizing the GluR
5
receptor, which comprises administering to a patient an effective amount of a compound of formula I.
In addition, the present invention provides a method for the treatment of pain, which comprises administering to a patient an effective amount of a compound of formula I.
The present invention further provides a method for the treatment of migraine, which comprises administering to a patient an effective amount of a compound of formula I.
The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of pain.
The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of migraine.
As used herein, the term “prodrug” refers to a diester derivative of a dicarboxylic acid functional drug, which derivative, when administered to a patient is converted into the diacid (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the parent dicarboxylic acid (drug ) is released.
As used herein the term “Compound A” refers to 3S,4aR,6S,8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid.
As used herein the term “Compound B” refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diethyl ester.
As used herein the term “Compound C” refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, dimethyl ester.
As used herein the term “Compound D” refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diisopropyl ester.
As used herein the term “Compound E” refers to 3S,4aR,6S, 8aR-6-(((4-carboxy)phenyl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid HCl, diisobutyl ester.
As used herein the term “C
1
-C
4
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term “C
1
-C
6
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
As used herein the term “C
1
-C
10
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like.
As used herein the term “C
1
-C
20
alkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-eicosyl and the like.
As used herein, the terms “Me”, “Et”, “Pr”, “iPr”, “Bu” and “t-Bu” refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein the term “C
2
-C
6
alkenyl” refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C
2
-C
6
alkenyl groups include ethenyl (also known as vinyl), 1-methylethenyl, 1-methyl-1-propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like.
As used herein, the term “aryl” refers to monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
As used herein, the term “C
1
-C
6
alkylaryl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term “C
1
-C
6
alkylaryl” are the following:
and the like.
As used herein the term “(C
3
-C
10
)cycloalkyl” refers to a saturated hydrocarbon ring structure containing from three to ten carbon atoms. Typical C
3
-C
10
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It is understood that “(C
3
-C
8
)cycloalkyl” and “(C
4
-C
6
)cycloalkyl” is included within the term “(C
3
-C
10
)cycloalkyl”.
As used herein, the term “C
1
-C
6
alkyl(C
3
-C
10
)cycloalkyl” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C
3
-C
10
)cycloalkyl attached to the aliphatic chain. Included within the term “C
1
-C
6
alkyl(C
3
-C
10
)cycloalkyl” are the following:
and the like
As used herein the term “N,N—C
1
-C
6
dialkylamine” refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term “N,N—C
1
-C
6
dialkylamine” are —N(CH
3
)
2
, —N(CH
2
CH
3
)
2
, —N(CH
2
CH
2
CH
3
)
2
, —N(CH
2
CH
2
CH
2
CH
3
)
2
, and the like.
As used herein the term “C
1
-C
6
alkyl-N,N—C
1
-C
6
dialkylamine” refers to straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N,N—C
1
-C
6
dialkylamine attached to the aliphatic chain. Included within the term “C
1
-C
6
alkyl-N,N—C
1
-C
6
dialkylamine” are the following:
and the like.
As used herein the term “C
1
-C
6
alkyl-pyrrolidine” refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope o

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