Peripherally selective kappa opioid agonists

Details Peripherally selective kappa opioid agonists Peripherally selective kappa opioid agonists

1999-06-24

2000-05-02

Richter, Johann

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

548525, A01N 4336, C07D40512

Patent

active

060573570

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The compounds of the instant invention are polar compounds designed to have a low log D and thereby have a limited ability to cross the blood-brain barrier. This means that the side effects associated with centrally acting kappa opioid agonists are greatly reduced upon administration of these compounds to a mammal, preferably a human, in need of treatment. Such side effects are various CNS problems and dysphoria.
The compounds of the instant invention are compared to [5R-(5.alpha.,7.alpha.,8.beta.)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro -[4,5]dec-8-yl]-4-benzofuranacetamide, monohydrochloride, which is described and claimed in U.S. Pat. No. 4,737,493 which patent is hereby incorporated by reference.


SUMMARY OF THE INVENTION

The compounds of the instant invention as those of Formula I ##STR2## or a pharmaceutically acceptable salt thereof wherein X, m, Y, n, and Z are as described below.
Preferred compounds of the invention are those of Formula I wherein Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, 2-thianaphthene, 3-thianaphthene, 4-thianaphthene, 5-thianaphthene, 6-thianaphthene, or 7-thianaphthene, and n is 1.
Other preferred compounds are those of Formula I wherein Z is diphenylcyclopropene or diphenylmethyl, and n is zero.
More preferred compounds are those selected from: phenoxy)-acetic acid; phenoxy)-acetic acid; olidin-1-yl)-ethyl]-phenoxy}-acetic acid; olidin-1-yl)-ethyl]-phenoxy}-acetic acid; and opentyl)-ethyl]-phenoxy}-acetic acid.
Other preferred compounds are: }-phenoxy)-acetic acid; ethoxy)-phenyl]-ethyl}-acetamide; idin-1-yl)-ethyl]-phenoxy}-acetic acid; phenoxy)-methanesulfonic acid; olidin-1-yl)-ethyl]-phenoxy}-acetic acid;
Other more preferred compounds are those selected from: -yl-ethyl)-phenoxy]-acetic acid tert-butyl ester, etyl]-methyl-amino}-ethyl)-phenoxy]-acetic acid, }-phenoxy)-acetic acid, ethoxy)-phenyl]-ethyl}-acetamide, lidin-1-yl)-ethyl]-phenoxy}-acetic acid, phenoxy)-methanesulfonic acid, and rolidin-1-yl)-ethyl]-phenoxy}-acetic acid.
Other compounds are: lidin-1-yl)-ethyl]-phenoxy}-acetic acid, ,R*)]-{3-[1-[(Benzofuran-4-yl-acetyl)-methyl-amino]-2-(3-methoxy-pyrlrolid in-1-yl)-ethyl]-phenoxy}-acetic acid, razol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, olidin-1-yl)-ethyl]-phenoxy}-methanesulfonic acid, azol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, razol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, lidin-1-yl)-ethyl]-phenoxy}-acetic acid, olidin-1-yl)-ethyl]-phenoxy}-acetic acid, azol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, azol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl -acetamide, razol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, olidin-1-yl)-ethyl]-phenoxy}-methanesulfonic acid, ethoxy)-phenyl]-ethyl}-acetamide, phenoxy)-methanesulfonic acid, )-ethyl]-phenoxy}-acetic acid, l)-ethyl]-phenoxy}-acetic acid, -phenyl]-ethyl}-N-methyl-2,2-diphenyl-acetamide, l)-ethyl]-phenoxy}-methanesulfonic acid, phenyl]-ethyl}-N-methyl-2,2-diphenyl-acetamide, -phenyl]-ethyl}-N-methyl-2,2-diphenyl-acetamide, -acetyl]-methyl-amino}-ethyl)-phenoxy]-acetic acid, ethoxy-pyrrolidin-1-yl)-ethyl]-phenoxy}-acetic acid, -phenyl]-ethyl}-2-(4-methanesulfonyl-phenyl)-N-methyl-acetamide, )-acetyl]-methyl-amino}-ethyl)-phenoxy]-methanesulfonic acid, phenyl]-ethyl}-2-(4-methanesulfonyl-phenyl)-N-methyl-acetamide, -[3-(2H-tetrazol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, lidin-1-yl)-ethyl]-phenoxy}-acetic acid, olidin-1-yl)-ethyl]-phenoxy}-acetic acid, etrazol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, azol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, razol-5-ylmethoxy)-phenyl]-ethyl}-N-methyl-acetamide, olidin-1-yl)-ethyl]-phenoxy}-methanesulfonic acid, ethoxy)-phenyl]-ethyl}-acetamide, and phenoxy)-methanesulfonic acid.
A pharmaceutical composition comprising a compound of Formula I in a therapeutically effective amount in combination with a pharmaceutically acceptable carrier in unit dosage form is another aspect of the insta

REFERENCES:
patent: 4737493 (1988-04-01), Horwell
patent: 5229414 (1993-07-01), Main

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