Diphenyl-cyclopropenes as selective K-agonists

Details Diphenyl-cyclopropenes as selective K-agonists Diphenyl-cyclopropenes as selective K-agonists

1998-12-08

1999-10-19

Ramsuer, Robert W.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514429, 548407, 548578, A01N 4356, C07D20706, C07D20708

Patent

active

059689684

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

The diphenyl-cyclopropene derivatives of the instant invention are kappa opioids useful in the treatment of pain, inflammation, Parkinsonism, dystonia, cerebral ischemia, diuresis, asthma, psoriasis, irritable bowel syndrome, and stroke.
The compounds are K-agonists which are centrally acting and peripherally selective acting.


SUMMARY OF THE INVENTION

The instant invention is a compound of Formula I ##STR1## or a pharmaceutically acceptable salt thereof wherein x is ##STR2## n is an integer of from 0 to 4; and
R' is halogen, CF.sub.3, NO.sub.2, OR.sup.2, CONR.sup.3 R.sup.4, or NHCOCH.sub.3 wherein R.sup.2, R.sup.3, and R.sup.4 are each independently selected from hydrogen and alkyl of from 1 to 6 carbons.
R is hydrogen, COOH, or COOCH.sub.3.
Particularly useful are the compounds selected from:
2,3-Diphenyl-cycloprop-2-enecarboxylic acid methyl-(2-pyrrolidin-1-yl-cyclohexyl)-amide;
2,3-Diphenyl-cycloprop-2-enecarboxylic acid methyl-(7-pyrrolidin-1-yl-1-oxa-spiro[4.5]dec-8-yl)-amide;
Ethyl 2-(3-chlorophenyl)-3-phenylcycloprop-2-ene-1-carboxylate;
2-(3-Chlorophenyl)-3-phenyl-cycloprop-2-ene-1-carboxylic acid;
2-(3-Chlorophenyl)-3-phenyl-cycloprop-2-enecarbcxylic acid methyl-(2-pyrrolidin-1-yl-cyclohexyl)-amide;
Ethyl 2-(4-chlorophenyl)-3-phenyl-cycloprop-2-ene-1-carboxylate;
2-(4-Chlorophenyl)-3-phenyl-cycloprop-2-ene-1-carboxylic acid;
2-(4-Chlorophenyl)-3-phenyl-cycloprop-2-enecarboxylic acid methyl-(2-pyrrolidin-1-yl-cyclohexyl)-amide;
1-[Methyl-(2-pyrrolidin-1-yl-cyclohexyl)-carbamoyl]-2,3-diphenyl-cycloprop- 2-enecarboxylic acid methyl ester; and
1-[Methyl-(2-pyrrolidin-1-yl-cyclohexyl)-carbamoyl]-2,3-diphenyl-cycloprop- 2-enecarboxylic acid.


DETAILED DESCRIPTION

In the compounds of Formula I above, the phenyl groups may be unsubstituted or substituted by 1 to 3 substituents each independently selected from halogen, CF.sub.3, NO.sub.2, OR.sup.2, CONR.sup.3 R.sup.4 wherein R.sup.2, R.sup.3, and R.sup.4 are each independently hydrogen or alkyl with from 1 to 6 carbons, and NHCOCH.sub.3. Preferred substituents are halogens, especially a monochloro group.
Compounds of the present invention contain one or more asymmetric carbon atoms and therefore exist in various stereoisomeric forms. Additionally, the compounds of this invention exist in different geometric isomeric forms. The instant invention is all geometric and stereoisomeric forms.
The compounds of the present invention and/or their nontoxic, pharmaceutically acceptable acid addition salts may be administered to mammals in pharmaceutical compositions which comprise one or more compounds of this invention and/or salts thereof in combination with a pharmaceutically acceptable nontoxic carrier.
As parenteral compositions, the compounds of this invention may be administered with conventional injectable liquid carriers such as sterile, pyrogen-free water, sterile peroxide-free ethyl oleate, dehydrated alcohols, polypropylene glycol, and mixtures thereof
Suitable pharmaceutical adjuvants for the injectable solutions include stabilizing agents, solubilizing agents, buffers, and viscosity regulators. Examples of these adjuvants include ethanol, ethylenediamine tetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators. These pharmaceutical formulations may be injected intramuscularly, intraperitoneally, or intravenously.
As solid or liquid pharmaceutical compositions, the compounds of the present invention may be administered to mammals orally in combination with conventional compatible carriers in solid or liquid form. These orally administered pharmaceutical compositions may contain conventional ingredients such as binding agents such as syrups, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, and mixtures thereof.
The compositions may further include fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methylcellulose, and mixtures thereof.
These oral compositions may also contain lubricants such as magnesium stearate, high mo

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