Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-06-30
2000-10-17
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548518, 5462841, C07D20714, C07D40112, A61K 314025
Patent
active
061333077
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The compounds covered below are selective kappa opioid agonists. These compounds and their salts are useful in the treatment of arthritis, hypertension, pain, particularly pain which is inflammatory in origin and post-operative pain, inflammation, migraine, inflammatory disorders of the gastrointestinal tract, Parkinsonism, and stroke.
These compounds with the (S)-hydroxyl group on the 3 position of the pyrrolidine ring are more potent kappa agonists in the rabbit vas deferens assay than those compounds lacking a hydroxyl and should, therefore, be more potent for the treatment of the above mentioned conditions.
SUMMARY OF THE INVENTION
The compounds are of the general structure: ##STR2## or a pharmaceutically acceptable salt thereof wherein: Ar is phenyl unsubstituted or substituted with from 1 to 5 substituents selected from methyl, hydroxy, methoxy, and halogen; 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, when n is 1;
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 instant invention.
The compounds of the invention are useful in the treatment of pain, inflammation, migraine, inflammatory disorders of the gastrointestinal tract, psoriasis, and irritable bowel syndrome (IBS).
Processes for the preparation of novel compounds are yet another aspect of the invention. The novel intermediates are still another aspect of the invention. They are: hyl-amine; and -1-phenyl-ethyl}-N-methyl-acetamide.
A novel process is a preparation of a compound of Formula I above which comprises: ##STR3## b.) coupling the diamine with an acid using a suitable coupling reagent to produce the corresponding amide; converting it, if desired, to the pharmaceutically acceptable thereof.
DETAILED DESCRIPTION OF THE INVENTION
Selective kappa opioid agonists are selected from: ##STR4## where: A is oxygen or sulfur; fluoro, iodo, or bromo.
Other selective kappa opioid agonists are: ##STR5## where: Ar is phenyl or phenyl substituted with methyl, hydroxyl, methoxy, chloro, fluoro, iodo, or bromo, and dihalo, where halo is fluoro, chloro, bromo, or iodo. ##STR6##
Reactions and conditions: MeOH; Cl, Et.sub.3 N, then MeNH.sub.2 (aqueous);
Synthesis of some key intermediates
##STR7##
Reactions and conditions: EtOH;
Synthesis of Key Intermediates
##STR8##
Reactions and conditions:
Preferred compounds of the instant invention are those of Formula I wherein 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, and n is 1.
Other preferred compounds of the instant invention are those of Formula I wherein Z is diphenylcyclopropene and n is 0.
More preferred compounds are: -acetamide; -acetamide; e; and -acetamide.
Another more preferred compound is 2,3-diphenyl-cycloprop-2-enecarboxylic acid [2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-methyl amide.
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 ethan
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Horwell David Christopher
Osborne Simon
Anderson Elizabeth M.
Rotman Alan L.
Warner-Lambert & Company
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