| STRUCTURE | Pyrrolidine-1-[CH2-CHPh-NMe-CO-(2-benzofuranyl)]-3-OH |
| PATENT ASSIGNEE'S COUNTRY | USA |
| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | 17.10.2000 |
| PATENT TITLE |
Certain benzofuranyl-N-[pyrrolidin-1-YL]-N-methyl-acetamide derivatives useful as opioid agonists |
| PATENT ABSTRACT |
The novel compounds of formula (I) of the instant invention are selective kappa opioid agonists useful in the treatment of arthritis, hypertension, pain, inflammation, migraine, inflammatory disorders of the gastrointestinal tract, IBS, and psoriasis. The compounds, novel intermediates useful in their preparations and pharmaceutical compositions containing them, are part of the invention. ##STR1## |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | June 30, 1999 |
| PATENT CT FILE DATE | April 17, 1998 |
| PATENT CT NUMBER | This data is not available for free |
| PATENT CT PUB NUMBER | This data is not available for free |
| PATENT CT PUB DATE | November 5, 1998 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A compound of Formula I ##STR10## 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; n is an integer of from 0 to 1; Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, when n is 1; and R is hydrogen or methyl. 2. A compound according to claim 1 wherein Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, and n is 1. 3. A pharmaceutical composition which comprises a therapeutically effective amount of a compound according to claim 1, of Formula I in combination with a pharmaceutically acceptable carrier in unit dosage form. 4. A method of treating arthritis which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 5. A method of treating pain which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 6. A method of treating inflammation which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 7. A method of treating migraine which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 8. A method of treating inflammatory disorders of the gastrointestinal tract which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 9. A method of treating irritable bowel syndrome which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 10. A method of treating psoriasis which comprises administering a therapeutically effective amount of a compound according to claim 1 to a mammal in need of said treatment. 11. A process for the preparation of a compound of Formula I above which comprises: a.) converting styrene oxide into a diamine of formula 3 ##STR11## b.) coupling the diamine with an acid using a suitable coupling reagent to produce the corresponding amide; c.) removing the protecting group to produce the compound of formula 1, and converting it, if desired, to the pharmaceutically acceptable thereof. 12. A compound according to claim 1 and selected from: 2-Benzofuran-4-yl-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -acetamide; 2-Benzofuran-3-yl-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -acetamide; and 2-Benzofuran-4-yl-N-[2-(3-methoxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -acetamide. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
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; n is an integer of from 0 to 1; Z is 2-benzofuranyl, 3-benzofuranyl, 4-benzofuranyl, 5-benzofuranyl, 6-benzofuranyl, 7-benzofuranyl, 4-(methylsulphonyl)phenyl, 3-(methylsulphonyl)phenyl, when n is 1; Z is diphenylcyclopropene when n is 0; and R is hydrogen or methyl. 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: 1-Benzyl-3-(tert-butyl-dimethyl-silanyl)-pyrrolidine; 3-(tert-Butyl-dimethyl-silanyl)-pyrrolidine; {2-[3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-1-phenyl-ethyl}-met hyl-amine; and 2-Benzofuran-4-yl-N-{2-[3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl] -1-phenyl-ethyl}-N-methyl-acetamide. A novel process is a preparation of a compound of Formula I above which comprises: a.) converting styrene oxide into a diamine of formula 3 ##STR3## b.) coupling the diamine with an acid using a suitable coupling reagent to produce the corresponding amide; c.) removing the protecting group to produce the compound of formula 1, and 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; Ar is phenyl or phenyl substituted with methyl, hydroxyl, methoxy, chloro, 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 Z is phenyl substituted with cyano, nitro, trifluoromethyl, halo, or dihalo, where halo is fluoro, chloro, bromo, or iodo. ##STR6## Reactions and conditions: a) Ph.sub.3 P+CH.sub.3 Br, BuLi, THF, -20.degree. C.; b) AD-mix-.alpha., H.sub.2 O-tBuOH; c) Me.sub.3 SiCl, MeC(OMe).sub.3, CH.sub.2 Cl.sub.2 then K.sub.2 CO.sub.3, MeOH; d) Pyrrolidine, ethanol, 90.degree. C., then concentrate: ether, MeSO.sub.2 Cl, Et.sub.3 N, then MeNH.sub.2 (aqueous); e) CDl, ZCH.sub.2 CO.sub.2 H, THF; f) TBAF Synthesis of some key intermediates ##STR7## Reactions and conditions: a) TBDMSiCl, imidazole, CH.sub.2 Cl.sub.2 ; then Pd(OH).sub.2 /C, H.sub.2, EtOH; b) Mel, NaH, THF; then Pd(OH).sub.2 /C, H.sub.2, EtOH; c) KF, Ph.sub.3 P, DEAD, THF; then Pd(OH).sub.2 /C, H.sub.2, EtOH Synthesis of Key Intermediates ##STR8## Reactions and conditions: a) Ph.sub.3 P=CHCO.sub.2 Et, toluene, reflux; b) LiOH, H.sub.2 O-MeOH; c) NBS, (PhCO.sub.2).sub.2, CCl.sub.4, reflux; d) KCN, DMF; e) HCl, reflux; f) Rh.sub.2 (OAc).sub.4,N.sub.2 CHCO.sub.2 Et Preferred compounds of the instant 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, 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: 2-Benzofuran-4-yl-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -acetamide; 2-Benzofuran-3-yl-N-[2-(3-hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -acetamide; N-[2-(3-Hydroxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl-2-phenyl-acetamid e; and 2-Benzofuran-4-yl-N-[2-(3-methoxy-pyrrolidin-1-yl)-1-phenyl-ethyl]-N-methyl -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 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 molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica, or agents to facilitate disintegration of the solid formulation such as starch, and wetting agents such as sodium lauryl sulfate. The oral pharmaceutical compositions may take any convenient form such as tablets, capsules, lozenges, aqueous or oily suspensions, emulsions, or even dry powders which may be reconstituted with water or other suitable liquids prior to use. The solid or liquid forms may contain flavorants, sweeteners, and/or preservatives such as alkyl p-hydroxybenzoates. The liquid forms may further contain suspending agents such as sorbitol, glucose, or other sugar syrups, methyl-, hydroxymethyl-, or carboxymethylcellulose, and gelatin, emulsifying agents such as lecithin or sorbitol monooleate, and conventional thickening agents. The liquid compositions may be encapsulated in, for example, gelatin capsules. As topically administered pharmaceutical compositions, the compounds of the present invention may be administered in the form of ointments or creams containing from about 0.1% to about 10% by weight of the active component in a pharmaceutical ointment or cream base. Compounds of the present invention may be rectally administered in the form of suppositories. For preparing suppositories a low-melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously in the melt. The mixture is then poured into convenient sized molds and allowed to cool and solidify. Preferably, the pharmaceutical compositions of this invention are in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component. The unit dosage can be a packaged preparation with the package containing discrete quantities of the preparation. For example, the package may take the form of packaged tablets, capsules, and powders in envelopes, vials, or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself or can be the appropriate number of any of these packaged forms. The quantity of active compound in the unit dosage form may be varied or adjusted from about 0.5 mg to about 350 mg according to the particular application and the potency of the active ingredient. When employed systematically in therapeutic use as pharmacologic agents in the pharmaceutical methods of this invention, the compounds are administered at doses of from about 0.05 mg to about 2.0 mg of active compound per kilogram of body weight of the recipient. The rabbit vas deferens is a specific test for activity at the K-receptor and allows comparison of potency and efficacy of a test ligand and its parent K-agonist. Rabbit vas deferens assay (Oka T., Negiski K. et al., Eur. J. Pharmacol., 1981;73:235) was used to test the compounds of the invention. One of the compounds of the invention, the compound of Example 4, 2,3-diphenyl-cycloprop-2-enecarboxylic acid methyl-(7-pyrrolidin-1-yl-1-oxa-spiro[4.5]dec-8-yl)-amide, exhibited agonist functional activity of EC.sub.50 (LVD)=12 nM. The relative potency of compounds in the rabbit vas deferens assay is given in Table 1 below. The compounds of invention are on the left side, with reference compounds on the right side. The potency is the EC.sub.50 of the compound/EC.sub.50 of [5R-(5.alpha.,7.alpha.,8.beta.)]-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro -[4,5]dec-8-yl]-4-benzofuranacetamide, monohydrochloride. TABLE 1 ______________________________________ Invention Compounds Reference Compounds ______________________________________ Compound 5 0.28 Compound 12 6.92 Compound 16 1.17 Compound 12 6.92 Compound 6 1.5 Compound 11 1.43 Compound 7 0.056 Compound 13 1.18 Compound 8 1.6 Compound 14 21.1 Compound 9 0.04 Compound 15 1.38 ______________________________________ The results of the testing shown in Table 1 above show that the compounds of the invention are kappa opioid agonists and thus are useful in the treatment of arthritis, hypertension, pain (particularly pain which is inflammatory in origin and post-operative pain), inflammation, migraine, and inflammatory disorders of the gastrointestinal tract, IBS, and psoriasis. Synthesis of key intermediates ##STR9## The above compounds (11, 12, 13, 14, and 15) are the reference compounds found in Table 1. The following examples are illustrative of the instant invention and are not intended to limit its scope in any way. |
| PATENT EXAMPLES | This data is not available for free |
| PATENT PHOTOCOPY | Available on request |
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