US3347856A - 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives - Google Patents

1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives Download PDF

Info

Publication number
US3347856A
US3347856A US431440A US43144065A US3347856A US 3347856 A US3347856 A US 3347856A US 431440 A US431440 A US 431440A US 43144065 A US43144065 A US 43144065A US 3347856 A US3347856 A US 3347856A
Authority
US
United States
Prior art keywords
methyl
pyrrolidyl
alkyl
chloride
carbon atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US431440A
Inventor
Carl D Lunsford
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AH Robins Co Inc
Original Assignee
AH Robins Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AH Robins Co Inc filed Critical AH Robins Co Inc
Priority to US431440A priority Critical patent/US3347856A/en
Priority to GB532/66A priority patent/GB1128351A/en
Priority to NL666600234A priority patent/NL143917B/en
Priority to GB3094/66A priority patent/GB1136104A/en
Priority to CH93866A priority patent/CH467798A/en
Priority to CH102266A priority patent/CH466282A/en
Priority to DE19661620184 priority patent/DE1620184A1/en
Priority to NL6601380A priority patent/NL6601380A/xx
Priority to FR48657A priority patent/FR1467524A/en
Priority to ES0322716A priority patent/ES322716A1/en
Priority to BE676170D priority patent/BE676170A/xx
Priority to LU50404A priority patent/LU50404A1/xx
Priority to MC607A priority patent/MC586A1/en
Priority to SE1603/66A priority patent/SE312804B/xx
Priority to FR48862A priority patent/FR5168M/fr
Priority to FR48863A priority patent/FR1490497A/en
Priority to BE676256D priority patent/BE676256A/xx
Priority to FR60388A priority patent/FR5480M/fr
Application granted granted Critical
Publication of US3347856A publication Critical patent/US3347856A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • E—FIXED CONSTRUCTIONS
    • E04—BUILDING
    • E04F—FINISHING WORK ON BUILDINGS, e.g. STAIRS, FLOORS
    • E04F19/00—Other details of constructional parts for finishing work on buildings
    • E04F19/02—Borders; Finishing strips, e.g. beadings; Light coves

Definitions

  • the invention relates to l-lower-alkyl-3-pyrrolidyl or 1-pyridyl-3-pyrrolidyl N-lower-alkyland N-lower-cycloalkyl-N-arylcarbamates.
  • the l-lower-alkyl group has 1 to 4 carbon atoms, inclusive.
  • the compounds are anticholinergics and antidepressives.
  • N-arylcarbamates (with hydrogen being the second N substituent)
  • N,N-dilower-cycloalkyl carbamates and carbamates wherein the nitrogen atom is a part of a heterocyclic ring are also included, although not preferred.
  • the present invention relates to novel therapeutic compounds and is more particularly concerned with certain organic compounds having anticholinergic activity, a method for their preparation, a method of employing such compounds for purposes for exploiting their anticholin ergic activity in the treatment of a living animal body, and compositions containing such an anticholinergically active compound as active ingredient.
  • Anticholinergic agents are useful in treating spasm of various types, such as commonly associated with spastic constipation, biliary duct spasm, arterial spasm, and similar conditions.
  • the compounds of the invention are active anticholinergics useful for treating spasm of the type induced by acetylcholine.
  • Employment of the anticholinergic agents of the invention in the treatment of Parkinsonism is of particular interest. Parkinsonism is a condition involving disturbance of certain brain centers, such as the mesodiencephalic activating center of the brain stem, which causes muscular rigidity and may impair normal movements and the ability to speak and write. It results from injury to basal ganglia and is frequently a sequel to virus-caused epidemic (lethargic) encephalitis. Symptoms include involuntary tremors, lack of facial expression, depressed emotional tone, and salivation.
  • Compounds which control these symptoms are, in general, anticholinergic agents which are capable of passing the blood brain barrier.
  • Atropine and extracts from various species of Slrammonium flora have long been used in treating Parkinsonism, and more recently other anticholinergic agents, such as trihexylphenidyl, procyclidine, ethopropazine, and diethazine have been so employed.
  • the degree of utilization of any such anticholinergic agent is restricted by the undesirable side-effects which it may concurrently produce. Dryness of the mouth, blurred vision, mydriasis, epigastric distress, nausea and constipation are examples of peripheral side effects.
  • the capacity to produce desired anticholinergic effects without the usual side effects is a highly desirable attribute of an anticholinergic.
  • Effective agents having such an attribute 3,347,355 Patented Oct. 17, 1967 have long been sought without the attainment of any complete solution to the problem.
  • a particular object of the present invention is to provide novel anticholinergic agents which are capable of passing the blood brain barrier, compositions thereof, and a method for the treatment of spasm including Parkinsonism therewith. Additional objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter.
  • the frequency and magnitude of peripheral side effects exhibited by pre-existing anticholinergic drugs would indicate that it is extremely unusual if not impossible to isolate the desired central anticholinergic activity from concurrent undesired peripheral side elfects.
  • the 1 loWer-alkyl-3-pyrrolidyl N,N disubstitutedcarbamates of the invention not only exhibit a high order of central anticholinergic activity, but also extremely low peripheral side effects.
  • the anticholinergic agents of the invention have valuable antidepressive activity.
  • the active anticholinergic agents of the present invention are compounds having the formula:
  • R is a loWer-alkyl radical having 1 to 4 carbon atoms inclusive, or pyridyl, and wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being other than hydrogen.
  • a in the foregoing formula is selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms inclusive and lower-cycloalkyl having 3 to 9 carbon atoms inclusive, and A is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifluoromethylphenyl, lower-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, naphthyl, and halophenyl.
  • the substituents can be in various available positions of the phenyl nucleus and, where more than one substituent is present, can be the same or difierent and can be in various position combinations relative to each other.
  • the number of substituents when present on the phenyl ring is l to 3, inclusive, any loWer-alkyl, lower-alkoxy, and dilower-alkylamino substituents each have 1 to 4 carbon atoms, inclusive, and all ring substituents, when present, have 1 to 9 carbon atoms, inclusive.
  • A is hydrogen and A has the value assigned for the first embodiment.
  • both A and A are selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive.
  • the radical is a heterocyclic amine radical having 4 to 12 carbon atoms, inclusive, such as indolino, tetrahydroquinolino, phenothiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrlidino, piperidino, piperazino, and loweralkylpiperazino.
  • lower-alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like.
  • lower-cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl.
  • the lower-alkyl group present as the N or l-substituent in the compounds of the invention includes only those straight and branched chain radicals containing up to four carbon atoms inclusive, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, and the like.
  • the lower-alkyl group contains more than four carbon atoms or is cycloalkyl or aralkyl, the anticholinergic activity is markedly reduced.
  • the compounds of the present invention are most conveniently employed in the form of water-soluble nontoxic pharmaceutically acceptable acid addition salts.
  • the free basic compounds of Formula I may be conveniently converted into these salts by reaction of the free base with the selected acid in the presence of an aprotic organic solvent (one which is inert to the reactants and reaction product under the conditions of reaction).
  • the acids which can be employed to prepare the preferred pharmaceutically acceptable acid addition salts are those which produce, when combined with the free bases, salts the anions of which are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side effects ascribable to the anions.
  • Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobrornic acid, hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, alkyl and arylsulfonic acids, and the like.
  • the preferred acid addition salt is the maleic acid salt.
  • Acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid, or to which the acid is subsequently added, and isolating the salt by evaporating the solution, or by reacting the free base and the selected acid in an organic solvent, in which case the salt ordinarily separates directly or can be conventionally recovered by concentration of the solution or the like.
  • the free basic amine is desired, this may be obtained conventionally by neutralizing the reaction product or a solution of the isolated salt with a base such as ammonia, ammonium hydroxide, sodium carbonate, or other suitable alkaline material, extracting the liberated base with a suitable solvent such as ethyl acetate or benzene, drying the extract and evaporating to dryness in vacuo or fractionally distilling, or in other conventional manner.
  • a base such as ammonia, ammonium hydroxide, sodium carbonate, or other suitable alkaline material
  • a suitable solvent such as ethyl acetate or benzene
  • compositions of the present invention contain a nontoxic pharmaceutical carrier in addition to the active anticholinergic agent.
  • exemplary carriers are: solids such as lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium phosphate, sucrose, talc, stearic acid, gelatine, agar, pectin, or acacia and liquids such as peanut oil, sesame oil, olive oil, or Water.
  • the active anticholinergic agent and pharmaceutical carrier may, for example, take the form of a pill, lozenge, tablet, capsule, or a liquid suspension; for parenteral administration the composition may be in the form of a sterile solution; and for rectal administration, the form may be a suppository.
  • the compounds of the present invention are usually administered in compositions containing from about 0.01 to 75 percent, by weight, of anticholinergic agent, preferably 0.05 to 25 percent.
  • the method of treating according to the invention comprises internally administering an anticholinergically effective amount of a compound of Formula 1, including non-toxic acid addition salts thereof, preferably admixed with a pharmaceutical carrier, for example, in the form of any of the above-mentioned compositions, to combat spasm and symptoms thereof in a living animal body.
  • a pharmaceutical carrier for example, in the form of any of the above-mentioned compositions.
  • the 1 lower-alkyl-3-pyrrolidyl N,N-disubstituted-carbamates of the present invention may be advantageously employed in a unit dosage of from 0.1 to 200 milligrams. This unit dosage may be given a suitable number of times daily so that the daily dose will vary from 0.3 to 600 milligrams.
  • the oral unit dosage will preferably vary from about 2.5 to 50 milligrams while the parenteral dosage will usually be approximately one-half the oral dosage so that the preferred parenteral unit dosage will be about 1 to 25 milligrams.
  • the preferred daily dosages will vary from about 7.5 to milligrams (oral) to about three to 75 milligrams (parenteral). However, with this type of drug there is considerable variation in individual dosage. The invention therefore should not be limited to the exact ranges stated. The exact dosages suitable for a particular patient will of course have to be as determined and directed by the physician or veterinarian in charge.
  • active ingredients of the present invention or compositions containing the same may either be administered together with or include other physiologically active materials and/ or medicaments, e.g., buffering agents, antacids, sedatives, tranquilizers, analgesics, or the like.
  • physiologically active materials and/ or medicaments e.g., buffering agents, antacids, sedatives, tranquilizers, analgesics, or the like.
  • the anticholinergic agents of the invention may be conveniently prepared by reacting an alkali or alkaline earth metal alcoholate of the corresponding l-lower-alkyl- 3-pyrrolidinol with the appropriate N,N-disubstituted (e.g., alkylor cycloalkyl-monocarbocyclic-aryl)-carbamyl chloride, such as methylor cyclohexyl-phenyl-carbamyl chloride, or other conventional methods for the production of carbamates may be employed.
  • an alkali or alkaline earth metal alcoholate of the corresponding l-lower-alkyl- 3-pyrrolidinol with the appropriate N,N-disubstituted (e.g., alkylor cycloalkyl-monocarbocyclic-aryl)-carbamyl chloride, such as methylor cyclohexyl-phenyl-carbamyl chloride, or other conventional methods for the production of carb
  • the metal alcoholates may in turn be produced by using as one reagent an alkali or alkaline earth metal, e.g., sodium, potassium, or calcium, or an alkali or alkaline earth metal hydride, e.g., lithium hydride, or an alkali or alkaline earth metal amide, e.g., sodium amide, or a similar alkali or alkaline earth metal reagent capable of reacting with the selected pyrrolidinol to produce a metal alcoholate.
  • an alkali or alkaline earth metal e.g., sodium, potassium, or calcium
  • an alkali or alkaline earth metal hydride e.g., lithium hydride
  • an alkali or alkaline earth metal amide e.g., sodium amide
  • a similar alkali or alkaline earth metal reagent capable of reacting with the selected pyrrolidinol to produce a metal alcoholate.
  • This reagent is accordingly mixed and reacted with the selected 1- lower-alkyl-3-pyrrolidinol, comprising unsubstituted or methylor polymethyl-l-loweralkyl-3-pyrrolidinols, e.g., 2, 2-di-, 2-, 3-, 4-, or S-methyl-l-lower-alkyl-3-pyrrolidinols and including polymethyl ring substituted l-loweralky1-3-pyrr0lidinols having more than one methyl group on the same ring carbon atoms, said pyrrolidinols being preparable as known in the art as illustrated by Lunsford U.S. Patent 2,830,997 and other sources cited therein.
  • alkylor cycloalkyl-monocarbocyclic aryl-carbamyl chlorides may for example be prepared by the reaction of phosgene with the corresponding alkylor cycloalkyl-monocarbocyclic aryl amine according to the procedure of Bielstein, XII, p. 428.
  • the 1-lower-alky1-3-pyrrolidinol or methyl-l-loweralkyl-3-pyrrolidinol is stirred and refluxed with an equimolar quantity of an alkali or alkaline earth metal compound capable of reacting therewith to form the 3-pyrrolidinol metal alcoholate, as already mentioned above, e.g., sodium amide, in an inert organic solvent such as a hydrocarbon, e.g., benzene, toluene, xylene, or an ether, e.g., dioxane, until hydrogen or ammonia, as the case may be, is no longer evolved.
  • an alkali or alkaline earth metal compound capable of reacting therewith to form the 3-pyrrolidinol metal alcoholate
  • an inert organic solvent such as a hydrocarbon, e.g., benzene, toluene, xylene, or an ether, e.g., dioxane, until
  • the dialkylor cycloalkyl-monocarbocyclic-aryl-carbamyl halide usually the chloride, preferably an equimolar quantity thereof.
  • This addition is preferably carried out at low temperature to control the exothermic character of the reaction. Reflux is continued until the inorganic salt is no longer formed (usually several hours).
  • the product is recovered in the normal manner. For example, the mixture is cooled, washed with water, dried over a drying agent such as anhydrous sodium sulfate, filtered, and concentrated, and the residue worked up in conventional manner, such as by fractional distillation and recrystallization.
  • the base is converted directly to a salt by reaction with an equimolar quantity of a pharmaceutically acceptable acid.
  • Acceptable acid addition salts include the hydrochloride, hydrobromide, ptoluenesulfonate, acetate, maleate, fumarate, sulfate, and the like. All of the acid addition salts prepared were found to be soluble in water.
  • the 3-pyrrolidinol used in the reaction need not necessarily be converted to its sodium or other metal salt, but may be reacted directly with the carbamyl chloride; however, the procedure described above is preferred for maximum yield in minimum reaction time.
  • N-cyclopentyl aniline was mixed and reacted with phosgene to give N-cyclopentyl-N-phenylcarbamyl chloride having a melting point of 77.5-79.5 degrees centigrade.
  • PREPARATION 10 N-CYCLOPENTYL-N- (o-CHLO- ROPHENYL)-CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclopentyl-ochloroaniline was mixed and reacted with phosgene to give N-cyclopentyl-N-(o-chlorophenyl)-carbamyl chloride.
  • PREPARATION 1 1 .N-PHENYLCARBAMYL CHLORIDE Using the method of Preparation 1, aniline was mixed and reacted together with phosgene to produce N-phenylcarbamyl chloride.
  • PREPARATION 12 N- (4-METHOXYPHENYL) CARBAMYL CHLORIDE Using the method of Preparation 1, 4-methoxy-aniline was mixed and reacted together with phosgene to produce N- (4-methoxyphenyl carb amyl chloride.
  • PREPARATION 1 8 .INDOLINOCARBONYL CHLORIDE Using the method of Preparation 1, l,2,3,4-tetrahydroquinoline was reacted with phosgene to form 1-(1,2,3,4- tetrahydroquinolino) carbonyl chloride.
  • PREPARATION 22 --1-(2,6-DIMETI-IYLMORPHO- LINO CARBONYL CHLORIDE Using the method of Preparation 1, 2,6'dimethylmorpholine was reacted with phosgene to produce 1-(2,6- dimethylrnorpholino)carbonyl chloride.
  • chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material.
  • methoxy or other lower-alkoxy group is present, other lower-alkoxy groups containing various lower-alkyl groups having up to eight carbon atoms inclusive are prepared in the same manner from the appropriate difierent lower-alkoxy starting material.
  • dilower-alkylamino group such as the dimethylamino group
  • other dilower-alkylamino compounds are prepared in the same manner starting only with the selected different dilower-alkylamino compound.
  • ortho and meta substituted compounds are produced instead of the para by utilizing the selected ortho or meta substituted starting compound.
  • other molecular changes are readily made.
  • Example 1 -1-methyl-3-pyrrolidyl N -methyl-N phenylcarbamnte maleate
  • the sodium salt of 1-methyl-3-pyrrolidinol (0.3 mole) was prepared by refluxing and mechanically stirring an equimolar mixture of l-rnethyl-Zv-pyrrolidinol and sodium amide in toluene solvent until ammonia was no longer evolved.
  • a toluene solution of crude N-methyl-N-phenylcarbamyl chloride (56.2 grams, 0.3 mole) was added and the reaction mixture was stirred and refluxed overnight, cooled and aqueous sodium hydroxide was added to the reaction mixture.
  • maleate salt was obtained by dissolving 23.4 grams (0.1 mole) of the free base and 11.6 grams (0.1 mole) of maleic acid in milliliters of 2-propanol. Isop-ropyl ether was added until the solution became turbid and crystallization initiated. The material was recrystallized from a 2-propanolisopropyl ether mixture.
  • the maleate salt is a white, water soluble, crystalline solid of melting point 8788.5 degrees centigrade.
  • Example 4 -1 -m ethyl-3-pyrr0lidyl N -cycl0p en ty 1- N -plzenylcarbamate 9
  • Example 5.1-metlzyl-3-pyrr0lidyl N-(cyclpentyl)- N-phenylcarbamale maleate Using the method of Example 1, l-methyl-B-pyrrolidyl- N-(cyclopentyl)-N-phenylcarbarnate was mixed and re acted together with maleic acid to produce 1-methyl-3- pyrrolidyl N-(cyclopentyl)-N-phenylcarbamate maleate.
  • Example 7.1-metlzyl-3-pyrr0lidyl N-cyclopentyl-N- (p-clzloroplzenyl) -carbamate maleaze Using the method of Example 1, the sodium salt of 1- methyl-3-pyrrolidinol was mixed and reacted together with N cyclopentyl N-(p-chlorophenyl)-carbamyl chloride, and the resulting produce subsequently mixed and reacted With maleic acid to form 1-methyl-3-pyrrolidyl N-cyclopentyl-N-(p-chlorophenyl)-carbarnate maleate.
  • Example 8 -methyl-3-pyrr0lidyl N -cycl0lz exyl-N (p-clzloroplzenyl) -carbamate maleate Using the method of Example 1, the sodium salt of 1- rnethyl-3-pyrrolidinol was mixed and reacted together with N-cyclohexyl-N-(p-chlorophenyl)-carbamyl chloride, and the resulting product subsequently mixed and reacted with maleic acid to form 1-rnethyl-3-pyrrolidyl N-cyclohexyl-N- (p-chlorophenyl) -carbamate maleate.
  • Example 9 -metlzyl-3-pyrr0lidylN-cyclopentyl-N- (3- trifluor'ometlzylplzenyl) -carbamate maleate
  • a chloroform solution of 0.2 mole of crude N-cyclopentyl N (3-trifluoromethylphenyl)-carbamyl chloride was added to a toluene solution of 0.15 mole of the sodium salt of 1-methyl-3-pyrrolidinol with stirring.
  • the sodium salt of the pyrrolidinol was prepared in the same manner as described in Example 1.
  • the reaction mixture was stirred and refluxed overnight, cooled, washed with aqueous 3N sodium hydroxide and Water, dried over sodium sulfate, concentrated and the residue distilled under reduced pressure. Boiling point; 145148 degrees centigrade at 0.005 millimeter. Yield, 29 percent. NE. calculated, 356.38, found, 357.
  • the maleate salt was prepared in the same manner as described in Example 1 and melted after recrystallization at 96-985 degrees centigrade. Yield of the salt from the free base was 85 percent.
  • Example J3.1-methyl-3-pyrr0lidyl N-(4-chl0r0phenyl) carbamate Using the method of Example 1, the sodium salt of 1-methyl-3-pyrrolidinol was mixed and reacted together With N-(4-chlorophenyl)carbamyl chloride to produce 1-methy1-3-pyrro1idyl N-(4-chlorophenyl)carbamate.
  • Example 14.1 methyl-3-pyrr0lidyl N-(I-naphthyl) carbamate Using the method of Example 1, the sodium salt of 1-methyl-3-pyrrolidinol was mixed and reacted together with N-(l-naphthyl) carbarnyl chloride to produce l-methyl-3 -pyrrolidy1 N- l-naphthyl) carbamate.
  • the free base was subsequently reacted the free base of 1-methyl-3-pyrrolidyl l-octahydroquinowith maleic acid to form 1-methy1-3-pyrrolidyl N-methyllinocarboxylate.
  • the free base was subsequently reacted N-cyclohexylcarbamate maleate.
  • the sodium salt of cwboxylate maleate 1-methyl-3-pyrrolidinol was mixed and reacted together
  • the sodium salt of 1- with N,N-diethylcarbamyl chloride to produce l-methylmethyl-3-pyrrolidinol was mixed and reacted together 3-pyrrolidyl N,N-diethylcarbamate.
  • Example 23 -1-methyl-3-pyrr0lidyl 1-(2,6-di777ethylmorpholinokarboxylale Using the method of Example 1, the sodium salt of 1- 0 methyl-Lpyrrolidinol was mixed and reacted together with 1-(2,6-dimethylmorpholino)carbonyl chloride to 1 Basic N.
  • chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material.
  • methoxy or other loweralkoxy grou is present, compounds having other lower alkoxy groups containing various lower-alkyl groups having up to eight carbon atoms inclusive are prepared in the same manner from the appropriate different loweralkoxy starting material.
  • diloweralkylamino group such as the dimethylamino group
  • other dilower-alkylarnino compounds are prepared in the same manner starting only with the selected different dilower-alkylamin-ocompound.
  • ortho and meta products are produced instead of the para by utilizing the selected ortho or meta substituted starting material.
  • other molecular changes within the scope of the invention are readily made.
  • the compounds of the invention are generally characterized by the pharmacological activity hereinbefore stated, making them useful in counteracting certain physiological abnormalities in a living animal body.
  • Effective quantities of the pharmacologically active compounds of the invention may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions, suspensions, or by pellet implantation, and in some cases intravenously in the form of sterile solutions.
  • Other modes of administration are cutaneous, subcutaneous, buccal, intramuscular, and intraperitoneal.
  • compositions are usually prepared from a predetermined quantity of one or more of the compounds of the invention, preferably in solid form.
  • Such formulations may take the form of powders, elixirs, solutions, pills, capsules, pellets, or tablets, with or without, but preferably with, any one of a large variety of pharmaceutically acceptable vehicles or carriers.
  • the active ingredient When in admixture with a pharmaceutical vehicle or carrier, the active ingredient usually comprises from about 0.01 to about75 percent, normally from about 0.05 to about 25 percent, by weight of the composition.
  • Carriers such as starch, sugar, talc, commonly used synthetic and natural gums, water, and the like, may be used in such formulations.
  • Binders such as gelatin, and lubricants such as sodium stearate, may be used to form tablets.
  • Disintegrating agents such as sodium bicarbonate may also be included in tablets.
  • unit dosages are usually five milligrams or above and preferably twenty-five, fifty, or one-hundred milligrams or even higher, depending of course upon the subject treated and the particular result desired. Usual broader ranges appear to be one to 200 milligrams per unit dose.
  • the active agents of the invention may be combined for administration with other 'pharmacologically active agents, such as analgesics,
  • the active ingredient of the invention constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed.
  • a suitable effective dosage will be obtained consistent with the dosage form employed.
  • several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to Well-established principles under the direction of a physician or veterinarian.
  • Example 24.-F0rmulati0ns The following formulations are representative for all of the pharmacologically active compounds of the invention, but have been particularly designed to embody as the active ingredient 1-methyl-3-pyrrolidyl N-cyclopcntyl-N-phenylcarbamate in the form of an acid addition salt thereof, e.g., the maleate.
  • Capsules Capsules of 2.5 milligrams, 10 milligrams, 25 milligrams, and 50 milligrams of active ingredient per capsule were prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
  • the active ingredient, the lactose, the starch, and the magnesium stearate are uniformly blended and encapsulated.
  • a typical formulation for a tablet containing 5.0 milligrams of active ingredient per tablet follows.
  • the formulation may be used for other strengths of active ingredient, in this case 1-methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate maleate, by adjustment of the weight of dicalcium phosphate.
  • Uniformly blend 1, 2, 4, and 5. Prepare 3 as a ten percent paste in water. Granulate the blend with starch paste and pass the wet mass through an eight-mesh screen. The Wet granulation is dried and sized through a twelve-mesh screen. The dried granules are blended with the calcium stearate and compressed.
  • R is a lower-alkyl radical having 1 to 4 carbon atoms inclusive, wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, wherein A is a radical selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive, and wherein A is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifiuoromethylphenyl, lowe'r-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, and halophenyl, and (b) pharmaceutical-ly acceptable acid addition salts thereof.
  • a l-methyl-3- pyrrolidyl N-methyl-N-phenyloarbamate pharmaceutically acceptable acid addition salt.
  • a 1-methyl-3-pyrrolidyl N-cyclohexyl-N-phenylcarbamate pharmaceutically acceptable acid addition salt.
  • R is a lower-alkyl radical having 1 to 4 carbon atoms, inclusive
  • R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, and
  • both A and A are selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms,
  • R is a lower-alkyl radical having 1 to 4 carbon atoms, inclusive, wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, and wherein forms a member having 4 to 12 carbon atoms, inclusive, selected from the group consisting of indolino, tetrahydroquinolino, phenothiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrolidino, piperidino, piperazino, and lower-alkylpiperazino, and (b) pharmaceutically acceptable acid addition salts thereof.
  • R is selected from the group consisting of a lower-alkyl radical having 1 to 4 carbon atoms, inclusive, and pyridyl,
  • R is selected from the group consisting of methy and hydrogen, a maximum of two R being methyl
  • A is selected from the group consisting of hydrogen, lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive, and
  • A is selected from the group consisting of a monocarbocyclic aryl group containing a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifluoromethylphenyl, loweralkoxyphenyl, dilower alkylaminophenyl, loweralkylphenyl, halophenyl and naphthyl, and, when A is lower-cycloalkyl, lower-alkyl having 1-6 carbon atoms inclusive, and lower-cycloalkyl having 3-9 carbon atoms, inclusive,
  • a and A together with the nitrogen atom forms a member having 4-12 carbon atoms inclusive, selected from the group consisting of indolino, tetrahydroquinolino, phen othiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrolidino, piperidino, piperazino, and lower-alkylpiperazino, and (b) pharmaceutically acceptable acid addition salts thereof.

Description

United States Patent 1 LQWER ALKYL 3 PYRRGLIDYL N LQWER- ALKYL- AND LOWER CYCLQALKYL N AR- YLCARBAMATE ANTISPASMODICS AND ANTI- DEPRESSIVES Carl D. Lunsford, Richmond, Va., assignor to A. H. Robins Company, Inc., Richmond, Va., a corporation of Virginia No Drawing. Filed Feb. 9, 1965, Ser. No. 431,440
21 Claims. (Cl. 260243) ABSTRACT OF THE DISCLOSURE The invention relates to l-lower-alkyl-3-pyrrolidyl or 1-pyridyl-3-pyrrolidyl N-lower-alkyland N-lower-cycloalkyl-N-arylcarbamates. The l-lower-alkyl group has 1 to 4 carbon atoms, inclusive. The compounds are anticholinergics and antidepressives. Related compounds which are N-arylcarbamates (with hydrogen being the second N substituent), N-lower-alkyl-N-1owercycloalkyl carbamates, N,N-dilower-cycloalkyl carbamates, and carbamates wherein the nitrogen atom is a part of a heterocyclic ring are also included, although not preferred.
The present invention relates to novel therapeutic compounds and is more particularly concerned with certain organic compounds having anticholinergic activity, a method for their preparation, a method of employing such compounds for purposes for exploiting their anticholin ergic activity in the treatment of a living animal body, and compositions containing such an anticholinergically active compound as active ingredient.
Anticholinergic agents are useful in treating spasm of various types, such as commonly associated with spastic constipation, biliary duct spasm, arterial spasm, and similar conditions. The compounds of the invention are active anticholinergics useful for treating spasm of the type induced by acetylcholine. Employment of the anticholinergic agents of the invention in the treatment of Parkinsonism is of particular interest. Parkinsonism is a condition involving disturbance of certain brain centers, such as the mesodiencephalic activating center of the brain stem, which causes muscular rigidity and may impair normal movements and the ability to speak and write. It results from injury to basal ganglia and is frequently a sequel to virus-caused epidemic (lethargic) encephalitis. Symptoms include involuntary tremors, lack of facial expression, depressed emotional tone, and salivation.
Compounds which control these symptoms are, in general, anticholinergic agents which are capable of passing the blood brain barrier. Atropine and extracts from various species of Slrammonium flora have long been used in treating Parkinsonism, and more recently other anticholinergic agents, such as trihexylphenidyl, procyclidine, ethopropazine, and diethazine have been so employed. The degree of utilization of any such anticholinergic agent is restricted by the undesirable side-effects which it may concurrently produce. Dryness of the mouth, blurred vision, mydriasis, epigastric distress, nausea and constipation are examples of peripheral side effects. The capacity to produce desired anticholinergic effects without the usual side effects is a highly desirable attribute of an anticholinergic. Effective agents having such an attribute 3,347,355 Patented Oct. 17, 1967 have long been sought without the attainment of any complete solution to the problem.
It is therefore an object of the present invention to provide novel compounds and compositions possessing valuable therapeutic properties, that is, anticholinergic activity, and a method for their preparation. Another object is to provide a novel method for the treatment of living animal and especially mammalian bodies, for purposes of combatting spasm therein. Still another object is to provide compositions which possess beneficial anticholinergic activity without deleterious peripheral activity, and which are therefore particularly useful in combatting spasm in a living animal body. A particular object of the present invention is to provide novel anticholinergic agents which are capable of passing the blood brain barrier, compositions thereof, and a method for the treatment of spasm including Parkinsonism therewith. Additional objects will be apparent to one skilled in the art and still other objects will become apparent hereinafter.
The foregoing and additional objects are accomplished by the provision of certain 1-lower-alkyl-3-pyrrolidyl N, N-disubstituted-carbamates, pharmaceutically acceptable acid-addition salts thereof, a method for their preparation, and compositions containing the same a active ingradient, and by employing such compounds and/ or compositions to combat, diminish, eliminate, or ameliorate spasm in a living animal body treated therewith.
The frequency and magnitude of peripheral side effects exhibited by pre-existing anticholinergic drugs would indicate that it is extremely unusual if not impossible to isolate the desired central anticholinergic activity from concurrent undesired peripheral side elfects. Unpredictably, the 1 loWer-alkyl-3-pyrrolidyl N,N disubstitutedcarbamates of the invention not only exhibit a high order of central anticholinergic activity, but also extremely low peripheral side effects.
In addition to the usefulness of the l-lower-alkyl-B-pyrrolidyl N,N-disubstituted-carbamates and their non-toxic salts as strong central anticholinergics, they may also be employed in the therapy and prevention of extra-pyramidal symptoms caused by other drugs. Moreover, the anticholinergic agents of the invention have valuable antidepressive activity.
I The active anticholinergic agents of the present invention are compounds having the formula:
and pharmaceutically acceptable acid addition salts thereof, wherein R is a loWer-alkyl radical having 1 to 4 carbon atoms inclusive, or pyridyl, and wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being other than hydrogen.
In the preferred embodiment, A in the foregoing formula is selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms inclusive and lower-cycloalkyl having 3 to 9 carbon atoms inclusive, and A is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifluoromethylphenyl, lower-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, naphthyl, and halophenyl. The substituents can be in various available positions of the phenyl nucleus and, where more than one substituent is present, can be the same or difierent and can be in various position combinations relative to each other. Preferably the number of substituents when present on the phenyl ring is l to 3, inclusive, any loWer-alkyl, lower-alkoxy, and dilower-alkylamino substituents each have 1 to 4 carbon atoms, inclusive, and all ring substituents, when present, have 1 to 9 carbon atoms, inclusive.
In a second embodiment, A is hydrogen and A has the value assigned for the first embodiment.
In a third embodiment, both A and A are selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive.
In a fourth embodiment, the radical is a heterocyclic amine radical having 4 to 12 carbon atoms, inclusive, such as indolino, tetrahydroquinolino, phenothiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrlidino, piperidino, piperazino, and loweralkylpiperazino.
The term lower-alkyl as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, tertiary butyl, amyl, isoamyl, hexyl, heptyl, octyl, and the like. The term lower-cycloalkyl as used herein includes primarily cyclic alkyl radicals containing three up to nine carbon atoms inclusive and encompasses such groups as cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, methylcyclohexyl, propylcyclohexyl, ethylcyclopentyl, propylcyclopentyl, dimethylcyclohexyl, cycloheptyl, and cyclooctyl. The lower-alkyl group present as the N or l-substituent in the compounds of the invention includes only those straight and branched chain radicals containing up to four carbon atoms inclusive, and is exemplified by such groups as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, and the like. When the lower-alkyl group contains more than four carbon atoms or is cycloalkyl or aralkyl, the anticholinergic activity is markedly reduced.
The compounds of the present invention are most conveniently employed in the form of water-soluble nontoxic pharmaceutically acceptable acid addition salts. The free basic compounds of Formula I may be conveniently converted into these salts by reaction of the free base with the selected acid in the presence of an aprotic organic solvent (one which is inert to the reactants and reaction product under the conditions of reaction). The acids which can be employed to prepare the preferred pharmaceutically acceptable acid addition salts are those which produce, when combined with the free bases, salts the anions of which are relatively innocuous to the animal organism in therapeutic doses of the salts, so that beneficial physiological properties inherent in the free bases are not vitiated by side effects ascribable to the anions. Appropriate acid addition salts are those derived from mineral acids such as hydrochloric acid, hydrobrornic acid, hydriodic acid, nitric acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, citric acid, lactic acid, tartaric acid, alkyl and arylsulfonic acids, and the like. The preferred acid addition salt is the maleic acid salt.
Acid addition salts are prepared either by dissolving the free base in an aqueous solution containing the appropriate acid, or to which the acid is subsequently added, and isolating the salt by evaporating the solution, or by reacting the free base and the selected acid in an organic solvent, in which case the salt ordinarily separates directly or can be conventionally recovered by concentration of the solution or the like. Where the free basic amine is desired, this may be obtained conventionally by neutralizing the reaction product or a solution of the isolated salt with a base such as ammonia, ammonium hydroxide, sodium carbonate, or other suitable alkaline material, extracting the liberated base with a suitable solvent such as ethyl acetate or benzene, drying the extract and evaporating to dryness in vacuo or fractionally distilling, or in other conventional manner.
In their most advantageous forms for administration, the compositions of the present invention contain a nontoxic pharmaceutical carrier in addition to the active anticholinergic agent. Exemplary carriers are: solids such as lactose, magnesium stearate, calcium stearate, starch, terra alba, dicalcium phosphate, sucrose, talc, stearic acid, gelatine, agar, pectin, or acacia and liquids such as peanut oil, sesame oil, olive oil, or Water.
A wide variety of pharmaceutical forms, suitable for many modes of administration and dosages, may be employed. For oral administration the active anticholinergic agent and pharmaceutical carrier may, for example, take the form of a pill, lozenge, tablet, capsule, or a liquid suspension; for parenteral administration the composition may be in the form of a sterile solution; and for rectal administration, the form may be a suppository.
The compounds of the present invention are usually administered in compositions containing from about 0.01 to 75 percent, by weight, of anticholinergic agent, preferably 0.05 to 25 percent.
The method of treating according to the invention comprises internally administering an anticholinergically effective amount of a compound of Formula 1, including non-toxic acid addition salts thereof, preferably admixed with a pharmaceutical carrier, for example, in the form of any of the above-mentioned compositions, to combat spasm and symptoms thereof in a living animal body. The 1 lower-alkyl-3-pyrrolidyl N,N-disubstituted-carbamates of the present invention may be advantageously employed in a unit dosage of from 0.1 to 200 milligrams. This unit dosage may be given a suitable number of times daily so that the daily dose will vary from 0.3 to 600 milligrams. The oral unit dosage will preferably vary from about 2.5 to 50 milligrams while the parenteral dosage will usually be approximately one-half the oral dosage so that the preferred parenteral unit dosage will be about 1 to 25 milligrams. The preferred daily dosages will vary from about 7.5 to milligrams (oral) to about three to 75 milligrams (parenteral). However, with this type of drug there is considerable variation in individual dosage. The invention therefore should not be limited to the exact ranges stated. The exact dosages suitable for a particular patient will of course have to be as determined and directed by the physician or veterinarian in charge. In addition, the active ingredients of the present invention or compositions containing the same may either be administered together with or include other physiologically active materials and/ or medicaments, e.g., buffering agents, antacids, sedatives, tranquilizers, analgesics, or the like.
The high order of activity of the active agents of the present invention, as evidenced by tests in lower animals, is indicative of utility based on their valuable activity in human beings as well as in lower animals. Clinical evaluation in human beings has not been completed, however. It will be clearly understood that the distribution and marketing of any compound or composition falling within the scope of the present invention for use in human beings will of course have to be predicated upon prior approval by governmental agencies such as the Federal Food and Drug Administration which are responsible for a determination of and authorized to pass on such questions.
The anticholinergic agents of the invention, the l-loweralkyl-3-pyrrolidyl N,N-disubstituted-carbamates, may be conveniently prepared by reacting an alkali or alkaline earth metal alcoholate of the corresponding l-lower-alkyl- 3-pyrrolidinol with the appropriate N,N-disubstituted (e.g., alkylor cycloalkyl-monocarbocyclic-aryl)-carbamyl chloride, such as methylor cyclohexyl-phenyl-carbamyl chloride, or other conventional methods for the production of carbamates may be employed. The metal alcoholates may in turn be produced by using as one reagent an alkali or alkaline earth metal, e.g., sodium, potassium, or calcium, or an alkali or alkaline earth metal hydride, e.g., lithium hydride, or an alkali or alkaline earth metal amide, e.g., sodium amide, or a similar alkali or alkaline earth metal reagent capable of reacting with the selected pyrrolidinol to produce a metal alcoholate. This reagent is accordingly mixed and reacted with the selected 1- lower-alkyl-3-pyrrolidinol, comprising unsubstituted or methylor polymethyl-l-loweralkyl-3-pyrrolidinols, e.g., 2, 2-di-, 2-, 3-, 4-, or S-methyl-l-lower-alkyl-3-pyrrolidinols and including polymethyl ring substituted l-loweralky1-3-pyrr0lidinols having more than one methyl group on the same ring carbon atoms, said pyrrolidinols being preparable as known in the art as illustrated by Lunsford U.S. Patent 2,830,997 and other sources cited therein. Representative starting methyl-1-lower-alkyl-3-pyrrolidinols are disclosed by Ryan et al., J. Org. Chem. 27, 2901- 2905 (1962) and references cited therein. The alkylor cycloalkyl-monocarbocyclic aryl-carbamyl chlorides may for example be prepared by the reaction of phosgene with the corresponding alkylor cycloalkyl-monocarbocyclic aryl amine according to the procedure of Bielstein, XII, p. 428.
In greater detail, the preferred procedure for the preparation of the compounds of the invention, representatively illustrated for the 1-lower-alkyl-3-pyrrolidyl-N-alkylor cycloalkyl-N-monocarbocyclic aryl-carbamates, is as follows. The 1-lower-alky1-3-pyrrolidinol or methyl-l-loweralkyl-3-pyrrolidinol is stirred and refluxed with an equimolar quantity of an alkali or alkaline earth metal compound capable of reacting therewith to form the 3-pyrrolidinol metal alcoholate, as already mentioned above, e.g., sodium amide, in an inert organic solvent such as a hydrocarbon, e.g., benzene, toluene, xylene, or an ether, e.g., dioxane, until hydrogen or ammonia, as the case may be, is no longer evolved. To the product of this reaction is added, without isolation, the dialkylor cycloalkyl-monocarbocyclic-aryl-carbamyl halide, usually the chloride, preferably an equimolar quantity thereof. This addition is preferably carried out at low temperature to control the exothermic character of the reaction. Reflux is continued until the inorganic salt is no longer formed (usually several hours). The product is recovered in the normal manner. For example, the mixture is cooled, washed with water, dried over a drying agent such as anhydrous sodium sulfate, filtered, and concentrated, and the residue worked up in conventional manner, such as by fractional distillation and recrystallization. The base is converted directly to a salt by reaction with an equimolar quantity of a pharmaceutically acceptable acid. Acceptable acid addition salts include the hydrochloride, hydrobromide, ptoluenesulfonate, acetate, maleate, fumarate, sulfate, and the like. All of the acid addition salts prepared were found to be soluble in water.
The 3-pyrrolidinol used in the reaction need not necessarily be converted to its sodium or other metal salt, but may be reacted directly with the carbamyl chloride; however, the procedure described above is preferred for maximum yield in minimum reaction time.
The following preparations are given by way of illustration only and are not to be construed as limiting.
PREPARATION 1.N-CYCLOPENTYL N (3-TRI- FLUOROMETHYLPHENYL)-CARBAMYL CHLO- RIDE pure carbamyl chloride, melting point 43.5-45 degrees centigrade.
PREPARATION 2.N-CYCLOPENTYL-N-(p-CHLO- ROPHENYL)-CARBAMYL CHLORIDE N-cyclopentyl-p-chloroaniline (78.4 grams, 0.4 mole) was added slowly with stirring at 10 degree centigrade to a toluene solution of 60 grams (0.6 mole) of phosgene. The resulting mixture was allowed to stand at room temperature for 1.5 hours and heated at degrees centigrade for four hours, filtered, and concentrated under reduced pressure, resulting in a yield of grams of the solid carbamyl chloride. This crude material was sufficiently pure for conversion to the carbamate esters. Recrystallization of the entire sample from ligroin (60100 degrees centigrade) gave 85.5 grams of the pure, white crystalline carbamyl chloridewhich melted at 8285 degrees centigrade.
PREPARATION 3.N-METHYL-N-PHENYLCAR- BAMYL CHLORIDE Using the method of Preparation 2, N-methyl-aniline was mixed and reacted with phosgene to give N-methyl- N-phenylcarbamyl chloride having a melting point of 8586.5 degrees centigrade.
PREPARATION 4.-N-ETHYL-N-PHENYLCAR- BAMYL CHLORIDE Using the method of Preparation 2., N-ethyl-aniline was mixed and reacted wtih phosgene to give N-ethyl- N-phenylcarbamyl chloride.
PREPARATION 5.N n-PROPYL) -N-PHENYL- CARBAMYL CHLORIDE Using the method of Preparation 2, N-(n-propylaniline was mixed and reacted with phosgene to give N- (n-propyl -N-phenylcarbamyl chloride.
PREPARATION 6.-N-CYCLOPENTYL-N-PHENYL- CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclopentyl aniline was mixed and reacted with phosgene to give N-cyclopentyl-N-phenylcarbamyl chloride having a melting point of 77.5-79.5 degrees centigrade.
PREPARATION 7.N-CYCLOHEXYL-N-PHENYL- CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclohexyl aniline was mixed and reacted with phosgene to give N-cyclohexyl-N-phenylcarbamyl chloride.
PREPARATION 8.N-CYCLOHEXYL-N- 3-TRIFLU- OROMETHYL-PHENYL) -CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclohexyl-3- trifluoromethylaniline was mixed and reacted with phosgene to give N-cyclohexyl-N-(3-trifluoromethylphenyl)- carbamyl chloride.
PREPARATION 9.-N-CYCLOHEXYL-N- p-CHLO- ROPHENYL) -CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclohexyl-pchloroaniline was mixed and reacted with phosgene to give N-cyclohexyl-N-(p-chlorophenyl)-carbamyl chloride.
PREPARATION 10.-N-CYCLOPENTYL-N- (o-CHLO- ROPHENYL)-CARBAMYL CHLORIDE Using the method of Preparation 2, N-cyclopentyl-ochloroaniline was mixed and reacted with phosgene to give N-cyclopentyl-N-(o-chlorophenyl)-carbamyl chloride.
PREPARATION 1 1 .N-PHENYLCARBAMYL CHLORIDE Using the method of Preparation 1, aniline was mixed and reacted together with phosgene to produce N-phenylcarbamyl chloride.
PREPARATION 12 .N- (4-METHOXYPHENYL) CARBAMYL CHLORIDE Using the method of Preparation 1, 4-methoxy-aniline was mixed and reacted together with phosgene to produce N- (4-methoxyphenyl carb amyl chloride.
PREPARATION l 3'.N- (4-CI-ILOROPHENYL) CARBAMYL CHLORIDE Using the method of Preparation 1, 4-chloro-aniline was mixed and reacted together with phosgene to produce N- (4-chlorophenyl carbamyl chloride.
PREPARATION l4.N-( 1 -NAPHTHYL) CARBAMYL CHLORIDE Using the method of Preparation 1, l-naphthylamine was mixed and reacted together with phosgene to produce N-(1-naphthyl)carbamyl chloride.
PREPARATION .-N,NDIMETHYLCARBAMYL CHLORIDE Using the method of Preparation 1, dimethylamine was mixed and reacted with phosgene to produce N,N- dimethylcarbamyl chloride.
PREPARATION l6.N-METHYL-N-CYCLOHEXYL- CARBAMYL CHLORIDE Using the method of Preparation 1, N-methyl-cyclohexylamine was mixed and reacted together with phosgene to produce N-methyl-N-cyclohexylcarbamyl chloride.
PREPARATION l7.-N,N-DIETHYLCARBAMYL CHLORIDE Using the method of Preparation 1, diethylamine was mixed and reacted together with phosgene to produce N,N-diethylcarbamyl chloride.
PREPARATION 1 8 .INDOLINOCARBONYL CHLORIDE Using the method of Preparation 1, l,2,3,4-tetrahydroquinoline was reacted with phosgene to form 1-(1,2,3,4- tetrahydroquinolino) carbonyl chloride.
PREPARATION 20.1-(l,2,3,4,5,6,7,8-OCTAHYDRO QUINOLINO CARBONYL CHLORIDE Using the method of Preparation 1, l,2,3,4,5,6,7,8-octahydroquinoline was reacted with phosgene to produce 1-(l,2,3,4,5,6,7,8-octahydroquinolino) carbonyl chloride.
PREPARATION 2 l .-1-PHENOTHIAZINOCAR- BONYL CHLORIDE Using the method of Preparation 2, the sodium salt of phenothiazine (prepared from phenothiazine and sodium amide in toluene) was reacted with phosgene to produce l-hepnothiazinocarbonyl chloride.
PREPARATION 22.--1-(2,6-DIMETI-IYLMORPHO- LINO CARBONYL CHLORIDE Using the method of Preparation 1, 2,6'dimethylmorpholine was reacted with phosgene to produce 1-(2,6- dimethylrnorpholino)carbonyl chloride.
Where the foregoing preparations produce a compound having a methyl or other lower-alkyl group, it is to be understood that compounds containing other lower-alkyl groups of straight or branched nature, such as methyl, ethyl, propyl, isopropyl, batyl, sec-butyl, t.-butyl, arnyl, isoarnyl, hexyl, heptyl, and octyl, are prepared in the same manner by substitution in the process of the appropriate different lower-alkyl starting material. Likewise, where chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material. Similarly, where methoxy or other lower-alkoxy group is present, other lower-alkoxy groups containing various lower-alkyl groups having up to eight carbon atoms inclusive are prepared in the same manner from the appropriate difierent lower-alkoxy starting material. Moreover, when one dilower-alkylamino group, such as the dimethylamino group, is present in a compound, other dilower-alkylamino compounds are prepared in the same manner starting only with the selected different dilower-alkylamino compound. In the same manner, ortho and meta substituted compounds are produced instead of the para by utilizing the selected ortho or meta substituted starting compound. Similarly, other molecular changes are readily made.
The following examples are given by way of illustration only and are not to be construed as limiting.
Example 1.-1-methyl-3-pyrrolidyl N -methyl-N phenylcarbamnte maleate The sodium salt of 1-methyl-3-pyrrolidinol (0.3 mole) was prepared by refluxing and mechanically stirring an equimolar mixture of l-rnethyl-Zv-pyrrolidinol and sodium amide in toluene solvent until ammonia was no longer evolved. A toluene solution of crude N-methyl-N-phenylcarbamyl chloride (56.2 grams, 0.3 mole) was added and the reaction mixture was stirred and refluxed overnight, cooled and aqueous sodium hydroxide was added to the reaction mixture. The toluene layer was separated, washed with water until the washings were neutral, dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated. The residue was distilled at reduced pressure, yield 50 percent; boiling point 115-117 degrees at 0.002
, millimeter; N.E. calculated, 234.29, found, 235.3. The
maleate salt was obtained by dissolving 23.4 grams (0.1 mole) of the free base and 11.6 grams (0.1 mole) of maleic acid in milliliters of 2-propanol. Isop-ropyl ether was added until the solution became turbid and crystallization initiated. The material was recrystallized from a 2-propanolisopropyl ether mixture. The maleate salt is a white, water soluble, crystalline solid of melting point 8788.5 degrees centigrade.
Example 2.-1-methyl-3-pyrr0lidyl N -ethyl-N plzenylcarbamate Using the method of Example 1, the sodium salt of l-methyl-3-pyrrolidinol was mixed and reacted together with N-ethyl-N-phenylcarbamyl chloride to produce 1- methyl-3-pyrrolidyl N-ethyl-N-phenylcarbamate.
Example 3.-1-methyl-3-pyrr0lidyl N-(n-propyl)- N-phenylca'rbamate Using the method of Example 1, the sodium salt of l-methyl-3-pyrrolidinol was mixed and reacted together with N-(n-propyl)-N-phenylcarbamyl chloride to produce 1 methyl-3-pyrrolidyl N-(n-propyl)-N-phenylcarbamate.
Example 4 .-1 -m ethyl-3-pyrr0lidyl N -cycl0p en ty 1- N -plzenylcarbamate 9 Example 5.1-metlzyl-3-pyrr0lidyl N-(cyclpentyl)- N-phenylcarbamale maleate Using the method of Example 1, l-methyl-B-pyrrolidyl- N-(cyclopentyl)-N-phenylcarbarnate was mixed and re acted together with maleic acid to produce 1-methyl-3- pyrrolidyl N-(cyclopentyl)-N-phenylcarbamate maleate.
Example 6.1-metlzyl-3-pyrr0lidyl N-cyclohexyl-N- phenylcarbamate maleate Using the method of Example 1, the sodium salt of 1- methyl-3-pyrrolidinoi was mixed and reacted together with N-cyclohexyl-N-phenylcarbamyl chloride, and the result- 1 0 Example 10.-1-methyl-3-pyrr0lidyl N -cycl0l2exyl-N-(3- trifluoromethylphenyl) -carbamate maleate Table I below lists the properties of the compounds of Examples 1-10.
TABLE I M.P. (B.P., Empirical C Percent H Percent N Percent Ex. CJmm.) Formula Oald. Cald. Cald. (M01. Wt.) Found Found Found ing product subsequently mixed and reacted with maleic acid to form 1 methyl 3 pyrrolidyl N-cyclohexyl-N- phenylcarbarnate maleate.
Example 7.1-metlzyl-3-pyrr0lidyl N-cyclopentyl-N- (p-clzloroplzenyl) -carbamate maleaze Using the method of Example 1, the sodium salt of 1- methyl-3-pyrrolidinol was mixed and reacted together with N cyclopentyl N-(p-chlorophenyl)-carbamyl chloride, and the resulting produce subsequently mixed and reacted With maleic acid to form 1-methyl-3-pyrrolidyl N-cyclopentyl-N-(p-chlorophenyl)-carbarnate maleate.
Example 8.] -methyl-3-pyrr0lidyl N -cycl0lz exyl-N (p-clzloroplzenyl) -carbamate maleate Using the method of Example 1, the sodium salt of 1- rnethyl-3-pyrrolidinol was mixed and reacted together with N-cyclohexyl-N-(p-chlorophenyl)-carbamyl chloride, and the resulting product subsequently mixed and reacted with maleic acid to form 1-rnethyl-3-pyrrolidyl N-cyclohexyl-N- (p-chlorophenyl) -carbamate maleate.
Example 9.]-metlzyl-3-pyrr0lidylN-cyclopentyl-N- (3- trifluor'ometlzylplzenyl) -carbamate maleate A chloroform solution of 0.2 mole of crude N-cyclopentyl N (3-trifluoromethylphenyl)-carbamyl chloride was added to a toluene solution of 0.15 mole of the sodium salt of 1-methyl-3-pyrrolidinol with stirring. The sodium salt of the pyrrolidinol was prepared in the same manner as described in Example 1. The reaction mixture was stirred and refluxed overnight, cooled, washed with aqueous 3N sodium hydroxide and Water, dried over sodium sulfate, concentrated and the residue distilled under reduced pressure. Boiling point; 145148 degrees centigrade at 0.005 millimeter. Yield, 29 percent. NE. calculated, 356.38, found, 357. The maleate salt was prepared in the same manner as described in Example 1 and melted after recrystallization at 96-985 degrees centigrade. Yield of the salt from the free base was 85 percent.
Example 11.-I-is0pr0pyl-3-pyrr0lidyl N-phenylcarbamate Using the method of Example 1, the sodium salt of 1-isopropyl-3-pyrrolidinol was mixed and reacted together with N-phenylcarbamyl chloride to form 1-is0propyl-3- pyrrolidyl N-phenylcarbamate.
Example 12.-1-methyl-3-pyrrolidyl N-(4-meth0xyph enyl) carbam'ate Using the method of Example 1, the sodium salt of 1-methyl-3-pyrrolidinol was mixed and reacted together With N-(4-methoxyphenyl)carbamyl chloride to produce 1-methyl-3-pyrrolidyl N-(4-methoxyphenyl)carbamate.
Example J3.1-methyl-3-pyrr0lidyl N-(4-chl0r0phenyl) carbamate Using the method of Example 1, the sodium salt of 1-methyl-3-pyrrolidinol was mixed and reacted together With N-(4-chlorophenyl)carbamyl chloride to produce 1-methy1-3-pyrro1idyl N-(4-chlorophenyl)carbamate.
Example 14.1-methyl-3-pyrr0lidyl N-(I-naphthyl) carbamate Using the method of Example 1, the sodium salt of 1-methyl-3-pyrrolidinol was mixed and reacted together with N-(l-naphthyl) carbarnyl chloride to produce l-methyl-3 -pyrrolidy1 N- l-naphthyl) carbamate.
Example 15.1-(2-pyridyl) -3-pyrr0lidyl N 4-chl0r0- phenyl) carbamate TABLE II M.P. (13.1. Empirical For- C Percent H Percent N Percent Ex. CJinm.) mula (M01. Wt.) Cald. Cald. Cald. Found Found Found 11 (162163/0.025) CMHQQN OZ 67.71 8.12 11.28 67. 70 7. 71 11.51 12 118120 C I-1. mm 62.38 7.25 11.19 250. 29 32. 70 7. 2s 11. 17 13 93.5-94.5 C zH ClNzOz 56.58 5.94 11.00 254.72 56. 66 5. 91 11. 0s 14 110-111 71.09 6. 71 10.36 270 32 71. 00 6. s1 10. 07 15 152-153 60.47 5.08 13.22 3 59. 50 4. 79 12. 70
Example 16.1-z's0pr0pyZ-S-pyrrolidyl N,N-dimethyl- 15 Example 20.-1-metl7yl-3-pyrr0lidyl 1-(1,2,3,4-tetracarbamate hydrochloride hydroquinolino)carboxylate maleate Using the method of Example 1, the sodium salt of Using the method of Example 1, the sodium salt of 1- 1-isopropy13-pyrrolidino1 was mixed and reacted together methyl-3pyrrolidinol was mixed and reacted together With N,N-dimethylcarbamyl chloride to form the free with 1- (1,2,3,4-tetrahydroquinolino)carbonyl chloride base of 1-isopropyl-3-pyrrolidyl-N,N-dimethylcarbamate. to produce the free base of 1-methyl-3-pyrro1idyl 1- The free base was subsequently reacted with hydrochloric (1,2,3,4 tetrahydroquinolino)carboxylate. The free base acid to form 1-isopropyl-3-pyrrolidyl N,N-dimethylcarwas subsequently reacted with maleic acid to form 1 bamate hydrochloride. methyl-Zv-pyrrolidyl 1 (1,2,3,4-tetrahydroquinolino)car- Exa'mple 17.1-methyl-3-pyrr0lidyl N-methyl-N-cyclobloxylate maleate' hexylcarbamate maleate Example 21.-1-methyl-3-pyrr0lidyl l-octahydro- Using the method of Example 1, the sodium salt of qmnolmomrboxylate maleate 1-methyl-3-pyrrolidinol was mixed and reacted together Using the method of Example 1, the sodium salt of 1- with N-rnethyl-N-cyclohexylcarbamyl chloride to form methyl-3-pyrrolidinol was mixed and reacted together the free base of 1-rnethyl-3-pyrrolidyl N-methyl-N-cyclowith 1-octahydroquinolinocarbonyl chloride to produce hexylcarba-mate. The free base was subsequently reacted the free base of 1-methyl-3-pyrrolidyl l-octahydroquinowith maleic acid to form 1-methy1-3-pyrrolidyl N-methyllinocarboxylate. The free base was subsequently reacted N-cyclohexylcarbamate maleate. with maleic acid to form 1-methyl-3-pyrrolidyl 1-octa- Example 18.1-methyl-3-pyrr0lidyl N,N-dzethylhydroqumhnocarboxylate maleatecarbamaze Example 22.1-methyl-3-pyrr0lidyl I-phenothiazino- Using the method of Example 1, the sodium salt of cwboxylate maleate 1-methyl-3-pyrrolidinol was mixed and reacted together Using the method of Example 1, the sodium salt of 1- with N,N-diethylcarbamyl chloride to produce l-methylmethyl-3-pyrrolidinol was mixed and reacted together 3-pyrrolidyl N,N-diethylcarbamate. with l-phenothiazinocarbonyl chloride to produce the Table III below lists the properties of the compounds of free base 1-methyl-3-pyrrolidyl l-phenothiazinocarboxyl- Examples 16-18. ate. The free base was subsequently reacted with maleic TABLE III Ex. M.P. C. (B.P. Empirical For- 0 Percent H Percent N Percent C./mrn.) mula (Mel. Wt.) Cald. Cald. Cald.
Found Found Found 16 167.5-168 C aH2 ClN20z [C'clld- 01, 14.98. Found 14.77] 17 112-114 CnHzaNzOs 57.23 7.92 7.36 (356.41) 57. 20 7.83 7. 35 18 (123/8I1'11I1.) .i CroHznNzOz Example 19.l-methyl-3-pyrr0lidyl indolinocarboxylaze maleate Using the method of Example 1, the sodium salt of 1- methyl-3-pyrrolidinol was mixed and reacted together with indolinocarbonyl chloride to form the free base of 1methyl-3-pyrrolidy1 indolino carboxylate. The free base was subsequently reacted with maleic acid to form 1- methyl-3-pyrrolidyl indolinocarboxylate malcate.
acid to form 1-methyl-3-pyrro1idyl l-phenothiazinocarboxylate maleate.
Example 23.-1-methyl-3-pyrr0lidyl 1-(2,6-di777ethylmorpholinokarboxylale Using the method of Example 1, the sodium salt of 1- 0 methyl-Lpyrrolidinol Was mixed and reacted together with 1-(2,6-dimethylmorpholino)carbonyl chloride to 1 Basic N.
13 produce l-methyl 3 pyrrolidyl 1-(2,6-dirnethylm0rpholino) carboxyl ate.
Table IV above lists the properties of the compounds of Examples 19-23.
Where the foregoing examples produce a compound having a methyl or other lower-alkyl group, it is to be understood that compounds containing other loWer-alkyl groups of straight or branched nature, such as methyl, eLhyl, propyl, isopropyl, butyl, sec.-butyl, t.-butyl, amyl, isoamyl, hexyl, heptyl, and octyl, are prepared in the same manner by substitution in the process of the appropriate different loWer-alkyl starting material. Likewise, where chloro or other halogen atom is present, although chlorine is preferred, further halogen compounds including iodo, bromo, chloro, and fluoro compounds are prepared starting from the appropriate halogenated starting material. Similarly, where methoxy or other loweralkoxy grou is present, compounds having other lower alkoxy groups containing various lower-alkyl groups having up to eight carbon atoms inclusive are prepared in the same manner from the appropriate different loweralkoxy starting material. Moreover, when one diloweralkylamino group, such as the dimethylamino group, is present in a compound, other dilower-alkylarnino compounds are prepared in the same manner starting only with the selected different dilower-alkylamin-ocompound. In the same manner, ortho and meta products are produced instead of the para by utilizing the selected ortho or meta substituted starting material. Similarly, other molecular changes within the scope of the invention are readily made.
The compounds of the invention are generally characterized by the pharmacological activity hereinbefore stated, making them useful in counteracting certain physiological abnormalities in a living animal body. Effective quantities of the pharmacologically active compounds of the invention may be administered to a living animal body in any one of various ways, for example, orally as in capsules or tablets, parenterally in the form of sterile solutions, suspensions, or by pellet implantation, and in some cases intravenously in the form of sterile solutions. Other modes of administration are cutaneous, subcutaneous, buccal, intramuscular, and intraperitoneal.
Pharmaceutical formulations are usually prepared from a predetermined quantity of one or more of the compounds of the invention, preferably in solid form. Such formulations may take the form of powders, elixirs, solutions, pills, capsules, pellets, or tablets, with or without, but preferably with, any one of a large variety of pharmaceutically acceptable vehicles or carriers. When in admixture with a pharmaceutical vehicle or carrier, the active ingredient usually comprises from about 0.01 to about75 percent, normally from about 0.05 to about 25 percent, by weight of the composition. Carriers such as starch, sugar, talc, commonly used synthetic and natural gums, water, and the like, may be used in such formulations. Binders such as gelatin, and lubricants such as sodium stearate, may be used to form tablets. Disintegrating agents such as sodium bicarbonate may also be included in tablets.
Although relatively small quantities of the active materials of the invention, even as low as 0.1 milligram, may be used in cases of administration to subjects having a relatively low body weight, unit dosages are usually five milligrams or above and preferably twenty-five, fifty, or one-hundred milligrams or even higher, depending of course upon the subject treated and the particular result desired. Usual broader ranges appear to be one to 200 milligrams per unit dose. The active agents of the invention may be combined for administration with other 'pharmacologically active agents, such as analgesics,
lid widely. It is only necessary that the active ingredient of the invention constitute an effective amount, i.e., such that a suitable effective dosage will be obtained consistent with the dosage form employed. Obviously, several unit dosage forms may be administered at about the same time. The exact individual dosages as well as daily dosages in a particular case will of course be determined according to Well-established principles under the direction of a physician or veterinarian.
Example 24.-F0rmulati0ns The following formulations are representative for all of the pharmacologically active compounds of the invention, but have been particularly designed to embody as the active ingredient 1-methyl-3-pyrrolidyl N-cyclopcntyl-N-phenylcarbamate in the form of an acid addition salt thereof, e.g., the maleate.
A. Capsules Capsules of 2.5 milligrams, 10 milligrams, 25 milligrams, and 50 milligrams of active ingredient per capsule were prepared. With the higher amounts of active ingredient, reduction may be made in the amount of lactose.
Per capsule, Blend for encapsulation: milligrams 1. 1 methyl 3 pyrrolidyl N-cyclopentyl-N- phenylcarbamate maleate 2.5 2. Lactose 299.2 3. Starch 129.0 4. Magnesium stearate 4.3
Total, milligrams 435.0
The active ingredient, the lactose, the starch, and the magnesium stearate are uniformly blended and encapsulated.
B. Tablets 1. A typical formulation for a tablet containing 5.0 milligrams of active ingredient per tablet follows. The formulation may be used for other strengths of active ingredient, in this case 1-methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate maleate, by adjustment of the weight of dicalcium phosphate.
Per tablet, Formulation for tablet: milligrams 1. 1 methyl 3 pyrrolidyl N-cyclopentyl-N- phenylcarbamate maleate 5.0 2. Corn starch 13.6 3. Corn starch (paste) 3.4 4. Lactose 79.2 5. Dicalcium phosphate 68.0 6. Calcium stearate 0.9
Total, milligrams 170.1
Uniformly blend 1, 2, 4, and 5. Prepare 3 as a ten percent paste in water. Granulate the blend with starch paste and pass the wet mass through an eight-mesh screen. The Wet granulation is dried and sized through a twelve-mesh screen. The dried granules are blended with the calcium stearate and compressed.
II. An additional tablet formulation containing a higher dosage of 1-methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate maleate is prepared a sfollows:
1.5 granules are-passed through an eightmesh screen and dried at 140 to 160 degrees Fahrenheit overnight. The dried granules are passed through a ten-mesh screen and blended with 5, and this blend is then converted into tablets using a suitable tablet press.
C. Injecfable 2.5 percent sterile solution Ingredients: Per cubic centimeter 1. 1-methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate maleate, milligrams 25 2. Preservative, e.g., chlorobutanol, percent weight/ volume 3. Water for injection, q.s.
Prepare solution, clarify by filtration, fill into vials, seal and autoclave.
It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds, compositions, or procedures shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.
I claim:
1. A compound selected from (a) those having the formula:
wherein R is a lower-alkyl radical having 1 to 4 carbon atoms inclusive, wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, wherein A is a radical selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive, and wherein A is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifiuoromethylphenyl, lowe'r-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, and halophenyl, and (b) pharmaceutical-ly acceptable acid addition salts thereof. 2. A pharmaceutically acceptable acid addition salt of a l-lower-alkyl-3-pyrrolidy1 N-lower-alkyl-N-arylcarbamate wherein the l-lower-alkyl group has 1 to 4 carbon atoms, inclusive, wherein the N-lower-alkyl group has 1 to 6 carbon atoms, inclusive, and wherein the aryl group is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifiuoromethylphenyl, lower-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, and halophenyl.
3. A pharmaceutically acceptable acid addition salt of a l-lower-alkyl-3-pyrrolidyl N-lower-cycloalkyl-N-arylcarbamate wherein the lower-alkyl group has 1 to 4 carbon atoms, inclusive, wherein the lower-cycloalkyl group has 3 to 9 carbon atoms, inclusive, and the aryl group is a monocarbocyclic aryl group having a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifluoromethylphenyl, lower-alkoxyphenyl, dilower-alkylaminophenyl, lower-alkylphenyl, and halophenyl. I
4. A 1-lower-alkyl-3-pyrrolidyl N-lower-alkyl-N-phenylcarbamate pharmaceutically acceptable acid addition salt wherein the l-lower-alkyl group has 1 to 4 carbon atoms, inclusive, and wherein the N-lower-alkyl group has 1 to 6 carbon atoms, inclusive.
5. A l-methyl-3- pyrrolidyl N-methyl-N-phenyloarbamate pharmaceutically acceptable acid addition salt.
6. A 1-methyl-3-pyrrolidyl N-(n-propyD-N-phenylcarbamate pharmaceutically acceptable acid addition salt.
16 7. 1 lower-alkyl-3-pyrrolidyl N-cycloalkyl-N-phenylcarbarnate wherein cycloalkyl has up to a maximum of nine carbon atoms and lower-alkyl has 1 to 4 carbon atoms, inclusive. 8. A l-lower-alkyl-3-pyrrolidyl Ncycl oalkyl-N-phenylcarbamate pharmaceutically acceptable acid addition 'salt wherein cycloalkyl has up to a maximum of nine carbon atoms and lower-alkyl has 1 to 4 carbon atoms, inclusive.
9. 1 methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate.
14 A 1-methyl-3-pyrrolidyl N-cyclopentyl-N-phenylcarbamate pharmaceutically acceptable acid addition salt.
11. A 1-methyl-3-pyrrolidyl N-cyclohexyl-N-phenylcarbamate pharmaceutically acceptable acid addition salt.
12. A 1-lower-alkyl-3-pyrrolidyl N-cycloalkyl-N-chlorophenyl-carbamate pharmaceutically acceptable acid addition salt wherein cycloalkyl has up to a maximum of nine carbon atoms and wherein lower-alkyl has 1 to 4 carbon atoms, inclusive.
13. A 1-methyl-3-pyrrolidyl N-cyclopentyl-N-(p-chlorophenyD-carbamate pharmaceutically acceptable acid addition salt.
14. A l-methyl-3-pyrrolidyl N-cyclohexyl-N-(p-chlorophenyl)-carbamate pharmaceutically acceptable acid addition salt.
15. A 1 lower-alkyl-3-pyrrolidyl N-cycloalkyl-N-trifluoromethylphenylcarbarnate pharmaceutically acceptable acid addition salt wherein cycloalkyl has up to a maximum of nine carbon atoms and wherein loweralkyl has 1 to 4 carbon atoms, inclusive.
16. A 1 methyl-3-pyrrolidyl N-cyclopentyl-N-(li-trifluoromethylphenyl)-carbamate pharmaceutically acceptable acid addition salt.
17. A 1 methyl-3-pyrrolidyl N-cyclohexyl-N-(S-trifiuoromethylphenyl)-carbamate pharmaceutically acceptable acid addition salt.
18. A compound selected from (a) those having the formula:
wherein R is a lower-alkyl radical having 1 to 4 carbon atoms, inclusive,
wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, and
wherein both A and A are selected from the group consisting of lower-alkyl having 1 to 6 carbon atoms,
17 inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive, and (b) pharmaceutically acceptable acid addition salts thereof, at least one of A and A being lower-cycloalkyl. 20. A compound selected from (a) those having the formula:
wherein R is a lower-alkyl radical having 1 to 4 carbon atoms, inclusive, wherein R is selected from the group consisting of methyl and hydrogen, a maximum of two R being methyl, and wherein forms a member having 4 to 12 carbon atoms, inclusive, selected from the group consisting of indolino, tetrahydroquinolino, phenothiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrolidino, piperidino, piperazino, and lower-alkylpiperazino, and (b) pharmaceutically acceptable acid addition salts thereof.
21. A compound selected from (a) those having the formula:
wherein R is selected from the group consisting of a lower-alkyl radical having 1 to 4 carbon atoms, inclusive, and pyridyl,
wherein R is selected from the group consisting of methy and hydrogen, a maximum of two R being methyl,
wherein A is selected from the group consisting of hydrogen, lower-alkyl having 1 to 6 carbon atoms, inclusive, and lower-cycloalkyl having 3 to 9 carbon atoms, inclusive, and
wherein A is selected from the group consisting of a monocarbocyclic aryl group containing a maximum of fifteen carbon atoms selected from the group consisting of phenyl, trifluoromethylphenyl, loweralkoxyphenyl, dilower alkylaminophenyl, loweralkylphenyl, halophenyl and naphthyl, and, when A is lower-cycloalkyl, lower-alkyl having 1-6 carbon atoms inclusive, and lower-cycloalkyl having 3-9 carbon atoms, inclusive,
and wherein A and A together with the nitrogen atom forms a member having 4-12 carbon atoms inclusive, selected from the group consisting of indolino, tetrahydroquinolino, phen othiazino, octahydroquinolino, morpholino, thiamorpholino, pyrrolidino, piperidino, piperazino, and lower-alkylpiperazino, and (b) pharmaceutically acceptable acid addition salts thereof.
References Cited Biel et al.: J. Am. Chem. Society, vol. 77, pp. 2250-55, 1955.
ALEX MAZEL, Primary Examiner.
J. TOVAR, Assistant Examiner.

Claims (2)

  1. 20. A COMPOUND SELECTED FROM (A) THOSE HAVING THE FORMULA:
  2. 21. A COMPOUND SELECTED FROM (A) THOSE HAVING THE FORMULA:
US431440A 1965-02-08 1965-02-09 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives Expired - Lifetime US3347856A (en)

Priority Applications (18)

Application Number Priority Date Filing Date Title
US431440A US3347856A (en) 1965-02-08 1965-02-09 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives
GB532/66A GB1128351A (en) 1965-02-08 1966-01-05 Substituted 3-pyrrolidyl carbamates
NL666600234A NL143917B (en) 1965-02-08 1966-01-07 PROCESS FOR PREPARING A MEDICINAL PRODUCT WITH ANTICHOLINERGIC AND ANTIDEPRESSIVE ACTION CONTAINING AS THE ACTIVE INGREDIENT A 1-METHYL-3-PYRROLIDINYLCARBAMATE.
GB3094/66A GB1136104A (en) 1965-02-08 1966-01-24 2--‡-piperidyl-1,3:dioxane derivatives
CH93866A CH467798A (en) 1965-02-08 1966-01-24 Process for the preparation of new 1,3-dioxane derivatives
CH102266A CH466282A (en) 1965-02-08 1966-01-26 Process for the preparation of new heterocyclic compounds
DE19661620184 DE1620184A1 (en) 1965-02-08 1966-02-01 Process for the preparation of new heterocyclic compounds
NL6601380A NL6601380A (en) 1965-02-08 1966-02-03
FR48657A FR1467524A (en) 1965-02-08 1966-02-07 New derivatives of dioxane-1, 3 and their preparation
BE676170D BE676170A (en) 1965-02-08 1966-02-07
LU50404A LU50404A1 (en) 1965-02-08 1966-02-07
MC607A MC586A1 (en) 1965-02-08 1966-02-07 New derivatives of dioxane 1.3 and their preparation
ES0322716A ES322716A1 (en) 1965-02-09 1966-02-07 Method for the production of an anticolinergic compound. (Machine-translation by Google Translate, not legally binding)
FR48862A FR5168M (en) 1965-02-08 1966-02-08
SE1603/66A SE312804B (en) 1965-02-08 1966-02-08
FR48863A FR1490497A (en) 1965-02-08 1966-02-08 Manufacturing process of novel naked, nu-disubstituted 1- (lower-alkyl) -3-pyrrolidyl carbamates and their addition salts
BE676256D BE676256A (en) 1965-02-08 1966-02-09
FR60388A FR5480M (en) 1965-02-08 1966-05-05

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US43115465A 1965-02-08 1965-02-08
US43143465A 1965-02-09 1965-02-09
US431440A US3347856A (en) 1965-02-08 1965-02-09 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives

Publications (1)

Publication Number Publication Date
US3347856A true US3347856A (en) 1967-10-17

Family

ID=27411711

Family Applications (1)

Application Number Title Priority Date Filing Date
US431440A Expired - Lifetime US3347856A (en) 1965-02-08 1965-02-09 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives

Country Status (10)

Country Link
US (1) US3347856A (en)
BE (2) BE676170A (en)
CH (2) CH467798A (en)
DE (1) DE1620184A1 (en)
FR (2) FR5168M (en)
GB (2) GB1128351A (en)
LU (1) LU50404A1 (en)
MC (1) MC586A1 (en)
NL (2) NL143917B (en)
SE (1) SE312804B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3976650A (en) * 1975-11-04 1976-08-24 Pfizer Inc. Process for preparing optically active 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid ester analgesics
US3978064A (en) * 1975-11-04 1976-08-31 Pfizer Inc. 3-Aminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid esters and intermediates leading thereto
US4013662A (en) * 1974-12-19 1977-03-22 Pfizer Inc. Alkyl and benzyl 6,7-dialkoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylates
WO1996008468A1 (en) * 1994-09-14 1996-03-21 H. Lundbeck A/S Carbamoyloxy amine compounds

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01230577A (en) * 1987-11-10 1989-09-14 Nippon Tokushu Noyaku Seizo Kk 3-substituted pyridine and fungicide and herbicide for agricultural and horticultural purposes
KR920702046A (en) * 1989-10-13 1992-08-12 원본미기재 Tape auto bonding

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
None *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4013662A (en) * 1974-12-19 1977-03-22 Pfizer Inc. Alkyl and benzyl 6,7-dialkoxy-2-methyl-4-oxo-1,2,3,4-tetrahydroquinoline-1-carboxylates
US3976650A (en) * 1975-11-04 1976-08-24 Pfizer Inc. Process for preparing optically active 6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid ester analgesics
US3978064A (en) * 1975-11-04 1976-08-31 Pfizer Inc. 3-Aminomethylene-6,7-dimethoxy-2-methyl-4-oxo-1,2,3,4-tetrahydro-1-quinoline carboxylic acid esters and intermediates leading thereto
WO1996008468A1 (en) * 1994-09-14 1996-03-21 H. Lundbeck A/S Carbamoyloxy amine compounds

Also Published As

Publication number Publication date
FR5480M (en) 1967-10-23
SE312804B (en) 1969-07-28
GB1136104A (en) 1968-12-11
LU50404A1 (en) 1966-08-08
CH466282A (en) 1968-12-15
FR5168M (en) 1967-06-19
NL6600234A (en) 1966-08-10
BE676256A (en) 1966-06-16
MC586A1 (en) 1966-11-02
BE676170A (en) 1966-08-08
CH467798A (en) 1969-01-31
DE1620184A1 (en) 1970-03-12
NL143917B (en) 1974-11-15
GB1128351A (en) 1968-09-25
NL6601380A (en) 1966-08-09

Similar Documents

Publication Publication Date Title
US3424760A (en) 3-ureidopyrrolidines
US3687965A (en) Novel 5-(n-substituted aminomethyl)-2-oxazolidinones and their process of preparation
US3029189A (en) S-aryl-z-mno-x-qxazolibinones
EP0536399B1 (en) Novel arylalkanoylamine derivative and drug containing the same
US3804849A (en) 2-amino-4,5,7,8-tetrahydro-6h-thiazolo or oxazolo(5,4-d)azepines and salts
US3732247A (en) 3-di-substituted methylene pyrrolidines wherein the 1-or n-lower-alkyl substituent contains at least two carbon atoms
US2862966A (en) archo
US3347856A (en) 1-lower-alkyl-3-pyrrolidyl nu-loweralkyl- and lower-cycloalkyl-nu-arylcarbamate antispasmodics and antidepressives
US4087428A (en) N-(1-substituted-3-pyrrolidinyl)-4-quinoline carboxamides
US3509171A (en) 3-amino-1-carbamyl and thiocarbamyl pyrrolidines
WO1985000811A1 (en) Novel 1-piperazinecarboxamide derivatives
DE2916140A1 (en) 1,3-DIPHENYL-2-IMINOIMIDAZOLIDINE AND 1,3-DIPHENYL-2-IMINOHEXAHYDROPYRIMIDINE, METHOD FOR THEIR MANUFACTURING AND DRUGS CONTAINING SUCH
CA1068707A (en) 4-piperidinylalkyl-3,3-diphenyl-2-pyrrolidinones
US4324791A (en) Heterocyclic antidiarrheal compositions & methods of use
US3499002A (en) 1-carbamoyl-3-aroylpyrrolidines
US4254135A (en) 3-Amino-4-hydroxypyrrolidines
US4638009A (en) Derivatives of 3-pyrrolidinopropiophenone and a process for preparation thereof
US2978454A (en) Lower alkyl-4-phenyl-1-[(diloweralkoxy phenyl)-aliphatic] piperidine-4-carboxylates
US3337539A (en) Tetraethoxy-1, 2, 3, 4-tetrahydroisoquinoline derivatives and salts thereof
US3228835A (en) Method and compositions for combating depression and spasm
US3419555A (en) 2-aryl-tetrahydropyran-3-amines
US3133924A (en) Amino-substituted cyclobutane carboxamides
US3586675A (en) Fused thiazines
US3320252A (en) Certain cycloalkyl benzylamines
GB1564091A (en) M-acyloxanilates and compositions containing them