CIS-N-(2-AMINOCYCLOALIPHATIC)BENZENE ACETAMIDE AND -BENZAMIDE ANTICONVULSANTS

Abstract: Certain cis-N-(2-amino-cycloaliphatic)benzeneacetamide and -benzamides of formula (I), where m is 0 or 1, n is 1 or 2, R is hydrogen or alkyl, R1 and R2 are separately alkyl, or, taken together with the nitrogen denote a pyrrolidine ring, and X and Y are hydrogen, fluorine, chlorine or bromine or one of X and Y is trifluoromethyl, e.g., cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide and salts thereof, have been found to have CNS seizure blocking or preventing drug action, e.g., anti-convulsant drug properties with little or no analgesic properties. Some of these compounds are new.

Description: CIS-N- (2-AKIN0CYCL0ALIPHATIC)BENZENE ACETAMIDE AND -BENZAMIDE ANTICONVULSANTS INTRODUCTION This invention relates to the use of certain N-(2-amino cycloa phatic)benzeneacetamide and -benzamide compovinds as Central Nerv System (CNS) anti-seizure, e.g. , anti-convulsant, drugs in valua warm-blooded animals, including humans. BACKGROUND OF THE INVENTION Szmuszkovicz U.S. Patent No. 4,098,904 discloses some N-(2-ami cycloaliphatic)benzamide compounds, e.g., N-methyl-N- [2-(l-pyrro dinyl)cyclohexyl]-3,4-dichlorobenzamide, and N-methyl-N- [2-(N' , dimethylamino)cyclohexyl]-4-bromobenzamide, and salts and hydra thereof as analgesic (pain reducing) drug compounds. Szmuszkovicz U.S. Patent No. 4,145,435 discloses some 2-ami cycloaliphatic alkanoyl amide compounds, e.g., N-methyl-N- [2-(N' , dimethylamino)-cyclohexyl]-2-(4-bromophenyl)acetamide and trans-2-(3 dichlorophenyl-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]acetamide, their pharmaceutically acceptable salts as analgesic compounds. In contrast to the disclosure in those Szmuszkovicz '904 and ' patents, the compounds of this invention have little or no signific analgesic activity (ED 50 >50) , but have been found to possess sig ficant CNS seizure preventing or blocking activity in standard lab atory animal tests. In Neuroscience Abstracts. 10. page 408 (October, 1984), F.C.To ella et al report the Seizure-specific, Dose- And Time- Depend Anti-convulsant Profile of Upjohn Compound, Trans-(±)-3,4-dichlo N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzeneacetamide by electroshock test method. This compound is described and claimed the above Szmuszkovicz '435 patent; however, as indicated hereinabo this compound is an analgesically active compound. Recent pharmacology articles that may be of interest as backgro are: J. Med. Chem.. 1984, 27, 779-782, "Anticonvulsant ... 4-Aminobe a ides" by C. Randall Clark et al, Science. 226. 16 November 1984, pp. 850-852, "Blockade ... Aga Ischemic Damage in the Brain" by R. P. Simon et al, and Neuropharmacology. 23, No. 3, pp. 367-371 (1984), "The A convulsant ... Electroshock Seizures in Rats" by E. F. Berman et although these references are not conceded to be prior art to invention described and claimed herein. OBJECTS OF THE INVENTION It Is an object of this invention to provide a new use for som (2-aminocycloaliphatic)benzeneacetamide and -benzamide compounds, of which are new, which have been found to have significant CNS seiz preventing and blocking activity, while having only minimal, if analgesic activity. It is a further object of this invention to provide a method preventing or blockin CNS seizures in warm-ilooded valuable ani patients, including humans with certain N-(2-aminocycloaliphati benzeneacetamides and -benzamides. Another object of the invention is to provide pharmaceutical c positions useful in dosage unit form for administration to valu warm-blooded animal patients, including humans, for prevention blocking of CNS seizures in such patients. Other objects, aspects and advantages of the invention will apparent from reading the remaining specification and the claims wh follow. SUMMARY OF THE INVENTION Briefly, this invention provides the new use of a group of cis [(2-aminocycloaliphatic)benzeneacetamide and -benzamide compounds, general formula I, and their pharmaceutically acceptable salts, w compounds have been discovered to have significant CNS seizure-prev ing activity, while also showing only minimal or non-signific analgesic activity, in standard laboratory animal tests. This invention also includes pharmaceutical compositions c taining these compounds and a method for treating warm-blooded ani patients, including humans, with these compositions to prevent or bl CNS seizures of various types in such patients. DETAILED DESCRIPTION OF THE INVENTION The group of compounds described herein have been found to effective anti-convulsant drug agents in standard animal tests. The compounds have been shown to be effective antagonists of electrosho seizures in mice. They will be useful in the treatment of grand m and other seizure disorders in man as well as in commercially importa and pet:animals. These compounds are active in the CNS electroshock animal test b they did not at similar dosage ranges block chemically induced (pe tylenetetrazol or bicucullin) seizures in the test animals suggesti that these compounds have a CNS anti-seizure utility similar to that the known drug phenytoin (THE MERCK INDEX. 10th. Edition, page 105 item 7204). Phenytoin is useful in the treatment of grand mal, fo and psychomotor seizures-(see Goodman and Gilman, The Pharmacologic Basis of Therapeutics). However, phenytoin and structurally rela anti-convulsant drugs are known to cause a number of side effe including hyperplasia of the gums, cerebellar degeneration, gast distress and serious skin rashes. In contrast, the compounds of this invention, while be anti-seizure drugs, e.g., anti-convulsant drugs, at reasonable dosag have little or no significant analgesic activity, and it is also ho that these cis-compounds will not show some of the other above-lis side effects as well. The anti-convulsant potency of these cis-ami amide compovinds in standard laboratory animal tests indicate that th compounds will be useful for preventing or treating CNS seizure d orders in warm-blooded animals such as cats, dogs, horses, as well humans at dosage ranges of approximately 0.1 to 100 mg./kg. of b weight/day via the oral or parenteral routes until the seizure thr or attack subsides. The compounds of this invention, of formula I in the GENE FORMULAS hereinbelow, are cis-N- [(2-aminocycloaliphatic)benze acetamide and -benzamide compounds where the two large filled cir positions in the ring are intended to depict the cis orientation of two nitrogen groups relative to each other and the ring, n is 1 or 2, to indicate a cyclopentyl or cyclohexyl ring; m is 0 or 1, to indicate that the compounds are benzeneacetamid (with the -CH 2 -) or benzamides (without the -CH 2 -), R is hydrogen or C x to C 3 -alkyl, e.g., methyl, ethyl, isopropyl n-propyl, preferably methyl, when R is C 1 to C 3 -alkyl, χ and j taken separately, are Independently C χ to C 3 -alkyl, defined above, or R χ and Rm can be taken together with the nitrogen to which th are bonded to complete a pyrrolidine ring, X and Y are each hydrogen, a halogen having an atomic number from 9 to 35, that is, fluorine, chlorine or bromine, trifluoromethy preferably chlorine, in the 3- and the 4-position or bromine in the position, or tri-fluoromethyl in the 4-position, and when X and Y are each hydrogen, R is preferably hydrogen, m is 0, n 1 or -2, and R χ and j are each C t to C 3 -alkyl, preferably methyl, or pharmaceutically acceptable salt thereof. Acid addition salts of these amino-amides (I) can be prepared reacting a Formula I free base with a stoichiometric amount of an aci such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfur acid, phosphoric acid, acetic acid, lactic acid, citric acid, succin acid, benzoic acid, salicyclic acid, pamoic acid, cyclohexanesulfam acid, methanesulfonic, naphthalenesulfonic, p-toluenesulfonic, malei fumaric, oxalic acids and the like. The reaction can be carried out aqueous or organic liquid solvent non-aqueous media such as dieth ether, ethyl acetate, and the like. Non-aqueous media are preferred. On occasion the compounds (I) or their acid addition salts their crystalline state are isolated as solvates, e.g., with a discre quantity of solvent, e.g., water, methanol, and the like, associat physically, and thus not affecting the chemical entity per se. This invention also relates to compositions containing a Formula compound as an active ingredient in a pharmaceutical carrier. The co positions are useful in pharmaceutical dosage unit forms of the Formu I compounds for systemic administration (oral, rectal and parenter (including intravenous, intramuscular and intra-arterial) administr tion form) for treating warm-blooded animal patients, cats, dog horses and other commercially valviable animals, and human patien suspected of being susceptible to or to stop CNS seizures, such convulsions, grand mal, petit mal and other seizure disorders. T term "dosage unit form" as used in this specification and in the clai refers to physically discrete units suitable as unitary dosages f mammalian subjects, each unit containing a predetermined quantity the essential active Ingredient compound of this invention calculat to. produce the desired effect in combination with the required pharm ceutical means which adapt the said ingredient for topical or system administration. The specifications for the novel dosage unit forms this invention are indicated by and directly dependent on the physic characteristics of the essential active ingredient and the particul effect to be achieved in view of the limitations inherent in the art compounding such an essential active material for beneficial effects humans and animals. Examples of suitable dosage unit forms in accor ance with this invention are tablets, capsules, orally administer liquid preparations in suitable liquid vehicles, sterile preparatio in suitable liquid vehicles for intramuscular and intravenous admini tration, suppositories, and sterile dry preparations for the extempo aneous preparation of sterile injectable preparations in a suitab liquid vehicle. Suitable solid diluents or carriers for the solid o pharmaceutical dosage unit forms are selected from the group consist of lipids, carbohydrates, proteins and mineral solids, for examp starch, sucrose, lactose, kaolin, dicalcium phosphate, gelatin, acac corn syrup, corn starch, talc and the like. Capsules both hard soft are filled with composition of these amino amide ingredients combination with suitable diluents and excipients, for example, edi oils, talc, calcium carbonate and the like and also calcium steara Liquid preparations for oral administration are prepared in water aqueous vehicles which advantageously contain suspending agents, example, methylcellulose, acacia, polyvinylpyrrolidone, polyvi alcohol and the like. In the case of injectable forms, the injecta formulation must be sterile and must be fluid to the extent that e syringeability exists. Such preparations must be stable under conditions of manufacture and storage, and ordinarily contain addition to the basic solvent or suspending liquid, preservatives the nature of bacteriostatic and fungistatic agents, for exampl parabens, chlorobutanol, benzyl alcohol, phenol, thimerosal, and t like. In many cases it is preferable to include osmotically acti agents, for example, sugars or sodium chloride in isotonic conce trations. Carriers and vehicles include vegetable oils, ethano polyols, for example, glycerol, propylene glycol, liquid polyethyle glycol, and the; like. Any solid preparations for subsequent exte poraneous preparation of sterile injectable preparations are ster lized, preferably by exposure to a sterilizing gas, for exampl ethylene oxide. The aforesaid carriers, vehicles, diluents, exci ients, preservatives, isotonic agents and the like constitute t pharmaceutical means which adapt the preparations for system administration. The pharmaceutical dosage unit forms are prepared in accordan with the preceding general description to provide from about 1.0 about 700 mg. of the essential active ingredient per dosage unit for which as aforesaid may be in the form of a solid, semi-solid, topica oral, or rectal preparation, a liquid oral preparation, an injectab preparation, including liquid preparations and solid dry preparatio f°r extemporaneous reconstitution to a liquid injectable preparatio The amount of the essential active ingredient provided in the pharm ceutical dosage unit forms is that amount sufficient to obtain reduction in the CNS seizure effects and a return to more normal C stability, or to prevent the occurrence of CNS seizures in a patie who is suspected to be subject to such seizure. Expressed otherwise amount of the essential active ingredient is provided to a recipie within a range from about 0.1 mg. per kg. to about 100 mg. per kg. body weight of the recipient. Preferred dosages for most applicatio are 1.0 to 10.0 mg. per kg. of body weight. The useful pharmaceutical dosage unit forms of these compounds pharmaceutical formulations is preferably adapted for systemic admini tration to obtain anti-convulsant effects comprising an effective, no toxic amount of a compound according to Formula I or as Its pharmac logically acceptable salt. Further the invention relates to methods obtaining such CNS anti-seizure effects in mammals, for example, huma and valuable warm-blooded animals such as dogs, cats, horses and ot commercially valuable animals, by administering systemically to mammals the aforesaid pharmaceutical dosage unit forms supplying effective, nontoxic amount for anticonvulsant effects. These specific cis-amino-amide compounds have an advantage, t greater or lesser extent, depending upon the particular compound having significant CNS antiseizure properties, while having little no significant analgesic activity (analgesic ED 50 >50 in the writhing test) . This combination of properties should prove benefic and advantageous where the doctor would prefer to treat the patient the single CNS seizure disorder without need to worry about any sig ficant analgesic side effects. The cis-amino-amide compounds involved in this invention can made by procedures described in the Szmuszkovicz U.S. Patents 4,098, and 4.145.435.. supra, using the cis-l,2-diamines referred to in th two patents, and the appropriate acylating form of the selected b zeneacetic acid, or -acetyl halide, or the selected benzoic ac benzoyl halide, as described generally therein. Described hereinbe are procedures used to prepare the compounds described and exemplif herein. SCHEME I and II attached hereto, show a typical procedure preparing the compounds involved In this invention. Scheme I outlines in general chemical symbol form a process preparing cis-diamine starting materials, which can be used to make cis-2-amIno-cycloaliphatic-benzeneacetamide and -benzamide compoun which are used according to the invention described herein. In general, the alkyl cycloalkanone carboxylate ester start material (II), which can be, e.g., the pure methyl, ethyl or pro esters or the commercially available mixed esters, and the selec HN J ^ J amine, e.g., pyrrolidine, dimethy1amine, diethylamine, di propylamine, di-ispropylamine, or a mixed amine such as N-methyl ethylamine, are mixed and reacted in a selected solvent such benzene, toluene, heptane, or the like, while heating under ref conditions to remove water by-product from the reaction mixture to f the respective alkyl 2-aminocycloalk-l-enylcarboxylate ester (II Alternatively, the alkyl 2-amino-cycloalk-l-enylcarboxylate ester (I can be prepared from a 1-cycloalkenylamine (IV) and a carboxylat agen . The resulting 2-aminocycloalk-l-enylcarboxylate ester (III) then be reduced, e.g., by hydrogenating the reaction mixture contain the ester (III) in the presence of a hydrogenation catalyst such platinum oxide to form the saturated cis 2-aminocycloaliphatic es (V). The cis- saturated ring amino-ester (V) can then be treated w hydrazine in the presence of an appropriate solvent, such as a C- ^ C -alkanol, under reflux conditions to form the cis-amino-hydraz (VI). The hydrazide (VI) can be subjected to a nitrosation-Curt rearrangement reaction to form the cis-2-aminocycloalkyl primary am (VII) which can be used directly to make end product compounds structure I herein where R is hydrogen. For compounds where R is to be a C χ to C 3 -alkyl, the cis-2-ami cycloalkylamine VII is further acylated with an alkyl formate (to f an R equals methyl compound, or with an acetyl halide or propio - halide, e.g., acetyl chloride or propionyl chloride, in the presence a tertiary amine hydrogen halide scavenger to form the cis-N-(2-ami cycloalkyl) z to C 3 -alkanoylamide (VIII), where R g is hydrogen or to C 2 -alkyl. This resulting amino-amide (VIII) can then be subjec to carbonyl group reduction, e.g., with lithium aluminum hydride, convert the R j -CζO)- group on the nitrogen in the 1-position of cycloalkyl ring to the defined R equals C χ to C 3 -alkyl group, and form cis-diamine (IX). Scheme II describes in chemical symbol form an amine nitro acylation process that can be used to make the cis N-[2-(aminocycloa phatic)-N-benzeneacetamide (m - 1) and -benzamide (m - 0) compou which can then be recovered from their reaction mixtures, and u according to this invention or converted to appropriate acid addit salt form for recovery from Its reaction mixture, and then re-form if desired or necessary, into an appropriate, pharmaceutica acceptable acid addition salt form for compounding into appropri marketing and dosage unit forms. Here, in Scheme II the cis-cycloaliphatic diamine (IX) can acylated, by known procedures, e.g., by reaction with a benzeneacet halide or benzoyl halide (X) , in the presence of a tertiary ami hydrogen halide scavenger, such as triethylamine or N-N-dimethylanili to form the N-[2-(aminocycloalkyl)-N-(H- or alkyl)benzeneacetamine o benzamide. These latter compounds can then be processed as indicat herein to put the compounds In pharmaceutically acceptable usef form. Preparation CIS-2-PYRROLIDINYLCYCLOHEXYLAMINE This preparation exemplifies how cis-l,2-cyclohexanedIamines we prepared, for use in preparing the cis-amino-amide compounds which a involved in the invention described and claimed herein. A. Ethyl cis-2-pyrrolidinylcyclohexanecarboxylate A solution of 164-.4 g. (1.0 mole) ethyl 2-cyclohexano carboxylate [also named ethyl 2-oxocyclohexanoate] , which al contained about 40 percent of the corresponding methyl ester, and 71 g. (1.0 mole) of pyrrolidine in 700 ml. of benzene was reflux overnight with azeotropic distillation of water therefrom (18 ml. H collected) to form the ethyl and methyl 2-(l-pyrrolidinyl)- cyclohexen-1-ylcarboxylate mixed ester. Then 10 g. of platinum oxi was added to this resulting reaction mixture, and the mixture w hydrogenated at 30 psig. until uptake of hydrogen ceased. About 0. mole of hydrogen was consumed. The resulting hydrogenated reacti mixture contained the cis-ethyl and methyl mixed 2-(1-pyrrolidiny cyclohexanecarboxylate esters. This reaction mixture was filte through a filter aid (CELITE ® ) to remove the platinum catal residue. The filtered liquid was then extracted with 200 ml. of hydrochloric acid. The resulting aqueous layer was washed with eth made basic with 15 percent sodium hydroxide and again extracted w ether. The original organic layer and the ether wash were combined one organic layer and washed with saturated sodium chloride in wa solution, dried (MgS0 4 ) and evaporated to remove solvents. Dist lation of the residue gave the cis-2-(1-pyrrolidinyl)-cyclohexa carboxylate, mixed methyl and ethyl esters, 143.5 g. (70 percent yie b.p. 95 β -105*C./0.5 mm. (Hg.). This cis-.amino-cyclohexanecarboxylate mixed ester material w used in the next step of the process without further purification. B. Cis-2-Pyrrolidinylcyclohexanecarboxhydrazide, and i hydrochloride. A solution of 143.5 g. (0.65 mole) of the named amino-mixed est material from Part A hereinabove and 162.5 g. (3.25 moles) of hydrazi hydrate; in 1300 ml. of absolute ethanol was stirred at room temperatu for 2 -hours, and then refluxed for 72 hours to form the 2-(1-pyrrol dinyϊ)cyclohexanecarboxhydrazide. The solvent was largely removed evaporation. The residue was diluted with 1500 ml. of methyle chloride, washed twice with 150 ml. portions of saturated aqueo sodium chloride solution, dried (MgS0 4 ) and evaporated to remove mo of the methylene chloride. The 2-(l-pyrrolidinyl)cyclohexanecarboxhydrazide hydrochlori salt was prepared by treatment of this hydrazide residue with hydrog chloride in ether solution and was recrystallized from a methanol/eth solvent mixture to give the cis-2-(l-pyrrolidinyl)cyclohexanecarbo hydrazide hydrochloride, 126.8 g. , (69 percent yield), m.p. 222 224*C. The UV, mass spectrum, IR and NMR spectra were consistent wi this named compound. Anal. Calcd. for C-^H^^O- 2HC1: % Calcd: C, 46.48; H, 8.16; N, 14.78; Cl, 24.95 Found : C, 45.49; H, 8.22; N, 15.20; Cl, 25.50 C. Cis-2-(l-Pyrrolidinyl)cyclohexaneamine To a solution of 53.4 g. (0.188 mole) of the 2-( pyrrolidinyl)cyclohexanecarboxhydrazide hydrochloride in 100 ml. water, prepared as in Part B hereinabove with ice cooling there w added 14.3 g. (0.207 mole) of sodium nitrite in 25 ml. of water over minutes, while stirring. After 30 minutes 30 ml. of 12N hydrochlor acid was added to the reaction mixture and the solution was slow heated to 70°C. on a water bath, when evolution of nitrogen by-produ had nearly ceased, the solution was heated on a steam bath for 1 hou The resulting solution was cooled, made basic with 15 percent sodi hydroxide solution, and extracted with ether. The ether extract w dried (MgS0 4 ) and evaporated to remove solvent. Distillation of t residue gave 25.7 g. (81 percent yield) of the diamine, cis-2-( pyrrolidinyl)cyclohexaneamine, b.p. 120"-123 β C./14 mm. (Hg.). The U IR, NMR and Mass spectra were consistent with this named compound. Anal. Calcd. for C 10 H 20 N 2 : % Calcd.: C, 71.37; H, 11.98; N, 16.65 Found : C, 71.05; H, 11.91; N, 16.49 D. N-Meth l-Cis-2-(l-Pγrrolidinyl)cyclohexylamine A solution of 20.0 g. (0.119 mole) of the cis-2-(1-pyrrolidinyl cyclohexaneamine, from Part C hereinabove in 250 ml. of ethyl forma solvent was refluxed overnight. The solution was evaporated to remo solvent and leave a crude amide intermediate as a colorless o product. The crude product was dissolved in 100 ml. of tetrahydrofur (THF) and added dropwise in one hour to a suspension of 20.0 g. lithium aluminum hydride in 1000 ml. of ether. The mixture w refluxed for 6 hours and then kept overnight at room temperature. T mixture was cooled in ice and . excess lithium aluminum hydride w decomposed by adding 20 ml. of water, 20 ml. of 15 percent sodi hydroxide aqueous solution and 60 ml. of water. The mixture w filtered and the filtered by-product aluminum salt solids were wash with ether. The filtrate and ether washings were dried (MgSO^) a evaporated to remove solvents. Distillation of the residue gave 16 g. (76 percent yield) of the cis-N-methyl-N-[2-(l-pyrrolidinyl)cycl hexaneamine, b.p. 120'-122 β C./14 mm. (Hg.). The UV, IR, NMR and Ma Spectra were consistent with this named compound. Anal. Calcd. for C χι H 22 N 2 : % Calcd: C, 72,46; H, 12.17; N, 15.37 Found : C, 72.64; H, 12.73; N, 15.42 Example 1 Cis-N- [2-(N' ,N' -dimethylamino)cyclohexyl]benzamide To a mixture of 1.42 -g. (0.01 mole) of cis-[2-(dimethy amino) ]cyclohexyla ine (prepared as described in U.S. Pate No. 4,098,904 starting at column 21, line 67) and 1.01 g. (0.01 mol of triethylamine in 100 ml. of diethyl-ether there was added 1. g. (0.01 mole) of benzoyl chloride in 25 ml. of ether over 30 minu with ice cooling of the reaction vessel. The reaction mixture stirred overnight at room temperature. Then, 100 ml. of a satura sodium bicarbonate In water solution was added to the result reaction mixture. The aqueous layer was separated from the orga liquid layer. The organic liquid layer was then washed with br (saturated aqueous sodium chloride), separated from the aqueous br 5. layers: and dried using anhydrous magnesium sulfate and then evapora to v remove solvent and to leave a yellow oil residue, which resi becamei solid on standing, and which weighed 2.43 g. (99 percent, cr yield) of the cis-N- [2-(dimethylamino)-cyclohexyl]-N-benzami a.p. 73 β= -76'C. 0 Th hydrochloride salt of this cis-N-[2-(dimethyLamino)cyc hexyl]benzamide was made by dissolving this amino-amide compound excess hydrogen chloride in ether solution, and then evaporat solvent therefrom to crystallize the hydrochloride salt therefr This amino-amide hydrochloride salt was recrystallized from a mixt 5 of 10 ml. of methanol and about 40 ml. of ether to obtain 2.13 g. percent yield) of the cis-N-[2-(dimethylamino)cyclohexyl]benzam hydrochloride, m.p. 247"-248°C. The elemental analysis for this amino-amide salt was: Anal. Calcd. for C 15 H 22 N 2 0-HC1(282.81) 0 % Calcd.: C, 63.70; H, 8.20; N, 9.91; Cl, 12.54 Found : C, 63.90; H, 8.53; N, 9.92; Cl, 12.69 The Nuclear Magnetic Resonance (NMR) Spectrum (D 2 0) was consist for this named product. The Infrared (IR) spectrum was a consistent. The Ultraviolet (UV) light spectrum showed (ethyl alcoh 5 end absorption 227 (11,650); 226 sh (846), 269 (769). The M S.pectrum showed a main ion of M* " 246. Following procedures known in the art or as described hereinab the following additional examples of these cis-amino-amide compou were prepared: 0 Example 2. Cis-3,4-dichloro-N- [2-(l-pyrrolidinyl)cyclopentyl]benzami and its 4-methylbenzenesulfonate salt, as its monohydrate M.P. Anal. Calcd. for C 16 H 20 Cl 2 N 2 O- C 7 H 8 S0 3 -H 2 0 215 β -216 β C. % Calcd.: C, 55.08; H, 6.03; N, 5.59; Cl, 14. (methanol/ether) S, 6.40 5 % Found : C, 55.08; H, 5.69; N, 5.63; Cl, 14.3 S, 6.53 Example 3_ Cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolldinyl)cyclopentyl] benzamide, and its monohydrochloride salt M.P. Anal. Calcd. for C 17 H 22 C1 2 N 2 0 245 β -247 β C. % Calcd.: C, 54.05; H, 6.14; N, 7.42; Cl, 28.16 (methanol/ether) % Found : C, 54.20; H, 6.08; N, 7.41; Cl, 28.31 Example 4 Cis-3,4-dichloro-N-[2-(l-pyrrolidinyl)cyclopentyl]"benzen ace amide M P. Anal. Calcd. for C 17 H 22 C1 2 N 2 0 106 β C. % Calcd.: C, 59.82; H. 6.50; N, 8.21; Cl, 20.78 (ether) % Found : C, 59.94; H, 6.51; N, 8.21; Cl, 20.66 Example 5 Cis - 3 , 4-dichloro-N-methyl-N- [2- (l pyrrolidinyl)cyclohexyl]benzeneacetamide M.P. Anal. Calcd. for C 19 H 2 6C1 2 N 2 0 None (oil) % Calcd.: C, 61.78; H, 7.10; N, 7.59; Cl, 19.20 % Found : C, 61.39; H, 7.15; N, 7.55; Cl, 18.51 Example 6. Cis-3,4-dichloro-N-[2-(l-pyrrolldinyl)cyclohexyl benzamide, and its hydrochloride salt M.P. Anal. Calcd. for C 17 H 22 C1 2 N 2 0-HC1 HC1 265 β -267*C. % Calcd.: C, 54.05; H, 6.14; N, 7.42; Cl, 28.16 (methanol/ether) % Found : C, 54.36; H, 6.30; N, 7.41; Cl, 28.16 Example 1_ Cis-3,4-dichloro-N-methyl-N- [2-(1-pyrrolidinyl cyclohexyljbenzamide and its monohydrochloride M.P. Anal. Calcd. for C 18 H 24 C1 2 N 2 0-HC1 229 β C. (methanol/ether) % Calcd.: C, 55.18; N, 6.43; N, 7.18; Cl, 27.15 % Found : C, 55.43; H, 6150; N, 7.18, Cl, 27.49 Examp le 8_ Cis-3, 4-dichloro-N-[ (dimethylamino)cyclohexyl]benzeneacetamide M.P. Anal. Calcd. for C 16 H 22 C1 2 N 2 0 lll'-112 β C. % Calcd.: C, 58.36; H, 6.74; N, 8.51; Cl, 21.54 (ether) % Found : C, 58.70; H, 6.75; N, 8.51; Cl, 21.39 Example 9 , Cis-3, 4-dichloro-N- [2- (dimethylamino)cyclohexyl]benzamid and its monohydrochloride M.P. Anal. Calcd. for C 15 H 20 C1 2 N 2 0-HC1 231 β -232'C. (mathanol/ether) % Calcd.: C, 51.22; H, 6.02; N, 7.97; Cl, 30.24 % Found : C, 51.59; H, 6.15; N, 7.84; Cl, 30.09 Example 10 Cis-3, 4-dichloro-N-methyl-N- [2-(dimethylamino)cyclohexyl rjϋβnzeneacetamide and its p-toluenesulfonate salt M.P. Anal. Calcd. for C 17 H 24 C1 2 N 2 0- C 7 H 8 S0 3 175 β -176 β C. % Calcd.: C, 55.91; H, 6.26; N, 5.44; Cl, 13.76; (methanol/ether) S, 6.22 % Calcd.: C, 55.89; H, 6.42; N, 5.69; Cl, 13.81, S, 6.51 Example 11 Cis -4..- (trif luoromethyl) - {2-(dimethylamino)cyclohexyl]benzamide, and its monohydrochloride M.P. Anal. Calcd. for C 16 H 21 N 2 F 3 0-HC1 183 β -184 β C. % Calcd.: C, 54.77; H, 6.32; N, 7.99; F, 16.25; (methanol/ether) Cl, 10.11 % Found : C, 54.57; H, 6.43; N, 7.94; Cl, 10.08, F, 16.37 Example 12 Cis-3,4-dichloro-N- [2-(l-pyrrolidinyl)cyclohexyl]benzen aceta ide M.P. Anal. Calcd. for C 18 H 24 C1N 2 0 133 β -I34 β C. % Calcd.: C, 60.79; H. 6,68; N, 7.89; Cl, 19.96 % Found : C, 60.79; H, 6.68; N. 7.89; Cl, 20.18 Example 13 Anticonvulsant Use Test Results - Electroshock Test This example exemplifies anticonvulsant activity properties representative compounds of this invention in a standard laborato animal electroshock test. Male CF-1 mice were injected subcutaneously with the te compound, and after the compound was absorbed, the test mice we subjected to maximal transpinnal electroshock (10mA, 0.2 sec. Protection from Central Nervous System (CNS) seizure by the te compound was judged by the absence of the tonic extensor convulsio Each test drug substance or compound was formulated into 0.25 perce w/v aqueous methylcellulose solution and administered at a volume do of 10 ml. per kilogr-am of body weight. A group of six mice was treat and tested at each dose level, and decreasing doses (0.3 log interval were administered to such groups of mice until response activity w 5. low enough so that ED 50 dose calculations within 95 percent confiden intervals could be established. Most of these exemplified compoun lack any significant analgesic activity (ED 50 greater than 50 standard HC1 writing analgesic test) . TABLE 1 0 ELECTROSHOCK TEST RESULTS (ED 50 , subcutaneous route, mg./kg.) (95 percent, Confidence Ind Range) Example No. Compound Electroshock (ED 50 . mg. kg.) 3 -. 32 5 4 " 50 6 18 7 13 (9-17) 8 50 (31-81) 9 31 10 40 11 25 (17-30) 12 62 Example 14 One thousand tablets for oral use, each containing 175 mg. of ci 3,4-dichloro-N-methyl-N- [2-(l-pyrrolidinyl)cyclohexyl]benzamide hydr chloride as the essential active ingredient are prepared from t following ingredients: Essential active ingredient: 175 gm. Methylcellulose, U.S.P. (15 cps.) - 6.5 gm. Talc - 20 gm. Calcium Stearate - 2.0 gm. The essential active ingredient and dicalcium phosphate are mi well, granulated with 7.5% aqueous solution of methylcellulose, pass through a No. 8 screen and dried carefully. The dried granules passed through No. 12 screen, mixed with the talc and stearate and c pressed into tablets. These tablets are useful in the treatment adult humans at a dose of 1 tablet to 4 times a day as needed prevent convulsions. Example 15 5. One thousand two-piece hard gelatin capsules for oral use, e capsule containing 100 mgs. of cis-3,4-dichloro-N-methyl-N-[2-(l-p rolidlnyl)eyelohexyl]benzamide hydrochloride as the essential acti ϋϊgradient are prepared from the following ingredients: Essential active ingredient - 100 gm. 0 Lactose, U.S.P. - 100 gm. Starch, U.S.P. - 10 gm. Talc, U.S.P. - 5 gm. Calcium Stearate - 1 gm. -The finely powdered materials are mixed thoroughly, then fil 5 into hard gelatin capsules of appropriate size. One capsule four times a day is useful for the treatment of ad humans to block the occurrence of CNS convulsive seizures. Example 16 A sterile aqueous suspension suitable for intramuscular inject 0 an containing in each milliliter 50 mg. of the Example 16 essent active ingredient is prepared from the following ingredients: Essential active ingredient - 5 gm. Polyethylene glycol 4000, U.S.P. - 3 gm. Sodium chloride - 0.9 gm. 5 Polysorbate 80, U.S.P. - 0.4 gm. Sodium metabisulfite - 0.1 gm. Meth lparaben, U.S.P. - 0.18 gm. Propylparaben, U.S.P. - 0.02 gm. Water for injection, q.s. to - 100 ml. 0 The preceding sterile injectable is useful in the treatment of convulsions in adult humans at a dose of 1/2 to 2 ml. 5 GENERAL FORMULAS 15 20 25 30 35 SCHEME I SCHEME I ~ CONTINUED From VII amine acylation SCHEME II tertiary amine

Claims: CLAIMS 1. A method for preventing or treating Central Nervous Syste seizures in a warm-blooded animal patient which comprises administerin to- such patient suffering from seizures or likely to experienc seizures an amount of a compound of the formula where the dotted line bonds between the ring and the two nitroge denotes the cis orientation, n is 1 or 2; m is 0 or 1; R is hydrogen or C 1 to C 3 -alkyl, K- i and R j taken separately, are each independently or C 1 to C 3 alkyl, R t and R j , taken together with the nitrogen to which they a bonded complete a pyrrolidine ring, X and Y are each selected from the group consisting of hydrog and a halogen having an atomic number of from 9 to 35, or X is hydrog and Y is trifluoromethyl, or a pharmaceutically acceptable salt thereof, which amou is effective to prevent or reduce the effects of such CNS seizu disorder in said patient. 2. A method as defined in Claim 1 wherein the CNS seizure preventi or treating compound I is a compound selected from the group consisti of (a) cis-N-[2-(dimethylamino)cyclohexyl]benzamide, -22- (b) cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclopent benz amide , (c) cis -3, 4 -dichloro -N-methyl-N- [2- (l-pyrrolidinyl)cyclohex benzeneacetamide , (d) cis-3, 4-dichloro-N- [2-(l-pyrrolidinyl)cyclohexyl]benzamid (e) cis- 3, 4 -dichloro- N-methyl-N- [2- (l-pyrrolidinyl)cyclohex benzamide , (f) cis-3,4-dichloro-N- [2- (dimethylamino) eye lohexyl] benze acetamide , (g) cis-3, 4-dichlororN-[2-(dimethylamino)cyclohexyl]benzamide, (h) cis -4- trif luoromethyl-N- [2- (dime th lamino)cyclohexy benzamide , and (i) cis-3 ,4-dichloro-N- [2- (l-pyrrolidinyl)cyclohexyl]benze acet amide , or a pharmacologically acceptable salt of such a compound. 3. A method as defined in Claim 2 wherein the CNS seizure -preven or treating compound administered to said patient is a compo selected from the group consisting of cis-3,4-dichloro-N-methyl-N- (l-pyrrolidinyl)cyclohexyl]benzamide, and cis-3, 4-dichloro-N-[2-(l-pyrrolidinyl)cyclohexyl]benzamide, o pharmaceutically acceptable salt thereof. 4. A method as defined in Claim 3 wherein the CNS seizure -preven or treating compound is cis-3,4-dichloro-N-[2-(l-pyrrolidinyl)cy hexyl-pyrrolidinyl)cyclohexyl]benzamide hydrochloride . 5. A method as defined in Claim 3 wherein the CNS seizure-preven or blocking compound is cis-3, 4-dichloro-N-methyl-N- [2-l(pyrrolidin cyclohexyl] benzamide hydrochloride. 6. A compound selected from the group consisting of cis-3 , 4-di-chloro-N- [2- (1 -pyrrol idinyl) cyclopentyl] b zeneacetamide , cis-3 ,4-dichloro -N-methyl-N- [2- (l-pyrrolidinyl)cyclope pentyl ] benzamide , cis-3, 4-dichloro-N- [2- (l-pyrrolidinyl)cyclohexyl]benz amide and cis -3, 4 -dichloro -N-meth l-N- [2- (l-pyrrolidinyl)cyclohexyl benzamide, or a pharmaceutically acceptable salt thereof. 7 " . A compound according to Claim 6 which is cis -3, 4- dichloro -N- [2- pyrrolidinyl)cyclopentyl]benzeneacetamide, or a pharmaceutica acceptable salt thereof. 8. A compound according to Claim 6 which is cis-3, 4-dichloro methyl-N- [2-(l-pyrrolidinyl)cyclopenty]benzamide, or a pharmaceutica acceptable salt thereof. 9. A compound according to Claim 6 which is cis-3,4-dichloro-N- [2- pyrrolidinyl)cyclohexyl]benzamide, or a pharmaceutically accepta salt thereof. 10. A compound according to Claim 6 which is cis-3,4-dichloro methyl-N-[2-(l-pyrrolidinyl)cyclohexyl]benzamide, or a pharmaceutica acceptable salt thereof. 11. A composition for preventing or treating Central Nervous Sys seizures in a warm-blooded animal patient which comprises a compound the formula where the dotted line bonds between the ring and the two nitrog denotes the cis orientation, n is 1 or 2; m is 0 or 1; R is hydrogen or C χ to C 3 -alkyl, R χ and R j taken separately, are each independently or C χ C 3 -alkyl, R χ and R j , taken together with the nitrogen to which they bonded complete a pyrrolidine ring, X and Y are each selected from the group consisting of hydro and a halogen having an atomic number of from 9 to 35, or X is hydro and Y is trifluoromethyl, or a pharmaceutically acceptable salt thereof as an act ingredient. 12. A composition as defined in Claim 11 wherein the CNS seiz preventing or treating compound I is a compound selected from the gr consisting of (a) cis-N-[2-(dimethylamino)cyclohexyl]benzamide, (b) cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclopenty benzamide, (c) cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexy benzeneacetamide, (d) cis-3,4-dichloro-N-[2-(1-pyrrolidinyl)cyclohexyl]benzamide (e) cis-3,4-dichloro-N-methyl-N-[2-(l-pyrrolidinyl)cyclohexyl benzamide, (f) cis-3, 4-dichloro-N- [2- (dimethylamino)cyclohexyl]benzen ace amide, (g) cis-3, 4-dichloro-N-[2-(dimethylamino)cyclohexyl]benzamide, (h) cis -4- trif luor.omethyl-N- [2- (dime thy lamino) eye lohexyl benzamide , and (i) cis-3 , 4-dichloro-N- [2- (1-pyrrolidinyl) cyclohexyl] benze acetamide, or a pharmacologically acceptable salt of such a compound. 13. A composition as defined in Claim 12 wherein the CNS seizu preventing or treating compound administered to said patient is compound selected from the group consisting of cis-3 ,4-dichloro- methyl-N- [2-(l-pyrrolidinyl)cyclohexyl]benzamide, and cis-3,4-dIchloro-N-[2-(l-pyrrolidinyl)cyclohexyl]benzamide, or pharmaceutically acceptable salt thereof. 14. A composition as defined in Claim 13 wherein the CNS seizu preventing or treating compound is cis-3, 4-dichloro-N-[2- pyrrolidinyl)cyclohexyl]benzamide hydrochloride . 15. A composition as defined in Claim 13 wherein the CNS seizu preventing or blocking compound is cis-3, 4-dichloro-N-methyl-N- [2- pyrrolidinyl) cyclohexyl ]benz.amide hydrochloride.

Inventors: SZMUSZKOVICZ JACOB, VON VOIGTLANDER PHILIP F, SZMUSZKOVICZ, JACOB, VON VOIGTLANDER, PHILIP, F.
Applicants: UPJOHN CO, THE UPJOHN COMPANY
Application year: 1986
Main classification: A61K31
IPC codes: A61K31, C07D295