GB1560218A - N - phenyl-n - (2-aminocyclopentyl)amides - Google Patents

Abstract

Novel N-(2-aminocyclopentyl)-N-alkanoyl anilides and 2-N-oxides thereof of the formula: <IMAGE> in which the substituents are defined in Claims 1 and 10, are prepared. These compounds are obtained by acylating N-(2-aminocyclopentyl)aniline on the nitrogen atom either with an anhydride of an organic carboxylic acid of the formula R-COOH or with a R-C (O)-chloride or R-C (O)-bromide. The corresponding N-oxides are prepared from these acylated compounds by oxidation with a percarbonic acid. The novel compounds which are obtained can be used as antidepressants.

Description

(54) N-PH ENYL-N-(2)-AMINOCYCLOPENTYL)AMIDES (71) We, THE UPJOHN COMPANY, a corporation organized and existing under the laws of the State of Delaware, Unitd States of America, of 301 Henrietta Street, Kalamazoo, State of Michigan, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- W.G. Still et al., in Helvetica Chemica Acta, Vol. 34, (1951), pp. 1937 to 1943, disclose N-[2-(dimethylamino)cyclohexyl]aniline and procedures for making it from N-(2-hydroxycyclohexyl)aniline and suggest that the compounds therein have antihistamine pharmacological properties.

J.W. Lewis et al., in an article entitled "The Reactions of Aromatic Nitrosocompounds with Enamines. Part 1. The Reaction of Nitrosobenzene with 1 Morpholin-l-cyclohexene" in J. Chem. Soc. (London) (1972), Perkins Transactions 1, Part III, pp. 2521-2524, disclose inter alia N-(2-morpholin-l- ylcyclohexyl)phenylhydroxylamine and its hydrochloride salt.

J.W. Lewis et al., in an article entitled "Chemistry and Biological Activity of N-Substituted Hydroxylamines" in J. Pharmaceutical Sciences, December, 1974, Vol. 63, No. 12, pp. 1951-1953, disclose some N-arylhydroxylamines such as N-[2 (N-pyrrolidinyl)cyclohexyl]-N-phenylhydroxylamine but these do not have useful CNS properties. Diuretic activity is alleged therein for the alcohols such as [2-(N piperidinylcyclohexyl]-(4-methoxyphenyl)methanol and, when the alcohol is acetylated, CNS depressant activity is said to appear. It also discloses the reaction of propionyl chloride with N-[2-(N-piperidinyl)-l, 1-dimethylethyl]-N phenylhydroxylamine to form the N-chloro compound which is then converted to a mixture of chlorinated aniline derivatives.

U.S. Patent Specification No. 3,510,492 discloses and claims some 2-anilinoand 2-anilinomethylcycloalkylamines which are useful as antidiabetic drugs in that they can be administered in low dosages for reducing blood sugar. However, in column 2 of that patent specification structure IV suggests some N-phenyl-N-(2aminocyclopentyl)amides as chemical intermediates en route to the 2anilinocycloalkyl amines, but it does not suggest any practical utility for those structure IV compounds.

The relevant compounds of U.S. Patent Specification No. 3,510,492 are of the formula

wherein R is C1~3alkyl; either R1 is C,~3alkyl and R2 is C1~3alkyl or benzyl or NR1R2 is pyrrolidinyl or piperidinyl; and Y and Z are the same or different and are each hydrogen, methyl, ethyl, methoxy, ethoxy, fluorine, chlorine, bromine or trifluoromethyl. Surprisingly, we have now discovered that such compounds, provided that (1) Z is hydrogen when Y is trifluoromethyl, (2) when Z is hydrogen and Y is methoxy or ethoxy, Y is at the m-position of the phenyl ring and (3) when Y and Z are both halogen, methoxy and/or ethoxy, neither substituent is present at the o-position of the phenyl ring, and their pharmacologically acceptable salts, have activity on the central nervous system, e.g. as anti-depressants. Accordingly this invention provides pharmaceutical compositions comprising such compounds and salts in association with a pharmaceutically acceptable carrier which is a solid or a sterile liquid. Further, this invention provides certain novel compounds within the scope of Formula I viz.

N-(trnns-2-dimethylaminocyclopentyl)-3',4'-dichloropropionanilide or a pharmacologically acceptable salt, e.g. the maleate thereof; and also N-(cis-2-dimethylaminocyclopentyl)-3' ,4'-dichloropropionanilide; N-(2-dimethylaminocyclopentyl)-3',4'-dibromopropionanilide; N-(2-dimethylaminocyclopentyl)-3'-methoxypropionanilide; N-(2-pyrrolidinylcyclopentyl)-3' ,4'-dichloropropionanilide; N-(2-dimethylaminocyclopentyl)-3'-chloro-4'-methylpropionanilide; N-(2-dipropylaminocyclopentyl)-3',4'-dichloropropionanilide; N-(2-dimethylaminocyclopentyl)propionanilide; N-(2-dimethylaminocyclopentyl)-3'-methylpropionanilide; N-(2-dimethylaminocyclopentyl)-3'-chloropropionanilide; N-(2-dimethylaminocyclopentyl)-3'-fluoropropionanilide; N-(2-dimethylaminocyclopentyl)-3'-bromopropionanilide; N-(2-dimethylaminocyclopentyl)-4'-bromopropionanilide; N-(2-dimethylaminocyclopentyl)-3',5'-dichloropropionanilide N-(2-dimethylaminocyclopentyl)-3'-tnfluoromethylpropionanilide; N-(2-dimethylaminocyclopentyl)-3'-methyl-4'-chloropropionanilide; N-(2-diethylaminocyclopentyl)-3 ',4'-dichloropropionanilide; N-(2-dimethylaminocyclopentyl)-3'-chloro-4'-fluoropropionanilide; N-(2-dimethylaminocyclopentyl)-3 ',4'-dimethylpropionanilide; N-(2-dimethylaminocyclopentyl)-3',4'-dichlorobutyranilide; and N-(2-dimethylaminocyclopentyl)-3' ,4'-dichloroisobutyranilide, and the pharmacologically acceptable salts thereof.

The active compounds of Formula I, and in particular the novel compounds of this invention, can give fast onset of their anti-depressant characteristics. The preferred compounds have, in addition, lower toxicity than a standard antidepressant drug, imipramine, in standard laboratory tests, and longer duration of activity of the test compound in the test animal. These characteristics make such compounds useful as anti-depressant drugs in smaller amounts and/or for longer durations between administration, e.g. once a day, for a given desired antidepressant response.

The compounds of this invention, including their salts, may be isolated as solvates in their crystalline state, i.e. with a discrete quantity of a solvent, e.g. water or methanol, physically associated therewith. The solvent is removable without effective alteration of the chemical entity per se and these solvates are included in the novel compounds herein.

For use in this invention, the compounds of Formula I are preferably in the 1,2-trans configuration. R is preferably ethyl.

One preferred group of compounds for use in this invention are those of Formula I wherein R is ethyl; R1 and R2 are each C13alkyl; and at least one of Y and Z is halogen, preferably in the 3- or 4-position, 3-trifluoromethyl (if Y is trifluoromethyl then Z is hydrogen) or methyl in the 3- or 4-position in combination with one of the above halogens at the adjacent 3- or 4-position, and the pharmacologically acceptable salts thereof. Examples of such compounds include the following: 3 ',4'-dichloro-N- [2-(dimethylamino)cyclopentyllpropionanilide; 3'-trifluoromethyl-N- [2-(dimethylamino)cyclopentyl]propionanilide, 31,4'-dichloro-N-[2-(diethylamino)cyclopentylipropionanilide, 3'-chloro-4'-methyl-N- [2-(dimethylamino)cyclopentyl]propionanilide 4'-chloro-3 '-methyl-N-[2-(dimethylamino)cyclopentyl] propionanilide, 3 '-chloro-N-[2-(dimethylamino)cyclopentyl]propionanilide, 4'-chloro-N-[2-(dimethylamino)cyclopentyl]propionanilide, 3 '-bromo-N-[2-(dimethylamino)cyclopentyl]propionanilide, and 3 '-fluoro-N- [2-dimethylamino)cyclopentyl]propionanilide, especially these compounds in the trans configurations, and the pharmacologically acceptable salts thereof.

Another preferred sub-group of the above compounds are those wherein NR,R2 is N-pyrrolidinyl or N-piperidinyl and at least one of Y and Z is halogen in the 3- and/or 4-positions. Examples of such compounds include: 3 '-fluoro-N- [2-(N-pyrrolidinyl)cyclopentyl]propionanilide, 3',4'-dichloro-N-[2-(N-piperidinyl)cyclopentyl]propionanilide - 3 '-bromo-N- L2-(N-pyrrolidinyl)cyclopentyl] propionanilide 4'-chloro-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, 3',4'-dichloro-N- [2-(N-pyrrolidinyl)cyclopentyl]propionanilide, 3',4'-difluoro-N- [2-(N-pyrrolidinyl)cyclopentyl]propionanilide, and 3',4'-dibromo-N-[2-(N-pyrrolidinyl)cyclopentyllpropionanilide, especially these compounds in their trans configuration and the pharmacologically acceptable salts thereof.

Examples of pharemacologically acceptable salts of the above formula I compounds include those of hydrochloric, methanesulfonic, hydrobromic, sulfuric, acetic, cyclohexanesulfamic, p-toluenesulfonic, succinic, p-naphthalene- sulfonic, maleic, tumaric, citric, lactic and oxalic acid.

To use these compounds of formula I in pharmaceutical anti-depressant drug products form they are compounded or formulated into usual pharmaceutical compositions, e.g., oral dosage forms such as tablets, powders, capsules and solutions or suspensions in a suitable solvent or suspending vehicle, and parenteral dosage forms such as dry powder in a sterile sealed container to be mixed with a sterile solvent just prior to administration, sterile solutions or suspensions in water or other suitable solvents or suspending agents, to provide a convenient means for administering daily doses of from I to 100 mg., preferably 10 to 90 mg., of the formula I compound or its pharmacologically acceptable salt, depending upon the potency of the formula I compound, the condition being treated, the weight of the patient and other factors of concern to the patient's physician.

The formula I compounds can be prepared by (a) heating a mixture of a compound of the formula

wherein R1, R2, Y and Z are as defined above, and an anhydride of the appropriate C24alkanecarboxylic acid of the formula R-COOH on a steam bath, or at an equivalent temperature, for a time sufficient to form the N-acylated product of formula I where R is as defined above, (b) adding an aqueous medium to the step (a) reaction mixture in an amount sufficient to decompose excess anhydride therein, (c) adding an alkali metal hydroxide or its equivalent to the step (b) reaction mixture in an amount sufficient to neutralize excess acid present therein and to make the mixture pH basic. (d) extracting the N-acylated product (I) into a water immiscible organic liquid solvent, e.g. as ether such as diethyl ether, tetrahydrofuran or dioxane, or chloroform, carbon tetrachloride, methylene chloride or ethylene dichloride, (e) separating the organic liquid phase containing the N-acylated product (I) from the aqueous phase, and (f) recovering the corresponding N-acylated compound (I) from the organic liquid phase, usually after washing the organic liquid phase one or more times with aqueous media such as sodium chloride solution, sodium bicarbonate solution or water to extract components soluble in those aqueous media, separating the aqueous phases, drying the washed organic phase with drying agents such as magnesium sulfate or sodium or calcium sulfate, and then evaporating off the organic solvent. Further purification can be done by forming an acid addition salt of the N-acylated amide product (I) and then recrystallizing the amide salt from an appropriate solvent or mixture of solvents.

The formula I compounds, can also be prepared by (a) adding a solution of a carboxylic acid halide of the formula R-COX where R is as defined above and X is chlorine or bromine to a cooled (-5" to +lO0C.) mixture of the diamine (II), and a tertiary amine which will form a tertiary amine chloride or bromide salt in the mixture, e.g., a (C,~4alkyl)amine, e.g., trimethylamine, triethylamine or tributylamine, or pyridine, lutidine or N,N-dimethylaniline, in an organic liquid solvent for the mixture e.g. an ether such as diethyl ether, THF or dioxane, while agitating the mixture until the corresponding N-acylated compound (I) is formed.

(b) adding an aqueous alkali metal bicarbonate solution to the reaction mixture of step (a), (c) separating the aqueous from the organic liquid phases, (d) washing the organic liquid phases with aqueous wash liquids as described above, (e) drying the organic phase, and (f) recovering the N-acylated compound (I) from the resulting organic liquid mixture. The N-acylated amide compound (I) can be further purified by formation of an acid addition salt thereof, e.g., the hydrochloric acid, or maleic acid addition salt thereof, and re-crystallization of the amide salt from an appropriate solvent or solvent mixture.

The trans-diamine starting materials (II) of the formula

wherein R1,R2, Y and Z are as defined above can be prepared by reacting 1,2cyclopentene oxide with the selected HNR,R2 amine in water to form the trans2-aminocyclopentanol of the formula IIIb

which amino-alcohol (IIIb) is treated with sodium hydride and then with methanesulfonyl chloride to form unrecovered mesylate of the formula IV

wherein Ms denotes CH3SO2-group and that reaction mixture is treated with the selected substituted aniline of formula V

to form the diamine (II).

It is of interest that the reaction of thionyl chloride with a cyclohexane-2aminoalcohol proceeds smoothly to give a cyclohexane-2-aminohalide which, on reaction with a selected amine, gives a cyclohexane-l,2-diamine. In the case of cyclopentane compounds, the reaction of thionyl chloride with the aminoalcohol, followed by reaction with the amine results in only a small yield of the desired cyclopentane diamine. The use of methanesulfonyl chloride, as indicated above, forms a good leaving group (mesylate) and gives respectable yields of the desired intermediate.

Examples of the carboxylic acid anhydrides which can be used to prepare the compounds of formula I include acetic anhydride, propionic anhydride, isobutanoic anhydride and n-butanoic anhydride. The preferred anhydride is propionic acid anhydride. The carboxylic acid halides are exemplified by acetyl chloride or bromide, propionyl chloride or bromide and n- and isobutanoylchloride or bromide.

Preparation of cis compounds of the invention: The method of J.W. Lewis et al., J. Pharm. Sci., 63, 1951 (1974) using 1dialkylaminocyclopentene (enamine) and a nitrosoaryl as starting materials can be used to obtain cis-l,2-diaminocyclopentane which is subsequently reacted with carboxylic acid anhydride or carboxylic acid halide as described above to give the product amino-amide.

A preferred method for use in preparing compounds of formula I involves reaction of cyclopentene oxide with an aniline in the presence of strong acid to give the compound of formula

which is subsequently reacted with carboxylic acid anhydride followed by reaction with base to isolate the alcohol of formula

Such alcohols are described and claimed in Application No. 46749/77 (Serial No. 1,560,217). Oxidation of the alcohol gives the corresponding ketone which, when reacted with a primary or secondary amine and a reducing agent such as sodium cyanoborohydride, gives a compound of formula I.

Examples of additional useful compounds of formula I including the following, preferably in their trans-configuration: N-(2-dimethylaminocyclopentyl)acetanilide, N-(2-dimethylaminocyclopentyl)butyranilide, 3'-trifluoromethyl-N-[2-(N-methy-N-benzylamino)cyclopentyllpropionanilide, 4'-bromo-3'-methyl-N-[2-(N-pyrrolidinyl)cyclopentyl]propionanilide, 3 '-bromo-N- [2-(N-methyl-N-benzylamino)cyclopentyl] butyranilide, 3 '-methyl-4'-chloro-N-[2-diethylaminocyclopentyl]propionanilide, and 3 '-ethoxy-4'-bromo-N-[2-dimethylaminocyclopentyl]propionanilide.

If desired, the formula I compounds can be resolved into their respective dand I-optical isomers by at least two known methods. In either case, known resolving agents can be used. Known resolving agents include optically active camphorsulfonic acid, bis-p-toluoyltartaric acid, tartaric acid and diacetyl tartaric acid, all of which are commercially available and which are commonly used for resolution of amines (bases) as, for example, in Organic Syntheses, Coll. Vol. V., p.

932 (1973), for the resolution of R < +) and S-(-)-a-phenylethylamine with (+tartaric acid.

By the first method for resolving the compounds of formula I, for example, one of the amino amide compounds can be converted into its optically active diastereoisomeric salts by reaction with an optically active acidexamples of which are mentioned above-in a manner standard in the isomer resolution art. These diastereoisomeric salts can then be separated by conventional means such as differential crystallization. Diastereoisomeric salts have different crystallization properties, which are taken advantage of in this separation. On neutralization each diastereoisomeric salt with aqueous base the corresponding optically active of the free amino-amide can be obtained, each of which can subsequently and separately be converted as previously described in the examples to the desired acid addition salt.

By the second method, which in the case of some of these compounds is preferred, the formula I compound can be made into their respective d- and 1isomers, by first resolving cis- or trans-i 2-cycloaliphatic unsymmetrically substituted diamine into its respective d- and isomers by treatment with the resolving agent, crystallization, separation, and regeneration of the respective irans-d-diamine, trans-l-diamine, or the cis-d-diamine and cis-l-diamine, and then reacting the respective resolved diamine starting material with the desired carboxylic acid anhydride or halide to form the respective cis- or trans-d- or 1compound of formula I, which can then be converted to any desired pharmaceutically acceptable acid addition salt by procedures exemplified above.

If the acid addition salt used to extract the formula I compound from its reaction mixture is not itself pharmacologically acceptable, the free amino-amide base (I) can be prepared from the acid salt, and thereafter converted to a pharmacologically acceptable salt, by known procedures.

In the use of these compounds of formula I as anti-depressant drugs the selected compound of formula I is mixed with suitable pharmaceutical diluents to obtain pharmaceutical compositions suited for oral, parenteral and rectal use as e.g., tablets, powder packets, cashets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories or bougies. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, corn starch, stearic acid and methylcellulose may be used as carriers or for coating purposes. Water and oils, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil, peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added. The specifications for the dosage unit forms of these formula I compounds will vary somewhat from compound to compound and will depend upon the physical characteristics of the formula I compound or its pharmacologically acceptable salt, the particular patient's weight and age, and the particular elect sougnt to be acnlevea. lne pnarmaceutlcal dosage unit forms of these compounds are prepared in accordance with the preceding general description to provide from 1 to 100 mg. of the formula I compound or its pharmacologically acceptable salt per dosage unit. The formula I compound will be prescribed in an amount sufficient to obtain in the patient a relief from the condition of depression at a non-toxic dosage level.

The following detailed procedures and examples further describe and illustrate how to make and use the starting amines and the compounds of formula I. All temperatures are in degrees Centigrade unless otherwise indicated. For brevity, the term THF means tetrahydrofuran, NMR means nuclear magnetic resonance spectrum, IR means infrared spectrum, UV means ultraviolet spectrum, ether means diethyl ether, NaOH means sodium hydroxide, MgSO4 means anhydrous magnesium sulfate, and MeOH means methanol, Preparation 1. trans-2-Dimethylaminocyclopentanol A mixture of cyclopentene oxide (188 g., 2.24 moles) and aqueous dimethylamine (40%, 750 ml., 6.67 moles) is stirred overnight (temperature rises to 45" after 1 hr. then subsides). The solution (750 ml.) is extracted several times with ether. The extract is dried (anhydrous MgSO4) and concentrated by distillation.

The residual oil is vacuum distilled to give 276 g. (90%) of trans-2-dimethylaminocyclopentanol, b.p. 98--1000/14 mm; uv (EtOH): end absorption; IR: OH 3370, 3200, N-alkyl 2780, C--O 1045 cm-'; mass spectrum: M+ 129; nmr (CDCl3): a var (br, lH exchanges with D2O, OH), 3.94.3 (m, 1H, CH), 2.3-2.6 (m, 1H, CH), 2.28 (s, 6H, N(CH3)2), 1.2-2.0 (m, 6H ring hydrogens). The analysis (fumaric acid salt) is given in Table I.

Table I which follows summarizes the physical analytical data for some 2aminocyclopentanols which were prepared. The particular 2-amino group for each such compound is indicated by the indicated group in theNR,R2 column. All samples for melting point data were recrystallized from methanol-ether. In the given formulae, C4H4O4 indicates fumaric acid and C7H7SO3H indicates p-toluenesulfonic acid, being the acids of the salt form in which the compound was isolated. All the compounds have NMR, IR, UV and mass spectra consistent with the indicated structures.

TABLE 1 trans-2-aminocyclopentanols

Starting Analysis Materials Number NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found A N(CH3)CH2CH3 102-4/13 mm 94-96 C8H17NO.C4H4O4 C, 55.58; C, 55.92; H, 8.16; H, 8.17; N, 5.40 N, 5.54 B N(CH2CH3)2 107-8/14 mm 134-5 C9H19NO.C4H4O4 C, 57.12; C, 57.20; H, 8.48; H, 8.54; N, 5.13 N, 5.10 C pyrrolidinyl 130-1/14 mm 115-6 C9H17NO.C7H7SO3H C, 58.67; C, 58.99; H, 7.70; H, 8.05; N, 4.29; N, 4.19 S, 9.79 S, 10.07 D N(CH3)CH2C6H5 134-40/0.3 mm 95-7 C13H19NO.C4H4O4 C, 63.53; C, 63.45; H, 7.21; H, 7.31; N, 4.36; N, 4.32 E N(CH3)2 98/12 mm 149-51 C7H15NO.C4H4O4 C, 57.73; C, 57.35; H, 9.15; H, 9.03 N, 7.48 N, 7.11 Preparation 2. trans-N,N-dimethyl-N'-(3',4'-dichlorophenyl)-1,2-cyclopentanediamine A solution of trans-2-(dimethylamino)cyclopentanol (32.3 g., 0.25 mole) in THF (50 ml.) is added in one portion to a stirred suspension of sodium hydride (10.5 g., 57% dispersion in mineral oil, 0.25 mole) in THF (50 ml.), and the mixture refluxed for 1 hr. The mixture is cooled in ice while methanesulfonyl chloride (28.6 g., 0.25 mole) is added dropwise over 30 min. 3,4-Dichloroaniline (81.0 g., 0.50 mole) is added in one portion when the methanesulfonyl chloride addition is complete. The solvent is removed by distillation, and the residue heated on a steam bath overnight. Sodium hydroxide (200 ml., 20%) is added and heating continued for I hr. The mixture is extracted with ether. The organic phase is washed with water and extracted with 10% hydrochloric acid. The aqueous phase is washed with ether, made basic with 40% sodium hydroxide, and extracted with ether. The ether layer is washed with saturated sodiuim chloride solution, dried (anhydrous MgSO4) and evaporated. The residual oil is distilled at reduced pressure to give, after a forerun consisting mainly of 3,4-dichloroaniline (65.7 g.), 36.2 g. (53%), 3,4dichloro-N-[2-(dimethylamino)cyclopentyl]aniline, bp 160-70 /0.3 mm. The distillate is further purified by formation of the maleic acid salt and recrystallization from methanol-ether; mp 128--29"; uv (EtOH): Amax (e) 210 (45,450), 257 (19,400), 310 (2300) nm; IR:NH 3380, NH/acid OH 2600, 2520, 2400, CO2/C=C/NH def 1600, 1580, 1480, C-H/C-N/CO2- 1430, 1350, 1330, other 985, 870, 865 cm-1; mass spectrum: M+ 272, 274 (free base); nmr (D2O): # 7.1 (m, 1H, aromatic), 6.7 (m, 1H, aromatic), 6.5 (m, 1H, aromatic), 6.1 (s, 2H, vinyl, maleic acid), 3.8 (m, 1H, CH), 3.35 (m, 1H, CH), 2.75 (s, 6H, N(CH3)2), 1.2-2.3 (m, 6H, ring hydrogens).

Anal. Calcd. for C,3H,8CI2N2-C4H404: Calcd. : C, 52.45; H, 5.70; Cl, 18.22; N, 7.20.

Found C, 52.48; H, 5.80; Cl, 18.41; N, 7.07.

Other trans- 1 ,2-diaminocyclopentanes which have been prepared are listed in Table II. All were recrystallized from methanol-ether except for G and N (both from petroleum ether) and A (none). S was isolated by silica gel chromatography.

The form of the salt which was isolated (where appropriate) is given but it should be noted that C4H4O4 indicates maleic acid for E, F, H, J, K, L, M, R and U and fumaric acid for T. All the compounds have NMR, IR, UV and mass spectra consistent with the indicated structures.

TABLE II trans-1,2-diaminocyclopentanes

Analysis No. Y/Z -NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found A H N(CH3)2 97-103/0.05 mm 31-2 C13H20N2 C, 76.42; C, 76.42; H, 9.87; H, 9.89; N, 13.71 N, 13.61 B 2-CH3 N(CH3)2 120-5/0.1 mm 180-1 C14H22N2.2HCl C, 57.73 C, 58.51 H, 8.31; H, 8.48; Cl, 24.35; C, 23.19; N, 9.62 N, 10.11 C 3-CH3 N(CH3)2 120-5/0.1 mm 188 C14H22N2.2HCl C, 57.73; C, 57.96 H, 8.31; H, 8.26; Cl, 24.35; Cl, 24.14; N, 9.62 N, 9.88 D 4-CH3 N(CH3)2 125-35/0.1 mm 198-200 C14H22N2.2HCl C, 57.73; C, 58.04 H, 8.31; H, 8.40; Cl, 24.35; Cl, 24.06; N, 9.62 N, 9.80 E 2-Cl N(CH3)2 125-35/0.1 mm 93-5 C13H19ClN2-C4H4O4 C, 57.74; C, 57.41; H, 6.53; H, 6.51; Cl, 9.99; Cl, 9.84; N, 7.90 N, 7.56 TABLE II (Continued)

Analysis No. Y/Z NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found F 3-Cl N(CH3)2 140-4/0.2 mm 125-7 C13H19ClN2-C4H4O4 C, 57,74; C, 57.40; H, 6.53; H, 6.60; Cl, 9.11; Cl, 9.80; N, 7.90 N, 8.00 G 4-Cl N(CH3)2 140-5/0.2 mm 41-2 C13H19ClN2 C, 65.39; C, 65.63; H, 8.02; H, 7.99; Cl, 14.85; Cl, 14.81; N, 11.74 N, 11.88 H 3-OCH3 N(CH3)2 125-32/0.01 mm 77-8 C14H22N2O.C4H4O4 C, 61.69; C, 61.69; H, 7.48; H, 7.40; N, 8.00 N, 7.93 J 4-OCH3 N(CH3)2 140-50/0.3 mm 85-7 C14H22N2O.C4H4O4 C, 61.69; C, 61.71; H, 7.48; H, 7.47; N, 8.00 N, 7.98 K 3-F N(CH3)2 115-18/0.3 mm 137-8 C13H19N2F.C4H4O4 C, 60.34; C, 60.38; H, <S TABLE II (Continued)

Analysis No. Y/Z NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found M 3-Br N(CH3)2 140-4/0.3 mm 114-15 C13H19BrN2-C4H4O4 C, 51.13; C, 51.54; H, 5.81; H, 5.97; N, 7.02; N, 19.74; Br, 20.02 Br, 7.02 N 4-Br N(CH3)2 130-7/0.1 mm 44-5 C13H19BrN2 C, 55.13; C, 55.08; H, 6.76; H, 6.84; Br, 28,22; Br, 28.43; N, 9.89; N, 9.54 P 4-CH2CH3 N(CH3)2 125-30/0.2 mm 125-7 C13H24N2.C10H8SO3.H2O C, 65.47; C, 65.87; H, 7.47; H, 7.52; N, 6.11; N, 6.06; S, 6.99 S; 7.14 R 3,4-diCl N(CH3)2 155-60/0.3 mm 128-9 C13H18Cl2N2.C4H4O4 C, 52.45; C; 52.48; H, 5,70; H, 5.80; Cl, 18.22; Cl, 18.41; N, 7.20 N, 7.07 S 3,5-diCl N(CH3)2 147-9 C13H18Cl2N2.2HCl C, 45.11; C, 45.13; H, 5.82; H, 5.72; Cl, 40.97; Cl, 40.46; N, 8.09 N, 7.97 T 3,4-diCH3 N(CH3)2 170-80/0.2 mm 158-9 C15H24N2O2.C4H4O4 C, 59.98; C, 60.21; H, 7.42; H, 7.56; N, 7.37 N, 7.18 TABLE II (Continued)

Analysis No. Y/Z -NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found U 3-CF3 N(CH3)2 115-17/0.2 mm 107-8 C14H19F3N2.C4H4O4 C, 55.66, C, 55.76; H, 5.97; H, 6.06; F, 14.68; F, 14.50; N, 7.21 N, 7.01 V 4-CF3 N(CH3)2 116-20/0.2 mm 95-6 C14H19F3N2.C10H6SO3.H2O C, 58.88; C, 58.47; H, 5.76; H, 6.07; F, 11.64; F, 11.47; N, 5.72; N, 5.35; S, 6.55 S, 6.56 W 3-Cl N(CH3)2 140-5/0.3 mm 207-8 C14H21ClN2.2HCl C, 51.62; C, 51.62; 4-CH3 H, 7.12; H, 7.12, Cl, 32.65; Cl, 32.26; N, 8.59 N, 8.60 AA 4-Cl N(CH3)2 140-50/0.3 mm 201-2 C14H21ClN2.2HCl C, 51.62; C, 51.55; 3-CH3 H, 7.12; H, 7.07; Cl, 32.65; Cl, 32.51; N, 8.59 N, 8.53 BB H N(CH3)CH2-CH3 116-30/0.2 mm 195-200 C14H22N2.2HBr C, 44.23; C, 44.14; H, 6.36; H, 6.46; Br, 42.02; Br, 42.29; N, 7.37 N, 7.04 TABLE II (Continued)

Analysis No. Y/Z -NR1R2 b.p. ( C) m.p. ( C) Formula Calcd. Found CC 3,4-diCl N(CH2CH3)2 155-60/0.3 mm 186-8 C15H22ClN2.2HCl C, 48.14; C, 48.40; H, 6.46; H, 6.37; Cl, 37.90; Cl, 37.49; N, 7.49 N, 7.70 DD 3,4-diCl pyrididinyl 160-70/0.3 mm 185-7 C15H20Cl2N2.2HCl C, 48.40; C, 48.53; H, 5.96; H, 6.00; Cl, 38.11; Cl, 38.35; N, 7.53 N, 7.44 EE H - N(CH3)-CH2C6H5 160-75/0.25 mm 109-10 C19H24N2.C4H4O4 C, 69.67; C, 69.60; H, 7.12; H, 7.43; N, 7.08 N, 6.90 Example 1. trans-N-[2-(dimethylaminocyclopentyl]-3',4'-dichloropropionanilide This example illustrates the use of alkanoic acid anhydrides.

A solution of 3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]aniline (2.73 g., 10.0 mmole) in propionic anhydride (10 ml.) is heated on a steam bath overnight.

Water (100 ml.) is added and the heating continued for 1 hr. to decompose excess anhydride. The solution is made basic with sodium hydroxide (25 ml., 20% aqueous) and extracted with ether. The extract is washed with saturated sodium chloride solution, dried (MgSO4) and evaporated to yellow oil. The crude amide product, 3',4'-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide is purified by formation of the maleic acid salt and recrystallization from methanol-ether; 3.3 g. (74%) mp 154-5 ; uv (EtOH): # max (#) and absorption, 203 (61,350), 264 (sh, 828), 272 (744), 281 (592) nm; IR:NH/acid OH 2720, 2530, 2490, C=O/CO-2/C=C 1665, 1620, 1560 C=O/C-N/other 1355, 1265, 1030, 865 cm-1; mass spectrum: M+ 328, 330, 332, (free base), nmr (D2O): # 7.6 (m, 1H, aromatic), 7.5 (m, 1H, aromatic), 7.3 (m, 1H, aromatic), 6.3 (s, 2H, maleic acid), 5.1 (m, 1H, CH), 3.8 (m, 1H, CH), 2.95 (s, 6H, N+(CH3)2), 2.0 (q, 2H, CH3CH2CO), 1.1-1.9 (m, 6H, ring hydrogens), 0.9 (t, 3H, CH3CH2CO).

Anal. Calcd. for C,6H22CI2N2OC4*H404: Calcd. . C, 53.94; H, 5.89; Cl, 15.95; N, 6.29.

Found C, 53.91: H, 5.82, Cl, 15.82; N, 6.33.

Example 2. trans-N-[(2-dimethylamino)cyclopentyl]-4-difluoromethylpropionanilide This example illustrates the use of alkanoyl halides.

A solution of propionyl chloride (2.11 g., 22.0 mmole) in ether (50 ml.) is added dropwise, with ice-cooling, in 30 min. to a solution of the 4-trifluoromethyl-N-[2 (dimethylamino)cyclopentyl]aniline (3.10 g., 11.0 mmole) and triethylamine (2.30 g., 22.0 mmole) in ether (100 ml.). After stirring at room temperature overnight, saturated sodium bicarbonate solution (100 ml.) is added. The organic layer is washed with water and saturated sodium chloride solution, dried (MgSO4) and evaporated to a yellow oil. The crude amide product, 4-trifluoromethyl-N-[2 (dimethylamino)cyclopentyl]propionanilide is purified by formation of the hydrochloride salt and recrystallization from methanol-ether; 3.20 g. (80%), mp 184-5 : uv (EtOH): A max.+(E) end absorption, 231 (sh, 2950), 255 (sh, 1100), 262 881), 268 (627) nm; IR:NH 2560, 2460, C=C 1660, C=C 1615, 1585, 1520, F,,/other 1325, 1320, 1175, 1140, 1115, 1075 cm-', mass spectrum: M+ 328 (free base); nmr (D2O): a 7.9 (m, 4H, aromatic), 2.9 (s, 6H, N+(CH3)2), 1.4-2.3 (m, 8H, ring hydrogens and CH3CH2CO), 0.9 (t, 3H, CH3CH2CO), other protons not observed due to broadening.

Anal. Calcd. for C,7H23F3N2O HCI: Calcd. : C, 55.96; H, 6.63; Cl, 9.72; F, 15.62; N, 7.68.

Found : C, 55.97; H, 6.85; Cl, 9.72; F, 15.48; N, 7.60.

The following Table III summarizes the physical and analytical data for some additional compounds of formula I in which R is ethyl, and indicates the procedure (A-l: via propionic acid anhydride, or B--l: via propionyl chloride) by which the compound is made. All the products were recrystallized from methanol-ether except for Examples 9 and 15 (from petroleum ether) and 12 (from ethanol-ether).

TABLE III

Starting Procedure Analysis Example material from used No. Table II A or B Y/Z -NR1R2 mp ( C) Calcd. Found 3 A A-1 H N(CH3)2 115-116 C, 62.55; C, 62.31; (p-toluenesulfonate) H, 7.53; H, 7.43; N, 6.34; N, 6.32; S, 7.24 S, 7.17 4 B B-1 2-CH3 N(CH3)2 129-30 C, 62.62; C, 62.82; (oxalate) H, 7.74; H, 7.86; N, 7.69 N, 7.57 5 C A-1 3-CH3 N(CH3)2 139-40 C, 62.62; C, 62.32; (oxalate) H, 7.74; H, 7.78; N, 7.69 N, 7.66 6 D A-1 4-CH3 N(CH3)2 167-8 C, 65.96; C, 66.25; (2-naphthalenesulfonate) H, 7.18; H, 7.03; N, 5.70; N, 5.69; S, 6.52 S, 6.56 7 E B-1 2-Cl N(CH3)2 156-7 C, 56.17; C, 56.09; (oxalate) H, 6.55; H, 6.59; Cl, 9.21; Cl, 9.27; N, 7.28 N, 7.24 8 F A-1 3-Cl N(CH3)2 152-3 C, 56.17; C, 55.96; (oxalate) H, 6.55; H, 6.60; Cl, 9.21; Cl, 9.12; N, 7.28 N, 7.14 TABLE III (Continued)

Starting Procedure Analysis Example material from used No. Table II A or B Y/Z -NR1R2 mp ( C) Calcd. Found 9 G A-1 4-Cl N(CH3)2 75-6 C, 65.18; C, 12.09; (free base) H, 7.86; H, 7.86; Cl, 12.03; Cl, 12.09; N, 9.50 N, 9.42 10 H A-1 3-OCH3 N(CH3)2 135-6 C, 59.07; C, 58.98; (oxalate) H, 7.63; H, 7.60; N, 7.07 N, 717 11 J A-1 4-OCH3 N(CH3)2 146-8 C, 65.03; C, 64.68; (2-naphthalenesulfonate) H, 6.87, H, 7.06; N, 5.62; N, 5.70; S, 6.43 S, 6.36 12 K A-1 3-F N(CH3)2 85-8 C, 58.02; C, 57.97; (oxalate) H, 6.96; H, 6.89; F, 5.10; F, 5.10; N, 7.29 N, 7.51 13 L A-1 4-F N(CH3)2 154-5 C, 64.17; C, 63.98; (2-naphthalene- H, 6.42; H, 6.65; sulfonate) F, 3.90; F, 3.76; N, 5.76; N, 5.69; S, 6.59 S, 6.83 14 M A-1 3-Br N(CH3)2 167-8 C, 50.35; C, 50.37; (oxalate) H, 5.87; H, 6.01; Br, 18.62; Br, 18.37; N, 6.53 N, 6.54 TABLE III (Continued)

Starting Procedure Analysis Example material from used No. Table II A or B Y/Z -NR1R2 mp ( C) Calcd. Found 15 N A-1 4-Br N(CH3)2 78-9 C, 56.64; C, 56.85; (free base) H, 6.83; H, 7.01; Br, 23.56; Br, 23.39; N, 8.26 N, 8.10 16 P A-1 4-CH2CH3 N(CH3)2 154-6 C, 67.71; C, 67.40; (2-naphthalene- H, 7.31; H, 7.53; sulfonate) N, 5.64; N, 5.55; S, 6.46 S, 6.64 17 R A-1 3,4-Di-Cl N(CH3)2 154-5 C, 53.94; C, 53.91; (maleate) H, 5.89; H, 5.82; Cl, 15.92; Cl, 15.82; N, 6.29 N, 6.33 18 S B-1 3,5-DiCl N(CH3)2 129-30 C, 53.94; C, 53.46; (maleate) H, 5.89; H, 6.04; Cl, 15.92; Cl, 15.78; N, 6.29 N, 6.52 19 T A-1 3,4-di-OCH3 N(CH3)2 155-6 C, 60.53; C, 60,47; (fumarate) H, 7.39; H, 7.38; N, 6.42 N, 6.67 20 U B-1 3-CF3 N(CH3)2 135-6 C, 54.54; C, 54.50; (oxalate)H, 6.02; H, 6.21; F, 13.62; F, 14.09; N, 6.70 N, 6.45 TABLE III (Continued)

Starting Procedure Analysis Example material from used No. Table II A or B Y/Z -NR1R2 mp ( C) Calcd. Found 21 V B-1 4-CF3 N(CH3)2 184-5 C, 55.96; C, 55.97; (HCl salt) H, 6.63; H, 6.85; Cl, 9.72; Cl, 9.72; F, 15.62; F, 15.48; N, 7.68 N, 7.60 22 W B-1 3-Cl, N(CH3)2 122-3 C, 57.21; C, 57.20; 4-Me (oxalate) H, 6.82; H, 6.84; Cl, 8.89; Cl, 8.84; N, 7.02 N, 6.78 23 AA B-1 4-Cl, N(CH3)2 131-2 C, 57.21; C, 57.09; 3-Me (oxalate) H, 6.82; H, 6.93; Cl, 8.89; Cl, 9.02; N, 7.02 N, 6.99 24 CC A-1 3,4-diCl N(CH2CH3)2 148-9 C, 50.33; C, 50.15; (methanesulfonate) H, 6.67; H, 6.80; Cl, 15.64; Cl, 15.82; N, 6.18; N, 6.06; S, 7.07 S, 6.96 25 DD A-1 3,4-diCl pyrrolidinyl 107-9 C, 52.86; C, 53.08; (oxalate) H, 5.99; H, 6.01; Cl, 15.61; Cl, 15.73; N, 6.16 N, 6.00 TABLE III (Continued)

Starting Procedure Analysis Example material from used No. Table II A or B Y/Z -NR1R2 mp ( C) Calcd. Found 26 R A-1 3-Cl, N(CH3)2 152-3 C, 53.66; C, 53.52; 4-F (oxalate) H, 6.00; H, 6.13; N, 6.96; N, 6.88; Cl, 8.80; Cl, 8.65; F, 4.72 F, 4.96 27 R A-1 3,4-diBr N(CH3)2 146-7 C, 42.54; C, 42.66; H, 4.76; H, 4.90; N, 5.51; N, 5.71; Br, 31.45 Br, 31.51 28 R A-1 3,4-diCH3 N(CH3)2 114-5 C, 62.72; C, 62.60; (oxalate) H, 8.03; H, 8.14; N, 7.32 N, 7.31 29 EE A-1 3,4-diCl N(CH3)CH2-C6H5 120-1 C, 56.14; C, 56.10; (oxalate) H, 5.89; H, 5.49; N, 5.46; N, 5.24; Cl, 13.81 Cl, 13.26 Example 30. trans-N-[(2-di-n-propylamino)cyclopentyl]-3',4'-dichloropropionanilide Following the procedure of Preparation 2, a trans-1,2-diaminocyclopentene in which NR1R2 is N(n-C3H7)2 is prepared. This compound, following the procedure of Example 1, is then reacted with propionic anhydride to form the title compound which is recrystallized from petroleum ether as the free base, m.pt. 58-9 .

Anal.

Calcd. C, 62.35; H, 7.85; N, 7.27; Cl, 18.40.

Found C, 62.64; H, 8.02; N, 7.41; Cl, 18.27.

Example 31. cis-3',4'-dichloro-N- [(2-dimethylamino)cyclopentyl]propionanilide Part (A) A solution of 3,4-dichloroaniline (200 g., 1.23 mol), cyclopentene oxide (400 ml.), and conc. HCI (2 ml.) is heated at reflux temperature for 7 days.

The unreacted epoxide is evaporated at 60 , and the residue is treated with excess ethereal HCI, and a syrup results. This is washed with 1000 ml. of ether. The residue is crystallized and recrystallized from methanol/ether, (1/5.5 v/v) to give 170.0 g.

(49% v yield) of 3,4-dichloro-N-[2-hydroxycyclopentyl]aniline, hydrochloride salt.

Part (B) Propionic anhydride (208 g., 1.6 mol), and the free base from part (A) (113.2 g., 0.40 mol base) are mixed and heated on a steambath overnight. Water (350 ml.) is added, and heating is continued for 1 hr. After ice cooling, the reaction mixture is neutralized with 240 ml. of 40% NaOH (2.4 mol), and extracted with ether. The ether extract is washed in succession with saturated NaHCO3, water, 10% HCI, water and saturated NaCI, the organic layer dried over MgSO4, and then evaporated to a brown oil. Subsequently, this oil is dissolved in 500 ml. 95% EtOH, and 26.4 g. (0.4 mol) of 85% KOH is added. The solution is stirred at room temperature (slight warming) for 3 hr. Evaporation removes the EtOH. The residue is treated with 800 ml. of ether and 250 ml. of water. The organic layer is washed successively with water, 10% HC1, and saturated NaCI, and dried (MgSO4). The solution is concentrated by distillation and subsequent treatment with petroleum ether results in 87.7 g. (72% yield) of 3',4'-dichloro-N-[2-hydroxycyclopentyl]propionanilide.

Part (C) To an ice-cooled solution of 60.4 g. (0.20 mol) of Part (B) product in 1000 ml. of acetone there is added, dropwise, 75 ml. of Jones Reagent (oxidizing).

The reaction mixture is stirred at room temperature for 30 min., then is filtered, and the filtrate concentrated at reduced pressure. The residue is dissolved in 500 ml. of ether and this solution is washed three times with water followed by saturated NaCI solution, is dried over MgSO4 and evaporated to a yellow oil which solidifies on standing. A tacky solid results (44.4 g, 74% yield) which is 3',4'dichloro-N- [2-oxocyclopentyl]propionanilide.

Part (D) A solution of dimethylamine (0.24 mol) and dimethylamine hydrochloride (9.8 g., 0.12 mol) in 250 ml. MeOH is prepared, and 18.0 g. (0.06 mol) of the ketone (from Part (C)) is added all at once. To this mixture is added all at once, 2.65 g. (0.042 mol) of sodium cyanoborohydride and 3A molecular sieves (25 g.). The entire mixture is stirred at room temperature for 8 days, after which time the solution is treated with 10% HCI until gas evolution ceases. Filtration through a filter aid (Celite -- *Registered Trade Mark) removes the sieves and a small amount of insoluble matter. The MeOH is evaporated and the remaining aqueous layer, after washing with ether, is made basic with 50 ml. of 40% NaOH, and is filtered to remove amorphous solid. the residue is washed with ether, and the filtrate is extracted with ether. The ether extracts are washed with saturated NaCI solution, dried (MgSO4) and evaporated to a yellow-brown oil (6.1 g.).

Chromatography on 150 g. silica gel (2% MeOH in CHCI3) gives several 20-ml. fractions; fractions 11-33 (homogeneous by TLC) are combined and evaporated to give 4.2 g. of yellow oil which is converted to the oxalic acid salt in MeOH/ether (1/5, v/v). A solid results (11% yld.), which has a m.p. 171--30. This solid is the cis 31,4'dichloro-N[2-(dimethylamino)cyclopentyl] propionanilide oxalic acid salt. The nmr differs from that of the trans compound (Example 1) in the coupling constant of the 1,2-cyclopentane H's. Also, on TLC on silica gel (EtOAc developing solvent), the free base from this reaction (cis) has a different Rf value than the corresponding trans aminoamide.

Anal. Calcd. for C,6H22N2CI2O.C2H204: Calcd. : C, 51.56; H, 5.77; N, 6.68; Cl, 16.91.

Found . C, 51.84; H, 5.85; N, 6.66: Cl, 17.11.

Example 32. cis-N- [(2-dimethylamino)cyclopentyl]propionanilide Following the procedure of Example 31, but substituting aniline for 3,4dichloroaniline, the title compound is prepared as the hydrochloride salt, with recrystallisation from methanol-ether, m.pt. 169--70".

Anal.

Calcd. : C, 63.45; H, 8.54; N, 9.25; Cl, 11.70.

C, 63.51; H, 8.61; N, 9.35; Cl, 11.90.

Further compounds of formula I have been prepared, in which R1 and R2 are both methyl, as indicated in Table IV. The procedures used were equivalent to Example 1 but using acetic anhydride (A-2) or butyric anhydride (A-3), or to Example 2 but using isobutyryl chloride (B-2). The free base of Example 33 was recrystallized from petroleum ether-ether, while the salts of Examples 34 to 37 were recrystallised from methanol-ether.

TABLE IV

Starting Analysis material from Example Table II Y/Z Procedure R mp ( C) Formula Calcd. Found 33 A H A-2 CH3 104 C15H22N2O C, 73.13; C, 73.21; H, 9.00; H, 8.96; N, 11.37 N, 11.23 34 A H A-3 isopropyl 115-16 C17H26N2O. C, 66.57; C, 66.42; C10H9SO3@ H, 7.14; H, 7.13; H2O N, 5.75; N, 5.70; S, 6.58 S, 6.48 35 R 3,4-diCl A-2 CH3 164-5 C15H20Cl2- C, 50.38; C, 50.28; N2O.C2H2O4 H, 5.47; H, 5.54; N, 6.91; N, 6.79; Cl, 17.50 Cl, 17.29 36 R 3,4-diCl A-3 isopropyl 120-1 C17H24Cl2- C, 52.66; C, 52.84; N2O.C2H2O4 H, 6.05; H, 6.16; N, 6.47; N, 6.69; Cl, 16.36 Cl, 16.47 37 R 3,4-diCl B-2 isopropyl 171-4 C17H24Cl2N2O. C, 52.66; C, 52.65; C2H2O4 H, 6.05; H, 6.15; N, 6.47; N, 6.50; Cl, 16.36 Cl, 16.26 Preparation 3. d- and 1-trans-3,4-dichloro-N-[2-dimethylaminocyclopentyl]aniline.

(I-isomer) the di-p-toluoyl-d-tartaric acid salt of the title trans-dl-diamine is prepared by mixing 103.9 g. (0.267 mol) of this tartaric acid with 103.2 g. (0.267 mol) the diamine in a solvent consisting of 500 ml. isopropanol and about 500 ml. of ether. This mixture is seeded with a crystal of the trans-l-diamine, obtained from a small test tube scale resolution preparation, and left to stand. Crystals form; these are collected (75.0 g.) by filtration and recrystallized twice from a mixture of methanol:acetone:ether::2:8:7.5 v/v/v to give 17.5 g. of salt which is converted to the free base with aqueous 20% NaOH, and subsequently to the maleate salt (as in Example 1). Mother liquor saved, Nmr, ir, and mass spectra conform to the assigned structure. m.p. 135-6 ; [a]2S (MeOH, C.=15.47 mg/2 ml)=-105 to give the 1-form of the compound.

Analysis Calcd. for C13H18N2Cl2.C4H4O4: Calcd. : C, 52.45; H, 5.70; N, 7.20; Cl, 18.22.

Found : C, 52.71; H, 5.76; N, 7.19; Cl, 18.23. d-isomer The mothor liquor from the initial filtration (above) is concentrated under reduced pressure to give a yellow oil which crystallizes in a solvent mixture of MeOH-acetone-ether to give 76.0 g. of crystals; these are then recrystallized twice from methanol-acetone-ether to give 55.0 g. of crystalline material which is converted to the free base and subsequently to the maleic acid addition salt.

Spectral data are correct for the assigned structure. m.p. 135-6 ; [&alpha;]D25 (MeOH, c.=15.63 mg./2 ml.) = +101 (i.e. the d-isomer).

Anal. Calcd. for C13H18N2Cl2C4H4O4: Calcd. : C, 52.45; H, 5.70; N, 7.20; Cl, 18.22.

Found : C, 52.73; H, 5.80; N, 7.28; Cl, 18.47.

Example 38.

Preparation of d-trans-3'.4'-dichloro-N-[2-dimethylaminocyclopentane]propion- anilide Following the procedure of Example 1, but substituting d-trans-aminoaniline (prepared in Preparation 3), for the trans-aminoaniline of Example 1 as starting diamine there is obtained the title compound as the maleic acid addition salt, m.p.

152 "". Circular Dichroism [o] 25 + 2800 + 300 (2.5% in 95% EtOH).

249m Anal. Calcd. for C18H22N2C12.C4H4O4: Calcd. : C, 53.94; H, 5.89; N, 6.29; Cl, 15.92.

Found : C, 54.19; H, 5.91; N, 6.19; Cl, 16.22.

Preparation of 1-trans-3,4-dichloro-N-[2-(dimethylamino)cyclopentyl]propionanilide.

Following the procedure of Example 1 but substituting l-trans-aminoaniline (prepared in Preparation 3), for the trans-aminoaniline in Example 1, as starting diamine there is obtained the title compound as the maleic acid addition salt, m.p.

152--4". Circular Dichroism 18i 25 -2900 + 300 (2.5% in 95% EtOH).

249 mu Anal. Calcd. for C10H22N2C12O.C4H4O4: Calcd. C, 53.94; H, 5.89; N, 6.29; Cl, 15.92.

Found . C, 54.09: H, 5.90: N, 6.54; Cl, 15.82.

For oral administration either solid or fluid dosage forms can be prepared. For preparing solid compositions such as tablets, the compound of Formula I is mixed with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminium silicate, calcium sulfate, starch, lactose, acacia and methylcellulose, as pharmaceutical diluents or carriers. Wafers are prepared in the same manner as tablets, differing only in shape and the inclusion of sucrose or other sweetener and flavour. In their simplest embodiment, capsules, like tablets, are prepared by mixing the compound with an inert pharmaceutical diluent and filling the mixture into a hard gelatin capsule of appropriate size. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum, or other inert oil.

Fluid dosage forms for oral administration such as syrups, elixirs, and suspensions can be prepared. the water-soluble forms can be dissolved in an aqueous vehicle together with sugar, aromatic flavoring agents and preservatives to form a syrup. An elixir is prepared by using a hydro-alcoholic (ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent.

Suspensions can be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth or methylcellulose.

For parenteral administration, fluid dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and aq accompanying vial of water for injection is supplied to reconstitute the liquid prior to use.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending in the sterile vehicle.

Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

Rectal suppositories as used herein mean solid bodies for insertion into the rectum which melt or soften at body temperature releasing one or more pharmacologically or therapeutically active ingredients.

Pharmaceutically acceptable subst administration. In the preferred embodiments of this invention, the dosage units can contain the compound in 0.5, 1, 5, 10, 20, 30, 50 and 100 mg. amounts for systemic treatment. A sterile preparation of the active material contains 0.1 percent to 25 percent w/v for parenteral treatment. The dosage of compositions containing a compound of formula I and one or more active ingredients is to be determined with reference to the actual dosage of each such ingredient.

In addition to the administration of a compound of formula I as the principal active ingredient of compositions for treatment of the conditions desired herein, the said compound can be combined with other compounds such as analgesics, for example, asprin, acetaminophen, PAC compound (phenacetin-asprin-caffeine), anti-inflammatory agents such as ibuprofen, and anxiolytics such as perphenazine, amitriptylene hydrochloride, chlordiazepoxide, alprazolam and doxepin hydrochloride.

Example 39.

A batch of 10,000 tablets, each containing 20 mg. of trans-3',4'-dichloro-N-[2 (dimethylamino)cyclopentyl]propionanilide maleate salt as the active ingredient, is prepared from the following: Active ingredient 200 gm.

Dicalcium phosphate 1,500 gm.

Methylcellulose, U.S.P.

(15 cps) 60 gm.

Talc 150gm.

Corn Starch 200 gm.

Magnesium stearate 12 gm.

The compound and dicalcium phosphate are mixed well, granulated with 7.5 percent solution of methylcellulose in water, passed through a No. 8 screen and dried carefully. The dried granules are passed through a No. 12 screen, mixed thoroughly with the talc, starch and magnesium stearate, and compressed into .tablets.

These tablets are useful in reducing depression in adults at a dose of 1 to 2 tablets per day, depending on the age and weight of the patient.

Example 40.

One thousand two-piece hard gelatin capsules each containing 10 mg. of 3' bromo-N-[2-(dimethylamino)cyclopentylipropionanilide, hydrochloride salt as the active ingredient are prepared from the following: Active ingredient 10 gm.

Lactose 75 gm.

Talc 25 gm.

Magnesium stearate 1.5 gm.

The ingredients are mixed well and filled into capsules of the proper size.

Capsules so prepared are useful for treating depression in adults at a dose of one-two capsules per day.

Example 41.

One thousand tablets for sublingual use are prepared from the following ingredients: 3'-trifluoromethyl-N-[2-(dimethylamino)- cyclopentyl]propionamide, micronized 5 gm.

Polyethylene glycol 4,000, powdered 150 gm.

Polyethylene glycol 6,000, powdered 75 gm.

The ingredients are mixed well and compressed into sublingual-type tablets.

These tablets (each containing 5 mg. of active ingredient) placed under the tongue are useful to reduce depression with a rapid reduction at a dose of 1 tablet per 6 hours.

Example 42.

Soft gelatin capsules for oral use, each containing 10 mg. of 3',4'-dichloro-N [2-(diethylamino)cyclopentyl)propionanilide, methanesulfonate salt are prepared by first dispersing the micronized compound in corn oil to render the material capsulatable and then encapsulating in the usual manner. These capsules are useful in treatment of depression at a dose of 1--2 capsules a day.

Example 43.

One thousand tablets, each containing 30 mg. of 3',4'-dichloro-N-[2-(N pyrrolidinyl)cyclopentylipropionanilide, salt are made from the following: 3',4'-dichloro-[2-(N-pyrrolidinyl)cyclopentyl]- propionanilide 30 gm.

Lactose 355 gm.

Microcrystalline cellulose NF 120 gm.

Starch 16 gm.

Magnesium stearate powder 4 gm.

The ingredients are screened and blended together and pressed into tablets.

The tablets are useful to overcome depression.

Example 44.

A sterile preparation suitable for intramuscular injection and containing 50 mg. of 3'-fluoro-N- [2-(dimethylamino)cyclopentyl] propionanilide, hydrochloride salt, in each milliliter is prepared from the following ingredients: 3 '-fluoro-N- [2-(dimethylamino)cyclopentyl] - propionanilide, hydrochloride 50 gm.

Benzyl benzoate 200 ml.

Methylparaben 1.5 gm.

Propylparaben 0.5 gm.

Cottonseed oil q.s. 1,000 ml.

One milliliter of this sterile preparation is injected to reduce depression in adults.

Example 45.

Following the procedure of the preceding Examples 39 to 44, dosage forms are similarly prepared substituting equivalent amounts of cis or trans variants of other Formula I compounds; for example 3'-chloro-4'-methyl-N [2-(dimethylamino)cyclopentyl]propionanilide, 3' ,4'-dimethoxy-N-[2-(dimethylamino)cyclopentyl]propionanilide, 3'-chloro-4'-fluoro-N-[2-(dimethylamino)cyclopentylipropionanilide, 3' ,4'-dibromo-N- [2-(dimethylamino)cyclopentyl] propionanilide, 31,4 '-dimethyl-N- [2-(dimethylamino)cyclopentyl]propionanilide, 3 ' ,4'-dichloro-N-L2-(dimethylamino)cyclopentyl]propionanilide, 3 '-methoxy-N-[2-(dimethylamino)cyclopentyl]propionanilide, 3'-chloro-4-methyl-N-[2-dimethylaminocyclopentylipropionanilide, or 3' ,4'-dichloro-N- [2-(diethylamino)cyclopentyl] propionanilide, or their pharmacologically acceptable acid addition salts for the respective active ingredients in those examples.

Claims (31)

WHAT WE CLAIM IS:

1. A pharmaceutical composition comprising a compound of formula I

wherein R is C,,alkyl; either R, is C,~3alkyl and R2 is C,~3alkyl or benzyl, or NR,R2 is pyrrolidinyl or piperidinyl; and Y and Z are the same or different and are each hydrogen, fluorine, chlorine, bromine, trifluoromethyl, methyl, ethyl, methoxy or ethoxy with the provisos that (I) Z is hydrogen when Y is trifluoromethyl, (2) when Z is hydrogen and Y is methoxy or ethoxy, Y is at the m-position of the phenyl ring, and (3) when Y and Z are both halogen, methoxy and/or ethoxy neither substituent is present at the oposition of the phenyl ring or a pharmacologically acceptable salt thereof; in association with a pharmaceutically acceptable carrier which is a solid or a sterile liquid.

2. A composition according to claim 1 in which, in the compound of formula I the 1- and 2-substituents are in the relative trans configuration.

3. A composition according to claim 1 in which, in the compound of formula I, the 1- and 2-substituents are in the relative cis configuration.

4. A composition according to any preceding claim in which, in the compound of formula I, R, and R2 are each C,~3alkyl and at least one of Y and Z is fluorine, chlorine, bromine, m-methoxy or m-ethoxy.

5. A composition according to any of claims 1 to 3 in which, in the compound of formula I NR,R2 is pyrrolidinyl or piperidinyl and at least one of Y and Z is halogen in the 3- and/or 4-position.

6. A pharmaceutical composition comprising a pharmaceutically acceptable solid or sterile liquid carrier and N-(2-pyrrolidinylcyclopentyl)-3' ,4'-dichloro- propionanilide or a pharmacologically acceptable salt thereof.

7. N-(trans-2-dimethylaminocyclopentyl)-3 ',4'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

8. N-(trans-2-dimethylaminocyclopentyl)-3',4'-dichloropropionanilide maleate.

9. N-(cis-2-dimethylaminocyclopentyl)-3 ',4'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

10. N-(2-dimethylaminocyclopentyl)-3',4'-dibromopropionanilide or a pharmacologically acceptable salt thereof.

I 1. N-(2-dimethylaminocyclopentyl)-3'-methoxypropionanilide or a pharmacologically acceptable salt thereof.

12. N-(2-pyrrolidinylcyclopentyl)-3',4'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

13. N-(2-dimethylaminocyclopentyl)-3'-chloro-4'-methylpropionanilids or a pharmacologically acceptable salt thereof.

14. N-(2-dipropylaminocyclopentyl)-3',4'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

15. N-(2-dimethylaminocyclopentyl)propionanilide or a pharmacologically acceptable salt thereof.

16. N-(2-dimethylaminocyclopentyl)-3'-methylpropionanilide or a pharmacologically acceptable salt thereof.

17. N-(2-dimethylaminocyclopentyl)-3'-chloropropionanilide or a pharmacologically acceptable salt thereof.

18. N-(2-dimethylaminocyclopentyl)-3'-fluoropropionanilide or a pharmacologically acceptable salt thereof.

19. N-(2-dimethylaminocyclopentyl)-3'-bromopropionanilide or a pharmacologically acceptable salt thereof.

20. N-(2-dimethylaminocyclopentyl)-4'-bromopropionanilide or a pharmacologically acceptable salt thereof.

21. N-(2-dimethylaminocyclopentyl)-3',5'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

22. N-(2-dimethylaminocyclopentyl)-3'-trifluoromethylpropionanilide or a pharmacologically acceptable salt thereof.

23. N-(2-dimethylaminocyclopentyl)-3'-methyl-4'-chloropropionanilide or a pharmacologically acceptable salt thereof.

24. N-(2-diethylaminocyclopentyl)-3',4'-dichloropropionanilide or a pharmacologically acceptable salt thereof.

25. N-(2-dimethylaminocyclopentyl)-3'-chloro-4'-fluoropropionanilide or a pharmacologically acceptable salt thereof.

26. N-(2-dimethylaminocyclopentyl)-3',4'-dimethylpropionanilide or a pharmacologically acceptable salt thereof.

27. N-(2-dimethylaminocyclopentyl)-3' ,4'-dichlorobutyranilide or a pharmacologically acceptable salt thereof.

28. N-(2-dimethylaminocyclopentyl)-3',4'-dichloroisobutyranilide or a pharmacologically acceptable salt thereof.

29. A pharmaceutical composition comprising a pharmaceutically acceptable solid or sterile liquid carrier and a compound as claimed in any of claims 7 to 28.

30. A composition according to any of claims 1 to 6 and 29 in unit dosage form.

31. A composition according to claim 1 substantially as herein described with reference to any of Examples 39 to 45.