US3366637A

US3366637A - N-[(guanylmercapto)alkyl]-c-diaryl-methyl-piperidines

Info

Publication number: US3366637A
Application number: US480136A
Authority: US
Inventors: Mull Robert Paul; Mizzoni Renat Herbert
Original assignee: Ciba Geigy Corp
Current assignee: BASF Corp; Novartis Corp
Priority date: 1964-12-04
Filing date: 1965-08-16
Publication date: 1968-01-30
Anticipated expiration: 1985-01-30
Also published as: NL6515775A; FR4894M; BE673290A; FR1481944A

Description

United States Patent N -[(GUANYLMERCAPTO)ALKYL]-C-DIARYL- I METHYL-PIPERIDINES Robert Paul Mull, Flor-ham Park, and. Renat Herbert Mizzoni, Long Valley, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 416,144, Dec. 4, 1964. This application Aug. 16, 1965, Ser. No. 480,136

18 Claims. (Cl. 260293.4)

ABSTRACT OF THE DISCLOSURE The invention is directed to compounds useful as gastric secretion inhibitors and having the formula in which one of the radicals R R and R stands for a monocyclic carbocyclic aryl radical and the other two stand for hydrogen, monocyclic cycle-lower alkyl or alkenyl and/ or monocyclic carbocyclic aryl, m stands for an integer from 1 to 4, n for an integer from '5 to 8, p for an integer from 2 to '8 and X for one of the groups 3,366,637 Patented Jan. 30, 1968 in which each of the radicals R, R' and R" represents hyin which each of the radicals R, R and R" stands for hydrogen, lower alkyl or alkenyl, monocyclic cycloalkyl or cycloalkenyl, monocyclic cycloalkyl-1ower alkyl or -alkenyl, monocyclic carbocyclic aryl-lower alkyl or -alkenyl or monocyclic carbocyclic aryl and acid addition salts thereof.

cyclic ring, quaternaries and salts of these compounds, I

as well as methods for their preparation.

The mercaptoalkyl group of these compounds attached to the imino-nitrogen, more especially is a mercaptolower alkyl group in which the mercapto group is separated from the imino-nitrogen by at least two carbon atoms. Its alkyl chain may be straight or branched and preferably contains 2 to 4 carbon atoms. Examples for the mercaptoalkyl group are the following: l-mercaptoy -P Py p w y y (3), -butyl-(4), -heXyl-(6), -heptyl-(5), -octy1-(4) or 2- methyl-propyl-(Z); 2-mercapto-propyl-(3), -butyl-(3), -butyl-(4) or pentyl-(S); 3-mercapto-butyl-(4) or -hexyl- (6). The mercapto group thereof may be free or substituted; it preferably stands for a member selected from drogen or a lower aliphatic, araliphatic or aromatic hydrocarbon radical, especially lower alkyl, such as methyl, ethyl, nor i-propyl, n-, i-, secondary-or tertiary-butyl, pentyl, hexyl or heptyl, lower alkenyl, such as allyl or methallyl, cycloalkyl or cycloalkenyl containing preferably 5 to 6 ring carbon atoms such as cyclopentyl, cyclohexyl, cyclopentenyl or cyclohevxenyl, cycloalkyl-lower alkyl or-alkenyl containing preferably 5 to 6 ring carbon atoms, such as cyclopentylethyl, cyclohexylmethyl or cyclopentylallyl, aryl-lower alkyl or-alkenyl, especially monocyclic carbocyclic aryl-lower alkyl or-alkenyl, such as benzyl, phenethyl -(1) or -(2) or cinnamyl or monocyclic carbocyclic aryl. These hydrocarbon radicals may be unsubstituted or substituted, especially in the aromatic part, by one or more than one of the same or of different substituents, such as lower alkyl, e.g. methyl ethyl, n-or i-propyl, free or etherified hydroxy or mercapto, e.g. methoxy, ethoxy or methylenedioxy, methylor ethyhnercapto, halogen, e.g. fiuoro, chloro or bromo, trifluoromethyl, nitro or amino, for example, lower alkylor di-lower alkylamino, e.g. methylamino, ethylamino, dimethylamino, diethylamino or methylethylamino.

The alkyleneimino ring of the compounds of this invention, more especially contains a straight or branched alkylene group and having from 3 to 8 ring carbon atoms. Above all, it represents piperidino, but also pyrrolidino, 1,5-, 1,6- of 2,5 hexamethyleneimino, 1,5-, 1,6-, 1,7- or 2,6 heptamethyleneimino or 1,8-, 3,6- or 3,7-octa' methyleneimino.

The unsaturated hydrocarbon radical attached to any of the ring carbon atoms of the alkyleneimino ring available for substitution above all is an aralkyl, cycloalkylor cycloalkenylaralkyl or a partially hydrogenated aryl radical. More especially it is a lower alkyl group containing one to three monocyclic, carbocyclic aryl radicals, such as benzyl, diphenylmethyl (benzhydryl), triphenylmethyl, phenethyl-(l) or -(2), 1,1- or 1,2- diphenylethyl, 1,1,1 triphenylethyl-(Z), phenylpropy1-( 1), -(2) or -(3), 1,1-, 2,2-, 3,3-, 1,2-, 1,3- or 2,3-diphenylpropyl-(S), 1,3 diphenylpropyl (2), 1,2,3 triphenylp w p y y or 2,-2-, 1,3-, or 2,3-diphenyl-butyl-(3) or -(4) or tribenzylmethyl; or a lower alkyl group containing at least one cyclo-lower alkyl or alkenyl group, containing preferably 5 or 6 ring carbon atoms, and at least one monocyclic carbocyclic aryl radical, but containing not more than 3 cyclic radicals, such as u-cyclopentyL, u-cyclohexylor a-cyclohexen (2) yl-benzyl, uor fi-cyclohexyl-phenethyl-(2) or l-cyclopentylor l-cyclopenten-(2)-yl-2,2- diphenylethyl-(Z); or a partially hydrogenated hior tricyclic carbocyclic aryl radical, such as indenyl-(l), hydrindenyl-(Z), tetralinyl-( 1) or -(2), fluorenyl-(9), acenaphthenyl-(l), 9,10 dihydro-anthrazenyl (9) or 1,2,3 trihydrophenalenyl (2). These hydrocarbon radicals-maybe unsubstituted or substituted, especially in the aromatic part, by one or more than one of the same or ofdiiierent substituents, such as those mentioned for R.

The new compounds possess valuable pharmacological properties. For example, they cause -a marked decrease of the gastric secretion, especially of gastric hydrochloric acid, which can be demonstrated, for example, at a dosage range between about 1-15 mg./kg./day, preferably 5-10 mgL/kg/ day, on the dog, of which the gastric secretion is induced either by food or by parenteral application of histamine. The compounds of this invention, are

therefore, useful in the management and treatment of gastric irritation or of gastric ulcers by reducing the anism of the gastric secretion. Furthermore, the new compounds are useful starting materials or intermediates in the manufacture of other valuable compounds, especially medicines.

Particularly useful are compounds of the general formula:

R1\ R2( m 2m2) in which each of the radicals R, R and R stands for hydrogen, lower alkyl or alkenyl, monocyclic cycloalkyl or cycloalkenyl, monocyclic cycloalkyl-lower alkyl oralkenyl, monocyclic carbocyclic aryl-lower alkyl or alkenyl or monocyclic carbocyclic aryl, and acid addition salts thereof.

Compounds that are especially valuable are those of the formula:

in which each of the groups R; and R stands for phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, halophenyl, trifluoromethylphenyl or di-lower alkylamino-phenyl, each of the groups R and R stands for hydrogen or lower alkyl and q stands for an integer from 2 to 4, and acid addition salts thereof.

Above all, the present invention concerns compounds of the formula:

H RfH-C H2 NH: 0 111 N-C qH2q-SO CID-CH2 \NH in which R.,, R and q have the meaning given above, and. acid addition salts thereof.

The new compounds are prepared by methods in themselves known. For example, the procedure is (a) To replace in an N-(R -alkyl)-alkyleneimine, containing in the ring an unsaturated hydrocarbon radical, the substituent R capable of being converted into mercapto, by a free or substituted mercapto group or (b) To add a compound, containing a free mercapto group, to an N-alkenyl-alkyleneimine containing in the ring an unsaturated hydrocarbon radical or (c) To react an N-unsubstituted alkyleneimine, containing in the ring an unsaturated hydrocarbon radical, with a reactive O-esterified mercapto-alkanol or (d) To reduce in an N-mercaptoalkyl-alkyleneimine containing in the ring an unsaturated hydrocarbon radical and in the ring and/or alkyl chain at least one carbamyl or ethenylene grouping, said grouping to the 'methyleneimino or ethylene grouping respectively, and, if desired, converting the final products into each other, converting a resulting free compound into a salt or quaternary ammonium compound or converting a resulting salt into the free compound or into another salt.

The substituent R capable of being converted into mercapto represents, for example, esterified hydroxy, preferably halogeno, e.g. chloro, bromo, or iodo, or aliphatic or aromatic sulfonyloxy, such as methane-, ethane, benzeneor p-toluene-sulfo nyloxy. The N-(R -alkynalkyleneimine starting compounds may be reacted with a compound containing a free mercapto group, such as hydrogen sulfide, a thio-alcohol or thiophenol, thiocyanic acid, a monoor dithiocarbamic acid, an ester thereof or a thiourea containing at least one hydrogen atom, or advantageously a metal salt thereof, especially an alkali metal, e.g. sodium or potassium salt thereof.

A reactive O-esterified mercapto-alkanol is, for example, a halo-or sulfonyloxy-alkane containing preferably a substituted mercapto group, which is separated from the halogen, e.g. chloro or bromo atom or the sulfonyloxy, e.g. p-toluene sulfonyloxy group, by at least two carbon atoms.

In the N-mercaptoalkyl-al'kleneimine starting compounds in which a carbonyl group is connected with the imino nitrogen atom (i.e. forming a carbamyl group), the carbonyl group can be reduced, for example, with a complex light metal hydride, e.g. lithium aluminum hydride. Said starting compounds that contain a double bond, (or ethenylene grouping respectively) it preferably extends from the ring carbon atom that carries the unsaturated hydrocarbon radical, may be reduced with catalytically activated hydrogen, e.g. hydrogen in the presence of a palladium catalyst.

The final products of this invention may be converted into each other by methods in themselves known. Thus, for example, a compound obtained containing the free mercapto group can be reacted with a reactively esterified lower aliphatic or araliphatic alcohol, e.g. a lower alkyl halogenide or sulfate, an aromatic diazonium compound, e.g. benzene diazonium chloride, a lower aliphatic or araliphatic hydrocarbon containing an olefinic double bond, e.g. ethylene, cyclopentene or styrene, a halocyan, e.g. bromocyan, an isocyanate or thioisocyanate, a carbamic or thiocarbamic acid halide or a cyanamide, in order to obtain the hereinbefore described compounds containing a substituted mercapto group. Furthermore the amidino-mercaptanes (isothioureas) obtained may be hydroyzed, for example, with aqueous alkali metal hydroxides in order to obtain the unsubstituted mercaptanes, the cyano-mercaptanes (rhodanides) may be additively combined with water, hydrogen sulfide, alcohols or thiols, preferably under acidic conditions, e.g. in the presence of hydrochloric acid, or carbamylor thiocarbamyl-mercaptanes (thioor dithiourethanes) with aliphatic or araliphatic halogenides. The quaternaries are obtained from the free compounds by reacting them preferably with reactively esterified lower alkanols.

The above mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/ or of inert atmospheres, at atmospheric or superatmospheric pressure, at low temperatures, room temperature or elevated temperatures. Condensing agents are preferably used in the reaction of compounds with a reactive esterified hydroxy group whereby an acid is split off. They are especially inorganic or organic bases, for example, alkali metal carbonates, such as potassium carbonate, or tertiary nitrogen bases, such as trimethylamine or pyridine.

The end products are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obtained can be converted into salts by reaction with organic or inorganic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, propionic, succinic, glycollic, lactic, malic, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, aminobenzoic, anthranilic, hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphtalenesulfonic and sultanilic acid; methionine, tryptophan, lysine and arginine.

These and other salts of the new compounds, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, Whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components may be used in the form of their salts.

Mainly, those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being especially valuable.

The starting materials are known, or if they are new, may be prepared by methods in themselves known. Several of the new starting materials are described in our copending applications Ser. No. 392,931, filed Aug. 28, 1964, U.S. Patent No. 3,252,983, Ser. No. 416,154, filed Dec. 4, 1964 (now abandoned) and Ser. No. 480,147 filed Aug. 16, 1965, now abandoned.

The N-mercaptoalkyl-alkyleneimino starting compounds, containing at least one carbamyl or ethenylene group, may by prepared analogous to the method described under (a) and (c) by selecting the appropriate reagents, for example, by reaction of an N-haloalkylalkenyleneimine or-oxoalkyleneimine containing in the ring an unsaturated hydrocarbon radical, with a compound containing a free mercapto group, eg. those mentioned above or by reaction of a corresponding N-unsubstituted alkenyleneimine or oxoalkyleneimine with a haloalkylmercapto compound or by reaction of a corresponding N-unsubstituted alkyleneimine or alkenyleneimine with a mercapto-alkanoyl halide.

Starting materials or final products that are mixtures of isomers may be separated into single isomers by methods in themselves known. For example, compounds that contain one or more asymmetrical carbon atoms may be in the form of racemate mixtures, pure racemates or optical antipodes.

Mixtures of racemates, by virtue of the physicochemical differences between the components, can be resolved into the stereoisomeric pure racemates (diastereoisomers), for example, by chromatogprahy and/or fractional crystallization. Racemic products can likewise be resolved into the optical antipodes, for example, by reaction with optically active acids, separation of the diastereomeric salts and liberation of the bases from the salts.

The new compounds can be used in the free form or in the form of their salts, for example, for the manufacture of pharmaceutical preparations containing the said compounds in admixture with organic or inorganic, solid or liquid pharmaceutical excipients suitable especially for enteral but also for parenteral administration. Suitable excipients are substances that do not react with the new compounds, for example, water, gelatine, lactose, starch, stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyl alcohols, gums, propylene glycols, white petroleum jelly and other known medicinal excipients. The pharmaceutical preparations may be, for example, tablets, dragees tor capsules, or in liquid form as solutions, suspensions, or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure or buffers. They may further contain other therapeutically valuable substances. The pharmaceutical preparations are prepared by conventional methods.

The following examples illustrate the invention, temperatures are given in degrees centigrade and all parts given are parts by weight.

Example 1 The solution of 3.55 g. of N-(2-chloro-ethyl)-3-benzhydryl-pipieridine hydrochloride in 50 m1. of ethanol is added with stirring to a solution of 0.86 g. of thiourea in 25 ml. of ethanol and the mixture refluxed for 6 hours. Thereupon it is concentrated under reduced pressure, the residue triturated with ether and the whole filtrated. The filter residue is recrystallized from ethanol-ether in order to obtain the pure N-(Z-guanylmercapto-ethyl)-3-benzhydryl-piperidine hydrochloride of the formula:

melting at 195-208.

Example 2 The suspension of 25.1 g. of 3-benzhydryl-piperidine, 11.0 g. of ,8-chloroethyl-methylsulfide, 15.0 g. of sodium carbonate in 250 ml. of butanol containing a trace of water, is refluxed with stirring for 24 hours. After cooling the reaction mixture is filtered, the filtrate concentrated under reduced pressure and the residue distilled in a high vacuum. There is obtained the N- (Z-methylmercapto-ethyl)-3-benzhydryl-piperidine of the formula:

Example 3 To the suspension of 3.9 g. of N-(2-guanylmercaptoethyl)-3-benzhydryl-piperidine hydrochloride in 10* ml. of water the solution of 8.1 g. of sodium hydroxide in 30 ml. of water is added with stirring and stirring is continued for 5 hours at room temperature. Thereupon the reaction mixture is saturated with sodium choride, extracted with diethyl ether and the extract concentrated in vacuo in a stream of nitrogen. The residue represents the N-(2- mercapto-ethyl)-3-benzhydryl-piperidine of the formula:

CaH5

Example 4 The boiling solution containing 25.0 g. of N-allyl-3- benzhydryl-piperidine and a trace of ben-zoyl peroxide in ml. of benzene is treated with methyl mercaptan for 24 hours. After concentration of the reaction mixture under reduced pressure and distillation of the residue in a Example Other compounds of this invention which are prepared according to the above described and illustrated procedure by selecting equivalent amounts of the appropriate starting materials are, for example, the following:

gradually adding 4,000 ml. of boiling purified Water. The mixed powders are granulated with the above paste, using additional Water as required.

The resulting moist mass is passed through a mill, using a No. 4A screen, placed on trays and dried at 3 8 C. until the moisture content is between 2 percent and 3 percent. The granules are broken on a mill, passed through a No. 16 screen, and treated with the stearic acid and the calcium stearate, both screened through a No. 20 screen. After mixing for twenty minutes, the granulation is compressed into tablets, each weighing 0.25 g., using inch dies, standard concave punches, uppers bisected, lowers monogrammed.

Reagent Final Product Starting Material N-(2-chloro-ethyl)-2-benzhydryl-piperidine hydrochloride. N-(2-chloro-ethyl-4-benzhydryl-piperidine hydrochloride. N-(3-ehloro-propyl)-3-(di-paratolyl-methyD-prperrdine hydrochloride. N-(2-chloro-ethyD-3-(di-para chlorophenyl-methyl)- piperidine. v N-(2-chloroethyl)-3-(u-cyclohexyl-benzyD-prperrdine hydrochloride. I 3-(di-para methoxy-phenyl-methyl)-p1per1d1ne Thiourea PotassiuJu thioeyanate N,N-diethyl-thiourea 'y-B romopropyl-b enzylsulfide N-(Z-guanylmercapto-ethyl)-2-benzhydryl-piperidine hydrochloride.

N-(Z-g-uanylmercaptoethyl)-4-benzhydryl-piperidine hydrochloride.

N-(3-guanylmercapto-propyl)-3-(di-paratolyl-rnethyD- piperidine hydrochloride.

N-(2-cyanomercapto-etliyl) 3 (di-para chlorophenylmethyD- iperidine.

N-[2-(N,N -diethyl guanylmercapto)-ethyl]'3-(acyclohexyl-b enzyl) -piperidine hydrochloride.

N -(3-benzylrnereaptopropyl)-3-(di-para methoxyphenyl-methyl)-piperidine.

3.flu 1e1 y1-(9)-piperidine B-chlorpethyl-phenylsulfide N-(2-phenylmercapto-ethyl)-3-flu0Ienyl-(9)- iperldine. 1 1 3-(a-para-fiuoro-phenyl-benZyD- N,N-d1methyltlnourea N-[2(N,N-din1ethylguanylmercanto -ethy -3(apiperidine hydrochloride. para fluorophenyl-benzyl)-piperidine hydrochloride. N.(2-qh1oro-ethy1)-3-benzhydryl-p1perldm8 Thiourethane S-[2-(3-benzhydryl- 'peridino)-ethyl]-tl1iourethane 3-(1,2-diphenyl-ethyl)-piperidine 3-(di-ortl1o methoxy phenyl-methyl)-piperidine N-(3-bromo-propyl)-3-(di-para diethylarninophenyl-rnethyl)-pip eridine. N-(Z-bromoethyl)-3-triphenyl-rnethyl-pip eridme fl-chloroethyl-eyelohexylsultlde ,5-chloropropyl-ethylsulfide hydrochloride.

N-(Q-cyclohexylmercapto-ethyl)-3-(1,2-diphenylethyl)-piperidine.

N-(3-ethylmereapto-propyl-Z)-3-(di-ortho methoxy phenyl-methyl)-piperidine.

N- (B-guanylrn ercapto-propyl) -3-(di-p ara dl-ethylaminophenyl-methyl)-piperidine hydrobromide.

N(iZ-guauylniereapto-ethyl)3-triphenyl-methyl- I piperidine hydrobromide. 3.benzyl-p1pend1ne 3-br0m0 -m hyl-propyl-cyclo- N-(3-cyclopentylrnethyl-mercapto-2-metl1yl-pr0py1)- pentylmethyl-sulhde. 3-benzyl-piperidine. N-(2- ;hl m-ethyl)-3-benzhydryl-pyrlolldme Thiourea N-(Z-guanylmercapto-ethyD-lH)eu hyd yl-pyrro din hydrochloride. hydrochloride. N-m thaHyLS-benzhydr'yl-plpelldlne Methyl mer apt n N-(a-meghylmereapto-2-methyl-propyl)-3-benzhydrylpiperi me. (3. t11 i-buten-(2)-yl)-3-benzhydryl-pipendm do N- (2-methylmercapto-B-methyl-butyl) -3-benzhydry1- piperidine.

Example 6 Example 8 Preparation of 500 capsules each containing 0.01 g. of the active ingredient.

Ingredients: G.

N-(Z-guanylmercapto-ethyl)-3-benzhydrylpiperidine hydrochloride 5.000 Lactose 85.000

PROCEDURE The ingredients are blended in a suitable mixer, sieved through a No. 40 screen and again mixed; portions weighing 0.18 g. each of the resulting mixture are filled into No. 4 capsules.

Example 7 Preparation of 160,000 tablets each containing 0.025 g.

of the active ingredient.

Purified water, q.s.

PROCEDURE The hydrochloride, the lactose, 2,500 g. of the corn starch, the confectioners sugar and the colloidal silica are passed through a No. 16 screen into a mixer and blended at low speed for twenty minutes. The remainder of the corn starch is suspended in a cold solution of the color in 1,000 ml. of purified water, and a paste is formed by The mixture of 10.0 g. 3-benZhydryl-piperidine, 8.62 g. Z-phenylmercapto-ethyi bromide, 15.0 g. sodium carbonate, 1 drop Water and ml. benzene is refluxed for 6 hours while stirring. Hereupon it is filtered, the filtrate concentrated and the crystals, separating on standing in the cold are filtered off. The so-obtained N-(2-phenylmercapto-ethyl)-3-benzhydryl-piperidine of the formula is recrystallized from ethanol and melts at 99-100.

Example 9 To the solution of 3.5 g. N-(2-chloroethyl)-3-benzhydryl-piperidine hydrochloride in 50 ml. absolute ethanol, the solution of 1.14 g. N,N-dimethyl-thiourea in 30 ml. absolute ethanol is added and the whole refluxed for 6 hours while stirring, and stirring is continued overnight at room temperature. The reaction mixture is concentrated in vacuo and the residue recrystallized from ethanoldiethyl ether to yield the N-[2-(N,N-dimethyl-guanylmercapto) -ethyl]-3-benzhydry1-piperidine dihydrochloride of the formula C 11 NH orp N-CHaCH:-S-C

Cam N (CH3) 1.212101 which melts after drying in a high vacuum at 149153.

'The' analogously prepared N-[2-(N,N-diethyl-guanylmercapto) -ethyl] -3-benzhydryl-piperidine dihydrochloride melts at 58-59" (at 119 clear melt).

Example melting at 8690.

Example 11 To the solution of 1.32 g. N,N'-diethy1-thiourea in 35 ml. absolute ethanol, the solution of 3.5 g. N-(2-chloroethyl)-3-benzhydryl-piperidine hydrochloride in 50 ml. absolute ethanol is added while stirring and the mixture is refluxed for 6 hours and stirred overnight at room temperature. Hereupon, it is evaporated under reduced pressure; the residue triturated with diethyl ether; the ether decanted off and the residue dried in a high vacuum. There is obtained the hygroscopic N-[2-(N,N-diethylguanylmercapto -ethyl] -3-benzhydryl-piperidine dihydrochloride of the formula In the analogous manner, the N-[2-(N,N-diallylguanylmercapto) -ethyl] -3-benzhydrylpiperidine dihydrochloride is prepared from the equivalent amounts of starting materials; it melts at 65 and has the following .formula Example 12 The stirred mixture of 3.5 g. N-(2-chloroethyl)-3- benzhydryl-piperidine hydrochloride, 1.52 g. N-phenylthiourea and 100 ml. anhydrous ethanol is refluxed for 6 hours and stirred overnight at room temperature. The mixture is evaporated in vacuo and the residue triturated with diethyl ether to yield the N-[Z-(N-phenyl-guanylmercapto) -ethyl] -3-benzhydryl-piperidine dihydrochloride of the formula melting at 90-100".

. 10 Example 13 The stirred mixture of 2.82 g. N,N'-dibenzyl-thiourea, 3.5 g. N-(2-chloroethy1)-3-benzhydryl-piperidine hydrochloride and 275 ml. anhydrous ethanol is refluxed for 6 hours, and stirring is continued at room temperature overnight. It is evaporated in vacuo and the residue recrystallized from anhydrous ethanolto yield the N-[2-(N,N'-dibenzyl guanylmercapto) ethyl] 3 benzhydrylpiperidine dihydrochloride of the formula melting at 150-155".

Example 14 The stirred mixture of 4.0 g. N-(Z-chloroethyl)-3-(dip-tolyl-methyD-piperidine, 0.865 g. thiourea and 80 ml. anhydrous ethanol is refluxed and stirred for 8 hours and left stirring overnight at room temperature. It is evaporated in vacuo, the residue recrystallized from ethanoldiethyl ether and dried in a high vacuum to yield the hygroscopic N-(Z-guanylmercapto-ethyl)-3-(di-p-tolyl-methy1)-piperidine dihydrochloride of the formula By replacing in the above example the thiourea by 1.37 g. N-allyl-thiourea, the N-[2-(N-allyl-guanylmercapto)- ethyl]-3- (di-p-tolyl-methyl)piperidine dihydrochloride to the formula is obtained.

Example 15 The mixture of 3.5 g. N-(2 chloroethyl)-2-(2,2-diphneyl-ethyl)-piperidine hydrochloride, 2.94 g. N,N-dimethyl-thiourea and ml. absolute ethanol is refluxed for 6 hours while stirring. It is evaporated in vacuo and the residue triturated with diethyl ether to yield the N- [2-(N,N dimethyl guanylmercapto) ethyl] -2-(2,2-dipheny1-ethyl)-piperidine dihydrochloride of the formula melting at 60.

- Example 16 The stirred mixture of 4.0 g. N-(2-chloroethyD-4-benzhydryl-piperid-ine hydrochloride, 0.95 g. thiourea and 80 ml. absolute ethanol is refluxed for 8 hours and stirred overnight at room temperature. It is evaporated under reduced pressure, the residue triturated with diethyl ether and the hygroscopic crystals dried in a high vacuum, to yield the N-(Z-guanylmercapto-ethyl)-4-benzhydry1-piperidine dihydr-ochloride of the formula 11 Example 17 The mixture of 4.0 g. N-(2-chloroethyl-4-benzhydrylpiperidine hydrochloride, 1.47 g. N-allyl-thiourea and 80 ml. anhydrous ethanol is refluxed for 6 hours while stirring and kept at room temperature overnight. It is evaporated in vacuo, the residue tritrated with petroleum ether and the crystals formed are filtered 01f, representing the N [2 (N allyl-guanylmercapto)-ethyl]-4-benzhydrylpiperidine dihydrochloride monohydrate of the formula which is very hygroscopic.

In the analogous manner, the N-[2(N-methyl-N- phenyl guanylmercapto) ethyl]-4-benzhydryl-piperidine dihydrochloride of the formula is prepared by substituting the N-allyl-thiourea by 2.07 g. N-methyl-N-phenyl-thiourea.

Example 18 The mixture of 4.0 g. 2-(2-chloroethyl)-3-(di-p-tolylmethyl)-piperidine hydrochloride, 1.52 g. N-ethyl-thiorea and 80 ml. anhydrous ethanol is refluxed for 8 hours while stirring and kept overnight at room temperature. It is evaporated in vacuo, the residue recrystallized from ethanol-diethyl ether and dried in a high vacuum to yield the hygroscopic N-[2-(N-ethyl-guanylmercapto)-ethyl]-3- (di-p-tolyLmethyl)-piperidine dihydrochloride of the formula The compounds of the present invention, mentioned in this and in previous examples, without melting or boiling point, are either too hygroscopic for estimating the MP. or not distillable; they do, however, analyze correctly.

What is claimed is:

1. A member selected from the group consisting of compounds having the formula:

in which one of the radicals R R and R stands for a R phenyl radical and the other two stand for a member selected from the group consisting of hydrogen, monocyclic cyclo-lower alkyl, monocyclic cyclo-lower alkenyl and R.,phenyl, and R stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, trifluoromethyl and di-lower alkylamino, m stands for an integer from 1 to 4, n for an integer from 5 to 8, p for an integer from 2 to 8 and each of the radicals R, R and R" stands for a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, monocyclic cyclo-lower alkyl, monocyclic cyclo-lower alkenyl, monocyclic cyclo-lower alkyl-lower alkyl, monocyclic cyclo-lower alkyl-lower alkenyl, R -phenyl-lower alkyl, R -phenyl-lower alkenyl and monocyclic carbocyclic aryl and acid addition salts thereof.

12 2. A member selected from the group consisting of compounds having the formula:

in which each of the groups -R.,, and R stands for a member selected from the group consisting of phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, halophenyl, trifluoromethyl-phenyl and di-lower alkylamino-phenyl, each of the groups R and R stands for a member selected from the group consisting of hydrogen and lower alkyl and q stands for an integer from 2 to 4 and therapeutically acceptable acid addition salts thereof.

3. A member selected from the group consisting of compounds having the formula:

in which each of the groups R and R stands for a member selected from the group consisting of phenyl, lower alkyl-phenyl, lower alkoxy-phenyl, halophenyl, trifluoromethyl-phenyl and di-lower alkylamino-phenyl and q stands for an integer from 2 to 4 and therapeutically acceptable acid addition salts thereof.

4. N (2 guanylmercapto ethyl) 3' piperidine.

5. N [2 (N,N dimethyl guanylmercapto)-ethyl]- S-benzhydryl-piperidine.

6. N [2 (N,N diethylguanylmercapto) ethy11-3- benzhydryl-piperidine.

7. N [2 (N ethyl guanylmercapto) ethyl] 3- benzhydryl-piperidine.

8. N [2:(N,N' diethyl-guanylmercapto) ethyl] 3- benzhydryl-piperidine.

9. N [2 (N,N diallyl guanylmercapto) ethyl]- 3-benZhydryl-piperidine.

10. N [2 (N phenyl guanylmercapto) benzhydryl-piperidine.

11. N [2 (N,N dibenzyl guanylmercapto) ethyl]-3-benzhydryl-piperidine.

12. N (2 guanylmercapto ethyl) 3 (di-p-tolylmethyl) -piperidine.

13. N [2 (N allyl guanylmercapto) (di-p-tolyl-methyl) pip eridine.

14. N [2 (N,N dimethyl guanylmercapto)- et-hyl] -2- (2,2-diphenyl-ethyl) -piperidine.

15. N (2 guanylmercapto ethyl) 4 benzhydrylpiperidine.

16. N [2 (N allyl guanylmercapto) benzhydryl-piperidine.

17. N [2 (N methyl N phenyl guanylmercaptoethyl]-4-benzhydryl-piperidine.

18. N [2 (N ethyl guanylmercapto) ethyl-3-(di p-tolyI-methyl)-piperidine.

benzhydrylethyl1-3- ethyl] 3- ethyl] 4- NORMA S. MILESTONE, Acting Primary Examiner. A. D. SPEVAQK, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 ,366 ,637 January 30 1968 Robert Paul Mull et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 12, lines 19 to 25, the formula should appear as shown below:

/CH 5 7 I CH CH NH CH N C H S C CH CH NH same column 12 line 40 "N- [2 (N,N should read N [2- (N,N

Signed and sealed this 3rd day of February 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR.

Attesting Officer Commissioner of Patents