US3366636A - 1-mercapto-4-diphenylmethyl piperidine compounds - Google Patents
1-mercapto-4-diphenylmethyl piperidine compounds Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
Description
United States Patent Ofiice 3,366,636 Patented Jan. 30, 1968 3,366,636 1MERCAPTO4-DIPHENYLMETl-IYL PIPERIDINE COMPOUNDS Robert Paul Mull, Florham Park, and Renat Herbert Mizzoni, Long Valley, N.J., assignors to Ciba Corporation, New York, N.Y., a corporation of Delaware N Drawing. Filed Dec. 4, 1964, Ser. No. 416,144 4 Claims. (Cl. 260-2914) 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 a member selected from the group consisting of hydrogen, monocyclic cyclo-lower alkyl, monocyclic cyclo-lower alkenyl and monocyclic carbocyclic aryl, m stands for an integer from 1 to 4, n for an integer from to 8, p, for an integer from 2 to 8 and X for a member selected from the group consisting of SR, SCN,
in which 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 cycle-lower alkenyl, monocyclic cyclolowcr alkyl-lower alkyl, monocyclic cyclo-lower alkyllower alkenyl, monocyclic carbocyclic aryl-lower alkyl, monocyclic carbocyclic aryl-lower alkenyl and monocyclic carbocyclic aryl and salts thereof. In this application, the compounds being claimed are those in which, in the above formula, X is SR.
The present invention concerns and has for its object the provision of N mercaptoalkyl alkyleneimines containing an unsaturated hydrocarbon radical in the heterocyclic ring and 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 mer-capto 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: 1 mercaptoethyl p py p py y butyl (3), butyl (4), hexyl (6), heptyl (5), octyl (4) or 2 methyl propyl (2); 2 mercaptopropyl (3), butyl (3), butyl (4) or pentyl (5); 3 mercapto butyl (4) or hexyl (6). The mercapto group thereof may be free or substituted; it preferably stands for a member selected from the group consisting of SR, SCN,
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, cyc'lopentenyl or cyclohexenyl, cycloalkyllower alkyl or alkenyl containing preferabl 5 to 6 ring carbon atoms, such as cyclopentylethyl, cyclohexylmethyl or cyclopentylallyl, aryl lower alkyl or alkenyl, especially monocyclic carbocyclic aryl lower alkyl oralkenyl, 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, nor i-propyl, free or etherified hydroxy or mercapto, e.g. methoxy, ethoxy or methylenedioxy, methylor ethylmercapto, halogen, e.g. fluoro, chloro or bromo, trifiuoromethyl, nitro or amino, for example, lower alky-lor 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- or 2,5 hexamethyleneimino, 1,5-, 1,6-, 1,7- or 2,6 heptamethyleneimino or 1,8-, 3,6- or 3,7 octamethyleneimino.
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-(1) or (2), 1,1- or 1,2- diphenylethyl, 1,1,1 triphenylethyl (2), phenylpropyl 1), (2) or (3), 1,1-, 2,2-, 3,3-, 1,2-, 1,3- or 2,3- diphenylpropyl- (3), 1,3 diphenylpropyl (2), 1,2,3 triphenylpropylp y y 0r 1,3-, or 2,3 diphenylbntyl (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 a cyclopentyl-, a cyclohexylor at cyclohexen (2) yl benzyl, oz or [i cyclohexylphenethyl (2) or 1 cyclopentyl or 1 cyclopenten- (2) yl 2,2 diphenylethyl (2); or a partially hydrogenated bior tricyclic carbocyclic aryl radical, such as indenyl (l), hydrindenyl (2), tetralinyl (1) or (2), fiuorenyl (9), acenaphthenyl (l), 9,10 dihydroanthrazenyl (9) 0r 1,2,3 trihydrophenalenyl (2). 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 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. The compounds of this invention are, therefore, useful in the management and treatment of gastric irritation or of gastric ulcers by reducing the amount of free acid in the stomach. They are also useful as research tools in the study of the releasing mechanism 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:
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 cyclo-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 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 oralkenyl or monocyclic carbocyclic aryl.
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, trifiuoromethylphenyl or di-lower alkylamino-phenyl, each of the groups R and R stands for hydrogen or lower alkyl and 6; stands for an integer from 2 to 4.
Above all, the present invention concerns compounds of the formula in which R R and q have the meaning given above.
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 carbarnyl or ethenylene grouping, said grouping to the methyleneimino or ethylene grouping respectively.
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-toluenesulfonyloxy, The N-(R -alkyl)- alkyleneiinine starting compounds may be reacted with a compound containing a free mercapto group, such as hydrogen sulfide, a thio-alcohol or thiophenol, thio-cyanic 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 haloor 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-alkyleneirnine 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 hydrolyzed, 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 halogeni-des.
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 for the starting material, of catalysts, condensing agents and/or of inert atmospheres, 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, arc-matic 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, cthylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalene sulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.
These or 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 starting materials, for example, those mentioned under (a) and (c) are described in our copending applications Ser. No. 392,931, filed Aug. 28, 1964, now US. Patent No. 3,252,983, and Ser. No. 416,154, filed Dec. 4, 1964, now abandoned.
The N-alkenyl-alkyleneimine starting compounds are prepared from the N-unsubstituted alkyleneimines by reaction with a reactive esterified alkenol, for example, an aryl sulfonyl-oxy, or halogeno-alkene in the presence of a suitable base. Finally the N-mercaptoalkyl-alkyleneimino starting compounds, containing at least one carbonyl or ethenylene group, may be prepared analogous to the method described under (a) and (c) by selecting the appropriate reagents, for example, by reaction of an N-haloalkyl-alkenyleneimine or -oxoalkyleneimine containing in the ring an unsaturated hydrocarbon radical, with a compound containing a free mercapto group, e.g. those mentioned above or by reaction of a corresponding N-unsubstituted alkenyleneimine or oxoalkyleneimine with a halo-alkylmercapto 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 dilferences between the components, can be resolved into the stereoisomeric pure racemates (diastereoisomers), for example, by chromatography 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 perenteral 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 or 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 6 contain other therapeutically valuable substances. The pharmaceutical preparations are prepared by conventional methods.
The present invention also comprises the corresponding new N-alkenyl-alkyleneirnines containing an unsaturated hydrocarbon radical in the heterocyclic ring, which are used as starting material for the mercapto compounds.
The following examples illustrate the invention.
Example 1 .HCI
melting at 195-208 C.
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:
CnHs
CH NCHzCHzS-CH3 C5115 Example 3 To the suspension of 3.9 g. of N-(Z-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 chloride, 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-piperidi.ne of the formula:
Example 4 The boiling solution containing 25.0 g. of N-allyl-3- benzhydryl-piperidine and a trace of benzoyl 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 high vacuum, there is obtained the N-(3-methylmercapto-propyl)-3benzhydryl-piperidine of the formula CBHB N-CHr-CHz-OH2-SCH: CsHs Example 5 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:
After mixing for twenty minutes, the granulation is cornpressed into tablets, each weighing 0.25 g., using inch Starting Material Reagent Final Product N-(Q-ehloroethyl)-2-benzhydryl-piperidine hydro- Thiourea N(fl-guanylmercnpto-ethyl)-2-benzhydrylpiperidine e ride. hydrochloride. N-(Z-chloro-ethyl)-4-benzhydry1-plperidine hydrodo N-(2-guanylmercapto-ethyl)-4-benzhydry1-piperidine chloride. hydrochloride. N-(3-chloro-propyl)-3-(di paret0lyl-methy1)-piperi- .d0 N-(3-g-uanyhnercapto-propyl)-3-(di-paratolylrnethdine hydrochloride. N-( 2-chloro-ethy1)r3-(di-para chlorophenyl-methyD- piperidine. N-(Z-chloro-ethy l)-3- (a-cyclohexyl-b enzyl) -piperidine hydrochloride. 3-(di-para niethoxyphenyl-rnethyl)piperidine 3-fluorenyl- (9) -piperidine N-(z-chloro-ethyl) 3'(a-para-fluorophenyl-benzyl)- piperidine hydrochloride.
N- (Z-chloro-ethyl) -3-benzhydril-piperidine 3- (1,2-dephenyl-ethyl) piperidine 3-(di-ortho methoxy phenylanethyl)-piperidine N-(3-brorno-propyl)3-(di-para diethylaminophenylinethyD-piperidine. N-(2-bromoethyl)-3-triphenyl-1nethyl-piperidine.
3-benzyl-piperidine methyl-sulfide. N-(Q-chloroethyl)-3 benzhydryl-pyrrolidine hydrochloride. N-methallyl-3-benzhydryLpiperidine N-(S-methyl-buten-(2)-yl)-3-benzhydry1-piperidine Potassium thiocyanate N ,N -diethyl-thiourea 'y-Bromopropyl-benzylsulfide d0hloroethyl-phenylsulfide N ,N-dimethyl-thionrea Thiourethane fl-Chloroethyl-cyclohexylsulfide B-Chloroporpyl-ethylsulfide Thiourea 3-brorno-2-Inethyl-propyl-cyclopentyl- Thiourea Methyl mereaptan yl)-piperidine hydrochloride. N(2-cyanomercapto-ethyl)-3-(di-para chlorophenylmethyD-piperidine. N-[2- (N,N' diethyl guanylmercapto) 3 GthYl]3-(ocyclohexyl-henzyl)piperidine hydrochloride. N-(3'beuzylmercapto-propyl)-3-(di-para methoxyphenylanethyl)piperidine. N32phenyhnereapto-ethyl)-3 fiuorenyl-(9)-piperime. N-[2-(N,N- dimethyl guanylmercapto) -ethyl]-3 (apara fluorophenylbenzyl)-piperidine hydrochloride. S-{2-(El-benzhydryl-piperidino)-ethyl]-thiourethane hydrochloride. N-(2-eyclohexylmercapto-ethyl)-3(i,2diphenylethyl) piperidine. N-(Bethyh'nereapto-propyl-2)-3 (di -ortho methoxy phenyl-niethyl)-piperidine. N (3-guanylrnercapto-propyl)-3-(di-para diethylaminophenyl-methyD-piperidine hydrobromide. N-(Z-guauylmercapto-ethyl)3-triphenylmethyl-piperidine hydrobromide. N-(B-eyelopentylmethyhnercapto-2-rnethyl-propyl)- 3-benzyl-piperidine. N-(Z-guanylmercapto-ethyl-3-benzhydryl-pyrrolidino hydrochloride. N-(3-methylinercapto-amethyl-propyl)-3-henzhydryl-piperidine. N-(Z-methylmercapto-3-methyl-butyl)-3-benzhydrylpiperidine.
Example 6 Preparation of 500 capsules each containing 0.01 g. of the active ingredient.
Ingredients: Grams N (Z-guanylmercapto-ethyl)-3-benzhydrylpiperidine hydrochloride 5.000
Lactose 85.000
Pr0cedure.-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.
Pr0cedwre.-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 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 38 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.
dies, standard concave punches, uppers bisected, lowers monogrammed.
Example 8 The new starting materials used in the previous examples can be prepared as follows:
A mixture of 25.1 g. of 3-benzhydryl-piperidine, 12.1 g. of allylbromide and 42 g. of sodium carbonate in 150 ml. of benzene and 3.5 g. of Water is refluxed for twenty hours while stirring. The hot solution is filtered, the residue washed with hot benzene and the filtrate evaporated under reduced pressure. The residue is distilled in vacuo, the fraction boiling at 162163/0.3 mm. collected and recrystallized from aqueous ethanol; it represents the N- allyl-3-benzhydryl-piperidine of the formula:
Cal-I5 CLI- melting at 59-64.
In the analogous manner the N-rnethallyland .N-(3- methylbuten-Z-yl)-3-benzhydryl-piperidine of the for- -rnulae:
B.P. l40l51/0.2 mm. and
B.P. 173-175"/0.5 .mm. can be prepared by using equivalent amounts of the reagents.
9 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 monocyclic carbocyclic aryl 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 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 -S-R, in which R is a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, monocyclic cycle-lower alkyl, monocyclic cycle-lower alkenyl, monocyclic cycle-lower alkyl-lower alkyl, monocyclic cyclolower alkyl-lower alkenyl, monocyclic, carbocyclic aryllower alkyl, monocyclic carbocyclic aryl-lower alkenyl and monocy-clic carbocyclic aryl and salts thereof.
2. A member selected from the group consisting of N- (2 methylmercapto-ethyl)-3-benzhydryl-piperidine and therapeutically acceptable acid addition salts thereof.
3. A member selected from the group consisting of N- (2 crnercapto-ethyl)-3-benzhydryl piperidine and therapeutically acceptable acid addition salts thereof.
4. A member selected from the :group consisting of N- (3 methylmercapto-propyl)-3-benZhydryl-piperidine and therapeutically acceptable acid addition salts thereof.
References Cited UNITED STATES PATENTS 2,483,671 10/ 1949 .Rievesc-hl 260-293 3,252,976 5/1966 Bruce 260293 3,101,340 8/1963 Rorig 260-294.7
NORMA S. MILESTONE, Acting Primary Examiner. A. D. SPEVACK, Assistant Examiner.
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US416144A US3366636A (en) | 1964-12-04 | 1964-12-04 | 1-mercapto-4-diphenylmethyl piperidine compounds |
| US480136A US3366637A (en) | 1964-12-04 | 1965-08-16 | N-[(guanylmercapto)alkyl]-c-diaryl-methyl-piperidines |
| FR40622A FR1481944A (en) | 1964-12-04 | 1965-12-02 | Process for the preparation of mercapto-compounds, in particular nu-mercapto-alkylalkyleneimines |
| NL6515775A NL6515775A (en) | 1964-12-04 | 1965-12-03 | |
| BE673290A BE673290A (en) | 1964-12-04 | 1965-12-03 | |
| FR51599A FR5106M (en) | 1964-12-04 | 1966-03-02 | |
| FR51597A FR5251M (en) | 1964-12-04 | 1966-03-02 | |
| FR51598A FR4894M (en) | 1964-12-04 | 1966-03-02 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US416144A US3366636A (en) | 1964-12-04 | 1964-12-04 | 1-mercapto-4-diphenylmethyl piperidine compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3366636A true US3366636A (en) | 1968-01-30 |
Family
ID=23648743
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US416144A Expired - Lifetime US3366636A (en) | 1964-12-04 | 1964-12-04 | 1-mercapto-4-diphenylmethyl piperidine compounds |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3366636A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
| US3101340A (en) * | 1960-07-18 | 1963-08-20 | Searle & Co | 4-tertiary-butyl-, 4-diphenylmethyl-, and 4-diphenylhydroxymethyl - piperidinopropionitriles |
| US3252976A (en) * | 1963-01-21 | 1966-05-24 | American Home Prod | Process for making 2-secondary and tertiary amino-1-phenyl-ethane thiols |
-
1964
- 1964-12-04 US US416144A patent/US3366636A/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2483671A (en) * | 1947-06-02 | 1949-10-04 | Parke Davis & Co | Aminoalkyl benzhydryl thioethers and their preparation |
| US3101340A (en) * | 1960-07-18 | 1963-08-20 | Searle & Co | 4-tertiary-butyl-, 4-diphenylmethyl-, and 4-diphenylhydroxymethyl - piperidinopropionitriles |
| US3252976A (en) * | 1963-01-21 | 1966-05-24 | American Home Prod | Process for making 2-secondary and tertiary amino-1-phenyl-ethane thiols |
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