JPH021834B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION US Pat. No. 3,759,974 shows antispasmodic and neuroleptic activity. A number of 4-cyano-4-phenylcyclohexane amines are described. U.S. Patent No. 4,076,821 describes long-acting psychotropic agents, anxio-lytics,
A number of 1-(4,4-diphenylcyclohexyl)piperidines have been described as useful as sedatives, analgesics, CNS depressants, anti-inflammatory agents, coronary vasodilators, and hypotensive agents. US Pat. No. 4,051,248 is a CNS depressant and neuroleptic for use as a tranquilizer. A number of 1-phenyl-1,3,8-triazaspiro[4,5]decane-4-ones have been described. The compounds of the invention are distinguished from compounds of the prior art by the presence of specific substituents on the cyclohexyl and/or the presence of a piperidine ring and/or their pharmacological activity. According to the invention, the formula where A is the group [Formula] or [Formula]; Ar ¹ is phenyl, thienyl, pyridinyl, naphthalenyl or substituted phenyl, where the substituted phenyl is halo, lower alkyl, lower alkyloxy, phenyl It has one or two substituents selected from the group consisting of methoxy and trifluoromethyl (however, no more than one phenylmethoxy and trifluoromethyl is included), or 1,3-benzo is dioxolyl; R ¹ is hydrogen, cyano, carboxyl, lower alkyloxycarbonyl, aminocarbonyl, mono- or di(lower alkyl)aminocarbonyl, hydroxy, lower alkyloxy, lower alkanoyl or benzoyl; is hydrogen or lower alkyl; Ar ² is phenyl or halophenyl;
and R ⁴ is hydrogen or a group of the following formula, -C _o H _2o - R ⁵ or [Formula], where n is an integer of 1 to 4; R ⁵ is hydrogen, cyano, amino, C _{1- 4} alkyloxy, naphthalenyl, phenyl, C _1-4 alkylcarbonyl, C _1-4 alkyloxycarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl,
di(C _1-4 alkyl)aminocarbonyl, carboxyl or C _1-4 alkyloxycarbonylamino; x is O or S; R ⁶ is phenyl, C _1-4 alkyl, C _1-4 alkyl Provided are a novel series of 1-(4-arylcyclohexyl)piperidines, pharmaceutically acceptable acid addition salts and stereochemical isomers thereof, which can be structurally represented by: amino or phenylamino; be done. As used in the above definitions, the term "halo" generally means fluoro, chloro, bromo and iodo; the term "lower alkyl"
Straight-chain and branched saturated hydrocarbon radicals having 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1'-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl etc. Compounds of formula () are generally suitably substituted cyclohexane of formula (), where Ar ¹ and R ¹ are as defined above, and A and R are as defined above. It can be produced by a reductive amination reaction with a suitable piperidine derivative of formula (). The reductive amination reaction is preferably carried out by catalytic hydrogenation of the mixture of reaction components in a suitable reaction-inert organic solvent with stirring and heating according to catalytic hydrogenation methods known in the art. This can be done by doing the following: Suitable solvents are, for example, water; lower alkanols, such as methanol, 2-propanol, etc.; cyclic ethers, such as 1,4-dioxane; halogenated hydrocarbons, such as trichloromethane; N,N-dimethyl Formamide; dimethyl sulfoxide, etc.; or two of such solvents.
It is a mixture of more than one species. The term "art-known catalytic hydrogenation process" means that the reaction is carried out in a hydrogen atmosphere in the presence of a suitable catalyst, such as palladium on charcoal, platinum on charcoal, and the like. In order to prevent undesired further hydrogenation of certain functional groups in the reaction components and reaction products, it is advantageous to add a suitable catalyst poison, such as thiophene, to the reaction mixture. The compound of formula () can also be produced by reacting cyclohexanone () with piperidine () and reducing the intermediately formed enamine of formula (). The enamine production reaction involves a catalytic amount of relatively strong acid,
in the presence of suitable reaction-inert organic solvents, such as aliphatic, cycloaliphatic or aromatic hydrocarbons, such as 4-methylbenzenesulfonic acid;
For example, it can be carried out by stirring the reactants together in n-hexane, cyclohexane, methylbenzene, etc. To increase the rate of reaction, slightly higher temperatures are suitable, preferably the reaction is carried out at the reflux temperature of the reaction mixture. Most preferably, this reaction is carried out with azeotropic removal of water formed during the reaction. Reduction of the enamine of formula () is carried out, for example, by stirring the enamine () in the presence of a suitable reducing agent, such as a complex metal hydride, e.g. sodium borohydride, in a suitable solvent. . Suitable solvents include, for example, alkanols,
e.g., methanol, 2-propanol, etc.; and cyclic ethers, e.g., tetrahydrofuran, 1,4
- Dioxane, etc.; if necessary, a mixture of these and water. Elevated temperatures can be used to increase reaction rates. In order to avoid the undesirable presence of reducing agents, it may be advantageous to carry out the reaction in an alkaline medium, for example in the presence of sodium methoxide in methanol, sodium hydroxide in water. Compounds of formula () further provide compounds in which R ¹ and Ar ¹ are as defined above and W is a suitable reactive leaving group, such as halo, preferably chloro, bromo or iodo, or a sulfonyloxy group;
For example, methylsulfonyloxy, 4-methylphenylsulfonyloxy, etc., a suitable cyclohexane of formula () and a suitably substituted piperidine of formula () are combined by N-alkylation methods known in the art. Therefore, it can be produced by reaction. The N-alkylation reaction is preferably carried out in an inert organic solvent, such as aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, etc.; lower alkanols, such as methanol, ethanol,
1-Butanol, etc.; ketones, e.g., 4-methyl-
2-pentanone, etc.; ethers, e.g., 1,4-dioxane, 1,1'-oxybisethane, etc.; N,
Performed in N-dimethylformamide; nitrobenzene, etc. A suitable base, e.g. an alkali metal carbonate or bicarbonate, or an organic base, e.g.
The acid liberated during the reaction can be removed by adding N,N-diethylethanamine or the like.
In some cases it may be appropriate to add an iodide salt, preferably an alkali metal iodide.
Slightly higher temperatures can be used to increase the reaction rate. Depending on the nature of R ¹ , compounds of formula () can be converted into each other according to art-known functional group exchange reactions. Several group exchange reactions are illustrated in Reaction Diagram 1. base here is represented by L. In reaction diagram 1, Ra is lower alkyl,
Rb and Rc are hydrogen or thealkyl, Rd
is lower alkyl. Nitrile functional groups are described, for example, in J. Am. Chem.
Soc. 56 , 1614-1616 (1934) and J.Am.Chem.
Soc., 91 , 2059-2062 (1969), in which the nitrile is stirred with thorium or sodium amide in the presence of a high-boiling hydrocarbon, e.g., methylbenzene. And by heating, it can be converted into a hydrogen group. The nitrile functionality can also be converted to an aminocarbonyl functionality by hydrolyzing the nitrile in a strongly acidic medium. The aminocarbonyl compounds thus obtained can be further hydrolyzed in a weakly acidic aqueous medium, thus yielding the corresponding carboxylic acids. Carboxylic acids can be derived directly from nitriles by hydrolyzing the nitriles in a weakly acidic aqueous medium, while esters can be derived from nitriles by alcoholizing the starting nitrile. The carboxyl functional group is prepared as an ester functional group, respectively, by stirring the starting carboxylic acid with a suitable alcohol, amine and halogenating agent and optionally heating, according to methods known in the art. The amide or halocarbonyl functionality can be varied. Suitable halogenating agents are, for example, phosphoryl chloride, phosphopentapromide, thionyl chloride and the like.
The carboxylic acid functionality can also be converted to an ester functionality by reacting the starting carboxylic acid with a suitable alkyl halide or aryl lower alkyl halide in the presence of a base, such as sodium methoxy. A halocarbonyl function can be converted to an amide or ester function, respectively, by stirring the starting halocarbonyl compound with a suitable amine or a suitable alcohol and optionally heating. Ester and amide functions can be converted to carboxyl functions according to art-known hydrolysis methods, for example, by stirring and heating the starting ester in an acidic or alkaline aqueous medium. The secondary amide functionality and the tertiary amide functionality are
primary amide and secondary amide compounds, respectively;
According to art-known N-alkylation methods, N-
It can be produced by alkylation. The cyanide functionality is removed in the presence of a suitable solvent, such as 1,1'-oxybisethane, for example, in the presence of lithium aluminum hydride or lithium triethoxyhydroaluminate, according to art-known reduction methods. By stirring the nitrile compound, it can be converted to formyl functionality. Lower alkylcarbonyl, arylcarbonyl and aryllower alkylcarbonyl functions are obtained by starting from a nitrile function and converting the nitrile into a suitable lower alkyl halide, aryl halide or aryl lower alkyl halide and the presence of magnesium as known in the art. It can be induced by reacting according to the Grignard reaction. A compound of formula () in which A is a group (b) and R ⁴ is hydrogen, this compound is represented by formula (-a), is a group (b) and R ⁴ is other than hydrogen. can be converted into a compound of formula (). This R ⁴ is represented by R ^4-a , and this compound is represented by formula (-b). A compound of formula (-b) in which R ^4-a is as defined above, with the proviso that n is not 0 in the group [formula], where R ^4-a is R ^4-a-1
and this compound has the formula (-b-
1) is the reaction of a suitable compound of formula (-a) with a reagent of formula () according to the art-known N-alkylation methods described above for the reaction of () with (). It can be manufactured by R ^4-a is the formula , R ⁷ , R ⁸ and R ⁹ are each independently hydrogen or lower alkyl, provided that their total does not exceed 4 carbon atoms, and Z
cyano or formula A compound of formula (-b) which represents a group of, this compound is represented by formula (-b-2), is formula ()
It can also be produced by a 1,4-addition reaction of a reagent of formula (-a) to a compound of formula (-a). The 1,4-addition reaction is generally carried out in a suitable solvent, such as an ether, e.g. 1,4-dioxane, tetrahydrofuran, etc., an alcohol, e.g. methanol, 2-propanol, etc., an aliphatic, alicyclic or aromatic hydrocarbon. , a suitable base, e.g., cyclohexane, pentane, methylbenzene, etc.
For example, in the presence of N,N,N-trimethylbenzenemethanamium hydroxy, etc., the reaction components can be stirred together and preferably heated. R ^4-a is the formula represents ^{a group} of the ^{formula (} -b), this compound is represented by the formula (-b-3), is the formula (
It can also be prepared by reacting a compound of -a) with a compound of formula () according to art-known N-alkylation methods. A compound of formula (-b) in which R ^4-a represents a group of formula [formula], provided that R ⁵ is other than hydrogen,
This R ⁵ is represented by R ^5-a , and this compound is represented by formula (-b-4), which is represented by formula (-a).
can be combined with a reagent of formula (), where hal is chloro, bromo or iodo, and a compound known in the art with N-
According to the acylation process, solvents inert to the reaction, such as ethers, e.g., 1,4-dioxane, tetrahydrofuran, etc., aliphatic, alicyclic and aromatic hydrocarbons, e.g., pentane, cyclohexane, methylbenzene, etc. It can also be prepared by reacting the reactants by stirring and heating the reactants. R ^4-a is a compound of formula (-b) representing a group of [formula], this compound is represented by formula (-b-5), and R 4-a is a compound of formula (-a) representing a group of formula ()
It can also be produced by reacting with a reagent. The reaction is carried out by stirring the reaction components in a suitable reaction-inert solvent, such as methylbenzene, preferably in the presence of a suitable acid, such as 4-methylbenzenesulfamic acid, and as necessary. This can be carried out by heating accordingly. A compound of formula (-b) in which R ^4-a represents a group of formula [formula], this compound is of formula (-b-6)
It is expressed as is a suitable base, e.g., N,
In the presence of N-dimethyl-4-pyridineamine, compounds of formula (XI) can also be prepared by reacting with (-a) by stirring the reaction components together and optionally heating. . Compounds of formula () can be converted into therapeutically active non-toxic acid addition salt forms by treatment with the appropriate acid. Suitable acids include, for example, inorganic acids such as hydrohalic acids, e.g.
Hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, propionic acid, 2-hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid,
Butanedioic acid, (Z)-2-butanedioic acid,
(E) -2-Butanedioic acid, 2-hydroxybutanedioic acid, 2,3-dihydroxybitadionic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid , α-hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, 2-hydroxybenzoic acid,
4-amino-2-hydroxybenzoic acid and the like. Conversely, the salt form can be converted to the free base form by treatment with calcali. As is clear from formula (), the compounds of the invention exist in different stereochemical isomers. Because of the substituents on the cyclohexyl ring, the compounds can exist in two different geometric isomers: cis and trans. Moreover, when R represents a lower alkyl group, 2
There are two additional asymmetric carbon atoms. Each of these chiral centers can exist in the R- and S-configurations, the R- and S-signs being R,S.
Cahn, C. Ingold and V. Prelog, Angew.
This corresponds to the rule described in Chem., Int.Ed.Engl., 5 , 385, 511 (1966). Because of the two asymmetric carbon atoms, the piperidine moiety can exist in cis and trans forms. Pure stereochemically isomeric forms of compounds of formula () can be obtained by methods known in the art. Diastereoisomers can be determined by physical methods, such as selective crystallization and chromatographic techniques,
For example, they can be separated by countercurrent partitioning, and the enantiomers can be separated from each other by selective crystallization of their diastereomeric salts using optically active acids. Purely stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials if the reaction does not occur stereospecifically. For most compounds and starting materials, stereochemical configuration is not determined experimentally. In those cases, it is not acceptable to label a stereochemical isomer as first isolated as "A" and second as "B" without further reference to the actual stereochemical form. It is commonly accepted. The subscript p or c indicates the piperidine and cyclohexyl moieties, respectively, to which the stereochemical sign is related. Stereochemical isomers of compounds of formula () are naturally included within the scope of the present invention. A large number of the intermediates and starting materials in the above preparations are known and all of them can be prepared according to art-known methods of preparing similar compounds. A number of such manufacturing methods are discussed in some detail below. The intermediate of formula () is an ester () of arylacetonitrile (XII) with a suitable acid (in the formula, R'' represents an optionally substituted lower alkyl group)
can be prepared by a Michael addition reaction with a cyclic Michael addition reaction product, followed by hydrolysis of the cyclic Michael addition reaction product thus obtained in an acidic medium. The Michael addition reaction is preferably carried out in a suitable solvent, such as an alkanol, e.g. ethanol,
1,1-dimethylethanol, etc.; aliphatic, alicyclic or aromatic hydrocarbons, e.g. n-hexane,
This is carried out by stirring the reaction components in cyclohexane, methylbenzene, etc. in the presence of a suitable strong base, e.g., sodium hydride, sodium methoxy, etc., depending on the solvent used, and, if necessary, heating. do. Hydrolysis is generally carried out by stirring and heating the Michael addition reaction product in an aqueous acidic medium, such as aqueous hydrochloric acid. Intermediates of formula () can be prepared by converting the hydroxyl functionality of a suitably substituted cyclohexanol () into a suitable reactive leaving group W. The conversion of this hydroxy functional group into a leaving group W is
For example, it can be carried out by stirring the alcohol () with a suitable halogenating or sulfonylating agent, such as thionyl chloride, methanesulfonyl chloride, etc. In order to neutralize the acid liberated during the reaction, it may be appropriate to add a suitable base to the reaction mixture or to carry out the reaction in a suitable alkaline organic solvent, such as pyridine. Cyclohexanol () can be derived from the corresponding cyclohexanone () by reduction methods known in the art. Depending on the nature of R ¹ , intermediates ( ) and ( ) can be changed from one another according to art-known exchange methods of functional groups, as illustrated in Reaction Scheme 1. In some cases it may be advantageous to protect other groups present in the starting intermediate before functional group exchange and to remove the protecting groups afterwards. Certain numbers of intermediates in formula () are described in U.S. Patent No.
3929801 and 3155670 and Helv.Chm.
Acta 1960 12981313, and all of them can be manufactured according to similar methods. The compounds of formula (), their pharmaceutically acceptable acid addition salts and their geometric isomers have psychotropic, especially sedative and antiemetic, activity. The activity of such psychotropic and antiemetic drugs is
This is evidenced by experimental data obtained in at least one of two different test methods: a combined apomorphine, tryptamine and norepinephrine test in rats and apomorphine test in dogs. The test was conducted according to the method described below. The experimental data obtained are summarized in Tables 1, 2 and 3. 1. Testing of apomorphine (APO), tryptamine (TRY) and norepinephrine (NOR) in rats The experimental animals used in this study were adult male Wistar rats (body weight
240±10g). After an overnight fast, animals were treated subcutaneously with an aqueous solution of the test compound (1
ml/100g) (time = 0) and isolated in a viewing cage.
Thirty minutes later (time = 30 minutes), 1.25 mg/Kg of apomorphine hydrochloride (APO) was injected intravenously and the rats were observed for 1 hour for the presence or absence of the following apomorphine-induced phenomena: excitement and habituation. Do the same. At the end of this 1-hour period (time = 90 minutes), the same animal was injected with 4 mg/Kg of tributamine (TRY) intravenously and the presence of typical tryptamine-induced bilateral tonic seizures was observed. Admitted. Finally, 2 hours after pretreatment (time = 120 minutes), the same animals were
1.25 mg/Kg of norepinephrine (NOR) intravenously and possible death.
Observation was continued until 60 minutes later. Tables 1, 2 and 3 list a number of the compounds in question.
Enter the _ED50 value. As used here,
The ED ₅₀ value represents the dose that protects 50% of the animals from apomorphine, triptan or norepinephrine induced phenomena. 2 Apomorphine test in dogs (APO-
The method used was that of PAJJanssen and CJE.
Niemegeers, Arzneim—Forsch. (Drug Res),
9, 765-767 (1959). Table 1,
The compounds described in 2 and 3 are administered subcutaneously to beagle dogs in different amounts, and the animals are
After hours, a standard dose of 0.31 mg/Kg apomorphine was administered subcutaneously. Tables 1, 2 and 3 list a number of the compounds in question.
Enter the _ED50 value. As used here,
The ED ₅₀ value represents the dose that protects 50% of the animals from vomiting. The compounds shown in Tables 1, 2 and 3 are not listed for the purpose of limiting the invention thereto, but exemplify all the significant anti-emetic and psychotropic properties of the compounds within formula (). Listed for purpose only. [Table] [Table]

Claims (1)

[Claims] 1 formula , pharmaceutically acceptable acid addition salts and stereochemical isomers thereof: where A is the group [Formula] or [Formula]; Ar ¹ is phenyl, thienyl, pyridinyl, naphthalenyl or substituted phenyl, wherein the substituted phenyl has one or two substituents selected from the group consisting of halo, lower alkyl, lower alkyloxy, phenylmethoxy, and trifluoromethyl, with the proviso that phenylmethoxy and R ¹ is hydrogen, cyano, carboxyl, lower alkyloxycarbonyl, aminocarbonyl, mono or di( lower alkyl) aminocarbonyl, hydroxy, lower alkyloxy, lower alkanoyl or benzoyl; R is hydrogen or lower alkyl; Ar ² is phenyl or halophenyl;
and R ⁴ is hydrogen or a group of the following formula, -C _o H _2o - R ⁵ or [Formula], where n is an integer of 1 to 4; R ⁵ is hydrogen, cyano, amino, C _{1- 4} alkyloxy, naphthalenyl, phenyl, C _1-4 alkylcarbonyl, C _1-4 alkyloxycarbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl,
di(C _1-4 alkyl)aminocarbonyl, carboxyl or C _1-4 alkyloxycarbonylamino; x is O or S; R ⁶ is phenyl, C _1-4 alkyl, C _1-4 alkyl Amino or phenylamino. 2. The compound according to claim 1, wherein the group A is a group of the formula [Formula]. 3 (B)-8-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-1-(4-fluorophenyl)-α-methyl-4-oxo-1,
3,8-triazaspiro[4,5]decane-3-
A compound according to claim 1 selected from the group consisting of propanenitrile and pharmaceutically acceptable acid addition salts thereof. 4 (B)-8-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5] A compound according to claim 1 selected from the group consisting of decane-3-acetamide and a pharmaceutically acceptable acid addition salt thereof. 5 formula where A is the group [Formula] or [Formula]; Ar ¹ is phenyl or substituted phenyl having 1 or 2 lower alkyl groups; R ¹ is cyano, lower alkyloxycarbonyl, amino carbonyl, lower alkyloxy or lower alkanoyl; Ar ² is phenyl or halophenyl;
and R ⁴ is hydrogen or a group of the following formula, -C _o H _2o - R ⁵ or [Formula], where n is an integer of 1 to 4; R ⁵ is hydrogen, C _1-4 alkyl carbonyl, aminocarbonyl, C _1-4 alkylaminocarbonyl, or di(C _1-4 alkyl)aminocarbonyl; R ⁶ is C _1-4 alkylamino; An antiemetic and sedative pharmaceutical composition in dosage unit form containing a pharmaceutically acceptable acid addition salt thereof as an active ingredient. 6. The pharmaceutical composition according to claim 5, wherein the group A is a group of the formula [Formula]. 7 (B)-8-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-1-(4-fluorophenyl)-α-methyl-4-oxo-1,
3,8-triazaspiro[4,5]decane-3-
6. The pharmaceutical composition according to claim 5, which contains as an active ingredient a compound selected from the group consisting of propanenitrile and pharmaceutically acceptable acid addition salts thereof. 8 (B)-8-[4-cyano-4-(4-fluorophenyl)cyclohexyl]-1-(4-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4,5] The pharmaceutical composition according to claim 5, which contains as an active ingredient a compound selected from the group consisting of decane-3-acetamide and its pharmaceutically acceptable acid addition salts.