CS205088B2 - Method of producing oxoderivatives of aryloxy-perhydro-aza-heterocycles - Google Patents

Description

The present invention relates to a process for the preparation of aryloxyperhydroazalieterocycles and their salts.

The compounds produced according to the invention correspond to the general formula I

O

Ar ~ (I) in which

R 1 is an aliphatic hydrocarbon radical having up to 4 carbon atoms, n 1 and n 2 each having a value of 1 to 3, the sum of n 1 + Π 2 being at most 4, and

Ar is optionally a phenyl radical substituted with up to 4 carbon atoms.

Aliphatic hydrocarbon radicals R @ 1 are preferably lower alkyl, but may also be lower alkenyl or lower alkynyl.

In connection with the present invention, the general terms used have, for example, the following meanings:

The defined alkyl such as R 1 and as the substituent Ar may be unbranched or the bull may be branched especially at the carbon atom and may be, for example, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl and in particular methyl .

Alkenyl such as R 1 contains one or more double bonds and is, for example, allyl, 1- or 2-methylallyl or 3,3-dimethylallyl, whereas lower alkynyl such as R 1 is, for example, propargyl.

The phenyl moiety Ar is substituted, for example, one or three times, and preferably with two, defined alkyls, in particular methyl.

Salts of the compounds of formula I are acid addition salts, especially pharmaceutically acceptable non-toxic addition salts with suitable inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or with suitable organic, such as aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid,

208088 glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methanesulfonic acid , ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, 4-chlorobenzenesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid, or cyclobexylamine sulfonic acid.

Due to the close relationship between the novel compounds in the free form and in the form of their salts, the free compounds and the salts according to the purpose and purpose are also to be understood as correspondingly corresponding salts or free compounds.

The compounds of the invention may optionally be in the form of racemates or optical antipodes.

The novel compounds of the formula I have valuable pharmacological properties and, in particular, have antidepressant activity, as can be shown by appropriate pharmacological tests. Thus, these agents suppress norepinephrine uptake, as exemplified by suppressing noradrenaline secretion caused by 3-hydroxy-4-methyl-α-methylphenethylamine in rat brain [A. Carlsson, H. Corrodi, K. Fuxe, and T. Hoekfelt: Europ. J. Pharmacol. 5, 367 (1969)] after oral administration at 100 mg / kg. Further, they potentiate the serotonin effect, as evidenced by potentiating the efficacy of 5-hydroxytryptophan-induced head tremor in mice after intraperitoneal administration of 3 to 100 milligrams per kg. In particular, these compounds are inherently suppressed by serotonin uptake, as can be shown by suppressing serotonin secretion caused by 2-hydroxy-4-methyl-α-ethylphenethylamine [A. Carlseon and Others: Europ. J. Pharmacol. 5, 357 (1969)] in rat brain following oral administration of a dose of 3 to 100 mg / kg.

These pharmacological properties are characterized by the novel compounds and their pharmacologically acceptable acid addition salts as antidepressants, which can be used in the form of pharmaceutical preparations for the treatment of depression of various kinds.

In particular, the invention relates to the preparation of compounds of the formula I in which R 1 represents an alkyl group having up to 4 carbon atoms and the phenyl radical Ar is optionally substituted by an alkyl radical having up to 4 carbon atoms, which radical may be present once or twice and the same or different from each other, and n1, n1 and n1-n2 are as defined above, and their acid addition salts, in particular pharmaceutically usable acid addition salts.

In particular, the invention relates to the preparation of compounds of the formula I in which R1 represents an alkyl group having up to 4 carbon atoms, in particular methyl and Ar represents one or preferably twice an alkyl group having 1 to 4 carbon atoms, in particular a methyl-substituted phenyl radical. the radicals may be the same or different from each other, n 1 and n together represent 3, and n 1 is predominantly 1 and n 2 is 2, as well as their acid addition salts, in particular pharmaceutically usable acid addition salts.

More particularly, the invention relates to the production of 4- (3,4-dimethylphenoxy) -1-methyl-1-3-piperidone and 4- (2,3-dimethylphenoxy) -1-methyl-3-piperidone, as well as 1 acid addition salts thereof. , in particular pharmaceutically usable acid addition salts, and hydrates thereof.

The novel compounds of the formula (I) according to the invention are prepared by the preparation of a compound of the formula (II)

in which

R 1, Ar, n 1, n 2 as well as n 1 -j-n 2 are as defined in formula I, oxidize.

The oxidation can be carried out, for example, according to the method of Pfitzner and Moffat, J. Amer. Chem. Soc. 85, 3027 (1963) and 87, 5661 to 5670 and 5670 to 5678, especially 5675 (1965) with dimethylsulfoxide and dicyclohexylcarbodiimide, for example in the presence of pyridine and trifluoroacetic acid, further according to the method described by Albright and Goldman, J. Amer. Chem. Soc. 89, 2416 (1967) using dimethyl sulfoxide and acetic anhydride, according to the method of Corey and Kim, J. Amer. Chem. Soc. 94, 7586 (1972) using N-chlorosuccinimide and dimethylsulfoxide, or according to the Oppenauer method, by reaction with aluminum tri-tert-butoxide in the presence of an excess of a ketone such as acetone or cyclohexanone.

The starting materials of the formula II can be obtained by methods known per se.

For example, a compound of formula IIIa may be used

in which

X is an easily cleaved group such as a benzyloxycarbonyl group or a trichloroethoxycarbonyl group, oxidized with an oxidizing agent such as a peroxide derivative, for example by treatment with hydrogen peroxide, in methylene chloride in the presence of trifluoroacetic anhydride to give the corresponding 3,4-epoxide derivative a compound of formula IIb

Ar — O — H (lib) in which

Ar is as defined in formula I, whereupon the group X attached to the nitrogen atom is cleaved, for example by hydrogenolysis or reduction, and finally the hydrogen atom now present on the nitrogen atom is replaced in a manner known per se, for example by direct alkylation, by reaction with a lower oxoalkane such as formaldehyde, in the presence of a reducing agent such as formic acid, or also in two stages by introducing a lower alkanoyl group, such as a formyl group, and reducing with a complex hydride such as lithium aluminum hydride, as defined above for R 1.

Depending on the process conditions and the starting materials, the novel compounds are obtained in free form or in the form of their salts, which are also within the scope of the invention, wherein the novel compounds or their salts may also be present in the form of hemihydrates, sesquihydrates or polyhydrates or in particular as monohydrates . The acid addition salts of the novel compounds can be converted into the free compounds in a manner known per se, for example by treatment with basic agents such as alkali metal hydroxides, carbonates or acid carbonates or ion exchangers, and these can be converted again if they contain acidic substituents such as phenolic hydroxyl groups; carboxylic acid groups, can be converted to base salts by treatment with suitable strong bases. On the other hand, the free bases obtained can form acid addition salts with organic or inorganic acids, for example with the abovementioned acids. In particular, acids and bases suitable for the preparation of pharmaceutically usable salts are used in the preparation of acid addition salts and base salts.

These or other salts, especially the acid addition salts of the novel compounds, such as picrates or perchlorate, can also be used to purify the free bases obtained by converting the free bases into salts, separating and purifying them, and from the salts. releases the base again.

Depending on the choice of starting materials and processes, the novel compounds can be present as optical antipodes or racemates or, if they contain at least two asymmetric carbon atoms, also as mixtures of racemates.

The racemate mixtures obtained can be separated into both stereoisomeric (diastereomeric) raceinates in a known manner, for example by chromatography and / or fractional crystallization, based on the physicochemical differences of the diastereoisomers.

The racemates obtained can be decomposed into antipodes by known methods, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reaction with an optically active substance which forms salts with a racemic compound, in particular an acid, and on the basis of various solubilities, to diastereomeric salts from which free antipodes can be released by treatment with suitable agents. Particularly suitable optically active acids are, for example, the D and L forms of tartaric acid, O, O-di-p-toluyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid. Preferably, the more effective of both antipodes is isolated.

The invention also relates to those embodiments of the process in which the starting material is formed under the reaction conditions or in which the reactants are optionally present in the form of their derivatives as salts.

Suitably, starting materials are used for carrying out the reaction according to the invention, which lead to the groups of final substances especially mentioned at the outset, and in particular to the particularly described or emphasized reaction products. The starting materials present in the cis- or trans-configuration provide the same reaction products with the two oxidations according to the invention.

The novel compounds can be used, for example, in the form of pharmaceutical preparations which are suitable for enteral, for example oral or rectal, or for parenteral administration, containing a therapeutically effective amount of the active ingredient optionally together with pharmaceutically acceptable carriers, which carriers can be inorganic or organic. solid or liquid. Thus, tablets or gelatin capsules containing the active ingredient, i.e. a compound of formula I or a pharmaceutically acceptable salt thereof, are used together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or and glidants such as silica gel, talc, stearic acid or its salts, such as magnesium or calcium stearic acid, and / or polyethylene glycol. The tablets may also contain binding agents, for example, aluminum magnesium silicate, starches such as corn, wheat, rice or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone, and / or optionally disintegrating tablets such as starches, agar, acid. alginic acid or a salt thereof, such as sodium alginate, or effervescent agents, or adsorbents, colorants, flavors, and sweeteners. Furthermore, the novel pharmacologically active compounds can be used in the form of parenterally administrable compositions or infusion solutions. Such solutions are preferably isotonous aqueous solutions or suspensions, which preparations may be prepared prior to use, for example in the case of freeze-dried preparations which contain the active substance alone or together with a carrier material, for example mannitol.

The pharmaceutical preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, cosolvents, osmotic pressure salts and / or buffers,

Said pharmaceutical compositions, which may optionally contain other pharmacologically active substances, are produced in a manner known per se, for example by means of conventional mixing, granulating, dragee dissolving and lyophilizing processes, and contain about 0.1 to 100%, in particular about 1 to about 50% active ingredients, lyophilizates up to 100% active ingredient.

The dosage may be dependent on various factors such as the mode of administration, the type, between. about 0.5 mg / kg and about 50 mg / kg, for age and / or individual condition. Daily dosages for oral administration range from about 70 kg to about 70 kg, especially from about 0.05 to about 3.0 g.

The following examples serve to illustrate the invention. Temperatures are given in degrees Celsius.

Example 1

2.0 g (0.0085 mol) of trans-3-hydroxy-4- (3,4-dimethylphenoxy] -1-methylpiperidine were dissolved together with 6.0 g (0.03 mol) of dicyclohexylcarbodiimide and 0.745 g (0.094 mol) of pyridine in 20 ml of absolute dimethylsulfoxide, the mixture was cooled to 0 ° C in an ice / water bath, 1.6 g (0.014 mol) of trifluoroacetic acid was added, and the cooling bath was removed and the white suspension was further stirred at The reaction mixture was diluted with 100 mL of methylene chloride and treated dropwise with a solution of 2.5 g (0.03 mol) of oxalic acid in 10 mL of methanol. The aqueous phase of the filtrate was basified with concentrated aqueous ammonia solution and extracted three times with 159 ml of methylene chloride. The combined organic phases were washed several times with water, dried over sodium sulfate and concentrated by evaporation. in The solution is acidified by addition of ethereal hydrogen chloride and evaporated to dryness. The residue obtained is taken up with a small amount of water and crystallized from acetone to give 1-methyl-4- (3,4-dimethylphonoxy) -3-piperidone hydrohydrochloride, m.p. 123-125 ° C.

The starting material can be produced as follows:

and 83.1 g (1 mol) of 1,2,5,6-tetrahydropyridine are dissolved in 300 ml of benzene. 83 g of sodium bicarbonate are added to this solution, the mixture is cooled to 0 ^{DEG C.} under a nitrogen atmosphere and 332 ml of a 50% solution of benzyl chloroformate in toluene (1 mol) are added dropwise over 1 hour at this temperature. The reaction mixture was stirred for a further 2 1/2 hours at 0 ° C and then poured over

1.5 liters of ice water. The benzene phase is separated, the aqueous phase is extracted three times with 250 ml of methylene chloride. The combined organic phases are then washed with 1 N hydrochloric acid solution, then with saturated sodium chloride solution, dried over sodium sulfate and evaporated in a water-jet vacuum. The oily residue was distilled under high vacuum to give 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine, bp 102-113 ° C / 1 mbar. gives 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine having a melting point of 102 to 113 ° C / 1.3 Pa.

(b) 108.5 g (0.5 mol) of 1-benzyloxycarbonyl-1,2,5,6-tetrahydropyridine are dissolved in 1000 ml of dichloroethane and 182 g (0.9 mol) of 85% m- chloroperbenzoic acid. The slightly exothermic reaction is maintained at room temperature using a water bath. After completion of the addition, the reaction mixture which forms a white suspension is stirred for 48 hours at room temperature, the precipitated m-chlorobenzoic acid is filtered off, the filtrate is washed successively with saturated sodium carbonate solution, then with ferrous sulphate solution, then with 0.1 N hydroxide solution. The organic phase is dried over sodium sulphate and evaporated under a water pump vacuum. The 3,4-epoxy-1-benzyloxycarbonylpiperidine, which remains as a yellowish oil, is spectroscopic and uniform according to thin layer chromatography, and can be used for further reactions without further purification. Distillation of this compound under high vacuum at a boiling point of 145-146 DEG C./53 mbar produces partial decomposition.

c) 116.5 g (0.5 mol) of 3,4-epoxy-1-benzyloxycarbonylpiperidine are dissolved together with 122 g (1 mol) of 3,4-dimethylphenol and 500 ml of 2 N sodium hydroxide solution (1 mol) in 2000 ml of acetonitrile. The solution was heated at reflux for 7 hours, then cooled to room temperature and concentrated in a water pump vacuum to about 1/3 of the original volume. The solution is diluted with 2000 ml of water, extracted three times with 300 ml of methylene chloride each time, the organic phase is washed with 2N sodium hydroxide solution, then with water, dried over sodium sulphate and evaporated in a water-jet vacuum. A mixture of trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine and trans-4-hydroxy-3- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine as a yellowish oil is obtained as a residue. The two isomers were separated by column chromatography on silica gel using benzene with a gradually increasing addition of ethyl acetate as the eluent to isolate the first major fraction and the major product trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine and then pure trans -4-hydroxy-3- (3,4-dimethylphenoxy} -1-benzyloxycarbonylpiperidine is isolated after the mixed fraction, both isomers being obtained in the form of pale yellow oils.

d) 71.8 g (0.2 mol) trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-benzyloxycarbonylpiperidine are dissolved in 1000 ml methanol and this solution is hydrogenated in the presence of 5.0 g 5% of palladium on carbon catalyst at atmospheric pressure and at room temperature. After the hydrogen uptake is complete, the catalyst is filtered off with diatomaceous earth and the filtrate is evaporated under a water pump vacuum. The crude base crystallizes from a mixture of methanol and ether and affords trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine, m.p. 125 DEG-127 DEG C. The acid fumarate prepared from this base by fumaric acid crystallizes from a mixture of ethanol and ether. Melting point 175-177 ° C.

8.85 g (0.04 mol) of trans-3-hydroxy-4- (3,4-dimethylphenoxy) piperidine are dissolved in 20 ml of formic acid and 10 ml of a 35% aqueous formaldehyde solution are added thereto. The mixture is heated at 80 DEG C. for 4 hours and then evaporated in a high vacuum after cooling, the residue is dissolved in 100 ml of methanol and this solution is acidified with about 6 N hydrogen chloride / ethanol solution. 300 ml of water and extracted twice with 50 ml of methylene chloride each time, the aqueous phase was made strongly alkaline with concentrated sodium hydroxide solution, then extracted three times with 100 ml of methylene chloride each time, the organic phase was washed once with water, dried over sodium sulfate and evaporated to dryness in a water pump. The residual oil is dissolved in an excess of ethanolic hydrogen chloride and the hydrochloride is precipitated with ether to give amorphous trans-3-hydroxy-4- (3,4-dimethylphenoxy) -1-methylpiperidine hydrate ochlorid.

Example 2

In an analogous manner to that described in Example 1, from 1.7 g (0.0072 mol) of trans-3-hydroxy-4- (2,3-dimethylphenoxy) -1-methylpiperidine, 5.1 g (0.0247 mol) was prepared. dicyclohexylcarbodiimide, 0.63 g pyridine and

1.36 g of trifluoroacetic acid in 20 ml of absolute dimethylsulfoxide gave 1-methyl-4- (2,3-dimethylphenoxy) -3-piperidine hydrohydrochloride as a crystalline solid, m.p. 138-140 ° C (dec.).

The starting material is prepared as follows:

a) Analogous to that described in Example 1c), from 50 g (0.21 mol) of 3,4-epoxy-1-benzyloxycarbonylpiperidine and 53.8 g (0.42 mol) of 2,3-dimethylphenol is obtained trans -3-hydroxy-4- (2,3-dimethylphenoxy) -1-benzyloxycarbonylpiperidine as a brownish oil.

b) In analogy to Example 1d), hydrogenation with 50.8 g (0.143 mol) of this product gave trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine. This base crystallizes from a mixture of methanol and ether. 127 DEG-129 DEG C., and reacted with fumaric acid to provide a neutral fumarate crystallizing from a mixture of methanol and ether, m.p. 176-178 ° C.

In an analogous manner to that described in Example 1e) trans-3-hydroxy-4- is obtained from 5.6 g (0.025 mol) of trans-3-hydroxy-4- (2,3-dimethylphenoxy) piperidine by reaction with formaldehyde and formic acid. (2,3-dimethylphenoxy) -1-methylpiperidine as an amorphous foam The reaction of this base with about 6 N ethereal hydrogen chloride solution affords the amorphous hydrochloride.

Claims (4)

SUBJECT A process for the preparation of aryloxyperhydroazaheterocycles of the general formula I O Ο N--γ4 / ^ _((I) OF THE INVENTION in which R1 is an aliphatic hydrocarbon radical having a maximum of 4 carbon atoms, n1 and n having in each case a value of 1 to 3, n1 being not more than 4, and Ar is optionally an alkyl group having up to 4 carbon atoms substituted phenyl, and their acid addition salts, characterized in that the compound of formula II Ar-Of (CH _{4 4} x X-R < in which R1, Ar, ni, nz as well as ni + 112 have the meaning given in formula I, oxidize, whereupon any racemate obtained is separated into optical antipodes and / or the free compound of formula I obtained is optionally converted into a salt or the obtained salt optionally converted to the free compound of formula I. 2. A process according to claim 1, wherein the compound of formula II is oxidized wherein R1 is alkyl of up to 4 carbon atoms, Ar is optionally alkyl of up to 4 carbon atoms of a phenyl radical not more than twice substituted with n and m, and nt + nz are as defined in 1 and optionally the racemate obtained is separated into optical antipodes, and / or the free compound of formula I obtained is optionally converted into a salt or the resulting salt is optionally converted into a free compound of formula I. 3. A process according to claim 1 wherein the compound of formula (II) is oxidized wherein R1 is alkyl of up to 4 carbon atoms, Ar is mono or phenyl substituted by one or two of alkyl of up to 4 carbon atoms; and n 2 is 2, and the racemate obtained is optionally resolved into optical antipodes, and / or the obtained free compound of formula I is optionally converted into a salt or the obtained salt is optionally converted into a free compound of formula I. 4. A process according to claim 1, wherein the compound of formula II is oxidized wherein R1 is methyl, Ar is 2,3-dimethylphenyl or 3,4-dimethylphenyl, n1 is l and n is 2, and optionally recovering the free compound of formula I into a salt, or converting the obtained salt into a free compound of formula I.