SE437516B - ANALOGY PROCEDURE FOR PREPARING N-PHENYL-N- (4-PIPERIDYL) AMIDE DERIVATIVES - Google Patents

Description

7sos11n-9 contains pharmaceutically acceptable acid addition salts thereof, wherein R represents hydrogen, lower alkyl, cyclopropyl or 2-thienylethyl; R 1 represents hydrogen, lower alkyl or phenyl; R 2 represents hydrogen or lower alkyl; R 3 represents lower alkyloxycarbonyl or lower alkyloxymethyl; R 4 represents lower alkyl, cyclopropyl, and n is the number 0 or 1.

The term "lower alkyl" is intended herein to include straight and branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl, hexyl and the like.

The compounds of formula (I) can generally be prepared by reacting a 4,5-dihydrogen-1H-tetrazol-5-one derivative of the formula RN / Nx (II) with an N-phenyl-N- (4-piperidinylgamide with formula R 1 X 1 - -R (III) wherein R, R 3 and R 4 have the meaning given above and either X 1 represents hydrogen and X represents a group of the formula -CH- (CH 2) n -CH-Y (IV ) R 1, R 2 or X represents hydrogen and X 1 represents a group of the formula Y-CH- (CH 2) n -CH- (V) - R 1 R 2 In the above formulas (IV) and (V), R 1, R 2 and n above have And Y represents a reactive ester group such as halo, especially chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylphenylsulfonyloxy. The reaction between (II) and (III) may are performed according to standard N-ulceration procedures well known in the art.

This reaction is conveniently carried out in a suitable reaction-inert organic solvent such as an aromatic hydrocarbon such as benzene, methylbenzene, dimethylbenzene and the like; a lower alkanol, for example methanol, ethanol, 2-propanol, 1-butanol and the like; a ketone, for example 4-methyl-2-pentanone and the like; an ether, for example 1,4-dioxane, 1,1'-oxybisethane and the like; N-N-dimethylformamide; nitrobenzene; and similar.

To the reaction mixture may be added a suitable base, such as an alkali metal carbonate or bicarbonate, or an organic base, such as N, N-diethylethanamine or N- (1-methylethyl) -2-propanamine to take up the acid released during the course of the reaction.

In some cases it is convenient to add an iodide salt, preferably an alkali metal iodide. A slightly elevated temperature is advantageously used to increase the reaction rate. In some cases, especially when one of the substituents R 1 and R 2 represents methyl and the other represents hydrogen, a partial conversion may take place during the reaction which gives a mixture of positional isomers wherein R 1 represents methyl and R 2 represents hydrogen and vice versa R hydrogen and R 2 is methyl. Such stand isomers can be easily separated from each other by known isolation techniques, such as selective crystallization from a suitable solvent system or column chromatography.

Compounds of formula (I) may also be prepared by acylation of an appropriate 4-piperidinamine of the formula ON / 'KN f * R- \ I -fH- (CH2) n-CH- __ H NN R1 2 (VI) This acylation reaction is carried out suitably according to known N-acylation processes, for example by reaction between (VI) and a suitable acyl halide, R 4 -CO-halo, which represents a lower alkyl carbonyl halide, a cycloalkyl carbonyl halide, an arylacetyl halide and a lower alkyl carbonohalide, respectively, according to known methods. When R 4 represents lower alkyl or cycloalkyl, the acylation can also be carried out with an anhydride derived from the acid R COOH.

Compounds of formula (I) wherein R represents hydrogen are conveniently derived from the corresponding (I) wherein R represents phenylmethyl by debenzylation of the latter in the usual manner, e.g. by ka-. talytic hydrogenation by means of a suitable catalyst, such as palladium-on-carbon.

In the above and subsequent preparations, the reaction products are isolated from the reaction mixture and, if necessary, further purified by the application of conventional isolation and purification procedures well known in the art.

A number of the compounds covered by formula (I) have one or more asymmetric carbon atoms in the structure and consequently exist in different stereochemically isomeric forms. When R 1 or R 2 have a meaning other than hydrogen, in particular the carbon atoms to which they are attached are asymmetric, while additional asymmetric carbon atoms may be present in the lower alkyl groups comprised by R, R 5 and R 4. Although in the above preparations essentially mixtures, including racemic mixtures, of such stereochemical isomers are obtained, these mixtures can generally be dissolved into stereochemically pure isomeric forms by using known dissolution techniques, for example by salt formation with optical isomers of asymmetric acids. and selective crystallization of salts thus obtained. Stereochemically isomeric forms of the compounds of formula (I) are encompassed by the formula (I) - Due to their basic properties, compounds of the formula (I) can be converted into a therapeutically active, non-toxic acid addition salt form by treatment with a suitable acid, such as an organic acid, such as hydrohalic acid, for example, hydrochloric acid, hydrobromic acid and the like, and sulfuric acid, nitric acid, phosphoric acid and the like; or an organic acid such as acetic acid, propanoic acid, hydroxyacetic acid, 2-hydroxypropanoic acid, 2-oxopropanoic acid, propanedioic acid, butanedioic acid, (Z) -2-butenedioic acid, (E) -2-butenedioic acid, 2-hydroxybutanedioic acid, 2,3-Dihydroxybutanedioic acid, Z-hydroxy-1,2,3-propanetricarboxylic acid, benzoic acid, 3-phenyl-2-propenoic acid, d; hydroxybenzeneacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, αk-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid and similar acids.

Conversely, the salt form can be transferred to the free base by treatment with alkali. 7865110-9 Starting materials of formula (II) wherein X represents hydrogen, (II-a), can be easily prepared by reacting a suitable isocyanate of formula (VII ') or an acyl chloride of formula (VII) and sodium azide in the presence of aluminum chloride in a suitable organic solvent, preferably an ether, such as tetrahydrofuran (THF).

R = N = c = o (V11) or NaN3 / Alc13 RN H THF IF: R-Cf: (11-a) 1 (v11 ') The reaction is conveniently carried out by stirring and heating the reactants together in the solvent under Several hours. When an acyl chloride of formula (VII ') is used as the reactant, at least two molar equivalents of the azide must be used and it is generally convenient to use an additional excess thereof.

Starting materials of formula (II), wherein X represents a group of formula (IV), (II-b), can be obtained by introducing the group into the corresponding (II-a) according to known methods.

In general, starting material (II-b) can be prepared according to the following steps: i) reaction between the appropriate (II-a) and a haloalkanol derivative of the formula halo-CH- (CH 2) n -CH-OH (VIII) R 1 Z according to known procedures for N-alkylation as described above, to give an intermediate of the formula -CH- (CH 2) n -CH-OH (IX): R 1 R 2 and; __ ,, ¿* ........ af -ï, -_ I 1J- (ï, .- ¿;:;. A * 's ..: \! ~' __Fl i _ _ W _ 7805110 -9 ii) subsequent conversion of the hydroxy group of the so obtained (IX) to a reactive ester group according to known procedures for the preparation of reactive esters from the corresponding alcohols. I (IX) reactive ester- >> R_N / f \\ N_CH_ (CH2) n_CH_Y formation \ t =: R1 R2 (II-b) Halides are conveniently obtained by reaction between (IX) and a suitable halogenating agent, such as sulfinyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride and the like. Since the reactive ester is an iodide, it is conveniently derived from the corresponding chloride or bromide by replacing this halogen with iodine. Reactive sulfonate esters such as methanesulfonate 19 and 4-methylbenzenesulfonate are conveniently prepared by reaction between the alcohol and a suitable sulfonyl halide such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively.

When Y in UI-b) represents chlorine, (II-b ~ 1), the introduction of the chloroalkyl chain can also be carried out by reaction between a suitable (II-a) and a suitable bromochloroalkane derivative of the formula (X) according to standard N-alkylation processes for the preparation of the corresponding (II-b-1).

(II-a) + Br-ï fl- (CH 2) n -CH-Cl; R1 L2 (X) 0 RN / L \ N-ca- (cH2) n-cH-c1 v = vg, p (II-b-1) Alternatively, starting material (II-b-1) wherein R has a different meaning than hydrogen and phenyl are obtained by introducing the substituent R into a starting compound of the formula ..._.._......_...._ ~ _.A ._. ~ .__ L __, ..u: -. . 10 15 20 -..___.-¿.; '_........ 7805110-9 7 i HN F-CH- (CHZ) n ~ CH-Cl (XI) === N 1 2 R This introduction of R is conveniently carried out by reaction between (XI) and a suitable reactive ester RY wherein R has above specified meaning, other than hydrogen or phenyl, followed by standard N-alkylation procedures specified above. It should be noted that when Y in RY represents iodine, the chlorine substituent in (XI) can be replaced during the reaction with iodine, especially when an excess of the alkylating iodide is used. The starting compound of formula (XI) can be prepared according to methods described in Tetrahedron, 31, 765 (1975) wherein a compound of formula (XI) wherein R 1 and R 2 both represent hydrogen and n is 1 is specifically described.

Starting materials of formula (III) wherein X 1 represents hydrogen, (III-a), can be prepared according to methods set forth in U.S. Pat. No. 3,998,834, wherein a number of such starting materials and their preparation are described.

Starting materials of formula (III) wherein X1 represents a group of formula (V), (III ~ b), can be prepared by N-alkylation of a piperidine derivative of formula (III-a) with a haloalkanol of formula (XII) in a conventional manner for preparation of an intermediate of formula (XIII) and subsequent conversion of the hydroxy group of the latter to a reactive ester group as previously described. 7so511o-9 8 '3 Hoc fi- (cH2) n-CH-ha10 + HQ> ¿P 4 | 1 [Z N-Å-R ~ _ "" "" "" "" ï> RIR (XII) (III- a) _ RS Hoc fl- (cH2) n-ca-Q> § 3 4 l] Iz '' RRRZI \ (XIII) reactive esterbíldníng \ / 3 in! 2 n _ _R4 R.

(III-b) Intermediates of formula (XIII) wherein n is 0 can also be obtained by reaction between (III-a) and an appropriately substituted oxirane of the formula (XIV) R1 R2 R2 1 and R2 in the formula ( XIV) represents methyl and the other represents hydrogen, essentially an intermediate (XIII) is obtained in which the methyl substituent is placed in the P-position relative to the piperidine nitrogen. Intermediates of formula (XIII) wherein R 1 represents phenyl and n is 0 and I It should be noted that when one of the groups R 10 processes for its preparation is also described in U.S. Pat. No. 3,998,834.

The reaction between (XIV) and (III-a) is conveniently carried out by stirring and heating the reactants together in a suitable organic solvent, such as an aromatic hydrocarbon, for example benzene, methylbenzene, dimethylbenzene and the like; a halogenated hydrocarbon such as dichloromethane and trichloromethane; or a lower alkanol, for example methanol, ethanol, 2-propanol and the like; preferably in a mixture of an aromatic hydrocarbon and a lower alkanol. The reaction may benefit from the addition of a suitable base, such as an alkali metal carbonate or bicarbonate.

Starting materials of formula (III-b) wherein Y represents chlorine, (III-b-1), can also be prepared directly by reaction between (III-a) and a bromo-chloroalkane of formula (XV) according to methods similar to those set forth herein. described for the preparation of starting material (II-b-1) from (II-a). cl-ca- (ca2) n-ca-Br + (111-a);> R1 R2 (XV) Rs? Cl ~ CH- (CH) -CH- | R 11 (111-b-1) Starting materials of formula (VI) can generally be prepared by reacting a reactive ester of formula (II) wherein R represents a group of formula (IV) and a 4 -piperidinamine of the formula 5 R3 HH 6 (XVI) 4: * »... |. |: i ..'.__ .. ¿. ___: ___.___. ~ "_-_._;: .. = ___., rofoa 10 15 20 7805110-9 10 according to similar procedures as described above for the preparation of compounds (Ia) from (II) and ( III) 4-Piperidinamines of the formula (XVI1 used as starting materials can also be prepared according to the procedures described in U.S. Pat. No. 3,998,834, wherein a number of such compounds are specifically described.

The original starting materials in each of the above processes are well known and can be prepared according to known methods described in the literature for the preparation of such known compounds.

Compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof have very interesting pharmacological properties. In particular, they are potent morphine-like analgesics and as such can be used to suppress pain in warm-blooded animals.

The useful analgesic properties of the compounds of formula (I) and acid addition salts thereof are clear from the results obtained in the rat tail retrieval experiment described in Arzneimíttel-Forschung, 13, 502 (1963) and 21, 862 (1971). ). The results in Table I below indicate the LED, ie the lowest 100 percent effective dose in mg / kg for intravenous administration, and the duration (expressed in min) of this effect at the indicated dose. 7805110-9 11 NP = N m.Nf _ oN = Nww ~ um wmNu «mooNNo N: Q | N = u | N = u wmNw -. N. , NP wp fl o N Nozm .wmNo ..nmooN = o ^ N = uv: o | N = o m = Nu.

NF nw.o Q =. oz:: No n = NoN = o Nmu | N = o Nm fl o fl NF NQJQ mN = .Ho = @ = No _. N = uoN = u N = o | N = u. . mmNU Pm mF, o. ^ mooov: Nu m = ooNmo N = o | N = u. Nmo om. Nm.oV N ^: ooov m = Nu mmoøoo NmoxN = o Næo | N = N4wm fl QN m.N N ^ = ooovN m = Nß mzuooo N: u | N = u ~ Pmmo = P. m.N N ^ = ooov m = No mmuoou Næu | N = u mmwow Pw n.N .N N ^ = ooov m = No. Nmooou N: o1N = u Nmmu fl P, 4 wP.o _ N fi mooov m = No Nmooou N = o | N = o ßmmof, N _ n NNNN _ N mf NF o ^ mooovN \ fF _ Na o zoooo mo: mo NN mn wwqø N ^ = ooov == Nu Nmuooo N: o | Nmu mmm: än H .Um mvim fi. N .. uaßw,. . . . um www. NES ». . . . . m .ii _ Q N _ M amg. ~ @ NH @; mNm _ Nm NN = u | s ^ Nmov | m N _ _ o vß1ï @ T: o \: ^ N = uv: mo1ÄwM \ mz | m. . . , 1.

... HM 7805110-9 12 m _ E _ o Vi 3626 90-90- få m o = u _ i o P _ o få ÉQONE. 90-5 get N o m Q.. 2 S ... Nêoouäš _ mmNu mäoou Nmukmu IA nä: w .uó mvQuE: mm m .Siw må X mm Nm c N _ pmšïüušš H QS mo- m: v15 H_HH @@@ H .mphow ... w -__ A preferred group of compounds of formula (I) are those wherein R represents a lower alkyl group. These preferred compounds are potent short-acting analgesics. Analgesics with such a short duration are highly desirable under such conditions where acute severe pain must be eliminated over a short period of time, for example in anesthesiology.

Due to the analgesic activity, the present compounds can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of the invention, an effective analgesic amount of the particular compound, in the form of base or acid addition salt, is combined as an active ingredient in an intimate mixture with a pharmaceutically acceptable carrier, which may take many different forms depending on the form of preparation you wish to administer. These pharmaceutical compositions are suitably in unit dosage form suitable for oral or rectal administration or for parenteral injection. In preparing the compositions in oral dosage form, for example, any conventional pharmaceutical medium may be used, such as water, glycols, oils, alcohols and the like for oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like for powders, pills, capsules and tablets. Due to the ease with which they are administered, tablets and capsules are the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually comprises sterile water, at least in large part, though other ingredients, for example, to increase solubility, may be incorporated. Injectable solutions may be prepared, for example, in which the carrier comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspension ions can also be prepared using suitable liquid carriers, suspending agents and the like. Due to the increased water solubility compared to the corresponding base form, acid addition salts of (I) are clearly more suitable for the preparation of aqueous compositions.

It is especially advantageous to prepare the above-mentioned pharmaceutical compositions in dosage unit form for ease of administration and uniform dosing. By dosage unit form is meant herein physically separated units which are suitable as unit dose, each unit containing a predetermined amount of active ingredient which is calculated to give the desired therapeutic effect together with the required pharmaceutical carrier. . Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like, and multiples thereof.

Due to the analgesic activity of the present compounds, the present invention provides a method of preventing or controlling pain in warm-blooded animals, by systemically administering an effective analgesic amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutical carrier. Although the amount of active ingredient to be administered may vary within fairly wide limits, depending on the particular circumstances of the particular case, doses of from about 0.01 mg / kg to about 1 mg / kg, which are administered once or repeatedly times have generally been shown to be effective.

The invention is further illustrated by the following examples. Unless otherwise stated, all parts therein are calculated with respect to weight.

Example 1.

To a stirred mixture of 14.2 parts of isocyanatoethane, 29.2 parts of sodium azide and 135 parts of dry tetrahydrofuran is added a solution of 39 parts of aluminum chloride in 225 parts of dry tetrahydrofuran. Stirring is continued overnight at reflux temperature. The reaction mixture is cooled and acidified with a 6N hydrochloric acid solution. The whole is evaporated to dryness and the product is extracted four times with 2-propanol. The combined extracts are dried, filtered and evaporated. The residue is dried overnight to give 18 parts (65%) of 1-ecyl-1,4-hydrogen-sa-terrazol-s-one. Example 2. According to the procedure of Example 1 and using an equivalent amount of isocyanatocyclohexane and 2-isocyanate-propane, respectively, as starting material, 1-cyclohexyl-1,4-dihydrogen-5H-tetrazol-S-one is obtained; and 1,4-dihydrogen-1- (1-methylethyl) -SH-tetrazol-5-one as a residue.

Example 3.

To 990 parts of tetrahydrofuran cooled in an ice bath is added portionwise 156 parts of aluminum chloride and the whole is stirred vigorously until all solids have gone into solution. This solution is rapidly added to a stirred suspension of 208 parts of sodium azide in 225 parts of tetrahydrofuran and stirring is continued for 1 hour at reflux temperature After cooling to room temperature, a solution of S4 parts of butanoyl chloride in 225 parts of tetrahydrofuran is added dropwise at a temperature below 30 ° C. The whole is heated slowly. to reflux and stirring is continued overnight at reflux temperature. While cooling, the reaction mixture is acidified with 800 parts of a 6N hydrochloric acid solution and the solvent is evaporated off. The residue is stirred in 2-propanol and the precipitate is filtered off and filtered an evaporator to give 32 parts of 1,4-dihydrogen-1-propyl-SH-tetrazol-5-one as a residue.

Example 4.

Following the procedure of Example 3 and using an equivalent amount of a suitable acyl chloride as a starting material, the following compounds are obtained: 1- (1,1-dimethylethyl) -1,4-dihydrogen-5H-tetrazol-5-one as a residue ; 1,4-dihydrogen-1-pentyl-5H-tetrazol-5-one; 1-cyclopropyl-1,4-dihydro-4H-tetrazol-5-one; mp 128 ° C.

Example 5.

A mixture of 22 parts of 1-ethyl-1,4-dihydrogen-SH-tetrazol-5-one, 45 parts of 1-bromo-2-chloroethane, 26 parts of sodium carbonate, 0.3 parts of potassium iodide and 240 parts of 4-methyl-2 -pentanone is stirred and refluxed- boiled overnight with a water separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted 3 times with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated to give 28.4 parts (80%) of 1- (2-chloroethyl) -4-ethyl-1,4-dihydrogen-5H-tetrazol-5-one as a residue.

Example 6.

According to the procedure of Example 5 and by means of equivalent amounts of a suitable 1,4-dihydrogen-SH-tetrazol-5-one and a suitable bromochloroalkane as starting material, the following 1-im (7-chloroalkyl) are obtained. 1,4-dihydrogen-SH-tetrazol-5-ones: 1- (α-chloroethyl) -1,4-dihydrogen-4-propyl-5H = tetrazo] -5; 1- (2-chloroethyl) -1,4-dihydrogen-4- (1-methylethyl) -SH-tetrazol-S-one as a residue; 1- (2-chloroethyl) -4- (1,1-dimethylethyl) -1,4-dihydrogen-5H-tetrazol-5-one as a residue; 1- (α-chloroethyl) -1,4-dihydrogen-4-pentyl-5H-tetrazol-5-one as a residue; 1- (3-chloropropyl) -4-ethyl-1,4-dihydrogen-5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -4-cyclopropyl-1,4-dihydrogen-5H-tetrazol-5-one as a residue.

Example 7.

A mixture of 49 parts of iodomethane, 10.5 parts of 1- (2-chloroethyl) -1,4-dihydrogen-SH-tetrazol-5-one, 15 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-Z -pentanone is stirred and refluxed- boiled overnight with a water separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 15 parts (85%) of 1,4-dihydrogen-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one as a residue.

Example.

A mixture of 19.6 parts of [E- (2-thienyl) ethyl 7-4-methylbenzenesulfonate, 10 parts of 1- (2-chloroethyl) -1,4-dihydrogen SH-tetrazol-5-one, 10 parts of sodium carbonate and 90 parts of N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted 3 times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and petroleum ether (70:30 by volume) as eluent. The pure fractions are collected and the eluent is evaporated to give 15 parts (46.5%) of 1- (2-chloroethyl) -1,4-dihydrogen-4- [E- (2-thienyl) ethyl] 35 40 '7805110-9 17 SH-tetrazol-S-one as a residue.

Example 9.

To 4.5 parts of sulfinyl chloride is added dropwise a mixture of 13 parts of N- [1- (2-hydroxy-2-phenylethyl) -4-C-methoxymethyl) -4-piperidinyl] -N-phenylpropanamide hydrochloride and 260 parts of dichloromethane.

When the addition is complete, stir the whole and reflux for a few hours. The reaction mixture is cooled and the solvent is evaporated. The residue is taken up in 2-propanone. The mixture is filtered and the filtrate is treated with activated carbon. The latter is filtered off and the filtrate is evaporated. The residue is crystallized from a mixture of 2-propanone and 2,2'-oxybispropane. The product is filtered off and dried, yielding 9.2 parts (61.7%) of N- [2- (2-chloro-2-phenylethyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride; melting point 145.3 ° C.

Example 10.

A mixture of 35 parts of 2-methyloxirane, 83 parts of N-β- (methoxymethyl) -4-piperidinyl7-N-phenylpropanamide, 25 parts of sodium bicarbonate, 450 parts of benzene and 80 parts of methanol is stirred and refluxed overnight. . The reaction mixture is evaporated and the residue is taken up in water. The product is extracted with trichloromethane.

The extract is dried, filtered and evaporated. The residue is transferred to the hydrochloride salt in Z-propanol. The salt is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol to give 41.5 parts (37%) of N- [T- (Z-hydroxypropyl) -4- (methoxymethyl) - 4-Piperidinyl-N-phenylpropanamide monohydrochloride. 14 parts of sulfinyl chloride are stirred and a solution of 37 parts of N- [N- (2-hydroxypropyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride in 360 parts of dichloromethane is added dropwise. After the addition is complete, stirring is continued overnight at reflux temperature. The reaction mixture is evaporated and the residue is suspended in Z-propanone. The product is filtered off and dried, yielding 31.5 parts (85%) of N- [N- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride.

Example 11.

A mixture of 1.8 parts of 1- (2-chloroethyl) -4-ethyl-1,4-dihydrogen-5H-tetrazol-5-one, 3.45 parts of N-α- (methoxymethyl) -4-piperidinyl N-phenylpropanamide, 5 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is poured into water and the layers are separated. The organic phase is dried, filtered; 10 15 20 25 30 35 40 780-5110-9 u; ras och índunstas. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (9713 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is transferred to the hydrochloride salt of 2-propanone. The salt is filtered off and crystallized from 2-propanone to give 1.5 parts (33.3%) of N- {1-N- (4-ethyl-4,5-dihydrogen-5-oxo-1H-tetrazole-1) yl) ethyl 7-4- (methoxymethyl) -4-piperidinyl} aphenylpropanamide monohydrochloride monohydrate; melting point 140.8 ° C.

Example 12.

Following the procedure of Example 11 and using equivalent amounts of suitable starting materials, the following compounds are obtained as acid addition salts after treatment of the free base with a suitable acid: N - {] - [2- (4, 5-dihydrogen-5-oxo- 4-propyl-1H-tetrazol-1-yl] ethyl 7- [4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide thanedioate (1: 2) monohydrate, mp 0g, 8 C; N- [ 2-14,5-dihydrogen (1-methyllegyl) -5-oxo-1H-tetrazol-1-yl7-ethyl-4- (methoxymethyl) -piperidinyl / -N-phenylpropanamide mononitrate monohydrate, mp 104.5 ° C; methyl 1- [2- {4, 5-dihydrogen-5-oxo-4-12-thienyl) ethyl] -1H-tetrazol-1-yl} ethyl / -4-Z (1-oxopropyl) phenylamino] -4 -piperidinecarboxylate tanedioate (1: 1) mp 162.9 ° C.

N- 1- [3- (4-ethyl-4,5-dihydrogen-5-oxo-1H-tetrazol-1-yl) propyl] -4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide hydrochloride hemihydrate; mp 182 ° C; Example 13

A mixture of 3.6 parts of 1- (2-chloroethyl) -4-ethyl-1,4-dihydrogen SH-tetrazol-5-one, 6.4 parts of methyl 4- [-(1-oxopropyl) - N-Phenylamine-4-piperidinecarboxylate hydrochloride, 4 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is cooled and poured into water. The organic phase is separated, dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is transferred to the ethanedioate salt of 2-propane. The salt is filtered off and dried, yielding 1.5 parts (13%) of methyl 1- [4- (4-ethyl] -4-alpha-s-oxo-1H-retrazol-1-yl] ethyl] -4- Oxo-propyl) phenylamine-4-piperidinecarboxylate thanate (2: 3); melting point 1ss, 9 ° C.

Example 14.

Following the procedure of Example 13 and using equivalent amounts of suitable starting materials, the following ethanedioate salts are obtained: methyl 1- [2- (4,5-dihydrogen-5-oxo-4-propyl-1H-tetrazol-1-yl) ethyl 7-4 - [(1-oxopropyl) phenylamino] -4-piperidinecarboxylate thanate (1: 1); mp 168.4 ° C; methyl 1- {2- [1,5-dihydrogen-4- (1-methylethyl) -5-oxo-1H-tetrazol-1-yl] -ethyl} -4-yl-oxopgopyl) phenylamino] -4-piperidinecarboxylate thanate ( 1: 1); mp 184.2 ° C; meg »- »Q-α-n, 1-dimethylethyn-4, guvate-s-oxomxy-tetrazol-1-yl / ethyl} -4- (1-oxopropyl) phenylamino] -4-piperidinecarboxylate tannioate (1: 1); mp 168.1 ° C; Methyl 1- [2- (4, 5-dihydrogen-5-oxo-4-pentyl-1H-tetrazol-1-yl) ethyl] -4- 1- (1-oxopropyl) phenylamino] -4-piperidinecarboxylate thanate (1: 1 ); mp 153.5 ° C; In methyl 1- [2- (4-cyclopropyl) -4,5-dihydrogen-5-oxo-1H-tetrazol-1-yl) -ethyl] -4- (1-oxopropyl) phenylamination] -4-piperidinecarboxylate thanate (2: 3) hemihydrate; mp 155.9 C; and methyl 1-42- (4-ethyl-4H-dihydrogen-5-oxo-1H-tetrazol-1-yl) ethyl764-C-phenylamino) -4-piperidinecarboxylate thandioate (2: 3); mp 172 ° C.

Example 15.

A mixture of 2.55 parts of 1,4-dihydrogen-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one, 3.45 parts of N- [α- (methoxymethyl) -4- piperidinyl 7-N-phenylpropanamide, 2 parts of sodium carbonate, 0.2 parts of potassium iodide and 160 parts of 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is transferred to the ethanedioate salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone to give 2.1 parts (42%) of N - {] - β 2- (4,5-dihydrogen-4-methyl-5-oxo-1H-tetrazol-1-yl ) ethyl 7-4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide thanedioate (1: 1); mp 15S, 9 ° C.

Example 16.

According to the procedure of Example 15, methyl 1- 1- fl- (4,5-dihydrogen-methyl-5-oxo-1H-tetrazol-1-yl) ethyl] -4- [1,4-oxopropyl) phenylamine-4- piperidinecarboxylate thanedioate (1: 1); melt- 20 7005110-9 i - 10 15 20 25 30 35 point 185.9 ° C; by reaction between 1,4-dihydrogen-1- (Z-iodoethyl) -4-methyl-5H-tetrazol-5-one and methyl 4- [1-oxopropyl) phenylamino] -4-piperidinecarboxylate.

Example 17.

A mixture of 3 parts of 1-ethyl-1,4-dihydrogen-5H-tetrazol-5-one, 9.4 parts of N- [1- (Z-chloropropyl) -4- (methoxymethyl) -4-piperidinyl] -N- Phenylpropanamide, 2.5 parts of sodium carbonate, 2.5 parts of N, N-diethylethanamine and 90 parts of N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is cooled, 100 parts of water are added and the product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel, first using a mixture of trichloromethane and methanol (97: 3 by volume) and then with a mixture of ethyl acetate and ethanol (99: 1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is transferred to the hydrochloride salt of 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried, yielding 2.1 parts (18%) of N- {1- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) -1-methylethyl ]- 4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide monohydrochloride; melting point 185.4 ° C.

Example 18.

A mixture of 1.2 parts of 1-ethyl-1,4-dihydrogen-5H-tetrazol-5-one, 3.9 parts of N-β- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl7- N-phenylpropanamide monohydrochloride, 2 parts sodium carbonate, 0.1 part potassium iodide and 120 parts 4-methyl-2-pentanone are stirred and refluxed overnight with a water separator. The reaction mixture is cooled, poured into water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is transferred to the nitrate salt of 2-propanone.

The salt is filtered off and crystallized twice: first from a mixture of 2,2'-oxybispropane and Z-propanone and then from 2-propanone to give 1.5 parts (30%) of N- {1-¿2- (4- ethyl 4,5-dihydro-5-oxo-1H-tetrazol-1-yl) -1-methylethyl-4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide mononitrate; melting point 146.6 ° C. 10 15 20 25 30 35 7805110-9 Exemgel 19.

A mixture of 3 parts of 1-ethyl-1,4-dihydrogen-5H-tetrazol-5-one, 8 parts of N- [(2-chloroacphenylethyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide, 0.2 parts of potassium iodide, 5 parts of sodium carbonate and 135 parts of N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is cooled to room temperature and 150 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The solid residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (9713 by volume) as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of petroleum ether and 2,2-oxybispropane. The product is filtered off and dried, yielding 5.7 parts (65%) of N-II- (2- (4-ethyl-4,5-dihydrogen-5-oxo-1H-tetrazol-1-yl) -2-phenylethyl7-4 - (methoxymethyl) -4-piperidinyl} N-phenylpropanamide, m.p. 125.7 ° C.

Example 20.

A mixture of 3 parts of 1-ethyl-1,4-dihydrogen-5-H-tetrazol-S-one, 9.4 parts of N-β- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl7- N-phenylpropanamide monohydrochloride, 2.5 parts of N, N-diethylethanamine, 2.5 parts of sodium carbonate and 90 parts of N, N-dimethylformamide are stirred and heated overnight at 70 ° C. The reaction mixture is cooled and 100 parts of water are added. The product is extracted three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified twice by column chromatography over silica gel, first using a mixture of trichloromethane and methanol (97: 3 by volume) and then a mixture of ethyl acetate and ethanol (99: 1 by volume). as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt of 2-propanone and 2,2'-oxybispropane. The salt is filtered off and dried to give 3.9 parts (33.4%) of N- {1-N- (4-ethyl-4,5-dihydrogen-5-oxo-1H-tetrazol-1-yl) propyl7 -4- (methoxymethyl) -4-piperidinylβ-N-phenylpropanamide monohydrochloride; melting point 192.7 ° C.

Example 21.

A mixture of 5.7 parts of methyl 1- [1- (4-ethyl-4β-divare-s-oxo-1H-tetrazol-1-yl) ethyl] -4- (phenylamino) -4-piperidine carboxylate, 1.9 parts of cyclopropanecarbonyl chloride, 2.7 parts of N, N-diethylethanamine and 68 parts of methylbenzene are stirred and refluxed over .- - .._._...._._.;: .'.._._. l.-_ _ ..._ FèÖOR QUALITY 10 15 7305110-9 i - n night. The reaction mixture is cooled, 100 parts of water are added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and treated with 1 part of ethanedioic acid. The ethanediate salt formed is filtered off and crystallized from a mixture of 2-propanone and 2,2'-oxybispropane to give 1.5 parts of [17%%) methyl-4-1-cyclopropylcarbonyl) phenylamine-1- [2- (4-ethyl-4,5-dihydrogen-5-oxo-1H-tetrazol-1-yl) ethyl 7-4-piperidinecarboxylethanate (z = s); smanapunkc 1s1, s ° c.

Example 22.

According to the procedures described here and with the aid of suitable starting materials, the following compounds of the formula I can also be prepared: 23 l- fi l fl ln Im CL 'NN N UU O .mmm: m än) u ”0-0 O 00 O QU U. mi: 21. ' About C 'About C MA 7so511o-9 "ß-Ä.Å --- ¿J' ~.-_ Y-.m ffg flfi“ M- "'' FfWW-ø æalï 1 10 15 7805110-9 24 Example23 A mixture of 5 parts N- [Ü- [δ- [α, 5-dihydro-5-oxo-4- (phenylmethyl) -1H-tetrazol-1-yl] -4- (methoxymethyl) -4-piperidinyl] - N-phenyl-propanamide and 120 parts of methanol are hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%.

After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent.

The pure fractions are collected and the eluent is evaporated. The residue is converted to the hydrochloride salt in 2-propanol. The whole is evaporated and the residue is crystallized from 2-propanone.

After cooling to room temperature, the product is filtered off and recrystallized from a mixture of 2-propanone, 2-propanol and methanol. The product is filtered off and dried in vacuo at SOOC to give 2.1 parts of N- [N- [4,5- dihydro-5-oxo-1H-tetrazol-1-yl) ethyl] -4-C-methoxymethyl. ) -4-piperidinyl] -N-phenylpropanamide monohydrochloride; melting point 2ss, 6 ° _c.

Claims (1)

ß 7seos11o-9 Patent claim A process for the preparation of a chemical compound consisting of an N-phenyl-N- (4-piperidinyl) amide derivative of the formula: 0 s R-NÄN-cH- (CH J CH Q XR 0 \ f | 2 n N - R 1 * N == N R 1 ë2 or a pharmaceutically acceptable acid addition salt thereof, wherein R represents hydrogen, lower alkyl, cyclopropyl or 2-thienylethyl; R 1 represents hydrogen, lower alkyl or phenyl; R 2 represents hydrogen or lower alkyl; R 3 represents lower alkyloxycarbonyl or lower alkyl; R4 represents lower alkyl or cyclopropyl, and n is the number 0 or 1, characterized in that a) a compound of the formula R- '-X (II) is reacted with an N-phenyl-N- (4-piperidinyl) amide of the X1- in 'mi-If (111) formula wherein R, R5, and R4 have the meaning given above and either X1 represents hydrogen and X represents a group of the formula -? H- (CH2) n-? HY (IV) R1 R 2 or X represent hydrogen and X 1 represents a group of the formula Y-Icn- (ca fi n-c fl- (v) 111 RZ some QUBLIT , or a sulfonyloxy group, such as methylsulfonyloxy or 4-methylphenylsulfonyloxy, which reaction is conveniently carried out at elevated temperature, in a suitable reaction-inert organic solvent in the presence of a suitable base; or b) a compound of the formula R fi 3 R- -cH- (CH J -cH- (VI) 1 2 n IHN = N R 1 R 2 N-acylated according to standard N-acylation procedures to prepare a compound of the formula R3 to || R-Nr '\ 7N-ï fl- (CH2) n ~ TH * _ O _ H R4 (Ia) N :: N R1' R2 or Q) compounds of formula (I) wherein R represents phenylmethyl deben- isylated according to known debenzylation techniques for the preparation of compounds wherein R represents hydrogen and, if desired, pharmaceutically acceptable acid addition salts are prepared from the products from steps a) to c), or, if desired, racemic mixtures are dissolved into stereochemically pure isomeric forms - solution technology. '