FI64364B - PROCEDURE FOR THE ANALYSIS OF ANALGETIC ACTIVE N-PHENYL-N- (4-PIPERIDINYL) -AMIDE DERIVATIVES - Google Patents

Description

____-.- 1 Γο, ANNOUNCEMENT r λ -> s a Β (11) UTLÄGGN! NGSSKRIFT 64 3 64 2¾¾ C (45) ratani, 'Λ cyönnctty 10 11 1933' (51) Kv.tk. ') Int.C! .3 c 07 D 401/06, 409/14, 211/58, 257 / 04 SU OMI —FI N LAND (21) P * t * nttlhak «mu * - P * t« nt »nseknlnj 781398 (22) Htkemiipllv * - Ar *» bknlnjtd »j 0-4.05.7 8 (23) Alkupftlvt · - GHtlgh «t * dag 0U.05.78 (41) Tullut | ulkl» «kil— Sllvlt offantilg Qg 11 78

National Board of Patents and Registration / 44) Date of issue and date of issue. -

Patent Registration Office Anabkan utlagd och utl.skrlftan pubtlcerad 29.07.83 (32) (33) (31) Request for Privilege —Begird prloHtet 05.05.77 13-03.73 USA (us) 79381U, 386188 (71) Janssen Pharmaceutica Naamloze Vennootscbap, Turnhout sebaar 30,

Beerse, Belgium-Belgien (BE) (72) Frans Eduard Janssens, Waver, Belgium-Belgien (BE) (7M Oy Kolster Ab (5U) Method for the preparation of analgesically active IJ-phenyl-N- (U-piperidir ± yyii) amide derivatives - Preparation of N-phenyl-N- (U-piperidine) amide derivatives

The invention relates to a process for the preparation of analgesically active N-phenyl-N- (4-piperidinyl) amide derivatives of the formula I and their pharmaceutically acceptable acid addition salts, A / "vr3 ° (i)

R-N TJ-CH- (CH.J -CH-N Λ. "_4 \ / 2 n, ^ \ - / N-C-R

N =. N R 1 wherein R is a hydrogen atom or a lower alkyl, cycloalkyl, aryl or aryl (lower alkyl) group, wherein the aryl is phenyl or thienyl; R 1 is a hydrogen atom or a lower alkyl or phenyl group; R is a hydrogen atom or a lower alkyl group; is a lower alkyloxycarbonyl or lower alkyloxymethyl group; R 1 is a lower alkyl or cyclopropyl group; and n is an integer 0 or 1.

"Lower alkyl" as used herein means straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl and hexyl groups. . "Cycloalkyl" refers to cycloalkyl groups having 3 to 6 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

Compounds of formula (I) are prepared by administering a) - (1) of a compound of formula (ΙΙ-b) RN IJ-CH- (CHO) -CH-Y (II-b) / n 2 n R 1 R 2 reacts with N-phenyl-N- (4-piperidinyl) amide of formula (III-a), -v R 3 "4 / NC-R 4.

| (III-a)

O

12 3 4 wherein R, R, R, R, R and n are as defined above and Y is a reactive ester residue such as halogen, especially chlorine, bromine or iodine, or a sulfonyloxy group such as methylsulfonyloxy or 4-methylphenylsulfonyloxy, wherein the reaction is carried out in a suitable reaction-inert organic solvent in the presence of a suitable base, preferably at elevated temperature; or

II

3 64 3 6 4 a) to (2) react a compound of formula (II-a) with 0 !! / \

R-N N-H

ta * / (H-a) with N-phenyl-N- (4-piperidinyl) amide of formula (III-b), -,, R3 V-CH- (CH2) n-CH-> X? R1 r2 N- ' (III-b) 12 3 4 wherein R, R, R, R, R n and Y are as defined above, in a suitable organic solvent in the presence of a suitable base, preferably at elevated temperature; or b) of formula 0 3

/ —V K

R-N is N-CH- (CH-) -CH-n / X

^ = i 'x n \ _Ah (VI)

R R L

the compound of formula I is N-acylated according to conventional N-acylation methods to prepare a compound of formula R3 ΙΙ-β> "1 ό; or 4 64364 c) debenzylating compounds of formula I wherein R represents a phenylmethyl group by known debenzylation methods to prepare compounds wherein R means a hydrogen atom, and if desired, pharmaceutically acceptable acid addition salts of the products of steps a) to c) are prepared.

The reaction of compound (II) with compound (III) is carried out using N-alkylation methods well known in the art. Said reaction is carried out in a suitable reaction-inert organic solvent (such as aromatic hydrocarbon, e.g. benzene, methylbenzene, dimethylbenzene and the like; lower alkanol, e.g. methanol, ethanol, 2-propanol, 1-butanol and the like; ketone, e.g. 4-methyl-2-pentanone and the like; ether, e.g. 1,4-dioxane, 1,1'-oxobisethane and the like; N, N-dimethylformamide; nitrobenzene and the like).

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 is added to the reaction mixture to scavenge the acid released during the reaction. In some cases, the addition of an iodide salt, preferably an alkali metal iodide, is preferred. Slightly elevated temperatures are preferably used to promote the reaction rate. Under some conditions, especially when one of R and R 1 is a methyl group and the other a hydrogen atom, a partial rearrangement may occur during the reaction to give a mixture of isomers in which, in one isomer, R is a methyl group and R is a hydrogen atom and the other is a hydrogen atom. and R 1 is a methyl group Such isomers can be readily separated from one another by known isolation methods, such as selective crystallization from a suitable solvent system or column chromatography.

Compounds of formula (I-a) may also be prepared by acylation of the appropriate 4-piperidine amine of formula (VI).

Jk / “λ / 3 1LT ′ ′ ′ ′ ′ vi λ (vi) r and

O

II

5 64364

Said acylation reaction is preferably carried out using known N-acylation methods, for example by reacting compound (VI) with a suitable acyl halide (R 1 -CO-halogen).

When R represents a lower alkyl or cycloalkyl group, the acylation can also be carried out with an anhydride derived from the acid R COOH.

Compounds of formula (I) in which R represents a hydrogen atom are preferably derived from the corresponding compound (I) in which R represents a phenylmethyl group by debenzylation of the latter in the usual manner, e.g. from catalytic hydrogenation using 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 using general isolation and purification methods well known in the art.

Some of the compounds of formula I have one or more asymmetric carbon atoms in their structure and, as a result, exist in different stereochemical isomeric forms. When R or R is other than a hydrogen atom, the carbon atoms to which they are attached are asymmetric, while additional asymmetric carbon atoms may be present in the lower alkyl groups of the R, R and R groups.

Racemic mixtures can generally be separated into their stereochemically pure isomeric forms using known separation techniques, e.g., salt formation with optical isomers of asymmetric acids and selective crystallization of the salts thus obtained.

Due to their basic properties, the compounds of formula (I) can be converted into their therapeutically active, non-toxic acid addition salt forms by treatment with a suitable acid such as an inorganic acid, e.g. hydrohalic acid, e.g. or an organic acid such as acetic, propanecarboxylic, hydroxyacetic, 2-hydroxypropanecarboxylic, 2-oxopropanecarboxylic, propanedicarboxylic, butanedicarboxylic, (Z) -2-butenedicarboxylic, (E) -2-buteneic 64364 Dicarboxylic, 2-hydroxybutanedicarboxylic, 2,3-dihydroxybutanedicarboxylic, 2-hydroxy-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenecarboxylic, 2'-hydroxybenzene- acetic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamine, cis-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with base into the free base form.

The starting materials of formula (II-a) can be readily prepared by reacting the appropriate isocyanate of formula (VII) or acyl chloride of formula (VII) with sodium azide in the presence of aluminum chloride in a suitable organic solvent, preferably an ether such as tetrahydrofuran (THF).

R = N = C = 0

, VII) A

tal NaNj / AlClj \ H

-> \ /

yO THF NZN

R - Άΐ (II-a) (VII)

The reaction is conveniently carried out by stirring and heating the reactants in a single solvent for several hours.

The starting materials of formula (ΙΙ-b) can be prepared from the corresponding compounds of formula (II-a).

In general, said starting materials (ΙΙ-b) can be prepared by carrying out the following reaction steps: i) reacting a suitable compound with a haloalkanol derivative of formula (VIII):

halo-C H (CH 2) n -CH-OH

'' (VIII)

RA R

7 64364 using well-known N-alkylation methods as described above to give an intermediate of formula (IX): Λ R-N N-CH- (CHO) -CH-OH (IX) 1, n = N n 2

R1 R

and ii) next converting the hydroxy group to a reactive ester group using methods known in the art for the preparation of reactive esters from the corresponding alcohols.

Λ, TV, formation of the reactive ester ^ R-N N-CH- (CH „) -CH-Y (II-b) (IX) --- ϋ \ j '2' n \ ./ ',' * = * R1 R2

The halides are conveniently obtained by reacting compound (IX) with a suitable halogenating agent (such as sulfonyl chloride, sulfuryl chloride, phosphorus pentachloride, phosphorus pentabromide, phosphoryl chloride and the like). When the reactive ester is iodide, it is preferably obtained as a derivative of the corresponding chloride or bromide by replacing this halogen with iodide. Reactive sulfonate esters such as methanesulfonates and 4-methylbenzenesulfonates are conveniently prepared by reacting the alcohol with a suitable sulfonyl halide such as methanesulfonyl chloride and 4-methylbenzenesulfonyl chloride, respectively.

When Y in compound (II-b) contains chlorine (II-b1), the coupling of the chloroalkyl chain can also be carried out by reacting the appropriate compound (II-a) with a suitable bromo-chloroalkane derivative of formula (X) following conventional N-alkylation procedures. to give compound (II-b-1).

8 64364

(II-a) + Br-CH- (CHO) -CH-Cl 2 n I

1 1 2

R R

(X) O 11 R-N N-CH- (CHO) -CH-Cl 1 / 1.2 / I, N-N R 1 R 2 (II-b-1)

Alternatively, the starting materials (II-b-1) in which R is other than a hydrogen atom or a phenyl group can be obtained by adding an R substituent to the preceding compound of formula (XI):

O

(CH0) -CH-C1 \ / I 2 n 1, N-N R1 r2 (XI)

Said coupling of R is conveniently carried out by reacting compound (XI) with a suitable reactive ester RY, wherein R is as defined above but other than a hydrogen atom or a phenyl group, using the usual N-alkylation method as described above. It should be noted that when said Y is iodine in said RY. The chlorine substituent of (XI) may be replaced during the reaction by iodine, especially when an excess of alkylating iodide is used.

Compounds of formula (XI) may be prepared using the methods described in Tetrahedron, 31, 765, (1975), wherein a compound of formula (XI) wherein R "1 and R 1 are both hydrogen and n is 1 is detailed described.

9 64364

The starting materials of formula (III) wherein X 1 is a hydrogen atom (III-a) may be prepared according to the methods set forth in U.S. Patent 3,998,834, which describes a number of such starting materials and their preparation.

The starting materials of formula (III-b) can be prepared by N-alkylating a piperidine derivative of formula (III-a) with a haloalkanol of formula (XII) in the usual manner to give an intermediate of formula (XIII) and then converting the latter hydroxy group to a reactive ester group as described above.

10 64364 / - \ r3 HOCH- (CH-) -CH-halo + HN Y {? „I. 2 n I, \ _Λ-ϋ-κ4 - * 'Ö (XII) ^ (III-a) / _ R3 H0CH- (CHJ -CH-N) (O // _v R3 Y-CH- (CH2) n “CH-N Y 0 I -i L - NCP.

* 'o (Ill-b)

Intermediates of formula (XIII) wherein n is 0 can also be obtained by reacting compound (III-a) with an appropriately substituted oxirane of formula (XIV).

(XIV, k1 k2 11 64364

It should be noted that in formula (XIV) when one of the radicals R 1 and R 2 is methyl, the other being hydrogen, substantially intermediate (XIII) is obtained in which the methyl substituent is located in the β-position relative to the piperidine nitrogen. Intermediates of formula (XIII) wherein R 1 is a phenyl group and n is 0, and methods for their preparation are also described in U.S. Patent 3,998,834.

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

The starting materials of formula (III-b) wherein Y is chlorine (III-b-1) can also be prepared by reacting the compound (III-a) with a bromo-chloroalkane of formula (XV) using methods similar to those used herein for the preparation of starting materials (II-b). -b-1) in the preparation from (II-a).

Cl-CH- (CHO) -CH-Br + (III-a) --- I * n i I 1 '2 R R ^ (XV)

Cl-CH-, ChA-h- {3 (1r4

R R / V

(III-b-1) 12 Ä 64364

The covalent starting materials of formula (VI) can generally be prepared by reacting a reactive ester of formula (II) (wherein R represents a radical of formula (IV)) with a 4-piperidinamine of formula (XVI): H \ ZX ™ (XVI) ö using similar methods , as described herein for the preparation of starting materials (Ia) starting from compounds (II) and (III).

The 4-piperidinamines of formula (XVI) used as starting materials herein may also be prepared using the methods described in U.S. Patent Specification detailing a number of such compounds.

The final starting materials for each of the methods described above are well known and can all be prepared using methods known in the art.

The compounds of formula (I) and their pharmaceutically acceptable acid addition salts have very interesting pharmacological properties. They are effective morphine-type analgesics and as such can be used to relieve pain in warm-blooded animals.

The beneficial analgesic properties of the compounds of formula (I) and their acid addition salts can be clearly demonstrated by therapeutic tests (rat tail retraction test described in Arzneimittel-Forschung, 13, 502 (1963) and 21, 862 (1971)). . The results in the following Table I indicate the value of the LED, i.e. the lowest 100% effective dose in mg / kg intravenously, and the duration of this effect (expressed in minutes) at the indicated dose.

il 13 64 36 4 I --------—-,

I G

I ** "* ε m o - o O O in r- cm co sr · χ 0 CO <- <-> r t— CJ in 0" COt-r-r-T-r-

P

cn <1> O '

\ 10 JO O CO OcOCOvO

ö1 t— r-r-inmin ο <- o vo in - jd O O OJ * c \ l OJ * O * O 0 0 0 * 0 0 04 _ 8 v -% J I Λ! I —i -—————-; <-> s / = \ “χ v \ i s g o ° cj

^> - M j CM O CJ CJ CM CM OJ OJ CM O J? J X

J 'H XXXXXX X XX X \ i ^ 2: / "5 ocmoooc o co> cococo <- I ^ o \ oooo Ο 0 0 x 0 0 0 ^ X OJ! 0 o r- O CJ OO CJ ο ^ ο zzz ο t: S 0 CS 3 Ίμ __

X

0 Ύ X t— m in tn in mm tn in in mmm in it o - (¾ x xxxxxx x XXXXXXXi 1 1¾ CJ C \ l W CJ OJ OJ OJ OJ C \ J CJ OJ X OJ oi CJ CJ O CJ ο ο ο ο O CJ ο O CJ O! <J! - ^ - 1

04 ιΟ X CO CO CO X

cO co co co co co co coXXXXXX *: co XXXXXX X X O O O O O O i 04 CJ CJ CJ ο ο ο O CJ ο o c ο ο O! OOOOOO O O OJ CM CJ OJ CM oj OOGQOO O O XX. X X X X1 OOOOOO o o ooooooj

____ {_ I

x oJ '^ ^ ro 0-044 n OI; I X X O j c o o i!

^ OJ CM OJ OJ OJ OJ OJ OJ CJ OJ OJ 'CJ

OJ XXXXXX X X XXXXXX 'X OOOOOO Ο OOOOOO O: O! I I I I I I I I! I i! I i

'OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ OJ CM CM CJ CM

M I XXXXXX X xxxxxxx O X T- OOOOOO o o o o o o o o J * o— «X ---— - 3 i

f “4 C \ 1 I

d rs i ^ i!

OJ I

r— O 'CO c ~ O O' ί x in x xxx _ [inxmm id co X co co <in Ρ'Λ I X I co X co x X z

X CMOOOO C'J O OJvöoJ

_ o o g -H »c 1 = / O O -H o o ... QJ

14 64364

With strong morphine-like analgesic meals, which are known e.g. UE patents 3,164,600 and 3,998,834, have a long-lasting analgesic effect and, as a side effect, a long-term paralytic effect on the respiratory system. When high doses are used or when these compounds are used in relatively short-term surgeries, the patient experiences difficulty breathing after surgery. Given that most surgeries are short-lived, there is an urgent need for an analgesic that has only a short-term effect. Of the compounds of the present invention, alfentanyl (R = -C2H3, R1 = H, R2 = H, R3 = -CH2-O-CH3, R4 = -C2, n = 0) has proven to be particularly advantageous in this respect.

In animal experiments, alfentanyl has been shown to be less effective than fentanyl known from U.S. Patent 3,164,600 and sufentanil, lofentanil and carfentanil known from U.S. Patent No. 3,998,834. However, alfentanyl has the advantage that its onset of action is much faster, with the maximum effect occurring within 2 minutes of compound administration. In addition, its effect is short, with twice the lowest dose of ED 2, the effect lasts for 10 minutes, while, for example, with fentanyl under the same conditions, the effect lasts for 30 minutes. The paralytic effect of alpha-tanyl on the respiratory system also lasts shorter than, for example, fentanyl.

Due to these properties, alfetanyl is particularly well suited for short-term surgical operations (less than 30 min.), Such as gynecological, urological, diagnostic and dental operations. A.Lententanyl can also be used for longer-term surgical operations (30-120 min.) Without said compound accumulating in the body. With alfentanil, respiration normalizes much faster after surgery than with fentanyl. In addition, postoperative complications and side effects occur less frequently with alfentanyl than with fentanyl.

Il 64364

In preferred compounds of formula I, R is lower alkyl. These preferred compounds are highly effective analgesics with a short duration of action. Analgesics with such a short duration of action are highly desirable in conditions where acute severe pain must be removed for a short time, e.g., in anaesthesiology.

The following examples are intended to illustrate the scope of the present invention. Unless otherwise indicated, all parts are by weight in the following.

Preparation of starting materials:

Preparation I

To a stirred mixture of 14.2 parts of isocyanate ethane, 29.2 parts of sodium azide and 135 parts of dry tetrahydrofuran is added a solution containing 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 6N hydrochloric acid solution. The mixture is evaporated to dryness and the product is extracted four times with 2-propanone. The combined extracts are dried, filtered and evaporated. The residue is dried overnight to give 18 parts (65%) of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one.

Preparation II

Following the procedure of Example I and using an equivalent amount of isocyanate cyclohexane and 2-isocyanate propane, respectively, as starting materials give: 1-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one; and 1,4-dihydro-1- (1-methylethyl) -5H-tetrazol-5-one as a residue.

Preparation III

To 990 parts of tetrahydrofuran cooled in an ice bath, 156 parts of aluminum chloride are added portionwise and the mixture is stirred vigorously until all the solid is in solution. This solution is added rapidly to a stirred suspension of 225 parts of sodium azide in 225 parts of tetrahydrofuran and stirring is continued for 1 hour at reflux temperature. After the mixture has cooled to room temperature, a solution of 16 64364 containing 54 parts of butanoyl chloride in 225 parts of tetrahydrofuran is added dropwise at a temperature below 30 ° C. The mixture is slowly heated to reflux and stirring is continued overnight at reflux. On cooling, the reaction mixture is acidified with 800 parts of 6N hydrochloric acid and the solvent is evaporated. The residue is taken up in sodium hydrogen carbonate solution, trichloromethane is added and the layers are separated. The aqueous phase is acidified with concentrated hydrochloric acid and the solvent is evaporated. The residue is taken up in 2-propanone. The precipitate is filtered off and the filtrate is evaporated to give 32 parts of 1,4-dihydro-1-propyl-5H-tetrazol-5-one as a residue.

Preparation IV

Following the procedure of Example III and using an equivalent amount of the appropriate acyl chloride as starting material, the following compounds are obtained: 1- (1/1-dimethylethyl) -1,4-dihydro-5H-tetrazol-5-one as a residue; 1,4-dihydro-1-pentyl-5H-tetrazol-5-one; 1,4-dihydro-1- (2-phenylethyl) -5K-tetrazol-5-one as a solid residue; 1,4-dihydro-1- (phenylmethyl) -5H-tetrazol-5-one; mp. 152 ° C; and 1-cyclopropyl-1,4-dihydro-5H-tetrazol-5-one; mp. 128 ° C.

Preparation V

A mixture of 22 parts of 1-ethyl, 4-dihydro-5H-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, stirred and refluxed overnight with a water separator. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted three 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, yielding 28.4 parts (80%) of 1- (2-chloroethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one as a residue.

Preparation VI

Following the procedure of Example V and using an equivalent amount of the appropriate 1,4-dihydro-5H-tetrazol-5-one and the appropriate bromochloroquane, respectively, as starting materials, the following

II

64364 17 1- (chloroalkyl) -1,4-dihydro-5H-tetrazol-5-init; 1- (2-chloroethyl) -1,4-dihydro-4-propyl-5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -1,4-dihydro-4- (1-methylethyl) -5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -4- (1,1-dimethylethyl) -1,4-dihydro-5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -1,4-dihydro-4-pent-5-yl-5-tetrazol-5-one as a residue; 1- (2-chloroethyl) -4-cyclohexyl-1,4-dihydro-5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -1,4-dihydro-4- (2-phenylethyl) -5H-tetrazol-5-one as a residue; 1- (3-chloropropyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one as a residue; 1- (2-chloroethyl) -1,4-dihydro-4- (phenylmethyl) -5H-tetrazol-5-one as a residue; and 1- (2-chloroethyl) -4-cyclopropyl-1,4-dihydro-5H-tetrazol-5-one as a residue.

Preparation VII

A mixture of 49 parts of iodomethane, 10.5 parts of 1- (2-chloroethyl) -1,4-dihydro-5H-tetrazol-5-one, 15 parts of sodium carbonate, 0.2 parts of potassium iodide and 240 parts of 4-methyl 2- per. tannin, stirred and heated overnight under reflux 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 on silica gel using trichloromethane as eluent. The pure fractions and eluent are evaporated to give 15 parts (85%) of 1,4-dihydro-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one as a residue.

Preparation VIII

A mixture of 19.6 parts of [2- (2-thienyl) ethyl] -4-methylbenzenesulfonate, 10 parts of 1- (2-chloroethyl) -1,4-dihydro-5H-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 three times with methylbenzene. The combined extracts are dried, filtered and evaporated. The residue is purified by flash chromatography on silica gel using a mixture of trichloromethane and petroleum ether (70:30 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 15 parts (46.5%) of 1- (2-chloroethyl) -1,4-dihydro-4- [2- (2-thienyl) ethyl] -5H-tetrazol-5- onia as a residue.

Preparation IX

4.5 parts of sulfinyl chloride are added dropwise to a mixture containing 13 parts of Ν- [- (2-hydroxy-2-phenylethyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropamide hydrochloride and 260 parts of dichloromethane. At the end of the addition, the mixture is stirred and refluxed for a few hours. The reaction mixture is cooled and the solvent is evaporated. The residue is dissolved 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 -, [1- (2-chloro-2-phenylethyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenyl -propanamide monohydrochloride, m.p. 145.3 ° C.

Preparation X

A mixture of 35 parts of 2-methyloxirane, 83 parts of N- [4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide, 25 parts of sodium hydrogen carbonate, 450 parts of benzene and 80 parts of methanol is stirred and refluxed overnight. The reaction mixture is evaporated and the residue is dissolved in water. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is converted into the hydrochloride salt in 2-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- [1- (2-hydroxypropyl) -4- (methoxymethyl) -4-piperidinyl] n-fenyylipropanamidimono hydrochloride.

14 parts of sulfinyl chloride are mixed and a solution of 37 parts of N- [1- (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 2-propanone. The product is filtered off and dried, yielding 31.5 parts (85%) of N- [1- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide monohydrochloride.

Il i9 64364

Manufacture of finished products

Example I

Mixture containing 1.8 parts of 1- (2-chloroethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 3.45 parts of N- [4- (methoxymethyl) -4-piperidinyl N-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 layer is 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 converted into the hydrochloride salt in 2-propanone. The salt is filtered off and crystallized from 2-propanone to give 1.5 parts (33.3%) of N- [1- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazole) -1-yl) ethyl 4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide monohydrochloride monohydrate; mp. 140.8 ° C.

Example II

Following the procedure of Example I and using equivalent amounts of the appropriate starting materials, the following compounds are obtained as acid addition salts after treatment of the free base form with the appropriate acid: N- {1- / 2- (4,5-dihydro-5-oxo-4-propyl-1H- tetrazol-1-yl) ethyl-4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamidethane dicarboxylate (1: 2) monohydrate; mp. 103.8 ° C.

N- [1- [2- [4,5-dihydro- (1-methylethyl) -5-oxo-1H-tetrazol-1-yl] ethyl] -4- (methoxymethyl) -4-piperidinyl] -N- phenylpropan-amidimononitraattimonohydraatti; mp. 104.5 ° C; methyl 1- [2- (4,5-dihydro-5-oxo-4- [2- (2-thienyl) ethyl] -1H-tetrazol-1-yl] ethyl] -4 - ['(1 (oxopropyl) phenylamino] -4-piperidinecarboxylate ethanedicarboxylate (1: 1) m.p. 162.9 ° C; Nf 1- [3- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) propyl] -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamide hydrochloride hemihydrate, m.p. . 182 ° C; and N- [1- {2- (4,5-dihydro-5-oxo-4- (phenylmethyl) -1H-tetrazol-1-yl] ethyl} -4- (methoxymethyl) -4-piperidinyl] -N -phenylpropanediethanedicarboxylate (1: 1), m.p. 166.4 ° C.

20 6 4 3 6 4

Example III

A mixture of 3.6 parts of 1- (2-chloroethyl) -4-ethyl-1,4-dihydro-5H-tetrazol-5-one, 6.4 parts of methyl 4- [N- (1-cyclo propyl) -NT-phenylamino-4-piperidinecarboxylate hydrochloride, 4 parts of sodium carbonate, 0.1 part 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 flash chromatography on 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 converted into the ethanedicarboxylate salt in 2-propanone. The salt is filtered off and dried, yielding 1.5 parts (13%) of methyl 1H-1- [2- (4-yl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ethyl] -N- 4 - [(1-oxopropyl) phenylamino] -4-piperidinecarboxylate ethane dicarboxylate (2: 3), m.p.

158.9 ° C;

Example IV

Following the procedure of Example III and using equivalent amounts of the appropriate starting materials, the following ethanedicarboxylate salts are obtained: methyl 1- [2- (4,5-dihydro-5-oxo-4-propyl-1H-tetrazol-1-yl) ethyl] -4- (j-1-oxopropyl) phenylamino] -4-piperidinecarboxylate ethane dicarboxylate (1: 1), m.p. 168.4 ° C, methyl 1- [2- [4,5-dihydro-4- (1-methylmethyl) -5-oxo-1H-tetrazol-1-yl] ethyl] -4- [7-oxopropyl ) phenylamino 4-7-piperidine carboxylate ethane carboxylate ethane dicarboxylate (1: 1), m.p. 184.2 ° C; Methyl 1- {2 - ["4- (1,1-dimethylethyl) -4,5-dihydro-5-oxo-1H-tetrazol-1-yl] ethyl] -4 - [(1-oxopropyl) phenylamino] - 4-Piperidinecarboxylate ethane dicarboxylate (1: 1), mp 168.1 ° C, methyl 1- [2- (4,5-dihydro-5-oxo-4-pentyl-1H-tetrazol-1-yl) ethyl] - 4 - [(1-oxopropyl) phenylamino] -4-piperidine carboxylate ethane dicarboxylate (1: 1), mp 153.5 ° C, 21 64364 methyl 1- [2- (4-cyclohexyl-4,5-dihydro- 5-oxo-1H-tetrazol-1-yl) ethyl [-4 - [(1-bisopropyl) phenylamino] -4-piperidinecarboxylate ethane dicarboxylate (1: 1), m.p. 173 ° C; Methyl 1- [2- (4,5-dihydro-5-oxo-4- (2-phenyl) -1H-tetrazol-1-yl] ethyl] -4 - [(1-oxopropyl) phenylamino--4-piperidinecarboxylate ethane dicarboxylate (2: 3), mp 162.2 ° C, methyl 1- [2- [4,5-dihydro-5-oxo-4- (phenylmethyl) -1H-tetrazole-1 -yl / ethyl} -4 - [(1-oxopropyl) phenylamino] -4-piperidinecarboxylate ethanedicarboxylate (1: 1), mp 191.7 ° C, methyl 1- [2- (4-cyclopropyl) - 4,5-Dihydro-5-oxo-1H-tetrazol-1-yl) -ethyl] -4 - [(1-oxopropyl) phenyl] amino] -4 - [ carboxylate ethane dicarboxylate (2: 3) dihydrate, mp 155.9 ° C and methyl 1- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ethyl] -4- (phenylamino) -4-piperidinecarboxylate octane dicarboxylate (2: 3), mp 172 ° C.

Example V

A mixture of 2.55 parts of 1,4-dihydro-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one, 3.45 parts of N- [4- (methoxymethyl) -4 -piperidinyl / -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 converted into the ethanedicarboxylate salt in 2-propanone.

The salt is filtered off and crystallized from 2-propanone to give 2.1 parts (42%) of N-1- [2- (4,5-dihydro-4-methyl-5-oxo-1H-tetrazole). 1-yl) ethyl -4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamidethane dicarboxylate (1: 1), m.p. 155.9 ° C.

Example VI

Following the procedure of Example V, 1- [2- (4,5-dihydro-4-methyl-5-oxo-1H-tetrazol-1-yl) ethyl] -4 / -4 - [(1-oxopropyl) phenylamino] -4 -piperidinecarboxylate ethane dicarboxylate 22 64 36 4 (1: 1), m.p. 185,9UC; In the reaction of 1,4-dihydro-1- (2-iodoethyl) -4-methyl-5H-tetrazol-5-one with methyl 4 - [(1-oxopropyl) phenylamine] -4-piperidinecarboxylate.

Example VII

A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 9.4 parts of N- [1- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl The N-N-phenylpropanamide, 2.5 parts of sodium carbonate, 2.5 parts of Ν, Ν-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 on 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 in 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; mp. 185.4 ° C.

Example VIII

A mixture of 1.2 parts of 1-ethyl-1,4-dihydro-5K-tetrazol-5-one, 3.9 parts of N- [1- (2-chloropropyl) -4- (methoxymethyl) -4 -piperidinyl / -NT-phenylpropanamide monohydrochloride, 2 parts of sodium carbonate, 0.1 part of potassium iodide and 120 parts of 4-methyl-2-pentanone, are stirred and boiled 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 converted into the nitrate salt in 2-propanone. The salt is filtered off and crystallized twice: first from a mixture of 2,2'-oxybispropane and 2-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; mp. 146.6 ° C.

li 23 64364

Example IX

Following the procedure of Example VIII, N-JL 1-./2- (4,5-dihydro-5-oxo-4-phenyl-1H-tetrazol-1-yl) -1-methyl-ethyl / -4- (methoxymethyl) is prepared. -4-piperidinyl and N-phenylpropanamide mononitrate; mp. 151.2 ° C; In the reaction of 1,4-dihydro-1-phenyl-5H-tetrazol-5-one with N- [1- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl] -N-phenylpropanamine monohydrochloride.

Example X

A mixture of 3 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 8 parts of N- [1- (2-chloro-2-phenylethyl) -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 on silica gel using a mixture of trichloroethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of Petro ether and 2,2'-oxybispropane. The product is filtered off and dried, yielding 5.7 parts (65%) of N- {1- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrasol. 1-yl) - 2-phenylethyl-4- (methoxymethyl) -4-piperidinyl} -N-phenylpropanamide; mp.

125.7 ° C.

Example XI

Mixture containing 3 parts of 1-ethyl-1,4-dihydro-5H-tetrazol-5-one, 9.4 parts of N- [1- (2-chloropropyl) -4- (methoxymethyl) -4-piperidinyl] ~N-phenylethanamine, 2.5 parts of sodium carbonate and 90 parts of Ν, Ν-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 on silica gel, first using a mixture of trichloromethane and methanol (97: 3 by volume) and then 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 in 2-propanone and 2,2'-oxobispropane. The salt is filtered off and dried, yielding 3.9 parts (33.4%) of 64364 24 N- (1- / 2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ) propyl-7- (4- (methoxymethyl) -4-piperidinyl} -N-phenyl-propanamide monohydrochloride, mp 192.7 ° C.

Example XII

A mixture of 5.7 parts of methyl 1- [2- (4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ethyl] -4- (phenylamino) -4-piperidine ridine carboxylate, 1.9 parts of cyclopropanecarbonyl chloride, 2.7 parts of N, N-diethylethanamine and 68 parts of methylbenzene are stirred and refluxed overnight. 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 methane (98: 2 by volume) as eluent. The pure fractions are collected and treated with 1 part of ethanedicarboxylic acid. The ethanedicarboxylate salt formed is filtered off and crystallized from a mixture of 2-propane and 2,2'-oxybispropane to give 1.5 parts (17.5%) of methyl 4- (cyclopropylcarbonyl) phenylamino] -1- [2- (4-ethyl- 4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ethyl-7- (4-piperidinecarboxylate-ethane dicarboxylate (2: 3); mp. 181.5 ° C.

Example XIII

A mixture of 5 parts of /- [/- [2- [4,5-dihydro-5-oxo-4-phenylmethyl] -1H-tetrazol-1-yl] ethyl] -4-methoxymethyl-4-piperidinyl -N-phenylpropaneamine and 120 parts of stanol are hydrogenated under normal pressure at room temperature using 2 parts of palladium / carbon catalyst (10%). After the calculated amount of hydrogen has elapsed, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column chromatography over silica gel using a trichloromethane / methanol mixture (95: 5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride solution in 2-propanol. Evaporation is carried out and the residue is crystallized from 2-propanone. The product is cooled to room temperature and then filtered off and recrystallized from a mixture of 2-oropanone, 2-propanol and methanol. The product is filtered off and dried in vacuo at 50 [deg.] C. to give 2.1 parts of .beta .- [2- (4,5-dihydro-5-oxo-1H-tetrazol-1-yl) ethyl] -4-methyl tox imetyl-4-piperidinyl-7-M-phenylpropanimide monohydrochloride, m.p. 235.6 ° C.

Claims (2)

A process for the preparation of analgesically active N-phenyl-N- (4-piperidinyl) amide derivatives of the formula I and their pharmaceutically acceptable acid addition salts, 0 3 A o RN, Ν-CH- (CHO-CH-N). 4 λ / »2 n, V / '' NC-R4 (I) 101 R1 R2 in which R is a hydrogen atom or a lower alkyl, cycloalkyl, aryl or aryl (lower alkyl) group in which aryl is phenyl or thienyl; R- is a hydrogen atom or a lower alkyl or phenyl group; is a hydrogen atom or a lower alkyl group; R 1 is a lower alkyloxycarbonyl or lower alkyloxymethyl group; R4 is a lower alkyl or cyclopropyl group; and n is an integer O or 1; characterized in that a) to (1) is administered a compound of formula (ΙΙ-b) R-N YcH-CH 3 -CH-Y 11. 2 n i_ <IX-b> NN KR to react with N-phenyl-N- (4-piperidinyl) -amide of formula (III-a) hOA 4 / _-HC-ir (III-a) 0 12 3 4 in which R, R, R, R, R and n are as defined above and Y is a reactive ester residue such as halogen, especially chlorine, bromine or iodine, or a sulfonyloxy group, such as methylsulfonyloxy or 4-methylphenylsulfonyloxy, the reaction being carried out in a suitable reaction-inert organic solvent in the presence of a suitable base, preferably at elevated temperature; or a) - (2) reacting a compound of formula (II-a) with N-phenyl-N- (4-piperidinyl) of formula (III-a) ) with an amide, / - \ R3 Y-CH- (CH.-,) CH-N Y 2 (1H-b) \ \ _Λν-OR RR i Λ 12 3 4 where R, R, R, R, R, n and Y are as defined above, in a suitable organic solvent in the presence of a suitable base, preferably at elevated temperature; or b) N-acylation of a compound of formula 0. N = N R1 R J ... [li] according to conventional N-acylation methods to prepare a compound of formula R-S_ (CH2> (I'a) t li 64364; ) debenzylating compounds of formula I wherein R represents a phenylmethyl group by known debenzylation methods to prepare compounds wherein R represents a hydrogen atom and, if desired, preparing pharmaceutically acceptable acid addition salts of the products of steps a) to c). 28 Patent: 64,364 For the preparation of an analgesic active N-phenyl-N- (4-piperidinyl) amide derivative with the formula I and a pharmaceutical formulation of a syrup addition salt, A. YS 4 ^ R1 R2 X. O i vilken formel R is a hydrogen atom or an alkyl, cycloalkyl, aryl or aryl (alkyl group) group, a color aryl or phenyl or a tie, Ί 2 nyl; alkyl or phenyl group; Fig a) - (1) is a mixture of compounds of formula (II-b) O RN N-CH- (CH,) -CH-Y 1 I! 2 n! (tt_u) 1. a; R med en N-phenyl-N- (piperidinyl) amide with formula (III-a) / R3 0 HN2-N-C-R4 (III-a) 12 3 4 color R, R, R, R, R and The reaction is preferably carried out with reactive esters, such as with free halogen, especially with chlorine, bromine or iodine or with sulfonyl groups, with free methyl sulfonyloxy or 4-methylphenylsulfonyl, with the addition of reactants in the presence of 29 64364 närvaro av en iäirvpiiq bas, företrädesvis vid en förhöjd tempera-tur; or a) - (2) to give compounds of formula (II-a) 0 RN ^ NH (II-a) 1 IN == N of N-phenyl-N- (4-piperidinyl) amide of formula (III -b) / - R3 Y-CH- (CH-) -CH-N X 2 'S \ / NCR (Ill-b) 12 3 4 colors temperatur; or b) in the case of the form / / R3 RN 'fc-CH-iCH,) -CH-l / Y> - «- n, \ / \„ 1 02' - 'N1J (VI) RR Λ ϋ N -acylers or compounds of the N-acylation moiety for the preparation of -S-R ~ Zs-CH- (CH ~) -CH ~ N, Y * '0 / * 2 n' 2 \ Α-γ- r4 da) NX R1 IT% 'N "CR: I