FI77024C - FOERFARANDE FOER FRAMSTAELLNING AV THERAPEUTISKT VERKSAMMA 2- / 4- (DIPHENYLMETHYLENE) -1-PIPERIDINYL / -ACETAMIDER. - Google Patents

Description

1 77024

Process for the preparation of therapeutically active 2- [4- (diphenylmethylene) -1-piperidinyl] acetamides - For the preparation of therapeutically active compounds 2- [4- (diphenylmethylene) -1-piperidinyl] acetamide

By division separated from patent application 812852 Avdelad ur patentansökningen 812852

The present invention relates to a process for the preparation of therapeutically active 2- [4- (diphenylmethylene) -1-piperidinyl] acetamides of the general formula C = (N-t- (CH2) n-0-4lnCH2-C (I) O 'w NR1R2 wherein

R 1 and R 2 are independently a hydrogen atom or phenyl, X is a hydrogen atom, a halogen atom or a lower alkoxy radical, m is 1 or 2, and n is 1 or 2, and non-toxic, pharmaceutically acceptable salts thereof.

Diphenylmethylene or phenylbenzylpiperidinyl derivatives have been described e.g. in GB 1 252 315, DOS 23 65 906, SE 382 455 and US 2 898 339. However, the side chain attached to the N atom of the piperidyl ring in these known compounds is clearly different from the compounds of formula 1, the pharmacological properties of which are also not apparent from said publications. In addition, it has been found that the compounds of the invention have very few undesirable side effects.

In addition, the compounds of the formula I in which R 1 and R 2 are 2 77024 hydrogens are also useful starting materials for the preparation of the corresponding 2- [4- (diphenylmethylene) -1-piperidinyl] acetic acids by the process according to FI patent application 812852.

The process according to the invention is characterized in that the 4- (diphenylmethylene) -piperidine of the formula (II) c = <NH (II) <y ^ where X has the same meaning as above is reacted in an inert solvent and in the presence of an acid acceptor of the omega of the formula (III). with haloacetamide Zf- (CH2) n-O-hhCH2-C (III) X NR] R2 wherein R1, R2, m and n are as defined above and Z is a halogen atom and optionally thereafter converted into the 2- [4 - (diphenylmethylene) -1-piperidinyl] -acetamide as its non-toxic, pharmaceutically acceptable salts.

This reaction is generally carried out by heating for several hours at 80 to 150 ° C in an inert solvent selected from aliphatic alcohols, benzene, toluene and xylene in the presence of an acid acceptor such as a tertiary organic base such as triethylamine or an inorganic base such as sodium carbonate.

When 2- [4- (diphenylmethylene) -1-piperidinyl] acetamides are obtained in the form of the free base, they can be converted, if necessary, into non-toxic, pharmaceutically acceptable acid addition salts by known methods.

3,77024

The following examples are provided to illustrate the invention:

Example 1 1.1. 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy} acetamide (hydrochloride

A mixture of 29.9 g of 4- (diphenylmethylene) piperidine, 36.3 g of 2- [2- (2-chloroethoxy) ethoxy] acetamide and 18 g of sodium carbonate in 80 ml of xylene is heated at 20 ° C for 20 hours. 90-110 ° C. 80 ml of benzene are then added. The precipitate obtained is filtered off and the organic phase is extracted with a dilute solution of hydrochloric acid (20 ml of concentrated hydrochloric acid and 80 ml of water). 30 ml of concentrated sodium hydroxide solution are added and the mixture is extracted with benzene, after which the benzene solution thus obtained is washed, dried over anhydrous potassium carbonate and the benzene is evaporated off under vacuum. The resulting 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy] acetamide was dissolved in diethyl ether to which a stoichiometric amount of ethereal hydrochloric acid was added to convert the base to the hydrochloride. This was recrystallized from acetone and acetonitrile to give 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy] acetamide hydrochloride, m.p. 145-146 ° C.

Analysis: C24H30N2O3 · HCl,%:

Calc .: C 66.9, H 7.20, N 6.50, Cl 8.25 Found: 66.5, 7.21, 6.17, 8.08 The 2- [2- (2 -chloroethoxy)] ethoxy] -acetamide is prepared by the method described in British Patent Publication 1,357,547.

The yield is 77% of theory; mp. 51-53 ° C.

* 77024 1.2. The following compounds are prepared according to Example 1.1. by the method: 2- [4- (diphenylmethylene) -1-piperidinyl] acetamide

Yield: 40% of theory; mp. 220 ° C.

Analysis: θ2θΗ22Ν2 ° '

Calculated: C 78.40, H 7.24, N 9.14

Found: 77.64 7.36 8.90 2- [4 - [(4-chlorophenyl) phenylmethylene] -1-piperidinyl) acetamide hydrochloride

Yield: 77% of theory; mp. 221-223 ° C.

Analysis: C20H21ClN2O · HCl,%:

Calc .: C 63.66, H 5.87, N 7.42, Total Cl 18.79

Found: 63.38 6.13 7.63 18.76 2- [2- [4 - [(4-chlorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide hydrochloride

Yield: 65% of theory; mp. 166-169 ° C.

Analysis: C22H25ClN2O2 * HCl,%:

Calc .: C 62.74, H 6.22, N 6.65, Cl 8.42, Total Cl 16.83

Found: 61.22 6.40 6.47 8.71 16.51 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] ethoxy] acetamide

Yield: 93% of theory.

Analysis: C24H29ClN2O3,%:

Calc .: N 6.53, Cl 8.63

Found: 5.59 8.74

Mass spectrum: molecular ion M +. 428 m / e 5,77024 2- [2- (4 - [(2-chlorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide hydrochloride

Yield: 86% of theory; mp. 240-241 ° C.

Analysis: C22H25ClN2O2 * HCl,

Calculated: C 62.70, H 6.21, N 6.64, Cl ”8.41, Total Cl 16.82

Found: 62.59 6.29 6.52 8.17 16.79 2- [2- [4 - [(4-fluorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide

Yield: 65% of theory? mp 118-119 ° C,

Analysis: C22 ^ 25 ^ 2 ^ 2 ·

Calc .: C 71.71, H 6.84, N 7.60

Found: 71.66 6.93 7.53 2- [2- [4 - [(4-methoxyphenyl) phenylmethylene] -1-piperidinyl] ethoxy 3-acetamide hydrochloride

Yield: 47% of theory; mp. 196-198 ° C.

Analysis: C23H28N2 ° 3'HCl1%!

Calc .: C 66.25, H 7.01, H 6.71, Cl "8.50

Found: 65.71 7.29 6.70 8.40 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy] -N-phenylacetamide hydrochloride

Yield: 38% of theory; mp. 133-134 ° C.

Analysis: C 30 H 34 N 2 O 3 * HCl,%:

Calc .: C 71.07, H 6.91, N 5.53

Found: 70.90 7.03 5.29

Pharmacology

The following compounds 6,77024 prepared according to the present invention were pharmacologically tested to give the results described below: 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy] acetamide hydrochloride (Compound A, prepared in Example 1.1.); 2- [2- [4-1- (4-chlorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide hydrochloride (Compound B, prepared in Example 1.2); 2- [2- [2- [4 - [(4-chlorophenyl) phenylmethylene) -1-piperidinyl] ethoxy] ethoxy] acetamide (Compound C, prepared in Example 1.2); 2- [2- [4 - [(2-chlorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide hydrochloride (Compound D, prepared in Example 1.2); 2- {2- [4 - [(4-fluorophenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide (Compound E, prepared in Example 1.2); 2- [2- [4 - [(4-methoxyphenyl) phenylmethylene] -1-piperidinyl] ethoxy] acetamide hydrochloride (Compound F, prepared in Example 1.2); 2- [2- [2- [4- (diphenylmethylene) -1-piperidinyl] ethoxy] ethoxy] -N-phenylacetamide hydrochloride (Compound G, prepared in Example 1.2.).

1. Antiallergic activity This activity is determined in rats by the passive subcutaneous anaphylaxis test (PCA) 7 77024 (see J. Goose and AMJN Blairs, Immunology, 1J5, (1969), 749-760; and U. Martin and D. Poemer, Arzneimittel- Forschung, 2iB, (5), (1978), 770-782.

Use female rats whose sides have been partially shaved clean. To sensitize the animals passively, 0.05 ml of IGE anti-albumin serum is injected intradermally into the shaved zone at such a dilution that, at the time of the PCA test, a clear spot with an area of approximately 100 mm2 is applied to the injection site.

72 hours after injection, 0.25 ml of the allergen solution containing the dye (5 mg of ovalbumin and 6 mg of Evans Blue in 0.25 ml of 0.9 S aqueous sodium chloride solution) is administered intravenously. A clear blue spot appears at the site of intradermal injection, the area of which is measured.

To test the activity of the compounds of formula I, the procedure is carried out in the same manner; however: - the test compound is administered orally 72 hours after the injection of the serum; - 15 minutes after this administration, 0.25 ml of allergen solution was injected intravenously; - 30 minutes after allergen administration, the blue spot area is measured.

The following table shows the immunological doses (ID 50, pnol / kg) that reduce the area of the colored spot by 50% based on the average of the total number of animals used in the experiment.

From this table it can be seen that the compounds of formula I are active when administered orally, whereas β 77024 sodium cromoglycate is not active in this route of administration, although its antiasthmatic activity is generally known in the case of intravenous administration.

TABLE

Test compound ID 50 per os, pmol / kg

Sodium cromoglycate inactive A 76 B 67.4 C 34 D 66 E 5.5 F 31.4 G 15.2 2. Spasmolytic and antihistamine activity These activities were measured in guinea pigs by the method of H. Konzett and R. Roessler (Naunyn- Schmiedebergs Arch, exp.Path.Pharmakol., 195, (1940), 71-74) and these activities were compared to theophylline activities.

Anesthetized and curated guinea pigs are artificially ventilated. Endotracheal pressure is recorded.

Sequential and progressive intravenous injection of acetylcholine, histamine, and serotonin, respectively, causes recurrent bronchospasm.

Test compounds are also administered intravenously.

The following table gives the doses of compounds (pfj / kg) that inhibit 50% of the induced bronchospasm, calculated from the mean total number of animals: 77024

TABLE

Test compound Serotine Histamine Acetylcholine Theophylline in 2560 2650 4130 A 9 31 470 C 85 348> 4285 D 55 551> 1347 E 23 93> 11776 F 180 26> 41650 G 86 192 1347 It can be seen from this table that, in comparison with theophylline, the following the compounds have moderate spasmolytic activity on acetylcholine-induced bronchospasms, but a marked effect on bronchospasms induced by serotonin and histamine, respectively.

In addition, this test has shown that some single-dose compounds have long duration of antihistamine activity.

3. General behavior in mice (Irwin * test) Behavior is studied using the Irwin test (see

S. Irwin, "General Philosophy and Methodology of Schreening: A Multidimensional Approach"; Gordon Research Conference on Medicinal Chemistry, August 3-7, 1959, Golby Junior College, New London).

The test compounds are administered in increasing doses intraperitoneally to groups of three male mice (weighing 18-22 g) and the general behavior of the animals is monitored according to known criteria. The reference compounds used are as follows: - hydroxycin = 1- (E-chloro-alpha-phenylbenzyl) -4- (2-hydroxyethoxyethyl) -piperazine (tranquilizing dose: 27 mg / kg), - oxazepam = 7-chloro-1,3 -dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (tranquilizing dose: 2.6 mg / kg).

The experiments show that the compounds prepared according to the present invention have a slight sedative effect compared to the reference compounds.

In addition, the toxicity of the compounds of formula I appears to be very low in this test. The following table gives this toxicity as determined by intraperitoneal administration of the compounds to mice (the dose that kills two out of three animals):

TABLE

Test compound Toxicity (mg / kg) A 258 B 126 C 128 D 421 E 368 F 416 4. Posology and method of administration

Pharmaceutical compositions containing compounds of formula I may be administered orally, parenterally or rectally. They can also be administered nasally (as an aerosol) or as ointments or cells. Pharmaceutical compositions that can be used for oral administration can be solid or liquid, for example, uncoated or coated tablets, pills, granules, gelatin capsules, solutions, syrups, and the like. The compositions that can be used for parenteral administration can be any of the pharmaceutical compositions known in this mode of administration, for example, aqueous or oily solutions, suspensions, or emulsions. For rectal administration, compositions containing the compounds of the present invention are usually used as suppositories.

Pharmaceutical forms such as injectable solutions, injectable suspensions, tablets, drops, suppositories and the like are prepared by conventional pharmaceutical methods. The compounds of this invention are mixed with a non-toxic and pharmaceutically acceptable solid or liquid carrier, and optionally with a dispersant, disintegrant, stabilizer and the like. If necessary, it is also possible to add preservatives, sweeteners, colorants and the like. The percentage of active substance in the pharmaceutical compositions can vary within wide limits depending on the patient and the mode of administration and in particular the frequency of administration.

The dosage may vary within a wide dosage unit range, for example, from 0.5 to 500 mg of active compound. Thus, the desired effects can be achieved by intravenous administration of a single dose of 30 mg or by oral administration of a 100 mg gelatin capsule once or twice a day.

The following examples illustrate pharmaceutical compositions containing compounds of formula I: 12,77024

Example A

Formulation of an ampoule for intravenous administration

Compound E 50 mg

Sodium chloride 90 mg

Sodium acetate 20 mg

Sodium hydroxide The pH is adjusted to 5.5

Distilled water 10 ml

Similarly, 10 ml ampoules containing 4, 20, 30 or 200 mg of active compound, respectively, may be used.

Example B

Gelatin capsule for oral administration

Compound E 100 mg

Lactose 344 mg

Cellulose (Avidel) 50 mg

Silica (Aerosil) 1 mg

Magnesium stearate 5 mg

Similarly, gelatin capsules containing 10 or 50 mg of active compound can be used.

Claims (1)

A process for the preparation of therapeutically active 2- [4- (diphenylmethylene] -1-piperidinyl] acetamides of the general formula c = / NH (CH2) n-O-hnCH2-C (I) ^ XNR1R2 wherein R1 and R 2 are independently a hydrogen atom or phenyl, X is a hydrogen atom, a halogen atom or a lower alkoxy radical, m is 1 or 2, and n is 1 or 2, and non-toxic, pharmaceutically acceptable salts thereof, characterized in that the 4- ( diphenylmethylene) -piperidine C = / NH (II) O '^ where X is as defined above is reacted with an omega-haloacetamide of formula (III) in an inert solvent and in the presence of an acid acceptor 77024 Z-4- (CH2) n-O-1hCH2 (c) (III) N, N 2 R 2 wherein R 1, R 2, tm and n are as defined above and Z is a halogen atom, and optionally thereafter the 2- [4- (diphenylmethylene) -1-piperidinyl] -acetamide thus obtained is converted non-toxic, pharmaceutically acceptable salts 77024 Förfarande för f The therapeutic network of 2- [4- (diphenylmethylene) -1-piperidinyl] -acetamide under the formula C = (N - E - (CH2) n-O-hmCH2-C (I) <yw NRiR2 for R1 and R2) a mixture of a substance or a hydrogen atom or a phenyl atom, a halogen atom or a alkoxy radical, a mixture of 1 or 2, and a mixture of 1 or 2 carbon monoxide toxic, a pharmaceutically acceptable salt, a pharmaceutical composition, a mixture of 4- [ diphenylmethylene] -piperidine with the formula (II) C = (NH (II) O ^ där X avser samma som ovan, omsats i et inert lingnmedel och and nervvaro av en cyraacceptor med omega-halohacetamid med formuleln (III)