FI98728C - Process for the preparation of a therapeutically useful 2,3,4,5,6,7-hexahydro-1- (4- 1- [4- (2-methoxyphenyl) piperazinyl / -2-phenylbutyryl) -1H-azepine or a pharmaceutical acceptable acid addition salt thereof - Google Patents

Description

98728

A process for the preparation of a therapeutically useful 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) -1H-azepine or a pharmaceutically acceptable This invention relates to a process for 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) - For the preparation of 1H-azepine or its pharmaceutically acceptable acid addition salts, the novel compounds act in the central nervous system by binding to 5-HT receptors (explained in more detail below) and thus can be used as medicaments in the treatment of humans and other mammals.

The novel compounds of the invention are those of the formula och3

/ "ί / ~ \ /" N

20 \ - / \ _ /, N-tCH2> 2-JHCON. J (A>

O

25 and pharmaceutically acceptable salts thereof.

Compound A is 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) -1H-azepine.

Co-pending GB Application No. 9008925.1 describes compounds of the general formula comprising the novel compounds to be prepared according to the present invention. The compounds of this application are compounds of the general formula 2,98728

R

, 2 3 R -N N-CCH.) CR R -X (I) / 2n 5 '-' and pharmaceutically acceptable salts thereof, wherein 1 n is an integer 1 or 2, R is hydrogen or lower alkyl, R 1 is aryl or a nitrogen-containing heteroaryl radical, R 2 is hydrogen or lower alkyl, R 3 is an aryl radical, an alkyl radical having 4 to 8 carbon atoms, or an aryl (lower) alkyl radical, X is -OCOR 10, -CO 2 R 6, -CONR 5 R 9, - OCO2R6, -NR4COR6, OCONHR11, -NHCO2R6, -NR4CONHR6, -CONHNHR6, -CONHRR6, - -Co "or R4 and R5 are each hydrogen or lower alkyl, R6 is -CHR7R8, cycloalkyl of 3 to 12 carbon atoms. 25 atoms, or aryl (lower) alkyl, wherein R7 and R8 are each hydrogen or lower alkyl, R9 is hydrogen, an alkyl group having 1 to 8 carbon atoms and which is not a tertiary alkyl group, cycloalkyl having 3 to 12 carbon atoms, cycloalkyl (lower) alkyl, aryl, aryl (lower) alkyl or 8-azaspiro [4.5] deca-7,9-dione-8-yl (lower) alkyl, provided that when R3 is aryl or aralkyl, R9 is not a phenyl group substituted in the ortho position by halogen or nitro, trifluoroalkyl, cyano, sulfonic acid, sulfonamido, carboxy, carbalkoxy, carboxyanilino or 4-carboxyl.

II

3,98728 with an aminobenzosulfonamido group, and when R 9 is hydrogen, alkyl, aryl or aryl (lower) alkyl, R 5 is hydrogen or -CHR 7 R 8, or R 5 and R 9 together with the nitrogen atom to which they are attached are azetidino, pyrrolidino, piperidino , a hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl (lower) alkyl, R 10 is cycloalkyl of 3 to 12 carbon atoms, 10 or 2,3-dihydro [1,4] benzodioxinyl , which is optionally substituted by lower alkyl, lower alkoxy or halogen, or when R 3 is an alkyl radical having 4 to 8 carbon atoms, R 10 may also be aryl; R 11 is cycloalkyl of 3 to 12 carbon atoms, aryl or aryl (lower) alkyl, R 12 and R 13 are each lower alkyl or are taken together with the carbon atom to which they are attached, C 4-6 cycloalkyl, R 14 is hydrogen, halogen, lower alkyl or lower alkyl and Y is CO or SO 2.

The compounds of the formula I can be prepared by various methods from known starting materials or from starting materials which can be prepared by known methods.

25 Some of the methods presented are described below.

In one process for preparing an amide of formula (I) wherein X is -CONR 5 R 6, an amine of formula NHR 5 R 9 (II) wherein R 5 and R 9 are as defined above is acylated with an acid of formula 4,98728

R

Ar- \ <i “>

r '- N 2 - N- (CH 2) n CR 2 R 3 COOH

wherein R, R1, R2 and R3 are as defined above, or an acylating derivative thereof. Examples of acylating derivatives are acid halides (e.g. chlorides), azides, anhydrides, imidazolides (e.g. derived from carbonyldiimidazole) and activated esters or O-acyl ureas derived from carbodiimides such as dialkylcarbodiimides, in particular dicyclohexylcarbodiimide. Preferably, the amine is acylated with an acid in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, iso-butyl chloroformate or diphenylphosphinyl chloride.

In an alternative process for the preparation of compounds of formula I, piperazine of formula

R

Wherein r and R 1 are as defined above, are alkylated with an alkylating agent to give the group -CH 2) n CR 2 R 3 X (V) wherein n, R 2, R 3 and X are as defined above.

The alkylating agent may be, for example, a compound of formula ZCH 2 CR 2 R 3 X (VI) wherein R 2, R 3 and X are as defined above, and Z is a leaving group such as halogen or alkyl or arylsulfonyl.

II

5,98728 oxy group. Alternatively, the alkylating agent may be an unsaturated compound of formula CH 2 = CR 3 X (VII) 5 wherein R 3 and X are as defined above, and the compound of formula VII is reacted with a piperazine of formula IV according to the Michael reaction. The reaction can be carried out at an elevated temperature in the presence of an alcohol. A small amount of acid catalyst can be used in the reaction when X is -CONR5R9.

The compound of formula A prepared according to the invention may be prepared in a similar manner using suitable starting materials. The process 15 according to the invention is characterized in that the compound of formula och3

N- (CH2,2-X

Wherein X is a leaving group such as halogen is reacted with an amide of formula oo and, if desired, (i) the free base is converted to 2,3,4,5,6,7-hexahydro-1 -30 (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) -1H-azepine to its pharmaceutically acceptable acid addition salt, or (ii) converted to 2,3,4,5,6, A pharmaceutically acceptable acid addition salt of 7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} -2-phenylbutyryl) -1H-6,98728 azepine to its free base, or (iii) decomposing the racemic 2,3,4 , 5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbut-5-thyryl) -1H-azepine.

The anion can be prepared by reacting the amide with a strong base, e.g. lithium diisopropylamide.

The methods described above can be carried out to give a compound of formula A in the form of a free base or an acid addition salt. If the compound of formula A is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product of the process is a free base, an acid addition salt, especially a pharmaceutically acceptable acid addition salt, may be obtained by dissolving the free base in a suitable organic solvent and treating the solution with acid according to known methods for preparing acid addition salts from base compounds.

Examples of acid addition salts are those formed from inorganic and organic acids, such as sulfuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, lemon, vinegar, ant, methanesulfonic, -toluenesulfonic, oxalic-25 and succinic acids.

The compounds of the invention have an asymmetric carbon atom, so the compounds may exist in different stereoisomeric forms. The compounds may be, for example, racemates or optically active forms.

Optically active forms can be obtained by resolution of racemates or by asymmetric synthesis. For example, resolution can be accomplished by forming diastereoisomeric salts of a racemic base with an optically active acid (e.g., dibenzoyl-L-tartaric acid).

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7 98728 The diastereoisomeric salts are separated and converted into an optically active base or other salts.

The compounds of the present invention have pharmacological activity. In particular, they function in the central nervous system by binding to 5-HT receptors. In pharmacological experiments, the compounds have been shown to bind specifically to 5-HT1A-type receptors. The compounds bind selectively to 5-HT1A-type receptors to a much greater extent than they bind to other receptors, such as α 2 -receptors. In pharmacological experiments, they act as 5-HT1A antagonists. The performance of pharmacological experiments on the compounds shows that they can be used for the treatment of central nervous system disorders, such as the pain of mammals, especially humans. They may also be useful as antidepressants, antihypertensive agents, and agents that regulate the sleep / wake cycle, eating behavior, and / or sexual activity.

The 5-HT1A receptor binding activity of the compounds of the invention was tested in a rat hippo-campus membrane homogenate by the method of B. S. Alexander and M. D. Wood, J. Pharm. Pharmacol. 40 (1988) 888-891.

The results show that the compounds of formula A prepared according to the invention are more potent than other compounds of formula I, including the related compound 2,3,4,5,6,7-hexahydro-1- (3- {1- [4 - (2-methoxyphenyl] piperazinyl]} - 2-phenylpropionyl) -1H-azepine (Compound B), described in Example 34 of the co-pending application. Compound B was one of the most potent compounds disclosed in said application. The results are given below and in which C is the isomer described in Example 2 (a) below: 8 98728 IC 50 (ηΜ)

Compound A 3

Compound B 9

Compound C 1 5

The 5HT1A antagonism activity of the compounds was also studied in an experiment involving antagonism of 8-hydroxy-2- (di-n-propylamino) tetralin- (8-OH DPAT) syndrome in the rat. Results are given below 10 MED (mg / kg; s.c.)

Compound A 0.03

Compound B 0.3 The potential analgesic effect of the compounds was also tested by an experimental method measuring mouse research activity in a two-compartment light / dark box. The method is based on the method of B. Costall et al., Neuropharmacology 26 (1987) 195-200, and J.N.

20 to the method of Crawley et al., Pharmac. Biochem. Behav. 13 (1980) 167-170. The results are shown below MED (mg / kg; s.c.)

Compound A 0.03 25 Compound B 1

The compounds of the invention are useful as a pharmaceutical composition comprising a compound of formula A, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art of pharmacy may be used to prepare the pharmaceutical composition.

In such a composition, the carrier is usually a solid or liquid, or a mixture of solid and liquid.

9,98728

Compositions in solid form include powders, granules, tablets, capsules (e.g., hard and soft gelatin capsules), suppositories, and pessaries. The solid may be, for example, one or more substances which may also act as flavoring agents, mold lubricants, solubilizers, suspending agents, fillers, granular lubricants, compression aids, binders, or tablet disintegrating agents; it may also be an encapsulating agent. In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Powders and tablets preferably contain up to 99%, e.g. 0.03 to 99%, preferably 1 to 80% of active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting point ionic melting point.

The term "composition" is intended to encompass a formulation comprising the active ingredient and encapsulating material as a carrier, thereby providing a capsule in which the active ingredient (with or without other carriers) is surrounded by a carrier, which is in association with with the active substance. The same goes for starch capsules.

Compositions in liquid form include, for example, solutions, suspensions, emulsions, syrups, elixirs, and pressure compositions. For example, the active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, excipients, colorants, viscosity regulators, stabilizers, stabilizers. . Suitable examples of liquid carriers which can be administered orally or parenterally include water (especially water containing additives such as those mentioned above, e.g. cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (e.g. glycerol and glycols) and their derivatives, and oils (for example, fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl 15 oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be employed, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. When the compound is effective when administered orally, it may be administered orally in the form of either a liquid or solid composition.

The pharmaceutical composition is preferably in unit dosage form, e.g. as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active component; unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquid. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The amount of active ingredient in a unit dose of 11,98728 may be varied or adjusted from 0.5 mg or less to 750 mg or more, depending on the particular need and the activity of the active ingredient.

The following examples illustrate the invention:

Example 1 2,3,4,5,6,7-Hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} -2-phenylbutyryl) -1H-azepine Butyllithium (1.5 M in hexane; 5 mL, 7.5 mmol) was added dropwise over 5 minutes, keeping the temperature below 8 ° C, to a stirred solution of 2,3,4,5,6,7-hexahydro-1- phenylacetyl-1H-azepine (1.48 g, 6.8 mmol) and diisopropylamine (2.0 mL, 1.4 g, 14 mmol) in dry toluene (16 mL) under argon. The mixture was stirred at 0 ° C for one hour, and a solution of freshly chromatographed 1- (2-chloroethyl) -4- (2-methoxyphenyl) piperazine (1.73 g, 6.8 mmol) in dry toluene (4 mL) was added. , was added dropwise. The mixture was stirred at 0 ° C to 20 ° C for 18 hours, and water (50 ml) was added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 50 mL). The combined organic phases were concentrated in vacuo. The crude product (2.91 g) was chromatographed on silica eluting with ethyl acetate to give the title compound as the free base (0.15 g). The product was dissolved in ethyl acetate (30 ml), and the solution was acidified with ethereal hydrogen chloride. The product was collected to give the title compound as dihydrochloride 3/4 hydrate (0.36 g), m.p. 175-178 ° C (Found 30: C, 62.05; H, 7.8; N, 7.75. Values required for C 27 H 37 N 3 O 2 .2HCl 1.0.75 H 2 O: C, 62.1; H, 7.8; N, 8.05%).

12,98728

Example 2 Resolution of 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} -2-phenylbutyryl) -1H-azepine (a) 2,3,4,5,6,7-Hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) -1H-azepine (12, 1 g) was dissolved in ethyl acetate (2.5 volumes, i.e. 30 ml) and a solution of dibenzoyl L-tartaric acid monohydrate (1 molar equivalent) in ethyl acetate (2.5 volumes) was added. The initially formed oil was redissolved by adding as little acetonitrile as possible (3.6 mL). After three days, crystals (6.2 g) with an optical purity of 28% as determined by chiral HPLC were obtained. Recrystallization from ethyl acetate-acetonitrile (3:10, 13 volumes) gave a sample of 84% optical purity and then from methanol (7.5 volumes) to give the first enantiomer of the product (Isomer I) as dibenzoyl L-tartrate ( 2.1 g), m.p. 147-150 ° C, [α] D = -26 ° (1% in MeOH) (Found: C, 66.7; H, 6.7; N, 5.1 for C 27 H 37 N 3 O 2. C18H1408.H2O). required values: C, 66.6; H, 6.6; N, 5.2%) with an optical purity of 97.4%. The sample was converted to the free base of isomer (I) (1.1 g), [α] 86 = + 53 ° (1% in CHCl 3) and then to the hydrochloride salt in the usual manner to give a colorless powder (0.65 g). mp. 181-184 ° C, [α] D = + 35 ° (1% in MeOH) (Found: C, 63.1; H, 7.8; N, 7.9; C27H37N3O2.2HCl1.2.25H2O Values required for C: 63.2; H, 7.7; N, 8.2%) with an optical purity of 97.6%.

(B) The second enantiomer (Isomer II) was formed in a similar manner from the racemate of Example 1 and dibenzoyl-D-tartaric acid monohydrate. Isomer II dibenzoyl-D-tartrate, m.p. 141-142 ° C, [α] D = + 25 ° (1%

In MeOH) (Found: C, 67.3; H, 6.7; N, 5.2.

Il 13 98728 C27H37N3O2. Values required for C 18 H 14 O 8 .0.25H 2 O: C, 67.3; H, 6.5; N, 5.2%). Isomer II base: [α] D 6 = -62 ° (1% solution in CHCl 3). Isomer II hydrochloride, m.p. 181-184 ° C, [α] 86 * -36 ° (1% in MeOH) (Found: C, 60.2; H, 7.7; 5 N, 7.75 C 27 H 37 N 3 O 2 .2HCl.1.75H 2 O) Values required for C: 60.05; H, 7.9; N, 7.8%) with an optical purity of 98.2%.

Claims (3)

A process for the preparation of a therapeutically useful 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} -2-phenylbutyryl) -H-azepine or a pharmaceutically acceptable acid addition salt thereof, characterized in that a compound of the formula AND, 10Μ -λ in which X is a leaving group, is reacted with an anion of an amide with formula (O) and if desired (i) the free base 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl]} - 2-phenylbutyryl) -1H-azepine is converted to a pharmaceutically acceptable acid addition salt thereof, (ii) a pharmaceutically acceptable acid addition salt of 2,3,4,5,6,7-hexahydro-1- (4- {1- [4 - (2-methoxyphenyl) piperazinyl] -2-phenylbutyryl) -1H-azepine is converted to a free base or 30. iii) racemic 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-Methoxyphenyl) piperazinyl]} -2-phenylbutyryl) -1H-azepine is separated into sinus enantiomers. Process according to Claim 1, characterized in that an enantiomer of 2,3,4,5,6,7-hexahydro-1- (4- {1- [4- (2-methoxyphenyl) piperazinyl) ]} -2-phenylbutyl) -1H-azepine, where [α] 6 of the free base is about + 53 ° (in 1%: in CHCl 3), or a pharmaceutically acceptable site thereof is prepared . 3. A process according to claim 1, characterized in that an enantiomer of 2,3,4,5,6,7-hexa-hydro-1- (4- (1- [4- (2-methoxyphenyl) ) piperazinyl] -2-phenylbutyryl) -1H-azepine, where [a] p6 of the free base is about -62 "(in 1% by weight CHCl3), or a pharmaceutically acceptable site thereof is prepared.