SK279528B6 - Piperazine derivatives, method of their preparation and pharmaceutical compositions them containing - Google Patents

Abstract

Disclosed are 2,3,4,5,6,7-hexahydro-1-{4-[1-[4-(2- -methoxyphenyl)-piperazinyl]]-2-phenylbutyryl}-1H-azepine compounds or the pharmaceutically acceptable acid addition salts thereof, a method of their preparation and pharmaceutical compositions them containing. These derivatives are 5-HT (especially of 1A type) binding agents useful, for example, as anxiolytic, antidepressants, and hypotensives or as awakening-sleeping cycle regulating agents or as fodder and/or sexual functions.

Description

The invention relates to piperazine derivatives, a process for their preparation, pharmaceutical compositions containing them and their use. The novel compounds act on the central nervous system by binding to 5-HT receptors (as explained in more detail below) and thus can be used as medicaments for the treatment of humans and other mammals.

BACKGROUND OF THE INVENTION

In UK application no. 9008925.1 describes compounds of formula (I)

R ¹⁴ represents hydrogen, halogen, lower alkyl or lower allyl,

X is CO or SO ₂ .

The compounds of the cited UK application may be prepared by a variety of methods from known starting materials, or starting materials may be prepared by conventional methods. Some of the methods of the invention are disclosed.

In one method of making an amide of formula (I) wherein X is -CONR ⁵ R ^{9 an} amine of formula (II)

NHR ⁵ R ⁹ wherein R ⁵ and R ⁹ are as defined above, is acylated with an acid of formula (III) (Π),

R

R '.

(III), and pharmaceutically acceptable acid addition salts thereof. In formula (I), n is an integer of 1 or 2,

R is hydrogen or lower alkyl,

R ¹ is aryl or nitrogen containing a heteroaryl radical,

R ² is hydrogen or lower-alkyl,

R ³ is an aryl radical, an alkyl radical containing 4 to 8 carbon atoms or an aryl (lower) alkyl radical,

X is -COR ¹⁰ , -CO 2 R ⁶ , -CONR ⁵ R ⁹ , -OCO ² R ⁶ , -NR ⁴ COR ⁶ , -OCONHR ¹¹ , -NHCO ₂ R ⁶ , -NR ⁴ -CONHR, -CONHOR ⁶ ,

R 1 = N - (CH ₂ ) _n CR ² R ³ COOH wherein R, R ¹ , R ² and R ³ are as defined above, or with an acylating derivative thereof. Examples of acylating derivatives include acid halides, for example acid chlorides, azides, anhydrides, imidazolides, for example, obtained from carbonyldiimidazole, activated esters or O-acylureas, obtained from carbodiimide, such as dialkylcarbodiimide, in particular dicyclohexylcarbodiimide. Preferably, the amine is acylated with an acid in the presence of a coupling agent such as 1,1'-carbonyldiimidazole, isobutyl chloroformate or diphenylphosphinyl chloride.

An alternative method of making compounds of formula (I) is by alkylating a piperazine of formula (IV)

R

(IV),

R ⁴ and R ⁵ are each hydrogen or lower alkyl,

R ⁶ is -CHR ⁷ R ⁸ , a cycloalkyl of 3 to 12 carbon atoms, or an aiyl (lower) alkyl group, wherein R ⁷ and R ⁸ are each hydrogen or lower alkyl,

R ⁹ is hydrogen, C 1 -C 8 alkyl other than tertiary alkyl, C 3 -C 12 cycloalkyl, cycloalkyl (lower) alkyl, aryl, allyl (lower) alkyl or 8-azaspiro [4] 5] deca-7,9-dion-8-yl (lower) group, provided that when R ³ is an aryl or aralkyl group, R ⁹ is not a furyl group substituted in the halogen ortho position, nitro, trifluoroalkyl, cyano, sulfonic acid, sulfonamido, carboxy, carbalkoxy, carboxyamino or 4-carboxyaminobenzosulfonamido, and that 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 represent an azetidine, pyrrolidine, piperidine, hexahydroazepine, morpholine or piperazine ring, which may optionally be substituted by a lower alkyl, aryl or aryl (lower) alkyl group,

R ¹⁰ is C 3 -C 12 cycloalkyl, or 2,3-dihydro [1,4] benzodioxinyl, optionally substituted with lower alkyl, lower alkoxy, or halogen, or when R ³ is an alkyl radical of 4 to 8 atoms carbon, R ¹⁰ can be an aryl group,

R ¹¹ is C 3 -C 12 cycloalkyl, aryl or aryl (lower) alkyl,

R ¹² and R ¹³ are each lower alkyl or together with the carbon atom to which they are both attached represent a cycloalkyl group having 4 to 6 carbon atoms,

R 1 -N NH W wherein R 1 and R ¹ are as defined herein, with an alkylating agent providing a group

- (CH ₂ ) n CR ² R ³ X wherein n, R ² , R ³ and X are as defined above. The alkylating agent may be, for example, a compound of formula (VI) Z-CH 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 arylsulfonyloxy. Alternatively, the alkylating agent may be an unsaturated compound of the formula

CH ₂ = CR ³ X (Vil), wherein R ³ and X are as defined above, and a compound of formula (VII) is reacted with a piperazine of formula (IV) by Michael reaction means. The reaction may be carried out by raising the temperature in the presence of an alcohol. A small amount of catalyst may be used in the reaction wherein X is -CONR ^S R ⁹ .

SUMMARY OF THE INVENTION (V),

The compounds of the invention are compounds of formula (A)

OCH

N- (CH 2 -CUCO

(A)

And their pharmaceutically acceptable salts.

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

The compound of the invention of formula (A) can be produced as follows using suitable starting materials. A preferred method of making compound (A) comprises treating the compound of formula and ₃

2-y / \ - _(CH2) 2-x wherein X is a leaving group such as halogen, the compound containing an anion of the amide of formula

The anion can be prepared by reacting an amide with a strong base such as lithium diisopropylamide.

The described process can be performed to provide a compound of the invention in the form of the free base or an acid addition salt. When the compound of the invention is obtained as an acid addition salt, the free base can be obtained by alkalizing the acid addition salt solution. Conversely, when the process product is a free base, an acid addition salt, in particular a pharmaceutically acceptable acid salt, can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from the acid. basic compounds.

Examples of acid addition salts are those formed from inorganic and organic acids such as sulfuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, methanesulfonic, p-toluenesulfonic, oxalic and succinic.

The compounds of the invention contain an asymmetric carbon atom, so that the compounds can exist in various steroisometric forms. The compounds may be, for example, racemates or optically active forms. Optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis. For example, resolution may be accomplished by forming diastereomeric salts of racemic bases with an optically active acid, for example dibenzoyl-L-tartaric acid, separating the diastereoisomeric salts and converting them into optically active bases or other salts.

The compounds of the invention have a pharmacological effect. In particular, they act on the central nervous system by binding to 5-HT receptors. In pharmacological tests, the compounds have been shown to bind mainly to 5-HT _1A type receptors. The compounds selectively bind to 5-HT _1A receptors to a much greater extent than they bind to other receptors, such as alpha, -receptors. In pharmacological tests, they act as 5-HT _1A antagonists. Pharmacological testing of the compounds shows that they can be used to treat CNS disorders such as anxiety in mammals, especially humans. They may also be useful as antidepressants, hypotensive agents and agents to regulate sleep and wake cycles, feeding behavior and / or sexual functions.

Compounds of the invention were tested for 5-HT _1A receptor binding activity on rat hippohampal membrane homogenate by BS Alexander and NO Wood, J. Pharm. Pharmacol., 1988, 40, 888-891.

The results indicate that the compounds of the invention are more effective than other compounds of formula (I), including the related compound 2,3,4,5,7-hexahydro-1- (3- (1- (4- (2-methoxyphenyl) piperazinyl) 1- (2-phenylpropionyl) -1H-azepine (compound B) described in Example 34 of our related application. Compound B was one of the most potent compounds of the related application. The results are shown, Compound C being the isomer described in Example 2 (a) above.

IC50 (nM) Compound A3 Compound B9 Compound C1

The compounds were also tested for 5-HT _1A receptor antagonist activity in assays involving antagonism of 8-hydroxy-2- (di-n-propylamino) -tetral (8-DH DPAT) syndrome in rats. The results are shown.

MED (mg / kg, s.c.) Compound A 0.03 Compound B 0.3

The compounds were also tested for potential anxiolytic activity, a test procedure measuring murine exploratory activity in a two-piece box with an illuminated and dark section, based on the procedure of B. Costall et al., Neuropharmacology, 1987, 26, 195-200 and J. N. Crawley et al., Pharmac. Biochem. Behav., 1980, 13, 167-170. The results are shown.

MED (mg / kg, s.c.) Compound A 0.03 Compound 1

The invention also provides pharmaceutical compositions 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 may be used in the preparation of pharmaceutical compositions. In such a composition, the carrier is generally a solid or liquid, or a mixture of a solid and a liquid carrier.

Solid form preparations include powders, granules, tablets, capsules, for example hard and soft gelatin capsules, suppositories and pessaries. For example, the solid carrier may be one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binding or disintegrating agents, and may also be an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having compression properties in suitable proportions and compressed to the desired shape and size. The powders and tablets preferably contain up to 99%, for example from 0.03 to 99%, preferably from 1 to 80%, of the 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 waxes and ion exchange resins.

The term composition includes treating the active ingredient with an encapsulating material, such as a carrier to provide a capsule, in which the active ingredient, with or without other carriers, is surrounded by a carrier that is both in association with it. Similarly, medicated capsules are included.

Liquid form preparations include, for example, solutions, suspensions, emulsions, syrups, elixirs, and pressurized formulations. For example, the active ingredient may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture thereof, or a pharmaceutically acceptable oil or fat. kva

The palm carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, colorants, viscosity regulators, stabilizers or osmoregulators.

Suitable examples of liquid carriers for oral and parenteral administration include water (especially containing additives as mentioned, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols, for example glycerol and glycols and derivatives thereof, and oils, for example fractionated coconut oil and peanut oil. oil. For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile hepatic carriers are used in sterile liquid form preparations for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used, for example, for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. When the compound is active after oral administration, it can be administered orally in either the liquid or solid form of the composition.

Preferably, the pharmaceutical composition is in unit dosage form, for example, as tablets or capsules. In such form, the composition is subdivided into a unit dose containing an appropriate amount of the active ingredient. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such composition in a milled form. The amount of active ingredient in a unit dose of the composition may be from 0.5 mg or less to 750 mg or more, depending on the particular needs and activity of the active ingredient.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

2.3.4.5.6.7-hexahydro-1- (4- (1- (4- (2-methoxyphenyl) piperazinyl)) - 2-phenylbutyryl) -1H-azepine ml of 1.5 M butyllithium in hexane (7.5 mmol) is added dropwise over more than 5 minutes, maintaining the temperature below 8 ° C, to a stirred solution of 1.48 g, 6.8 mmol

2.3.4.5.6.7-hexahydro-1-phenylacetyl-1H-azepine and 2 ml of 1.4 g, 14 mmol of diisopropylamine in 16 ml of anhydrous toluene under argon. The mixture was stirred at 0 ° C for 1 h and a solution of freshly chromatographed 1- (2-chloroethyl) -4- (2-methoxyphenyl) piperazine in 4 mL of anhydrous toluene was added dropwise. The mixture was stirred at 0 ° C to 28 ° C for 18 hours and 50 mL of water was added. The layers were separated and the aqueous phase was extracted with 2 x 58 mL ethyl acetate. The combined organic phases are concentrated in vacuo. 2.91 g of crude product is chromatographed on silica eluting with ethyl acetate to give 0.15 g of the title compound as the free base. The product was dissolved in 30 ml of ethyl acetate and the solution was acidified with ethereal hydrogen chloride solution. The product was collected to give 0.36 g of the title compound dihydrochloride as a 0.75% hydrate, mp 175-178 ° C.

Analysis for C ₂₇ H ₃₇ N ₃ O ₂ .2HC1.0,75 _H2O requires C 62.1, H 7.8, N 8.5% Found C 62.05, H 7.8, N 7.75%.

Example 2

Distribution of 2,3,4,5,6,7-hexahydro-1- (4- (1- (4- (2-methoxyphenyl) piperazinyl)) - 2-phenylbutyryl) -1H-azepine

a) 12.1 g of 2,3,4,5,6,7-hexahydro-1- (4- (1- (4- (2-methoxyphenyl) piperazinyl)) - 2-phenylbutyryl) -1H-azepine are dissolved in 2.5 volumes, i.e. 30 ml of ethyl acetate, and a solution of dibenzoyl-L-tartaric acid monohydrate (1 mol equivalent) in ethyl acetate (2.5 volumes) is added. The initially formed oil was redissolved by adding a minimum amount (3.6 mL) of acetonitrile. After 3 days, 6.2 g of crystals are obtained by filtration which have an optical purity of 28% as judged by chiral HPLC. Recrystallization first from a mixture of ethyl acetate and acetonitrile (3: 10, 13 volumes) to give an optical purity of 84% and secondly from methanol (7.5 volumes) yields the first enantiomer (isomer I) of the product as 2.1 g of dibenzoyl-L 147 DEG-150 DEG C., [.alpha.] _D @ ²² = -26 DEG (1% in MeOH).

Analysis calculated for C ₂₇ H ₃₇ N ₃ O ₂ .C ₁₈ H _M O ₂ .H ₂ O Calcd C 66.6, H 6.6, N 5.2% Found C 66.7, H 6.7, N 5 , 1% with an optical purity of 97.4%. The sample was converted to 1.1 g of the free base of isomer (I), [α] _D ²⁶ = + 53 ° (1% in CHCl ₃ ), and from this the hydrochloride salt was obtained in the usual manner as 0.65 g of a colorless powder, mp 181 to 184 ° C, [α] _D ²³ = + 35 ° (1% in MeOH).

Analysis for C ₂₇ H ₃₇ N ₃ O ₂ .2 HCl.0,25 _H2O requires C 63.2, H 7.7, N 8.2% Found C 63.1, H, 7.8, N 7, 9% with an optical purity of 97.6%.

b) The second enantiomer (isomer II) is formed in a similar manner from the racemate of Example I and dibenzoyl-D-tartaric acid monohydrate. Isomer II dibenzoyl-D-tartrate, mp 141-142 ° C. [.alpha.] _D @ ²³ = + 25 DEG (1% in MeOH). Analysis for C 7 H ₃₇ N ₂ O ₃ .C ₂ H _{18 14} H ₈ .0.25 _H2O requires C 67.3, H 6.5, N 5.2% Found C 67.3, H 6.7 , N 5.2%

Isomer II base: [α] _D ²⁶ = -62 ° (1% solution in CHCl ₃ ).

Isomer II hydrochloride, mp 181-184 ° C, [α] _D ²⁶ = -36 ° (1% in MeOH).

Analysis for C ₂₇ H ₃₇ N ₃ O ₂ .2 HCl.1,75 _H2O requires C 60.05, H 7.9, N 7.8% Found C 60.2, H 7.7, N 7, 75% with an optical purity of 98.2%.

Claims (7)

PATENT CLAIMS Piperazine derivatives such as 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} -1H-azepine or a pharmaceutical salt thereof an acceptable acid addition salt in the form of stereoisomers, or a mixture of stereoisomers. The piperazine derivative according to claim 1, which is the enantiomer of 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl] -2-phenylbutyryl} -1H -azepine, wherein the free base has [α] _D ²⁶ = + 53 °, at a concentration of 1% in CHCl ₃ , or a pharmaceutically acceptable salt thereof. The piperazine derivative according to claim 1, which is the enantiomer of 2,3,4,5,6,7-hexahydro-1- {4- [1- [4- (2-methoxyphenyl) piperazinyl]] - 2-phenylbutyryl} - 1H-azepine, in which the free base has [α] _D ²⁶ = -62 °, at a concentration of 1% in CHCl ₃ , or a pharmaceutically acceptable salt thereof. A process for the preparation of a piperazine derivative according to claim 1, characterized in that it is: a) reacting a compound of formula 276 and ₃ l - (CH ₂ ) ₂ - X, in which X is a leaving group with an amide anion of formula and / or b) converting the base according to claim 1 into its pharmaceutically acceptable acid addition salt and / or is c) converting the pharmaceutically acceptable acid addition salt of claim 1 into the free base and / or is d) resolving the racemic compound of claim 1. A pharmaceutical composition for use as an anxiolytic, antidepressant, hypotensive, or agent for controlling wake and sleep cycles, regulating food intake and / or sexual functions, comprising a compound of claim 1 in association with a pharmaceutically acceptable carrier. A piperazine derivative according to any one of claims 1, 2 and 3 for use as a pharmaceutical active ingredient. A piperazine derivative according to any one of claims 1, 2 and 3 for use as an anxiolytic agent, antidepressant agent, hypotensive agent or as an agent for regulating wake and sleep cycles, regulating food intake and / or sexual functions.