SK64492A3 - Piperazine derivatives, method of production and pharmaceutical compound containing them - Google Patents

Abstract

piperazinyl))-2-butyryl) -1H-azepine of formula (I) and its pharmaceutically acceptable acid addn. salts are new. Both enantiomers are claimed.

Description

b and b of the invention

The invention relates to piperazine derivatives, processes for their preparation, their use and pharmaceutical preparations containing them. The clay compounds act by binding to the central nervous system

5-HT receptors (as more fully explained below) and thus can be used as medicines for treating humans and other mammals.

The clay compounds according to the invention are compounds of formula A

(A) and pharmaceutically acceptable salts thereof.

Compound A is 2,3,4,5,6,7-hexahydro-1- [4- [1- [4- (2-methoxyphenyl) piperazinyl] -2-phenylbutyryl] -11-azepine.

In UK related application no. 930: 3925.1 discloses compounds having the general formula comprising the novel compounds of this invention. The compounds of the related applications have the general formula

N- (CH ₉ ) _n CR

I I

V-x (I) and their pharmaceutically acceptable acid addition salts.

In formula I n is an integer of 1 or 2,

R is hydrogen or lower alkyl,

R 4 is an aryl or nitrogen containing a non-heteroaryl residue,

R is hydrogen or lower alkyl, P is aryl, C 4 -C 3 alkyl, or aryl (lower) alkyl,

X is -COR ^U1, -C02R ^6, -C0NR ⁵ R ^9, -0C02R ^6, -íIR ⁴ C0R ^6,

-0C0MHR ¹¹ , -IIIICO ₂ R ⁶ , - JR ⁴ - CQ MH R ⁶ , -C0MH ⁰ R ⁰ ,

R ¹²

the sky

R ⁴ and R ^? are each hydrogen or lower alkyl,

R ⁶ is -C? II ^'7 R \ cycloalkyl of 3 to 12 carbon atoms, or Ar y1 (n A d d) a1k y 1o in the A group wherein R ⁷ and R are each hydrogen or lower alkyl,

K ⁷ is hydrogen, C 1 -C 3 alkyl other than tertiary alkyl, C 3 -C 12 cycloalkyl, cycloalkyl (lower) alkyl, aryl, aryl (lower) alkyl or

8-azaspiro [4,5] deca-7,9-dion-3-yl (lower) group, provided that when R 6 is an aryl or aralkyl group,

Q

R is not a furyl group substituted by halogen, nitro, nitro, trifluoroalkyl, cyano, sulfonic acid, sulfonamido, carboxy, carbalkoxy, carboxyanilino or 4-carboxylaminobenzosulfonamido, and that when R is hydrogen, alkyl 5, 3 or aryl R is hydrogen or -C (R 1) R ', or

9

R @ 1 and R @ 2 together with the nitrogen atom to which they are attached represent an azetidine, pyrrolidine, piperidine, hexahydroazeoin, morpholine or piperazine ring, which may optionally be substituted by a lower alkyl, aryl or aryl (lower) alkyl group, is cycloalkyl a group having from 3 to 12 carbon atoms, or a 2,3-dihydro (1,4) benzodioxinyl group, optionally substituted by a lower alkyl, lower alkoxy, or halogen atom, or, when R @ 1 is an alkyl radical containing from 4 to 3 carbon atoms, it may also be an aryl group, R 11 is a cycloalkyl group having 3 to 12 carbon atoms, an aryl or an aryl (lower) alkyl group; 13

R and R are each lower alkyl or together with the carbon atom to which they are both attached represent a C 4 -C 4 cycloalkyl group,

R14 is hydrogen, halogen, lower alkyl or lower allyl,

X is Cl or SJ;

The compounds of our related application may be made by a variety of methods from known starting materials, or starting materials may be converted by conventional methods, some of the methods disclosed are listed below.

One method for making an amide of formula I wherein X 5 9 is -COHR R amine of formula II

9 nhr ⁷ (II) ve

Wherein R 1 and R 2 are as defined above, is acylated with an acid of formula III wherein R 1

x

(III) has the above-defined meaning, or with its acylating derivative. 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 carbodiirnide, such as dialkylcarbodiimide, especially dicyclohexycarbodiimide. 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 the compounds of formula I is by alkylating the piperazine of formula IV

(IV) wherein R a is as defined above, with an alkylating agent providing a group

- (CH ₂ ) _n CR ² R ³ X (V) wherein n, R, R and X are as defined above.

The alkylating agent may be, for example, a compound of formula VI

Z-CH ₂ CR ² F! ³ X (VI) wherein R, R 'and X are as defined above, and

Z is a leaving group, such as halogen or an alkyl or aryl-sulfonyloxy group. Alternatively, the alkylating agent may be an unsaturated compound of formula ch ₂ = CR ³ X (VII) in which R ³ and X are as defined above, and the compound of formula VII is reacted with a piperazine of formula IV by means of a lichael reaction. 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 where X is -CO 2 R R.

The compound of the invention of formula (A) may be prepared in an analogous manner using appropriate starting materials. A preferred method of making compound A is by reacting a compound of formula

wherein X is a leaving group, such as halogen, with an amide anion of formula

G

The anion can be prepared by reacting an amide with a strong base, for example lithium diisopropylamide.

The above process can be carried out to provide the compound of the invention in the form of a free base or an acid addition salt. When the compound of the invention is obtained as an acid addition salt, the base base can be obtained by alkalizing the acid addition salt solution, whereas when the product of the invention is a free base, the acid addition salt, especially a pharmaceutically acceptable acid addition salt, can be obtained by dissolution. the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for the preparation of acid addition salts from 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, rare, methanesulfonic, p-toluenesulfonic, oxalic and succinic acids. .

The compounds of the invention containing an asymmetric carbon atom such that the compounds may exist in cutting steroisometric forms. The compounds may be, for example, racemates or optically active forms. Optically active forms can be obtained by racemate resolution or asymmetric synthesis. For example, resolution may be accomplished by forming diastereolsomeric salts of racemic bases with an optically active acid, for example, dibenzoyl-L-tarteric acid, separating the di / fe stereoisomeric salts and converting them into an optically active base 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 particularly to receptors of the type. The compounds selectively bind to 5-HT 1A receptors to a much greater extent than they bind to other receptors such as alpha 1 -receptors. In pharmacological tests, they have the effect of 5-HT 1A antagonists. Pharmacological testing of the compounds shows that they can be used to treat CUS disorders such as anxiety in mammals, especially humans. They may also be useful as antidepressants, hyootensives and agents to regulate the sleep and waking cycle, feeding behavior and / or sexual functions.

The compounds of the invention were tested for 5-HT 2β receptor binding activity on rat hippohampal membrane homogenates by B. S. Alexander and M. Π. Uood, J. Pharm. Pharmacol. 1933, 40, 333-391.

The results indicate that the compounds of the invention are more potent than the other compounds of formula I, including the related compounds 2,3,4,5,7-hexahydro-1- [3- [1-] - 4- (2-methoxyphenyl) piperazines] - 2-phenylpropionyl] -111-azeoin (compound 3) described in Example 34 of our related application. Compound 3 was one of the most potent compounds discovered in the related application. The results are shown below in which compound C is an isomer as described in Example 2 (a) below.

i ^ q ^l1; I) Compound A3 Compound 39 Compound C1

The compounds were also tested for 5 µT-1 receptor antagonistic activity in assays involving the 8-hydroxy-2- (di-n-propylamino) -tatral (8-OH DPAT) syndrome antigenicity in rats. The results are shown below.

MED (mg / kg, s.c.) Compound A '3.03 Compound 3 0.3

The compounds were also tested for potential anxiolytic activity, by a test procedure measuring mouse exolorative activity in a two-compartment box with an illuminated and dark part, based on the procedure of Costalla et al., Ileuropharmacology, 1987, 26, 195-200 and J. II. Crawleys et al., Pharmac. Biocom. 3ehav., 1930, 22, 167-170. The results are shown below:

Compound A Compound B

MED (mg / kg, s.c.)

0.03

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 formulation, 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, lace and oesars. The solid carrier may, for example, be one or more substances which can also be used as flavoring agents, a lubricant.

Solubilizers, suspending agents, fillers, glidants, compression aids, binders or disintegrants may also be encapsulating material. For a powder, 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 'S, for example, 0.03 to 99%, preferably from 1 to 30 ^p on the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

The term formulation is intended to encompass treating the active ingredient with the encapsulating material as a carrier to provide a capsule in which the active ingredient, with or without other carriers, is surrounded by a carrier which is thus in association with it. Similarly, medicinal capsules are included.

Kaal formulations 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 of both, or a pharmaceutically acceptable oil or fat. The liquid 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, but are not limited to, those containing, for example, other ingredients such as cellulose derivatives, a preferred solution of sodium carboxyinethylcellulose, alcohols such as glycerol and glycols, and derivatives thereof, and oils, for example, fractionated coconut oil and peanut oil. For parenteral administration, the carrier may also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile and sterile carriers are used in sterile liquid form preparations for parenteral administration.

Liquid pharmaceutical preparations 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 liquid or solid form preparations.

The preferred pharmaceutical preparation is in unit dosage form, for example, as tablets or capsules. In such form, the preparation is dispensed into a unit dose containing appropriate quantities of the active ingredient; the unit dosage forms may be packaged preparations, for example, packaged powders, vials, ampoules, pre-filled 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 formulation in packaged form. The amount of active ingredient in a unit dose of preparation may be made or adjusted from 0.5 mg or less to 750 mg or more, depending on the needs and activity of the active ingredient.

The following examples illustrate the invention:

1.1

Example 1

2,3,4,5,6,7-hexahydro-1- [4- [1- (2-methoxyphenyl) oiperazinyl] -2-phenylphenyryl] -L-11-azspine 11.5 M butyl lithium in hexane (7.5 mmol) is added dropwise over 5 minutes, while maintaining the temperature below 3 ° C, to a stirred solution of 1.43 g, 6.3 min. Of 2,3,4,5,6,7-hoxa-yydro. -1-phenyl 1-acsty 1-III-azopine and 2 ml, 1.4 g, 14 mmol of diisopcopylamine in 16 ml of anhydrous toluene under argon. The mixture was stirred at 0 ° C for 1 hour and a solution of 1.73 g was added dropwise.

6.3 mmol of fresh chromatographed 1- (2-chlocethyl) -4- (2-methoxyphenyl) piperazine in 4 ml of anhydrous rolus. 5més .'lichá of the D ^U C 3 ⁰ to 2 C for 13 hours was added to 53 ml of water. The layers were separated and the aqueous phase was extracted with 2 x 50 mL ethyl acetate. The combined organic phases were concentrated in vacuo. 2.91 g of crude product was chromatographed on silica eluting with ethyl acetate to give the title compound as a free base (0.15 g). 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 dinydrochloride as 0.75% hydrate, mp 175-173 ° C.

Analysis for 2HCl 1. 0.75 H? O requires C, 62.1, 7.8 .mu.l, II 3.05% found C 62.05, II 7.3 II 7.75 ^N 5th

Example 2: 2, 3,4,5,6,7-hexahydro-1- / 4- / 1- / 4- (2-ethoxyphenyl) plpecazinyl // -2-phenylbutyryl-1H-azepine

(a) 12,1 g of 2, 3,4,5,6,7-hexahydro-1- [4- / 1- [4- (2-methoxyphenyl) piperazines] -1H-2-phenylethyl] Of .alpha.1 -azepine is dissolved in

2.5 volumes, i.e. 30 ml of ethyl acetate, and a solution of dibenzoyl-L-tartaric acid monohydrate (1 mol eq) in ethyl acetate (2.5 volumes) was added. The initially formed oil was redissolved by adding a minimum amount (3.6 mL) of acetonitrile. After 3 days, 6.2 g of a crystal having an optical purity of 23% as judged by cniary HPLC was obtained by filtration. a second time from methanol (7.5 volumes) provides orvý enantiomer (isomer I) of the product as 2.1 g dibonzoyl-L-tartrate, m.p. 147-150 C ^Q, / alpha / ^ '= -26 ° (1 to ⁵ o MeOŕl).

Analysis for ^ 27 ^ 37 ^ 3 ^ 2 ^ 13 ^ 14 ^ 4 ^ 4 ³

Found u 66,6, II 6.6, i 1 5,2 0, u to Lezeno n 'f 7 L 0 0, /, clay 6.7, i 1 5.1 with optical purity 97.4 E from 0 y ek by L black at 1.1 g v 01 no

[.alpha.] D @ ²⁰ = + 53 DEG (L @ + in CH2Cl2) and the hydrochloride salt is obtained in the usual manner as 0.65 g of a colorless powder, m.p. [.alpha.] D @ ²⁵ = + 35 DEG, (15.5 DEG to 10 DEG C.).

For C _O7 11 ₅₇ 110 ₂ 2HC1 _0,25.H? 0 requires C 63.2, H 7.7, 8.2 ^II? Found: C 63.1, U 7.3, H 7.9 °, optical purity 97.6

b) The second enantiomer (isomer IT) was formed in a similar manner from the racemate of Example 1 and dibenzoyl-O-tartaric acid monohydrate. 141-142 ° C isomer II dibenzoyl-t-tartrate. [.alpha.] D @ 20 = + 25 DEG (L @ 3 in Ile @ 1 H).

Analysis for ^c 27 ' ¹ 37' ¹ 3 ⁰ L-3 ^H 14 ³ 3 ' ³ ' “ ⁵ '4 ³ calculated C 67.3, H 6.5, H 5.2 ⁹ δ found C 67.3, il 6.7, 11.2 's.

Isomer II base: / alpha / g ° = -62 ° (another solution in CUCL ^).

Isomer II hydrochloride m.p. L-3 to 134 L / alpha /, * ⁶ = -36 ° (MeOH light L ^5).

- 13 Analysis for C? H? M 0 _? . 2 HC L. 1,75 _? Found: C, 60.2; H, 7.7; Ί 7.75%, optical purity 93.2%.

Claims (7)

P Λ T E Π T □ V Č II Ä 2 O K Y Piperazine derivatives, namely 2,3,4,5,6,7-hexahydro-L- [4- [1- (2-methoxyphenyl) piperazinyl] -2-phenylbutyryl] -1,1-azspine or its pharmaceutically acceptable acid addition salt. A compound according to claim 1, which is an enantion 2.3.4.5.6.7-Hexahydro-L- [4-] 1- [4- (2-methoxyphenyl) biperazinyl] -2H-phenylbutyl] -1H-azepine; which free base has [.alpha.] ^D @ ²⁰ = + 53 DEG (1 DEG C.), or a pharmaceutically acceptable salt thereof. The compound of claim 1, which is an enantioiner 2.3.4.5.6.7-Hexahydro-1- [4- [1- (4- (2-methoxyphenyl) piperazinyl] -2-phonylbutyryl] -1H-azepine, in which the free base is obtained. ° ^(1? CilCl light-j) or a pharmaceutically acceptable salt thereof. 4. A process for the preparation of a compound according to claim 1, which comprises: (a) acetylates an amine of formula with an acid of formula or an acylating derivative thereof; or (b) alkylated by a process of alkylation with an inactivating agent; or c) reacting a compound of formula: - (CH ₂ ) ₂ -χ in which X is a leaving group, with an amide anion of formula ··· or d) converting the base of claim 1 into its pharmaceutically acceptable acid addition salt, or (e) a blackening of the pharmaceutically acceptable acid addition salt of claim 1 to the free base; or f) resolving the racemic compound of claim 1. 5. A pharmaceutical composition comprising the compound of claim 1 in association with a pharmaceutically acceptable carrier. A compound according to any one of claims 1, 2 and 3 for use as a pharmaceutical. A compound according to any one of claims 1, 2 and 3 for use as an auxiolytic, anti-expression, bypass, or an agent for regulating the wake-up and sleep cycle, the feed and / or the susceptibility.