GB2271930A - Pharmaceutical piperazine derivatives - Google Patents

Abstract

4-(4-(2-methoxyphenyl)piperazin-1-yl)-2-phenylbutanoic acid and the pharmaceutically acceptable salts thereof are useful as 5-HT1A-antagonists. The compounds act primarily at peripheral 5-HT1A sites and can be used in treating gastrointestinal disorders in humans and other mammals.

Description

PIPERAZINE DERIVATIVES This invention relates to piperazine derivatives.

U.K. Patent Application GB 2230781 A discloses acids of formula

where n is one of the integers 1 or 2 R is hydrogen or lower alkyl R 1. an aryl or nitrogen containing heteroaryl is radical R2 is hydrogen or lower alkyl and R3 is an aryl radical, an alkyl radical containing 4 to 8 carbon atoms or an aryl(lower)alkyl radical.

The above mentioned acids are disclosed in GB 2230781 A as being useful as intermediates for preparing specified amides or esters which are useful as 5-HTlA-antagonists and hence can be used as medicaments for treating humans and other mammals.

UK Patent Application No 2248836A discloses a specific acid falling within formula A. This has the formula

The acid of formula B is disclosed as an intermediate for preparing 2,3,4,5,6,7-hexahydro-1-[4-[1-[4-(2- methoxyphenyl)-piperazinyl]]-2-phenylbutyryl]-lH- azepine which is disclosed as being useful as a 5-HT1A antagonist.

We have now found that the acid of formula B, i.e.

4-(4-(2-methoxyphenyl )piperazin-l-yl )-2-phenylbutanoic acid (which is hereinafter sometimes referred to as Compound B) and the pharmaceutically acceptable salts thereof are themselves useful as 5-HTlA-antagonists.

Accordingly the present invention provides in one aspect a pharmaceutical composition comprising Compound B or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

In another aspect the invention provides Compound B or a pharmaceutically acceptable salt thereof for use as a pharmaceutical eg for use as a pharmaceutical for treating, mammals, particularly humans requiring administration of a 5-HTlA-antagonist.

In a third aspect the invention provides a method of treating mammals in need thereof with a 5-HTlA-antagonist characterised in that the 5-HTlA-antagonist is compound B or a pharmaceutically acceptable salt thereof.

As described below it has been found that Compound B and its salts act primarily at peripheral 5-HT1A sites in contrast to the amides of UK Patent Applications 2230781A and 2248836A which act on 5-HT1A sites in the CNS. Accordingly in a preferred aspect Compound B and its salts are used in treating gastro-intestinal disorders in humans and other mammals.

The 5-HT1A-antagonist activity of compound B is surprising since the general class of acids disclosed in GB 223078A, particularly the two acids specifically disclosed therein exhibit very little SHTlA receptor binding activity. Compounds were tested for 5 -HT1A receptor binding activity in rat hippocampal membrane homegenate by the method of B.S. Alexander and M.D. Wood, J. Pharm. Pharmacol, 1988, 40, 888-891.The results for compound B and the acids specifically disclosed in GB 2230781 A are given below Compound 5-HT1A receptor binding IC50 (n N) a-l-[4-(2-methoxyphenyl )- piperazinyl]methyl)benzene- 3000 acetic acid. [Example 1 of GB 2230781 A] 2-C1-[4-(2-methoxyphenyl)- 3335 piperazinylmethyl)-3-benzene- propanoic acid. [Example 2 of GB 2230781 AJ Compound B 16 Compound B was tested for 5-HTlA-receptor antagonism activity in a test involving the antagonism of 5-carboxamidotryptamine in the guinea-pig ileum in vitro (based upon the procedure of Fozard et al, Br. J.

Pharmac. 1985, 86, 601 p). In this procedure compound B had a pA2 of 7.6.

5-HTlA-agonists which penetrate the blood-brain barrier of animals produce the typical and distinctive behavioural effect known as the 5-HT syndrome.

Compound B when administered to conscious rats at a dose of 10 mgikg s.c. failed to block the 5-HT syndrome induced 30 min. later by i.v. administration of the 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT). This result indicates that compound B fails to cross the blood-brain barrier. In conjunction with the evidence cited above that compound B is a potent 5-HT1A antagonist in the guinea-pig ileum assay, these studies indicate that Compound B acts a peripheral 5-HT1A antagonist. This is in contrast to the amides of GB 2230781A which additionally act on SHTlA sites in the CNS.

Compound B or a salt thereof can be used in treating gastro-intestinal disorders in humans and other mammals. For example the compounds can be used to increase gastric motility (eg in post surgical intestinal statis).

Compound B selectively binds to receptors of the S.HT1A type to a much greater extent that it binds to other receptors such as al receptors. Thus, as measured by the procedure of A.L. Morrow et al, Mol.

Pharmacol., 1986, 29, 321 the IC50 for a1 binding of compound B is 8456 nM.

Compound B may be prepared by methods known in the art.

For example it may be prepared by hydrolysing the corresponding nitrile of formula

The nitrile may be prepared by condensing benzyl cyanide with a 4-(2-haloethyl)-1-(2-methoxyphenyl)- piperazine (particularly the 2-chloroethyl derivative) under basic conditions.

The acid of formula B can form salts with inorganic or organic bases eg alkali metal (such as sodium) or ammonium (eg trimethylammonium) salts and inorganic and organic acids eg hydrogen chloride.

Compound B and its salts can exist in different stereoisomeric forms. The compounds can be, for example, racemates or optically active forms. The optically active forms can be obtained by resolution or can be prepared from optically active starting materials.

Any suitable carrier known in the art can be used to prepare the pharmaceutical composition of the present invention. In the compositions, the carrier is generally a solid or liquid or a mixture of a solid or liquid.

Solid form compositions include powders, granules, tablets, capsules (eg hard and soft gelatine capsules), suppositories and pessaries. A solid carrier can be, for example3 one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aides, binders or tablet-disintegrating agents; it can 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 the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, eg from 0.03 to 99%, preferably 1 to 80% of the active ingredient.Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

The term composition is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient, for example, can 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 can contain other suitable pharmaceutical additives such as solubilisers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators.

Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols, eg glycerol and glycols) and their derivatives, and oils (eg fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.

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

Preferably the pharmaceutical composition is in unit dosage form, eg as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged composition, 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 quantity of the active ingredient in unit dose of composition may be varied or adjusted from 0.5 mg or less to 750 mg or more, according to the particular need and the activity of the active ingredient.

The following Examples illustrate the invention: Example 1 4-(4-(2-Methoxyphenyl)piperazin-l-yl)-2- phenylbutanonitrile A stirred suspension of potassium hydride, 35% w/w in oil (11 g, 0.1 mol) in anhydrous toluene (50 ml) was treated dropwise with benzyl cyanide (8.11 g, 0.069 mol) in anhydrous toluene (50 ml) under argon.

Evolution of hydrogen occurred more rapidly upon the addition of tetrahydrofuran (10 ml). After 1 h, the suspension was treated dropwise with 4-(2-chloroethyl)l-(2-methoxyphenyl)piperazine (17.0 g, 0.067 mol) in anhydrous toluene (100 ml) and after 2 h treated with propan-2-ol (20 ml) and water (100 ml). The suspension was evaporated in vacuo to leave a brown oil which was taken up into dilute hydrochloric acid (100 ml), washed with ethyl acetate (3 x 200 ml), basified with NaOH, and extracted into ethyl acetate (3 x 200 ml). The extracts were dried (MgSO4), evaporated in vacuo, and the residue purified by chromatography [alumina; hexane-ethyl acetate (5:2)] to give the product as a colourless oil (8.9 g).

Example 2 4-(4-(2-Methoxyphenyl)piperazin-l-yl)-2- phenylbutanoic acid The product of Example 1 (8.5 g, 0.024 mol) was dissolved in 5N-HCl (100 ml) and the solution heated under reflux for 18 h. Evaporation in vacuo gave the product contaminated with ammonium chloride.In order to purify the product, it was taken up into dilute NaOH solution, evaporated in vacuo (to remove ammonia), taken up into dilute hydrochloric acid, evaporated in vacuo, taken up into methanol, filtered (to remove sodium chloride), heated at reflux for 18 h (to form methyl ester), evaporated in vacuo, taken up into dilute NaOH solution, extracted with ethyl acetate (to ensure no inorganic contamination), dried (MgSO4), evaporated in vacuo, taken up into SN-hydrochloric, heated at reflux for 18 h, then evaporated in vacuo to give the dihydrochloride salt of the product (7.61 g) as white crystals m.p. 222-225 C (Found: C, 58.1; H, 6.8; N, 6.45. CH2 C21H26N203. n 2HC1. 0.33 H2 0 requires C, 58.2; H, 6.7; N, 6.5%).

Example 3 Preparation of Tablets Amount per tablet mg Compound B 1 5 10 Microcrystalline cellulose 49.25 47.25 44.75 Modified food corn starch 49.25 47.25 44.75 Magnesium stearate 0.5 0.5 0.5 Tablets are prepared from bulk amounts of ingredients in the proportions given above.

All of the compound B, cellulose and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 1, 5 and 10 mg of the active ingredient per tablet.

Claims (5)

1. A pharmaceutical composition comprising 4-(4-(2 methoxyphenyl )piperazin-l-yl )-2-phenylbutanoic acid or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier.

2. A pharmaceutical composition as claimed in claim 1 in the form of a tablet or capsule.

3. 4-(4-(2-Methoxyphenyl)piperazin-l-yl)-2phenylbutanoic acid or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

4. 4-(4-(2-Methoxyphenyl)piperazin-l-yl)-2- phenylbutanoic acid or a pharmaceutically acceptable salt thereof for use as a 5 HT1 antagonist.

5. 4-(4-(2-Methoxyphenyl)piperazin-l-yl)-2phenylbutanoic acid or a pharmaceutically acceptable salt thereof for use in treating gastro-intestinal disorders in mammals.