GB2307858A - Compositions containing piperazine derivatives for the treatment of cancer - Google Patents

Abstract

The use of a piperazine derivative of general formula I: or a pharmaceutically acceptable acid addition salt thereof, in the treatment of cancer, wherein: R is hydrogen or lower alkyl, R 1 is an aryl or heteroaryl (especially nitrogen containing heteroaryl) radical, and X is a group of formula -(CH 2 )n CR 2 R 3 .CONR 4 R 5 ```(IIa) or -A-NR 6 COR 7 ```(IIb) R 2 -R 7 are as defined herein.

Description

MEDICAL TREATMENT This invention relates to the use of certain piperazine derivatives in the treatment of cancer.

The piperazine derivatives are those of general formula

and the pharmaceutically acceptable acid addition salts thereof In formula (I) R is hydrogen or lower alkyl, R1 is an aryl or heteroaryl (preferably nitrogen containing heteroaryl) radical, and X is a group of formula -(CH2)n CR2R3.CONR4R5 (IIa) or -A-NR6COR7 (IIb) where n is one of the integers 1 or 2; R2 is hydrogen or lower alkyl;; R3 is an aryl radical or an aryl(lower)alkyl radical, R4 is hydrogen or lower alkyl R5 is hydrogen, an alkyl group of 1 to 8 carbon atoms, cycloalkyl of 3 to 12 carbon atoms or cycloalkyl(lower)alkyl, or R4 and R5 together with the nitrogen atom to which they are attached represent an azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl.

A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups, R6 is a mono or bicyclic heteroaryl radical and R7 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR8R9 [where R8 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R9 is hydrogen, lower alkyl, -CO(lower)alkyl, aryl, COaryl, aryl(lower)alkyl, cycloalkyl or cycloalkyl(lower)alkyl or R8 and R9 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom] or a group of formula OR10[where R10 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].

Preferred compounds of formula I are those of formula II

or the pharmaceutically acceptable acid addition salts thereof (where n, R, R1, R2, R3, R4 and R5 are as defined above).

The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms. Preferably such radicals contain 1 to 4 carbon atoms. Examples of "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and isopentyl.

Examples of cycloalkyl groups are cyclopentyl, cyclohexyl and cycloheptyl. A preferred example is cyclohexyl. Cycloalkyl groups include bicyclic, tricyclic and tetracyclic groups, eg adamantyl. Preferably the cycloalkyl group contains 3 to 12 carbon atoms.

When used herein "aryl" means an aromatic radical having 6 to 12 carbon atoms (eg phenyl or naphthyl) which optionally may be substituted by one or more substituents.

Preferred substituents are lower alkyl, lower alkoxy (eg methoxy, ethoxy, propoxy, butoxy), halogen, halo(lower)alkyl (eg trifluoromethyl), nitro, nitrile, amido, (lower)alkoxycarbonyl, amino, (lower)alkylamino or di(lower)alkylamino substituents. Two substituents on the aromatic ring may be connected together to form another ring system.

When R1 is an aryl radical it is preferably a phenyl radical containing a substituent in the ortho position. A preferred example of R1 is o-(lower)alkoxyphenyl eg o- methoxyphenyl. R1 can also be, for example a l-naphthyl radical optionally substituted in the 2 or 7 positions by, for example, (lower)alkoxy.

Preferred examples of aryl(lower)alkyl are benzyl and phenethyl in which the phenyl rings may be substituted by substituents as given above.

When used herein "nitrogen containing heteoraryl radical" means an aromatic ring containing one or more nitrogen atoms as heteroatoms (eg pyridinyl, pyrimidinyl or pyrazinyl) which may optionally be substituted by one or more lower alkyl, lower alkoxy, halogen, trifluoromethyl, amino, (lower)alkylamino or di (lower) alkylamino substituents. Preferably the heteroaryl radical is monocyclic.

When R6 is a bicyclic heteroraryl radical both rings of the radical may contain hetero ring atoms or only one ring may contain a hetero atom or atoms. In the latter instance the radical R6 is connected to the rest of the molecule of formula (I) via the ring containing the hetero atom(s).

Examples of the heteroaryl radical R6 include monocyclic radicals containing one hetero atom, eg optionally substituted pyridyl (particularly 2-pyridyl), monocyclic radicals containing two hetero atoms, eg thiazolyl (particularly 2-thiazolyl) and bicyclic radicals containing one or two hetero atoms eg quinolinyl or isoquinolinyl (particularly 2quinolinyl).

The piperazine derivatives of formula (I) and their method of preparation are disclosed, for example, in GB 2230780A GB 2230781A GB 2248836A and GB 2255337A.

The compounds disclosed in GB 2230780A are described as antidepressant and/or anxiolytic agents. The compounds disclosed in GB 2230781 A, GB 2248836A and GB 2255337A are disclosed as 5-HT1A antagonists useful as antidepressants hypotensives and as agents for regulating the sleep/wake cycle, feeding behaviours and/or sexual function.

The preferred compounds of formula (I) are: N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin- 1-yl]-2phenylpropanamide and its (+)-enantiomer 2,3,4,5,6,7-hexahydro- 1 -[4-[ 1 -[4-(2-methoxyphenyl)- piperazinyl]]-2-phenyl]butanoyl- lH-azepine (-)-(R) -2,3,4,5,6,7 -hexahydro- 1 -[4-[4-(2methoxyphenyl)piperazin- 1 -yl] -2-phenyl]butanoyl- 1 H- azepine N- [2- [4-(2-methoxyphenyl)- l-piperazinyl]ethyl] N-(2-pyridinyl)cyclohexanecarboxamide and their pharmaceutically acceptable acid addition salts.

The present invention provides in one aspect, a method of treating cancer which comprises administering to a mammal in need thereof an effective amount of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof. In a second aspect the invention provides the use of a compound of formula (I) as defined above or a pharmaceutically acceptable acid addition salt thereof for the manufacture of a medicament for the treatment of cancer. Suitably, the mammal is a human.

In this specification the terms "treatment" and "treating" relate to the administration of the compounds to prevent the disorder as well as to treat the disorder or to alleviate the symptoms of the disorder.

The term 'cancer' as used herein includes carcinoma, especially small cell lung carcinoma and prostatic carcinoma.

The compounds may be used in treating cancer in their free base form or as acid addition salts.

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

The compounds of formula I contain one or more asymmetric carbon atoms, so that the compounds can exist in different steroisomeric forms. The compounds can, for example, exist as racemates or optically active forms.

The compounds may be used for treating cancer in the form of pharmaceutical compositions which comprise a compound of formula I or a pharmaceutically acceptable acid addition salt thereof in association with a pharmaceutically acceptable carrier. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition.

In such a composition, 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 example, 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 Preparation of Tablets Amount per tablet mg (-)-(R)-2,3,4,5,6,7 Hexahydro- 1 -[4-[4-(2- methoxyphenyl)piperazin- 1 - yl]-2-phenyl]butanoyl-1H- azepine 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 active compound, 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.

Example 2 Preparation of powder filled capsules Amount mg N-tert.butyl-3-[4-(2 methoxyphenyl)piperazin- 1 - yl]-2-phenylpropanamide 10 15 Avicel 45 Lactose 153 Starch (1500 NF) 117 Sodium starch glycollate - 6 Magnesium stearate 2 2 The formulations are prepared by admixing the ingredients in the proportions given above and filling two-part hard gelatin capsules with the required amount of the resulting mixture to give capsules containing 10 or 15 mg of the active compound.

Claims (4)

CLAIMS:

1. The use of a piperazine derivative of general formula I:

or a pharmaceutically acceptable acid addition salt thereof, in the treatment of cancer, wherein: R is hydrogen or lower alkyl, R1 is an aryl or heteroaryl (especially nitrogen containing heteroaryl) radical, and X is a group of formula -(CH2)n CR2R3.CONR4R5 (IIa) or -A-NR6COR7 (ITh) where n is one of the integers 1 or 2; R2 is hydrogen or lower alkyl;; R3 is an aryl radical or an aryl(lower)alkyl radical, R4 is hydrogen or lower alkyl R5 is hydrogen, an alkyl group of 1 to 8 carbon atoms, cycloalkyl of 3 to 12 carbon atoms or cycloalkyl(lower)alkyl, or R4 and R5 together with the nitrogen atom to which they are attached represent an azetidino, pyrrolidino, piperidino, hexahydroazepino, morpholino or piperazino ring which may be optionally substituted by lower alkyl, aryl or aryl(lower)alkyl.

A is an alkylene chain of 2 to 4 carbon atoms optionally substituted by one or more lower alkyl groups, R6 is a mono or bicyclic heteroaryl radical and R7 is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl, heteroaryl(lower)alkyl, a group of formula -NR8R9 [where R8 is hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R9 is hydrogen, lower alkyl, -CO(lower)alkyl, aryl, COaryl, aryl(lower)alkyl, cycloalkyl or cycloalkyl(lower)alkyl or R8 and R9 together with the nitrogen atom to which they are both attached represent a saturated heterocyclic ring which may contain a further hetero atom] or a group of formula OR 10[where R10 is lower alkyl, cycloalkyl, cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or heteroaryl(lower)alkyl].

2. A compound as claimed in claim 1 for use in the treatment of cancer.

3. The use of a compound as claimed in claim 1 in the manufacture of a medicament for the treatment of cancer.

4. A use as claimed in any one of the preceding claims wherein the compound is a compound of the formula II:

or the pharmaceutically acceptable acid addition salts thereof (where n, R, R1, R2, R3, R4 and R5 are as defined in claim 1).