GB2227018A

GB2227018A - Piperazinylalkylcarboxylic acid adamantylamides

Info

Publication number: GB2227018A
Application number: GB9000349A
Authority: GB
Inventors: Ian Anthony Cliffe; Magid Abdel-Megid Abou-Gharbia; John Patrick Yardley; Jr Wayne Everitt Childers
Original assignee: John Wyeth and Brother Ltd; American Home Products Corp
Current assignee: John Wyeth and Brother Ltd; Wyeth LLC
Priority date: 1989-01-13
Filing date: 1990-01-08
Publication date: 1990-07-18
Anticipated expiration: 2010-01-08
Also published as: GB9000349D0; GB2227018B

Abstract

Compounds of the formula <IMAGE> wherein Ad is 1-adamantyl, 2-adamantyl or 3-noradamantyl; n is 1, 2, 3, 4, or 5: R<1> is hydrogen, alkyl, phenyl, benzyl, or substituted phenyl or benzyl in which the substitutent is alkyl, alkoxy, halo, cyano, nitro or trifluoromethyl; R<2> is phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl, alkoxy, halo, nitro, cyano or perhalomethyl, 2-, 3-, or 4-pyridinyl, 2-, 4- or 5-pyrimidinyl or 2- or 3-pyrazinyl; R<3> and R<4> are, independently, hydrogen, methyl, phenyl, benzyl or substituted phenyl or benzyl in which the substitutent is alkyl, alkoxy, halo, cyano or trifluoromethyl; or a pharmaceutically acceptable salt thereof, are useful anxiolytic and/or antidepressant agents, with elements of antipsychotic activity.

Description

PIPERAZINYLALKYLCARBOXYLIC ACID ADAMANTYLAMIDES This invention relates to piperazinylalkylcarboxylic acid adamantylamides.

Derwent Abstract 85-000957/01 of German Application 3321969 discloses l-pyrimidyl-4-substituted piperazine derivatives which possess a broad variety of CNS activity including anxiolytic and antidepressant properties. Netherlands Patent 7017031 discloses 8-(heteroarylpiperazinylalkyl )-8-azaspiro[ 4,5 )decane- 7,9-diones as tranquillizers. US Patent 4640921 (Derwent Abstract 87-049798/07) discloses the use of the buspirones of the Netherlands patent in the treatment of sexual dysfunction in anxious patients.

The anxiolytic activity of buspirone-like compounds has been attributed to their selective activity at a serotonin (5-hydroxytryptamine; 5-HT) subtype receptor designated the 5 HT1A receptor. US Patent 4202898 discloses the treatment of anxiety and depression with aromatically substituted piperazine derivatives.

5-HT2 antagonists, such as Ritanserin, lack 5-HT1A affinity but demonstrate clinical efficacy as anxiolytic-antidepressant agents (Barone et al, Drug Clin. Pharm., 20, 770, 1986).

In accordance with this invention there is provided a group of novel compounds, some of which exhibit selective serotonin 5HUT, receptor affinity which characterises them as antidepressants and/or anxiolytics and some of which exhibit both 5HUT,, receptor affinity and dopamine D2 receptor binding which characterises them as anxiolytic/antidepressant agents with elements of antipsychotic activity. The compounds of this invention are of the following structural formula:

wherein Ad is l-adamantyl, 2-adamantyl, or 3-noradamantyl; n is 1, 2, 3, 4 or 5; R 1.

is is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl, benzyl, or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, cyano, nitro or trifluoromethyl; R is 2-, 3-, or 4-pyridinyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazinyl, phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, nitro, cyano or perhalomethyl; and R3 and R4 are, independently, hydrogen, methyl, phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, cyano, nitro or trifluoromethyl; or a pharmaceutically acceptable salt thereof.

1 may be reacted with an amine of formula AdNHR , eg noradamantan-3-amine or 1- or 2-adamantanamine, in the presence of a coupling agent conventionally used to produce amides, such as dicyclohexylcarbodiimide or preferably 1,1' -carbonyldiimidazole, iso-butylchloroformate or diphenylphosphinyl chloride.

Similarly, the reactant

may be employed to alkylate the amine

conventionally.

The following examples illustrate, without limitation, the specific methods employed in production of a representative number of compounds embraced by this invention.

EXAMPLE 1 4-(2-Pyrimidyl)-N-tricyclo[3.3.1.1(3.7)]dec- 1-yl-1-piperazinepropanamide To a suspension of 4-t2-pyrimidinyl)-1-piperazine hydrochloride (4.56 g, 0.019 mol) in 150 ml of dry dimethylformamide was added diisopropylethylamine (7.62 g, 0.06 mol) and 3-bromo-N-tricyclo[3.3.1.1(3,7)]dec-1-ylpropanamide hydrochloride (5.51 g, 0.019 mol). The stirred mixture was heated at 38"C for 18 hours, and then at 54"C for an additional 24 hours. The reaction mixture was then concentrated on a rotary evaporator, diluted with methylene chloride, washed with three portions of water, dried over anhydrous magnesium sulphate, and concentrated on a rotary evaporator.The desired product (TLC on silica gel using a 10% methanol in ethyl acetate solvent system, Rf = 0.3) was isolated by preparative high pressure liquid chromatography (HPLC) on silica gel using a gradient consisting of from 10% ethyl acetate in hexane to 10% methanol in ethyl acetate) and converted to the trihydrochloride salt (0.7 g, 8%), mp = 273-275"C.

Elemental Analysis for C21H3lN5O.3H2O Calculated: C, 52.67; H, 7.16; N, 14.63 Found: C, 52.46; H, 6.89; N, 14.54 EXAMPLE 2 4-(2-Methoxyphenyl)-N-tricyclo[3.3.l.l(3,7)jdec l-yl-l-piperazinepropanamide To a suspension of 4-(2-methoxyphenyl)-1-piperazine (0.67 g, 0.0035 mol) in 50 ml of methylene chloride was added diisopropylethylamine (0.49 g, 0.0038 mol) and 3-bromo-N-tricyclo[3.3.1.1(3,7)]dec-1-yl propanamide (0.98 g, 0.0034 mol). The resulting mixture was then washed with two portions of water, dried over anhydrous sodium sulphate, and concentrated on a rotary evaporator.The desired product (TLC on silica gel using a 10% methanol in ethyl acetate solvent system, Rf = 0.45) was isolated by preparative high pressure liquid chromatography on silica gel (using a solvent gradient consisting of from ethyl acetate to 4% methanol in dry acetate) and converted to the dihydrochloride salt (0.33 g, 20%), mp = 232-234"C.

Elemental Analysis for C24H35N3O2. 2HCl.l/2H2O Calculated: C, 60.12; H, 7.99; N, 8.76 Found: C, 60.45; H, 8.11; N, 8.79 EXAMPLE 3 N-(l-Tricyclo[3.3 .1.1(3,7) ]decyl)-3-[l-[4-(2- methoxyphenyl)piperazinyl]]-2-phenylpropanamide l-(2-Methoxyphenyl)piperazine (22.6 g, 0.118 mol) and atropic acid (174 g, 0.118 mol) in ethanol (300 ml) were heated under reflux for 18 hours, cooled to room temperature, and evaporated in vacuo. The solid was triturated with acetone (3 x 100 ml) to give a first crop of a-[l-[4-(2-methoxyphenyl)piperazinyl]methyl]- phenyl acetic acid (13.8 g) as white crystals. The filtrate was evaporated in vacuo to give an oil which slowly crystallized over a one month period of time.

The solid was triturated with acetone (200 ml) to give a second crop of the hemihydrate of the a-[1-[4-(2 methoxyphenylZpiperazinyl]methyl]phenylacetic acid (9.01 g) as white crystals, mp 160-163"C.

Elemental Analysis for C20H24N203.0.5H2O Calculated: C, 68.8; H, 7.2; N, 8.0 Found: C, 68.4; H, 7.2; N, 7.9 A stirred suspension of N-methylmorpholine (0.61 ml, 5.6 mmol) and the product of the preceding paragraph (1.894 g, 5.6 mmol) in dimethylformamide (10 ml) at -15 C was treated with isobutyl chloroformate (0.73 ml, 5.6 mmol). After 5 minutes, l-adamantylamine (0.885 g, 5.85 mmol) was added and the suspension warmed to room temperature. After 1 hour, the viscous suspension was diluted with dimethylformamide (10 ml). After 72 hours, the mixture was poured into water (200 ml) and extracted with chloroform (2 x 200 ml). The extracts were washed with brine (100 ml), dried (MgSO4), and evaporated in vacuo. The residue was purified by chromatography (silica; diethyl ether) to give the title compound as a foam.

The dihydrochloride salt of the product was prepared from methanol-diethyl ether with ethereal hydrogen chloride as white crystals (0.392 g), mp 244-246"C (dec).

Elemental Analysis for C30H39N3O2. 2HCl Calculated: C, 65.9; H, 7.6; N, 7.7 Found: C, 65.7; H, 7.7; N, 7.6 The compounds of this invention are antidepressant and/or anxiolytic agents useful in the treatment of depression and/or anxiety as a singular, primary mental problem as well as secondary, attending problems such as sexual dysfunction. Some of the compounds possess sufficient dopaminergic activity to be useful in treating psychoses such as schizophrenia or paranoia.

Examples of compounds with sufficient limbic D2 (dopamine) receptor affinity to be considered to have an antipsychotic parameter are those of Example 2 which 3 exhibited 74 percent inhibition of 3H-spiroperidol binding to limbic brain tissue at 1 pM concentration of the test compound. The D2 receptor affinity of the compounds of this invention was determined by a modification of the test procedure of Fields et al, Brain Res. 136, 578 (1977) and Yanamura et al, eds., Neurotransmitter Receptor Binding, Raven Press, N.Y.

(1978) as discussed in US 4636563. The percentage 3 reduction of H-spiroperidol binding at 1 uM concentration of test compound is reported, infra.

The serotoninergic properties of the compounds of this invention were established by the procedure of Hall et al, J Neurochem. 44, 1685-1696 (1985) by demonstrating that representative compounds exemplified herein 3 displace H-8-OH DPAT (dipropylaminotetralin) from the SHTlA serotonin receptor subtype. The results of this standard pharmacological procedure are reported, infra, as the percent inhibition at 1 pM concentration of test compound and by providing the inhibition constant Ki for the specific test compound where that calculation has been made from appropriate IC50 values. Buspirone exhibits a Ki value of 10 nM (97% inhibition at 1 pM) in this test procedure.

Affinity for 5-HT1A Receptor Sites Compounds % Inhibition at 1 uM % Inhibition of Example (Ki in nM) at 100 nM 1 79% (130 nM) 2 100% ( 9 nM) 86% 3 ( 83 nM) Affinity for D2 Receptor Sites Compound of Example % Inhibition at 1 uM 1 14% 2 74% In qualitatively evaluating the above data, high affinity values for 5-HT1A receptors correlate (by analogy with buspirone) with anxiolytic-antidepressant activity, while lower values reflect a lesser activity.

High affinity values for D2 receptor binding begin to show some antipsychotic activity.

Hence, the compounds of this invention are antidepressant/anxiolytic agents useful in the treatment of depression and in alleviating anxiety and in the case of the product of Example 2 and analogously substituted phenyl containing compounds, they have some meaningful antipsychotic activity which is useful in the treatment of psychoses such as paranoia and schizophrenia. As such, the compounds of this invention may be administered to a patient in need thereof, either neat or with a conventional pharmaceutical carrier. The pharmaceutical carrier may be solid or liquid as suitable for oral or parenteral administration.

A solid carrier can include one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, 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. 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.

Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurised compositions. The active ingredient 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, viscocity regulators, stabilisers or osmo-regulators.Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additivies as above, eg cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, eg glycols) and their derivatives, and oils (eg fractioned coconut oil and arachis oil). For parenteral administration the carrier can also be an oil ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, fsr 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 subdivided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example3 a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The dosage to be used in the treatment of anxiety, depression, psychoses, etc must be subjectively determined by the attending physician. The variables involved include the specific state of depression, anxiety or phychoses and the size, age and response pattern of the patient.

Claims

1. A compound of the formula

wherein Ad is l-adamantyl, 2-adamantyl or 3-noradamantyl; n is 1, 2, 3, 4 or 5; R1 is hydrogen, alkyl of 1 to 3 carbon atoms, phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, cyano, nitro or trifluoromethyl; R2 is 2-, 3- or 4-pyridinyl, 2-, 4- or 5-pyrimidinyl, 2- or 3-pyrazinyl, phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, nitro, cyano or perhalomethyl; and R3 and R4 are, independently, hydrogen, methyl, phenyl, benzyl or substituted phenyl or benzyl in which the substituent is alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, halo, cyano of trifluoromethyl; or a pharmaceutically acceptable salt thereof.

2. A compound as claimed in claim 1 in which Ad is l-adamantyl.

3. A compound as claimed in claim 1 or 2 in which R3 is hydrogen and R4 is phenyl, benzyl or substituted phenyl or benzyl.

4. A compound as claimed in any one of claims 1 to 3 in which n is 1.

5. 4-(2-Pyrimidyl)-N-tricyclo[3.3.1.1(3,7)]dec-1-yl- l-piperazinepropanamide, or a pharmaceutically acceptable salt thereof.

6. 4-(2-Methoxyphenyl)-N-tricyclo[3.3.1.1(3,7)]dec- l-yl-piperazinepropanamide, or a pharmaceutically acceptable salt thereof.

7. N-(l-Tricyclo[3.3.1.1(3,7)]decyl)-3-[1-[4-(2- methoxyphenyl )piperazinyl -2-phenylpropanamide.

8. A method of preparing a compound claimed in claim 1 which comprises (a) reacting an amine of formula AdNHR with a compound of formula

where Ad, R1 R , R3 R4 and n are as defined in claim 1 and Hal is halogen or (b) coupling an amine of formula AdNHR with a carboxylic acid of formula

where Ad, R1 R2 R3 R4 and n are as defined in claim 1 or (c) alkylating an amine of formula

with

where Ad, R1 R2 R3 R4 and n are as defined in claim 1 and Hal is halogen.

9. A method of preparing a compound as claimed in claim 1 substantially as hereinbefore described with reference to any one of the Examples.

10. A compound as claimed in claim 1 whenever prepared by the method of claim 9 or 10.

11. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 7 or 10 and a pharmaceutical carrier.

R 1.

Preferably n is 1 and preferably R is hydrogen.

The pharmaceutically acceptable salts are conveniently derived by conventional means from such acids as hydrochloric, hydrobromic, sulphuric, phosphoric, methane sulphonic, nitric, p-toluene sulphonic, acetic, citric, maleic, succinic acid, and the like. The halogens embraced by the term halo are chlorine, bromine, iodine and fluorine, preferably chlorine, bromine or fluorine. The preferred compounds are those in which Ad is l-adamantyl.

The compounds of the invention may contain chiral centres so that the compounds can exist in different steroisomeric forms, eg as racemates or optical isomers. The optical isomers may be obtained by conventional methods, eg resolution of the racemates or by preparing the compounds from optically active starting materials.

The compounds of this invention may be prepared by a variety of synthetic routes using conventional methods.

For instance, an amine of formula AdNHR , eg noradamantan-3-amine or 1- or 2-adamantanamine may be conveniently reacted with the appropriately substituted

The reaction may be carried out in an organic solvent, eg CH2C12 or CHCl3, and in the presence of an acid acceptor such as triethylamine. "Hal" is a halogen, preferably chlorine. Alternatively, the carboxylic acid