MXPA97002089A - Biciclic carboxamides as antagonists de5-h - Google Patents

Abstract

The present invention relates to a compound of formula I: or a pharmaceutically acceptable salt thereof, characterized in that X reoresebta --CR2 = CR2-- or - (CR2) q; M represents 0, 1 or 2; n represents 0, 1 and 2, p represents 0, 1, 2 or 3 and q represents 0, 1, 2, or 3 A is an alkylene chain of 1 to 2 carbon atoms optionally substituted by one or more lower alkyl groups, R is a mono or bicyclic aryl or heteroaryl radical, wherein Aryl is a phenyl, naphthyl or tetrahydronaphthyl radical optionally substituted by one or more substituents selected from C 1-6 alkyl alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 alkoxy, halogen, haloalkyl, C 1-6, (for example trifluoromethyl), hydroxy, nitrile, C 1-6 alkylcarbonyl, C 1-6 alkoxycarbonyl, amino, C 1-6 alkylamino, C 1-6 alkylamino, aminocarbonyl, C 1-6 alkylaminocarbonyl 6, C 1-6 di-alkylaminocarbonyl, nitro, -CHO or thio-C 1-6 alkyl, or a bicyclic radical containing oxygen not of the formula: wherein the heterocyclic ring containing the oxygen atom contains a total of 5 to 7 atoms in the ring, is non-aromatic, optionally contains an additional oxygen atom and can be optionally substituted as above, and heteroaryl is a selected aromatic radical of a monocyclic heteroaryl radical containing from 5 to 7 atoms in the ring or a bicyclic heteroaryl radical containing from 8 to 10 atoms in the ring, one or two atoms in the ring which is selected from nitrogen, oxygen and sulfur, The radical can be optionally substituted as above by aryl, R1 is an aryl radical or aryl-lower alkyl, and each R2 is independently hydrogen or lower alkyl.

Description

CARBOXA IDAS BICICLICAS AS ANTAGONISTS OF 5-HT1A DESCRIPTION OF THE INVENTION This invention relates to novel bicyclic carboxamide derivatives, to processes for their preparation, to their use and to pharmaceutical compositions containing them. The novel compound acts on the central nervous system by binding to 5-HT receptors (as explained more fully in the following) and therefore can be used as medicaments for the treatment of humans and other mammals. The novel compounds of the invention are those of the general formula (I) and their pharmaceutically acceptable acid addition salts. In the formula I REF: 24089 X represents -CR2 = CR2- or - (CR2) -; m represents 0, 1 or 2; n represents 0, 1 or 2; p represents 0, 1, 2 or 3 and q represents 0, 1, 2 or 3 A is an alkylene chain of 1 or 2 carbon atoms, optionally substituted by one or more lower alkyl groups, R is an aryl or heteroaryl radical mono or bicyclic, R1 is a lower aryl or arylalkyl radical and each R2 is independently hydrogen or lower alkyl. The term "lower" as used herein means that the mentioned radical contains from 1 to 6 carbon atoms. Preferably such radicals contain from 1 to 4 carbon atoms. Examples of the "lower alkyl" radicals are methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and isopentyl. When used herein "aryl" means an aromatic radical having from 6 to 10 carbon atoms (for example phenyl or naphthyl), which optionally may be substituted by one or more substituents. Preferred substituents are substituents lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy (for example methoxy, ethoxy, propoxy, butoxy), halogen, lower haloalkyl (for example trifluoromethyl), hydroxy, nitrile, lower alkylcarbonyl, lower alkoxycarbonyl, amino , lower alkylamino, lower dialkylamino, ammocarbonyl, lower alkylaminocarbonyl, dialkylated lowercarbonyl, nitro, -CHO or lower thioalkyl. Two substituents on the aromatic ring can be joined together to form another ring system. For example R may be a tetrahydronaphthyl radical optionally substituted (for example 5-tetralinyl) or a radical containing bicyclic oxyiscene of the formula wherein the heterocyclic ring containing the oxygen atom contains a total of 5 to 7 members in the ring, the heterocyclic ring is non-aromatic and optionally contains 1 or more members in the hetero ring (e.g., O, N or S) in addition to the illustrated oxygen atom and the bicyclic oxygen radical which is optionally substituted by one or more substituents, such as the substituents mentioned in the above in relation to "aryl". A preferred imploy of such a bicyclic oxygen radical is 8-: mannyl or an optionally substituted radical of the formula The term "heteroaryl" refers to an aromatic radical containing one or more heteroatoms (for example oxygen, nitrogen, sulfur) and which may be optionally substituted by one or more substituents. Examples of suitable substituents are given in the above in relation to the "aryl" radicals. The heteroaryl radical can, for example, contain up to 12 ring atoms. For example, the heteroaryl radical can be a monocyclic radical containing from 5 to 7 ring atoms or a bicyclic radial containing from 8 to 12 ring atoms. Preferably, the hetero ring contains one of the two heteroatoms selected from nitrogen, oxygen and sulfur. When R is a heteroaryl radical, an optionally substituted pyrimidyl (particularly 2-pyrimidyl), optionally substituted pyridyl (for example pyrid-2-yl), optionally substituted indolyl, particularly indole-4-yl and indol-7-yl), pyrazinium is preferable. optionally substituted (particularly 2-pyrazinyl), quinolinyl z "isoquinolinyl optionally substituted in particular 1-isoquinolinyl) or optionally substituted benzofuran (particularly 4 and 7-benzofuranyl) where the optional substituents are given in the above in relation to the aryl radicals. Preferred formula I have the following characteristics either individually or in any possible combination: (a) the ring system (CH2) - CR2- CH2 represents (i) ii) o ii) a radical of the formula where p is 2 or 3 and q is 0, 1, 2, 3 for example a radical of the formula (iv) A is --H 'C i ~ (c) R is an optionally substituted phenyl radical, for example 2-lower alkoxyphenyl (for example 2-methoxyphenyl), an optionally substituted pyridyl radical or an optionally substituted indolyl radical (for example a radical optionally substituted indole-4-yl) and id) R 1 is a substituted or unsubstituted phenyl. The compounds of the invention can be prepared by methods known in the art from known materials or starting materials that can be prepared by conventional methods. The methods comprise alkylation of a compound of the formula R-N NH (10 (where R is as defined above) with an alkylating agent that provides the group (ip) 'where X, m, n, p, A, R1 and R2 have the meanings given in the above)? The alkylating agent can be, for example, a compound of the formula Z-A- (IV) where m, n, p, q, A, R1, R2 are as defined above and Z is a leaving group, such as halogen, or an alkyl- or aryl-sulfonyloxy group. Alternatively to prepare the compounds where -A- is -CH2- the alkylaryl- agent may be an unsaturated compound of the formula (V) (where X, m, n, p, R1 and R2 are as defined in the above) and the compound of the formula (V) is reacted with the piperazm of the useful formula) by means of a Michael reaction. The alkylation can also be carried out by condensing an aldehyde of the formula (where X, m, n, p, A and R1 are as defined above and B is a direct bond or a methyl group optionally substituted by one or two lower alkyl groups) with the piperazine of the formula (II). The condensation can be carried out with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride. In an alternative method for preparing the compound of the invention, an amine of the formula (VII) where X, m, n, p and R2 sin as defined in the above) is acylated with an acid of the formula (VIII) (where A, R, R1 are as defined in the above) or with its acylation derivative. Examples of acylation derivatives include acid halides (for example acid chlorides), azides, anhydrides, imidazolides (for example obtained from carbonyldiimidazole), activated esters or O-acylureas obtained from a carbodiimide such as dialkylcarbodiimide, particularly dicyclohexylcarbodiimide. Preferably, the amine is acylated with the acid by the use of a coupling agent such as 1, 1'-carbonyldiimized, isobutyl chloroformate or diphenylphosphinyl chloride. The processes described above can be carried out to give a compound of the invention in the form of a free base or as an acid addition salt. If the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. On the contrary, if the product of the process is a free base and acid addition salt, particularly a pharmaceutically acceptable acid addition salt, it can be obtained by dissolving the free base in a suitable organic solvent and treating the solution with an acid, of according to conventional methods for preparing acid addition salts from basic compounds. Examples of the acid addition salts are those formed from inorganic and organic acids, such as sulfuric, hydrochloric, hydrobromic, phosphoric, tartaric, fumaric, maleic, citric, acetic, formic, lactic, methanesulfonic, malonic, -Toluenesulfonic, oxalic and succinic. The compounds of the invention contain one or more asymmetric carbon atoms such that the compounds can exist in different stereoisomeric forms. All stereoisomeric forms are included within the invention. The compounds can be, for example racemate or optically active forms. The optically active forms can be obtained by resolution of the racemates or by asymmetric synthesis. The compounds of the present invention possess pharmacological activity. In particular, they act on the central nervous system by binding to 5-HT receptors, particularly receptors of the 5HT1A type. In general, the compounds selectively bind to the 3H7 ^ type receptors to a much greater extent than those that bind to other receptors such as a ^. The compounds can be used for the treatment of CNS disorders, such as anxiety in mammals, particularly humans. They may also be useful as antidepressants, antipsychotics (for example to be used in schizophrenia, paranoia and manic-depressive illness), hypotensive agents and as agents to regulate the sleep / wake cycle, eating behavior and / or sexual function and as agents that increase Cognition The compounds of the invention are tested for binding activity to the 5-HT1A receptor in a homogenate of hippocampal membranes in rats by the method of B. S. Alexander and M. D. Wood, J. Pharm. Pharmacol. , 1988, 40-888-891. The results for some representative compounds of the invention are given in the following.

Compound Link to 5-HT1A (CEcQ) Example 1 3.3 nM Example 2 1.48 nM Example 5 3.73 nM Example 8 3.5 nM Example 10 17.9 nM Example 14 1.96 nM Example 15 0.58 nM Example 16 4.46 nM The invention also provides a pharmaceutical composition comprising a compound of the formula (I) or its pharmaceutically acceptable acid addition salt, in association with a pharmaceutically acceptable carrier.

Any carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition the carrier is usually a solid or liquid or a mixture of a solid or liquid. The compositions in solid form include powders, granules, tablets, capsules (for example hard and soft gelatin capsules), suppositories and vaginal suppositories. A solid carrier can be, for example, one or more substances, which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents; they can also be in an encapsulation 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 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 carboxymethyl cellulose, polyvinylpyrrolidone, low melting point waxes, and ion exchange resins. . The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as a 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 him. In a similar way, the bags are included. The composition in liquid form includes, for example, solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient, for example, may 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 may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (containing particularly additives as in the above, for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (for example glycerol and glycols) and their derivatives and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be a fatty ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid form for parenteral administration. Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be used for example by 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 the form of a liquid or solid composition. Preferably, the pharmaceutical composition is in the form of a dosage unit, for example as tablets or capsules. In such form, the composition is subdivided into dosage units containing appropriate properties of the active ingredient; Dosage unit forms can be a packaged composition, for example packaged powders, flasks, ampoules, pre-filled syringes or bags containing liquid. The dosage unit form for example, may be a capsule or tablet by itself or may be the appropriate number of any such compositions in package form. The amount of the active ingredient in the dosage unit of the composition can be varied or adjusted from 0.5 milligrams or less to 750 milligrams or more, according to the particular need and activity of the active ingredient. The following examples illustrate the invention.

E1 ampio 1 1- (8-azabicyclo3.2.11 oct-8-yl) -4- 4-methoxyphenyl) -pjperazin-1-ill-2-phenyl-butan-1-one A mixture of 4- [4- (2-methoxyphenyl) piperazin-1-yl] -2-phenylbutanoic acid (4.0 g, 11.3 mmol), desmethylpropane (1.7 g, 15.3 mmol, prepared from tropane by the method used by RA Olofson et al., J. Org. Chem., 1984, 49 (11), 2081, for the conversion of O-acetyltropine to O-acetyldesmethyltropine), l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 2.2 g, 11.3 mmole) and triethylamine (0.198 mmole) in methylene chloride (25 ml) were added. I set the environment for 43 hours. The mixture NaHCO 2 1 100 ml) and extracted with ethyl acetate. 3 x 103 ml). The ethyl acetate layer is washed with water (100 ml of brine and 100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated or vacuum to give the product without purification. this material by silica gel column chromatography with 1% ammonia in ethyl acetate as an elastomer) followed by treatment with 1.1 equivalents of 1N hydrogen chloride in ether gives 2.5 g of the title compound as the hydrochloride hemihydrate, e.g. F. 225-228 ° C decomposition).

Elemental Analysis for: C28H37N3 ° 2 '^ Cl' ° -5 H2 ° Calculated: C, 63.20; H, 7.97; N, 8.52. Found: C. 68.54; H, 7.72; N, 8.35.

E1ffff] -9 2 1- (3-aza-bicyclo-3.2.11-oct-8-yl) -4- -4- (5-fluoro-2-methoxy-phenyl) -piperazin-l-yl-2-fgnil-butan-1-one A mixture of 4- (5-fluoro-2-methoxyphenyl) -p-perazine (2.1 g, 10.0 mmol, prepared by the method described in U.S. Patent No. 4,585,773), - l 1- 3 - aza-ciciclo .3.2. , oct-3-l -4-clcro-2-phen l -cutan-1 -na 3.4: g, 10.0 mmoles), diisopropylethylamine '1.4 g, 11; -ol potassium iodide 1.66 g, 13.3 moies) is heated in dimethylformamide (35 i 'at 80 ° C for 5 hours.) After cooling to room temperature, the mixture is poured into water (100 ml) and extracted with water. Ethyl acetate (2 x 333 mL) The combined ethyl acetate layer is washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give an Unpurified product The purification of this material by column chromatography, silica gel with 2% methanol in ethyl acetate as a follower followed by treatment with 1.1 equivalents of 1 N hydrogen chloride in ether of 1.3 g of the title compound as hydrochloride hydrated in the fourth part, mp 203-206 ° C.

Elemental Analysis oara: C28H36FN3? 2 -HC1 • 0.25 H20 Calculated: C. 66.39; H, 7.46; N, 8.29. Found: C, 66.18; H, 7.46; N, 8.07.

Example 3 - -: -1- -aza-bicyclo r3.2. I1 oct-3- l? -4- r4- .'S-fluoro-2- ~ etcxi-fer.il) -or perazin-l-1 -2-phenyl-butan-1-one The title compound is separated from the racemic base, 1- '8-aza-b? c? clo [3.2.1] oct-8-yl) -4 - [4- (5-fluoro- 2 - tetoxif nl -piperazin-1-yl] -2-f nyl-butan-1-one (see example 2), by preparative CLAP 'Chiralpak, 10 u, 4.6 x 13 250 m, 1: 1 ethyl acetate: ethanol, the retention time was 8,865 minutes) and the resulting enantiomer was treated with 1.1 equivalents of 1N hydrogen chloride in ether to give 0.097 g of the product as the hydrochloride, mp. 160-i52 ° C, [a] 25D = + 14.97 (DMSC 1? Elemental Analysis for: ^ 28H36FN3 ° 2 '^ Cl Calculated: C, 66.98; H, 7.43; N, 8.37. Found: C, 67.09; H, 7.61; N, 8.35.

Ahem 4? '-) - (2R) -1- (S-aza-bicycloi3.2.1.1cct-8-il) -4-f4 - (5-fluoro-2-methoxy-phenyl) -piperazin-1-ill -2- phenyl-butan-l-one The title compound is separated from the racemic base, 1- 3-aza-bicyclo [3.2.1] oct-8-yl) -4- [4 - (5-fluoro-2- c peraz? n-1 -? i] -2 - phen l -cutan-1 -one [see - e-plo 2, per CLAP preparative cemo was described in the e: lo 2 co of retention of 9.394 minutes) and the enantiér. Basic pure water is treated, 1.1 equivalents of 1N hydrogen chloride in ether to give 0.170 g of the product as hydrochloride 0.6 hydrated, mp 17Q-172 ° C, [x] 25n = -27.91 [MSC? . Elemental Analysis for: C2SH36FN302 '^ Cl' ° -6 H2 ° Calculated: C, 65.67; H, 7.51; N, 8.19. Encentered: C, 65.30; H, 7.95; N, 8.01.

Example 5 1- (3-aza-b-cyclo3.2.l1 oct-8-yl) -4- IV- (lH-indol-4-yl) -cperazin-1-ill-2-phenol-butan-l- ona The compound of the title was prepared from the 4- lH-indol-4-yl) -piperazine (1.0 g, 4.97 mmol), l- (8-aza-bicyclo [3.2.1] oct-8-yl) -4-chloro-2-enyl-butan- 1-one (1.6 g, 4.97 mmoies) diisopropylethylamine «0.65 g, 4.97 mmol) and potassium iodide (0.83 g, 4.97 mmol) in dimethylformamide 3 mi) in the manner described in example 2 to produce 3. 5 g of the product such as 0.75 hydrated hydrochloride, m.p. 150-170 ° C. Elemental Analysis for: C29N36 40 HCl - 0.75 H20.c bundled: C, 53.76; H, .56; , • entered: C, 63.59; K, 7.74; N, 30 Example 6 - - 2R'-1- 3-aza-bicyclo3.2.11 cct-3-yl) -4- f4- (lH-indol-4-yl, -oiperazin-1-yl] -2-phenyl-butan-l- cna The title compound was separated from the racemic base, 1- (8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4-1H-indol-4-yl) -piperazine. -1- l] -2-phenyl-butan-1-one (see example 5), per preparative CLAP as in example 3 or by chiral synthesis to give the title product as hydrochloride 1.5 hydrated, mp 160-240 ° C (decomposition). Elemental Analysis for: 29H3gN40 • HCl • 1.5 H20 Calculated: C. 66.74; H, 7.76; N, 10.73. Found: C. 67.02; H, 7.74; N, 10.33.

Example 7 1- (8-aza-biciclor3.2.poct-3? L) -4- T4- (2-methoxy-5-trifluoromethyl-phenyl) -piperazin-1-ill-2-phenyl-butan-1-one The title compound was prepared from 4- '' 2-methox? -5-trifluoromethyl-phenyl) -piperazine (0.7 g, 1.2-mole, prepared according to the method cut out in ei? -emple 2). , the 1- v 3 -aza-bicyclo [2.2.1] oct-3-ii) -4 -clerc-2-phen l-but n- - cna (0.7 g, 2.3 mmol), diisoprepilethiamine 3.4 g, 3.3 mmol ) and potassium iodide (0.5 g, 3.0 mmol) in dimetiifer amide (25 ml) in the manner described in Example 2 to yield 0.3 g of the title product co or the hydrochloride emihydrate, mp. 195-_99 ° C.

Elemental Analysis for: c25H3gF3N302 • HCl • 0.5 H20 Calculated: C, 62.08; H, 6.33 N, 7.49. Encentered: C, 62.26; H, 6.56; N, 7.40.

Example 8 1- 8-aza-biciclof3.2.11 oct-8-yl) -2-phenyl-4- Í4- (oyridin-2-yl) -piperazin-1-ill-butar.-1-one The title compound was prepared from 4 - (pyridin-2-yl) -piperazine (1.0 g, 5.0 mmol), the l- (3-aza-bicyclo [3.2.1] oct-8-il) -4-bromo-2- f nyl-but-α-one (1.6 g, 4.76 mmol), diisoprcp? Leti-.ami- -., G, 7.0 mmol) and potassium iodide (0.8 g, 5.0 mmol) in dimethylformamide (30 ml) in the manner described in Example 2 to produce 1.1 g of the product as the dihydrochloride, mp 196-236 ° C.

I .3 - S Elemental face: -, 5H34N4C • 2HC1: alc lad ?: C, 63.54; H, ~ > .33 N, 11.40. go. centered: C, 63.05; H, 7.47; N, 11.31.

Example 9 1-! 3 affixed 33.2.11 oct-8-il? -4- Í4- (3 -me oxy -oiridin-2 - 11 -piperazin-1-ill -2 -f n l-butan-1-cna The title compound was prepared from the 4 - . 4-i 3-methoxy? -pyr? Din-2-yl) -piperazm (1.0 g, 5.0 mmol), the l- (3-aza-b? Cyclo [3.2.1] oct-3-yl) -4 -bromo-2-phenyl-butan-1 -one "1.6 g, 4.76 mmol), diisopropylethylamine (0.9 g, 7.3 mmol) and potassium iodide (0.8 g, 5.0 mmol) in dimethylformamide (30 ml) in the manner described in Example 2 to yield 0.87 g of the title product as the hydrate uel hydrochloride, mp 14Q-147 ° C.

Elemental Analysis for: C27H36N402 -HC1 H20 Calculated: C, 64.46; H, 7.81 N, 11.14. Encentered: C, '.ZZ, H, ".., 10.64.

Example 10 1- (3-aza-bicyclo3.2.11 oct-8-yl) -2-phenyl-4- (4- (- rifluoro-? Iridin-2-yl) -piperazin-1-ill-butan-1-one The title compound was prepared from 4- (3-trifluoromethyl-pyridin-2-yl) -piperazine (0.9 g, 3.9 mmol), 1- (8-aza-bicyclo [3.2.1] oct-8 -yl) -4-chloro-2-phenyl-butan-1-one (1.6 g, 5.50 mmol), diisopropylethylamine (0.7 g, 5.4 mmol) and potassium iodide (0.8 g, 4.8 mmol) in dimethylformamide (30 ml) in the manner described in Example 2 to yield 0.98 g of the title product as 1.75 of the hydrochloride, mp. 108-118 ° C. Elemental Analysis for: C27H33N40- 1.75 Calculated HCl: C, 58.92; H, 6.36 N, 10.18. Found: C, 58.87; H, 6.49; N, 10.04.

Example 11 1- (8-aza-bicyclo Í3.2.11 oct-8-il) -2-phenyl-4- Í- (5- trifluoromethyl-Prididin-2-yl) -piperazin-1-ill-butan-1-one The title compound was prepared from 4- (3-trifluoromethyl-pyridin-2-yl) -piperazine (0.9 g, 3.9 mmol), 1 - (8-aza-bicyclo [3.2.1] ] oct-8-yl) -4-chloro-2 -: in? _- cutan- 1-; na .... og, DD -.rc ^ s,, aii = epropylethyla. "g, 5.4-moles) and potassium iodide (3.3 g, 4.3 rr.): n dirretilf cr-a ida (33 ml) in the manner described in the err.pio 2 to produce 3.47 g of the title product as: .3 hydrate hydrochloride, solid foam, mp 35-120 ° C decomposition.) Elemental Analysis for: C27K33N40 • HCl • 0 .H20 Calculated: C, 61.37; H, 6.60 N, 10.60.Encentrate: C, 61.50; H, 7.01; N, 10.47.

Example 12 4- I "4- '2-methoxyphenyl) -oiperazin-1-yl-2-phenyl-1- (1,3,3-trimethyl-6-aza-bicyclo -3.2.11ect-6-ii ^ -butan- 1-one A mixture of 4- [4-2 2-methoxyphenyl) piperazin-1-l] -2-phenylbutanoic acid (170 g, 5.0 mmol), 1,3,3-trimethy-6-azabicyclo [3.2.1] -octane (0.77 g, 5.0 mmol), 1- (3-dimethylapropyl) -3-ethyldicarbodii hydrochloride ida (0.96 g, 5.0 mmol) and triethyla (0.55 g, 5.0 mmol) in methylene chloride (10 mL) is stirred at room temperature. environment for 43 hours. The mixture is poured into 1N sodium hydroxide (75 ml) and extracted with ethyl acetate (3 x 75 ml). The combined ethyl acetate layer is washed with water (100 ml) and brine (130 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to give the product without purification. This material is treated with 1.1 equivalents of 1 N hydrogen chloride in ether (100 ml) to give 1.15 g of the title compound as the hydrochloride sesquihydrate, m.p. 110-145 ° C (decomposition). Elemental Analysis for: C31H43N302 • HCl • 1.5 H20 Calculated: C, 67.31; H, 8.56; N, 7.60. Found: C, 66.94; H, 8.48; N, 7.63.

Example 13 1- (3-aza-bicycloi3.2.11 non-3-yl) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-ill-2-phenyl-butan-1-one The title compound was prepared from the 4 - . 4- (5-fluoro-2-methoxyphenyl) piperazine (2.1 g, 10.0 mmol), 1- (3-aza-bicyclo [3.2.1] non-3-yl) -4-bromo-2-phenyl-butan -1-one (3.5 g, 10.0 mmol), diisopropylethyla (1.40 g, 11.0 mmol) and potassium iodide (1.66 g, 10.0 mmol) in dimethylformamide (30 mL) and the purified basic intermediate is treated with 1.1 equivalents of sodium chloride. hydrogen in ether to yield 2-5 g of the title product as 1.25 hydrochloride hydrate, mp 105-112 ° C.

Elemental Analysis for: C25.:38FN302 -HCl • 1.25 H2 O Calculated: C, 64.67; H, 7.77; N, 7.30. Encentered: C, 64.74; H, 7.66; N, 7.56.

Example 14 1- (3-aza-bicyclo3.2.21 non-3-yl) -4- T4- (lH-indol-4-yl) -piperazin-1-l-2-phenylbutan-1-one A mixture of 4-piperazinindole (1.03 g, 5.1 mmol), 1- (3-azabicyclo [3.2.2] non-3-yl) -4-chloro-2-phenyl-butan-1-one (1.44 g, 4.7 mmol) and diisopropylethyla (0.66 g, 0.89 ml, 5.1 mmol) in anhydrous dimethylformamide (50 ml) are stirred and heated at 80 ° C for 1 hour. The dimethylformamide is removed under reduced pressure and the brown residue is dissolved in dilute hydrochloric acid, washed with ether, basified with potassium carbonate solution and the extracted oil in dichloromethane, dried, (MgSO4) and evaporated under reduced pressure to give a brown oil. The oil is purified by chromatography on alu (30% ethyl acetate in hexane) to yield 1.3 g of the oil. The solution of the oil in ethyl acetate and the addition of an ethereal solution of hydrogen chloride precipitated the title compound as the hydrochloride salt 1.25 g, m.p. 175-179.5 ° C.

Elemental Analysis for: 30H33N4 ° > 2HC1- H20 Calculated: C, 64.4; H, 7.4; 9.9% ? nc entered: C, 54.1; H, 7.54; , 10.3 Example 15 1- 3-azabicyclo Í3.2.1.1 non-3-il) -4- (4- (2-etex f nil) p? Perazin-1-ill -2- enyl butan-1-one A mixture of 4- [4 - (2-methoxyphenii-piperazin-1-yl] -2-phen-butanoic acid (1.77 g, 5.0 mmol), d-cyclohexycarbodiimide (1.03 g, 5.0 mmol), 3-azabicyclohydrochloride [3.2 .2] nonane (308 mg, 5.0 mmol) and triethyla (0.75 ml, 0.55 g, 5.4 mmol) in dichloromethane are stirred at room temperature for 18 h.The reaction mixture is filtered and the precipitate is washed with dichloromethane 2 x 10 mi). Concentration under reduced pressure gives a yellow foam, which is subjected to chromatography on silica, using ethyl acetate as eluent to give a colorless gum (1.83 g). The dihydrochloride is obtained by precipitation from a solution of ethyl acetate with a solution of ethereal hydrogen chloride yielding 1.62 g. p.f. 194-198 ° C.

Elemental Analysis for: 29H39 302 • 2HC1 • O.5 H20 Found: C, 64.0; H, 7.9; N, 7.9%. Calculated: C, 64.1; H, 7.8; N, 7.7%.

Example 16 (a) 1- (1,3, 3a, 4, 7, 7a-hexahydro-isoindol-2-yl) -4-chloro-2-phenyl-butan-1-one 4-Bromo-2-phenylbutanoic acid (4.86 g) 0. 02 moles), dimethylformamide (0.05 ml), and thionyl chloride (2.2 ml, 0.03 mol) is brought to reflux in dichloromethane (50 ml) for 2.5 hours under nitrogen. The reaction evaporates. The residue is evaporated 3 times with benzene and then dissolved in diethyl ether (50 ml). The solution is cooled in ice and diisopropylethylamine (2.6 g, 0.02 mol) and 1, 3, 3a, 4, 7, 7a-hexahydroindole (2.46 g, 0.02 mol) are added. After 2 hours, the reaction was essentially complete (CCF Uniplate / EtAc). One half of the solution is washed with 10% citric acid, NaHCO 3, brine and dried over Na 2 SO 4. The solution evaporates. Yield 2.7 g, 89%. The oil is chromatographed on silica gel on a dry column (ICO ml) and eluted with ethyl acetate. Yield 2.4 g (68.9%). (b) 1-: i, 3,3a, 4,7, 7a-hexahydreisoindole -2-yl) -4- Í4-2- me exiphenyl) piperazin-1-yl -2-phenylbutan-1-one One half of the ether solution of the chloroamide product of example 16 (a) (0.01 mol) is diluted with DMF (75 ml), the ether is evaporated and 2-methoxyphenylpiperazine (1.93 g, 0.01 mol) and diisopropylethylamine (1.75 ml, 0.01 mol) are added. The mixture is stirred for 72 hours at room temperature. Water (75 mL) is added and the solution is extracted with ethyl acetate (4x75 mL) ethyl acetate is washed with NaHCO3 saturated, brine and dried (Na2SO4). Performance 4. 4 g (95.7%). The product is purified by chromatography on silica in a dry column (400 ml) eluted with ethyl acetate. Yield 2.5 g. The amine is dissolved in diethyl ether (100 ml) and acidified with 3.6 N HCl in ethyl acetate (4.0 ml). The dihydrochloride is filtered, washed with ether and dried in vacuo at room temperature to give the title product as the hemihydrate of the dihydrochloride.

Yield 1.85 g, m.p. 209-211 ° C.

Elemental Analysis for: C29H37N302 • 2HC1 • 1/2 H20 Calculated: C, 64.32; H, 7.45; N, 7.76. Found: C, 64.04; H, 7.40; N, 7.44.

Example 17 ia) 1- (octahydro-isoindol-2-yl) -4-bromo-2-phenyl-butan-l-one The 4-bromo-2-phenylbutanoic acid (4.86 g, 0. 02 mol) and thionyl chloride (2.2 ml, 0.03 mol) are brought to reflux in dichloromethane (100 ml) under nitrogen for 3 hours. The solution is evaporated and washed with benzene 3 times. The residue is dissolved in diethyl ether (50 ml) and cooled in an ice bath. Octahydroisoindole (2.5 g, 0. 02 moles) and diisopropylethylamine (3.5 ml, 0.02 moles) is dissolved in diethyl ether (50 ml) are added and the reaction is stirred for 60 hours at room temperature. The CCF (Uniplate / EtOAc) essentially showed the complete reaction. The solution is washed with water, saturated NaHC03 and dried (Na2SO4). Evaporation of the solvent leaves the product unpurified. Yield 6.46 g. (b) 4- Í4- (2-methoxyphenyl) iperazin-1-ill -1- (octahydroisoindol-2-yl) -2-phenyl-butan-1-one 1- (Octahydro-isoindol-2-yl) -4-bromo-2-phenyl-butan-1-one (3.23 g, 0.0092 mol), diisopropylethylamine (1.75 ml, 0.01 mol) and 2-methoxyphenylpiperazine (1.93 g, 0.01 mol) are stirred in DMF (50 ml) for 48 hours at room temperature. Water (100 ml) is added and the solution is extracted with ethyl acetate (4X50 ml). The ethyl acetate solution is washed with brine and dried (Na 2 SO 4). The crude product is purified by chromatography on a dry 200 ml silica column. Elution with ethyl acetate-hexane (2: 1) removed the less polar impurities. The product is eluted with ethyl acetate. Performance 1.8 g, '39%). The gum is dissolved in acetone (50 ml), acidified with 3.7 N HCl in ethyl acetate, and precipitated by the addition of diethyl ether (100 ml) to give the title compound as the hydrate of the dihydrochloride. Performance 1.4 g (25%); p.f. 190-193 ° C. Elemental Analysis for: C29H39N3 ° 2 '2HC1' H2 ° Calculated: C, 63.04; H, 7.84; N, 7.60. Found: C, 63.01; H, 7.76; N, 7.48.

Example 18 (+) - (2S) -1- (3-aza-bicichlor3.2.11 oct-8-yl) -4- f4- (lH-indol-4-yl) -pjperazin-1-ill -2-phenyl-butan -canvas The title compound is separated from the racemic base, 1- (8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- (lH-indol-4-yl) -piperazin-1 -yl] -2-phenyl-butan-1-one (see Example 5), by preparative CLAP as in Example 3 or by chiral synthesis to give the title product as the hydrochloride hemihydrate, mp. 227-230 ° C (decomposition). Elemental Analysis for: C29H3gN40 -HCl • 0.5 H20 Calculated: C, 69.37; H, 7.63; N, 11.16. Found: C, 69.44; H, 7.68; N, 11.09.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, property is claimed as contained in the following:

Claims (11)

1. A compound of the formula I R- N (N-A- (I) or its pharmaceutically acceptable salt, characterized in that X represents -CR2 = CR2- or - (CR2) -; m represents 0, 1 or 2; n represents 0, 1 or 2; p represents 0, 1, 2 or 3 and q represents 0, 1, 2 or 3; A is an alkylene chain of 1 or 2 carbon atoms optionally substituted by one or more lower alkyl groups, R is a mono or bicyclic aryl or heteroaryl radical, R1 is an aryl or arylalkyl lower radical and each R2 is independently hydrogen or lower alkyl .
2. 2. The compound according to claim 1, characterized in that (CH,) - CR-CH, represents (i) eleven, iii) a radical of the formula where p is 2 or 3 and q is 0, 1, 2, 3
3. 3. The compound according to claim 1 or 2, characterized in that A is -CH2CH2-.
4. . The compound according to any of claims 1 to 3, characterized in that R is 2- (lower alkoxy) phenyl, pyridyl or indolyl.
5. 5. The compound according to claim 1, characterized in that 1- '8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- (2-methoxy-phenyl) -piperazin-1-yl] - 2-phenyl-butan-1-one or i- (8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- (5-fluoro-2-methoxy-phenyl) iperazin-1 -yl] -2-phenyl-butan-1-one or 1- (8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- (lH-indol-4-yl) -piperazine -1-yl] -2-phenyl-butan-l-one or i- (3-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- (2-methoxy-5-trif luoromethyl) phenyl) -piperazin-1- ii] -2-phenyl-butan-1-one or 1- (3-aza-bicyclo [3.2.1] oct-3-yl) -2-phenyl-4- [4- ! c_ridin-2-yl) -piperazin-1-yl] -butan-1-one or 1- i 8-aza-bicyclo [3.2.1] oct-8-yl) -4- [4- < 3-methoxy-p? Ridin-2-yl) piperazin-1-yl] -2-phenyl-butan-1-one or 1- (3-aza-bicyclo [3.2.1] oct-8-yl) -2 phenyl-4- [4- (3-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] butan-1-one or 1- (8-aza-bicyclo [3.2.1] oct-8-yl) ) -2-phenyl-4- [4- (5-trifluoromethyl-pyridin-2-yl) -piperazin-1-yl] -butan-1-one or 4- [4- (2-methoxy-phenyl) -piperazine) 1-yl] -2-phenyl-1 (1,3,3-trimethyl-6-aza-bicyclo [3.2.1] oct-6-yl) butan-1-one or 1- (3-aza-bicyclo) [3.2.1] non-3-yl) -4- [4- (5-fluoro-2-methoxy-phenyl) -piperazin-1-yl] -2-phenyl-butan-1-one or 1- (3 -aza-bicyclo [3.2.2] non-3-yl) -4- [4- (lH-indol-4-yl) -piperazin-1-yl] -2-phenylbutan-1-one or 1- (3 -azabicyclo [3.2.2] non-3 -yl) -4- [4- (2-methoxyphenyl) piperazin-1-yl] -2-phenyl] -butan-1-one or l- (l, 3.3a , 4,7, 7a-hexahydroisoindol-2-yl) -4- [4- (2-methoxyphenyl) piperazin-1-yl] -2-phenylbutan-1-one or 4- [4 - (2-methoxyphenyl) piperazine - 1-il] -1- > , ectahydroisoindol-2-yl) -2-phenylbutan-1-one, or its pharmaceutically acceptable salt.
6. 6. A process for preparing a compound according to claim 1, which process is characterized in that it comprises (a) alkylating a compound of the formula / \ R-N NH \ _ / (ID (where R is as defined in claim 1) with an alkylating agent that provides the group (CH ^ - CR - CH2 (ffl) (wherein X, m, n, p, A, R1 and R2 are as defined in claim 1) or (b) acylating an amine of the formula (VII) (where X, m, n, p and R2 are as defined in claim 1) with an acid of the formula (VIII) (wherein A, R and R1 are as defined in claim 1) or with an acylation derivative thereof or (c) converting a base according to claim 1 into its pharmaceutically acceptable salt or converting the pharmaceutically acceptable salt into the free base.
7. 7. The process according to claim 6, characterized in that it comprises alkylating the compound of the formula (I) with an alkylating agent of the formula ZA- (IV) f where m, n, p, q, A, R1, and R2 -on as defined in claim 1 and Z is a leaving group) or alkylating the compound of the formula (II) with a msatured compound of the formula (V) (wherein X, m, n, p, R1 and R2 are as defined in claim 1) by means of a Michael reaction or alkylating the compound of the formula (II) by condensing it with an aldehyde of the formula (VI) (CH2) m- CR - ^ 2 (VI) (where X, m, n, p, A and R1 are as defined in claim 1 and B is a direct bond or a methylene group optionally substituted by 1 or 2 lower alkyl groups) in the presence of a reducing agent .
8. 8. The pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1 to 5 in association with a pharmaceutically acceptable carrier.
9. 9. The compound according to any of claims 1 to 5 for use as a pharmaceutical agent.
10. 10. The compound according to any of claims 1 to 5 for use as a 5HT1A antagonist.
11. 11. A method for the treatment of anxiety in a mammal, characterized in that it comprises administering to the mammal an effective amount of a compound according to any of claims 1 to 5.