BRPI0312175B1 - Compound, pharmaceutical composition, use of a compound - Google Patents

Abstract

"compound, pharmaceutical composition, use of a compound, method of treatment and method of reducing morbidity and mortality associated with overweight." The present invention relates to new arylalkyl tetracyclic indoles, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, the novel intermediates described herein and the pharmaceutical compositions. containing them. The present invention particularly relates to novel arylalkyl tetracyclic indoles having the general formula (I), their derivatives, their analogs, their tautomeric forms, their isomeric stereos, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, and the novel ones. intermediates described herein and to pharmaceutically acceptable compositions containing them. The present invention also relates to the process (s) for preparing such compound (s) having the general formula (i), compositions containing effective amount (s) of such compound and the use of such compound. / composition in therapies.

Description

Field of the Invention The present invention relates to novel tetracyclic arylalkyl indoles, their derivatives, their analogs, their tautomeric forms, their stereo isomers, their polymorphs, their pharmaceutically acceptable salts, and the like. their pharmaceutically acceptable solvates, their novel intermediates described herein and the pharmaceutically acceptable compositions containing them. General Formula (I) The present invention also relates to the process for the preparation of compounds having the general formula (I), its derivatives, its analogs, its tautomeric forms, its stereo isomers, its geometric forms, its N-oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their novel intermediates described herein and the pharmaceutically acceptable compositions containing them.

The compounds having the general formula (I) according to the present invention are 5-HT (serotonin) bandages for example agonists and antagonists.

Accordingly, compounds having the general formula (I) according to the present invention are useful for the treatment of diseases in which modulation of 5-HT (serotonin) activity is desired. More specifically, the compounds according to the present invention are useful in the treatment and / or prophylaxis of psychosis, paraphenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine and headache, depression, drug addiction, disorders. seizures, personality disorders, hypertension, autism, post traumatic stress syndrome, alcoholism, panic attacks, obsessive and compulsive disorders, and sleep disorders.

Compounds having the general formula (I) according to the present invention are also useful for treating the psychotic, affective, vegetative and psycho-motor symptoms of schizophrenia and the extra-pyramidal motor side effects of other antipsychotic drugs.

The compounds having the general formula (I) according to the present invention are also useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's chorea and chemotherapy-induced vomiting.

Compounds having the general formula (I) according to the present invention are also useful in modulating eating behavior and thus are useful in reducing morbidity and mortality associated with overweight. Background of the Invention Many diseases of the central nervous system are influenced by the neurotransmitter, adrenergic, dopaminergic and serotenergic systems. Serotonin has been implicated in a number of diseases and conditions which originate from the central nervous system, including diseases and conditions related to sleep, eating, pain perception, body temperature control, blood pressure control. blood pressure, depression, anxiety, schizophrenia and other body states. (References: Fuller, RW, Drugs Acting on Serotonergic Neuronal Systems, Biology of Serotonergic Transmission. John Wiley & Sons Ltd. (1982), 221-247; Boullin DJ, Serotonin in Mental Abnormalities (19878), 1, 316; Barchas J et al., Serotonin and behavior (1973)). Serotonin also plays an important role in peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contraction, secretion, and electro physiological effects.

Due to the widespread distribution of serotonin within the body, there is much interest and use in drugs that affect serotonergic systems. In particular, compounds which have specific receptor agonism and / or antagonism for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntington's chorea, and chemotherapy-induced vomiting (References: Gershon MD et al., The peripheral actions of 5-Hydroxitryptamine (1989) , 246; Saxena PR et al., Journal of Cardiovascular Pharmacology (1990), supplement 7, 15). The major serotonin receptor class (5-HT 1-7) contains fourteen to eighteen separate receptors that have been formally classified (References: Glennon et al., Neuroscience and Behavioral Reviews (1990), 14, 35 and Hoyer D. et al, Pharmacol (1994), 46, 157-203). Newly discovered information regarding subtype identity, distribution, structure and function suggests that it is possible to identify innovative subtype-specific agents having an improved therapeutic profile as fewer side effects. The 5-HT 6 receptor was identified in 1993 (References: Monsma et al., Mol. Pharmacol. (1993), 43, 320-327 and Ruat M. et al., Biochem. Biophys. Res. Com. (1993 ), 193, 269-276). Several atypical antidepressants and antipsychotics bind to the 5-HT 6 receptor with a high affinity and this binding may be a factor in its activity profile (References: Roth et al. J. Pharm. Exp. Therapeut. (1994), 268, 1403-1410, Sleight et al., Exp. Opinion, Ther Patents (1998), 8, 1217-1224; Bourson et al., Brit J. Pharmacol. (1988), 125, Boess et al, Mol. Pharmacol., 1998, 54, 577-583, Sleight et al., Brit. J. Pharmacol. (1998), 124, 556-562). In addition, the 5-HT 6 receptor has been linked to generalized stress and anxiety states (References: Yoshioka et al., Life Sciences (1998). 17/18, 1472-1477). Together these studies and observations suggest that 5-HT 6 receptor antagonizing compounds will be of use in the treatment of various central nervous system disorders. U.S. Patent No. 4,839,377 and U.S. Patent No. 4,855,314 refer to 5-substituted 3-aminoalkyl indoles. These compounds are said to be useful for treating migraine. British Patent No. 2,035,310 relates to 3-aminoalkyl-1H-indole-5-thioamides and carboxamides. The compounds are said to be useful in treating hypertension, Raymond's disease and migraine. European patent application published under No. 303,506 relates to 3-polyhydropyridyl-5-substituted-1H-indoles. The compounds are said to have β 1 receptor agonists. 5-HT 1 and vessel constricting activity and are useful in treating migraine. European patent application published under No. 354,777 relates to N-piperidineylindolylethyl alkane sulfonamide derivatives. The compounds are said to be 5-HT 1 receptor agonists and have vasoconstrictor activity and are useful in treating headache pain. European patent application published under No. 438,230 relates to 5-membered substituted indole hetero aromatic compounds. The compounds are said to have similar 5-HT 1 receptor agonist activity and are useful in the treatment of migraine and other disorders for which a selective receptor agonist is indicated. European patent application published under No. 313,397 relates to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, crowded headache and headache associated with vascular disorders. These compounds are also said to have exceptional receptor agonism similar to 5-HT1. International patent application published under No. WO 91/18897 refers to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, crowded headache and headache associated with vascular disorders. These compounds are also said to have an exceptional receptor agonism similar to 5-HT 1. European patent application published under No. 457,701 refers to aryloxy amino derivatives as having a high affinity for 5-HT 1 receptors. D of serotonin. These compounds are said to be useful for treating diseases related to serotonin receptor dysfunction, e.g. migraine. European patent application published under No. 497,512 A2 relates to a class of imidazole, triazole and tetrazole derivatives which are selective 5-HT 1 receptor selective agonists. These compounds are said to be useful for the treatment of migraine and associated disorders. International patent application published under No. WO 93/0086 describes a series of tetrahydrocarbazole derivatives as 5-HT 1 receptor agonists useful for treating migraine and related conditions. International patent application published under No. WO 93/23396, refers to fused imidazole and triazole derivatives as 5-HT 1 receptor agonists for the treatment of migraine and other disorders.

Schoeffter P. et al. Refer to methyl 4- {4- [4- (1,1,3-trioxo-2H-1,2-benzoisothiazol-2-yl) butyl] -1-piperazinyl} -1H- indole-3-carboxylate as a selective antagonist for the 5-HT1A receptor in his article "SDZ216-525, Selective and Potent 5-HT1A Antagonist Receptor" European Journal of Pharmacology, 244, 251-257 (1993). International patent application published under No. WO 94/06769, refers to 2-substituted-4-piperazine benzothiophene derivatives which are 5-HT1A and 5-HT1D serotonin receptor agents useful in treating anxiety. , depression, migraine, stroke, angina and hypertension.

SUMMARY OF THE INVENTION The present invention relates to new arylalkyl tetracyclic indoles, their derivatives, their analogs, their tautomeric forms, their stereo isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their novel intermediates described herein and to pharmaceutically acceptable compositions containing them.

More particularly, the present invention relates to new arylalkyl tetracyclic indoles having the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereo isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their novel intermediates described herein and the pharmaceutically acceptable compositions containing them and the use of these compounds in medicine. General Formula (I) wherein R 0 is either hydrogen or a linear or branched (C 1 -C 6) alkyl, R 1 / R 2, R 3, R 4 / R 5 / R 6 / R 7, Re / 1 9 / R 5 Ru 6 R-12 may be the same or different and each independently represent hydrogen, halogen, peraloalkyl, amino, substituted or unsubstituted groups such as (C1-C12) alkyl, (C3-C7) cycloalkyl, (C1-C12) alkoxy ), (C3 -C7) cycloalkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaralkyl, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylaminoalkylalkylalkylaminoalkylaminoalkylaminoalkylaminoalkyl , linear or branched carboxylic acid and derivatives thereof. R 13 and R 14 may be the same or different and each independently represents hydrogen, substituted or unsubstituted groups such as (C 1 -C 12) alkyl, (C 2 -C 12) alkenyl, (C 3 -C 7) cycloalkyl, (C 3 -C 7) cycloalkenyl ), bicycloalkyl, bicycloalkenyl, aryl, straight or branched aralkyl, optionally R 13 and R 14 together with the nitrogen atom, may form a 3, 4, 5, 6, or 7 membered heterocyclic ring into which the ring may be substituted in addition, and it may have one, two or three double bonds or "additional hetero atoms" as defined above, and "n" is an integer ranging from 1 to 6. It is preferred that "n" is of 1 to 4. The carbon chains which "n" represents may be either linear or bifurcated. The Partial List of such compounds having the general formula (I) is as follows: 11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole hydrochloride salt; 2-chloro-1- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole maleic acid salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole D, L- malic acid salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole oxalate salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-chloro-11- (2-N, N-diethylaminoethyl) -6H-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2-N, N-diethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-chloro-11- (2- N -cyclopropyl-N-methylaminoethyl) -6H-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2- N -cyclopropyl-N-methylaminoethyl) -6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -2-methyl-6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -2-methoxy-6H-isoindolo [2,1-a] indole; 2-bromo-11- (2-N, N-diethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-bromo-11- (2-N-methyl-N-cyclopropylaminoethyl) -6H-isoindolo [2,1-a] indole; 4-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 3,4-dichloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 1-chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6H-isoindolo [2,1-a] indole; 3-chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6H-isoindolo [2,1-a] indole; 3-chloro-11 - [(2-N-methylamino) ethyl] -4-methyl-6H-isoindolo [2,1-a] indole; 3-chloro-11 - [(2-N-methylamino) ethyl] -2-methoxy-6H-isoindolo [2,1-a] indole; 3-chloro-11 - [(2-N-methylamino) ethyl] -2-sulfoamido-6H-isoindolo [2,1-a] indole; 3-iodo-11 - [(2-N-methylamino) ethyl] -2-methoxy-6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -4-trifluoromethyl-6H-isoindolo [2,1-a] indole; 2,4-difluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 11- (2-pyrrolidin-1-ylethyl) -6H-isoindolo [2,1-a] indole; 2-bromo-11- (2-pyrrolidin-1-ylethyl) -6H-isoindolo [2,1-a] indole; 11- (2- (piperidin-1-yl) ethyl) -6H-isoindolo [2,1-a] indole; 11- (2- (4-methylapiperazine-1-yl) ethyl) -6H-isoindolo [2,1-a] indole; 11- (3- (pyrrolidin-1-yl) -1-hydroxyprop-1-yl) -6H-isoindolo [2,1-a] indole; 2-bromo-11- (3- (piperidin-1-yl) -1-hydroxyprop-1-yl) -6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -4-ethyl-6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylamino-1-hydroxyethyl) -6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -4-methoxy-6H-isoindolo [2,1-a] indole; 2-bromo-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 4-bromo-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 4-fluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 2-bromo-11- (2- (4-methylapiperazine-1-yl) ethyl) -6H-isoindolo [2,1-a] indole; and their stereoisomers, their N oxides, their polymorphs, their salts and their pharmaceutically acceptable solvates. The present invention also provides for some useful bioactive metabolites of the compounds having the general formula (I).

Compounds having the general formula (I) according to the present invention are useful in the treatment and / or prophylaxis of a condition in which modulation of 5-HT activity is desired. The present invention provides for the use of compounds having the general formula (I) according to the above for the manufacture of medicaments for potential use in the treatment and / or prophylaxis of certain CNS disorders such as anxiety, depression, disorders. seizures, obsessive compulsive disorders, migraine and headaches, cognitive memory disorders eg Alzheimer's disease and cognitive decline related to old age, attention deficit disorder / hyperactivity syndrome, personality disorders, psychosis, paraphenia, depression psychotic, mania, schizophrenia, schizophreniform disorders, abstinence from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, panic attacks, sleep disorders (including Circadian rhythm disorders) and also disorders associated with spinal trauma and / or head injuries such as hydrocephalus. The compounds of the invention are expected to be of use in the treatment of mild cognitive impairment and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's chorea.

The compounds of the invention are also expected to be of use in the treatment of certain gastrointestinal (GI) disorders such as bowel irritation syndrome or chemotherapy-induced emesis.

The compounds of the present invention are also expected to be useful in modulating eating behavior and these compounds may also be used to reduce morbidity and mortality associated with overweight. The present invention provides a method for treating a human or animal subject subject to certain CNS disorders such as anxiety, depression, seizure disorders, obsessive compulsive disorders, migraine and headaches, cognitive memory disorders e.g. Alzheimer's disease and cognitive decline related to old age, attention deficit disorder / hyperactivity syndrome, personality disorders, psychosis, paraphenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, abstinence from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines, panic attacks, sleep disorders (including Circadian rhythm disorders) and also disorders associated with spinal trauma and / or head injuries such as hydrocephalus. The compounds of the invention are expected to be of use in treating mild cognitive impairments and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and Huntington's chorea. The present invention also provides a method for modulating 5-HT receptor function something that is desired in some cases. The present invention also includes isotopically identified compounds which are identical to those defined in general formula (I), except that one or more atoms are replaced by an atom having an atomic mass or a different mass number at from the atomic mass or mass number usually found in nature. Examples of isotopes which may be incorporated into the compounds of the invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, bromine and mTecnitium isotopes, exemplified by 2H, 3H , 11C, 13C, 14C, 13N, 15N, 150, 18F, 99mTc, 31P, S, 1231 and 1251. The compounds of the present invention and the pharmaceutically acceptable salts and prodrugs of said compounds containing the above mentioned isotopes and / or other isotopes of other atoms are within the scope of the present invention.

The isotopically identified compounds of the present invention are useful in drug and / or substrate distribution in tissues and in occupancy testing of a particular target. For example, isotopically identified compounds are particularly useful in single-photon emission computed tomography and positron emission tomography.

An effective amount of a compound having the general formula (I) or salt thereof is used for the manufacture of the medicaments of the present invention, together with conventional pharmaceutical adjuvants, carriers and additives. The present invention also relates to a pharmaceutical composition for the treatment and / or prophylaxis of disorders, as a condition in which 5-HT modulation is desired in a mammal, preferably a human, comprising: a. a pharmaceutically acceptable carrier, b. a compound having the general formula (I) as defined above, and c. a 5-HT re-ingestion inhibitor and / or pharmaceutically acceptable salt thereof; wherein the amounts of each of the active compounds (a compound having the general formula (I) and a 5-HT re-ingestion inhibitor) are such that the combination is effective in treating such a condition. The present invention also relates to a method of treating and / or prophylaxing disorders, as a condition in which 5-HT modulation is desired in a mammal, preferably a human, comprising: a. a pharmaceutically acceptable carrier, b. a compound having the general formula (I) as defined above, and c. a 5-HT re-ingestion inhibitor and / or pharmaceutically acceptable salt thereof; wherein the amounts of each of the active compounds (a compound having the general formula (I) and a 5-HT re-ingestion inhibitor) are such that the combination is effective in treating such a condition. The present invention also relates to a pharmaceutical composition for the treatment and / or prophylaxis of disorders, a condition in which 5-HT and / or melatonin modulation is desired in a mammal, comprising: a. a pharmaceutically acceptable carrier; B. a compound having the general formula (I) as defined above, and c. a serotonergic or melatonergic ligand, or pharmaceutically acceptable salts thereof; wherein the amounts of each of the active compounds (a compound having the general formula (I) and a serotonergic ligand) is such that the combination is effective in treating such a condition. The present invention also relates to a method for the treatment and / or prophylaxis of disorders, a condition in which 5-HT and / or melatonin modulation is desired in a mammal, comprising: a. a pharmaceutically acceptable carrier; B. a compound having the general formula (I) as defined above, and c. a serotonergic or melatonergic ligand, or pharmaceutically acceptable salts thereof; wherein the amounts of each of the active compounds (a compound having the general formula (I) and a serotonergic or melatonergic ligand) is such that the combination is effective in treating such a condition. The present invention also relates to a process for the preparation of the above-mentioned novel compound, its derivatives, analogs, tautomeric forms, stereoisomers thereof, geometric forms, N-oxides, polymorphs, pharmaceutically acceptable salts thereof, pharmaceutically acceptable solvates thereof, their novel intermediates described herein and the pharmaceutical compositions containing them. Detailed Description of the Invention The present invention relates to new arylalkyl tetracyclic indoles, their derivatives, their analogs, their tautomeric forms, their stereo isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their novel intermediates described herein and to pharmaceutically acceptable compositions containing them.

More particularly, the present invention relates to new arylalkyl tetracyclic indoles having the general formula (I), their derivatives, their analogs, their tautomeric forms, their stereo isomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their novel intermediates described herein and the pharmaceutically acceptable compositions containing them and the use of these compounds in medicine. General Formula (I) wherein R 0 is either hydrogen or a linear or branched (C 1 -C 2) alkyl, R 1, R 2> R 3 R R 4, R 5 R 6 I R 9 R 1 R 1 R 1 R 1 and R 12 may be the same or different and each independently represent hydrogen, halogen, peraloalkyl, amino, substituted or unsubstituted groups such as (C1-C12) alkyl, (C3-C7) cycloalkyl, (C1-C12) alkoxy, (C3-C7) cycloalkoxy ), aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaralkyl, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, ariland.no, diarylamino, aralkylamino, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, alkylalkylaminoalkyl, dialkylamino R13 and R44 may be the same or different and each independently represents hydrogen, substituted or unsubstituted groups such as (C1-C12) alkyl, (C2-C12) alkenyl, (C3-C7) cycloalkyl, cycloalk C3 -C7 enyl, bicycloalkyl, bicycloalkenyl, aryl, straight or branched aralkyl, optionally R13 and R14 together with the nitrogen atom, can form a 3-, 4-, 5-, 6-, or 7-membered heterocyclic ring in which the ring may be substituted in addition and may have one, two or three double bonds or "additional hetero atoms" as defined above, and "n" is an integer ranging from 1 to 6. It is preferred that "n" is from 1 to 4. The carbon chains which "n" represents may be either linear or bifurcated.

Suitable groups represented by R 1, R 2, R 3, R 4, R 5, R 5, R 7, R 7, R 9, Rio, R 11 and R 12 may be a halogen atom such as fluorine, chlorine, bromine or iodine; peraloalkyl particularly C 1-6 alkylamino such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like; substituted or unsubstituted (C1-C12) alkyl group, straight or branched (C1-C8) alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl n-pentyl, iso-pentyl, hexyl, isohexyl, heptyl, octyl and the like; C3 -C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cycloalkyl group may be substituted; C1 -C4 alkoxy, especially C1 -C6 alkoxy such as methoxy, ethoxy, propyloxy, butyloxy, isopropyloxy and the like, which may be substituted; the C3 -C7 alkoxy cyclo group such as cyclopropyloxy, cyclobutyloxy, cyclopenyloxy, cyclohexyloxy, cycloheptyloxy and the like, the cycloalkoxy group may be substituted; the aryl group such as phenyl or naphthyl, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl, C6H5CH2CH2CH2, naphthylamethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as. CH3C6H4CH2, HA1-C6H4CH2, CH3OC5H4CH2, CH3OC6H4CH2CH2 and the like; aralkoxy group such as benzyloxy, phenethyloxy, naphthylamethyloxy, phenylpropyloxy and the like, the aralkoxy group may be substituted; heterocyclyl groups such as aziridinyl, pyrrolidinyl, morpholinyl, piperidinyl, piperazinyl and the like, the heterocyclyl group may be substituted; the heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; (C1 -C6) alkyl heterocycle, such as pyrrolidinylalkyl, piperidinylalkyl, morpholinyl alkyl, thiomorpholinylalkyl, oxazolinylalkyl and the like, the (Cx-Cg) alkyl heterocycle group may be substituted; the heteroaralkyl group such as furanylamethyl, methyl pyridinyl, oxazolylamethyl, oxazolylethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy, heteroaralkoxy, heterocycloalkoxy, wherein the halo of heteroaryl, heteroaralkyl, heterocycloalkyl and heterocyclylalkyl are as previously defined and may be substituted; acyl groups such as acetyl, propionyl or benzoyl, the acyl group may be substituted; the acyloxy group such as CH3COO, CH3CH2COO, CeHsCOO and the like which may be optionally substituted, the acylamino group such as CH3CONH, CH3CH2CONH, C3H7CONH, C6H5CONH which may be substituted, the (C1 -C6) monoalkylamino group CH 3 NH, C 2 H 5 NH, C 3 H 7 NH, C 5 H 13 NH and the like, which may be substituted, the (C 1 -C 6) dialkylamino group such as N (CH 3) 2, CH 3 (C 2 Hs) N and the like, which may be substituted; arylamino group such as C6H5NH, CH3 (C6H5) N, C6H4 (CH3) NH, NH-C6H4-HA1 and the like which may be substituted; arylalkylamino group such as C 6 H 5 CH 2 NH, C 6 H 5 CH 2 CH 2 NH, C 6 H 5 CH 2 NCH 3 and the like, which may be substituted; hydroxy (C1 -C6) alkyl which may be substituted; amino (C1 -C6) alkyl which may be substituted; mono (C 3 -C 6) alkylamino (C 1 -C 6) alkylamino, di (C 1 -C 6) alkylamino (C 1 -C 6) alkyl groups which may be substituted, the alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like which may be substituted; the aminocarbonylamino group; the (C1 -C6) alkylaminocarbonylamino group; carboxylic acid and derivatives thereof such as starches such as CONH2, alkylaminocarbonyl such as CH3NHCO, (CH3) 2NCO, C2H5NHCO, (C2H5) 2NCO, arylaminocarbonyl such as PhNHCO, NaphthylNHCO and the like, aralkylaminocarbonyl such as PhCH2NHCO, PhCH2CHN group, PhCH2CHN, heteroarylaminocarbonyl carbonyl and heteroaryalkylamino in which heteroaryl groups are as defined above, heterocyclylaminocarbonyl in which the heterocyclyl group is as defined above, carboxylic acid derivatives such as esters, in which ester moieties are alkoxycarbonyl groups such as unsubstituted or substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylamethoxycarbonyl and the like, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group is as defined above, heterocycliccarbonyl in which the heterocycle is as defined above and these carboxylic acid derivatives may be substituted. R 13 and R 14 represent hydrogen, straight or branched substituted or unsubstituted (C 1 -C 2) alkyl such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, pentyl, hexyl, octyl and the like; (C 2 -C 12) alkanoyl such as acetyl, propanoyl and the like; the aryl group such as phenyl or naphthyl, the aryl group may be substituted; the C3 -C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cycloalkyl group may be substituted; suitable heterocyclic rings formed between R 13 and R 14 together with the "Nitrogen atom" may be such as pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, 1,2,3,4-tetrahydro-pyridinyl, imidazolyl, pyrimidinyl, piperazinyl, diazolinyl and the like; the heterocyclyl group may be substituted; the heteroaryl group such as pyridyl, imidazolyl, tetrazolyl and the like, the heteroaryl group may be substituted; (C1 -C6) alkyl heterocycle, such as pyrrolidinal alkyl, piperidinal alkyl, morpholine alkyl, thiomorpholinal alkyl, oxazolinal alkyl and the like, the (C1 -C6) alkyl heterocycle group may be substituted; the heteroaralkyl group such as furanomethyl, pyridinamethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy, heteroaralkoxy, heterocycloalkoxy, wherein the heteroaryl, heteroaralkyl, heterocycloalkyl and heterocyclylalkyl moieties are as defined above and may be further substituted.

In the case of compounds having the general formula (I) having an asymmetric carbon atom, the present invention relates to mixtures of form D, form L and form D, L- and in the case of a number of atoms of asymmetric carbon forms, the diastereomeric forms and the invention extend to each of these isomeric stereo forms and mixtures thereof including "racemates". Those compounds having the general formula (I) which have an asymmetric carbon and as a rule are obtained as "racemates" may be separated from each other by the usual methods, or any given isomer may be obtained by specific or asymmetric stereo synthesis. . However, it is also possible to employ an optically active compound from the beginning, a correspondingly optically active or diaestereomeric compound and then the final compound is obtained.

In the case of compounds having the general formula (I) in which tautomerism may occur, the present invention relates to all possible tautomeric forms and possible mixtures thereof.

In the case of compounds having the general formula (I) containing a geometric isomerism the present invention relates to all those geometric isomers.

Suitable pharmaceutically acceptable acid addition salts of the compounds having the general formula (I) which may be prepared by the above-mentioned base compounds according to the present invention are those which form non-toxic acid addition salts, include the following: pharmaceutically acceptable anion-containing salts such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, scarate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, palmoate and oxalate.

Suitable pharmaceutically acceptable base salts of the compounds having the general formula (I) which may be prepared by the above-mentioned acid compounds are those which form non-toxic base salts including the pharmaceutically acceptable cation-containing salts, such as lithium, sodium, potassium, calcium and magnesium, organic base salts such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like; salts of ammonia or substituted ammonia.

Pharmaceutically acceptable salts forming part of the present invention are intended to define but are not limited to the above list.

In addition, pharmaceutically acceptable salts of the compound of formula (I) may be obtained by converting derivatives which have tertiary amino groups to the corresponding quaternary ammonium salts in the methods known in the literature by the use of quaternizing agents. Possible quaternizing agents are, for example, alkyl halides such as methyl iodide, ethyl bromide and n-propyl chloride, including arylalkyl halides such as benzyl chloride or 2-phenylethyl bromide.

In addition to pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in purifying the compounds, preparing other salts, or identifying and characterizing the compounds or intermediates.

Pharmaceutically acceptable salts of the compounds having formula (I) may occur as solvates, such as with water, methanol, ethanol, dimethylformamide, such as ethyl acetate, and the like. Mixtures of such solvates may also be prepared. The source of such solvate may be from the crystallization solvent, inherent in the preparation or crystallization of the solvent, or accidentally to such solvent. Such solvates are within the scope of the present invention. The invention also encompasses pharmaceutically acceptable prodrugs of the compound having the general formula (I). A prodrug is a drug which has been chemically modified and may be biologically inactive at the site of action, but which may be degraded or modified by one or more enzymatic processes or other processes in vivo to parent form. This prodrug should have a different pharmacokinetic profile than that of the parent, allowing for easier absorption throughout the mucosal epithelium, better salt formation or solubility, and / or improved systemic stability (eg increased half life). of plasma). Typically, such chemical modifications include the following: 1. ester or starch derivatives which may be cleaved by esterase or lipase; 2. peptides which may be recognized by specific or non-specific protease; or 3. derivatives that accumulate at the site of action by membrane selection of a prodrug from a modified form of prodrug; or any combination of 1 to 3 above.

Conventional procedures for selecting and preparing suitable prodrug derivatives are described, for example, in H. Bundgard, Design of Prodrugs, (1985).

Compounds having the general formula (I) may be prepared by any of the methods described below. The present invention also provides processes for the preparation of compounds having the general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereo isomers, their geometric forms, their polymorphs, their pharmaceutically acceptable salts and their pharmaceutically acceptable solvates, their novel intermediates described herein, wherein R 1, R 2, R 3, R 4, R 5, R 5, R 7, R 6, R 9, Rio, R 11, R 12, R 13, R 14 and "n" are as defined above and may be prepared by any of the methods described below: Compounds having the general formula (I) may be prepared by cyclizing an intermediate of the formula (II) given below, wherein X is a halogen such as chlorine, bromine or iodine, R 0, R 1, R 2, R 3, R 1, R s, R 6, R 7, R s, R 9, R 10, R 11, R 12, R 14, "s" are as defined above using a derivative of Pd (0 ) or Pd (II) as a catalyst, for example triphenylphosphine pal tetrakis audio, (Bis-tri-o-tolylphosphine) palladium and the like; and thereafter if necessary: i) converting a compound having formula (I) into another compound having formula (I); and / or ii) remove any protecting group; and / or iii) forming a pharmaceutically acceptable salt, solvate, polymorph or prodrug.

This cyclization reaction can be accomplished using a variety of palladium catalysts. The reaction may be carried out in the presence of a base such as CH3COOK. This reaction may be performed in the presence of solvents such as THF, DMF, DMSO, DMA, DME, acetone and the like and preferably using dimethylacetamide. The inert atmosphere may be maintained by the use of inert gases such as N2, Ar or He. The reaction temperature may range from 50 ° C to 200 ° C based on the choice of solvent and preferably at a temperature of 160 ° C. The reaction time may range from 1 to 24 hours, preferably from 10 to 20 hours.

Compounds having the general formula (I) may be prepared by the reaction of a compound having the formula (III) given below, wherein Ro r R1 / R2 / R31 R4 r R5 r R6 / R7, R8j R9 R10 / R11 / R12 ® "n" are as previously defined, with a suitable alkylating agent such as R13 X or R14 X or XR13 R144X in successive steps or in one step, wherein X is a good leaving group such as halogen. hydroxyl and the like; and thereafter if desired or necessary to perform steps (i), (ii) and / or (iii) as described above. The reaction is preferably carried out in an inert organic solvent for the reaction conditions, such as acetone, THF or DHF and the like or mixtures thereof. Inert atmosphere can be maintained by the use of inert gases such as N2, Ar or He. The reaction may be affected in the presence of a base such as K2C03, Na2C03, TEA or mixtures thereof. The temperature reaction may range from 20 ° C to 200 ° C based on the solvent employed and preferably at a temperature ranging from 30 ° C to 150 ° C. The reaction time may range from 1 to 24 hours, preferably from 2 to 6 hours.

Compounds having the general formula (I) may be prepared by reacting a compound having the formula (IV) given below, wherein R0, R1, R2, R3 / R4, R51 R-6 / R7 '. Re and "n" are as previously defined, with formaldehyde and a compound having the formula (V) given below, NHR: 3R14 (V) wherein R13 and R14 are as previously defined; and thereafter if desired or necessary to perform steps (i), (ii) and / or (iii) as described above. The above reaction is preferably conducted at a temperature of 50 ° C to 150 ° C. The formaldehyde may be in the form of an aqueous solution, for example 40% of a formalin solution, or a polymeric form of formaldehyde such as paraformaldehyde or trioxymethylene. When such polymeric forms are used, a molar excess of mineral acid, for example hydrochloric acid, is added to regenerate the free aldehyde from the polymer. The reaction is preferably conducted in an inert organic solvent for the reaction conditions, such as methanol, ethanol or 3-methylabutanol and the like or a mixture thereof, and preferably using either acetone or DMF. The inert atmosphere may be maintained by the use of inert gases such as N2, Ar or He. The reaction temperature may range from 20 ° C to 150 ° C based on the choice of solvent and preferably a temperature ranging from 30 ° C to 100 ° C. The reaction time may range from 1 to 24 hours, preferably from 2 to 6 hours.

Compounds having the general formula (I) may be prepared from another compound having the formula (I) containing a side chain group (s) of -C (= O) by known methods. reduction to the corresponding C (OH, H) or -C (H, H) compound; and thereafter if desired or if necessary perform steps (i), (ii) and / or (iii) as described above.

Innovative intermediates having the general formula (II), their stereoisomers and their salts are represented as given below, wherein R 0, R 1, R 2, R 3, R 1, R 5, R 6, R 7, R s and "n" are as follows. previously defined. The present invention also provides processes for the preparation of intermediate having the general formula (IV) which comprises cyclizing the compounds having the formula (VIII), wherein R 1, R 4, R 4, R 5, R 6, R 7 and R 8 are as defined above; using a Pd (0) or Pd (II) derivative as a catalyst, for example palladium tetrakis triphenylphosphine, palladium (Bis-tri-tollylphosphine) and the like in a suitable solvent.

During any of the above synthetic sequences it may be necessary and / or desirable to protect sensitive or reactive groups on any of the related molecules. This can be accomplished by conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, Ed J. F. W. Mcomie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. For example, suitable protecting groups for the piperazine group include BOC, COCC13, COCF3. Protective groups can be removed according to standard procedures.

The protecting groups may be removed at a convenient subsequent stage using methods known in the art.

The compounds of the present invention may contain one or more asymmetric centers and therefore they also occur as stereo isomers. Stereo isomers of the compounds of the present invention may be prepared in one or more of the following ways: i) One or more of the reagents may be used in their optically active forms. ii) An optically pure catalyst or chiral ligands together with a metal catalyst may be employed in the reduction process. The metal catalyst may be rhodium, ruthenium, indium and the like. The chiral ligands may preferably be chiral phosphines (principles of Asymetric Synthesis, J.E. Baldwin Ed., Tetrahedron series, 14, 311-316). iii) The mixture of stereoisomers may be resolved by conventional methods such as the formation of diastereomeric salts with chiral or chiral amino acids, or chiral amino alcohol. The resulting mixture of diastereomers can then be separated by methods such as fractional crystallization, chromatography and the like, which are followed by an additional step of isolating the optically active product by hydrolyzing the derivative (Jacques et al., "Enantiomers, racemates and resolution ", Wiley Interscience, 1981). iv) The mixture of stereoisomers may be solved by conventional methods such as microbial solution, by dissolving the diastereomeric salts formed with chiral acids or chiral bases.

Chiral acids that may be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral bases which may be employed may be cinchona alkaloids, brucine or a basic amino acid such as lysine, arginine and the like.

Pharmaceutically acceptable salts forming part of the present invention may be prepared by treating the compound having formula (I) with 1-6 equivalents of a lithium, ammonia, substituted ammonium, sodium hydride base, sodium methoxide, sodium ethoxide, sodium hydroxide, potassium t-butoxide, calcium hydroxide, calcium acetate, calcium chloride, magnesium hydroxide, magnesium chloride and the like. Solvents such as water, acetone, ether, THF, methanol, ethanol, t-butanol, dioxane, isopropanol, isopropyl ether or mixtures thereof may be used. Organic bases such as lysine, arginine, methyl benzylamine, ethanolamine, diethanolamine, tromethamine, choline, guanidine and derivatives thereof may be used. Addition acid salts, wherever applied may be prepared by treatment with acids such as tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, salicylic acid, citric acid, ascorbic acid, benzene sulfonic acid, p-toluene sulfonic acid, hydroxynaphthoic acid, methane sulfonic acid, malic acid, acetic acid, benzoic acid, succinic acid, palmitic acid, oxalic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and the like in solvents such as water, alcohols ethers, ethyl acetate, dioxane, DMF or a low alkyl ketone such as acetone, or mixtures thereof.

Different polymorphs may be prepared by crystallization of compounds having the general formula (1) under different conditions such as different solvents or solvent mixtures in varying proportions for recrystallization, by various ways of crystallization such as slow cooling, rapid cooling. either a very rapid cooling or a gradual cooling during crystallization. Different polymorphs can also be obtained by heating the compound, melting the compound and solidifying by gradual or rapid cooling, heating or melting under vacuum or under an inert atmosphere and cooling under either vacuum or inert atmosphere. The various polymorphs can be identified by either one or more of the following techniques such as differential scanning calorimeter, X-ray powder diffraction, IR spectroscopy, solid probe NMR spectroscopy and thermal microscopy.

Another aspect of the present invention comprises a pharmaceutical composition containing at least one of the compounds having the general formula (I), its derivatives, its analogs, its derivatives, its tautomeric forms, its stereo isomers, its geometric forms, its polymorphs, its salts pharmaceutically acceptable solvents thereof, pharmaceutically acceptable solvates thereof as an active ingredient, together with the pharmaceutically employed carriers and adjuvants and the like.

The pharmaceutical compositions of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers. Accordingly, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g. intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The dose of active compounds may vary depending on factors such as the route of administration, the age and weight of the patient, the nature of the severity of the disease being treated and similar factors. Therefore, any of the references cited herein with respect to a pharmacologically effective amount of the compounds having the general formula (I) refer to the factors mentioned above.

For oral administration, the pharmaceutical compositions may be in the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinated cornstarch, polyvinylpyrrolidone or hydroxypropyl methylcellulose) ; fillers (e.g. lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrators (e.g. potato starch or sodium starch glycolate); or wetting agents (e.g. lauryl sodium sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may be in the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicles prior to use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose, or hydrogenated edible fats); emulsifying agents (eg, ■ lecithin or acacia); non-aqueous vehicles (eg almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid).

For oral administration, the composition may be in the form of conventionally shaped tablets or lozenges.

The active compounds of the invention may be formulated for parenteral injection administration, including using conventional catheterization or infusion techniques. Formulations for injection may be presented in unit dosage form, for example in ampoules or in multiple dose containers with an added condom. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for reconstitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

The active compounds of the invention may also be formulated as rectal compositions such as suppositories or retention enemas, for example, containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal or inhalation delivery, the active compounds of the invention are conveniently delivered as an aerosol spray from a pressurized container or nebulizer, or from a capsule using an inhaler or insufflator. . In the case of a pressurized aerosol, a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas and the dosage unit may be determined by the proportion of a valve to release a metered amount. The medicament for the pressurized container or nebulizer may contain a solution or suspension of the active compound while the capsule itself should be in powder form. Capsules and cartridges (made from, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The proposed dose of the active compounds according to the present invention for any oral, parenteral, nasal or buccal administration to an average adult human being for the treatment of the above conditions is 0.1 to 200 mg of the active ingredient per dose unit which should be given, for example, 1 to 4 times a day.

Formulations for treating the conditions referred to above (e.g., migraine) for an average adult human are preferably arranged such that each of the metered doses or each aerosol spray contains 20 μg to 1000 μ9 of the compound of the invention. . The general daily dose with an aerosol will be within the range of 100 μg to 10 mg. The ministry may occur several times a day, for example, 2, 3, 4, or 8 times, giving as an example 1, 2 or 3 doses each time.

The affinities of the compound of the present invention for the various serotonin receptors are evaluated using standard Radioligand binding assays and are described herein.

Radioligand binding assays for various 5-HT receptor subtypes: i) 5HT1A Test Materials and Methods: Receptor Source: Human radioligand-expressed HEK-293 cells: [3H] -8- OH-dPAT (221 Ci / mmol) Final Binding Concentration - [0.5 nM] Reference Compound: 8-OH-dPAT Positive Control: 8-OH-dPAT Incubation Conditions: Reactions are performed in 50 mM TRIS-HCl ( pH 7.4) containing 10 mM MgSO4, 0.5 mM EDTA and 0.1% ascorbic acid at room temperature for 1 hour. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained by the filters is determined and compared for the control of values for the correctness of any interaction of the test compound with the 5HT1A binding site. Reference Literature: • Hoyer D., Engel G., et al. Molecular Pharmacology of 5HTi and 5-HT2 Recognition Sites in Rat and Pig Brain Membranes: "Radioligand" Binding Studies with [3H] -5HT, [3H] -8-OH-dPAT, [1251] -iodocyanopindolol, [3H] -mesulergine and [3H] -Ketanserin.

Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications. * Schoeffter P. and Hoyer D. How Selective is GR 43175?

Interactions with Functional 5-HT1A, 5HT1B, 5-HT1c, and 5-HT1D Receptors. Naunyn-Schmiedeberg's Arch. Pharmac. 340: 135-138 (1989) with modifications. ii) 5HTib Test Materials and Methods: Receptor Source: Rat Striated Membrane "Radioligand [125I] Iodocianopindolol (2200 Ci / mmol) Final Binding Concentration - [0.15 nM] Non-Specific Determinant: serotonin - [10 μΜ] Reference: serotonin Positive Control: serotonin Incubation conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.4) containing 60 mM (-) of isoproterenol at 37 ° C for 60 minutes.The reaction is terminated by rapid vacuum filtration. over the fiberglass filters The radioactivity contained over the filters is determined and compared to control values for the accuracy of any interaction of the test compound with the 5HT1A binding site.

Reference Literature: * Hoyer D., Engel G., et al. Molecular Pharmacology of δΗΤχ and 5-HT2 Recognition Sites in Rat and Pig Brain Membranes: "Radioligand" Binding Studies with [3H] -5HT, [3H] -8-OH-dPAT, [125I] -iodocyanopindolol, [3H] -mesulergine and [3H] -Ketanserin. Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications. * Schoeffter P. and Hoyer D. How selective is GR 43175?

Interactions with Functional 5-HT1A, 5HT1B, 5-HT1c, and 5-ΗΊτ Receptors. Naunyn-Schmiedeberg's Arch. Pharmac. 340: 135-138 (1989) with modifications. iii) Tests for 5HTip Materials and Methods: Receptor Source :: Human Cortex "Radioligand [3H] 5-carboxamidotriptamine (20-70 Ci / mmol) Final Binding Concentration - [2.0 nM) Non-specific determinant: 5-carboxamidotriptamine (5 -cT) - [1.0 μΜ] Reference compound: 5-carboxamidotriptamine (5-cT) Positive control: 5-carboxamidotriptamine (5-cT) Incubation conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.7) containing 4 mM CaC12, 100 nM 8-OH-dPAT, 100 nM Mesulergine, 10 µM Pargillin and 0.1% ascorbic acid at 25 ° C for 60 minutes The reaction is terminated by rapid vacuum filtration over filter filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT1D binding site.

Reference Literature: • Waeber C., Schoeffter, Palaces J.M. and Hoyer D. Molecular Pharmacology. of the 5-HTw Recognition Sites: "Radioligand" Binding Studies in Human, Pig, and Calf Brain Membranes. Naunyn-Schmiedeberg's Arch. Pharmacol. 337: 595-601 (1988) with modifications.

iv) Tests for 5HT2A

Materials and Methods: Receptor Source :: Radioligand Human Cortex: [3H] Ketanserine (60-90 Ci / mmol) Final Binding Concentration - [2.0 nM] Non-Specific Determinant: Ketanserine - [3.0 μΜ] Reference Compound: Ketanserin Positive Control: Ketanserin Incubation Conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.5) at room temperature for 90 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT2A binding site. Reference Literature: * Leysen J.E., Niemegeers C.J., Van Nueten J.M. and Laduron Ρ. Μ [3Η] Ketanserin: A Selective Tritiated Ligand for serotonin 2 Receptor Binding Sites. Mol. Pharmacol. 21: 301-314 (1982) with modifications. * Martin, G. R. and Humphrey, P. P. A. Classification Review: Receptors for 5-HT: Current Perspectives on Classification and Nomenclature. Neuropharmacol. 33 (3/4): 261-273 (1994). v) Tests for 5HT2C Materials and Methods: Recipient Source :: "Radioligand" Pig Choroid Plexus Membranes: [3H] Mesulergine (50-60 Ci / mmol) Final Binding Concentration - [1.0 nM] Non-Specific Determinant: serotonin - [100 μΜ] Reference compound: Mianserin Positive control: Mianserin Incubation conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.5) at room temperature for 90 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT2A binding site. Reference Literature: * A. Pazos, D. Hoyer, and J. Palacios. The Binding of Serotonergic Ligands to the Poreine Choroid Plexus: Characterization of a New Type of Serotonin Recognition Site. Eur. Jrnl. Pharmacol. 106: 539-546 (1985) with modifications. Hoyer, D., Engel, G., et al. Molecular Pharmacology of 5HT2 and 5-ΗΪ2 Recognition Sites in Rat and Pig Brain Memhranes: "Radioligand" Binding Studies with [3HJ-5HT, [3H] -8-OH-dPAT, [125I] -iodocyanopindolol, [3Η] -mesulergine and [3HJ -Ketanserin.

Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications. vi) Tests for 5HT3 Materials and Methods: Receptor Source :: N1E-115 "Radioligand" Cells: [3H] -GR 65630 (30-70 Ci / mmol) Final Binding Concentration - [0.35 nM] Non-specific determinant: MDL-72222 - [1.0 μΜ] Reference Compound: MDL-72222 Positive Control: MDL-72222 Incubation Conditions: Reactions are performed in 20 mM HEPES (pH 7.4) containing 150 mM NaCl at 25 ° C for 60 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT3 binding site.

Reference Literature: * Lummis S.C. R., Kilpatrick G.J. Characterization of 5HT3 Receptors in Intact N1E-115 Neuroblastoma Cells. Eur. Jrnl. Pharmacol. 189: 223-227 (1990) with modifications. * Hoyer D. and Neijt H. C. Identification of Serotonin 5-HT3 Recognition Sites in Membranes of N1E-115 Neuroblastoma Cells by "Radioligand" Binding. Mol. Pharmacol. 33: 303 (1988). * Tyers Μ. B. 5-HT3 Receptors and the Therapeutic Potential of 5HT3 Receptor Antagonists. Therapie 4.6: 431-435 (1991). vii) Tests for 5HT4 Materials and Methods: Receptor Source :: Radioligand Guinea Pig Striatal Membranes: [3H] GR-113808 (30-70 Ci / mmol) Final Binding Concentration - [0.2 nM] Non-Specific Determinant : serotonin (5-HT) - [30 μΜ] Reference compound: serotonin (5-HT) Positive control: serotonin (5-HT) Incubation conditions: Reactions are performed in 50 mM HEPES (pH 7.4) at 370 ° C for 60 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT14 binding site.

Reference Literature: • Grossman Kilpatrick, C., et al. Development of a "Radioligand" Binding Tests for 5HT4 Receptors in Guinea Pig and Rat Brain. Brit. J Pharmco. 109: 618-624 (1993). viii) Tests for 5HT5a Materials and Methods: Recipient Source :: Re-Human Combinant Expressed in ΗΕΚ 293 "Radioligand" Cells: [3H] LSD (60-87 Ci / mmol) Final Binding Concentration - [1.0 nM] Determinant No Specific: Methiotepine Mesylate - [1.0 μΜ] Reference Compound: Methiotepine Mesylate Positive Control: Methiotepine Mesylate Incubation Conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgSO4, 0.5 mM EDTA a 37 ° C for 60 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared for the control of values for the correctness of any interaction of the test compound with the 5HT5A binding site.

Reference Literature: * Rees S., et al. FEBS Letters, 355: 242-246 (1994) with modifications ix) Tests for 5ΗΤβ Materials and Methods: Receptor Source :: Re Human Combinant Expressed in HEK293 "Radioligand" Cells: [3H] LSD (60-80 Ci / mmol ) Final Binding Concentration - [1.5 nM] Non-Specific Determinant: Methiotepine Mesylate - [0.1 μΜ] Reference Compound: Methiotepine Mesylate Positive Control: Methiotepine Mesylate Incubation Conditions: Reactions are performed.in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl2, 0.5 mM EDTA for 60 minutes at 37 ° C. The reaction is terminated by rapid vacuum filtration over glass fiber filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT6 binding site.

Reference Literature: * Monsma F. J. Jr., et al., Molecular Cloning and Expression of Novel Serotonin Receptor with High Affinity for Tricyclic Psychotropic Drugs. Mol. Pharmacol. (43): 320-327 (1993). x) Tests for 5-HT7 Materials and Methods: Recipient Source :: Human Radioligand CHO Cell Re-Combinant: [3H] LSD (60-80 Ci / mmol) Final Binding Concentration - [2.5 nM] Determinant unspecific: 5-carboxamidotriptamine (5-cT) - [0.1 μΜ] Reference compound: 5-carboxamidotriptamine Positive control: 5-carboxamidotriptamine Incubation conditions: Reactions are performed in 50 mM TRIS-HCl (pH 7.4) containing 10 mM MgCl 2, 0.5 mM EDTA for 60 minutes. The reaction is terminated by rapid vacuum filtration over fiberglass filters. The radioactivity contained over the filters is determined and compared to control values for the correctness of any interaction of the test compound with the 5HT7 binding site.

Reference Literature: • Y. Shen, E. Monsma, M. Metcalf, P. Jose, M. Hamblinr D. Sibley, Molecular Cloning and Expression of a 5-hydroxytryptamine7 Serotonin Receptor Subtype. J. Biol. Chem. 268: 18200-18204. The following description illustrates the method of preparing variably substituted compounds having the general formula (I) according to the methods described herein. These are provided for illustrative purposes only and should not be construed as limiting the scope of the invention.

Commercial reagents were used without purification in addition. Room temperature refers to 25-30 ° C. Melting points are uncorrected. The IR spectra were extracted using KBr and in a solid state. Unless otherwise stated, all mass spectra a were performed using ESI conditions. The 1 H NMR spectrum was recorded at 300 MHz on a Bruker instrument. Deuterium-loaded chloroform (99.8% D) was used as a solvent. TMS was used as an internal reference standard. The chemical change values that are expressed are recorded in parts per million (δ) values. The following abbreviations are used for multiplicity for NMR signals: s = "singlet", bs = "broad singlet", d = double, t = trio, q = quartet, chi = quintet, h = heptet, dd = double folded, dt = triple folded, tt = triple of triples, m = multiple. NMR mass a was corrected for background peaks. Specific rotations were measured at room temperature using sodium D (589 nm). Chromatography refers to the chromatography column performed using a 60 - 120 mesh silica gel and performed under nitrogen pressure conditions (flash chromatography). Description 1: N, N-Dimethyl-1- (2'-bromobenzyl) tryptamine (Dl) A suspension of sodium hydride (9.0 mol, 0.36 g) (60% suspension in mineral oil), washed with THF before use. ), in THF was mixed and cooled to 0 - 5 ° C. To this cooled solution was added a solution of N, N-dimethyltriptamine (6.0 mmoles) in THF slowly over a period of more than 15 minutes, maintaining the temperature below 10 ° C. Upon completion of the addition, the mixture was heated to 25 - 30 ° C and held for 60 minutes. The reaction mixture was then cooled to 0 - 5 ° C and a solution of bromobenzyl chloride in THF (6.0 mmol, 1.5 g. In 7 mL of THF) was then added to the well-mixed mixture above, keeping the reaction temperature below 10 ° C (exothermic reaction). The reaction mixture was kept at 20 - 25 ° C for a further 2-4 hours in addition. After completion of the reaction (TFL), excess THF was distilled out and the concentrate was diluted with ice water and extracted with ethyl acetate. A combined ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure below 50 ° C. The crude residue was purified by silica gel column chromatography using 30% methanol in acetate. of ethyl as a mobile phase to obtain the intermediate, N, N-dimethyl-1- (2'-bromobenzyl) tryptamine, which was identified by IR, NMR spectral analysis and mass a.

Description 2-26 (D2 - D26) Several indole intermediates were treated with substituted 2-bromobenzyl bromide according to the procedure described in description 1. These compounds were identified by IR, NMR and mass a spectral analysis. The following list includes a list of such compounds.

List - 1 Description Ion Mass (M + H) + D 1 2- [1- (2-bromobenzyl) indol3-yl] ethyl-N, N-357 dimethylamino D 2 2- [1- (2-bromobenzyl) - 5-bromoindol3-yl] ethyl-N, N-435 dimethylamino D 3 2- [1- (2-bromobenzyl) -7-bromoindol3-yl] ethyl-N, N-435 dimethylamino D 4 2- [1- (2 -bromobenzyl) -5-chloroindol3-yl] ethyl-N, N-391 dimethylamino D 5 2- [1- (2-bromobenzyl) -5-fluoroindol3-yl] ethyl-N, N-375 dimethylamino D 6 2- [ 1- (2-bromobenzyl) -7-fluoroindol3-yl] ethyl-N, N-375 dimethylamino D 7 2- [1- (2-bromobenzyl) -5-methylindol3-yl] ethyl-N, N-371 dimethylamino D 8 2- [1- (2-bromobenzyl) -5-methoxyindol3-yl] ethyl-N, N-387 dimethylamino D 9 2- [1- (2-bromobenzyl) -7-methoxyindol3-yl] ethyl-N, N-387 dimethylamino D 10 2- [1- (2-bromobenzyl) -5-bromoindol3-yl] ethyl-N, N-463 diethylamino D 11 2- [1- (2-bromobenzyl) -5- bromoindol3-yl] ethyl-N-461 cyclopropyl-N-methylamino D 12 2- [1- (2-bromobenzyl) -7-chloroindol3-yl] ethyl-N, N-391 dimethylamino D 13 2- [1- (2 -bromobenzyl) -6,7-dichloroindol3-yl] ethyl-425 N, N-dimethylamino D 14 2- [1- (2-bromobenzyl) -4-chloro-7-methylindol3-405-yl] ethyl-N, N-dimethylamino D 15 2- [1- (2-bromobenzyl) -6-chloro-7- methyl-indol 3-405-yl] ethyl-N, N-dimethylamino D 16 2- [1- (2-bromobenzyl) -7-trifluoromethylindol-425-yl] ethyl-N, N-dimethylamino D 17 2- [1- (2-bromobenzyl ) -5,7-difluoroindol3-yl] ethyl-393 N, N-dimethylamino D 18 1- (2-bromobenzyl) -3- (2-pyrrolidin-1-yl-ethyl) -1H-383 indole D 19 1- (2-bromobenzyl) -5-bromo-3- (2- (pyrrolidin-1- 461-yl) ethyl) -1H-indole D 20 1- (2-bromobenzyl) -5-bromo-3- (2- (piperidine -1- 475-yl) ethyl) -1H-indole D 21 1- (2-bromobenzyl) - (2- (4-methylapiperazine-1-412-yl) ethyl) -1H-indole D 22 1- (2-bromobenzyl) -5-bromo-3- (3- (pyrrolidin-1-yl) -491-1-hydroxypropyl) -1H-indole D 23 1- (2-bromobenzyl) -5-bromo-3- (3- (piperidine-1 -ila) -1- 505 hydroxypropyl) -1H-indole D 24 2- [1- (2-bromobenzyl) -7-ethylindol3-yl] ethyl-β, Ν-385 dimethylamino D 25 2- [1- (2- bromobenzyl) indol3-yl] -1-hydroxyethyl-N, N-373 dimethylamino D 26 1- (2-bromobenzyl) -5-bromo-3- (2- (4- methylapiperazine-490 1-yl) ethyl) -1H-indole Example 1: 11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole-1- (2'-bromobenzyl) -N N-dimethyltriptamine (0.286 mmol, 0.102 g) was placed in a 100-neck, 3-neck round bottom flask, together with N, N-dimethyl acetamide (40 mL), potassium acetate (0.286 mmol, 0.281 g). ) and dichloro bis (tri-o-toliphosphine) palladium (0.0143 moles, 0.01123 g. ). The reaction mixture was kept under a nitrogen atmosphere and was heated to 140 to 160 ° C by mixing for 3 to 4 hours. After completion of the reaction (TLC), excess dimethyl acetamide was distilled off under reduced pressure.

The obtained residue was purified by silica gel column chromatography using 20% methanol in ethyl acetate as an eluent to afford the title compound, which was identified by IR, NMR spectral analysis and mass a. The desired final compound having the general formula (I) may be further purified by preparing its addition acid salts. Melting range (° C): 94-96; the IR spectrum (cm -1): 2942, 2762, 1458, 1443; Mass at (m / z): 277 (M + H) +; 1H-NMR (δ ppm): 2.4 (6H, s), 2.60 - 2.68 (2H, m), 3.17 - 3.26 (2H, m), 5.0 (2H, s), 7.10 - 7.77 (8H, m).

Example - 2: 2-chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Melting range (° C): 76-78; the IR spectrum (cm -1): 2938, 2778, 1469, 1445; Mass at (m / z): 311 (M + H) +; 1H-NMR (δ ppm): 2.37 (6H, s), 2.59 - 2.63 (2H, m), 3.12 - 3.18 (2H, m), 5.01 (2H, s), 7.07 - 7.75 (8H, m) .

Example - 3: 2-Chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-aj indole hydrochloride salt] Example No. 2 (236 mg) was dissolved in 30 mL of ether . To this clear solution was added a mixture of isopropylalcohydrochloric acid (10 mL). Immediately a white precipitate was separated which was filtered, washed with ether and dried. The melting range (° C):> 250 (dec).

Example - 4: 2-Chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole maleic acid salt Example No. 2 (228 mg) was dissolved in 30 mL of ether. To this clear solution was added a maleic acid solution (90 mg, dissolved in 30 mL ether = 5 mL methanol). Immediately a white precipitate was separated which was filtered, washed with ether and dried. De melting range (° C): 202-204 (dec).

Example - 5: 2-Chloro-11- (2-N, N-dimethylaminoethyl) -6-isoindole [2,1-a] indole malic acid salt Example No. 2 (190 mg) was dissolved in 30 mL of ether. To this clear solution was added a solution of malic acid D, L- (86 mg, dissolved in 30 mL ether = 5 mL methanol). Immediately a white precipitate was separated which was filtered, washed with ether and dried. The melting range (° C): 173 - 176 (dec).

Example 6: 2-Chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole oxalate salt Example No. 2 (198 mg) was dissolved in 30 mL of ether. To this clear solution was added a solution of oxalic acid (86 mg, dissolved in 30 mL ether = 5 mL methanol). Immediately a white precipitate was separated which was filtered, washed with ether and dried. The melting range (° C): 222 -224 (dec).

Example 7: 2-Chloro-11- (2-N, N-dimethylaminoethyl) -6,7-isoindole [2,1-a] indole citrate salt Example No. 2 (213 mg) was dissolved in 30 mL of ether. To this clear solution was added a citric acid solution (133 mg, dissolved in 30 mL ether = 5 mL methanol). Immediately a white precipitate was separated which was filtered, washed with ether and dried. The melting range (° C): 150-152 (dec).

Example _____-_____ 8j ____ 2-fluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. Melting range (° C): 96-100; the IR spectrum

(cm -1): 2941, 2784, 1458, 798; Mass at (m / z): 295 (M + H) +; 1H-NMR (δ. Ppm): 2.38 (6H, s), 2.560 - 2.65 (2H, m), 3.11 - 3.19 (2H, m), 5.02 (2H, s), 6.91 - 7.77 (8H, m) .

Example _____-_____ 9j ______ 11- (2-N, N-Dimethylaminoethyl) -4-methyl-ephisoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. Melting range (° C): 102-106; the IR spectrum

(cm -1): 2934, 2761, 1439, 765; Mass (m / z): 291 (M + H) +; 1 H NMR (δ ... ppm): 2.38 (6H, s), 2.46 (3H, s), 2.56 - 2.65 (2H, m), 3.12 - 3.20 (2H, m), 4.99 (2H, s), 6.98 - 7.73 (7H, m).

Example _____-____ 10: ____ 11- (2-N, N-Dimethylaminoethyl) -2-methoxy-6ff-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Melting range (° C): 140-143; IR spectrum (cm -1): 2903, 2781, 1621, 1459, 769; Mass (m / z): 307 (M + H) +; 1H-NMR (δ ... ppm): 2.40 (6H, s), 2.57 - 2.66 (2H, m), 3.13 - 3.21 (2H, m), 3.88 (3H, s), 5.00 (2H, s), 6.82 - 7.73 (7H, m).

Example _____-_____ 11: _____ 2-Bromo-11- (2-N, N-diethylaminoethyl) -6H-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . IR spectrum (cm -1): 2964, 1613, 1444, 1261, 795;

Mass (m / z): 383 (M + H) +.

Example 12: 2-bromo-11- (2-N-methyl-N-cyclopropylaminoethyl) -6fl-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative has been prepared. IR spectrum (cm -1): 2926, 1469, 1358, 1169, 793;

Mass (m / z): 381 (M + H) +; 1H-NMR (δ ppm): 0.44-0.61 (4H, m), 1.82-1.87 (1H, m), 2.48 (3H, s), 2.72 - 2.80 (2H, m), 2.95 - 3.07 (2H, m), 5.25 (2H, s), 7.06 - 7.32 (7H, m).

Example 13: 4-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. IR spectrum (cm -1): 2938, 2778, 1469, 1445; Mass (m / z): Example - 14: 3,4-dichloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some Non-critical variations, the above derivative was prepared. Mass (m / z): 345 (M + H) +.

Example - 15: 1-Chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the derivative above was prepared. Mass (m / z): 325 (M + H) +.

Example 16: 3-chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6H-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the derivative above was prepared. Mass (m / z): 325 (M + H) +.

Example - 17: 11- (2-N, N-dimethylaminoethyl) -4-trifluoromethyl-6-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Mass (m / z): 345 (M + H) +.

Example 18: 2,4-difluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative has been prepared. Melting range (° C): 76-78; IR spectrum (cm -1): 2938, 2778, 1469, 1445; Mass (m / z): 84 - 86; IR spectrum (cm -1): 2941, 2784, 1458, 798; Mass (m / z): 313 (M + H) +; 1H-NMR (δ ppm): 2.38 (6H, m), 2.55 - 2.63 (2H, m), 3.09 - 3.17 (2H, m), 5.22 (2H, s), 6.63 - 7.78 (6H, m) .

Example 19: 11- (2-pyrrolidin-1-ylethyl) -6β-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. Melting range (° C): 86-90; IR spectrum (cm -1): 2832, 2807, 1361, 1334; Mass (m / z): 303 (M + H) +; 1H-NMR (δ ppm): 1.79-1.85 (4H, m), 2.55 - 2.68 (6H, m), 2.75 - 2.82 (2H, m), 5.28 (2H, s), 7.10 - 7.34 (8H, m).

Example - 20: _____ 2-Bromo-11- (2-pyrrolidin-1-ylethyl) -6,7-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared .. Mass (m / z): 381 (M + H) +.

Example 21: 11- (2- (piperidin-1-yl) ethyl) -67f-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. Melting range (° C): 102 - 104; IR spectrum (cm -1): 2929, 2840, 1455, 1162; Mass (m / z): 317 (M + H) +; 1H-NMR (δ ppm): 1.44-1.52 (2H, m), 1.60-1.66 (4H, m), 2.38 - 2.43 (2H, m), 2.64 - 2.76 (6H, m), 5.28 (2H, s), 7.08 - 7.73 (8H, m).

Example 11- (2- (4-methylapiperazine-1-yl) ethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. IR spectrum (cm -1): 2937, 2803, 1634, 1455; Mass (m / z): 332 (M + H) +.

Example - 23: 11- (3- (pyrrolidin-1-yl) -1-hydroxyprop-1-yl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations , the above derivative was prepared. Mass (m / z): 333 (M + H) +.

Example - 24: 2-Bromo-11- (3- (piperidin-1-yl) -1-hydroxyprop-1-yl) -6'-isoindolo [2,1-a] indole Using essentially the procedure described in Example 1 and For some non-critical variations, the above derivative was prepared. Mass (m / z): 425 (M + H) +.

Example _____-_____ 25: ____ 11- (2-N, N-Dimethylaminoethyl) -4-ethyl-6ff-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Mass (m / z): 305 (M + H) +.

Example _____-___ 26: ___ 11- (2-N, N-Dimethylamino-1-hydroxyethyl) -6H-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. .. Mass (m / z): 293 (M + H) +.

Example _____-_____ 27: __ 11- (2-N, N-Dimethylaminoethyl) -4-methoxy-6β-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Mass (m / z): 307 (M + H) +.

Example ____-_____ 28: ___ 2-bromo-11- (2-N, N-dimethylaminoethyl) -6H-isoindole [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. .. Mass (m / z): 355 (M + H) +.

Example - 29: 4-Bromo-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. .. Mass (m / z): 355 (M + H) +.

Example - 30: 4-fluoro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, the above derivative was prepared. . Mass (m / z): 295 (M + H) +.

Example - 31: 2-Bromo-11- (2- (4-methylapiperazine-1-yl) ethyl) -6H-isoindolo [2,1-a] indole Using essentially the procedure described in example 1 and some non-critical variations, The above derivative was prepared. Mass (m / z): 410 (M + H) +.

Claims

Claims (14)

A compound having the general formula (I), the general formula (I) pharmaceutically acceptable salts and solvates thereof, wherein R 0 is either hydrogen or straight or branched (C 1 -C 2) alkyl; R 1, R 2, R 3 / R 4, R s, R 6, R 7, R 8, R 9, Rio, Ru and R 12 may be the same or different and each independently represents hydrogen, halogen, perhaloalkyl, amino, substituted or unsubstituted groups such as alkyl ( C 1 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl, C 1 -C 12 alkoxy, straight or branched C 3 -C 7 cycloalkoxy, acyl, monoalkylamino, dialkylamino, alkylthio, carboxylic acid and its linear or branched derivatives; R13 and R14 may be the same or different and each independently represents hydrogen or substituted or unsubstituted groups such as (C1-C4) alkyl, (C3-C7) cycloalkyl, (C3-C7) cycloalkenyl, bicycloalkenyl, aryl, aralkyl linear or branched; optionally R13 and R14 together with the nitrogen atom may form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring where the ring may be additionally substituted and may have one, two or three bonds or "additional hetero atoms", as appropriate. defined above; and "n" is an integer ranging from 1 to 4; and the carbon chains that "n" represents may be straight or branched. Compound according to Claim 1, characterized in that it is selected from the group consisting of: 11- (2-N, N-dimethylaminoethyl) -6.ff-isoindole [2,1-a] indole; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6'-isoindolo [2,1-a] indole; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole hydrochloride salt; 2-chloro-11- (2- N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole maleic acid salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole D, L malic acid salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6'-isoindolo [2,1-a] indole oxalate salt; 2-chloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2-N, N-dimethylaminoethyl) -o-isoindolo [2,1-a] indole; 2-chloro-11- (2-N, N-diethylaminoethyl) -6-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2-N, N-diethylaminoethyl) -6β-isoindolo [2,1-a] indole; 2-chloro-11- (2- N -cyclopropyl-N-methylaminoethyl) -6α-isoindolo [2,1-a] indole citrate salt; 2-fluoro-11- (2-N-cyclopropyl-N-methylaminoethyl) -6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -2-methyl-6β-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -2-methoxy-6'-isoindolo [2,1-a] indole; 2-bromo-11- (2-N, N-diethylaminoethyl) -6'-isoindolo [2,1-a] indole; 2-bromo-11- (2-N-methyl-N-cyclopropylaminoethyl) -6H-isoindolo [2,1-a] indole; 4-chloro-11- (2-N, N-dimethylaminoethyl) -6β-isoindolo [2,1-a] indole; 3.4-dichloro-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; I-chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6-isoindolo [2,1-a] indole; 3-chloro-11- (2-N, N-dimethylaminoethyl) -4-methyl-6Î ± -isoindolo [2,1-a] indole; 3-chloro-11 - [(2-N-methylamino) ethyl] -4-methyl-6β-isoindolo [2,1-a] indole; 3-chloro-11 - [(2-N-methylamino) ethyl] -2-methoxy-6H-isoindolo [2,1-a] indole; 3-iodo-11 - [(2-N-methylamino) ethyl] -2-methoxy-6β-isoindolo [2,1-a] indole; II- (2-N, N-dimethylaminoethyl) -4-trifluoromethyl-6H-isoindolo [2,1-a] indole; 2,4-difluoro-11- (2-N, N-dimethylaminoethyl) -6 H -isoindolo [2,1-a] indole; 11- (2-pyrrolidin-1-ylethyl) -6β-isoindolo [2,1-a] indole; 2-bromo-11- (2-pyrrolidin-1-ylethyl) -6 ° Z-isoindolo [2,1-a] indole; 11- (2- (piperidin-1-yl) ethyl) -6β-isoindolo [2,1-a] indole; 11- (2- (4-methylapiperazine-1-yl) ethyl) -61f-isoindolo [2,1-a] indole; 11- (3- (pyrrolidin-1-yl) -1-hydroxyprop-1-yl) -6H-isoindolo [2,1-a] indole; 2-bromo-11- (3- (piperidin-1-yl) -1-hydroxyprop-1-yl) -6H-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -4-ethyl-6'-isoindolo [2,1-a] indole; 11- (2-N, N-dimethylamino-1-hydroxyethyl) -6 # -isoindolo [2,1-a] indole; 11- (2-N, N-dimethylaminoethyl) -4-methoxy-6'-isoindolo [2,1-a] indole; 2-bromo-11- (2-N, N-dimethylaminoethyl) -6'-isoindolo [2,1-a] indole; 4-bromo-11- (2-N, N-dimethylaminoethyl) -6H-isoindolo [2,1-a] indole; 4-fluoro-11- (2-N, N-dimethylaminoethyl) -6-isoindolo [2,1-a] indole; 2-bromo-11- (2- (4-methylapiperazine-1-yl) ethyl) -6 H-isoindolo [2,1-a] indole; and their pharmaceutically acceptable stereoisomers, N-oxides, polymorphs, salts and solvates. Pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent (s), excipient (s) or solvate (s) together with a therapeutically effective amount of a compound as defined in claim 1, its N-oxides, and their pharmaceutically acceptable salts and solvates. Pharmaceutical composition according to Claim 3, characterized in that it is in the form of a tablet, capsule, powder, pellet, suppository, syrup, solution, suspension or injection, administered in units as a single dose or as multiple doses. Use of a compound having the general formula (I) as defined in claim 1 or a composition as defined in claim 3, characterized in that it is for the preparation of medicaments. Use of a compound having the general formula (I) as defined in claim 1 or a composition as defined in claim 3, characterized in that it is for the treatment and / or prevention of clinical conditions for which selective action on 5-HT receptors is indicated. Use of a compound as claimed in claim 1 for the preparation of medicaments for the treatment and / or prevention of clinical conditions such as anxiety, depression, seizure disorders, obsessive-seizure disorders, migraine and pain. headache, cognitive memory disorders, attention deficit / hyperactivity disorder, personality disorders, psychosis, paraphenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, withdrawal symptoms from drug abuse, panic attacks, reproduction, glaucoma, sleep disorders and also disorders associated with spinal trauma and / or head injuries. Use of a compound as claimed in claim 1 for the preparation of medicaments for the treatment of mild cognitive impairment and other neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease and Huntingdon's chorea. . Use of a compound as claimed in claim 1, characterized in that it is for the preparation of medicaments for the treatment of certain gastrointestinal (GI) disorders such as bowel irritation syndrome or as chemotherapy induced emesis. Use of a compound as claimed in claim 1 for the preparation of medicaments for reducing morbidity and mortality associated with overweight. Use of a radiolabeled compound as claimed in claim 1, characterized in that it is for the preparation of a diagnostic tool for modulation for 5-HT receptor function. Use of a compound as claimed in claim 1 for the preparation of medicaments in combination with a 5-HT re-ingestion inhibitor and / or a pharmaceutically acceptable salt thereof. A compound having the general formula (I), pharmaceutically acceptable salts and solvates thereof, characterized in that it is for the preparation of a medicament. Use of a compound as defined in claim 1, in combination with a 5-HT ingestion inhibitor or melatonin or melatoninergic modulator and / or pharmaceutically acceptable salts thereof, characterized in that it is for the preparation of medicaments for treatment of anxiety, seizure disorders, obsessive-seizure disorders, migraine and headache, cognitive memory disorders, attention deficit / hyperactivity disorder, personality disorders, psychosis, paraphenia, psychotic depression, mania, schizophrenia, disorders schizophreniformes, withdrawal symptoms from drug abuse, panic attacks, reproduction, glaucoma, sleep disorders and also disorders associated with spinal trauma and / or head injuries, Alzheimer's disease, Parkinson's disease and Huntington's chorea .