WO2004048331A1

WO2004048331A1 - N-arylalkyl-3-aminoalkoxyindoles and their use as 5-ht ligands

Info

Publication number: WO2004048331A1
Application number: PCT/IN2003/000371
Authority: WO
Inventors: Venkata Satya Nirogi Ramakrishna; Vikas Shreekrishna Shirsath; Rama Sastri Kambhampati; Venkata Satya Veerabhadra Vadlamudi Rao; Venkateswarlu Jasti
Original assignee: Suven Life Sciences Limited
Priority date: 2002-11-28
Filing date: 2003-11-25
Publication date: 2004-06-10
Also published as: AU2003292508A1

Abstract

The present invention describes substituted 3-Aminoalkoxyindoles, as compounds of the general formula (I), its stereoisomers, its radioisotopes, its geometric forms, its N-oxides, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolites and any suitable combination of the above. The invention also discloses the processes for preparing such compounds of the general formula (I), its stereoisomers, its radioisotopes, its geometric forms, its N-oxides, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bio-active metabolites and also includes any suitable combination of the above. Further described are various methods of administering these compounds of general formula (I), i.e. pharmaceutically acceptable dosage forms, their composition and their use in either therapy or diagnosis.

Description

IM-ArylalkyI-3-aminoalkoxyindoles

Field of Invention:

The present invention includes compounds described by general formula (I), its stereoisomers, its radioisotopes, its geometric forms, its N-oxides, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolites and any suitable combination of the above.

General Formula (I)

Further the present invention also includes the processes for preparing such compounds of the general formula (I), its stereoisomers, its radioisotopes, its geometric forms, its N-oxides, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolites and also includes any suitable combination of the above.

The invention also describes various methods of administering these compounds of general formula (I), i.e. pharmaceutically acceptable dosage forms compositions and the use of such compounds and compositions in either therapy or diagnosis. The compounds of the general formula (I) of this invention are 5-HT (Serotonin) ligands e.g. agonists or antagonists. The compounds of the general formula (I) of this invention, by the virtue of its chemical characteristic, could either independently or simultaneously modulate the melatonin receptor i.e. either these compounds are melatonergic ligands e.g. agonists or antagonists, or they interact with both 5-HT and/or as Melatonin receptors.

Thus, compounds of general formula (I) of this invention are useful for treating diseases wherein activity of either 5-HT (Serotonin) and/or Melatonin is modulated to obtain the desired therapeutic effect. Specifically, the compounds of this invention are useful in the treatment and / or prophylaxis of conditions such as psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, anxiety, migraine headache, depression, drug addiction, convulsive disorders, personality disorders, hypertension, autism, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, chronobiological abnormalities, circadian rhythms, anxiolytic, osteoporosis, ischemic stroke, lower the risk of SIDS in young infants with low endogenous melatonin levels, reproduction, glaucoma and sleep disorders.

Hence, the compounds of general formula (I) of this invention could also be useful in treating the psychotic, affective, vegetative and psychomotor symptoms of schizophrenia and the extrapyramidal motor side effects of other antipsychotic drugs; neurodegenerative disorders like Alzheimer's disease, Parkinson's and Huntington's chorea and chemotherapy-induced vomiting; and in modulation of eating behavior and thus are useful in reducing the morbidity and mortality associated with excess weight. Background of the Invention Many diseases of the central nervous system are influenced by the adrenergic, the dopaminergic and the serotoninergic neurotransmitter systems. Serotonin has been implicated in numerous diseases and conditions, which originate from central nervous system. The list includes diseases and conditions related to sleeping, eating, perceiving pain, controlling body temperature, controlling blood pressure, depression, anxiety, schizophrenia and other bodily states. (References: Fuller, R. W., Drugs Acting on Serotoninergic Neuronal Systems, in "Biology of Serotoninergic Transmission", ed. by Osborne N. N., J Wiley & Sons Inc. (1982), 221-247; Boullin D. J., et. al., in "Serotonin in Mental Abnormalities", International Association for The Scientific Study of Mental Deficiency, Wiley, Checester, 1978, pp. 1-340; Barchas J. et. al., in "Serotonin and Behavior", Academic Press, NY (1973)). Serotonin also plays an important role in the peripheral systems, such as the gastrointestinal system, where it has been found to mediate a variety of contractile, secretory and electrophysiologic effects.

Due to the broad distribution of serotonin within the body, there is a lot of interest and use, in the drugs that affect serotoninergic systems. Particularly, preferred are the compounds which have receptor-specific agonism and/or antagonism for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, compulsive disorders, schizophrenia, autism, certain other neurodegenerative disorders like Alzheimer, Parkinson, Huntington's chorea and chemotherapy-induced vomiting (References: Gershon M. D. et. al., 5-Hydroxytryptamine and enteric neurons. In: The Peripheral Actions of 5- Hydroxytryptamine, edited by J. R. Fozard. New York: Oxford, 1989, p. 247-273; Saxena P. R. et. al., Journal of Cardiovascular Pharmacology (1990), supplement 15, 17-34).

The major classes of serotonin receptors (5-HTι.₇) contain 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. Rev. (1994), 46, 157-203). Recently discovered information regarding sub-type identity, distribution, structure and function suggests that it is possible to identify novel, sub-type specific agents having improved therapeutic profiles with lesser side effects. The 5-HT₆ 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 antidepressants and atypical antipsychotics bind to the 5-HT₆ receptor with high affinity and this binding may be a factor in their profile of activities (References: Roth et al, J. Pharm. Exp. Therapeut. (1994), 268, 1403-1410; Sleight et al, Exp. Opin. Ther. Patents (1998), 8, 1217-1224; Bourson et al, Brit. J. Pharmacol. (1998), 125, 1562-1566; Boess et al, Mol. Pharmacol., 1998, 54, 577-583; Sleight et al, Brit. J. Pharmacol. (1998), 124, 556-562). In addition, 5-HT₆ receptor has been linked to generalized stress and anxiety states (Reference: Yoshioka et al, Life Sciences (1998), 17/18, 1473-1477). Together these studies and observations suggest that the compound, which ^"antagonizes 5-HT₆ receptors, will be useful in treating various disorders of the central nervous system.

There is very strong evidence that Melatonin is important for the regulation of a variety of neural and endocrine functions, especially those that exhibit circadian and circannual rhythmicity. Great interest therefore lies in the possibility of making available to the clinician melatonin analogues that are metabolically more stable and have an agonist or antagonist character and of which the therapeutic effect may be expected to be superior to that of the hormone itself. PCT patent application WO 00/72815 and U.S. patent No 6,465,660B1 gives extensive literature on studies with Melatonin and potential therapeutic application of various ligands reported till date.

Those various effects are exerted via the intermediary of specific Melatonin receptors. Molecular biology studies have demonstrated the existence of a number of receptor sub-types that are capable of binding that hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97 04094). Melatonin acts on the CNS to affect neural mechanisms through receptors located in the brain. Additionally, a number of studies indicate the existence of direct effects of Melatonin in peripheral organs via peripheral melatonin receptors. Melatonin receptors are present in the heart, lungs, prostate gland, gonads, white blood cells, retina, pituitary, thyroid, kidney, gut and blood vessels (Withyachumnarnkul et al., Life Sci, 12 65, 1986). Three Melatonin receptor subtypes have been identified so far MT-I , MT-2 and Mel 1 c (Barreft et al., Biol. Signals Recept., 1999, 8: 6-14).

There is evidence suggesting both Melatonin agonists and antagonists would be of potential therapeutic use for a variety of maladies and conditions. PCT application WO 00/72815, discuss in depth applications and use of such compounds and details of which are incorporated herein by reference. Also U. S. patent No. 6,465,660 and U. S. patent application publication number US 2003/0105087 discuss some tricyclic indole and tricyclic azaindole derivatives having very valuable pharmacological characteristics in respect of melatoninergic receptors. U. S. Pat. No. 4,839,377 and U. S. Pat. No. 4,855,314 refers to 5-substituted 3- aminoalkyl indoles. The compounds are said to be useful for the treatment of migraine.

British Patent 2,035,310 refers to 3-aminoalkyl-1 H-indole-5-thioamides and carboxamides. The compounds are said to be useful in treating hypertension,

Raymond's disease and migraine. European Patent Publication 303,506 refers to 3-polyhydropyridyI-5- substituted-1 H-indoIes. The compounds are said to have 5-H^ receptor agonists and vasoconstrictor activity and to be useful in treating migraine. European Patent Publication 354,777 refers to N-piperidinylindolylethyl-alkane sulfonamide derivatives. The compounds are said to be 5-HTi receptor agonists and have vasoconstrictor activity and are useful in treating cephalic pain.

European Patent Publication 438,230, refers to indole-substituted five- membered heteroaromatic compounds. The compounds are said to have "5-HT like" receptor agonist activity and to be useful in the treatment of migraine and other disorders for which a selective agonist of these receptors is indicated. European Patent Publication 313,397 refers to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, cluster headache and headache associated with vascular disorders. These compounds are also said to have exceptional "5-HTrlike" receptor agonism. International Patent Publication WO 91/18897 refers to 5-heterocyclic indole derivatives. The compounds are said to have exceptional properties for the treatment and prophylaxis of migraine, cluster headache, and headache associated with vascular disorders. These compounds are also said to have exceptional "5-HTrlike" receptor agonism. European Patent Publication 457,701 refers to aryloxy amine derivatives as having high affinity for 5-HTm serotonin receptors. These compounds are said to be useful for treating diseases related to serotonin receptor dysfunction, for example, migraine.

European Patent Publication 497,512 A2, refers to a class of imidazole, triazole and tetrazole derivatives that are selective agonists for "5-HT like" receptors. These compounds are said to be useful for treating migraine and associated disorders.

International Patent Publication WO 93/00086 describes a series of tetrahydrocarbazole derivatives, as 5-HT_! receptor agonists, useful for the treatment of migraine and related conditions.

International Patent Publication WO 93/23396, refers to fused imidazole and triazole derivatives as 5-HTi 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}1 H-indole-3-carboxylate as a selective antagonist for the 5- HT_IA receptor in their paper "SDZ216-525, a selective and potent 5-HTIA receptor antagonist" European Journal of Pharmacology, 244, 251-257 (1993).

International Patent Publication WO 94/06769, refers to 2-substituted-4- piperazine-benzothiophene derivatives that are serotonin 5-HT_1A and 5-HTι_D receptor agents useful in the treatment of anxiety, depression, migraine, stroke, angina and hypertension. Summary of the Invention:

The present invention relates to compounds of general formula (I), its stereoisomers, its radioisotopes, its geometric forms, its N-oxide, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolite and any suitable combination of the above. The compounds of general formula (I) are as follows,

General Formula (I) wherein Ri, R₂, R₃, R , R₅, R₆, R , R₈, R9, R₁0, Rn and R₁₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R^ and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R and R₈ or R₈ and R₉ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms;

R₁₃ and R₁ represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, R₁3 and R₁₄ together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, Rn and R₁₃ together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated;

"A" represents one or two hydrogens, oxygen, hydroxy, lower(CrC₆)alkyl or lower(C C₆) alkoxy; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains, which "n" represents, may be either linear or branched; with the proviso that, i) whenever n =2, all of Ri, R₂, R₃, R and R₁₀ are together hydrogens, and R₁₃ and Rι₄ are methyl or ethyl; then A is never either of =0 or -(H)₂ and also includes the salts of such compounds, ii) whenever n =2, all of R^ R₃, R₄ and R₁₀ are together hydrogens, R₂ is methoxy, and R₁₃ and R₁₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, iii) whenever n =2, all of Ri, R₃, R and Rio are together hydrogens, R₂ is chloro, and R₁₃ and R₁₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, iy) whenever n =2, all of Ri, R₃, R₄ and R₂ are together hydrogens, R-|₀ is phenyl, and R₁₃ and R₁₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, y) whenever n =3, all of R-i, R₂, R₃, R and R-io are together hydrogens then R₁₃ and

Rι₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds. Partial list of such compounds of general formula (!) is as follows: [2-(1-(Benzoyl)-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)-1H-indol-3-yloxy)ethyl]dimethyIamine ; [2-(1-(Benzyl)-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)-1W-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(Benzoyl)-2-phenyl-1/-/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 2-phenyl-1 H-indol-3-yIoxy)ethyl]dimethylamine ; [2-(1 -(Benzyl)- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 2-phenyl-1 -/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(Benzoyl)-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 2- methyl -1H-indol-3-yloxy)ethyl]dimethyIamine ; [2-(1 -(Benzyl)- 2- methyl -1 --indoI-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(Benzoyl)-5-bromo-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5-bromo-1ry-indol-3-yIoxy)ethyl]dimethylamine ; [2-(1 -(Benzyl)- 5-bromo-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5-bromo-1 --indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(Benzoyl)- 5-bromo-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-bromo-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine [2-(1-(Benzyl)- 5-bromo-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5-bromo- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5-bromo-2-methyl-1H-indol-3-yloxy)ethyl]dimethyIamine ;

[2-(1-(2'-Bromobenzoyl)- 5-bromo- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5-bromo-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5-bromo- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine

[2-(1-(Benzoyl)-5-chloro-1 --indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzyl)- 5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5-chloro-1H-indol-3-yIoxy)ethyl]dimethylamine ; [2-(1 -(Benzoyl)- 5-chloro-2-phenyI-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-chloro-2-phenyl-1 -/-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 5-chloro-2-phenyl-1H-indoI-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5-chloro- 2-phenyl-1r-/-indoI-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5-chloro-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5-chloro- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5-chloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine

[2-(1-(Benzoyl)-6-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 6-chloro-1 -/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(Benzyl)- 6-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 6-chloro-1 --indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 6-chloro-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 6-chloro-2-phenyl-1ry-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 6-chloro-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 6-chloro- 2-phenyl-1r--indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzoyl)- 6-chloro-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 6-chloro- 2- methyl -1r--indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 6-chloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 6-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine [2-(1-(Benzoyl)-5,7-dichloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5,7-dichloro-1r7-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 5,7-dichloro-1 -/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dichloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5,7-dichloro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5,7-dichloro-2-phenyl-1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dichloro-2-phenyl-1 ry-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dichloro- 2-phenyl-1 indol-3-yloxy)ethyl] dimethylamine ; [2-(1 -(Benzoyl)- 5,7-dichloro-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5,7-dichloro- 2- methyl -1r7-indol-3-yloxy)ethyl] dimethylamine

[2-(1-(Benzyl)- 5,7-dichloro-2- methyl - H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5,7-dichloro- 2- methyl -1H-indoI-3-yloxy)ethyl] dimethylamine;

[2-(1-(Benzoyl)-5,7-dibromo-1ry-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5,7-dibromo-1 H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dibromo-1 --indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dibromo-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(Benzoyl)- 5,7-dibromo-2-phenyl-1H-indol~3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5,7-dibromo-2-phenyl-1 --indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dibromo-2-phenyl-1 /-/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dibromo- 2-phenyl-1/W-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzoyl)- 5,7-dibromo-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5,7-dibromo- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dibromo-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dibromo- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine;

[2-(1-(Benzoyl)-7-bromo-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine

[2-(1 -(Benzyl)- 7-bromo-5-chloro-1 r7-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 7-bromo-5-chloro-2-phenyl-1H-indol-3-yloxy)ethyI]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro-2-phenyl-1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 7-bromo-5-chloro-2-phenyl-1 H-indol-3-yloxy)ethyϊ]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro- 2-phenyl-1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzoyl)- 7-bromo-5-chloro-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro- 2- methyl -1/-/-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 7-bromo-5-chloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl] dimethylamine; [2-(1-(Benzoyl)-5-methoxy-1 -/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-methoxy-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-( -(Benzyl)- 5-methoxy-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-BromobenzyI)- 5-methoxy-1 H-indor-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5-methoxy-2-phenyl-1 --indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-methoxy-2-phenyl-1rV-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5-methoxy-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine [2-(1-(2'-Bromobenzyl)- 5-methoxy- 2-phenyl-1b-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1-(Benzoyl)- 5-methoxy-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 5-methoxy- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5-methoxy-2- methyl -1 --indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzyl)- 5-methoxy- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine; or a stereoisomer, or a polymorph, or any suitable combination of above such as a nitrogen oxide thereof; a prodrug of the compound or the nitrogen oxide; a pharmaceutically acceptable salt of the compound, the nitrogen oxide, or the prodrug; or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug or the pharmaceutically acceptable salt. The present invention also relates to the process for preparing the compound of the general formula (I) its stereoisomers, its radioisotopes, its geometric forms, its

N-oxide, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bioactive metabolites and any suitable combination of above. In the case of the compounds of general formula (I), where tautomerism may exist, the present invention relates to all of the possible tautomeric forms and the possible mixture thereof.

The present invention also relates to the stereoisomers, which as a rule are obtained as racemates that can be separated into the optically active isomers in a manner known per se.

The present invention also relates to radio-labeled isotopes, which are identical to those defined in the general formula (I), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number found usually in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, bromine and mTecnitium, exemplified by ²H, ³H, ¹C, ¹³C, ⁴C, ¹³N, ¹⁵N, ⁵0, ¹⁸F, ^99mTc, ³¹P, S, ¹²³l and ¹²⁵l. Those compounds of general formula (I) as described earlier containing the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. In the case of the compounds of general formula (I) containing geometric isomerism the present invention relates to all of these geometric isomers. The term "nitrogen oxide" or "N-oxide" refers to the oxidation of at least one of the two nitrogens in the compounds of general formula (I) (e.g., mono- or di-oxide).

The nitrogen mono-oxides may exist as a single positional isomer or a mixture of 2° positional isomers (e.g., a mixture of 1-N-oxide and 4-N-oxide piperazine or a mixture of 1-N-oxide and 4-N-oxide piperazines).

Suitable pharmaceutically acceptable acid addition salts of compounds of the general formula (I) can be prepared of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, includes, salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benezenesulfonate, p- tolunesulfonate, palmoate and oxalate. Pharmaceutically acceptable salts forming part of this invention are intended to define but not limited to the above list. Suitable pharmaceutically acceptable base addition salts of compounds of the general formula (I) can be prepared of the aforementioned acid compounds of this invention are those which form non-toxic base addition salts, includes, salts containing pharmaceutically acceptable cations, such as Lithium, sodium, potassium, calcium and magnesium, salts of organic bases such as lysine, arginine, guanidine, diethanolamine, choline, tromethamine and the like; ammonium or substituted ammonium salts.

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

In addition, pharmaceutically acceptable salts of the compound of formula (I) can be obtained by converting derivatives which have tertiary amino groups into the corresponding quarternary ammonium salts in the methods known in the literature by using quarternizing agents. Possible quartemizing 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 the addition to pharmaceutically acceptable salts, other salts are included in the invention. They may serve as intermediates in the purification of the compounds, in the preparation of other salts, or in the identification and characterization of the compounds or intermediates.

The pharmaceutically acceptable salts of compounds of formula (I) may exists as solvates, such as with water, methanol, ethanol, dimethylformamide, ethyl acetate, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent preparation or crystallization, or adventitious to such solvent. Such solvates are within the scope of this invention.

The invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of the formula (I). A prodrug is a drug which has been chemically modified and may be biologically in-active at the site of action, but which may be degraded or modified by one or more enzymatic or other in-vivo processes to the parent form. This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation, or solubility, and/or improved systemic stability (an increase in the plasma half-life, for example). Typically, such chemical modifications include the following:

1. ester or amide derivatives which may be cleaved by esterases or lipases;

2. peptides which may be recognized by specific or non-specific proteases; or

3. derivatives that accumulate at a site of action through membrane selection of a prodrug from or a modified prodrug form; or 4. any combination of 1 to 3, above.

Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in H. Bundgard, Design of prodrugs, (1985).

Another aspect of the present invention comprises of a pharmaceutical composition, containing at least one of the compounds of the general formula (I), their derivatives, their analogs, their derivatives, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates thereof as an active ingredient, together with pharmaceutically employed carriers, auxiliaries and the like.

An effective amount of a compound of general formula (I) or its salt is used for producing medicaments of the present invention, along with conventional pharmaceutical auxiliaries, carriers and additives.

The present invention also relates to the pharmaceutically acceptable compositions containing them, and the use of these compounds and compositions in medicine. The compounds of general formula (I) of this invention are useful in the treatment and/ or prophylaxis of a condition wherein modulation of 5-HT activity is desired.

The compounds of general formula (I) of this invention are useful in the treatment and/ or prophylaxis of a condition wherein modulation of melatonin activity is desired. The compounds of general formula (I) of this invention are useful in the treatment and/ or prophylaxis of a condition wherein modulation of 5-HT and melatonin activities gives desired effect.

The present invention provides for use of the compounds of general formula (I) according to above, for the manufacture of the medicaments for the potential use in the treatment and/ or prophylaxis of certain CNS disorders such as, anxiety, depression, convulsive disorders, obsessive-compulsive disorders, migraine headache, cognitive memory disorders e.g. Alzheimer's disease and age-related cognitive decline, ADHD (Attention Deficient Disorder/ Hyperactivity Syndrome), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, withdrawal from drug abuse such as ***e, ethanol, nicotine and benzodiazepines, panic attacks, chronobiological abnormalities, circadian rhythms, anxiolytic, osteoporosis, ischemic stroke, lower the risk of SIDS in young infants with low endogenous melatonin levels, reproduction, glaucoma, sleep disorders (including disturbances of Circadian rhythm) and also disorders associated with spinal trauma and / or head injury such as hydrocephalus. Compounds of the invention are further expected to be of use in the treatment of mild cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinson's and Huntington's chorea. The compounds of the invention are also expected to be of use in the treatment of certain Gl (Gastrointestinal) disorders such as IBS (Irritable bowel syndrome) or chemotherapy induced emesis.

The compounds of the invention are also expected to be of use in the modulation of eating behavior and these compounds can also be used to reduce morbidity and mortality associated with the excess weight.

The present invention provides a method for the treatment of a human or a animal subject suffering from certain CNS disorders such as, anxiety, depression, convulsive disorders, obsessive-compulsive disorders, migraine headache, cognitive memory disorders e.g_; Alzheimer's disease and age-related cognitive decline, ADHD (Attention Deficient Hyperactivity Disorder), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, withdrawal from drug abuse such as ***e, ethanol, nicotine and benzodiazepines, panic attacks, chronobiological abnormalities, circadian rhythms, anxiolytic, osteoporosis, ischemic stroke, lower the risk of SIDS in young infants with low endogenous melatonin levels, reproduction, glaucoma, sleep disorders (including disturbances of Circadian rhythm) and also disorders associated with spinal trauma and /or head injury such as hydrocephalus. Compounds of the invention are further expected to be of use in the treatment of mild cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinson's and Huntington's chorea. The present invention also provides a method for modulating 5-HT and/ or melatonin receptor function desired in certain cases.

Compounds of the present invention may be administered in combination with other pharmaceutical agents, such as apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, adrenergic receptor agonists, dopamine agonists, meianocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists, melanin concentrating hormone antagonists, leptins, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors, AGRPs (human agouti-related proteins), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, and the like, in a therapeutically effective amount via a suitable pharmaceutical composition, to achieve the desired effect in mammals as well as humans.

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith. The terms "treating", "treat", or "treatment" embrace both preventative, i.e., prophylactic, and palliative treatment.

The term "compounds of the present invention" (unless specifically identified otherwise) refer to compounds of Formulae (I), nitrogen oxides thereof, prodrugs of the compounds or nitrogen oxides, pharmaceutically acceptable salts of the compounds, nitrogen oxides, and/or prodrugs, and hydrates or solvates of the compounds, nitrogen oxides, salts, is and/or prodrugs, as well as, all stereoisomers (including diastereoisomers and enantiomers), tautomers and isotopically labeled compounds.

The present invention also relates to the novel intermediates, represented by general formulae (II), (IV), (VI), (VII), (IX) and (X), their stereoisomers, their radioisotopes, their geometric forms, their N-oxide, their salts, their solvates and any suitable combination of above, involved in preparing the compounds of general formula (I) and the process of preparation of such intermediates. Detailed Description of the Invention:

The present invention relates to compounds of general formula (I), their stereoisomers, its radioisotopes, their geometric forms, their N-oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and any suitable combination of above.

The present invention relates to compounds of general formula (I), described as follows,

General Formula (I) wherein Ri, R₂, R₃, R₄, R5, Re, R7, Re, R9, R10, Rn and R₁₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-C ₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)aIkoxy, cyclo(C-₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R- and R₂ or R₂ and R₃ or R₃ and R₄ or R5 and R₆ or Re and R or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms.

R₁3 and R represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, R₁3 and Rι together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, Rn and R₁₃ together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated. "A" represents one or two hydrogens, oxygen, hydroxy or lower(C C₆)alkoxy;

"n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; with the proviso that i. whenever n =2, all of Ri, R₂, R₃, R and Rio are together hydrogens, and R-|₃ and R-| are methyl or ethyl; then A is never either of =0 or -(H)₂ and also includes the salts of such compounds, ii. whenever n =2, all of R_1f R₃, R and Rio are together hydrogens, R₂ is methoxy, and R₁₃ and R₁₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, iii. whenever n =2, all of Ri, R₃, R₄ and Rio are together hydrogens, R₂ is chloro, and R₁3 and Rι₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, jy. whenever n =2, all of Ri, R₃, R₄ and R₂ are together hydrogens, R₁₀ is phenyl, and R₁3 and Rι₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, v. whenever n =3, all of R_1t R₂, R₃, R₄ and R 0 are together hydrogens then R₁₃ and Rι₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds.

Suitable groups represented by Ri, R₂, R₃, R₄, R₅, R₆, R_7, R₈, R₉, R₁0, Rn and

R₁₂ wherever applicable may be selected from halogen atom such as fluorine, chlorine, bromine or iodine; perhaloalkyl particularly perhalo(CrC₆)alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like; substituted or unsubstituted (C|-Cι₂)alkyl group, especially, linear or branched (C C₈)alkyl group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, n- pentyl, iso-pentyl, hexyl, iso-hexyl, heptyl, octyl and the like; cyclo(C₃-C₇)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cycloalkyl group may be substituted; cyclo(C₃-C₇)alkenyl group such as cyclopentenyl, cyclohexenyl, cycloheptynyl, cycloheptadienyl, cycloheptatrienyl and the like, the cycloalkenyl group may be substituted; (C C₁₂)alkoxy, especially, (CrC₆)alkoxy group such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; cyclo(C₃-C₇) alkoxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like, the cycloalkoxy group may be substituted; aryl group such as phenyl or naphthyl, the aryl group may be substituted; aralkyl group such as benzyl, phenethyl, C₆H₅CH₂CH₂CH₂, naphthylmethyl and the like, the aralkyl group may be substituted and the substituted aralkyl is a group such as CH₃C₆H CH₂, HaI-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like; aralkoxy group such as benzyloxy, phenethyloxy, naphthylmethyloxy, 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; heteroaryl group such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl, benzofuranyl and the like, the heteroaryl group may be substituted; heterocyclo(C C6)alkyl, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl and the like, the heterocycIo(CrC₆)alkyl group may be substituted; heteroaralkyl group such as furanylmethyl, pyridinylmethyl, oxazolylmethyl, oxazolylethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy, heteroaralkoxy, heterocycloalkoxy, wherein heteroaryl, heteroaralkyl, heterocycloalkyl and heterocyclylalkyl moieties are as defined earlier and may be substituted; acyl groups such as acetyl, propionyl or benzoyl, the acyl group may be substituted; acyloxy group such as CH₃COO, CH₃CH₂COO, C₆H₅COO and the like which may optionally be substituted, acylamino group such as CH₃CONH, CH₃CH₂CONH, C₃H₇CONH, C₆H₅CONH which may be substituted, (CrC₆)monoalkylamino group such as CH₃NH, C₂H₅NH, C₃H7NH, C₆H₁₃NH and the like, which may be substituted, (C_r C₆)dialkylamino group such as N(CH₃)₂, CH₃(C₂Hs)N and the like, which may be substituted; arylamino group such as C₆H₅NH, CH₃(C₆H₅)N, C₆H (CH₃)NH, NH-C₆H₄- Hal and the like, which may be substituted; arylalkylamino group such as C₆HsCH₂NH, C₆H₅CH₂CH₂NH, C₆H₅CH₂NCH3 and the like, which may be substituted; hydroxy(C C₆)alkyl which may be substituted, amino(CrC₆)alkyl which may be substituted; mono(CrC₆)alkylamino(CrC₆)alkyl, di(CrC₆)alkylamino(CrC₆)alkyl group which may be substituted, alkoxyalkyl group such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like, which may be substituted; aryloxyalkyl group such as C₆H5θCH₂, C₆H5θCH₂CH₂, naphthyloxymethyl and the like, which may be substituted; aralkoxyalkyl group such as C₆H₅CH₂OCH₂, C₆H₅CH₂OCH₂CH₂ and the like, which may be substituted; (CrC₆)alkylthio, thio(CrC₆)alkyl which may be substituted, alkoxycarbonylamino group such as C₂H₅OCONH, CH₃OCONH and the like which may be substituted; aryloxycarbonylamino group as C₆H₅OCONH, C₆H₅OCONCH₃, C₆H₅OCONC₂H₅, C₆H₄CH₃OCONH, C₆H₄(OCH₃)OCONH and the like which may be substituted; aralkoxycarbonylamino group such C₆HsCH₂OCONH,

C₆H₅CH₂CH₂OCONH, C₆H₅CH₂OCON(CH₃), C₆H₅CH₂OCON(C₂H₅), C₆H₄CH₃CH₂OCONH, C₆H₄OCH₃CH₂OCONH and the like, which may be substituted; aminocarbonylamino group; (CrC₆)alkylaminocarbonylamino group, di(C Cβjalkylaminocarbonylamino group; (Cή-C₆)alkylamidino group, (Cι-C₆)alkylguanidino, di(CrC₆)alkylguanidinogroups, hydrazino and hydroxylamino groups; carboxylic acid or its derivatives such as amides, like CONH₂, alkylaminocarbonyl like CH₃NHCO, (CH₃)₂NCO, C₂H₅NHCO, (C₂H₅)₂NCO, arylaminocarbonyl like PhNHCO, NapthylNHCO and the like, aralkylaminocarbonyl such as PhCH₂NHCO, PhCH₂CH₂NHCO and the like, heteroarylaminocarbonyl and heteroaralkylamino carbonyl groups where the heteroaryl groups are as defined earlier, heterocyclylaminocarbonyl where the heterocyclyl group is as defined earlier, carboxylic acid derivatives such as esters, wherein the ester moieties are alkoxycarbonyl groups such as unsubstituted or substituted phenoxycarbonyl, naphthyloxycarbonyl and the like; aralkoxycarbonyl group such as benzyloxycarbonyl, phenethyloxycarbonyl, naphthylmethoxycarbonyl and the like, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, wherein the heteroaryl group is as defined earlier, heterocycloxycarbonyl where heterocycle is as defined earlier and these carboxylic acid derivatives may be substituted; sulfonic acid or its derivatives such as S0₂NH₂, S0₂NHCH₃, S0₂N(CH₃)₂, S0₂NHCF₃, S0₂NHCO(C_rC₆)alkyl, S0₂NHCOaryl where the aryl group is as defined earlier and the sulfonic acid derivatives may be substituted; phosphoric acid and its derivatives as P(0)(OH)₂, P(O)(OCrC₆-alkyl)₂, P(0)(0-aryl)₂ and the like.

Suitable cyclic structures formed by the two adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R or R5 and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg or Rn and R₁ together with the carbon atoms to which they are attached contain 5 to 6 ring atoms which may optionally contain one or more heteroatoms selected from oxygen, nitrogen or sulfur and optionally contain one or more double bonds and optionally contain combination of double bond and hetero atoms as described earlier. The cyclic structures may be optionally substituted phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like. Suitable substituents on the cyclic structure formed by R-i and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg or Rn and R₁₂ together with the adjacent carbon atoms to which they are attached include oxo, hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, formyl, (CrC₃)alkyl, (C C₃)alkoxy, thioalkyl, alkylthio phenyl or benzyl groups.

R₁3 and R₁₄ preferably represents hydrogen, substituted or unsubstituted linear or branched (C C₁₂)alkyl like methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, pentyl, hexyl, octyl and the like; aryl group such as phenyl or naphthyl, the aryl group may be substituted; cyclo(C₃-C₇)alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cycloalkyl group may be substituted; the aralkyl group may be substituted and the substituted aralkyl is a group such as CH₃C₆H₄CH₂, Hal-C₆H₄CH₂, CH₃OC₆H₄CH₂, CH₃OC₆H₄CH₂CH₂ and the like; (C₃- C₇)cycloheteroalkyl with heteratoms like "Oxygen", "Nitrogen" and "Sulfur" and optionally containing one or two double or triple bonds.

Suitable hetero cyclic rings formed by either Rn and R₁₃ or R₁ and Rι₄ be selected from pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolinyl, diazolinyl and the like, the heterocyclyl group may be substituted; heteroaryl group such as pyridyl, pyrrolyl, oxazolyl, imidazolyl, oxadiazolyl, tetrazolyl, benzopyranyl and the like, the heteroaryl group may be substituted; heterocyclo(CrC₆)alkyl, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl and the like, the heterocyc!o(Cr Cβjalkyl group may be substituted; heteroaralkyl group such as furanmethyl, pyridinemethyl, oxazolemethyl, oxazolethyl and the like, the heteroaralkyl group may be substituted; heteroaryloxy, heteroaralkoxy, heterocycloalkoxy, wherein heteroaryl, heteroaralkyl, heterocycloalkyl and heterocyclylalkyl moieties are as defined earlier and may be further substituted.

Compounds of the present invention may be synthesized by synthetic routes that include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, Wl) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-1 9, Wiley, New York (1 967-1999 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Veriag, Berlin, including supplements (also available via the Beilstein online database)). For illustrative purposes, the reaction schemes depicted below provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For a more detailed description of the individual reaction steps, see the Examples section. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

Suitable substituents for -Lg are for example, a halogeno, for example a chloro, bromo, iodo, or aryl or alkyl sulfonyloxy group, for example, a methanesulfonyloxy or toluene-4-sulfonyloxy group or trifluoroacetate.

In the preparation of compounds of the present invention, protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. Suitable amino-protecting groups (NH-Pg) include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection is readily determined by one skilled in the art. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

The present invention also provides processes for preparing compounds of general formula (I) as defined above their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and novel intermediates involved therein, which are as described below. There are few methods already reported in the literature including GB patent specification 1 306 230, US patent 3 509 163. These methods and references therein are included herein by reference.

In the description and the reaction scheme, which follow Ri, R₂, R₃, R₄, R₅, R₆, R7, Rs, R9, R10, R11, R12, R13, R14, and n are as defined previously, while Lg, R, R_a and R_b are as defined elsewhere in the specification. Scheme I: Compounds of general formula (I) may be prepared by reacting a compound of formula (II) given below,

(ll) wherein R_{1 (} R₂, R₃, R , and Rio are as defined in relation to formula (I), further Rio could be protected form thereof; R represents either of a suitable N-protecting group, or a group such as,

where A, Rs, Re, R₇, Rs and R₉ are as defined earlier for compound of formula (I), with a compound of formula (III) or its acid addition salt,

(III) wherein n, Rn, Rι₂, R₁₃, and R₁₄ are as defined in relation to compound of formula (I) or precursor thereof and Lg is a leaving group; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula

ii) removing any protecting groups; or forming a pharmaceutically acceptable salt, solvate or a prodrug thereof.

In case when R is a suitable protecting group, an additional step as described in Scheme 2 is required to prepare compounds of formula (I).

The above reaction is preferably carried out in a solvent such as THF, toluene, acetone, ethyl acetate, DMF, DMSO, DME, N-methylpyrrolidone, methanol, ethanol propanol and the like and preferably using either acetone or DMF. The inert atmosphere may be maintained by using inert gases such as N₂, Ar or He. The reaction may be affected in the presence of a base such as K₂C0₃, NaOH, Na₂Cθ₃,

NaH and the like as well as the mixtures thereof. The reaction mixture is generally heated to an elevated temperature or reflux temperature of the solvent, until the reaction is complete. A wide variety of basic agents can be used in this condensation. However, preferred basic agents are amines, such as trimethylamine, triethylamine, tributylamine, N-methylmorpholine, piperidine, N-methylpiperidine, pyridine and 4- (N,N- dimethyIamino)pyridine, with a preferred basic agent being K₂C0₃. Reaction times of about 30 minutes to 72 hours are common. At the end of reaction, the volatile components are removed under reduced pressure. The reaction mixture can be optionally acidified before workup. The product can be isolated by precipitation, washed, dried and further purified by standard methods such as recrystallization, column chromatography etc.

Optional step (i) and (ii) can be carried out using conventional methods. These will depend upon the precise nature of the substituents R , R₂, R₃, R₄, R o, Rn, Rι₂, R₁₃, and Rι in each case. Examples of suitable reactions are illustrated hereinafter. Scheme 2:

Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (IV) given below,

(IV) wherein n, Ri, R₂, R3, R₄, Rn, R12, R₁3, and Rι₄ are as defined in relation to formula (I), R₁₀ is as defined elsewhere in the definition of compounds of formula (IV), with a compound of formula (V)

(V) where A, R5, Re, R7, R₈ and Rg, are as defined in relation to formula (I); and Lg is a leaving group as defined earlier; and thereafter if desired or necessary carrying out additional steps described above. Compounds of formula (IV) and (V) are suitably reacted together in an inert organic solvent which includes, aromatic hydrocarbons such as toluene, o-, m-, p- xylene; halogenated hydrocarbons such as methylene chloride, chloroform, and chlorobenzene; ethers such as diethylether, diisopropyl ether, tert-butyl methyl ether, dioxane, anisole, and tetrahydrofuran; nitriles such as acetonitrile and propionitrile; ketones such as acetone, methyl ethyl ketone, diethyl ketone and tert-butyl methyl ketone; alcohols such as methanol, ethanol, n-propanol, n-butanol, tert-butanol and also DMF (N.N-dimethylformamide), DMSO (N.N-dimethyl sulfoxide ) and water. The preferred list of solvents includes DMSO, DMF, acetonitrile and THF. Mixtures of these in varying ratios can also be used. Suitable bases are, generally, inorganic compounds such as alkali metal hydroxides and alkaline earth metal hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide and calcium hydroxide; alkali metal oxides and alkaline earth metal oxides, lithium oxide, sodium oxide, magnesium oxide and calcium oxide; alkali metal hydrides and alkaline earth metal hydrides such as lithium hydride, sodium hydride, potassium hydride and calcium hydride; alkali metal amides and alkaline earth metal amides such as lithium amide, sodium amide, potassium amide and calcium amide; alkali metal carbonates and alkaline earth metal carbonates such as lithium carbonate and calcium carbonate; and also alkali metal hydrogen carbonates and alkaline earth metal hydrogen carbonates such as sodium hydrogen carbonate; organometallic compounds, particularly alkali-metal alkyls such as methyl lithium, butyl lithium, phenyl lithium; alkyl magnesium halides such as methyl magnesium chloride, and alkali metal alkoxides and alkaline earth metal alkoxides such as sodium methoxide, sodium ethoxide, potassium ethoxide, potassium tert- butoxide and di-methoxymagnesium, further more organic bases e.g. triethylamine, triisopropylamine, and N-methylpiperidine, pyridine. Sodium hydroxide, Sodium methoxide, Sodium ethoxide, potassium hydroxide potassium carbonate and triethylamine are especially preferred. Suitably the reaction may be effected in the presence of phase transfer catalyst such as tetra-n-butylammonium hydrogensulphate and the like. The inert atmosphere may be maintained by using inert gases such as N₂, Ar or He. Reaction times may vary from 1 to 24 hrs, preferably from 2 to 6 hours, whereafter, if desired, the resulting compound is continued into a salt thereof.

Compounds of formula (IV) may be prepared as reported in the literature or by the method analogous to that described in Scheme 1, between the compound of formula (II) and (III), wherein ring nitrogen is protected before the reaction. Scheme 3:

Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (VI)

(VI) wherein R_1t R₂, R₃, R and R ₀ are as defined in relation to formula (I), R₁₀ could also be protected form thereof; R_a is defined as either hydrogen, halogen (such as chloro or bromo), lithio, trimethylsilyl, lower alkoxy, boronic acid or trifluoromethanesulfonate groups; R is defined as a suitable N-protecting group or a group such as,

where A, Rs, Re, R₇, R₈ and R₉ are as defined earlier for compound of formula (I), and with a compound of formula (III) or its acid addition salt

(IN) wherein n, Rn, Rι₂, R₁₃, and R ₄ are as defined in relation to compound of formula (I) or precursor thereof and Lg is a leaving group; and thereafter if desired or necessary carrying out additional steps described above.

Suitable substituents for Lg are hydroxy, sulfonyloxy group or a halogeno as defined earlier and the selection is based upon the nature of substitution at R_a.

The above reaction is preferably carried out in a solvent such as THF, toluene, ethyl acetate, acetone, water, DMF, DMSO, DME, and the like or a mixture thereof, and preferably using either acetone or DMF. The inert atmosphere may be maintained by using inert gases such as N₂, Ar or He. The reaction may be affected in the presence of a base such as K₂C0₃, Na₂C0₃, NaH or mixtures thereof. The reaction temperature may range from 20 °C to 150 °C based on the choice of solvent and preferably at a temperature in the range from 30 °C to 100 °C. The duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.

Scheme 4:

Alternatively, compounds of formula (I) may be prepared by reacting a compound of formula (VII),

N-protecting group or

(VII)

Where n, Ri, R₂, R₃, R₄, Rs, Re, R7, Rs, R9, Rn, R₁₂ and A are as defined in relation to formula (I); or R₁0 is also a protected form thereof; with a compound of formula (VIII)

NRι₃Rι₄H (VIII) wherein R₁3 and Rι₄ are as defined in relation to compound of formula (I) or precursor thereof or with its acid addition salt thereof; and thereafter if desired or necessary carrying out additional steps described above.

Suitable values for Lg are for example, a halogeno or sulfonyloxy group, for example a chloro, bromo, iodo, methanesulfonyloxy or toluene-4-sulfonyloxy group or trifluoroacetyl. Scheme 5:

Alternatively, compounds of formula (I) may be prepared by reductive alkylation of compounds of formula (IX)

wherein n, R_{1 f} R₂, R₃, R , R₁0, Rn and R ₂ are as defined in relation to formula (I), Rι₀ could also be a protected form thereof; R is defined as a suitable N-protecting group or a group such as,

where A, R₅, Re, R7, Rs and Rg are as defined earlier for compound of formula (I); by reductively alkylating a compound of formula (VIII) or its acid addition salt ,

NR₁₃Rι₄H (VIII) wherein Rι₃ and Rι are as defined in relation to compound of formula (I) or precursor thereof; and thereafter if desired or necessary carrying out additional steps described above. The reaction may be performed in a solvent such as methanol or ethanol in the presence of hydrogen and a suitable catalyst such as palladium on carbon, sodium cyanoborohydride/acetic acid.

Compounds of formula (IX) wherein R is acetyl, benzoyl are described in British patent application 1 306 230, the methods described therein are incorporated herein by reference. Scheme 6:

Alternatively, compounds of formula (I) in which Rι₃ is lower alkyl radical such as C|.₆alkyl, a cycloalkyl containing 3-8 carbon atoms or a benzyl radical in which phenyl ring is substituted and Rι₄ is hydrogen may be prepared from another compound of formula (X)

where n, Ri, R₂, R₃, R , R₁₀, Rn and Rι₂ are as defined in relation to formula (I), Rm is a group R₁0 as defined in relation to formula (I) or protected form thereof; and in which R_b represents hydrogen atom or a benzyl group in which phenyl ring is substituted and is removable by hydrogenolysis, R is defined as a suitable N-protecting group or a group such as,

where A, R₅, R₆, R7, R₈ and Rg are as defined earlier for compound of formula (I), with a compound of formula (XI) 13

C

I

^R14

(XI) wherein R₁₃ and Rι₄ are as defined in relation to compound of formula (I) or precursor thereof or with its acid addition salt thereof; and thereafter if desired or necessary carrying out additional steps described above.

Similarly, when R₁₀, R₁₃ and R₁₄ represents hydrogen atoms, these compounds may be prepared according to this invention by hydrogenolysing the corresponding indole derivative, in which above substituents represent one or more benzyl groups removable by hydrogenolysis.

Furthermore, indole derivatives of the general formula (I) in which R₁3 is benzyl or a substituted benzyl group removable by hydrogenolysis and R_M is hydrogen, may according to this invention be prepared by partially hydrogenolysing the corresponding indole derivative in which Rι₄ is identical to the substituent R_u above. The said hydrogenolysis is performed in a solvent such as ethanol in the presence of a suitable catalyst, e.g. palladium on carbon.

The reaction is performed in a solvent such as methanol or ethanol in the presence of hydrogen and a suitable catalyst such as palladium on carbon.

Novel intermediates of general formula (II) are represented as given below,

p or

(ID wherein R-i, R₂, R₃, R₄, R5, Re, R7, Rs, R9 and Rm may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrC₁₂)alkyl, (C₂-C ₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoaϊkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and R₉ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; and R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above; and its stereoisomers and its salts; with the proviso that whenever A is either of -CO or -CH₂, then all of R^ R₂, R₃, R₄ and R together are never hydrogens.

Numerous processes to prepare the compounds of formula (II) can be found in literature. Some of them include US patent 3 860 608, J. Heterocyclic Chemistry, 16, 221 (1979), JP patent publication 57200362 A, and DE 111890. Alternatively, compounds of formula (II) may suitably be prepared by conventional methods for oxidization of indole-3-carboxaldehydes as described in literature (Chem. Pharm. Bull, 1985, 33, 1843, wherein HMPA, mCPBA are used as oxidizing agent).

Novel intermediates of general formula (IV) are represented as given below,

(IV) wherein Ri, R₂, R₃, R₄, R and R ₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrCι₂)alkyl, (C₂- C₁₂)alkenyl, (C₂-Cι₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrC ₂)aIkoxy, cyclo(C₃-C₇)a!koxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R-_\ and R₂ or R₂ and R₃ or R₃ and R₄ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and R₁₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms;

Rm represents hydrogen, formyl, substituted or unsubstituted groups selected from linear or branched (CrCι₂)alkyl, (C₂-Cι₂)alkenyl, (C₂-C ₂)alkynyl, (C₃- C₇)cycloalkyl, (C₃-C )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, sulfonic acids and its derivatives, phosphoric acid and its derivatives.

Rm and Rι₄ represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, Rm and Rι₄ together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, R and R₁₃ together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; and "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; and its stereoisomers and its salts; with the proviso that, i) whenever n =2, all of R^ R₂, R₃, R₄ and R₁₀ are together hydrogens then Rm and Rι are methyl or ethyl; then either of Rn or R ₂ is other than hydrogen, ii) whenever n =2, all of R_1t R₃, R₄ and Rm are together hydrogens, R₂ is methoxy, and Rm and R_M are methyl or ethyl; then either of Rn or Rι₂ is other than hydrogen, iii) whenever n =2, all of Rι,_^R₃, R₄ and R₁₀ are together hydrogens, R₂ is chloro,⁵ and R and R₁ are methyl or ethyl; then either of Rn or Rι₂ is other than hydrogen, iv) whenever n =2, all of Ri, R₃, R and R₂ are together hydrogens, Rm is phenyl, and Rm and Rι₄ are methyl or ethyl; then either of Rn or Rι₂ is other than hydrogen, v) whenever n =3, all of R^ R₂, R₃, R₄ and Rm are together hydrogens then R₁₃ and Rι₄ are methyl or ethyl; then either of Rn or R ₂ is other than hydrogen. Numerous processes to prepare the compounds of formula (IV) can be found in literature. Some of them include US patent 3,509,163 and GB patent application 1 ,306,230. Novel intermediates of general formula (VI) are represented as given below,

or

(VI) wherein Ri, R₂, R₃, R , Rs, Re, R7, Rs, R9 and Rm may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-C ₂)alkenyl, (C₂-Cι₂) alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C₁₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R and R₂ or R₂ and R₃ or R₃ and R or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above wherein A represents one or two hydrogens, oxygen, hydroxy or lower(C C₆)alkoxy; R_a is defined as either hydrogen, halogen (such as chloro or bromo), lithio, trimethylsilyl, lower alkoxy, bpronic acid or trifluoromethanesulfonate groups; and its stereoisomers and its salts.

Novel intermediates of general formula (VII) are represented as given below,

N-protecting group or

( N) wherein Ri, R₂, R₃, R , R₅, R₆, R₇, R₈, Rg, Rm, Rn and R ₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C_rCι₂)alkyl, (C₂-C ₂)alkenyl, (C₂-C ₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C₁₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R₁ and R₂ or R₂ and R₃ or R₃ and R or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rm together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; and Lg is a leaving group as defined earlier; and its stereoisomers and its salts.

Novel intermediates of general formula (IX) are represented as given below,

N-protecting group or

wherein Ri, R₂, R₃, R₄, R₅, Re, R7, Rs, R9, Rm, Rn and Rι₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-Cι₂)alkynyl, (C₃-C )cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R and R or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R7 and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or R and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluorenylmethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrCe)alkoxy; and its stereoisomers and its salts. Novel intermediates of general formula (X) are represented as given below,

R = N-protecting group or

(X) wherein R _t R₂, R₃, R₄, R5, Re, R7, Rs, R9, R10, Rn and Rι₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrC₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C Cι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(Cr C₆)alkoxy; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; and R is either benzyl or hydrogen; and its stereoisomers and its salts.

Procedure to prepare compounds of formula (X) is as reported in GB patent 1,306,230. The process includes hydrogenolysis of compounds of formula (I) wherein Rm and/or R_M are benzyl groups or hydrogens according to the method known in the art.

The stereoisomers of compounds of general formula (I) may be prepared by one or more ways presented below: i) One or more of the reagents may be used in their optically active form. ii) Optically pure catalyst or chiral ligands along with metal catalyst may be employed in the reduction process. The metal catalysts 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 Asymmetric synthesis, J. E. Baldwin Ed., Tetrahedron series, 14, 311-316). iii) The mixture of stereoisomers may be resolved by conventional methods such as forming a diastereomeric salts with chiral acids or chiral amines, or chiral amino alcohols, chiral amino acids. The resulting mixture of diastereomers may then be separated by methods such as fractional crystallization, chromatography and the like, which is 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 resolved by conventional methods such as microbial resolution, resolving the diastereomeric salts formed with chiral acids or chiral bases.

Chiral acids that can be employed may be tartaric acid, mandelic acid, lactic acid, camphorsulfonic acid, amino acids and the like. Chiral bases that can be employed may be cinchona alkaloids, brucine or a basic amino group such as lysine, arginine and the like. Isotopically labelled compounds of the present invention are useful in drug and/or substrate tissue distribution and target occupancy assays. For example, isotopically labelled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography).

The pharmaceutically acceptable salts forming a part of this invention may be prepared by treating the compound of formula (I) with 1-6 equivalents of a base such as sodium hydride, 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 lysine, arginine, methyl benzylamine, ethanolamine, diethanolamine, tromethamine, choline, guanidine and their derivatives may be used. Acid addition salts, whereever applicable may be prepared by treatment with acids such as tartaric acid, mandelic acid, fumaric acid, maleic acid, lactic acid, salicyclic 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 lower alkyl ketone such as acetone, or the mixtures thereof.

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

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parental (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or a form suitable for administration by inhalation or insufflation.

"Therapeutically effective amount" is defined as 'an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein'.

The dose of the active compounds can vary depending on factors such as the route of administration, age and weight of patient, nature and severity of the disease to be treated and similar factors. Therefore, any reference herein to a pharmacologically effective amount of the compounds of general formula (I) refers to the aforementioned factors. A proposed dose of the active compounds of this invention, for either oral, parenteral, nasal or buccal administration, to an average adult human, for the treatment of the conditions referred to above, is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.

For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take 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 vehicle before 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 (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).

For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner. The active compounds of the invention may be' formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use. The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of an aerosol spray from a pressurized container or a nebulizer, or from a capsule using a inhaler or insufflator. In the case of a pressurized aerosol, a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas and the dosage unit may be determined by providing a valve to deliver a metered amount. The medicament for pressurized container or nebulizer may contain a solution or suspension of the active compound while for a capsule it preferably should be in the form of powder. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch. Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or "puff of aerosol contains 20 μg to 1000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 μg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

The affinities of the compound of this invention for the various serotonin receptors are evaluated using standard radioligand binding assays and are described here. Radio ligand binding assays for various 5-HT receptor sub-types:

i) Assay for 5HT1A

Materials and Methods: Receptor source: Human recombinant expressed in HEK-293 cells Radio ligand: [3HJ-8-OH-DPAT (221 Ci/mmol) Final ligand concentration - [0.5 nM] Reference compound: 8-OH-DPAT Positive control: 8-OH-DPAT

Incubation conditions:

Reactions are carried out in 50 mM TRIS-HCI (pH 7.4) containing 10 mM

MgS0₄, 0.5 mM EDTA and 0.1% Ascorbic acid at room temperature for 1 hour. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HTι A binding site.

Literature Reference: ^• Hoyer D., Engel G., et al. Molecular Pharmacology of 5HTι and 5-HT₂ Recognition

Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [³H]-5HT,

[³H]-8-OH-DPAT, [¹²⁵l]-lodocyanopindolol, [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-HTι_A, 5HTIB, 5-HTI_C, and 5-HTι_D Receptors. Naunyn-Schmiedeberg's

Arch. Pharmac. 340: 135-138 (1989) with modifications.

ii) Assay for 5HT1B

Materials and Methods: Receptor source : Rat striatal membranes

Radioligand : [¹²⁵l]lodocyanopindolol (2200 Ci/mmol)

Final ligand concentration - [0.15 nM]

Non-specific determinant : Serotonin - [10 μM]

Reference compound : Serotonin Positive control : Serotonin

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.4) containing 60 μM (-) isoproterenol at 37°C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HT1B binding site.

Literature Reference: ^• Hoyer D., Engel G., et al. Molecular Pharmacology of 5HTι and 5-HT₂ Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [³H]-5HT, [³H]-8-OH-DPAT, [¹²⁵l]-lodocyanopindolol, [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-HTι_A, 5HTι_B, 5-HTic, and 5-HTi Receptors. Naunyn-Schmiedeberg's

Arch. Pharmac. 340: 135-138 (1989) with modifications.

iii) Assay for 5HT1D

Materials and Methods: Receptor source : Human cortex

Radioligand : [³H] 5-Carboxamidotryptamine (20-70 Ci/mmol)

Final ligand concentration - [2.0 nM]

Non-specific determinant : 5-Carboxamidotryptamine (5-CT) - [1.0 μM]

Reference compound : 5-Carboxamidotryptamine (5-CT) Positive control : 5-Carboxamidotryptamine (5-CT)

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.7) containing 4 mM CaCI₂, 100 nM 8-OH-DPAT, 100 nM Mesulergine, 10 uM Pargyline and 0.1 % ascorbic acid at 25 °C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the cloned 5HTI_D binding site.

Literature Reference:

^• Waeber C, Schoeffter, Palacios J.M. and Hoyer D. Molecular Pharmacology of the 5-HTID Recognition Sites: Radioligand Binding Studies in Human, Pig, and Calf Brain Membranes. Naunyn-Schmiedeberg's Arch. Pharmacol. 337: 595-601 (1988) with modifications. iv) Assay for 5HT2A

Materials and Methods:

Receptor source : Human Cortex Radioligand : [³H] Ketanserin (60-90 Ci/mmol) Final ligand concentration - [2.0 nM]

Non-specific determinant : Ketanserin - [3.0 μM] Reference compound : Ketanserin Positive control : Ketanserin

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.5) at room temperature for

90 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters.

Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HT_2A binding site.

Literature Reference:

^• Leysen J. E., Niemegeers C. J., Van Nueten J. M. and Laduron P. M.

[³H]Ketanserin: A Selective Tritiated Ligand for Serotonin₂ 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) Assay for 5HT2C Materials and Methods:

Receptor source : Pig choroid plexus membranes

Radioligand : [³H] Mesulergine (50-60 Ci/mmol)

Final ligand concentration - [1.0 nM]

Non-specific determinant : Serotonin - [100 μM] Reference compound : Mianserin

Positive control : Mianserin

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.7) containing 4 mM CaCI₂ and 0.1% ascorbic acid at 37 °C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HT2C binding site.

Literature Reference: ^• A. Pazos, D. Hoyer, and J. Palacios. The Binding of Serotonergic Ligands to the Porcine 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 5HT| and 5-HT₂ Recognition Sites in Rat and Pig Brain Membranes: Radioligand Binding Studies with [3HJ-5HT, [3H]-8-OH-DPAT, [¹²⁵l]-lodocyanopindolol, [3H]-Mesulergine and [3H]- Ketanserin. Eur. Jrnl. Pharmacol. 118: 13-23 (1985) with modifications.

vi) Assay for 5HT3

Materials and Methods: Receptor source : N1 E-115 cells

Radioligand : [³H]-GR 65630 (30-70 Ci/mmol)

Final ligand concentration - [0.35 nM]

Non-specific determinant : MDL-72222 - [1.0 μM]

Reference compound : MDL-72222 Positive control : MDL-72222

Incubation conditions :

Reactions are carried out 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 onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HT₃ binding site.

Literature Reference: ^• Lummis S. C. R., Kilpatrick G. J. Characterization of 5HT₃ Receptors in Intact N1 E- 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 M. B. 5-HT₃ Receptors and the Therapeutic Potential of 5HT₃ Receptor Antagonists. Therapie. 46:431-435 (1991).

vii) Assay for 5HT4 Materials and Methods:

Receptor source : Guinea pig striatal membranes Radioligand : [³H] GR-113808 (30-70 Ci/mmol) Final ligand concentration - [0.2 nM] Non-specific determinant : Serotonin (5-HT) - [30 μM] Reference compound : Serotonin (5-HT)

Positive control : Serotonin (5-HT)

Incubation conditions :

Reactions are carried out in 50 mM HEPES (pH 7.4) at 370C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the 5HT₄ binding site.

Literature Reference: ^• Grossman Kilpatrick, C, et al. Development of a Radioligand Binding Assay for 5HT₄ Receptors in Guinea Pig and Rat Brain. Brit. J Pharmco. 109: 618-624 (1993).

viii) Assay for 5HT5A

Materials and Methods: Receptor source : Human recombinant expressed in HEK 293 cells

Radioligand : [³H] LSD (60-87 Ci/mmol)

Final ligand concentration - [1.0 nM]

Non-specific determinant : Methiothepin mesylate - [1.0 μM]

Reference compound : Methiothepin mesylate Positive control : Methiothepin mesylate

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.4) containing 10 mM

MgS0 and 0.5 mM EDTA at 37 °C for 60 minutes. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound with the cloned 5HT_5A binding site.

Literature Reference: ^• Rees S., et al. FEBS Letters, 355: 242-246 (1994) with modifications

ix) Assay for 5HT6

Materials and Methods:

Receptor source : Human recombinant expressed in HEK293 cells Radioligand : [³H]LSD (60-80 Ci/mmol)

Final ligand concentration - [1.5 nM] Non-specific determinant : Methiothepin mesylate - [0.1 μM] Reference compound : Methiothepin mesylate Positive control : Methiothepin mesylate

Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.4) containing 10 mM

MgCI₂, 0.5 mM EDTA for 60 minutes at 37 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HT₆ binding site.

Literature Reference:

^• 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) Assay for 5-HT7

Materials and Methods: Receptor source : Human recombinant expressed in CHO cells

Radioligand : [³H]LSD (60-80 Ci/mmol)

Final ligand concentration - [2.5 nM]

Non-specific determinant : 5-Carboxamidotryptamine (5-CT) - [0.1 μM]

Reference compound : 5-Carboxamidotryptamine Positive control : 5-Carboxamidotryptamine Incubation conditions :

Reactions are carried out in 50 mM TRIS-HCI (pH 7.4) containing 10 mM MgCI₂, 0.5 mM EDTA for 60 minutes at 37 °C. The reaction is terminated by rapid vacuum filtration onto glass fiber filters. Radioactivity trapped onto the filters is determined and compared to control values in order to ascertain any interactions of test compound(s) with the cloned serotonin - 5HT₇ binding site. Literature Reference:

^• Y. Shen, E. Monsma, M. Metcalf, P. Jose, M Hamblin, 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 preparation of variously substituted compounds of general formula (I), according to the methods described herein. These are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention. Commercial reagents were utilized without further purification. Room temperature refers to 25 - 30 °C. Melting points are uncorrected. IR spectra were taken using KBr and in solid state. Unless otherwise stated, all mass spectra were carried out using ESI conditions. 1 H NMR spectra were recorded at 200 MHz on a Bruker instrument. Deuterated chloroform (99.8 % D) was used as solvent. TMS was used as internal reference standard. Chemical shift values are expressed in are reported in parts per million (δ)-values. The following abbreviations are used for the multiplicity for the NMR signals: s=singlet, bs=broad singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, tt=triplet of triplets, m=multiplet. NMR, mass were corrected for background peaks. Specific rotations were measured at room temperature using the sodium D (589 nm). Chromatography refers to column chromatography performed using 60 - 120 mesh silica gel and executed under nitrogen pressure (flash chromatography) conditions.

Description 1 : General procedure for the preparation of monoperphthalic acid (D 1)

To the mixture containing phthalic anhydride (2.22g.; 0.015 mole) and diethyl ether (25 mL), hydrogen peroxide solution (3.4 g.; 0.03 moles; as 30 % aqueous solution) was added and the reaction mixture was stirred at 25 °C to dissolve the anhydride. The reaction mixture was transferred to a separating funnel, ether layer was separated and aqueous layer was extracted with ether (3 X 10 mL). Combined ether extracts are dried over sodium sulfate and this solution of monoperphthalic acid was used.

Description 2 : 1-Benzyl-1H-indole (D 2)

ROUTE I :

In a three-necked round bottom flask equipped with pressure equalizing funnel, sodium hydride (0.6 g of 50 % suspension; 0.0125 mole) and DMF (8 mL) were taken. Indole (0.01 mole) was added slowly at 0° C and the reaction mixture was stirred well. Then it was warmed to 25° C and stirring was continued for one hour, afterwards the reaction mixture was cooled and Benzyl bromide (2.05 g; 0.012 mole in 5 mL DMF) was added slowly from the pressure equalizing funnel over 5 minutes, and further stirred at 25 °C for 3 hours. After the completion of reaction (3 - 5 hours), the reaction mixture was poured in cold water and the product was extracted in ethyl acetate (2 X 25 mL). The combined organic extracts were washed with water, followed by brine, dried over anhydrous sodium sulfate and the product was isolated by distillation of solvent under reduced pressure. The product usually was an oily compound, which was used as such for the next step.

The crude residue was purified by silica gel column chromatography using 30 % methanol in ethyl acetate as a mobile phase, to obtain the title compound, which was identified by IR, NMR and mass spectral analyses. ROUTE II :

Instead of sodium hydride (0.6 g; 0.0125 mole), either sodium hydroxide (0.03 moles) or potassium hydroxide (0.03 moles) was taken and similar procedure was followed.

Various substituted indole were treated with substituted benzyl bromide as described above. These compounds were identified by IR, NMR and mass spectral analyses. Following is the partial list of such compounds: List - 1 :

Description Mass ion

(M+H)⁺ D 2 1-Benzyl-2-phenyl-1 /-/-indole 284

D 3 1-Benzyl-2-phenyl-5-methoxy-1H-indole 314

D 4 1-Benzyl-2-phenyl-5-methyl-1r7-indole 298

D 5 1-Benzyl-5-bromo-2-phenyl-1H-indole 362 /

364 D 6 1-Benzyl-5-chloro-2-phenyl-1H-indole 318 /

320 D 7 1-Benzyl-5-fluoro-2-phenyl-1H-indole 302

D 8 1-(2'-Bromobenzyl)-2-phenyl-1H-indole 362 /

364 D 9 1-(4'-Methylbenzyl)-5-fluoro-2-phenyl-1H-indole 316

D10 1-(4'-Methylbenzyl)-5-chloro-2-phenyl-1H-indoIe 332 /

334 D11 1-(2'-Bromo-4'-methylbenzyl)-2-phenyl-1H-indole 376 /

378 D12 1-(2'-Bromo-4'-isopropylbenzyl)-2-phenyl-1 /-/-indole 404 /

406 D13 1-(4'-Fluorobenzyl)-5-chIoro-2-phenyl-1f -indole 336 /

338 D14 1-Benzyl-2-methyl-1H-indole 222

D15 1-Benzyl-2-methyl-5-methoxy-1/7-indole 252

D16 1-Benzyl-2,5-dimethyl-1 H-indole 236

D17 1-Benzyl-5-bromo-2-methyl-1H-indole 300 /

302 D18 1-Benzyl-5-chloro-2-methyl-1H-indole 256 /

258 D19 1-Benzyl-5-fluoro-2-methyl-1H-indole 240

D20 1-(2'-Bromobenzyl)-2-methyl-1H-indole 300 /

302 D21 1-(4'-MethyIbenzyl)-5-fluoro-2-methyl-1H-indoIe 254

D22 1-(4'-Methylbenzyl)-5-chloro-2-methyl-1H-indole 270 /

272 D23 1-(2'-Bromo-4'-methylbenzyl)-2-methyl-1H-indole 314 /

316 D24 1-(2'-Bromo-4'-isopropylbenzyl)-2-methyl-1 -/-indole 342 /

344 D25 1-(4'-Fluorobenzyl)-5-chloro-2-methyl-1 -/-indole 274

Description 26 : 1-Benzyl-2-phenyl-1W-indol-3-ol (D 26) ROUTE 1: 1 -Benzyl indole (0.01 mole) dissolved in glacial acetic acid (15 mL) was transferred to three-necked flask. To this mixture monoperphpthalate solution (0.02 mole) in ether was added and stirred at 25 °C for 3 hours. After the completion of reaction, the volatile substances were removed under reduced pressure. To the residue was added ethyl acetate : water (1 : 1) mixture, followed by sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 X 20 mL). The combined organic extracts were washed with brine and the ethyl acetate was distilled off to obtain the crude intermediate.

This intermediate was taken as such to the next step without purification. ROUTE 2:

Alternatively 1 -Benzyl- 1 r-/-indol-3-ol derivatives can also be obtained as reported in the Heterocycles, Vol. 30, No. 1 , 1990, by reacting corresponding benzylindole with magnesium monoperphthalate.

Various other derivatives of general formula (II) were prepared as described above. These compounds were identified by IR, NMR and mass spectral analyses. Following is the partial list of such compounds.

List - 2:

Description Mass ion

(M+H)⁺

D26 1-Benzyl-2-phenyl-1H-indol-3-ol 300

D27 1-Benzyl-2-phenyl-5-methoxy-1H-indol-3-ol 330

D28 1-Benzyl-2-phenyl-5-methyl-1b-indol-3-ol 314

D29 1-Benzyl-5-bromo-2-phenyl-1H-indoi-3-ol 378 /

380 D30 1-Benzyl-5-chloro-2-phenyl-1H-indol-3-oI 334 /

336 D31 1-Benzyl-5-fluoro-2-phenyl-1H-indol-3-ol 318

D32 1-(2'-Bromobenzyl)-2-phenyl-1W-indol-3-ol 378 /

380 D33 1-(4'-Methylbenzyl)-5-fluoro-2-phenyl-1ry-indol-3-ol 332

D34 1-(4'-Methylbenzyl)-5-chloro-2-phenyl-1H-indol-3-ol 348 /

350 D35 1-(2'-Bromo-4'-methylbenzyl)-2-phenyl-1r7-indol-3-ol 392 /

394 D35 1-(2'-Bromo-4'-isopropylbenzyl)-2-phenyl-1H-indol-3-ol 420 /

422 D37 1-(4'-Fluorobenzyl)-5-chloro-2-phenyl-1H-indol-3-ol 352 /

354 D38 1-Benzyl-2-methyl-1rY-indol-3-ol 238

D39 1-Benzyl-2-methyl-5-methoxy-1H-indol-3-ol 268

D40 1-Benzyl-2,5-dimethyl-1H-indol-3-ol 252

D41 1-Benzyl-5-bromo-2-methyl-1H-indol-3-ol 316 /

318 D42 1-Benzyl-5-chloro-2-methyl-1ry-indol-3-ol 272 /

274 D43 1-Benzyl-5-fluoro-2-methyl-1r-/-indol-3-ol 256

D44 1-(2'-Bromobenzyl)-2-methyl-1rY-indol-3-ol 316 /

318 D45 1-(4'-Methylbenzyl)-5-fluoro-2-methyl-1H-indol-3-ol 270

D46 1-(4'-Methylbenzyl)-5-chloro-2-methyl-1H-indol-3-ol 286 /

288 D47 1-(2'-Bromo-4'-methylbenzyl)-2-methyl-1r-/-indoI-3-oI 330 /332

D48 1-(2'-Bromo-4'-isopropylbenzyl)-2-methyl-1H-indol-3-ol 358 /

360 D49 1-(4'-Fluorobenzyl)-5-chloro-2-methyl-1 -/-indol-3-ol 290 /

292

Description 50: 1-(3-Hydroxy-indol-1-yl)ethanone (D 50)

According to the methods given in literature, the following N-acetylindoxyls were prepared and are listed below. These compounds were identified by IR, NMR and mass spectral analyses. List - 3:

Description Mass ion

(M+H)⁺ D50 1-(3-Hydroxy-indol-1-yl)ethanone 176

D51 1-(5-Bromo-3-hydroxy-indol-1-yl)ethanone 254 /

256 D52 1-(5-Chloro-3-hydroxy-indol-1-yl)ethanone 210 /

212 D53 1-(5-Fluoro-3-hydroxy-indol-1-yl)ethanone 194

D54 1-(6-Chloro-3-hydroxy-indol-1-yl)ethanone 210 /

212 D55 1-(3-Hydroxy-5-methoxy-indol-1-yl)ethanone 206

D56 1-(5,7-Dibromo-3-hydroxy-indol-1-yl)ethanone 332 /

334 /

336 D57 1-(6-Chloro-5-methoxy-3-hydroxy-indol-1-yl)ethanone 240 /

242 D58 1-(6-ChIoro-5-fluoro-3-hydroxy-indol-1-yl)ethanone 228 /

230 D59 1-(6-Bromo-5-methoxy-3-hydroxy-indol-1-yl)ethanone 284 /

286 D60 1-(6-Bromo-5-fluoro-3-hydroxy-indol-1-yl)ethanone 272 /

274 D61 1-(4-Chloro-5-fluoro-3-hydroxy-indol-1-yl)ethanone 228 /

230 D62 1-(4-Methoxy-5-fluoro-3-hydroxy-indol-1-yl)ethanone 224

D63 1-(3-Hydroxy-2-phenyl-indol-1-yl)ethanone 252

D64 1-(5-Bromo-3-hydroxy-2-phenyl-indol-1-yl)ethanone 330 /

332 D65 1-(5-ChIoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 286 /

288 D65 1-(5-Fluoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 270

D67 1-(6-Chloro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 286 /

288 D68 1-(3-Hydroxy-5-methoxy-2-phenyl-indol-1-yl)ethanone 282

D69 1-(5,7-Dibromo-3-hydroxy-2-phenyl-indol-1-yl)ethanone 408 /

410 /

412 D70 1-(6-Chloro-5-methoxy-3-hydroxy-2-phenyIindol-1-yl)ethanone 316 /

318 D71 1-(6-Chloro-5-fluoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 304

D72 1-(6-Bromo-5-methoxy-3-hydroxy-2-phenyl-indol-1-yl)ethanone 360 /

362 D73 1-(6-Bromo-5-fluoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 348 /

350 D74 1-(4-Chloro-5-fluoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 304 /

306 D75 1-(4-Methoxy-5-fluoro-3-hydroxy-2-phenyl-indol-1-yl)ethanone 300

D76 1-(3-Hydroxy-2-methyl-indol-1-yl)ethanone 190

D77 1-(5-Bromo-3-hydroxy-2-methyl-indol-1-yl)ethanone 268 /

270 D78 1-(5-Chloro-3-hydroxy-2-methyl-indol-1-yl)ethanone 224

D79 1-(5-Fluoro-3-hydroxy-2-methyl-indol-1-yl)ethanone 208

D80 1-(6-Chloro-3-hydroxy-2-methyl-indol-1-yl)ethanone 224 /

226 D81 1-(3-Hydroxy-5-methoxy-2-methyl-indol-1-yl)ethanone 220

D82 1-(5,7-Dibromo-3-hydroxy-2-methyl-indol-1-yl)ethanone 346 /

348 /

350 D83 1-(6-Chloro-5-methoxy-3-hydroxy-2-methyl-indol-1-yl)ethanone 254 /

256 D84 1-(6-Chloro-5-fluoro-3-hydroxy-2-methyl-indol-1-yl)ethanone 242 /

244 D85 1-(6-Bromo-5-methoxy-3-hydroxy-2-methyl-indol-1-yl)ethanone 298 /

300 D86 1-(6-Bromo-5-fluoro-3-hydroxy-2-methyl-indol-1-yl)ethanone 286 /

288 D87 1-(4-Chloro-5-fluoro-3-hydroxy-2-methyl-indol-1-yl)ethanone 242 /

244 D88 1-(4-Methoxy-5-fluoro-3-hydroxy-2-methyl-indol-1-yl)ethanone 238

Description 89: [2-(1-Acetyl-1r -indol-3-yloxy)ethyl]dimethylamine (D 89)

According to the methods given in literature (US patent 3 860 608) following derivatives were prepared and listed as below. These compounds were identified by IR, NMR and mass spectral analyses. The following procedure also describes the method of synthesis of the same.

1-AcetyI-3-indoxyl (0.015 mole), was taken in three necked flask along with potassium carbonate (0.030 mole); tetrahydrofuran (ca 15 mL) and N,N- dimethylaminoethyl chloride (ca 15 % solution in toluene; 0.015 mole) and the mixture was refluxed for 3 hours. Another lot of N,N-dimethylaminoethyI chloride (ca 15 % solution in toluene; 0.015 mole) was added and the reaction mixture was refluxed for further 3 hours. The reaction mixture was cooled to 25 °C and filtered. The filtrate was washed with water and brine; dried over sodium sulfate; organic solvens were removed under reduced pressure and the residue was purified by column chromatography, on silica gel; using hexane (100%) to triethylamine : ethyl acetate (2 : 98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (X) can be further purified by preparation of their acid addition salts.

List - 4:

Description Mass ion (M+H)⁺

D89 [2- 1-Acetyl-1H-lndol-3-yIoxy)ethyI]dimethylamine 247

D90 [2- 1-Acetyl-2-Phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 323

D91 [2- 1 -Acetyl-2-Methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 261

D92 [2- 1-Acetyl-5-Bromo-1H-indol-3-yloxy)ethyl]dimethylamine 325/327

D93 [2- 1-Acetyl-5-Bromo-2-phenyl-1f -indol-3-yloxy)ethyl]dimethylamine 401/403

D94 [2- 1-Acetyl-5-Bromo-2-methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 339/341

D95 [2- 1-Acetyl-5-Chloro-1ry-indol-3-yloxy)ethyl]dimethylamine 281/283

D96 [2- 1-Acetyl-5-Chloro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 357/359

D97 [2- 1-Acetyl-5-Chloro- 2- methyl -1/--indol-3-yloxy)ethyI]dimethylamine 295/297

D98 [2- l-Acetyl-e-Chloro-IH-indol-S-yloxyJethylJdimethylamine 281/283

D99 [2- 1-Acetyl-6-Chloro-2-phenyl-1r7-indol-3-yloxy)ethyl]dimethylamine 357/359

D 100 [2- 1-Acetyl-6-Chloro-2-methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 295/297

D 101 [2- 1-Acetyl-5,7-Dichloro-1r--indol-3-yloxy)ethyl]dimethylamine 315/317/

319

D 102 [2- 1-Acetyl-5,7-Dichloro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 391/393/

395

D 103 [2- 1-AcetyI-5,7-Dichloro-2-methyl-1 V-indol-3-yloxy)ethyl]dimethylamine 329/331/

333

D 104 [2- 1-Acetyl-5,7-Dibromo-1ry-indol-3-yloxy)ethyl]dimethylamine 403/405/

407

D 105 [2- 1-Acetyl-5,7-Dibromo-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 479/481/

483

D 106 [2- 1-Acetyl-5,7-Dibromo-2-methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 417/419/

421

D 107 [2- 1-Acetyl-7-Bromo-5-chloro-1H-indoI-3-yloxy)ethyl]dimethyIamine 359/361 D 108 [2- 1-Acetyl-7-Bromo-5-chloro-2-phenyl-1H-indol-3- 435/437 ylo x. y)ethyl]dimethylamine

D 109 [2 1-Acetyl-7-Bromo-5-chloro-2-methyl-1 -/-indol-3- 373/375 ylo: xy)ethyl]dimethylamine

D110 [2- 1-Acetyl-5-Methoxy-1 --indol-3-yloxy)ethyl]dimethylamine 277 D 111 [2- 1-Acetyl-5-Methoxy-2-phenyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 353 D112 [2- 1-Acetyl-5-Methoxy-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine 291 Description 113: [2-(1r -indol-3-yloxy)ethyl]dimethylamine (D 113)

According to the methods given in literature (US patent 3 860 608) the above derivatives were deacetylated. These compounds were identified by IR, NMR and mass spectral analyses. The following procedure also describes the method of synthesis of above compounds,

[2-(1-Acetyl-1H-indol-3-yloxy)ethyl]dimethylamine (0.015 mole), was taken in three necked flask along with sodium hydroxide (0.022 mole), water (ca 15 mL) and methanol (ca 15 mL). The reaction mixture was refluxed for 30 minutes to 2 hours. The reaction mixture was cooled to 25 °C and poured on to ice-cold water. The compound was extracted with ethyl acetate (3 X 20 mL), the combined organic extracts were washed with water and brine; dried over sodium sulfate; organic solvents were removed under reduced pressure and the residue was purified by column chromatography, on silica gel; using hexane (100 %) to triethylamine : ethyl acetate (2 : 98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (IV) can be further purified by preparation of their acid addition salts. List - 5:

Description Mass ion (M+H)⁺

D113 [2-( 1H-lndol-3-yloxy)ethyl]dimethylamine 205

D114 [2-(. 2-Phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine 281

D 115 [2-(: 2-Methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine 219

D 116 [2-(, 5-Bromo-1H-indol-3-yloxy)ethyl]dimethylamine 283/285

D 117 [2-(. 5-Bromo-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 359/361

D 118 [2-( 5-Bromo-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine 297/298

D 119 [2-( 5-Chloro-1H-indol-3-yloxy)ethyl]dimethylamine 239/241

D120 [2-( 5-Chloro-2-phenyl-1/-/-indol-3-yloxy)ethyl]dimethylamine 315/317

D 121 [2-( 5-Chloro- 2- methyl -1rY-indol-3-yloxy)ethyl]dimethylamine 253/255

D122 [2-( 6-Chloro-1/-/-indol-3-yloxy)ethyl]dimethylamine 239/241

D123 [2-(⁽ 6-Chloro-2-phenyl-1H-indol-3-yloxy)ethyI]dimethylamine 315/317

D 124 [2-( 6-Chloro-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine 253/255

D 125 [2-( 5,7-Dichloro-1 --indol-3-yloxy)ethyl]dimethylamine 273/275/ 277

D126 [2-( 5,7-Dichloro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine 349/351/ 353 D 127 [2-(5,7-Dichloro-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine 287/289/

291

D 128 [2-(5,7-Dibromo-1 H-indol-3-yloxy)ethyl]dimethylamine 361/363/

365

D 129 [2-(5,7-Dibromo-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine 437/439/

441

D 130 [2-(5,7-Dibromo-2-methyl-1 --indol-3-yloxy)ethyl]dimethylamine 375/377/

379

D 131 [2-(7-Bromo-5-chloro-1 H-indol-3-yloxy)ethyl]dimethylamine 317/319/

321

D 132 [2-(7-Bromo-5-chloro-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine 393/395/

397

D 133 [2-(7-Bromo-5-chloro-2-methyl-1 --indoI-3-yloxy)ethyl]dimethylamine 331/333/

335

D 134 [2-(5-Methoxy-1 --indol-3-yloxy)ethyl]dimethylamine 235

D 135 [2-(5-Methoxy-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethyIamine 311

D 136 [2-(5-Methoxy-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine 249

Example - 1 : [2-(1-(Benzyl)-1H-indol-3-yloxy)ethyl]dimethylamine

Sodium hydride (60 % in mineral oil, 16.5 mmoles) was stirred with dimethyl formamide (ca 8 mL) in a ice-cooled, three necked round bottom flask. A solution of [2- (1H-indol-3-yloxy)ethyl]dimethylamine (15 mmole), in dimethyl formamide (ca 5 mL) was then added dropwise to this cooled suspention of sodium hydride. After the addtion was complete, the reaction mixture was allowed to attain the room temperature (25 °C). After about one hour of stirring at 25 °C, a solution of Benzyl bromide (18 mmole) was added dropwise to this solution. The reaction was further stirred at 25 °C for next 3 - 4 hours. After the completion of reaction (TLC), reaction mixture was poured onto the ice cooled water and extracted by Ethyl acetate (3 X 20 mL). The combined organic extract was washed with water and brine, dried over sodium sulphate and the volatiles were evaporated under vacuume to get the product as a thick dark oil. The residue was purified by column chromatography, on silica gel; using hexane (100 %) to triethylamine : ethyl acetate (2 : 98) gradual gradient as mobile phase, to obtain the compound of general formula (I) as thick oil, which was identified by IR, NMR and mass spectral analyses. The final desired compound of general formula (I) can be further purified by preparation of their acid addition salts. Melting range (°C) : Isolated as thick oil; Mass (m/z): 295.3(M+H)⁺ .

Example - 2 : [2-(1-(2'-Bromobenzyl)-1H-indol-3-yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 373, 375(M+H)⁺ Example - 3 : [2-(1-(Benzoyl)-1H-indol-3-yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^"1) : 1680., Mass (m/z) : 309.3 (M+H)⁺ ; ¹H-NMR (ppm) : 2.34 (s, 6H); 2.74-2.80 (t, 2H, J=5.4 Hz); 4.01-4.07 (t, 2H, J=5.4 Hz); 6.72 (s, 1 H); 7.26-7.74 (m, 7H); 8.23-8.27 (d, 1 H).

Example - 4 : [2-(1-(Benzyl)-2-methyl-1H-indol-3-yl)oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil, Mass (m/z) : 309.3 (M+H)⁺

Example - 5 : [2-(1-(2'-Bromobenzoyl)-2-methyl-1H-indol-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^-1) :1680 (C=0), Mass (m/z) : 401 (M+H)⁺

Example - 6 : [2-(1-(2'-Bromobenzoyl)-2-phenyl-1H-indol-3-yI)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^-1) :1680(C=O), Mass (m/z) : 463, 465 (M+H)⁺

Example - 7 : [2-(1-(Benzyl)-5-chloro-1H-indol-3-yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 329, 331 (M+H)⁺

Example - 8 : [2-(1-(2'-Bromobenzyl)-5-chloro-1H-indol-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) isolated as thick oil ; Mass (m/z) : 407, 409, 411 (M+H)⁺ Example - 9 : [2-(1-(Benzoyl)-5-chloro-1H-indol-3-yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; IR spectra (cm^"1) :1680(C=O), Mass (m/z) : 343, 345 (M+H)⁺

Example - 10 : [2-(1-(2'-Bromobenzyl)-5-chloro-2-methyl-1H-indol-3- yl)oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ;Mass (m/z) : 421 , 423, 425 (M+H)⁺

Example - 11 : [2-(1-(2'-Bromobenzoyl)-5-chloro-2-phenyl-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^"1) :1680 (C=0), Mass (m/z) : 497, 499, 501 (M+H)⁺

Example - 12 : [2-(1-(2'-Bromobenzyl)-5-bromo-1H-indol-3-yl)oxyethyl] dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 451 , 453, 455 (M+H)⁺ ; ¹H-NMR (ppm):D 2.36 (s, 6H); 2.74-2.79 (t, 2H, J=5.4 Hz); 4.05-4.13 (t, 2H, J=5.4 Hz); 5.24 (s, 2H); 6.47-6.52 (dd, 1H);6.62 (s,1 H) ;7.00-7.26 (m, 4H); 7.56-7.6 (dd, 1H); 7.82 (d, 1H).

Example - 13 : [2-(1-(Benzoyl)-5-bromo-1H-indol-3-yl)oxyethyI]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^"1) :1680 (C=0); Mass (m/z) : 387, 389 (M+H)⁺

Example - 14 : [2-(1-(2'-Bromobenzoyl)-5-bromo-1H-indoI-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR^pectra (cm^"1) :1680(C=O); Mass (m/z) : 465, 467, 469 (M+H)⁺ ;¹H-NMR (ppm) :D 2.35 (s, 6H); 2.75-2.81 (t, 2H); 4.00 (t, 2H); 7.26-7.47 (m, 4H); 7.68-7.77(dd, 2H).

Example - 15 : [2-(1-(Benzoyl)-5-bromo-2-methyl-1H-indol-3-yl)oxyethyl] dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; IR spectra (cm^"1) :1680(C=O); Mass (m/z) : 401 , 403 (M+H)⁺

Example - 16 : [2-(1-(2'-Bromobenzyl)-5-bromo-2-phenyl-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 527, 529, 531 (M+H)⁺

Example - 17 : [2-(1-(Benzyl)-5-chloro-7-bromo-1H-indol-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil, Mass (m/z) : 407, 409, 411 (M+H)⁺

Example - 18 : [2-(1-(Benzoyl)-5-chloro-7-bromo-2-phenyl-1H-indol-3-yl) oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^"1) :1680(C=O), Mass (m/z) : 497, 499, 501 (M+H)⁺

Example - 19 : [2-(1-(Benzyl)-5,7-dichloro-1H-indoI-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; Mass (m/z) : 363, 365, 367 (M+H)⁺

Example - 20 : [2-(1-(2'-Bromobenzyl)-5,7-dichloro-2-methyl-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; Mass (m/z) : 455, 457, 459 (M+H)⁺ Example - 21 : [2-(1-BenzoyI)-5,7-dichloro-2-phenyl-1H-indol-3-yl) oxyethyljdimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ;IR spectra (cm^"1) :1680 Mass (m/z) : 453, 455, 457 (M+H)⁺

Example - 22 : [2-(1-(Benzyl)-5,7-dibromo-1H-indol-3-yl)oxyethyl] dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 451 , 453, 455 (M+H)⁺

Example - 23 : [2-(1-(Benzoyl)-5,7-dibromo-2-phenyl-1H-indol-3- yl)oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; IR spectra (cm^"1) :1680; Mass (m/z) : 541 , 543, 545 (M+H)⁺

Example - 24 : [2-(1-(2'-Bromobenzyl)-5-methoxy-1H-indol-3-yl)oxyethyl] dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil Mass (m/z) : 403, 405 (M+H)⁺

Example - 25 : [2-(1-(Benzoyl)-5-methoxy-1H-indol-3-yl)oxyethyl] dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ;IR spectra (cm^"1) :1680; Mass (m/z) : 339.4 (M+H)⁺

Example - 26 : [2-(1-(2'-Bromobenzyl)-5-methoxy-2-methyl-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil; Mass (m/z) : 417, 419 (M+H)⁺

Example - 27 : [2-(1-(2'-Bromobenzyl)-5-methoxy-2-phenyl-1H-indol-3- yl)oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; Mass (m/z) : 479, 481 (M+H)⁺

Example - 28 : [2-(1-(Benzoyl)-5-methoxy-2-phenyI-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as , thick oil ; IR spectra (cm^"1) : 1680; Mass (m/z) : 415.5 (M+H)⁺

Example - 29 : [2-(1-(Benzoyl)-2-(4'-Methoxyphenyl)-1H-indol-3- yl)oxyethyl]dimethylamine Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared. Melting range (°C) : Isolated as thick oil ; IR spectra (cm^"1) :1680; Mass (m/z) : 415 (M+H)⁺

Example - 30 : [2-(1-(Benzyl)-5-chloro-2-(4'-methoxyphenyl)-1H-indol-3- yl)oxyethyl]dimethylamine

Using essentially the general procedure described in example 1 and some non- critical variations, the above derivative was prepared.

Melting range (°C) : Isolated as thick oil; Mass (m/z) : 435 (M+H)⁺

Claims

We Claim:

1. A compound of the general formula (I),

General Formula (I) its stereoisomers, its radioisotopes, its geometric forms, its N-oxide, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bio-active metabolite, any suitable combination of the above, wherein Ri, R₂, R₃, R₄, Rs, Re, R7, Rs, R9, R₁0, Rn and Rι₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C Cι₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-Cι₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R or R₅ and R₆ or R₆ and R₇ or R and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; Rm and R₁₄ represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, Rm and Rι together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, Rn and Rm together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; "A" represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; with the proviso that, i) whenever n =2, all of Ri, R₂, R₃, R₄ and R₁₀ are together hydrogens, and R₁₃ and Rι are methyl or ethyl; then A is never either of =0 or -(H)₂ and also includes the salts of such compounds, ii) whenever n =2, all of Ri, R₃, R₄ and R are together hydrogens, R₂ is methoxy, and R₁₃ and R₁₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, iii) whenever n =2, all of Ri, R₃, R₄ and R are together hydrogens, R₂ is chloro, and R and R ₄ are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, iv) whenever n =2, all of R-i, R₃, R₄ and R₂ are together hydrogens, R₁₀ is phenyl, and R and R are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds, y) whenever n =3, all of R₁₍ R₂, R₃, R and R₁₀ are together hydrogens then Rm and Rι are methyl or ethyl; then A is never -(H)₂ and also includes the salts of such compounds.

2. A compound according to Claim -1, which is selected from the following list: [2-(1-(Benzoyl)-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)-1 -/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(Benzyl)-1 /V-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(Benzoyl)-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzoyl)- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(Benzyl)- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

12- 1-(2'-Bromobenzyl)- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(Benzoyl)-2-methyl-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzoyl)- 2- methyl -1 7-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(Benzyl)- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzyl)- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine; [2- 1-(Benzoyl)-5-bromo-1 H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzoyl)- 5-bromo-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1 -(Benzyl)- 5-bromo-1 -indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzyl)- 5-bromo-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1 -(Benzoyl)- 5-bromo-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzoyl)- 5-bromo-2-phenyl-1Λ/-indol-3-yloxy)ethyl]dimethylamine

[2 1 -(Benzyl)- 5-bromo-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzyl)- 5-bromo- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine;

[2- l-(Benzoyl)- 5-bromo-2-methyl-1 -/-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzoyl)- 5-bromo- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2- 1-(Benzyl)- 5-bromo-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzyl)- 5-bromo- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine [2-. 1-(Benzoyl)-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzoyl)- 5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1 -(Benzyl)- 5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzyl)- 5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine;

[2- 1 -(Benzoyl)- 5-chloro-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine ;

[2- 1-(2'-Bromobenzoyl)- 5-chloro-2-phenyl-1 -indol-3-yloxy)ethyl]dimethylamine; [2- 1-(Benzyl)- 5-chloro-2-phenyl-1 /- indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzyl)- 5-chloro- 2-phenyl-1 r7-indol-3-yloxy)ethyl]dimethylamine; [2-(1 -(Benzoyl)- S-chloro^-methyl-IH-indol-S-yloxyJethylldimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5-chloro- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine

[2- 1 -(Benzyl)- 5-chloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzyl)- 5-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine [2- 1-(Benzoyl)-6-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ; [2- 1-(2'-Bromobenzoyl)- 6-chloro-1H-indol-3-yloxy)ethyl]dimethylamine; [2- 1-(Benzyl)- 6-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(2'-Bromobenzyl)- 6-chloro-1 -/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(Benzoyl)- 6-chIoro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzoyl)- 6-chloro-2-phenyl-1 -/-indol-3-yloxy)ethyI]dimethylamine; [2-(1 -(Benzyl)- 6-chloro-2-phenyl-1fy-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 6-chloro- 2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzoyl)- 6-chloro-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 6-chloro- 2- methyl -1 -/-indol-3-yloxy)ethyl] dimethylamine

[2-(1 -(Benzyl)- 6-chloro-2- methyl -1 -/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 6-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl]dimethylamine

[2-(1-(Benzoyl)-5,7-dichloro-1 --indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 5,7-dichloro-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 5,7-dichloro-1r-/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dichloro-1/7-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(Benzoyl)- 5,7-dichloro-2-phenyl-1 -/-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 5,7-dichloro-2-phenyl-1ry-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dichloro-2-phenyl-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzyl)- 5,7-dichloro- 2-phenyl-1 /-/-indol-3-y!oxy)ethyl] dimethylamine ;

[2-(1 -(Benzoyl)- 5,7-dichloro-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 5,7-dichloro- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dichloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzyl)- 5,7-dichloro- 2- methyl -1 H-indol-3-yloxy)ethyl] dimethylamine;

[2-(1-(Benzoyl)-5,7-dibromo-1/-/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5,7-dibromo-1rτ'-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 5,7-dibromo-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5,7-dibromo-1r -indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5,7-dibromo-2-phenyl-1 --indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 5,7-dibromo-2-phenyl-1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dibromo-2-phenyl-1r7^,-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzyl)- 5,7-dibromo- 2-phenyl-1 --indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzoyl)- 5,7-dibromo-2-methyl-1 H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzoyl)- 5,7-dibromo- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5,7-dibromo-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5,7-dibromo- 2- methyl -1 H-indol-3-yloxy)ethyl] dimethylamine;

[2-(1-(Benzoyl)-7-bromo-5-chloro-1/-/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1 -(Benzyl)- 7-bromo-5-chloro-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro-1r-/-indol-3-yloxy)ethyl]dimethylamine ; [2-(1 -(Benzoyl)- 7-bromo-5-chloro-2-phenyl-1 H-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro-2-phenyI-1 --indol-3-yIoxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 7-bromo-5-chloro-2-phenyl-1ry-indol-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro- 2-phenyl-1 -/-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1-(Benzoyl)- 7-bromo-5-chloro-2-methyl-1 -/-indoI-3-yloxy)ethyl]dimethylamine;

[2-(1-(2'-Bromobenzoyl)- 7-bromo-5-chloro- 2- methyl -1r-/-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 7-bromo-5-chloro-2- methyl -1H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzyl)- 7-bromo-5-chloro- 2- methyl -1 H-indol-3-yloxy)ethyl] dimethylamine;

[2-(1-(Benzoyl)-5-methoxy-1H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-methoxy-1 H-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzyl)- 5-methoxy-1H-indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzyl)- 5-methoxy-1rY-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1 -(Benzoyl)- 5-methoxy-2-phenyl-1 /-/-indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzoyl)- 5-methoxy-2-phenyl-1H-indol-3-yloxy)ethyl] dimethylamine ;

[2-(1 -(Benzyl)- 5-methoxy-2-pheny!-1H-indol-3-yloxy)ethyl]dimethylamine; [2-(1-(2'-Bromobenzyl)- 5-methoxy- 2-phenyl-1/W-indol-3-yloxy)ethyl] dimethylamine

[2-(1 -(Benzoyl)- 5-methoxy-2-methyl-1r--indol-3-yloxy)ethyl]dimethylamine ; [2-(1-(2'-Bromobenzoyl)- 5-methoxy- 2- methyl -1 --indol-3-yloxy)ethyl] dimethylamine ; [2-(1 -(Benzyl)- 5-methoxy-2- methyl -1r--indol-3-yloxy)ethyl]dimethylamine ;

[2-(1-(2'-Bromobenzyl)- 5-methoxy- 2- methyl -1H-indol-3-yloxy)ethyl] dimethylamine; or a stereoisomer, or a polymorph, or any suitable combination of above such as a nitrogen oxide thereof; a prodrug of the compound or the nitrogen oxide; a pharmaceutically acceptable salt of the compound, the nitrogen oxide, or the prodrug; or a solvate or hydrate of the compound, the nitrogen oxide, the prodrug or the pharmaceutically acceptable salt.

3. A pharmaceutical composition comprising of one or more pharmaceutically acceptable carrier, diluent/s, excipient/s or solvates along with a therapeutically effective amount of a compound according to Claim-1, its stereoisomers, its geometric forms, its N-oxides, its polymorphs, its pharmaceutically acceptable salts, or solvates.

4. A pharmaceutical composition according to Claim 3, in the form of a tablet, capsule, powder, lozenges, suppositories, syrup, solution, suspension or injectable, administered in, as a single dose or multiple dose units.

5. A process for the preparation of a compound of general formula (I),

General Formula (I) its stereoisomers, its radioisotopes, its geometric forms, its N-oxide, its polymorphs, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its useful bio-active metabolite, any suitable combination of the above,

wherein R , R₂, R , R , Rs, Rε, R7, Rs, Rg, R10, Rn and Rm may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrCι₂)alkyl, (C₂-Cι₂)alkenyl, (C₂-C ₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrC₁₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R^ and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or R and Rι₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms;

Rm and Rι₄ represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, R and Rι together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, Rn and Rm together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated;

"A" represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; which comprises of any one of the following routes, Route i): reacting a compound of formula (II) given below,

(ll) wherein all the symbols are as defined above; R represents either of a suitable N- protecting group, or a group such as,

wherein all symbols are as defined above, with a compound of formula (III) or its acid addition salt,

(III) wherein all the symbols are as defined above and Lg is a leaving group;

Route ii): reacting a compound of formula (IV) given below,

(IV) wherein all symbols except R are as defined above; R₁₀ herein represents hydrogen, formyl, substituted or unsubstituted groups selected from linear or branched (C_rC ₂)alkyl, (C₂-Cι₂)alkenyl, (C₂-Cι₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C₁₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, sulfonic acids and its derivatives, phosphoric acid and its derivatives; with a compound of formula (V)

(V) where A, R₅, R₆, R₇, R₈ and R₉, are as defined in relation to formula (I); and Lg is a leaving group as defined earlier;

Route iii): reacting a compound of formula (VI)

wherein all symbols are as defined above, R_a is defined as either hydrogen, halogen (such as chloro or bromo), lithio, trimethylsilyl, lower alkoxy, boronic acid or trifluoromethanesulfonate groups; and R is defined as a suitable N-protecting group or a group such as,

where all symbols are as defined earlier, and with a compound of formula (III) or its acid addition salt,

(III) wherein all the symbols are as defined above and Lg is a leaving group either sulfonyloxy or halogeno;

Route iv): reacting a compound of formula (VII)

wherein all the symbols are as defined above and R is defined as a suitable N- protecting group, or a group such as,

wherein all the symbols are as defined above, with a compound of formula (VIII)

(VIII) wherein all the symbols are as defined above;

Route v): reacting a compound of formula (IX)

wherein all the symbols are as defined above and R is defined as a suitable N- protecting group or a group such as,

wherein all the symbols are as defined above with a compound of formula (VIII),

NRmRi₄H (VIII) wherein all the symbols are as defined above, followed by reduction;

Route vi): reacting a compound of formula (X)

wherein all the symbols are as defined above, R_b represents hydrogen atom or a benzyl radical and R is defined as a suitable N-protecting group or a group such as,

wherein all the symbols are as defined above with a compound of formula (XI) or precursor thereof, o^_c/Rm

I

^R1

(XI) wherein all the symbols are as defined above; Route vii): displacing any of the substituent group/s in theceoqinof formula (I) by hydrogen atom/s by carrying out complete hydrogenolysis or partial hydrogenolysis;

Route viii): chemically or catalytically reducing compounds containing -

C(=0) group/s in the side chain, to the corresponding -C(OH,H) or -C(H,H) compound;

6. A process according to Claim 5, comprising of carrying out one or more of the following optional steps: i) removing any protecting group; ii) resolving the racemic mixture into pure enantiomers by the known methods and iii) preparing a pharmaceutically acceptable salt of a compound of formula (I) and/or iv preparing a pharmaceutically acceptable a prodrug thereof.

7. Novel intermediates defined by general formula (II),

R = N-protecting group or

(») wherein Ri, R₂, R₃, R₄, R₅, R₆, R _| R₈, Rg and R₁₀ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C Cι₂)alkyl, (C₂-C ₂)alkenyl, (C₂-C ₂)alkynyl, (C₃-C₇)cycloalkyl,

(C₃-C )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C₁₂)alkoxy, cyclo(C₃-

C )alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino,' hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and Rs or R₈ and R₉ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; R is suitable protecting group such as acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy;; with the proviso that whenever A is either of =0 or-(H)₂, then all of R-i, R₂, R₃, R₄ and R together are never hydrogens.

Novel intermediates of general formula (IV) are represented as given below,

(IV) wherein Ri, R₂, R₃, R , Rn and Rm may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio,^' amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-Cι₂)alkenyl, (C₂-Cm)alkynyl, (C₃-C₇)cycloalkyl, (C₃- C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and R₁₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms;

Rm represents hydrogen, formyl, substituted or unsubstituted groups selected from linear or branched (CrCι₂)alkyl, (C₂-Cι₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrC ₂)alkoxy, cyclo(C₃- C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, sulfonic acids and its derivatives, phosphoric acid and its derivatives; Rm and Rι₄ represents hydrogen, alkyl, aryl, aralkyl or together with nitrogen atom form a cyclic three to seven membered ring, optionally, R and Rι₄ together may form a part of cyclic structure along with the intervening nitrogen; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; optionally, Rn and Rm together may form a part of cyclic structure along with the intervening nitrogen and carbon atoms; the heterocycle may have either one, two or three double bonds; optionally it may also contain one to three heteroatom selected from the group of oxygen, nitrogen and sulfur, and includes ring fused with any carbocyclic or heterocyclic ring, which can be saturated or unsaturated; and "n" is an integer ranging from 1 to 8, preferably 1 to

4, wherein the carbon chains which "n" represents may be either linear or branched; and its stereoisomers and its salts; with the proviso that, i) whenever n =2, all of R_{1 f} R₂, R₃, R₄ and R are together hydrogens then R and Rι₄are methyl or ethyl; then either of Rn or Rm is other than hydrogen, ii) whenever n =2, all of R_1f R₃, R and Rm are together hydrogens, R₂ is methoxy, and Rm and R₁ are methyl or ethyl; then either of Rn or Rm is other than hydrogen, iii) whenever n =2, all of R , R₃, R₄ and R₁₀ are together hydrogens, R₂ is chloro, and R and R₁₄ are methyl or ethyl; then either of Rn or R ₂ is other than hydrogen, iv) whenever n =2, all of R_{1 (} R₃, R₄ and R₂ are together hydrogens, R is phenyl, and Rm and R ₄ are methyl or ethyl; then either of Rn or R ₂ is other than hydrogen, and v) whenever n =3, all of Ri, R₂, R₃, R₄ and R₁₀ are together hydrogens then Rm and Rι₄ are methyl or ethyl; then either of Rn or Rm is other than hydrogen.

Novel intermediates defined of general formula (VI),

R = N-protecting group or

(VI) wherein R₁₍ R₂, R₃, R₄, Rs, Re, R7, Rs, Rg and R may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C C₁₂)alkyl, (C₂-C ₂)alkenyl, (C₂-C ₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrC₁₂)alkoxy, cyclo(C₃- C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R or R₇ and R₈ or R₈ and R₉ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; R_a is defined as either hydrogen, halogen (such as chloro or bromo), lithio, trimethylsilyl, lower alkoxy, boronic acid or trifluoromethanesulfonate groups; and its stereoisomers and its salts.

10. Novel intermediates of general formula (Vll) are represented as given below,

R = N-protecting group or

(VII) wherein R_{1 (} R₂, R₃, R₄, R₅, R₆, R7, Rs, Rg, R₁0, Rn and Rm may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrC ₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-Cι₂)alkynyl, (C3-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCi₂)alkoxy, cyclo(C₃-C )alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R^ and R₂ or R₂ and R₃ or R₃ and R₄ or R5 and R₆ or R₆ and R or R₇ and R₈ or R₈ and R₉ together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rm together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; Lg is a leaving group as defined earlier; and its stereoisomers and its salts.

11. Novel intermediates of general formula (IX) are represented as given below,

R = N-protecting group or

(IX) wherein R_1f R₂, R₃, R₄, Rs, Re, 7, Rs, Rg, R10, Rn and R ₂ may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrCι₂)alkyl, (C₂-Cm) alkenyl, (C₂-Cι₂)alkynyl, (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (CrCι₂)alkoxy, cyclo(C₃-C₇) alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, mohoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like R-_\ and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, 2004

optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and Rm together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; R is suitable protecting group such as acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(C C₆)alkoxy; its stereoisomers and its salts.

12. Novel intermediates of general formula (X) are represented as given below,

R = N-protecting group or

(X) wherein R , R₂, R₃, R₄, R₅, R₆, R7, Rs, R9, R₁0, Rn and R may be same or different, and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (CrC₁₂)alkyl, (C₂-C₁₂)alkenyl, (C₂-C₁₂)alkynyl, (C₃- C₇)cycloalkyl, (C₃-C₇)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C Cι₂)alkoxy, cyclo(C₃-C₇)alkoxy, aryl, aryloxy, aralkyl, aralkoxy, heterocyclyl, heteroaryl, heterocyclylalkyl, heteroaralkyl, heteroaryloxy, heteroaralkoxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl arylalkyl, aralkoxyalkyl, alkylthio, thioalkyl, alkoxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, carboxylic acid and its derivatives, sulfonic acids and its derivatives, phosphoric acid and its derivatives; or the adjacent groups like Ri and R₂ or R₂ and R₃ or R₃ and R₄ or R₅ and R₆ or R₆ and R₇ or R₇ and R₈ or R₈ and Rg together with carbon atoms to which they are attached may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; or Rn and R₁₂ together with carbon atoms to which they are attached may form a three to a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, S and combinations of double bond and heteroatoms; R is suitable protecting group such as acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluoromethyleneoxycarbonyl (Fmoc) or a group defined as above, wherein A represents one or two hydrogens, oxygen, hydroxy or lower(CrC₆)alkoxy; "n" is an integer ranging from 1 to 8, preferably 1 to 4, wherein the carbon chains which "n" represents may be either linear or branched; and R_b is either benzyl or hydrogen; and its stereoisomers and its salts.

13. Use of the compounds as claimed in Claim 1, in combination with other pharmaceutical agents, such as apo-B/MTP inhibitors, MCR-4 agonists, CCK-A agonists, monoamine reuptake inhibitors, sympathomimetic agents, adrenergic receptor agonists, dopamine agonists, meianocyte-stimulating hormone receptor analogs, cannabinoid 1 receptor antagonists, melanin concentrating hormone antagonists, leptins, leptin analogs, leptin receptor agonists, galanin antagonists, lipase inhibitors, bombesin agonists, neuropeptide-Y antagonists, thyromimetic agents, dehydroepiandrosterone or analogs thereof, glucocorticoid receptor agonists or antagonists, orexin receptor antagonists, urocortin binding protein antagonists, glucagon-like peptide-1 receptor agonists, ciliary neurotrophic factors,

AGRPs (human agouti-related proteins), ghrelin receptor antagonists, histamine 3 receptor antagonists or reverse agonists, neuromedin U receptor agonists, in a therapeutically effective amount via a suitable pharmaceutical composition, to achieve the desired effect in mammals as well as humans.

14. Use of compound of general formula (I), as defined in Claim 1 or a pharmaceutical composition as defined in Claim-3 for preparing the medicaments.

15. Use of a compound as claimed in Claim 1 for the treatment and/or prevention of clinical conditions such as anxiety, depression, convulsive disorders, obsessive- compulsive disorders, migraine headache, cognitive memory disorders, ADHD (Attention Deficient Disorder/ Hyperactivity Syndrome), personality disorders, psychosis, paraphrenia, psychotic depression, mania, schizophrenia, schizophreniform disorders, withdrawal from drug abuse, panic attacks, chronobiological abnormalities, circadian rhythms, anxiolytic, osteoporosis, ischemic stroke, lower the risk of SIDS in young infants with low endogenous melatonin levels, reproduction, glaucoma, sleep disorders and also disorders associated with spinal trauma and /or head injury.

16. Use of a compound as claimed in Claim 1 for the treatment of mild cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinsonism and Huntington's chorea.

17. Use of a compound as claimed in Claim 1 for the treatment of certain Gl (Gastrointestinal) disorders such as IBS (Irritable bowel syndrome) or chemotherapy induced emesis.

18. Use of a compound as claimed in Claim 1 to reduce morbidity and mortality associated with the excess weight.

19. Use of a radiolabelled compound as claimed in Claim 1, as a diagnostic tool for modulating 5-HT and/or Melatonin receptor function.