WO2005005439A1 - Benzothiazino indoles - Google Patents

Benzothiazino indoles Download PDF

Info

Publication number
WO2005005439A1
WO2005005439A1 PCT/IN2004/000200 IN2004000200W WO2005005439A1 WO 2005005439 A1 WO2005005439 A1 WO 2005005439A1 IN 2004000200 W IN2004000200 W IN 2004000200W WO 2005005439 A1 WO2005005439 A1 WO 2005005439A1
Authority
WO
WIPO (PCT)
Prior art keywords
dioxide
benzothiazino
indole
dimethylaminoethyl
heteroatoms
Prior art date
Application number
PCT/IN2004/000200
Other languages
English (en)
Inventor
Venkata Satya Nirogi Ramakrishna
Rama Satri Kambhampati
Vikas Shreekrishna Shirsath
Venkateswarlu Jasti
Original Assignee
Suven Life Sciences Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Suven Life Sciences Limited filed Critical Suven Life Sciences Limited
Publication of WO2005005439A1 publication Critical patent/WO2005005439A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • R ⁇ R 2 , R 3 , R 4 , R5, Re, R7, Re, R9, R10, Ru, R12, 13 and R 14 may be same or different and each independently represent hydrogen, halogen, oxo, thio, perhaloalkyl, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C- ⁇ -C 12 )alkoxy cycio(C 3 -C 7 )alkoxy, aryl, aryloxy, aralkyl, aralkoxy,
  • the invention also envisages that certain tautomeric forms, stereoisomers, geometric forms, N-oxides, polymorphs, isotopically radiolabelled derivatives, salts, solvates, bio-active metabolites or any combination of above derivatives; may possess a beneficial physico-chemical, pharmacological characteristics having distinct major/minor advantageous over their corresponding compounds of general formulae (I), hence making them equally useful in either the therapy or experimental procedures (such as radioligand binding studies) as a substitute.
  • the present invention also provides method to prepare the compounds of general formula (I), and their related derivatives such as salts.
  • GPCRs G- protein-coupled receptors
  • Majority of drugs exert their action by interacting with GPCRs which result into pharmacologically beneficial effect.
  • the mode and general functioning of GPCR is well understood and can be found in the literature. (References : Bohm S. K., and et. al., Biochem. J. (1997), 322, 1 - 18; McConalogue, Karen, and NigelW. Bunnett, G-Protein-Coupled Receptors in Gastrointestinal Physiology. II. Regulation of neuropeptide receptors in enteric neurons. Am. J. Physiol. 274 (Gastrointest. Liver Physiol.
  • the compounds of general formulae (i), are useful in treating neuropsychiatric diseases which involve receptors, modulated by ligands such as 5-HT (Serotonin), melatonin and dopamine, in order to obtain the desired therapeutic effect.
  • ligands such as 5-HT (Serotonin), melatonin and dopamine.
  • the compounds of general formula (I) are 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.
  • International Patent Publication WO 03/066056 A1 reports that antagonism of 5-HT 6 receptor could promote neuronal growth within the central nervous system of a mammal.
  • the present invention describes novel benzothiazinoindole derivatives, represented below as compounds with the general formula (I): GENERAL FORMULA (I)
  • the invention also includes certain tautomeric forms, stereoisomers, geometric forms, N-oxides, polymorphs, isotopically radiolabelled derivatives, biologically active metabolites, biologically active derivatives, pharmaceutically acceptable salts, pharmaceutically acceptable solvates or hydrates of the compounds or any combination of above derivatives; which may possess a beneficial physico-chemical, pharmacological characteristics having distinct major/minor advantageous over their corresponding compounds of general formulae (I), hence making them equally useful in either the therapy or experimental procedures (such as radioligand binding studies) as a substitute.
  • the compounds of general formula (I) are defined as follows,
  • R-i, R 2 , R 3 , R 4 , R 5 , R 6 , R 7, R 9 , R 10 , Ru, R 12 , ⁇ 3 and R 14 may be same or different and each independently represent hydrogen, halogen, oxo, thio, perhaloalkyl, hydroxy, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C r C 12 )alkyl, (C 2 -C 12 )alkenyl, ⁇ C 2 -C 12 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C 12 )alkoxy cyclo(C 3 -C 7 )alkoxy, aryl, aryloxy, aralky
  • R- 1 5 and R 16 may be same or different and each independently represents hydrogen, substituted or unsubstituted groups selected from linear or branched (C-r C ⁇ 2 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 7 )cycloalkyl, (C 3 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl; optionally R 15 and R 16 along with the nitrogen atom may form a 3, 4, 5, 6 or 7 membered heterocyclic ring, which may further optionally contain one or more double bonds, and may include additional one or more heteroatoms such as the group "Oxygen", “Nitrogen”, “Sulfur” or “Selenium” and also includes combination of one or more double bonds with “heteroatoms", as above defined. "n” ranges
  • the present invention also provides method to prepare the compounds of general formula (I), and their related derivatives for example, salts, solvates.
  • Other chemical derivatives such as pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides, bio-active metabolites, isotopically radiolabelled compounds and can be prepared according to the known literature.
  • the chemistry of compound of formula (I) provides certain specialized derivatives such as tautomers, stereoisomers, geometric isomers and polymorphs, the compound can be prepared as a mixture containing variable proportions of individual compounds or individual compounds can be isolated.
  • 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.
  • pharmacologically acceptable anions such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate
  • 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.
  • salts of the compound of general 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 quarternizing 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.
  • 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 exist 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 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.
  • 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 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 0, 18 F, 99m Tc, 31 P, S, 123 l and 125 l.
  • 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.
  • nitrogen 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, a mixture of 2° positional isomers or oxide of aromatic nitrogen.
  • the present invention relates to all of the possible tautomeric forms and the possible mixture thereof.
  • the stereoisomers as a rule are generally obtained as racemates that can be separated into the optically active isomers in a manner known per se.
  • the present invention relates to the D-form, the L-form and D,L- mixture's and in the case of a number of asymmetric carbon atoms, the diastereomeric forms and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • Those compounds of general formula (I) which have an asymmetric carbon and as a rule are obtained as racemates can be separated one from the other by the usual methods, or any given isomer may be obtained by stereospecific or asymmetric synthesis.
  • Ester or amide derivatives which may be cleaved by esterases or lipases; _ 2. Peptides which may be recognized by specific or nop-specific proteases; 3. N-glycosyl or O-glycosyl derivatives; 4. Derivatives that accumulate at a site of action through membrane selection of a prodrug from or a modified prodrug form; or 5. PEG (polyethylene giycol) is covalently bonded to the compound of formula (I); 6. any combination of 1 to 5, above.
  • a “biological derivative” is a drug which has been chemically modified and may be in-active as such in-vitro or at the site of action, but which l ⁇ pon degradtion in body via chemical or enzymatic means or as such (in case of PEG) may give beneficial effect.
  • One such reference is 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 general formula (I) as defined earlier elsewhere in the specification or a derivatives such as salt, solvate, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, N-oxides, bio-active metabolites, isotopically radiolabelled compound, tautomers, stereoisomers, geometric isomers, polymorphs; either in pure or impure forms forming an active ingredient, together with pharmaceutically employed carriers, auxiliaries and the like.
  • An effective amount of a compound of general formula (I), or their derivatives as defined above can be used to produce a medicament, along with conventional pharmaceutical auxiliaries, carriers and additives.
  • Such pharmaceutically acceptable compositions containing compounds of formula (I) form the part of this invention.
  • the use of compounds and compositions defined are useful in therapy and are the part of this invention.
  • 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 / or melatonin activities gives desired effect.
  • the present invention provides the compounds of general formula (I), to prepare the medicaments useful in the treatment and/ or prophylaxis of certain disorders such as psychosis, paraphrenia, anxiety, depression, mania, schizophrenia, schizophreniform disorders, migraine headache, drug addiction, convulsive disorders, personality disorders, hypertension, autism, post-traumatic stress syndrome, alcoholism, panic attacks, obsessive-compulsive disorders, chronobiological abnormalities and circadian rhythms, cognitive memory disorders e.g.
  • Alzheimer's disease and age-related cognitive decline ADHD (Attention Deficient Disorder/ Hyperactivity Syndrome), amylotrophic lateral sclerosis, withdrawal from drug abuse such as ***e, ethanol, nicotine and benzodiazepines, panic attacks, and also disorders associated with spinal trauma and / or head injury s * uch as hydrocephalus.
  • Other conditions where there are low endogenous melatonin levels benefits may be obtained in cases of osteoporosis, ischemic stroke, SIDS in young infants, reproduction, glaucoma and sleep disorders.
  • Compounds of this invention are expected to be of use in the treatment of mild cognitive impairment and other neurodegenerative disorders like Alzheimer's disease, Parkinsonism and Huntington's chorea.
  • the compounds of this invention could be of use in the treatment of certain Gl (Gastrointestinal) disorders such as IBS (Irritable bowel syndrome) or chemotherapy induced emesis. Also these compounds can help in modulation of eating behavior and thereby reduce morbidity and mortality associated with the excess weight.
  • Gl Gastrointestinal
  • IBS Irritable bowel syndrome
  • chemotherapy induced emesis chemotherapy induced emesis.
  • the present invention provides a method for the treatment of a human or a animal subject suffering from disorders such as, anxiety, depression, convulsive disorders, obsessive-compulsive disorders, migraine headache, cognitive memory disorders e.g.
  • ADHD Alzheimer's disease and age-related cognitive decline
  • personality disorders 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, Parkinsonism and Huntington's chorea.
  • 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, melanocyte-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, glucocortioord " receptor " agonists " or " antagonists, orexin receptor antagonists
  • Such therapy includes multiple choices: for example, administering two compatible compounds simultaneously in a single dosage form or administering each compound individually in a separate dosage; or if required at some time interval or separately in order to maximize the beneficial effect or minimize the potential side- effects of the drugs according to the known principles of pharmacology.
  • 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 all the meanings such as preventative, prophylactic and palliative.
  • compound of the present invention refers 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.
  • Suitable groups represented by Ri, R 2 , R 3 , R , R5, Re, R7, R9, R10, u, R12, R13 and R- 14 wherever applicable may be selected from halogen atom such as fluorine, chlorine, bromine or iodine; perhaloalkyl particularly such as fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl and the like; substituted or unsubstituted group, especially, linear or branched (C 1 -C 8 )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; substituted or un
  • the cyclic structures may be optionally substituted phenyl, naphthyl, pyridyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrimidinyl, pyrazinyl and the like.
  • Suitable substituents on the 'cyclic structures' as defined above includes hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, formyl, ⁇ CrC 3 )alkyl, (C C ⁇ alkoxy, thioalkyl, alkylthio, phenyl or benzyl groups.
  • R 15 and R 16 preferably represents hydrogen, substituted or unsubstituted linear or branched (C ⁇ -C 12 )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(C 3 -C 7 )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 CH 3 C 6 H 4 CH 2 , Hal-C 6 H 4 CH 2 , CH 3 OC 6 H 4 CH 2 , CH 3 OC 6 H 4
  • Suitable hetero cyclic rings formed between R ⁇ 5 and R ⁇ 6 along with "Nitrogen atom” be such as pyrrolyl, pyrrolidinyl, piperidinyl, pyridinyl, 1 ,2,3,4-Tetrahydro- pyridinyl, imidazolyl, pyrimidinyl, pyrazinyl, piperazinyl, diazolinyl and the like; the heterocyclyl group may be substituted; heteroaryl group such as pyridyl, imidazolyl, tetrazolyl and the like, the heteroaryl group may be substituted; heterocyclo(d- C 6 )alkyl, such as pyrrolidinealkyl, piperidinealkyl, morpholinealkyl, thiomorpholinealkyl, oxazolinealkyl and the like, the heterocyclo(C ⁇ -C 6 )alkyl group may be substituted; heteroaralkyl group such as fur
  • Compounds of general formula (I) can be prepared by any of the methods described below.
  • the present invention also provides processes for preparing compounds of general formula (I) as defined above, including salts, solvates, pharmaceutically acceptable salts and pharmaceutically acceptable solvates.
  • R 1 ? R 2 , R 3 , R , R 5 , Re, R 7 , R 9 , Rio, Ru, R 12 , R ⁇ 3 , Ru, i5, R- I 6 and n are as defined previously for the compounds of general formula (I).
  • the . method to synthesize tryptamines, 3- substitutedindolylalkylamines is very well described in the literature.
  • X is halogen such chloro, bromo or iodo, Ri, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 3 , R 9 , R 10 , Ru, R 12 , R ⁇ 3 , R 14 Ri5, R ⁇ 6 and "n" are as defined previously, using a Pd(0) or Pd (II) derivative as a catalyst, for example tetrakis triphenylphosphine palladium, (Bis-tri- o-tolylphosphine) palladium(ll) chloride and the like; and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); and/or ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, solvate, polymorph or prodrug thereof.
  • a Pd(0) or Pd (II) derivative as a catalyst, for example tetrakis triphen
  • This cyclization reaction can be achieved using variety of palladium catalysts.
  • the reaction may be affected in the presence of a base such as CH 3 COOK.
  • This reaction may be carried out in the presence of solvents such as THF, DMF, DMSO, DMA, DME, acetone and the like and preferably using Dimethylacetamide.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction temperature may range from 50 °C to 200 °C based on the choice of solvent and preferably at a temperature of 160 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 10 to 20 hours.
  • Scheme - 2 Compounds of general formula (I), may be prepared by reacting a compound of formula (III) given below, (ill) wherein R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Re, R 9 , R 10l Ru, ⁇ 2 , R ⁇ 3 , R M and "n" are as defined previously, with a suitable alkylating agent such as R 15 X or R 16 X or XR 15 R 16 X in successive steps or in one step, wherein X is good leaving group such as * halogen and the like.
  • the reaction is preferably carried in an organic solvent inert to the conditions of the reaction, such as acetone, THF or DMF and the like or mixtures thereof.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , Ar or He.
  • the reaction may be affected in the presence of a base such as K 2 C0 3 , Na 2 C0 3 , TEA or mixtures thereof.
  • the reaction temperature may range from 20 °C to 200 °C based on the solvent employed and preferably at a temperature in the range from 30 °C to 150 °C.
  • the duration of the reaction may range from 1 to 24 hours, preferably from 2 to 6 hours.
  • R ⁇ R 2 , R 3 , R , R 5 , R 6 , R 7 and R 8 are as defined previously, with formaldehyde and a compound of formula (V) given below, (V) wherein R 15 and R 16 are as defined earlier.
  • the above reaction is preferably carried out at a temperature of 50 °C to 150 °C.
  • the formaldehyde can be in the form of as aqueous solution i.e. 40 % formalin solution, or a polymeric form of formaldehyde such as paraformaldehyde or trioxymethylene. When such polymeric forms are used, a molar excess of mineral acid, for example hydrochloric acid, is added to regenerate the free aldehyde from the polymer.
  • the reaction is preferably carried in an organic solvent inert to the conditions of the reaction, such as methanol, ethanol or 3-methylbutanol 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 N 2 , Ar or He.
  • 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.
  • 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 Lithium, ammonia, substituted ammonia, 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 wherever applicable may be prepared by treatment with acids such as tarta c 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, sulfuhc acid, nitric acid and the like in solvents such as water, alcohols, ethers, ethyl acetate, dioxane, DMF or a lower alkyl ket
  • protecting groups such as those described in Protective Groups in Organic Chemistry, Ed J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • suitable protecting groups for the piperazine group include BOC, COCCI 3 , COCF 3 .
  • the protecting groups may be removed according to the standard procedures. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
  • stereoisomers of the compounds of the present invention 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 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).
  • 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).
  • 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 acid such as iysine, arginine and the like.
  • 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 recrystallizatro ⁇ r, various ways ofcrystaiiization sirclr 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 microscopy.
  • Isotopically labelled compounds of the present invention are useful in drug and/or substrate tissue distribution and target occupancy assays.
  • isotopically labelled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography).
  • compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers.
  • 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.
  • 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.
  • 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).
  • 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
  • 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).
  • 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
  • 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.
  • 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.
  • rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ g to 1000 ⁇ g of the compound of the invention.
  • the overall daily dose with an aerosol will be within the range 100 ⁇ g 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.
  • Radioligand binding assays for various receptor sub-types International Patent Publication WO 04/000205, i/O 04/000845, WO 04/000849, (Suven Lifesciences Limited) gives detailed list of methods used for Radioligand assays and related prior art, all of which is incorporated herein along with the references.
  • reaction mixture was poured onto ice-water mixture and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with water and brine and dried over sodium sulfate. Volatile impurities were distilled off under reduced pressure to obtain the crude residue. The residue obtained was purified by flash chromatography (silica gel, EtOAc/TEA, 9.9/0.1) to afford the compound, which was identified by IR, fiMR and mass spectral analyses as the title compound. All the other intermediates were prepared in the similar manner and their cyclization to the final compounds of formula - I is as described in the following examples.
  • Example - 1 3-(N,N-Dimethylaminoethyl)-2,5-dimethyl-1,2-benzothiazino- [2,3,4-ab]indole-S,S-dioxide ⁇ 2-[1-(2-Bromophenylsulfonyl)-2,5-dimethyl-1H-indol-3-yl)ethyl ⁇ dimethylamine (0.286 mmoles) was taken in a 100 mL 3 necked round bottomed flask, along with N,N-dimethyl acetamide (40 mL), potassium acetate (0.286 mmoles, 0.0281 g.) and Tetrakis triphenyl phosphine palladium (0.0143 mmoles, 0.0165 g.).
  • Example - 2 3-(N,N-Dimethylaminoethyl)-5-chloro-2-methyl-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 375 (M+H) + .
  • Example - 3 3-(N,N-Dimethylaminoethyl)-2-methyl-5-fluoro-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 359 (M+H) + ; 1 H-NMR ( ⁇ , ppm) : 2.36 (6H, s), 2.48 - 2.57 (2H, m), 2.76 (3H, s), 2.84 - 3.0 (2H, m), 7.27 - 8.25 (6H, m).
  • Example - 4 3-(N,N-Dimethylaminoethyl)-2-methyl-5-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was p ' repare ⁇ '. ' Mass (m/z) : 371 (M+H) + .
  • Example - 5 3-(N,N-Dimethylaminoethyl)-2-methyl-8-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 6 3-(N,N-Dimethylaminoethyl)-2,5-dimethyI-8-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 385 (M+H) + .
  • Example - 7 3-(N,N-Dimethylaminoethyl)-5-chloro-2-methyl-8-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 405 (M+H) + .
  • Example - 8 3-(N,N-Dimethylaminoethyl)-2-methyl-5-fluoro-8-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 389 (M+Hf ; 1 H-NMR ( ⁇ , ppm) : 2.34 (6H, s), 2.46 - 2.54 (2H, m), 2.74 (3H, s), 2.82 - 2.9 (2H, m), 3.98 (3H, s), 7.1 - 8.16 (5H, m).
  • Example - 9 3-(N,N-DimethylaminoethyI)-2-methyl-5,8-dimethojc -1,2- ben ⁇ othiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 401 (M+H) + .
  • Example - 10 3-(N,N-Dimethylaminoethyl)-8-fluoro-1,2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R.
  • Example - 11 3-(N,N-Dimethylaminoethyl)-8-isopropyl-1,2-benzothiazino- [2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 12 3-(N,N-Dimethylaminoethyl)-8-chloro-1,2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 13 3-(N,N-Dimethylaminoethyl)-8-methyl-1,2-benzothiazino-[2,3,4- ab
  • Example - 14 3-(N,N-Dimethylaminoethyl)-1,2-benzothiazino-[2,3,4-ab]indole- S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R.
  • Example - 15 3-(N,N-Dimethylamino ⁇ thyl)-5-fluoro-8-methyl-1,2- benzothiazino-[2,3 ⁇ 4-ab3ind ⁇ le-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • M.P 215 -218 °C ;I.R. (KBr, crrf 1 ) : 2921 , 1602, 1473,
  • Example - 16 3-(N,N-Dimethylaminoethyl)-5-chloro-8-fluoro-1 ,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R. (KBr, cm “1 ) : 2763, 1603, 1330, 1174, 1126, 865, 551;
  • Example - 17 3-(N,N-Dimethylaminoethyl)-5-chloro-8-methyl-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range: 155 - 160 °C ;I.R. (KBr, cm “1 ) : 2923, 1332,
  • Example - 18 3-(N,N-Dimethylaminoethyl)-5,8-difluoro-1,2-benzothia ⁇ ino- [2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range ( °C):150 - 152.5; I.R.
  • Example - 19 3-(N,N-Dimethylaminoethyl)-5-fluoro-1,2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range (°C): 126 -129 ;I.R.
  • Example - 20 3-(N,N-DimethyIaminoethyl)-8-methoxy-2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 21 3-(N,N-Dimethylaminoethyl)-5-fluoro-8-methoxy-1,2- benzothiazino-[2,3,4-ab]indole-S.S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range (°C) : 186 -187.5 °C ; I.R.
  • Example - 22 3-(N,N-Dimethylaminoethyl)-5-fluoro-8-chloro-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range (°C) : 152 -153.4; I.R.
  • Example - 23 3-(N,N-Dimethylaminoethyl)-5-methyl-8-fluoro-1,2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 24 3-(N,N-Dimethylaminoethyl)-5-methyl-1,2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R. (KBr, cm “1 ) : 2919, 1338, 1175, 1127, 786, 763;
  • Example - 25 3-(N,N-Dimethylaminoethyl)-5,8-dimethyl-1,2-benzothiazino- [2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R. (KBr, cm “1 ) : 2918, 1463, 1327, 1174, 1139, 807, 607,
  • Example - 26 3-(N,N-Dimethylaminoethyl)-5-methyl-8-methoxy-2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2918, 1596, 1323, 1303, 1240, 1169, 811 ,
  • Example - 27 3-(N,N-Dimethylaminoethyl)-5,8-dichloro-2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as ' described in example 1 , above derivative was prepared.
  • Example - 28 3-(N,N-Dimethylaminoethyl)-5-fIuoro-9,10-dichloro-2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 29 3-(N,N-Dimethylaminoethyl)-5,9,10-trichloro-2-benzothia ⁇ ino- [2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range (°C) : 210.4 - 214.9; I.R (KBr, cm 1 ) : 2946,
  • Example - 30 3-(N,N-Dimethylaminoethyl)-5-chloro-2-benzothiazino-[2,3,4- ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 31 3-(N,N-Dimethylaminoethyl)-9,10-dichloro-2-benzothiazino- [2,3,4-ab] indole-S,S-dioxide Using essentially the same-procedure as described in example 1 , above derivative was prepared.
  • Example - 32 3-(N,N-Dimethylaminoethyl)-5-chloro-8-methoxy-2- benzothiazino-[2,3,4-ab] indole-S.S-dioxide Using essentially the same procedure as describes in example 1 , above derivative was prepared.
  • Example - 33 3-(N,N-Dimethylaminoethyl)-5-methyl-8-isopropyl-2- ben ⁇ othiazino-[2,3,4-ab] indole-S.S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 34 3-(N,N-Dimethylaminoethyl)-5-fluoro-8-isopropyl-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 35 3-(N,N-Dimethylaminoethyl)-8,10-difluoro-2-benzothiazino- [2,3,4-ab] indole-S.S-dioxide • Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 36 3-(N,N-Dimethylaminoethyl)-5,8,10-trifluoro-2-benzothiazino- [2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 37 3-(N,N-Dimethylaminoethyl)-5-methyl-9,10-dichloro-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2936, 1460, 1333, 1175, 1132, 816, 609,
  • Example - 38 3-(N,N-Dimethylaminoethyl)-5-methoxy-2-benzothiazino-[2,3,4- ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1595, 1460, 1320, 1170, 1130, 860; Mass(m/z) : 357.1 (M+H) + .
  • Example - 39 3-(N,N-Dimethylaminoethyl)-6-metho ⁇ y-2-benzothiazino-[2,3,4- ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2932, 1596, 1460, 1322, 1171 , 1129, 865; Mass(m/z) : 357.1 (M+H) + .
  • Example - 40 3-(N,N-Dimethylaminoethyl)-5,8-methoxy-2-benzothiazino-[2,3,4- ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1592, 1462, 1322, 1171 , 1130, 864; Mass(m/z) : 387 (M+H) + .
  • Example - 41 3-(N,N-Dirheth " ylaminoethyl) 5-methoxy-8-chloro-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1595, 1460,*1320, 1170, 1130, 860; Mass(m/z) : 391.1 , 393 (M+H) + .
  • Example - 42 3-(N,N-Dimethylaminoethyl)-5-methoxy-8-fluoro-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1, above derivative was prepared. Mass(m/z) : 375.2 (M+H) + .
  • Example - 43 3-(N,N-DimethyIaminoethyl)-5-methoxy-8-bromo-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 436, 438 (M+H) + .
  • Example - 44 3-(N,N-DimethylaminoethyI)-5-methoxy-8-methyl-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 371 (M+H) + .
  • Example - 45 3-(N,N-Dimethylaminoethyl)-5-methoxy-8-isopropyl-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/ ⁇ ) : 399 (M+H) + .
  • Example - 46 3-(2-N,N-Dimethylaminopropyl)-5-methoxy-2-benzothiazino- [2,3,4-ab] indole-S.S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1595, 1460, 1320, 1170, 1130, 860; Mass(m/z) : 371 (M+H) + .
  • Example - 47 3-(2-N,N-Dimethylaminopropyl)-6-methoxy-2-benzothiazino- [2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2932, 1596, 1460, 1322, 1171 , 1129, 865; Mass(m/z) : 371 (M+H) + .
  • Example - 48 3-(2-N,N-Dimethylaminopropyl)-5,8-methoxy-2-benzothiazino- [2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1592, 1462, 1322, 1171 , 1130, 864; Mass(m/z) : 401 (M+H) + .
  • Example - 49 3-(2-N,N-Dimethylaminopropyl)-5-methoxy-8-chloro-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2934, 1595, 1460, 1320, 1170, 1130, 860; Mass(m/z) : 405, 407(M+H) + .
  • Example - 50 3-(2-N s N-Dimethylaminopropyl)-5-methoxy-8-fluoro-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 389 (M+H) + .
  • Example - 51 3-(2-N,N-Dimethylaminopropyl)-5-methoxy-8-bromo-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 450, 452 (M+H) + .
  • Example - 52 3-(2-N,N-Dimethylaminopropyl)-5-metho ⁇ y-8-methyl-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 385 (M+H) + .
  • Example - 53 3-(2-N,N-Dimethylaminopropyl)-5-methoxy-8-isopropyl-2- benzothiazino-[2,3,4-ab] indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass(m/z) : 413 (M+H) + .
  • Example - 54 3-(N,N-Dimethylaminoethyl)-5-chloro-8,10-difluoro-2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 55 3-(N,N-DimethylaminoethyI)-5-methyl-8-chloro-2-benzothiazino- [2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2918, 2762, 1330, 1177, 1096, 790;
  • Example - 56 3-(N,N-Dimethylaminoethyl)-5-chloro-8-isopropyl-2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 57 3-(N,N-Dimethylaminoethyl)-5-methyl-8,10-difluoro-2- henzofhiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 58 3-(N,N-Dimethylaminoethyl)-7-trifluoromethyl-10-chloro-2- ' benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 59 3-(N,N-Dimethylaminoethyl)-5-fluoro-7-trifluoromethy!-10- chloro-2-benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2943, 1435, 1349, 1298, 1170, 868;
  • Example - 60 3-(N,N-Dimethylaminoethyl)-5,10-dichloro-7-trifluoromethyl-2- benzothiazino-[2,3,4-ab]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 61 3-(N,N-Dimethylaminoethyl)-5-chloro-9-trifluoromethyl-2- benzothiazino-[2,3,4-ab]indoIe-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2941 , 1328, 1175, 1128, 811 , 573; Mass(m/z) : 429.1 , 431.2 (M+H) + .
  • Example - 62 3-(N,N-Dimethylaminoethyl)-9-trifluoromethyl-2-benzothiazino- [2,3,4-ah]indole-S,S-dioxide Using essentially the same procedure as described in example 1 , above derivative was prepared. I.R (KBr, cm 1 ) : 2917, 1329, 1175, 1134, 751 , 597; Mass(m/z) : 395 (M+H) + .

Landscapes

  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux dérivés de benzothiazinoindole représentés par le formule (I), dans laquelle R1, R2, R3, R4, R5, R6,, R7, R8, R9, R10, R11, R12, R13 et R14, peuvent être identiques ou différents et représentent chacun indépendamment hydrogène, halogène, oxo, thio, perhaloalkyle, hydroxy, amino, nitro, cyano, formyle, amidino, guanidino, des groupes substitués ou non substitués choisis parmi (Cl-C,12) alkyle linéaire ou ramifié, (C2-C12)alcényle, (C2-C12) alkynyle, (C3-C7) cycloalkyle, (C3-C7) cycloalcényle, bicycloalkyle, bicycloalcényle, (C1-C12) alkoxy, cyclo (C3-C7) alkoxy, aryle, aryloxy, aralkyle, aralkoxy, hétérocyclyle, hétéroaryle, hétérocyclylalkyle, hétéroaralkyle, hétéroaryloxy, hétéroaralkoxy, hétérocyclylalkyloxy, acyle, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, diarylamino, aralkylamino, alkoxycarbonyle, aryloxycarbonyle, aralkoxycarbonyle, hétérocyclylalkoxycarbonyle, hétéroaryloxycarbonyle, hydroxyalkyle, aminoalkyle, monoalkylaminoalkyle, dialkylaminoalkyle, alkoxyalkyle, aryloxyalkyle, aralkoxyalkyle, alkylthio, thioalkyle, alkoxycarbonyamino, aryloxycarbonylamino, dialkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, hydroxylamino, acide carboxylique et ses dérivés, acides sulfoniques et ses dérivés, acide phosphorique et ses dérivés; ou deux groupes adjacents peuvent former des « structures cycliques », par exemple, R1 et R2, R2 et R3, R5 et R6, R6, et R7, R7 et R8 avec les atomes de carbone adjacents auxquels ils sont fixés peuvent former un noyau à 5, 6, ou 7 éléments, et peuvent aussi facultativement contenir une ou plusieurs liaisons doubles et/ou un ou plusieurs hétéroatomes tel le groupe 'Oxygène', 'Azote', « Soufre » ou 'Sélénium' et des combinaisons de liaisons doubles et d'hétéroatomes; ou R9 et R10 ou R11 et R12 ou R13 et R14 représentent ensemble une double liaison fixée à 'Oxygène' ou 'Soufre'; ou deux groupes adjacents peuvent former des « structures cycliques », par exemple R11 et R12, R11 et R13, R11 et R14, R13 et R14 avec le/les atome(s) de carbone auquel/auxquels ils sont liés peuvent former un noyau à 3, 4, 5, ou 6 éléments, pouvant facultativement contenir une ou plusieurs liaisons doubles, et/ou un ou plusieurs hétéroatomes tel le groupe 'Oxygène', 'Azote', 'Soufre' ou 'Sélénium' et comprendre aussi une combinaison d'une ou plusieurs liaisons doubles avec des 'hétéroatomes', tel que susmentionné, R15 et R16 peuvent être identiques ou différents et représente chacun indépendamment hydrogène, des groupes substitués ou non substitués choisis parmi (C1-C12) alkyle linéaire ou ramifié, (C2-C12) alcényle, (C2-C12) alkynyle, (C3-C7) cycloalkyle, (C3-C7) cycloalcényle, bicycloalkyle, bicycloalcényle, aryle, aralkyle, hétéroaryle, hétérocyclylalkyle; facultativement R15 et R16 peuvent former avec l'atome d'azote un noyau hétérocyclique à 3, 4, 5, 6 ou 7 éléments, pouvant facultativement contenir aussi une ou plusieurs liaisons doubles, et pouvant inclure encore un ou plusieurs hétéroatomes tel le groupe 'Oxygène', 'Azote', 'Soufre » ou 'Sélénium' et également contenir une combinaison d'une ou plusieurs liaisons doubles avec des 'hétéroatomes', tels que susmentionnés; 'n' étant compris entre 0 et 4, les chaînes de carbone que 'n' représent
PCT/IN2004/000200 2003-07-09 2004-07-07 Benzothiazino indoles WO2005005439A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN564/CHE/2003 2003-07-09
IN564CH2003 2003-07-09

Publications (1)

Publication Number Publication Date
WO2005005439A1 true WO2005005439A1 (fr) 2005-01-20

Family

ID=34044515

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2004/000200 WO2005005439A1 (fr) 2003-07-09 2004-07-07 Benzothiazino indoles

Country Status (1)

Country Link
WO (1) WO2005005439A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006095360A1 (fr) * 2005-03-08 2006-09-14 Suven Life Sciences Limited Procede pour preparer des benzothiazinoindoles substitues
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
EP2258357A3 (fr) * 2005-08-26 2011-04-06 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3481953A (en) * 1967-12-18 1969-12-02 American Home Prod 1-arylsulfonyl-3-(2-substituted ethyl) indoles
EP0375133A1 (fr) * 1988-11-14 1990-06-27 The Upjohn Company Acides alpha-amino-indole-3-acétiques, utiles comme agents antidiabétiques, antiobésité et antiartériosclérotiques
WO1992013856A1 (fr) * 1991-02-12 1992-08-20 Pfizer Inc. Derives d'indoles de 5-heteroyle
WO2000063203A1 (fr) * 1999-04-21 2000-10-26 Allelix Biopharmaceuticals Inc. Composes piperidine-indol ayant une affinite avec 5-ht¿6?
WO2002051837A2 (fr) * 2000-12-22 2002-07-04 Wyeth Composes heterocyclylindazole et azaindazole utilises en tant que ligands 5-hydroxytryptamine-6
WO2003035061A1 (fr) * 2001-10-23 2003-05-01 Biovitrum Ab Utilisation de derives d'indole et d'indoline pour le traitement de l'obesite ou la reduction de l'apport alimentaire
WO2003068220A1 (fr) * 2002-02-12 2003-08-21 Akzo Nobel N.V. Derives d'indole et d'indoline 1-arylsulfonyl-3-substitues utiles dans le traitement de troubles du systeme nerveux central
WO2004048330A1 (fr) * 2002-11-28 2004-06-10 Suven Life Sciences Limited Indoles n-arylsulfonyl-3-substitues presentant une affinite pour le recepteur de la serotonine, methode de preparation et composition pharmaceutique contenant ces indoles
WO2004055026A1 (fr) * 2002-12-18 2004-07-01 Suven Life Sciences Limited Indoles tetracycliques 3-substitues a affinite pour le recepteur de serotonine

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3481953A (en) * 1967-12-18 1969-12-02 American Home Prod 1-arylsulfonyl-3-(2-substituted ethyl) indoles
EP0375133A1 (fr) * 1988-11-14 1990-06-27 The Upjohn Company Acides alpha-amino-indole-3-acétiques, utiles comme agents antidiabétiques, antiobésité et antiartériosclérotiques
WO1992013856A1 (fr) * 1991-02-12 1992-08-20 Pfizer Inc. Derives d'indoles de 5-heteroyle
WO2000063203A1 (fr) * 1999-04-21 2000-10-26 Allelix Biopharmaceuticals Inc. Composes piperidine-indol ayant une affinite avec 5-ht¿6?
WO2002051837A2 (fr) * 2000-12-22 2002-07-04 Wyeth Composes heterocyclylindazole et azaindazole utilises en tant que ligands 5-hydroxytryptamine-6
WO2003035061A1 (fr) * 2001-10-23 2003-05-01 Biovitrum Ab Utilisation de derives d'indole et d'indoline pour le traitement de l'obesite ou la reduction de l'apport alimentaire
WO2003068220A1 (fr) * 2002-02-12 2003-08-21 Akzo Nobel N.V. Derives d'indole et d'indoline 1-arylsulfonyl-3-substitues utiles dans le traitement de troubles du systeme nerveux central
WO2004048330A1 (fr) * 2002-11-28 2004-06-10 Suven Life Sciences Limited Indoles n-arylsulfonyl-3-substitues presentant une affinite pour le recepteur de la serotonine, methode de preparation et composition pharmaceutique contenant ces indoles
WO2004055026A1 (fr) * 2002-12-18 2004-07-01 Suven Life Sciences Limited Indoles tetracycliques 3-substitues a affinite pour le recepteur de serotonine

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RUSSELL M G N ET AL: "N-Arylsulfonylindole derivatives as serotonin 5 - HT6 receptor ligands", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, no. 23, 8 November 2001 (2001-11-08), pages 3881 - 3895, XP002234833, ISSN: 0022-2623 *

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006095360A1 (fr) * 2005-03-08 2006-09-14 Suven Life Sciences Limited Procede pour preparer des benzothiazinoindoles substitues
JP2008532996A (ja) * 2005-03-08 2008-08-21 スヴェン・ライフ・サイエンシズ・リミテッド 置換ベンゾチアジノインドール類の合成法
NO339034B1 (no) * 2005-03-08 2016-11-07 Suven Life Sciences Ltd Fremgangsmåte for fremstilling av substituerte benzotiazinoindoler
KR101097415B1 (ko) 2005-03-08 2011-12-23 수벤 라이프 사이언시스 리미티드 치환된 벤조티아지노인돌의 제조 방법
EA012750B1 (ru) * 2005-03-08 2009-12-30 Сувен Лайф Сайенсиз Лимитед Способ получения замещенных бензотиазиноиндолов
CN101166746B (zh) * 2005-03-08 2011-09-28 苏文生命科学有限公司 制备取代苯并噻嗪吲哚的方法
EP2258358A3 (fr) * 2005-08-26 2011-09-07 Braincells, Inc. Neurogenèse avec un inhibiteur de l'acetylcholinestérase
EP2258359A3 (fr) * 2005-08-26 2011-04-06 Braincells, Inc. Neurogenèse par modulation des récepteurs muscariniques avec sabcomeline
EP2258357A3 (fr) * 2005-08-26 2011-04-06 Braincells, Inc. Neurogenèse avec inhibiteur de l'acetylcholinestérase
US7803830B2 (en) 2005-11-30 2010-09-28 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and AZA-substituted indoles and uses thereof
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US11059828B2 (en) 2009-10-23 2021-07-13 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators
USRE48841E1 (en) 2009-10-23 2021-12-07 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US11667644B2 (en) 2009-10-23 2023-06-06 Janssen Pharmaceutica Nv Disubstituted octahydropyrrolo[3,4-c]pyrroles as orexin receptor modulators
US10828302B2 (en) 2016-03-10 2020-11-10 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists
US11241432B2 (en) 2016-03-10 2022-02-08 Janssen Pharmaceutica Nv Methods of treating depression using orexin-2 receptor antagonists

Similar Documents

Publication Publication Date Title
EP1581492B1 (fr) Indoles n-arylsulfonyl-3-substitues presentant une affinite pour le recepteur de la serotonine, methode de preparation et composition pharmaceutique contenant ces indoles
ZA200504042B (en) Tetracyclic-3-substituted indoles having serotonin receptor affinity
US20060173193A1 (en) N-arylsulfonyl-3-aminoalkoxyindoles
WO2004048331A1 (fr) N-arylalkyl-3-aminoalcoxyindoles et leur utilisation en tant que ligands des recepteurs 5-ht
WO2004108671A1 (fr) Indoles substitues dotes d'une affinite pour le recepteur de la serotonine, leur procede de fabrication et compositions pharmaceutiques les contenant
US7649097B2 (en) Tetracyclic arylsulfonyl indoles having serotonin receptor affinity useful as therapeutic agents, process for their preparation and pharmaceutical compositions containing them
WO2005005439A1 (fr) Benzothiazino indoles
US7297711B2 (en) Arylalkyl indoles having serotonin receptor affinity useful as therapeutic agents, process for their preparation and pharmaceutical compositions containing them
US7317035B2 (en) Tetracyclic arylcarbonyl indoles having serotonin receptor affinity useful as therapeutic agents, process for their preparation and pharmaceutical compositions containing them
US7388024B2 (en) Indeno[2,1A]indenes and isoindolo[2,1-A]indoles

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DPEN Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed from 20040101)