WO2004108671A1 - Indoles substitues dotes d'une affinite pour le recepteur de la serotonine, leur procede de fabrication et compositions pharmaceutiques les contenant - Google Patents

Indoles substitues dotes d'une affinite pour le recepteur de la serotonine, leur procede de fabrication et compositions pharmaceutiques les contenant Download PDF

Info

Publication number
WO2004108671A1
WO2004108671A1 PCT/IN2004/000154 IN2004000154W WO2004108671A1 WO 2004108671 A1 WO2004108671 A1 WO 2004108671A1 IN 2004000154 W IN2004000154 W IN 2004000154W WO 2004108671 A1 WO2004108671 A1 WO 2004108671A1
Authority
WO
WIPO (PCT)
Prior art keywords
indole
methylpiperazin
ylmethyl
methanone
benzenesulfonyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IN2004/000154
Other languages
English (en)
Inventor
Venkata Satya Nirogi Ramakrishna
Vikas Shreekrishna Shirsath
Rama Sastri Kambhampati
Venkateswarlu Jasti
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Suven Life Sciences Ltd
Original Assignee
Suven Life Sciences Ltd
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 Ltd filed Critical Suven Life Sciences Ltd
Publication of WO2004108671A1 publication Critical patent/WO2004108671A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring

Definitions

  • the present invention relates to the compounds described by general formula (I), including the stereoisomers, radioisotopes, N-oxides, polymorphs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates, bio-active metabolites or any suitable combination of the above chemical forms of compounds defined by general formula (I).
  • the present invention also includes the process for preparing such compounds of general formula ⁇ ]). These processes also include some additional steps that may be required to obtain the stereoisomers, the radioisotopes, the N- oxides, the polymorphs, the pharmaceutically acceptable salts, the pharmaceutically acceptable solvates, bio-active metabolites and also includes any suitable combination of the above. There are variety of methods to administer the compounds of general formula ⁇ ]). These processes also include some additional steps that may be required to obtain the stereoisomers, the radioisotopes, the N- oxides, the polymorphs, the pharmaceutically acceptable salts, the pharmaceutically acceptable solvates, bio-active metabolites and also includes any suitable combination of the above. There are variety of methods to administer the compounds of general formula ⁇ ]). These processes also include some additional steps that may be required to obtain the stereoisomers, the radioisotopes, the N- oxides, the polymorphs, the pharmaceutically acceptable salts, the pharmaceutically acceptable solvates, bio-active metabolites and also includes any suitable combination
  • GPCRs G- protein-coupled receptors
  • Majority of drugs exerts their action by interacting with GPCRs, which results into pharmacologically beneficial effect.
  • the mode and general functioning of GPCRs 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 Nigel W. Bu ⁇ nett., G-Protein-Coupled Receptors in Gastrointestinal Physiology. II. Regulation of neuropeptide receptors in enteric neurons. Am. J. Physiol. 274 (Gastrointest. Liver Physiol. 37): G792-G796, 1998.)
  • 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.
  • the present invention relates to the compounds of general formula (I), their stereoisomers, their radioisotopes, their N-oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their useful bio-active metabolites and also includes any suitable combination of the above.
  • Methylpiperazine-1-yl)-methanone 5-methoxy -l-(Benzenesulfonyl) -2- (4-Methylpiperazine-1-yl)-methyl)-1 H-indole;
  • Methylpiperazine-1 -yl)-methanone (1-(4'-lsopropyl)benzenesuIfonyl-5-isopropyl-1H-indole-2-yl)-(4-Methylpiperazine-1- yl)-methanone;
  • the present invention also relates to the numerous processes for preparing the compounds of general formula (I) their stereoisomers, their radioisotopes, their N- oxides, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, their useful bio-active metabolites and also includes any suitable combination of the above.
  • 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.
  • 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 O, 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 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, a mixture of 2 positional isomers or oxide of aromatic nitrogen.
  • 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.
  • pharmaceutically acceptable 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.
  • 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.
  • 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).
  • chemical modifications include any-one of the following:
  • ester or amide derivatives which may be cleaved by esterases or lipases;
  • Another aspect of the present invention comprises of a pharmaceutical composition, containing at least one of the compounds of 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 their salt can be used to produce a medicament, 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 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 .
  • disorders/ Hyperactivity Syndrome amylotrophic lateral sclerosis
  • withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines
  • panic attacks and also disorders associated with spinal trauma and / or head injury such 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.
  • these compounds can help in modulation of eating behavior and thereby 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 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 cocaine, 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
  • 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, 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),
  • phrases "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.
  • treating embrace all the meanings such as preventative, prophylactic and palliative.
  • the present invention relates to compounds of general formula (I), are described in the summary above.
  • Suitable groups represented by R 1? R 2 , R 3 , R 4 , Rs, Re, R7, Rs, R9, R10, R11, R ⁇ 2 , R13, R ⁇ , R 1 5, Rie and R1 7 , wherever applicable, may be selected be from the
  • halogen atom such as fluorine, chlorine, bromine or iodine
  • perhaloalkyl particularly perhalo (C C 6 )alkyl such as fluoromethyl, difluoromethyl, trifluoromethyl, triflu ⁇ roethyl, fluoroethyl, difluoroethyl and the like
  • perhaloalkoxy particularly perhalo(d-C 6 )alkoxy such as fluoromethoxy, difluoromethoxy, trifluoromethoxy and the like
  • substituted or unsubstituted (C C 12 )alkyl group
  • linear or branched (CrC 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 unsubstituted (C 2 -C ⁇ 2 )alkenyl group such as ethylene, n- propylene pentenyl, hexenyl, heptynyl, heptadienyl and the like; (C 2 -C ⁇ 2 )alkynyl substituted, or unsubstituted (C 2 -C ⁇ 2 )alkynyl group such as acetylene and the like;
  • cyclo(C 3 -C 7 )alkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, the cycloalkyl group may be substituted; cyclo(C 3 -C 7 )alkenyl group such as cyclopentenyl, cyclohexenyl, cycloheptynyl, cycloheptadienyl, cycloheptatrienyl and the like, the cycloalkenyl group may be substituted; (CrC 12 )alkoxy, especially, (C C 6 )alkoxy group such as methoxy, ethoxy, propyloxy, butyloxy, iso-propyloxy and the like, which may be substituted; cyclo(C 3 -C 7 ) alkoxy group such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy
  • Suitable cyclic structures formed by the two adjacent groups such as R ⁇ and R 2 or R 2 and R 3 or R and R 5 or R 5 and R 6 or R 6 and R 7 or R 7 and R 8 or R 8 and R 9 ; optionally R ⁇ 3 along with either R ⁇ 6 or R 17 and the two nitrogen atoms may form a 5-, 6- or 7- membered heterocyclic ring, which * may be further substituted with R 4 and R 1S , and may have either one, two or three double bonds; optionally R 12 and R ⁇ 6 or R 14 and R 16 together with carbon atoms to which they are attached may contain either 4, 5 or 6 ring atoms, which optionally contains one or more heteroatoms, selected from the group containing oxygen, nitrogen or sulfur, and/or one or more double bonds and other possible combinations such as both double bond and hetero atoms.
  • An example, of suitable structures thus formed at the 2-position of indole nucleus includes, an optionally substituted piperazinyl, imidazolyl, pyrimidinyl, pyrazinyl, N,N,N',N'-tetraalkyldiaminoalkane, N,N,N',N'-tetraalkyldiaminoalkene, N-aryl,N,N',N'-trialkyldiaminoalkane, N-arylcarbonyl,N,N',N'-trialkyldiaminoalkane, N- arylthiocarbonyl,N,N',N'-trialkyldiaminoaIkane and the like.
  • Suitable substituents on these include hydroxy, halogen atom such as chlorine, bromine and iodine; nitro, cyano, amino, formyl, (C C 3 )alkyl, (C C 3 )alkoxy, thioalkyl, alkylthio, phenyl or benzyl groups.
  • 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- Verlag, Berlin, including supplements (also available via the Beilstein online database)).
  • 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 amino-protecting groups ⁇ NH-Pg) include acetyl, trifluoroacetyl, t- butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and Fluorenylmethyleneoxycarbonyl (Fmoc).
  • Preferred indole -NH protecting groups are trimethylsilylethoxymethyl, benzyl, tosyl, carbamate, amide, alkyl or aryl sulfonamide, while maleimide protecting groups include alkoxy, benzyl, dialkoxybenzyl, benzyloxyalkyl or allyl.
  • Preferred hydroxy protecting groups are ether or ester derivatives of the hydroxy group such as tert-butyldiphenylsilyloxy (TBDPS), tert-butyldimethylsilyloxy (TBDMS), triphenylmethyl (trityl), mono- or di- methoxytrityl, or an alkyl or aryl ester.
  • TDPS tert-butyldiphenylsilyloxy
  • TDMS tert-butyldimethylsilyloxy
  • triphenylmethyl trityl
  • mono- or di- methoxytrityl or an alkyl or aryl ester.
  • 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.
  • R 1( R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Rs, Rg, Rio, R11, R12, R ⁇ 3 , R- ⁇ 4 , R ⁇ s, R ⁇ e, R17, Q, A and n are as defined previously for the compounds of general formula (I) and R is as defined elsewhere in the specification.
  • Compounds of general formula (I) can be prepared by any of the methods described below. Reference includes PCT application WO 99/09025, which has incorporated herein by reference.
  • the present invention also provides processes for preparing compounds of general formula (I) as defined above, their derivatives, their analogs, their tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their isotopically-labeled derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates and novel intermediates involved therein, which are as described below:
  • R 1( R 2 , R 3 , R 4 , R 0 and A are as defined in relation to formula (I)
  • X is halogeno, for example, a chloro, bromo or iodo
  • R represents either of a suitable N- protecting group such as acetyl, triflouroacetyl, trityl, t-butyloxycarbonyl (t-BOC) or a group such as, where R 5 , R 6 , z, Rs and R 9 are as defined earlier; with a compound of formula (III) or its acid addition salt,
  • R ⁇ 3 , R ⁇ 4 , R ⁇ 5 , R ⁇ e and R 17 are as defined in relation to compound of formula (I) or precursor thereof; 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 or prodrug thereof.
  • substituents selected for the compounds of formulae (II) and (III) are either inert to the reaction conditions or the sensitive groups are protected using suitable protecting groups. Whenever 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, acetone, DMF, xylene, toluene, methanol, ethanol, propanol and the like and preferably using either acetone or DMF.
  • a solvent such as THF, acetone, DMF, xylene, toluene, 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 N 2 , Ar or He.
  • the reaction mixture is generally heated to an elevated temperature or reflux temperature of the solvent, until the reaction is complete.
  • acid-acceptor agents can be used in this condensation.
  • preferred basic agents are sodium carbonate, sodium bicarbonate, potassium carbonate, sodium acetate, sodium alkoxides and the like, with a preferred basic agent being K 2 CO 3 . Reaction times of about 30 minutes to 72 hours are common.
  • reaction mixture can be optionally acidified before work-up.
  • product can be isolated by precipitation, washed, dried and further purified by standard methods such as recrystallization, column chromatography etc.
  • Optional steps (i), (ii) and (iii) can be carried out using conventional methods. These will depend upon the precise nature of the substituents on the indole in each case. Examples of suitable reactions are illustrated hereinafter.
  • R 5 , R 6 , R 7 ⁇ R 8 and R 9 are as defined in relation to formula (I) and X is a halogeno, preferably chloro or bromo; and thereafter if desired or necessary carrying out steps (i), (ii) and/or (iii) as described above.
  • substituents selected for the compounds of formula (IV) and (V) are either not affected by the reaction conditions or else the sensitive groups are protected using suitable groups.
  • 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-propranol, n-butanol, tert-butanol and also DMF (N.N-dimethylformamide), DMSO (dimethyl sulfox
  • 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
  • reaction may be effected in the presence of phase transfer catalyst such as tetra-n-butylammonium hydrogen sulphate and the like.
  • phase transfer catalyst such as tetra-n-butylammonium hydrogen sulphate and the like.
  • the inert atmosphere may be maintained by using inert gases such as N 2 , 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.
  • R 1t R 2l R 3 , R 4 , and R 10 are as defined in relation to formula (I), R represents either of a suitable N-protecting group such as acetyl, triflouroacetyl, or a group such as,
  • R 5 , R 6 , R ⁇ R 8 and R 9 are as defined earlier; with a compound of formula (III) or its acid addition salt,
  • R 13 , R 1 , R 15 , ⁇ 6 and R ⁇ 7 are as defined in relation to compound of formula (I) or precursor thereof; by standard peptide coupling for example using bis(2-oxo-3- oxazolidinyl) phosphoric chloride (BOP-CI) and thereafter if desired or necessary carrying out steps (i), (ii) and/or (iii) as described above.
  • BOP-CI bis(2-oxo-3- oxazolidinyl) phosphoric chloride
  • N,N'-thionyl-diimidazole is first prepared by reacting imidazole with thionyl chloride. The former is then reacted with the compound of formula (VI) N-(substituted indolyl)alkanoic acid and the resulting N- (substituted indolyI-alkanoyl)imidazole is reacted with N-substituted amine compound of formula (III).
  • N,N'-thionyl-diimidazole and N-(substituted indolylalkanoyl)imidazole intermediates can be isolated prior to the next reaction in the succeeding step, but it is advantageous to carry out the entire sequence of steps upto formation of N-(substituted indolyl-alkanoyl)-4-substituted-amine in essentially one operation, that is by reacting each intermediate without isolation with the next succeeding reactant using the same solvent medium for the entire sequence of reactions.
  • Suitable solvents are organic solvents inert under the conditions of the reactions, for example tetrahydrofuran, diethylether, dibutylether and the like.
  • the reactions are preferably conducted at a temperature in the range from about -10 °C to about 50 °C.
  • reducing agents capable of converting the amido functionality to an amino moiety.
  • Such agents are, for example, lithium aluminum hydride or other complex aluminum hydrides.
  • the reducing reactions are, performed in diethyl ether or tetrahydrofuran, or in a stable diborane complex such as boran- tetrahydrofuran or borane-dimethylsulphide or others (J. Org. Chem. 1982, 47, 1389) used in an appropriate solvent (e.g. tetrahydrofuran).
  • Many other useful reducing agents are known to those skilled in the art (March J., Advanced Organic Chemistry, Wiley Interscience Ed., 1992, 1212).
  • R 1( R 2 , R 3 , R and R ⁇ 0 are as defined in relation to formula (I)
  • X is a halogeno, for example a chloro, bromo or iodo
  • R represents either of a suitable N-protecting group such as acetyl, triflouroacetyl, benzyl, trityl, t-butyloxycarbonyl (t- BOC) or a group such as,
  • R 5 , R 6 , R 7 , Rs and R 9 are as defined earlier, with a compound of formula (III) or its acid addition salt,
  • the reaction is preferably carried out at a temperature in the range from about -5 °C to about 65 °C, in the presence of acid acceptor in an organic solvent inert under the conditions of the reactions, for example tetrahydrofuran, diethylether, ethylene chloride and the like.
  • acid acceptor is to take up the hydrogen halide which is split out during the course of the reaction and includes sodium carbonate, sodium bicarbonate, potassium -carbonate, sodium acetate, sodium alkoxides and the like.
  • the acid acceptor can also be in the form of an excess quantity of substituted amine.
  • Certain amines such as N-substituted piperazines, can be prepared by acylation or alkylation of the appropriate NH-piperazine compound according to the standard procedures.
  • the compounds of the present invention may contain one or more asymmetric centers and therefore they also exist as stereoisomers.
  • the 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, Racerriates 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 lysine, arginine and the like.
  • 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 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,
  • 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 microscopy.
  • R ⁇ , R2, R 3 , R , R10, R11, R12, R1 and R-15 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 ⁇ -C ⁇ 2 )alkyl, (C 2 -C ⁇ 2 )alkenyl, (C 2 -C ⁇ 2 )alkynyl, (C 3 - C )cycloalkyl, (C 3 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C C 12 )al
  • R 1 3, R 1 6 and R 17 may be same or different and each independently represents hydrogen, substituted or unsubstituted groups selected from linear or branched (C C ⁇ 2 )alkyl, (C 2 -C ⁇ 2 )alkenyl, (C 2 -C 12 )alkynyl, ⁇ C 3 -C 7 )cycloaIkyl, (C 3 -C 7 )cycloalkenyl, bicycloalkyl, bicycloalkenyl, aryl, aralkyl, heteroaryl, heterocyclylalkyl; alternatively R 13 along with either R ⁇ 6 or R17 and the two nitrogen atoms may form a 5-, 6- or 7- membered heterocyclic ring, which may be further substituted with R 14 and ⁇ 5 , and may have either one, two or three double bonds, with the proviso that, When Ri3 along with R 16 together with the intervening nitrogens form a piperazine or a substituted piperazine ring, then R
  • 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 tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their isotopically-labeled derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates thereof as an active ingredient, together with pharmaceutically employed carriers, auxiliaries and the like.
  • a pharmaceutical composition containing at least one of the compounds of the general formula (I), their derivatives, their analogs, their derivatives, their tautomeric forms, their stereoisomers, their geometric forms, their N-oxides, their polymorphs, their isotopically-labeled derivatives, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates thereof as an active ingredient, together with pharmaceutically employed carriers, auxiliaries and the like.
  • 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 orpropyl p-hydroxybenzoates or sorbic acid).
  • 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.
  • 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 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.
  • the affinities of the compound of this invention for the various serotonin receptors are evaluated using standard radioligand binding assays and are described here.
  • Radioligand binding assays for various 5-ht receptor sub-types International Patent Publication WO 04/000205, WO 04/000845, WO
  • D 12 5-lsopropyl-1H-indol-2-carboxylic acid, N-(N',N'- 288 dimethylaminoethyl)-N-methylamide.
  • D 13 6,7-Dimethyl-1H-indol-2-carboxylic acid, N-(N',N'- 274 dimethyIaminoethyl)-N-methylamide.
  • D 14 5,7-Dimethyl-1H-indol-2-carboxylic acid, N-(N',N'- 274 dimethylaminoethyl)-N-methylamide.
  • Example - 1 1-Benzenesulfonyl-2-(4-methylpiperazin-1-ylmethyl)-1 H-indole ; 2-(4-Methylpiperazin-1-ylmethyl)-1 H-indole (2.59 g, 0.01 moles) in DMF (30 mL) was added slowly to a suspension of sodium hydride (0.26 g, 0.011 moles, (0.52 g of 50 % suspension in mineral oil)) in DMF (10 mL) maintaining the temperature below 10 °C. The mixture was stirred for 1 hr at 25 °C.
  • reaction mixture was poured onto an 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.
  • Example - 2 1-(4-Fluorobenzenesulfonyl)-2-(4-methylpiperazin-1-ylmethyl)-1H- indole ; Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 3 1-(4-lsopropyIbenzenesulfonyl)-2-(4-methylpiperazin-1-ylmethyl)- 1 H-indole
  • Example - 5 1-(2-Bromo-4-methoxybenzenesulfonyl)-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole
  • Example - 6 1-(4-Methoxybenzenesulfonyl)-5-methoxy-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole
  • Example - 7 1-(4-Methoxybenzenesulfonyl)-5-methoxy-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole Hydrochloride salt
  • Example - 8 1-(4-lsopropylbenzenesulfonyl-5-methoxy-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole Using essentially the same procedure as described in example 1 , above derivative was prepared. IR spectra (cm '1 ) : 1168, 1207, 1366, 1474; Mass (m/z) : 442 (M+H) + ;
  • Example - 9 3-Chloro-1-(4-isopropylbenzenesulfonyl-5-methoxy-2-(4- methylpiperazin-1-ylmethyl)-1 H-indole Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 10 1-(4-lsopropylbenzenesulfonyl-5-methoxy-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole Hydrochloride salt Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 11 3-Chloro-1-(4-methoxybenzenesulfonyl)-5-methoxy-2-(4- methylpiperazin-1-ylmethyl)-1 H-indole Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 12 3-Chloro-1-(4-methoxybenzenesulfonyl)-5-methoxy-2-(4- methylpiperazin-1-ylmethyl)-1 H-indole Hydrochloride salt Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 464 (M+H) + .
  • Example - 13 1-(2-Bromobenzenesulfonyl)-2-(4-methylpiperazin-1-ylmethyl)-1H- indole Using essentially the same procedure as described in example 1 , above derivative was prepared. IR spectra (cm "1 ): 1112, 1213, 1368, 1573; Mass (m/z): 478, 480 (M+H) + .
  • Example - 14 1-(2-BromobenzenesuIfonyl)-3-chloro-2-(4-methylpiperazin-1- ylmethyl)-1 H-indole Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • IR spectra (cm '1 ) 1112, 1169, 1368, 1578; Mass (m/z): 512, 514, 516 (M+H) + .
  • Example - 15 N-(1-Benzenesulfonyl-1H-indol-2-yl)methyl-N,N',N'- trimethylethylene-1 ,2-diamine Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z) : 372 (M+H) + .
  • Example - 16 N-O-Benzenesulfony -S-bromo-I trimethylethylene-1 ,2-diamine Using essentially the same procedure as described in example 1 , above derivative was prepared. IR spectra (cm "1 ): 1175,1262,1380,1448. Mass (m/z): 450, 452
  • Example - 18 1-(2-Bromo-4-methoxybenzenesulfonyl-1H-indol-2-yl)methyl- N.N'.N'-trimethylethylene-l ⁇ -diamine Using essentially the same procedure as described in example 1 , above derivative was prepared. Mass (m/z): 480 (M+H) + .
  • Example - 19 1-((2-Bromo-4-methoxybenzenesuIfonyl)-3-chloro-1H-indol-2- yl)methyl-N,N ⁇ N'-trimethylethylene-1,2-diamine, hydrochloride.
  • Reaction mixture was diluted with dichloromethane 20 mL), washed with water, brine and saturated, solution of sodium bicarbonate. T,he organic layer was dried over sodium sulfate and the organic solvents were evaporated under vacuo.
  • the product was purified using column chromatography on silica gel G stationary . phase and suitable combinations of ethyl acetate and methanol in increasing gradient as the mobile phase. The residue obtained was identified by IR, NMR and mass spectral analyses as the title compound. Mass (m/z) : 384 (M+H) + .
  • Example - 21 [1-(4-Fluorobenzenesulfonyl)-1H-indol-2-yl]-(4-methylpiperazin-1- yl)methanone Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 402 (M+H) + .
  • Example - 25 [1-(4-Methoxybenzenesulfonyl)-5-methoxy-1 H-indol-2-yl]-(4- methylpiperazin-1-yl)methanone
  • Example - 27 [3-Chloro-1-(4-isoprbpylbenzenesulfonyl)-5-methoxy-1H-indol-2- yl]-(4-methylpiperazin-1-yl)methanone Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 490 (M+H) + .
  • Example - 28 [3-Chloro-1 -(4-Methoxybenzenesulfonyl)-5-methoxy-1 H-indol-2-yl]-
  • Example - 31 1-Benzenesulfonyl-1H-indole-2-carboxylic acid (2- dimethylaminoethyl)-N-methylamide Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 386 (M+H) + .
  • Example - 32 1-Benzenesulfonyl-3-bromo-1 H-indole-2-carboxylic acid (2- dimethylaminoethyl)-N-methylamide Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 464, 466 (M+H) + .
  • Example - 33 N-(1-(4-Methylbenzenesulfonyl)-3-bromo-1 H-indole-2-carboxylic acid (2-dimethylaminoethyl)-N-methylamide Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 478 (M+H) + .
  • Example - 34 1-(2-Bromo-4-methoxybenzenesulfonyl-1H-indole-2-carboxylic acid (2-dimethylaminoethyl)-N-methylamide Using essentially the same procedure as described in example 20, above derivative was prepared. Mass (m/z) : 494, 496 (M+H) + .
  • Example - 35 1-(2-Bromo-4-methoxybenzenesulfonyl-3-bromo-1 H-indole-2- carboxylic acid (2-dimethylaminoethyl)-N-methylamide
  • Example- 36 (1-Benzenesulfonyl-5-methoxy-1 H-indole-2-yl)-(4-Methylpiperazine- 1-yl)-methanone Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 37 (1-(4'-Fluorobenzenesulfonyl-5-methyl-1 H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 39 (1,-(3'-trifluoromethyl)benzenesulfonyl-5-methyl-1 H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone. Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 40 (1-(Benzenesulfonyl-5-ethoxy-1 H-indole-2-yl)-(4-Methylpiperazine-
  • Example - 41 (1-(4'-lsopropylbenzenesulfonyl-5-ethoxy-1H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone.
  • above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • IR spectra (cm "1 ) : 1181, 1382, 1438, 1640; Mass (m/z) : 470 (M+H) + .
  • Example - 42 (1-Benzenesulfonyl-5-thiomethyl-1 H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone.
  • Example - 46 5-methoxy -l-(Benzenesulfonyl) -2- (4-Methylpiperazine-1-yl)- methyl)-1 H-indole. Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 47 5-methoxy -1-(4'-Bromobenzenesulfonyl)-2-(4-Methylpiperazine-1- yl)-methyl)-1 H-indole. Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 48 5-methoxy -1-(3'-Trifluoro methyl-benzenesulfonyl)-2-(4- methylpiperazine-1-yl)-methyl)-1 H-indole. Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 49 (1-(4'-Bromobenzenesulfonyl-5-methyl-1H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone. Using essentially the same procedure as described in example 1 , above derivative was prepared, using corresponding 1 -unsubstituted indole.
  • Example - 50 (1-(4'-Bromobenzenesulfonyl-5-methoxy-1 H-indole-2-yl)-(4-
  • Example - 51 (1-(4'-Fluorobenzenesulfonyl-5-methoxy-1H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone. Using essentially the same procedure as described in example 1 , above derivative was prepared. Melting range (°C): 77-87.4, IR spectra (cm "1 ) : 1163, 1223, 1375, 1639.
  • Example - 52 3-Chloro-5-methoxy-1-(2'-bromobenzenesulfonyl )-2-yl-(4- methylpiperazine-1 -yl-methyl)-1 H-indole Using essentially the same procedure as described in example 1 , above derivative was prepared.
  • Example - 58 (1-Benzenesulfonyl-6,7-dimethyl-1 H-indole-2-yl)-(4- Methylpiperazine-1-yl)-methanone.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (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 les composés représentés par la formule générale (I) telle que représentée ci-après.
PCT/IN2004/000154 2003-06-06 2004-06-04 Indoles substitues dotes d'une affinite pour le recepteur de la serotonine, leur procede de fabrication et compositions pharmaceutiques les contenant Ceased WO2004108671A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN459/MAS/2003 2003-06-06
IN459MA2003 2003-06-06

Publications (1)

Publication Number Publication Date
WO2004108671A1 true WO2004108671A1 (fr) 2004-12-16

Family

ID=33495850

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2004/000154 Ceased WO2004108671A1 (fr) 2003-06-06 2004-06-04 Indoles substitues dotes d'une affinite pour le recepteur de la serotonine, leur procede de fabrication et compositions pharmaceutiques les contenant

Country Status (1)

Country Link
WO (1) WO2004108671A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
JP2010515674A (ja) * 2007-01-08 2010-05-13 スベン ライフ サイエンシズ リミティド ５−（ヘテロシクリル）アルキル−ｎ−（アリールスルホニル）インドール化合物および５−ｈｔ６リガンドとしてのそれらの使用
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8546431B2 (en) 2008-10-01 2013-10-01 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8697730B2 (en) 2007-10-26 2014-04-15 Panmira Pharmaceuticals, Llc 5-lipoxygenase activating protein (FLAP) inhibitor
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
WO2014133008A1 (fr) 2013-02-27 2014-09-04 塩野義製薬株式会社 Dérivés d'indole et d'azaindole ayant chacun une activité d'activation d'ampk
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
CN110357833A (zh) * 2019-06-03 2019-10-22 杭州维坦医药科技有限公司 芳杂乙酰胺类衍生物及其制备和应用

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1400934A (en) * 1972-09-25 1975-07-16 Hoffmann La Roche Indolo-2,3-c quinolinone derivatives
US4014883A (en) * 1973-09-10 1977-03-29 Hoffmann-La Roche Inc. Indoloquinolines, intermediates and processes
WO1991009849A1 (fr) * 1989-12-28 1991-07-11 The Upjohn Company Composes anti-sida diaromatiques substitues
WO1996039384A1 (fr) * 1995-06-06 1996-12-12 Pfizer, Inc. (indole-2-carbonyl-)-glycinamides substitues en n et leurs derives, servant d'inhibiteurs de la glycogene phosphorylase
WO1999007351A2 (fr) * 1997-08-07 1999-02-18 Zeneca Limited Composes chimiques
WO1999009025A2 (fr) * 1997-08-15 1999-02-25 Pfizer Products Inc. Derives de 2-(4-aryl- ou heteroaryl-piperazin-1-ylmethyl)-1h-indole
WO1999033800A1 (fr) * 1997-12-24 1999-07-08 Aventis Pharma Deutschland Gmbh Utilisation de derives indoliques comme inhibiteurs du facteur xa
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
US6184244B1 (en) * 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
WO2001014330A2 (fr) * 1999-08-23 2001-03-01 Solvay Pharmaceuticals B.V. Nouvelles phenylpiperazines
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
WO2002024685A1 (fr) * 2000-09-21 2002-03-28 Yang Ji Chemical Company Ltd. Derives de l'indole et leur utilisation en tant qu'agents antifongiques et/ou antiparasitaires
WO2002032863A1 (fr) * 2000-10-20 2002-04-25 Biovitrum Ab N1-(benzensulfonyl)indoles substitues en 2, 3, 4 ou 5 et leur utilisation a des fins de traitement
WO2002044150A1 (fr) * 2000-11-28 2002-06-06 Sanofi-Synthelabo Processus chimique et nouveaux intermediaires
WO2002072548A2 (fr) * 2001-03-09 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Composes heterocycliques
EP1314733A1 (fr) * 2001-11-22 2003-05-28 Aventis Pharma Deutschland GmbH Indole-2-carboxamides comme inhibiteurs du facteur Xa
US20030100757A1 (en) * 2001-04-25 2003-05-29 Pfizer Inc. 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives interacting with the dopamine D4 receptor

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1400934A (en) * 1972-09-25 1975-07-16 Hoffmann La Roche Indolo-2,3-c quinolinone derivatives
US4014883A (en) * 1973-09-10 1977-03-29 Hoffmann-La Roche Inc. Indoloquinolines, intermediates and processes
WO1991009849A1 (fr) * 1989-12-28 1991-07-11 The Upjohn Company Composes anti-sida diaromatiques substitues
WO1996039384A1 (fr) * 1995-06-06 1996-12-12 Pfizer, Inc. (indole-2-carbonyl-)-glycinamides substitues en n et leurs derives, servant d'inhibiteurs de la glycogene phosphorylase
US6184244B1 (en) * 1996-12-16 2001-02-06 Idun Pharmaceuticals, Inc. C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases
WO1999007351A2 (fr) * 1997-08-07 1999-02-18 Zeneca Limited Composes chimiques
WO1999009025A2 (fr) * 1997-08-15 1999-02-25 Pfizer Products Inc. Derives de 2-(4-aryl- ou heteroaryl-piperazin-1-ylmethyl)-1h-indole
WO1999033800A1 (fr) * 1997-12-24 1999-07-08 Aventis Pharma Deutschland Gmbh Utilisation de derives indoliques comme inhibiteurs du facteur xa
WO1999057113A1 (fr) * 1998-05-02 1999-11-11 Astrazeneca Ab Derives heterocycliques inhibant le facteur xa
WO2001014330A2 (fr) * 1999-08-23 2001-03-01 Solvay Pharmaceuticals B.V. Nouvelles phenylpiperazines
WO2001096328A1 (fr) * 2000-06-14 2001-12-20 H. Lundbeck A/S Derives indoliques utilises dans le traitement de troubles du systeme nerveux central (snc)
WO2002024685A1 (fr) * 2000-09-21 2002-03-28 Yang Ji Chemical Company Ltd. Derives de l'indole et leur utilisation en tant qu'agents antifongiques et/ou antiparasitaires
WO2002032863A1 (fr) * 2000-10-20 2002-04-25 Biovitrum Ab N1-(benzensulfonyl)indoles substitues en 2, 3, 4 ou 5 et leur utilisation a des fins de traitement
WO2002044150A1 (fr) * 2000-11-28 2002-06-06 Sanofi-Synthelabo Processus chimique et nouveaux intermediaires
WO2002072548A2 (fr) * 2001-03-09 2002-09-19 Ortho-Mcneil Pharmaceutical, Inc. Composes heterocycliques
US20030207893A1 (en) * 2001-03-09 2003-11-06 Carruthers Nicholas I. Heterocyclic compounds
US20030100757A1 (en) * 2001-04-25 2003-05-29 Pfizer Inc. 2-(4-aryl or heteroaryl-piperazin-1-ylmethyl)-1H-indole derivatives interacting with the dopamine D4 receptor
EP1314733A1 (fr) * 2001-11-22 2003-05-28 Aventis Pharma Deutschland GmbH Indole-2-carboxamides comme inhibiteurs du facteur Xa

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8841295B2 (en) 2005-11-04 2014-09-23 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8710081B2 (en) 2005-11-04 2014-04-29 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
JP2010515674A (ja) * 2007-01-08 2010-05-13 スベン ライフ サイエンシズ リミティド ５−（ヘテロシクリル）アルキル−ｎ−（アリールスルホニル）インドール化合物および５−ｈｔ６リガンドとしてのそれらの使用
US8697730B2 (en) 2007-10-26 2014-04-15 Panmira Pharmaceuticals, Llc 5-lipoxygenase activating protein (FLAP) inhibitor
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
WO2010032258A1 (fr) 2008-09-17 2010-03-25 Suven Life Sciences Limited Composés amines d'arylsulfonamide et leur utilisation en tant que ligands de 5-ht<sb>6</sb>
US8546431B2 (en) 2008-10-01 2013-10-01 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
WO2011083487A1 (fr) 2010-01-05 2011-07-14 Suven Life Sciences Limited Composés sulfones comme ligands du récepteur 5-ht6
WO2014133008A1 (fr) 2013-02-27 2014-09-04 塩野義製薬株式会社 Dérivés d'indole et d'azaindole ayant chacun une activité d'activation d'ampk
US9890119B2 (en) 2013-02-27 2018-02-13 Shionogi & Co., Ltd. Indole and azaindole derivative having AMPK-activating activity
US9974785B2 (en) 2014-07-08 2018-05-22 Sunshine Lake Pharma Co., Ltd. Aromatic heterocyclic derivatives and pharmaceutical applications thereof
CN110357833A (zh) * 2019-06-03 2019-10-22 杭州维坦医药科技有限公司 芳杂乙酰胺类衍生物及其制备和应用
CN110357833B (zh) * 2019-06-03 2022-05-24 杭州维坦医药科技有限公司 芳杂乙酰胺类衍生物及其制备和应用
US12391660B2 (en) 2019-06-03 2025-08-19 Hangzhou Westan Pharmaceutical Technology Co., Ltd Heteroaromatic acetamide derivative, and preparation and use thereof

Similar Documents

Publication Publication Date Title
AU2003237599B2 (en) N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them
US7718690B2 (en) N-arylsulfonyl-3-aminoalkoxyindoles
CA2507923C (fr) Indoles tetracycliques 3-substitues a affinite pour le recepteur de serotonine
JP2016518324A (ja) Ｉｄｏ阻害剤
WO2004048331A1 (fr) N-arylalkyl-3-aminoalcoxyindoles et leur utilisation en tant que ligands des recepteurs 5-ht
CA2490254C (fr) Nouveaux indoles tetracycliques arylsulfonyle ayant une affinite du recepteur de la serotonine et utiles comme agents therapeutiques, leur procede de preparation et compositions pharmaceutiques les contenant
US20100197668A1 (en) 1,2,3,4-TETRAHYDROPYRROLO[1,2-A]PYRAZINE-6-CARBOXAMIDE AND 2,3,4,5-TETRAHYDROPYRROLO[1,2-a][1,4]-DIAZEPINE-7-CARBOXAMIDE DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF
WO2005005439A1 (fr) Benzothiazino indoles
HK1083217B (en) N-arylsulfonyl-3-substituted indoles having serotonin receptor affinity, process for their preparation and pharmaceutical composition containing them
HK1133002B (en) Alternative process for preparing n-arylsulfonyl-3-substituted indoles
HK1159617A (en) N-arylsulfonyl-3-aminoalkoxyindoles

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): BW GH 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)
122 Ep: pct application non-entry in european phase