WO2014181357A1 - Nouveaux dérivés pyrazoles à silicium incorporé - Google Patents

Nouveaux dérivés pyrazoles à silicium incorporé Download PDF

Info

Publication number
WO2014181357A1
WO2014181357A1 PCT/IN2014/000317 IN2014000317W WO2014181357A1 WO 2014181357 A1 WO2014181357 A1 WO 2014181357A1 IN 2014000317 W IN2014000317 W IN 2014000317W WO 2014181357 A1 WO2014181357 A1 WO 2014181357A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
substituted
hydrogen
formula
Prior art date
Application number
PCT/IN2014/000317
Other languages
English (en)
Inventor
Dumbala Srinivasa REDDY
Remya RAMESH
Rahul Dilip SHINGARE
Original Assignee
Council Of Scientific & Industrial Research
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 Council Of Scientific & Industrial Research filed Critical Council Of Scientific & Industrial Research
Publication of WO2014181357A1 publication Critical patent/WO2014181357A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to novel sila analogs of pyrazole compounds of Formula (I) and process for preparation thereof.
  • compositions comprising of novel sila analogs of pyrazole compounds of Formula (I), which show better activity than other analogs as antiobesity molecules and also show antitubercular activities.
  • Rimonabant is one of the potentially newer therapies discovered for the treatment of obesity, smoking cessation, overweight and related diseases. This compound possesses a very good affinity to the cannabinoid receptor and is useful in the therapeutic areas in which cannabis is known to be involved.
  • the therapeutic indications of cannabinoids concern a variety of areas such as the immune system, the central nervous system and the cardiovascular or- and endocrine system.
  • Rimonabant chemically 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)- 4-mefhyl-N-(piperidin- l -yl)-pyrazole-3-carboxamide is a promising CBi receptor antagonist with potent and selective activity in binding and functional assays, and which has been shown to inhibit motivational and consummatory aspects of feeding and reduce alcohol and nicotine intake in animal models.
  • Obesity remains a poorly treatable, chronic, essentially intractable metabolic disorder. Accordingly, a need exists for new therapies useful in weight reduction and/or weight maintenance in a subject also counteracting any related diseases or disorders. Such therapies would lead to a profound beneficial effect on the subject's health.
  • Rimonabant is advantageous in several ways such as, it is reported to increase HDL-C and decrease atherogenic LDL-C levels.
  • the unique property of this drug may, in turn, improve cardiovascular risk factors and metabolic syndrome.
  • rimonabant is reported to produce improvement in HbA [C levels and may be helpful in diabetes. Further it also prevents weight gain in persons who are quitting smoking.
  • Rimonabant is an approved drug, with established safety. Rimonabant and its analogues are also shown to have promising activities and also are proved safe to human. Since Rimonabant was recently withdrawn from the market following postmarketing surveillance studies, which confirmed a risk of depressive disorders amongst users and hence there is need for modification or elimination of the carboxamide side chain in the core structure of Rimonabant , which is responsible for crossing the blood-brain barrier to reduce the side effects. Some of the organometallic complexes such as organosilicon and its biological activity have been described and well reported in the prior art.
  • SILA 409 [l ,3-dimethyl-l ,3-bis(4-fluorophenyl)-l ,3-bis(3- morpholino-propyl)-disiloxane dihydro chloride] and SILA 421 [ 1 ,3 -dimethyl- 1 , 3 -bis(4- fluorophenyl)-l ,3-bis ⁇ 3-[l(4-butyl piperazinyl)] -propyl ⁇ -disiloxan-tetrahydrochlorid] against intracellular extensively drug-resistant tuberculosis (XDR-TB) is disclosed in Int. J Antimicrob Agents. 2009 May; 33(5):479-82 by Martins M et al.
  • organosilicon molecules with medicinal applications is reported in J. Med. Chem., 2013, 56 (2), pp 388-405 by Annaliese . Franz et al.
  • synthesis, characterization, and pharmacological evaluation of silicon-containing aminoquinoline organometallic complexes as antiplasmodial, antitumor, and antimycobacterial agents is disclosed in organometallics, 2013, 32 (1), pp 141-150 by Yiqun Li et al.
  • WO 2002040490 describes substituted disiloxanes of the general formula I, their preparation and their biologically activity such as resistance of parasitic cells, fungi and bacteria and anticancer activity.
  • the inventors have considered the modification in Rimonabant core structure with silicon analogues to enhance the activity and to reduce the side effects.
  • the invention herein discloses novel Si incorporated pyrazole derivatives i.e. sila analogs of Rimonabant core structure which becomes the objective of the present invention, for which protection is sought.
  • the instant invention discloses an industrially feasible synthesis for the preparation of sila analogs of pyrazole compounds of Formula-I.
  • the novel compounds are expected to have better physico-chemical properties, in particular lipophilicity and in vivo metabolism, which in turn may lead to drug candidates with improved brain penetration and better safety profile.
  • the compounds are additionally shown to have anti-tubercular properties also.
  • the main objective of the current invention is to provide novel sila analogs of pyrazole compounds of general formula (I).
  • Another objective of the invention is to provide novel sila analogs pyrazole compound of Formula (I) having better physico-chemical properties, in particular lipophilicity and invivo metabolism, which in turn may lead to drug candidates with improved brain penetration and better safety profile.
  • Yet another objective of the invention is to provide a process to synthesize the sila-analogs of pyrazole compound of Formula (I) with high selectivity, yield and commercially feasible.
  • Another objective of the invention is to provide pharmaceutical compositions containing the novel compounds of general formula (I) to treat obesity and other related diseases and disorders like diabetes, tuberculosis, malaria, etc.
  • the current invention discloses a Si incorporated pyrazole derivatives of general formula (I),
  • n represents number 1 to 6;
  • R 1 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, thioalkyl,
  • R', R" are independently selected from the group consisting of hydrogen or (un) substituted (C[-C 8 ) alkyl, aryl orR' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un)substituted (Ci-C 8 ) alkyl
  • aryl R 2 , R 3 and R 4 each are individually selected from the group consisting of Ci to Ci alkyl, aryl, heteroaryl, aralkyl, C 1 -C5 alkoxy or any two of R 2 , R 3 and R 4 may form 4-8 membered ring which optionally may be further substituted and/or may contain additional hetero atoms
  • R 5 is selected from hydrogen, C ⁇ to C 12 alkyl, aryl, heteroaryl, aralkyl or R 5 together with any one of R 2 , R 3 and R 4 may form a ring;
  • Ar and Ar represent independently aryl, aralkyl or heteroaryl, unsubstituted or substituted with one or more substituents selected independently from halo, hydroxy, alkyl, aralkyl, cycloalkyl, alkoxy, alkylthio, alkyl sulfinyl, alkyl sulfonyl, heterocyclyl, aryl, nitro, sulfonyl, -NR'R", -CONR'R", -COOR' " ;
  • R', R" are independently selected from hydrogen or (un) substituted alkyl, aryl; R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un) substituted alkyl, aryl
  • X CO, CS, CONH, CR'R" ;
  • R' and R" are independently selected from the group consisting of hydrogen or (un) substituted alkyl, aryl and
  • R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms.
  • the invention provides industrially feasible synthetic routes for the preparation of the compound of general Formula (I)
  • the invention provides a pharmaceutical composition of compound of general formula I, its analogues, positional isomers, stereoisomers, derivatives, and pharmaceutically acceptable salts thereof useful for the treatment of obesity and other related diseases and disorders like diabetes, tuberculosis, malaria, etc.
  • the instant invention provides novel alternatives in obesity and related diseases and disorders therapy, moreover it provides novel sila analogues of pyrazole compounds and its analogues of formula-I, and process for preparation thereof.
  • the invention provides novel sila analogues of pyrazole compounds of Formula-I and tautomeric forms, positional isomers, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts, thereof.
  • n represents number 1 to 6;
  • R 1 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, thioalkyl, C1 -C5 alkoxy, C r C 5 alkoxyalkyl, -NR'R", -CH 2 NR'R" -CONR'R",-COOR' " ;
  • R', R" are independently selected from the group consisting of hydrogen or (un) substituted (Cj-Cg) alkyl, aryl orR' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un)substituted (Ci-C 8 ) alkyl, aryl
  • R 2 , R 3 and R 4 each are individually selected from the group consisting of Q to Q 2 alkyl, aryl, heteroaryl, aralkyl, C 1 -C5 alkoxy or any two of R 2 , R 3 and R 4 may form 4-8 membered ring which optionally may be further substituted and/or may contain additional hetero atoms;
  • R 5 is selected from hydrogen, C ⁇ to C 12 alkyl, aryl, heteroaryl, aralkyl or R 5 together with any one of R 2 , R 3 and R 4 may form a ring; 1
  • Ar and Ar represent independently aryl, aralkyl or heteroaryl, unsubstituted or substituted with one or more substituents . selected independently from halo, hydroxy, alkyl, aralkyl, cycloalkyl, alkoxy, alkylthio,: alkyl sulfinyl, alkyl sulfonyl, heterocyclyl, aryl, nitro, sulfonyl, -NR'R", -CONR'R", -COOR” ' ;
  • R', R" are independently selected from hydrogen or (un) substituted alkyl, aryl; R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un) substituted alkyl, aryl
  • X CO, CS, CONI-I, CR'R" wherein IV and R" are independently selected from hydrogen or (un) substituted alkyl, aryl and
  • R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms.
  • the compounds of Formula (I) has better physico-chemical properties, in particular lipophilicity and invivo metabolism, which in turn may lead to drug candidates with improved brain penetration and better safety profile.
  • the invention provides the library of the novel sila analogues of pyrazole compound of Formula-I, selected from the group consisting of; i. 5-(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-N-(4,4-dimethyl- 1 ,4-azasilinan- 1 -yl)-4- methyl- 1 H-pyrazole-3-carboxamide (NDS-100240);
  • the invention provides process for the synthesis of novel sila analogues of pyrazole compound of Formula-I,
  • the process for the synthesis of compounds of formula I is carried out by employing two synthetic routes (route I and route II).
  • the first synthetic route for the preparation of compounds of formula I which comprises peptide coupling of pyrazole carboxylic acid (A) with appropriate silicon amine C or D using suitable coupling agents to obtain compound of formula-I as depicted in below scheme 1.
  • n represents number 1 to 6;
  • R 1 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, thioalkyl, C1-C5 alkoxy, C,-C 5 alkoxyalkyl, -NR'R", -CH 2 NR'R" -CONR , R",-COOR' ";
  • R', R" are independently selected from the group consisting of hydrogen or (un) substituted (Ci-C 8 ) alkyl, aryl or R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • ' " is hydrogen or (un)substituted (C1-C8) alkyl, aryl;
  • R ⁇ R 3 and R 4 each are individually selected from the group consisting of C
  • R 5 is selected from hydrogen, Ci to Ci 2 alkyl, aryl, heteroaryl, aralkyl or R 5 together with any one of R 2 , R 3 and R 4 may form a ring;
  • Ar 1 and Ar 2 represent independently aryl, aralkyl or heteroaryl, unsubstituted or substituted with one or more substituents selected independently from halo, hydroxy, alkyl, aralkyl, cycloalkyl, alkoxy, alkylthio, alkyl sulfinyl, alkyl sulfonyl, heterocyclyl, aryl, nitro, sulfonyl, -NR'R", -CONR'R", -COOR' " ;
  • R', R" are independently selected from hydrogen or (un) substituted alkyl, aryl; R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • the pyrazole carboxylic acid compounds of Formula (A) is not limited to 5-(4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lFI-pyrazole-3-carboxylic acid (NDS-100226).
  • the silicon amine C and D is not limited to 4,4-dimethyl-l,4-azasilinane hydrochloride, 4,4-dimethyl-l ,4-azasilinan- l-amine,gamma-aminopropyltriethoxysilane, aminoethyltri methylsilane.
  • the peptide coupling agent is selected from the group consisting of N-(3- Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.FIC1),
  • FIOBt Hydroxybenzotriazole
  • FIBTU O-Benzotriazole- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyl-uronium-hexafluoro-phosphate
  • TBTU O-(Benzotriazol-l -yl)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethyluronium tetrafluoroborate
  • FIATU l-[Bis(dimethylamino)methylene]- l H- l ,2,3-triazolo[4,5-b
  • FIATU (l-Cyano-2- ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluoro phosphate (COMU) and mixture thereof.
  • the reaction temperature is maintained in between 0°C to 40°C or ambient or room temperature.
  • the invention provides the second synthetic route for the preparation of compounds of formula I, which comprises acylating pyrazole compound (B) with appropriate silicon amines C or D, optionally in presence of base to obtain compound of formula-I, with high yield as depicted in below scheme 2.
  • LG is leaving group selected from the group consisting of OH, halogen, anhydride, n represents number 1 to 6;
  • R 1 is selected from hydrogen, halogen, alkyl, haloalkyl, hydroxyalkyl, thioalkyl, C
  • R', R" are independently selected from the group consisting of hydrogen or (un) substituted (CpCs) alkyl, aryl or R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un)substituted (Cj-Cg) alkyl, aryl
  • R 2 , R 3 and R 4 each are individually selected from the group consisting of C ⁇ to C
  • R is selected from hydrogen, Q to Cj 2 alkyl, aryl, heteroaryl, aralkyl or R 5 together with any one of R 2 , R 3 and R 4 may form a ring;
  • Ar 1 and Ar 2 represent independently aryl, aralkyl or heteroaryl, unsubstituted or substituted with one or more substituents selected independently from halo, hydroxy, alkyl, aralkyl, cycloalkyl, alkoxy, alkylthio, alkyl sulfinyl, alkyl sulfonyl, heterocyclyl, aryl, nitro, sulfonyl, -NR'R", -CONR'R", -COOR” ' ;
  • R', R" are independently selected from hydrogen or (un) substituted alkyl, aryl; R' and R" together form a ring with up to six carbon atoms which optionally may be substituted and/or may contain hetero atoms;
  • R' " is hydrogen or (un) substituted alkyl, aryl
  • X is CI 2 .
  • the pyrazole compound of Formula (B) is 5-(4- chlorophenyl)- l -(2,4-dichlorophenyl)-4-methyl-l/-/-pyrazol-3-yl]methanol.
  • the acylating agent is selected from the group consisting of tosyl chloride, mesyl chloride, benzoyl chloride, butyric anhydride, acetic anhydride or acetyl chloride and like thereof.
  • the base employed in the process is selected from the group consisting of triethylamine, diisopropylethyl amine or mixture thereof.
  • solvent used in the process is selected from the group consisting of DCM, DMF, THF, Ethyl acetate, Acetone, DMSO, Acetonitrile or mixture thereof.
  • the invention provides synthetic route for the preparation of 5 -(4-chlorophenyl)- 1 -(2,4-dichlorophenyl)-N-(4,4-dimethyl- 1 ,4-azasilinan- 1 -yl)-4-methyl- l H-pyrazole-3-carboxamide (NDS-100240) comprises the coupling of 5-(4-chlorophenyl)-l- (2,4-dichlorophenyl)-4-methyl-lFI-pyrazole-3-carboxylic acid (NDS-100226) (made according to literature procedures, Bioorg. Med. Chem. Lett.
  • the invention provides synthetic route for the preparation of l -((5- (4-chlorophenyl)-l-(2,4-dichlorophenyl)-4-methyl- lH-pyrazol-3-yl)methyl)-4,4-dimethyl- 1 ,4-azasilinane (NDS-100218), comprises mesylation of 5-(4-chlorophenyl)-l -(2,4- dichlorophenyl)-4-methyl-lH-pyrazol-3-yl]methanol (NDS-100217) (see WO 2010/020762 for preparation) in presence of mesylchloride and triethylamine followed by reaction with 4,4-dimethyl- l ,4-azasilinane hydrochloride in suitable organic solvent like dry dimethyl formamide (DMF) at RT.
  • DMF dry dimethyl formamide
  • the invention provides process for converting carbonyl group of sila analogues of pyrazole compounds of Formula I to its corresponding thiocarbonyl derivative by treatment with Lawsson's reagent.
  • Lawsson's reagent i.e. 2,4- bis(4-methoxyphenyl)-l ,3,2,4-dithiadiphosphetane-2,4-disulfide is used as thiation agent.
  • NDS-100264 and NDS-100275 were prepared as depicted below in the Scheme 8.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a stereoisomer, or ester or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • compositions of general Formula (I) are used to treat obesity, related diseases and disorders such as pathogenic and parasitic infections like tuberculosis and malaria, CNS disorders and smoking cessation.
  • compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres.
  • the present invention relates to administering 'an effective amount' of the 'composition of invention ' to the subject suffering from said disease.
  • compound of formula (I) pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease.
  • Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.
  • compositions of the invention are formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient.
  • Compositions that will be administered to a subject or patient may take the form of one or more dosage units.
  • the dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.
  • the invention provides a method of treating obesity, related diseases and disorders such as antipathogenic and antiparasitic infections like tuberculosis and malaria, CNS disorders and smoking cessation.
  • a subject comprising administrating novel sila analogues of pyrazone compounds of Formula-I, optionally with at least one additional active compound with pharmaceutically acceptable excipients and/or vehicles.
  • the invention provides sila analogues of pyrazole compounds of Formula-I for use in treating antipathogenic and antiparasitic infections in a subject.
  • the subject according to the invention is an animal or human.
  • the invention furnishes sila analogues of pyrazole compounds of Formula-I for the preparation of medicament useful for treating or inhibiting the growth of pathogens or parasites in human.
  • the synthesized novel analogues of pyrazole compounds of Formula- I are characterized by means of 13C-NMR, 1H-NMR, IR, Mass and other known techniques. Advantages of the invention:
  • Compound has better physico-chemical properties, in particular lipophilicity and invivo metabolism, which in turn may lead to drug candidates with improved brain penetration and better safety profile (cf J. Med. Chem. 2013, 56, 388-405; Expert Opin. Investig. Drugs 2004, 13 (9): 1 149- 1 157).
  • NDS- 100218 showed very good antitubercular activity (MIC 0.78 ⁇ g/ mL) against H37RV.
  • NDS-100226 NDS-100240 To a solution of the compound NDS-100226 (76 mg, 0.20 mmol)in dry dichloromethane, was added N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HC1, 40 mg, 0.26 mmol), Hydroxybenzotriazole (HOBt, 35 mg, 0.26 mmol) and diisopropylethyl amine (0.1 mL, 0.60 mmol) at 0°C. Then the amine 3 was added and stirred at RT for 6 h. To the reaction mixture water was added and the organic layer was separated, washed with saturated NaHC0 3 , IN HQ, dried over Na 2 S0 4 and concentrated under reduced pressure. This crude mixture was purified by column chromatography to give the title compound
  • NDS-100240 (90 mg) as a white fluffy solid in 89% yield.
  • NDS-100217 NDS-100218 To a solution of the compound NDS-100217 (80 mg, 0.22 mmol) in dry dichloromethane (DCM), was added Triethylamine (76 ⁇ , 0.56 mmol) followed by Mesylchloride (19 ⁇ ⁇ , 0.24 mmol) at 0°C and stirred at the same temperature for 2 h. To the reaction mixture water was added and the organic layer was separated, dried over Na 2 S0 4 and concentrated under reduced pressure. This crude product was immediately taken to the next step.
  • DCM dry dichloromethane
  • NDS-100203 (100 mg, 0.20 mmol) was taken in a sealed tube and dry tetrahydrofuran (THF) was added followed by Lawesson's reagent (41 mg, 0.10 mmol). It was then sealed and heated at 70 °C for 5 h. The reaction mixture was cooled; solvent was removed under reduced pressure and purified by column chromatography to give the title compound NDS-100219 as a yellow solid (100 mg, 98 %).
  • THF dry tetrahydrofuran
  • NDS-100264 To a solution of the compound NDS-100257 (100 mg, 0.25 mmol) in.
  • NDS-100257 40 mg, 0.10 mmol
  • EDC.HCl N-(3-Dimethylaminopropyl)-N'- ethylcarbodiimide hydrochloride
  • HOBt Hydroxybenzotriazole
  • diisopropylethyl amine 0.06 mL, 0.30 mmol
  • Example 10 l-((l,5-bis(4-chlorophcnyl)-lH-pyrazoI-3-yl)methyI)-4,4-dimethyl-l,4-azasilinane (NDS- 100529)
  • NDS- 100530 prepared according to the reported procedure in patent US 6,350,892 B l
  • DCM dry dichloromethane
  • Triethylamine 109 ⁇ , 0.78 mmol
  • Mesylchloride 30 ⁇ 0.37 mmol
  • the compounds were tested for antitubercular activity through inhibition of growth of the virulent strain of Mycobacterium tuberculosis H 37 Rv using Alamar-Blue assay method.
  • MIC values of the compounds against H 37 Rv were determined in 7H9-OADC media supplemented with 0.5% glycerol and 1 mg ml '1 tryptone at 37 °C in 96-well microtiter plates using the colorimetric resazurin microtiter assay, and growth was measured by visual readout.
  • Rifampicin was used as a positive drug control.
  • Sample code MIC ( ⁇ & mL)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Epidemiology (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des nouveaux sila-analogues de composés pyrazoles de formule I et leur procédé de préparation. L'invention concerne en outre des compositions pharmaceutiques comprenant de nouveaux sila-analogues de composés pyrazoles de formule I, qui présentent une meilleure activité que d'autres analogues en tant que molécules anti-obésité et qui présentent également des activités de médicament antituberculeux.
PCT/IN2014/000317 2013-05-09 2014-05-09 Nouveaux dérivés pyrazoles à silicium incorporé WO2014181357A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1390DE2013 2013-05-09
IN1390/DEL/2013 2013-05-09

Publications (1)

Publication Number Publication Date
WO2014181357A1 true WO2014181357A1 (fr) 2014-11-13

Family

ID=51033256

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2014/000317 WO2014181357A1 (fr) 2013-05-09 2014-05-09 Nouveaux dérivés pyrazoles à silicium incorporé

Country Status (1)

Country Link
WO (1) WO2014181357A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017141272A1 (fr) * 2016-02-19 2017-08-24 Council Of Scientific & Industrial Research Composés cycliques à base de silicium et compositions pharmaceutiques pour le traitement du paludisme et de la toxoplasmose

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350892B1 (en) 1997-09-23 2002-02-26 Bristol-Myers Squibb Company Trifluoromethyl ketone analogs as selective cPLA2 inhibitors
WO2002040490A1 (fr) 2000-11-15 2002-05-23 Andras Varga Disiloxanes substitues, leur procede de preparation et leur utilisation pour inverser la resistance pleiotrope
US20030087933A1 (en) * 2000-02-09 2003-05-08 Blanchard Jean Charles Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
WO2008153632A2 (fr) * 2007-06-15 2008-12-18 Vivus, Inc. Compositions et méthodes de traitement de l'obésité et de troubles connexes
WO2010020762A1 (fr) 2008-08-19 2010-02-25 The University Court Of The University Of Aberdeen 1,5-diaryl-pyrazoles et leur utilisation comme antagonistes neutres des récepteurs cannabinoïdes
US20120135958A1 (en) * 2009-07-27 2012-05-31 Sanofi Tetrahydroquinoxaline urea derivatives, preparation thereof, and therapeutic use thereof
WO2013054275A1 (fr) * 2011-10-11 2013-04-18 Council Of Scientific & Industrial Research Sila-analogues de dérivés d'oxazolidinone et synthèse de ceux-ci

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350892B1 (en) 1997-09-23 2002-02-26 Bristol-Myers Squibb Company Trifluoromethyl ketone analogs as selective cPLA2 inhibitors
US20030087933A1 (en) * 2000-02-09 2003-05-08 Blanchard Jean Charles Use of central cannabinoid receptor antagonist for preparing medicines designed to facilitate smoking cessation
WO2002040490A1 (fr) 2000-11-15 2002-05-23 Andras Varga Disiloxanes substitues, leur procede de preparation et leur utilisation pour inverser la resistance pleiotrope
WO2008153632A2 (fr) * 2007-06-15 2008-12-18 Vivus, Inc. Compositions et méthodes de traitement de l'obésité et de troubles connexes
WO2010020762A1 (fr) 2008-08-19 2010-02-25 The University Court Of The University Of Aberdeen 1,5-diaryl-pyrazoles et leur utilisation comme antagonistes neutres des récepteurs cannabinoïdes
US20120135958A1 (en) * 2009-07-27 2012-05-31 Sanofi Tetrahydroquinoxaline urea derivatives, preparation thereof, and therapeutic use thereof
WO2013054275A1 (fr) * 2011-10-11 2013-04-18 Council Of Scientific & Industrial Research Sila-analogues de dérivés d'oxazolidinone et synthèse de ceux-ci

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
ANNALIESE K. FRANZ, J. MED. CHEM., vol. 56, no. 2, 2013, pages 388 - 405
BIOORG. MED. CHEM. LETT., vol. 21, 2011, pages 4913
BIOORG. MED. CHEM. LETT., vol. 21, 2011, pages 562
BIORG. MED. CHEM. LETT., vol. 21, 2011, pages 562
EXPERT OPIN. INVESTIG. DRUGS, vol. 13, no. 9, 2004, pages 1149 - 1157
MARTINS M, INT. J ANTIMICROB AGENTS, vol. 33, no. 5, May 2009 (2009-05-01), pages 479 - 82
MED. CHEM., vol. 56, 2013, pages 388 - 405
YIQUN LI, ORGANOMETALLICS, vol. 32, no. 1, 2013, pages 141 - 150

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017141272A1 (fr) * 2016-02-19 2017-08-24 Council Of Scientific & Industrial Research Composés cycliques à base de silicium et compositions pharmaceutiques pour le traitement du paludisme et de la toxoplasmose
US10562922B2 (en) 2016-02-19 2020-02-18 Council Of Scientific And Industrial Research Silicon based cyclic compounds and pharmaceutical compositions for treating malaria and toxoplasmosis

Similar Documents

Publication Publication Date Title
US9493441B2 (en) Acyclic cyanoethylpyrazoles as janus kinase inhibitors
DE60008372T2 (de) Pharmazeutisch aktive verbindungen
JP4740115B2 (ja) 置換ピラゾール
JP4177435B2 (ja) 治療薬
EA007720B1 (ru) Производные триазола в качестве антагонистов рецептора тахикинина
JP2008526887A (ja) カンナビノイド受容体に作用する新規なヘテロピロール類似体
JPH11508553A (ja) ピペリジン及びモルホリン誘導体並びに治療剤としてのそれらの使用
SK112893A3 (en) Benzofuran derivatives, method of their preparation and pharmaceutical compositions containing them
CN111065639B (zh) 一类细胞周期依赖性激酶的降解剂、其制备方法、药物组合物及其用途
TW297813B (fr)
FR2849032A1 (fr) Derive de 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-n -(piperidin-1-yl)-1h-pyrazole-3-carboxamide, sa preparation, son application en therapeuthique
SA520412473B1 (ar) مركب أميد حلقي غير متجانس معالج بالنيتروجين واستخدامه لأغراض طبية
CA3047002A1 (fr) Nouveaux composes utiles en tant qu'inhibteurs de l'indoleamine 2,3-dioxygenase et/ou du tryptophane dioxygenase
JP4740116B2 (ja) 精神疾患および神経障害の処置のための５−ｈｔ受容体アンタゴニスト
CA3068083A1 (fr) Derive d'indole-formamide, son procede de preparation et son utilisation en medecine
JP2009501771A (ja) Ｃｂ１モジュレーターとしてのピラゾール誘導体
JP6219955B2 (ja) ベンゾフラザン抗アミロイド化合物および方法
EP2616460B1 (fr) Composés hétérocycliques pour le traitement ou la prévention de troubles provoqués par une neurotransmission réduite de la sérotonine, de la norépinephrine ou de la dopamine
CA3110576A1 (fr) Composes destines au traitement de certaines leucemies
EP0514192A1 (fr) Dérivés de benzofuranne à activité anti-hypertensive, substituées par des groupes N-pyrimidinyle- ou N-imidazolyle-methyle variables
WO2014181357A1 (fr) Nouveaux dérivés pyrazoles à silicium incorporé
US20240116899A1 (en) Beta-lactam derivatives for the treatment of diseases
CA2520281A1 (fr) Derives de benzimidazole et leur utilisation pour moduler le complexe du recepteur gaba<sb>a</sb>
EP1915375B1 (fr) DÉRIVÉS DE -PYRIDINYL-i-AZABICYCLO[3.2.1]OCTANE, A LEUR PRÉPARATION ET LEUR APPLICATION EN THÉRAPEUTIQUE
JP5872591B2 (ja) ピラゾール化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 14734240

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 14734240

Country of ref document: EP

Kind code of ref document: A1