WO2003087059A2 - Composes anti-histaminiques - Google Patents

Composes anti-histaminiques Download PDF

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Publication number
WO2003087059A2
WO2003087059A2 PCT/IN2003/000150 IN0300150W WO03087059A2 WO 2003087059 A2 WO2003087059 A2 WO 2003087059A2 IN 0300150 W IN0300150 W IN 0300150W WO 03087059 A2 WO03087059 A2 WO 03087059A2
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formula
hydrogen
compound
branched
cyclo
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WO2003087059A3 (fr
Inventor
Isha Harshang Bhatt
Biswajit Samanta
Ranjan Kumar Pal
Trinadha Rao Chitturi
Rajamannar Thennati
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Sun Pharmaceutical Industries Ltd
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Sun Pharmaceutical Industries Ltd
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Priority to AU2003231925A priority Critical patent/AU2003231925A1/en
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Publication of WO2003087059A3 publication Critical patent/WO2003087059A3/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/04—Ortho- or peri-condensed ring systems
    • C07D221/06—Ring systems of three rings
    • C07D221/16—Ring systems of three rings containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates to antihistaminic compounds which are (E)-oxime ether derivatives of 5,6-dihydro-benzo[5,6]cyclohepta[l ,2-b]pyridin- l 1 -ones (earlier referred to as 4-aza-5-oxo- 10, 1 l -dihydro-dibenzo[a,d]cycloheptenes), compound of formula I,
  • and R 2 are as defined in the later part of the text.
  • the compounds of the present invention are antihistaminic compounds useful in the treatment of histamine mediated disorders.
  • the oxime IVA prepared (route a) is not purified as per the procedure described in the said patent, and would contain- both E & Z oximes of fo ⁇ nulas IVa & IVa' respectively. This was indeed found to be the case when we prepared in our laboratory the oxime as described in '524. HPLC analysis of several batches of the oxime preparation as described in '524 revealed that it was a mixture of E & Z isomers of formulas IVa & IVa' in the ratio averaging about 58:42.
  • the object of the present invention is to provide antihistaminic compounds of formula I and phamiaceutically acceptable salts thereof.
  • the present invention provides (E)-ox ⁇ me ether derivative of 5,6-dihydro- benzo[5,6]cyclohepta[l,2-b]pyridin-l 1 -one, compound of formula I
  • R in formula I is selected from
  • R', R", R"', R 3 , R , R 5 , Ro & R 7 are selected from hydrogen, alkyl (Ci to C 6 linear, branched or cyclo), tricylic fused ring such as adamantyl, unsaturated alkyl (C
  • alkylaryl optionally further wherein any of R', R", R"', R 3 , R , R 5 , R 6 & R 7 groups above may be further substituted with one or more groups selected from saturated or unsaturated alkyl(C' ⁇ to C 6 linear, branched or cyclo), alkoxy(C
  • E is selected from O, S, NH, NR 8 wherein R 8 maybe C
  • D is O, NR S , S or SO 2 ; x and y are independently 1 to 6; and R 8 , R 9 & Rio are independently H, (C ⁇ -C 6 linear, branched or cyclo) alkyl group; optionally B is part of arylheterocycles containing one or more of hetero atoms (viz., N, S, O);
  • Ri and R 2 are selected from hydrogen, halogen, saturated or unsaturated C
  • R', R", R"', R 3 , R- , R 5 , R 6 & R 7 are selected from hydrogen, alkyl (C
  • D is O, NR 8 , S or SO 2 ; x and y are independently 1 to 6; and R 8 , R & Rio are independently H, (C ⁇ -C 6 linear, branched or cycio) alkyl group; optionally B is part of arylheterocycles containing one or more of hetero atoms (viz., N. S. O);
  • R ⁇ and R 2 are selected from hydrogen, halogen, alkyl (C ⁇ -C 6 linear, branched or cyclo), alkoxy (C ⁇ -C 6 linear, branched or cyclo), haloalkoxy or haloalkyl; and n is 2 to 6 and pharmaceutically acceptable salts thereof.
  • R, R. and R? are as described above.
  • formula le referred to herein as formula le.
  • R is referred to herein as formula Ii.
  • Compounds of the present invention may be prepared using different routes. For instance, by a process comprising (a) reacting ketone of fo ⁇ nula III with hydroxylamine or salts of hydroxylamine to yield oxime of formula IV(E/Z); (b) purifying the oxime of formula 1N(E/Z) with a suitable solvent to obtain pure (E)-oxime of formula IV; and (c) treating the pure (E)- oxime of formula IN with an alkylating agent, optionally further derivatizing the alkylated compound, to yield compound of formula I.
  • step (a) of the process comprises reaction of ketone of fo ⁇ nula III with hydroxylamine or its acid addition salts in an alcoholic solvent such as ethanol or methanol, using an organic or an inorganic base, preferably an inorganic base such as alkali metal hydroxides or carbonates or acetates to yield oxime of fo ⁇ nula IVE/Z.
  • an alcoholic solvent such as ethanol or methanol
  • an organic or an inorganic base preferably an inorganic base such as alkali metal hydroxides or carbonates or acetates
  • step (b) comprises purifying the oxime of formula IVE/Z obtained in step (a) with a suitable solvent preferably an aprotic solvent, more preferably a ketonic solvent, to get pure (E)-oxi Q of formula IN.
  • a suitable solvent preferably an aprotic solvent, more preferably a ketonic solvent
  • step (c) the antihistaminic compounds of the general fo ⁇ nula I are obtained by a simple and an efficient process comprising reaction of oxime of formula IV with a suitable alkylating agent.
  • the alkylated compound could, if required, be farther derivatized to compounds of the general formula I as described above.
  • step (c) comprises reaction between the oxime of fomiula IV with an alkylating agent in the presence of a base and a facilitator, in an inert aprotic solvent, at desired temperature for requisite time.
  • the resulting crude (E)-oxime ether is purified by standard methods.
  • the base used in the process of the present invention step (c) may be an organic base or an inorganic base, preferably an inorganic base selected from alkali metal hydroxides, such as potassium hydroxide.
  • the inert aprotic solvent used in the process of the present invention step (c) may be an hydrocarbon solvent, preferably an aromatic hydrocarbon solvent such as toluene.
  • the facilitator used in the process of the present invention step (c) may be a quaternary ammonium salt or a cyclic or acyclic polyethers, preferably an acyclic polyether such as polyethylene glycol)-400 (PEG-400).
  • L is a leaving group selected from halo, or an alkyl or arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like.
  • the starting material for the preparation of IV may be prepared as in Belgian patent Number 647,043
  • L is a leaving group selected from halide, or an alkyl/arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like.
  • L is a leaving group selected from halide, or an alkyl/arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like.
  • L is a leaving group selected from a halide, aryloxy such as 4-nitrophenoxy and the like.
  • X is a halide
  • Y is a group displaceable by amine such as imidazolyl, aryloxy such as 4-nitrophenoxy, and the like.
  • L is a . leaving group selected from halide, X is halide or aryloxy such as 4-;nitrophenoxy and the like and X and Y are as defined above
  • Another aspect of the present invention relates to formulation of compound of formula I in suitable form, which can be administered to the patient.
  • X is halide or aryloxy such as 4-nitrophenoxy and the like and X and Y are as defined above
  • Another aspect of the present invention relates to formulation of compound of fo ⁇ nula I in suitable fo ⁇ u, which can be administered to the patient.
  • Compounds of the present invention can be provided as a pharmaceutical composition for use in the treatment of histamine mediated diseases.
  • the composition comprises compound of formula I and pha ⁇ naceutically acceptable ingredients.
  • compositions may be prepared by admixing compound of fonuula I and phannaceutically acceptable ingredients.
  • the compositions are adapted for oral administration. However, they may be adapted for other modes of administration, for example parenteral administration, sublingual, transde ⁇ nal or opthalmic administration.
  • compositions may be in the fo ⁇ n of tablets, capsules, powders, granules, nasal spray, aerosols, lozenges, ointments, creams, transde ⁇ nal patches, reconstitutable powders, or liquid preparations, such as oral or sterile solutions or suspensions.
  • composition of the invention is in the fonu of a unit dose.
  • Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystaliin.e cellulose; or phannaceutically acceptable wetting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stea
  • compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
  • the solid oral compositions may be prepared by conventional methods of blending, filling or tabletting known to those skilled in this art. Repeated blending operations may be used to distribute the active agent tliroughout those compositions employing large quantities of fillers.
  • the tablets may be coated according to
  • Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan onooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p- hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose,
  • fluid unit dosage fo ⁇ ns are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, a preservative and buffering agent can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • sterile solution or suspension can be prepared.
  • Ophthalmic solution can be prepared by dissolving the compound in water for injection along with suitable preservative, chelating agent, osmogen, viscosity enhancing agent, antioxidant and buffering agent. Solution is aseptically filtered and filled into suitable vials or bottles of suitable material.
  • suspension can be prepared by aseptically dispersing the sterile compound in a sterile aqueous vehicle containing suitable preservative, chelating agent, osmogen, suspending agent, anti-oxidant and buffering agent.
  • Preservative-free unit doses can also be prepared in similar way for solution as well as suspension and aseptically filled into unit dose containers.
  • compositions may contain from 0.01 % to 99.0% by weight of the active material, depending upon the method of administration.
  • Composition may, if desired, be in the fo ⁇ n of a pack accompanied by written or printed instructions for use.
  • the compound of fonuula I on being formulated is useful for various histamine mediated diseases.
  • IC50' s were determined for the compounds prepared by the present invention (using Guinea pig ileum functional assay method) for the estimation of antihistaminic potency (Table 10).
  • I C-NMR of Ia'l (CDCI 3 , ⁇ ppm): 156.19(s), 153.86(s), 147.77(d), 140.18(s), 136.32(d), 135.66(s), 134.26(s), 131.83(s), 131.32(d), 130.76(d), 127.18(d), 124.43(d), 71.15(f), 58.19(t), 46.13(2q), 33.62(t), 30.31(t).
  • These compounds are prepared by alkyiation of Ia5 with the conesponding alkyl halide in acetone using anhydrous potassium carbonate as a base.
  • Compounds IalO to Ial6 are prepared by alkyiation of Ia6 with the conesponding alkyl halide or haloalklyester in acetone using anhydrous potassium carbonate as a base.
  • This compound is prepared by hydrolysis of lal 6 with potassium hydroxide in ethanol.
  • Methyl iodide (O.OOl mol) is added into the stirred mixture of potassium carbonate (0.0015mol) and Ial9 (O.OOlmol) in acetone (20ml) at 10-15°C over a period of 5 minutes. After stirring at 15° C for 30 minutes the mixture is concentrated under reduced pressure, water is added and extracted in methylene chloride ' (3x 10 ml). The organic extract is washed with water and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get compound of fomiula Ia26.
  • Compound Ia36, Ia43 & Ia44 are prepared by similar alkyiation of Ia6, Ia23 & Ia20 respectively, with 2-chloroethanol
  • Example 7 Preparation of Ia37 To a solution of Ia6 (0.002mol) in 2-propanol (15ml) is added propylene oxide (O.Oimol) at 0-5° C. The mixture is stined for 12 hours and concentrated under reduced pressure. The crude product obtained is purified by flash chromatography to obtain pure compound of formula Ia37.
  • compound of formula Id2 is prepared using ethyl chlorofomiate in the place of methyl chlorofomiate.
  • compound of formula Id3 is prepared using acetic anhydride in the place of methyl chlorofomiate and pyridine as base.
  • Compound Id6 & Id7 are prepared from Ia5 & Ia6 respectively, using (4-carbethoxy-3- ethoxyphenyl)acetic acid in the place of (2-chlorophenyl)acetic acid followed by hydrolysis of the ester.
  • Cyclohexyl isocyanate (0.00132mol) is added to a solution of Ia5 (0.00132mol) in tetrahydrofuran (10ml) at ambient temperature. After stirring for 2 hrs, the reaction mixture is concentrated under reduced pressure and the residue is purified by flash column chromatography on silica gel to get pure Iel.
  • Compound Ii9 is prepared in a similar manner using Ia6 and 3-methoxy-4-(2,6- dichlorophenyl)amino-cyclobut-3-en-l,2-dione at reflux condition.
  • Triethylamine (0.023mol) and 30% aqueous methylamine solution (0.0167mol) are added sequentially to a solution Ihl (0.00068mol) in methanol (15ml) at 0-5° C.
  • the mixture is gradually brought to ambient temperature and then concentrated under reduced pressure.
  • the residue is quenched with water and is extracted into methylene chloride (2x15 ml). Combined extract is washed with brine and degassed under reduced pressure.
  • the residue is purified by flash column chromatography on silica gel to get the pure Iil.
  • Example 17 IC 50 determination using isolated guinea pig ileum functional assay
  • Terminal segment of ileum of junction of Dunken Hartley guinea pig, of about 10 crh from the ileo-caecal, separated from mesenteric attachments was immediately removed and placed in Tyrode solution of composition, NaCl 137.0mM, KC1 2.7 mM, CaCl 2 1.8 mM, MgCl 2 1.05 mM, NaHCO 3 11.9 mM, NaH 2 PO 4 0.42 mM and glucose 5.6 mM, maintained at 35° C.
  • the lumen of the ileum was gently cleaned with Tyrode so as to remove any particle without affecting the mucosal layer of the tissue.
  • Pieces of 1.5-2 .0 cm length were cut and placed in the organ bath of 20ml capacity, attaching one end to the tissue holder and other to the transducer by a fine cotton thread.
  • the system was previously calibrated before start of each experiment. Tissue was kept under a resting tension of 0.5-0.75g.
  • the bath solution was continuously bubbled with 95 % O 2 and 5% CO 2 and maintained at 35° C temperature. After an initial 30 min of equilibration time the baseline was recorded and non-cumulative responses with sub maximal dose of histamine (7.2 X 10 " M) were initially recorded until the responses were reproducible.
  • the contractions to this typical dose of histamine in absence (only vehicle) and presence of at least 3 different concentrations of the test compounds were recorded after 15min constant incubation time.
  • the percentage inhibitions caused by different concentrations of test compounds were plotted against the log of molar concentrations of the test compounds for the determination oflCso.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un dérivé d'éther d'oxime-(E) de 5,6-dihydro-benzo[5,6]cyclohépta[1,2-b]pyridine-11-one, un composé de formule (I), dans laquelle R est sélectionné parmi les composés de formules (a, b, c, d, e, f, g, h, i). L'invention concerne également leurs sels pharmaceutiquement acceptables utilisés en tant que composés anti-histaminiques.
PCT/IN2003/000150 2002-04-08 2003-04-08 Composes anti-histaminiques Ceased WO2003087059A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003231925A AU2003231925A1 (en) 2002-04-08 2003-04-08 (e)-oxime ether derivative of 5,6-dihydro-benzo(5,6)cyclohepta(1,2-b)pyridin-11-one

Applications Claiming Priority (2)

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IN332-MUM-2002 2002-04-08
IN332MU2002 2002-04-08

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WO2003087059A2 true WO2003087059A2 (fr) 2003-10-23
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Cited By (4)

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US10112915B2 (en) 2015-02-02 2018-10-30 Forma Therapeutics, Inc. 3-aryl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10183934B2 (en) 2015-02-02 2019-01-22 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
CN112552305A (zh) * 2020-11-26 2021-03-26 广东省测试分析研究所（中国广州分析测试中心） 一种新型苯并环庚烷并咪唑并吡啶类阻燃抗紫外线分子材料及其制备方法与应用

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3458524A (en) * 1968-03-27 1969-07-29 Schering Corp Novel 5-alkylaminoalkoximino-aza-dibenzo-(a,d)-cycloheptenes
KR920014799A (ko) * 1991-01-18 1992-08-25 나오가따 다이도 신규벤조[5,6]시클로헵타[1,2-b]피리딘 유도체 및 이를 함유하는 항알레르기제

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US10494354B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494353B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10494352B2 (en) 2015-02-02 2019-12-03 Forma Therapeutics, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10214500B2 (en) 2015-02-02 2019-02-26 Forma Therapeutics, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10239845B2 (en) 2015-02-02 2019-03-26 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10377726B2 (en) 2015-02-02 2019-08-13 Forma Therapeutics, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10407418B2 (en) 2015-02-02 2019-09-10 Forma Therapeutics, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US10414738B2 (en) 2015-02-02 2019-09-17 Forma Therapeutics, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10822316B2 (en) 2015-02-02 2020-11-03 Valo Early Discovery, Inc. 3-aryl-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US10829462B2 (en) 2015-02-02 2020-11-10 Valo Early Discovery, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US12264137B2 (en) 2015-02-02 2025-04-01 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11891365B2 (en) 2015-02-02 2024-02-06 Valo Health, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US10988450B2 (en) 2015-02-02 2021-04-27 Valo Early Discovery, Inc. 3-alkyl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11274084B2 (en) 2015-02-02 2022-03-15 Valo Health, Inc. 3-aryl-4-amido-bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
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US11279681B2 (en) 2015-02-02 2022-03-22 Valo Health, Inc. 3-alkyl bicyclic [4,5,0] hydroxamic acids as HDAC inhibitors
US11702412B2 (en) 2015-02-02 2023-07-18 Valo Health, Inc. Bicyclic [4,6,0] hydroxamic acids as HDAC inhibitors
US11730721B2 (en) 2016-06-17 2023-08-22 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US12213969B2 (en) 2016-06-17 2025-02-04 Valo Health, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10874649B2 (en) 2016-06-17 2020-12-29 Valo Early Discovery, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
US10555935B2 (en) 2016-06-17 2020-02-11 Forma Therapeutics, Inc. 2-spiro-5- and 6-hydroxamic acid indanes as HDAC inhibitors
CN112552305A (zh) * 2020-11-26 2021-03-26 广东省测试分析研究所（中国广州分析测试中心） 一种新型苯并环庚烷并咪唑并吡啶类阻燃抗紫外线分子材料及其制备方法与应用

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AU2003231925A8 (en) 2003-10-27
AU2003231925A1 (en) 2003-10-27
WO2003087059A3 (fr) 2003-11-20

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