WO2003042202A1 - Isobenzofuran derivatives - Google Patents

Isobenzofuran derivatives Download PDF

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Publication number
WO2003042202A1
WO2003042202A1 PCT/IB2002/004742 IB0204742W WO03042202A1 WO 2003042202 A1 WO2003042202 A1 WO 2003042202A1 IB 0204742 W IB0204742 W IB 0204742W WO 03042202 A1 WO03042202 A1 WO 03042202A1
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WIPO (PCT)
Prior art keywords
process according
acid
formula
compound
group
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Application number
PCT/IB2002/004742
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English (en)
French (fr)
Inventor
Yatendra Kumar
Ram Chander Aryan
Kumar Hari Bhushan
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2003042202A1 publication Critical patent/WO2003042202A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to certain isobenzofuran derivatives and to a process for the synthesis of the same.
  • the compounds of the present invention are analogs of a well known potent anti-depressant drug citalopram and hold promise to have anti-depressant activity.
  • the invention also relates to pharmaceutical compositions containing the compounds of the present invention as potential anti-depressants.
  • Isobenzofuran derivatives as well as their salts have strong potentiating effect on 5-hydroxytryptamine (5-HT) and, at the same time, these compounds have practically no potentiating effect on nor-adrenaline or adrenaline.
  • Citalopram is useful as a first line agent for the treatment of major depression, when compared with other SSRI's (selective seretonin reuptake inhibitors) for example fluoxetine, sertraline and fluvoxamine. Citalopram is known to be the most selective SSRI available.
  • Citalopram is rapidly absorbed following oral administration and is extensively metabolized in the liver.
  • the principal metabolites are demethylcitalopram (DCT), di- demethyl citalopram (DDCT), citalopram N-oxide and a deaminated metabolite propionic acid derivative of structural formulae II, III, IV and V, respectively.
  • citalopram Some of the metabolites of citalopram, including demethylcitalopram, are pharmacologically active, demonstrating selective inhibition of serotonin uptake. However, they are less potent than citalopram itself and their plasma levels are considerably lower than those of the parent compound. Demethylcitalopram and di- demethylcitalopram are, respectively, 6 and 10 times less lipophilic than citalopram. As a consequence, the metabolites of citalopram achieve lower concentrations in the brain than does the parent compound. Therefore, it seems likely that the therapeutic effects of citalopram are caused mainly by the drug itself rather than by its metabolites. Didemethylcitalopram is also known to possess cardiotoxic properties.
  • U.S. Patent No. 3,467,675 discloses certain aminoalkylene derivatives of phthalanes, iso-chromanes and iso-chromenes useful as anti-depressants.
  • An objective of the present invention is to provide certain isobenzofuran derivatives which are not metabolized in the system and bind to 5-HT receptor with high affinities and are reckoned to have superior anti-depressant activity.
  • Ri and R 2 together with nitrogen atom represent a five or six membered ring;
  • A is a -CH 2 - group and m is an integer from 2 to 6 and defines the number of carbons in group A.
  • the five or six membered ring may further be substituted with 1- 2 hetero atoms selected from oxygen, sulphur or nitrogen.
  • the compounds of Formula VI of the present invention may be prepared by the process comprising reacting a compound of structural formula VII
  • R-i, R 2 together with nitrogen atom represent a five or six membered ring;
  • A is a -CH 2 -group;
  • m is an integer from 2 to 6 and defines the number of carbons in group A; and
  • X is a leaving group.
  • the five or six membered ring may further be substituted with 1-2 hetero atoms selected from the group consisting of oxygen, sulphur and nitrogen. Examples include pyrrolidine, piperidine, morpholine, thia- morpholine N-lower-alkyl-piperazine such as N'-methylpiperazine, N-lower- hydroxyalkyl-piperazine or piperazine.
  • the leaving group "X" is selected form chloride, bromide, iodide, mesylate or tosylate.
  • the reaction of the compound of Formula VII with the halide chain of Formula VIII is carried out in the presence of a base selected from sodium hydride, sodamide, potassium amide, butyllithium, phenyllithium, or the like.
  • the organic solvent used in the reaction is selected from solvents such as N, N-dimethylformamide, dimethylsulfoxide, sulfolane, 1-methyl-2-pyrrolidinone and mixtures thereof.
  • the reaction is performed at a temperature from about 0°C to 100°C, for example, preferably from about 10°C to about 60°C or from about 30° to about 50°C.
  • the reaction is suitably worked up after it is completed.
  • the suitable work up involves cooling the reaction mixture, pouring it into water, followed by the extraction of the product with an organic solvent, purifying it by silica gel column chromatography and its conversion to pharmaceutically acceptable salt.
  • the organic solvent for extraction is selected from chloroform, dichloromethane, 1 ,2-dichloromethane, hexanes, cyclohexane, toluene, methyl acetate or ethyl acetate.
  • the pharmaceutically acceptable acid addition salts are formed with organic or inorganic acids.
  • organic acids are maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline.
  • inorganic acids are hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids.
  • the acid addition salts of the compounds may be prepared by methods known in the art.
  • the base is reacted with either the calculated amount of acid in a water miscible solvent, such as acetone or ethanol, with subsequent isolation of the salt by concentration and cooling, or with an excess of the acid in a water immiscible solvent, such as ethyl ether, ethylacetate or dichloromethane, with the salt separating spontaneously.
  • a water miscible solvent such as acetone or ethanol
  • a water immiscible solvent such as ethyl ether, ethylacetate or dichloromethane
  • the methods known in the art may be used with the process of this invention to enhance any aspect of the process.
  • the product obtained may be further purified by any technique known to a person skilled in the art, for example, crystallization, column chromatography, preparative high pressure liquid chromatography, preparative thin layer chromatography, extractive washing in solution or a combination of these procedures.
  • the compounds of this invention may exist in unsolvated or solvated form with pharmaceutically acceptable solvents such as water, ethanol, methanol and the like.
  • pharmaceutically acceptable solvents such as water, ethanol, methanol and the like.
  • the solvated forms are considered equivalent to the unsolvated form for the purpose of invention.
  • the compounds of the present invention contain a chiral center and such compounds exist in the form of isomers (e.g. enantiomers).
  • the invention includes all such isomers and any mixture thereof including racemic mixtures.
  • Optical isomers can be obtained by resolving the racemic forms by known methods, for example, by separation of diastreoisomeric salts thereof with an optically active acid and liberating the optically active amine compound by treatment with a base.
  • racemates can be resolved upon chromatography on an optically active matrix or by simulated moving bed technique.
  • the fractional crystallization process can be used for resolving racemic mixture of the compounds as their tartarates, mandalates or chlorosulfonate salts. Additional methods for the resolution of optical isomers known to those skilled in the art may be used. Such methods include those discussed by J. Jaques, A. Collet and S. William in "Enantiomers, Racemates and Resolution". John Wiley and Sons, New York (1981 ).
  • Enantiomerically pure materials can also be prepared from optically active starting material.
  • the compounds of formula VIII are commercially available or may be prepared from commercially available starting materials using commercial techniques.
  • the compounds of Formula VII may be prepared, for example, as described in U.S. Patent No. 4,136,193 or as described in WO 98/019511.
  • the following compounds of structural formulae IX, X, XI, XII are exemplified:
  • the compound represented by structural formula XI was prepared by reacting 1-[4-fluorophenyl]1 ,3,-dihydroisobenzofuran-5-carbonitrile of structural formula VII with N-(3-chloroethyl) pyrrolidine and isolated as oxalate salt.
  • the compound represented by structural formula XII was prepared by reacting 1-[4-fluorophenyl]1 ,3,-dihydroisobenzofuran-5-carbonitrile of structural formula VII with N-(3-chloroethyl) piperidine and isolated as oxalate salt.
  • the compounds of the present invention were characterized using NMR (Nuclear Magnetic Resonance), IR (Infra-Red), Mass Spectroscopy and were purified by column chromatography using silica gel (100-200 or 60-120 mesh) as stationary phase. The mass spectra were recorded on an LCMS/MS Perkin Elmer SCI EX-API
  • the infrared Spectra were recorded on a FTIR Perkin Elemer IC instrument.
  • This compound was analoguously prepared as that of Example 1 using N-(2- chloropropyl) piperidine instead of N-(3-chloropropyl) pyrrolidine.
  • the product (free amine) was obtained as an oily mass which after chromatography was converted into its oxalate salt by dissolving the oily mass in acetone, followed by the addition of oxalic acid solution in acetone to obtain the title compound (1.5g).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychiatry (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pain & Pain Management (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)
  • Plural Heterocyclic Compounds (AREA)
PCT/IB2002/004742 2001-11-13 2002-11-13 Isobenzofuran derivatives WO2003042202A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1144DE2001 IN192863B (en, 2012) 2001-11-13 2001-11-13
IN1144/DEL/2001 2001-11-13

Publications (1)

Publication Number Publication Date
WO2003042202A1 true WO2003042202A1 (en) 2003-05-22

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IN (1) IN192863B (en, 2012)
WO (1) WO2003042202A1 (en, 2012)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009057974A3 (en) * 2007-11-02 2009-07-16 Dong A Pharm Co Ltd Novel 1,3-dihydro-5-isobenzofurancarbonitrile derivatives and pharmaceutical composition thereof for the treatment of premature ejaculation

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3467675A (en) * 1965-03-18 1969-09-16 Kefalas As Antidepressant basic derivatives of phthalanes,iso-chromanes and iso-chromenes
US4136193A (en) * 1976-01-14 1979-01-23 Kefalas A/S Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans
WO2002050067A2 (en) * 2000-12-20 2002-06-27 Eli Lilly And Company Pharmaceutical heterocyclic compounds

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3467675A (en) * 1965-03-18 1969-09-16 Kefalas As Antidepressant basic derivatives of phthalanes,iso-chromanes and iso-chromenes
US4136193A (en) * 1976-01-14 1979-01-23 Kefalas A/S Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans
WO2002050067A2 (en) * 2000-12-20 2002-06-27 Eli Lilly And Company Pharmaceutical heterocyclic compounds

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009057974A3 (en) * 2007-11-02 2009-07-16 Dong A Pharm Co Ltd Novel 1,3-dihydro-5-isobenzofurancarbonitrile derivatives and pharmaceutical composition thereof for the treatment of premature ejaculation
JP2011502981A (ja) * 2007-11-02 2011-01-27 ドン・ア・ファーム・カンパニー・リミテッド 新規な１，３−ジヒドロ−５−イソベンゾフランカルボニトリル誘導体およびそれを含む早漏症治療用医薬組成物
KR101103118B1 (ko) 2007-11-02 2012-01-04 동아제약주식회사 신규한 1,3-디히드로-5-이소벤조퓨란카르보니트릴 유도체 화합물 및 이를 함유하는 조루증 치료용 약학조성물
AU2008319628B2 (en) * 2007-11-02 2012-03-29 Dong-A Pharmaceutical. Co., Ltd Novel 1,3-dihydro-5-isobenzofurancarbonitrile derivatives and pharmaceutical composition thereof for the treatment of premature ejaculation
RU2448963C2 (ru) * 2007-11-02 2012-04-27 Донг-А Фармасьютикал. Ко., Лтд Новые производные 1,3-дигидро-5-изобензофуранкарбонитрила и фармацевтическая композиция на их основе для лечения преждевременной эякуляции
US8242159B2 (en) 2007-11-02 2012-08-14 Dong-A Pharmaceutical. Co., Ltd 1,3-dihydro-5-isobenzofurancarbonitrile derivatives and pharmaceutical composition thereof for the treatment of premature ejaculation

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Publication number Publication date
IN192863B (en, 2012) 2004-05-22

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