WO1999002512A1 - Dl-2,3-diaryl-2h-1-benzopyrans - Google Patents

Dl-2,3-diaryl-2h-1-benzopyrans Download PDF

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Publication number
WO1999002512A1
WO1999002512A1 PCT/DK1998/000301 DK9800301W WO9902512A1 WO 1999002512 A1 WO1999002512 A1 WO 1999002512A1 DK 9800301 W DK9800301 W DK 9800301W WO 9902512 A1 WO9902512 A1 WO 9902512A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
piperidino
ethoxy
benzopyran
carbon atoms
Prior art date
Application number
PCT/DK1998/000301
Other languages
English (en)
Inventor
Kanchan Hajela
Jaya Pandey
Janak Dulari Dhar
Suprabhat Ray
Virender Mohan Labroo
Original Assignee
Novo Nordisk A/S
Central Drug Research Institute
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 Novo Nordisk A/S, Central Drug Research Institute filed Critical Novo Nordisk A/S
Priority to AU81023/98A priority Critical patent/AU8102398A/en
Publication of WO1999002512A1 publication Critical patent/WO1999002512A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2

Definitions

  • the present invention relates to optically active d- and /-isomers of ⁇ 7-2, 3-diaryl-2H-1-benzopyran and its derivatives, their preparation by the process of resolution, preparation of pharmaceutical compositions containing such isomers as active ingredients and their use as contraceptives, in the treatment and prophylaxis of breast cancer, osteoporosis, hypercholesteremia, endometriosis, vasoconstriction and endometrial disorders.
  • R 1 and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom.
  • R 1 and R 2 are each independently H, OH or C ⁇ -alkoxy.
  • Other preferred embodiments include (i) R 1 being H or (ii) R 1 and R 2 each being an acyl, alkyl, alkoxy or a halide group.
  • R 3 is preferably a 2-piperidinoethoxy group.
  • the present invention therefore provides as new compounds laevo and dextro forms of d/-2,3-diaryl-2H-1-benzopyrans specifically: d-2-(4-(2-(1-Piperidino)ethoxy)phenyl)- 3-phenyl-2H-1-benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl) -3-phenyl-2H -1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-2H-1 -benzopyran, /-2-(4-(2-(1-Piperidino)ethoxy)phenyl)-3-phenyl-7-methoxy-2H-1-benzopyran, /-2-(4-(2-(1 -Piperidino)ethoxy)phenyl)-3-(4-hydroxyphenyl)-7-hydroxy
  • R , R and R 3 have the meanings as stated above.
  • the invention includes within its scope the optically active /-acid and d-acid salts of the new compounds referred to above. These salts are characterized by the general formula
  • the present invention provides a process for the preparation of optically active / and d isomers of d/-2,3-diaryl-2H-1-benzopyrans and optically active salts thereof which comprises reacting a d/-2,3-diaryl-2H-1 -benzopyran compound of the general formula
  • R 1 and R 2 which may be the same or different are each H, OH, linear or branched chain alkyl or alkoxy of 1 to 17 carbon atoms, linear or branched chain acyloxy of 2 to 18 carbon atoms or a halide group and R 3 is a tertiary amino alkoxy group such as O(CH 2 ) n NR 4 R 5 wherein R 4 and R 5 are same or different, linear or branched chain alkyl substituents of 1-18 carbon atoms or a cyclic ring containing 2 - 10 carbon atoms containing the N atom with an optically active acid in a protic solvent to produce optically active salt of the formula
  • X denotes the optically active acid anion
  • the invention provides a process for the preparation of /-2-4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
  • R 1 , R 2 , R 3 have the meanings stated herein and optically active /-acid salts thereof, which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H -1 -benzopyran of the general formula
  • R 1 , R 2 , R 3 have the meanings stated above with an optically active /-acid in a protic solvent to produce on fractional crystallization of the reaction mixture /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran /-acid salt of the general formula
  • the invention provides a process for the preparation of d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran of the general formula
  • R ⁇ R 2 and R 3 have the meanings stated as above and optically active d-acid salt thereof which comprises reacting d/-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran of the general formula
  • R ⁇ R 2 , R 3 have the meanings as stated above with an optically active d-acid in a protic solvent to produce on fractional crystallization of the reaction mixture d-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1-benzopyran d-acid salts of the general formula
  • the preferred optically active /-acid is di-p-toluoyl-/-tartaric acid while the preferred optically active d-acid is di-p-toluoyl-d-tartaric acid monohydrate.
  • the protic solvents which may be employed in the reaction include ethanol or methanol.
  • the invention provides a post-coital antifertility composition
  • a post-coital antifertility composition comprising as active ingredient /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran or an optically ac- tive acid derivative thereof in combination with a pharmaceutically acceptable carrier or excipient thereof.
  • the carriers or excipients with which the active ingredient may be combined to provide the above-mentioned composition include starch, dicalcium phosphate and calcium stearate and combinations of any of these.
  • novel /-2-(4-(2-(1-piperidino)ethoxy)phenyl)-3-phenyl-2H-1 -benzopyran was found to be two folds more active as an antifertility agent in female albino rats as compared to the corresponding d/-compound in a single day post-coital oral administration schedule.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 100 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 0.1 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively transports the active compound to the appropriate or desired site of action, such as oral or par- enteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or par- enteral e.g. rectal, transdermal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other con- tainer.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other con- tainer.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in poly- hydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 0.1 to about 100 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • the compounds according to this invention may be suitable for administration to an animal.
  • animals include both domestic animals, for example livestock, laboratory animals, and household pets, and non-domestic animals such as wildlife. More preferably, the animal is a vertebrate.
  • a compound according to this invention shall be administered to a mammal. It is especially preferred that the animal is a domestic mammal or a human. The most preferred mammal is a human.
  • a compound of this invention may be administered as a feed additive or in bulk form.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne des 2,3-diaryl-2H-1-benzopyrans thérapeutiquement actifs, un procédé de préparation de ce dernier et des compositions pharmaceutiques renfermant les composés. Les nouveaux composés sont utiles pour la prévention ou le traitement de maladies ou de syndromes liés aux oestrogènes.
PCT/DK1998/000301 1997-07-09 1998-07-02 Dl-2,3-diaryl-2h-1-benzopyrans WO1999002512A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU81023/98A AU8102398A (en) 1997-07-09 1998-07-02 (dl)-2,3-diaryl-2h-1-benzopyrans

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US5202297P 1997-07-09 1997-07-09
US60/052,022 1997-07-09
DK92297 1997-08-11
DK0922/97 1997-08-11

Publications (1)

Publication Number Publication Date
WO1999002512A1 true WO1999002512A1 (fr) 1999-01-21

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AU (1) AU8102398A (fr)
WO (1) WO1999002512A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068634A1 (fr) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrannes a activite anti-oeoestrogenique
JP2002522533A (ja) * 1998-08-14 2002-07-23 シェーリング コーポレイション エナンチオ選択的合成
WO2003044006A1 (fr) * 2001-11-19 2003-05-30 Eli Lilly And Company Benzopyrans substitues convenant comme agonistes du recepteur aux oestrogenes beta
US6630508B1 (en) 2002-02-11 2003-10-07 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor β agonists
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
EP1790644A1 (fr) * 2001-11-19 2007-05-30 Eli Lilly And Company Benzopyranes substitués comme agonists du receptor beta-estrogen
US7279499B2 (en) 2003-04-21 2007-10-09 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7442812B2 (en) 2003-04-21 2008-10-28 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8853423B2 (en) 2010-06-17 2014-10-07 Seragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US10865199B2 (en) 2015-10-27 2020-12-15 Sun Pharma Advanced Research Company Limited Heterocyclic antiestrogens
WO2021014386A1 (fr) 2019-07-22 2021-01-28 Sun Pharma Advanced Research Company Limited Agent de dégradation sélectif de récepteur des œstrogènes

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993010741A2 (fr) * 1991-12-02 1993-06-10 Endorecherche Inc. Inhibiteurs de l'activite des steroides sexuels
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1996026201A1 (fr) * 1995-02-21 1996-08-29 Endorecherche, Inc. Composes contenant du benzopyranne et techniques d'application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5254568A (en) * 1990-08-09 1993-10-19 Council Of Scientific & Industrial Research Benzopyrans as antiestrogenic agents
WO1993010741A2 (fr) * 1991-12-02 1993-06-10 Endorecherche Inc. Inhibiteurs de l'activite des steroides sexuels
WO1996026201A1 (fr) * 1995-02-21 1996-08-29 Endorecherche, Inc. Composes contenant du benzopyranne et techniques d'application

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002522533A (ja) * 1998-08-14 2002-07-23 シェーリング コーポレイション エナンチオ選択的合成
US6710059B1 (en) * 1999-07-06 2004-03-23 Endorecherche, Inc. Methods of treating and/or suppressing weight gain
US8609695B2 (en) 1999-07-06 2013-12-17 Endorecherche, Inc. Methods of treating and/or suppressing insulin resistance
WO2001068634A1 (fr) * 2000-03-15 2001-09-20 Schering Aktiengesellschaft 4-fluoroalkyl-2h-benzopyrannes a activite anti-oeoestrogenique
US6844336B2 (en) 2000-03-15 2005-01-18 Schering Ag 4-fluoroalkyl-2h-benzopyrans with anti-estogenic activity
WO2003044006A1 (fr) * 2001-11-19 2003-05-30 Eli Lilly And Company Benzopyrans substitues convenant comme agonistes du recepteur aux oestrogenes beta
EA007382B1 (ru) * 2001-11-19 2006-10-27 Эли Лилли Энд Компани Замещенные бензопираны в качестве селективных агонистов бета-рецептора эстрогена
CN1312147C (zh) * 2001-11-19 2007-04-25 伊莱利利公司 作为选择性雌激素受体－β激动剂的取代的苯并吡喃类化合物
US7217734B2 (en) 2001-11-19 2007-05-15 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
EP1790644A1 (fr) * 2001-11-19 2007-05-30 Eli Lilly And Company Benzopyranes substitués comme agonists du receptor beta-estrogen
US6630508B1 (en) 2002-02-11 2003-10-07 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor β agonists
US7585985B2 (en) 2003-04-21 2009-09-08 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7442812B2 (en) 2003-04-21 2008-10-28 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7842822B2 (en) 2003-04-21 2010-11-30 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US7279499B2 (en) 2003-04-21 2007-10-09 Eli Lilly And Company Substituted benzopyrans as selective estrogen receptor-beta agonists
US9078871B2 (en) 2010-06-10 2015-07-14 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8703810B2 (en) 2010-06-10 2014-04-22 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US8853423B2 (en) 2010-06-17 2014-10-07 Seragon Pharmaceuticals, Inc. Indane estrogen receptor modulators and uses thereof
US9187460B2 (en) 2011-12-14 2015-11-17 Seragon Pharmaceuticals, Inc. Estrogen receptor modulators and uses thereof
US9193714B2 (en) 2011-12-14 2015-11-24 Seragon Pharmaceuticals, Inc. Fluorinated estrogen receptor modulators and uses thereof
US9018244B2 (en) 2011-12-16 2015-04-28 Olema Pharmaceuticals, Inc. Benzopyran compounds, compositions and uses thereof
US10865199B2 (en) 2015-10-27 2020-12-15 Sun Pharma Advanced Research Company Limited Heterocyclic antiestrogens
US11465990B2 (en) 2015-10-27 2022-10-11 Sun Pharma Advanced Research Company Ltd. Heterocyclic antiestrogens
WO2021014386A1 (fr) 2019-07-22 2021-01-28 Sun Pharma Advanced Research Company Limited Agent de dégradation sélectif de récepteur des œstrogènes
US11014915B2 (en) 2019-07-22 2021-05-25 Sun Pharma Advanced Research Company Limited Selective estrogen receptor degrader

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Publication number Publication date
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