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WO2001042181A1 - Benzyl-tetralines, formulations et utilisations associees - Google Patents

Benzyl-tetralines, formulations et utilisations associees Download PDF

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Publication number
WO2001042181A1
WO2001042181A1 PCT/GB2000/004700 GB0004700W WO0142181A1 WO 2001042181 A1 WO2001042181 A1 WO 2001042181A1 GB 0004700 W GB0004700 W GB 0004700W WO 0142181 A1 WO0142181 A1 WO 0142181A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzyl
tetralin
hydroxy
halogen
group
Prior art date
Application number
PCT/GB2000/004700
Other languages
English (en)
Inventor
Harold John Smith
Peter Mason
Masoud Ahmadi
Paul Joseph Nicholls
Valerie Greer
Original Assignee
University College Cardiff Consultants 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.)
Filing date
Publication date
Application filed by University College Cardiff Consultants Limited filed Critical University College Cardiff Consultants Limited
Priority to AU21914/01A priority Critical patent/AU2191401A/en
Publication of WO2001042181A1 publication Critical patent/WO2001042181A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/62—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by hydrogenation of carbon-to-carbon double or triple bonds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton

Definitions

  • the present invention is concerned with benzyl tetralins, formulations and products containing the same, and uses thereof .
  • benzyl tetralins of the present invention are useful as inhibitors of 17 beta-hydroxysteroid dehydrogenase (17 ⁇ - HSD) isoforms operable in the steroidogenesis pathway and have therapeutic applications in the treatment of androgen or oestrogen dependent or mediated diseases.
  • 17 ⁇ -HSD isoforms The role of 17 ⁇ -HSD isoforms in the steroidogenesis pathway is shown in Figure 1.
  • Type 3 17 ⁇ -HSD isozyme converts the weak androgen androstenedione to testosterone.
  • Type 1 17 ⁇ - HSD isozyme converts oestrone to oestradiol .
  • Inhibitors of human 17 ⁇ -HSD isoforms are, therefore, generally expected to be useful in the treatment of androgen or oestrogen dependent or mediated diseases substantially as hereinafter described in greater detail.
  • Androgen ablation strategies for the treatment of prostatic cancer in the early hormone-dependent stage have to date included castration, androgen receptor antagonism and inhibition of androgen synthesis.
  • Inhibition has generally employed inhibitors of cytochrome P450 17 and 5 ⁇ -steroid reductase, as well as GnRH agonists.
  • Prostatic cancer growth is, however, dependent on dihydrotestosterone produced by the action of 5 ⁇ -steroid reductase on testosterone, which is itself derived from androstenedione by the action of type 3 17 ⁇ -HSD isozyme.
  • Type 3 17 ⁇ -HSD isozyme is, therefore, central to the conversion of weak androgen to its potent form and inhibitors of type 3 17 ⁇ - HSD isozyme are generally expected to be useful in the treatment of prostatic cancer.
  • steroidal inhibitors of 17 ⁇ -HSD isozyme are widely known, but generally such steroidal inhibitors (or metabolites thereof) often possess undesirable side effects. Typical such undesirable side effects include inherent hormone receptor activity or the like, and can be particularly seen at the relatively high doses generally required for a clinical effect.
  • non- steroidal inhibitors of the type 3 17 ⁇ -HSD isozyme capable of substantially blocking the conversion of androstenedione to testosterone in the steroidogenesis pathway and which non-steriodal inhibitors are substantially devoid of the above described undesirable side effects associated with steroidal inhibitors.
  • Oestrogen ablation strategies employed to date to remove stimulation of growth of metastases in essential organs after surgical removal of a breast tumour have generally initially required administration of an oestrogen-receptor antagonist, such as tamoxifen or the like. Relapse of this therapy has often been followed by treatment with a non- steroidal aromatase (typically P450 Arom ) inhibitor (such as arimidex, letrozole, vorozole or the like) to substantially block production of oestrone from androstenedione.
  • Aromatase inhibitors have, to date, been of limited success and this may be due to intake of phyto-oestrogens in food or synthesis of oestradiol by an alternative mechanism.
  • Oestrone mainly circulates (stored) as oestrone sulphate and it is considered that this provides a source of oestradiol within breast tissue and elsewhere through the consecutive actions of an oestrogen sulphatase and type 1 17 ⁇ -HSD isozyme present in the tissue.
  • X is selected from the group consisting of halogen, C 1 .
  • Y is selected from the group consisting of hydrogen and halogen
  • X and Y together form the residue of a carbocyclic ring .
  • the OH group is attached to position 6 of the tetralone ring of the benzyl tetralins of formula (I) above according to the present invention.
  • Halogen as used herein includes bromine, chorine, fluorine and iodine.
  • a fused bicyclic ring system represented by X can be according to following general formula (A)
  • a fused bicyclic ring system represented by X can be naphthyl , tetralin or the like.
  • X can preferably be selected from the group consisting of bromine, chlorine, fluorine, trifluoromethyl and methyl.
  • Y represents hydrogen or chlorine, preferably hydrogen, although it may be preferred that Y represents chlorine typically when X represents chlorine.
  • X and Y together form the residue of a carbocyclic ring.
  • X and Y together form the residue of a benzene ring.
  • a preferred sub-group of benzyl tetralins according to the present invention is represented by general formula (1A), or pharmaceutically acceptable salts or prodrugs thereof.
  • X is selected from the group consisting of halogen and
  • Y is selected from the group consisting of hydrogen and halogen
  • X and Y together form the residue of a carbocyclic ring.
  • a still further preferred sub-group of benzyl tetralins according to the present invention is represented by general formula (IB) , or pharmaceutically acceptable salts or prodrugs thereof ;
  • An alternative preferred sub-group of benzyl tetralins according to the present invention can represented by general formula (IC), or pharmaceutically acceptable salts or prodrugs thereof .
  • X is selected from the group consisting of halogen, ( 6 alkyl optionally substituted by at least one halogen, a fused bicyclic hydrophobic ring system and phenyl optionally substituted by at least one halogen; and Y is hydrogen.
  • Preferred compounds according to the present invention include :
  • a preferred compound according to the present invention can be selected from the group consisting of :
  • Benzyl tetralins according to the present invention may be prepared in racemic form, or as individual enantiomers that may be prepared by either enantiospecific synthesis or by resolution.
  • the enantiomer can be provided in substantially pure form, such as, for example, having an isomeric purity of at least about 95%.
  • Benzyl tetralins according to the present invention can suitably be prepared from compounds of formula (II)
  • an inorganic acid such as hydrochloric acid or the like
  • stirring typically at a temperature in the range of 40° to 70° C.
  • an alkali metal hydroxide such as potassium hydroxide or the like
  • the present invention further includes within its scope prodrugs of benzyl tetralins substantially as hereinbefore described and in general such prodrugs will be functional derivatives of benzyl tetralins according to the present invention which are readily convertible in vivo into the required compound. Conventional procedures for selection and preparation of suitable prodrug derivatives are well known in the art .
  • Benzyl tetralins according to the present invention are inhibitors of human 17 ⁇ -HSD isoforms and are, therefore, useful as therapeutic agents for treating androgen or oestrogen dependent or mediated diseases.
  • benzyl tetralins according to the present invention are useful as therapeutic agents for treating prostatic cancer, benign prostatic hyperplasia, virilis , breast cancer, endometrial cancer, endometriosis , ovarian cancer and the like.
  • benzyl tetralins according to the present invention are useful as therapeutic agents where inhibition of type 1 and / or type 3 17 ⁇ -HSD isozyme is required.
  • Benzyl tetralins according to the present invention are particularly useful in the treatment of hormone-dependent prostatic and breast cancer.
  • treatment includes both the amelioration of the symptoms of established androgen or oestrogen dependent diseases and the prophylaxis of such diseases.
  • a benzyl tetralin substantially as herein before described for use in therapy. More particularly, there is further provided by the present invention a benzyl tetralin substantially as herein before described, for use in the manufacture of a medicament for the treatment of androgen or oestrogen dependent or mediated diseases, substantially as herein before described.
  • benzyl tetralins according to the present invention are included in pharmaceutical formulations.
  • a pharmaceutical formulation comprising a benzyl tetralin substantially as herein before described, together with at least one acceptable carrier, diluent or excipient therefor, and optionally other therapeutically acceptable ingredients.
  • the carriers must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to a recipient thereof.
  • compositions according to the present invention include at least one further inhibitor of the steroidogenesis pathway.
  • a further inhibitor can be selected from the group consisting of inhibitors of any of the following steroidogenesis pathway enzymes- 17 ⁇ -HSD isoforms, 5 -steroid reductase (5 ⁇ -SR) , aromatase (P450 arom ) and oestrogen sulphatase.
  • a benzyl tetralin substantially as herein before described is used in conjunction with at least one inhibitor of 5 ⁇ -SR and there is, therefore, provided by the present invention a pharmaceutical formulation comprising a benzyl tetralin substantially as herein before described and at least one inhibitor of 5 ⁇ -SR, together with one or more acceptable carriers, excipients or diluents therefor.
  • a benzyl tetralin substantially as hereinbefore described is preferably used together with at least one inhibitor selected from the group consisting of aromatase (P450 aro and oestrogen sulphatase.
  • a pharmaceutical composition comprising a benzyl tetralin substantially as hereinbefore described and at least one inhibitor selected from the group consisting of aromatase (P450 arom ) and oestrogen sulphatase, together with one or more acceptable carriers, excipients or diluents therefor.
  • the present invention also provides a product comprising a benzyl tetralin substantially as hereinbefore described and at least one further inhibitor of the steroidogenesis pathway substantially as herein before described, as a combined preparation for simultaneous, separate or sequential use in the treatment of androgen or oestrogen dependent or mediated diseases substantially as herein before described.
  • Formulations according to the present invention include those suitable for oral, parenteral and topical administration, although the most suitable route will generally depend upon the condition of a patient and the specific androgen or oestrogen dependent or mediated disease being treated.
  • the precise amount of a benzyl tetralin substantially as hereinbefore described to be administered to a patient will be the responsibility of an attendant physician, although the dose employed will depend upon a number of factors, including the age and sex of the patient, the specific androgen or oestrogen dependent or mediated disease being treated and the route of administration substantially as described above.
  • a method of treating androgen or oestrogen dependent or mediated diseases comprises administering to a patient suffering from or susceptible to such a disease a therapeutically effective amount of a benzyl tetralin substantially as hereinbefore described or a pharmaceutically acceptable salt or prodrug thereof.
  • the cytoplasmic Type 1 isozyme is considered the main isozyme for reduction of oestrone to oestradiol and the microsomal Type 2 isozyme for the reverse oxidation reaction in a cellular environment, although in vi tro either type can convert in both directions in the presence of the required substrate and co-enzyme .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne une benzyl-tétraline représentée par la formule générale (I), ou un sel ou promédicament de celui-ci pharmaceutiquement acceptable. X est choisi dans le groupe constitué d'halogène, de C1-6 alkyle éventuellement substitué par au moins un halogène, d'un système cyclique hydrophobe bicyclique thermofixé et de phényle éventuellement substitué par au moins un halogène; Y est choisi dans le groupe constitué d'hydrogène et d'halogène; ou X et Y forment ensemble le résidu d'un cycle carbocyclique.
PCT/GB2000/004700 1999-12-10 2000-12-08 Benzyl-tetralines, formulations et utilisations associees WO2001042181A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21914/01A AU2191401A (en) 1999-12-10 2000-12-08 Benzyl tetralins, formulations and uses thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9929302.9 1999-12-10
GBGB9929302.9A GB9929302D0 (en) 1999-12-11 1999-12-11 Benzyl tetralins compositions and uses thereof

Publications (1)

Publication Number Publication Date
WO2001042181A1 true WO2001042181A1 (fr) 2001-06-14

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/004700 WO2001042181A1 (fr) 1999-12-10 2000-12-08 Benzyl-tetralines, formulations et utilisations associees

Country Status (3)

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AU (1) AU2191401A (fr)
GB (1) GB9929302D0 (fr)
WO (1) WO2001042181A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007003934A2 (fr) 2005-07-04 2007-01-11 Sterix Limited Compose
US7465739B2 (en) 2003-06-10 2008-12-16 Solvay Pharmaceuticals B.V. Compounds and their use in therapy
WO2009066072A2 (fr) 2007-11-20 2009-05-28 Sterix Limited Composé
US7754709B2 (en) 2003-06-10 2010-07-13 Solvay Pharmaceuticals Bv Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds
US8080540B2 (en) 2006-09-19 2011-12-20 Abbott Products Gmbh Therapeutically active triazoles and their use
US8288367B2 (en) 2006-11-30 2012-10-16 Solvay Pharmaceuticals Gmbh Substituted estratriene derivatives as 17BETA HSD inhibitors
WO2014207310A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés thérapeutiquement actifs d'estratriène-thiazole à substitution azote en position 17 en tant qu'inhibiteurs de la 17bêta.-hydroxystéroïde déshydrogénase
WO2014207309A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés d'estratriénthiazole thérapeutiquement actifs utilisés comme inhibiteurs de la 17β-hydroxystéroïde déshydrogénase de type 1
WO2014207311A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés d'estratriène thiazole thérapeutiquement actifs en tant qu'inhibiteurs de déshydrogénase 17.bêta-hydroxy-stéroide de type 1
WO2016102776A1 (fr) 2014-12-23 2016-06-30 Forendo Pharma Ltd Promédicaments d'inhibiteurs de la 17β-hsd1
WO2016102775A1 (fr) 2014-12-23 2016-06-30 Forendo Pharma Ltd Promédicaments d'inhibiteurs de 17β-hsd1
WO2018224736A2 (fr) 2017-06-08 2018-12-13 Forendo Pharma Ltd Dérivés stéroïdiens thérapeutiquement actifs
WO2020115371A1 (fr) 2018-12-05 2020-06-11 Forendo Pharma Ltd Composés estra-1,3,5(10)-triène condensés en position 16(17) avec un cycle pyrazole utilisés comme inhibiteurs de la 17-hsd1

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0902003A1 (fr) * 1997-01-29 1999-03-17 Snow Brand Milk Products Co., Ltd. Nouveaux derives de tetralone ou de benzopyranone et procede de fabrication correspondant
WO1999035115A1 (fr) * 1998-01-02 1999-07-15 University College Cardiff Consultants Limited Tetralines de benzyle et benzylidene et derives associes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0902003A1 (fr) * 1997-01-29 1999-03-17 Snow Brand Milk Products Co., Ltd. Nouveaux derives de tetralone ou de benzopyranone et procede de fabrication correspondant
WO1999035115A1 (fr) * 1998-01-02 1999-07-15 University College Cardiff Consultants Limited Tetralines de benzyle et benzylidene et derives associes

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7465739B2 (en) 2003-06-10 2008-12-16 Solvay Pharmaceuticals B.V. Compounds and their use in therapy
US7754709B2 (en) 2003-06-10 2010-07-13 Solvay Pharmaceuticals Bv Tetracyclic thiophenepyrimidinone compounds as inhibitors of 17β hydroxysteroid dehydrogenase compounds
WO2007003934A2 (fr) 2005-07-04 2007-01-11 Sterix Limited Compose
US8119627B2 (en) 2005-07-04 2012-02-21 Sterix Limited Heterocyclic compounds as inhibitors of 17beta-HSD3
US8080540B2 (en) 2006-09-19 2011-12-20 Abbott Products Gmbh Therapeutically active triazoles and their use
US8288367B2 (en) 2006-11-30 2012-10-16 Solvay Pharmaceuticals Gmbh Substituted estratriene derivatives as 17BETA HSD inhibitors
WO2009066072A2 (fr) 2007-11-20 2009-05-28 Sterix Limited Composé
US8558028B2 (en) 2007-11-20 2013-10-15 University Of Bath Of Claverton Down Compound capable of inhibiting 17-beta hydroxysteriod dehydrogenase
WO2014207311A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés d'estratriène thiazole thérapeutiquement actifs en tant qu'inhibiteurs de déshydrogénase 17.bêta-hydroxy-stéroide de type 1
US9850272B2 (en) 2013-06-25 2017-12-26 Forendo Pharma Ltd. Therapeutically active estratrienthiazole derivatives as inhibitors of 17.beta-hydroxy-steroid dehydrogenase, type 1
WO2014207310A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés thérapeutiquement actifs d'estratriène-thiazole à substitution azote en position 17 en tant qu'inhibiteurs de la 17bêta.-hydroxystéroïde déshydrogénase
WO2014207309A1 (fr) 2013-06-25 2014-12-31 Forendo Pharma Ltd Dérivés d'estratriénthiazole thérapeutiquement actifs utilisés comme inhibiteurs de la 17β-hydroxystéroïde déshydrogénase de type 1
US10377791B2 (en) 2013-06-25 2019-08-13 Forendo Pharma Ltd. Therapeutically active estratrienthiazole derivatives as inhibitors of 17 B-hydroxysteroid dehydrogenase, type 1
US9663549B2 (en) 2013-06-25 2017-05-30 Forendo Pharma Ltd. Therapeutically active 17-nitrogen substituted estratreinthiazole derivatives as inhibitors of 17β-hydroxysteroid dehydrogenase
US10626140B2 (en) 2014-12-23 2020-04-21 Forendo Pharma Ltd Prodrugs of 17β-HSD1-inhibitors
WO2016102775A1 (fr) 2014-12-23 2016-06-30 Forendo Pharma Ltd Promédicaments d'inhibiteurs de 17β-hsd1
US10413557B2 (en) 2014-12-23 2019-09-17 Forendo Pharma Ltd. Prodrugs of 17.BETA.-HSD1-inhibitors
WO2016102776A1 (fr) 2014-12-23 2016-06-30 Forendo Pharma Ltd Promédicaments d'inhibiteurs de la 17β-hsd1
WO2018224736A2 (fr) 2017-06-08 2018-12-13 Forendo Pharma Ltd Dérivés stéroïdiens thérapeutiquement actifs
US10717761B2 (en) 2017-06-08 2020-07-21 Forendo Pharma Ltd Therapeutically active steroidal derivatives
US11254703B2 (en) 2017-06-08 2022-02-22 Forendo Pharma Ltd Therapeutically active steroidal derivatives
WO2020115371A1 (fr) 2018-12-05 2020-06-11 Forendo Pharma Ltd Composés estra-1,3,5(10)-triène condensés en position 16(17) avec un cycle pyrazole utilisés comme inhibiteurs de la 17-hsd1

Also Published As

Publication number Publication date
AU2191401A (en) 2001-06-18
GB9929302D0 (en) 2000-02-02

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