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WO1994007866A1 - Inhibiteur d'aromatase - Google Patents

Inhibiteur d'aromatase Download PDF

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Publication number
WO1994007866A1
WO1994007866A1 PCT/JP1993/001433 JP9301433W WO9407866A1 WO 1994007866 A1 WO1994007866 A1 WO 1994007866A1 JP 9301433 W JP9301433 W JP 9301433W WO 9407866 A1 WO9407866 A1 WO 9407866A1
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WO
WIPO (PCT)
Prior art keywords
compound
reaction
nmr
yield
methoxy
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Application number
PCT/JP1993/001433
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English (en)
Japanese (ja)
Inventor
Rolf W. Hartmann
Gerald Anton Wachter
Original Assignee
Tokyo Tanabe Company 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 Tokyo Tanabe Company Limited filed Critical Tokyo Tanabe Company Limited
Priority to AU51184/93A priority Critical patent/AU5118493A/en
Publication of WO1994007866A1 publication Critical patent/WO1994007866A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine

Definitions

  • the present invention relates to benzocycloalkane compounds. More specifically, the present invention relates to a benzocycloalpine compound having an aromatase inhibitory action.
  • Aromatase is a cytochrome P-450 enzyme located at the end of a series of steroid hormone biosynthesis systems that begins with the cleavage of cholesterol side chains, and produces estrogens using androgens as substrates. Therefore, aromatase drugs inhibit estrogen biosynthesis and are used for the treatment of estrogen-dependent cancers such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, feminization of males, and breast and endometriosis. can do.
  • Aminoglutethimide (hereinafter referred to as “AG”) is known as an aromatase inhibitor and has already been used for the treatment of breast cancer. However, AG also inhibits desmolase (a cholesterol side-chain cleavage enzyme), which suppresses adrenal steroid production, and cannot be avoided in combination with corticosteroids.
  • an object of the present invention is to provide a compound which is potent and has a selective aromatase inhibitory action which does not have a desmolase inhibitory activity. Disclosure of the invention
  • a benzocycloalkane compound represented by the following general formula (Hereinafter referred to as “the compound of the present invention”).
  • R represents a hydrogen atom, a lower alkoxyl group having 1 to 4 carbon atoms, a nitro group, or a lower alkoxycarbonyl group having 1 to 4 carbon atoms
  • XY is a hydrogen atom or is a hydrogen atom together.
  • Z represents a hydrogen atom
  • the dashed line arbitrarily represents a bond
  • X represents a hydrogen atom
  • YZ together represents a single bond
  • n represents an integer of 0 or 1.
  • the compound of the present invention has an asymmetric carbon at the 2-position and has optical isomers.
  • 4- and 5-substituted compounds related to the imidazole ring.
  • YZ together represent a single bond, there may be end- and exo-forms, and when the dashed line represents a bond, there may be E- and Z-isomers.
  • the compounds of the present invention include all of these isomers and mixtures of these isomers.
  • the compound of the present invention can be converted into a physiologically acceptable salt by a conventional method.
  • the salt examples include inorganic salts such as hydrochloride, hydrobromide and sulfate, methanesulfonate, acetate, oxalate, citrate, succinate, tartrate, and fumarate.
  • Organic acid salts such as hydrochloride, hydrobromide and sulfate, methanesulfonate, acetate, oxalate, citrate, succinate, tartrate, and fumarate.
  • the compound of the present invention refers to compound B, compound C, Refers to compound D and compound E
  • Benzocycloalkanones (compound A) and imidazole-4 (5) -force aldehyde (hereinafter referred to as “imidazo-l-41-carbaldehyde”.
  • the imidazolyl group is also indicated as a 4-position substituent, but is also in the 5-position And an unsubstituted ketone (compound B) by an aldol condensation reaction.
  • the reaction is carried out by reacting benzocycloalkanonone with imidazo-l-4-carba: aldehyde in a suitable solvent in the presence of an acid or a base.
  • the acid include inorganic acids such as hydrochloric acid, sulfuric acid, and nitric acid, and organic acids such as formic acid, acetic acid, oxalic acid, methanesulfonic acid, and tosylic acid.
  • the base include metal hydroxides such as sodium hydroxide and hydroxylating power, metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, pyrrolidine, and pyridinium. Resin, morpholine, etc. Equipment.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, but water, alcohols such as methanol, ethanol and propanol, ethers such as dimethyl ether, tetrahydrofuran, dioxane and glyme, dichloromethane, and chloroform Halogenated hydrocarbons such as mouth form, and mixtures thereof.
  • compound C is subjected to a catalytic reduction reaction to obtain a saturated ketone (compound C).
  • the reaction is carried out by absorbing a calculated amount of hydrogen in a suitable solvent in the presence of a catalyst.
  • a catalyst Noble metal catalysts such as radium, nickel, cobalt, ruthenium, rhodium and platinum are included. These noble metal catalysts can be used alone in particulate metal, supported on activated carbon, diatomaceous earth, silica or alumina, or used in tris (triphenylphosphine) rhodium chloride. Used as a homogeneous complex catalyst such as rhodium and hydride carbonyl tris (triphenylphosphine).
  • the solvent is not particularly limited as long as it does not inhibit the reaction, but alcohols such as water, methanol, ethanol and propanol, ethers such as getyl ether, tetrahydrofuran, dioxane and lime, dichloromethane, Examples include halogenated hydrocarbons such as black form and the like, and mixtures thereof.
  • an acid such as hydrochloric acid or acetic acid or a base such as ammonia or triethylamine can be added.
  • the hydrogen pressure is from 1 atm to 100 atm, preferably from 1 atm to 100 atm.
  • reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds and the solvent, but the reaction temperature is 0 to 200 ° C, preferably room temperature to 100 ° C, and 30 minutes to 30 minutes. Perform the reaction for several days. (3rd step)
  • the reaction is carried out by reacting hydrazine on compound C in the presence of a base.
  • a base include a metal hydroxide such as sodium hydroxide or hydroxylated hydrogen or a metal alkoxide such as sodium methoxide or potassium tert-butoxide.
  • the solvent is not particularly limited as long as it does not inhibit the reaction.
  • alcohols such as water, methanol, ethanol, propanol, butanol, tert-butyl alcohol, ethylene glycol, diethylene glycol and triethylene glycol
  • examples include ethers such as trahydrofuran, dioxane, glyme, diglyme and triglyme, non-protonic dipolar solvents such as DMF, DMSO and HMPA, and mixtures thereof, and preferably alcohols, particularly preferably alcohols.
  • Ethylene glycol Ethylene glycol.
  • hydrazine hydrazine hydroxide or anhydrous hydrazine can be used.
  • Hydrazine hydrazine is preferable, and it is preferably from 1 to 100 equivalents, more preferably 5 equivalents to Compound C. Use up to 50 equivalents.
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the starting compounds used and the solvent, but the reaction temperature is 0 to 300 ° C., preferably 100 to 250 ° C., and 1 hour. Perform the reaction for several days.
  • Compound D is obtained by isolating a hydrazone compound, which is a condensate of compound C and hydrazine, and subjecting it to a base, or subjecting compound B to a catalytic reduction reaction or reduction reaction with a metal hydride. Can also be obtained.
  • the reaction is carried out by reacting hydrazine with compound B in the presence of a base.
  • the base include a metal hydroxide such as sodium hydroxide or hydroxylated water, and a metal alkoxide such as sodium methoxide or potassium tert-butoxide.
  • the solvent is not particularly limited as long as it does not inhibit the reaction, but includes water, methanol, ethanol, propanol, butanol, tert-butyl alcohol, ethylene glycol, diethylene glycol, triethylene glycol, and the like.
  • Alcohols such as tetrahydrofuran, dioxane, glyme, diglyme and triglyme, non-protonic dipolar solvents such as DMF, DMSO and HMPA, and mixtures thereof, and preferably alcohols. And particularly preferably ethylene glycol.
  • hydrazine hydrazine hydrate or anhydrous hydrazine can be used.Hydrazine hydrate is preferable, and 1 to 100 equivalents, preferably 5 to 5 equivalents to compound C is used. Use 0 equivalents.
  • the reaction conditions such as the reaction temperature and the reaction time vary depending on the used starting compounds and the solvent, but the reaction temperature is 0 to 300 ° C, preferably 100 to 250 ° C, and 1 hour to several hours. Perform the reaction for a day.
  • the benzocycloalkane compound of the present invention has potent and selective aromatase inhibitory activity.
  • the pharmacological actions of representative compounds of the present invention are shown below.
  • Aromatase was obtained from the microsomal fraction of postpartum fresh placental tissue according to the method of Thompson and Siteri (J. Biol. Chem., Vol. 249, 5364 (1974)). The separated microsomes were added to a minimal amount of phosphate buffer (0.05 M, pH 7.4). Suspended and stored at 30 ° C. No inactivation was observed within 4 months. Inhibition test;
  • test substance was previously dissolved in ethanol and diluted with a buffer. Final ethanol concentrations in control and inhibitor cultures were 2%. Each tube was pre-incubated for 5 minutes in a water bath at 30 ° C, and the reaction was started by adding microsome and evening protein (0.5 mg). Each culture solution had a total volume of 0.5 ml. Take a 100/1 partial sample at 0, 7, 14 and 21 minutes and pour the sample into a 1 mM mercuric chloride HgC12 solution 200 H1 The reaction was thereby terminated. To this was added a suspension of activated carbon (DCC) (2%) coated with 200 aqueous dextran, and the vial was shaken for 20 minutes and centrifuged at 1500 g for 5 minutes.
  • DCC activated carbon
  • Substrate testosterone concentration is 2.5 ⁇ M
  • Tesmolase was obtained from the mitochondrial fraction of the pulmonary adrenal cortex according to the method of Hochberg et al. (Biochemistry, vol. 13, 63 (1974)). The separated mitochondria were resuspended in a buffer using sucrose as a minimum volume buffer, and then stored at 170 ° C. Within three months, desmolase activity was stable.
  • Protein and T ris—Inhibitor (0 or 25 // M) dissolved in HC1 buffer (0.1 M mercury chloride, 0.01 M, pH 7.4) was added. The test substance was previously dissolved in ethanol and diluted with a buffer. Final ethanol concentrations in control and inhibitor cultures were 1%. Each tube was pre-incubated for 3 minutes with shaking in a water bath at 30 ° C, and the NADP (1 mM) and NADP production system (1 OmM glucose-16-phosphate and 1 EU glucose-6 -Phosphate dehydrogenase) was added to start the reaction. Each culture solution had a total volume of 1 ml.
  • adrenocorticotropic hormone (_ ACTH i, 4?; 1 sm 1) to stimulate Koruchikoi de generate culture medium and fresh medium containing Aromataze inhibition And cultured for 2 hours under the conditions described above.
  • Supernatant corticosterone and The aldosterone content was measured by radioimmunoassay without extraction (using a kit of DRGI nstruments, Marbur, Germany).
  • IC c0 values were calculated by interpolation with logarithmic ratios by comparison with ACTH stimulated controls.
  • the tetrahydrodronafullerene compound can be used as a solid preparation such as tablets, hard or soft capsules, granules, powders, fine granules or suppositories, injections, syrups, etc.
  • Solution, solution, suspension or emulsion can be prepared.
  • Solid preparations may be prepared as enteric-coated preparations or sustained-release preparations.
  • the formulation carrier to be mixed includes, for example, excipients, binders, disintegrants, lubricants, coating agents, dissolution aids, emulsifiers, suspending agents, surfactants, absorption aids And a stabilizer or a solvent.
  • the compound of the present invention has a potent and selective aromatase inhibitory action, estrogen-dependent cancer such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, gynecomastia of male and endometrium It is useful as a therapeutic agent for the disease.
  • the 1 H-NMR spectrum was measured with a Bruker AW-80 using TMS as an internal standard.
  • I R (KB r): 3 1 1 5, 3060, 2920, 2620, 1 668, 16 0 5, 1 5 9 5, 1 3 0 5, 6 2 5, 6 1 3, 4 9 0.
  • IR (KB r): 3110, 3010, 2930, 2840, 2665, 2600, 1 665, 1 6 1 2, 1 593, 1 100, 625, 595.
  • Example 2 It was synthesized according to the method of Example 1 from 7-two-row 1-tetrabutyl and imidazole-41-carbaldehyde. Yellow crystals, melting point 250 ° C or higher, yield 30%.
  • E-2- (4-imidazolylmethylene) 111-indanone (Compound 17); synthesized from 1-indanone and imidazole-41-carbaldehyde according to the method of Example 1. Yellow crystals, mp 203-206 ° C, yield 65%.
  • I R (KB r): 3125, 2955, 2915, 2865, 1670, 1615, 16600, 1088, 7482, 625.
  • I R (KB r): 3 1 30, 2970, 2920, 2840, 1695, 1645, 1 635, 1 490, 1 280, 1 270, 742, 660, 62 0, 5 7 0.
  • Example 2 It was synthesized according to the method of Example 1 from 6-methoxy-11-indanone and imidazole-4 carbaldehyde. Yellow crystals, melting point 1 98-20 1 ° C, yield 84%.
  • I R (KB r): 3 1 40, 2970, 2880, 1695, 1 630,
  • I R (KB r): 3100, 3045, 2835, 2585, 1685, 16500, 1585, 1265, 945, 665.
  • the compound was synthesized from compound-3 according to the method of Example 11. Colorless crystals, melting point 148-150 ° C, yield 67%.
  • the compound was synthesized from compound-4 according to the method of Example 11. Colorless crystals, mp 161-162 ° C, 86% yield. .
  • I R (KB r): 3060, 3000, 2840, 2630, 1 7 1 5, 1 6 0 5, 1 5 9 5, 7 6 0, 6 2 5.
  • the compound was synthesized from compound-6 according to the method of Example 11. Colorless crystals, mp 160-162 ° C, yield 73%.
  • I R (KB r): 3 1 30, 3065, 2970, 2940, 2905, 2840, 1712, 1 602, 1 596, 1 487, 1 258, 780,
  • the compound was synthesized from compound-8 according to the method of Example 11. Colorless crystals, melting point 150-153 ° C, yield 68%.
  • I R (KB r): 3200, 3060, 2920, 2900, 2840, 2600, 1 595, 1 582, 1 497, 1 483, 1 11 0, 950, 8 18 and 6 63.
  • the compound was synthesized from compound-12 according to the method of Example 19. Colorless crystal, melting point 157-159. C, yield 56%.
  • the compound was synthesized from compound-13 according to the method of Example 19. Colorless crystals, melting point 100-102 ° C, yield 48%.
  • I R (KB r): 3200, 3 1 20, 2925, 2835, 16 1, 4, 150, 1, 27, 0, 1, 2, 3, 5, 0 3, 8, 8, 26, 66 2.
  • the compound was synthesized from compound-14 according to the method of Example 19. Colorless crystals, melting point 113-114 ° C, yield 42%.
  • Exo-1 1- (4-imidazolyl) 1-1a, 2,3,7b-tetrahydro1H-cyclopropa [a] naphthalene (compound 31);
  • Exo-1-1 (4-imidazolyl) -1-5-methoxy 1a, 2,3,7b-tetrahydro 1H-cycloprono [a] naphthalene (Compound-33); From Compound 13 to Example 23 Synthesized according to the method. Colorless crystals, mp 155-157 ° C, yield 67%.
  • Exo-1-1 (4-I-midazolyl) -1-6-Methoxy-1a, 2, 3, 7b —Tetrahydro-1H-cycloprono, “[a] naphthalene (compound 34); synthesized from compound 14 according to the method of Example 23. Purified by chromatography to give the title compound as a colorless oil. Was obtained (yield 85%).
  • the benzocycloalkane compound I can be used as a therapeutic agent for estrogen-dependent cancer such as breast cancer, uterine cancer or ovarian cancer, prostatic hypertrophy, gynecomastia of males, and endometriosis.

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

Abstract

Composé de benzocycloalcane représenté par la formule générale (I), dans laquelle R représente hydrogène, alcoxy inférieur C1-C4, nitro ou alcoxycarbonyle inférieur C1-C4; lorsque X et Y représentent chacun hydrogène ou X et Y sont combinés ensemble pour représenter oxygène, alors Z représente hydrogène et la ligne hachurée représente une liaison arbitraire; lorsque X représente H, alors Y et Z sont combinés ensemble pour représenter une liaison simple; et n représente 0 ou 1. Ce composé présente un effet inhibiteur d'aromatase sélectif puissant et il est utile comme remède contre les cancers dépendants de l'÷strogène, tel que le cancer du sein, de l'utérus ou des ovaires, la prostatomégalie, la gynécomastie et l'endométriose.
PCT/JP1993/001433 1992-10-06 1993-10-06 Inhibiteur d'aromatase WO1994007866A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51184/93A AU5118493A (en) 1992-10-06 1993-10-06 Aromatase inhibitor

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JP4/267130 1992-10-06
JP26713092 1992-10-06

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WO1994007866A1 true WO1994007866A1 (fr) 1994-04-14

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028300A1 (fr) * 1997-12-04 1999-06-10 Allergan Sales, Inc. Derives imidazoles substitues ayant une activite de type agoniste vis a vis des recepteurs adrenergiques alpha 2b ou 2b/2c
EP1010693A1 (fr) * 1998-12-18 2000-06-21 Adir Et Compagnie Nouveaux composés imidazoliniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
US6329369B1 (en) 1997-12-04 2001-12-11 Allergan Sales, Inc. Methods of treating pain and other conditions
WO2002076950A3 (fr) * 2001-03-21 2003-03-13 Allergan Inc Procede et composes de traitement presentant une activite selective similaire a celle d'agonistes des recepteurs adrenergiques alpha 2b ou 2b/2c
AU2002254265B2 (en) * 1997-12-04 2008-05-15 Allergan, Inc. Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 113, No. 23, (1990), Abstract No. 204499f. *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999028300A1 (fr) * 1997-12-04 1999-06-10 Allergan Sales, Inc. Derives imidazoles substitues ayant une activite de type agoniste vis a vis des recepteurs adrenergiques alpha 2b ou 2b/2c
JP2001524542A (ja) * 1997-12-04 2001-12-04 アラーガン・セイルズ・インコーポレイテッド α２Ｂまたは２Ｂ／２Ｃアドレナリン受容体において作動剤様活性を示す置換イミダゾール誘導体
US6329369B1 (en) 1997-12-04 2001-12-11 Allergan Sales, Inc. Methods of treating pain and other conditions
EP1413576A3 (fr) * 1997-12-04 2004-09-01 Allergan, Inc. Dérivés d'imidazoles substituées et leur utilisation en tant qu'agonistes des récepteurs adrénergiques alpha 2B ou 2B/2C
US6841684B2 (en) 1997-12-04 2005-01-11 Allergan, Inc. Imidiazoles having reduced side effects
KR100544787B1 (ko) * 1997-12-04 2006-01-23 알러간, 인코포레이티드 알파 2비 또는 2비/2씨 아드레날린성 수용체에서 선택적인유사-작용 활성을 가지는 화합물 및 치료방법
AU2002254265B2 (en) * 1997-12-04 2008-05-15 Allergan, Inc. Imidiazole derivatives and their use as agonists selective at alpha 2B or 2B/2C adrenergic receptors
JP2010209111A (ja) * 1997-12-04 2010-09-24 Allergan Inc α２Ｂまたは２Ｂ／２Ｃアドレナリン受容体において作動剤様活性を示す置換イミダゾール誘導体
JP2014012724A (ja) * 1997-12-04 2014-01-23 Allergan Inc α２Ｂまたは２Ｂ／２Ｃアドレナリン受容体において作動剤様活性を示す置換イミダゾール誘導体
EP1010693A1 (fr) * 1998-12-18 2000-06-21 Adir Et Compagnie Nouveaux composés imidazoliniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
FR2787451A1 (fr) * 1998-12-18 2000-06-23 Adir Nouveaux composes imidazoliniques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
WO2002076950A3 (fr) * 2001-03-21 2003-03-13 Allergan Inc Procede et composes de traitement presentant une activite selective similaire a celle d'agonistes des recepteurs adrenergiques alpha 2b ou 2b/2c

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