WO1995021834A1 - Optically active 4,1-benzoxazepine derivatives useful as squalene synthase inhibitors - Google Patents
Optically active 4,1-benzoxazepine derivatives useful as squalene synthase inhibitors Download PDFInfo
- Publication number
- WO1995021834A1 WO1995021834A1 PCT/JP1995/000148 JP9500148W WO9521834A1 WO 1995021834 A1 WO1995021834 A1 WO 1995021834A1 JP 9500148 W JP9500148 W JP 9500148W WO 9521834 A1 WO9521834 A1 WO 9521834A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- neopentyl
- chloro
- benzoxazepine
- tetrahydro
- oxo
- Prior art date
Links
- 239000004059 squalene synthase inhibitor Substances 0.000 title claims description 13
- YAVSXFRYNGAFRN-UHFFFAOYSA-N 4,1-benzoxazepine Chemical class O1C=CN=C2C=CC=CC2=C1 YAVSXFRYNGAFRN-UHFFFAOYSA-N 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 241000124008 Mammalia Species 0.000 claims abstract description 9
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 9
- 229910021645 metal ion Chemical group 0.000 claims abstract description 9
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 8
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 238000011321 prophylaxis Methods 0.000 claims abstract description 6
- 238000011282 treatment Methods 0.000 claims abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 63
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- 238000000034 method Methods 0.000 claims description 24
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000001617 2,3-dimethoxy phenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 2
- VTYJANRVLSSNCJ-UHFFFAOYSA-N 4,1-benzoxazepin-2-one Chemical class O=C1COC=C2C=CC=CC2=N1 VTYJANRVLSSNCJ-UHFFFAOYSA-N 0.000 abstract description 3
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- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229960002965 pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000006456 reductive dimerization reaction Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- TZHVYFBSLOMRCU-YFKPBYRVSA-N tert-butyl (2s)-2-aminopropanoate Chemical compound C[C@H](N)C(=O)OC(C)(C)C TZHVYFBSLOMRCU-YFKPBYRVSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000721 toxic potential Toxicity 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
Definitions
- This invention relates to an optically active 4,1- benzoxazepin-2-one derivative or a salt thereof and to a squalene synthase inhibitor composition and an 0 antimycotic composition each comprising said derivative as an active ingredient.
- hypercholesterolemia is one of the three major risk factors of ischemic heart disease and a judicious control of the blood cholesterol level is essential to the prophylaxis and therapy of ischemic heart disease and coronary atherosclerosis.
- agents adapted to capture bile acid to inhibit its absorption typically cholestyramine and colestipol (disclosed in, for example, US Patent 4027009), and agents designed to inhibit acyl coenzyme A-cholesterol O-acyltransferase (ACAT) to depress the intestinal absorption of cholesterol, typically melinamide (disclosed in French Patent 1476569), are known.
- ACAT acyl coenzyme A-cholesterol O-acyltransferase
- drugs inhibiting the biosynthesis of cholesterol are also attracting attention.
- lovastatin Dislosed in US Patent 4231938
- simvastatin Dislosed in US Patent 444478
- pravastatin Dislosed in US Patent 4346227
- HMG-CoA reductase 3-hydroxy-3-methylglutaryl coenzyme A reductase
- Squalene synthase is an enzyme associated with an essential stage in the de novo cholesterol biosynthesis pathway. This enzyme catalizes the reductive dimerization of farnesyl pyrophosphate to synthesize squalene.
- EP 567026 discloses certain 4,1- benzoxazepin-2-one derivatives.
- This invention therefore, relates to (1) an optically active 4,l-benzoxazepin-2-one derivative of the following formula (I)
- R x represents a lower alkyl group
- X represents a hydrogen atom or a metal ion
- ring A represents a phenyl group substituted with halogen
- ring B represents a phenyl group substituted with a lower alkoxy
- a squalene synthase inhibitor composition comprising a compound of formula (I) as an active ingredient
- an antimycotic composition comprising a compound of formula (I) as an active ingredient
- a method for the prophylaxis or treatment for hypercholesterolemia or coronary sclerosis in a mammal which comprises administering a pharmaceutical effective amount of a compound of formula (I), to a mammal is need thereof, (5) a method for the prophylaxis or treatment for mycotic diseases in a mammal which comprises administering a pharmaceutical effective amount of a compound of formula (I) , to a mammal in need thereof, (6) use of a compound of formula (I) , for the manufacture of a medicament to be used as a prophylactic or therapeutic drug for hypercholesterolemia or coronary sclerosis,
- the substituent groups in the 3- and 5-positions are oriented trans to each other, viz. in opposite directions, with respect to the plane of the 7-membered ring and (R) stands for R-configuration.
- the lower alkyl group indicated by the symbol Ri includes straight-chain or branched C ⁇ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl neopentyl, tert- pentyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1- ethylpropyl, etc. and is preferably a C 4 _ 5 alkyl group and most desirably isobutyl or neopentyl.
- C ⁇ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl,
- the metal ion indicated by the symbol X includes sodium ion, potassium ion, calcium ion and aluminum ion, among others, and is preferably sodium ion or potassium ion.
- the halogen atom of the halogen-substituted phenyl group, represented as ring A, includes fluorine, chlorine, bromine and iodine and is preferably chlorine.
- the lower alkoxy group of the lower alkoxy-substi- tuted phenyl group, represented as ring B, includes straight-chain or branched C*,. 6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. and is preferably a C ⁇ alkoxy group and most desirably methoxy or ethoxy.
- R lf ring A and ring B are as defined herein ⁇ before, can be produced by subjecting the corresponding compounds of the following formula (II) to optical resolution.
- the reaction from (III) to (IV) and that from ( V III) to (VI) can be respectively carried out by utilizing the per se known acylation procedures.
- the acylation reaction for purposes of this invention can be carried out in a solvent, typically an ether such as diethyl ether, tetrahydrofuran, dioxane, etc.
- a halogen-containing solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., a hydrocarbon solvent such as benzene, toluene, hexane, heptane, etc., dimethylformamide or dimethyl sulfoxide, where necessary in the presence of water and a base, typically an organic base such as 4- dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc., or an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride, potassium hydride and so on.
- a base typically an organic base such as 4- dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc.
- an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate,
- fumaric acid chloride monoalkyl or aralkyl ester is used in a proportion of generally about 1-10 moles and preferably about 1-3 moles.
- the reaction time is generally about 1-48 hours and preferably about 5-10 hours.
- the reaction temperature is generally about -50 to 100°C and preferably about 0-50°C.
- the reaction from (III) to (VII) and that from (V) to (VI) can respectively be carried out by treating the starting compound with a metal hydrogen complex compound, typically lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, etc., in a protic solvent such as methanol, ethanol, propanol, butanol, etc. or an aprotic solvent such as ethyl ether, tetrahydrofuran, dioxane and so on.
- a metal hydrogen complex compound typically lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, etc.
- a protic solvent such as methanol, ethanol, propanol, butanol, etc.
- an aprotic solvent such as ethyl ether, tetrahydrofuran, dioxane and so on.
- the metal hydride complex compound is used in
- the reaction temperature is generally about -20 to 100°C and preferably about 20-50°C.
- the reaction from (VII) to (VIII) and that from (IV) to (V) can respectively be carried out by permitting an alkyl halide, typically neopentyl chloride, neopentyl bromide, neopentyl iodide, isobutyl chloride, isobutyl bromide or isobutyl iodide, to act on (VII) or (IV) in a solvent, e.g.
- the alkyl halide is used in a proportion of generally about 1-10 moles or preferably about 1-2 moles.
- the reaction temperature is about 0-100°C and preferably about 20-50°C.
- the reaction time is generally about 1-24 hours and preferably about 3-10 hours.
- Production of (VIII) from (VII) can also be carried out in the manner of catalytic reduction by using Pd or Pd on activated carbon as the catalyst or in the manner of reductive amination in the presence of sodium borohydride or sodium cyanoborohydride between compound (VII) and straight-chain or branched alkyl aldehydes and ketones such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, trimethylacetaldehyde, acetone, 2- butanone, etc. in a solvent, e.g.
- the aldehyde is used in a proportion of generally 1-10 moles and preferably 1-2 moles and the reducing agent is used in a proportion of 0.3-5 moles or preferably 0.5-1 mole.
- the reaction temperature is 0-100°C and preferably 10 - 30°C.
- the reaction time is generally about 1-24 hours and preferably about 3-10 hours.
- the reaction from (VI) to (IX) can be carried out in a solvent, e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., hydrocarbons such as benzene, toluene, hexane, heptane, etc., alcohols such as methanol, ethanol, propanol, butanol, etc., acetone, and dimethylformamide, where necessary in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and so on.
- a solvent e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, etc.
- hydrocarbons such as benzene, toluene, hexane, heptane, etc.
- alcohols such as methanol, ethanol, propanol, butano
- the base is used in a proportion of generally about 1-5 moles and preferably about 1-2 moles .
- the reaction temperature is generally -20 to 200°C and preferably 20-100°C.
- the reaction time is generally 1-20 hours and preferably about 2-5 hours.
- the reaction from (IX) to (II) can be carried out by treating (IX) with an acid or a base.
- this reaction can be carried out in an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or alkali metal hydroxide (e.g. sodium hydroxide, potas ⁇ sium hydroxide, barium hydroxide, lithium hydroxide, etc.) at a temperature of 0-150°C, preferably 20-50°C.
- the proper strength of the acid or base is about 1-10 normal, preferably 4-10N.
- the reaction time which depends on the reaction temperature, is generally about 1-24 hours and preferably about 2-10 hours.
- the optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active a ine.
- the optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active amine, such as an amino acid (e.g. alanine, valine, leucine, isoleucine, serine, threonine, lysine, phenylalanine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, methionine, etc.) whose carboxyl function has been esterified with an alkyl or aralkyl group of 1-8 carbon atoms, subjecting the resulting amide to distillation, recrystallization, column chromatography or other procedure to fractionate the desired optical isomer and cleaving the amide linkage to provide the object compound (la).
- an optically active amine such as an amino acid (e.g. alanine, valine, leucine, isoleucine, serine, threonine, lysine, phenylalanine, tyrosine,
- the amide mentioned above can be synthesized by condensing compound (II) with said amino acid ester using a condensing agent in a solvent, where necessary in the presence of a base.
- the solvent that can be used includes hydrocarbons such as benzene, toluene, hexane, heptane, etc., halogen-containing solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., ethers such as ethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide and so on.
- the base may for example be triethylamine, 4-dimethylaminopyridine, triethylenediamine, or tetramethylethylenediamine.
- the condensing agent includes those used in peptide synthesis, such as dicyclohexylcarbodiimide, diethyl cyanophosphonate, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and so on.
- the amino acid ester is used generally in a proportion of 0.5-2 molar equivalents, preferably 1-1.2 molar equivalents
- the condensing agent is used in a proportion of 0.5-5 molar equivalents, preferably 1-2 molar equivalents.
- the reaction temperature is 0-100°C and preferably 20- 50°C.
- the reaction time is 0.5-24 hours and preferably about 1-5 hours.
- Cleavage of the amide linkage can be carried out in a solvent, such as water, methanol, ethanol, propanol, butanol, etc., in the presence of an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.), sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc., or in the presence of a mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) at a temperature of 10-150°C, preferably 10-50°C.
- the reaction time which depends on the reaction temperature is generally 1-24 hours and preferably about 2-10 hours.
- the optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active amine (e.g. quinine, cinchonidine, brucine, dehydroabiethy1amine, nicotine, etc.) and subjecting the resulting salt to fractional crystallization to provide the object compound (la).
- an optically active amine e.g. quinine, cinchonidine, brucine, dehydroabiethy1amine, nicotine, etc.
- compound (la) can be produced after optical resolution of compound (VII) or (VIII).
- X' represents a metal ion and the other symbols have the same meanings as defined hereinbefore, can be produced by dissolving compound (la) and an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) in equimolar proportions in an alcoholic solvent such as methanol, ethanol, propanol or butanol.
- an alkali metal hydroxide e.g. sodium hydroxide, potassium hydroxide, etc.
- the compound (I) of this invention has squalene synthase inhibitory activity, some species have activity to inhibit other enzymes, as well, in the cholesterol biosynthesis pathway. In any event, the compound (I) of this invention inhibits the biosynthesis of cholesterol and is, therefore, useful for the prevention and therapy of hypercholesterolemia and coronary atherosclerosis in mammalian animals (e.g. mouse, rat, rabbit, dog, cat, bovine, swine, man, etc. ) .
- mammalian animals e.g. mouse, rat, rabbit, dog, cat, bovine, swine, man, etc.
- composition for oral administration includes solid and liquid dosage forms such as tablets (inclusive of dragees, film- coated tablets, etc.), pills, granules, powders, capsules (inclusive of soft capsules), syrups, emulsions, suspensions, and so on.
- These compositions can be manufactured by per se known procedures and generally contain some carrier or vehicle which is conventionally used in the pharmaceutical field. Taking the carrier for tablet use as an example, lactose, starch, sucrose, magnesium stearate, etc. can be mentioned.
- compositions for administration by other routes are injections and suppositors.
- the former includes subcutaneous, intradermal and intramuscular injections, among others.
- Such injections can be manufactured by suspending or emulsifying the compound of this invention in a sterile aqueous or oily vehicle which is conventionally used.
- the aqueous vehicle for injection includes physiological saline or other isotonic solution and may contain a suitable suspending agent such as carboxymethylcellulose sodium, a nonionic surfactant or the like.
- the oily vehicle includes sesame oil and soybean oil as typical examples and may contain a solubilizer such as benzyl benzoate, benzyl alcohol, etc.
- the injection so prepared is filled in appropriate ampules.
- the compound (I) has only a low toxic potential which provides for safe use. While the daily dosage is dependent on the patient's clinical condition and body weight, species of the compound, route of admin ⁇ istration, etc., the recommended daily dose as an anti- hypercholesterolemic agent for an adult is about 1-500 mg, preferably about 10-200 mg, for an oral regimen and about 0.1-100 mg, preferably about 1-20 mg, for administration by other routes (e.g. in the case of an injection or a suppository) . Within the above- mentioned dose range, no toxic reactions have been observed.
- the compound (I) has a broad antimicrobial spectrum as assayed by the broth or agar dilution assay.
- the effective daily dose for an adult is about 0.1-100 mg, preferably about 1-50 mg, for oral administration and about 0.1-100 mg, preferably 1-50 mg for administration by other routes (e.g. in the case of an injection or a suppository).
- the unit dose of 2-5 mg/kg can be generally employed. Examples
- Example 1 (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (I) and (3R,5S)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid
- the extract was washed with IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium hydrogen carbonate (100 ml x 2) and dried over anhydrous magnesium sulfate.
- Squalene synthase inhibitory activity is assayed by the following method using the enzyme preparations described in Test Examples 1 and 2.
- the reaction is stopped by adding 150 ⁇ l of chloroform-methanol (2:1) followed by addition of 50 ⁇ l of chloroform and 50 ⁇ l of 3N-sodium hydroxide solution.
- the chloroform layer (bottom layer, 50 ⁇ l) containing the reaction product composed predominantly of squalene is mixed with 3 ml of toluenic liquid scintillator and its radioactivity was measured using a liquid scintillation counter.
- a male SD rat (6 weeks old) is bled to death and the liver is enucleated.
- About 10 g of the heptic tissue was washed with ice-cooled saline and homogenized in 15 ml of ice-cooled buffer [100 mM potassium phosphate buffer (pH 7.4), 15 mM nicotinamide, 2mM MgCl 2 ] and the homogenate was centrifuged at 10000 x g (4°C) for 20 minutes.
- HepG2 Human hepatocarcinoma cells HepG2 (ca. 1 x 10 cells) grown in Dulbecco's modified Eagle's medium containing 10% fetal calf serum (37°C, 5% C0 2 ) were suspended in 10 ml of ice-cooled buffer [100 mM potassium phosphate buffer (pH 7.4), 30 mM nicotinamide, 2.5 mM MgCl 2 ] and disrupted by sonication (30 seconds x 2). From the sonicate, a microsome fraction was separated by the same procedure as described in Test Example 1. This fraction was suspended in ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (protein ca. 4 mg/ml) to provide an enzyme preparation. The results are shown below.
- Example 3 I 15.8% ⁇ II 0.022 0.0086
- Example 8 0.029 0.019
- the squalene synthase inhibitor composition compris ⁇ ing the optically active 4,l-benzoxazepin-2-one derivative (I) or its salt as an active ingredient for the therapy of hypercholesterolemia in accordance with this invention can be provided typically in the following formulations and dosage forms.
- Each capsule contains 180 mg
- Each tablet contains 230 mg
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
Disclosed is an optically active 4,1-benzoxazepin-2-one derivative of formula (I), wherein R1 represents a lower alkyl group; X represents a hydrogen atom or a metal ion; ring A represents a phenyl group substituted with halogen; ring B represents a phenyl group substituted with a lower alkoxy, which is useful for the prophylaxis or treatment of hypercholesteremia or coronary sclerosis of mammals.
Description
DESCRIPTION
OPTICALLY ACTIVE 4,1-BENZOXAZEPINE DERIVATIVES USEFUL AS SQUALENE SYNTHASE INHIBITORS
Technical Field
This invention relates to an optically active 4,1- benzoxazepin-2-one derivative or a salt thereof and to a squalene synthase inhibitor composition and an 0 antimycotic composition each comprising said derivative as an active ingredient. Background Art
It is known that hypercholesterolemia, alongside hypertension and smoking, is one of the three major risk factors of ischemic heart disease and a judicious control of the blood cholesterol level is essential to the prophylaxis and therapy of ischemic heart disease and coronary atherosclerosis.
As drugs capable of lowering the blood cholesterol 0 level, agents adapted to capture bile acid to inhibit its absorption, typically cholestyramine and colestipol (disclosed in, for example, US Patent 4027009), and agents designed to inhibit acyl coenzyme A-cholesterol O-acyltransferase (ACAT) to depress the intestinal absorption of cholesterol, typically melinamide (disclosed in French Patent 1476569), are known. Furthermore, drugs inhibiting the biosynthesis of cholesterol are also attracting attention. Particu¬ larly, lovastatin (disclosed in US Patent 4231938), simvastatin (disclosed in US Patent 4444784) and pravastatin (disclosed in US Patent 4346227), which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, are already in clinical use. However, since inhibition of HMG-CoA reductase leads to inhibition of the biosynthesis of not only cholesterol but also ubiquinones, dolichols, heme A and other factors
necessary for the body, the risk of consequent side effects is a serious concern.
Squalene synthase is an enzyme associated with an essential stage in the de novo cholesterol biosynthesis pathway. This enzyme catalizes the reductive dimerization of farnesyl pyrophosphate to synthesize squalene.
Meanwhile, a series of compounds which are expected to inhibit cholesterol biosynthesis through inhibition of squalene synthase have been disclosed in Journal of Medicinal Chemistry, Vol. 51(10), pp, 1869- 1871 (1988), Japanese published unexamined patent application No. Hl-213288/1989 (JP Kokai Hl- 213288/1989), JP Kokai H2-101088/1990, JP Kokai H2- 235820/1990, JP Kokai H2-235821/1990, JP Kokai H3- 20226/1991, JP Kokai H3-68591/1991, JP Kokai H3- 148288/1991, USP 5,019,390, USP 5,135,935, WO 9215579, JP-Kokai H6-9668/1994, WO 9318039 and WO 9318040.
On the other hand, various compounds are known as antimycotic agents. In particular, compounds showing antimycotic activity through inhibition of squalene biosynthesis are described in JP Kokai H4-279589/1992, EP 475706, EP 494622 and EP 503520.
Referring, now, to 4,1-benzoxazepine derivatives and, more particularly, to 4,l-benzoxazepin-2-one derivatives which have a ketone group in the 2- posit on, compounds derivatized by substituting one hydrogen atom in the 3-position, with a different atomic group are disclosed in JP Kokai S57-35576/1982 and Chem. Pharm. Bull. 34, 140 (1986).
Furthermore, EP 567026 discloses certain 4,1- benzoxazepin-2-one derivatives.
It is known that ubiquinones, dolichols, heme A and other factors are biosynthesized from farnesyl pyrophosphate in the cholosterol biosynthesis pathway and, therefore, in order to avoid side effects arising
from their deficiencies, it appears to be a worthwhile attempt to inhibit enzymes subsequent to farnesyl pyrophosphate, particularly squalene synthase. Disclosure of Invention Under the circumstances described above the inventors of this invention did much research and discovered that an optically active 4,l-benzoxazepin-2- one derivative has excellent squalene synthase inhibiting activity. This invention has been developed on the basis of the above finding.
This invention, therefore, relates to (1) an optically active 4,l-benzoxazepin-2-one derivative of the following formula (I)
wherein Rx represents a lower alkyl group; X represents a hydrogen atom or a metal ion; ring A represents a phenyl group substituted with halogen; ring B represents a phenyl group substituted with a lower alkoxy;
(2) a squalene synthase inhibitor composition comprising a compound of formula (I) as an active ingredient, (3) an antimycotic composition comprising a compound of formula (I) as an active ingredient, (4) a method for the prophylaxis or treatment for hypercholesterolemia or coronary sclerosis in a mammal which comprises administering a pharmaceutical effective amount of a compound of formula (I), to a mammal is need thereof,
(5) a method for the prophylaxis or treatment for mycotic diseases in a mammal which comprises administering a pharmaceutical effective amount of a compound of formula (I) , to a mammal in need thereof, (6) use of a compound of formula (I) , for the manufacture of a medicament to be used as a prophylactic or therapeutic drug for hypercholesterolemia or coronary sclerosis,
(7) use of a compound of formula (I) , for the manufacture of a medicament to be used as a prophylactic or therapeutic drug for mycotic diseases,
(8) a method for producing a compound of formula (I) which comprises (i) subjecting a compound of the following formula:
wherein all symbols are of the same meanings as above, to optical resolution and (ii), if necessary, dissolving the resultant compound and an alkali metal hydroxide in an alcoholic solvent, and
(9) The method according to the above-mentioned (8) , which comprises reacting the compound with an optically active amine. Best Mode for Carrying Out the Invention The invention further provides a production tech¬ nology for novel compounds which was fallen under the purview of formula (I) .
Referring to the formula (I) of this invention, the substituent groups in the 3- and 5-positions are oriented trans to each other, viz. in opposite directions, with respect to the plane of the 7-membered
ring and (R) stands for R-configuration.
Referring, further, to formula (I), the lower alkyl group indicated by the symbol Ri includes straight-chain or branched C^ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, isopentyl neopentyl, tert- pentyl, 1-ethylpropyl, hexyl, 1,1-dimethylbutyl, 2,2- dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, 1- ethylpropyl, etc. and is preferably a C4_5 alkyl group and most desirably isobutyl or neopentyl.
The metal ion indicated by the symbol X includes sodium ion, potassium ion, calcium ion and aluminum ion, among others, and is preferably sodium ion or potassium ion. The halogen atom of the halogen-substituted phenyl group, represented as ring A, includes fluorine, chlorine, bromine and iodine and is preferably chlorine.
The lower alkoxy group of the lower alkoxy-substi- tuted phenyl group, represented as ring B, includes straight-chain or branched C*,.6 alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, etc. and is preferably a C^ alkoxy group and most desirably methoxy or ethoxy.
Practical examples of the compounds of this invention are disclosed as follows: (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2- oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt,
(3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt, (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-
acetic acid or its sodium salt.
Among compounds of formula (I), compounds of the following formula (la)
wherein Rlf ring A and ring B are as defined herein¬ before, can be produced by subjecting the corresponding compounds of the following formula (II) to optical resolution.
Compounds of formula (II) can be produced by the following processes as described in EP 567026. Inci¬ dentally the starting compound 2-aminobenzophenone can be synthesized by any of the processes described in D. A. Walsh: Synthesis 677, 1980, the processes referred to in the same literature, and processes analogous thereto.
wherein R2 represents an alkyl or aralkyl group of 1-8 carbon atoms; the other symbols have the meanings defined hereinbefore.
The reaction from (III) to (IV) and that from (VIII) to (VI) can be respectively carried out by utilizing the per se known acylation procedures. For example, the acylation reaction for purposes of this invention can be carried out in a solvent, typically an
ether such as diethyl ether, tetrahydrofuran, dioxane, etc. , a halogen-containing solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., a hydrocarbon solvent such as benzene, toluene, hexane, heptane, etc., dimethylformamide or dimethyl sulfoxide, where necessary in the presence of water and a base, typically an organic base such as 4- dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine, etc., or an inorganic base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride, potassium hydride and so on. Relative to each mole of (III) or (VIII), fumaric acid chloride monoalkyl or aralkyl ester is used in a proportion of generally about 1-10 moles and preferably about 1-3 moles. The reaction time is generally about 1-48 hours and preferably about 5-10 hours. The reaction temperature is generally about -50 to 100°C and preferably about 0-50°C.
The reaction from (III) to (VII) and that from (V) to (VI) can respectively be carried out by treating the starting compound with a metal hydrogen complex compound, typically lithium aluminum hydride, sodium aluminum hydride, sodium triethoxyaluminum hydride, sodium borohydride, etc., in a protic solvent such as methanol, ethanol, propanol, butanol, etc. or an aprotic solvent such as ethyl ether, tetrahydrofuran, dioxane and so on. The metal hydride complex compound is used in a proportion of generally 0.3-5 moles and preferably 0.5-2 moles per mole of (III) or (V). The reaction temperature is generally about -20 to 100°C and preferably about 20-50°C. The reaction from (VII) to (VIII) and that from (IV) to (V) can respectively be carried out by
permitting an alkyl halide, typically neopentyl chloride, neopentyl bromide, neopentyl iodide, isobutyl chloride, isobutyl bromide or isobutyl iodide, to act on (VII) or (IV) in a solvent, e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., hydrocarbons such as benzene, toluene, hexane, heptane, etc., alcohols such as methanol, ethanol, propanol, butanol, etc., acetone, dimethylformamide, etc., where necessary in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and so on. Relative to each mole of (VII) or (IV), the alkyl halide is used in a proportion of generally about 1-10 moles or preferably about 1-2 moles. The reaction temperature is about 0-100°C and preferably about 20-50°C. The reaction time is generally about 1-24 hours and preferably about 3-10 hours.
Production of (VIII) from (VII) can also be carried out in the manner of catalytic reduction by using Pd or Pd on activated carbon as the catalyst or in the manner of reductive amination in the presence of sodium borohydride or sodium cyanoborohydride between compound (VII) and straight-chain or branched alkyl aldehydes and ketones such as formaldehyde, acetaldehyde, propionaldehyde, butyraldehyde, isobutyraldehyde, trimethylacetaldehyde, acetone, 2- butanone, etc. in a solvent, e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., hydrocarbons such as benzene, toluene, hexane, heptane, etc., and alcohols such as methanol, ethanol, propanol, butanol, etc. Relative to each mole of (VII), the aldehyde is used in a proportion of generally 1-10 moles and preferably 1-2 moles and the reducing agent is used in a proportion of 0.3-5 moles or preferably 0.5-1 mole. The reaction temperature is 0-100°C and
preferably 10 - 30°C. The reaction time is generally about 1-24 hours and preferably about 3-10 hours.
The reaction from (VI) to (IX) can be carried out in a solvent, e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., hydrocarbons such as benzene, toluene, hexane, heptane, etc., alcohols such as methanol, ethanol, propanol, butanol, etc., acetone, and dimethylformamide, where necessary in the presence of a base such as sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and so on. Relative to each mole of compound (VI), the base is used in a proportion of generally about 1-5 moles and preferably about 1-2 moles . The reaction temperature is generally -20 to 200°C and preferably 20-100°C. The reaction time is generally 1-20 hours and preferably about 2-5 hours.
The reaction from (IX) to (II) can be carried out by treating (IX) with an acid or a base. For example, this reaction can be carried out in an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) or alkali metal hydroxide (e.g. sodium hydroxide, potas¬ sium hydroxide, barium hydroxide, lithium hydroxide, etc.) at a temperature of 0-150°C, preferably 20-50°C. The proper strength of the acid or base is about 1-10 normal, preferably 4-10N. The reaction time, which depends on the reaction temperature, is generally about 1-24 hours and preferably about 2-10 hours. The optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active a ine.
The optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active amine, such as an amino acid (e.g. alanine, valine, leucine, isoleucine, serine, threonine, lysine,
phenylalanine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, methionine, etc.) whose carboxyl function has been esterified with an alkyl or aralkyl group of 1-8 carbon atoms, subjecting the resulting amide to distillation, recrystallization, column chromatography or other procedure to fractionate the desired optical isomer and cleaving the amide linkage to provide the object compound (la).
The amide mentioned above can be synthesized by condensing compound (II) with said amino acid ester using a condensing agent in a solvent, where necessary in the presence of a base. The solvent that can be used includes hydrocarbons such as benzene, toluene, hexane, heptane, etc., halogen-containing solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., ethers such as ethyl ether, tetrahydrofuran, dioxane, etc., acetonitrile, dimethylformamide and so on. The base may for example be triethylamine, 4-dimethylaminopyridine, triethylenediamine, or tetramethylethylenediamine. The condensing agent includes those used in peptide synthesis, such as dicyclohexylcarbodiimide, diethyl cyanophosphonate, l-ethyl-3-(3- dimethylaminopropyl)carbodiimide and so on. Relative to each mole of compound (II), the amino acid ester is used generally in a proportion of 0.5-2 molar equivalents, preferably 1-1.2 molar equivalents, and the condensing agent is used in a proportion of 0.5-5 molar equivalents, preferably 1-2 molar equivalents. The reaction temperature is 0-100°C and preferably 20- 50°C. The reaction time is 0.5-24 hours and preferably about 1-5 hours.
Cleavage of the amide linkage can be carried out in a solvent, such as water, methanol, ethanol, propanol, butanol, etc., in the presence of an alkali metal hydroxide (e.g. sodium hydroxide, potassium
hydroxide, barium hydroxide, lithium hydroxide, etc.), sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, etc., or in the presence of a mineral acid (e.g. nitric acid, hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, etc.) at a temperature of 10-150°C, preferably 10-50°C. The reaction time which depends on the reaction temperature is generally 1-24 hours and preferably about 2-10 hours. Also, the optical resolution of compound (II) can be carried out by reacting compound (II) with an optically active amine (e.g. quinine, cinchonidine, brucine, dehydroabiethy1amine, nicotine, etc.) and subjecting the resulting salt to fractional crystallization to provide the object compound (la). As an alternative, compound (la) can be produced after optical resolution of compound (VII) or (VIII). Among the compounds of formula (I), the compound of formula (lb)
wherein X' represents a metal ion and the other symbols have the same meanings as defined hereinbefore, can be produced by dissolving compound (la) and an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, etc.) in equimolar proportions in an alcoholic solvent such as methanol, ethanol, propanol or butanol.
While the compound (I) of this invention has squalene synthase inhibitory activity, some species have activity to inhibit other enzymes, as well, in the
cholesterol biosynthesis pathway. In any event, the compound (I) of this invention inhibits the biosynthesis of cholesterol and is, therefore, useful for the prevention and therapy of hypercholesterolemia and coronary atherosclerosis in mammalian animals (e.g. mouse, rat, rabbit, dog, cat, bovine, swine, man, etc. ) .
For use of the compound in man, it can be admin¬ istered orally or by other routes. The composition for oral administration includes solid and liquid dosage forms such as tablets (inclusive of dragees, film- coated tablets, etc.), pills, granules, powders, capsules (inclusive of soft capsules), syrups, emulsions, suspensions, and so on. These compositions can be manufactured by per se known procedures and generally contain some carrier or vehicle which is conventionally used in the pharmaceutical field. Taking the carrier for tablet use as an example, lactose, starch, sucrose, magnesium stearate, etc. can be mentioned.
Typical compositions for administration by other routes are injections and suppositors. The former includes subcutaneous, intradermal and intramuscular injections, among others. Such injections can be manufactured by suspending or emulsifying the compound of this invention in a sterile aqueous or oily vehicle which is conventionally used. The aqueous vehicle for injection includes physiological saline or other isotonic solution and may contain a suitable suspending agent such as carboxymethylcellulose sodium, a nonionic surfactant or the like. The oily vehicle includes sesame oil and soybean oil as typical examples and may contain a solubilizer such as benzyl benzoate, benzyl alcohol, etc. The injection so prepared is filled in appropriate ampules.
The compound (I) has only a low toxic potential
which provides for safe use. While the daily dosage is dependent on the patient's clinical condition and body weight, species of the compound, route of admin¬ istration, etc., the recommended daily dose as an anti- hypercholesterolemic agent for an adult is about 1-500 mg, preferably about 10-200 mg, for an oral regimen and about 0.1-100 mg, preferably about 1-20 mg, for administration by other routes (e.g. in the case of an injection or a suppository) . Within the above- mentioned dose range, no toxic reactions have been observed.
Furthermore, the compound (I) has a broad antimicrobial spectrum as assayed by the broth or agar dilution assay. For use of compound (I) as a therapeutic agent for mycotic diseases (e.g. in man), the effective daily dose for an adult is about 0.1-100 mg, preferably about 1-50 mg, for oral administration and about 0.1-100 mg, preferably 1-50 mg for administration by other routes (e.g. in the case of an injection or a suppository). For the treatment of mycotic infection, the unit dose of 2-5 mg/kg can be generally employed. Examples
The following examples, formulation examples and test examples are now presented to illustrate this invention in further detail and should by no means be construed as defining the scope of the invention. Example 1 (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (I) and (3R,5S)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid
(II)
(1) N-[ (3S,5R)-7-chloro-5-(2-methoxyphenyl)-l- neopentyl-2-oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine tert-butyl ester and N-[3R,5S)-7-
chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetyl]-L-alanine tert- butyl ester
Trans-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (3.0 g) and L-alanine tert-butyl ester hydrochloride (1.51 g) were dissolved in dimethylformamide (20 ml), and after the solution was cooled to 0°C, diethyl cyanophosphonate (1.43 g) and triethylamine (2.42 ml) were added. The mixture was stirred at room temperature for 30 minutes, after which it was diluted with water and extracted with ethyl acetate (50 ml). The extract was washed with 1N-HC1 (20 ml x 2) and a saturated aqueous solution of sodium hydrogen carbonate (20 ml x 2) and dried over anhydrous magnesium sulfate. The solvent was then removed and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate = 3:1 - 1:1). As a result, 1.55 g of N-[ (3S,5R)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4, l-benzoxazepine-3-acetyl]-L- alanine tert-butyl ester was obtained as a first eluate. Colorless crystals (m.p. 94-97°C). Elemental analysis for C3oH39ClN206 Calcd.: C, 64.55; H, 7.03; N, 5.01 Found : C, 64.05; H, 7.27; N, 4.72
In addition, 1.8 g of N-[ (3R,5S)-7-chloro-5-(2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetyl]-L-alanine tert-butyl ester was obtained as a second eluate. An oil. H-NMR (CDC13) δ: 0.93 (9H, s), 1.35 (3H, d, J=7.0
Hz), 1.45 (9H, s), 2.69 (1H, dd, J=14.6, 5.7 Hz), 2.87 (1H, dd, J=14.4, 7.2 Hz), 3.34 (1H, d, J=14.0 Hz), 3.62 (3H, s), 4.3-4.5 (2H, m) , 4.49 (1H, d, J=14.0 Hz), 6.27 (1H, s), 6.3-6.4 (1H, brd) , 6.6- 6.7 (1H, m), 6.8-7.7 (6H, m)
(2) N-[ (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-l-
neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine
N-[ (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-1-neo- pentyl-2-oxo-l,2 ,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine tert-butyl ester (1.4 g) as obtained in (1) was dissolved in 4N-HC1 in dioxane (20 ml) and the solution was stirred at room temperature for 5 hours . The reaction mixture was then diluted with water (50 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off to provide N-[ (3S,5R)-7-chloro-5-(2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetyl]-L-alanine (1.20 g) as an amorphous solid.
^-NMR (CDC13) δ: 0.93 (9H, s), 1.44 (3H, d, J=7.2
Hz), 2.71 (1H, dd, J=14.4, 5.5 Hz), 2.93 (1H, dd, J=14.4, 7.6 Hz), 3.35 (1H, d, J=13.9 Hz), 3.63 (3H, s), 4.3-4.4 (1H, m) , 4.4-4.6 (2H, m) , 6.27 (1H, s), 6.63 (1H, d, J=1.9 Hz), 6.71 (1H, brd,
J=6.8 Hz), 6.8-7.7 (6H, m) Elemental analysis for C26H31ClN2θ6 Calcd.: C, 62.09; H, 6.21; N, 5.57 Found : C, 62.38; H, 6.51; N, 5.34 (3) N-[ (3R,5S)-7-Chloro-5-(2-methoxyphenyl)-l-neo- pentyl-2-oxo-l , 2,3, 5-tetrahydro-4 , l-benzoxazepine-3- acetyl ] -L-alanine
N-[ (3R,5S)-7-Chloro-5-(2-methoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine tert-butyl ester (1.8 g) as obtained in (1) was treated in the same manner as (2) to provide N-[ (3R,5S)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetyl]-L- alanine (1.35 g) as an amorphous solid. :H-NMR (CDCI3) δ: 0.93 (9H, s), 1.43 (3H, d, J=7.2
Hz), 2.73 (1H, dd, J=14.6, 5.8 Hz), 2.89 (1H, dd.
J=14.6, 5.8 Hz), 3.35 (1H, d, J=14.0 Hz), 3.63 (3H, s), 4.38 (1H, t, J=7.4 Hz), 4.45-4.6 (2H, m) , 6.28 (1H, s), 6.55 (1H, brd, J=6.8 Hz), 6.64 (1H, d, J=2.0 Hz), 6.8-7.7 (6H, ) Elemental analysis for C26H31ClN2θ6
Calcd.: C, 62.09; H, 6.21; N, 5.57 Found : C, 61.96; H, 6.23; N, 5.38 (4) (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (I)
N-[ (3S,5R)-7-Chloro-5-(2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine (1.0 g) as obtained in (2) was dissolved in methanol (10 ml) followed by addition of concentrated hydrochloric acid (10 ml) and the mixture was refluxed for 24 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate (50 ml). The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was dissolved in dimethylformamide (20 ml) followed by addition of methyl iodide (0.19 ml) and potossium carbonate (0.55 g) and the mixture was stirred at room temperature for 1 hour. This reaction mixture was diluted with water and extracted with ethyl acetate (50 ml). The extract was washed with IN-hydrochloric acid (20 ml x 2) and a saturated aqueous solution of sodium hydrogen carbonate (20 ml x 2) and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 3:1) to provide methyl (3S,5R)- 7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetate (0.51 g) . This compound was dissolved in a mixture of water (10 ml) and methanol (10 ml) followed by addition of potassium carbonate (0.32 g) and the mixture was refluxed for 2.5
hours . The reaction mixture was then acidified with 1N-HC1 (20 ml) and extracted with ethyl acetate (50 ml). The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 2:1- dichloromethane:methanol = 2:1) to provide 0.46 g of (3S,5R)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid as colorless crystals (m.p. 179-183°C) .
[ ]D 25 + 248.7° (c=0.45, MeOH)
Elemental analysis for C23H26C1N0S»H20
Calcd.: C, 61.40; H, 6.27; N, 3.11
Found : C, 61.12; H, 5.99; N, 3.28 (5) (3R,5S)-7-Chloro-5-(2-methoxyphenyl)-l-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (II)
N-[ (3R,5S)-7-Chloro-5-(2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine (1.0 g) as obtained in (3) was subjected to the same procedure as (4) to provide 0.32 g of (3R,5S)-7-chloro-5-(2-methoxyphenyl)-l-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid as colorless crystals (m.p. 176-180°C) . [α]D 25 " 246.2° (c=0.42, MeOH)
Elemental analysis for C23H26C1N05«1.5H20 Calcd.: C, 60.19; H, 6.37; N, 3.05 Found : C, 60.05; H, 5.88; N, 3.22 Example 2 (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (I) and (3R,5S)-7-chloro-5-(2,3-dimethoxy- phenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1- benzoxazepine-3-acetic acid (II) Using trans-7-chloro-5-(2,3-dimethoxyphenyl)-l- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-
acetic acid, the title compound was sythesized in the same manner as Example 1.
(1) N-[ (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-1- neopentyl-2-oxo-l ,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine tert-butyl ester
Colorless crystals (m.p.: 120-122°C) Elemental analysis for C31HA1ClN2O7«0.5H2O
Calcd.: C, 62.25; H, 7.08; N, 4.68
Found : C, 62.45; H, 6.89; N, 4.68 (2) N-[(3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-l- neopentyl-2-oxo-l , 2,3, 5-tetrahydro-4 , l-benzoxazepine-3- acetyl] -L-alanine tert-butyl ester Colorless crystals (m.p.: 136-137°C) Elemental analysis for C31H41ClN2O7»0.8H20 Calcd.: C, 61.69; H, 7.11; N, 4.64
Found : C, 61.60; H, 7.45; N, 4.58
(3) N-[ (3S,5R)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine Colorless crystals (m.p.: 182-185°C) Elemental analysis for C27H33C1N207 Calcd.: C, 60.84; H, 6.24; N, 5.26 Found : C, 60.78; H, 6.09; N, 4.99
(4) N-[ (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-alanine
Colorless crystals (m.p.: 137-140°C) Elemental analysis for C27H33ClN2O7»0.3C6Hlή»0.3H20 Calcd.: C, 61.11; H, 6.77; N, 4.95 Found : C, 61.21; H, 6.91; N, 5.05
( 5 ) ( 3S , 5R) -7-Chloro-5- ( 2 , 3-dimethoxyphenyl ) -1- neopentyl-2-oxo-l , 2,3, 5-tetrahydro-4 , l-benzoxazepine-3- acetic acid (I)
Colorless crystals (m.p.: 227-230°C) [α]D 25 + 242.7° (c=0.41, MeOH)
Elemental analysis for C24H28ClNO6»0.5H20
Calcd.: C, 61.21; H, 6.21; N, 2.97 Found : C, 61.20; H, 6.07; N, 2.91 (6) (3R,5S)-7-Chloro-5-(2,3-dimethoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (II)
Colorless crystals (m. p . : 218-222 °C ) [α]D 25 - 246 . 8 ° ( c=0 . 43 , MeOH) Elemental analysis for C2AH28ClNO6» 0 . 75H2O Calcd . : C, 60 . 63 ; H, 6 . 25 ; N, 2 . 95 Found : C, 60 .58 ; H, 6 . 05 ; N, 2 . 95
Example 3
(3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2- oxo-1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (I) and (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-l- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (II)
(1) N-[ (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro- ,l-benzoxazepine-3- acetyl]-L-leucine methyl ester and N-[ (3R,5S)-7-chloro- 5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetyl]-L-leucine methyl ester
Trans-7-chloro-5-(2 ,4-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (11.0 g) and L-leucine methyl ester hydrochloride (5.2 g) were dissolved in dimethylformamide (50 ml) . The solution was cooled to 0°C and diethyl cyanophosphonate (4.9 g) and triethylamine (8.3 ml) were added. The mixture was stirred at room temperature for 30 minutes, after which it was diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract was washed with IN-hydrochloric acid (100 ml x 2) and a saturated aqueous solution of sodium hydrogen carbonate (100 ml x 2) and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the residue was
purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 2:1-1:1). As a first eluate, 6.7 g of N-[ (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-l- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-leucine methyl ester was obtained as colorless crystals (m.p. 93-96°C). Elemental analysis for C31HA1ClN2O7»0.5H20 Calcd.: C, 62.25; H, 7.08; N, 4.68 Found : C, 62.38; H, 7.42; N, 4.43 As a second eluate, 6.5 g of N-[ (3S,5R)-7-chloro- 5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetyl]-L-leucine methyl ester was obtained as oil.
^-NMR (CDC13) δ: 0.8-1.1 (15H, m) , 1.5-1.75 (1H, m) , 2.70 (1H, dd, J=14.4, 6.0 Hz), 2.88 (1H, dd,
J=14.4, 6.6 Hz), 3.35 (1H, d, J=14.0 Hz), 3.60 (3H, s), 3.71 (3H, s), 3.86 (3H, s), 4.33 (1H, t, J=6.2 Hz), 4.51 (1H, d, J=14.0 Hz), 4.5-4.7 (1H, m), 6.21 (1H, m), 6.45-6.7 (4H, ) , 7.2-7.6 (3H, m) .
(2) (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (I)
N-[ (3S,5R)-7-Chloro-5-(2,4-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetyl]-L-leucine methyl ester (1.0 g) as obtained in (1) was dissolved in methanol (20 ml) followed by addition of concentrated sulfuric acid (4 ml) and the mixture was refluxed for 24 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate (50 ml) . The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 5:1) to provide methyl (3S,5R)- 7-chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-
1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetate (0.22 g) . This compound was dissolved in a mixture of water (10 ml), methanol (10 ml) and tetrahydrofuran (5 ml) followed by addition of potassium carbonate (0.13 g) and the mixture was refluxed for 2 hours. The reaction mixture was then acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium suflate and the solvent was distilled off to provide 0.20 g of (3S,5R)-7- chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo- l , 2 , 3 , 5-tetrahydro-4 , l-benzoxazepine-3-acetic acid as colorless crystals (m.p . 233-234 °C ) . [α]D 22 + 228. 1° ( c=0 .51 , MeOH) Elemental analysis for C2AH28C1N06 Calcd.: C, 62.40; H, 6.11; N, 3.03 Found : C, 62.28; H, 6.41; N, 2.89 (3) (3R,5S)-7-Chloro-5-(2,4-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (II) Using N-[ (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)- l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetyl]-L-leucine methyl ester (6.0 g) as obtained in (1) , the procedure of (2) was otherwise repeated to provide 0.7 g of (3R,5S)-7-chloro-5-(2,4- dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetic acid as colorless crystals (m.p. 234-235°C). [ ]D 25 - 232.5° (c=0.41, MeOH) Elemental analysis for C24H28C1N06 Calcd.: C, 62.40; H, 6.11; N, 3.03 Found : C, 62.39; H, 6.20; N, 2.81 Example 4
Sodium (3R,5S)-7-chloro-5-(2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetate
(3R,5S)-7-Chloro-5-(2-methoxyphenyl)-1-neopentyl-
2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid (12 g) as obtained in Example 1 was suspended in methanol (250 ml) and dissolved by adding IN-aqueous sodium hydroxide (27.7 ml). After the solvent was distilled off under reduced pressure, ethyl acetate
(200 ml) was added to the residue and the solvent was distilled off under reduced pressure. This procedure was performed a second time and the resulting crystals were treated with ethyl acetate and filtered to provide 11.8 g of sodium (3R,5S)-7-chloro-5-(2-methoxyphenyl)- l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetate as colorless crystals (m.p. >300°C) . [α]D 22 - 263.6° (c=0.64, MeOH) Elemental analysis for C23H25ClNO5Na»0.75H20 Calcd.: C, 59.10; H, 5.71; N, 3.00 Found : C, 59.27; H, 5.97; N, 2.75 Example 5
Sodium (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4 ,l-benzoxazepine-3- acetate
Using (3R,5S)-7-chloro-5-(2,3-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (30 g) , the procedure of Example 4 was otherwise repeated to provide 31.9 g of sodium (3R,5S)- 7-chloro-5-(2,3-dimethoxyphenyl)-1-neopentyl-2-oxo- 1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetate as colorless crystals (m.p. >300°C) . [α]D 23 - 235.1° (c=0.60, MeOH) Elemental analysis for C24H27ClN06Na»1.5HzO Calcd.: C, 56.42; H, 5.92; N, 2.74 Found : C, 56.49; H, 6.02; N, 2.75 Example 6
Sodium (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetate
Using (3R,5S)-7-chloro-5-(2,4-dimethoxyphenyl)-1-
neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (24 g), the procedure of Example 4 was otherwise repeated to provide 24.7 g of sodium (3R,5S)- 7-chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo- 1,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetate as colorless crystals (m.p. >300°C) . [ ]D 23 - 231.1° (c=0.70, MeOH) Elemental analysis for C24H27ClNO6Na»0.75H20 Calcd.: C, 57.95; H, 5.78; N, 2.82 Found : C, 57.86; H, 6.08; N, 2.81 Example 7
Trans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid (1) 2-Amino-4'-benzyloxy-5-chloro-2 '-methoxy- benzophenone
A mixture of 4-bromo-3-methoxyphenol (21 g) , benzyl bromide (13.5 ml), potassium carbonate (21.4 g) and acetone (200 ml) was stirred at room temperature for 24 hours. The insoluble matter was then filtered off and the filtrate was distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 20:1) to provide 4-benzyloxy-2-methoxybromobenzene (25 g) as colorless oil.
XH-NMR (CDC13) δ: 3.85 (3H, s), 5.04 (2H, s), 5.04 (2H, s), 6.47 (1H, dd, J=8.6, 2.6 Hz), 6.57 (1H, d, J=2.6 Hz), 7.3-7.5 (8H, m) .
Starting with this compound, the process described in L. H. Sternbach et al. : J. Org. Chem. , 2 _, 378, 1962 was followed to provide 20.4 g of 2-amino-4'-benzyloxy- 5-chloro-2 '-methoxybenzophenone as light-yellow crystals (m.p. 97-98°C) . Elemental analysis for C21H18C1N03 Calcd.: C, 68.57; H, 4.93; N, 3.81 Found : C, 68.62; H, 5.09; N, 3.65
(2) 2-Amino- -(4-benzyloxy-2-methoxyphenyl)-5-chloro- benzyl alcohol
2-Amino-4'-benzyloxy-5-chloro-2'-methoxy- benzophenone (10 g) was dissolved in methanol (100 ml) followd by addition of sodium borohydride (1.4 g) and the mixture was stirred for 24 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water (200 ml) and extracted with ethyl acetate (300 ml). The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 4:1-2:1) to provide 9.5 g of 2-amino-α-(4-benzyloxy-2- methoxyphenyl)-5-chlorobenzyl alcohol as colorless crystals (m.p. 101-103°C) . Elemental analysis for C2ιH20ClNO3 Calcd.: C, 68.20; H, 5.41; N, 3.79 Found : C, 67.97; H, 5.42; N, 3.58 (3) α-(4-Benzyloxy-2-methoxyphenyl)-2-neopentylamino- 5-chlorobenzyl alcohol
A mixture of 2-amino-α-(4-benzyloxy-2- methoxyphenyl)-5-chlorobenzyl alcohol (9.5 g) , pivalaldehyde (3.35 ml), acetic acid (1.85 g) and ethanol (200 ml) was stirred at room temperature for 30 minutes. Then, sodium cyanoborohydride (2.33 g) was added and the mixture was stirred for 24 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water (200 ml) and extracted with ethyl acetate (200 ml) . The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 5:1) to provide -(4-benzyloxy-2-methoxyphenyl)-2- neopentylamino-5-chlorobenzyl alcohol (10 g) as
colorless oil.
^-NMR (CDCI3) δ: 0.91 (9H, s), 2.82 (2H, s), 3.10 (1H, br), 3.85 (3H, s), 4.75 (1H, br) , 5.06 (2H, s), 5.94 (1H, s), 6.45-6.7 (3H, m) , 6.95-7.5 (7H, m) (4) Ethyl 3-[N-[4-chloro-2-(4-benzyloxy- -hydroxy-2- methoxybenzyl)phenyl]-N-neopentylcarbamoyl]acrylate -(4-Benzyloxy-2-methoxyphenyl)-2-neopentylamino- 5-chlorobenzyl alcohol (10 g) in dichloromethane (200 ml) was added sodium hydrogen carbonate (6.3 g) and while the mixture was stirred, fumaric acid monochloride monoethyl ester (4.43 g) was added dropwise. The mixture was stirred at room temperature for 30 minutes. This reaction mixture was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent, hexane:ethyl acetate = 5:1-2:1) to provide ethyl 3-[N-[4-chloro-2-(4-benzyloxy-α- hydroxy-2-methoxybenzyl)phenyl]-N-neopentylcarbamoyl]- acrylate (12 g) as colorless oil.
:H-NMR (CDCI3) δ: 0.7-1.0 (9H, m) , 1.1-1.3 (3H, m) ,
2.5-3.15 (2H, m), 3.69, 3.77 (3H, each s), 3.9-4.5 (3H, m), 4.95, 5.07 (2H, each s), 5.9-6.85 (5H, m) , 6.95-7.9 (10H, m) (5) Ethyl trans-7-chloro-5-(4-benzyloxy-2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4, l-benzoxazepine-3-acetate
To a solution of ethyl 3-[N-[4-chloro-2-(4- benzyloxy-α-hydroxy-2-methoxybenzyl)phenyl]-N- neopentylcarbamoyl]acrylate (12 g) in ethanol (150 ml) was added potassium carbonate (5.9 g) and the mixture was stirred for 24 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water (200 ml) and extracted with ethyl acetate (200 ml) . The extract was washed with water and dried over anhydrous magnesium sulfate and
the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane:ethyl acetate = 3:1) to provide 9.8 g of ethyl trans-7-chloro-5-(4-benzyloxy-2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro-
4,l-benzoxazepine-3-acetate as colorless crystals (m.p. 130-131°C) .
Elemental analysis for C32H36C1N06 Calcd.: C, 67.90; H, 6.41; N, 2.47 Found : C, 67.73; H, 6.35; N, 2.33
(6) Ethyl trans-7-chloro-5-(4-hydroxy-2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxyazepine-3-acetate
In ethyl acetate (150 ml) was dissolved ethyl trans-7-chloro-5-(4-benzyloxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxyazepine- 3-acetate (7.0 g) followed by addition of 1N-HC1 (0.1 ml) and 10% palladium-on-carbon (50% hydrous, 1.0 g) and the catalytic reduction reaction was carried out at room temperature under atmospheric pressure. After a stoichiometric amount of hydrogen had been absorbed, the palladium-on-carbon was filtered off and the filtrate was distilled under reduced pressure to recover 5.6 g of ethyl trans-7-chloro-5-(4-hydroxy-2- methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-
4,l-benzoxazepine-3-acetate as colorless crystals (m.p. 197-199°C) .
Elemental analysis for C25H30C1N06 Calcd.: C, 63.09; H, 6.35; N, 2.94 Found : C, 62.97; H, 6.57; N, 2.81
(7) Ethyl trans-7-chloro-5-(4-ethoxy-2-methoxyphenyl)- 1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetate
A mixture of ethyl trans-7-chloro-5-(4-hydroxy-2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetate (0.25 g) , ethyl iodide
(0.06 ml), potassium carbonate (0.15 g) and N,N- dimethylformamide (20 ml) was stirred at room temperature for 3 hours . The reaction mixture was then diluted with water (50 ml) and extracted with ethyl acetate (100 ml). The extract was washed with 1N-HC1 (30 ml x 2) and a saturated aqueous solution of sodium hydrogen carbonate and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to provide 0.24 g of ethyl trans-7- chloro-5-(4-ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo- 1,2,3,5-tetrahydro-4, l-benzoxazepine-3-acetate as colorless crystals (m.p. 164-166°C) . Elemental analysis for C27H34C1N06 Calcd.: C, 64.34; H, 6.80; N, 2.78 Found : C, 64.18; H, 6.70; N, 2.74
(8) trans-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1-neo- pentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid
A mixture of ethyl trans-7-chloro-5-(4-ethoxy-2- methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetate (0.18 g) , potassium carbonate (0.1 g) , methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was refluxed for 1.5 hours. The reaction mixture was then concentrated under reduced pressure, 1N-HC1 (50 ml) was added, and the mixture was extracted with ethyl acetate (50 ml). The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to provide 0.15 g of trans-7- chloro-5-(4-ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid as colorless crystals (m.p. 230-232°C) . Elemental analysis for C25H30ClNO6 Calcd.: C, 63.09; H, 6.35; N, 2.94 Found : C, 62.92; H, 6.60; N, 3.01 Example 8
(3R,5S)-7-Chloro-5-(4-ethoxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetic acid
In the same manner as Example 1, trans-7-chloro-5- (4-ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid (2.2 g) was reacted with L-alanine tert-butyl ester and the reaction product purified by silica gel column chromatography to provide N-[ (3S,5R)-7-chloro-5-(4- ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetyl]-L-alanine tert- butyl ester (1.0 g) and N-[ (3R,5S)-7-chloro-5-(4- ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetyl]-L-alanine tert- butyl ester (1.1 g).
Repeating the procedure described in Example 1 (2) , N-[ (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)- l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetyl]-L-alanine tert-butyl ester (0.8 g) was reacted to provide 0.33 g of (3R,5S)-7-chloro-5-(4- ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid as colorless crystals (m.p. 162-165°C) . Elemental analysis for C25H30C1N06 Calcd.: C, 63.09; H, 6.35; N, 2.94 Found : C, 62.87; H, 6.23; N, 2.66 [α]D 23 - 212.0° (c=0.94, MeOH) Example 9 Sodium (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1- neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3- acetate
Using (3R,5S)-7-chloro-5-(4-ethoxy-2- methoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetic acid (3.65), the procedure of Example 4 was repeated to provide 3.54 g of sodium (3R,5S)-7-chloro-5-(4-ethoxy-2-methoxyphenyl)-1-
neopentyl-2-oxo-l,2,3,5-tetrahydro-4,l-penzoxazepine-3- acetate as colorless crystals (230-250°C, decomp.). Elemental analysis for C25H29ClNO6Na«0.7H20 Calcd.: C, 58.81; H, 6.00; N, 2.74 Found : C, 58.91; H, 6.24; N, 2.71 [α]D 23 - 218.8° (c=0.48, MeOH) Reference Example 1
Sodium (3R,5S)-7-chloro-5-(2-chlorophenyl)-1-neopentyl- 2-oxo-l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetate Starting with (3R,5S)-7-chloro-5-(2-chlorophenyl)- l-neopentyl-2-oxo-l,2,3,5-tetrahydro-4,1-benzoxazepine- 3-acetic acid (1.2 g) as described in Example 118 of EP 567026, the procedure of Example 4 was otherwise repeated to provide 1.1 g of sodium (3R,5S)-7-chloro-5- (2-chlorophenyl)-l-neopentyl-2-oxo-l,2,3,5-tetrahydro- 4,l-benzoxazepine-3-acetate as colorless crystals (m.p. >300°C) .
[α]D 22 - 237 . 1 ° ( c=0 . 57 , MeOH) Elemental analysis for C22H22Cl2NO Na»H20 Calcd.: C, 55.47; H, 5.08; N, 2.94 Found : C, 55.41; H, 5.26; N, 2.83 Assay of squalene synthase inhibitory activity
Squalene synthase inhibitory activity is assayed by the following method using the enzyme preparations described in Test Examples 1 and 2.
To a solution containing 5 μM[l-H] farnesyl pyrophosphate (specific activity 25 μCi/mole) , 1 mM NADPH (nicotinamide adenine dinucleotide phosphate, reduced form) , 5mM MgCl2, 6 mM glutathione, 100 mM potassium phosphate buffer (pH 7.4) and the test drug (dissolved in water or DMSO) (total volume: 50 μl) is added the enzyme solution (0.8 μg protein) prepared in Test Example 1 or 2 and the reaction is carried out at 37°C for 45 minutes. The reaction is stopped by adding 150 μl of chloroform-methanol (2:1) followed by addition of 50 μl of chloroform and 50 μl of 3N-sodium
hydroxide solution. The chloroform layer (bottom layer, 50 μl) containing the reaction product composed predominantly of squalene is mixed with 3 ml of toluenic liquid scintillator and its radioactivity was measured using a liquid scintillation counter.
The squalene synthase inhibitory activity was ex¬ pressed in the concentration which caused 50% inhibition of the radioactivity uptake by the chloroform layer [IC50, molar concentration (M) ] . Test Example 1 Preparation of a rat enzyme
A male SD rat (6 weeks old) is bled to death and the liver is enucleated. About 10 g of the heptic tissue was washed with ice-cooled saline and homogenized in 15 ml of ice-cooled buffer [100 mM potassium phosphate buffer (pH 7.4), 15 mM nicotinamide, 2mM MgCl2] and the homogenate was centrifuged at 10000 x g (4°C) for 20 minutes. The supernatant was further centrifuged at 105000 x g (4°C) for 90 minutes and the resultant pellet was suspended in ice-cooled 100 mM potassium phosphate buffer (pH 7.4) and recentrifuged at 105000 x g (4°C) for 90 minutes. The pellet (microsome fraction) was suspended in ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (protein concentration ca. 40 mg/ml, as determined with Pias BCA Protein Assay Kit) to provide an enzyme preparation. Test Example 2 Preparation of a human enzyme
Human hepatocarcinoma cells HepG2 (ca. 1 x 10 cells) grown in Dulbecco's modified Eagle's medium containing 10% fetal calf serum (37°C, 5% C02) were suspended in 10 ml of ice-cooled buffer [100 mM potassium phosphate buffer (pH 7.4), 30 mM nicotinamide, 2.5 mM MgCl2] and disrupted by sonication (30 seconds x 2). From the sonicate, a microsome fraction was separated by the same procedure as described in Test Example 1. This fraction was
suspended in ice-cooled 100 mM potassium phosphate buffer (pH 7.4) (protein ca. 4 mg/ml) to provide an enzyme preparation. The results are shown below.
[Table 1]
Squalene synthase inhibitory activity (in vitro)
Rat enzyme Human hepG2 enzyme IC50 (μM) IC50 (μM)
Example 1 I 43% II 0.026 0.011
Example 2 I 7.7 II 0.017 0.011
Example 3 I 15.8%υ II 0.022 0.0086 Example 8 0.029 0.019
Example 9 0.041 0.022
Reference Example 1 0.067 0.020
1) % Inhibition at IO"5 M
Formulation Examples
The squalene synthase inhibitor composition compris¬ ing the optically active 4,l-benzoxazepin-2-one derivative (I) or its salt as an active ingredient for the therapy of hypercholesterolemia in accordance with this invention can be provided typically in the following formulations and dosage forms. 1. Capsule (1) Compound of Example 5 10 mg (2) Lactose 90 mg
(3) Microcrystalline cellulose 70 mg
(4) Magnesium stearate 10 mg
Each capsule contains 180 mg
The whole amounts of (1), (2) and (3) and one-half
amount of (4) are blended and granulated. To the granula¬ tion is added the balance of (4) and the whole composition is filled in a gelatin capsule. 2. Tablet (1) Compound of Example 5 10 mg
(2) Lactose 35 mg
(3) Corn starch 150 mg
(4) Microcrystalline cellulose 30 mg (4) Magnesium stearate 5 mg Each tablet contains 230 mg
The whole amounts of (1), (2) and (3), 2/3 amount of (4) and 1/2 amount of (5) are blended and granulated. To the granulation is added the remainders of (4) and (5) and the whole composition is compressed into a tablet. 3. Capsule
(1) Compound of Example 9 10 mg
(2) Lactose 90 mg
(3) Microcrystalline cellulose 70 mg
(4) Magnesium stearate 10 mg Each capsule contains 180 mg
The whole amounts of (1), (2) and (3) and one-half amount of (4) are blended and granulated. To the granula¬ tion is added the balance of (4) and the whole composition is filled in a gelatin capsule. 4. Tablets
(1) Compound of Example 9 10 mg
(2) Lactose 35 mg
(3) Corn starch 150 mg
(4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg
Each tablet contains 230 mg
The whole amounts of (1), (2) and (3), 2/3 amount of (4) and 1/2 amount of (5) are blended and granulated. To the granulation are added the remainders of (4) and (5) and the whole composition is compressed into a tablet.
Claims
1. An optically active 4,l-benzoxazepin-2-one derivative of the following formula (I):
2. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 wherein said lower alkyl group is isobutyl or neopentyl.
3. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 wherein said metal ion is sodium ion or potassium ion.
4. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 wherein said halogen is chlorine.
5. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 wherein said lower alkoxy is methoxy or ethoxy.
6. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 which is (3R,5S)-7-chloro-5-
(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
7. The optically active 4,l-benzoxazepin-2-one deriva¬ tive according to claim 1 which is (3R,5S)-7-chloro-5-
(2,4-dimethoxyphenyl)-1-neopentyl-2-oxo-1,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
8. The optically active 4, l-benzoxazepin-2-one deriva¬ tive or salt according to claim 1 which is (3R,5S)-7- chloro-5-(4-ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
9. A squalene synthase inhibitor composition comprising an optically active 4,l-benzoxazepin-2-one derivative of the following formula (I) as an active ingredient.
wherein R: represents a lower alkyl group; X represents a hydrogen atom or a metal ion; ring A represents a phenyl group substituted with halogen; ring B represents a phenyl group substituted with a lower alkoxy.
10. The squalene synthase inhibitor composition according to claim 9 wherein said lower alkyl group is isobutyl or neopentyl.
11. The squalene synthase inhibitor composition according to claim 9 wherein said metal ion is sodium ion or potassium ion.
12. The squalene synthase inhibitor composition according to claim 9 wherein said halogen is chlorine.
13. The squalene synthase inhibitor composition according to claim 9 wherein said lower alkoxy is methoxy or ethoxy.
14. The squalene synthase inhibitor composition according to claim 9 wherein said active ingredient is (3R,5S)-7- chloro-5-(2,3-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
15. The squalene synthase inhibitor composition according to claim 9 wherein said active ingredient is (3R,5S)-7- chloro-5-(2,4-dimethoxyphenyl)-l-neopentyl-2-oxo-l,2,3,5- tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
16. The squalene synthase inhibitor composition according to claim 9 wherein said active ingredient is (3R,5S)-7- chloro-5-(4-ethoxy-2-methoxyphenyl)-l-neopentyl-2-oxo- l,2,3,5-tetrahydro-4,l-benzoxazepine-3-acetic acid or its sodium salt.
17. An antimycotic composition comprising an optically active 4,l-benzoxazepin-2-one derivative of the following formula (I) as an active ingredient.
wherein Rλ represents a lower alkyl group; X represents a hydrogen atom or a metal ion; ring A represents a phenyl group substituted with halogen; ring B represents a phenyl group substituted with a lower alkoxy.
18. A method for the prophylaxis or treatment for hypercholesterolemia or coronary sclerosis in a mammal which comprises administering a pharmaceutical effective amount of the compound claimed in claim 1, to a mammal in need thereof.
19. A method for the prophylaxis or treatment for mycotic diseases in a mammal which comprises administering a pharmaceutical effective amount of the compound claimed in claim 1, to a mammal in need thereof.
20. Use of the compound claimed in claim 1, for the manufacture of a medicament to be used as a prophylactic or therapeutic drug for hypercholesterolemia or coronary sclerosis.
21. Use of the compound claimed in claim 1, for the manufacture of a medicament to be used as a prophylactic or therapeutic drug for mycotic diseases.
22. A method for producing the compound claimed in claim 1 which comprises (i) subjecting a compound of the following formula:
23. The method according to claim 22, which comprises reacting the compound with an optically active amine.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU15898/95A AU1589895A (en) | 1994-02-09 | 1995-02-06 | Optically active 4,1-benzoxazepine derivatives useful as squalene synthase inhibitors |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP1553194 | 1994-02-09 | ||
JP6/15531 | 1994-02-09 |
Publications (1)
Publication Number | Publication Date |
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WO1995021834A1 true WO1995021834A1 (en) | 1995-08-17 |
Family
ID=11891401
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP1995/000148 WO1995021834A1 (en) | 1994-02-09 | 1995-02-06 | Optically active 4,1-benzoxazepine derivatives useful as squalene synthase inhibitors |
Country Status (2)
Country | Link |
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AU (1) | AU1589895A (en) |
WO (1) | WO1995021834A1 (en) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0705607A3 (en) * | 1994-10-07 | 1996-05-08 | Takeda Chemical Industries Ltd | |
EP0710725A1 (en) * | 1994-11-01 | 1996-05-08 | Takeda Chemical Industries, Ltd. | Production of optically active compounds |
WO1997010224A1 (en) * | 1995-09-13 | 1997-03-20 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use as lipid lowering agents |
EP0814080A1 (en) * | 1996-06-20 | 1997-12-29 | Pfizer Inc. | Squalene synthetase inhibitors |
US5726306A (en) * | 1992-04-20 | 1998-03-10 | Takeda Chemical Industries, Ltd. | 4,1-benzoxazepin derivatives and their use |
US6110909A (en) * | 1995-09-13 | 2000-08-29 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use as lipid lowering agents |
WO2003002147A1 (en) * | 2001-06-28 | 2003-01-09 | Takeda Chemical Industries, Ltd. | Preventives/remedies for organ functional disorders and organ dysfunction |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0567026A1 (en) * | 1992-04-20 | 1993-10-27 | Takeda Chemical Industries, Ltd. | 4,1-Benzoxazepin derivatives as squalene synthase inhibitors and their use in the treatment of hypercholesteremia and as fungicides |
-
1995
- 1995-02-06 AU AU15898/95A patent/AU1589895A/en not_active Abandoned
- 1995-02-06 WO PCT/JP1995/000148 patent/WO1995021834A1/en active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0567026A1 (en) * | 1992-04-20 | 1993-10-27 | Takeda Chemical Industries, Ltd. | 4,1-Benzoxazepin derivatives as squalene synthase inhibitors and their use in the treatment of hypercholesteremia and as fungicides |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACTS, vol. 97, no. 15, 11 October 1982, Columbus, Ohio, US; abstract no. 127667f, page 731; * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5885979A (en) * | 1992-04-02 | 1999-03-23 | Takeda Chemical Industries, Ltd. | N-containing condensed heterocyclic compounds, their production, and their uses |
US5726306A (en) * | 1992-04-20 | 1998-03-10 | Takeda Chemical Industries, Ltd. | 4,1-benzoxazepin derivatives and their use |
EP0705607A3 (en) * | 1994-10-07 | 1996-05-08 | Takeda Chemical Industries Ltd | |
EP0710725A1 (en) * | 1994-11-01 | 1996-05-08 | Takeda Chemical Industries, Ltd. | Production of optically active compounds |
US5770438A (en) * | 1994-11-01 | 1998-06-23 | Takeda Chemical Industries, Ltd. | Process for enantioselective hydrolysis of α-(2-amino)-phenyl-benzenemethanol ester type compounds using bacillus, pseudomonas or streptomyces |
WO1997010224A1 (en) * | 1995-09-13 | 1997-03-20 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use as lipid lowering agents |
US6110909A (en) * | 1995-09-13 | 2000-08-29 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use as lipid lowering agents |
EP1097928A1 (en) * | 1995-09-13 | 2001-05-09 | Takeda Chemical Industries, Ltd. | 5-(2,3-Dialkoxyphenyl)-4,1-benzoxazepin-2-ones as anti-hyperlipidemics |
CN1072649C (en) * | 1995-09-13 | 2001-10-10 | 武田药品工业株式会社 | Benzoxazepine compounds, their production method and use |
US6613761B1 (en) | 1995-09-13 | 2003-09-02 | Takeda Chemical Industries, Ltd. | Benzoxazepine compounds, their production and use |
EP0814080A1 (en) * | 1996-06-20 | 1997-12-29 | Pfizer Inc. | Squalene synthetase inhibitors |
WO2003002147A1 (en) * | 2001-06-28 | 2003-01-09 | Takeda Chemical Industries, Ltd. | Preventives/remedies for organ functional disorders and organ dysfunction |
Also Published As
Publication number | Publication date |
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AU1589895A (en) | 1995-08-29 |
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