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WO1997032837A1 - Derives estrogenes non steroidiens - Google Patents

Derives estrogenes non steroidiens Download PDF

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Publication number
WO1997032837A1
WO1997032837A1 PCT/JP1997/000600 JP9700600W WO9732837A1 WO 1997032837 A1 WO1997032837 A1 WO 1997032837A1 JP 9700600 W JP9700600 W JP 9700600W WO 9732837 A1 WO9732837 A1 WO 9732837A1
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WIPO (PCT)
Prior art keywords
methyl
hydroxy
reference example
ppm
acid
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PCT/JP1997/000600
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English (en)
Japanese (ja)
Inventor
Michihiro Yamamoto
Hiroyuki Nakahira
Shoji Watanabe
Takashi Katsumata
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Sumitomo Pharmaceuticals Co., Ltd.
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Publication of WO1997032837A1 publication Critical patent/WO1997032837A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a novel non-speroidal compound having estrogenic activity and Z or antiestrogenic activity, and a pharmaceutically acceptable salt thereof.
  • Estrogen is a steroidal or non-speroidal estrus hormone, and many substances are known not only in nature but also synthetically (Env ⁇ ro nmental Health Therapeutics, Nos. 61, 97). ⁇ 110 pages (1 985)).
  • Naturally occurring estrogen in humans is 17-estradiol, mainly produced by the ovaries, which develops female secondary sexual characteristics, endometrial growth, regulates sexual function, regulates bone metabolism, It plays an important role in regulating lipid metabolism.
  • estrogen deficiency in the body can lead to certain medical conditions, such as menopause-related autonomic imbalance, lipid metabolism disorders and vasomotor disorders, menopause, Atrophic vaginitis, sexual dysfunction, osteoporosis, etc. are caused, and estrogen replacement therapy is administered for these.
  • menopause-related autonomic imbalance lipid metabolism disorders and vasomotor disorders
  • menopause menopause
  • Atrophic vaginitis sexual dysfunction
  • osteoporosis etc.
  • Estrogens have also been used in combination with other female hormones, such as progesterone, which promote gonadotropin suppression and are used as oral contraceptives. You.
  • estrogen can cause side effects such as breast pain, irregular genital bleeding, obesity, endometrial hyperplasia, endometrial and breast cancer, myocardial infarction, thromboembolism, and cerebrovascular disease.
  • a drug showing a more selective estrogenic effect is desired.
  • antiestrogen an estrogen receptor antagonist
  • Tamoxifen, a Lloyd antiestrogen has widespread clinical application.
  • antiestrogen includes a compound which expresses an estrogen action (agonist action) in a tissue-specific manner.
  • raloxifene like estrogen, suppresses postmenopausal bone loss, but has a very low uterine stimulatory effect (Internal Medicine, Vol. 76, pp. 939-942 (1959)).
  • most of the estrogen and antiestrogen known so far have a phenolic or alcoholic hydroxyl group at a position similar to 17 estradiol in terms of chemical structure, but slightly It has been described that certain types of ribonucleic acid conductors have estrogenic activity, such as doisynolicacid and methanolic acid (meSteroid Biochem. Vol. 31, 393-404 (1 988) and Bui in Soc. Chim. Fr., 71 1-718 (1 960)).
  • the present invention relates to a therapeutically useful and novel non-speroidal peptide having an estrogen activity and / or an anti-estrogen activity and exhibiting a tissue-selective agonist or antagonist action against various estrogen-dependent diseases. It is an object to provide a trogen derivative. Means for solving the problem
  • the present inventors have conducted intensive studies to find a novel carboxylic acid derivative having estrogenic activity in order to solve the above-mentioned problems.
  • a novel carboxylic acid derivative represented by the following general formula (I) The present inventors have found that a group of compounds exhibit not only strong estrogenic activity but also strong anti-estrogenic activity and remarkably restore bone mineral density in ovariectomized rats, thereby completing the present invention. That is, the present invention
  • R ° represents a hydrogen atom or a hydroxyl-protecting group.
  • R 1 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, a hydroxyl group or a protected hydroxyl group.
  • R 2 is a hydrogen atom or a formula (CH 2 ) k — X—R 3 (where k is an integer of 0 to “! 0, X is a single bond, formula 1 O—, 1 S—, 1 SO —, One S0 2 —
  • R 4 represents a hydrogen atom or an alkyl group having from 6 to 6 carbon atoms
  • R 3 represents the number of carbon atoms which may have a substituent.
  • R 4 represents a hydrogen atom or an alkyl group having from 6 to 6 carbon atoms
  • R 3 represents the number of carbon atoms which may have a substituent.
  • R 4 represents a hydrogen atom or an alkyl group having from 6 to 6 carbon atoms
  • R 3 represents the number of carbon atoms which may have a substituent.
  • a solid line with a dashed line indicates a single bond or a double bond, and R 1 Q is absent when the bond between carbon and carbon in each of R 2 and R 1Q is a double bond.
  • A-E is a single bond
  • A is a methylene group, an oxygen atom or Represents a single bond
  • E is wherein one GR 7 - (wherein, G represents a methine group or a nitrogen atom, the R 7 represent the same meaning as R 2 above), the formula one CR 8 R 9 i (wherein, R 8 and R 9 represent an alkyl group having 1 to 6 carbon atoms which may be the same or different) or one CO—, but when A is a single bond and R 2 is not a hydrogen atom, , E may represent an oxygen atom or a sulfur atom,
  • R 1 °, R 1 'and R 12 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a haloalkyl group having 1 to 6 carbon atoms, but R''and R 12 are simultaneously hydrogen atoms It cannot be an atom.
  • Z is a carboxyl group, carbamoyl group, hydroxyamino carbonyl group
  • R 2 , R 7 , R "and R 12 represent the same meaning as in [1]
  • R 13 represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • X is a single bond, one O— or one CO—
  • R 3 is an alkyl group having 10 to 10 carbon atoms, an alkenyl group having 3 to 10 carbon atoms, and a cycle having 3 to 7 carbon atoms. Mouth alkyl group or formula
  • Y is a carboxyl group, an alkoxycarbonyl group having 2 to 7 carbon atoms or a formula NR 5 R 6 (wherein, R 5 and R 6 represents an alkyl group having 1 to 6 carbon atoms which may be the same or different, and R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group. Which can be formed)
  • Y is a group represented by the formula NR 5a R 6a (wherein, R 5a and represents an alkyl group having 1 to 6 carbon atoms which may be the same or different), a pyrrolidino group, a pyridino group or a morpholino group [7]
  • R 5a represents an alkyl group having 1 to 6 carbon atoms which may be the same or different
  • a pyrrolidino group a pyridino group or a morpholino group
  • R ′, R 2 , R ′′, R 12 , E and Z have the same meanings as in claim 1] or a geometrical isomer relating to a double bond. Or a pharmaceutically acceptable salt thereof,
  • E is a group represented by the formula: NR 7 — (wherein R 7 has the same meaning as [1]).
  • the body, or a pharmaceutically acceptable salt thereof, is a group represented by the formula: NR 7 — (wherein R 7 has the same meaning as [1]).
  • E is -O- or 1S-
  • R 2 is a group represented by the formula (CH 2 ) k- XR 3 (where k, X, and R 3 have the same meanings as [1].
  • the compound according to [9], which is a group represented by the following formula: ⁇ > is a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof;
  • a pharmaceutical comprising the compound according to [1] or a geometric isomer relating to a double bond, or a pharmaceutically acceptable salt thereof,
  • examples of the alkyl group having 1 to 6 carbon atoms include a linear or branched alkyl group, and specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, Monomethylpropyl, 2-methylpropyl, pentyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl pill, 1-methylbutyl, 3-methylbutyl, 2-ethylbutyl, hexyl, 2-methylpentyl, 4-methylpentyl And the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • Examples of the alkyl group having 1 to 10 carbon atoms for R 3 include a linear or branched alkyl group.
  • Examples include 1-ethylpentyl, 1-methylheptyl, octyl, 1,5-dimethylhexyl, 2-ethylhexyl, nonyl, and decyl.
  • alkenyl group having 3 to 10 carbon atoms for R 3 examples include a straight-chain or branched-chain alkenyl group, specifically, 2-probenyl, 2-butenyl, 3-butenyl, and 2-methyl- 2-Propenyl, 2-pentenyl, 4-dipenyl, 3-methyl-1-butenyl, 2-hexenyl, 3-heptenyl, 1-ethyl-3-pentenyl, 1-methyl-2-d And p-thenyl, 4-octenyl, 1,5-dimethylhexenyl, 2-ethylhexenyl, 7-nonenyl, 5-decenyl and the like.
  • cycloalkyl group having 3 to 7 carbon atoms for R 3 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • haloalkyl group having 1 to 6 carbon atoms examples include a linear or branched alkyl group substituted with 1 to 5 halogen atoms which may be the same or different (specific examples are the same as described above). , Specifically, fluoromethyl, 2- Loroethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 2,2,3,3-tetrafluoropropyl, 2,2,3 , 3,3-pentafluoropropyl, 3-bromopropyl, 4-chlorobutyl, 4,4,5,5,5-pentafluoropentyl and the like.
  • aryl group for R 3 examples include aryl groups having 10 or less carbon atoms, such as phenyl and naphthyl.
  • alkyl group or aryl group in R 3 has an S substituent
  • substituents include halogens such as fluorine, chlorine, bromine, and iodine; alkylamino having 1 to 6 carbon atoms such as amino, methylamino, and ethylamino; and acetylamino.
  • JSft such as dialkylamino having 2 to 12 carbon atoms such as ethylmethylamino, aminoalkyl having 1 to 6 carbon atoms such as aminomethyl and aminoethyl, JSft having 3 to 18 carbon atoms such as dimethylaminoethyl and dimethylaminoethyl Dialkylaminoalkoxy having 3 to 18 carbon atoms such as aminoalkyl and dimethylaminoethoxy, hydroxyl group, alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy and propoxy, and alkoxy having 1 to 6 carbon atoms such as acetoxy and methyl.
  • C2-C7 alkoxycarbonyloxy such as toxiccarbonyloxy, Alkoxycarbonyl having 2 to 7 carbon atoms, such as moyloxy, carboxy, methoxycarbonyl, etc.
  • Alkoxycarbonyl having 1 to 6 carbon atoms such as alkamoyl, acetyl, oxo, formyl, cyano, nitro, methyl, ethyl, propyl, butyl, etc.
  • Alkenyl having 2 to 6 carbon atoms such as alkenyl, ethynyl, alkynyl having 2 to 6 carbon atoms such as ethynyl, aryl having 6 to 10 carbon atoms such as phenyl, heterocyclic group such as pyridyl, furyl, phenyl and aryl.
  • Aralkyl having 7 to 11 carbon atoms such as benzyl, benzyl and phenyl, among which one or more arbitrary groups are selected.
  • substituted alkyl group and aryl group examples include, for example, those represented by the general formula
  • Y is a carboxyl group, an alkoxycarbonyl group having 2 to 2 carbon atoms or a formula NR 5 R 6 (wherein, R 5 and R 6 represents an alkyl group having 1 to 6 carbon atoms which may be the same or different, but R 5 and R 6 together with the nitrogen atom to which they are attached form a 5- to 6-membered heterocyclic group. Which can be formed).
  • alkoxycarbonyl group having 2 to 7 carbon atoms in Y examples include a straight-chain or branched-chain alkoxycarbonyl group. Specifically, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n —Butoxycarbonyl, t-butoxycarbonyl, 2-methylpropoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl and the like.
  • R ° represents a hydroxyl-protecting group
  • examples of the hydroxyl-protecting group include ether-type protecting groups such as methyl, t-butyl, aryl, 3-methyl-2-butenyl, benzyl, and triphenylmethyl; , Acetal-type protecting groups such as pentahydrobiranil, etc .; silyl ether-type protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc .; Ester-type protecting groups such as t-butoxycarbonyl, 2,2,2-dichloroethoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, and 4-nitrobenzyloxy Carbonate-type protecting groups such as xyloxycarbonyl;
  • Examples of the protecting group in the case where 1 is a protected hydroxyl group include the same examples as described above.
  • R 5 and R 6 forces When combined with the nitrogen atom to which they are bonded to form a 6-membered saturated heterocyclic group, the 5- to 6-membered heterocyclic group has a total number of atoms of 5 to 6
  • the heterocyclic group may be substituted with lower alkyl such as methyl and ethyl, and may be, for example, 4-methylpiperazino.
  • the protecting group may be any of various commonly used protecting groups, and is preferably, for example, methyl or ethyl.
  • Linear or branched such as isopropyl, t-butyl, and 1 carbon
  • Alkyl groups of up to 6 such as haloalkyl groups having 1 to 6 carbon atoms such as 2-iodyl thiol and 2,2,2-trichloroethyl, such as 1 to 6 carbon atoms such as methoxymethyl, ethoxymethyl and isobutoxymethyl.
  • 6-alkoxymethyl group for example, an aliphatic acyloxymethyl group having 3 to 7 carbon atoms such as acetoxymethyl, propionyloxymethyl, butyryloxymethyl, and bivaloyloxymethyl, for example, 1-ethoxycarbonyloxyxetyl 1 - (C, ⁇ C 6) alkoxycarbonyl O key Chez butyl group, for example benzyl, 4-main Tokishibenjiru, 2 two Torobenjiru, 4-nitro base Ararukiru groups such as Njiru, e.g. Ariru, 2- Mechiruariru, C3-C7 alkenyl, such as 3-methylaryl, benzhydryl, or phthalidyl Groups.
  • Njiru e.g. Ariru, 2- Mechiruariru
  • C3-C7 alkenyl such as 3-methylaryl, benzhydryl, or phthalidyl Groups.
  • the protecting group for the hydroxyl group may be any of various protecting groups which are usually used, and preferably, for example, methyl, t-butyl, aryl Ether-type protecting groups such as, 3-methyl-1-butenyl, benzyl and triphenylmethyl, acetal-type protection such as methoxymethyl and tetrahydroviranyl Groups, silyl ether-type protecting groups such as trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, etc .; , 2,2-dichloromouth ethoxycarbonyl, aryloxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 412-trobenzoyloxycarbonyl, etc. And the like.
  • a to E is a single bond
  • A is a methylene group or a single bond
  • a to E is a double bond
  • A is a methine group.
  • E is preferably a compound of the formula GR 7 — (where G and R 7 are Which represents the same meaning as described above).
  • X in R 2 or R 7 is preferably a single bond, one O— or one CO—
  • R 3 in R 2 or R 7 is preferably an alkyl group having 1 to 10 carbon atoms.
  • Y is preferably a group represented by the formula: NR 5 R 6 (wherein R 5 and R 6 have the same meanings as described above), and particularly preferably a pyrrolidino group, a piperidino group or a morpholino group.
  • Pharmaceutically acceptable salts of the compound (I) of the present invention include, for example, inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like, triethylammonium salt, triethanol Ammonium And organic base salts such as salts, pyridinium salts and diisopropylammonium salts.
  • inorganic salts such as hydrochloric acid, hydrobromide, nitrate and sulfate, and acetate, propionate, trifluoroacetate
  • Organic acid salts such as acid, maleate, tartrate, methanesulfonate and benzenesulfonate
  • the compound (I) of the present invention or a pharmaceutically acceptable salt thereof may be a solvate such as a hydrate.
  • the compound of the present invention represented by the general formula (I) can be produced, for example, according to the following method.
  • R has the same meaning, and R represents a phosphorus substituent such as dimethylphosphono, getylphosphono, or triphenylphosphonium bromide, or a silicon substituent such as trimethylsilyl.
  • a known compound represented by the general formula (VI) or a compound which can be prepared by a known method is dissolved in a suitable solvent in a strong base (eg, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium). , Lithium diisopropylamide, potassium hexamethyldisilazide, dimsyl sodium, etc.) to form a carbanion, which is then reacted with a carbonyl compound represented by the formula (V) to obtain a compound of the formula (I)
  • Suitable solvents may be those that do not adversely affect the reaction, but are preferably tetrahydrofuran or dimethylformamide.
  • the isomers around the newly formed double bond ((E) -isomer and (Z) -isomer) generally depend on the type of surrounding substituents, but generally R 2 ° is phosphorus
  • the isomer represented by the above formula (I) is usually selectively obtained.
  • R 2 ° is a gay substituent
  • the formation of an isomer represented by the formula ( II ) described below is advantageous, and in some cases, the isomer (Ni) force ⁇ selectively can get.
  • the content of the isomer (I ′) can be increased by performing a photoisomerization reaction using a high-pressure mercury lamp or the like.
  • These can be separated into the (E)-and (Z) isomers by a usual method, for example, chromatography or the like, if necessary.
  • R ° is a protecting group for a hydroxyl group or when R 1 is a protected hydroxyl group, deprotection or conversion of the protecting group is carried out as required.
  • This deprotection and conversion of the protecting group can be performed according to a general method, for example, the method described in Protective 'Groups' Inorganic Synthesis Second Edition (
  • the starting carbonyl compound represented by the formula (V) is known or can be produced by a known method.
  • a formyl form in which R 11 is a hydrogen atom in the formula (V) it is produced by a method similar to a known technique.
  • Naphthalene, dihydronaphthalene, indene, and the like according to the method described in European Patent No. 298466 or Journal of Chemistry, Vol. 33, 2856-2864 (1990).
  • R 11 is an acyl group representing an alkyl group having 1 to 6 carbon atoms
  • an organometallic agent suitable for the formyl body produced by the above-mentioned technology, for example, ethylmagnesium bromide, methyllithium, pentafluore It is produced by the reaction of tyllithium or the like to form an alcohol, followed by a usual oxidation reaction of alcohol to ketone, for example, a method using a ruthenium catalyst and N-oxide, a method using a chromate salt, or the like.
  • the compound can be produced by introducing an acyl group into the corresponding aryl compound by a Friedel-Crafff reaction, and the compound represented by the formula (V) has a naphthalene skeleton and R 2 Is a 2-phenylethyl group which may be substituted, according to known techniques [for example, the method described in JP-A-7-82205].
  • Ri is expressed by the corresponding compounds wherein R 2 is a hydrogen atom (also formula (V) (Corresponding to a compound) with a styrene compound.
  • aryl compound or aryl halide is led to aryl anion, and then, for example, dimethylformamide is introduced into the formyl compound by introducing an R 1 'CO group by a reaction with an acyl halide or the like. And an acyl form can also be produced.
  • R 2 contains one or more reactive groups such as a halogen, a hydroxyl group, a carbonyl group, a carboxyl group, a primary or secondary amine, a mercapto group, etc.
  • reactive groups such as a halogen, a hydroxyl group, a carbonyl group, a carboxyl group, a primary or secondary amine, a mercapto group, etc.
  • portions other than R 2 for example, R °, R 1 , a carbonyl group in the formula (V), and a free carboxyl group Z in the formula (I) are protected by an appropriate protecting group. You may. Also, when E represents the formula GR 7 and R 7 contains one or more reactive groups as described above, it can optionally carry out the same conversion reaction as described above.
  • step A Other methods for synthesizing compound (I) from compound (V) in the same manner as in step A include a method in which an Aldol reaction is performed using a compound in which R 2 ° is a hydrogen atom in formula (VI); )), A method of performing a Reformatsky reaction using a compound in which R 2 ° is a halogen atom such as bromine or the like may be mentioned.
  • the geometrical isomer represented by the formula (II) (may be a mixture containing up to about 30% of the isomer represented by the formula (I)) is dissolved in a suitable solvent, for example, acetone, and nitrogen gas is dissolved. Is irradiated with light from a high-pressure mercury lamp at room temperature for 1 to 3 hours while stirring, whereby an isomer mixture containing 40 to 60% or more of isomer (I) can be obtained.
  • the resulting geometric isomer mixture can be subjected to a usual method, for example, silica gel column chromatography to separate the isomer (I) and the isomer (ni). If the separated isomer is re-irradiated with light to be isomerized, further isomer (I) can be obtained. Conversely, it is also possible to irradiate the isomer (I) with light to cause isomerization (
  • R ", R ', A , E, R' °, R '', k and FT represents the same meaning as above
  • R P represents a protecting group of a hydroxyl group.
  • the protecting group at R ° is removed, if desired.
  • the protecting group for Z is removed as required.
  • Q and Q ′ represent a cyclic or linear acetal structure, they are treated in a dilute mineral acid, preferably dilute hydrochloric acid, at a temperature of from 140 ° C.
  • Q represents a hydrogen atom and Q
  • deprotection is carried out by a usual method, followed by a method using pyridinium chloromouth mart or Swern oxidation (Swern Oxidation).
  • the oxidation reaction of the alcohol is carried out to convert the alcohol into a liponyl compound corresponding to the compound represented by the formula (V).
  • a substituent is introduced into the hydroxyl group of the compound represented by the formula (VIIe) in the same manner as in Step C described above.
  • the protecting group at R ° is removed, if desired.
  • the protecting group for Z is removed as required.
  • Q and Q ′ represent a cyclic or chain acetal structure, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above formula (V) can be obtained by the same method as described in the step C.
  • G is a single bond, formula (CH 2 ) e one (g is an integer of 1 to 10), formula — (CH 2 ) h- 1 O— (CH 2 ) g represents one (h is 0 or an integer of 1 to 10, g represents the same meaning as described above), or represents one CO—. )
  • the protecting group R p for the hydroxyl group of the compound represented by the formula (VII la) is removed by a general method.
  • the compound represented by the formula (IX) is added to the compound represented by the formula (IX) in a suitable solvent such as dimethylformamide in the presence of a suitable base such as sodium hydride. React at 0 ° C to 80 ° C.
  • a suitable solvent such as dimethylformamide
  • a suitable base such as sodium hydride.
  • the protecting group at R ° is removed.
  • the protecting group of Z is optionally removed.
  • the compound is converted to a carbonyl compound corresponding to the compound represented by (V).
  • the hydroxyl group of the compound represented by the formula (VIIb ′) (which can be obtained in the same manner as the compound of the formula (VI lb)) can be obtained by a usual method, for example, a method using pyridinium chlorochromate, (Swern
  • Oxidation etc., to oxidize the hydroxyl group to convert to the formyl form (X).
  • a compound represented by the general formula (XI) is dissolved in a suitable solvent, for example, dimethylformamide in a strong base (for example, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium, lithium diisopropylamide, potassium). Hexamethyldisilazide, Jimsil sodium, etc.) To form a carbanion and react with a formyl compound represented by the formula (X) to obtain an olefin compound represented by the formula (XII).
  • a suitable solvent for example, dimethylformamide in a strong base (for example, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium, lithium diisopropylamide, potassium). Hexamethyldisilazide, Jimsil sodium, etc.)
  • a strong base for example, sodium hydroxide, potassium t-butoxide, sodium hydride, n-butyllithium, lithium diisoprop
  • the compound represented by the formula (XII) is hydrogenated and reduced in an inert solvent such as methanol in the presence of a suitable catalyst such as a palladium carbon catalyst under a hydrogen atmosphere of 1 to 5 atm, preferably at room temperature.
  • a suitable catalyst such as a palladium carbon catalyst under a hydrogen atmosphere of 1 to 5 atm, preferably at room temperature.
  • a compound represented by the formula (XIII) can be obtained.
  • the protecting group at R ° is removed, if desired. Further, when the compound (XIII) corresponds to the compound of the formula (I), the protecting group of Z is optionally removed.
  • Q and Q ′ represent a cyclic or chain acetal structure, or when Q represents a hydrogen atom and Q ′ represents a protected hydroxyl group, the above formula (V) can be obtained by the same method as described in the step C.
  • Process F ' The hydroxyl group of the compound represented by the formula (VIIg) is converted to a formyl compound (Xa) in the same manner as in the above step F.
  • the compound represented by the general formula (Xa) is reacted with the compound represented by the general formula (XI) in the same manner as in the step G to convert the compound into the polyolefin compound (XIIa).
  • the compound represented by the formula (XIla) is hydrogenated and reduced in the same manner as in the above step H to obtain a compound (XIla).
  • R °, R ′, R 2 , A, E, R ′ °, and R 11 represent the same meaning as described above (however, R is not a hydrogen atom).
  • organometallic reagent such as methyllithium, ethylmagnesium bromide, and pentafluoroethyllithium
  • the compound represented by the formula (XIV) is converted to a ketone compound of the formula (Vb) by an oxidation reaction of an alcohol to a ketone, for example, a method using a ruthenium catalyst and N-oxide, a method using a chromate salt, or the like.
  • organolithium reagent such as methyllithium, phenyllithium, p-methoxymethoxyphenyllithium (P-methoxymethoxybromobenzene and n-butyllithium in a conventional manner) is added to the compound represented by the formula (XV).
  • a suitable solvent for example, tetrahydrofuran at a reaction temperature of 78 to 80 ° C to obtain a compound of the formula (XVI).
  • the compound represented by the formula (XVI) is converted to a carbonyl compound corresponding to the compound represented by the formula (V) by the same method as described in the above step C.
  • R ′ 4 represents a protecting group for a hydroxyl group, or has the same meaning as in the above formula R 3 .
  • the compound represented by the formula (XV) is reacted with a suitable reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a suitable solvent such as tetrahydrofuran at a reaction temperature of 78 ° C. React at ⁇ 80 ° C.
  • a suitable reducing agent such as lithium aluminum hydride or diisobutylaluminum hydride in a suitable solvent such as tetrahydrofuran
  • R 1, R 2, Q and Q ′ represent the same meaning as described above, and T f represents a trifluoromethanesulfonyl group.
  • the triflate represented by the formula (XIX) is converted to methanol and triethylamine in the presence of a phosphine, for example, triphenylphosphine or 1,3-bis (diphenylphosphino) propane and a palladium complex catalyst formed in the system from palladium acetate.
  • a phosphine for example, triphenylphosphine or 1,3-bis (diphenylphosphino) propane
  • a palladium complex catalyst formed in the system from palladium acetate.
  • the compound represented by the formula (XIX) can be produced, for example, by using 6-methoxytetralone as a starting material.
  • 1-hydroxy-6-methoxy-2-carbaldehyde J. Med. Chem.), Vol. 22, 363-365 (1987)] and the 1-position hydroxy group is protected with triflate by a usual method, and if desired, the formyl group is protected as an acetal under general conditions.
  • the formyl group of the above triflate by an ordinary method, for example, using sodium borohydride or the like to obtain an alcohol form, and then protecting the hydroxyl group under general conditions.
  • step J by converting the formyl group of the above carbaldehyde (the hydroxyl group may be protected if necessary) to the ketone form by carrying out the above-mentioned step and the same reaction as in step J to give a ketone body.
  • the 1-position hydroxyl group and triflate after that, and a method of manufacturing provides protection of if desired carboxy group.
  • the compound represented by the formula (XX) is reacted with a suitable reducing agent such as diisobutylaluminum hydride in a suitable solvent such as methylene chloride at a reaction temperature of 78 ° C to 80 ° C.
  • a suitable reducing agent such as diisobutylaluminum hydride
  • a suitable solvent such as methylene chloride
  • the compound represented by the formula (XX) protects the carboxyl group of, for example, 3-hydroxy-7-methoxy-2-naphthoic acid with a usual protecting group, for example, an ester, and then the 3-position hydroxyl group is formed by a usual method. It can be obtained by, for example, a method of manufacturing with protection by triflate.
  • a compound represented by the formula (XXII) is reacted with a phosphine, for example, trif; a suitable solvent containing methanol and triethylamine in the presence of a palladium complex catalyst formed in a system from Lnyl phosphine or diphenylphosphinopropane and palladium acetate.
  • a phosphine for example, trif
  • a suitable solvent containing methanol and triethylamine in the presence of a palladium complex catalyst formed in a system from Lnyl phosphine or diphenylphosphinopropane and palladium acetate.
  • a palladium complex catalyst formed in a system from Lnyl phosphine or diphenylphosphinopropane and palladium acetate.
  • the reaction is carried out in dimethylformamide under a carbon monoxide atmosphere at a reaction temperature of 50 to 120 ° C.
  • the compound represented by the formula (XXIII) is reacted with a suitable reducing agent such as diisobutylaluminum hydride in a suitable solvent such as methylene chloride at a reaction temperature of 178 ° C to 80 ° C. Let it.
  • a suitable reducing agent such as diisobutylaluminum hydride
  • a suitable solvent such as methylene chloride
  • the compound represented by the formula (XXIV) is subjected to a real alcohol oxidation reaction by a method using pyridinum chromatography or Swane oxidation (Swern Oxidation) to formyl represented by the formula (Vc). Convert to body.
  • the production method described above exemplifies and describes in detail the production steps of the compound represented by the general formula (I) in the present invention, whereby the starting material, the production process, the reaction conditions, or the treatment
  • the manufacturing method such as conditions is not limited.
  • Some of the compounds (I) of the present invention may have optical isomers based on asymmetric carbon, and these isomers are all represented by a single formula for convenience.
  • compositions for oral administration include tablets, capsules, pills, granules, powders, solutions, suspensions, and the like.
  • compositions for parenteral administration include injections Aqueous or oily agent, Ointments, creams, lotions, aerosols, suppositories, patches and the like.
  • the dose varies depending on the patient's condition such as age and weight, symptoms, and the administration route, but it is usually 0.05 to 500 mg, preferably 5 to 500 mg, per day for an adult as the amount of the active ingredient of the present invention.
  • the dose can be administered once to three times daily, continuously, or intermittently or intermittently.
  • Specific examples of the compounds included in the present invention include the following compounds. However, these compounds are for illustration only, and the present invention is not limited to these.
  • Example 8 Using the (E) -ester (2.04 g) obtained in Example 8 as the starting material, a method similar to that described in Example 6 (1.82 g) was obtained.
  • Example 9 Using the ester obtained in Example 9 (1.82 g) as the starting material, a method similar to that described in Example 7 was used (0.90 g).
  • Example 11 Using the (E) -ester (0.53 g) obtained in Example 11 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.45 g).
  • Example 12 Using the ester (0.45 g) obtained in Example 12 as the starting material, it was obtained in a similar manner to that described in Example 7 (0.35 g).
  • Example 14 Using the ester (1. Og) obtained in Example 14 as the starting material, it was obtained in a similar manner to that described in Example 5 (0.24 g).
  • Example 15 Using the ester obtained in Example 15 (0.48 g) as the starting material, a method similar to that described in Example 6 was used (0.2 g).
  • Example 16 Using the ester (0.2 g) obtained in Example 16 as the starting material, a method similar to that described in Example 7 (0.15 g) was obtained.
  • Example 1 The ketone (3. Og) obtained in Reference Example 17 was used as a starting material, and the silyl ester obtained in Reference Example 4 was used instead of t-butyl 2-trimethylsilylbutanoate. It was obtained in a similar manner to that described in 4. (4.69 g). This is a 2:98 mixture of (E) and (Z) bodies.
  • Example 18 Using the ester (4.69 g) obtained in Example 18 as the starting material, a compound was obtained in a similar manner to that described in Example 5 (1.83 g).
  • Example 19 Using the ester (0.5 g) obtained in Example 19 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.42 g).
  • Example 20 Using the ester obtained in Example 20 as the starting material, it was obtained in the same manner as described in Example 7 (0.1 Og).
  • Example 22 Using the ester obtained in Example 22 (1.19 g) as starting material, it was obtained in a similar manner to that described in Example 5 (0.45 g).
  • the starting material used was the (E) -ester (0.45 g) obtained in Example 23. It was obtained in the same manner as described in Example 6 (0.40 g).
  • Example 26 Using the ester obtained in Example 26 (2.14 g) as the starting material, it was obtained in a similar manner to that described in Example 6 (1.59 g).
  • Example 27 Using the ester (1.59 g) obtained in Example 27 as the starting material, a compound was obtained in a similar manner to that described in Example 3 (1.04 g).
  • Example 29 Using the (E) -ester (0.50 g) obtained in Example 29 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.43 g).
  • boron tribromide (2.17 g) was added dropwise to a solution of the ester obtained in Example 32 (1.73 g) in dichloromethane (17 mL) at 20 ° C. The mixture was stirred at C for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Organics were collected, washed with saturated saline, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane ethyl acetate: 10: 1) to obtain the desired product (1.18 g).
  • Example 33 Using the ester obtained in Example 33 (1.18 g) as a starting material, the same procedure as described in Example 3 was carried out to obtain a crude product. Recrystallization from 2-propanol Z hexane gave the desired product (0.71 g). 1 H-NMR (CD CI a) ⁇ 5: ppm
  • Example 35 Using the (E) -ester (0.4 g) obtained in Example 35 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.28 g).
  • Example 36 Using the (E) -ester (0.25 g) obtained in Example 36 as the starting material, it was obtained in a similar manner to that described in Example 31 (0.20 g).
  • Example 4 was repeated using the ketone (3.1 g) obtained in Reference Example 33 and the silyl ester (2.83 g) obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate. (0.3 Og) o obtained in the same manner as described in
  • Example 38 Using the (E) -ester (0.30 g) obtained in Example 38 as the starting material, it was obtained in the same manner as described in Example 6 (0.17 g).
  • Example 39 Using the ester (0.16 g) obtained in Example 39, it was obtained in the same manner as described in Example 31 (0.13 g).
  • Example 4 The method described in Example 4 was repeated using the ketone (3.36 g) obtained in Reference Example 34 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate. Obtained in a similar manner (0.50 g).
  • Example 41 Using (E) -espile (0.5 Og) obtained in Example 41 as a starting material, it was obtained in the same manner as described in Example 6 (0.45 g).
  • Example 42 The ester obtained in Example 42 (0.45 g) was used in a similar manner to that described in Example 31 (0.31 g).
  • Example 44 Using the ester (1.09 g) obtained in Example 44, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.1 3g) was obtained.
  • Example 4 Described in Example 4 using the ketone (1.5 g ) obtained in Reference Example 35 and using t-butyl trimethylsilylacetate (1.35 g) instead of t-butyl 2-trimethylsilylbutanoate (0.52g) o obtained in the same manner as
  • Example 46 Using the ( ⁇ ) -ester (0.52 g) obtained in Example 46 as the starting material, a method similar to that described in Example 6 was used (0.44 g).
  • Example 47 Using the ester (0.44 g) obtained in Example 47, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.4%). 32g) was obtained.
  • Example 49 Using the ester obtained in Example 49 (2.83 g) as the starting material, it was obtained in a similar manner to that described in Example 5 (0.71 g).
  • Example 50 Using the (E) -ester (0.70 g) obtained in Example 50 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.59 g).
  • Example 51 Using the ester (0.59 g) obtained in Example 51, the crude product obtained in the same manner as described in Example 31 was recrystallized from hexane / dichloromethane to obtain the desired product (0.46 g). ).
  • Example 4 The method described in Example 4 using the ketone (1 4. Og) obtained in Reference Example 40 and the silyl ester obtained in Reference Example 4 instead of t-butyl 2-trimethylsilylbutanoate (4.0 g). This is a 1: 3 mixture of (E) and (Z) bodies.
  • Example 53 Using the ester (1. Og) obtained in Example 53 as the starting material, a method similar to the method described in Example 5 was carried out, and the obtained crude product was subjected to silica gel column chromatography (hexane). Purification with Z ethyl acetate 20: 1) gave the desired product (0.1 Og).
  • Example 54 Using the (E) -ester (0.25 g) obtained in Example 54 as the starting material, it was obtained in the same manner as described in Example 6 (0.22 g ).
  • Example 55 Using the ester (0.22 g) obtained in Example 55, the desired product (0.15 g) was obtained in the same manner as described in Example 31.
  • Example 57 Using the (E) -ester (0.85 g) obtained in Example 57 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.75 g).
  • Example 58 The ester obtained in Example 58 (0.85 g ) was used and described in Example 31.
  • the desired product (0.18 g) was obtained in the same manner as described above.
  • (Z) -ester [1.13 g, obtained by the method described in Example 29, which is 1- (1-butyl-6-methoxymethoxyxinaphthalene-1-yl) propane-one-one (Z) -3- (1-Phtyl-6-hydroxysinaphthalene-12T) 1-2-Methyl-2- in a manner similar to that described in Example 6 using There was obtained t-butyl pentenoate [1.07 g, which is an approximately 40% mixture with 1- (1-1-butyl-6-hydroxynaphthalene-1-yl) propan-1-one].
  • Example 62 Using the ester (0.37 g) obtained in Example 62, the desired product (0.23 g) was obtained in the same manner as described in Example 31.
  • Example 64 Using the (E) -ester (0.50 g) obtained in Example 64 as the starting material, it was obtained in a similar manner to that described in Example 6 (0.32 g).
  • Example 66 Example 66
  • Example 65 Using the ester (0.31 g) obtained in Example 65, the desired product (0.20 g) was obtained in the same manner as described in Example 31.
  • Example 6 Using the ester obtained in 9 (0.23 g), a method similar to that described in Example 6 (0.21 g) was obtained.
  • Example 70 Using the ester obtained in Example 70 (0.45 g ), a crude product was obtained in the same manner as described in Example 31 and obtained by preparative high performance liquid chromatography.
  • Example 73 Using the ester (0.58 g) obtained in Example 73, the desired product (0.52 g) was obtained in the same manner as described in Example 31.
  • Example 67 Using the (E) -ester (0.88 g) obtained in Example 67, it was obtained in the same manner as described in Example 6 (0.60 g).
  • Example 75 To the ester (0.60 g) obtained in Example 75, trifluoroacetic acid was added at room temperature and stirred for 10 minutes. Dichloromethane (30 mL) was added, the mixture was vigorously reduced under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane Z methanol 20: 1) to obtain the desired product (0.30 g).
  • Example 78 Using the ester (0.78 g) obtained in Example 78, the crude product obtained in the same manner as described in Example 6 was subjected to silica gel column chromatography (dichloromethane Zmethanol 50: 1). Purification yielded (E) -isomer (0.52 g) and (Z) -isomer (0.1 Og).
  • the target product (3.03 g) was obtained in the same manner as described in Example 1 using the aldehyde (2.86 g) obtained in Reference Example 51.
  • the desired product (2.83 g) was obtained by the method described in Example 6 using the ester (2.96 g) obtained in Example 80.
  • Example 81 Using the phenol obtained in Example 81 (2.65 g), The desired product (3.12 g) was obtained by the method described.
  • n-octanethiol (10.4 mL) was added to a suspension of aluminum chloride (5.63 g) in 1,2-dichloroethane (67 mL) and stirred for 15 minutes to dissolve the aluminum chloride. .
  • Trahydrofuran 60 mL was added, and water (300 mL) containing glaucoma hydrochloride (6 mL) was added. Separate the organic layer and add dichloromethane (1 O OmL x 2) and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol 9: 1) to obtain the desired product (2.83 g).
  • Example 81 Using the phenol (1. Og) obtained in Example 81, the desired product (0.60 g) was obtained by the method described in Example 83.
  • Example 85 Using the ester (0.89 g) obtained in Example 85, the desired product (0.78 g ) was obtained by the method described in Example 84.
  • Example 87 Using the (Z) -ester (3.14 g) obtained in Example 87, a mixture of the (E) -isomer and the (Z) -isomer was obtained by the method described in Example 5 and subjected to silica gel column chromatography (He Purification was performed using xanthine ethyl acetate 50: 1) to separate the desired product (0.93 g).
  • Example 6 Described in Example 6 using the ester (0.90 g) obtained in Example 88 Thus, the desired product (0.76 g) was obtained.
  • Example 90 Using the ester (0.44 g) obtained in Example 90, the desired product (0.15 g) was obtained by the method described in Example 83.
  • the desired product (0.1 Og) was obtained by the method described in Example 84 using the ester (0.15 g) obtained in Example 91.
  • the desired product (1.01 g) was obtained in the same manner as described in Example 1 using the aldehyde (1.0 Og) obtained in Reference Example 57.
  • the desired product (0.81 g) was obtained by the method described in Example 6 using the ester (0.91 g ) obtained in Example 93.
  • Example 95 Using the ester (2.35 g) obtained in Example 95, the desired product (2.40 g) was obtained by the method described in Example 83.
  • the target product (2.22 g) was obtained by the method described in Example 84 using the ester (2.35 g) obtained in Example 96.
  • n-propyltriphenylphosphonium bromide (0.93 g) azeotropically dried with benzene (0.93 g) in tetrahydrofuran (8 mL). 30 mL) solution and stirred for 10 minutes.
  • the aldehyde (0.17 g) obtained in Example 98 was extracted.
  • a solution of trahydrofuran (1 mL) was added, and the mixture was stirred for 10 minutes.
  • Methyl 2-pentanoate (0.19 g), followed by a hydrogenation reaction using a catalyst containing palladium on coal (E) — 3— (3-butyl-6-methoxynaphthalene) M) 1-2-Methyl-2-pentenoate methyl (0.18 g) was obtained.
  • the desired product (0.08 g) was obtained by the method described in Example 83 using the ester (0.18 g) thus obtained.
  • the desired product (0.08 g) was obtained by the method described in Example 84 using the ester (0.08 g) obtained in Example 99.
  • propionyl chloride (7.5 g) was added dropwise to a solution of aluminum trichloride (10.78 g) and 2-methoxynaphthalene (1 Og) in nitrobenzene (50 mL) under ice cooling over 20 minutes. . After stirring at the same temperature for 30 minutes, the reaction solution was added to concentrated hydrochloric acid (50 mL) to which ice chips had been added, and extracted three times with dichloroethane. The organic layer was washed with 1N hydrochloric acid, water, and saturated saline, and the solvent was removed under reduced pressure.
  • the residue is purified by silica gel column chromatography (hexane to ethyl hexanenoacetate 50: 1), followed by repulping and washing with hexane to give the desired product (4.26 g) as a colorless crystal having a melting point of 104 to 105 ° C. As obtained.

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Abstract

L'invention concerne des composés de formule générale (I) ayant une activité estrogénique et/ou anti-estrogénique, des isomères géométriques de ceux-ci et des sels pharmaceutiquement acceptables de ceux-ci. Dans la formule (I), R0 représente hydrogène ou un groupe de protection hydroxyle, R1 représente hydrogène, halogéno, alkyle C¿1?-C6, hydroxyle ou hydroxyle protégé; R?2¿ représente hydrogène ou -(CH¿2?)k-X-R?3¿; les lignes pleines à tirets parallèles représentent chacune une liaison simple ou double; A représente (1) méthylène, oxygène ou une liaison simple, ou (2) méthyne; E représente (1) -GR7- ou -CO-, ou (2) =CR7- ou azote; et Z représente carboxyle, carbamoyle, hydroxyaminocarbonyle, hydroxyméthyle ou un groupe fonctionnel protégé dérivé de ces derniers.
PCT/JP1997/000600 1996-03-06 1997-02-27 Derives estrogenes non steroidiens WO1997032837A1 (fr)

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WO2015135061A1 (fr) 2014-03-10 2015-09-17 Endorecherche, Inc. Traitement des symptômes ou des maladies de carence en androgènes par des précurseurs de stéroïdes sexuels en combinaison avec des serm
EP3178480A1 (fr) 2009-06-16 2017-06-14 Endorecherche, Inc. Traitement de bouffées de chaleur, de symptômes vasomoteurs et de sueurs nocturnes par des précurseurs de stéroïdes sexuels en combinaison avec des modulateurs sélectifs du récepteur de l' strogène
US20220112233A1 (en) * 2019-06-28 2022-04-14 Fujifilm Corporation Method for producing peptide compound, protective group-forming reagent, and condensed polycyclic aromatic hydrocarbon compound
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EP0955286A1 (fr) * 1998-05-06 1999-11-10 Hoechst Marion Roussel Dérivés du dihydro ou tétrahydronaphtalène ayant une activité (anti-)oestrogène
FR2778404A1 (fr) * 1998-05-06 1999-11-12 Hoechst Marion Roussel Inc Derives du dihydro ou tetrahydronaphtalene, et les compositions pharmaceutiques les renfermant
JPH11349527A (ja) * 1998-05-06 1999-12-21 Hoechst Marion Roussel ジヒドロ又はテトラヒドロナフタレンの誘導体及びそれらを含む医薬組成物
US6005003A (en) * 1998-05-06 1999-12-21 Hoechst Marion Roussel Derivatives of dihydro or tetrahydronaphthalene, and the pharmaceutical compositions containing them
US6465445B1 (en) 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6670346B1 (en) 1998-06-11 2003-12-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7429576B2 (en) 1998-06-11 2008-09-30 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US7943603B2 (en) 1998-06-11 2011-05-17 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
EP2386305A2 (fr) 1998-06-11 2011-11-16 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
EP2386304A2 (fr) 1998-06-11 2011-11-16 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
EP2399582A1 (fr) 1998-06-11 2011-12-28 Endorecherche Inc. Modulateur sélectif de récepteur d'ýstrogène combiné avec déhydroépiandrostérone (DHEA) ou des analogues
EP3682880A1 (fr) 2009-06-16 2020-07-22 Endorecherche, Inc. Traitement de bouffées de chaleur, de symptômes vasomoteurs et de sueurs nocturnes par des précurseurs de stéroïdes sexuels en combinaison avec des modulateurs sélectifs du récepteur de l' strogène
EP3178480A1 (fr) 2009-06-16 2017-06-14 Endorecherche, Inc. Traitement de bouffées de chaleur, de symptômes vasomoteurs et de sueurs nocturnes par des précurseurs de stéroïdes sexuels en combinaison avec des modulateurs sélectifs du récepteur de l' strogène
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