WO2001055102A1 - Nouveau derive difluoroprostaglandine - Google Patents

Nouveau derive difluoroprostaglandine Download PDF

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Publication number
WO2001055102A1
WO2001055102A1 PCT/JP2001/000540 JP0100540W WO0155102A1 WO 2001055102 A1 WO2001055102 A1 WO 2001055102A1 JP 0100540 W JP0100540 W JP 0100540W WO 0155102 A1 WO0155102 A1 WO 0155102A1
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group
carbon atoms
ethylene
compound
trans
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PCT/JP2001/000540
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English (en)
Japanese (ja)
Inventor
Takayuki Tanaka
Yasushi Matsumura
Nobuaki Mori
Takashi Nakano
Nobuaki Miyawaki
Takeshi Matsugi
Atsushi Shimazaki
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Asahi Glass Company, Limited
Santen Pharmaceutical Co., Ltd.
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Priority to AU2001228836A priority Critical patent/AU2001228836A1/en
Publication of WO2001055102A1 publication Critical patent/WO2001055102A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0025—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing keto groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • Natural prostaglandins are a group of physiologically active substances synthesized in the body, and regulate local cell functions of various tissues in living organisms as local hormones having various physiological activities. ing.
  • PGEs which are a kind of natural PG, have various effects related to pain and inflammation in addition to vasodilatory effect, bronchodilator effect, gastric acid secretion inhibitory effect, gastric mucosal protective effect, uterine contractile effect, etc. Since it has it, it is used as a blood flow improving agent, a gastric ulcer treatment agent, a labor-inducing agent and the like.
  • PGFs are used as a birth inducer, an agent for treating glaucoma, an agent for regulating estrous cycle of livestock, and the like.
  • PGDs are said to be involved in various actions related to allergy, immune response, and inflammation, in addition to central nervous action, sleep-inducing action, platelet aggregation inhibitory action, and the like.
  • these PGs have the potential to be applied to anticancer drugs, osteoporosis drugs, analgesics, drugs for central nervous system inflammation, etc.Therefore, the development potential of PG derivatives with higher effects and fewer side effects is being studied. .
  • the present inventors have synthesized novel PGs in order to impart the unique properties possessed by the fluorine atom to PGs, and studied to clarify their physical properties and physiological activities.
  • the carboxy group at position 1 of the prostanoic acid skeleton is reduced, and
  • a new 15-dexoxy 15,5-difluoro PG derivative, in which two fluorine atoms are bonded to an elemental atom, has excellent physical properties and physiological activities.
  • it is used in medicine, especially glaucoma and ocular hypertension. It has been found that the compound is an excellent compound as a prophylactic or therapeutic agent for eye diseases such as.
  • the 15-doxy-1,5,15-difluoro PG derivative of the present invention in which the carboxy group at the 1-position has become —C (OR 3 ) R 4 R 5 has the same carbon skeleton as that of the 15-doxy mono PG derivative. It has been found that it has higher lipophilicity and better absorbability to the living body than the 15,5-difluoro PG derivative.
  • the present invention provides a 15-deoxy 15,15-difluoro PG derivative represented by the following formula (1), and a drug containing the PG derivative as an active ingredient.
  • A Ethylene group, vinylene group, ethinylene group, 100 CH 2 —, or 1 SCH 2 X: — CH 2 —, — O—, or — S—.
  • P, Q each independently —CO—, -CH (OR 2 )-(R 2 is each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 20 carbon atoms. ), Or one CH 2 —.
  • P and Q do not become one CO at the same time ⁇
  • R 1 a linear alkyl group having 3 to 8 carbon atoms, a linear alkenyl group having 3 to 8 carbon atoms, a linear alkynyl group having 3 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkyl group, And a group selected from aryloxyalkyl groups, or a group in which one or more hydrogen atoms in the selected groups are substituted.
  • R 3 hydrogen atom, alkyl group, alkenyl group, alkynyl group, having 3 to 8 carbon atoms A group selected from a cycloalkyl group, an aryl group, an aralkyl group, and an acyl group, or a group in which one or more hydrogen atoms in the selected group are substituted.
  • R 4 and R 5 each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, Aryl group or aralkyl group.
  • a number corresponding to a number in the prostanoic acid skeleton is used as a number indicating a position in the PG skeleton.
  • a group in which a hydrogen atom of an alkyl group has been substituted is also referred to as a substituted alkyl group.
  • the “lower group” means a group having 6 or less carbon atoms. The carbon number of the lower group is preferably 4 or less.
  • alkyl group may be straight-chain or branched. Unless otherwise specified, the alkyl group is preferably a lower alkyl group having 1 to 6 carbon atoms. Examples of the alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.
  • alkenyl group may be straight-chain or branched.
  • the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms unless otherwise specified.
  • Examples of the alkenyl group include a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 3-butenyl group, a 3-pentenyl group, and a 4-hexenyl group.
  • alkynyl group may be straight-chain or branched.
  • the alkynyl group is preferably a lower alkynyl group having 2 to 6 carbon atoms unless otherwise specified.
  • Examples of the alkynyl group include a 1-propynyl group, a 2-propynyl group, a 3-butynyl group, a 3-pentynyl group, and a 4-hexynyl group.
  • alkoxy group may be straight-chain or branched.
  • An alkoxy group is A lower alkoxy group having 1 to 6 carbon atoms is preferred, and an alkoxy group having 1 to 4 carbon atoms is particularly preferred.
  • Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group.
  • Halogen atom refers to a fluorine, chlorine, bromine, or iodine atom.
  • Aryl group refers to a monovalent aromatic hydrocarbon group, and a phenyl group is preferred.
  • the t- substituted araryl group one or more hydrogen atoms in the aryl group are a lower alkyl group, a halogen atom, or a halogen atom.
  • a group substituted with a substituted (lower alkyl) group, a lower alkoxy group, or a (lower alkyl) amino group is preferred.
  • the substituted aryl group is preferably a substituted phenyl group, particularly a monohalophenyl group (for example, chlorophenyl group, fluorophenyl group, bromophenyl group, etc.), a dihalophenyl group (for example, dichlorophenyl group, difluorophenyl group, dibromophenyl group, etc.).
  • a monohalophenyl group for example, chlorophenyl group, fluorophenyl group, bromophenyl group, etc.
  • a dihalophenyl group for example, dichlorophenyl group, difluorophenyl group, dibromophenyl group, etc.
  • Trihalophenyl group for example, trichlorophenyl group, trifluorophenyl group, tribromophenyl group, etc.
  • (lower alkyl halide) phenyl group for example, trifluoromethylphenyl group, etc.
  • (lower alkoxy) phenyl group Eg, methoxyphenyl, ethoxyphenyl, etc.
  • di (lower alkoxy) phenyl eg, dimethoxyphenyl, diethoxyphenyl, etc.
  • tri (lower alkoxy) phenyl eg, trimethoxyphenyl
  • mono (lower alkyl) phenyl group e.g., tolyl group, etc.
  • Alkyl group refers to an alkyl group substituted with an aryl group.
  • aryl group a phenyl group is preferred.
  • the alkyl group in the aralkyl group is preferably an alkyl group having 1 to 4 carbon atoms. Examples of the aralkyl group include a benzyl group, a benzhydryl group, a trityl group, and a phenylethyl group.
  • the “cycloalkyl group” refers to a cyclic alkyl group having three or more members, and is preferably a 3- to 8-membered cycloalkyl group.
  • substituent in the substituted cycloalkyl group low Lower alkyl groups, halogen atoms, lower alkoxy groups and the like.
  • Examples of the cycloalkyl group and the substituted cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, methylcyclohexyl group, dimethylcyclopentyl group, and dimethylcyclohexyl. Group, chlorocyclyl hexyl group, or dichlorocyclohexyl group.
  • Halogenated alkyl group refers to a group in which at least one hydrogen atom in the alkyl group has been replaced by a halogen atom, and a lower halogenated alkyl group having 1 to 6 carbon atoms is preferable.
  • the halogenated alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, and a bromomethyl group.
  • the 15-dexoxy15,15-difluoro PG derivative represented by the formula (1) (hereinafter, also referred to as the PG derivative (1) of the present invention), the following compounds are considered from the viewpoint of physiological activity and physical properties. preferable.
  • A is preferably a vinylene group or an ethylene group.
  • the vinylene group may be in a cis form or a trans form, and a trans vinylene group is particularly preferable.
  • A is —OCH 2 — or SCH 2 —
  • the direction of the bond is not particularly limited, and the bond is preferably bonded to the ring by an oxygen atom or a sulfur atom.
  • X is preferably —CH 2 —.
  • the overlap between the solid line and the broken line is preferably a cis double bond.
  • R 1 is a straight-chain alkyl group having 3 to 8 carbon atoms, a group in which a hydrogen atom in the straight-chain alkyl group having 3 to 8 carbon atoms is substituted (hereinafter referred to as “substituted (straight-chain alkyl group having 3 to 8 carbon atoms)” No Write down.
  • substituted (straight-chain alkyl group having 3 to 8 carbon atoms) No Write down.
  • Group hereinafter collectively referred to as these groups
  • the linear alkyl group, the linear alkenyl group, and the linear alkynyl group each preferably have 5 to 6 carbon atoms.
  • a methyl group is preferred, and the number of substituted methyl groups is preferably one or two.
  • the group ( ⁇ ') is preferably an ⁇ -pentyl group, a 2-methylhexyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, or a 1,1-dimethyl-3-hexynyl group.
  • the group (r 1 ) has a substituent other than a methyl group, the substituent is preferably a cycloalkyl group.
  • examples of the group ( ⁇ ′) substituted by a cycloalkyl group include a cycloalkyl-substituted (C 3-8 straight-chain alkyl) group, a cycloalkyl group-substituted (C 3-8 straight-chain alkenyl) group, and the like.
  • a cycloalkyl group as the substituent a cyclopentyl group or a cyclohexyl group is preferable.
  • R 1 is a cycloalkyl group having 3 to 8 carbon atoms, substituted (3 to 8 carbon atoms) cycloalkyl group, aralkyl group, substituted aralkyl group, aryloxyalkyl group, substitution (aryloxyalkyl) ) is a group also referred to as (collectively these groups groups (r 2).
  • the ring structure in the group (r 2 ) is substituted with an alkyl group having 1 to 6 carbon atoms, a halogen atom, an oxygen atom-containing substituent, a sulfur atom-containing substituent, or a nitrogen atom-containing substituent. It is preferable that the alkyl group or the halogen atom having 1 to 3 carbon atoms is substituted.
  • an aryloxyalkyl group and a substituted (aryloxyalkyl) group are preferred.
  • the group (r 2 ) is a cycloalkyl group having 3 to 8 carbon atoms
  • a cyclopentyl group or a cyclohexyl group is preferable
  • the group is a substituted (3 to 8 carbon atoms) cycloalkyl group
  • a C 3 -C 8 substituted with one or more lower alkyl groups when the group is a substituted (3 to 8 carbon atoms) cycloalkyl group, A C 3 -C 8 substituted with one or more lower alkyl groups.
  • a cycloalkyl group is preferred, and a cyclopentyl group substituted with an alkyl group having 1 to 4 carbon atoms, and a cyclohexyl group substituted with an alkyl group having 1 to 4 carbon atoms are preferred.
  • the group (r 2 ) is an aralkyl group
  • an aralkyl group having a benzene ring or a naphthalene ring is preferable.
  • examples of the substituent include a lower alkyl group, a halogen atom, a halogenated alkyl group, an alkoxy group, and a hydroxyl group.
  • the number of carbon atoms in the alkylene group in the aralkyl group and the substituted alkyl group is preferably 1 to 4.
  • the aralkyl group a benzyl group and a phenylethyl group are preferable.
  • a phenyl group in a benzyl group or a phenylethyl group is preferably a methyl group, a ethyl group, or a group substituted with a halogen atom.
  • the group (r 2 ) is an aralkyl group or a substituted aralkyl group
  • specific examples include a benzyl group, a 2-phenylethyl group, a 3-methylphenylmethyl group, and a 2- (3-methylphenyl) ethyl group , 3-trifluoromethylphenylmethyl, 2- (3-trifluoromethylphenyl) ethyl, 3-chlorophenylmethyl, 2- (3-chlorophenyl) ethyl, 2- (3 , 5-dichloromouth phenyl) group or 2- (3,4-dichlorophenyl) ethyl group.
  • the group (r 2 ) is an aryloxyalkyl group
  • an aryloxyalkyl group having a benzene ring is preferred, and a phenyloxyalkyl group is particularly preferred.
  • the group (r 2 ) is a substituted aryloxyalkyl group
  • the hydrogen atom of the aryl group is preferably substituted with a halogen atom, a halogenated alkyl group, an alkoxy group, or a hydroxyl group.
  • the alkyl group moiety in the aryloxyalkyl group and the substituted aryloxyalkyl group preferably has 1 to 3 carbon atoms.
  • substituted aryloxyalkyl group a phenoxyalkyl group substituted with 1 to 3 halogen atoms or a phenyloxy group alkyl group substituted with 1 to 3 halogenated alkoxy groups is preferable.
  • Examples of the aryloxyalkyl group or the substituted aryloxyalkyl group include phenoxymethyl, 3-chlorophenoxymethyl, and 3-fluorophenoxy.
  • phenoxymethyl group, 3-chlorophenoxymethyl group, 3,5-dichloro A phenoxymethyl group or a 3,4-dichlorophenoxymethyl group is particularly preferred.
  • R ' is a linear alkyl group having 3 to 8 carbon atoms, an aryloxyalkyl group, or a substituted aryloxyalkyl group.
  • P and Q are each independently —CO—, —CH (OR 2 ) —, or —CH 2 —.
  • R 2 is each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an acyl group having 1 to 20 carbon atoms, and is preferably a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.
  • R 2 is an alkyl group having 1 to 6 carbon atoms, the group is preferably a linear group, and particularly preferably a methyl group or an ethyl group.
  • the PG derivative (1) of the present invention in which R 2 is an acyl group having 1 to 20 carbon atoms is useful as a prodrug because it can be converted into a physiologically active compound by hydrolysis in a living body.
  • R 2 is an acyl group having an alkyl group having 4 to 18 carbon atoms
  • the PG derivative (1) of the present invention is useful as a prodrug having improved lipophilicity, and is preferable.
  • the PG derivative (1) of the present invention as the PG skeleton (the PG skeleton is a skeleton based on prostanoic acid) in the compound, a compound having a basic skeleton of PGF is preferable. That is, the PG derivative (1) of the present invention is preferably a 15-doxy-15,15-difluoro PGF derivative.
  • R 3 is a group selected from a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group having 3 to 8 carbon atoms, an aryl group, an aralkyl group, and an acyl group, or a hydrogen atom in the selected group. At least one is a substituted group.
  • a hydrogen atom, an alkyl group, or an alkylcarbonyl group is preferable, and particularly, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkylcarbonyl group having an alkyl group having 1 to 6 carbon atoms is preferable.
  • the PG derivative (1) in which R 3 is an alkylruponyl group is useful as a prodrug because it can be converted to PG having bioactivity by hydrolysis in vivo.
  • the type of the alkyl group can be selected to control the lipophilicity of the compound.
  • R 4 and R 5 are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, an alkynyl group having 2 to 6 carbon atoms, or a cycloalkyl group having 3 to 6 carbon atoms , An aryl group, or an aralkyl group, and R 4 and R 5 are preferably a hydrogen atom.
  • the PG derivative (1) of the present invention is a compound obtained by reducing a 1-carboxy group or a 1-ester group of a 15-doxy-1,15-difluoro PG having the same basic skeleton to form a first alcohol (for example, It is preferable to use the following PGF 2a ) as a raw material.
  • 15-deoxy-15,15-difluoro PGs those having a carbon skeleton similar to that of the natural type can be produced by referring to a general PG production method.
  • a general PG production method starting from a Co lactone lactone as a starting material, an ⁇ chain is introduced into the lactone, and the obtained ketones (3) are subjected to a fluorination reaction to form carbon atoms corresponding to the 15-position. It is converted to lactones (4) with an introduced ⁇ chain to which two fluorine atoms are bonded.
  • scale 1 in the formula, R 2, A, and X are the same meaning as the meaning in formula (1)
  • Z represents a hydroxyl group or an alkoxy group having 1 to 20 carbon atoms.
  • Y represents a hydrogen atom or a logen atom, preferably a chlorine atom, a bromine atom or an iodine atom.
  • R 6 represents a group selected from an alkyl group, an aryl group, and an aralkyl group, a group in which one or more hydrogen atoms in the selected group are substituted, or a dialkylamino group.
  • Compounds in which Z is a hydroxyl group may form a salt with a base.
  • Alkali metal salts such as salts and potassium salts; alkaline earth metal salts such as potassium salts and magnesium salts; and ammonium salts such as ammonium salts and N-alkyl-substituted ammonium salts.
  • the PGF 2a derivative (2) having an unnatural skeleton can be synthesized with reference to the method described in JP-A-11-07344. For example, keto with the desired ⁇ chain The lactones (3) are subjected to a fluorination reaction to produce lactones (4) with an ⁇ chain having two fluorine atoms at the 15-position, and then the lactones (4) are reduced to lactols (
  • the PGF 2a derivative (2) can be obtained by converting the lactol (5) with a phosphorane (6) to introduce a heavy chain unit. Phosphoranes (6) are obtained from phosphonium salts (7).
  • ketones (3) are known compounds.
  • the novel ketones (3) in which R ′ has a specific substituent are known ketones
  • a novel ketone (3) can be produced by reacting a dialkyl 3-substituted 1-2-oxopropyl phosphonate with a colilactone having a formyl group.
  • Various known fluorination methods can be applied to carry out the fluorination reaction of the ketones (3) to the lactones (4).
  • a method of reacting in an inert solvent using various nucleophilic fluorinating agents is employed.
  • the ketone (3) has a functional group that can be fluorinated during the fluorination reaction, it is preferable that the functional group be protected in advance by a protecting group.
  • a protecting group For example, when R 2 is a hydrogen atom, it is preferable to protect with a protecting group, fluorinate the carbonyl group at the 15-position, and then perform deprotection.
  • R 2 of the final compound may be used without deprotection, and after deprotection, new R 2 may be introduced. Is also good.
  • the method for deprotection of the protected hydroxyl group can be a conventional method.
  • a fluorinating agent a known or well-known nucleophilic fluorinating agent can be used.
  • nucleophilic fluorinating agents described in "Chemistry of Fluorine” by Tomoya Kitazume, Takashi Ishihara, and Takeo Taguchi (Kodansha Scientifits).
  • the carbonyl group at the 15-position of ketones (3) is reacted with an oxime, hydrazone, thioacetal, or diazo compound.
  • a fluorinating agent may act.
  • the method of Olah et al. Syn 1 et 1990, 594, Syn let t., 1994, 425
  • Kat Ka enelle nb og en et al. J.
  • the nucleophilic fluorinating agent is preferably used in the presence of an inert solvent.
  • the inert solvent include a halogen-based solvent, an ether-based solvent, a hydrocarbon-based solvent, an ester-based solvent, a polar solvent, and a mixed solvent thereof.
  • the lactones (4) are preferably reduced by a method in which a reducing agent is allowed to act in an inert solvent.
  • a reducing agent for example, "New Experimental Chemistry Lecture 15 Oxidation and Reduction (II)" (Maruzen), “4th Edition Experimental Chemistry Lecture 26 Organic Synthesis VIII, Asymmetric Synthesis, Reduction, Sugar, Labeled Compounds” (Maruzen) Method can be used.
  • hydrides are preferable as the reducing agent used for the reduction of lactones and (4).
  • examples include hydrides of metal containing silicon, metal hydride complex compounds, borohydride compounds, diisobutylaluminum hydride [DI BAH], sodium bis (2-methoxyethoxy) aluminum hydride, etc. Is preferred.
  • DI BAH diisobutylaluminum hydride
  • Examples of the inert solvent used for the reduction in (4) include an ether solvent, a hydrocarbon solvent, a polar solvent, and a mixed solvent thereof.
  • the configuration of the hydroxyl group of the lactols (5) formed by the reduction reaction is not particularly limited.
  • B z represents a benzyl group
  • Me represents a methyl group
  • i Pr represents an isopropyl group.
  • the reduction of the carboxy group at the 1-position of the PGF 2a derivative (2) can be performed by a method of converting a carboxylic acid or a derivative thereof to an alcohol, and it is preferable to carry out a chemical reduction reaction in an inert solvent.
  • Examples of the method include the methods described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen), “4th Edition Experimental Chemistry Course 20 Organic Synthesis II. Alcohol and Amin” (Maruzen) and the like. Can be adopted.
  • the reduction reaction may be performed as it is, reduced after conversion to carboxylic acid, or performed after conversion of carboxylic acid to ester.
  • the amount of the reducing agent used in this reduction reaction is preferably 0.01 to 50 equivalents, and particularly preferably 1 to 20 equivalents to the PGF 2a derivative (2).
  • the reaction temperature is preferably from -150 to +100, particularly preferably 180 °. ⁇ 0 ⁇ is preferred.
  • the reducing agent used in the reduction reaction of the PGF 2a derivative (2) is preferably a hydride, particularly diisobutylaluminum hydride [DIB AH], dialkylaluminum alkoxide, lithium aluminum hydride [LAH] , Triethylsilane, trichlorosilane, sodium borohydride, sodium trimethoxyborohydride, trialkoxyaluminum lithium hydride, sodium bis (2-methoxyethoxy) aluminum hydride, diborane, and the like are preferable, and aluminum hydride is particularly preferable.
  • DIBAH sodium bis (2-methoxyethoxy) aluminum hydride, disiamilporan, or lithium tri (sec-butyl) borohydride is preferred.
  • the reduction reaction of the PGF 2a derivative (2) is preferably performed in the presence of an inert solvent.
  • an inert solvent an ether solvent, a hydrocarbon solvent, a polar solvent, or a mixed solvent thereof is preferable, and getyl ether, tetrahydrofuran (THF), tert-butyl methyl ether, or toluene is particularly preferable.
  • PG derivatives (Formula (1b), Formula (1c), Formula (1d)) It can be synthesized from the GF 2a derivative (la). However, ⁇ scale 5 in the formula, A, and X represents the same meaning as in the formula (1).
  • P ′ and Q ′ are each independently —CO—, —CH (OR 20 ) — (R 2 ° is each independently a hydrogen atom or a hydroxyl-protecting group.) Or one CH 2 Indicates-.
  • the PGE derivative (lc) in which Q ′ is —CH (OH) — is protected after protecting the hydroxyl group at the 11-position of the PGF 2a derivative (lb) and, if a hydroxyl group is present at the 1-position, after protecting the hydroxyl group.
  • the hydroxyl group at position 9 is oxidized to a carbonyl group, and then the protected water It can be synthesized by deprotecting the acid group.
  • Another method for producing the PGE derivative (lc) is to protect the hydroxyl group at position 11 of the lactones (4), convert them to lactols (5), introduce the ⁇ -chain by the Itttig reaction, The 9-position is oxidized to a carbonyl group, and the 11-position is further deprotected to a hydroxyl group.
  • the PGD derivative (Id) in which P 'is -CH ( ⁇ ) is a PGF 2a In the derivative (la), if the 9-position and 1-position hydroxyl groups are present, protect the hydroxyl group, oxidize the 11-position hydroxyl group, and then deprotect the protected 9-position hydroxyl group Can be synthesized by
  • Examples of the carbonyl group-protecting group include acetals such as ethylene acetal, propylene acetate and distil acetal, and ketones; dithioacetals such as 1,2-dithiane and 1,3-dithiane; Evening varieties.
  • R 3 of the PG derivative (1) of the present invention is an alkyl group, an alkenyl group, an alkynyl A group selected from the group consisting of a cycloalkyl group having 3 to 8 carbon atoms, an aryl group and an aralkyl group, or a group in which at least one hydrogen atom in the selected group is substituted, R 3 is hydrogen It can be produced by a method of reacting a halogen compound with the PG derivative (1) as an atom. For example, the method described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (I)” (Maruzen) can be adopted.
  • the PG derivative (1) of the present invention has a hydroxyl group at the 9-position and the Z-position or the 11-position, for example, it is described in “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (V)” (Maruzen) It is preferable to carry out the above-mentioned reaction after protecting the hydroxyl group with a protecting group by the above method.
  • the protecting group include a triorganosilyl group, an alkyl group, an aralkyl group, and a monovalent group having a cyclic ether structure.
  • the triorganosilyl group is preferably a group in which three alkyl groups, aryl groups, aralkyl groups or alkoxy groups are bonded to a silicon atom, and in particular, a lower alkyl group or aryl group is bonded to a silicon atom by three groups. Individually bonded groups are preferred.
  • Specific examples of the protecting group include a tetrahydrovinylyl group, t tert -butyldimethylsilyl group, t tert -butyldiphenylsilyl group, triethylsilyl group, triphenylsilyl group, and triisopropylsilyl group.
  • the hydroxyl protecting group can be easily deprotected.
  • the PG derivative (1) of the present invention When the PG derivative (1) of the present invention has an alkoxy group at the 9-position or the 11-position, it can be produced by a method of reacting a halogen compound with the PG derivative (1) wherein R 2 is a hydrogen atom.
  • R 2 is a hydrogen atom.
  • the PG derivative (1) of the present invention has a hydroxyl group at the 1-position
  • the hydroxyl group at the 1-position in the PG derivative having a hydroxyl group at the 1-position and R 2 being a hydrogen atom is as described above. It is preferable to produce by a method of reacting with a halogen compound after protection by the method described above.
  • the PG derivative (1) of the present invention has an acyloxy group at the 1-, 9-, or 11-position
  • the PG derivative (1) has high lipophilicity and is hydrolyzed in vivo. It can be a useful prodrug that can be converted to a biologically active compound.
  • the compound is preferably produced by esterifying a PG derivative (1) having a hydroxyl group at the 1-, 9- or 11-position. Esterification is based on hydroxyl group And a method of bonding a thiol group. Examples of such methods include “New Experimental Chemistry Course 14, Synthesis and Reaction of Organic Compounds (11)” (Maruzen), “4th Edition Experimental Chemistry Course 22 Organic Synthesis IV, Acids, Amino Acids and Peptides” (Maruzen), etc. Can be adopted. Examples of the compound that becomes the group of the acyl group include carboxylic acid, acid anhydride, and carboxylic acid halide.
  • the acyl group that can be bonded to the 1-position hydroxyl group of the PG derivative (1) is a saturated or unsaturated aliphatic acyl group, a saturated or unsaturated cycloaliphatic acyl group, an aromatic acyl group, or a heterocyclic acyl group. And an alkyl group-containing acyl group.
  • an acyl group bonded to the 9-position or the 11-position an acyl group having 1 to 20 carbon atoms is preferable.
  • oxidation method examples include those described in “New Experimental Chemistry Course 15 Oxidation and Reduction (I-I 1), (I-I 2)” (Maruzen), “4th Edition Experimental Chemistry Course 23 Organic Synthesis V” (Maruzen), etc. Oxidation with chromic acid or dimethyl sulfoxide is preferred. Jones oxidation, Collins oxidation, acid oxidation with pyridinum chromatochromate, or Swern oxidation is particularly preferred.
  • the PG derivative (1) of the present invention has an asymmetric carbon in its structure, there are various stereoisomers and optical isomers. In the present invention, all of these stereoisomers are used. , Optical isomers, and mixtures thereof.
  • ID-133 Ethylene group Pentyl group Methyl group Acetyl group
  • ID-135 Ethylene group Phenoxymethyl group Methyl group Acetyl group
  • ID-148 trans-Hinylene 3 ⁇ 4 3,5-dichlorophenoxymethyl group Methyl group Bivaloyl group
  • ID-2 compounds ((1D-201) to (1D-248)) in which A, RR 2 , and R 3 have the structures shown in the following table are mentioned.
  • Nanore J with nanore l u-Z o t rans-Hiniren no eno no ten nasore winding nano rema J J ⁇ nanore 3 ⁇ 4 amenareno kami 6- u u nono ten nanorema
  • ID-248 ans-Hinylene 3,5-dichlorophenoxymethyl methyl Methyl Bivaloyl [Example of PGE derivative]
  • IF-mt rans—Pinylene 3,5-dichlorophenoxymethi JbS Methi H Vivaloy
  • RR 21 , R 22, and R 3 is a structure shown in the following table 6 ((1 F- 20 1) ⁇ (1 F- 272)) can be mentioned.
  • the novel PG derivative (1) of the present invention has higher lipophilicity and better absorbability in a living body than the 15-dexoxy15,15-difluoro PG derivative having the same carbon skeleton.
  • the PG derivative (1) of the present invention has high chemical stability. In particular, those in which an alcoholic hydroxyl group or an etheric oxygen atom is bonded to the carbon atom at position 1 are not hydrolyzed. It is a compound that is not easily decomposed.
  • the PG derivative (1) of the present invention is useful as a medicament, and is used as an ophthalmic disease, inflammatory disease, allergic / immune disease, digestive system disease, central nervous system disease, circulatory system disease, analgesic, osteoporosis therapeutic agent, It can exhibit excellent effects as a drug such as an anticancer drug.
  • Eye diseases include glaucoma, ocular hypertension, retinopathy, conjunctivitis, uveitis, retinitis and the like.
  • Inflammatory diseases include acute hepatitis, chronic hepatitis, cirrhosis, cholecystitis, cholangitis, acute knee inflammation, chronic tengitis, chronic peritonitis, acute peritonitis, cystitis, acute nephritis, chronic nephritis, encephalitis, polyneuritis Includes inflammation, meningitis, myelitis, arthritis, rheumatoid arthritis, bronchitis, pneumonia, pleurisy, phlebitis, pericarditis, rhinitis, pharyngitis, otitis media, otitis externa.
  • Immunological diseases include bronchial asthma, allergic dermatitis, allergic rhinitis, atopy, rheumatism, collagen disease, etc.
  • Gastrointestinal disorders include gastric ulcer, gastritis, duodenal ulcer, ulcerative colitis, Crohn's disease and the like.
  • Central nervous system disorders include insomnia, anxiety, depression, schizophrenia, and dementia.
  • Cardiovascular diseases include peripheral circulatory disorders, Bajja's disease, Reino's disease, angina, myocardial infarction, heart failure, pulmonary hypertension, pulmonary embolism, diabetes, cerebral infarction, cerebral thrombosis, hearing loss, Meniere's disease, etc. It is.
  • the PG derivative (1) of the present invention has an excellent intraocular pressure lowering effect, and has little effect on eye irritation and eye tissues such as cornea, iris and conjunctiva. Furthermore, its usefulness as a medicine is extremely high because of its high corneal permeability and high intraocular absorption. Therefore, the medicament of the present invention is particularly effective as an agent for preventing or treating glaucoma or ocular hypertension.
  • the medicament of the present invention is used by topically administering a preparation containing the above-mentioned compound of the present invention as an active ingredient to the eye by a method such as eye drops.
  • Examples of the dosage form include eye drops such as eye drops and ointments, injections, and the like, and the compound of the present invention can be formulated using commonly used techniques.
  • eye drops such as eye drops and ointments, injections, and the like
  • isotonic agents such as sodium chloride and concentrated glycerin
  • buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbine monomonolate (hereinafter referred to as polysorbate 80), polyoxyl stearate 40
  • surfactants such as polyoxyethylene hydrogenated castor oil
  • It can be formulated as necessary using stabilizers such as sodium phosphate and sodium edetate, and preservatives such as benzalkonium chloride and paraben, and the pH should be within the acceptable range for ophthalmic preparations.
  • the range of ⁇ 8 is preferred.
  • the dose can be appropriately selected in consideration of symptoms, age, dosage form, etc., but if it is an ophthalmic solution, 0.0005 to 1% (wZv), preferably 0.0005 to 0.5 (w / v) It should be instilled once to several times a day.
  • Example 10 15-Doxy-15,15-difluoro-9,11-bis (t-butyldimethylsilyloxy) _16-phenoxy-17,18,19,20- Tetranor PGF 2a isopropyl ester (hereinafter referred to as disilyl ether), and 15-deoxy-15,15-difluoro-11-t-butyldimethylsilyloxy-16-phenoxy-17,18,1 Synthesis of 9,20-tetranor PGF 2a isopropyl ester (hereinafter referred to as monosilyl ether) A solution of the isopropyl ester (12.00 g) synthesized in Example 5 in dimethylformamide (117 mL) was diluted to zero.
  • Example 11 In a similar manner to Example 8, using the compound (0.93 g) obtained in Example 11, 337 mg of the title compound was obtained.
  • Example 8 Using the compound (0.202 g) obtained in Example 11 and tyl iodide (0.156 mL), 69 mg of the title compound was obtained in the same manner as in Example 8.
  • Example 19 Synthesis of 15-dexoxy 15,15-difluoro-9-methoxy-11-tert-butyldimethylsilyloxy-16-phenoxy-1,17,18,19,20-tetranor PGF 2a isopropyl ester Using the monosilyl ether (6.00 g) obtained in Example 10 as in Example 8, 34 lmg of the title compound was obtained.
  • the amount of compound 6 was changed, and the amount of the additive was appropriately increased or decreased, so that 0.0005% (wZv) ophthalmic solution, 0.0001% (w / v) ophthalmic solution, 0.0 01% (w / v) ophthalmic solution, 0.005% (w / v) ophthalmic solution, 0.05% (wZv) ophthalmic solution and 0.1% (wZV) ophthalmic solution can be prepared.
  • a physiological saline solution of the test compound (Polysorbate 80 was used as a solubilizer) 0.005% (w / v) was used as an ophthalmic solution.
  • a solution containing only the base without the test compound was used as a control.
  • the compound of the present invention exhibited an excellent intraocular pressure lowering effect, and continuity of the intraocular pressure reduction was observed even 6 to 8 hours after instillation.
  • the intraocular pressure lowering effect was superior to the control. This confirms that the compound of the present invention exhibits an excellent intraocular pressure lowering effect and is useful as an intraocular pressure lowering agent.

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Abstract

La présente invention concerne un composé représenté par la formule (1) et un médicament contenant le composé en tant qu"ingrédient actif. Dans la formule, A représente un groupe éthylène ou vinylène, etc. ; X représente -CH2-, etc. ; P et Q représentent chacun -CO- ou -CH(OR2)- (R2 représentant hydrogène, etc.) ; R1 représente alkyle linéaire C¿3-8?, etc. ; R?3¿ représente hydrogène, acyle, etc. ; R4 et R5 représentent chacun hydrogène, etc. .; et la ligne double formée d"une ligne continue et d"une ligne discontinue indique une liaison simple ou une double liaison cis ou trans.(1)
PCT/JP2001/000540 2000-01-28 2001-01-26 Nouveau derive difluoroprostaglandine WO2001055102A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026149A1 (fr) * 2011-08-24 2013-02-28 Apotex Pharmachem Inc. Phosphonate de diméthyl-(3,3-difluoro-2,2-dihydroxyheptyle) et ses procédés de préparation
WO2014023256A1 (fr) * 2012-08-10 2014-02-13 Scinopharm (Changshu) Pharmaceuticals, Ltd. Procédé de préparation de tafluprost et de ses intermédiaires

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019490A1 (fr) * 1990-06-14 1991-12-26 Allergan, Inc. Alcools de pgf 1 et leur emploi en tant qu'hypotenseurs oculaires
EP0639563A2 (fr) * 1993-08-03 1995-02-22 Alcon Laboratories, Inc. Utilisation de cloprostenol, fluprostenol et ses analogues pour la fabrication d'un médicament pour le traitement du glaucome et de l'hypertension oculaire
EP0850926A2 (fr) * 1996-12-26 1998-07-01 Asahi Glass Company Ltd. Dérives difluoroprostaglandines et leur application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991019490A1 (fr) * 1990-06-14 1991-12-26 Allergan, Inc. Alcools de pgf 1 et leur emploi en tant qu'hypotenseurs oculaires
EP0639563A2 (fr) * 1993-08-03 1995-02-22 Alcon Laboratories, Inc. Utilisation de cloprostenol, fluprostenol et ses analogues pour la fabrication d'un médicament pour le traitement du glaucome et de l'hypertension oculaire
EP0850926A2 (fr) * 1996-12-26 1998-07-01 Asahi Glass Company Ltd. Dérives difluoroprostaglandines et leur application

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013026149A1 (fr) * 2011-08-24 2013-02-28 Apotex Pharmachem Inc. Phosphonate de diméthyl-(3,3-difluoro-2,2-dihydroxyheptyle) et ses procédés de préparation
WO2014023256A1 (fr) * 2012-08-10 2014-02-13 Scinopharm (Changshu) Pharmaceuticals, Ltd. Procédé de préparation de tafluprost et de ses intermédiaires

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