JP2019085413A - Pharmaceutical containing novel prostaglandin derivative as active ingredient - Google Patents

Abstract

To provide a pharmaceutical that can be orally administered, and has less side effect, higher safety, and excellent effectiveness and pharmacokinetic properties, and contains a compound useful for a blood flow improver, especially, a therapeutic agent for a blood flow disorder and pain caused by spinal stenosis, as an active ingredient.SOLUTION: The present invention provides a compound of formula 1 [R: -CH=CZ(COX) or the like; Z: H or the like; X: ORor the like; R: H or the like; Y: S or the like; A-B: a carbon-carbon single bond or the like; a hydroxy group bound by a wave line: a hydroxy group such as α-arrangement; R, R: independently H or the like; n is an integer of 0-2; Ris a C2-3 alkyl group or a C3-5a cycloalkyl group].SELECTED DRAWING: None

Description

  The present invention relates to a novel prostaglandin derivative having an alkynyl group in the ω chain of prostaglandins, or a pharmaceutically acceptable salt thereof, or a medicament containing as its active ingredient a cyclodextrin clathrate thereof, in particular, the bloodstream The present invention relates to a medicine for the prevention or treatment of a disorder.

  Peripheral artery occlusion is a disease that causes arteriosclerosis and thrombosis to narrow and occlude the artery, and the periphery, especially the lower limbs, becomes ischemic, presenting symptoms such as cold sensation, intermittent claudication, pain, ulcers and necrosis of the lower limbs, etc. . For improvement of lower extremity symptoms, it is important to improve blood flow to the ischemic part, and treatment for resuming circulation by medicine or physical method is performed. As drug therapy, drugs having vasodilator activity and platelet aggregation inhibitory activity are used.

  Peripheral vascular disease also manifests as atherosclerotic stenosis of the renal arteries, which can lead to renal ischemia and renal dysfunction. Chronic diabetes can also lead to atherosclerosis and vascular complications involving large blood vessels, arterioles and capillaries. Diabetic patients are at high risk of developing foot ulcers due to long term complications such as neuropathy and ischemia.

  Spinal canal stenosis is a disease in which the spinal canal is narrowed due to hypertrophy or degeneration of the spine and yellow ligament that constitute the spinal canal, or the projection of an intervertebral disc, and nerve tissues such as nerve roots and caudas are compressed and show various symptoms. is there. Spinal canal stenosis is classified into wide spinal canal stenosis, thoracic spinal canal stenosis, lumbar spinal canal stenosis and the like according to the narrowing portion of the spinal canal. The symptoms include back pain due to nerve compression, pain in the upper or lower limbs, numbness and the like. In particular, when the cauda equina nerve is injured, back pain, leg pain, numbness, and feeling of weakness become worse during walking, and this symptom is called intermittent claudication.

  Natural prostaglandins (hereinafter referred to as prostaglandins as PGs) are a group of physiologically active substances synthesized in vivo, which regulate the cellular functions of various tissues as local hormones having various physiological activities. There is. In particular, PGE1s, which are a type of natural PG, have, for example, vasodilator action, angiogenic action, platelet aggregation suppressive action, epithelial regeneration promoting action and the like, and in drug therapy of the above diseases, antiplatelet agent And peripheral blood flow disorder. Although PGEs may be applicable to other indications as well, natural PGEs are extremely unstable chemically and metabolically, so development research on PGE derivatives with more stable and high efficacy and few side effects Have been studied diligently.

  About the PG derivative which has a double bond in 2 position of PG, and its manufacturing method, it is reported by following patent documents 1-5 and nonpatent literature 1 -2. Moreover, about PG derivative which has an alkynyl group in the (omega) chain | strand of PG, and its manufacturing method, it is reported by the following patent documents 6-7.

Japanese Patent Application Laid-Open No. 50-71649 Japanese Patent Application Laid-Open No. 50-116452 JP-A-52-85151 JP-A-53-149954 Japanese Patent Application Laid-Open No. 55-100360 Japanese Patent Application Laid-Open No. 51-131860 JP-A-54-12352

Ann. Acad. N. Y. Sci., 1971, vol. 180, p. Prostaglandins, 1974, vol. 8, p. 341.

  It is an object of the present invention to be a blood flow improving agent which can be orally administered, has less side effects, is more safe, and is excellent in efficacy and pharmacokinetics, especially blood flow disorder associated with spinal stenosis or the like It is an object of the present invention to provide a medicament comprising, as an active ingredient, a compound useful for treating pain. Among the compounds described in the literature, especially, (2E) -7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 5S) -3-hydroxy-5-methylnon-1-ene- 1-yl) -5-oxocyclopentyl) hept-2-enoic acid (limaprost) is a compound showing excellent efficacy, and a blood flow improving agent containing the limaprost as an active ingredient is obstructive in actual medical practice It is used for the treatment of pain and cold associated with thromboangiitis and spinal stenosis. However, limaprost has side effects on the digestive tract, and there is still room for improvement in blood flow increase action and drug efficacy persistence. In particular, limaprost's smooth muscle contraction action is high, and the side effect of causing diarrhea remains as a problem to be solved. Therefore, development of a PGE1 derivative having the same physiological activity as that of the natural type and having high side effects and high durability has been intensively studied in and outside.

However, PGs having a double bond at position 2 of PG and an alkynyl group in the ω chain have not been reported. Furthermore, PGEs having a double bond at the 2-position of PG and a triple bond at the 18-position have not been reported at all for examples of their synthesis, physical properties, physiological activity and the like.
In addition, PGEs having a triple bond at position 18 of PG and a cycloalkyl group at the end of the triple bond have not been reported at all with respect to synthesis examples, physical properties, physiological activity and the like.

The present inventors have synthesized novel PGs and studied to clarify their physical properties and physiological activities. As a result, a compound represented by the following formula (1) (hereinafter sometimes referred to as compound (1)) or a pharmaceutically acceptable salt thereof (hereinafter, compound (1) and its pharmaceutically acceptable salt) It may be collectively referred to as “the present compound”) or cyclodextrin clathrates thereof have excellent physical properties and pharmacological actions, and furthermore, agents for improving blood flow, especially those associated with spinal canal stenosis It has been found that the compound is an excellent compound as a therapeutic agent for blood flow disorders and pain, and the present invention has been completed.
That is, the present invention is as follows.
[1] lower equation (1):

[In the formula (1),
R ^A represents —CH ₂ —CZ ¹ Z ² (COX) or —CH = CZ ¹ (COX), Z ¹ and Z ² each independently represent a hydrogen atom or a fluorine atom, and X represents OR ⁴ or NR ⁵ R ⁶ is represented, R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms having a substituent, R ⁵ is a hydrogen atom, 1 carbon atom R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms having a substituent, An alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms having a substituent, an arylsulfonyl group having 6 to 10 carbon atoms or an arylsulfonyl group having 6 to 10 carbon atoms having a substituent;
Y represents CH ₂ , S or O;
A-B represents a carbon-carbon single bond or a carbon-carbon double bond;
The hydroxyl group bound by a wavy line represents a hydroxyl group which is α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration;
R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms having a substituent;
n represents an integer of 0 to 2;
R ³ represents a cycloalkyl group alkyl or 3 to 5 carbon atoms having 2 to 3 carbon atoms. Or a pharmaceutically acceptable salt thereof, or a medicament containing the cyclodextrin clathrate thereof as an active ingredient;
[2] The medicament according to [1], wherein Y is CH ₂ ;
[3] The medicament according to [1] or [2], wherein R ^A is —CH = CZ ¹ (COX);
[4] The medicament according to [1] or [2], wherein R ^A is —CH ₂ —CZ ¹ Z ² (COX);
[5] The medicine according to any one of [1] to [4], wherein n is 1.
[6] The medicament according to any one of [1] to [5], wherein AB is a carbon-carbon double bond;
[7] The medicament according to any one of [1] to [6], wherein R ¹ is a hydrogen atom and R ² is an alkyl group having 1 to 3 carbon atoms;
[8] The medicine according to any one of [1] to [7], wherein R ³ is a cycloalkyl group having 3 to 5 carbon atoms;
[9] The medicine according to any one of [1] to [8], wherein X is OR ⁴ ;
[10] The medicament according to any one of [1] to [9], which is an agent for preventing or treating blood flow disorder;
[11] The medicine according to [10], wherein the blood flow disorder is nerve blood flow disorder;
[12] The medicine according to [11], wherein the nerve blood flow disorder is a blood flow disorder associated with spinal stenosis.
[13] The medicine according to [10], wherein the blood flow disorder is a blood flow disorder in a peripheral artery, skin or brain;
[14] The medicament according to [13], wherein the peripheral blood flow is impaired due to chronic arterial occlusion or pulmonary hypertension;
[15] The medicine according to [13], wherein the blood flow disorder in the skin is a blood flow disorder associated with a pressure sore wound;
[16] The medicament or the like according to [13], wherein the cerebral blood flow disorder is a blood flow disorder associated with suppression of recurrence after cerebral infarction.

The present compound, or its cyclodextrin inclusion compound, has a very strong inhibitory action on platelet aggregation in humans and rats, and also has an excellent blood flow increase action in the equine blood flow test when intravenously administered to rats Are useful as a preventive or therapeutic agent for blood flow disorders.
In addition, since the present compound or its cyclodextrin inclusion compound has an alkyl group (especially a methyl group) bound to the carbon atom at position 16 adjacent to the hydroxyl group at position 15 of its PG skeleton, oxidative metabolism by PG dehydrogenase is Resistant, high metabolic stability. Therefore, the half-life in blood is longer and the effective blood concentration can be maintained longer as compared with the natural type PG compound. Also, the improvement of metabolic stability can significantly improve the bioavailability of the drug containing the present compound.

Hereinafter, the definition of each symbol in Formula (1) is explained in full detail.
The nomenclature of compounds in the present specification uses IUPAC nomenclature in principle, but may be denoted using a numbering numeral based on a prostanoic acid skeleton as appropriate to indicate the position of the PG skeleton. In the present specification, a group in which a hydrogen atom of an alkyl group is substituted is also referred to as a substituted alkyl group. The same applies to other groups. In addition, "lower" means that the carbon number is 1 to 6, and 1 to 4 is preferable.

  The "alkyl group" may be linear or branched. The alkyl group is preferably an alkyl group having 1 to 6 carbon atoms, and particularly preferably an alkyl group having 1 to 4 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, a hexyl group and the like.

  The "alkenyl group" may be linear or branched. The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms. Examples of the alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 3-pentenyl group, and a 4-hexenyl group.

  The "alkynyl group" may be linear or branched. The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms. Examples of the alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group, 3-butynyl group, 3-pentynyl group, 4-hexynyl group and the like.

  The "alkoxy group" refers to a group in which an oxygen atom is bonded to the terminal of the alkyl group. The alkoxy group may be linear or branched. The alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms, and particularly preferably an alkoxy group having 1 to 4 carbon atoms. Examples of the alkoxy group include a methoxy group, an ethoxy group, a propoxy group, or a butoxy group.

  The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

  The "aryl group" refers to an aromatic hydrocarbon group, preferably an aryl group having 6 to 18 carbon atoms, and particularly preferably an aryl group having 6 to 10 carbon atoms. As an example of an aryl group, a phenyl group, a naphthyl group, an anthryl group etc. can be illustrated, A phenyl group is especially preferable.

  The "aralkyl group" refers to an alkyl group to which an aryl group is bonded. As an aryl group in the aralkyl group, an aryl group having 6 to 10 carbon atoms is preferable, and a phenyl group is particularly preferable. The alkyl group in the aralkyl group is preferably an alkyl group having 1 to 4 carbon atoms. Examples of aralkyl group include benzyl group, benzhydryl group, trityl group, and phenylethyl group.

  The "cycloalkyl group" refers to a 3- or more-membered cyclic alkyl group, preferably a 3- to 6-membered cycloalkyl group. Examples of the cycloalkyl group include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group and the like.

The “alkylsulfonyl group” refers to a monovalent group in which —S (O) ₂ — is bonded to the terminal of the alkyl group. The carbon number of the alkyl group in the alkylsulfonyl group is preferably 1 to 6. Examples of the alkylsulfonyl group include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, a hexanesulfonyl group and the like.

The “arylsulfonyl group” refers to a monovalent group in which —S (O) ₂ — is bonded to the bonding end of the aryl group. The aryl group in the arylsulfonyl group is preferably a group having 6 to 10 carbon atoms, and the same groups as the above-mentioned aryl group are preferable. Examples of the arylsulfonyl group include arylsulfonyl groups having 6 to 10 carbon atoms, such as benzenesulfonyl group, 1-naphthalenesulfonyl group, 2-naphthalenesulfonyl group and the like, with preference given to benzenesulfonyl group.

The "acyl group" refers to a monovalent group formed by removing a hydroxyl group from a carboxy group of a carboxylic acid. As the carboxylic acid, carboxylic acids having 1 to 10 carbon atoms are preferable, and formic acid, saturated aliphatic carboxylic acids (for example, alkylcarboxylic acids such as acetic acid, propionic acid, and butyric acid etc.), unsaturated aliphatic carboxylic acids (for example, And alkenyl carboxylic acids such as acrylic acid), carbocyclic carboxylic acids, heterocyclic carboxylic acids and the like.
Examples of carbocyclic carboxylic acids include saturated cyclic aliphatic carboxylic acids (eg, cycloalkyl carboxylic acids such as cyclopropyl carboxylic acid, cyclopentyl carboxylic acid, cyclohexyl carboxylic acid and the like), unsaturated cyclic aliphatic carboxylic acids (eg, cyclohexenyl) And cycloalkenyl carboxylic acids such as carboxylic acids) or aromatic carboxylic acids. The aromatic carboxylic acid is a compound in which the aryl group is bonded to a carboxy group, and examples thereof include aryl carboxylic acids such as benzoic acid and naphthyl carboxylic acid. The heterocyclic carboxylic acid refers to a compound in which a heterocyclic group is bonded to a carboxy group.

  The “heterocyclic group” is a 3- to 10-membered monovalent saturated or unsaturated heterocyclic group containing at least one hetero atom selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom preferable. Examples of 3- to 10-membered saturated or unsaturated heterocyclic rings include aziridine, azetidine, pyrrole, pyrroline, pyrrolidine, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, pyridine, piperidine, pyrazine, piperazine, pyrimidine And pyridazine, thiazole, thiazoline, thiazolidine, isothiazole, isothiazoline, isothiazolidine, oxazole, oxazoline, oxazolidine, isoxazole, isooxazoline, isoxazolidine, morpholine, azepane, azepine and the like.

In the present specification, it is called halogenation that one or more of the hydrogen atoms in the group are substituted by a halogen atom. For example, a halogenated alkoxy group refers to a group in which one or more of the hydrogen atoms of the alkoxy group are substituted with a halogen atom. The same applies to other groups. As a halogen atom, a fluorine atom or a chlorine atom is preferable.
In the case where a halogenated alkyl group is present in the structure of the halogenated group, a halogenated lower alkyl group is preferable, and a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a penta group is preferable. A fluoroethyl group, a chloromethyl group, or a bromomethyl group etc. are mentioned.

  The "alkoxyalkyl group" refers to an alkyl group in which one of the hydrogen atoms in the alkyl group is substituted with an alkoxy group. The alkoxy group in the alkoxyalkyl group is preferably an alkoxy group having 1 to 4 carbon atoms. The alkyl group in the alkoxyalkyl group is preferably an alkyl group having 1 to 4 carbon atoms. 2-6 are preferable and, as for carbon number of an alkoxy alkyl group, 2-4 are more preferable. Examples of the alkoxyalkyl group include methoxymethyl group, ethoxymethyl group, propoxymethyl group, methoxyethyl group, ethoxyethyl group and the like.

  The "hydroxyalkyl group" refers to a group in which at least one hydrogen atom in an alkyl group is substituted with a hydroxyl group. The carbon number of the hydroxyalkyl group is preferably 2 to 6. The hydroxyl group of the hydroxyalkyl group is preferably one. Examples of hydroxyalkyl groups include 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 4-hydroxybutyl and the like.

  An "alkoxy carbonyl group" means the group which the said alkoxy group couple | bonded with the carbonyl group. As the alkoxycarbonyl group, an alkoxycarbonyl group in which an alkoxy group having 1 to 6 carbon atoms is bonded to a carbonyl group is preferable. Examples of the alkoxycarbonyl group include methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, n-butoxycarbonyl group, t-butoxycarbonyl group, amyloxy carbonyl group and the like.

  The alkyl group having a substituent refers to a group in which at least one hydrogen atom of the alkyl group is substituted with a substituent. As a substituent, a halogen atom, a hydroxy group, an alkoxy group, a halogenated alkoxy group, an acyl group, an acyloxy group, a halogenated acyloxy group, an alkylsulfonyloxy group, a halogenated alkylsulfonyloxy group, an arylsulfonyloxy group, a halogenated alkyl Examples thereof include an arylsulfonyloxy group substituted with a group, an alkoxycarbonyloxy group, an amino group, an amino group having a substituent, an aryl group, a heterocyclic group and the like, and preferably a halogen atom, a hydroxy group or an alkoxy group.

The cycloalkyl group having a substituent refers to a group in which one or more of the hydrogen atoms in the cycloalkyl group are substituted with a substituent. As a substituent, an alkyl group, a halogenated alkyl group, a halogen atom, a hydroxy group, an alkoxy group, a halogenated alkoxy group, an acyloxy group, a halogenated acyloxy group, an alkylsulfonyloxy group, a halogenated alkylsulfonyloxy group, an arylsulfonyloxy Groups, halogenated arylsulfonyloxy groups, arylsulfonyloxy groups substituted with alkyl, alkoxycarbonyloxy groups and the like are mentioned, with preference given to alkyl groups, halogen atoms or alkoxy groups.
Examples of the cycloalkyl group having a substituent include a 2-methylcyclopropyl group, a 2,2-dimethylcyclopropyl group, a 2-fluorocyclopropyl group, a 2-methylcyclobutyl group, and a 2,2-dimethylcyclobutyl group And 2-methylcyclopentyl group, 2-methylcyclohexyl group and the like.

The aryl group having a substituent refers to a group in which at least one hydrogen atom of the aryl group is substituted with a substituent. As a substituent in the substituted aryl group, a halogen atom, an alkyl group, a halogenated alkyl group, a hydroxy group, an alkoxy group, a halogenated alkoxy group, an alkylenedioxy group having 1 to 3 carbon atoms (eg, methylene di) And the like, and preferably a halogen atom, an alkyl group, a halogenated alkyl group and an alkoxy group.
Examples of the aryl group having a substituent include monohalophenyl groups (eg, 1-, 2- or 3-chlorophenyl group, 1-, 2- or 3-fluorophenyl group, 1-, 2- or 3-bromo Phenyl group etc., (halogenated alkyl) phenyl group (eg, 1-, 2- or 3-trifluoromethylphenyl group etc.), or alkoxyphenyl group (eg 1-, 2- or 3-methoxyphenyl group, 1-, 2- or 3-ethoxyphenyl group etc. are mentioned.

  The alkylsulfonyl group having a substituent refers to a group in which at least one hydrogen atom of the alkylsulfonyl group is substituted by a substituent. As a substituent in the alkylsulfonyl group having a substituent, a halogen atom is preferable. Examples of the substituted alkylsulfonyl group include trifluoromethanesulfonyl group, pentafluoroethanesulfonyl group and the like.

  The arylsulfonyl group having a substituent refers to a group in which one or more of the hydrogen atoms in the arylsulfonyl group are substituted with a substituent. The substituent in the substituted arylsulfonyl group is preferably a halogen atom, an alkyl group, a halogenated alkyl group or an alkoxy group. Examples of the arylsulfonyl group having a substituent include monohalogenated phenylsulfonyl group (eg, 1-, 2- or 3-chlorobenzenesulfonyl group, 1-, 2- or 3-fluorobenzenesulfonyl group, 1-, 2 -Or 3-bromobenzenesulfonyl group etc.), (alkyl) phenylsulfonyl group (eg p-toluenesulfonyl group etc.), (halogenated alkyl) phenylsulfonyl group (eg trifluoromethylbenzenesulfonyl group etc.), or ( And alkoxy) phenyl groups (eg, methoxybenzenesulfonyl group, ethoxybenzenesulfonyl group, etc.).

The amino group having a substituent means a group in which one or two of the hydrogen atoms of the amino group are substituted, and the substituent when two of the hydrogen atoms of the amino group are substituted by a substituent May be the same or different. Examples of substituents on amino groups having substituents include, for example, “Green's / Protective / Groups / In / Organic / Synthesis 4th Edition” (P. G. M. Wuts, T. W. Greene, J. Protecting groups of the amino group described in Wiley & Sons, 2007) and the like, and specifically, an alkyl group having 1 to 6 carbon atoms, an alkoxy 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, an aryl group having 6 to 10 carbon atoms, a monovalent heterocyclic group, an aralkyl group having 7 to 14 carbon atoms, a benzhydryl group, a trityl group, an acyl group, a triorganosilyl group, etc. Groups are mentioned. When the substituent is a group containing a hydrogen atom, one or more of the hydrogen atoms may be further substituted by a substituent (hereinafter referred to as a substituent 2). The substituent 2 may, for example, be a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 1 to 6 carbon atoms, a cyano group or a nitro group.
Examples of the substituent of the amino group having a substituent are methyl, ethyl, isopropyl, benzyl, phenyl, pyridyl, methoxy, acetyl, trifluoroacetyl, pivaloyl, benzoyl, naphthoyl Group, tert-butoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethyloxycarbonyl group, benzhydryl group, trityl group, phthaloyl group, allyloxycarbonyl group, methanesulfonyl Groups, trifluoromethanesulfonyl group, p-toluenesulfonyl group, o-nitrobenzenesulfonyl group, trimethylsilylethoxycarbonyl group, dimethylcarbamoyl group and the like.
In the present compound, when the substituent is a group selected from an alkyl group, a halogenated alkyl group, an alkoxy group and a halogenated alkoxy group, or a group having the selected group as a partial structure, the selected group Is preferably a lower group.

In compound (1), R ^A in the α chain is —CH ₂ —CZ ¹ Z ² (COX) or —CH = CZ ¹ (COX). That is, the compound (1) is a compound represented by the following formula (α1) or a compound represented by the following formula (α2).

Each of Z ¹ and Z ² in the compound (α1) is preferably a hydrogen atom or a fluorine atom.
The configuration of the group bonded to the double bond of CH = CZ ¹ (COX) in the compound (α2) may be E or Z, and when Z ¹ is a hydrogen atom, E is preferred, Z ¹ When is a fluorine atom, Z is preferred.
Furthermore, as the compound (α1), the compound (α1-1) or the compound (α1-2) is preferable, and as the compound (α2), the compound (α2-1) or (α2-2) is preferable.

In the above formula, X represents OR ⁴ or NR ⁵ R ⁶ , and X is preferably OR ⁴ . ^{R 4} in OR ⁴ represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms and having an alkyl group or a substituent having 1 to 4 carbon atoms preferred. Examples of the substituent include a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group, a heterocyclic group and the like, with an acyl group and a heterocyclic group being particularly preferable.
^{R 4} when X is OR ⁴ is a compound which is an alkyl group having 1 to 6 carbon atoms having an alkyl group or a substituent having 1 to 6 carbon atoms, COX moiety (i.e. _CO 2 ^{R 4} moiety) carboxylic It can also be derived from compounds of structures that can be acid prodrugs.
Specifically, R ⁴ is a hydrogen atom, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, benzyl group, pivaloylmethyl group , (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, 2-hydroxyethyl group, 2- (dimethylamino) ethyl group, 2- (morpholino) ethyl group, 4-pyridylmethyl Group, pivaloyloxymethyl group, 1-{[(1-cyclohexyloxy) carbonyl] oxy} ethyl group, etc., and a hydrogen atom, an alkyl group having 1 to 4 carbon atoms (eg, methyl group, ethyl group etc.) ), Pivaloylmethyl group, (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl group is preferable, and a hydrogen atom, a methyl group or an ethyl group is particularly preferable. Preferred.
R ⁵ in the case where X is NR ⁵ R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkyl group having 1 to 6 carbon atoms having a substituent. As an example of a C1-C6 alkyl group, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, an isobutyl group, a sec-butyl group, a tert- butyl group etc. are mentioned. As R ⁵ , a hydrogen atom, a methyl group, an ethyl group and the like are preferable.

R ⁶ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms having a substituent, an alkylsulfonyl group having 1 to 6 carbon atoms, an alkyl having 1 to 6 carbon atoms having a substituent And a sulfonyl group, an arylsulfonyl group having 6 to 10 carbon atoms, or an arylsulfonyl group having 6 to 10 carbon atoms having a substituent.
When R ⁶ is an alkyl group having 1 to ⁶ carbon atoms or an alkyl group having 1 to ⁶ carbon atoms having a substituent, examples thereof include a methyl group, an ethyl group, an n-propyl group, an isopropyl group and an n-butyl group , Lower alkyl groups such as isobutyl group, sec-butyl group, tert-butyl group, etc., hydroxyalkyl groups such as 2-hydroxyethyl group, 3-hydroxypropyl group, 2-hydroxypropyl group, 2,3-dihydroxypropyl group etc. Can be mentioned.
Examples of the case where R ⁶ is an alkylsulfonyl group having 1 to ⁶ carbon atoms or an alkylsulfonyl group having 1 to 6 carbon atoms having a substituent include a methanesulfonyl group, an ethanesulfonyl group, etc. Examples of the arylsulfonyl group of 10 or the arylsulfonyl group having 6 to 10 carbon atoms having a substituent include a phenylsulfonyl group and a p-toluenesulfonyl group.
As R ⁶ , a hydrogen atom, a methyl group, an ethyl group, a hydroxyethyl group, a methanesulfonyl group, an ethanesulfonyl group and the like are preferable.
Structure of the portion is expressed as A-B, said A-B structure carbon - be carbon double bond (i.e. -CH = CH-) - carbon single bond (i.e. _-CH 2 -CH ₂ -) or carbon Represents When the structure of the A-B moiety is a carbon-carbon double bond, the configuration of the group bonded to the double bond is preferably E.
In the case of a hydroxyl group bound by a wavy line, the bonding direction of the hydroxyl group is α-configuration (downward binding on paper), β-configuration (upward binding on paper), or a mixed configuration of α-configuration and β-configuration Represents The arrangement of the hydroxyl group is preferably the α-configuration or a mixed configuration of the α-configuration and the β-configuration, and the α-configuration is particularly preferred.
Y represents CH ₂ , S or O, preferably CH ₂ or S, particularly preferably CH ₂ .
In the structure represented as (CH ₂ ) _n , n represents the number of methylene units. When n is 0, it means that a methylene unit does not exist, and in that case, a carbon atom to which R ¹ and R ² are bonded and a carbon atom of a triple bond are directly bonded. n is preferably 1 or 2, and particularly preferably 1.

R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms having a substituent. One of R ¹ and R ² is a hydrogen atom, and the other is an alkyl group having 1 to 2 carbon atoms (preferably a methyl group), or R ¹ and R ² are alkyl groups having 1 to ² carbon atoms (preferably methyl) It is more preferable that R ¹ is a hydrogen atom and R ² is an alkyl group having 1 to ² carbon atoms, and it is particularly preferable that R ¹ is a hydrogen atom and R ² is a methyl group.

R ³ represents an alkyl group having 2 to 3 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, and a cycloalkyl group having 3 to 5 carbon atoms is preferable. Specific examples of R ³ include ethyl group, n-propyl group, isopropyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group and the like, and ethyl group, cyclopropyl group or cyclobutyl group is preferable, and cyclopropyl group is particularly preferable preferable.

In the present compound (1), compounds in which the ω chain has the following structure are preferred.
[Compound (ω-1)]

The symbol in the formula (ω-1) has the same meaning as the meaning in the formula (1).
Y is CH ₂ or S, R ¹ is a hydrogen atom, R ² is an alkyl group having 1 to ² carbon atoms, R ³ is an alkyl group having 2 to ³ carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, Is preferably OR ⁴ , R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms having a substituent. Furthermore, the substituent in the C1-C6 alkyl group having a substituent is preferably a group selected from a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group and a heterocyclic group .

From the viewpoint of pharmacological activity and physical properties, the compound (1) is preferably a compound having a structure of α chain and ω chain as follows.
[Compound (ω-10)]

The symbol in the formula (ω-10) has the same meaning as the meaning in the formula (1). R ³⁰ represents a cycloalkyl group alkyl or 3 to 5 carbon atoms having 2 to 3 carbon atoms.

R ¹ is a hydrogen atom, R ² is an alkyl group having 1 to ² carbon atoms, X is OR ⁴ , and R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[Compound (ω-11)]

The symbols in the formula (ω-11) have the same meanings as the meanings in the formula (1). R ³⁰ represents a cycloalkyl group alkyl or 3 to 5 carbon atoms having 2 to 3 carbon atoms.

R ¹ is a hydrogen atom, R ² is an alkyl group having 1 to ² carbon atoms, X is OR ⁴ , and R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms. It is preferred that each of Z ¹ and Z ² be a hydrogen atom, or both be a fluorine atom.

  Below, a suitable compound (1) is shown.

[Compound (1) -A]

In the formula (1) -A, the arrangement of hydroxyl groups bound by a wavy line is α-configuration, β-configuration, or a mixed configuration of α-configuration and β-configuration, Y is CH ₂ , S or O, R ¹ is preferably a hydrogen atom, R ² is preferably an alkyl group having 1 to 2 carbon atoms, R ³ is an alkyl group having 2 to ³ carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms, R ^A is —CH ₂ —CZ ¹ Z ² (COX) or —CH = CZ ¹ (COX), Z ¹ and Z ² are each independently a hydrogen atom or a fluorine atom, and X is preferably OR ⁴ And R ⁴ is preferably selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group and a heterocyclic group The substituents to be It is a C1-C6 alkyl group which it has. When R ^A is —CH = CZ ¹ (COX), the arrangement of the group bonded to the double bond may be E or Z, and when Z ¹ is a hydrogen atom, E is preferred, When Z ¹ is a fluorine atom, Z is preferred.

[Compound (1) -B]

In the formula (1) -B, the arrangement of hydroxyl groups bound by a wavy line is α-configuration, β-configuration, or a mixed configuration of α-configuration and β-configuration, Y is preferably CH ₂ or S, R ¹ is preferably a hydrogen atom, R ² is preferably an alkyl group having 1 to 2 carbon atoms, and R ³ is preferably an alkyl group having 2 to 3 carbon atoms or a cycloalkyl group having 3 to 5 carbon atoms And R ^A is —CH ₂ —CZ ¹ Z ² (COX) or —CH = CZ ¹ (COX), Z ¹ and Z ² are each independently a hydrogen atom or a fluorine atom, and X is preferably OR ⁴ R ⁴ is preferably a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group and a heterocyclic group Choose from It is a C1-C6 alkyl group which has a substituted group. When R ^A is —CH = CZ ¹ (COX), the arrangement of the group bonded to the double bond may be E or Z, and when Z ¹ is a hydrogen atom, E is preferred, When Z ¹ is a fluorine atom, Z is preferred.

[Compound (1) -C]

In the formula (1) -C, the arrangement of hydroxyl groups bound by a wavy line is α-configuration, β-configuration, or a mixed configuration of α-configuration and β-configuration, and R ¹ is preferably a hydrogen atom, R ² Is preferably an alkyl group having 1 to 2 carbon atoms, R ³ is preferably an alkyl group having 2 to 3 carbon atoms, Z ¹ is a hydrogen atom or a fluorine atom, and X is preferably OR ⁴ , R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[Compound (1) -D]

In the formula (1) -D, the arrangement of the hydroxyl group bound by a wavy line is α-configuration, β-configuration, or a mixed configuration of α-configuration and β-configuration, and R ¹ is preferably a hydrogen atom, R ² Is preferably an alkyl group having 1 to 2 carbon atoms, R ³ is preferably a cycloalkyl group having 3 to 5 carbon atoms, Z ¹ is a hydrogen atom or a fluorine atom, and X is preferably OR ⁴ And R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[Compound (1)-E]

In the formula (1) -E, the arrangement of the hydroxyl group bonded by a wavy line are α- arrangement, a mixing arrangement of the β- configuration, or α- arrangement and β- configuration, R ¹ is preferably a hydrogen atom, R ² Is preferably an alkyl group having 1 to 2 carbon atoms, R ³ is preferably an alkyl group having 2 to 3 carbon atoms, Z ¹ and Z ² are each independently a hydrogen atom or a fluorine atom, and X is preferably Is OR ⁴ and R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

[Compound (1)-F]

In the formula (1) -F, the arrangement of hydroxyl groups bound by a wavy line is α-configuration, β-configuration, or a mixed configuration of α-configuration and β-configuration, and R ¹ is preferably a hydrogen atom, R ² Is preferably an alkyl group having 1 to 2 carbon atoms, R ³ is preferably a cycloalkyl group having 3 to 5 carbon atoms, Z ¹ and Z ² are each independently a hydrogen atom or a fluorine atom, and X is Preferably it is OR ⁴ and R ⁴ is preferably a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.

Particularly preferred compounds (1) include the following examples.
4-((2-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxocyclopentyl) ethyl) thio) butanoic acid methyl ester [compound (1) -1],
(2E) -4-((2-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-en-6-yne- 1-yl) -5-oxocyclopentyl) ethyl) thio) but-2-enoic acid methyl ester [compound (1) -2],
((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxocyclopentyl) Heptanoic acid methyl ester [compound (1) -3],
7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxo Cyclopentyl) heptanoic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester [compound (1) -4],
7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxo Cyclopentyl) heptanoic acid 3,3-dimethyl-2-oxobutyl ester [compound (1) -5],
7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxo Cyclopentyl) heptanoic acid [compound (1) -6],
(2E) -7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-oxocyclopentyl) hept-2-enoic acid [compound (1) -7],
2,2-Difluoro-7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-ene-6-yne-1-) Yl) -5-oxocyclopentyl) heptanoic acid [compound (1) -8],
7-((1R, 2R, 3R) -2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yn-1-yl) -3- Hydroxy-5-oxocyclopentyl) heptanoic acid [compound (1) -9], or
(2E) -7-((1R, 2R, 3R) -2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yn-1-yl ) 3-Hydroxy-5-oxocyclopentyl) hept-2-enoic acid [compound (1) -10].

The compound may be a pharmaceutically acceptable salt of compound (1). Examples of the base, a salt of a carboxylic acid moiety and a basic substance (toxic inorganic or nontoxic organic bases), the carboxylic acid moiety is -COO ^-, and the hydrogen atom of carboxylic acid has a structure which is a cation.
Pharmaceutically acceptable salts include salts derived from non-toxic inorganic bases or salts derived from non-toxic organic bases, preferably salts derived from non-toxic inorganic bases.
Examples of bases derived from inorganic salts include sodium salts, potassium salts, calcium salts, magnesium salts, zinc salts, aluminum salts, ammonium salts, etc., as well as lithium salts, copper salts, ferric salts, ferrous salts, Manganese salts, manganous salts and the like are also mentioned, and sodium salts, potassium salts, calcium salts, magnesium salts and ammonium salts are preferred, and sodium salts and potassium salts are particularly preferred.
Examples of salts derived from organic bases include primary amines, secondary amines, tertiary amines, substituted amines thereof (including naturally occurring substituted amines), cyclic amines, basic amino acids, and basicity The salt of ion exchange resin etc. are mentioned. Examples of organic amines and amino acids include isopropylamine, diethylamine, triethylamine, trimethylamine, tripropylamine, ethylenediamine, N, N'-dibenzylethylenediamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, morpholine, N-ethyl- Morpholine, piperazine, piperidine, N-ethyl piperidine, betaine, caffeine, choline, glucamine, glucosamine, histidine, hydramine, methyl glucamine, lysine, arginine, polyamine resin, procaine, purine, theobromine and the like can be mentioned.
Compound (1) or a pharmaceutically acceptable salt thereof may be in the form of a hydrate or a solvate.

  Compound (1) can be derived from pharmaceutically acceptable prodrugs of compound (1). The pharmaceutically acceptable prodrug is a compound having a group that can be converted to a hydroxyl group, a carboxy group or the like by solvolysis or under physiological conditions. Examples of the group forming a prodrug include, for example, Prog. Med., 1985, vol. 5, p. 2157-2161, “Development of pharmaceuticals” (Ashikawa Shoten, 1990), Volume 7, Molecular design, p. And the groups described in .163-198.

The prodrug of compound (1) is preferably a compound which is converted into a compound by a reaction with an enzyme or gastric acid in vivo.
Examples of the compound include the following compound (1-1) to compound (1-4).
The compound (1-1) by which the hydroxyl group in compound (1) was acylated, alkylated, phosphorylated and borated. Specifically, a compound in which the hydroxyl group in compound (1) is acetylated, propanoylated, butanoylated, pivaloylated, oleylated, palmitoylated, succinylated, fumarylated, analylated, dimethylaminomethylcarbonylated.
The compound (1-2) by which the carboxy group of compound (1) was esterified or amidated. Specifically, the compound etc. by which the carboxy group of compound (1) was phenylesterified, phthalidyl esterified, etc.
The compound (1-3) in which the carboxy group of a compound (1) replaced the hydroxymethyl group.
The compound (1-4) by which the carbonyl group of the 5-membered-ring part of compound (1) was enol-esterified.
These compounds (1-1) to (1-4) can be produced by known methods. Compounds (1-1) to (1-4) may be either hydrates or non-hydrates.

The compound (1) or a pharmaceutically acceptable salt thereof may be a clathrate compound of cyclodextrin. As cyclodextrin, for example, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, sulfobutylether-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and a mixture of two or more selected from these are used. Be As cyclodextrin, α-cyclodextrin or β-cyclodextrin is preferred, and α-cyclodextrin is particularly preferred.
As a method for producing a cyclodextrin clathrate compound, generally known methods such as an emulsification method, a saturated aqueous solution method, a kneading method, and a mixing and grinding method can be used. Specifically, using Compound (1) or a pharmaceutically acceptable salt thereof, and cyclodextrin, it is preferable to use Japanese Patent Publication No. 50-3362, Japanese Patent Publication No. 2-31404, or Japanese Patent Publication No. 61-52146. It can be manufactured by the method described. By making the compound (1) into a cyclodextrin inclusion compound, properties such as stability and water solubility can be increased, and properties preferable as a pharmaceutical can be imparted.

(Method for producing the present compound)
This compound can be synthesized by a general PG synthesis method. The concept of the synthetic route is shown below.
For example, a compound in which -AB- moiety is a double bond is a ω chain introduced by Horner-Wadsworth-Emmons reaction from a compound obtained by introducing an α chain into corey lactone as a starting material (W in the following formula is H After reducing the 15-position carbonyl group of the α, β-unsaturated carbonyl site in a certain compound), optionally introducing a double bond into the α chain to oxidize the 9 position and deprotect the hydroxyl protecting group Can be synthesized by
The PG derivative having a fluorine at the 2-position can be synthesized, for example, by introducing an α chain having a difluoro unit into corey lactone to synthesize a starting material, and via the same reaction as described above.
Compounds in which the -A-B- moiety is a single bond are a striker reagent (an α, β-unsaturated carbonyl moiety in the ω chain (W in the following formula is H) introduced by the Horner Wadsworth-Emmons reaction ( It can be synthesized by 1,4-reduction using a reducing agent such as [(Ph ₃ P) CuH] ₆ ) or sodium dithionite.

(Wherein, R ⁷ , R ⁸ and R ⁹ each independently represent a hydroxyl protecting group, W represents a hydrogen atom or a bromine atom, and the other symbols are as defined above).

As a hydroxyl-protecting group for R ^{7 to} R ⁹ , for example, “Green's / Protective / Groups / In / Organic / Synthesis 4th Edition” (P. G. M. Wuts, T. W. Greene, The hydroxyl protecting group described in J. Wiley & Sons, 2007), p. 16-430 can be used. Specific examples thereof include an acyl group, a triorganosilyl group, an alkoxyalkyl group, and a monovalent group having a cyclic ether structure. The acyl group is preferably an acetyl group, benzoyl group, chloroacetyl group, dichloroacetyl group, trichloroacetyl group, trifluoroacetyl group, and the like. As the triorganosilyl group, an alkyl group, an aryl group, an aralkyl group or a group in which three alkoxy groups are bonded to a silicon atom is preferable. Specifically, for example, a tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group Groups, trimethylsilyl groups, triethylsilyl groups, triphenylsilyl groups, triisopropylsilyl groups and the like are preferable. As the alkoxyalkyl group, a methoxymethyl group, a benzyloxymethyl group, a tert-butoxymethyl group, a 2-methoxyethoxymethyl group, a 1-ethoxyethyl group, a 1-methyl-1-methoxyethyl group and the like are preferable. As a monovalent group having a cyclic ether structure, a tetrahydropyranyl group, a tetrahydrofuranyl group and the like are preferable. An acetyl group, benzoyl group, tetrahydropyranyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like are particularly preferable.
The hydroxyl protecting group can be easily deprotected by a conventional method. Specifically, for example, "Green's / Protective / Groups / In / Organic / Synthesis 4th Edition" (P. G. M. Wuts, T. W. Greene, J. Wiley & Sons, 2007), It can be deprotected by the method described on p. 16-430.

  In addition, a PG derivative in which the 5-position (Y) of the α chain is a hetero atom is first reduced from the lactone moiety to a diol to introduce an α chain, using a corey lactone having an ω chain constructed as a starting material as described below Then, it can be synthesized by oxidizing the 9-position and deprotecting other hydroxyl protecting groups.

(Each symbol in the formula is as defined above.)

A representative example of the method for producing compound (1) can be represented by the following formula.
In the following formula, the following abbreviations are used:
Me: methyl Ac: acetyl THP: tetrahydro-2H-pyran-2-yl

  The starting material in the above formula is the aldehyde (A-1) described in JP-B 60-36422, etc., and it is α, β- from the aldehyde (A-1) and the phosphonate (A-2) by the Horner Wadsworth-Emmons reaction. The unsaturated ketone (A-3) is obtained. After reducing the carbonyl group at position 15, deprotection is performed to obtain diol (A-4). After protecting the hydroxyl group, it is hydrolyzed to obtain a carboxylic acid (A-5). The unprotected hydroxyl group on the 5-membered ring can be oxidized and deprotected to synthesize a compound (A-6) (compound (1) -9).

Moreover, after protecting two hydroxyl groups of a compound (A-4), it deacetylates and alcohol (A-7) is obtained. The α-position of the ester is phenylselenated, and after elimination reaction with hydrogen peroxide water, ester hydrolysis is performed to obtain an α, β-unsaturated carboxylic acid (A-8). The unprotected hydroxyl group on the 5-membered ring is oxidized and deprotected to give compound (A-9) (compound (1) -10).
In order to esterify the carboxy group of the compound (A-6) or the compound (A-9), it is possible to use, for example, a method such as “Synthesis and Reaction (II) of New Experimental Chemistry Lecture 14 Organic Compound” (maruzen) etc. The methods described can be used. For example, methods such as esterification by condensation with alcohols and phenols, esterification with O-alkylating agents, esterification with alkenes and alkynes, esterification with dialkyl sulfates and halogenated hydrocarbons are used. Be For conversion to acylamides and sulfonamides, for example, the method of Tithereley et al. (J. Chem. Soc., 1904, vol. 85, p. 1673), the method of Lynch et al. (Can. J. Chem., 1972). , vol. 50, p. 2143), the method of Davidson et al. (J. Am. Chem. Soc., 1958, vol. 80, p. 376) or the like can be employed. In addition, after converting a carboxylic acid to an acid halide or active ester, a condensation reaction is directly performed with an amide or sulfonamide, or reacted with an amine to be once converted to an amide, and then acylated or sulfonylated. A method or the like is used.

  The present compound has asymmetric carbons in its structure, so various stereoisomers and optical isomers exist. In the present invention, all these stereoisomers, optical isomers, and their mixtures Include.

  The present compound is a derivative which is less susceptible to metabolism in vivo and has improved stability. Since the compound (1) has an alkyl group at the carbon atom at position 16, the hydroxyl group at position 15 of the PG skeleton is less susceptible to metabolism by PG dehydrogenase and has high metabolic stability. For this reason, compared with natural type PG, the half life of blood is long, and effective blood concentration can be maintained long. Also, improved metabolic stability can improve the bioavailability of the drug.

  By having an alkynyl group in the ω chain, the present compound is very potent in action such as platelet aggregation inhibitory activity. In particular, derivatives having a cycloalkyl group at the end of the alkynyl group exhibit stable and strong activity.

  The present compound and its cyclodextrin inclusion compound are useful as medicaments, and can exhibit excellent effects as drugs for cardiovascular diseases, central nervous system diseases, inflammatory diseases, pain and the like. Specifically, as circulatory diseases, peripheral circulatory disorders, burger's disease, Raynaud's angina, myocardial infarction, heart failure, pulmonary hypertension, pulmonary embolism, pulmonary embolism, diabetes, cerebral infarction, cerebral thrombosis, deafness, Meniel's disease, etc. Is included. Central nervous system diseases include insomnia, anxiety, depression, schizophrenia, dementia and the like. Inflammatory diseases include acute hepatitis, chronic hepatitis, cirrhosis, cholangitis, cholangitis, acute pancreatitis, chronic pancreatitis, chronic peritonitis, acute peritonitis, cystitis, acute nephritis, chronic nephritis, encephalitis, polyneuritis, meninges Inflammation, myelitis, arthritis, rheumatoid arthritis, bronchitis, pneumonia, pleuritis, phlebitis, pericarditis, rhinitis, pharyngitis, otitis externa, otitis externa etc. are included.

  The medicament containing the present compound or its cyclodextrin clathrate (hereinafter referred to as "the medicament of the present invention") is particularly useful as a medicament for the prevention or treatment of blood flow disorders. The medicament of the present invention may be a medicament comprising the present compound or its cyclodextrin clathrate, and optionally also a pharmaceutically acceptable carrier and other therapeutic ingredients.

  When the medicament of the present invention is administered to a patient as an agent for the prophylaxis or treatment of the aforementioned diseases, the daily dosage varies depending on the patient's age, body weight, condition and severity, etc. It is desirable to administer 00001 mg to 1 mg, preferably 0.0001 mg to 0.3 mg, in one to several doses. For example, for oral administration 0.0001 to 0.3 mg, especially 0.001 to 0.1 mg is preferred. On the other hand, for intravenous administration, 0.00001 mg to 0.1 mg, and particularly 0.0001 mg to 0.03 mg is preferable. The dosage may be adjusted as appropriate depending on the disease or condition, and in the case of injections, it may be desirable to perform continuous infusion.

  The medicament of the present invention can be administered in vivo by oral administration, parenteral administration (eg, intravascular (intravenous, intraarterial) administration, rectal administration, intraarticular administration, etc.). The dosage form includes, for example, tablets (including orally disintegrating tablets and sublingual tablets), films (including oral films), capsules (including soft capsules and microcapsules), granules, powders, troches , Oral dosage forms such as syrups, liquid injections such as solutions, emulsions, suspensions etc. (eg subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drips), suppositories (Eg, rectal suppositories, vaginal suppositories), eye drops, nasal drops, external preparations (eg, transdermal preparations such as patches, ointments, creams), pulmonary agents (inhalants etc.) An oral dosage form is exemplified. In addition, these preparations may be controlled release preparations such as immediate release preparations or sustained release preparations.

  In the preparation of the above dosage form, the pharmaceutical preparation of the present invention is combined with additives necessary for formulation such as usual carriers, excipients, lubricants, disintegrants, binders, stabilizers, etc. It can be manufactured by formulation. For example, when the preparation is a tablet, a granule, a powder and the like, it may be manufactured using any pharmaceutical carrier suitable for producing a solid preparation, such as an excipient, a lubricant, a disintegrant, a binder and the like. Can.

  As an excipient, for example, lactose, glucose, fructose, maltose, isomerized lactose, reduced lactose, lactose crystal, sucrose, D-mannitol, erythritol, maltitol, xylitol, palatinose, trehalose, sorbitol, corn starch, potato starch And wheat starch, rice starch, crystalline cellulose, dextrans (eg, dextran, dextran 40, dextran 70, etc.), pullulan, dextrin, talc, anhydrous silicic acid, anhydrous calcium phosphate, precipitated calcium carbonate, calcium silicate and the like.

  As the lubricant, for example, magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, stearic acid, talc, polyethylene glycol, beeswax and the like can be mentioned.

  As the disintegrant, for example, starch, carboxymethylcellulose, hydroxypropyl cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl starch and the like can be mentioned.

  As the binder, for example, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose, partially gelatinized starch, gelatinized starch, sodium alginate, pullulan, gum arabic, dextrin, polyvinyl pyrrolidone, polyvinyl Alcohol, gelatin and the like can be mentioned.

  In addition, an inert diluent, a lubricant, a stabilizer, a solubilizer, a flavoring agent and the like may be added to the preparation of the above-mentioned administration form as required. As the inert diluent, for example, calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate and the like can be mentioned. As the lubricant, for example, magnesium stearate, stearic acid, colloidal silica, talc and the like can be mentioned. Examples of the stabilizing agent include ascorbic acid, sodium sulfite, glycine, L-aspartic acid, tocopherol acetate, β-cyclodextrin, fumaric acid and the like. As the solubilizer, for example, polyethylene glycol, propylene glycol, glutamic acid, aspartic acid and the like can be mentioned. As a flavoring agent, for example, citric acid, ascorbic acid, lactic acid, acetic acid, tartaric acid, malic acid, aspartame, acesulfame potassium, thaumatin, saccharin sodium, glycyrrhizin dipotassium, sodium glutamate, 5'-inosinic acid sodium, 5'-guanylate Sodium etc. are mentioned.

  These tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate, or glyceryl distearate may be used.

  The medicament of the present invention may be provided as a hard gelatin capsule mixed with an inert solid diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate or kaolin. Also, the medicament of the present invention may be provided as a soft gelatin capsule mixed with a water-miscible solvent, for example, an alcohol such as propylene glycol, polyethylene glycol, glycerin and ethanol or an oil medium.

  Examples of the oil medium include fatty acid esters, liquid paraffin, and vegetable oils such as peanut oil and olive oil. A fatty acid ester is a compound in which a carboxy group of a fatty acid is ester-bonded to an alcohol, and specifically, it is composed of an ester compound of a glyceride or a fatty acid and a monohydric alcohol which may have a saturated or unsaturated branched chain. Fatty acid ester etc. are mentioned. Preferred fatty acids are medium- or high-chain fatty acids having carbon atoms of 6 to 24 carbon atoms, and caproic acid, caprylic acid, capric acid, capric acid, lauric acid, myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid And linoleic acid, linolenic acid, ricinoleic acid, and arachidonic acid. Further, preferable alcohols include monohydric alcohols having 1 to 6 carbon atoms, and polyols which are polyhydric alcohols such as glycerin, polyethylene glycol and propylene glycol. Preferred fatty acid esters include saturated or unsaturated branched glycerides, glycerin fatty acid esters and propylene glycol fatty acid esters. Also, two or more glycerides can be used as a mixture. Mixtures of glycerides include mixtures of caprylic acid and caprylic acid triglycerides, castor oil, corn oil, olive oil, sesame oil, rapeseed oil, rapeseed oil, salad oil, cottonseed oil, camellia oil, peanut oil, palm oil, sunflower oil and other vegetable oils. Moreover, as a fatty acid ester consisting of an ester compound of a fatty acid and a monohydric alcohol, for example, isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate and the like can be mentioned.

  The main components of the capsule shell are not particularly limited, and include, for example, various known components such as gelatin, carrageenan, pectin, pullulan, sodium alginate, starch, hypromellose, hydroxypropyl cellulose and the like.

  Examples of plasticizers used for producing a soft capsule film include polyhydric alcohols such as glycerin, ethylene glycol, polyethylene glycol, propylene glycol and polypropylene glycol, and sorbitol, mannitol, xylitol, maltitol, and sugars derived from corn starch. Alcohol alcohol, sugar alcohol such as reduced maltose sugar cane, etc. are preferable. These plasticizers may be used in combination of 2 or more types.

  When the preparation is a solution such as syrup, solution, emulsion, suspension, etc., for example, a stabilizer, a suspending agent, a flavoring agent, an aromatic agent, a soothing agent, etc. may be appropriately selected and manufactured. it can. In order to produce an injection, the active ingredient may be a pH adjusting agent such as hydrochloric acid, sodium hydroxide, sodium lactate, acetic acid, sodium monohydrogenphosphate or sodium dihydrogenphosphate; sodium chloride, glucose, D-sorbitol, glycerin, Isotonicity agents such as D-mannitol; Stearyl ethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, surfactants such as benzalkonium chloride; polyvinyl alcohol, polyvinyl pyrrolidone, sodium carboxymethyl cellulose, It can be prepared aseptically by dissolving it in distilled water for injection together with a soothing agent such as methyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and so on; and soothing agent such as benzyl alcohol. In addition, it may be prepared using an inert non-aqueous diluent such as propylene glycol, polyethylene glycol, olive oil, ethanol, polysorbate 80 and the like. Furthermore, mannitol, dextrin, cyclodextrin, gelatin and the like may be added, vacuum freeze-dried, and used as an injection for dissolution at the time of use. In addition, liposome preparations can be prepared and used as injections by known methods for improving stabilization and lesion accessibility. Furthermore, it may be a so-called lipopized preparation (fat emulsion) in which the present compound is dissolved in fine fat emulsion particles, oil components such as fatty acid glycerides; phospholipids such as egg yolk lecithin and soya lecithin; And additives such as an emulsifying aid, a stabilizer, a polymer substance, and a tonicity agent.

  In addition, rectal preparations may be prepared using suppository bases such as cocoa butter, triglycerides of fatty acids, diglycerides of fatty acids, monoglycerides of fatty acids, polyethylene glycol and the like. The viscosity is adjusted to an appropriate viscosity using a water-soluble base such as polyethylene glycol, polypropylene glycol, glycerin and glycerogelatin, an oil-based base such as white petrolatum, hard fat, paraffin, liquid paraffin, plastibase, lanolin and purified lanolin. Rectal injection ointments can also be prepared.

  The medicament of the present invention can be locally administered to the skin or mucous membrane, ie, transdermally or transmucosally. Usual dosage forms for this purpose are gels, hydrogels, lotions, solutions, creams, ointments, dusting agents, dressings, foams, films, skin patches, handles, implants, sponges, fibers, bandages, micro An emulsion etc. are mentioned. Common carriers include alcohol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, propylene glycol and the like.

  It can also be administered directly to the eye or ear in the form of isotonic, pH adjusted, sterile saline sterile powder suspensions or solutions. Other dosage forms suitable for ocular and aural administration include ointments, biodegradable and non-biodegradable implants, oblates, lenses, microparticles such as liposomes, and the like. Polymers such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, for example, cellulose polymers such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl cellulose, or complex polysaccharides such as, for example, gellan gum, are mixed with preservatives such as benzalkonium chloride can do.

  In order to produce a preparation for pulmonary administration, the medicament of the present invention is dissolved or dispersed in a conventional spray and filled into a pressure resistant container. Furthermore, they can be administered pulmonary as liposome preparations by known methods.

  In order to improve its solubility, dissolution rate, bioavailability and / or stability for use in any of the aforementioned dosage forms, the medicament of the invention further comprises cyclodextrin and its suitable derivative or polyethylene glycol It can be mixed with soluble polymer units such as containing polymers. For example, mixtures, complexes and the like of these have generally been found useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can also be used as auxiliary additives, ie as carriers, excipients or solubilizers. For these purposes, α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, γ-cyclodextrin and the like are generally used.

  In addition, the present compound may be a pharmaceutically acceptable salt of the compound represented by the general formula (1), and examples of the salt include those described above.

  As other therapeutic ingredients (hereinafter, also simply referred to as "other drugs") which can be contained in the medicament of the present invention, the prevention and / or treatment of the blood flow disorder (eg, spinal canal stenosis etc.) etc. of the present compound It is not particularly limited as long as it is a drug that complements and / or enhances the effect, a drug that can improve the pharmacokinetics and absorption of the present compound to reduce the dose of the present compound, a drug that reduces the side effects of the present compound, etc. .

  Other agents for complementation and / or enhancement of the preventive and / or therapeutic effects of the present compound on blood flow disorders (eg, spinal stenosis and the like) include, for example, prostaglandins, prostaglandin derivative preparations Examples include, but are not limited to, vasodilators, antiplatelet agents (platelet aggregation inhibitors), analgesics, vitamins, muscle relaxants, antidepressants and the like.

  Examples of prostaglandins include PG receptor agonists, PG receptor antagonists and the like. As PG receptors, PGE receptor (EP1, EP2, EP3, EP4), PGD receptor (DP, CRTH2), PGF receptor (FP), PGI receptor (IP), TX receptor (TP), etc. It can be mentioned. In addition, as prostaglandin derivative preparations, limaprost, beraprost and the like can be mentioned.

  Examples of the vasodilator include angiotensin converting enzyme inhibitors (eg, captopril, enalapril, delapril), angiotensin II antagonists (eg, candesartan cilexetil, losartan, eprosartan, valsantan, telbesartan, irbesartan, olmesartan, mexoxomil, tasosartan, 1) -{[2 '-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl} -2-ethoxy-1H-benzimidazole -7-carboxylic acid), calcium channel blocker (eg, manidipine, nifedipine, nicardipine, amlodipine, efonidipine), potassium channel opener (eg, levocrokalim, L-27152, AL0671, NIP-121), Clonidine etc. are mentioned.

  Examples of antiplatelet agents (platelet aggregation inhibitors) include clopidogrel sulfate, ticlopidine hydrochloride, cilostazol, ethyl icosapentate, sarpogrelate hydrochloride and the like.

  Analgesics include acetaminophen, non-steroidal anti-inflammatory drugs, neuropathic pain relieving drugs, pyrazolone drugs, etc. For example, sodium salicylate, aspirin, combination with aspirin and dialaminate, diflunisal, indomethacin, suprofen, ufenamate , Dimethylisopropyl azulene, bufexamac, fervinac, diclofenac, tolmetin sodium, clinoliol, fenbufen, napmetone, progumetacline, indomethacin farnesyl, acemetacin, progumetacin maleate, anfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol , Naproxen, flurbiprofen, flurbiprofen axeticl, ketoprofen, fenoprofen calci , Thiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamic acid, tolfenamic acid, floctaphenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, anpiloxicam, epilisoles, Thiaramide hydrochloride, tinoridine hydrochloride, emorfazone, neurotropin, pregabalin, sulpyrin, migrenin, pirin-based cold remedies, dimethothiazine mesylate, cimetride combination drug, non-pilin-based cold remedies, etc. may be mentioned.

  Mecobalamin etc. are mentioned as a vitamin agent.

  As a muscle relaxant, for example, triperisone hydrochloride, chlorzoxazone, chlormezanone, methocarbamol, fenprobamate, pridinol mesylate, clophenesin, baclofen carbamate, eperisone hydrochloride, afloquerone, tizanidine hydrochloride, alcuronium chloride , Squisametonium chloride, tubocurarine chloride, dantrolene sodium, pancuronium bromide, vecuronium bromide and the like.

  Examples of antidepressants include tricyclic and tetracyclic antidepressants, SSRI (selective serotonin reuptake inhibitor), SNRI (serotonin and noradrenaline reuptake inhibitor) and the like. For example, as a tricyclic antidepressant, imipramine hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, trimipramine maleate, amitryptyline hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, amoxapine, dosulein hydrochloride, etc. Examples of tetracyclic antidepressants include maprotiline, mianserin and the like. In addition, as SSRI, paroxetine hydrochloride hydrate and the like can be mentioned, and as SNRI, milnacipran hydrochloride, duloxetine hydrochloride and the like can be mentioned.

  The weight ratio of the present compound or its cyclodextrin clathrate compound to the other agent is not particularly limited, and other agents may be administered in combination of any two or more.

Preferred embodiments of the present invention are the following inventions.
<1> A medicament comprising the compound (1) or a pharmaceutically acceptable salt thereof, or a cyclodextrin clathrate thereof as an active ingredient;
<2> The medicament according to <1>, wherein Y is CH ₂ or S;
<3> The medicament according to <2>, wherein Y is CH ₂ ;
<4> The medicament according to any one of the above <1> to <3>, wherein R ^A is —CH = CZ ¹ (COX);
<5> The medicament according to any one of the above <1> to <3>, wherein R ^A is —CH ₂ —CZ ¹ Z ² (COX);
The medicament according to any one of the above <1> to <5>, wherein <6> n is 1.
The medicament according to any one of the above <1> to <6>, wherein <7> AB is a carbon-carbon double bond; <8> the above <1> to <8 wherein Z ¹ and Z ² are hydrogen atoms The medicine according to any one of 7>;
The medicine according to any one of the above <1> to <8>, wherein <9> R ¹ is a hydrogen atom, and R ² is an alkyl group having 1 to 3 carbon atoms;
<10> The medicament according to <9>, wherein R ² is a methyl group;
<11> The medicament according to any one of <1> to <10>, wherein R ³ is an ethyl group or a cycloalkyl group having a carbon number of 3 to 5;
The drug according to <1> to <11>, wherein <12> R ³ is a cycloalkyl group having 3 to 4 carbon atoms;
The medicament according to any one of the above <1> to <12>, wherein <13> R ³ is a cyclopropyl group;
The medicament according to any one of the above <1> to <13>, wherein <14> X is OR ⁴ ;
<15> The medicament according to <14>, wherein R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms having a substituent;
<16> R ⁴ is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group and a heterocyclic group The medicament according to the above <15>, which is a C1-C6 alkyl group having a substituted group;
<17> The medicament according to <15>, wherein R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkyl group having 1 to 4 carbon atoms having a substituent;
<18> R ⁴ is selected from the group consisting of a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or a hydroxyl group, an acyl group, an acyloxy group, an alkoxycarbonyloxy group, an amino group having a substituent, an aryl group and a heterocyclic group The medicament according to the above <17>, which is a C1-C4 alkyl group having a substituted group;
The <19> R ⁴ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, a pivaloylmethyl group or a (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl group described in the above <18> Of medicine;
<20> The medicament according to any one of the above <1> to <19>, which is an agent for the prophylaxis or treatment of blood flow disorder;
<21> The medicament according to the above <20>, wherein the blood flow disorder is nerve blood flow disorder;
<22> The medicament according to <21>, wherein the nerve blood flow disorder is a blood flow disorder associated with spinal stenosis.
<23> The medicament according to the above <20>, wherein the impaired blood flow is impaired blood flow in a peripheral artery, skin or brain;
<24> The medicament according to <23>, wherein the blood flow disorder in the peripheral artery is a blood flow disorder associated with chronic arterial occlusion or pulmonary hypertension;
<25> The medicament according to <23>, wherein the blood flow disorder in the skin is a blood flow disorder associated with a pressure sore wound;
<26> The medicament according to the above <23>, wherein the cerebral blood flow disorder is a blood flow disorder associated with suppression of recurrence after cerebral infarction;
<27> The medicament according to any one of the above <1> to <19> for use in the prevention or treatment of blood flow disorder;
<28> The medicament according to the above <27>, wherein the bloodstream disorder is a nerve bloodstream disorder;
<29> The medicament according to the above <28>, wherein the nerve blood flow disorder is a blood flow disorder associated with spinal stenosis.
<30> The medicament according to the above <27>, wherein the impaired blood flow is impaired blood flow in a peripheral artery, skin or brain;
<31> The medicament according to <30>, wherein the blood flow disorder in the peripheral artery is a blood flow disorder associated with chronic arterial occlusion or pulmonary hypertension;
<32> The medicament according to <30>, wherein the blood flow disorder in the skin is a blood flow disorder associated with a pressure sore wound;
<33> The medicament according to the above <30>, wherein the blood flow disorder in the brain is associated with the suppression of recurrence after cerebral infarction;
<34> A method for preventing or treating blood flow disorder in a mammal, comprising administering an effective amount of the medicament according to any one of <1> to <19> to a mammal;
<35> The method for the prophylaxis or treatment according to <34>, wherein the blood flow disorder is a nerve blood flow disorder; <36> the nerve blood flow disorder is a blood flow disorder associated with spinal stenosis. 35> The preventive or therapeutic method according to
<37> The method for the prophylaxis or treatment according to <34>, wherein the blood flow disorder is a blood flow disorder in a peripheral artery, skin or brain;
<38> The method according to the above <37>, wherein the blood flow disorder in the peripheral artery is a blood flow disorder associated with chronic arterial occlusion or pulmonary hypertension;
<39> The method according to the above <37>, wherein the blood flow disorder in the skin is a blood flow disorder associated with a pressure sore wound;
<40> The method according to <37>, wherein the blood flow disorder in the brain is a blood flow disorder associated with suppression of recurrence after cerebral infarction.

Hereinafter, the present invention will be described in more detail based on Reference Examples, Examples, Formulation Examples and Test Examples, but the present invention is not limited by these Examples and the like, and does not deviate from the scope of the present invention. The range may be changed.
The devices, reagents and the like used in the Examples and the like are easily obtainable or prepared according to methods commonly practiced in the art, or commercially available, unless otherwise noted.
"Room temperature" in the following Reference Examples and Examples usually indicates about 10 ° C to about 30 ° C. The ratio shown in the mixed solvent indicates the volume ratio unless otherwise specified. % Indicates mol / mol% for the yield and weight% for the others.
The following abbreviations are used in the reference examples and examples.
Me: methyl Et: ethyl Pr: propyl Bu: butyl Ph: phenyl Ac: acetyl THP: tetrahydro-2H-pyran-2-yl TBS: tert-butyldimethylsilyl KHMDS: potassium bistrimethylsilylamide DBU: 1,8-diazabicyclo [ 5.4.0] Undec-7-ene DMAP: 4-dimethylaminopyridine Py: pyridine DMSO: dimethylsulfoxide DME: 1,2-dimethoxyethane p-TsOH: p-toluenesulfonic acid aq: aqueous solution

Reference Example 1: (S) -5-Cyclopropyl-2-methylpent-4-ynoic acid methyl ester

Lithium chloride (4.24 g) and zinc powder (9.15 g) were dried under reduced pressure and then tetrahydrofuran (THF) (100 mL), 1,2-dibromoethane (0.433 mL) and trimethylchlorosilane (0.127 mL) at room temperature Was added. A solution of methyl (R) -3-iodo-2-methylpropionate (22.8 g) in THF (30 mL) was added dropwise to the mixture, and the mixture was stirred at 40 ° C. for 1.5 hours to prepare an organozinc reagent. . In a separate reaction vessel lithium chloride (7.63 g), copper (I) cyanide (8.06 g) and THF (90 mL) were added and the mixture was stirred for 1 hour. The mixture was cooled to −10 ° C., and the organozinc reagent was added dropwise thereto. The reaction mixture is stirred at −10 ° C. for 10 minutes and then cooled to −78 ° C., and a solution of 2- (bromoethynyl) cyclopropane (14.5 g) in THF (50 mL) is added dropwise and stirred at the same temperature for 15 hours The mixture was poured into aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with water, then the insolubles were filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (diethyl ether: hexane = 1: 30 to 1: 5) to give the title compound (9.93 g). 66% yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.69 (s, 3 H), 2.59 (dq, J = 6.8, 7.2 Hz, 1 H), 2.46 (ddd, J = 2.0, 6.0, 16.4 Hz, 1 H), 2.29 (dd, J = 2.0, 7.8, 16.4 Hz, 1 H), 1.23 (d, J = 7.2 Hz, 3 H), 1.22 (m, 1 H), 0.71 (m, 2 H), 0.60 (m, 2 H).

Reference Example 2: (S)-(+)-(6-Cyclopropyl-3-methyl-2-oxohex-5-yn-1-yl) phosphonic acid dimethyl ester

THF (25 mL) was added to dimethyl methylphosphonate (4.34 mL), and 1.6 M n-butyllithium (23.7 mL) was added dropwise at -78 ° C. The reaction mixture was stirred at -78 ° C for 1 hour, and then a solution of (S) -5-cyclopropyl-2-methylpent-4-ynoic acid methyl ester obtained in Reference Example 1 in THF (10 mL) was added, and the same temperature was added. Stir for 4 hours. To the reaction mixture was added aqueous ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 3 to ethyl acetate only) to give the title compound (2.36 g). 61% yield.
¹ H NMR (400 MHz, CDCl ₃ ) δ 3.81 (s, 3 H), _3. 78 (s, 3 H), _3. 20 (ddd, J = 14.4, 22.8, 28.4 Hz, 2 H), 2.91 (q, J = 6.8 Hz , 1H), 2.33 (dddd, J = 2.0, 6.8, 16.8, 44.4 Hz, 2H), 1.18 (d, J = 7.2 Hz, 3H), 1.18 (m, 1H), 0.71 (m, 2H), 0.60 (0.62) m, 2H).

Reference Example 3: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester

To a suspension of 4- (carboxybutyl) triphenylphosphonium bromide (14.06 g) in THF (86 mL) was added 1 M potassium bistrimethylsilylamide (64 mL) and stirred for 1 hour. The mixture is cooled to −78 ° C. and (3aR, 4S, 5R, 6aS) -4-(((tert-butyldimethylsilyl) oxy) methyl) hexahydro-5-((tetrahydro-2H-pyran-2-yl) A solution of (oxy) -2H-cyclopenta [b] furan-2-ol (3.92 g) in THF (50 mL) was added, and the mixture was stirred for 30 minutes at the same temperature, then warmed to room temperature and stirred overnight. The reaction mixture was added with water and extracted with tert-butyl methyl ether, then acidified with disodium citrate and then extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, acetone (390 mL) is added, and diisopropylethylamine (9.16 mL) at 0 ° C., iodomethane (2.95 mL) and 1,8-diazabicyclo [5.4.0 ] Undec-7-ene (7.85 mL) was added. The mixture was stirred at room temperature for 3.5 hours, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give a viscous oil (3.21 g). Methanol (220 mL) was added to the oil (3.13 g), and the mixture was stirred with 5% Pd / C (1.13 g) for 40 minutes under a hydrogen atmosphere. The catalyst was filtered off and the filtrate was concentrated in vacuo. Pyridine (14 mL), acetic anhydride (14 mL) and 4-dimethylaminopyridine (170 mg) were added to the residue and stirred for 1 hour. Water was added to the reaction mixture and extracted with a hexane-ethyl acetate mixed solvent. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, THF (32 mL) was added to the residue and ice-cooled, 1 M tetrabutylammonium fluoride (6.7 mL) was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 3) to give the title compound (2.60 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.07 (m, 1 H), 4.71 (m, 0.55 H), 4.54 (m, 0.45 H), 4.15-4.04 (m, 1 H), 4.04-3.88 (m, 1H), 3.88-3.73 (m, 2H), 3.66 (s, 3H), 3.60-3.48 (m, 2H), 2.29 (m, 2H), 2.04 (t, J = 7.5 Hz, 2H), 1.95-1.15 (m, 20H).

Reference Example 4: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester (3.0 g) It was dissolved in ethyl acetate (48 mL), and N, N-diisopropylethylamine (7.6 mL) was added under ice-cooling. A solution of SO ₃ -pyridine (3.6 g) in dimethyl sulfoxide (24 mL) was added to the mixture, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was poured into ethyl acetate (50 mL) and water (50 mL), aqueous sodium bicarbonate solution was added for separation, and the organic layer was concentrated under reduced pressure. To the residue was added hexane, and the mixture was washed successively with aqueous copper sulfate solution, saturated brine and water. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.75 g).
¹ H NMR (300 MHz, CDCl ₃ ) δ 9.77 (dd, J = 16.1, 3.2 Hz, 1 H), 5.13 (m, 1 H), 4.704-5.50 (m, 1 H), 4.41 (m, 1 H), 3.81 (m, 2H), 3.66 (s, 3H), 3.46 (m, 2H), 3.40-2.92 (m, 0.46H), 2.88-2.78 (m, 0.54H), 2.28 (t, J = 7.5 Hz, 2H ), 2.50-2.20 (m, 1 H), 2.06 (s, 3 H), 1. 98-1.52 (m, 16 H).

Reference Example 5: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -7-cyclopropyl-4-methyl-3-oxohept-1-en-6-yne) -1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester

1, 2-Dimethoxyethane (126 mL) was added to sodium hydride (60%, oil dispersion) (575 mg), and (S)-(+)-(6-cyclopropyl) synthesized in Reference Example 2 with ice cooling. A solution of 3-methyl-2-oxohex-5-yn-1-yl) phosphonic acid dimethyl ester (3.41 g) in 1,2-dimethoxyethane (20 mL) was added dropwise. The mixture was stirred under ice-cooling for 1 hour, and then 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-formyl-3-((tetrahydro-2H-pyran-) synthesized in Reference Example 4 A solution of 2-yl) oxy) cyclopentyl) heptanoic acid methyl ester (2.75 g) in 1,2-dimethoxyethane (40 mL) was added dropwise and stirred at the same temperature for 3 hours. Ethyl acetate (290 mL) and saturated brine (290 mL) were added to the reaction mixture, diluted with water and partitioned, and the aqueous layer was extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 86: 14-ethyl acetate only) to give the title compound (3.43 g) as a colorless oil I got it as a thing. Yield 61% (7-((1R, 2R, 3R, 5S) -5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl) oxy obtained in Reference Example 3)) Two step yield from cyclopentyl) heptanoic acid methyl ester).
¹ H NMR (400 MHz, CDCl ₃ ) δ 6.80 (m, 1 H), 6.28 (m, 1 H), 5.12 (brt, J = 5.7 Hz, 1 H), 4.54 (dt, J = 12.8, 3.0 Hz, 1 H ), 4.12-3.96 (m, 1H), 3.83-3.58 (m, 2H), 3.65 (s, 3H), 3.50-3.38 (m, 1H), 3.14-2.83 (m, 1H), 2.75-2.16 (m , 4H), 2.06 (s, 3H), 1.95-1.05 (m, 20H), 1.18 (d, J = 7.2 Hz, 3H), 0.75-0.54 (m, 4H).

Reference Example 6: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6) -In-1-yl) -3-hydroxycyclopentyl) heptanoic acid methyl ester

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -7-cyclopropyl-4-methyl-3-oxohept-1-en-6 synthesized in Reference Example 5) -In-1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester (2.47 g) is dissolved in methanol (42 mL), cerium chloride heptahydrate Add (1.74 g) and cool to -40 ° C. Sodium borohydride (90.2 mg) was added to the mixture and stirred at the same temperature for 75 minutes. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate solution and water were added for separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (2.45 g) as a crude product.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.65-5.45 (m, 2H), 5.09 (brs, 1H), 4.60 (m, 1H), 4.14-3.98 (m, 1H), 3.92-3.78 (m, 3H) 2H), 3.66 (s, 3H), 2.60-2.30 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.30-2.13 (m, 2H), 2.04 (s, 3H), 1.85-1.10 (m, 23H), 0.96 (m, 3H), 0.72 to 0.58 (m, 4H).

The crude product (2.45 g) was dissolved in THF (9.3 mL), 65% aqueous acetic acid solution (93 mL) was added, and the mixture was stirred at 45 ° C. for 2 hours. The reaction solution was allowed to cool to room temperature, 100 mL of water was added, and the mixture was extracted with a mixed solvent of ethyl acetate-hexane (1: 1). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 67: 33-ethyl acetate only) to give the title compound (723 mg) and its stereoisomer (1.23 g).
¹ H NMR (400 MHz, CDCl ₃ )
Title compound: δ 5.58 (dd, J = 15.2, 7.4 Hz, 1 H), 5.45 (dd, J = 15.2, 9.2 Hz, 1 H), 5.14 (brt, J = 4.6 Hz, 1 H), 3.97 (t, J = 7.4 Hz, 1 H), 3. 87 (q, J = 8.5 Hz, 1 H), 3. 66 (s, 3 H), 2. 72-2.56 (m, 2 H), 2.50 (dq, J = 8.5, 6.5 Hz, 1 H), 2. 28 (t, J = 7.6 Hz, 2H), 2.30-2.17 (m, 2H), 2.05 (s, 3H), 1.80-1.49 (m, 6H), 1.49-1.00 (m, 9H), 0.93 (d, J = 6.5 Hz, 3 H), 0.75-0.68 (m, 2 H), 0.62-0.57 (m, 2 H).
Isomers of the title compound: δ 5.61 (dd, J = 15.2, 5.6 Hz, 1 H), 5.50 (dd, J = 15.2, 8.6 Hz, 1 H), 5.15 (brt, J = 4.6 Hz, 1 H), 4.18 ( t, J = 4.8 Hz, 1 H), 3. 90 (m, 1 H), 3. 65 (s, 3 H), 2. 48 (dq, J = 8.6, 6.4 Hz, 1 H), 2. 28 (t, J = 7.6 Hz, 2 H), 2.05 (s, 3H), 1.86-1.17 (m, 10H), 1.49-1.00 (m, 9H), 0.96 (d, J = 6.4 Hz, 3H), 0.72-0.68 (m, 2H),
0.62-0.58 (m, 2H).

Reference Example 7: 7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-Cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran-2-yl) ) Oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-ene synthesized in Reference Example 6 Dissolve -6-in-1-yl) -3-hydroxycyclopentyl) heptanoic acid methyl ester (67.6 mg) in methylene chloride (1 mL) and 3,4-dihydro-2H-pyran (41.3 μL at 0 ° C. ), P-toluenesulfonic acid monohydrate (2.9 mg) was added, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture were added diethyl ether (10 mL) and saturated aqueous sodium bicarbonate (10 mL) to separate the layers, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give acetoxy-bistetrahydropyranyl (THP) ether (117.1 mg) as a crude product.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.56-5.26 (m, 2H), 5.10 (m, 1H), 4.81-4.58 (m, 2H), 4.20-3.80 (m, 6H), 3.65 (s, 6H) 3H), 3.48-3.40 (m, 2H), 2.60-2.31 (m, 1H), 2.28 (t, J = 7.6 Hz, 2H), 2.31-2.10 (m, 3H), 2.04 (s, 3H), 1.90 -1.10 (m, 22H), 0.93 (m, 3H), 0.70-0.68 (m, 2H), 0.62-0.58 (m, 2H).

The crude product of the acetoxy-bis THP ether product obtained above (117 mg) is dissolved in methanol (0.7 mL), and 1 N aqueous sodium hydroxide solution (0.45 mL) is added at 0 ° C. Stir for hours. To the reaction mixture, aqueous citric acid solution was added and extracted with ethyl acetate. The organic layers are combined, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1 to 1: 3) to give the title compound (70.9 mg) Obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.55-5.25 (m, 2 H), 4.71 (m, 2 H), 4.15-3.84 (m, 6 H), 3.47 (m, 2 H), 2.50-2.35 (m, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.25-2.10 (m, 2H), 1.97-1.20 (m, 28H), 0.94 (m, 3H), 0.71-0.68 (m, 2H), 0.60 -0.58 (m, 2H).

Reference example 8: 7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran-2-yl) ) Oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester

Methanol (6 mL) and potassium carbonate (382.8 mg) were added to the acetoxy-bis THP ether compound (682.4 mg) synthesized in the same manner as in Reference Example 7, and the mixture was stirred at 40 ° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, neutralized with acetic acid, and saturated aqueous sodium bicarbonate was added to separate the layers. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 84: 16 to ethyl acetate only) to give the title compound ( 566.6 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.58-5.42 (m, 1.5 H), 5.28-5.18 (m, 0.5 H), 4.77-4.60 (m, 2 H), 4.18-4.08 (m, 2 H), 3.90-3.75 (m, 3H), 3.66 (s, 3H), 3.51-3.38 (m, 2H), 2.50-2.00 (m, 5H), 2.29 (t, J = 7.4 Hz, 2H), 2.00-1.40 ( m, 26H), 0.92 (dddd, J = 17.2, 17.2, 6.8, 6.8 Hz, 3H), 0.74-0.68 (m, 2H), 0.62-0.58 (m, 2H).

Reference Example 9: (2E) -7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran) -2-yl) oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) hept-2-enoic acid

7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran-2) synthesized in Reference Example 8) -Yl) oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester (364.4 mg Pyridine (2 mL) was added to and after cooling to 0 ° C., trimethylchlorosilane (0.12 mL) was added and stirred at the same temperature for 30 minutes. The reaction mixture was diluted with a mixed solvent of hexane and ethyl acetate (10: 1), saturated aqueous sodium bicarbonate solution was added for separation, and the organic layer was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the silyl ether (366.1 mg) as a crude product.
The crude product (366.1 mg) of the silyl ether is dissolved in THF (2.5 mL), and a THF solution (1.41 mL) of 1.12 M lithium diisopropylamide is added at -78 ° C, and the reaction is continued for 30 minutes. It stirred. A solution of diphenyl diselenide (412.9 mg) in THF (1 mL) was added dropwise to the mixture at -78 ° C, and the mixture was stirred at the same temperature for 45 minutes and at 0 ° C for 1 hour. The reaction mixture was diluted with ethyl acetate, saturated ammonium chloride was added for separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the selenoated compound (763 mg) as a crude product.
Ethyl acetate (4 mL), THF (2 mL) and sodium bicarbonate (179.2 mg) were added to the crude selenated product (763 mg) and the mixture was stirred. To the mixture was added 30% aqueous hydrogen peroxide (0.21 mL), and the mixture was stirred at 35 ° C. for 1 hour. The reaction mixture was diluted with ethyl acetate, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved by adding methanol (5 mL), 1N aqueous sodium hydroxide (1.9 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 43 hours. The reaction mixture was diluted with ethyl acetate, neutralized with saturated aqueous disodium citrate solution, and extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to ethyl acetate to ethyl acetate: methanol = 20: 1) to give the title compound (169.8 mg) Obtained.
¹ H NMR (400 MHz, CDCl ₃ ) δ 7.00-6.87 (m, 1 H), 5.81 (d, J = 14.8 Hz, 1 H), 5.63-5.41 (m, 2 H), 5.30-1.18 (m, 1 H) , 4.82-4.60 (m, 2H), 4.20-3.52 (m, 6H), 3.72 (s, 3H), 3.53-3.39 (m, 2H), 2.59-1.00 (m, 25H), 0.92 (m, 3H) , 0.74-0.63 (m, 2H), 0.60-0.52 (m, 2H).

Reference Example 10: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -4-methyl-3-oxonon-1-en-6-yn-1-yl) -3-((Tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester

Dimethyl ((S) -3-methyl-2-oxoocta-5-yn-1-yl) phosphonate and 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-one synthesized in Reference Example 4 The title compound was synthesized from formyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester in the same manner as in Reference Example 5.
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.76 (m, 1 H), 6.29 (m, 1 H), 5.13 (m, 1 H), 4.58 (m, 1 H), 4.12-3.44 (m, 3 H), 3.66 (s, 3H), 2.89 (m, 1H), 2.74-2.10 (m, 5H), 2.07 (s, 3H), 1.99-1.08 (m, 21H), 1.20 (d, J = 7.2 Hz, 3H), 1.10 (t, J = 7.4 Hz, 3 H).

Reference Example 11: 7-((1R, 2R, 3R, 5S) -5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) -2,2-difluoro Heptanoic acid methyl ester

Using 3- (1-carboxy-2,2-difluorobutyl) triphenylphosphonium bromide instead of 4- (carboxybutyl) triphenylphosphonium bromide, the procedure of Reference Example 3 is repeated ((3aR, 4S, 5R, 6aS) -4-(((tert-Butyldimethylsilyl) oxy) methyl) hexahydro-5-((tetrahydro-2H-pyran-2-yl) oxy) -2H-cyclopenta [b] furan-2-ol The compound was synthesized.
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.64 (dt, J = 5.2, 5.2, 2.0 Hz, 1 H), 4.70 (dd, J = 4.0, 0.8 Hz, 0.5 H), 4.53 (dd, J = 5.1) , 2.4 Hz, 0.5 H), 4.08 (dddd, J = 8.4, 6.6, 4.8, 4.4 Hz, 0.5 H), 4.53 (dd, J = 8.0, 6.2, 4.4, 4.4 Hz, 0.5 H), 3.96-3.71 ( m, 2H), 3.85 (s, 3H), 3.58-3.43 (m, 2H), 3.00 (brs, 1H), 2.29 (m, 2H), 2.12-1. 15 (m, 18H), 2.03 (d, J = 2.4 Hz, 3 H). ¹⁹ F NMR (282.65 MHz, CD ₃ OD) δ -106.26 (t, J = 17.3 Hz, 2 F).

Reference Example 12: 2-((1S, 2R, 3R, 5S) -5-hydroxy-2-((1E, 3RS, 4S) -4-methyl-3-((tetrahydro-2H-pyran-2-yl)) Oxy) non-1-en-6-yn-1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) ethanol

(3aR, 4R, 5R, 6aS) -hexahydro-5-hydroxy-4-((1E, 3RS, 4S) -3-hydroxy-4-methyl-1-nonene-6-ynyl) -2H-cyclopenta [b] Furan-2-one (3.50 g) is dissolved in methylene chloride (61 mL), and under ice-cooling, 2,3-dihydropyran (3.3 mL) and p-toluenesulfonic acid monohydrate (24.5 mg) Was added and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 85 / 15-ethyl acetate) to obtain bis THP ether (7.26 g) . The bis THP ether (994 mg) was dissolved in THF (4 mL), added to a suspension of lithium aluminum hydride (75 mg) in THF (4 mL) under ice cooling, and stirred at the same temperature for 40 minutes. The reaction mixture was diluted with diethyl ether, aqueous sodium sulfate solution was added, filtered through celite, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (953 mg) as a viscous oil.
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.60-5.26 (m, 2H), 4.77-4.65 (m, 2H), 4.30-3.60 (m, 7H), 3.48 (m, 2H), 2.20-1.40 (2. m, 25 H), 1. 13 (t, J = 6.9 Hz, 3 H), 0.96 (m, 3 H).

Reference Example 13: 4-((2-((1R, 2R, 3R, 5S) -5-hydroxy-2-((1E, 3RS, 4S) -4-methyl-3-((tetrahydro-2H-pyran- 2-yl) oxy) non-1-en-6-yn-1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) ethyl) thio) butanoic acid methyl ester

2-((1S, 2R, 3R, 5S) -5-hydroxy-2-((1E, 3RS, 4S) -4-methyl-3-((tetrahydro-2H-pyran-2-) synthesized in Reference Example 12) A solution of (yl) oxy) non-1-en-6-yn-1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) ethanol (122 mg) in THF (2 mL), Diisopropylethylamine (91 μL) and methanesulfonyl chloride (30 μL) were added at −20 ° C. and stirred for 1 hour. After adding diisopropylethylamine (44 μL) and methanesulfonyl chloride (10 μL) to the reaction mixture and stirring at −10 ° C. for 1 hour, diisopropylamine (91 μL) and chlorotrimethylsilane (40 μL) were added and stirred for 1 hour. Furthermore, after adding the N, N- dimethylformamide (2.5 mL) solution of S-potassium thioacetate (92 mg) at -10 degreeC, potassium carbonate (211 mg) was added and it stirred at room temperature overnight. Water was added to the reaction mixture, extraction was performed with a mixed solvent of ethyl acetate and hexane (1: 1), the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (1 mL), methyl 4-iodobutanoate (72 mg) and potassium carbonate (86 mg) were added and stirred at room temperature for 1.5 hours. Thereafter, a saturated aqueous solution of ammonium chloride is added, extracted with tert-butyl methyl ether, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel chromatography (hexane: ethyl acetate = 4: 1 to 1: 1) The title compound (71 mg) was obtained by
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.55 (m, 2 H), 4.68 (m, 2 H), 4.30-3.70 (m, 5 H), 3.67 (s, 3 H), 3.46 (m, 2 H), 2.60 -2.40 (m, 4H), 2.23 (m, 2H), 2.10-1.40 (m, 26H), 1.13 (t, J = 6.9 Hz, 3H), 0.96 (m, 3H).

Example 1: 4-((2-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-en-6-yne- 1-yl) -5-oxocyclopentyl) ethyl) thio) butanoic acid methyl ester [compound (1) -1]

4-((2-((1R, 2R, 3R, 5S) -5-hydroxy-2-((1E, 3RS, 4S) -4-methyl-3-((tetrahydro-2H-) synthesized in Reference Example 13) Pyran-2-yl) oxy) non-1-en-6-yn-1-yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) ethyl) thio) butanoic acid methyl ester Ethyl acetate (0.8 mL) and N, N-diisopropylethylamine (0.15 mL) are added to 70 mg), and a solution of SO ₃ -pyridine (63 mg) in dimethyl sulfoxide (0.67 mL) is slowly added at 0 ° C. Stir for 20 minutes. After that, it was diluted with ethyl acetate and water was added to separate it. The organic layer is washed with 1N hydrochloric acid and saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: ethyl acetate = 93/7 to 20/80) to correspond. The 5-oxobis THP ether body (52 mg) was obtained. THF (0.2 mL) and 65% acetic acid (3.6 mL) were added to the 5-oxo-bis THP ether (52 mg), and the mixture was stirred at 45 ° C. for 1 hour, diluted with water, hexane and ethyl acetate (1 It extracted with the mixed solvent of: 1). The organic layer was dried over anhydrous sodium sulfate and dried under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 50: 50 to 35:65) to give the title compound (29 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.64 (dddd, J = 15.1, 15.1, 8.0, 6.9 Hz, 2H), 4.12-4.03 (m, 2H), 3.70 (s, 1H), 3.68 (s, 2H), 2.76 (dd, J = 7.5, 6.6 Hz, 1 H), 2.62 (dt, J = 7.2, 3.2 Hz, 2 H), 2.51 (t, J = 7.4 Hz, 2 H), 2.43 (t, J = 7.4 Hz, 2H), 2.39-2.10 (m, 7H), 2.10-1.61 (m, 7H), 1.12 (t, J = 7.5 Hz, 3 H), 0.97 (d, J = 6.6 Hz, 3 H).

Example 2: (2E) -4-((2-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-ene- 6-in-1-yl) -5-oxocyclopentyl) ethyl) thio) but-2-enoic acid methyl ester [compound (1) -2]

2-((1S, 2R, 3R, 5S) -5-hydroxy-2-((1E, 5) synthesized in Reference Example 12 using methyl 4-bromo-2-butenoate instead of methyl 4-iodobutanoate 3RS, 4S) -4-Methyl-3-((tetrahydro-2H-pyran-2-yl) oxy) non-1-en-6-yn-1-yl) -3-((tetrahydro-2H-pyran) The title compound was obtained in the same manner as in Reference Example 13 and Example 1 from 2-yl) oxy) cyclopentyl) ethanol.
¹ H NMR (300 MHz, CDCl ₃ ) δ 6.86 (ddd, J = 15.6, 7.6, 7.6 Hz, 1H), 6.07 (dt, J = 15.6, 9.5 Hz, 1H), 5.92-5.56 (m, 2H) , 4.30-4.00 (m, 2H), 3.75 (s, 3H), 3.60-3.00 (m, 2H), 2.90-2.70 (m, 2H), 2.70-2.08 (m, 9H), 2.05-1.64 (m, 2) 4H), 1.13 (t, J = 7.2 Hz, 3H), 1.02-0.95 (m, 3H).

Example 3: ((1R, 2R, 3R) -3-hydroxy-2-((1E, 3RS, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5 -Oxocyclopentyl) heptanoic acid methyl ester [compound (1) -3]

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -4-methyl-3-oxonona-1-en-6-yne-1-one synthesized in Reference Example 10) (Ethyl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester (44 mg) is dissolved in methanol (0.5 mL), and under ice-cooling, cerium chloride heptahydrate ( 9.5 mg) and sodium borohydride (1.9 mg) were added and stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate, saturated aqueous ammonium chloride solution was added to separate the layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is dissolved in methylene chloride (1 mL), 3,4-dihydro-2H-pyran (10.5 μL), p-toluenesulfonic acid monohydrate (0.73 mg) are added at 0 ° C., and the temperature is 1 Stir for hours. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the reaction mixture to separate it, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Methanol (0.5 mL) and potassium carbonate (10.6 mg) were added to the residue and stirred at room temperature for 16 hours. Ethyl acetate and a saturated aqueous solution of ammonium chloride were added to the reaction mixture for separation, and the aqueous layer was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane: ethyl acetate = 84: 16 to 50:50) to give 7-((1R, 2R, 3R, 5S) -2-((1E, 3RS, 4S)-). 4-Methyl-3-((tetrahydro-2H-pyran-2-yl) oxy) non-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2) -Yl) oxy) cyclopentyl) heptanoic acid methyl ester (33 mg) was obtained. The obtained compound was subjected to the same treatment as in Example 1 to give the title compound.
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.75-5. 55 (m, 2 H), 4.22-3. 98 (m, 2 H), 3. 66 (s, 3 H), 2. 75 (dd, J = 18.4, 7.2 Hz, 1 H) , 2.43-1.28 (m, 22H), 1.12 (t, J = 7.3 Hz, 3H) 0.97 (d, J = 6.9 Hz, 3H).

Example 4: 7-((1R, 2R, 3R) -2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yn-1-yl ) -3-Hydroxy-5-oxocyclopentyl) heptanoic acid [compound (1) -9]

7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-cyclopropyl-4-methyl-3-((tetrahydro-2H-pyran-2) synthesized in Reference Example 7) -Yl) oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid (70.9 mg) It was dissolved in acetone, 2.67 M Jones reagent (70.8 μL) was added dropwise at -20 ° C, and after stirring for 30 minutes at the same temperature, Jones reagent (7.1 μL) was added and stirred for another 10 minutes. The reaction mixture was partitioned by adding 2-propanol (0.15 mL), diethyl ether (10 mL) and water (6 mL). The aqueous layer was extracted with diethyl ether, then the organic layers were combined and washed successively with water and brine. After drying over anhydrous magnesium sulfate and concentration under reduced pressure, oxo-bis THP ether (53.7 mg) was obtained as a crude product.
The obtained crude product of oxo-bis THP ether (53.7 mg) is dissolved in THF (0.252 mL), 65% aqueous acetic acid solution (2.52 mL) is added, 1 hour at 45 ° C., room temperature Stir for hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2-ethyl acetate to ethyl acetate: methanol = 20: 1) to give the title compound (29.5 mg).
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.69 (dd, J = 15.2, 7.6 Hz, 1 H), 5.60 (dd, J = 15.2, 8.8, 1 H), 4.13-4.03 (m, 2 H), 2.75 ( dd, J = 18.4, 7.2 Hz, 1 H), 2.43-1.20 (m, 22 H), 0.94 (d, J = 6.4 Hz, 3 H), 0.75-0.71 (m, 2 H), 0.63-0.59 (m, 2 H) ).

Example 5: (2E) -7-((1R, 2R, 3R) -2-((1E, 3S, 4S) -7-cyclopropyl-3-hydroxy-4-methylhept-1-en-6-yne) -1-yl) -3-hydroxy-5-oxocyclopentyl) hept-2-enoic acid [compound (1) -10]

(2E) -7-((1R, 2R, 3R, 5S) -2-((1E, 3S, 4S) -7-cyclopropyl-4-methyl-3-((tetrahydro-2H) synthesized in Reference Example 9 -Pyran-2-yl) oxy) hept-1-en-6-yn-1-yl) -5-hydroxy-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) hepta-2- The title compound was synthesized by Jones oxidation and removal of THP in the same manner as in Example 4 using enoic acid. Yield 66.4%.
¹ H NMR (400 MHz, CDCl ₃ ) δ 6.98 (dt, J = 15.6, 6.9 Hz, 1 H), 5.98 (brs, 2 H), 5.77 (d, J = 15.6 Hz, 1 H), 5.58 (dddd, J = 15.3, 15.3, 7.4, 6.8 Hz, 2H), 4.05-3.93 (m, 2 H), 2.71 (dd, J = 18.2, 7.4 Hz, 1 H), 2.40-1.00 (m, 16 H), 0.89 (d, J = 6.8 Hz, 3H), 0.71-0.67 (m, 2H), 0.59-0.55 (m, 2H).

Example 6: 7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-Oxocyclopentyl) heptanoic acid [compound (1) -6]

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -4-methyl-3-oxonona-1-en-6-yne-1-one synthesized in Reference Example 10) The title compound was synthesized in the same manner as in Reference Example 6, Reference Example 7 and Example 4 from yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.65 (dddd, J = 15.3, 15.3, 8.3, 7.2 Hz, 2 H), 4.12-4.01 (m, 2 H), 2.74 (dd, J = 18.0, 7.2 Hz, 1H), 2.45-1.96 (m, 11 H), 1. 79 (m, 1 H), 1.50-1. 40 (m, 4 H), 1.40-1. 30 (m, 7 H), 1. 13 (t, J = 6.9 Hz, 3 H), 0.96 (d, J = 6.9 Hz,
3H).

Example 7: (2E) -7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yne- 1-yl) -5-oxocyclopentyl) hept-2-enoic acid [compound (1) -7]

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-((1E, 4S) -4-methyl-3-oxonona-1-en-6-yne-1-one synthesized in Reference Example 10) Yl) -3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) heptanoic acid methyl ester in the same manner as in Reference Example 6, Reference Example 7, Reference Example 8, Reference Example 9 and Example 5 The title compound was synthesized.
¹ H NMR (300 MHz, CDCl ₃ ) δ 7.01 (dt, J = 15.4, 7.0 Hz, 1 H), 5.80 (d, J = 15.4 Hz, 1 H), 5.62 (dddd, J = 15.3, 15.3, 8.2, 7.7 Hz, 2 H), 4.08 to 3.80 (m, 2 H), 2. 73 (dd, J = 18.3, 7.5 Hz, 1 H), 2.46 to 1.70 (m, 11 H), 1.87 to 1.30 (m, 8 H), 1.14 (t , J = 7.4 Hz, 3 H), 0.94 (t, J = 6.9 Hz, 3 H).

Example 8: 7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) 5-Oxocyclopentyl) heptanoic acid (5-methyl-2-oxo-1,3-dioxole-4-yl) methyl ester [compound (1) -4]

In a similar manner to Example 4, the oxo-bis THP ether product (250 mg) obtained as an intermediate in Example 6 was dissolved in acetone (4.5 mL), 4-chloromethyl-5-methyl-1, 3-Dioxole-2-one (20.8 mg) was added dropwise. Sodium iodide (68.4 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (82.2 mg) were added there, and it stirred at the same temperature for 21 hours. To the reaction mixture were added diethyl ether and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with diethyl ether. The extract is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane only to hexane: ethyl acetate = 16: 84-ethyl acetate only to ethyl acetate: methanol = 98: 2) to obtain an ester ( 278 mg) was obtained. Next, THF (0.95 mL) and 65% aqueous acetic acid solution (9.5 mL) were added to the obtained ester (278 mg), and the mixture was stirred at 45 ° C. for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to 1: 5: ethyl acetate alone to ethyl acetate: methanol = 50: 1) to give the title compound (168.2 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.64 (dddd, J = 15.2, 15.2, 8.4, 7.1 Hz, 2H), 4.83 (s, 2H), 4.13-3.99 (m, 2H), 2.74 (dd, J = 17.7, 7.5 Hz, 1 H), 2.46-1.94 (m, 11 H), 1.85-1. 19 (m, 14 H), 1. 13 (d, J = 7.4 Hz, 3 H), 0.95 (d, J = 4.2 Hz, 3 H ).

Example 9: 7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-yn-1-yl) -5-Oxocyclopentyl) heptanoic acid 3,3-dimethyl-2-oxobutyl ester [compound (1) -5]

In the same manner as in Example 4, the oxo-bis THP ether product (200.9 mg) obtained as an intermediate in Example 6 was dissolved in acetone (3.7 mL), and 1-chloropinacolone (28.2 mg) at 0 ° C. Sodium iodide (14 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (16.6 mg) were added and stirred at the same temperature for 17 hours. To the reaction mixture were added diethyl ether and saturated aqueous sodium bicarbonate, and the aqueous layer was extracted with diethyl ether. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (hexane only-hexane: ethyl acetate = 16: 84-ethyl acetate only-ethyl acetate: methanol = 95: 5) , Ester form (163.6 mg) was obtained. Next, THF (0.95 mL) and 65% aqueous acetic acid solution (9.5 mL) were added to the obtained ester (21.6 mg), and the mixture was stirred at 45 ° C. for 2.5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1 to ethyl acetate only) to give the title compound (116.6 mg).
¹ H NMR (300 MHz, CDCl ₃ ) δ 5.76-5.57 (m, 2H), 4.88 (s, 2H), 4.18-4.00 (m, 2H), 2.82-2.68 (m, 1H), 2.46-1 .95 ( m, 10 H), 1.85-1. 17 (m, 12 H), 1.21 (d, J = 4.7 Hz, 9 H), 1. 14 (dt, J = 7.4, 4.7 Hz, 3 H), 0.97 (dd, J = 6.9, 4.5 Hz , 3H).

Example 10: 2,2-Difluoro-7-((1R, 2R, 3R) -3-hydroxy-2-((1E, 3S, 4S) -3-hydroxy-4-methylnon-1-en-6-) In-1-yl) -5-oxocyclopentyl) heptanoic acid [compound (1) -8]

7-((1R, 2R, 3R, 5S) -5-acetoxy-2-hydroxymethyl-3-((tetrahydro-2H-pyran-2-yl) oxy) cyclopentyl) -2,2 synthesized in Reference Example 11 The title compound was synthesized from-difluoroheptanoic acid methyl ester in the same manner as in Reference Example 4-Reference Example 7 and Example 4.
¹ H NMR (400 MHz, CDCl ₃ ) δ 5.60 (dddd, J = 15.2, 15.2, 8.4, 7.4 Hz, 2 H), 4.03 (dd, J = 17.2, 8.4 Hz, 1 H), 3.97 (t, J = 7.6 Hz, 1 H), 2.86-2.65 (m, 1 H), 2.51-1. 88 (m, 9 H), 1. 74 (m, 1 H), 1.72-1. 17 (m, 11 H), 1. 12 (t, J = 7.4 Hz, 3 H ¹⁹ F NMR (282.65 M Hz, CD ₃ OD) δ -106.42 (t, J = 15.4 Hz, 2 F).), 0.94 (d, J = 6.8 Hz, 3 H).

Formulation Example 1: Production of tablet 1) Compound (1) 0.003 g
2) Lactose 50 g
3) Corn starch 15 g
4) Carboxymethylcellulose calcium 44 g
5) Magnesium stearate 1 g
1000 tablets total 110.003 g
The whole of 1), 2) and 3) and 30 g of 4) are kneaded with water, dried under vacuum and then sized. The sieved powder is mixed with 14 g of 4) and 1 g of 5) and compressed with a tablet press. In this way, 1000 tablets each containing 3 μg of the example compound are obtained.

Formulation Example 2 Production of Capsule 1) Compound (1) 0.003 g
2) Fine powder cellulose 10 g
3) Lactose 19 g
4) Magnesium stearate 1 g
30.03 g in total
1), 2), 3) and 4) are mixed and filled into gelatin capsules to give 1000 capsules, each containing 3 μg of the example compound.

Test Example 1: Evaluation of Human Platelet Aggregation Inhibitory Effect in Vitro (1) Preparation of Human Platelet Rich Plasma Using 3.8 w / v% sodium citrate as an anticoagulant, sodium citrate solution: blood (volume ratio) = 1 Blood was collected from human brachial vein at a ratio of 9: 9 and centrifuged (120 xg, 10 minutes) to obtain upper layer platelet-rich plasma (PRP). Furthermore, the blood from which PRP was removed was centrifuged (1700 × g, 10 minutes) to obtain platelet poor plasma (PPP). The platelet count of PRP was measured, and the platelet count was diluted with PPP to 25 × 10 ⁴ / μL.

(2) Measurement of platelet aggregation ability Measurement of platelet aggregation ability is based on the method of Born (Nature, 1962, vol. 194, p. 927-929), platelet aggregation ability measuring apparatus (PRP 313 M, IMI Co., Ltd.) ) Was performed. After placing 190 μL of PRP in a glass cuvette and attaching it to a platelet aggregation measuring device, add 5 μL of the present compound, limaprost (positive control substance) or control (0.25 vol% dimethyl sulfoxide [DMSO]) as a test substance, and Incubate for a minute. Agglomeration was induced by adding 5 μL of ADP (LMS Co., Ltd.) as a coagulant to a final concentration of 3 μmol / L, and the maximum reaction of aggregation was measured.

(3) Evaluation of Platelet Aggregation Inhibitory Action The aggregation suppressive rate of the test substance is determined with the maximum aggregation rate of the control as 100%, and SAS System Version 9.1.3 (Stat Preclinica Client Ver. 1.1 SAS Institute Japan Co., Ltd. The IC ₅₀ was determined using “Dx calculation (straight line fitting): no logit conversion” in). Furthermore, the relative activity (%) of each test substance when the activity of limaprost's IC ₅₀ value was 100 was calculated.
The results are shown in Table 1. According to Table 1, the present compounds showed very potent activity in in vitro human platelet aggregation inhibitory activity test, and some showed 10 times or more activity over limaprost.

Test Example 2 Evaluation of Rat Platelet Aggregation Inhibitory Action in Vitro (1) Preparation of Rat Platelet Rich Plasma In the same manner as (1) in Test Example 1 above, blood was collected from the abdominal aorta of 8- to 9-week-old male SD male rats. Then, PRP was prepared by diluting the platelet count to 63.2 × 10 ⁴ / μL with PPP.

(2) Measurement of platelet aggregation ability As a test substance, the present compound, prostaglandin E1 (PGE1: positive control substance) or the same as Test Example 1 (2) except that the final concentration of ADP is 2 μmol / L. The maximal response of aggregation was determined when the control was added.

(3) Similar to (3) Evaluation of Test Example 1 of inhibiting platelet aggregation, the test substance when calculated _{IC 50} values from the aggregation inhibitory rate of the test substance, as 100 the activity of _{an IC 50} value of PGE1 The relative activity (%) of was calculated.
The results are shown in Table 2. The present compound showed potent activity in the in vitro rat platelet aggregation inhibitory activity test. The compounds (1) -1 to (1) -3, which are test substances, are all diastereomeric mixtures of R-form and S-form in the stereochemistry of the hydroxyl group of the ω chain. Therefore, if only the effective active substance (one diastereomer) is separated from the mixture and the above test is performed in the same manner, the activity may be approximately doubled.

Test Example 3: Evaluation of persistence of guinea pig platelet aggregation inhibitory action ex vivo (1) Measurement of IC ₅₀ value The present compound (3 doses of 79, 132 and 263 nmol / kg) as a test substance, limaprost (positive control substance: 79, A single oral administration of 3 doses of 263 and 789 nmol / kg) or a control (water for injection containing 0.26 vol% DMSO) at 10 mL / kg to 4 to 10 week old Hartley male guinea pigs, and 4 hours later abdominal aorta Blood was collected and platelet aggregation was measured, and the IC ₅₀ value of aggregation inhibitory activity (induced aggregation with 0.5 μmol / L ADP) was calculated in the same manner as in Test Example 1 (3).

(2) Administration of test substance and preparation of platelet-rich plasma Compound (1) -7 (168 nmol / kg), Compound (1) -9 (178 nmol / kg) of a dose showing IC ₅₀ calculated in the test of (1) above ), Compound (1) -10 (187 nmol / kg) and limaprost (266 nmol / kg) were orally administered once, and after 1, 2, 4, 6, 10, 16 and 24 hours, Test Example 1 (1) above Similarly to the above, blood was collected from the guinea pig abdominal aorta, and PRP was prepared by diluting the platelet count to about 60 × 10 ⁴ / μL with PPP (n = 3 to 4).

(3) Measurement of Platelet Aggregation Ability The platelet aggregation ability was measured according to the method of Born in the same manner as in (2) of Test Example 1 above. One hundred ninety μL of PRP was placed in a glass cuvette, and after mounting on a platelet aggregation measuring device, it was incubated at 37 ° C. for 10 minutes. 10 μL of ADP as a coagulant was added to a final concentration of 0.5 μmol / L to induce aggregation, and the maximum reaction of aggregation was measured.

(4) Evaluation of the persistence of the platelet aggregation inhibitory action From the maximum aggregation rate of the control group at the time of calculation of IC ₅₀ and the maximum aggregation rate of the test substance, the maximum aggregation suppression rate of the test substance when the control group is 0% is determined The Furthermore, in the graph showing the time course of the maximum aggregation inhibition rate with the maximum aggregation inhibition rate (%) on the vertical axis and the time (hour) after administration of the test substance on the horizontal axis, the maximum aggregation inhibition rate plotted at each measurement time The area of the part surrounded by the straight line connecting the points and the horizontal axis was determined as AUC. In addition, the estimated time when the maximum aggregation suppression rate is 0 on the graph was determined as the time when the aggregation suppression disappears (0 hour of suppression).

The results are shown in Table 3. According to Table 3, in the ex vivo guinea pig platelet aggregation inhibitory activity test, the AUC value (AUC: 1-inhibition 0 hours) from 1 hour after administration to 0 hours of inhibition
It was confirmed that the present compound is higher than limaprost, and the present compound has a stronger platelet aggregation inhibitory action than limaprost. In addition, when the aggregation inhibition rate after 6 hours after administration, which is an indicator of sustainability, is evaluated, the present compound has an AUC value of 6 hours after administration to 0 hours of inhibition (AUC: 6-suppression 0 hour) compared to limaprost It is also confirmed that this compound is superior in sustainability to limaprost because it is high and the time for the aggregation suppression to disappear (0 hour for suppression) is also long.

Test Example 4 Evaluation of Rat Equine Blood Flow Increasing Action (1) Administration of Test Substance As a test substance, Slc at 0.263, 0.789 and 2.63 nmol / kg of the present compound or limaprost (positive control substance) in principle: The tail vein of a Wistar male rat (body weight: about 200 to 250 g) was continuously injected for 10 minutes at a flow rate of 0.2 mL / min using an infusion pump (model 11, Harvard Apparatus). The control group was similarly administered 1 vol% DMSO-saline (5-6 animals in each group).

(2) Measurement of horse-tail blood flow The rat was kept in the prone position under halothane anesthesia, and was kept warm by a heater (Nippon Medical). The lumbar back of the rat was shaved and dissected to expose the spine, and the fifth lumbar vertebral arch was excised to expose the cauda equina nerve. Laser Doppler flowmeter (TBF-LN1) through a non-contact probe (LP-NC special type, unique medical) fixed so that the cauda equina blood flow is vertical about 1 mm above the exposed cauda equina nerve Using Unique Medical, it was measured from before administration of each test substance until 60 minutes after administration. The wound area was filled with liquid paraffin to prevent drying of the exposed cauda equina nerve.

(3) Data Analysis The obtained data was taken into a personal computer via PowerLab 8/30 (registered trademark, ML 870, ADInstruments) every 1/400 seconds and analyzed using LabChart (registered trademark, ADInstruments). The analysis time point is before administration (administration 0 min), administration 3, 5, 8, 10, 13, 15, 18, 20, 30, 40, 50 and 60 minutes, or before administration (administration 0 min), administration 3, After 5, 10, 15, 20, 30, 40, 50 and 60 minutes, the average value for 10 seconds at each time point was taken as the measured value, and the change rate (%) with respect to the pre-dose value was determined by the following equation.
Change rate (%) = (measured value after administration at each time point-measured value before administration) / measured value before administration x 100
Further, the difference [% change rate (%)] of change rate (%) with respect to the control group at each time point was calculated by the following equation, and the maximum value of this Δ change rate was taken as the maximum change rate.
Δ change rate (%) = change rate of each individual at each time point-average value of change rate of control group A dose that increases the horsetail blood flow by 20% according to linear regression from the maximum change rate of each dose of the test substance (ED ₂₀ values were determined, and relative activity (%) of each test substance was calculated when the activity of ED ₂₀ value of limaprost was 100.
The results are shown in Table 4. The present compound showed strong activity in the rat cauda equina blood flow test.

  The prostaglandin derivative of the present compound is useful as an active ingredient of medicine. A medicament comprising the prostaglandin derivative of the present compound as an active ingredient is particularly useful as a medicament for the prevention or treatment of blood flow disorders, for the prevention or treatment of blood flow disorders associated with spinal stenosis or chronic arterial occlusion. It is useful as a medicine for

Claims (16)

The following formula (1):


[In the formula (1),
R ^A represents —CH ₂ —CZ ¹ Z ² (COX) or —CH = CZ ¹ (COX), Z ¹ and Z ² each independently represent a hydrogen atom or a fluorine atom, and X represents OR ⁴ or NR ⁵ R ⁶ is represented, R ⁴ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, or an alkyl group having 1 to 6 carbon atoms having a substituent, R ⁵ is a hydrogen atom, 1 carbon atom R ⁶ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms having a substituent, An alkylsulfonyl group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms having a substituent, an arylsulfonyl group having 6 to 10 carbon atoms or an arylsulfonyl group having 6 to 10 carbon atoms having a substituent;
Y represents CH ₂ , S or O;
A-B represents a carbon-carbon single bond or a carbon-carbon double bond;
The hydroxyl group bound by a wavy line represents a hydroxyl group which is α-configuration, β-configuration or a mixed configuration of α-configuration and β-configuration;
R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, or an alkyl group having 1 to 3 carbon atoms having a substituent;
n represents an integer of 0 to 2;
R ³ represents a cycloalkyl group alkyl or 3 to 5 carbon atoms having 2 to 3 carbon atoms. Or a pharmaceutically acceptable salt thereof, or a cyclodextrin inclusion compound thereof as an active ingredient. The medicament according to claim 1 Y is is CH _2. The medicament according to claim 1 or 2, wherein R ^A is -CH = CZ ¹ (COX). The medicament according to claim 1 or 2, wherein R ^A is -CH ₂ -CZ ¹ Z ² (COX).   The pharmaceutical according to any one of claims 1 to 4, wherein n is 1.   The medicine according to any one of claims 1 to 5, wherein AB is a carbon-carbon double bond. The medicament according to any one of claims 1 to 6, wherein R ¹ is a hydrogen atom and R ² is an alkyl group having 1 to 3 carbon atoms. The medicament according to any one of claims 1 to 7, wherein R ³ is a cycloalkyl group having 3 to 5 carbon atoms. X pharmaceutical according to any one of claims 1 to 8 is OR ^4.   The medicament according to any one of claims 1 to 9, which is an agent for preventing or treating blood flow disorder.   The medicine according to claim 10, wherein the blood flow disorder is nerve blood flow disorder.   The medicine according to claim 11, wherein the nerve blood flow disorder is a blood flow disorder associated with spinal stenosis.   The medicine according to claim 10, wherein the blood flow disorder is a blood flow disorder of a peripheral artery, skin or brain.   The medicine according to claim 13, wherein the peripheral blood flow disorder is a blood flow disorder associated with chronic arterial occlusion or pulmonary hypertension.   The medicine according to claim 13, wherein the blood flow disorder in the skin is a blood flow disorder associated with a pressure sore wound.   The medicine according to claim 13, wherein the cerebral blood flow disorder is a blood flow disorder associated with suppression of recurrence after cerebral infarction.