JPH10259179A - Prostaglandins having multi-substituted aryloxy groups and their use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a multi-substituted aryloxy group on the ω chain of a prostaglandin and useful for preventing and treating eye diseases. SOLUTION: A compound of the formula [A is vinylene group, etc.; B is CH(OR<3> ), etc.; R<1> , R<2> , R<3> are each H, an acyl, etc.; Ar is phenyl having two or more halogen groups, etc., X is CH2 , O, etc.; Z is OR<4> , NHSO2 R<6> , SR<7> , etc.; R<4> , R<6> , R<7> are each H, an alkyl, an aryl, an aralkyl, etc.], e.g. 16-(3,5- dichlorophenoxy)17,18,19,20-tetranorprostaglandin F2α methyl ester. The compound of the formula is synthesized by the application of a general PFG2α synthetic method comprising introducing an ω-chain having a multi-substituted aryloxy group to Corey lactone as a starting raw material, converting the product into a lactone, reducing the lactone into a lactol, subjecting the reduction product to a Wittig reaction, converting the carboxylic acid portion into an ester portion, etc., and, if necessary, subsequently subjecting the product to a protecting group-removing reaction or an acylation reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a prostaglandin having a polysubstituted aryloxy group in the ω chain of prostaglandin (or a salt thereof), and a medicament containing the prostaglandin as an active ingredient, particularly for preventing or preventing ocular diseases. It relates to a medicament for treatment.

[0002]

2. Description of the Related Art Natural prostaglandin (PG) is a group of physiologically active substances synthesized in a living body, and regulates cell functions of various tissues of a living body as local hormones having various physiological activities. PGFs, which are a kind of natural PG, have a uterine contractile action, an anti-pregnancy action and an estrous cycle controlling action, and are therefore used as a labor-inducing agent and an animal sexual cycle synchronizing agent. Therefore, the development of PGF derivatives which are more effective as these pharmaceuticals and have no side effects is being studied in Japan and overseas.

[0003] Since prostaglandins generally have various physiological activities, in order to obtain a derivative which selectively exhibits a desired action, a difference in selectivity to a receptor due to a subtle structural change is skillfully utilized. There is a need. The present inventors have focused on the ω chain of PG and have predicted that the position, type and number of substituents of the terminal aryl group or heteroaromatic ring will greatly affect the selectivity. It was also predicted that the lipophilicity of the compound greatly contributes to the absorption and pharmacological action in the living body, and that in the case of carboxylic acid derivatives, the rate of hydrolysis of the ester in the living body is involved in the sustainability.

On the other hand, PGFs, which are a kind of natural PG, are known to reduce intraocular pressure when administered locally to the eye, and are expected to be applied as therapeutics for ocular hypertension and glaucoma. (US Pat. No. 4,599,353). However, it has a problem that it is irritating to the eyes and is accompanied by inflammatory side effects such as hyperemia and corneal injury. For this reason,
Research and development of PGF derivatives without these side effects are being actively conducted inside and outside Japan. PGF derivatives having a ring structure in the ω chain are also known. Have reported that specific derivatives of PGA, PGB, PGD, PGE, and PGF modified to have a ring structure have a weak irritating effect and a hyperemic effect on eyes (Japanese Patent Application Laid-Open No. Hei 8-10913).
2). However, these have not yet been sufficiently reduced in irritation to the eyes.

[0005] A topical ophthalmic composition for treating glaucoma and ocular hypertension using an analog of cloprostenol or fluprostenol has also been reported (JP-A-7-165703). 13, 14 which are representative compounds described in this document
It has been reported that -dihydro-17-phenyl-18,19,20-trinor PGF2α isopropyl ester (latanoprost) has a strong intraocular pressure-lowering effect and low conjunctival congestion. However, there is still room for improvement.

[0006]

The prostaglandin having a polysubstituted aryloxy group in the ω chain of the prostaglandin has a DE2,
223, 365 and the like. However, other prostaglandins having a polysubstituted aryloxy group in the ω chain and their use as pharmaceuticals are not known. Further, including the known prostaglandins, prostaglandins having a polysubstituted aryloxy group in the ω chain of the prostaglandin, wherein the carboxylic acid portion of the prostaglandin is an acylamide, a sulfonamide, or a thioester; There is no known use of prostaglandins having a polysubstituted aryloxy group in the ω chain of a glandin and having an acylated hydroxyl group as a therapeutic agent for ophthalmic diseases, particularly as a therapeutic agent for glaucoma.

[0007] Since prostaglandins generally have various physiological activities, in order to obtain a derivative selectively exhibiting a desired action, a difference in selectivity to a receptor due to a subtle structural change is skillfully utilized. There is a need. The present inventors have focused on the ω chain of prostaglandin and have predicted that the position, type and number of substituents of the terminal aryl group or heteroaromatic ring will greatly affect the selectivity. It was also predicted that the lipophilicity of the compound greatly contributes to intraocular transfer and intraocular pressure-lowering action when instilled, and that in the case of a carboxylic acid derivative, the rate of ester hydrolysis in vivo contributes to sustainability.

[0008]

DISCLOSURE OF THE INVENTION The present inventors have developed novel prostaglandins which have a polysubstituted aryloxy group in the ω chain of prostaglandin and in which the carboxylic acid or hydroxyl group of the prostaglandin is derivatized. I found
In addition, the physiological activity of such prostaglandins was measured, and the usefulness as a medicament was examined. As a result, the present inventor has found that prostaglandins having a polysubstituted aryloxy group in the ω chain of prostaglandin, and in which the carboxylic acid portion or the hydroxyl portion of the prostaglandin are derivatized, are naturally-occurring prostaglandins F It has an intraocular pressure-lowering effect similar to that of the same, and it has been found that eye irritation and effects on eye tissues such as the cornea, iris, and conjunctiva are further improved and long-lasting. The present invention is the following invention relating to such novel prostaglandins and their use as pharmaceuticals, and the pharmaceutical use of such prostaglandins having a polysubstituted aryloxy group in the ω chain for ocular diseases.

A compound selected from prostaglandins represented by the following general formula (1) and salts thereof (provided that A
There vinylene group, B is -CH (OH) -, X is -CH ₂
-, And when R ¹ and R ² are both hydrogen atoms,
Z is not -OR ^4), and a pharmaceutical which it as an active ingredient. A medicament for preventing or treating eye diseases comprising a prostaglandin represented by the following general formula (1) or a salt thereof as an active ingredient.

[0010]

Embedded image

[In the general formula (1), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , B: -CH (OR ³ )-or -C (= O)-, R ¹ , R ² , R ³ : each independently represents a hydrogen atom, an acyl group, or A bond, Ar: a phenyl group or a heteroaromatic group having two or more substituents, X: —CH ₂ —, —O—, or —S—, Z: —OR ⁴ , —NHCOR ⁵ , and —NHSO ₂ R ⁶ ,-
SR ⁷ , or a single bond in cooperation with any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ : each independently a hydrogen atom,
An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or an aralkyl group; an overlapping portion between a solid line and a broken line: a single bond, or a cis or trans double bond. ]

Among the prostaglandins represented by the general formula (1), as a medicament for preventing or treating an ophthalmic disease, R.sup.
^At least ^one of R ¹ and R ² is an acyl group, or Z is —OR ⁴ (where R ⁴ is not a hydrogen atom), —NHCOR ⁵ , —NHSO ₂ R ⁶ or —SR
⁷ is preferred.

[0013]

DESCRIPTION OF THE PREFERRED EMBODIMENTS In the following description of the present specification,
When the organic group is “lower”, it means 1 to 6 carbon atoms. More preferred lower organic groups are organic groups having 1 to 4 carbon atoms. The “alkyl group” may be linear or branched, and a lower alkyl group is preferable unless otherwise specified.
Suitable examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl and the like.

The "alkenyl group" is preferably a lower alkenyl group unless otherwise specified, more preferably a straight-chain or branched alkenyl group having 2 to 6 carbon atoms and one unsaturated group. Examples include vinyl groups,
Allyl group, 1-propenyl group, isopropenyl group, 3-
Butenyl group, 3-pentenyl group, 4-hexenyl group and the like.

The "alkynyl group" is preferably a lower alkynyl group unless otherwise specified, more preferably a straight-chain or branched alkynyl group having 2 to 6 carbon atoms and one unsaturated group. Examples include 1-propynyl, 2-propynyl, 3-butynyl, 3-pentynyl, 4-hexynyl and the like.

As the "alkoxy group", a wide range of general alkoxy groups is used, but a lower alkoxy group is preferable, and a linear or branched alkoxy group having 1 to 4 carbon atoms is more preferable. Examples include methoxy, ethoxy, propoxy, butoxy and the like.

"Halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. “Aryl group” refers to a monovalent aromatic hydrocarbon group, which may have a substituent (eg, a lower alkyl group, a halogen atom, a lower alkoxy group, a lower alkylamino group, etc.),
Preferable is a phenyl group or a derivative thereof. For example, a phenyl group, a tolyl group, a halophenyl group (eg, a chlorophenyl group, a fluorophenyl group, a bromophenyl group, etc.), a dihalophenyl group (eg, a dichlorophenyl group,
Examples include a difluorophenyl group, a dibromophenyl group, and the like, a trihalophenyl group (eg, a trichlorophenyl group, a trifluorophenyl group, a tribromophenyl group, and the like), an alkoxyphenyl group (eg, a methoxyphenyl group, an ethoxyphenyl group, and the like). .

The "aralkyl group" refers to an alkyl group substituted with an aryl group. The aryl group as the substituent includes those described above, and the alkyl group has 1 to 4 carbon atoms.
Is preferred. Suitable examples thereof include a benzyl group, a benzhydryl group, a trityl group, a phenethyl group and the like.

"Cycloalkyl group" represents an unsubstituted or substituted 3- to 8-membered cycloalkyl group. When substituted, examples of the substituent include a lower alkyl group, a halogen atom, and an alkoxy group. Examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a methylcyclohexyl group, a dimethylcyclopentyl group, a dimethylcyclohexyl group, a chlorocyclohexyl group, a dichlorocyclohexyl group, and the like.

"Halogenated alkyl group" means a lower halogenated alkyl group halogenated with one or more halogen atoms. Fluoromethyl group, difluoromethyl group, trifluoromethyl group, trifluoroethyl group,
Examples include a pentafluoroethyl group, a chloromethyl group, a dichloromethyl group, a trichloromethyl group, and a bromomethyl group.

The term "acyl group" refers to a monovalent or polyvalent group formed by removing a hydroxyl group from all carboxyl groups of a carboxylic acid. The carboxylic acids include saturated or unsaturated aliphatic carboxylic acids, carbocyclic carboxylic acids, and heterocyclic carboxylic acids. The carbocyclic carboxylic acid represents a saturated or unsaturated cyclic aliphatic carboxylic acid and an aromatic carboxylic acid.

In the prostaglandins represented by the general formula (1), the overlap between the solid line and the broken line represents a single bond or a cis or trans double bond, and a cis double bond is most preferred. A is preferably a vinylene group or an ethylene group, particularly preferably a vinylene group. Vinylene groups include cis and trans vinylene groups. Particularly, a vinylene group of trans is preferable. The X -CH ₂
-Is particularly preferred.

B is particularly preferably -CH (OR ³ )-. In this case, the carbon to which the hydroxyl group is bonded is usually an asymmetric carbon, but the two isomers resulting from the difference in the absolute configuration may have different physical properties and physiological activities. Usually, the absolute configuration of the hydroxyl group is preferably an R-configuration.

R ¹ , R ² and R ³ each independently represent a hydrogen atom, an acyl group or a single bond in combination with Z. Z
Representing a single bond in combination with -OR ¹ , -OR ² ,-
If any of OR ³ is a hydroxyl group (ie, R ¹ , R ² , R
Either ³ is a hydrogen atom), and -COZ carboxy groups (i.e., Z may -OR ⁴ a and R ⁴ is a hydrogen atom), and cyclizing an ester bond by the reaction of the hydroxyl group and a carboxyl group (Lactone ring structure). The compound cyclized by this ester bond is useful as a prodrug because it can be converted into a biologically active compound by hydrolysis in vivo.

When Z is --OH, R ¹ , R ² , R ³
Is preferably an acyl group. In particular, it is preferable that at least one of R ¹ and R ² is an acyl group and the other R ¹ , R ² and R ³ are hydrogen atoms. When Z is other than -OH, R ¹ , R ² , R
³ may be both hydrogen atoms, at least one of them may be a hydrogen atom and the other may be an acyl group, or all may be acyl groups.

In the case of an acyl group, the carboxylic acid of the acyl group includes a saturated or unsaturated aliphatic carboxylic acid, carbocyclic carboxylic acid, and heterocyclic carboxylic acid. The carbocyclic carboxylic acid represents a saturated or unsaturated cyclic aliphatic carboxylic acid and an aromatic carboxylic acid. R ¹ , R ² , R ³
May form a ring with a bifunctional acyl group. As the acyl group derived from a saturated or unsaturated aliphatic carboxylic acid, an acetyl group, a propanoyl group, a butyryl group, an isobutyryl group, a pivaloyl group, and the like are preferable.As the acyl group derived from a carbocyclic carboxylic acid, a cyclohexanecarbonyl group, Pentanecarbonyl group, cyclobutanecarbonyl group, cyclopropanecarbonyl group, benzoyl group, toluoyl group, xyloyl group, methoxybenzoyl group, naphthaloyl group, acyl group derived from heterocyclic carboxylic acid include pyridinecarbonyl group, furoyl group, piperidinecarbonyl group Are preferred.

Ar represents a phenyl group or a heteroaromatic group having two or more substituents. Examples of the heteroaromatic ring include a pyridine ring, a furan ring, and a thiophene ring. As the substituent, a halogen atom, a lower alkyl group, an alkoxy group, a halogenated alkyl group, a halogenated alkyloxy group, an alkylthio group, a halogenated alkylthio group, an acylamino group, and the like are preferable. Particularly preferred is a halogen atom, and among them, a chlorine atom or a fluorine atom is preferred. Preferred Ar is a phenyl group having two or more halogen atoms, and particularly preferred specific examples thereof include:
3,5-dichlorophenyl group, 3,4-dichlorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 3,5-difluorophenyl group, 3,4-
Examples include a difluorophenyl group, a 2,3-difluorophenyl group, and a 2,4-difluorophenyl group.

Z is -OR ⁴ , -NHCOR ⁵ , -NH
SO ₂ R ⁶ , —SR ⁷ , or R ¹ , R
Either ² or R ³ and Z together represent a single bond. R
⁴ The to R ⁷ a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, can be used aralkyl group. Alkyl group, alkenyl group,
The alkyl group portion of the alkynyl group and the aralkyl group may be linear or branched, and may have various substituents such as a halogen atom. Also,
The ring of the cycloalkyl group, the aryl group, and the aralkyl group may have an alkyl group or another substituent. These substituents include, for example, the substituents described in the description of R ¹ .

As the alkyl group, alkenyl group and alkynyl group as R ^{4 to} R ⁷ , those having 20 or less, particularly 8 or less, carbon atoms are preferable. Specific examples of these chain hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. , N-decyl group, 1-methylpentyl group, 1,1-dimethylpentyl group, 1-methylhexyl group, 2-methylpentyl group, 2-methylhexyl group and the like.
Examples of the alkenyl group include an allyl group, 2-butenyl group, and 3
-Pentenyl group, 1-methyl-3-pentenyl group, 1-
Examples thereof include a methyl-3-hexenyl group, a 1,1-dimethyl-3-pentenyl group, and a 1,1-dimethyl-3-hexenyl group. Examples of the alkynyl group include a propargyl group, a 3-pentynyl group, a 1-methyl-3-pentynyl group, a 1-methyl-3-hexynyl group, a 1,1-dimethyl-3-pentynyl group, and a 1,1-dimethyl-3- group. And a hexynyl group.

Examples of the substituted alkyl group as R ^{4 to} R ⁷ include a halogen atom-substituted alkyl group and a cycloalkyl group-substituted alkyl group. The halogen atom-substituted alkyl group preferably has 6 or less carbon atoms. The alkyl group portion of the group-substituted alkyl group preferably has 1 to 2 carbon atoms. Examples of the halogen-substituted alkyl group include a trifluoromethyl group and a pentafluoroethyl group. Examples of the cycloalkyl group-substituted alkyl group include a cyclobutylmethyl group, a cyclopentylmethyl group, and a cyclohexylmethyl group.

The cycloalkyl group as R ^{4 to} R ⁷ preferably has 10 or less carbon atoms. Specific examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a 2,2-dimethylcyclopropyl group, a 3-cyclopentenyl group, a 3-cyclohexynyl group, and a cyclooctanyl group.

The aryl group as R ^{4 to} R ⁷ is preferably a substituted or unsubstituted phenyl group. Examples of the substituent include an alkyl group (preferably having 4 or less carbon atoms), a halogenated methyl group, a halogen atom, an alkoxy group, an acyl group,
Acylamino, nitro and the like are preferred. Specifically, a phenyl group, a 4-methylphenyl group, a 4- (t-butyl) phenyl group, a 3-trifluoromethylphenyl group, a 4-trifluoromethylphenyl group, a 4-chlorophenyl group, a 4-acetylphenyl group , 4-benzoylphenyl, 4-acetylaminophenyl, 4-benzoylaminophenyl, 3-nitrophenyl, 4-nitrophenyl, and the like.

The aralkyl group as R ^{4 to} R ⁷ has a phenyl group and has 4 or less carbon atoms (preferably 1 to
An aralkyl group comprising the alkyl group of 2) is preferred.
Examples of the phenyl group include an alkyl group (preferably having 4 or less carbon atoms), a halogenated methyl group, a halogen atom,
It may have a substituent such as an alkoxy group, an acyl group, an acylamino group, and a nitro group. The alkyl group portion of the aralkyl group may have a branch.

Specifically, a benzyl group, a phenethyl group,
Diphenylmethyl group, (3-methylphenyl) methyl group, (3-chlorophenyl) methyl group, (3-fluorophenyl) methyl group, (3-bromophenyl) methyl group, {(3-trifluoromethyl) phenyl} methyl Group, 1- (3-methylphenyl) ethyl group, 1- (3-
Chlorophenyl) ethyl group, 1-{(3-trifluoromethyl) phenyl} ethyl group, 1- (3-fluorophenyl) ethyl group, 1- (3-bromophenyl) ethyl group, 2- (3-methylphenyl) Ethyl group, 2- (3-
Chlorophenyl) ethyl group, 2-{(3-trifluoromethyl) phenyl} ethyl group, 2- (3-fluorophenyl) ethyl group, 2- (3-bromophenyl) ethyl group, 1-methyl-2- (3 -Methylphenyl) ethyl group, 1-methyl-2- (3-chlorophenyl) ethyl group, 1-methyl-2-{(3-trifluoromethyl) phenyl} ethyl group, 1-methyl-2- (3-fluoro Phenyl) ethyl group, 1-methyl-2- (3-bromophenyl) ethyl group, and the like.

Each of R ^{4 to} R ⁷ is preferably an alkyl group, a cycloalkyl group or an aralkyl group which may have a substituent. As the substituent, a halogen atom or an alkyl group having 4 or less carbon atoms bonded to a ring is preferable. More preferably, R ^{4 to} R ⁷ are each an alkyl group, and in addition, R ⁶ is an alkyl group substituted with a halogen atom.

As Z, particularly -OR ⁴ , -NHSO ₂
It is preferably a group represented by R ⁶ and —SR ⁷ . In this case, R ⁴ , R ⁶ , and R ⁷ are preferably a hydrogen atom or a hydrocarbon group having 1 to 20 carbon atoms such as an alkyl group, a cycloalkyl group, an aralkyl group, and an aryl group. Compounds in which R ⁴ , R ⁶ , and R ⁷ are hydrocarbon groups are useful as prodrugs because they can be converted to biologically active compounds by hydrolysis in vivo. Particularly preferred R ⁴ is a lower alkyl group such as an ethyl group, an isopropyl group or an isobutyl group, a hydrogen atom, a cyclohexyl group, and a benzyl group, and a preferred R ⁶ is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, etc. R ⁷ is a lower alkyl group such as a methyl group, an ethyl group, an isopropyl group or an isobutyl group, and a phenyl group.

When the prostaglandins in the present invention have an acidic group such as a carboxy group, for example, when Z is a hydroxyl group, the prostaglandins may be a salt with a base. Similarly, when it has a basic group such as an amino group, it may be a salt with an acid. Examples of the salt with a base include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts, and ammonium salts such as unsubstituted ammonium salts and alkyl-substituted ammonium salts. Examples of the salt with an acid include inorganic acid salts such as hydrochloride, sulfate and phosphate, acetate, oxalate, citrate, succinate, p
-Organic salts such as toluenesulfonate.

Specific examples of the compound represented by the general formula (1) are shown below, but are not limited thereto.

16- (3,5-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α methyl ester. 16- (3,5-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16-
(3,5-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α isopropyl ester. 16- (3,5-dichlorophenoxy)
-17,18,19,20-tetranorprostaglandin F2α t-butyl ester. 16- (3,5-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α n-butyl ester.

16- (3,5-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α cyclohexyl ester. 16- (3,5-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α phenyl ester.
16- (3,5-dichlorophenoxy) -17,18,
19,20-tetranorprostaglandin F2α benzyl ester. 16- (3,5-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α 1,9-lactone. 16- (3,5-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α 1,11-lactone. 16- (3,5-dichlorophenoxy) -17,1
8,19,20-tetranor prostaglandin F2α
1,15-lactone. 16- (3,5-dichlorophenoxy) -9-pivaloyl-17,18,19,20-
Tetranorprostaglandin F2α methyl ester.

16- (3,5-dichlorophenoxy)-
9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16-
(3,5-dichlorophenoxy) -9-pivaloyl-1
7,18,19,20-tetranorprostaglandin F2α isopropyl ester. 16- (3,5-dichlorophenoxy) -9-pivaloyl-17,18,1
9,20-tetranorprostaglandin F2α t-
Butyl ester. 16- (3,5-dichlorophenoxy) -9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α n-butyl ester. 16- (3,5-Dichlorophenoxy) -11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α methyl ester. 16- (3,5
-Dichlorophenoxy) -11-pivaloyl-17,1
8,19,20-tetranor prostaglandin F2α
Ethyl ester.

16- (3,5-dichlorophenoxy)-
11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.
16- (3,5-Dichlorophenoxy) -11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α t-butyl ester. 16- (3,5
-Dichlorophenoxy) -11-pivaloyl-17,1
8,19,20-tetranor prostaglandin F2α
n-butyl ester. 16- (3,5-dichlorophenoxy) -15-pivaloyl-17,18,19,20
-Tetranorprostaglandin F2α methyl ester. 16- (3,5-Dichlorophenoxy) -15-pivaloyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16- (3,5
-Dichlorophenoxy) -15-pivaloyl-17,1
8,19,20-tetranor prostaglandin F2α
Isopropyl ester. 16- (3,5-dichlorophenoxy) -15-pivaloyl-17,18,19,2
0-tetranorprostaglandin F2α t-butyl ester.

16- (3,5-dichlorophenoxy)-
15-pivaloyl-17,18,19,20-tetranorprostaglandin F2α n-butyl ester. N
-Acetyl-16- (3,5-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α carboxamide. N-benzoyl-16-
(3,5-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α carboxamide. N-cyclohexanecarbonyl-16- (3,
5-dichlorophenoxy) -17,18,19,20-
Tetranorprostaglandin F2α carboxamide. N-isobutyroyl-16- (3,5-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N-pivaloyl-16- (3,5-dichlorophenoxy) -17,1
8,19,20-tetranor prostaglandin F2α
Carboxamide.

N-methanesulfonyl-16- (3,5-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N
-Ethanesulfonyl-16- (3,5-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N-benzenesulfonyl-16- (3,5-dichlorophenoxy) -1
7,18,19,20-tetranorprostaglandin F2α carboxamide. N-toluenesulfonyl-1
6- (3,5-dichlorophenoxy) -17,18,1
9,20-tetranorprostaglandin F2α carboxamide. N- (n-butane) sulfonyl-16-
(3,5-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α carboxamide. 16- (3,5-dichlorophenoxy) -1
7,18,19,20-Tetranorprostaglandin F2α S-methyl carbothioate. 16- (3,5-Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α S-ethyl carbothioate.

16- (3,5-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α S-isopropyl carbothioate. 16-
(3,5-dichlorophenoxy) -17,18,19,
20-Tetranorprostaglandin F2α S- (t-butyl) carbothioate. 16- (3,5-Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α S- (n-butyl) carbothioate. 16- (3,5-dichlorophenoxy) -17,
18,19,20-tetranorprostaglandin F2
α-S-cyclohexyl carbothioate. 16- (3,5
-Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carbothioic acid S-
Phenyl. 16- (3,5-dichlorophenoxy) -1
7,18,19,20-tetranorprostaglandin F2α S-benzyl carbothioate.

16- (3,4-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α methyl ester. 16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16-
(3,4-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α isopropyl ester. 16- (3,4-dichlorophenoxy)
-17,18,19,20-tetranorprostaglandin F2α t-butyl ester. 16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α n-butyl ester.
16- (3,4-dichlorophenoxy) -17,18,
19,20-tetranorprostaglandin F2α cyclohexyl ester. 16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α phenyl ester.

16- (3,4-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α benzyl ester. 16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α 1,9-lactone. 16-
(3,4-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α 1,11
-Lactone. 16- (3,4-dichlorophenoxy)-
17, 18, 19, 20-tetranorprostaglandin F2α 1,15-lactone. 16- (3,4-dichlorophenoxy) -9-pivaloyl-17,18,1
9,20-tetranorprostaglandin F2α methyl ester. 16- (3,4-dichlorophenoxy)-
9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester.

16- (3,4-dichlorophenoxy)-
9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester. 1
6- (3,4-Dichlorophenoxy) -9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α t-butyl ester. 16- (3,4-dichlorophenoxy) -9-pivaloyl-17,18,1
9,20-tetranorprostaglandin F2α n-
Butyl ester. 16- (3,4-Dichlorophenoxy) -11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α methyl ester.
16- (3,4-Dichlorophenoxy) -11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16- (3,4-dichlorophenoxy) -11-pivaloyl-17,18,
19,20-tetranorprostaglandin F2α isopropyl ester. 16- (3,4-dichlorophenoxy) -11-pivaloyl-17,18,19,20-
Tetranorprostaglandin F2α t-butyl ester. 16- (3,4-dichlorophenoxy) -11-
Pivaloyl-17,18,19,20-tetranorprostaglandin F2α n-butyl ester.

16- (3,4-dichlorophenoxy)-
15-pivaloyl-17,18,19,20-tetranorprostaglandin F2α methyl ester. 16-
(3,4-dichlorophenoxy) -15-pivaloyl-
17,18,19,20-tetranorprostaglandin F2α ethyl ester. 16- (3,4-dichlorophenoxy) -15-pivaloyl-17,18,19,
20-tetranorprostaglandin F2α isopropyl ester. 16- (3,4-dichlorophenoxy)
-15-pivaloyl-17,18,19,20-tetranorprostaglandin F2α t-butyl ester.

16- (3,4-dichlorophenoxy)-
15-pivaloyl-17,18,19,20-tetranorprostaglandin F2α n-butyl ester. N
-Acetyl-16- (3,4-dichlorophenoxy)-
17,18,19,20-tetranorprostaglandin F2α carboxamide. N-benzoyl-16-
(3,4-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α carboxamide. N-cyclohexanecarbonyl-16- (3,
4-dichlorophenoxy) -17,18,19,20-
Tetranorprostaglandin F2α carboxamide. N-isobutyroyl-16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N-pivaloyl-16- (3,4-dichlorophenoxy) -17,1
8,19,20-tetranor prostaglandin F2α
Carboxamide.

N-methanesulfonyl-16- (3,4-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N
-Ethanesulfonyl-16- (3,4-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide. N-benzenesulfonyl-16- (3,4-dichlorophenoxy) -1
7,18,19,20-tetranorprostaglandin F2α carboxamide. N-toluenesulfonyl-1
6- (3,4-dichlorophenoxy) -17,18,1
9,20-tetranorprostaglandin F2α carboxamide. N- (n-butane) sulfonyl-16-
(3,4-dichlorophenoxy) -17,18,19,
20-tetranorprostaglandin F2α carboxamide.

16- (3,4-dichlorophenoxy)-
17, 18, 19, 20-tetranorprostaglandin F2α S-methyl carbothioate. 16- (3,4-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α S-ethyl carbothioate. 16- (3,4-dichlorophenoxy) -17,
18,19,20-tetranorprostaglandin F2
α-S-isopropyl carbothioate. 16- (3,4-
Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carbothioic acid S-
(T-butyl).

16- (3,4-dichlorophenoxy)-
17,18,19,20-Tetranorprostaglandin F2α S- (n-butyl) carbothioate. 16-
(3,4-dichlorophenoxy) -17,18,19,
20-Tetranorprostaglandin F2α S-cyclohexyl carbothioate. 16- (3,4-Dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α S-phenyl carbothioate. 1
6- (3,4-dichlorophenoxy) -17,18,1
9,20-Tetranorprostaglandin F2α S-benzyl carbothioate.

Since the prostaglandins represented by the general formula (1) have an asymmetric carbon in their structure, there are various stereoisomers and optical isomers. The prostaglandins represented by 1) include all these stereoisomers, optical isomers and mixtures thereof.

For the prostaglandins of the present invention, a general PGF2α synthesis method can be applied. For example, Corey
Using a lactone as a starting material, an ω chain having a polysubstituted aryloxy group is first introduced to convert it into a Corey lactone with an ω chain. Lactone reduced to lactol and wittig
After introducing the α-chain unit in the reaction, the carboxylic acid moiety is subjected to a conversion reaction to an ester, an acylamide, a sulfonamide, a thioester, etc., and if necessary, deprotection or acylation of a hydroxyl group, and the above-described prostaglandins Can be synthesized.

The medicament for eye diseases of the present invention is used by topically administering a preparation containing the above-mentioned compound of the present invention as an active ingredient to eyes by a method such as instillation. Dosage forms include eye drops such as eye drops and eye ointments, injections and the like, and the compounds of the present invention can be formulated using commonly used techniques. For example, in the case of eye drops, isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate (hereinafter referred to as polysorbate 80), polyoxyl stearate 40, a surfactant such as polyoxyoxyethylene hydrogenated castor oil, a stabilizer such as sodium citrate and sodium edetate, a preservative such as benzalkonium chloride, paraben, and the like can be formulated as necessary using a preservative. May be within the range acceptable for ophthalmic preparations,
Is preferable.

The dose can be appropriately selected depending on the symptom, age, and dosage form. For eye drops, 0.001 to 5% (w /
v), preferably 0.01 to 0.5% (w / v) may be applied once to several times a day.

With respect to the physiological activity of the compound of the present invention, it has an intraocular pressure lowering activity almost equal to or higher than that of natural PGF2α, and furthermore has an eye irritation property and influence on eye tissues such as cornea, iris and conjunctiva. Has been improved. In vivo, it is very resistant to degradation by metabolism such as hydrolysis and oxidation, and is very useful as a pharmaceutical because of its high corneal permeability and high ocular absorbability. Therefore, the medicament of the present invention is particularly effective as a therapeutic agent for glaucoma or ocular hypertension.

[0059]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Examples 1-2
2 is a synthesis example of the prostaglandins of the present invention and intermediates thereof, and Examples 9, 10, 13, 15, 17, 18, and 20
And 22 are examples in which prostaglandins represented by the formula (1) were obtained. Example 23 is an example of preparation of a pharmaceutical preparation of the present invention. Example 24 is an example in which the prostaglandins represented by the formula (1) were evaluated as drugs for ophthalmic diseases.
In the following, THF refers to tetrahydrofuran.

Example 1 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6- [4- (3,5-dichlorophenoxy) -3-oxo-1-butenyl] bicyclo [ 3.3.
0] Synthesis of octane-3-one.

Sodium hydride (60% dispersion in mineral oil)
(8.55 g) in THF (1500 ml) was suspended in dimethyl [3- (3,5-dichlorophenoxy) -2-oxopropyl] phosphonate (211 g) in THF (70 g).
0 ml) solution was added under ice cooling. After stirring for 1 hour, (-)-
Corey lactone aldehyde benzoate (53.9
g) in THF (600 ml) was added dropwise. 4 at 0 ° C
After stirring for 0 minutes and room temperature for 1 hour, acetic acid was added for neutralization, water was added, and the mixture was extracted with ethyl acetate. Silica gel column chromatography (hexane / ethyl acetate: 2/1 to 3 /
Purification in 2) gave 51 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 2.31 (ddd, J = 2.0,4.9,1
5.6Hz, 1H), 2.51 (m, 1H), 2.65 (dt, J = 6.5,15.6Hz, 1H), 2.87
-2.98 (m, 3H), 4.67 (s, 2H), 5.11 (dt, J = 2.0,6.5Hz, 1H), 5.3
5 (m, 1H), 6.54 (d, J = 16.1Hz, 1H), 6.77 (d, J = 2.0Hz, 2H), 6.9
2 (dd, J = 7.8,16.1Hz, 1H), 6.99 (t, J = 2.0Hz, 1H), 7.45 (m, 2
H), 7.60 (m, 1H), 7.98 (m, 2H).

Example 2 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3RS) -4- (3,5-dichlorophenoxy) -3-hydroxy-1- Synthesis of butenyl] bicyclo [3.3.0] octan-3-one.

A solution of enone (51 g) synthesized in Example 1 in methylene chloride (250 ml) was added to methanol (500 ml).
l), 16 g of cerium trichloride heptahydrate was added. -78
C., 3.3 g of sodium borohydride was added, and the mixture was stirred for 2 hours.
The reaction was stopped with l. After evaporating the reaction solution under reduced pressure, the residue was dissolved in ethyl acetate and washed with saturated saline. Silica gel column chromatography (hexane / ethyl acetate: 2 /
Purification was performed in 3) to obtain 47 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 2.2 (m, 1H), 2.4-2.9 (m, 5
H), 3.7-3.9 (m, 2H), 4.48 (m, 1H), 5.04 (m, 1H), 5.24 (m, 1H),
5.6-5.8 (m, 2H), 6.66 (m, 2H), 6.92 (m, 1H), 7.2-7.6 (m, 3H),
7.95 (m, 2H).

Example 3 (1S, 5R, 6R, 7R) -2-oxa-7-benzoyloxy-6-[(3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1- Synthesis of butenyl] bicyclo [3.3.0] octan-3-one.

The enone synthesized in Example 1 was reduced in the same manner as in Example 2, and then the isomers were separated to obtain the title compound.

¹ H NMR (CDCl ₃ ): δ 2.26 (ddd, J = 2.0, 5.4, 1
5.3Hz, 1H), 2.52 (m, 1H), 2.63 (dt, J = 6.8,15.3Hz, 1H), 2.7-
2.9 (m, 3H), 3.76 (dt, J = 2.0,7.3Hz, 1H), 3.89 (dt, J = 2.0,7.
3Hz, 1H), 3.91 (dt, J = 3.4,7.3Hz, 1H), 4.50 (s, 1H), 5.07 (m,
1H), 5.28 (m, 1H), 5.70 (dd, J = 5.9,15.1Hz, 1H), 5.80 (dd, J =
7.8Hz, 1H), 6.75 (d, J = 2.0Hz, 1H), 7.46 (m, 2H), 7.57 (m, 1
H), 7.99 (m, 2H).

Example 4 (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3R) -4- (3,5-dichlorophenoxy) -3-hydroxy-1-butenyl Synthesis of bicyclo [3.3.0] octan-3-one.

The benzoate synthesized in Example 3 (800 m
197 mg of potassium carbonate was added to a methanol solution of g), and the mixture was stirred for 5 hours, then neutralized with acetic acid, extracted with ethyl acetate, and washed with water. The solid obtained by distilling off the solvent was recrystallized from methanol-ethyl acetate to obtain 371 mg of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.96-2.80 (m, 6H), 3.86
(m, 1H), 3.96-4.05 (m, 2H), 4.54 (m, 1H), 4.93 (m, 1H), 5.66
-5.77 (m, 2H), 6.82 (s, 2H), 7.00 (s, 1H).

Example 5 16- (3,5-dichlorophenoxy) -17,18,
Synthesis of 19,20-tetranorprostaglandin F2α.

A solution of the lactone (371 mg) synthesized in Example 4 in THF (10 ml) was added at -78 ° C. to a toluene solution of diisobutylaluminum hydride (1 M, 3.98 m 2).
l) was added. Two hours later, methanol was added to stop the reaction, and a saturated saline solution was added, followed by extraction with ethyl acetate. The solvent was distilled off to obtain a crude product of lactol. 1.76 g of 4-carboxybutyltriphenylphosphonium bromide in THF
(15 ml) Potassium t-butoxide 892m in suspension
g was added and stirred at room temperature for 8 hours. The reaction solution was cooled on ice, lactol crude THF (10 ml) was added, and the mixture was added at room temperature for 14 hours.
Stirred for hours. Water was added and extracted with ether. The aqueous layer was acidified with citric acid, extracted with ethyl acetate, and the solvent was distilled off to obtain 1.17 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.49-1.83 (m, 4H), 2.11
2.40 (m, 8H), 3.80-4.05 (m, 3H), 4.19 (m, 4H), 4.53 (m, 1H),
5.33-5.46 (m, 2H), 5.62-5.76 (m, 2H), 6.82 (s, 2H), 6.96 (s,
1H).

Example 6 (1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(3RS) -4- (3,5-dichlorophenoxy) -3-hydroxy-1-butenyl Synthesis of bicyclo [3.3.0] octan-3-one.

Using the benzoate synthesized in Example 2, Example 4
The title compound was obtained in the same manner as described above.

¹ H NMR (CDCl ₃ ): δ 1.96-2.80 (m, 6H), 3.86
(m, 1H), 3.96-4.04 (m, 2H), 4.52 (m, 1H), 4.93 (m, 1H), 5.69-
5.74 (m, 2H), 6.82 (s, 2H), 7.00 (s, 1H).

Example 7 (1S, 5R, 6R, 7R) -2-oxa-7- (2-
Tetrahydropyranyloxy) -6-[(3RS) -4
Synthesis of-(3,5-dichlorophenoxy) -3- (2-tetrahydropyranyloxy) -1-butenyl] bicyclo [3.3.0] octan-3-one.

To a suspension of the lactone (10.5 g) synthesized in Example 6 in methylene chloride (100 ml) was added dihydropyran (12.8 ml) and p-toluenesulfonic acid (53%) at room temperature.
6 mg) was added. After stirring for 1 hour, pyridine (6.0 m
l) was added to stop the reaction. Chloroform 25 here
0 ml was added, and this was washed successively with 200 ml of saturated aqueous sodium hydrogen carbonate and then with 200 ml of saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent, silica gel column chromatography (hexane / ethyl acetate: 4/1).
To 2/1) to give 15.2 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.45-1.84 (m, 12H), 2.15
(m, 1H), 2.37-2.80 (m, 5H), 3.46-3.53 (m, 2H), 3.77-3.97
(m, 4H), 4.09 (m, 1H), 4.44 (m, 1H), 4.64-4.85 (m, 2H), 4.96
(m, 1H), 5.46-5.70 (m, 2H), 6.79-6.82 (m, 2H), 6.96 (s, 1H).

Example 8 (15RS) -16- (3,5-dichlorophenoxy)
Synthesis of -11,15-bis (2-tetrahydropyranyloxy) -17,18,19,20-tetranorprostaglandin F2α.

T of the lactone (4.8 g) synthesized in Example 7
A toluene solution of diisobutylaluminum hydride (1 M, 46 ml) was added to the HF (120 ml) solution at -78 ° C. After 1.5 hours, the reaction was stopped by adding 1N HCl and extracted with ethyl acetate. The solvent was distilled off to obtain 3.9 g of a crude product of lactol.

To a suspension of 12.5 g of 4-carboxybutyltriphenylphosphonium bromide in 150 ml of THF was added 6.35 g of potassium t-butoxide, and the mixture was added at room temperature.
Stirred for hours. The reaction solution was ice-cooled, and the above lactol crude product (3.8 g) in THF (50 ml) was added.
Stirred for hours. Water was added and extracted with ether. The aqueous layer was made acidic with citric acid, extracted with ethyl acetate, and the solvent was distilled off to obtain 2.5 g of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.24-2.70 (m, 24H), 3.35
-4.25 (m, 8H), 4.40-4.95 (m, 3H), 5.30-5.85 (m, 4H), 6.80-
6.95 (m, 3H).

Example 9 16- (3,5-dichlorophenoxy) -17,18,
Synthesis of 19,20-tetranorprostaglandin F2α isopropyl ester.

The carboxylic acid synthesized in Example 5 (1.17 g)
0.819 ml of 1,8-diazabicyclo [5.4.0] undec-7-ene and 2 in acetone (15 ml) solution.
-0.595 ml of iodopropane was added and stirred for 5 hours. Saturated saline was added, extracted with ethyl acetate, and silica gel column chromatography (chloroform / methanol:
100 / 1-50 / 1), the title compound 144
mg was obtained.

¹ H NMR (CDCl ₃ ): δ 1.20-1.26
(M, 6H), 1.52-1.80 (m, 4H), 2.
02-2.42 (m, 9H), 3.74-3.98
(M, 3H), 4.17 (m, 1H), 4.58 (m,
1H), 4.98 (m, 1H), 5.34-5.48.
(M, 2H), 5.50-5.77 (m, 2H), 6.
83 (s, 2H), 6.97 (s, 1H).

Example 10 16- (3,5-dichlorophenoxy) -17,18,
Synthesis of 19,20-tetranorprostaglandin F2α methyl ester.

The title compound was synthesized in the same manner as in Example 9 except that methyl iodide was used instead of 2-iodopropane.

¹ H NMR (CDCl ₃ ): δ 1.51-1.80 (m, 4H), 2.08-
2.42 (m, 8H), 3.66 (s, 3H), 3.89-3.98 (m, 3H), 4.19 (m, 1H),
4.50 (m, 1H), 4.98 (m, 1H), 5.33-5.45 (m, 2H), 5.52-5.76 (m,
2H), 6.83 (s, 2H), 6.97 (s, 1H).

Example 11 (15RS) -16- (3,5-dichlorophenoxy)
-11,15-bis (2-tetrahydropyranyl) -1
Synthesis of 7,18,19,20-tetranorprostaglandin F2α isopropyl ester.

The carboxylic acid synthesized in Example 8 was esterified in the same manner as in Example 9 to synthesize the title compound.

¹ H NMR (CDCl ₃ ): δ 1.22 (m, 6H), 1.37-2.56
(m, 24H), 3.4-4.2 (m, 9H), 4.45-5.03 (m, 3H), 5.35-5.77 (m,
4H), 6.80-6.95 (m, 3H).

Example 12 (15RS) -16- (3,5-dichlorophenoxy)
Synthesis of -9-pivaloyl-11,15-bis (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

268 mg of the compound synthesized in Example 9 was dissolved in 5 ml of pyridine, a solution of pivaloyl chloride (75 mg) in pyridine (1 ml) was added, and the mixture was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The oil obtained by evaporating the solvent under reduced pressure was subjected to column chromatography (hexane / ethyl acetate:
3/1 to 2/1) to give 98 mg of the title compound, starting material 1
66 mg were obtained.

¹ H NMR (CDCl ₃ ): δ 1.20-1.27 (m, 15H), 1.33
-2.64 (m, 24H), 3.66-4.11 (m, 8H), 4.50-5.05 (m, 4H), 5.35
(m, 2H), 5.56-5.75 (m, 2H), 6.80-6.85 (m, 2H), 6.94 (m, 1H).

Example 13 Synthesis of 16- (3,5-dichlorophenoxy) -9-pivaloyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

93 mg of the compound synthesized in Example 12 was dissolved in 5 ml of methanol, 5 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The oil obtained by evaporating the solvent under reduced pressure was purified by column chromatography (hexane / ethyl acetate: 2/1 to 1/1) to obtain 29 mg of the title compound and 37 mg of 15S isomer.

¹ H NMR (CDCl ₃ ): δ 1.21 (d, J = 6.3 Hz, 6H), 1.
21 (s, 9H), 1.57-1.72 (m, 2H), 1.63 (t, J = 7.3Hz, 2H), 1.97-
2.20 (m, 4H), 2.24 (t, J = 7.3Hz, 2H), 2.36 (m, 1H), 2.51 (m, 1
H), 3.92 (ddd, J = 7.3,9.3Hz, 1H), 3.95 (m, 1H), 3.99 (dd, J =
3.9,9.3Hz, 1H), 4.54 (m, 1H), 4.97 (dq, J = 5.9,6.3Hz, 1H),
5.12 (m, 1H), 5.31-5.38 (m, 2H), 5.69-5.77 (m, 2H), 6.83 (d,
J = 1.5Hz, 2H), 6.98 (d, J = 1.5Hz, 1H).

Example 14 (15RS) -16- (3,5-dichlorophenoxy)
Synthesis of -11-pivaloyl-15- (2-tetrahydropyranyl) -17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

(1S, 5R, 6R, 7R) -2-oxa-7-hydroxy-6-[(1E, 3RS)-(4-
(3,5-dichlorophenoxy) -3-hydroxy-1
-Butenyl] -bicyclo [3.3.0] octane-3-
To a solution of ON (0.50 g) in pyridine (5 ml) was added pivaloyl chloride (0.18 ml) under ice-cooling, followed by stirring at room temperature for 2 hours. The mixture was poured into a saturated aqueous solution of sodium bicarbonate, extracted with ethyl acetate and concentrated by drying. The obtained pivaloyl ester was dissolved in anhydrous THF, cooled to -78 ° C, 2.9 ml of 1M lithium tris-butylborohydride was added, and the mixture was stirred for 1 hour. The mixture was poured into aqueous sodium bicarbonate, dried and concentrated to obtain lactol.

In another flask, 0.15 g of 4-carboxybutyltriphenylphosphonium bromide was added in anhydrous TH.
A suspension of F (14 ml) was prepared, 1.09 g of potassium t-butoxide was added, and the mixture was stirred at room temperature for 2 hours. Then, the mixture was poured into a solution of lactol in anhydrous THF (4 ml) to cause a reaction. Thereafter, the mixture was extracted with chloroform, dried and concentrated, and dissolved in acetone (12 ml). 1,
8-Diazabicyclo [5.4.0] undec-7-ene (1.8 ml) and 2-iodopropane (1.2 ml) were added at room temperature and stirred for 12 hours. Poured into saturated aqueous sodium hydrogen carbonate, extracted with ethyl acetate, dried and concentrated, and then subjected to silica gel column chromatography (hexane / ethyl acetate: 10/1 to 5/1).
Then, 0.34 g of the title compound was obtained.

¹ H NMR (CDCl ₃ ): δ 0.93 (m, 9H), 1.1-2.6 (m,
18H), 3.6-4.2 (m, 4H), 4.6-4.9 (m, 3H), 5.3-5.8 (m, 4H), 6.8
0 (s, 2H), 6.91 (s, 1H).

Example 15 (15RS) -16- (3,5-dichlorophenoxy)
Synthesis of 11-pivaloyl-17,18,19,20-tetranorprostaglandin F2α isopropyl ester.

In the same manner as in Example 13, (15RS) -16
-(3,5-dichlorophenoxy) -11-pivaloyl-15- (2-tetrahydropyranyl) -17,18,
The title compound was obtained from 19,20-tetranorprostaglandin F2α isopropyl ester.

¹ H NMR (CDCl ₃ ): δ 1.14 (s, 9H), 1.19 (m, 6
H), 1.5-2.6 (m, 12H), 3.6-3.9 (m, 3H), 4.8-4.9 (m, 2H), 5.3-
5.5 (m, 2H), 5.6-5.8 (m, 2H), 6.77 (s, 2H), 6.93 (s, 1H).

Example 16 (15RS) -16- (3,5-dichlorophenoxy)
-11,15-bis (2-tetrahydropyranyl) -1
Synthesis of 7,18,19,20-tetranorprostaglandin F2α S-isopropyl carbothioate.

326 mg of the carboxylic acid synthesized in Example 8 was dissolved in 1.5 ml of methylene chloride, and a solution of isopropylthiol (122 mg) in methylene chloride (0.8 ml) was added.
After adding 8 mg of -dimethylaminopyridine and cooling to 0 ° C, a solution of 155 mg of dicyclohexylcarbodiimide in 0.7 ml of methylene chloride was added, and the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium bicarbonate was added to stop the reaction, extracted with chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The oil obtained by distilling off the solvent under reduced pressure was subjected to column chromatography (hexane / ethyl acetate: 3/1).
２2/1) to give 214 mg of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.26-1.30 (m, 6H), 1.5-
2.5 (m, 24H), 3.41-4.13 (m, 9H), 4.46-4.77 (m, 2H), 5.35-5.
75 (m, 4H), 6.80-6.85 (m, 2H), 6.95 (m, 1H).

Example 17 16- (3,5-dichlorophenoxy) -17,18,
Synthesis of 19,20-tetranorprostaglandin F2α S-isopropyl carbothioate.

202 mg of the compound synthesized in Example 16 was dissolved in 5 ml of methanol, 5 mg of p-toluenesulfonic acid monohydrate was added, and the mixture was stirred at room temperature for 2.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous sodium sulfate. The oil obtained by distilling off the solvent under reduced pressure was purified by column chromatography (hexane / ethyl acetate: 1/3) to give the title compound (43m).
g, 52 mg of the 15S isomer.

¹ H NMR (CDCl ₃ ): δ 1.28 (d, J = 6.8 Hz, 6H), 1.
5-2.4 (m, 10H), 2.51 (t, J = 7.3Hz, 2H), 3.63 (dq, J = 3.4,6.8H
z, 1H), 3.90 (dd, J = 7.3,9.3Hz, 1H), 3.96 (dd, J = 3.9,9.3Hz,
1H), 3.98 (m, 1H), 4.18 (m, 1H), 4.51 (m, 1H), 5.34-5.45 (m, 2
H), 5.59 (dd, J = 6.3,15.6Hz, 1H), 5.73 (dd, J = 8.8,15.6Hz, 1
H), 6.83 (d, J = 1.5Hz, 2H), 6.97 (d, J = 1.5Hz, 1H).

Example 18 16- (3,5-dichlorophenoxy) -17,18,
Synthesis of 19,20-tetranorprostaglandin F2α S-phenyl carbothioate.

Using thiophenol in place of isopropylthiol, 123 mg of the title compound was obtained in the same manner as in Examples 16 and 17.

¹ H NMR (CDCl ₃ ): δ 1.47 (m, 1 H), 1.65-1.78
(m, 3H), 2.04-2.38 (m, 6H), 2.64 (t, J = 7.3Hz, 2H), 3.82-3.9
7 (m, 3H), 4.06 (m, 1H), 4.42 (m, 1H), 5.34-5.44 (m, 2H), 5.62
-5.64 (m, 2H), 6.79 (d, J = 2.0Hz, 2H), 6.82 (d, J = 2.0Hz, 1H),
7.38 (s, 5H).

Example 19 N-methanesulfonyl-15RS-16- (3,5-dichlorophenoxy) -11,15-bis (2-tetrahydropyranyl) -17,18,19,20-tetranorprostagland Synthesis of gin F2α carboxamide.

To a solution of 4- (N-methanesulfonylcarbamoylbutyl) triphenylphosphonium bromide (2 g) in dimethylsulfoxide (5 ml) was added 4 ml of 2M sodium methylsulfinylcarbamide. To this was added a solution of lactol (500 mg) synthesized in the same manner as in the previous section of Example 8 in dimethyl sulfoxide (8 ml), and the mixture was added at room temperature.
After stirring for 6 hours, the mixture was poured into a mixture of ice water and ethyl acetate, saturated saline was added, and the mixture was extracted with ethyl acetate. After drying and concentration, the residue was purified by silica gel column chromatography (hexane / ethyl acetate: 2/1 to 0/1) to give the title compound 612.
mg was obtained.

¹ H NMR (CDCl ₃ ): δ 1.4-2.6 (m, 24H), 3.26
(s, 3H), 3.4-3.6 (m, 2H), 3.8-4.2 (m, 5H), 4.4-4.5 (m, 1H),
5.3-5.6 (m, 4H), 5.6-5.8 (m, 2H), 6.83 (s, 2H), 6.95 (s, 1H).

Example 20 (15RS) -N-methanesulfonyl-16- (3,5
Synthesis of (-dichlorophenoxy) -17,18,19,20-tetranorprostaglandin F2α carboxamide.

Using the compound synthesized in Example 19, deprotection of the hydroxyl group was carried out in the same manner as in Example 5, and silica gel column chromatography (chloroform / methanol: 20/1 to 9/9).
Purification in 1) gave the title compound.

¹ H NMR (CDCl ₃ ): δ 1.5-2.5 (m, 12H), 3.22
(s, 3H), 3.8-4.0 (m, 2H), 4.1 (m, 1H), 4.2 (m, 1H), 4.5 (m, 1
H), 5.3-5.5 (m, 2H), 5.6-5.8 (m, 2H), 6.82 (s, 2H), 6.97 (s, 1
H).

Example 21 16- (3,5-dichlorophenoxy) -11,15-
Bis (2-tetrahydropyranyl) -17,18,1
9,20-tetranorprostaglandin F2α1,9
-Synthesis of lactones.

100 mg of the carboxylic acid synthesized in Example 8 was dissolved in 2 ml of methylene chloride, 5 mg of 4-dimethylaminopyridine was added, the mixture was cooled to 0 ° C., and a solution of 36 mg of dicyclohexylcarbodiimide in methylene chloride (0.5 m
l) was added and the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium bicarbonate was added to stop the reaction, extracted with chloroform, washed with water and saturated saline, and dried over anhydrous sodium sulfate. The oil obtained by evaporating the solvent under reduced pressure was purified by column chromatography (hexane / ethyl acetate: 3/1 to 2/1) to obtain 31 mg of the title compound.

¹ H NMR (CDCl ₃ ): δ 1.37-2.67 (m, 24H), 3.4-
4.2 (m, 8H), 4.45-4.90 (m, 4H), 5.20-5.77 (m, 5H), 6.79-6.9
5 (m, 3H).

Example 22 16- (3,5-dichlorophenoxy) -17,18,
19,20-tetranorprostaglandin F2α
Synthesis of 1,9-lactone.

Using the compound synthesized in Example 21, deprotection of the hydroxyl group was carried out in the same manner as in Example 17, followed by purification by silica gel column chromatography to obtain the title compound.

¹ H NMR (CDCl ₃ ): δ 1.6-2.6 (m, 12H), 3.89 (d
d, J = 7.6,9.4z, 1H), 3.90 (m, 1H), 3.98 (dd, J = 3.7,9.4Hz, 1
H), 4.53 (m, 1H), 5.24-5.36 (m, 3H), 5.67-5.73 (m, 2H), 6.82
(d, J = 1.7Hz, 2H), 6.99 (t, J = 1.7Hz, 1H).

[Example 23] (Formulation example) 16- (3,5-Dichlorophenoxy) -17,18,
A typical formulation example of an ophthalmic solution and an eye ointment using 19,20-tetranorprostaglandin F2α isopropyl ester (hereinafter, referred to as compound A) is shown.

1) Ophthalmic solution 1 mg of Compound A, 250 mg of concentrated glycerin, 200 mg of polysorbate 80, 20 mg of sodium dihydrogen phosphate dihydrate in 10 ml of Formulation 1 (Formulation 1), 20 mg of sterilized purified water, appropriate amount of sterilized purified water, 1N hydrochloric acid or 1N hydroxide Sodium qs, pH 6.0.

Formulation 2 (Formulation 2) 5 mg of Compound A, 250 mg of concentrated glycerin, 200 mg of polysorbate 80, 20 mg of sodium dihydrogen phosphate dihydrate, 20 mg of sterilized purified water, appropriate amount of sterilized purified water, appropriate amount of 1N hydrochloric acid or 1N sodium hydroxide, pH in 10 ml 6.0.

Formulation 3 (Formulation 3) 10 mg of compound A in 10 ml, concentrated glycerin 250 mg, polysorbate 80 200 mg, sodium dihydrogen phosphate dihydrate 20 mg, appropriate amount of sterilized purified water, appropriate amount of 1N hydrochloric acid or 1N sodium hydroxide, pH 6.0.

Formulation 4 (Formulation 4) Compound A 50 mg, concentrated glycerin 250 mg, polysorbate 80 500 mg, sodium dihydrogen phosphate dihydrate 20 mg, appropriate amount of sterilized purified water, appropriate amount of 1N hydrochloric acid or 1N sodium hydroxide, pH in 10 ml, pH 6.0.

2) Ophthalmic ointment 0.1 g of compound A, 20 g of liquid paraffin, 77.9 g of white petrolatum and 2 g of purified lanolin in 100 g of Formulation 1 (Formulation 5).

[0134] Formulation examples of latanoprost ophthalmic solution used as a comparative drug in the section of pharmacological test are also shown.

Formulation 1 (Reference formulation 1) Latanoprost 10 mg, concentrated glycerin 250 mg, polysorbate 80 200 mg, sodium dihydrogen phosphate dihydrate 20 mg in 10 ml, sterile purified water appropriate amount, appropriate amount of 1N hydrochloric acid or 1N sodium hydroxide, pH 6.0.

[Example 24] (Pharmacological test) In order to find usefulness of the compound of the present invention as a medicament for ocular diseases, effects on intraocular pressure and eye irritation were examined.

1) Influence on intraocular pressure As an example of studying the effect of tromethamine salt and isopropyl ester of PGF2α on intraocular pressure, there is a report using cynomolgus monkeys (Exp. Eye Res., 61, 677-683 (199).
Five) ). Therefore, the effect of the compound of the present invention on intraocular pressure was examined according to the method described in the above literature.

(Experimental method) Body weight 5-7.5 kg (5-1)
Male cynomolgus monkeys (age 0) were subjected to the experiment. The intraocular pressure was measured immediately before administration of the test compound and at 2, 4, and 6 hours after administration. Intraocular pressure measurement was performed using ketamine (5-10 mg / k
g, intramuscular administration) under anesthesia using a pneumatic applanation tonometer.

(Results) As an example of the experimental results in Table 1, 0.1% (w / v) ophthalmic solution of Compound A (Preparation 3) was added to 20 μl.
The time-dependent change in the intraocular pressure with respect to the initial intraocular pressure (the intraocular pressure immediately before instillation) when l is applied is shown. In addition, 0.1% of latanoprost known as a glaucoma treatment drug
(W / v) The results when the ophthalmic solution (Reference Preparation 1) was instilled are also shown.

[0140]

[Table 1]

As shown in Table 1, the intraocular pressure decreased from 2 hours after the instillation of Compound A, and a remarkable decrease in the intraocular pressure was observed 4 hours and 6 hours after the instillation. In addition, the degree of decrease in intraocular pressure was about 1.5 times that of latanoprost. From this, it became clear that the compound of the present invention has an intraocular pressure lowering action with excellent durability.

2) Eye irritation test The eye irritation of the compound of the present invention was examined according to the method of Fukui et al. (Modern clinic, 4277-89 (1970)).

(Experimental method) Japanese white male rabbits weighing about 2.5 kg were subjected to the experiment. The test compound was instilled 10 times into the right conjunctival sac at 30 minute intervals. Immediately before and 1 hour and 4 hours after the last instillation, the anterior segment symptoms and anterior chamber symptoms were observed, and 4 hours after the last instillation, corneal dysfunction was observed. Note that only a base containing no test compound was instilled into the left eye conjunctival sac.

A) Anterior segment symptoms: Improved Drai shown below
The scoring was performed in accordance with the scoring criteria for eye disorders according to the se method.

[Scoring Criteria for Ocular Disorders] Cornea a) Opaque • No cloudiness (normal); 0 • Scattered in dysphagic region (iris details are clearly visible); 1 • Translucent easily distinguishable Opaque areas, iris details not visible, barely discernible pupil size; 3 obscured, iris not visible; 4

B) The size of the corneal region corresponding to the above. No corresponding region; 0. 1/4 or less, not 0; 1 * 1/4 and smaller than 1/2; 2 * 1 / More than 2 and less than 3/4; 3-more than 3/4 and up to the whole; 4

[0147] Iris-Normal; 0-Above normal folds, congestion, swelling, hyperemia around the cornea (any or a combination thereof), Iris still responds to light (slow positive response); 1-Light Unresponsive to bleeding, severe destruction (any or all); 2

Conjunctiva a) Eyelid conjunctival redness-No hyperemia; 0-Mucosa is very light reddish and mild dilation of blood vessels at eyelid margin is observed; 0.5-Apparent hyperemia beyond normal The degree of redness of the mucous membrane is clear and irritable; 1 ・ The redness of the mucous membrane of the eye is very remarkable and the movement of the blood vessels at the ends is somewhat unclear; Show; 3

B) Eyelid conjunctival edema-no swelling; 0-slight edema tendency; 0.5-some swelling above normal; 2 • swelling and closing about half of the eyelid; 3 • swelling and closing completely from about half of the eyelid; 4

C) Redness of the bulbar conjunctiva ・ No hyperemia; 0 ・ Slightly dilated blood vessels around the cornea; 0.5 ・ More severe vasodilation; 1 ・ Results of running toward eyelid margin When the extension is noticeable or has a significant red color; 2

D) State of nictitating membrane ・ No hyperemia; 0 ・ A degree to which a tendency of vasodilation and edema is observed;
5 ・ Dilation of blood vessels becomes more remarkable and eyelid margin turns red; 1 ・ Vascular vasodilation is remarkable and the entire nictitating membrane is remarkably reddish; 2

E) Secretions • No secretion; 0 • Some amount different from normal (except for the small amount found in the internal canthus of normal animals); 1 • There is secretion, and the hair in contact with the eyelid and the eyelid Wet; 2 · Has secretions, wets eyelids and hair and considerable area around eye; 3

B) Symptoms in the anterior chamber: After observing the anterior eye symptoms, the presence or absence of flare in the anterior chamber was observed using a slit lamp.

C) Corneal impairment: After observation of anterior eye symptoms and anterior chamber symptoms 4 hours after the last instillation, the cornea was stained with fluorescein, and the stored state of the stain on the cornea was measured using a slit lamp. Observed.

(Results) As an example of the experimental results in Table 2, 0.1% (w / v) of an ophthalmic solution of Compound A (Formulation 3) was added to 50 μl.
The score of the anterior ocular segment symptom (average value of three cases) when l was instilled is shown. Table 3 shows the results obtained when 0.1% (w / v) ophthalmic solution of latanoprost, which is known as a therapeutic agent for glaucoma, was instilled. Furthermore, in order to comprehensively evaluate the degree of the anterior segment damage, the total value of each score was calculated and shown as a comprehensive evaluation.

[0156]

[Table 2]

[0157]

[Table 3]

As shown in Table 2, only slight hyperemia was observed in the conjunctiva, and almost no eye irritation was observed in the anterior segment symptoms due to Compound A instillation. Also,
As shown in Tables 2 and 3, it is clear that the degree of eye irritation in anterior segment symptoms is weaker for Compound A than for Latanoprost, and in the comprehensive evaluation, the results after Compound A instillation are lower than for Latanoprost. Approximately 2/3 at 1 hour and 1/2 at 4 hours were always found to be weaker than latanoprost. On the other hand, in the case of instillation of the base alone, the score value was 0 in all anterior eye segment symptoms.

It should be noted that flare and corneal damage in the anterior chamber were not observed in all cases. From this, it became clear that the compound of the present invention hardly showed eye irritation.

[0160]

Industrial Applicability The present invention provides prostaglandins having a polysubstituted aryloxy group in the ω chain, particularly prostaglandins in which the carboxylic acid or hydroxyl group of the prostaglandin is derivatized, and the prostaglandins having the same. A novel drug for preventing or treating eye diseases as a component is provided. The medicament of the present invention is a medicament for eye diseases having high pharmacological action and low side effects.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Masaaki Kageyama 8916-16 Takayama-cho, Ikoma City, Nara Prefecture Santen Pharmaceutical Co., Ltd. Central Research Laboratory (72) Inventor Nobuaki Mori 1150 Hazawa-machi, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Asahi Glass Co., Ltd. (72) Inventor Takashi Nakano 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture 72) Inventor Yasushi Matsumura 1150 Hazawa-cho, Kanagawa-ku, Yokohama-shi, Kanagawa Prefecture Inside the Central Research Laboratory, Asahi Glass Co., Ltd.

Claims (13)

[Claims] 1. A prostaglandin represented by the following general formula (1) or a salt thereof. Embedded image [In the general formula (1), A: ethylene group, vinylene group, ethynylene group, -OCH
₂ -, or _{-SCH 2 -, B: -CH (} OR 3) - or -C (= O) -, R 1, R 2, R 3: each independently, a hydrogen atom, an acyl group or a group represented by a single, A bond, Ar: a phenyl group or a heteroaromatic ring having two or more substituents, X: —CH ₂ —, —O—, or —S—, Z: —OR ⁴ , —NHCOR ⁵ , and —NHSO ₂ R ⁶ , −
SR ⁷ , or a single bond in cooperation with any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ : each independently a hydrogen atom,
An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or an aralkyl group, an overlapping portion of a solid line and a dashed line: a single bond or a cis or trans double bond, (where A is a vinylene group and B is- C
H (OH) -, X is -CH ₂ - if it is, and a hydrogen atom both R ¹ and R ^2, Z is representative of a non--OR ^4). ] 2. The compound according to claim 1, wherein A is a vinylene group. 3. The method according to claim 1, wherein X is —CH ₂ —.
A compound as described. 4. The method of claim 1, wherein B is -CH (OH)-.
4. The compound according to 2 or 3. 5. The method according to claim 1, wherein Ar is a 3,5-dichlorophenyl group or a 3,4-dichlorophenyl group.
5. The compound according to 3 or 4. 6. The compound according to claim 1, wherein R ¹ and R ² are both hydrogen atoms. 7. The method of claim 1, wherein Z is —OR ⁴ .
7. The compound according to 4, 5 or 6. 8. Z is -SR ^7, claim 1, 2, 3,
7. The compound according to 4, 5 or 6. 9. Z is -NHSO ₂ R ^6, claim 1,
The compound according to 2, 3, 4, 5 or 6. 10. The method according to claim ¹ , wherein ^one of R ¹ and R ² is an acyl group, the other is a hydrogen atom, and Z is —OR ⁴ .
The compound according to 3, 4 or 5. (11) A pharmaceutical comprising the compound according to any one of (1) to (10) as an active ingredient. 12. A medicament for preventing or treating eye diseases comprising a prostaglandin represented by the following general formula (1) or a salt thereof as an active ingredient. Embedded image [In the general formula (1), A: ethylene group, vinylene group, ethynylene group, -OCH
_2- or -SCH _2- , B: -CH (OR ³ )-or -C (= O)-, R ¹ , R ² , R ³ : each independently represents a hydrogen atom, an acyl group, or A bond, Ar: a phenyl group or a heteroaromatic group having two or more substituents, X: —CH ₂ —, —O—, or —S—, Z: —OR ⁴ , —NHCOR ⁵ , and —NHSO ₂ R ⁶ ,-
SR ⁷ , or a single bond in cooperation with any of R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ : each independently a hydrogen atom,
An alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or an aralkyl group; an overlapping portion between a solid line and a broken line: a single bond, or a cis or trans double bond. ] 13. The eye disease is glaucoma or ocular hypertension.
The medicament according to claim 12.