JPH0739343B2 - Ocular hypotensive agent - Google Patents

Description

TECHNICAL FIELD OF THE INVENTION The present invention relates to a carbon atom at position 20 substituted with a hydrocarbon group at position 13
The present invention relates to an intraocular pressure-lowering agent and a therapeutic agent for glaucoma, which comprises Δ ¹³ -15-keto-prostaglandins in which the 14th carbon is bound by an unsaturated bond.

2. Description of the Related Art Prostaglandins (hereinafter referred to as PGs) are names given to a group of fatty acids showing various physiological actions contained in human and animal tissues and organs. PGs are prostanoic acid represented by the following formula Is used as the basic skeleton, but synthetic products include those obtained by modifying the above skeleton.

PGs have a five-membered ring structure, Etc. In addition, the 5-6 position PG ₁ such carbon bond is a single bond: And PG ₂ 's in which the carbon at the 5-6 position is a double bond: Further 5,6 PG ₃ such atoms of carbon and 17-18 positions are each double bond: Classified as and.

PGs have various pharmacological and physiological actions, such as vasodilation, inflammation action, platelet aggregation action, uterine muscle contraction action, and intestinal contraction action, but PGs have various actions at the same time. It has problems in its use as a medicine because it has That is, when PGs are administered with one effect as a medicinal effect, they also have other effects at the same time, so that these other effects often appear as side effects. So far
The study of PGs as a medicine has focused on how to enhance the expression of the action expected as the main drug effect. However, these examinations are still insufficient.

Further, among PGs, for example, PGAs, PGDs, PGEs, PGFs, etc. are known to have an intraocular pressure lowering action. For example, Japanese Patent Publication No. Sho 59-1418 is a slight and that the 15-keto-PGF ₂ alpha with the PGF ₂ alpha is high ocular hypotensive effect, but it is described that also have an effect intraocular pressure reducing and JP-A-63-66122, describes that PGA, PGB and PGC are effective in treating glaucoma. However, when instilled in the rabbits etc. of these PGs,
Along with a transient increase in intraocular pressure, strong hyperemia in the conjunctiva and iris is observed, and side effects such as tearing, eye oil, and eye closure are also observed. Therefore, there is a problem in using PGs as a glaucoma therapeutic agent or an intraocular pressure-lowering agent.

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The present invention is a novel PG-type eye that does not show or has significantly reduced unfavorable side effects such as hyperemia and eye closure as described above that accompany when PGs are used as intraocular pressure-lowering agents. The purpose is to provide a pressure reducing agent.

Means for Solving the Problems The present invention provides that the carbon atom at the 15-position forms a carbonyl group, and
It is based on the finding that PGs in which the carbon atom at the 20-position is extended by a hydrocarbon group show an excellent intraocular pressure-lowering effect and that side effects such as hyperemia and eye closure as described above are significantly reduced.

That is, the present invention provides an intraocular pressure-lowering agent and a therapeutic agent for glaucoma, which comprises, as an active ingredient, Δ ¹³ -15-keto-prostaglandins in which the 20th carbon atom is substituted with a hydrocarbon group.

In the present invention, Δ ¹³ -15-keto-PGs means 13 and 14
PGs in which the bond at position 15 is unsaturated and the carbon at position 15 is a carbonyl group.

In the present specification, Δ ¹³ -15-keto-PGs are represented by the following nomenclature. That is, Δ ¹³ -15-keto-PGs have the following basic skeleton: Based on the above, the carbon numbers constituting the α chain, ω chain and 5-membered ring of this basic skeleton are used as they are. That is, the number of carbons constituting the basic skeleton is 1 for the carboxyl carbon, and 2 to 7 are sequentially assigned to carbons on the α chain toward the 5-membered ring, and 8 to
Up to 12 are attached to the carbon of the 5-membered ring, and up to 13 to 20 are attached to the ω chain, but if the carbon number decreases on the α chain, the number is deleted sequentially from the 2nd position and increases on the α chain. In this case, the carbon atom at the 2-position has a substituent in place of the carboxyl group (1-position). If the carbon number increases on the omega chain, the 21st and subsequent carbon atoms are designated as substituents. Regarding the stereoscopic configuration, the stereoscopic configuration of the basic skeleton is used unless otherwise specified. Also, for example, PGD, P
GE and PGF refer to compounds having a hydroxyl group at the 9- and / or 11-position carbons, but in the present specification, include compounds having other groups instead of the 9- and / or 11-position hydroxyl groups.
PGs, in which case they are named in the form of 9-dehydroxy-9-substituted or 11-dehydroxy-11-substituted.

20 of delta ^{13-15-keto--PG} such carbon atom is substituted with a hydrocarbon group used in the present invention (hereinafter, delta ^13-15-
Keto-20-substituted -PG referred to earth), the 5-6 position delta ^{13-15-keto-20-substituted} -PG ₁ such carbon bond is a single bond, double bond in a delta ^13-15- Keto-20-substituted-PG _2's , 5-
It may be any of Δ ¹³ -15-keto-20-substituted-PG ₃ 's in which both the carbon bond at the 6-position and the carbon bond at the 17-18 position are double bonds.

PGs are PGA ₁ , PGA ₂ , PGA ₃ , PGB ₁ , PGB ₂ , PGB ₃ , PGC ₁ , PG
C ₂ , PGC ₃ , PGD ₁ , PGD ₂ , PGD ₃ , PGE ₁ , PGE ₂ , PGE ₃ , PG
It includes basic compounds such as F ₁ , PGF ₂ , PGF ₃ , PGJ ₁ , PGJ ₂ and PGJ ₃ and their substitution products, esters, salts and the like.

The Δ ¹³ -15-keto-20-substituted-PGs of the present invention exhibit a strong intraocular pressure-lowering effect, and also have side effects such as conjunctiva and erythremia that are strong with PGs such as hyperemia, eye closure, and tearing. Not possible or significantly reduced. Therefore these Δ
^13-15 -keto-20-substituted-PGs are extremely effective as ocular hypotensive agents. Further, it can be used as a therapeutic agent for glaucoma on the basis of such an intraocular pressure-lowering effect.

In the present invention, the Δ ¹³ -15-keto-20-substituted-PGs have an intraocular pressure-lowering action, especially in the general formula: [Where A is Or (Wherein R represents a hydroxyl group, a hydroxyalkyl group or an alkyl group); Y represents a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (a part of the carbon atoms constituting the hydrocarbon chain is a carbonyl group; And a hydrocarbon chain may be substituted with an atom or a group); Z is an aliphatic hydrocarbon group which may have a saturated or unsaturated side chain having 1 to 10 carbon atoms, Representing an alicyclic group, an aliaromatic group, or a hydrocarbon group constituting the aromatic group (the hydrocarbon group may be substituted by a group or an atom); or a prostaglandin represented by This is remarkable in physiologically acceptable salts or those in which the carboxyl group is esterified.

Examples of the hydrocarbon chain having 2 to 6 carbon atoms in which Y is saturated or unsaturated include straight chain hydrocarbon chains such as alkyl chains, alkenyl chains and alkynyl chains, and particularly preferably 6 carbon atoms.
Is a hydrocarbon chain of.

Y is an unsaturated hydrocarbon chain, for example, PG in which the carbon bond at the 2-3 position or the 5-6 position is a double bond or a triple bond.
The kind is illustrated.

The hydrocarbon chain represented by Y may partially form a carbonyl group, and a typical example thereof is a 6-keto-PG ₁ group in which the 6-position carbon forms a carbonyl group. .

The hydrocarbon chain represented by Y may be substituted with an atom or a group. An example of such an atom or group is fluorine,
Examples thereof include halogen atoms such as chlorine, alkyl groups such as methyl and ethyl, and hydroxyl groups, and typical examples thereof are PGs having an alkyl group at the 3-position carbon.

The hydrocarbon group Z is an alkyl group which may have a side chain having 1 to 10 carbon atoms, and preferably an alkyl group which may have a side chain having 1 to 4 carbon atoms, for example, methyl, ethyl, n
-Propyl, isopropyl, n-butyl, t-butyl and the like are preferable, and linear ones are particularly preferable.

The omega chain may be substituted by atoms or groups. These atoms or groups are a halogen atom such as fluorine and chlorine; an alkyl group such as methyl, ethyl, isopropyl and isopropenyl; an alkoxy group such as methoxy and ethoxy; a hydroxyl group; a phenyl group; a phenoxy group and the like. The position of the substituting atom or group is not particularly limited, but it is typically at the 16-position, 17-position, 19-position and / or 20-position represented by the carbon number of the ω chain. In particular, 1 or 2 identical or different atoms at the 16-position, such as a halogen atom such as fluorine or a substituent, such as an alkyl group such as methyl or ethyl, a hydroxyl group
A phenyl group which may have a substituent, a benzyl group, a phenoxy group, or a cycloalkyl group such as cyclopentyl or cyclohexyl having 16-position carbon as a member; 1
A compound having an alkyl group such as methyl at the 7- or 19-position is preferable.

PGs include compounds having a hydroxyl group at the 9- and / or 11-position carbon such as PGD, PGE, and PGF, but in the present specification,
A compound having a hydroxyalkyl group or an alkyl group in place of the 9th and / or 11th hydroxyl group is also treated as being included in PGs. Therefore, Δ ¹³ −15− of the present invention
In the keto-20-substituted-PGs, R in the general formula [I] is a hydroxyl group,
Included are compounds that are hydroxyalkyl groups or alkyl groups. The hydroxyalkyl group is preferably a hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group or 1-methyl-1-hydroxyethyl group,
As the alkyl group, a lower alkyl group, particularly a methyl group, an ethyl group and the like are preferable.

The configuration of R with respect to the 9th and / or 11th carbon may be α, β or a mixture thereof.

The PGs of the present invention may be a salt or an esterified carboxyl group. Examples of the salt include physiologically acceptable salts, for example, salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium and magnesium, or physiologically acceptable ammonium salts such as ammonia, methylamine and dimethyl. Amine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanolamine, tromethamine, lysine,
It may be a tetraalkylammonium salt or the like. Examples of the ester include methyl, ethyl, propyl, butyl,
Isopropyl, t-butyl, 2-ethyl-hexyl, alkyl ester having a straight chain or a side chain which may have an unsaturated bond, etc .; for example, ester having an alicyclic group such as cyclopropyl, cyclopentyl, cyclohexyl;
For example, an ester having an aromatic group such as benzyl and phenyl (the aromatic group may have a substituent); for example, hydroxyethyl, hydroxyisopropyl, hydroxypropyl, polyhydroxyethyl, polyhydroxyisopropyl, methoxyethyl. And hydroxyalkyl or alkoxyalkyl esters such as ethoxyethyl and methoxyisopropyl; alkylsilyl esters such as trimethylsilyl and triethylsilyl; and tetrahydropyranyl esters.

Preferred esters are eg methyl, ethyl, propyl,
A lower alkyl ester having a straight chain or a side chain such as butyl, isopropyl and t-butyl; a benzyl ester; and a hydroxyalkyl ester such as hydroxyethyl and hydroxyisopropyl.

The carboxyl group at the α chain end of the Δ ¹³ -15-keto-20-substituted-PGs in the present invention may be any of the above, but in view of the expression of the intraocular pressure lowering effect, an ester form, Particularly, an alkyl ester having 1 to 4 carbon atoms, especially an isopropyl ester is preferable.

The Δ ¹³ -15-keto-20-substituted-PGs of the present invention include isomers of the above compounds. Examples of these isomers are keto-hemiacetal tautomers between the 6-position carbonyl group and the 9-position hydroxyl group, between the 11-position hydroxyl group and the 15-position carbonyl group, or optical isomers, geometric isomers, etc. Is exemplified.

The tautomer between the 11-position hydroxyl group and the 15-position carbonyl group is
Particularly, in the Δ ¹³ -15-keto-20-substituted-PGEs, an electron-withdrawing group at the 16-position, such as a fluorine atom, is likely to be formed.

Mixtures of isomers, for example racemic, equilibrium mixtures of keto-hemiacetal tautomeric hydroxy compounds and hemiacetal, also show the same effects as in the case of each alone.

In the present invention, particularly preferred Δ ¹³ -15-keto-20-substituted-PGs are those in which the carbon bond at the 5-6 position is a single bond or a double bond or the carbon at the 6 position forms a carbonyl group. . Another preferred group also is 16-position a halogen atom or an alkyl group substituted with delta ^{13-15-keto-20-substituted} -PG compound.

In the present specification, PGs are named based on the prostanoic acid skeleton. Name it based on IUPAC, for example PGE ₁
Is 7-{(1R, 2R, 3R) -3-hydroxy-2 [(E)-
(3S) -3-Hydroxy-1-octenyl] -5-oxo-cyclopentyl} -heptanoic acid; PGE ₂ is (Z) -7.
-{(1R, 2R, 3R) -3-hydroxy-2-[(E)-
(3S) -3-Hydroxy-1-octenyl] -5-oxo-cyclopentyl] -hept-5-citric acid; thus
15-keto-20-ethyl-PGE ₁ is 7-{(1R, 2R, 3R) -3
-Hydroxy-2-[(E)-(3S) -3-oxo-1
-Decenyl] -5-oxo-cyclopentyl} -heptanoic acid. Also, PGF ₁ α is 7-[(1R, 2R, 3R, 5R)-
3,5-dihydroxy-2-{(E)-(3S) -3-hydroxy-1-octenyl} -cyclopentyl] -heptanoic acid; PGF ₂ α is (Z) -7-[(1R, 2R, 3R, 5S)-
3,5-dihydroxy-2-{(E)-(3S) -3-hydroxy-1-octenyl} -cyclopentyl] -5-heptenoic acid; 15-keto-20-ethyl-PGF ₁ α is 7-
[(1R, 2R, 3R, 5S) -3,5-dihydroxy-2-{(E)
-(3S) -3-oxo-1-decenyl} -cyclopentyl] -heptanoic acid. Also, other PGs can be similarly named.

The present invention delta ^{13-15-keto-20-substituted} -PG compounds may be prepared as shown in Synthetic Chart 1 and 2. That is, commercially available (-) corey lactone is used as a starting material, and this is Collins-oxidized to obtain an aldehyde.
-Oxoalkyl) phosphonate anion to give an α, β-unsaturated ketone, which is reduced to give the ketone, the carbonyl group of which is protected as a ketal by reaction with a diol, and then de-p- The alcohol is obtained by phenylzenzoylation and the newly formed hydroxyl group is protected with dihydropyran to give tetrahydropyranyl ether. As a result, a precursor of PGs into which the ω chain is introduced is obtained. The alkyl group of dimethyl (2-oxoalkyl) phosphonate used for introducing the ω chain may be selected according to the desired ω, and when the substituted hydrocarbon group at the 20-position is ethyl, dimethyl (2-oxononyl) A phosphonate may be used.

PGs having a methyl group instead of the 11-position hydroxyl group are 11-
The 11-dehydro-11-methyl-PGE type is obtained by reacting the PGA type obtained by Jones oxidation of the 9-position hydroxyl group of the tosylate with a dimethyl copper complex. Alternatively, the alcohol obtained after elimination of the p-phenylbenzoyl group of the tetrahydropyranyl ether is tosylate, the unsaturated lactone obtained by DBU treatment of this is used as lactone, and the α-chain is introduced using the Wittig reaction. After that, the obtained alcohol (9-position) is oxidized to PGA type, and 11-dehydroxy-11-methyl-PGE type can be synthesized by reacting this with a dimethyl copper complex. The 11-dehydroxy-11-methyl-PGF type can be synthesized by reducing this with, for example, sodium borohydride.

PG having a hydroxymethyl group instead of the 11th hydroxyl group
As a class, 11-dehydroxy-11-hydroxymethyl-PGE type can be synthesized by photoadding methanol with benzophenone as a sensitizer to the PGA type obtained above. For example, 11-dehydroxy-11-hydroxymethyl-PGE type can be synthesized by reducing this with sodium borohydride.

For 16-fluoro-PGs, the dimethyl (3-fluoro-2-oxoalkyl) phosphonate anion may be used in obtaining α, β-unsaturated ketones, and for 19-methyl-PGs, dimethyl (6-methine- A 2-oxoalkyl) phosphonate anion may be used.

In the present invention, the synthetic method is not limited to this, and a suitable method such as a protection method and a redox method may be adopted.

The Δ ¹³ -15-keto-20-substituted-PGs of the present invention may be used as a drug for animals and humans, and usually systemically or topically, orally, intravenously, subcutaneously, suppositories, and eye drops. It is used by methods such as a drug and an eye ointment. The dose varies depending on the animal, human, age, body weight, symptoms, therapeutic effect, administration method, treatment time and the like.

Solid compositions for oral administration according to the present invention include tablets, powders, granules and the like. In such solid compositions one or more of the active substances is at least one inert diluent such as lactose, mannitol,
It is mixed with glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminometasilicate. According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin gluconate, α, β or γ-cyclodextrin, dimethyl- Etherified cyclodextrins such as α-, dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branched cyclodextrins such as glucosyl-, maltosyl-cyclodextrin, formylated cyclodextrins, sulfur-containing cyclodextrins , May also contain stabilizers such as misoprotol, phospholipids. When the above cyclodextrins are used, they may form an inclusion compound with the cyclodextrins to increase the stability. In addition, stability may be increased by forming a liposome using a phospholipid.

If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or may be coated with two or more layers. Further, it may be a capsule of an absorbable substance such as gelatin.

Liquid compositions for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents such as It may contain purified water, ethanol or the like. This composition may contain, in addition to an inert diluent, auxiliary agents such as a lubricant and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, a preservative and the like.

Other compositions for oral administration include sprays which contain one or more active substances and are formulated in a manner known per se.

The injection for parenteral administration according to the present invention may be a sterile aqueous or non-aqueous solution, suspension, emulsion or the like.

Examples of diluents for aqueous solutions and suspensions include distilled water for injection, physiological saline and Ringer's solution.

Examples of diluents for non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbates and the like. Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents and stabilizers. These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a sterilizing agent, gas sterilization or radiation sterilization. These can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

The eye drop according to the present invention may be a sterile aqueous or non-aqueous solution, suspension or the like. Distilled water and physiological saline are included as an aqueous solution and a diluent for dissolving a suspension. Non-aqueous solutions and diluents for suspensions include food oil, liquid paraffin, mineral oil, propylene glycol, p-octyldodecanol and the like. In addition, isotonic agents such as sodium chloride, benzalkonium chloride, fedrin chloride, procaine chloride, chloramphenicol, sodium citrate, etc. for the purpose of making isotonic with tear fluid, and to keep the pH constant. A buffer such as a borate buffer solution or a phosphate buffer solution can be used. Also, stabilizers such as sodium sulfite, sodium carbonate, EDTA, propylene glycol, glycerin, carboxymethyl cellulose,
It may contain a thickener such as carboxyvinyl polymer, a diluent such as polysorbate, macrogol and aluminum monostearate, a preservative such as paraben, benzyl alcohol and sorbic acid, or a solubilizer and an excipient. These are sterilized by, for example, filtration through a bacteria retaining filter and heat sterilization. Particularly important points in the preparation of eye drops are pH and ionic strength of the eye drops, which may be appropriately adjusted to optimum values depending on the type and amount of the active substance or other additives used.

The ophthalmic ointment according to the present invention is based on petrolatum, xylene 50, plastibase, macrogol, etc., for the purpose of increasing hydrophilicity, polysorbate, surfactants such as purified lanolin, carboxymethylcellulose, methylcellulose, carboxyvinyl polymer, etc. The jelly agent and the like may be included.

The intraocular pressure-lowering agent of the present invention can be used as a therapeutic agent for glaucoma by utilizing this intraocular pressure-lowering effect. When used as a remedy for glaucoma, conventional choline-type intraocular pressure-lowering agents (such as pilocarpine, carbachol, which has an excellent miosis effect), anticholinesterases (such as demepotassium, DFP, ecothiophate, etc.), and mizotics such as physostigmine salicylate,
Other inflammatory diseases such as mannitol, glycerin, isosorbide, etc. as intravenous hyperosmolarity agents such as pilocarpine hydrochloride, chlorobutanol, benzalkonium chloride, propylparaben, methylparaben, ethylparaben, butylparaben, etc. as preservatives for eye drops For prevention and treatment, penicillin, sulfa drugs, chloramphenicol,
Cortinezone, chlorpheniramine and the like may be added. Hereinafter, the present invention will be described with reference to examples.

Example (1) Synthesis of Δ ¹³ -15-keto-20-substituted PGs: (1) Synthesis of 15-keto-20-ethyl-PGF ₂ α isopropyl ester (10) (see Synthesis Chart I): 1- 1) Synthesis of 1S-2-oxa-3-oxo-6R- (3-oxo-1-trans-decenyl) -7R- (4-phenylbenzoyloxy) -cis-bicyclo [3.3.0] octane (3) A commercially available (−)-cory lactone (1) (7 g) was used to obtain Collins oxidation 1 in dichloromethane and an aldehyde (2).
This was added to dimethyl (2-oxonyl) phosphonate (4.97
g) reacted with anion to give 1S-2-oxa-3-oxo-6R- (3,3-ethylenedioxy-1-trans-decenyl) -7R- (4-phenylbenzoyloxy) -cis-bicyclo [3.3 .0] Octane (3) was obtained.

1-2) 1S-2-oxa-3-oxo-6R- (3,3-ethylenedioxy-1-trans-decenyl) -7R- (4
-Phenylbenzoyloxy) -cis-bicyclo [3.3.
0] Synthesis of octane (4): Unsaturated ketone (3) (2.0 g) in benzene (100 ml),
Using ethylene glycol (12 g) and p-toluenesulfonic acid (catalytic amount), the resulting water was distilled off, and the mixture was refluxed overnight. Chromatography (hexane / ethyl acetate = 2 /
1 to 1/1) to obtain the ketal (4).

Yield: 1.98 g 1-3) 1S-2-oxa-3-oxo-6R- (3,3-ethylenedioxy-1-trans-decenyl) -7R-hydroxy-cis-bicyclo [3.3.0] octane ( Synthesis of 5): Ketal (22) (1.98 g) was used in methanol (50 ml) with potassium carbonate (0.6 g) to obtain alcohol (5).

Yield: 1.12 g 1-4) 1S-2-oxa-3-oxo-6R- (3,3-ethylenedioxy-1-trans-decenyl) -7R- (tetrapyranyloxy) -cis-bicyclo [3.3 .0] Synthesis of octane (6): Alcohol (5) (0.88g) in methylene chloride (50ml)
Tetrapyranyl ether (6) was obtained using dihydropyran and pyridinium-p-toluenesulfonic acid (catalytic amount) in the medium.

Yield: 1.07g 1-5) Synthesis of lactol (7): Tetrapyranyl ether (6) (1.07g) in toluene (2
(0 ml) in DIBAL-H. After the usual treatment, lactol (7) was obtained.

1-6) 15,15-Ethylenedioxy-20-ethyl-11R-
Synthesis of tetrapyranyloxy-PGF ₂ α (8): (4-Carboxybutyl) triphenylphosphonium bromide (4.5 g) was added to sodium methylsulfinyl carbanion to give an ylide. To this, lactol (7)
DMSO solution of was added and left at room temperature. By conventional processing,
A carboxylic acid (8) was obtained.

1-7) 15,15-Ethylenedioxy-20-ethyl-11R-
Synthesis of tetrapyranyloxy-PGF ₂ α isopropyl ester (9): Carboxylic acid (8) was converted to isopropyl ester (9) using isopropyl iodide and DBU in acetonitrile (20 ml).

Yield: 1.0 g 1-8) Synthesis of 15-keto-20-ethyl-PGF ₂ α-isopropyl ester (10): 15,15-ethylenedioxy-20-ethyl-11R-tetrapyranyloxy-PGF ₂ α-isopropyl Ester (9) (0.
195g) in acetic acid / THF / water (3/1/1) mixed solvent (15ml), 40
Hold at -50 ° C for 3 hours. The crude product obtained by concentration under reduced pressure was subjected to chromatography 1 to obtain 15-keto-20-ethyl-PGF ₂ α isopropyl ester (10) as a colorless oily substance.

Yield: 0.142 g The obtained 15-keto-20-ethyl-PGF ₂ α isopropyl ester had the following NMR and Mass.

δ: 0.87 (3H, t, J = 6Hz), 1.10 (6H, d, J = 7Hz), 1.05〜
2.65 (26H, m), 4.05 (1H, m), 4.19 (1H, m), 4.96 (1H, h)
ept, J = 6Hz), 5.34 (2H, m), 6.12 (1H, d, J = 16Hz), 6.
65 (1H, dd, J = 16Hz, J = 9Hz) Mass (EI) m / z 422 (M +), 404 (M + -H 2 O), 386 (M + -2
H ₂ O), 360,345 (2) Synthesis of 15-keto-20-ethyl-PGE ₂ isopropyl ester (12) 2-1) 15,15-Ethylenedioxy-20-ethyl-11R-
Synthesis of (2-tetrapyranyloxy) -PGE ₂ isopropyl ester (11): 15,15-ethylenedioxy-20-ethyl-11R- (2-tetrapyranyloxy) -PGF ₂ α isopropyl ester (9) (0.311 g) was subjected to Jones oxidation in acetone (15 ml) at -40 ° C to give 15,15-ethylenedioxy-20-ethyl-11R- (2-tetrapyranyloxy) -PGE ₂ isopropyl ester (11). Obtained.

Yield: 0.245 g 2-2) Synthesis of 15-keto-20-ethyl-PGE ₂ isopropyl ester (12): Compound (11) (0.240 g) was mixed with acetic acid / THF / water (3/1/1) mixed solvent ( 15 ml) and kept at 35-45 ° C for 2 hours. The crude product obtained by concentration under reduced pressure was chromatographed 1, colorless oily substance 15
-Keto-20-ethyl-PGE ₂ isopropyl ester (12)
Got

Yield: 0.148 g The NMR and Mass of the obtained 15-keto-20-ethyl-PGE ₂ isopropyl ester are shown below.

δ: 0.87 (3H, t, J = 6Hz), 1.20 (6H, d, J = 6Hz), 1.03〜
2.95 (25H, m), 4.01 to 4.38 (1H, m), 4.94 (1H, hept, J =
6Hz), 5.32 (2H, m), 6.21 (1H, d, J = 16Hz), 6.71 (1H, d
d, J = 16Hz, J = 8Hz) Mass (EI) m / z 420 (M +), 402 (M + -H 2 O), 343 (M + -2
_{H 2 O-i-C 3} H 7) (3) see Synthesis (Synthesis Chart II of 15-keto-20-ethyl-PGA ₂ isopropyl ester (23)): 3-1) 1S -2- oxo -6R- (3S-hydroxy-1-
Synthesis of trans-decenyl) -7R- (4-phenylbenzoyloxy) -cis-bicyclo [3.3.0] octane (13): α, β-unsaturated ketone (3) (3.03g) in dry THF (7m
l) and dissolved in a mixed solvent of dry methanol (60 ml), cerium chloride (2.38 g) was added, and the mixture was stirred at -20 ° C for 10 minutes, sodium borohydride (0.249 g) was added, and the mixture was stirred for 5 minutes. The crude product obtained after the usual treatment was chromatographed.

Yield: 1.18 g 1.39 g of a mixture of 3S-hydroxy form and 3R-hydroxy form was Jones-oxidized to recover an α, β-unsaturated ketone (3) and reduced again. This reaction was repeated to obtain 4.58 g of 3S-hydroxy compound (13) in total.

3-2) Synthesis of tetrapyranyl ether (14): Alcohol (13) (4.58 g) was added to dry dichloromethane (100
dihydropyran and p-toluenesulfonic acid (catalytic amount) in (ml) to give tetrapyranyl ether (14).

Yield: 5.03 g 3-3) 1S-2-oxa-3-oxo-6R- [3S- (2
-Tetrapyranyloxy) -1-trans-decenyl]
Synthesis of -7R-Hydroxy-cis-bicyclo [3.3.0] octane (15): Tetrapyranyl ether (14) (5.03g) in dry methanol (300ml) was added potassium carbonate (1.49g) and room temperature was adjusted to 6 The mixture was stirred for an hour and treated by a conventional method to obtain an alcohol derivative (15).

Yield: 3.25g 3-4) Synthesis of lactol (16): DIBA of alcohol (15) in toluene (60ml) at -78 ° C.
Reduction with L-H gave lactol (16).

3-5) Synthesis of 15α- (2-tetrapyranyloxy) -20-ethyl-PGF ₂ α (17): A solution of (4-carboxybutyl) triphenylphosphonium bromide (13.5g) in DMSO was added to methylsulfinylcarbanion. In addition, the ylide was adjusted. A DMSO solution of lactol (16) was added thereto, and the mixture was left at room temperature overnight. By conventional treatment, 15α- (2-tetrapyranyloxy) -20-
Ethyl-PGF ₂ α (17) was obtained.

Yield: 4.53 g 3-6) Synthesis of 15S- (2-tetrapyranyloxy) -20-ethyl-PGF ₂ α isopropyl ester (18): Carboxylic acid (17) (2.8 g) in acetonitrile (50 ml)
Medium isopropyl iodide (2.5 g) and DBU (1.1 g) were used and the temperature was kept at 45 ° C. for 5 hours to obtain isopropyl ester (18).

Yield: 1.0 g 3-7) 15S- (2-tetrapyranyloxy) -20-ethyl-11R- (t-butyldimethylsilyloxy) -PGF
₂ Synthesis of α-isopropyl ester (19): Diol (18) (0.37 g) was added to silyl ether (19) using t-butyldimethylsilyl chloride (0.132 g) and imidazole (0.0594 g) in DMF (3 ml). did.

Yield: 0.26g 3-8) 15S- (2-tetrapyranyloxy) -11R-
Synthesis of (t-butyldimethylsilyloxy) -PGE ₂ α isopropyl ester (20): Silyl ether (19) (0.302 g) in acetone (20 ml)
Jones oxidize at -40 to -35 ° C.

Yield: 0.27g 3-9) 20-ethyl-PGA ₂ isopropyl ester (22)
And synthesis of 20-ethyl-PGE ₂ isopropyl ester (21): 15S- (2-tetrapyranyloxy) -11R- (t-butyldimethylsilyloxy) -PGE ₂ α isopropyl ester (20) (0.27 g) Dissolved in 70% acetic acid (23 ml), 65 ℃
Kept for 15 hours. The crude product obtained by concentration under reduced pressure was chromatographed.

Yield: (22) 0.080 g, (21) 0.040 g 3-10) Synthesis of 15-keto-20-ethyl-PGA ₂ isopropyl ester (23): 20-Ethyl-PGA ₂ isopropyl ester (22) (0.025)
g) was subjected to Jones oxidation in acetone (5 ml) at -40 to -35 ° C to obtain a colorless oily substance, 15-keto-20-ethyl-PGA ₂ isopropyl ester.

Yield: 0.023 g The NMR of the obtained 15-keto-20-ethyl-PGA ₂ isopropyl ester is shown below.

δ: 0.87 (3H, t, J = 5.5Hz), 1.22 (6H, d, J = 7Hz), 1.03
~ 2.75 (21H, m), 3.35 (1H, m), 4.96 (1H, hept, J = 7H
z), 5.37 (2H, m), 6.12 (1H, d, J = 16Hz), 6.23 (1H, d, J
= 6Hz), 6.69 (1H, dd, J = 16Hz, J = 7.5Hz), 7.46 (1H, d
d, J = 6 Hz, J = 2.5 Hz) In the above test, ¹ H NMR was measured using a Hitachi NMR spectrometer (R-90H, solvent: deuterated chloroform). Mass was measured using a Hitachi mass spectrometer (M-80B, EI method: ionization voltage, 70 eV).

Test example To measure intraocular pressure, Japanese white male rabbits (body weight 2.5-3.0
(kg) was fixed to a fixture and anesthetized with 0.4% oxyprocaine hydrochloride, and then the intraocular pressure was measured using a pneumatic pressure flat type electronic tonometer manufactured by Alcon Japan. A solution of the test drug suspended in physiological saline was instilled into one eye at 50 μm, the intraocular pressure was measured, and the intraocular pressure drop (%) of each test drug was determined. At the same time, the degree of redness in the eyes was observed. The results are shown in Table-1.

* Degree of hyperemia-: Almost none ±: Very weak hyperemia +: Weak hyperemia ++: Clear hyperemia +++: Severe hyperemia Test drug 1.15-keto-20-ethyl-PGF ₂ α 2.15-keto-20-ethyl-PGF ₂ α isopropyl ester 3.15-keto-20-ethyl-PGE ₂ isopropyl ester 4.15-keto-20-ethyl-PGA ₂ isopropyl ester 5.15-keto-PGF ₂ α 6.15-keto-PGE ₂ 7.PGF ₂ α 8.PGF ₂ α isopropyl ester 9.PGE ₂ EFFECTS OF THE INVENTION The Δ ¹³ -15-keto-20-substituted-PGs of the present invention have an excellent intraocular pressure-lowering effect and are free from unfavorable side effects such as hyperemia, closed eyes, and tear eyes, which are observed in conventional PGs. Or significantly reduced. Therefore, it is useful as an intraocular pressure-lowering agent and a therapeutic agent for glaucoma.

Claims (9)

[Claims] 1. A Δ in which a carbon atom at the 20-position is substituted with a hydrocarbon group.
An intraocular pressure-lowering agent containing ^13-15 -keto-prostaglandins as an active ingredient. 2. A carbon atom at position 20 is substituted with a hydrocarbon group.
^13-15 -keto-PGs have the general formula: [Where A is (Wherein R represents a hydroxyl group, a hydroxyalkyl group or an alkyl group); Y represents a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (a part of the carbon atoms constituting the hydrocarbon chain is a carbonyl group; And the hydrocarbon chain may be substituted with a halogen atom or an alkyl group); Z is an aliphatic hydrocarbon which may have a saturated or unsaturated side chain having 1 to 10 carbon atoms. Groups, alicyclic groups, aliaromatic groups, and hydrocarbon groups constituting the aromatic groups (the hydrocarbon groups may be substituted by groups or atoms); Alternatively, the intraocular pressure-lowering agent according to claim 1, which is a physiologically acceptable salt or ester thereof. 3. The intraocular pressure-lowering agent according to claim 1 or 2, wherein the carboxyl group at the α chain terminal of Δ ¹³ -15-keto-prostaglandins is alkyl esterified. 4. The intraocular pressure-lowering agent according to claim 3, wherein the alkyl ester is isopropyl ester. 5. The intraocular pressure-lowering agent according to claim 1 or 2, wherein the hydrocarbon group is a saturated or unsaturated alkyl group which may have a side chain having 1 to 4 carbon atoms. 6. The intraocular pressure-lowering agent according to claim 1, wherein the Δ ¹³ -15-keto-prostaglandins are Δ ¹³ -15-keto-prostaglandins A. 7. The intraocular pressure-lowering agent according to claim 1, wherein the Δ ¹³ -15-keto-prostaglandins are Δ ¹³ -15-keto-prostaglandins E. 8. The intraocular pressure-lowering agent according to claim 1, wherein the Δ ¹³ -15-keto-prostaglandins are Δ ¹³ -15-keto-prostaglandins F. 9. A Δ in which a carbon atom at the 20-position is substituted with a hydrocarbon group.
^A therapeutic agent for glaucoma containing ^13-15 -keto-prostaglandins.