JPH0296528A - Intraocular pressure depressing agent - Google Patents

Abstract

PURPOSE:To obtain an intraocular depressing agent containing a specific 15-keto- prostaglandin as active ingredient, useful as a remedy for glaucoma being free from side effects such as afflux, closure of eye and flowing of tears or reduced in side effects. CONSTITUTION:The aimed intraocular pressure depressing agent containing 15-keto-prostaglandins (hereinafter referred to as 15-keto-20-substituted PGs) as active ingredients. Intraocular pressure depressing action of 15-keto-20- substituted-PGs is especially remarkable in PGs expressed by formula I (A is formula II, etc.; Y is 2-6C hydrocarbon chain; Z is 1-10C aliphatic hydrocarbon, alicyclic hydrocarbon, etc.) and salt thereof or the above-mentioned PGs whose carboxyl groups are esterified. As the esterified substance, especially 1-4C alkyl ester, more especially isopropyl ester is preferably used.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to 15
-Relating to an ocular hypotensive agent and a glaucoma treatment containing keto-prostaglandins.

Background Art Prostaglandins (hereinafter referred to as PGs) are the name given to a group of fatty acids that are contained in human and animal tissues and organs and exhibit various physiological actions. PGs have a basic skeleton of brostanoic acid represented by the following formula, but synthetic products also include those with modifications to the above skeleton.

PGs are classified into the following groups depending on their five-membered ring structure. In addition, PG, which is a bond, class: 5-6 carbon bond is a single H and 5-6 carbon is a double bond, class: Kaba Furthermore, carbon at 5-6 position and carbon at 17-18 position PG, each of which is a double bond, is classified into Class: PG.

PGs have various pharmacological and physiological effects,
Examples include vasodilation, inflammatory action, platelet aggregation action, uterine muscle contraction action, and intestinal tract contraction action, but since PGs have various actions at the same time, there are problems in their use as medicines. That is, when PGs are administered with one effect as a medicinal effect, since they also simultaneously have other effects, these other effects often appear as side effects. Therefore, the studies on PGs as medicines have focused on how to increase the expression of the expected main drug effect.However, these studies are still not sufficient.

Also, among the PGs, for example, PGAs, PGDs, PGE
It is known that PGFs, PGFs, and the like have an effect on lowering intraocular pressure. For example, JP-A-59-1418 discloses that PGF2α has a high intraocular pressure-lowering effect and that 15
It has been described that -keto-PGF and α have the same effect on lowering intraocular pressure, albeit to a lesser extent, and also in JP-A-63-66
Publication No. 122 states that PGA, PGB, and PGC are effective in treating glaucoma. However, when these PGs are instilled into the eyes of rabbits, etc., there is a temporary increase in intraocular pressure, and severe hyperemia in the conjunctiva and iris is observed, as well as side effects such as lacrimation, eye discharge, and eye closure. is recognized. Therefore, there are problems in using PGs as therapeutic agents for glaucoma or agents for lowering intraocular pressure.

Problems to be Solved by the Invention The present invention provides a novel PG-type ocular that does not exhibit or has significantly reduced undesirable side effects such as hyperemia and eye closure as described above, which occur when PGs are used as an intraocular hypotensive agent. The purpose is to provide a hypotensive agent.

Means for Solving the Problems The present invention provides that PGs in which the carbon atom at the 15th position forms a carbonyl group and the carbon atom at the 20th position is extended with a hydrocarbon group exhibit an excellent intraocular hypotensive effect and the above-mentioned This is based on the knowledge that side effects such as hyperemia and eye closure are significantly reduced.

That is, the present invention provides an intraocular hypotensive agent and a therapeutic agent for glaucoma, which contain as an active ingredient a 15-keto-prostaglandin in which the carbon atom at position 20 is substituted with a hydrocarbon group.

In the present invention, 15-keto PGs refer to PGs in which the carbon at the 15th position is a carbonyl group.

In this specification, 15-keto PGs are expressed by the following nomenclature. That is, 15-keto PGs are based on the following basic skeleton: 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 carbon numbers constituting the basic skeleton start with carboxyl carbon 1, and in order toward the 5-membered ring, 2 to 7 are carbons on the α chain, 8 to 12 are carbons on the 5-membered ring, and 13 to 20. However, when the number of carbon atoms decreases on the α chain, the numbers are deleted sequentially from the 2nd position, and when the number increases on the α chain, a carboxyl group (1st position) is added to the 2nd carbon. Named with a substituent in place of . When the number of carbon atoms increases due to ω rust prevention, carbon atoms after the 21st are named as substituents.

Further, regarding the steric configuration, unless otherwise specified, the steric configuration of the basic skeleton described above shall be followed.
Also, for example, PGD, PGE%PGF is ranked 9th and/or
Or, it refers to a compound having a hydroxyl group at the 11th carbon position,
In this specification, those having other groups in place of the hydroxyl group at the 9- and/or 11-position are collectively referred to as PGs, and in that case, 9-dehydroxy-9-substituted or 11-dehydroxy-11 - Naming in the form of substitutions.

The 15-keto-20-substituted PGs (hereinafter referred to as 15-keto-20-substituted PGs) in which the carbon atom at the 20th position is substituted with a hydrocarbon group used in the present invention are 15-keto-20-substituted-PG, in which the carbon bond is a single bond;
15-keto-20-substituted-PG, which is a double bond, 5
It may be any of the 15-keto-20-substituted-PGs in which the carbon bond at the -6-position and the carbon bond at the 17-18th position are double bonds.

PGs are PGA, PGA2, PGA, PGB, P
GB,,PGB,,PGC,,PGC,,PGC,,P
GD,,PGD2,PGD,,PGE,,PGE,,P
GE,,PGF,,PGF2,PGF,,PGJ,,P
Basic compounds such as GJ2, PGJ, and substituted products, esters, and salts thereof are included.

The 15-keto-20-substituted PGs of the present invention exhibit a strong intraocular pressure-lowering effect, and have no side effects such as severe hyperemia, eye closure, and lacrimation in the conjunctiva and iris that are observed with PGs. has been significantly reduced. Therefore, these 15-keto-20-substituted-PGs are extremely effective as intraocular hypotensive agents. Furthermore, based on such an intraocular pressure-lowering effect, it can be used as a therapeutic agent for glaucoma.

In the present invention, the intraocular hypotensive effect of 15-keto-20-substituted-PGs is particularly expressed by the general formula: [wherein A represents a hydroxyl group, a hydroxyalkyl group, or an argyl group; Y is a saturated or unsaturated hydrocarbon chain having 2 to 6 carbon atoms (some of the carbons constituting the hydrocarbon chain may form a carbonyl group, and the hydrocarbon chain is substituted with an atom or group) ); Z is a hydrocarbon constituting an aliphatic hydrocarbon group, alicyclic group, aliphatic group, or aromatic group that may have a saturated or unsaturated side chain having 1 to 10 carbon atoms; a group (the hydrocarbon group may be substituted with a group or an atom); in prostaglandins represented by 1 or physiologically acceptable salts thereof, or in which the carboxyl group is esterified; Remarkable.

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

Examples of Y being an unsaturated hydrocarbon chain include P in which the carbon bonds at the 2-3 or 5-6 positions are double or triple bonds;
Group G is exemplified.

Some of the constituent carbons of the hydrocarbon chain represented by Y may form a carbonyl group, and a typical example thereof is 6-kedo PG, in which the carbon at the 6th position forms a carbonyl group.

The hydrocarbon chain represented by Y may be substituted with atoms or groups. Examples of such atoms or groups are fluorine,
These 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 3rd carbon position.

The hydrocarbon group Z is an alkyl group which may have a side chain having 1 to 10 carbon atoms, preferably an alkyl group which may have a side chain having 1 to 4 carbon atoms, such as methyl, ethyl,
Preferred are n-propyl, isopropyl, n-butyl, t-butyl and the like, with linear ones being particularly preferred.

The omega chain may be substituted with atoms or groups. These atoms or groups include halogen atoms such as fluorine and chlorine; alkyl groups such as methyl, ethyl, isopropyl, and isopropenyl; alkoxy groups such as methoxy and ethoxy; hydroxyl groups; phenyl groups; and phenoxy groups. The position of the substituent atom or group is not limited, but may be the 16th, 17th, 19th, and/or 2nd carbon number of the ω chain.
0th place is typical. in particular in position 16 one or two identical or different atoms, e.g. halogen atoms such as fluorine or substituents, e.g. alkyl groups such as methyl, ethyl,
A phenyl group, benzyl group, phenoxy group that may have a hydroxyl group, a substituent, or a cycloalkyl group such as cyclopentyl or cyclohexyl whose member is carbon at the 16th position; an alkyl group such as methyl at the 17th or 19th position, etc. Compounds having the following are preferred.

PGs include compounds having a hydroxyl group at carbon position 9 and/or 11, such as PGD, PGE, and PGF, but in this specification, hydroxyalkyl group or Compounds having an alkyl group are also treated as being included in PGs. Therefore, the 15-keto-20-substituted-PGs of the present invention have the general formula [I]
Included are compounds in which R is a hydroxyl group, a hydroxyalkyl group, or an alkyl group. Hydroxyalkyl groups include hydroxymethyl group, l-hydroxyethyl group, 2-
Hydroxyethyl group and 1-methyl 1-hydroxyethyl group are preferred, and as the alkyl group, lower alkyl groups, particularly methyl group, ethyl group, etc. are preferred.

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

The PGs of the present invention may be in the form of salts or may have carboxyl groups esterified. Salts include physiologically acceptable salts, such as 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, dimethyl Amine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, jetanolamine, monomethylmonoethanolamine, tromethamine, lysine,
It may be a tetraalkylammonium salt or the like. Examples of esters include methyl, ethyl, propyl, butyl,
Isopropyl, t-butyl, 2-ethyl-hexyl, alkyl esters having linear or side chains that may have unsaturated bonds; esters having alicyclic groups such as cyclopropyl, cyclopentyl, cyclohexyl;
For example, esters with aromatic groups such as benzyl and phenyl (the aromatic group may have a substituent); for example, hydroxyethyl, hydroxyisopropyl, hydroxypropyl, polyhydroxyethyl, polyhydroxyisopropyl, methoxyethyl , ethoxyethyl, methoxyisopropyl, and other hydroxyalkyl or alkoxyalkyl esters; trimethylsilyl, triethylsilyl, and other alkylsilyl esters; and tetrahydropyranyl esters.

Preferred esters are, for example, methyl, ethyl, propyl,
Lower alkyl esters having a linear or side chain such as butyl, isopropyl, t-butyl; benzyl esters; hydroxyalkyl esters such as hydroxyethyl and hydroxyisopropyl.

The carboxyl group at the terminal of the α chain of the 15-keto-20-substituted-PGs in the present invention may be any of the above, but from the viewpoint of the ability to lower intraocular pressure, it is preferable to use an ester, especially a carbon Alkyl esters of numbers 1 to 4 are preferred, especially inglobil ester.

The 15-keto-20-substituted-PGs of the present invention include isomers of the above-mentioned compounds. Examples of these isomers are between the carbonyl group at position 6 and the hydroxyl group at position 9, and between the hydroxyl group at position 11 and the hydroxyl group at position 15.
ketohemiacetal tautomer between the carbonyl groups at position,
Alternatively, optical isomers, geometric isomers, etc. are exemplified.

The tautomer between the hydroxyl group at the 11th position and the carbonyl group at the 15th position is particularly 1 in 15-keto-20-substituted-PGEs.
When the 6-position has an electron-withdrawing group, for example, a fluorine atom, it is likely to be formed.

Mixtures of isomers, such as racemic and equilibrium mixtures of the keto-hemiasecur tautomer hydroxy compound and hemiacetal, also exhibit similar effects as each alone.

Particularly preferred 15-keto-20-substituted-P in the present invention
Group G is one 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 is 15-keto-20-substituted-PGs substituted with a halogen atom or an alkyl group at the 16th position.

In this specification, PGs are named based on the brostanic acid skeleton. Named based on I UPAC, for example, PGE is 7-((IR,2R,3R)-3-hydroxy-2[(E)-(3S)-3-hydroxy-1-
octenyl]-5-oxo-cyclopentyl)-hebutanoic acid; PGE, is (Z)-7-(-(IR,2R,3
R)-3-hydroxy-2-[(E)-(3S)-3-
hydroxy-1-octenyl 1-5-oxo-cyclopentyl]-hepto-5-citric acid; thus 15-keto-
20-ethyl-PGE1 is 7-((lR,2R,3R)
-3-hydroxy-2-[(E)-(3S)-3-oxo-1-decenyl]-5-oxo-cyclopentyl)-
Hebutanoic acid. Also, what about PGF and α? −[(l R
, 2R, 3R.

5R)-3,5-dihydroxy-2-((E)-(35
)-3-hydroxy-1-octenyl)-cyclopentyl]-hebutanoic acid; pGF2σ is (2)-7-[
(IR,2R,3R,5S)-3,5-dihydroxy-2-((E)-(3S)-3-hydroxy-1=octenyl)-cyclopentyl]-5-heptenoic acid:
15-keto-20-ethyl-PG F +a is 7-
[(IR,2R,3R,55)-3,5-dihydroxy-2-((E)-(3S)-3-oxo-1-decenyl)-cyclopentyl]-hebutanoic acid. Further, other PGs can be similarly named.

The 15-keto-20-R-PGs of the present invention can be produced as shown in Synthetic Char].1 and 2. That is, commercially available (-)Coley lactone is used as a starting material, and this is subjected to Collins oxidation to obtain an aldehyde, and to this, for example, dimethyl (
Reaction of a 2-oxoalkyl)phosphonate anion gives a σ,β-unsaturated ketone, which is reduced to give a ketone whose carbonyl group is protected as a ketal by reaction with a diol, and then dep. - An alcohol is obtained by phenylbenzoylation, and this newly generated hydroxyl group is protected with dihydropyran to give a tetrahydropyranyl ether. As a result, a precursor of PGs into which an ω chain has been introduced is obtained. Dimethyl (2-
The alkyl group of the oxoalkyl)phosphonate has the desired ω
It may be selected depending on the chain, and when the substituted hydrocarbon group at the 20th position is ethyl, dimethyl (2-oxononyl) phosphonate may be used.

PGs having a methyl group instead of the hydroxyl group at position 11 are:
11-dehydro-11-methyl-PG was obtained by reacting a dimethyl copper complex with the PGA type obtained by Jones oxidation of the 9-hydroxyl group of the 1l-1-sylate compound.
E type is obtained. Alternatively, the alcohol obtained after elimination of the p-phenylbenzoyl group of the above-mentioned tetrahydropyranyl ether is used as a tosylate, and this is converted into DBU
The unsaturated lactone obtained by the treatment is converted into lactol, and after introducing a σ-chain using the Wittig reaction, the resulting alcohol (9-position) is oxidized to form a PGA type, and this is reacted with a hedimethyl copper complex to form 11- Dehydroxy-11-methyl-PGE tag can be synthesized. For example, by reducing this with sodium borohydride, l
1-Dehydroxy-11-methyl-PGF type can be synthesized.

PGs having a hydroxymethyl group instead of the hydroxyl group at the 11-position can be obtained by photoadding methanol to the PGA type obtained above using benzophenone as a sensitizer. -PGE type can be synthesized. By reducing this with, for example, sodium borohydride, 11-dehydroxy-11-hydroxymethyl-PGF type can be synthesized.

16-Fluoro-PGs are dimethyl (3-fluoro-2-oxoalkyl) when obtaining α,β-unsaturated ketones.
A phosphonate anion may be used, and I9-methyl-
PGs are dimethyl (6-methyl-2-oxoalkyl)
A phosphonate anion may be used.

In the present invention, the synthesis method is not limited to this, and any suitable protection method, oxidation-reduction method, etc. may be employed as appropriate.

The 15-keto-20-substituted-PGs of the present invention may be used as drugs for animals and humans, and are generally administered systemically or locally by oral, intravenous injection, subcutaneous injection, skewering, eye drops, or eye drops. Used as an ointment. The dosage varies depending on the animal, human, age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, dextrose, human mixipro, bicellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metacalcine, etc. The acid is mixed with magnesium aluminate. The composition is prepared according to conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrillar calcium gluconate, α-, β- or γ-cyclodextrin, dimethyl- Etherified cyclodextrin such as α-dimethyl-β-, trimethyl-β- or hydroxypropyl-β-cyclodextrin, branched cyclodextrin such as glucosyl-, maltosyl-cyclodextrin, formylated cyclodextrin, sulfur-containing cyclodextrin, Stabilizers such as misoprodol and phospholipids may also be included. When the above-mentioned cyclodextrins are used, stability may be increased by forming an inclusion compound with the cyclodextrins. Furthermore, stability may be increased by forming into liposomes using phospholipids.

Tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose hetatalate, etc., or may be coated with two or more layers, if necessary. Additionally, the capsule may be made of an absorbable material such as gelatin.

Liquid compositions for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, liquid compositions, etc. Diluents such as purified water, ethanol, etc. may be included. In addition to inert diluents, the compositions may also contain adjuvants such as lubricants, suspending agents, sweeteners, flavoring agents, aromatics, preservatives, and the like.

Other compositions for oral administration include sprays containing one or more active substances and 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, and polysorbates.

Such compositions may further contain preservatives, wetting agents, emulsifying agents,
Auxiliary agents such as dispersants and stabilizers may also be included. These are sterilized, for example, by filtration through bacteria-retaining filters, by incorporation of disinfectants, by gas sterilization or by radiation sterilization. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

The eye drops according to the present invention may be sterile aqueous or non-aqueous solutions, suspensions, and the like. Diluents for aqueous solutions and suspensions include distilled water and physiological saline. Examples of diluents for non-aqueous solutions and suspensions include food oil, liquid paraffin, mineral oil, 70-pyrene glycol, and p-octyltotecanol. In addition, tonicity agents such as sodium chloride, benzalkonium chloride, fethrin chloride, propyroine chloride, chloramphenicol, and sodium citrate are used to maintain the pH constant in order to make it isotonic with the tear fluid. Buffers such as borate buffer and phosphate buffer can be used for this purpose.

Also, sodium sulfite, sodium carbonate, EDTA,
Stabilizers such as propylene glycol, thickening agents such as glycerin, carboxymethylcellulose, carboxyvinyl polymers, diluents such as polysorbate, macrogol, aluminum monostearate, preservatives such as parabens, benzyl alcohol, sorbic acid, etc. or further dissolution. It may also contain auxiliary agents and excipients. These are sterilized, for example, by filtration through a bacteria retention filter or heat sterilization. Particularly important points in the preparation of eye drops are p) (and ionic strength) of the eye drops, which may be adjusted to optimal values depending on the type and amount of the active substance or other additives used.

Eye ointments according to the invention include petrolatum, Zelen 50,
It is based on plastibase, macrogol, etc., and may contain surfactants such as polysorbate and purified lanolin, jelly agents such as carboxymethylcellulose, methylcellulose, and carboxyvinyl polymer, etc., for the purpose of increasing hydrophilicity.

The intraocular pressure-lowering agent of the present invention can be used as a glaucoma treatment by utilizing this intraocular pressure-lowering effect. When used as a treatment for glaucoma, conventional cholinergic intraocular hypotensive agents (e.g. pilocarpine, carbachol with excellent miosis effect, etc.), anticholinesterase (e.g. demecarium, D, F, P, ecothio7ate, etc.), miosis Agents include puizostigmine salicylate, vilocarpine hydrochloride, etc. Hyperosmotic agents for intravenous injection include mannitol, glycerin, isosorbite, etc. Preservatives for eye drops include chlorobutanol, benzalkonium chloride, propylparaben, methylparaben, ethylparaben, butylparaben. Penicillin, sulfa drugs, chloramphenicol, cortisone, chlorpheniramine, etc. may be added to prevent and treat other inflammatory diseases. The present invention will be explained below with reference to Examples.

1-1) Is-2-oxa-3-xo6R-(3-
Synthesis of oxo-t-trans-decenyl)-7R-(4-phenylbenzoyloxylo[3.3.0]octane (3): Commercially available (-)
-Collins oxidation of Cory lactone (1) (7 g) in dichloromethane to give 11 aldehyde (2). This was reacted with dimethyl(2-oxonyl)phosphonate (4.97g) anion and Is-2-oxa-3-oquine-6
R-(3.3-ethylenedioxy-1-trans-decenyl)-7R-(4-phenylbenzoyloxy)-cis-bicyclo[3.3.0]octane (3) was obtained.

1-2) is-2-oxa-3-oxo-6R-(3.
3-ethylenedioxy-11-lans-decenyl)-
7 R-(4-Phenylbenzoyloxy)-cis-bicyclo[3.3.01 Synthesis of octane (4): The unsaturated ketone (3X2.09) was dissolved in benzene (100 mQ), ethylene glycol (12 g), p- Toluene sulfone #
(catalytic amount) and refluxed overnight while distilling off the water produced. Chromatography (hexane/ethyl acetate = 2
/l-1/1)L, ketal (4) was obtained.

Yield: 1.98g 1-3) Is-2-oxa-3-oxo-6R-(3.
3-ethylenedioxy-1-)lans-decenyl)-7
R-Hydroxy-cis-bicyclo[3.

Synthesis of 3,01 octane (5): Mix ketal (22X1.981?) with methanol (50
Alcohol (5) was obtained using potassium carbonate (0.8 g) in m.a.

Yield: 1.129 1-4) 15-2--oxa-3-oxo-6R-(3
．． 3-ethylenedioxy-1-1-lans-decenyl)
-7R-(tetrapyranyloxy)-cis-bicyclo[
3.3. Synthesis of O]octane (6): alcohol (5)
(0.88 g) in methylene chloride (50 uQ) using dihydrobilane and pyridium-p-toluenesulfonic acid (catalytic amounts) to give tetrapyranyl ether (6).

Yield: 1.079 1-5) Synthesis of lactol (7): Tetrapyranyl ether (6X1.07g) was reduced with DI BAL-H in Toluev (20uQ). After conventional treatment, lactol (7) was obtained.

1-6) 15.15-ethylenedioxy-20-ethyl-11R-tetrapyranyloxy-PGF.

Synthesis of a(8): (4-Carboxybutyl)triphenylphosphonium bromide (4.59) was added to sodium methylsulfinyl carbanion to obtain a ylide. To this, lactol (
The DMSO solution of 7) was added, and the mixture was left at room temperature. Carboxylic acid (8) was obtained by treatment in a conventional manner.

1-7) Synthesis of 15.15-ethylenedioxy-20-ethyl-11R-tetrapyranyloxy-PGF2α isopropyl ester (9): Carboxylic acid (8) was mixed with inglovir iodide and DBU in acetonitrile (2M). was used to obtain isopropyl ester (9).

Yield: 1.09 1-8) Synthesis of 15-keto-20-ethyl-PGF, α-isopropyl ester (10): 1 5, 1 5-ethylenedioxy-20-ethyl-l IR-tetrapyranyloxy- PGFtα isoglobil ester (9X0.
195 g) was kept at 40-50° C. for 3 hours in acetic acid/THF/water (3/l/l) mixed solvent (15++o2).

Chromatography of the crude product obtained by concentration under reduced pressure - 11 15 Keto-20-ethyl-PGF, σ isopropyl ester (10) was obtained as a colorless oil.

Yield: 0.142g The NMR and mass of the obtained 15-keto-20-ethyl-PGF2α isopropyl ester were as follows.

δ: 0.87 (38, t, J=6Hz), 1.10 (
6H, d, J = 7 Hz), 1.05-2.
65 (26H, m).

4.05 (I H, m), 4.19 (I H, m), 4.
96 (IH, hept, J = 6 Hz), 5
．． 34 (2H, m), 6.12 (l H, d, J =
16Hz), 6.65 (IH, dd, J = 16
Hz, J-9Hz) Mass (E I) m/z 422 (M, 404
(M+H20), 386 (M"-2H20), 360.
342-1) 15.15-ethylenedioxy-20ethyl-+ 1R-(2-tetrapyranyloxy)PGE2
Synthesis of isopropyl ester (11) = 15.15-ethylenedioxy-20-ethyl-IIR-(2-tetrapyranyloxy)-PGF2σ1 sopropyl ester (
9X0.3119) in acetate 7 (15m(2), -4
Jones oxidation was performed at 0°C to obtain 15.15-ethylenedioxy-20-ethyl-11R-(2-tetrapyranyloxy)-PGE2 isopropyl ester (11).

Yield: 0.245g 2-2) + 5-keto-20-ethyl-PGE, synthesis of inpropyl ester (12): Compound (11X0.240g) was dissolved in acetic acid/THF/water (
3/1/l) in mixed solvent (15mff), 35-45°
It was kept at C for 2 hours. Chromatography of the crude product obtained by concentration under reduced pressure - 11 15-keto 20-ethyl-PGE2 isopropyl ester (12) was obtained as a colorless oil.

Collection fk: O, 148g The obtained 15-keto-20-ethyl-PGE.

The NMR and mass of isopropyl ester are shown below.

8: 0.87 (3H, t, J=-6Hz), 1.20
(6H, d, J = 6 Hz), I, 03~
2.95 (25H, m).

4.01-4.38 (L H, m), 4.94 (I
H, hept.

J = 6Hz), 5.32 (2H, m), 6.21 (I
H,d.

J = 16Hz), 6.71(lH
, dd, J = 1 6Hz, J = 8Hz) Mass (E I) m/z 420 (M, 402
(M”H2O), 343 (M”H2O1C3H7)
(See ■): 3-1) Synthesis of Is-2-oxo-6R-(3S-hydroquine-1-1-lans-decenyl)-7R-(4phenylbenzoylox3,01 octane (13): σ, β - unsaturated ketone (3x3.03g) in dry THF
(7 m12), dissolved in dry methanol (60 m + 2) mixed solvent, added cerium chloride (2.38 g), -20
Stir at °C for 10 min, then use sodium borohydride (0,
249 g) was added and stirred for 5 minutes. The crude product obtained after conventional work-up was chromatographed.

Yield: 1.18g 3S-hydroxy and 3R-hydroxy mixture 1.
Jones oxidation of 39g of σ,β-unsaturated ketone (
3) was collected and reduced again. Repeat this reaction, 3
A total of 4.58 g of S-hydroxy compound (13) was obtained.

3-2) Synthesis of tetrapyranyl ether (14): Alcohol (13×4.5 8g) was synthesized using dihydrobilane and I)-toluenesulfonic acid (catalytic amount) in dry dichloromethane (100+++12) ) was obtained.

Yield 1: 5.039 3-3) is-2-oxa-3-oxo-6R-[3
S-(2-tetrapyranyloxy)- 1-h lance-
Decenyl]-7 R-hydroxy-cis-bicyclo[
3.3.0] Synthesis of octane (15): Tetrapyranyl ether (14X5.0 3g) was dissolved in dry methanol (
Potassium carbonate (1.49 g) was added to the solution (1.49 g), stirred at room temperature for 6 hours, and treated in a conventional manner to obtain the alcohol (1.49 g).
5) was obtained.

Yield: 3.259 3-4) Synthesis of lactol (16): Alcohol (15) in toluene (60 mQ), -78
Reduction with DI BAL-H at °C yielded lactol (16).

3-5) +5α-(2-tetrapyranyloxy)-20
Synthesis of -ethyl-PGF2α (17): (4-carboxybutyl)triphenylphosphonium bromide (13,
A DMSO solution of 59) was added to the methylsulfinyl carbanion to prepare the ylide. This includes lactol (16
) was added to the mixture, and the mixture was left at room temperature overnight. By conventional treatment, 15 a-(2-tetrapyranyloxy)-
20-ethyl-PGFza (17) was obtained.

Yield: 4.53g 3-6) 155-(2-tetrapyranyloxy)20-
Synthesis of ethyl-PGF, α-isopropyl ester (18): Carboxylic acid (17
mQ), isopropyl iodide (2.5 g) and DBU
(1.1 g) was kept at 45°C for 5 hours to obtain isopropyl ester (18).

Yield: 1.09 3-7) 15s-(2-tetrapyranyloxy)-20
Synthesis of -ethyl-11R-(t-butyldimethylsilyloxy)-PGF2α isopropyl ester (19) Nidiol (18
and imidazole (0,0594 g) to prepare silyl ether (19).

Yield: 0.26g 3-8)l 5S-(2-tetrapyranyloxy)-1
1R-(t-butyldimethylsilyloxy)-PGE,
Synthesis of α-isopropyl ester (20): Jones oxidation of the silyl ether (19×0.302 g) in acetone (20 m<1) at −40 to −35° C.

Yield: 0.279 3-9) Synthesis of 20-ethyl-PGA2 isopropyl ester (22) and 20-ethyl-PGE2 isoglobil ester (21): 155-(2-tetrapyranyloxy)-11R-(t
-butyldimethylsilyloxy)-PGF2α isopropyl ester (20X0.27g) in 70% acetic acid C23
mQ) and kept at 65°C for 15 hours.

The crude product obtained by concentration under reduced pressure was chromatographed.

Yield: (22) 0.0809. (21) 0.040
y3-1o) Synthesis of 15-keto-20-ethyl-PGA2 isopropyl ester (23): 20-ethyl-PG
A2 isopropyl ester (22X0.0259) was Jones oxidized in acetone (5 mQ) at -40 to -35°C to give 15keto-20-ethyl-pGAt isopropyl ester as a colorless oil.

Yield: 0.023g NMR of the obtained 15-keto-20-ethyl-PGA2 isopropyl ester is shown below.

δ: 0.87 (3H, t, J=5.5Hz), l-2
2 (6H, d, J -7Hz), 1.03-2.7
5 (21H, m).

3.35 (I H, m), 4.96 (l H, hep
t, J = 7 Hz), 5.37 (2H, m), 6.1
2 (LH, d, J = 16Hz), 6.23 (IH, d,
J = 6Hz), 6.69 (IH, dd, J = 16H
z, J = 7.5Hz), 7.46 (IH, dd, J
= 6 Hz, J = 2.5 Hz) In the above test, 'HNM
R is Hitachi's family NMR spectrometer (R-90
H, solvent: deuterated chloroform). Mas
s is Hitachi Mass spectrometer (M-80
Measured using B%EI method (ionization voltage, 70 eV).

Test Example: For intraocular pressure measurement, Japanese domestic colored male rabbits (weight 2.5~
After fixing the patient (3,0 kg) in a fixator and administering ophthalmic anesthesia with 0.4% oxylbroin hydrochloride, intraocular pressure was measured using a pneumatic applanation electronic tonometer manufactured by Nippon Alcon Co., Ltd. Suspend the test drug in physiological saline in one eye; add 50μQ of the solution.
Instillation was applied to the eyes, the intraocular pressure was measured, and the degree of intraocular pressure reduction (%) of each test drug was determined.
) was sought. At the same time, the degree of bloodshot eyes was observed. The results are shown in Table-1.

*Degree of hyperemia ±: Very weak hyperemia +: Weak hyperemia +"-2 Clear hyperemia 10++: Severe hyperemia 1.15-keto-20 2,15-keto-20 Propyl ester 3.15- Keto-20 lopylester 4.15-keto-20 lopylester 15-keto-PGF2σ 15-keto-PGE2 PGF2α PGF, α isoglobil ester PGE2 Ethyl-PGF, α Ethyl-PGF2α Isoethyl-PGE2 Isopuethyl-PGA2 Imp Invented by Effects The 15-keto-20-substituted PGs of the present invention have excellent intraocular hypotensive action and also reduce hyperemia and hyperemia seen in conventional PGs.
Unfavorable side effects such as closed eyes and watery eyes are absent or significantly reduced. Therefore, it is useful as an intraocular hypotensive agent and a treatment for intraocular disease.

Claims (1)

[Scope of Claims] An intraocular hypotensive agent characterized by containing as an active ingredient 15-keto-prostaglandins in which carbon atoms at the 1st and 20th positions are substituted with hydrocarbon groups. Among 2,15-keto-prostaglandins, the first one in which the carboxyl group at the terminal of the α chain is alkyl esterified
The intraocular hypotensive agent described in Section 1. 3. The intraocular hypotensive agent according to item 2, wherein the alkyl ester is isopropyl ester. 4. The intraocular hypotensive agent according to item 1, wherein the hydrocarbon group is a saturated or unsaturated alkyl group that may have a side chain having 1 to 4 carbon atoms. 5,15-keto-prostaglandins are 15-keto-
2. The intraocular hypotensive agent according to item 1, which is prostaglandin A class. 6,15-keto-prostaglandins are 15-keto-
2. The intraocular hypotensive agent according to item 1, which is prostaglandin E class. 7,15-keto-prostaglandins are 15-keto-
2. The intraocular hypotensive agent according to item 1, which is a prostaglandin F class. A therapeutic drug for glaucoma containing 15-keto-prostaglandins in which carbon atoms at positions 8 and 20 are substituted with hydrocarbon groups.