DE4229051A1 - Pharmaceutical prepns. for treatment of elevated intraocular pressure - contg. 9-chloro-prostaglandin derivs. - Google Patents

Abstract

The following are claimed: pharmaceutical prepns. for treatment of elevated intraocular pressure comprising one or more 9-chloro-prostaglandin derivs. of formula (I), or their cyclodextrin clathrates X = O or CH2; R1 = COOR2 or CONHR3; R2 = an opt. substd. 1-10C alkyl, 3-10C cycloalkyl, 6-10C aryl or 6-10C aryl (1-4C) alkyl gp.; R3 = an opt. substd. 1-10C alkyl gp.. Also claimed are the cpds. (5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-entanor-5,13-prostadienoic acid- phenacyl ester, (5Z,13E)-(9R,11R,15S)-9-chloro-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13-prostadienoic acid(3-hydroxypropyl)amide, and the corresp. 3-oxa cpds.. Dosage is esp. 5-500ng/cm2, or 1-100ng/cm2 for treatment of elevated intraocular pressure. USE/ADVANTAGE - The new cpds. are also useful, e.g, for treatment of ulcers or hypertension, or for inhibition of gastric acid secretion or platelet aggregation. They also has a cytoprotective effect. Admin. is esp. in the form of a plaster, salve, soln., cream of lotion. (I) are stabler, and have longer and more specific activity than corresp. natural prostaglandins.

Description

The present invention relates to esters and amides of 9-chloro-prostaglandinana loga and pharmaceutical preparations containing it. 9-chloro prostaglandin analogues are pharmacologically and medically valuable active ingredients, their manufacture and application z. B. for cytoprotection, ulcer healing, inhibition of Gastric acid secretion, luteolysis, lowering blood pressure, or inhibiting platelet aggregation in EP 299 914 and WO 86/05488 are described. These substances possess against the a corresponding natural prostaglandins with a similar spectrum of activity improved specificity and effectiveness.

It has now been found that esters or amides of 9-chloro-Δ ⁵ - or 9-chloro-3-oxa-Δ ⁵ - prostaglandins are particularly suitable for external use, in particular for the treatment of increased intraocular pressure (glaucoma). This application is not mentioned in the prior art mentioned above.

The invention relates to pharmaceutical preparations containing esters and amides of 9-chloro Formula I prostaglandins

wherein
X is oxygen or CH ₂ ,
R ¹ COOR ²
where R ^{2 is} an optionally substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ ar (C ₁ -C ₄ ) alkyl Represents rest
or CONHR ³ with R ³ as an optionally substituted C ₁ -C ₁₀ alkyl radical,
mean for the treatment of increased intraocular pressure as well as the connections
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor-5,13-prostadienoic acid phenacylester,
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor-5,13-prostadienoic acid- (3- hydroxypropyl) amide,
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11.15-dihydroxy-16-, 17.18, 19.20-pen tanor-5.13- prostacylic acid and
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11.15-dihydroxy-16-, 17.18, 19.20-pen tanor-5.13- prostadienoic acid (3-hydroxypropyl) amide
as medically valuable active ingredients for use for. B. the treatment of increased intraocular pressure, cytoprotection, ulcer healing, inhibition of gastric acid secretion, luteolysis, lowering blood pressure or inhibiting platelet aggregation.

As alkyl groups R ² straight or branched alkyl groups with 1-10 C atoms are to be considered, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, decyl. The alkyl groups R ² can optionally be substituted several times by halogen atoms, hydroxyl groups, alkoxy groups, dialkylamino and trialkylammonium groups, or optionally substituted aryl or aroyl groups. Examples of substituents are fluorine, chlorine or bromine, hydroxy, methoxy, ethoxy, dimethylamino, diethylamino, trimethylammonium, phenyl, benzoyl, bromobenzoyl, iodobenzoyl, methylbenzoyl. As preferred alkyl groups R ² are those with 1-5 carbon atoms, such as. As methyl, ethyl, propyl, isobutyl, butyl, tert-butyl and fluorine, hydroxy, methoxy and benzoyl as preferred substituents. Particularly preferred substituents are hydroxy and benzoyl.

Suitable aryl groups R ² are both substituted and unsubstituted aryl groups, such as, for example, phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, one phenyl group, 1-3 alkyl groups, each with 1-4 C. - Atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxyl or alkoxy group with 1-4 carbon atoms. The substituents in the 3 and 4 position on the phenyl ring are preferred, for example by fluorine, chlorine, alkoxy or trifluoromethyl or in the 4 position by hydroxy.

The benzyl group is preferred as the aralkyl group R ² .

The cycloalkyl group R ² can contain 3-10, preferably 5 and 6 carbon atoms in the ring. The rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.

The alkyl groups R ³ are straight-chain or branched alkyl groups with 1-10 C atoms, such as methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, decyl. The alkyl groups R ³ can optionally be mono- to polysubstituted by halogen atoms, hydroxyl groups, alkoxy groups, optionally substituted aryl groups. Examples of substituents are fluorine, chlorine or bromine, hydroxy, methoxy, ethoxy, phenyl. As preferred alkyl groups R ³ are those with 1-5 carbon atoms, such as. As methyl, ethyl, propyl, isobutyl, butyl, and fluorine, hydroxy and methoxy as preferred substituents.

The invention further relates to a process for the preparation of the new esters and amides of the 9- Chlorine prostaglandin analogs of formula I, characterized in that

• a) a compound of formula II wherein
  X has the meaning given above,
  with the addition of a suitable base with an optionally substituted haloaceto phenone derivative of the general formula III where R ^{4 is} CH ₃ , bromine, iodine and Hal are chlorine or bromine,
  in a polar solvent to give compounds of the general formula (Ia) or
• b) an alkyl ester of the general formula Ib wherein
  X has the meaning given above,
  without solvent with an amine of the general formula IVH₂N-R³ (IV) to give compounds of the general formula Ic implements.

As a base for the reaction of compounds of general formula II with compounds general formula III are the bases known to the person skilled in the art, e.g. B. triethylamine, Diisopropylethylamine, diazabicycloundecene, diazabicyclononane, N, N-dimethylaminopyri din, potassium carbonate or cesium carbonate particularly suitable.

The reaction can be carried out in all polar solvents, e.g. B. acetone acetonitrile, dimethyl formamide, or dimethyl sulfoxide.

The introduction of the ester group CO ₂ R ² for R ¹ , in which R ^{2 represents} an alkyl group with 1-10 C atoms, takes place according to the methods known to the person skilled in the art. The carboxyver compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. The esterifications with diazo hydrocarbons take place, for. Example, that a solution of the diazo hydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in a different solvent, such as. B. methylene chloride mixed. When the reaction has ended in 1 to 30 minutes, the solvent is removed and the ester is purified in the customary manner. Diazoal kane are either known or can be prepared by known methods [Org. Reactions Vol. 8, pages 389-394 (1954)].

The introduction of the ester group CO ₂ R ² for R ¹ , in which R ^{2 represents} an alkyl group with 1-10 C atoms, which can optionally also be substituted, is carried out according to methods known to the person skilled in the art. The carboxy compounds are, for example, with the corresponding alkyl halide, preferably alkyl bromide or alkyl iodide, in the presence of a base such as triethylamine, diazabicylononane (DBN), diazabicycloundecane (DBU) in an inert solvent such as acetonitrile, tetrahydrofuran, methylene chloride or dimethylformamide at temperatures between -80 ° C and 100 ° C, preferably before at 0 ° C to 30 ° C, esterified.

The synthesis of the phenacyl esters (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid phenacyl ester and (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-, 20-pentanor-5,13- Phenyl prostadienoate in Examples 4 and 9 is generally applicable as a method ren for the production of phenacyl esters of 9-chloro-prostaglandin derivatives.  

Especially esters of tertiary alcohols are made from the carboxy compound in an inert solvent solvent preferably methylene chloride with acid catalysis and boron trifluoride etherate the corresponding alkene at temperatures between -100 ° C and + 50 ° C, preferably between -78 ° C and 0 ° C. Orthophos is preferred for acid catalysis phosphoric acid used.

The introduction of the ester group CO ₂ R ² for R ¹ , in which R ^{2 represents} a substituted or unsubstituted aryl group, is carried out according to the methods known to the person skilled in the art. For example, the carboxy compounds with the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine, DMAP, triethylamine, diazabicyclononane (DBN), diazabicycloundecane (DBU), in an inert solvent. Suitable solvents are methylene chloride, ethylene chloride, chloroform, ethyl acetate, tetrahydrofuran, preferably chloroform. The reaction is carried out at temperatures between -30 ° C and + 50 ° C, preferably at temperatures between 0 ° C and room temperature.

The introduction of the amide group CONHR ³ for R ¹ is preferably carried out from the ester group by aminolysis with the corresponding amine R ³ NH ₂ , ie the corresponding ester is preferably without a solvent or in an inert solvent, such as acetonitrile or dimethylformamide, with the corresponding amine for heated for several hours between 40 ° C and 140 ° C, preferably 60 ° C to 90 ° C.

The synthesis of the amides (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13-prostadienoic acid- (3-hydroxypropyl) -amide and (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19-, 20-pentanor-5,13- prostadienoic acid (3-hydroxypropyl) amide in Examples 5 and 10 is generally applicable as a process for the preparation of the amides of 9-chloro-prostaglandin derivatives.

The starting materials required for the synthesis of the esters and amides are as above to obtain documents from EP 299 914 and WO 86/05488.

Cyclodextrin clathrates can be obtained analogously to a regulation in WO 87/05294.

The esters and amides of 9-chloro-prostaglan prepared according to this invention Din analogues are chemically stable PGD derivatives. They are valuable pharmaceuticals because they are with a similar spectrum of activity a much improved (higher specificity) and before all have a much longer effect than the corresponding natural prostaglan dine.  

The new esters and amides:
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor-5,13-prostadienoic acid phenacylester,
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor-5,13-prostadienoic acid- (3- hydroxypropyl) amide,
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20-pentanor-5,13-prostadienoic acid phenacylester and
(5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20-pentanor-5,13-prostadienoic acid - (3-hydroxypropyl) amide
can also be used in combination, e.g. B. with β-blockers, diuretics. Phosphodiesterase inhibitors, calcium antagonists, thromboxane antagonists, thromboxane synthetase and cyclooxy genase inhibitors, anticoagulants, as well as fibrinolytics, leukotriene antagonists, leukotriene synthetase inhibitors and antigestagens can be used.

In rabbits, local application of the compounds causes the eye to lower pressure. In monkeys with experimental glaucoma, local application of the Compounds normalize the pathologically increased intraocular pressure.

The single dose of the compounds is 1 ng - 100 µg / eye, once or several times a day, when administered locally to the human patient.

Solutions, lotions or ointments, for example, are suitable for local application.

The invention also relates to medicaments based on the compounds of the formula I, and their cyclodextrin clathrates, with the usual auxiliaries and carriers.

The active compounds according to the invention are intended to be used in conjunction with those known in galenics and usual auxiliaries, e.g. B. increased for the preparation of preparations for treatment Serve intraocular pressure.

The following examples are intended to explain the invention in more detail without restricting it should be made.  

Examples example 1 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor- 5,13-prostadienoic acid methyl ester

To a solution of 27 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid in 10 ml of methylene chloride is added dropwise at 0 ° C under argon an ethereal diazomethane solution until the color changes to yellow, the mixture is stirred for 5 minutes at 0 ° C and then concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 24 mg of the title compound is obtained as a colorless oil.
IR (CHCl ₃ ): 3610, 3420 (br.), 3030, 3002, 2931, 2857, 1732, 1447, 1435, 1365, 1314, 1230 (br.), 1083, 995, 970 cm ^-1 .

Example 2 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor- 5,13-prostadienoic acid ethyl ester

To 250 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor-5,13-prostadienoic acid 6.25 ml of a solution of acetonitrile, diazabicyclo undecane (DBU) and iodoethane (50 ml of acetonitrile, 0.8 ml of DBU, 0.8 ml of iodoethane) and stirred for 22 hours at 24 ° C under argon. Then diluted with 150 ml of ethyl acetate, washed once with 5% sodium hydrogen carbonate solution, three times with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 129 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3608, 3410 (br.), 3020, 3000, 2980, 2928, 2857, 1726, 1450, 1376, 1245, 1095, 1085, 973 cm ^-1 .

Example 3 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor- 5,13-isopropyl prostadienate

To 100 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13-prostadienoic acid are added 2.5 ml of a solution of acetonitrile, diazabicyclo undecane (DBU) and 2-iodopropane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml 2-iodopropane) and stirred for 22 hours at 24 ° C under argon. Then it is diluted with 70 ml of ethyl acetate, washed twice with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as eluent, 50.1 mg of the title compound is obtained as a colorless oil.
IR (CHCl ₃ ): 3609, 3415 (br.), 3030, 3000, 2983, 2928, 2857, 1723, 1453, 1377, 1247, 1207, 1085, 973 cm ^-1 .

Example 4 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyciohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor- 5,13-prostadienoic acid phenacylester

To a solution of 100 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid and 75 mg of ω-bromoacetophenone in 2.6 ml of acetonitrile are added 0.057 ml of triethylamine in 1.25 ml of acetone and then stirred for 18 hours at 24 ° C under argon. Another 40 mg of ω-bromoacetophenone are then added and the mixture is stirred for a further 16 hours at 24 ° C. under argon. Then diluted with 80 ml of vinegar, washed once with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as eluent, 114 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3607, 3400 (br.), 3065, 3030, 3003, 2928, 2857, 1742, 1705, 1600, 1450, 1376, 1155, 1084, 1002, 972 cm ^-1 .

Example 5 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11,15-dihydroxy-16,17,18-, 19,20-pentanor- 5,13-piostadienoic acid (3-hydroxypropyl) amide

86.4 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11.15-dihydroxy-16.17, 18-, 19.20-pentanor-5.13-prostadienoic acid methyl ester from example 1 are mixed with 157.3 mg of 3-amino-1-propanol and stirred for 24 hours at 80 ° C. under argon. The reaction mixture is purified by column chromatography on silica gel. With CH ₂ Cl ₂ / 0-50% methanol as the eluent, 30.5 mg of the title compound are obtained as a colorless oil.
IR (liquid cap.): 3310 (br.), 3100, 3008, 2927, 2853, 1643, 1630, 1553, 1448, 1348, 1260, 1080, 1072, 1003, 970 cm ^-1 .

Example 6 (5Z.13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid methyl ester

To a solution of 300 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor- 5,13-prostadienoic acid in 30 ml of methylene chloride is added dropwise at 0 ° C. under argon to an ethereal diazomethane solution until the color changes to yellow, the mixture is stirred at 0 ° C. for 10 minutes and then concentrated in vacuo. The residue thus obtained is purified by chromatography on silica gel. With hexane / 0-80% ethyl acetate, 235 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3607, 3408 (br.), 3033, 3000, 2927, 2854, 1752, 1450, 1442, 1377, 1347, 1280, 1123, 997, 973 cm ^-1 .

Example 7 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid ethyl ester

To 92 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid is added 2.3 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and iodoethane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml iodoethane) and stirred for 18 hours at 24 ° C under argon. Then again 0.73 ml of a solution of 100 mg DBU in 10 ml acetonitrile was added and the mixture was stirred for a further 20 hours at 24 ° C. under argon. Then diluted with 70 ml of ethyl acetate, washed once with 10 ml of a 5% sodium hydrogen carbonate solution, three times with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo a. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 75.5 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3605, 3415 (br.), 3030, 2997, 2985, 2926, 2853, 1745, 1447, 1380, 1300, 1273, 1125, 1020, 997, 972 cm ^-1 .

Example 8 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid isopropyl ester

To 190 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16,17,18,19,20-pentanor-5,13 -prostadienic acid is added 4.7 ml of a solution of acetonitrile, diazabicycloundecane (DBU) and 2-iodopropane (50 ml acetonitrile, 0.8 ml DBU, 0.8 ml 2-iodine propane) and stirred for 18 hours at 24 ° C under argon. Then diluted with 70 ml of ethyl acetate, washed twice with 20 ml of a mixture of saturated sodium chloride solution and water (1: 1), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 83.1 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3605, 3410 (br.), 3030, 3000, 2983, 2925, 2853, 1738, 1448, 1376, 1125, 1102, 997, 973 cm ^-1 .

Example 9 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid phenacylester

To a solution of 92 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-di hydroxy-16,17,18,19,20-pentanor -5,13-prostadienoic acid and 105 mg ω-bromoacetophenone in 2.5 ml acetonitrile are added 0.052 ml triethylamine in 1.0 ml acetone and then stirred for 18 hours at 24 ° C under argon. Then diluted with 60 ml of ethyl acetate, washed twice with 10 ml of a mixture of saturated sodium chloride solution and water (1: 1), dry over sodium sulfate and concentrated in vacuo. The crude product is purified by column chromatography on silica gel. With hexane / 0-80% ethyl acetate as the eluent, 82.6 mg of the title compound are obtained as a colorless oil.
IR (CHCl ₃ ): 3605, 3410 (br.), 3030, 2998, 2927, 2853, 1763, 1730, 1704, 1600, 1450, 1375, 1245, 1190, 1180, 1127, 1000, 972 cm ^-1 .

Example 10 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid (3-hydroxypropyl) amide

80 mg (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy- 16,17,18,19,20-pentanor-5,13- Methyl prostadienate from Example 6 are mixed with 149.7 mg of 3-amino-1-propanol and stirred for 24 hours at 80 ° C. under argon. The reaction mixture is purified by column chromatography on silica gel. With CH ₂ Cl ₂ / 0-50% methanol as the eluent, 49.6 mg of the title compound are obtained as a colorless oil. IR (liquid cap.): 3362 (br.), 3023, 2928, 2854, 1657, 1543, 1450, 1335, 1304, 1273, 1102, 1006, 972 cm ^-1 .

Example 11 (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11.15-dihydroxy-3-oxa-16-, 17.18, 19.20- pentanor-5,13-prostadienoic acid tert-butyl ester

To a solution of 2.54 g (5Z, 13E) - (9S, 11R, 15S) -15-cyclohexyl-9-hydroxy-3-oxa-11,15- bis- (tetrahydropyran-2-yloxy) -16, 17,18,19,20-pentanor-5,13-prostadienoic acid tert-butyl ester in 25 ml pyridine are 773 mg methanesulfonyl chloride at 0 ° C. The mixture is stirred for 4 hours at 20 ° C. and then the solution is added to a suspension of 25.37 g of tetrabutylammonium chloride in 20 ml of toluene. After stirring for 15 hours at 0 ° C., stirring is continued at 40 ° C. for 7 hours. Then it is added to 250 ml of ice water and extracted three times with 100 ml of ether. After washing the organic phase twice with 40 ml of saturated sodium chloride solution, drying over magnesium sulfate and evaporating in vacuo, a residue is obtained which is chromatographed on silica gel with hexane / 0-40% ether. 2.32 g of oily (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15cyclohexyl-3-oxa-11,15-bis- (tetrahydropyran-2-yloxy) -16,17,18 are kept , 19,20-pentanor-5,13-re-tert-butyl prostadienoate. To remove the protective groups, the ester obtained is stirred with 85 ml of a mixture of acetic acid / water / tetrahydrofuran (65/35/10) at 20 ° C. for 24 hours. After adding toluene and evaporating the solution in vacuo, the residue is chromatographed on silica gel. With methylene chloride / 0.5% acetone as the eluent, 915 mg of the title compound are obtained as a colorless oil.
IR (CHCI ₃ ): 3605, 3410, 2928, 1742, 1020, 974 cm ^-1 .

Claims (8)

1. Pharmaceutical preparations for the treatment of increased intraocular pressure, characterized in that they contain one or more 9-chloro-prostaglandin derivatives of the general formula I. wherein
X is oxygen or CH ₂ ,
R ¹ COOR ² ,
where R ^{2 is} an optionally substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ ar (C ₁ -C ₄ ) alkyl Represents rest
or CONHR ³ with R ³ as an optionally substituted C ₁ -C ₁₀ alkyl radical,
mean, or contain their cyclodextrin clathrates. 2. Use of 9-chloro-prostaglandin derivatives according to claim 1 for the production a medicine to treat increased pressure in the eye. 3. A process for the preparation of pharmaceutical preparations for the treatment of increased intraocular pressure, characterized in that they contain one or more 9-chloro prostaglandin derivatives of the general formula I. wherein
X is oxygen or CH ₂ ,
R ¹ COOR ² ,
where R ^{2 is} an optionally substituted C ₁ -C ₁₀ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl or C ₆ -C ₁₀ ar (C ₁ -C ₄ ) alkyl Represents rest
or CONHR ³ with R ³ as an optionally substituted C ₁ -C ₁₀ alkyl radical,
mean, or contain their cyclodextrin clathrates. 4. (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11.15-dihydroxy-16.17, 18-, 19.20- pentanor-5,13-prostadienoic acid phenacylester. 5. (5Z, 13E) - (9R, 11R, 15S) -9-chloro-15-cyclohexyl-11.15-dihydroxy-16.17, 18-, 19.20- pentanor-5,13-prostadienoic acid (3-hydroxypropyl) amide. 6. (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid phenacylester. 7. (5Z, 13E) - (9R, 11R, 15S) -9-chloro-3-oxa-15-cyclohexyl-11,15-dihydroxy-16-, 17,18,19,20- pentanor-5,13-prostadienoic acid (3-hydroxypropyl) amide. 8. Pharmaceutical preparations containing one or two compounds according to claim 4 to 7 or their cyclodextrin clathrates.