DE2803058A1 - Prostanoic acid ergolinyl alkyl ester(s) and derivs. - with prostaglandin activity, lowering arterial blood pressure and inhibiting blood platelet aggregation - Google Patents

Abstract

Ergolin-8-yl-alkyl esters, -thioesters and -amides of prostane acids are new and are of formula (I). In (I), D is a gp. of formula (II)-(VI); A is a gp. of formula (VII) or (VIII); in which 1-3 of the CH2 gps. marked alpha, beta, gamma and gamma replaced by N and one of L and M is N and the other is CH2, or both L and M are N; and the l-membered ring in (b) is opt. mono-substd. by alkylamino, dialkylamino, alkoxy, alkylthio or halogen (all alkyl gps. having 1-5C atoms). X is -CH2-CH2- or -CH=CH- (trans); Y is -CH2-CH2 or -CH=CH- (cis or trans); Z is -CH2-CH2- or -CH - CH- (cis or trans); R1 is 1-10C alkyl or 3-9C cycloalkyl; R2 is H or 1-7C alkyl; R3 and R4 are each H, 1-20C alkanoyl; or benzoyl; W is O, S or -NH-; and R1 the alkylergolin part, is a gp. of formula (IX); n is 1 or 2; R5 is H, 1-4C alkyl or benzyl; R6 and R10 are each H or halogen; R7 is 1-4C alkyl (but not t-butyl); and R8=R9=H, or R8=H and R9 = 1-4C alkoxy, or R8 and R9 together form a bond. (I) have better pharmacological prostaglandin-like effects than the corresp. prostan acids. In partic. (I) lower arterial blood pressure.

Description

The invention relates to prostaglandins, in particular

Special ergolin-8-yl-alkyl esters, thioesters and amides of prostanoic acids.

The invention relates in particular to compounds of the formula wherein, in the prostanoic acid moiety, D is a group of the formula stands, in which A is a radical of the formula a) wherein 1 to 3 of the methine groups denoted by α, ß, # or g have been replaced by nitrogen or a radical of the formula b) denotes in which either one of the ring members L and M is nitrogen and the other is methine, or t and M each denote nitrogen, 1 to 3 of the methine groups denoted by a, ß, # or # can be replaced by nitrogen, and the six-membered group Ring unsubstituted or monosubstituted by alkylamino, dialkylarnino, alkoxy, alkylthio or halogen, the alkyl groups independently of one another have 1-5 carbon atoms, X for -CH2-CH2- or -CH = CH- (trans), Y for -CH2- CH2 - or -CH = CH- (cis or trans), Z for -CH -CH - or (cis or trans), R1 is an alkyl group with 1-10 carbon atoms or a cycloalkyl group with 3-9 carbon atoms, h is hydrogen or an alkyl group with 1-7 carbon atoms, R3 and R4 are independently hydrogen, an alkanoyl group with 1-20 carbon atoms or the benzoyl group, W denote oxygen, sulfur or the -NH group, and the alkylergoline part R denotes the remainder of the formula II where n is 1 or 2, R5 is hydrogen, an alkyl group with 1-4 carbon atoms or the benzyl group, R6 and R10 are independently hydrogen or halogen, R7 is an alkyl group with 1-4 carbon atoms, but not tert. Butyl means 1) R8 and R9 each represent hydrogen, or 2) R8 and R9 together form a bond, or 3) R8 represents hydrogen and R9 represents an alkoxy group with 1-4 carbon atoms.

In formula I, the 15-OR3 groups are in the a or p configuration and the 8-ergoline side chain in a- or p-configuration.

It should be noted that the term prostanoic acid used here includes natural or synthetic prostaglandins. The term used here Ergoline includes natural or synthetic ergoline derivatives.

If A stands for a radical of the formula å), this means, for example Pyrazolyl, imidazolyl, triazolyl, e.g. 1,2,4-triazol-1-yl, or tetrazolyl, e.g. 1,2,3,4-tetrazol-1-yl.

If A stands for a radical of the formula b), the values are preferably 0 up to 2 methine groups of the six-membered ring are replaced by nitrogen. Preferably M represents nitrogen and the remainder of the formula b) preferably represents benzimidazolyl or purinyl. The remainder of the formula b) is preferably unsubstituted and, if If this is monosubstituted, the ring substituents are preferably located in the positions CL or &. The alkyl group of the ring substituents preferably has 1-2 carbon atoms and especially represents the methyl group.

The preferred ring substituent is the dialkylamino group.

If R1 stands for an alkyl group, this preferably has 5-8 carbon atoms. The a-position can be branched. Suitable examples are the 1-pentyl, 1-heptyl, 2-methyl-2-hexyl, 2-hexyl or the 2-octyl group.

If R1 is a cycloalkyl group, this is for example for cyclopentyl or cyclohexyl, If R3 is an alkanoyl group stands, then this conveniently has 2-5 carbon atoms and means, for example, the acetyl group.

If R4 stands for an alkanoyl group, this conveniently has it 8-20 carbon atoms and is e.g.

for the n-octanoyl or lauroyl group.

If R5 is an alkyl group, this is expediently for methyl.

The alkyl group of the substituent R7 conveniently has 1-3 Carbon atoms and stands, for example, for methyl or isopropyl.

If R9 is an alkoxy group, this is expediently for methoxy.

A suitable halogen is chlorine or bromine, in particular bromine.

The following individual meanings in the prostanoic acid part are preferred: D preferably for D4 or -D6; A preferably for imidazolyl; X preferably for -CH = CH- (trans); Y is preferably -CH = CH- (cis) or -CH2-CH2-; Z preferably for -CH2-CH2 - or (trans); R1 is preferably alkyl; R2, R3 and R4 are preferably hydrogen; the -OR3 group is preferably in the α configuration; W preferably for oxygen or especially -NH-.

The following individual meanings in the alkylergoline part R are preferred: n preferably for 1; for hydrogen or methyl; for methyl; (i) R8, R9, R6 and R10 in each case for hydrogen; (ii) R8 and Rg together form a bond, R6 and R10 in each case for hydrogen; (iii) R8, Rg and R10 each for hydrogen, R6 for Bromine; (iv) R8 and R9 each represent hydrogen, R6 and R10 each represent bromine; (v) R8 and R9, together form a bond, R6 for bromine and R10 for hydrogen.

The present invention relates to a method for producing the already mentioned esters, thioesters and amides by adding a corresponding prostanoic acid or their reactive acid derivative with a corresponding 8-hydroxyalkylercoline, 8-thioalkylergoline or B-aminoalkylercoline converts.

The invention relates in particular to a process a) for the preparation of compounds of the formula I by adding compounds of the formula III, in which D, R1, R2, R3, X, Y and Z have the above meanings, or reacts their reactive acid derivatives with compounds of the formula IV, H-WR IV in which R and al have the above meanings, or b) for the preparation of compounds of the formula Yes, in which R, R1, R2, R3, W, X, Y. and Z have the above meaning by starting from compounds of the formula Ib, in which A, R, R1, R2, R3, W, X, Y and Z have the above meanings, the radical A splits off.

Process a) can be used in the preparation of esters, thioesters and amides of prostanoic acid in a known manner, taking into account the other substituents be performed. It is expediently a reactive acid derivative of prostanoic acid formed in situ using carbonyldiimidazole. For activation in particular of hydroxyalkylergoline or

Thioalkylerfolins are conveniently catalytic amounts of a Solution of imidazole sodium in tetrahydrofuran added. When using a connection of the formula III, in which D stands for D2, there is an addition of the imidazole formed instead of forming a compound of the formula I in which D is D6 and A is imidazoll-yl stand. For the preparation of compounds of the formula I in which D is D2 and for alternative production of amides can therefore be preferred other reactive acid derivatives, e.g. 2-thiopyridyl derivatives, are used noble.

Process b) is preferably carried out in the presence of an alkanol, e.g. Methanol. Suitable temperatures are, for example, between about Oo and 500C, for example room temperature.

The reaction times are generally up to 30 hours. That Process can be in the presence of an inert organic solvent, for example Tetrahydrofuran or methylene chloride. The procedure can also be carried out in water as a solvent. At pH values greater than 7.0 e.g. up to 9.0 the response time can be shortened.

To accelerate the splitting off, sodium or potassium bicarbonate, Sodium acetate or a tert. Amine, such as pyridine or triethylamine, can be used.

Method b) is the more advantageous method of making Compounds of the formula Ia, especially when W is oxygen or sulfur.

The invention also relates to the compounds of the formula IIIa used as starting compounds for process a), in which A, R1, R2, R3, X, Y and Z have the above meaning, which can be obtained by c) compounds of the formula Ilib, in which R1, R2, R3, X, Y and Z have the above meanings, reacts with amines introducing the radical A.

Process c) can be carried out in a manner known per se. The reaction is more conveniently carried out at temperatures from 0 ° to 40 ° C., preferably at room temperature, carried out in an inert organic solvent.

In certain cases, e.g. when using purine, a Isomerization of the amine takes place, so that two end products of the formula IIIa are obtained (see e.g. example 4).

The invention also relates to the compounds of the formula III in which D is D8, which can be obtained, for example, by d) for the preparation of compounds of the formula III in which D is D8, and one of the substituents and Ra is hydrogen and the others of these sub-4 substituents mean an alkanoy group with 120 carbon atoms or benzoyl, from compounds of the formula V, wherein A, R1, R2, X, Y and Z are as defined above, and one of the substituents R11 and R12 is an alkanoyl group having 1-20 carbon atoms or benzoyl and the other is a protecting group that splits off the protecting group, or e) for the preparation of Compounds of the formula III in which D is D8 and at least one of the substituents R3 and R4 is an alkanoyl group or benzoyl, compounds of the formula III in which D is D8 and at least one of the substituents R3 and R4 is hydrogen, acylated, or f) for the preparation of compounds of the formula IIIc in which A, R1, R2, R3, X, Y and Z have the above meanings, the carbonyl group in position 9 is selectively reduced in compounds of the formula IIIa.

The process d) can be carried out in a for example the tetrahydro-2H-pyran-2-yl group, common in prostaglandin chemistry Way to be carried out. The reaction conditions suitable for the process are described in example 6e).

The acylation of process e) can be carried out in one for the acylation such compounds in a known manner, taking into account the other substituents be performed. Suitable reaction conditions are described in example 6d).

The reduction of process f) can be carried out using suitable reducing agents, which do not act on the other substituents are carried out. For example sodium borohydride can be used.

Suitable reaction conditions are described in Example 6c). the and isomers obtained can be separated in a manner known per se.

It should be noted that the methods mentioned are preferred using pure starting compounds and reagents, e.g. anhydrous will.

The methods are preferably carried out in a nitrogen atmosphere.

The prostaglandins are cleaned in a manner known per se.

The compounds of the formula occurring in the form of free bases I and compounds of the formula III in which D is D6 or D8 can be incorporated into their Acid addition salts are converted and vice versa. Among those for salt formation suitable acids are tartaric acid and methanesulfonic acid.

The prostaglandins can be racemic or in either of the two optically active forms are present. The optically active forms can be known per se Way, e.g.

from optically active starting compounds.

Insofar as the manufacture of the starting products is not described, are these according to methods known per se or analogous to those described here (e.g. in the examples) or can be prepared analogously to processes known per se.

The ergolin-8-yl-alkyl esters, thioesters and amides of prostanoic acids show more beneficial pharmacological prostaglandin-like effects than their counterparts Prostanoic acids. In particular, they bring about a decrease in arterial blood pressure.

The ergolin-8-yl-alkyl esters, thioesters and amides, in particular, where D stands for D6 or D8, moreover, have the effect of inhibiting platelet aggregation.

The compounds of the formula III, in which D is D6 or D8, have an effect also a decrease in arterial blood pressure and an increase in platelet aggregation in the doses indicated for the esters, thioesters and amides.

The ergolin-8-yl-alkyl esters, thioesters and amides and the compounds of the formula III, in which D is D6 or D8, can be used in the form of pharmaceuticals harmless acid addition salts are administered, the salts being of the order of magnitude have the same effectiveness as the corresponding free bases. The salts can can be produced in a manner known per se.

The invention also relates to pharmaceutical preparations, the ergolen-8-yl-alkyl esters, thioesters or amides as defined above, or compounds of the formula III, in which D is D6 or D8, in free form or in their form pharmaceutically acceptable acid addition salts as well as pharmaceutically acceptable ones Diluents or carriers included. The preparations can, for example, in the form administered in a solution.

In the following examples, which explain the invention in more detail, all temperatures are given in degrees Celsius and are uncorrected.

IR refers to the IR spectrum of one dissolved in ethylene chloride Sample unless otherwise stated.

The N> 1R data are consistent with the proposed structures.

The vacuum commonly used is 10 mm Hg and the high vacuum 0.1 mm Hg. The term lysergyl used here stands for 6-methyl-9, l0-didehydro- 8p-hydroxymethyl-ergoline.

Unless otherwise noted, those below are manufactured Connections optically active and correspond to the absolute configurations at C-8 or C-12 those of prostanoic acid.

The term “cis- or trans- (+) - or (-) - methylene used in the following refers to the respective (+) or (-) optically active forms of the cis- or trans-2- (2'-bromine- ethyl) cycloprop-1-yl-carboxylic acid, which is used for the preparation of the corresponding optically active compound of the formula III, wherein Z is can be used in a manner known per se.

Example 1: 11α, 15S-dihydroxy-9-keto-13-trans-prosten acid dihydroisole sercylanide [Method a)) A solution of 150 mg of pure prostaglandin E1 in 4 ml of absolute Dimethylformamide is mixed with 76 mg carbonyldiimidazole and under nitrogen stirred at room temperature for 3 1/2 hours. Thereupon 130 mg of finely powdered Dihydroisolysergylamine, added. After 7 days of stirring at room temperature, the Solvent evaporated at room temperature under high vacuum and the oily residue chromatographed on 250 g of Sephadex LH 20 with methylene chloride with the addition of 1% methanol, whereby one arrives at the title compound.

IR: 1740, 1660, 1520 cm The free base is obtained by reaction with methanesulfonic acid converted into the methanesulfonate.

Preparation of esters of the formula I: Analogously to Example 1 and using corresponding prostaglandins of the formula III and compounds of the formula IV, in which W stands for oxygen, along with a freshly prepared catalytic amount of imidazole sodium in tetrahydrofuran are added, one arrives at the following Esters of the formula I: a) 9 «, 11a, 15S-trihydroxy-5cis, 13trans-prostadienoic acid lysgyl ester, M.p. of the hydrogen tartrate 117-120 ° C., b) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid lysgyl ester, m.p. of the hydrogen tartrate 158-160 ° C, c) 11α, 15S-dihydro-9-keto-13-trans-prostenoic acid (2 ', 13'-dibromo) dihydrolysergyl ester, IR: 1740 cm-1 (wide) d) 11α, 15S-dihydroxy-9-keto-5cis, 13trans-prostadienoic acid lysgyl ester, IR: 1740 cm 1 (wide) e) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid- (1'-methyl) lysergyl ester, IR: 1740, 1735 (shoulder) cm 1 f) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid (10'α-methoxy) dihydrolysergyl ester IR: 1740 cm (wide) g) lla, 15S-dihydroxy-9-keto-13-trans-prostenic acid-2- (2'-chloro-6'-methylergolin-8'ß-yl) ethyl ester, IR: 1740, 1735 cm-1 h) lla, 15S-dihydroxy-9-keto-15-methyl-2,3trar.s - (-) - methylene-13-trans-prostenic acid lysergylester, IR: 1740, 1730 cm i) 11α, 15S-dihydroxy-9-keto-15-methyl-5cis, 13transprostadienoyl lysgyl ester, IR: 1745, 1735 (shoulder) cm-1 j) llatl5S-dihydroxy-9-keto-prostanoic acid lysgyl ester, IR: 1749 (broad) cm-1 k) 11α, 15S-dihydroxy-9-keto-16R-methyl-5cis-prostenic acid lysgyl ester, -1 IR: 1740, 1735 (shoulder) cm 1) 11α, 15R-dihydroxy-9-keto-16R-methyl-2,3-trans - (+) - methylene-5cis-prostenic acid lysgyl ester, IR: 1740, 1735 (shoulder) cm m) 15-Cyclohexyl-11 ", 15R-dihydroxy-9-keto-16tl7tl8tl9t 20-pentanor-5cis-prostanoic acid lysergyl ester, IR: 1740 (broad) cm-1 n) 11 ", 15R-dihydroxy-9-keto-16R-methyl-2,3-trans - (-) - methylene-5cis-prostanoic acid lysergyl ester, IR: 1740, 1735 (shoulder) cm-1 As in Example 1 and using prostaglandins of the formula III, in which D is D2, or the corresponding prostaglandins of Formula III, in which D stands for D6, and corresponding compounds of the formula IV, wherein W is oxygen, along with a catalytic amount of imidazole sodium in tetrahydrofuran. the following esters of the formula I are obtained, in which D is D6 stands: aa) 15S-Hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13transprostadienoic acid lysgyl ester, IR: 3450, 1740, 1730 cm-1 from) 15R-Hydroxy-II «-i.midazol-l'-yl-9-keto-5cis, 13th transprostadienic acid lysgyl ester, IR: 3550, 3450, 1745-1740 cm ac) 15S-Hydroxy-11α-imidazol-1'-yl-9-keto-13-trans-prostenic acid lysgyl ester, M.p. of the hydrogen tartrate 104-106 ° C, ad) 15S-hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13transprostadienäuredihydroisolysergylester, -1 IR: 3450, 1740, 1720, 1500 cm ae) 15S-hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13transprostadienoic acid- (2 ', 13'-dibromo) dihydrolyseryl ester, -1 IR: 3450, 1740, 1715, 1500 cm af) 15S-hydroxy-9-keto-11α-1 ', 2', 4'-triazol-1'-yl-5cis, 13 trans-prostatic acid lysgyl ester, -1 IR: 1740, 1720 cm ag) 15R-Hydroxy-II «-imidazol-l'-yl-9-keto-16R-methyl-5-cisprostenic acid lysgyl ester, IR: 1740, 1720, 1500 cm ah) 15S-hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13-transsprostadienoic acid (1'-methyl) -lysergyl ester, IR: 1740, 1725 cm-1 ai) 15-cyclohexyl-15R-hydroxy-11 "-imidazol-1-yl-9-keto-16t 17,18,19,20-pentanor-5cis, 13trans-prostadienoic acid lysgyl ester, IR: 1740, 1720 cm 1 aj) 15R-Hydroxy-lla-imidazol-l'-yl-9-keto-16R-methyl-2,3-trans - (-) - methylene-scis-prostenic acid lysgyl ester, IR: 1740, 1720 cm, ak) 15S-HyGroxy-lla-imidazol-l'-yl-9-keto-13-trans-prostenic acid / 2 ', 13'-dibromo) dihydrolysergyl ester, IR: 1740, 1715, 1500 cm, al) 15R-Hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13transprostadienäuredihydroisolysergylester, IR: 3450, 1740, 1720, 1500 cm.

Preparation of thioesters of the formula I: Analogously to Example 1, but using suitable prostaglandins and suitable thiols of the formula IV with catalytic amounts of imidazole natritin in tetrahydrofuran the following results are obtained Compounds of the formula I: ba) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid lysergylthioester, IR: 1740, 1695 cm bb) 15S-Hydroxy-imidazol-l'-yl-9-keto-5cis, 13-trans-prostadienoic acid lysergylthioester (based on prostaglandin A2), IR: 1740, 1700 cm Production of amides of the formula I: As in Example 1, but using suitable prostaglandins and suitable ones Amines of the formula IV lead to the following compounds of the formula I: ca) IIIa, 15S-dihydroxy-9-keto-13-trans-prostenic acid lysgylamide, IR: (CH2C12 + CH30H): 3400 (broad), 1740, 1660, 1520 cm cb) 11α, 15S-dihydroxy-9-keto-13-trans-prostenic acid dihydrolysergylamide, IR: 1740, 1665, 1520 cm cc) 11α-15S-dihydroxy-9-keto-13-trans-prostenic acid-2- (6'-methylergolin-8'ß-yl) -ethylamide, IR: 3400, 1740, 1660, 1520 cm cd) 11α, 15R-dihydroxy-9-keto-16R-methyl-2,3-trans - (-) - methylene-5cis-prostenic acid lysgylamide, IR: 1740, 1665, 1520 cm ce) 9α, 11α, 15S-trihydroxy-5cis, 13trans-prostadienoic acid lysgylamide, IR: 1660, 1520 cm cf) 11α, 15α-dihydroxy-9-keto-prostanoic acid lysergylamide, IR: (CH2C12 + CH3CH): 3400 (broad), 1740, 1660, 1520 cm cg) 15S-hydroxy-9-keto-5cis, 13trans-prostadienic acid lysgylamide, IR: 1740, 1660, 1520 cm -1 ch) 15S-Hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13-transprostadienoic acid (1'-methyl) -lysergylamide, IR: 1725, 1660, 1520 cm ci) 15S-hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13-transprostadienoic acid-2- (6'-methyl-ergolin-8'β-yl) -ethylam. id, IR: 1725, 1665, 1525 cm: cj) 15S-acetoxy-lla-imidazol-l'-yl-9-keto-5cis, 13-transprostadienoic acid lysgylamide, IR: 1730 (broad), 1660, 1520 cm ck) 15S-Hydroxy-11α-imidazol-1'-yl-9-keto-5cis, 13transprostadienoic acid lysgylamide, IR: 3450, 1740, 1665, 1520 cm cl) 15S-hydroxy-lla-imidazol-r-yl-9-keto-13-transprostansåurelysergylamid, IR: 1725, 1665, 1525 cm, with a suitable prostaglandin for the examples ch) to cl) of the formula I, in which D is D2, is used.

Using the procedure described in Example 1, obtained one to the following esters, thioesters and amides.

of the formula I, in which the part R has the meanings Lysergy), Dihydrolysergyl, Isolysergyl, Dihydroisolysergyl, 2-Erom-lyserc.

13-Bromdihydrolysergyl, 2,13-Dibromdihydrolysergyl, 10α-Methoxydihydrolysergyl, 10α-methoxydihydroisolysergyl, 2,13-dibromo-10α-methoxydihydrolysergyl, Has 2- or 13-bromo-10α-methoxydihydrolysergyl and the prostanoic acid part the meanings 16,16-dimethyl PGE2 16, 16-dimethyl PGF2a 15-methyl PGE2 15-methyl PGF2a 16R- and S-methyl-13,14-dihydro PGE2 ll-deoxy-PGE2, its 15epi isomer and its 5,6-dihydro and 5,6,13,14-tetrahydro derivative PGE2, its 15epi isomer and its 5,6-dihydro- and 5,6,13,14-tetrahydro derivative PGFla, its 15epi isomer and its 13,14 dihydro derivative.

Example 2: 15S-hydroxy-9-keto-5cis, 10cis, 13 trans-prostatrienoic acid lysgylamide a) 159 mg prostaglandin A2 are combined with 167 mg 2,2-dithiodipyridine and 199 mg triphenylphosphine stirred in 5 ml of xylene at 20 ° C for 24 hours. After evaporation of the solvent is the remaining oil on 100 g Sephadex LH 20 with methylene chloride + 2% methanol chromatographed, the 2-thiopyridyl ester of prostaglandin A2 being obtained.

b) 131 mg prostaglandin A2-2-thiopyridyl ester are mixed with 93 mg lysergylamine stirred in 5 ml of tetrahydrofuran at 200 ° C. for 24 hours. The reaction mixture is chromatographed on 100 g of Sephadex LH 20 with methylene chloride + 0.5% methanol, the title compound is obtained, IR: 3450, 1730, 1710 cm 1 Analogue Example 2 leads to a) 15S-hydroxy-9-keto-10cis, 13trans-prostadienoic acid dihydrolysergylamide, (IR: 3450, 1705, 1665, 1520 cm-1) b) 15R-Hydroxy-9-keto-16R-methyl-2t3-trans - (-) - methylene-5, 10cis-prostadienoic acid lysgylamide, (IR: 3450, 1700, 1665, 1520 cm-1) and for compounds of Examples 1 and I ca) to cg).

Example 3: 15S-Hydroxy-9-keto-5cis, 10cis, 13trans-prostatrienoic acid lysgyl ester [Method b)] 248 mg of 15S-hydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13tr2nsprostadienoic acid lysgyl ester are left to stand in 9 ml of methanol at room temperature for 30 hours and then the methanol evaporates at room temperature. The methanol-free oily residue is chromatographed immediately with methylene chloride + 0.25% ethanol on 100 g Sephadex LH 20, where-one arrives at the title compound, IR: 3450, 1730, 1710 cm Analogously to Example 3 and using corresponding compounds of the formula IIIa, in which A is imidazolyl one arrives at 15R-hydroxy-9-keto-5cis, 10cis, 13trans-prostatrienoic acid lysergyiester (IR: 3560, 3350, 1720, 1695, 1600 cm) and for 15s-hydroxy-9-k.eto-5cisllocistl3trans-prostatrienoic acid dihydrolyseryl ester (IR: 3555, 3350, 1730, 1705 cm 1) and Examples 2, 2a) and 2b).

Example 4: 15S-Hydroxy-9-keto-purin-7'-yl-5cis, 13transprostadienoic acid and 15S-hydroxy-9-keto-11α-purin-9'-yl-5cis, 13-trans-prostadic acid method c)) 356 mg of pure prostaglandin A2 and 127 mg of purine are in 4 ml of absolute dimethylformamide dissolved and left to stand for 6 weeks at room temperature, observing the course of the reaction checked by means of thin-layer chromatography on silica gel sheets (eluent CHCl3 / 20 9 CH3OH + 1% glacial acetic acid). When the reaction is complete, the dimethylformamide becomes evaporated at room temperature in a high vacuum and the oil obtained on 80 g of Sephadex LH 20 chromatographed with methylene chloride + 1% methanol, causing a separation in a mixture of the 11α-purin-7'-yl and IIa-purin-9'-yl derivatives a)) and a mixture of the II «-purin-9'-yl derivative and prostaglandin A2 [mixture b)) is achieved.

The mixture a) is chromatographed twice on Sephadex 'whereby one 15S-Hydroxy-9-keto-11α-purin-7'-yl-5cis, 13transprostedienoic acid as that with stronger polarity wins.

IR: 1745, 1705, 1600, 1560 cm-1 Isolation of 15S-Hydroxy-9-keto-11α-purin-9'-yl-Seis, 13 trans-prostadienoic acid 148 mg of the mixture b) defined above are mixed with 23 mg Imidazole is added and the mixture is left to stand at room temperature for 1 1/2 hours. After that, will the reaction product is dissolved in 100 ml of methylene chloride and mixed with 20 ml of approx.

0.01 N hydrochloric acid shaken. The organic phase will separated, dried, filtered and evaporated to give the pure title compound receives.

-1 IR: 1745, 1705, 1600, 1580, 1500 cm Example 5: 15S-Hydroxy-11α-imidazol-1'-yl-9-keto-5cis 13 trans-prostadienoic acid [method c)] 315 mg prostaglandin A2 and 96 mg imidazole are combined in 3 ml of methylene chloride, so that a clear solution is formed. To Evaporation of the solvent at room temperature leaves the remaining oil three Stand for days at room temperature and chromatograph the reaction product on 100 g Sephadex LH 20 with methylene chloride + 1% methanol to give the title compound will.

IR: 3350, 3300, 1740, 1710, 1695 (shoulder), 1600 cm UV: 208 nm (= 6500), 276 nm (= 800) Analogously to example 5 one arrives at a) 15S-hydroxy-lla-imidazol-l'-yl-9-keto-13-trans-prosten-acid, IR: 3450, 1740, 1710, 1695 (shoulder) cm b) 15S-hydroxy-9-keto-11α-1 ', 2', 4'-triazol-1'-yl-5cis, 13trans-prostadienoic acid, IR: 1745, 1705, 1505 cm c) 15S-hydroxy-9-keto-11α-pyrazol-1'-yl-5cis, 13transprostadienoic acid, IR: 1745, 1705, 1505 (small) cm d) 15R-Hydroxy-9-keto-11α- (6'-dimethylamino) -purin-9'-yl-5cis, 13-trans-prostadic acid IR: 1745, 1705, 1600, 1560 cm-1 IR: 1745, 1705, 1600, 1560 cm e) 15R Bydroxy-lla-imidazol-l'-yl-9-keto-5cis, 13-transprestadienoic acid, IR 1740, 1700, 1500 cm f) 16H16-dimethyl-15R-hydroxy-11 "-imidazol-1'-yl-9-keto-2,3-trans - (-) - methylene-5cis, 13trans-prostadic acid IR: 1740, 1700 cm-1 g) 15S-hydroxy-9-keto-11α- (6'-dimethylamino) -purin-9'-yl-5cis, 13-trans-prostadic acid, IR: 1745, 1705, 1600, 1565 cm h) llR-hydroxy-lla-irnidazol-l'-yl-9-keto-16R-methyl-scis7 prostenic acid, IR: 1745, 1705, 1500 cm-1 i) 15S-acetoxy-lla-imidazol-l'-yl-9-keto-5cis, 13transprostadienoic acid, IR: 1745, 1735 (shoulder), 1700 cm j) 15-cyclohexyl-11α-imidazol-1'-yl-15R-hydroxy-9-keto-16,17,18,19,20-pentanor-5cis, 13trans- prostadic acid, IR: 1740, 1700 cm-1 k) 15R-hydroxy-lla-imidazol-l'-yl-9-keto-16R-methyl-2,3-trans (-) - methylen-5cis-prostadienoic acid, IR: 1740, 1700 cm-1 Example 6: 15S-Hydroxy-11α-imidazol-1'-yl-9α and 9β-noctanoyl-5cis, 13trans-prostadienoic acid a) 150 mg prostaglandin A2 with one equivalent of dihydropyran and a catalytic amount of p-toluenesulfonic acid added in 10 ml of methylene chloride at 00 C and worked up in a manner known per se, whereby the prostaglandin A2-15-tetrahydro? yran-2'-yl ether is obtained.

b) Using the procedure described in Example 5, the ether obtained under a) into 11α-imidazol-1'-yl-9-keto-15S-tetrahydropyran-2'-yloxy-5cis, 13trans-prostadienoic acid convicted.

c) 180 mg of the compound obtained under b) are dissolved in 10 ml of dioxane reduced with 35 mg of sodium borohydride at room temperature and worked up, whereby one 9α-hydroxy and 9β-hydroxy-11α-imidazol-1'-yl-15S-tetrahydropyran-2'-yloxy-5cis, 13trans-prostadienoic acid receives.

d) 300 mg of the mixture of 9a and 9P-hydroxy derivatives obtained under c) in 10 ml of acetone and 3 ml of pyridine are mixed with 0.4 ml of n-octanoyl chloride at -10 ° C added in 10 ml of acetone. The reaction mixture is at room temperature for 16 hours left to stand, then diluted with methylene chloride, with aqueous phosphate buffer (pH 7.5) washed and concentrated, whereby a mixture of the 9α- and 9β-n-octanoyloxyderivate receives.

e) the elimination of the tetrahydropyranyl group of the 9α- and 9p-n-octanoyloxy derivatives [obtained under d)) is carried out using 4.5 ml of a mixture of acetic acid / water / acetone (1: 1: 1) and heating to 60 ° C for 30 minutes. The reaction mixture is customary Manner using chromatography on Sephadex LH 20 (eluent methylene chloride + 1% methanol) worked up, the pure a- and ß-title compounds being separated receives.

Claims (6)

Ergolin-8-yl-alkyl esters, thioesters and amides of prostanoic acids, their production and use. Claims 1. Ergolin-8-yl-alkyl esters, thioesters and amides of prostanoic acids wherein, in the prostanoic acid moiety, D is a group of the formula stands in which A - is a radical of the formula a) wherein 1 to 3 of the methine groups denoted by a, ß, r or # have been replaced by nitrogen or a radical of the formula b) denotes in which either one of the ring members L and M is nitrogen and the other is methine, or L and M each denote nitrogen, 1 to 3 of the methine groups denoted by a, ß, # or # can be replaced by nitrogen, and the six-membered Ring unsubstituted or monosubstituted by alkylamino, dialkylamino, alkoxy, alkylthio or halogen, the alkyl groups independently of one another have 1-5 carbon atoms, X for -CH2-CH2- or -CH = CH- (trans), Y for -CH2- CH2- or -CH = CH- (cis or trans), 2 for -CH, -CH - or (cis or trans), R1 is an alkyl group with 1-10 carbon atoms or a cycloalkyl group with 3-9 carbon atoms, hydrogen or an alkyl group with 1-7 carbon atoms, R3 and R4 independently of one another are hydrogen, an alkanoyl group with 1-20 carbon atoms or the benzoyl group, W oxygen, sulfur or the -NH group, and the alkylergoline part R for the remainder of the formula II where n is 1 or 2, R5 is hydrogen, an alkyl group with 1-4 carbon atoms or the benzyl group, R6 and R10 are independently hydrogen or halogen, R7 is an alkyl group with 1-4 carbon atoms, but not tert. Butyl means 1) R8 and R9 each represent hydrogen1 or 2) R8 and Rg together form a bond, or 3) R8 represents hydrogen and R9 represents an alkoxy group with 1-4 carbon atoms. 2. Process for the preparation of compounds of the formula I according to claim 1, characterized in that a) for the preparation of compounds of the formula I, compounds of the formula III, in which D, R1, R2, R3, X, Y and Z have the above meaning, or their reactive acid derivatives with compounds of the formula IV, H-WR IV in which R and W have the above meaning, or b) for the preparation of compounds of Formula Ia, in which R, R1, R2, R3, W, X, Y and Z have the above meaning by starting from compounds of the formula Ib, in which A, R, R1, R2, R3, W, X, Y and Z have the above meanings, the radical A splits off. 3. Prostanoic acids of the formula IIIa, wherein A is a radical of the formula a), wherein 1 to 3 of the methine groups denoted by a, ß, # or g have been replaced by nitrogen or a radical of the formula b) denotes in which either one of the ring members L and M denotes nitrogen and the other denotes methine, or L and M each denote nitrogen, 1 to 3 of the methine groups denoted by CL, β, # or # can be replaced by nitrogen, and the six-membered ring can be unsubstituted or monosubstituted by alkylamino, dialkylamino, alkoxy, alkylthio or halogen, the alkyl groups independently of one another having 1-5 carbon atoms, X for -CH2-C2- or -CH = CH- (trans), Y for -CH-CH- or -CH = CH- (cis or trans), Z for -CH2-CH2- or (cis or trans), R1 is an alkyl group with 1-10 carbon atoms or a cycloalkyl group with 3-9 carbon atoms, R2 is hydrogen or an alkyl group with 1-7 carbon atoms, and R3 is hydrogen, an alkanoyl group with 1-20 carbon atoms or the benzoyl group . 4. Process for the preparation of compounds of the formula IIIa according to claim 3, characterized in that compounds of the formula IIIb, in which R1, R2, R3, X, Y and Z are as defined above, with amines introducing the radical A. 5. Pharmaceutical preparation characterized by the content of a Compound of formula I. 6. Pharmaceutical preparation characterized by the content of a A compound of the formula III in which D is D6 or D8.