IE54554B1 - Novel carbacyclins, process for the preparation thereof, and use thereof as medicinal agents - Google Patents

Novel carbacyclins, process for the preparation thereof, and use thereof as medicinal agents

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IE54554B1
IE54554B1 IE246/83A IE24683A IE54554B1 IE 54554 B1 IE54554 B1 IE 54554B1 IE 246/83 A IE246/83 A IE 246/83A IE 24683 A IE24683 A IE 24683A IE 54554 B1 IE54554 B1 IE 54554B1
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general formula
carbaprostaglandin
didehydro
colorless oil
title compound
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Schering Ag
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/72—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 spiro-condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
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    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
    • C07C405/005—Analogues or derivatives having the five membered ring replaced by other rings
    • C07C405/0075—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system
    • C07C405/0083—Analogues or derivatives having the five membered ring replaced by other rings having the side-chains or their analogues or derivatives attached to a condensed ring system which is only ortho or peri condensed, e.g. carbacyclins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/59—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/40—Esters thereof
    • C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
    • C07F9/4015—Esters of acyclic unsaturated acids

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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Abstract

1. Carbacyclin derivatives of the general formula I see diagramm : EP0086404,P12,F1 wherein R1 , R2 , R3 and R4 are hydrogen or alkyl of 1-2 C-atoms. R5 is alkyl of 1-2 C-atoms, as well as their salts with pharmaceutically acceptable bases.

Description

The present invention relates to (5E)-13,14,18,18,19,19-hexadehydro-6a-carbaprostaglandin l2 derivatives, their physiologically compatible salts, a process for the preparation thereof, and pharmaceutical compositions containing same.
German Laid-Open Application [DOS] 2,845,770 claims carbacyclin derivatives of the general formula COOR I 10 wherein CH A-W-D-E-R Rlo is hydrogen, alkyl, cycloalkyl, aryl, or a heterocyclic residue, A is a -CH2-CH2-, trans-CH=CH-, or -C=C-group W is a free or functionally modified hydroxymethylene group or a free or functionally modified CH3 - C — group, wherein the OH-group is in the aposition I» - 2 54554 P anil Ε together mean a direct bond or I) is a straight-chain or branched, saturated or unsaturated alkylene group of 1-10 carbon atoms optionally substituted by fluorine atoms, E is an oxygen atom or a -C=C-bond or a direct bond, R20is an alkyl, cycloalkyl, optionally substituted aryl, or heterocyclic group, Rj) is a free or functionally modified hydroxy □roup, and, if Rj^means a hydrogen atom, the salts thereof with physiologically compatible bases.
The compounds possess the properties typical for prostacyclins, such as, for example, lowering of peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation, and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure, without simultaneously lowering stroke volume and coronary blood flow, treatment for stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis, and thrombosis, shock therapy, inhibition of branchoconstxiction, inhibition of gastric acid secretion and cytoprotection for gastric and intestinal mucosa; antiallergic properties, lowering of pulmonary vascular resistance and pulmonary blood pressure, promotion of kidney blood flow, utilization in place of heparin or as adjuvant in dialysis of hemofiltration, preservation of blood plasma -3stores, especially blood platelet preserves, inhibition of labor, treatment of gestational toxicosis, enhancement of cerebral blood flow, etc. Furthermore, the novel prostaglandin analogs exhibit antiproliferative properties. In Angew. Chem. Int. Ed. Engl. 20 (1981), 1046 carbacyclins with a 13 - 14 double bond are described which are partly unsaturated in a triple bond in the 18position. In Chem. Abstr. 95 (1981), 91359 carbacyclins with a triple bond are mentioned.
Among the compounds claimed in DOS 2,845,770, the (5E) -13,14,18,18,19,19-hexadehydro-6a-carbaprostaglandin l2 compounds show such outstanding properties as bloodpressure-lowering agents and agents inhibiting thrombocyte aggregation, that the dose can be further reduced whereby undesirable side effects are likewise even more strongly suppressed. The (5E)-13,14,18,18,19,19-hexadehydro-6acarbaprostaglandin I2 compounds have not been disclosed by name in DOS 2,845,770. Compounds wherein A means a -C=Cgroup have not been emphasized over the other compounds wherein A is a -CH2-CH2- or trans-CH=CH-group.
The nomenclature of the compounds is based on a proposal by Morton and Brokaw (J. Org. Chem. 44 :2280 [19791). (5E)-6a-Carbaprostaglandin I2 accordingly has the following structural formula: -454554 Accordingly, the invention concerns (5E)-13,14,18,18,19,19-hexadehydro-6a-carbaprostaglandin derivatives of general Formula I R1, r2> r3» alkyl group of 1-2 R4 represent a hydrogen atom or an carbon atoms, R5 is an alkyl group of 1-2 carbon atoms, as well as the salts thereof with physiologically compatible bases.
Suitable alkyl groups R-|, R2, R3, R4, R5 are methyl and ethyl. The invention also relates to (5E)-(16RS)-20ethyl-1 3,1 4-didehydro-16-methyl-18,18,19,19-tetradehydro6a-carbaprostaglandin-l2.
Suitable for the salt formation are inorganic and organic bases as known to those skilled in the art for the preparation of physiologically compatible salts. Examples are alkali hydroxides, such as sodium and potassium hydroxide, alkaline earth hydroxides, such as calcium hydroxide, ammonia, amines, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris(hydroxymethyl)methylamine, etc.
The invention furthermore relates to a process for the preparation of the prostacyclin derivatives of this invention according to general Formula I, characterized by reacting a compound of general Formula II o OTHP '5 OTHP wherein R]j R2, > r4* r5 have the meanings given above and THP means the tetrahydropyranyl residue, with a Wittig reagent of Formula ill (III) , wherein Ph is a phenyl group, simultaneously splitting-off HBr and subsequently separating isomers, splitting off blocking groups, and optionally converting the carboxy group into a salt with a physiologically compatible base.
The reaction of the compound of general Formula II with the Wittig reagent of Formula III, which is produced from the corresponding phosphonium salt with methanesulfinylmethyl sodium or methanesulfinylmethyl potassium or potassium tert-butylate in dimethyl sulfoxide or dimethyl sulfoxide10 tetrahydrofuran mixtures, is conducted at temperatures of 0-100° C, preferably 20-60° C, in an aprotic solvent or solvent mixture, preferably dimethyl sulfoxide, dimethylformamide, or tetrahydrofuran. The thus-obtained olefins of a Zand E-configuration are separated in the usual way, for ex15 ample by column or layer chromatography. During the aforedescribed Wittig olefin-forming reaction, the formation of the 13,14-acetylene bond also takes place, with hydrogen bromide being split off, at the same time.
The splitting off of the blocking groups is effected in an aqueous solution of an organic acid, such as, for example, acetic acid, propionic acid, or others, or in an aqueous solution of an inorganic acid, e.g. hydrochloric acid. To enhance solubility, a water-miscible, inert organic solvent is suitably added. Organic solvents which can be 2-j used for this purpose are, for example, alcohols, such as methanol and ethanol, and ethers, such as dimethoxyethane, dioxane, and tetrahydrofuran. Tetrahydrofuran is preferably i employed. The splittinu-off step is preferably conducted at temperatures of between 20° and 30° C.
The carboxylic acids of general Formula I can be converted into salts with suitable amounts of the correspond5 ing inorganic bases, with neutralization. For example, the solid inorganic salt is obtained when dissolving the corresponding acids in water containing the stoichiometric quantity of the base, after evaporation of the water or after the addition of a water-miscible solvent, e.g. alcohol or acetone. For the production of an amine salt, the PG acid is dissolved in a suitable solvent, e.g. ethanol, acetone, diethyl ether, or benzene, and at least the stoichiometric amount of the amine is added to this solution. During this process, the salt is ordinarily obtained in the solid form, or is isolated in the usual way after evaporation of the solvent.
The compounds of general Formula II serving as the starting materials can be prepared, for example, by conventionally reacting an aldehyde of Formula IV (DOS 2,845,770) (IV) - 8 54554 with a phosphonate of general Formula V R, K_ R CH_O, V23 ^P-CH -C-C-C-C=C-R (v) CH?0 wherein R-,, R_, R , R,, and R_ have the meanings 1 2 3 4 5 given above, in the presence of a deprotonating agent, such as, for example, sodium hydride or potassium tert-butylate, and a brominating agent, such as, for example, N-bromosuccinimide, to obtain a ketone of general Formula VI: (VI) 'CH-CBr\ /2 \3 / '* .C--C---C--c =C-Rc oco < After reduction of the keto group with sodium borohydride and optionally separation of epimers, saponification of the ester group, for example with potassium carbonate in methanol, and ketal cleavage with aqueous acetic acid, as well as optionally epimer separation, the ketone of general Formula VII is obtained: 4 5 5 4 (νχχ} Etherification of the hydroxy groups with dihydropyran in the presence of catalytic amounts of p-toluenesulfonic acid yields the compounds of general Formula XI.
The phosphonates of general Formula V are produced conventionally by reacting an alkyl halogenide (producible from the corresponding alcohol by halogenation) of general Formula VIII Hal-C-Csc-Rg (VIII) with the dianion formed from the phosphonate of general Formula IX: ru n 0 OR, R„ "All |l /2XP—ch2_c---C—H (IX) CHqo/ J wherein Rj, R2, R3, R4, and Rg have the meanings given above. 5455 4 - 10 Another method for obtaining the phosphonates of general Formula V resides in reacting the anion of the dimethyl ester of methylphosphonic acid with an ester of general Formula X: C-CSC-R. (X) wherein R O-C R,, R„, R,, R., and Rc have the above-indicated 1 ά J 4 □ meanings and Rg is an alkyl group of 1-5 carbon atoms, obtainable from the corresponding malonic acid ester by alkylating with the halogenide of general Formula VTII and subsequent decarbalkoxylation. The ester of general Formula X is also obtainable from the carboxylic acid of general Formula XI: HO-C (XX) wherein and R2 have the meanings given above, by alkylation with the halogenide of general Formula VIII and subsequent esterification. 4 5 5 1 The compounds of this invention have bloodpressure-lowering and bronchodilatory effects. They axe furthermore suitable fox inhibition of thrombocyte aggregation. Consequently, the novel prostacyclin derivatives of Formula I represent valuable pharmaceutically active agents. Moreover, they exhibit, with a similar spectrum of activity as compared with corresponding prostaglandins, a higher specificity and, above all, a considerably longer duration of efficacy. As compared with PG^, they are distinguished by greater stability. The high tissue specificity of the novel prostaglandins is demonstrated on studies on smoothmuscle organs, such as, for example, on the guinea pig ileum or on the isolated rabbit trachea, where a substantially lesser stimulation can be observed than that caused by the administration of natural prostaglandins of the E, A, or F type.
The novel carbacyclin derivatives possess the properties typical for prostacyclins, such as, for example, lowering of peripheral arterial and coronary vascular resistance, inhibition of thrombocyte aggregation, and dissolution of platelet thrombi, myocardial cytoprotection and thus lowering of systemic blood pressure without simultaneously lowering the stroke volume and coronary blood flow; treatment for stroke, prophylaxis and therapy of coronary heart disease, coronary thrombosis, cardiac infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, therapy of shock, - 12 inhibition of bronchoconstriction, inhibition of gastric acid secretion, cytoprotection for gastric and intestinal mucosa, cytoprotection in liver and pancreas; antiallergic properties, lowering of pulmonary vascular resistance and pulmonary blood pressure, promotion of kidney blood flow, utilization in place of heparin or as adjuvant in dialysis of hemofiltration, preservation of blood plasma stores, especially blood platelet preserves, inhibition of labor, treatment of gestational toxicosis, enhancement of cerebral blood flow, etc. Furthermore, the novel carbacyclin derivatives possess antiproliferative properties. The carbacyclins of this invention can also be employed in combination with β-blockers or diuretics, for example.
The dosage of the compounds is 1-1,500 ug/kg/day if administered to human patients. The unit dosage for the pharmaceutically acceptable vehicle is 0.01 - 100 mg.
When injected intravenously into nonanesthetized, hypertonic rats in doses of 5, 20, and 100 ug/kg body weight, the compounds of this invention show a stronger bloodpressure-lowering effect of a longer duration as compared with PGE2 and PGA2, without triggering diarrhea, as does PGE2 or cardiac arrhythmias, as does PGA2.
When injected intravenously into anesthetized rabbits, the compounds of this invention, as compared with PGE2 and PGA2, exhibit a stronger blood-pressure-lowering effect of a considerably longer duration, without affecting other smooth-muscle organs or organ functions. - 13 5 4 5 5s Sterile, injectable, aqueous or oily solutions are used for parenteral administration. Suitable for oral administration are, for example, tablets, dragees, or capsules.
The invention consequently also relates to medicinal agents based on the compounds of general Formula I and customary auxiliary agents and excipients.
The active agents of this invention are to serve, in conjunction with the auxiliary agents known and usual in galenic pharmacy, for the preparation of blood-pressurelowering agents, for example. - 14 Example 1 (5E)-(16RS)-13,14-Didehydro-16-methyl18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 At 5° C, 4.75 g of potassium tert-butylate is added 5 within 45 minutes to a solution of 9.4 g of 4-carboxybutyltriphenylphosphonium bromide in 20 ml of dimethyl sulfoxide and 7.8 ml of tetrahydrofuran; the reaction mixture is stirred for 45 minutes at 5° C. Theredylene solution is combined with a solution of 1.83 g of (IR,5S,6R,7R)-710 (tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3(tetrahydropyran-2-yloxy)oct-l-en-6-ynyl]bicyclo[3.3.0]octan3-one in 3 ml of tetrahydrofuran and agitated for 4 hours at 40° C. The reaction mixture is poured on ice water, acidified with 35% citric acid solution to pH 4-5, and extracted three times with methylene chloride. The organic phase is shaken with brine, dried over magnesium sulfate, and evaporated under vacuum. The residue is purified by chromatography on silica gel. With hexane/ethyl acetate (3+2), 180 mg of the 5Z-configured olefin is initially obtained, and as the more polar component, 680 mg of (5E)-(16RS)-13,14-didehydro-16~ methyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 ll,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR (CHClj): 3500 (broad), 2940, 2860, 2225, 1710, 1440 cm-1. - 15 To split off blocking groups, 680 mg of the above-obtained olefin-forming product is stirred for 20 hours at 25° C with 25 ml of a mixture of acetic acid/water/tetrahydrofuran (65/35/10). The mixture is then evaporated under vacuum and the residue chromatographed on silica gel. With ethyl acetate/acetic acid (99.9 + 0.1), 345 mg of the title compound is produced as a colorless oil.
IR: 3600, 3400 (broad), 2930, 2225, 1710, 1603, 1020 cm-1.
The starting material for the above title compound is prepared as follows: (a) (IR,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy6-[(4RS)-2-bromo-4-methyl-3-oxooct-l-en-6ynyl]bicyclo[3,3,0]octane At 0° C, a solution, of 10.5 g of 3-methyl-2oxohept-5-ynephosphonic acid dimethyl ester in 70 ml of dimethoxyethane is added dropwise to a suspension of 1.81 g of sodium hydride in 180 ml of dimethoxyethane; the mixture is stirred for one hour at 0° C and then 7.4 g of finely pulverized N-bromosuccinimide is added thereto. Agitation is continued for 30 minutes at 0° C; the reaction mixture is combined with a solution of 11.4 g of (IR,5S,6R,7R)-3,3ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane in 90 ml of dimethoxyethane, and stirred for 2 hours at 0° C.
The reaction mixture is poured on saturated ammonium chloride solution and extracted with ether. The organic extract is - 16 washed with water to render it neutral, dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (3+2) 8.2 g of the unsaturated ketone as a colorless oil.
IR: 2930, 2880, 1712, 1688, 1602, 1595, 1450, 1275, 945 cm-1. (b) (1R,5S,6R,7R)-7-Hydroxy-6-((3S,4RS)-2-bromo3-hydroxy-4-methyloct-l-en-6-ynyl]bicyclo(3.3.0]octan-3-one At -40° C, 2.5 g of sodium borohydride is added in incremental portions to a solution of 5.9 g of the ketone produced according to Example 1(a) in 140 ml of methanol, and the mixture is stirred for 30 minutes at -40° C. Subsequently the mixture is diluted with ether, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum.
The crude product (mixture of 15-epimers) is dissolved in 200 ml of methanol, 2.5 g of potassium carbonate is added and the mixture is stirred for 17 hours at 23° C under argon. Thereafter the mixture is concentrated under vacuum, diluted with ether, and washed neutral with brine.
The mixture is dried over magnesium sulfate and evaporated under vacuum.
The evaporation residue is stirred for 16 hours at room temperature with 300 ml of a mixture of acetic acid/ water/tetrahydrofuran (65/35/10) and then evaporated under - 17 vacuum. Column chromatography on silica gel with ether/ methylene chloride yields first of all 1.6 g of the 15(3configured alcohol, as well as 2.1 g of the title compound (PG nomenclature 15a-hydroxy) as the more polar component, in the form of colorless oils.
IR: 3600, 3430 (broad), 2960, 2920, 2870, 1738, 1600, 1400 cm-1. (c) (IR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6l(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran10 2-yloxy)oct-l-en-6-ynyl}bicyoIo[3.3.Oloctan3-one A solution of 1.6 g of the α-alcohol prepared according to Example 1(b), 16 mg of p-toluenesulfonic acid, and 1.5 g of dihydropyran in 50 ml of methylene chloride is 15 agitated at 0° C for 35 minutes. The mixture is then diluted with ether, shaken with dilute sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. Chromatography of the residue on silica gel yields with hexane/ether (7+3) 2.17 g of the title compound as a colorless oil.
IR: 2940, 2870, 1735, 1450, 1120, 1018, 965 cm-1. 4 5 5 4 - 18 Example 2 (5E)-(ICRS)-13,14-Didehydro-16,20-dimethyl18,18,19,19-tetradehydro-6a-carbaprostaglandin X2 Γη analogy to Example 1, 1.6 g of (1R,5S,6R,7R)7-(tetrahydxopyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3(tetrahydropyran-2-yloxy)non-l-en-6-ynyl]bicyclo[3.3.OJoctan3-one yields 640 mg of (5E)-(16RS)-13,14-didehydro-16,20dimethyl-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2942, 2860, 2224, 1710 cm1.
After splitting off the blocking groups as described in Example 1, 0.3 g of the title compound is obtained as a colorless oil.
IR: 3600, 3350 (broad), 2932, 2224, 1710, 1602 cm-1.
The starting material for the above title compound is prepared as follows: (a) (IR, 5S, 6R, 7R) - 3,3-Ethylenedioxy-7-benzoyloxy6-[(4RS)-2-bromo-4-methyl-3-oxonon-l-en-6ynylJ bicyclo[3.3.0]octane Analogously to Example 1(a), 6 g of 3-methyl2-oxooct-5-ynylphosphonic acid dimethyl ester, 3.7 g of Nbromosuccinimide, and 5.6 g of (lR,5S,6R,7R)-3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.OJoctane yield 4.0 g of the unsaturated ketone as a colorless oil.
IR: 2935, 2883, 1713, 1687, 1602, 1596, 1275, 947 cm~l. ! - 54554 - 19 (b) (IR, 5S, 6R, 7R) -7-IIydroxy-6- [ (3S, 4RS) -2-bromo3-hydroxy-4-methylnon-1-en-6-ynyl]bicyclo[3.3.0]octan-3-one Analogously to Example 1(b), 3 g of the ketone 5 prepared according to Example 2(a) yields, after reduction with 1.3 g of sodium borohydride, saponification with 1.2 g of potassium carbonate and subsequent ketal splitting with 150 ml of a mixture of acetic acid/water/tetrahydrofuran, 1.2 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3610, 3400 (broad), 2960, 2870, 1739, 1600 cm"1· (c) (IR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6t(3S,4RS)-2-bromo-4-methyl-3-(tetrahydropyran2- yloxy)non-l-en-6-ynyl]bicyclo[3.3.0]octan3- one In analogy to Example 1(c), 0.78 g of the diol produced according to Example 2(b) and 0.7 g of dihydropyran yield 1.1 g of the title compound as a colorless oil.
IR: 2940, 2872, 1736, 1450, 1120, 965 cm-1.
Example 3 (5E)-(16RS)-20-Ethyl-13,14-didehydro-16-methyl18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 Analogously to Example 1, 2 g of (lR,5S,6R,7R)-7tetrahydropyran-2-yloxy)-6-[(3S,4RS)-2-bromo-4-methyl-3tetrahydropyran-2-yloxy)dec-l-en-6-ynyllbicyclo[3.3.01octan25 3-one yields, in the form of a colorless oil, 900 mg of S4554 - 20 (5E)-(16RS)-20-ethyl-l3,14-didehydro-16-methyl-18,18,19,19tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether).
IR: 3500 (broad), 2948, 2862, 2220, 1708 cm-1.
After the blocking groups have been split off according to Example 1, 420 mg of the title compound is obtained as a colorless oil.
IR: 3600, 3360 (broad), 2930, 2858, 2220, 1708, 1601 cm-1.
The starting material for the above title compound is prepared as follows: (a) (IR,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy6-[(4RS)-2-bromo-4-methyl-3-oxodec-l-en-6ynyl]bicyclo[3.3.0]octane In analogy to Example 1(a), 6.25 g of 3methyl-2-oxonon-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bxomosuccinimide, and 5.6 g of (IR,5S,6R,7R)-3,3ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane result in 4.5 g of the unsaturated ketone as a colorless oil.
IR: 2940, 2880, 1712, 1688, 1601, 1592, 1275, 948 cm-·*·.
I - 21 (b) (IR,5S,6R,7R)-7-Hydroxy-6-[(3S,4RS)-2-bromo3-hydroxy-4-methyldec-l-en-6-ynyl]bicycΙοί 3. 3. 0]octan-3-one Analogously to Example Kb), 4 g of the ketone 5 prepared according to Example 3(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal cleavage with acetic acid/ water/tetrahydrofuran (65/35/10), 1.5 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3610, 3400 (broad), 2955, 2868, 1738, 1601 cm-1. (c) (lR,5S,6R,7R)-7-(Tetrahydxopyran-2-yloxy)-6[(3S,4 RS)-2-bromo-4-methyl-3-(tetrahydropyran2-yloxy)dec-l-en-6-ynyl]bicyclo(3.3.0]octan15 3-one In analogy to Example 1(c), 1.2 g of the diol prepared according to Example 3(b) yields 1.81 g of the title compound as a colorless oil.
IR: 2942, 2868, 1738, 1450, 1125, 960 cm-1. (d) 3-Methyl-2-oxonon—5-ynylphosphonic Acid Dimethyl Ester At 20° C, 120 g of methylmalonic acid diethyl ester is added dropwise to a solution of 15.8 g of sodium in 340 ml of ethyl alcohol. After 30 minutes, 135 g of 1-bromo25 2-hexyne (prepared from hex-2-yn-l-ol with phosphorus tribromide in pyridine) is added dropwise thereto and the - 22 mixture heated for 16 hours under reflux. The mixture is thereafter filtered, the residue washed with methylene chloride and concentrated under vacuum. The residue is dissolved in 500 ml of methylene chloride, shaken twice with respectively 50 ml of water, dried over magnesium sulfate, and concentrated under vacuum. The residue is distilled under vacuum at 14 torr and 148-152° C, thus obtaining as the distillate 155 g of the alkylated methylmalonic acid ester which latter is heated under reflux for 4.5 hours in 1200 ml of dimethyl sulfoxide and 12 ml of water with 52 g of lithium chloride. The mixture is then poured on 5 1 of ice water, extracted with ether, the extract shaken with water, dried over magnesium sulfate, and concentrated under vacuum. Distillation of the residue yields, at 94-96° C and 14 torr, 95 g of the ethyl ester of 2-methyloct-4-ynoic acid as a colorless liquid.
At -70° C, 640 ml of a 1.5-molar butyllithium solution in hexane is added dropwise to a solution of 176 g of the dimethyl ester of methanephosphonic acid in 2 1 of tetrahydrofuran. After 15 minutes, a solution of 90 g of the ethyl ester of 2-methyloct-4-ynoic acid in 300 ml of tetrahydrofuran is gradually added thereto. The mixture is stirred for 4 hours at -70° C, neutralized with acetic acid, and evaporated under vacuum. The residue is combined with 200 ml of water, extracted three times with respectively 500 ml of methylene chloride, the extract is shaken with 100 ml of water, dried over magnesium sulfate, and -23concentrated under vacuum. Distillation of the residue yields, at 0.35 torr and 126-128° C, 80 g of the title compound as a colorless liquid.
Example 4 (5E)-13,14-Didehydro-16,16-dimethyl-18,18,19,19tetradehydro-6a-carbaprostaglandin I2 Analogously to Example 1, 1.5 g of (1R,5S,6R,7R)7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3(tetrahydropyran-2-yloxy)oct-1-en-6-ynyl]bicyclo(3.3,0]octan10 3-one yields 610 mg of (5E)-13,14-didehydro-16,16-dimethyl18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 11,15bis(tetrahydropyran-2-yl ether) as a colorless oil.
IR: 3500 (broad), 2944, 2862, 2222, 1708 cm"1.
After the blocking groups have been split off ac15 cording to Example 1, 290 mg of the title compound is obtained as a colorless oil.
IR: 3600, 3400 (broad), 2930, 2862, 1708, 1600 cm1. 4 5 5 4 - 24 (a) (IR,5S,6R,7R)-3, 3-Ethylenedioxy-7-benzoyloxy6-(2-bromo-4,4-dimethyl-3-oxooct-l-en-6-ynyl)bicyclo(3.3.0]octane In analogy to Example 1(a), 6.25 g of 3,35 dimethyl-2-oxohept-5-ynephosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide, and 5.6 g of (lR,5S,6R,7R)-3,3ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane yield 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2940, 2878, 1710, 1688, 1602, 1594, 1448, 1270, 944 cm*1. (b) (IR,5S,6R,7R)-7-Hydroxy-6-((3S)-2-bromo-4,4dimethyl-3-hydroxyoct-l-en-6-ynyl]bicyclo13.3.0]octan-3-one In analogy to Example 1(b), 4 g of the ketone 15 prepared according to Example 4(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal splitting, 1.40 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3600, 3410 (broad), 2958, 2865, 1738, 1600 cm-3·. - 25 (c) (lR,5S>6R,7R)-7-(Tetrahydropyran-2-yloxy)-6[ (3S)-2-bromo-4,4-dimethyl-3-(tetrahydropyran2- yloxy)oct-l-en-6-ynyl1bicyclo[3.3.0 J octan3- one In analogy to Example 1(c), 1.2 g of the diol produced according to Example 4(b) yields, with dihydropyran, 1.6 g of the title compound as an oil.
IR: 2942, 2870, 1738, 1450, 1132, 960 cm-1.
Example 5 (5E)-13,14-Didehydro-18,18,19,19-tetradehydro16,16,20-trimethyl-6a-carbaprostaglandin I2 Analogously to Example 1, 1 g of (lR,5S,6R,7R)-7(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-4,4-dimethyl-3(tetrahydropyran-2-yloxy)non-l-en-6-ynyl]bicyclo[3.3.0]octan15 3-one yields 400 mg of (5EJ-13,14-didehydro-18,18,19,19tetradehydro-16,16,20-trimethyl-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3510 (broad), 2940, 2858, 2220, 1708 cm'1.
After splitting off the blocking groups according 20 to Example 1, 410 mg of the title compound is obtained as a colorless oil.
IR: 3600, 3340 (broad), 2940, 2832, 2220, 1708, 1600 cm1. - 26 The starting material for the above title compound is prepared as follows: (a) (IR,5S,6R,7R)-3,3-Ethylenedioxy-7-benzoyloxy6-(2-bromo-4,4-dimethyl-3-oxonon-l-en-6-ynyl)5 bicyclo[3.3.0]octane Xn analogy to Example 1(a), 12.6 g of 3,3dimethyl-2-oxooct-5-ynylphosphonic acid dimethyl ester, 7.4 g of N-bromosuccinimide, and 11.2 g of (1R,5S,6R,7R)3,3-ethylenedioxy-7-benzoyloxy-6-formylbicyclo[3.3.0]octane yield 8.7 g of the unsaturated ketone as a colorless oil.
IR: 2946, 2880, 1712, 1687, 1601, 1594, 1272, 948 cm 3. (b) (lR,5S,6R,7R)-7-Hydroxy-6-((3S)-2-bromo-4,4dimethyl-3-hydroxynon-l-en-6-ynyl)bicyclo15 (3.3.0]octan-3-one Analogously to Example 1(b), 5 g of the ketone produced according to Example 5(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal splitting, 1.80 g of the title compound (15a-hydroxy) as a colorless oil.
IR: 3600, 3404 (broad), 2958, 2864, 1738, 1601 cm 3. - 27 (c) (IR,5S,6R,7R)-7-(Tetrahydropyran-2-yloxy)-6[(3S)-2-bromo-4,4-dimethyl-3-(tetrahydropvxan2- yloxy)non-l-en-6-ynyl]bicyclo[3.3.0]octan3- one In analogy to Example 1(c), 1.5 g of the diol prepared according to Example 5(b) produces 2.20 g of the title compound as a colorless oil.
IR: 2942, 2878, 1738, 1125, 968 cm-1.
Example 6 (5E)-13,14-Didehydro-18,18,19,19-tetradehydro-6acarbaprostaglandin I2 Analogously to Example 1, 400 mg of (1R,5S,6R,7R)7-(tetrahydropyran-2-yloxy)-6-[(3S)-2-bromo-3-(tetrahydropyr an-2-yloxy)oct-l-en-6-ynyl]bicyclo(3.3.0]octan-3-one yields 130 mg of (5E)-13,14-didehydro-18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 11,15-bis(tetrahydropyranyl ether) as a colorless oil.
IR: 3500 (broad), 2948, 2862, 2226, 1708 cm-1. After splitting off the blocking groups as described in Example 1, 62 mg of the title compound is obtained as a colorless oil.
IR: 3610, 3350 (broad), 2930, 2862, 2226, 1709, 1600 cm*1. - 28 The starting material for the above title compound is produced as follows: (a) (IP., 5S,6R, 7R)-3,3-Ethylenedioxy-7-benzoyloxy6-(2-bromo-3-oxooct-l-en-6-ynyl)bicyclo[3.3.0]5 octane Analogously to Example 1(a), 5.8 g of 2-oxohept-5-ynylphosphonic acid dimethyl ester, 3.7 g of N-bromosuccinimide, and 5.6 g of (lR,5S,6R,7R)-3,3-ethylenedioxy-7benzoyloxy-6-formylbicyclo[3.3.0]octane yield 4.7 g of the unsaturated ketone as a colorless oil.
IR: 2932, 2880, 1712, 1688, 1600, 1592, 1272, 948 cm-1. (b) (lR,5S,6R,7R)-7-Hydroxy-6-((3S)-2-bromo-3hydroxyoct-l-en-6-yny1]bicyclo[3.3.0]octan15 3-one Analogously to Example 1(b), 4 g of the ketone prepared according to Example 6(a) yields, after reduction with sodium borohydride, saponification with potassium carbonate, and subsequent ketal cleavage, 1.35 g of the title compound as a colorless oil.
IR: 3600, 3410 (broad), 2962, 2866, 1740, 1601 cm-1. 54534 - 29 (c) (IR,5S,6R,7R)-7-(Tetrahydropytan-2-yloxy)6-[(3S)-2-bromo-3-(tetrahydropyran-2-yloxy)oct-l-en-6-ynyl]bicyclo(3.3.0]octan-3-one In analogy to Example 1(c), 1.20 g of the 5 diol prepared according to Example 6(b) yields, with dihydropyran, 1.61 g of the title compound as a colorless oil.
IR: 2945, 2882, 1739, 1125, 968 cm1.
Example 7 (5E)-(16RS)-13,14-Didehydro-16-methyl-18,18,19,1910 tetradehydro-6a-carbaprostaglandin I2 Tris(hydroxymethyl)aminomethane Salt At 65° C, a solution of 121 mg of tris(hydroxymethyl) aminomethane in 0.4 ml of water is added to a solution of 358 mg of (5E)-(I6RS)-13,14-didehydro-16-methyl15 18,18,19,19-tetradehydro-6a-carbaprostaglandin I2 in 60 ml of acetonitrile. The mixture is allowed to cool under agitation, decanted from the solvent after 16 hours, and the residue is dried at 25° C and 0.1 torr, thus obtaining 310 mg of the title compound as a waxy mass.

Claims (6)

1. R-j, R 2 , R3, alkyl group of 1-2 R4 represent a hydrogen atom or an carbon atoms, 5 R5 is an alkyl group of 1-2 carbon atoms, as well as the salts thereof with physiologically compatible bases.
2. (5E){16RS)-20-Ethyl-13,14-didehydro-16-methyl18,18,19,19-tetradehydro-6a-carbaprostaglandin I 2 . 10
3. Process for the preparation of the carbacyclin derivatives of general Formula I, characterized by reacting a compound of general Formula II R-|, R2, R3, R
4. , R5 have the meanings given above and THP means the tetrahydropyranyl residue, with a 5. Wittig reagent of Formula XIX ..0 Ph,P=CH-(CH ) -C^ & (Ill), wherein Ph is a phenyl group, with simultaneous HBr cleavage followed by separating isomers, splitting off blocking groups, and optionally converting the carboxy group into a salt with a physiologically compatible base. 10 4. A pharmaceutical composition, consisting of one or more compounds of claim 1 and 2 and conventional auxiliary agents and excipients.
5. (5E)-(16RS)-13,14-Didehydro-16,20-dimethyl-18,18,19tetrahydro-6a-carbaprostaglandin-l2. 15 6. A compound substantially as described herein with reference to the Examples. -327. A process substantially as described herein with reference to the Examples.
6. 8. A pharmaceutical composition substantially as described herein with reference to the Examples.
IE246/83A 1982-02-08 1983-02-08 Novel carbacyclins, process for the preparation thereof, and use thereof as medicinal agents IE54554B1 (en)

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