EP0139731A1 - 5-ethinyl-prostacycline, son procede de fabrication et son utilisation pharmaceutique - Google Patents

5-ethinyl-prostacycline, son procede de fabrication et son utilisation pharmaceutique

Info

Publication number
EP0139731A1
EP0139731A1 EP19840901743 EP84901743A EP0139731A1 EP 0139731 A1 EP0139731 A1 EP 0139731A1 EP 19840901743 EP19840901743 EP 19840901743 EP 84901743 A EP84901743 A EP 84901743A EP 0139731 A1 EP0139731 A1 EP 0139731A1
Authority
EP
European Patent Office
Prior art keywords
group
ethynyl
methyl
prostacyclin
atoms
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19840901743
Other languages
German (de)
English (en)
Inventor
Helmut VORBRÜGGEN
Bernd Radüchel
Werner Skuballa
Claus-Steffen Stürzebecher
Martin Haberey
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering AG filed Critical Schering AG
Publication of EP0139731A1 publication Critical patent/EP0139731A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • C07D307/937—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans with hydrocarbon or substituted hydrocarbon radicals directly attached in position 2, e.g. prostacyclins

Definitions

  • Prostacyclin and its analogues are suitable for the treatment of mammals, including humans, due to their biological and pharmacological properties. However, their use encounters difficulties because they are chemically unstable and have a short duration of action for therapeutic purposes. All structural changes have the goal of increasing the duration of action and the selectivity.
  • the compounds according to the invention have an antihypertensive and bronchodilatory effect. They are suitable for vasadilation, inhibition of platelet aggregation and gastric acid secretions, and for cytoprotection on the stomach, heart and liver.
  • the invention relates to prostacyclin derivatives of the general formula I.
  • R 1 is hydrogen, alkyl, cycloalkyl, aryl, a heterocyclic radical or a -CH 2 - aryl group
  • R 2 is an ⁇ or ⁇ hydrogen atom or an ⁇ or ⁇ methyl group
  • R 3 is an alkyl, cycloalkyl or an optionally substituted aryl group or a heterocyclic group
  • B is a straight-chain alkylene group with 1-5 C atoms
  • D is a straight-chain, saturated alkylene group with 1 to 5 C atoms, a branched saturated or a straight-chain unsaturated alkylene group with 2 to 5 C atoms, which can optionally be substituted by fluorine atoms
  • E is an oxygen atom, a -C ⁇ C group or a
  • -CR 4 CR 5 group, where R 4 and R 5 differ and can mean a hydrogen atom or an alkyl group having 1 to 3 carbon atoms and if
  • R 1 has the meaning of a hydrogen atom, the physiologically compatible salts of which mean with inorganic or organic bases.
  • alkyl groups straight or branched chain alkyl groups with 1 to 10 carbon atoms are to be considered, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert. -Butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl.
  • the alkyl groups R 1 can optionally be substituted 1 to more times by halogen atoms, hydroxyl groups, C 1 -C 4 alkoxy groups, optionally substituted C6-C 10 aryl groups, di-C 1 -C 4 alkylamines and tri-C 1 -C 4 alkylammonium. Preferably sinu. those alkyl groups which are monosubstituted.
  • substituents are fluorine, chlorine or eromatome, phenyl, dimethylamino, diethylamino, methoxy, ethoxy.
  • Preferred alkyl groups R 1 are those with 1-4 C atoms, such as, for example, methyl, ethyl, propyl, dimethylaminopropyl, isobutyl, butyl.
  • Aryl groups R 1 are substituted as well as unsubstituted aryl groups in Eestracht, such as phenyl, 1-naphthyl and 2-naphthyl, which can each be substituted by 1-3 halogen atoms, a phenyl group, 1-3 alkyl groups each with 1-4 C. -Atoms, a chloromethyl, fluoromethyl, trifluoromethyl, carboxyl, hydroxy or alkoxy group with 1-4 C-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 cycloalkyl group R 1 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, methylclohexyl and adamantyl.
  • the aryl radical in the -CH 2 - aryl group of R 1 can be phenyl, ⁇ - or ß-naphthyl, which are represented by 1-3-phenyl groups, which in turn are represented by 1-3 halogen atoms such as F, Cl or Br or 1-3 C 1 -C 4 alkoxy groups or 1-3 halogen atoms (F, Cl, Br ) may be substituted. Simple substitutions with phenyl, C 1 -C 2 alkoxy, chlorine or bromine are preferred.
  • Suitable alkyl groups R 3 are straight-chain and branched-chain, saturated and unsaturated alkyl radicals, preferably saturated, with 1-10, in particular 1-7, carbon atoms, which can optionally be substituted by optionally substituted aryl. Examples include methyl, ethyl, propyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, butenyl, isobutyl, propenyl, pentenyl, Hexenyl, benzyl and p-chlorobenzyl.
  • the cycloalkyl group R 3 can contain 3-10, preferably 3-6 carbon atoms in the ring.
  • the rings can be substituted by alkyl groups with 1-4 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and adamantyl.
  • Suitable substituted or unsubstituted aryl groups R 3 are: phenyl, 1-IIaphthyl 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, C 1 -C 4 alkoxy or hydroxyl group.
  • the substitution in the 3- and 4-position on the phenyl ring is preferred, for example by fluorine, chlorine, C 1 -C 4 -alkoxy or trifluoromethyl or in the 4-position by hydroxy.
  • Suitable heterocyclic groups R 3 are 5- and 6-membered heterocycles which contain at least 1 heteroatom, preferably nitrogen, oxygen or sulfur. Examples include 2-furyl, 2-thienyl, 2-pyridyl, 4-pyridyl, 3-furyl, 3-thienyl and others
  • Suitable alkylene groups D are straight-chain or branched-chain, saturated and unsaturated alkylene radicals, preferably saturated ones with 1-5 C atoms, which can optionally be substituted by fluorine atoms. Examples include: methylene, fluoromethylene, ethylene, 1,2-propylene, ethyl ethylene, trimethylene, tetramethylene, pentamethylene, 1-methyltetramethylene, 1-methyltrimethylene.
  • the alkyl groups R 4 and R 5 represent straight-chain or branched saturated alkyl groups with 1-3 C atoms.
  • inorganic and organic bases are suitable, as are known to the person skilled in the art for the formation of physiologically compatible salts.
  • examples include: alkali metal hydroxides such as sodium and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, ammonia, amines such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, tris (hydroxymethyl) methylamine, etc.
  • the invention further relates to a process for the preparation of the prostacyclin derivatives of the general formula I according to the invention, characterized in that a compound of the general formula II
  • R 2 , R 3 , A, B, D and E have the meaning given above, reacted with bromethylene triphenylphosphorane and the resulting
  • the carboxyl group can then be esterified or salts can be formed in the process products obtained.
  • these products are optionally converted into an ester, preferably the methyl ester, purified by column chromatography or preparative thin-layer chromatography on silica gel, and the ester is then saponified.
  • aprotic solvent or solvent mixture for example diethyl ether, tetrahydrofuran or dioxane in a mixture of diethyl ether or tetrahydrofuran.
  • the reaction of the bromoolefins of the general formula III to the products of the general formula I is carried out with bases, such as e.g. Potassium tert-butoxide, sodium ethylate, potassium butoxide, diazabicyclonones, diazabicycloundecene, diazabicyclooctane in solvent such as e.g. Tetrahydrofuran, toluene, xylene at temperatures between 0 ° C and 120 ° C.
  • bases such as e.g. Potassium tert-butoxide, sodium ethylate, potassium butoxide, diazabicyclonones, diazabicycloundecene, diazabicyclooctane in solvent such as e.g. Tetrahydrofuran, toluene, xylene at temperatures between 0 ° C and 120 ° C.
  • the reaction can also be achieved with alkali metal hydroxides, e.
  • the esterification in which R 1 represents an alkyl group with 1-10 C atoms, takes place according to methods known to the person skilled in the art.
  • the carboxyl compounds are reacted, for example, with diazo hydrocarbons in a manner known per se. Esterification with diazo hydrocarbons is carried out, for example, by mixing a solution of the diazohydrocarbon in an inert solvent, preferably in diethyl ether, with the carboxy compound in the same or in another inert solvent, such as, for example, methylene chloride.
  • Diazoalkanes are either known or can be prepared by known methods [Org.Reactions Vol. 8, pages 389-384 (1954)].
  • R 1 represents a substituted or unsubstituted aryl group
  • the esterification is carried out by the methods known to the person skilled in the art.
  • the carboxy compounds and the corresponding arylhydroxy compounds are reacted with dicyclohexylcarbodiimide in the presence of a suitable base, for example pyridine or triethylamine, in an inert solvent.
  • a suitable base for example pyridine or triethylamine
  • 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 + 10 ° C.
  • the esterification can also be carried out by reacting the carboxylate anion with the corresponding alkyl halide or ⁇ -halo ketone (Hal-CH 2 - -Ar, where Ar is phenyl or diphenyl, which can be substituted by C 1 -C 2 alkoxy or chlorine or bromine).
  • alkyl halide or ⁇ -halo ketone Hal-CH 2 - -Ar, where Ar is phenyl or diphenyl, which can be substituted by C 1 -C 2 alkoxy or chlorine or bromine.
  • the prostacyclin derivatives of the general formula I with -R 1 in the meaning of a hydrogen atom can be converted into salts with suitable amounts of the corresponding inorganic bases with neutralization.
  • suitable amounts of the corresponding inorganic bases with neutralization For example, when the corresponding acids are dissolved in water which contains the stoichiometric amount of the base, the water is evaporated off or water is added miscible solvent, for example alcohol or acetone, the solid inorganic salt.
  • the amine salts are prepared in a conventional manner.
  • the prostacyclic acid is dissolved, for example, in a suitable solvent, such as ethanol, acetone, diethyl ether or benzene, and at least the stoichiometric amount of the amine is added to this solution.
  • a suitable solvent such as ethanol, acetone, diethyl ether or benzene
  • the salt is usually obtained in solid form or is isolated in a conventional manner after evaporation of the solvent.
  • R 2 , R 3 , A, B, D and E have the meaning described above, can be prepared by reduction with diisobuty aluminum hydride.
  • the new prostacyclin analogues have the properties typical of prostacyclins, such as a reduction in peripheral arterial and coronary vascular resistance, inhibition of platelet aggregation and dissolution of platelet thrombi, myocardial cytoprotection and thus a reduction in systemic blood pressure, without simultaneously reducing stroke volume and coronary blood flow; Treatment of stroke, prophylaxis and therapy of coronary heart diseases, coronary thrombosis, myocardial infarction, peripheral arterial diseases, arteriosclerosis and thrombosis, prophylaxis and therapy of ischemic attacks of the CNS system, therapy of shock, inhibition of bronchoconstriction, inhibition of gastric acid secretion, gastric acid secretion inhibition Intestinal mucosa, cytoprotection in the liver and pancreas, anti-allergic properties, reduction of pulmonary vascular resistance and pulmonary blood pressure, promotion of renal blood flow, use in place of heparin or as an adjuvant in di
  • the dose of the compounds is 1-1500 ⁇ g / kg / day when administered to the human patient.
  • the unit dose for the pharmaceutically acceptable carrier is 0.01-100 mg.
  • the compounds according to the invention show a greater hypotensive and longer-lasting effect than PGE 2 and PGA 2 , without triggering cardiac arrhythmias like PGE 2 or PGA 2 .
  • the compounds according to the invention show, compared to PGE 2 and PGA 2, a stronger and more prolonged drop in blood pressure without influencing other smooth-muscular organs or organ functions.
  • Sterile, injectable, aqueous or oily solutions are used for parenteral administration.
  • Tablets, coated tablets or capsules, for example, are suitable for oral administration.
  • the invention thus also relates to medicaments based on the compounds of the general formula I and customary auxiliaries and carriers.
  • the active compounds according to the invention are to be used in conjunction with the auxiliaries known and customary in galenics, for example for the production of hypotensive agents.
  • example 1 the auxiliaries known and customary in galenics, for example for the production of hypotensive agents.
  • the product is dissolved in 5 ml of tetrahydrofuran, 75 mg of potassium tert-butoxide are added and the mixture is stirred at 20 ° C. for 18 hours. The mixture is then cooled to 0 ° C., diluted with 10 ml of ice-cold 1 M citrate buffer (pH 6.2) and extracted three times with 15 ml of ethyl acetate each time, the extract is washed with 5 ml of brine, dried over magnesium sulfate and evaporated in vacuo.
  • Example 2 Analogously to Example 1, 50 mg of the title compound is obtained as a colorless oil from 300 mg of 5-formyl-16-methyl-prostacyclin.
  • IR 3600, 3400 br., 3305, 2935, 2863, 2090, 1711, 1630, 1177, 972 / cm.
  • IR 3605, 3400 br., 3305, 2948, 2855, 2098, 1711, 1631, 1185, 976 / cm.
  • IR 3605, 3400 br., 3304, 2925, 2852, 2082, 1712, 1638, 1185, 972 / cm.
  • Example 2 Analogously to Example 1, 42 mg of the title compound are obtained as a colorless oil from 200 mg of 5-formyl- (16RS) -16-methyl-18, 18, 19, 19-tetradehydro-prostacyclin. IR: 3600, 3400 br., 3302, 2930, 2845, 2130, 2085, 1710, 1635, 1168, 976 / cm.
  • the starting material for the above title compound is prepared as follows:
  • IR 3520, 2955, 2930, 2859, 2198, 1712, 1649, 1250, 972, 935, 908, 833 / cm.
  • IR 2955, 2931, 2859, 1730, 1626, 1250, 972, 937, 908, 833 / cm.
  • the starting material is obtained from 5-cyano-16,16-dimethyl-18,13,19,19-tetradehydro-prostacyclin in analogy to Example 5a - 5c.
  • Example 2 Analogously to Example 1, 35 mg of the title compound is obtained as a colorless oil from 200 mg (16RS) - 16,20-dimethyl-5-formyl-18,18,19,19-tetradehydro-prostacyclin. IR: 3600, 3400 br., 3305, 2930, 2861, 2120, 2088, 1710, 1635, 1185, 976 / cm.
  • the starting material is obtained from 5-cyano-16,20-dimethyl-18,18,19,19-tetradehydro-prostacyclin in analogy to Examples 5a - 5c.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Dérivés de 5-éthinyl-prostacycline de formule (I), où R1 représente un hydrogène, un alcoyle, un cycloalcoyle, un aryle, un résidu hétérocyclique ou un groupe$(4,)$, R2 représente un atome d'hydrogène en alpha ou beta ou un groupe méthyle en alpha ou beta, R3 représente un groupe alcoyle, cycloalcoyle ou aryle le cas échéant substitué, ou un groupe hétérocyclique, A représente un groupe -CH2-CH2-, -CH=CH- trans ou -C=C-, B représente un groupe alcène à chaîne droite comportant de 1 à 5 atomes de C, D et E forment ensemble une liaison directe ou D représente un groupe alcène saturé à chaîne droite comportant de 1 à 5 atomes de C, un groupe alcène saturé à chaîne ramifiée ou non saturé à chaîne droite comportant de 2 à 5 atomes de C qui peuvent, le cas échéant, être substitués par des atomes de fluor, E représente un atome d'oxygène, un groupe -C=C- ou un groupe -CR4=CR5-, où R4 et R5 sont différents l'un de l'autre, peuvent représenter un atome d'hydrogène ou un groupe alcoyle comportant de 1 à 3 atomes de C et, si R1 représente un atome d'hydrogène, représentent les sels physiologiquement acceptables desdits composés avec des bases organiques ou inorganiques; leur procédé de fabrication et leur utilisation pharmaceutique.
EP19840901743 1983-04-20 1984-04-17 5-ethinyl-prostacycline, son procede de fabrication et son utilisation pharmaceutique Withdrawn EP0139731A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3314207 1983-04-20
DE19833314207 DE3314207A1 (de) 1983-04-20 1983-04-20 5-aethinyl-prostacycline, verfahren zu ihrer herstellung und ihre pharmazeutische verwendung

Publications (1)

Publication Number Publication Date
EP0139731A1 true EP0139731A1 (fr) 1985-05-08

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ID=6196807

Family Applications (1)

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EP19840901743 Withdrawn EP0139731A1 (fr) 1983-04-20 1984-04-17 5-ethinyl-prostacycline, son procede de fabrication et son utilisation pharmaceutique

Country Status (4)

Country Link
EP (1) EP0139731A1 (fr)
JP (1) JPS60501106A (fr)
DE (1) DE3314207A1 (fr)
WO (1) WO1984004307A1 (fr)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4038308A (en) * 1976-09-13 1977-07-26 American Home Products Corporation Prostaglandin derivatives
DE2809733A1 (de) * 1978-03-03 1979-09-13 Schering Ag Neue prostacyclinderivate und verfahren zu ihrer herstellung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8404307A1 *

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Publication number Publication date
DE3314207A1 (de) 1984-10-25
JPS60501106A (ja) 1985-07-18
WO1984004307A1 (fr) 1984-11-08

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Inventor name: HABEREY, MARTIN

Inventor name: RADUECHEL, BERND

Inventor name: VORBRUEGGEN, HELMUT

Inventor name: SKUBALLA, WERNER

Inventor name: STUERZEBECHER, CLAUS-STEFFEN