DE3151377A1 - Novel O-carbamoylglycero-2-phosphocholines, process for their preparation and pharmaceutical compositions containing them - Google Patents
Novel O-carbamoylglycero-2-phosphocholines, process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- DE3151377A1 DE3151377A1 DE19813151377 DE3151377A DE3151377A1 DE 3151377 A1 DE3151377 A1 DE 3151377A1 DE 19813151377 DE19813151377 DE 19813151377 DE 3151377 A DE3151377 A DE 3151377A DE 3151377 A1 DE3151377 A1 DE 3151377A1
- Authority
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- Germany
- Prior art keywords
- phosphocholine
- glycero
- octadecyl
- hexadecyl
- formula
- 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- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 10
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims description 13
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 4
- 239000012948 isocyanate Substances 0.000 claims description 4
- 150000002513 isocyanates Chemical class 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229930195733 hydrocarbon Natural products 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 239000002879 Lewis base Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 150000007527 lewis bases Chemical class 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 229930195734 saturated hydrocarbon Natural products 0.000 claims description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 claims description 2
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims 1
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical class NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 229940124531 pharmaceutical excipient Drugs 0.000 claims 1
- 239000002516 radical scavenger Substances 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 4
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- HAMGRBXTJNITHG-UHFFFAOYSA-N methyl isocyanate Chemical compound CN=C=O HAMGRBXTJNITHG-UHFFFAOYSA-N 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- OQURWGJAWSLGQG-UHFFFAOYSA-N 1-isocyanatopropane Chemical compound CCCN=C=O OQURWGJAWSLGQG-UHFFFAOYSA-N 0.000 description 2
- GSLTVFIVJMCNBH-UHFFFAOYSA-N 2-isocyanatopropane Chemical compound CC(C)N=C=O GSLTVFIVJMCNBH-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical class OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 150000002170 ethers Chemical class 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 150000002314 glycerols Chemical class 0.000 description 2
- 150000007928 imidazolide derivatives Chemical class 0.000 description 2
- HNHVTXYLRVGMHD-UHFFFAOYSA-N n-butyl isocyanate Chemical compound CCCCN=C=O HNHVTXYLRVGMHD-UHFFFAOYSA-N 0.000 description 2
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 208000025747 Rheumatic disease Diseases 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 238000005904 alkaline hydrolysis reaction Methods 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 230000003143 atherosclerotic effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- WIKQEUJFZPCFNJ-UHFFFAOYSA-N carbonic acid;silver Chemical compound [Ag].[Ag].OC(O)=O WIKQEUJFZPCFNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- GYZLOYUZLJXAJU-UHFFFAOYSA-N diglycidyl ether Chemical class C1OC1COCC1CO1 GYZLOYUZLJXAJU-UHFFFAOYSA-N 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- -1 ester alcohols Chemical class 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910044991 metal oxide Inorganic materials 0.000 description 1
- 150000004706 metal oxides Chemical class 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- OFCCYDUUBNUJIB-UHFFFAOYSA-N n,n-diethylcarbamoyl chloride Chemical compound CCN(CC)C(Cl)=O OFCCYDUUBNUJIB-UHFFFAOYSA-N 0.000 description 1
- OWRABTHGOKNUDV-UHFFFAOYSA-N n,n-dipropylcarbamoyl chloride Chemical compound CCCN(C(Cl)=O)CCC OWRABTHGOKNUDV-UHFFFAOYSA-N 0.000 description 1
- XZVYDRLPXWFRIS-UHFFFAOYSA-N n-ethyl-n-methylcarbamoyl chloride Chemical compound CCN(C)C(Cl)=O XZVYDRLPXWFRIS-UHFFFAOYSA-N 0.000 description 1
- YEMRRHHMLASGRQ-UHFFFAOYSA-N n-methyl-n-propylcarbamoyl chloride Chemical compound CCCN(C)C(Cl)=O YEMRRHHMLASGRQ-UHFFFAOYSA-N 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002831 pharmacologic agent Substances 0.000 description 1
- 238000003408 phase transfer catalysis Methods 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000000552 rheumatic effect Effects 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- KQTXIZHBFFWWFW-UHFFFAOYSA-L silver(I) carbonate Inorganic materials [Ag]OC(=O)O[Ag] KQTXIZHBFFWWFW-UHFFFAOYSA-L 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
Classifications
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/10—Phosphatides, e.g. lecithin
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Beschreibungdescription
Die vorliegende Erfindung betrifft neue O-Carbamoyl-glycero-2-phosphocholine, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Wirkstoff in Arzneimitteln, insbesondere zur Behandlung von Hochdruck und entzündlichen Erkrankungen.The present invention relates to new O-carbamoyl-glycero-2-phosphocholine, Process for their production and their use as an active ingredient in medicinal products, especially for the treatment of hypertension and inflammatory diseases.
Die erfindungsgemäßen O-Carbamoyl-glycero-2-phosphocholine entsprechen der allgemeinen Formel I worin R1 einen geradkettigen gesättigten oder ungesättigten Kohlenwasserstoffrest-mit 10 - 20 Kohlenstoffatomen bedeutet. R2, R3 können gleich oder verschieden sein und stellen einen geradkettigen oder verzweigten Kohlenwasserstoffrest mit 1 - 6 Kohlenstoffatomen oder ein Wasserstoffatom dar.The O-carbamoyl-glycero-2-phosphocholines according to the invention correspond to the general formula I. where R1 is a straight-chain saturated or unsaturated hydrocarbon radical with 10-20 carbon atoms. R2, R3 can be the same or different and represent a straight-chain or branched hydrocarbon radical with 1 - 6 carbon atoms or a hydrogen atom.
Verbindungen gemäß der Erfindung sind be1.spielsweise: 1-0-Hexadecyl-3-0-methylcarbamoyl-glycero-2-phosphocholin, 3-o-Ethylca-rbamoyl-1-0-hexadecyl-glycero-2-phosphocholin, i-O-Hexadecyl-3-0-propylcarbamoyl-glycero-2-phosphocholin, 1-O-Hexadecyl-3-0-isopropylcarbamoyl-glycero-2-phosphocholin, 3-0-Butylcarbamoyl-1-0-hexadeyl-glycero-2-phosphocholin, 1-0-Hexådecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholin, 1-0-Hexadecyl-3-0-hexylcarbamoyl-glycero-2-phosphocholin, 3-0-Methyl carbamoyl-1-O-octadecyl -glycero-2-phosphocholin, 3-O-Ethylcarbamoyl-1-O-octadecyl-glycero-2-phosphocholin, 1-0-Octadecyl-3-0-propylcarbamoyl-glycero-2-phosphocholin, 3-O-Isopropylcarbamoyl-1-O-octadecyl-glycero-2-phosphocholin, 3-0-Butyl carbamoyl -1-O-octadecyl -glycero-2-phosphochol in, 1-0-Octadecyl-3-0-pentylcarbamoyl--glycero-2-phosphocholin, 3"0-HeXylcarbamoyJ-1-0-octadecyl-glycero-2-phosphocholin, 3-O-Methylcarbamoyl-1-O-oleyl-glycero-2-phosphocholin, 3-0-Ethylcarbamoyl-1-0-linolyl-glycero-2-phosphocholin, 3-0-Dimethylc.arbamoyl-1-0-octadecyl-glycero-2-phosphocholin, 3-0-Dimethylcarbamoyl-1-0-hexadecyl-glycero-2-phosphocholin Die erfindungsgemäßen Verbindungen zeigen eine sehr stark blutdrucksenkende Wirkung. Die genannten Verbindungen können daher bzw. darüberhinaus zur Behandlung des Hochdrucks, verschiedener rheumatischer, asthmatischer und atherosklerotischer Beschwerden am Menschen genutzt werden.Compounds according to the invention are, for example: 1-0-hexadecyl-3-0-methylcarbamoyl-glycero-2-phosphocholine, 3-o-ethylcarbamoyl-1-0-hexadecyl-glycero-2-phosphocholine, i-O-hexadecyl-3-0-propylcarbamoyl-glycero-2-phosphocholine, 1-O-hexadecyl-3-0-isopropylcarbamoyl-glycero-2-phosphocholine, 3-0-butylcarbamoyl-1-0-hexadeyl-glycero-2-phosphocholine, 1-0-hexadecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholine, 1-0-hexadecyl-3-0-hexylcarbamoyl-glycero-2-phosphocholine, 3-0-methyl carbamoyl-1-O-octadecyl-glycero-2-phosphocholine, 3-O-ethylcarbamoyl-1-O-octadecyl-glycero-2-phosphocholine, 1-0-octadecyl-3-0-propylcarbamoyl-glycero-2-phosphocholine, 3-O-isopropylcarbamoyl-1-O-octadecyl-glycero-2-phosphocholine, 3-0-butyl carbamoyl -1-O-octadecyl -glycero-2-phosphocholine in, 1-0-octadecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholine, 3 "0-HeXylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine, 3-O-methylcarbamoyl-1-O-oleyl-glycero-2-phosphocholine, 3-0-ethylcarbamoyl-1-0-linolyl-glycero-2-phosphocholine, 3-0-dimethylc.arbamoyl-1-0-octadecyl-glycero-2-phosphocholine, 3-0-Dimethylcarbamoyl-1-0-hexadecyl-glycero-2-phosphocholine Compounds show a very strong antihypertensive effect. The mentioned connections can therefore or in addition to the treatment of high pressure, various rheumatic, asthmatic and atherosclerotic complaints in humans.
Die erfindungsgemäßen Substanzen werden durch Reaktion der Lysoverbindungen -II, worin R1 die in Formel 1 genannte Bedeutung hat, mit Isocyanaten der Formel III, worin R2 die in formel I angegebene Bedeutung hat, nach folgender Gleichung hergestellt: Die Reaktion wird zweckmäßig in organischen aprotischen Lösungsmitteln, wie z.B. Chloroform, Aceton, Dimethylformamid bzw. deren Mischungen, ggfs. unter Anwendung eines Katalysators, insbesondere einer Lewis-Base, wie z.B. Triethylamin, Pyridin, 4-Dimethylaminopyridin, Dimethylformamid, bei Temperaturen zwischen O° und 1OObC, vorzugsweise bei 40 - 60°C, durchoefUhrt.The substances according to the invention are prepared by reacting the lyso compounds -II, in which R1 has the meaning given in formula 1, with isocyanates of the formula III, in which R2 has the meaning given in formula I, according to the following equation: The reaction is expediently carried out in organic aprotic solvents such as chloroform, acetone, dimethylformamide or mixtures thereof, if necessary using a catalyst, in particular a Lewis base, such as triethylamine, pyridine, 4-dimethylaminopyridine, dimethylformamide, at temperatures between 0 ° and 100bC, preferably at 40 - 60 ° C.
Die Isocyanate können auch in Form Ihrer Imidazolide mit der allgemeinen Formel V worin R2 die in Formel r angegebene Bedeutung hat, unter den obengenannten Bedingungen eingesetzt werden, da sich die.The isocyanates can also be in the form of their imidazolides with the general formula V in which R2 has the meaning given in formula r, can be used under the conditions mentioned above, since the.
Imidazolide wie freie Isocyanate verhalten (vergl. H.A.Staa'b und W. Rohr, in: Neuere Methoden der präparativen organischen Chemie, S. 79, Weinheim 1967). Imidazolides behave like free isocyanates (see H.A.Staa'b and W. Rohr, in: Newer methods of preparative organic chemistry, p. 79, Weinheim 1967).
Als Ausgangsverbindungen II kommen in Frage: 1-0-Decyl-glycero-2-phosphocholin, 1-0-Undecyl-glycero-2-phosphocholin, 1-0-Dodecyl-glycero-2-phosphocholin, 1-0-Tridecyl-glycero-2-phosphocholin, 1-0-Tetradecyl-glycero-2-phosphocholin, 1-0-Pentadecyl-glycero-2-phosphocholin, 1-0-Hexadecyl-glycero-2-phosphocholin, 1-0-Heptadecyl-glycero-2-phosphocholin, 1-0-Octadecyl-glycero-2-phosphocholin, 1-0-Nonadecyl-glycero-2-phosphocholin, 1-0-Eicosyl-glycero-2-phosphocholin, 1-0-Oleyl-glycero-2-phosphocholin, 1-0-Linolyl-glycero-2-phosphocholin, wobei die Lysoverbindungen in der natürlichen sn-Form, in Form der Spiegelbildisomeren oder als Racemate eingesetzt werden können.Possible starting compounds II are: 1-0-decyl-glycero-2-phosphocholine, 1-0-Undecyl-glycero-2-phosphocholine, 1-0-Dodecyl-glycero-2-phosphocholine, 1-0-Tridecyl-glycero-2-phosphocholine, 1-0-tetradecyl-glycero-2-phosphocholine, 1-0-pentadecyl-glycero-2-phosphocholine, 1-0-hexadecyl-glycero-2-phosphocholine, 1-0-heptadecyl-glycero-2-phosphocholine, 1-0-octadecyl-glycero-2-phosphocholine, 1-0-nonadecyl-glycero-2-phosphocholine, 1-0-eicosyl-glycero-2-phosphocholine, 1-0-oleyl-glycero-2-phosphocholine, 1-0-linolyl-glycero-2-phosphocholine, the lyso compounds being in the natural sn form, in the form of the mirror image isomers or as racemates can be used.
Die als Ausgangsverbindungen verwendeten O-Alkyl-glycero-2-phosphochollne II können durch milde alkalische Hydrolyse aus O-Acyl-O-alkyl-glycero-2-phosphocholinen erhalten werden, die sich aus den Glycerinderivaten der Formel VI in der R1 die in Formel 1 angegebene Bedeutung hat, und R4 einen geradkettigen oder verzweigten Kohlenwasserstoffrest mit 1 - 6 Kohlenstoffatomen bedeutet, nach.bekannten Phosphorylierungsverfahren, wie z.B. durch Umsetzen mit 5-Bromethylphosphorsäuredichiorid in Gegenwart einer Base und nachfolgendes Behandeln mit Trimethylamin herstellen lassen (vergl. z.B. T. Muramatsu et al., Chemistry and fhysics of Lipids 29, 121-127,(1981)).The O-alkyl-glycero-2-phosphocholne II used as starting compounds can be obtained by mild alkaline hydrolysis from O-acyl-O-alkyl-glycero-2-phosphocholines, which are obtained from the glycerol derivatives of the formula VI in which R1 has the meaning given in formula 1, and R4 is a straight-chain or branched hydrocarbon radical with 1 - 6 carbon atoms, according to known phosphorylation processes, such as reacting with 5-bromoethylphosphoric acid dichloride in the presence of a base and subsequent treatment with trimethylamine ( See, for example, T. Muramatsu et al., Chemistry and physics of Lipids 29, 121-127, (1981)).
Die Glycer-inderivate VI sind ihrerseits aus 2,3-Epoxypropylethern durch Umsetzung mit den entsprechenden Säuren R COOH analog dem von U.Zeidler, Fette, Seifen,Anstrichmittel 83.(2), 57 (1981) für Esteralkohole beschriebenen Verfahren zugänglich. 2,3-Epoxyether erhält man aus Epichlorhydrinen und den.entsprechenden Alkoholen R1OH am besten durch Phasen-Transferkatalyse nach literaturbekannten Verfahren. Andererseits lassen sich Glycerinderivate VI auch durch Isomerisierung aus den entsprechenden 2-0-Acyl-glycerineth'ern VII z.B. durch einfaches Erwärmen gewinnen. Die Synthese der 2-0-Acylglycerinether wird von K.Mangold, Angew. Chemie 91, 550-560 (1979) beschrieben.The glycerine derivatives VI are in turn obtainable from 2,3-epoxypropyl ethers by reaction with the corresponding acids R COOH analogously to the process described by U.Zeidler, Fette, Seifen, Anstrichmittel 83. (2), 57 (1981) for ester alcohols. 2,3-Epoxy ethers are best obtained from epichlorohydrins and the corresponding alcohols R1OH by phase transfer catalysis using processes known from the literature. On the other hand, glycerol derivatives VI can also be isomerized from the corresponding 2-0-acyl-glycerol ethers VII eg win by simply heating. The synthesis of the 2-0-acylglycerol ethers is described by K. Mangold, Angew. Chemie 91, 550-560 (1979).
Die Lys.overbindungen II können auch aus 1-0-Alkyl-3-0-benzylglycerinen synthetisiert werden, indem man diese -in Form der einzelnen Enantiomeren oder des Racemats durch Umsetzen mit -Bromethylphosphorsäuredichlorid' in Gegenwart einer Base und nachfolgendes Behandelnwmit Trimethylamin in die 1-O-Alkyl-3-0-benzyl-glycero-2-phosphocholine überführt, die ihrerseits durch Hydrieren in Gegenwart eines Katalysators, wie z.B. Palladium/Aktivkohle, die Verbindungen. II ergeben. The Lys.overbindungen II can also from 1-0-alkyl-3-0-benzylglycerols can be synthesized by converting them in the form of the individual enantiomers or of the Racemats by reacting with -Bromethylphosphorsäuredichlorid 'in the presence of a Base and subsequent treatment with trimethylamine to form the 1-O-alkyl-3-0-benzyl-glycero-2-phosphocholines transferred, which in turn by hydrogenation in the presence of a catalyst, such as e.g. Palladium / activated carbon, the compounds. II result.
Aus den genannten Lysoverbindungen II lassen sich durch Umsetzung mit Dialkylcarbamidsäurehaloqeniden, insbesondere mit Chloriden der Formel IV wie z.B.The lyso compounds II mentioned can be converted by reaction with dialkylcarbamic acid halides, in particular with chlorides of the formula IV such as
N,N-Dimethylcarbamidsäurechlorid, N-Ethyl-N-methylcarbamidsäurechlorid, N,N-Diethylcarbamidsäurechlorid, N-Methyl-N-prppylcarbamidsäurechlorid, N,N-Dipropylcarbamidsäurechlorid, in indifferenten organischen Lösungsmitteln, wie z.B. Chloroform, sowie Lösungsmittelgemischen, ggfs. unter Zusatz von üblichen Basen, wie z.B. tertiären Aminen, Metalloxiden, Metallcarbonaten,1-O-Alkyl-3-O-dialkylcarbamoyl-glycero-2-phosphocholine der Formel I ( R3=Alkyl) herstellen.N, N-dimethylcarbamic acid chloride, N-ethyl-N-methylcarbamic acid chloride, N, N-diethylcarbamic acid chloride, N-methyl-N-propylcarbamic acid chloride, N, N-dipropylcarbamic acid chloride, in inert organic solvents such as chloroform, as well as solvent mixtures, if necessary with the addition of common bases such as tertiary amines, metal oxides, Metal carbonates, 1-O-alkyl-3-O-dialkylcarbamoyl-glycero-2-phosphocholines of the formula I (R3 = alkyl).
bie vorliegende Erfindung betrifft ebenfalls pharmazeutische Präparate, welche Verbindungen der Formel 1 enthalten. Bei den erfindungsgemäßen pharmazeutischen Präparaten handelt es sich um solche zur enteralen, wie. oralen oder rektalen sowie par-enteralen Verabreichung, welche die pharmakologischen Wirkstoffe allein oder zusammen mit einem üblichen pharmazeutisch an-wendbaren Trägermaterial enthalten. Vorteilhafterweise liegt die pharmazeutische Zubereitung des Wirkstoffes in Form von Einzeldosen vor, die auf die gewtinschte Verabreichung abgestimmt sind; wie z.B. Tabletten, Dragees, Kapseln, Suppositorien, Granulate, Lösungen, Emulsionen oder Suspensionen. Die Dosierung der Verbindungen liegt üblicherweise zwischen 1 - 500 mg pro Dosis, vorzugsweise zwischen 5 - 150 mg je Dosis und kann eine oder mehrmals, bevorzugt zwei - bis dreimal täglich, verabreicht werden.The present invention also relates to pharmaceutical preparations, which compounds of formula 1 contain. In the pharmaceutical according to the invention Preparations are those for enteral, such as. oral or rectal as well par-enteral administration, which contains the pharmacological agents alone or together with a conventional pharmaceutically applicable carrier material. The pharmaceutical preparation of the active ingredient is advantageously in the form of single doses that are tailored to the desired administration; how e.g. tablets, coated tablets, capsules, suppositories, granulates, solutions, emulsions or Suspensions. The dosage of the compounds is usually between 1 and 500 mg per dose, preferably between 5 and 150 mg per dose and can administered one or more times, preferably two to three times daily.
Die Herstellung der erfindungsgemäßen Verbindungen wird durch die folgenden Beispiele näher erläutert. Da sich die Verbindungen der Formel I aufgrund ihrer wachsartigen Konsistenz nicht durch Schmelzpunkte charakterisieren lassen, sind die jeweiligen IR-Daten sowie die Rf-Werte der Substanzen aus Formel I angegeben. The preparation of the compounds according to the invention is carried out by the following examples are explained in more detail. Since the compounds of formula I due to their waxy consistency cannot be characterized by melting points, the respective IR data and the Rf values of the substances from formula I are given.
Die IR-Spektren wurden mi-t dem Gerät Perkin-Elmer 257 aufgenommen, wobei die Substanzen als Chioroformlösungen vermessen wurden. The IR spectra were recorded with the Perkin-Elmer 257 device, whereby the substances were measured as chloroform solutions.
Dünnschichtchromatographie: Kieselgel 60F-254, Fa. Merck, Art 5719 .Laufmittel: Chloroform/Methanol/Wasser = 65/25/4 (v/v/v) Beispiel 1 1-0-Hexadecyl-3-0-methylcarbamoyl-glycero-2-phosphocholin. Thin-layer chromatography: silica gel 60F-254, Merck, Art 5719 Eluent: chloroform / methanol / water = 65/25/4 (v / v / v) example 1 1-0-hexadecyl-3-0-methylcarbamoyl-glycero-2-phosphocholine.
Eine Mischung aus 50 mg 1-O-Hexadecyl-glycero-2-phosphocholin, 24 mg Methylisocyanat, 5 ml absol. Chloroform und 0,1 ml Dimethylformamid wird bei 40 - 600C gerührt, bis das Lysophospholipid dünnschich-tchromatographisch nicht mehr nachweisbar ist (Rf = 0,23). Die Lösungsmittel und überschüssiges Methylisocyanat werden im Vakuum entfernt und der Rückstand durch Säulenchromatographie (Kieselgel//Chloroform/Methanol/Wasser) gereinigt. A mixture of 50 mg 1-O-hexadecyl-glycero-2-phosphocholine, 24 mg methyl isocyanate, 5 ml absol. Chloroform and 0.1 ml of dimethylformamide is used at 40 - 60 ° C until the lysophospholipid does not show up on thin-layer chromatography more is detectable (Rf = 0.23). The solvents and excess methyl isocyanate are removed in vacuo and the residue by column chromatography (silica gel // chloroform / methanol / water) cleaned.
Ausbeute: 45 mg, Rf = 0,26, # (C=O) = 1712 cm 1 Analog dieser Vorschrift werden hergestellt: Beispiel 2 3-0-Ethylcarbamoyl-1-0-hexadecyl-lycero-2-phosphocholin aus 50 mg 1-O-Hexadecyl-glycero-2-phosphocholin 28 mg Ethylisocyanat in 5 ml Chlorofotm und 0,1 ml Dimethylformamid. Yield: 45 mg, Rf = 0.26, # (C = O) = 1712 cm 1 analogous to this procedure are prepared: Example 2 3-0-Ethylcarbamoyl-1-0-hexadecyl-lycero-2-phosphocholine from 50 mg of 1-O-hexadecyl-glycero-2-phosphocholine 28 mg of ethyl isocyanate in 5 ml of chloroform and 0.1 ml of dimethylformamide.
Ausbeute: 49 mg, Rf = 0,30, # (C=O) = 1715 cm 1 Beispiel 3 1-0-Hexadecyl-3-0-propylca.rbamoyl-glycero-2-phosphocholin aus 50 mg 1-O-Hexadecyl-glycero-2-phosphocholin 34 mg Propylisocyanat. Yield: 49 mg, Rf = 0.30, # (C = O) = 1715 cm 1 Example 3 1-0-hexadecyl-3-0-propylca.rbamoyl-glycero-2-phosphocholine from 50 mg 1-O-hexadecyl-glycero-2-phosphocholine 34 mg propyl isocyanate.
in 5 ml Chloroform und 0,1 ml Dimethylformamid Ausbeute: 40 mg, Rf = 0,33, # (C=O) = 1710 cm 1 Beispiel 4 1-0-Hexadecyl-3-0-isopropylcarbamoyl-glycero-2-phosphocholin aus 50 mg 1-O-Hexadecyl-glycero-2-phosphocholin 34 mg Isopropylisocyanat in 5 ml Chloroform und 0,1 mi Dimethylformamid Ausbeute: 30 mg, Rf = 0,34, # (C=O) = 1715 cm 1 Beispiel 5 3-0-Butylcarbamoyl-1-P-hexadecyl-lycero-2-phosphocholin aus 50 mg 1-O-Hexadecyl-glycero-2-phosphocholin 40 mg Butylisocyanat In 5 ml Chloroform und 0,1 ml Dimethylformamid Ausbeute: 35 mg, Rf = 0,37, # (C=O) = 1710 cm 1 Beispiel 6 3-0-Methylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin aus 50 mg 1-O-Octadecyl-glycero-2-phosphocholin 24 mg Methylisocyanat in 5 ml Chloroform und 0,1 ml Dimethylformamid Ausbeute 40 mg, Rf = 0,27, # (C=O) = 1715 cm l Beispiel 7 3-0-Ethylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin aus 50 mg 1-O-Octadecyl-glycero-2-phosphocholin 28 mg Ethylisocyanat in 5 ml Chloroform und 0,1 ml Dimethylformamid Ausbeute: 45 mg, Rf - 0,30, r (C=O) = 1712 cm 1 Beispiel 8 1-O-Octadecyl-3-O-propylcarbamoyl-glycero-2-phosphocholin aus 50 mg 1-O-Octadecyl-glycero-2-phosphocholin 34 mg Propylisocyanat in 5 ml Chloroform und~ 0,1 ml Dimethylformamid Ausbeute: 35 mg, Rf = 0,34, t (C=O) = 1715 cmß1 Bespiel 9 3-O-Isopropylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin aus 50 mg 1-O-Octadecyl-glycero-2-phosphocholin 34 mg Isopropylisocyanat in 5 ml Chloroform und 0,1 ml- Dimethylformamid Ausbeute: 32 mg, Rf = 0,34, # (C=O) = 1715 cm 1 Beispiel 10 3-0-Butylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin aus 50 mg 1-0-Octadecyl-glycero-2-phosphocholin 40 mg Butylisocyanat in 5 ml Chloroform und 0,1 ml Dimethylformamid Ausbeute: 38 mg, Rf = 0,38, f (C=O) = 1712 com 1 Beispiel 11 3-0-Dimethylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin. in 5 ml of chloroform and 0.1 ml of dimethylformamide Yield: 40 mg, Rf = 0.33, # (C = O) = 1710 cm 1 Example 4 1-0-hexadecyl-3-0-isopropylcarbamoyl-glycero-2-phosphocholine from 50 mg 1-O-hexadecyl-glycero-2-phosphocholine 34 mg isopropyl isocyanate in 5 ml Chloroform and 0.1 ml of dimethylformamide Yield: 30 mg, Rf = 0.34, # (C = O) = 1715 cm 1 Example 5 3-0-Butylcarbamoyl-1-P-hexadecyl-lycero-2-phosphocholine from 50 mg 1-O-hexadecyl-glycero-2-phosphocholine 40 mg butyl isocyanate in 5 ml chloroform and 0.1 ml of dimethylformamide Yield: 35 mg, Rf = 0.37, # (C = O) = 1710 cm 1 example 6 3-0-Methylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine from 50 mg 1-O-octadecyl-glycero-2-phosphocholine 24 mg of methyl isocyanate in 5 ml of chloroform and 0.1 ml of dimethylformamide, yield 40 mg, Rf = 0.27, # (C = O) = 1715 cm-l Example 7 3-0-Ethylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine from 50 mg of 1-O-octadecyl-glycero-2-phosphocholine 28 mg of ethyl isocyanate in 5 ml of chloroform and 0.1 ml of dimethylformamide Yield: 45 mg, Rf - 0.30, r (C = O) = 1712 cm 1 example 8 1-O-Octadecyl-3-O-propylcarbamoyl-glycero-2-phosphocholine from 50 mg 1-O-octadecyl-glycero-2-phosphocholine 34 mg propyl isocyanate in 5 ml chloroform and ~ 0.1 ml dimethylformamide Yield: 35 mg, Rf = 0.34, t (C = O) = 1715 cm -1 Example 9 3-O-Isopropylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine from 50 mg 1-O-octadecyl-glycero-2-phosphocholine 34 mg isopropyl isocyanate in 5 ml Chloroform and 0.1 ml-dimethylformamide Yield: 32 mg, Rf = 0.34, # (C = O) = 1715 cm 1 Example 10 3-0-Butylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine from 50 mg 1-0-octadecyl-glycero-2-phosphocholine 40 mg butyl isocyanate in 5 ml chloroform and 0.1 ml dimethylformamide Yield: 38 mg, Rf = 0.38, f (C = O) = 1712 com 1 example 11 3-0-Dimethylcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine.
Eine Mischung aus 50 mg 1-0-Octadecyl-glycero-2-phosphocholin, 20 mg Dimethylcarbamidsäurechlorid und 55 mg Silbercarbonat in 5 ml Chloroform wird 24 Stunden bei 50 0C gerührt, das Lösungsmittel im Vakuum abgezogen und der Rückstand durch Säulenchromatographie (Kieselgel//Chloroform/Methanol/ Wasser) gereinigt.A mixture of 50 mg 1-0-octadecyl-glycero-2-phosphocholine, 20 mg of dimethylcarbamic acid chloride and 55 mg of silver carbonate in 5 ml of chloroform Stirred for 24 hours at 50 ° C., the solvent was stripped off in vacuo and the residue purified by column chromatography (silica gel // chloroform / methanol / water).
Ausbeute: 35 mg, Rf = 0,47 Analog dieser Vorschrift wird hergestellt: Beispiel 12 3-0-Dimethylcarbamoyl-1-0-hexadecyl-glycero-2-phosphocholin aus 50 mg 1-0-Hexadecylglycero-2-phosphocholin 21 mg Dimethylcarbamidsäurechlorid 55 mg Ag2CO3 in 5 ml Chloroform Ausbeute: 40 mg, Rf = 0,46 Analog den Beispielen 1 - 10 werden hergestellt: 1-0-Hexadecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholin, t-O-Hexadecyl-3-0-hexylcarbamoyl-glycero-2-phosphocholin, 1-0-Octadecyl-3-0-pentylcarbamoyl--glycero-2-phosphocholin, 3-0-HeXytcarbamoyl-1-0-octadecyl-glycero-2-phosphocholin, 1-0-Linolyl -3-0-methyl carbamoyl -glycero-2-phosphochol in, 3-0-Ethylcarbamoyl-1-0-linolyl-glycero-2-phosphocholin, 1-O-Linolyl-3-0-propylcarbamoyl-glycero-2-phosphocholin, 3-0-Butylcarbamoyl-1-0-linolyl-glycero-2-phosphocholin,-- 1-0-Linolyl-z-O-pentylcarbamoyl-glycero-2-phosphocholin, 3-O-Hexylcarbamo'yl-1-0-l inolylglycero-2-phosphocholin, 3-o-Methylcarbamoyl-1-0-oleyl-glycero-2-phosphocholin, 3-0-Ethylcarbamoyl-1-0-oleyl-glycero-2-phosphocholin, 1-0-Oleyl-3-0-propylcarbåmoyl-glycero-2-phosphocholin, 3-O-Butylcarbamoyl-1-O-oleyl-glycero-2-phosphocholin, 1-0-Oleyl-3-0-pentylcarbamoyl-glycero-2-phosphocholin, 3-Q-HeXylcarbamoyl-1-0-oleyl-glycero-2-phosphocholin,Yield: 35 mg, Rf = 0.47 The following is produced analogously to this specification: Example 12 3-0-Dimethylcarbamoyl-1-0-hexadecyl-glycero-2-phosphocholine from 50 mg 1-0-hexadecylglycero-2-phosphocholine 21 mg dimethylcarbamic acid chloride 55 mg Ag2CO3 in 5 ml of chloroform Yield: 40 mg, Rf = 0.46 Analogous to Examples 1-10 manufactured: 1-0-hexadecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholine, t-O-hexadecyl-3-0-hexylcarbamoyl-glycero-2-phosphocholine, 1-0-Octadecyl-3-0-pentylcarbamoyl-glycero-2-phosphocholine, 3-0-HeXytcarbamoyl-1-0-octadecyl-glycero-2-phosphocholine, 1-0-linolyl -3-0-methyl carbamoyl -glycero-2-phosphochol in, 3-0-ethylcarbamoyl-1-0-linolyl-glycero-2-phosphocholine, 1-O-linolyl-3-0-propylcarbamoyl-glycero-2-phosphocholine, 3-0-butylcarbamoyl-1-0-linolyl-glycero-2-phosphocholine, - 1-0-linolyl-z-O-pentylcarbamoyl-glycero-2-phosphocholine, 3-O-hexylcarbamoyl-1-0-l inolylglycero-2-phosphocholine, 3-o-methylcarbamoyl-1-0-oleyl-glycero-2-phosphocholine, 3-0-Ethylcarbamoyl-1-0-oleyl-glycero-2-phosphocholine, 1-0-oleyl-3-0-propylcarbamoyl-glycero-2-phosphocholine, 3-O-butylcarbamoyl-1-O-oleyl-glycero-2-phosphocholine, 1-0-oleyl-3-0-pentylcarbamoyl-glycero-2-phosphocholine, 3-Q-HeXylcarbamoyl-1-0-oleyl-glycero-2-phosphocholine,
Claims (1)
Priority Applications (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813151377 DE3151377A1 (en) | 1981-12-24 | 1981-12-24 | Novel O-carbamoylglycero-2-phosphocholines, process for their preparation and pharmaceutical compositions containing them |
| AT82106875T ATE17007T1 (en) | 1981-08-12 | 1982-07-30 | NEW O-ALKYL-O-CARBAMOYL-GLYCERO-PHOSPHOCHOLINES AND PROCESS FOR THEIR PRODUCTION. |
| DE8282106875T DE3268024D1 (en) | 1981-08-12 | 1982-07-30 | 0-alkyl-0-carbamoyl-glycero-phospho-cholines and process for their preparation |
| EP82106875A EP0072936B1 (en) | 1981-08-12 | 1982-07-30 | 0-alkyl-0-carbamoyl-glycero-phospho-cholines and process for their preparation |
| GR68948A GR76280B (en) | 1981-08-12 | 1982-08-03 | |
| DK361282A DK361282A (en) | 1981-08-12 | 1982-08-11 | PROCEDURE FOR THE PREPARATION OF O-ALKYL-O-CARBAMOYL GLYCEROPHOSPHOCHOLINES |
| US06/621,131 US4552869A (en) | 1981-08-12 | 1984-06-15 | O-Alkyl-O-carbamoylglycerophosphocholines and the use for treating hypertension |
| IE1855/82A IE53402B1 (en) | 1981-08-12 | 1988-07-30 | New o-alkyl-o-carbamoylglycerophosphocholines and processes for their preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19813151377 DE3151377A1 (en) | 1981-12-24 | 1981-12-24 | Novel O-carbamoylglycero-2-phosphocholines, process for their preparation and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE3151377A1 true DE3151377A1 (en) | 1983-07-07 |
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ID=6149720
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19813151377 Withdrawn DE3151377A1 (en) | 1981-08-12 | 1981-12-24 | Novel O-carbamoylglycero-2-phosphocholines, process for their preparation and pharmaceutical compositions containing them |
Country Status (1)
| Country | Link |
|---|---|
| DE (1) | DE3151377A1 (en) |
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1981
- 1981-12-24 DE DE19813151377 patent/DE3151377A1/en not_active Withdrawn
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