EP0037422A1 - Prostaglandines et prostacyclines substituees par le fluor - Google Patents

Prostaglandines et prostacyclines substituees par le fluor

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Publication number
EP0037422A1
EP0037422A1 EP80902203A EP80902203A EP0037422A1 EP 0037422 A1 EP0037422 A1 EP 0037422A1 EP 80902203 A EP80902203 A EP 80902203A EP 80902203 A EP80902203 A EP 80902203A EP 0037422 A1 EP0037422 A1 EP 0037422A1
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Prior art keywords
compound
difluoro
alkyl
title compound
procedure
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German (de)
English (en)
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EP0037422A4 (fr
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Josef Fried
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University of Chicago
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University of Chicago
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • C07C29/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C35/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C07C35/48—Halogenated derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C405/0008—Analogues having the carboxyl group in the side-chains replaced by other functional groups
    • C07C405/0016—Analogues having the carboxyl group in the side-chains replaced by other functional groups containing only hydroxy, etherified or esterified hydroxy groups
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • 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
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
    • C07D303/14—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms by free hydroxyl radicals
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/32—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • 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
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • This invention relates to and has as its objective the production of pharmacologically active prostaglandin and prostacyclin compounds which possess a chemical structure whereby they are fluorine substituted in any one or more of the following positions on the molecule 4,4; 7,7; 10,10; and 5,
  • prostaglandin and prostacyclin compounds are those organic compounds possessing generic chemical structures which may be characterized as possessing the following basic skeletal structural formulae derived from prostanoic acid:
  • the compounds of this invention may be generically characterized as prostaglandin and prostacyclin compounds whose chemical structures from the C 4 to C 12 positions of the molecule may be represented by the following formulae:
  • the remaining positions of the molecule of the respective prostaglandin and prostacyclin compounds of this invention may be comprised of those substituents as are well known to and understood by the skilled worker, as more specifically set forth hereinafter, More particularly, it is a specific objective of this invention to produce useful prostaglandin and prostacyclin compounds possessing chemical structural configurations from the C 4 to C 12 positions which may be represented by the following formulae:
  • Y,X,T and W may be H or F, with the proviso that at least one of Y,X,T and W must be F; and wherein V may be H, OH, acyloxy and alkoxy.
  • this invention relates to the production of prostaglandin and prostacyclin compounds possessing the following general chemical structures:
  • Y, T, W, and X may each be H or F; provided that at least one of Y, T, W, and X is F;
  • L may be any side chain which is known in the art to be part of and incorporable in the respective prostaglandin or prostacyclin compound involved, for example, those side chains which are disclosed and taught to the skilled worker in Belgian Patent 851,122, U.S. Patent 4,110,532, U.S. Patent 4,158,667, U.S. Patent 4,191,824, U.S. Patent 4,124,599 and U,S, Patent 4,174,441 to be possible to incorporate in the said compounds, the teachings and disclosures of which patents are incorporated herein by specific reference thereto;
  • Z may also be any side chain which is known in the art to be part of and be possible of incorporation in the respective prostaglandin or prostacyclin compound involved, for example, those side chains which are disclosed and taught to the skilled worker in Belgian Patent 851,122, U.S. Patent 4,110,532, U.S. Patent 4,124,599, U.S. Patent 4,158,667, U.S. Patent 4,191,824, and U.S.
  • Patent 4,174,441 to be possible to incorporate in the said compounds, the teachings and disclosures of which patents are incorporated herein by specific reference; and V may also be any substituent which is known in the art and by the skilled worker to be present at those positions in prostaglandin and prostacyclin compounds as is taught and disclosed to the skilled worker by various prior art publications, such as Belgian Patent 851,122, U.S. Patent 4,110,532, U.S. Patent 4,124,500, U.S. Patent 4,158,667, U.S. Patent 4,191,824, and U.S. Patent 4,174,441, which teachings and disclosures are incorporated hereby by specific reference.
  • V may be hydrogen, hydroxy, acyloxy, lower alkoxy, hydroxy lower alkyl, or oxo
  • Z may be -Z 1 -E, wherein Z 1 is (CH 2 ) -CH 2 ----CH 2 , or - (CH 2 ) -O-CH 2 - , or 2 g / 2 ⁇ g ⁇ -•
  • X 1 is hydrogen, alkyl, cycloalkyl, aralkyl, phenyl, phenyl substituted with chloro or alkyl, an alkali metal or a substituted ammonium cation; or -CH 2 OH; o
  • L 2 or L 3 are hydrogen, alkyl or
  • L 4 is a) amino of the formula -NR 21 R 22 , wherein R 21 and R 22 are hydrogen, alkyl of 1 to 12 carbon atoms inclusive aralkyl of 7 to 12 carbon atoms inclusive, phenyl, phenyl substituted with 1,2 or 3 chloro or alkyl substituents of 1 to 3 carbon atoms inclusive, or phenyl substituted with hydroxy carbonyl or alkoxy carbonyl of 1 to 4 carbon atoms inclusive; or b) carbonylamino of the formula -NR 23 COR 21 , wherein R restroom, is hydrogen or alkyl of 1 to 4 carbon atoms and R 21 is as defined above; or c) sulfonylamino of the formula -NR 23 S0 2 R 21 , wherein R restroom. and R-., are as defined above; or
  • L 5 is p-substituted phenyl selected from the group consisting of:
  • R 24 is methyl, phenyl, acetamidophenyl, benzamidophenyl or -NH 2 ;
  • R 25 is methyl, phenyl, -NH 2 , or methoxy; and
  • R 26 is hydrogen or acetamido;
  • R 3 and R 4 may be H, OH, alkoxy, acyloxy, or fluoro with the proviso that one of R 3 and R 4 is fluoro only when the other is fluoro or hydrogen and when taken together R 3 and R 4 is oxo; and R 7 may be a) -(CH 2 ) g -CH- 3 , wherein g is 3, 4 or.5;
  • R 20 is lower alkyl, lower alkenyl, aralkyl or substituted aralkyl; M, Q, V, W, X, Y and T are as hereinbefore defined.
  • a 1 is Y, W, X and T are H or F; Q is H; R 30 is H or F 20 is lower alkyl; V is H or OH; and M is OR., wherein R. is lower alkyl or an alkali metal, for example, sodium.
  • the compounds of this invention are physiologically active compounds which possess prostacyclin-like activity.
  • the products of this invention may be employed for the purpose of lowering elevated blood pressure and of increasing peripheral blood flow. Therefore, the products of this invention . may be employed in the treatment of hypertension or for the relief of circulatory problems.
  • the compounds of this invention prevent the aggregation of blood platelets thereby removing one of the contributory factors to the formation of atherosclerotic plaques.
  • the products of this invention may be employed prophylactically in patients with a tendency of coronary infarcts.
  • the products of this invention may be employed in hemodialysis and during open heart surgery where it is important to prevent aggregation of platelets thereby impeding the flow of blood through the filter pads.
  • some of the products of this invention cause regression of the corpus luteum, and they can therefore be used for estrus synchronization in farm animals so as to achieve greater economy in the practice of artificial insemination, or as contraceptive agents in the human female. Being protected from metabolic inactivation these compounds can be administered perorally or intravenously, in contrast to the corresponding natural prostaglandins.
  • some of the products of this invention have been found to be resistant to the action of the major prostaglandin inactivating enzyme, 15-hydroxy- prostaglandin dehydrogenase. Such failure to be destroyed in the body has the effect of prolonging or enhancing the action of these substances when compared with the naturally occurring prostaglandins.
  • one of the most important properties of the products of this invention is the considerable chemical stability which is imparted to them by the presence of the fluorine substitutents the 4,4; 7 ,7; 10,10; or 5 positions. As a result of this greatly increased chemical stability the products of this invention retain their biological activity considerably longer than is the case with the naturally occurring prostacyclins .
  • the pharmacologically active compounds of this invention may be administered to the animal or patient being treated therewith in any manner known and convenient to the skilled worker practicing the invention, the dosage and concentration of the final products being adjusted to the requirement of the patient and the properties of the respective compound being employed.
  • the skilled worker may prepare the final products in such compositions and dosage forms as are usually employed for such purposes, depending upon the route of administration selected for the ultimate composition, for example, parenteral, peroral or topical final dosage and routes of administration.
  • R ' ,X', and M ' are as defined herein .
  • cyclopentane-1, 3-dione is converted into the isobutyl ether with isobutanol and a strong acid such as p-tolunesulfonic acid.
  • the resultant racemic enol ether may than be further treated in accordance with this invention with allyl bromide in the presence of a strong base such as lithium diisopropylamide to yield the allyl derivative which is hydrolyzed with a mineral acid such as HC1 and the hydrolysis product (lIb) treated with perchloryl fluoride in the presence of potassium bicarbonate.
  • the intermediate difluoro derivative resulting from this reaction is not isolated but immediately reduced with a hydride reducing agent such as potassium tri-sec-butylborohydride to form the difluoro diol (III).
  • a hydride reducing agent such as potassium tri-sec-butylborohydride
  • This compound is subjected to ozonolysis followed by reductive cleavage of the ozonide, the reducing agent selected being, for example, dimethyl sulfide.
  • the resolution of the lactone (V) involves hydrol- ysis of the latter with a base, such as potassium hydroxide, by the reaction of the resultant salt with optically active ⁇ - (1-naphthyl) -ethylamine yielding crystalline salts which are recrystallized to constant specific rotation and then treated with a base to decompose the salts and to remove the ⁇ - (1-naphthyl) - ethylamine by extraction with ether.
  • the resultant optically active salts are then directly converted into the iodo lactones (Via) and VIb) by treatment with iodine and dilute KOH.
  • the resultant iodo lactones may then be carried forward by the process of this invention either in optically active form or as the racemate, which latter alternative is shown in the center of the formula charts.
  • the iodo lactone (VI) are then converted into the epoxy lactones (VII) by treatment with base followed by mild acid treatment. Some of the resultant epoxy acid which fails to lactonize is converted into the methyl ester with diazomethane and then subjected to chromatography on silica gel which causes the methyl ester to lactonize,
  • the epoxy lactones (VII) are then subject to treatment with lithium aluminum hydride at low temperature to form diol epoxides (VIII). These epoxide derivatives are treated with a dialkyl alkynyl aluminum derivative A to form the various acetylenic derivatives (IX) of this invention.
  • Z' lower Alkyl, preferably CH 3 or C 2 H 5 ;
  • X H or F;
  • T' is lower alkyl from 3 to 6 carbon atoms, for example butyl or pentyl; and
  • Y' is an alcohol protecting group for example, lower alkyl, such as tert-butyl .
  • the resultant triols IX may then be oxidized with oxygen in the presence of a noble metal catalyst, such as Pt, to form the lactones X,
  • a noble metal catalyst such as Pt
  • the lactones may then be reduced with a hydride reagent such as diisobutylaluminum hydride at low temperature to form the hemiacetals of this invention XI which, when treated with the ylid prepared from 5-triphenylphosphonio-pentanoic acid yield after removal of the t-butyl protecting group with trifluoroacetic acid the 10,10-difluoro-13-dehydroprostaglandins XII of this invention, which are new products of this invention.
  • a hydride reagent such as diisobutylaluminum hydride
  • the above prostaglandins of structure XII can then be treated with a diazo-alkane, such as CH 2 N 2 and the resulting ester derivates cyclized by treatment with a halogen or halogenimide such as iodine and sodium bicarbonate to form the iodo ethers XIII.
  • a base such as for instance diazabicyclo[5,4,0] undec-5-ene results e formation of the prosta- cyclins XIV and thei -isomers XV in the form of their esters which form physiologically active end products of this invention. Additional physiologically active products are formed by hydrolysis of the esters with sodium hydroxide, which gives rise to the corresponding sodium salts XIV and XV, respectively.
  • further object of this invention is the production of the 10 ,10-difluoroprostaglandins and the 10,10-difluoro- prostacyclins possessing a trans-double bond in place of the acetylenic bond present in the compounds heretofore described.
  • the synthesis of these compounds starts with the triol-t-butyl ethers IX. Removal of the t-butyl protecting group with trifluoroacetic acid and anisole gives rise to the tetrol IXc, in which the triple bond may now be reduced with lithium aluminum hydride to form the allylic alcohol XVI.
  • the difluoro-lactones (Compounds 1A may be prepared in accordance with the procedures set forth hereinabove. In order to prepare the tetrafluoro (Compounds IC) or the difluoro-analogs (Compounds IB), the following procedure may be employed.
  • Compounds 2 may then be treated in accordance with the procedures set forth herein and treated with a substituted triphenylphosphonioalkanoic acid (Compounds 3) to yield the corresponding prostaglandin (PGF) compounds (Compounds 4) .
  • the known difluoro acid 1A will be converted into the anhydride 2A with acetic anhydride and the anhydride opened selectively with an alcohol e.g., methanol to form the monomethyl ester 3A.
  • an alcohol e.g., methanol
  • the latter will be reduced with a borohydride, e.g., NaBH 4 to the alcohol acid 4A.
  • Compound 4A may then be treated with (CF-.SO-,) somebody0 and pyridine to obtain the triflate 5A which can be converted into the triphenylphosphonio derivative with triphenylphosphine .
  • the latter will be hydrolyzed with acid to form the phosphonio acid salts 7A which may be employed for the synthesis of the compounds 4.
  • the other triphenylphosphonio reactants which are employable in the practice of this invention to yield the 5-fluoro substituted final products, may be prepared in accordance with the following procedure:
  • the difluorophosphonio acid 7A or its hydrogen analog 7B is treated with dimsyl sodium and FC10 3 to form the corresponding 5-fluoro derivatives, 8A and 8B which may be employed for the synthesis of yet additional compounds 4
  • the resultant prostaglandin compounds 4 may then be further treated in accordance with the process of this invention to yield the desired prostacyclin compounds of the invention.
  • the prostaglandin compounds may be treated as follows: Compounds 4 will then be further treated with I 2 or an active halogen compound such as N-bromosuccinimide or N-bromodimethylhydantoin to give the compounds 9 usually as a mixture of diaestereomers which will be separated.
  • the major product will be treated with a base, e.g., DBU as detailed herein followed by alkaline hydrolysis to give the end products, the 5-fluoro; 4,4-, 7,7-difluoro; 4,4,5-, 7,7,5- 10 ,10 , 5-trifluoro; 4,4,7,7-, 7,7,10,10-, 4,4,10,10-hexafluoro and 4,4,5,7,7,10,10- heptafluoroprostacyclin sodium salts 5.
  • a base e.g., DBU as detailed herein followed by alkaline hydrolysis to give the end products, the 5-fluoro; 4,4-, 7,7-difluoro; 4,4,5-, 7,7,5- 10 ,10 , 5-trifluoro; 4,4,7,7-, 7,7,10,10-, 4,4,10,10-hexafluoro and 4,4,5,7,7,10,10- heptafluoroprostacyclin sodium salts 5.
  • diethyl 2-ketoglutarate (Compound a) is converted into diethyl 2 ,2-difluoro-glutarate (Compound b) by treatment with SF. is methylene chloride.
  • Compound b is then selectively reduced with a borohydride, for example, sodium borohydride, to yield the alcohol acid (Compound C) , which may then be oxidized, for example, by the Moffatt-Pfitzner method using DMSO-oxalyl chloride to obtain the aldehyde ester (Compound d) .
  • Compound d is then converted into Compounds 4 by treatment with the ylid compound (Compound e) in a Wittig reaction.
  • Compounds 1 are treated in accordance with the procedures set forth hereinabove in the production of Compounds IXa - IXd, to yield the corresponding poly- fluorinated substituted derivatives (Compounds f_) .
  • Compounds f are then reacted with a triaryl chloro- methane, for example, triphenyl chloromethane in pyridine to form the ether
  • Compounds g which are then treated with an acylating agent, such as, acetic anhydride in pyridine to yield the diester Compounds h.
  • the diesters are then reacted with a dilute organic acid, for example, 90% acetic acid to yield the alcohol Compounds i, which may then be treated with a sulfonating agent, for example, methane sulfonyl chloride in a base, such as pyridine to yield the sulfonated es.ter Compounds j.
  • a sulfonating agent for example, methane sulfonyl chloride in a base, such as pyridine
  • a base such as pyridine
  • These sulfonated Compounds j may then be halogenated by reaction with a metal halide, for example, lithium bromide to yield the corresponding bromide Compounds k.
  • Compounds k may then be treated with a phosphine, such as, triphenyl phosphine to yield the desired acylated phosphonium compounds, which may then be hydrolyzed by treatment with a mild mineral acid, such as hydrochloric acid to yield the corresponding dihydroxy phosphonium compounds, which are then reacted with a strong base, such as butyl lithium to yield the desired ylid compound (Compound e) , which may then be employed to obtain the desired prostaglandin compounds (Compounds 4) of this invention, as hereinbefore described.
  • a phosphine such as, triphenyl phosphine to yield the desired acylated phosphonium compounds
  • a mild mineral acid such as hydrochloric acid
  • a strong base such as butyl lithium
  • the invention may be further illustrated by the following examples.
  • FC10 3 A stream of FC10 3 , purified by passing successively through 2N NaOH solution, 5% Na 2 S 2 O 3 solution and methanol was bubbled at 20° through a solution of 2 g (14.5 mole) of 4-allylcyclopentane-l,3-dione (lib) in 360 ml of methanol containing 3,19 g (31,9 mole) of KHCO-- until the reaction mixture was neutral.
  • the reaction proceeds with formation of a white precipitate of KC10 3 , Excess FC10 3 was removed by bubbling N 2 through the mixture. Toluene (50ml) was added and the methanol was evaporated under reduced pressure.
  • the organic layer was washed successively with 15 ml of 3M NaOH, 15 ml of 4N HC1, 10 ml of saturated NaCl and 10 ml of 3M NaOH. The organic layer was then dried and evaporated. The residue was placed on 50 g silica gel and the column washed with 500 ml of benzene, which completely eluted the compound added as stabilizer to tetrahydrofuran. The column was then washed with a further 1 liter portion of benzene containing 10% ethyl acetate and the solvents evaporated in vacuo. The residue was rechromatographed on 350 g of silica gel.
  • the aqueous layer was then extracted with 400 ml (200 + 100 + 100 ml) of ethyl acetate, and the organic layer washed with 15 ml (10 + 5 ml) of water containing little Na 2 SO 3 and KI .
  • the ethyl acetate layer was dried over anhydrous Na 2 SO 4 , evaporated and finally azeotroped with benzene for 1 1/2 hrs in a flask fitted with a Dean stark water separator. All the benzene was evaporated and the crude residue was chromatographed on 100 g of silica gel.
  • Fractions 59 through 110 contained
  • Trifluoromethanesulfonic anhydride (.825 ml, 4.09 mmole) was added through a syringe over a period of 3-4 min, to a solution of 610 mg (3.43 mmole) of all cis-1,1- difluoro-2,5-dihydroxy-3-carboxymethylcyclopentane
  • the mixture was brought to room temperature and most of the pyridine was evaporated by a stream of N 2 .
  • the last trace of pyridine was evaporated with 8 ml of benzene and the residue was extracted with 24 ml (3x8 ml) of benzene.
  • the benzene extract was evaporated and the crude triflate was taken up in 4 ml of pyridine and refluxed for 12 min.
  • the mixture was cooled and poured into 20 ml of 4N HCl and extracted with 160 ml (2x80ml) of benzene.
  • the benzene layer was washed with 10 ml of water, dried and evaporated.
  • Pieces of dry ice were added to lower the pH to 8-9, followed by solid iodine in one portion (400 mg, 1.57 mmole, 14 fold excess).
  • the contents were strirred at room temperature (24°) for 14 hours in the dark, the methanol evaporated (N 2 ) , ethyl acetate (2 ml) added and evaporated (N 2 ) .
  • the residue was dissolved in ethyl acetate (8 ml) and washed successively with saturated NA 2 SO 3 , water and brine. Removal of ethyl acetate after drying (MgSO 4 ) gave the iodolactone Via as a sticky solid (34.9 mg, quantitative).
  • the crude product was crystallized from CHCI 3 (0.7-0.8 ml) at 60° to give colorless crystals (15.5 mg , 44.5%).
  • the aqueous solution was extracted with 70 ml (40 + 30 ml) of ethyl acetate, the ethyl acetate layer treated with diazomethane and evaporated. The residue was taken up in chloroform, separated from insoluble matter and evaporated to give 29.5 mg of crude compound which is mostly all cis-1 ,1-difluoro- 2-hydroxy-3-carboxymethyl-4,5-epoxycyclopentane methyl ester. This compound was dissolved in little benzene and poured on to 9 g silica gel. After 20 hrs the column was eluted with 100 ml of benzene.
  • Example 14 (2R,3R,4S,5S)-1,1-Difluoro-2-hydroxy-3[2'-hydroxyethyl]- 4 ,5-epoxycyclopentane (Villa). Following the procedure of Example 13 but substituting the [2S ,3S ,4R, 5R-lactone Vila for the racemate there is obtained the title compound (Villa). M p 59-59.5°; [ ⁇ ] D 25 -23° (CHCl 3 ).
  • Example 18 (8S,9S,llR,12R,15S)-l,2,3,4,5-Pentanor-6,9,ll,15- tetrahydroxy-10,10-difluoro-13-prostyne-15-tert-butyl ether (IXc) Following the procedure of Example 16 but substituting the diol epoxide Vlllb for the racemate there is obtained the title compound (IXc). [ ⁇ ] D 25 +29.5°
  • Example 21 (15S ) -1 , 2 , 3 , 4 , 5-Pentanor-9,11,15-trihydroxy-10,10- difluoro-13-prostyn-6-oic acid 6,9-lactone 15-tert butyl ether (Xa) + (Xc) .
  • the test tube containing the triol was therefore rinsed with an additional 6 ml of acetone and this solution was also added.
  • Into the reaction mixture was bubbled O 2 with stirring and heating at 58° for 5 hrs. It was then passed through a pad of celite (15 g), and washed repeatedly with EtOAc. The aqueous layer was separated and concentrated in vacuum to 6-7 ml, saturated with NaCl and extracted again with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated to yield the crude title compound Xa + Xc as a yellow gum. It was purified by tic, and yielded 41.7 mg of pure reaction product, (75%).
  • Example 22 (8R, 9R, US , 12S , 15S) 1,2,3,4, 5-Pentanor-9,ll,15-trihydroxy- 10,10-difluoro-13-prostyn-6-oic acid 6,9-lactone 15- tert butyl ether (Xa) .
  • Example 24 (8R,9R, US, 12S,15S,16S)-1,2,3,4,5-Pentanor-9,11,15- trihydroxy-10,10,16-trifluoro-13-prostyn-6-oic acid 6,9-lactone 15-tert butyl ether (Xb) Following the procedure of Example 21 but substituting the trifluoro triol IXb for the triol IXa + IXc there is obtained the title compound (Xb) .
  • Example 28 (8S,9S,11R,12R,15S)-1,2,3,4,5-Pentanor-9,11,15- trihydroxy-10,10-difluoro-13-prostyn-6-al hemiacetal 15-tert butyl ether (XIc). Following the procedure of Example 26 but substituting the lactone Xc for the lactone Xa + Xc there is obtained the title compound (XIc) . [ ⁇ ] D 25 -39.0 (CHC1 3 ).
  • Example 30 (8S,9S,llR,12R,15S,16S)-l,2,3,4,5-Pentanor-9,ll,15- trihydroxy-10,10,16-trifluoro-13-prostyn-6-al hemiacetal 15-tert butyl ether (Xld), Following the procedure of Example 26 but substituting the lactone Xd for the lactone Xa + xc there is obtained the title compound (Xld).
  • the Na 2 CO 3 layer was acidified with cold 10% HCl to pH 1 and extracted repeatedly with EtOAc.
  • the EtOAc extract was washed with brine, dried, (Na 2 S0 4 ) and evaporated to yield 18.2 mg of a yellow gum, which was purified by tic.
  • the weight of pure 10 10-difluoro-13-dehydro-PGF.
  • Example 44 10,10,16-Trifluoro-5-iodo-9-deoxy-6,9-oxido-13-dehdyro- prostaglandin F 1 ⁇ Methyl ester (Xlllb). Following the procedure of Example 41 but substituting the trifluoro compound Xlld for the difluoro compound XIIc + XIIi there is obtained the title compound (XHIb).
  • Example 46 10 , 10-Difluoro-13-dehydro prostacyclin Methyl ester (XlVa) + (XlVe) and its ⁇ 4 -Isomer (XVA) + (XVe) .
  • Example 47 10 ,10-Difluoro-13-dehydro prostacyclin Methyl ester (XlVa) and its ⁇ 4 -isomer (XVa) .
  • Example 49 10,10 ,16-Trifluoro-13-dehydroprostacyclin Methyl ester (XIVc) and its ⁇ 4 -isomer (XVe) .
  • XIVc Trifluoro-13-dehydroprostacyclin Methyl ester
  • XVe ⁇ 4 -isomer
  • Example 52 10-Difluoro-13-dehydroprostacyclin sodium salt (XlVb) Following the procedure of Example 51 but substituting the methyl ester XlVa for the mixture XlVa + XlVe there is obtained the title compound (XlVb) .
  • Example 53 10-Difluoro-13-dehydroprostacyclin sodium salt (XlVf) . Following the procedure of Example 51 but substituting the methyl ester XlVe for the mixture XlVa + XlVe there is obtained the title compound (XlVf).
  • Example 54 10 ,10,16-Trifluoro-13-dehydroprostacyclin sodium salt (XlVd) .
  • Example 56 10,10-Difluoro-13-dehydroprostacyclin (4E) -Isomer Sodium Salt (XVb) + (XVf) .
  • XVb 10-Difluoro-13-dehydroprostacyclin
  • XVf 10-Isomer Sodium Salt
  • Trifluoroacetic acid (2.50 ml) was added in one portio to 146 mg of the t-butyl-triol-yne (IXa) cooled to 0-5°.
  • the magnetically stirred solution was placed in a cold room at -15°, and the reaction followed by tic. After completion (4 hr), workup of the reaction was performed at 0-5° with addition of saturated Na 2 CO 3 solution (approx. 17 ml) until pH 10 followed by addition of 13 ml of MeOH. The contents were stirred at room temperature of 0.5 hr, 10% HC1 was added until the solution was neutral followed by addition of 50 ml of saturated NaCl solution.
  • reaction vessel was cooled to 0-5° and 10% HC1 was added until the evolution of gas ceased followed by addition of 30 ml of saturated NaCl solution.
  • the aqueous solution was extracted with EtOAc (8 X 50 ml) the EtOAc extracts washed with saturated NaCl solution (Ix) , and then dried over anhydrous Na 2 SO 4 . Filtration and removal of solvent under vacuum gave 40 mg (88%) of crude material.
  • Example 63 (8R,9R,US,12S)-1,2,3,4,5-Pentanor-9,11,15-trihydroxy- 10,10-difluoro-13-prosten-6-oic acid 6,9-lactone (XVII), Following the procedure of Example 21 but substituting the tetrol-ene XVI for the triol-yne IXa + IXc there is obtained the title compound (XVII)
  • Example 64 (8R,9RAlSfl2S,15SH,2,3,4,5-Pentanor-9,11,15-trihydroxy- 10,10-difluoro-13-prostyn-6-al hemiacetal (XVIII).
  • Example 65 10-Difluoroprostaglandin F 2 ⁇ (XIX).
  • Example 68 10,10-Difluoroprostacyclin (XXIIa). Following the procedure of Example 51 but substituting 10 , 10-difluoro-prostacyclin methyl ester XXII for the 13-dehydro methyl ester XlVa + XlVe there is obtained the title compound (XXIa) .
  • Example 69 Following the procedure set forth in Example 16, but substituting equivalent amounts of either dimethyl- 3-t-butyloxy-l-nonynylalane, or dimethyl-3-t-butyloxy- 4-fluoro-l-nonynylalane for the dimethyl-3-t-butyloxy- 1-octynylalane the corresponding homologous derivatives are obtained.
  • Example 70 2 ,2-Difluoroglutaric Anhydride.
  • a solution of 5 g of 2 ,2-difluoroglutaric acid in 20 ml of acetic anhydride is refluxed for two hrs, 5 ml of the resulting solution is distilled off at ordinary pressure and the residual solution freed from acetic anhydride under reduced pressure.
  • the resulting oil consists of 2 ,2-difluoroglutaric anhydride.
  • Example 72 4,4-Difluoro-5-hydroxy-n-pentanoic Acid Methyl Ester, To a solution of 2 g of 2 ,2-difluoroglutaric acid 1-methyl ester in 20 ml of methanol is added at 25° 250 mg of sodium borohydride and the mixture allowed to remain at 25° for 2 hrs. The solution is diluted with water and acidified to pH 1 with IN HCl and the methanol removed in vacuo. The residual suspension is extracted with methylene chloride and the extract dried with sodium sulfate and evaporated to dryness in vacuo. The residual oil is treated with ethereal diazomethane until the yellow color persists and the ether is removed in vacuo. There remains behind the title compound.
  • Example 73 4,4-Difluoro-5-triphenylphosphoniopentanoic Acid Hydrochloride.
  • Example 74 5-Fluoro-5-triphenylphosphoniopentanoic Acid, To a solution of dimsyl sodium in 5 ml of dimethylsulfoxide prepared from 84 mg of sodium hydride is added 888 mg of 5-triphenylphosphonio- pentanoic acid hydrochloride in 15 ml of DMSO. Into this solution is bubbled at 25° purified perchloryl- fluoride until the solution is neutral. Water is then added and dilute HCl and the fluoroacid extracted with methylene chloride. The organic extract is dried over sodium sulfate and evaporated to dryness in vacuo leaving behing the fluoroacid.
  • Example 75 4,4, 5-Trifluoro-5-triphenylphosphoniopentanoic Acid .
  • Example 76 Following the procedure of Example 74 but substituting an equivalent amount of 4 ,4-difluoro-5- triphenylphosphoniopentanoic acid hydrochloride in the reaction there is obtained the title compound.
  • Example 76 Following the procedure of Example 74 but substituting an equivalent amount of 4 ,4-difluoro-5- triphenylphosphoniopentanoic acid hydrochloride in the reaction there is obtained the title compound.
  • Example 77 2 3-c ⁇ s-2-Hydroxy-3-Carboxydifluoromethyl- ⁇ 4 -cyclopentene 2,2'-Lactone Following the procedure of Example 76 but substituting an equivalent amount of 2 , 3-cis-2-hydroxy- 3-carboxydifluoromethyl- ⁇ 4 -cyclopentene 2,2'-lactone in the reaction there is obtained the title compound.
  • the aqueous solution was extracted with 70 ml (40+30 ml of ethyl acetate, the ethyl acetate layer treated with diazomethane and evaporated. The residue was taken up in chloroform, separated from insoluble matter and evaporated to give 29.5 mg of crude compound which is mostly all cis-1,1-difluoro-2-hydroxy-3-carboxydifluoro methyl-4,5-epoxycyclopentane methyl ester. This compound was dissolved in little benzene and poured on to 9 g silica gel. After 20 hrs the column was eluted with 100 ml of benzene.
  • Example 85 (15S)-1,2,3,4,5-Pentanor-6,9,11,15-tetrahydroxy-7,7- difluoro-13-prostyne 15-tert-butyl ether.
  • Example 86 (15S)-1,2,3,4,5-Pentanor-9,11,15-trihydroxy-7,7,10,10- tetrafluoro-13-prostyn-6-oic acid 6,9-lactone 15-tert butyl ether.
  • the test tube containing the triol was therefore rinsed with an additional 6 ml of acetone and this solution was also added.
  • Into the reaction mixture was bubbled O 2 with stirring and heating at 58° for 5 hrs. It was then passed through a pad of celite (15 g), and washed repeatedly with EtOAc. The aqueous layer was separated and concentrated in vacuum to 6-7 ml, saturated with NaCl and extracted again with EtOAc. The combined EtOAc extracts were washed with brine, dried (Na 2 SO 4 ) and evaporated to yield the crude title compound as a yellow gum. It was purified by tic, and yielded 41.7 mg of pure reaction product.
  • Example 87 (15S) -1,2,3,4,5-Pentanor-9,11,15-trihydroxy-7,7, - difluoro-13-prostyn-6-oic acid 6,9-lactone 15-tert- butyl ether. Following the procedure of Example 86 but substituting an equivalent amount of the triol of Example 85 in the reaction there is obtained the title compound.
  • Example 88 (15S)-1,2,3,4,5-Pentanor-9,11,15-trihydroxy-7,7,10,10- tetrafluoro-13-prostyn-6-al hemiacetal 15-tert-butyl ether
  • Diisobutyl aluminum hydride (141 ⁇ l) was added dropwise to a stirred solution of 29.4 mg of the lactone of Example 86 in 0.45 mg of toluene at -70° over a 30 second period and the reaction mixture stirred at this temperature for 1 hr.
  • To the mixture was added dropwise a saturated Na 2 SO 4 solution.
  • Example 89 (15S)-1, 2 ,3,4,5-Pentanor-9,11,15-trihydroxy-7,7,- difluoro-13-prostyn-6-al hemiacetal 15-tert-butyl ether Following the procedure of Example 88 but substituting an equivalent amount of the lactone of Example 87 in the reaction there is obtained the title compound.
  • Example 88 was hemiacetal (25.0 mg) of Example 88 in 150 ⁇ l of DMSO was injected into the above solution of the ylide at 25°, followed by two rinsings of a total of 40 ⁇ l. The reaction mixture was then allowed to stir at room temperature for 1 hr, following which it was cooled in ice water and acidified with N/10 HCl, to a pH of 1.
  • PGF 2 was 17.3 mg.
  • the ether extract was washed with brine, dried (Na 2 SO 4 ) and evaporated to yield the crude title compound as a light yellow oil, which was purified by tic.
  • the weight of the pure iodo compound was 5.8 mg (81%).
  • Example 105 Following the procedure of Example 105 but substituting an equivalent amount of the 4,4 ,10 ,10-tetrafluoro compound of Example 103 there is obtained the title compound.
  • Example 105 Following the procedure of Example 105 but substituting an equivalent amount of the 5 ,10 ,10-trifluoro compound of Example 104 there is obtained the title compound.
  • Trifluoroacetic acid (2.50 ml) was added in one portion to 146 mg. of the t-butyl-triol-yne of Example 84 cooled to 0-5°. The magnetically stirred solution was placed in a cold room at -15°, and the reaction followed by tic.
  • Lithium aluminum hydride (0.148 g, 4.10 mmole)
  • the tetraol-yne of Example 46 45 mg, 0.15 mmole
  • 1.5 ml of dry THF were placed in a round bottom flask fitted with a spiral reflux condenser and drying tube. The contents were heated at gentle reflux in an oil bath maintained at 70°, and the reaction followed by glc. After 4 hrs, the reaction vessel was cooled to 0-5° and 10% HCl was added until the evolution of gas ceased followed by addition of 30 ml of saturated NaCl solution.
  • EXAMPLE 120 7,7,10,10-Tetrafluoroprostaglandin F 2 ⁇ . Following the procedure of Example 95 but substituting an equivalent amount of the 7,7,10,10-tetrafluoroprosta- glandin F 2 ⁇ tert-butyl ether of Example 119 there is obtained the title compound.
  • EXAMPLE 138 1,2,3,4 ,5-Pentanor-6, 9 ,ll,15-tetrahydroxy-13-prostyne 15-tert-butyl ether 9,11-diacetate 6-mesylate
  • the ether solution was washed several times with water, dried over sodium sulfate and evaporated to dryness in vacuo leaving the 6-trityl ether 9,11-diacetate 15-tert-butyl ether as an oily residue, which was now treated with 3 ml of 90% acetic acid at room temperature for 18 hrs.
  • the mixture was then taken up in methylene chloride and extracted with bicarbonate to remove acetic acid.
  • the organic phase was dried over sodium sulfate and evaporated to dryness in vacuo .
  • EXAMPLE 140 1,2,3,4, 5-Pentanor-6,9,11,15-tetrahydroxy-7,7,10,10-tetra- fluoro-13-prostyne 15-terjb-butyl ether 9,11-diacetate 6-mesylate
  • a solution of the acetate mesylate of Example 138 (75 mg) and lithium bromide (250 mg) in 5 ml of methyl ethyl ketone is refluxed for 4 hrs .
  • the mixture is taken up in dilute sodium bicarbonate and methylene chloride, the organic phase washed with sodium bicarbonate , the solution dried with Na 2 SO 4 and the solvent evaporated in vacuo.
  • the residual bromide (65 mg) is taken up in acetonitrile and after addition of an equivalent amount of PPH 3 is refluxed for 5 hrs. Removal of the solvent leaves the title compound.
  • reaction mixture was then allowed to stir at 25° for 1 hr following which it was cooled in ice water and acidified with N/10 HCl to a pH of 1. Extraction with ethyl acetate yielded the title compound which was purified by tic .
  • Example 84 Following the procedure of Example 144 but substitutin an equivalent amount of the 7,7 ,10 ,10-tetrafluoroprosty of Example 84 in the reaction there is obtained the title compound.
  • Example 157 Following the procedure of Example 157 but substituting an equivalent amount of 4,4,10,10-tetrafluofo-PGF 2 ⁇ tert butyl ether of Example 144 in this reaction sequence there is obtained the title compound.
  • the invention may be variously otherwise embodied within the scope of the appended Claims.

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Abstract

Composes de prostaglandines et prostacyclines substituees par le fluor dans une ou plusieurs des positions suivantes, 4, 4; 7, 7; 10, 10; et 5.
EP19800902203 1979-10-10 1981-04-21 Prostaglandines et prostacyclines substituees par le fluor. Withdrawn EP0037422A4 (fr)

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US8339879A 1979-10-10 1979-10-10
US83398 1979-10-10
US10852579A 1979-12-31 1979-12-31
US108525 1979-12-31

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
AU642818B2 (en) * 1991-05-23 1993-10-28 Hughes Aircraft Company Dual reflection scanning antenna system

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DE3176313D1 (en) * 1980-12-09 1987-08-20 Teijin Ltd Novel halogenated prostacyclins, process for the production thereof, and pharmaceutical use thereof
CH651033A5 (de) * 1981-03-11 1985-08-30 Hoffmann La Roche Fluorprostacycline.
ES511067A0 (es) * 1981-04-02 1983-06-16 Searle & Co Procedimiento para preparar un derivado de prostaglandina.
US4579958A (en) * 1983-12-23 1986-04-01 G. D. Searle & Co. 5-fluoro-3-oxa-6,7-didehydro-PGI1 compounds
US4616034A (en) * 1985-02-28 1986-10-07 G. D. Searle & Co. 15(R)-5-fluoroprostacyclins, pharmaceutical compositions and anti-thrombotic method of use thereof
JPH01102059A (ja) * 1987-10-16 1989-04-19 Asahi Glass Co Ltd ６−フルオロプロスタグランジン誘導体
DE69502517T2 (de) * 1994-02-17 1998-10-01 Asahi Glass Co Ltd Difluorprostacycline, Zwischenprodukte und Verfahren zu deren Herstellung
IN2015DN02814A (fr) 2012-10-26 2015-09-11 Asahi Glass Co Ltd

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Title
See references of WO8101002A1 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU642818B2 (en) * 1991-05-23 1993-10-28 Hughes Aircraft Company Dual reflection scanning antenna system

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DK251481A (da) 1981-06-09
IT8025285A0 (it) 1980-10-13
JPS56501319A (fr) 1981-09-17
EP0037422A4 (fr) 1982-01-26
WO1981001002A1 (fr) 1981-04-16

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