FI77847C - Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. - Google Patents
Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. Download PDFInfo
- Publication number
- FI77847C FI77847C FI822205A FI822205A FI77847C FI 77847 C FI77847 C FI 77847C FI 822205 A FI822205 A FI 822205A FI 822205 A FI822205 A FI 822205A FI 77847 C FI77847 C FI 77847C
- Authority
- FI
- Finland
- Prior art keywords
- ester
- preparation
- acid derivatives
- formula
- therapeutically useful
- Prior art date
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- 239000002253 acid Substances 0.000 title description 8
- 238000000034 method Methods 0.000 title description 5
- 238000002360 preparation method Methods 0.000 title description 3
- 125000003545 alkoxy group Chemical group 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 22
- 150000002148 esters Chemical class 0.000 claims description 10
- 150000003839 salts Chemical class 0.000 claims description 8
- 150000003573 thiols Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 2
- 150000001340 alkali metals Chemical class 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004185 ester group Chemical group 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 208000006673 asthma Diseases 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 206010006482 Bronchospasm Diseases 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000001590 oxidative effect Effects 0.000 description 3
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- 208000009079 Bronchial Spasm Diseases 0.000 description 2
- 208000014181 Bronchial disease Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 208000019693 Lung disease Diseases 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002118 epoxides Chemical class 0.000 description 2
- 210000003405 ileum Anatomy 0.000 description 2
- 238000007273 lactonization reaction Methods 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- OROGUZVNAFJPHA-UHFFFAOYSA-N 3-hydroxy-2,4-dimethyl-2H-thiophen-5-one Chemical class CC1SC(=O)C(C)=C1O OROGUZVNAFJPHA-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- KIYVEQBMKSOTSH-UUEFVBAFSA-N COC(C(N(C(C)=O)S)[C@@H](C)CC)=O Chemical compound COC(C(N(C(C)=O)S)[C@@H](C)CC)=O KIYVEQBMKSOTSH-UUEFVBAFSA-N 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 241000272201 Columbiformes Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000002027 dichloromethane extract Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- COQRGFWWJBEXRC-UHFFFAOYSA-N hydron;methyl 2-aminoacetate;chloride Chemical compound Cl.COC(=O)CN COQRGFWWJBEXRC-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000013123 lung function test Methods 0.000 description 1
- YECBIJXISLIIDS-UHFFFAOYSA-N mepyramine Chemical compound C1=CC(OC)=CC=C1CN(CCN(C)C)C1=CC=CC=N1 YECBIJXISLIIDS-UHFFFAOYSA-N 0.000 description 1
- 229960000582 mepyramine Drugs 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical group 0.000 description 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- -1 monomethyl ester Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
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
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B45/00—Formation or introduction of functional groups containing sulfur
- C07B45/04—Formation or introduction of functional groups containing sulfur of sulfonyl or sulfinyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
- C07C317/46—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
- C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
-
- 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
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
-
- 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
- C07D303/38—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D303/40—Compounds containing oxirane rings with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals by ester radicals
- C07D303/42—Acyclic compounds having a chain of seven or more carbon atoms, e.g. epoxidised fats
-
- 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
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/10—Oxygen atoms
- C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
-
- 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
- C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D309/28—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D309/30—Oxygen atoms, e.g. delta-lactones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/04—Seven-membered rings not condensed with other rings
-
- 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
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5304—Acyclic saturated phosphine oxides or thioxides
-
- 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
- C07F9/50—Organo-phosphines
- C07F9/53—Organo-phosphine oxides; Organo-phosphine thioxides
- C07F9/5325—Aromatic phosphine oxides or thioxides (P-C aromatic linkage)
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Biophysics (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
χ 77847
Menetelmä terapeuttisesti käyttökelpoisten alkeenihappo-johdannaisten valmistamiseksi
Keksinnön kohteena on menetelmä farmaseuttisesti 5 aktiivisen yhdisteen valmistamiseksi, jolla on kaava
OH
I COOZ1 C11H23CH=CHNAV^^^ T CH3 ^^NHCOCH3
10 S-C-CH
^H^^COOZ2 1 2 jossa Z ja Z kumpikin on vety, alkalimetalli tai alempi alkyyli.
15 Yhdisteet ovat farmaseuttisesti aktiivisia SRS-A:n antagonisteina.
Läheisiä yhdisteitä tunnetaan mm. EP-hakemusjulkaisusta 36 663 sekä julkaisuista J. of American Chem. Soc. 102 (1980) s. 1436-39 (erityisesti s. 1438 kaava 17) ja 20 Chem. Abstr. 94 (1981), 154001 d sekä Chem. Abstr. 95 (1981), 59785 z.
Keksinnön mukaiset yhdisteet valmistetaan siten, että yhdiste, jolla on kaava . C11H23CH=CH—-—CH^^-^^COOH (IV) tai sen suola tai esteri saatetaan reagoimaan tiolin kanssa, jolla on kaava 30 CH3 ___^nhcoch3 - (V)
“ I "''•-COOH
C2H5 35 Δ 5 tai sen suolan tai esterin kanssa, 2 77847 minkä jälkeen esteriryhmä/esteriryhmät haluttaessa hydrolysoidaan .
Menetelmä suoritetaan vahvan emäksen (pKa<12), kuten trialkyyliamiinin, esim. trietyyliamiinin läsnäollessa 5 ja inertissä polaarisessa liuottimessa, kuten alkanolissa, esim. metanolissa. Sopiva reaktiolämpötila on 10° - 50°C, edullisesti huoneenlämmössä. Reaktiota voidaan katalysoida adsorboimalla kaavan (V) mukainen tioli aktiiviseen alumiinioksidiin .
10 Menetelmässä on edullista käyttää yhdistettä (IV) esterimuodossa, edullisesti C^_4-alkyyliesterimuodossa ja erikoisesti metyyliesterimuodossa. Keksinnön mukainen yhdiste valmistetaan siten aluksi vastaavassa esterimuodossa.
Tässä reaktiossa isomeerinen 5-tio-6-hydroksiyhdis-15 te voi muodostua samalla kun haluttu 5-hydroksi-6-tio- yhdiste. Isomeerinen sivutuote voidaan poistaa seoksesta happomuodon muodostuksella, jota seuraa laktonisaatio, esim. kuumentamalla inertissä luottimessa kuten tolueenis-sa ja vain 5-hydroksi-yhdiste läpikäy laktonisaation.
20 Saadut keksinnön mukaiset yhdisteet voidaan erot taa ja puhdistaa tavanomaisesti.
Keskinäinen muuttaminen useiden keksinnön mukaisten yhdisteiden muotojen välillä, esim. suola-, vapaa happo- ja esterimuotojen välillä voidaan suorittaa tavanomai-25 sesti. Esimerkiksi esterimuodot voidaan muuttaa suolamuo-doiksi käsittelemällä sopivalla vesipitoisella laimealla emäksellä pH-arvossa 9-10. Suolamuodot voidaan muuttaa vapaiksi happomuodoiksi hapon muodostuksella vesipitoisessa väliaineessa. Suola- tai vapaat happomuodot voidaan 30 muuttaa esterimuodoiksi emäksen tai hapon katalysoimalla esteröinnillä käyttäen sopivaa alkoholia. Välituoteyhdis-teet ovat joko tunnettuja tai ne voidaan valmistaa saatavissa olevista lähtöaineista tavanomaisesti.
Kaavan (IV) mukaiset epoksidit voidaan valmistaa 35 hapettamalla kaavan (II) mukaisia yhdisteitä
C11H23CH=CH>^^\^^>S\ COOK
3 77847 edullisesti esterimuodossa käyttäen hapettimena m-kloori-perbentsoehappoa tai vetyperoksidia. Kun hapettimena käytetään m-klooriperbentsoehappoa, hapetus suoritetaan kloroformissa ja kun käytetään vetyperoksidia# hapetus suori-5 tetaan metanolissa.
Keksinnön mukaiset yhdisteet ovat farmaseuttisesti aktiivisia SRS-A:n antagonisteina, kuten on osoitettu seuraavilla kokeilla: in vitro kokeella marsun sykkyräsuo-lisegmentillä väkevyyksissä 10-50 yug julkaisussa Schild, 10 1947 Brit. J. Pharm. 2 197-206 kuvatun menetelmän mukaan (keksinnön mukaisilla yhdisteillä ICj-q SRS-A:ta vastaan on alle 10 4 moolia); in vivo marsun keuhkotoimintakokeel-la (Austen ja Drazen 1974 J. Clin. Invest. 53:1679-1685) laskimonsisäisillä annospitoisuuksilla 0,05 yug - 5,0 mg/kg 15 ja modifioidussa "Herxheimer"-kokeessa annospitoisuuksilla 25-200 mg/kg. "Herxheimer"-koe perustuu marsuihin aikaansaatuun allergiseen keuhkoputken kouristukseen, joka läheisesti muistuttaa astmaattista kohtausta ihmisellä. Keuhkoputken kouristuksen aiheuttavat mediaattorit ovat 20 hyvin samanlaisia kuin ne, jotka vapautuvat kun ihmisen herkistettyyn keuhkokudokseen vaikuttaa antigeeni. Modifioidussa kokeessa, jota käytettiin keksinnön mukaisilla yhdisteillä, eläimet esikäsiteltiin histamiinin antagonistilla, mepyramiinilla aluksi annospitoisuudella 0,5 mg/kg 25 30 min ennen varsinaista annostusta. Tämä modifikaatio peittää histamiinin vaikutuksen niin että SRS-A:n vaikutus tulee paremmin esille.
Esimerkin 1 mukaisen yhdisteen IC^-arvo SRS-A:ta vastaan marsun sykkyräsuolikokeessa (Schild, Brit. J.
30 Pharm. 2 (1947) 197-206) oli 10 ^ ja esimerkin 2 mukaisen -5 yhdisteen 10
Yhdisteet ovat niin ollen sopivia terapeuttista käyttöä varten hoidettaessa keuhkojärjestelmän allergisia reaktioita, joissa SRS-A:ta pidetään keuhkoputken kouris-• · 35 tusta aiheuttavana mediaattorina, so. allergisissa keuhko sairauksissa kuten ulkosyntyisessä astmassa ja teollisuus- A 77847 4 astmoissa kuten maanviljelijän ja kyyhkyskasvattajän keuhkoastmassa, samoin kuin muissa allergisissa sairauksissa, tulehdussairauksissa tai keuhkosairauksissa, joissa SRS-A:ta pidetään mediaattorina.
5 Aktiiviset yhdisteet ovat tehokkaita laajalla an- nostusalueella ja esimerkiksi päivittäiset annostukset ovat 0,5-300 mg/kg, useimmiten 5-100 mg/kg.
Seuraavat esimerkit valaisevat keksintöä.
Esimerkki 1 10 (a) (DL-N-asetyyli-3-merkaptoisoleusyyli)glysiinimetyy- liesteri
Etyyliklooriformaatti (0,12 ml) lisätään sekoitettuun liuokseen, jossa on DL-N-asetyyli-3-merkapto-isoleu-siiniä (0,20 g) dikloorimetaanissa (10 ml) ja trietyyli-15 amiinia (0,28 ml) -10°C:ssa. Liuoksen annetaan lämmetä huoneenlämpöön, pestään laimealla suolahapolla ja sen jälkeen natriumbikarbonaattiliuoksella, kuivataan ja haihdutetaan, jolloin saadaan 3-asetamido-4-etyyli-4-metyyli-2-tioetanoni vaaleana öljynä.
20 Tämän tiolaktonin liuokseen dikloorimetaanissa (5 ml) lisätään kiinteää glysiinimetyyliesterihydrokloridia (0,15 g) ja trietyyliamiinia (0,20 ml) ja seosta sekoitetaan 16 tuntia. Kirkas liuos pestään laimealla suolahapolla ja sen jälkeen natriumbikarbonaattiliuoksella, kuiva-25 taan ja haihdutetaan ja jäännös kiteytetään metanoli-ve-*: destä, jolloin saadaan otsikoitu yhdiste, sp. 136°C.
(b) 5- (S) -hydroksi-6 (R) -Z.T2- (N-asetyyliamino) -2-metok- sikarbonyyli-l-etyyli-l-metyylietyyli)-tiQ/-7-(Z)-nonadekeenihappo ja sen 5-(R)-6-(S)-isomeeri 30 Metyyli-5,6-(E)-oksido-7-(Z)-nonadekenoaatin (162 mg) annetaan reagoida 50°C:ssa 3-4 päivää liuoksen \ kanssa, jossa oli DL-N-asetyyli--merkaptoisoleusiinime- tyyliesteriä (216 mg) ja trietyyliamiinia (200 ^ul) kuivas-; sa metanolissa (500 pl). Kun metanoli on poistettu typpi- 35 virran avulla, jäännös liuotetaan seokseen, jossa on di-etyylieetteri-heksaania 50/50 v/v ja kromatografoidaan 5 77847 käyttäen silikageeliä. Kehittäminen samalla liuotinseok-sella antoi aluksi reagoimattoman epoksidin. Edelleen eluoiminen dikloorimetaani/metanolin 95/5 v/v seoksen kanssa antaa halutun dimetyyliesterin, joka sisältää epäpuh-5 tautena vähän vapaata tiolia, vaaleankeltaisena öljynä.
Sen jälkeen dimetyyliesteri liuotetaan metanoliin (3 ml) ja lisätään 2 M natriumkarbonaattiliuosta (1,5 ml) ja muutama pisara vettä, jolloin saadaan samea liuos. Hydrolyy-sin annetaan jatkua huoneenlämmössä 3 päivää, jonka jäl-10 keen melkein kirkas liuos tehdään varovasti happameksi pH-arvoon 3,5 (käyttäen laimeaa suolahappoa) ja uutetaan dikloorimetaanilla. Yhdistetyt uutteet pestään vedellä, kuivataan magnesiumsulfaatilla ja haihdutetaan tyhjössä, jolloin saadaan otsikoitu yhdiste vaaleankeltaisena vis-15 koosina öljynä.
Esimerkki 2 5- (S) -hydroksi-6- (R) -Z_l2- (N-asetyyliamino) -2-karb-oksi-l-etyyli-l-metyylietyyli)tig7-7-(Z)-nonadekee-nihappo ja sen 5-(R)-6-(S)-isomeeri 20 Esimerkin 1 monometyyliesteri (89 mg) liuotetaan tetrahydrofuraaniin (4 ml) ja lisätään 4 M litiumhydroksi-diliuosta (1 ml) ja sen jälkeen edelleen vettä (3 ml), jolloin saadaan homogeeninen liuos, jota kuumennetaan 48°C:ssa 4 päivän ajan. Tetrahydrofuraani poistetaan haih-25 duttamalla tyhjössä ja jäännös jaetaan dikloorimetaanin ja veden kesken pH-arvossa 3 (säädetty laimealla suolahapolla) . Dikloorimetaaniuute kuivataan magnesiumsulfaatilla ja haihdutetaan typpivirrassa, jolloin saadaan haluttu dikarboksyylihappo värittömänä viskoosina öljynä.
Claims (3)
- 6 77847 Patenttivaatimus Menetelmä farmaseuttisesti aktiivisen yhdisteen valmistamiseksi, jolla on kaava
- 5 OH I COOZ1 C H?1CH=CH 1. ch3 ^^nhcoch3 S-C-CH^ J^—COOZ^
- 10 C2H5 1 . 2 jossa Z ja Z kumpikin on vety, alkalimetalli tai alempi alkyyli, tunnettu siitä, että yhdiste, jolla on kaava 15 ^ C11H 2<3Η-(ίΗ--CH * COOH (IV) tai sen suola tai esteri saatetaan reagoimaan tiolin kanssa, jolla on kaava 20 ^Η3 ^^^NHCOCH3 HS-C -ClC" (V) I ^^-COOH C2H5 25 tai sen suolan tai esterin kanssa, minkä jälkeen esteriryhmä/esteriryhmät haluttaessa hydrolysoidaan .
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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GB8118720 | 1981-06-18 | ||
GB8118720 | 1981-06-18 | ||
GB8213211 | 1982-05-07 | ||
GB8213211 | 1982-05-07 |
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Publication Number | Publication Date |
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FI822205A0 FI822205A0 (fi) | 1982-06-18 |
FI822205L FI822205L (fi) | 1982-12-19 |
FI77847B FI77847B (fi) | 1989-01-31 |
FI77847C true FI77847C (fi) | 1989-05-10 |
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FI822205A FI77847C (fi) | 1981-06-18 | 1982-06-18 | Foerfarande foer framstaellning av terapeutiskt anvaendbara alkensyraderivat. |
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US (1) | US4513005A (fi) |
EP (1) | EP0068739B1 (fi) |
KR (1) | KR890000622B1 (fi) |
AU (1) | AU549814B2 (fi) |
BG (1) | BG37226A3 (fi) |
CA (1) | CA1224795A (fi) |
CS (1) | CS241109B2 (fi) |
DD (1) | DD202697A5 (fi) |
DE (1) | DE3261237D1 (fi) |
DK (1) | DK271682A (fi) |
ES (3) | ES8307212A1 (fi) |
FI (1) | FI77847C (fi) |
GB (1) | GB2101594B (fi) |
GR (1) | GR76838B (fi) |
HU (1) | HU192105B (fi) |
IE (1) | IE53522B1 (fi) |
IL (1) | IL66056A0 (fi) |
NZ (1) | NZ200984A (fi) |
PH (1) | PH23051A (fi) |
PL (4) | PL137766B1 (fi) |
PT (1) | PT75058B (fi) |
RO (1) | RO83706B (fi) |
ZA (1) | ZA824294B (fi) |
Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2480747A1 (fr) * | 1980-04-17 | 1981-10-23 | Roques Bernard | Derives d'acides amines et leur application therapeutique |
US4537723A (en) * | 1982-02-04 | 1985-08-27 | The Upjohn Company | Derivatives of leukotrienes A and C |
US4775662A (en) * | 1983-03-07 | 1988-10-04 | Smithkline Beckman Corporation | Leukotriene antagonists |
DK130984A (da) * | 1983-03-07 | 1984-09-08 | Smithkline Beckman Corp | Leukotrien-antagonister |
DE3469169D1 (en) * | 1983-04-21 | 1988-03-10 | Merck Frosst Canada Inc | Leukotriene antagonists, their production and use and compositions containing them |
US4609744A (en) * | 1983-04-21 | 1986-09-02 | Merck Frosst Canada Inc. | 4-oxo-benzopyran carboxylic acids |
US5017583A (en) * | 1983-04-21 | 1991-05-21 | Merck Frosst Canada, Inc. | Leukotriene antagonists |
US4720505A (en) * | 1983-06-27 | 1988-01-19 | Merck Frosst Canada, Inc. | Leukotriene antagonists |
GB8320943D0 (en) * | 1983-08-03 | 1983-09-07 | Lilly Industries Ltd | Organic compounds |
AU572615B2 (en) | 1983-12-27 | 1988-05-12 | Sony Corporation | Electrically conductive adhesive sheet circuit board and electrical connection structure |
CA1288107C (en) * | 1983-12-27 | 1991-08-27 | Yves Girard | Leukotriene antagonists |
US4761425A (en) * | 1983-12-27 | 1988-08-02 | Merck Frosst Canada, Inc. | Leukotriene antagonists |
US4769386A (en) * | 1984-06-18 | 1988-09-06 | Smithkline Beckman Corporation | Imidazolylthioalkenoic acids and -alkenols and leukotriene antagonistic composition containing them |
EP0170048B1 (de) * | 1984-06-28 | 1991-04-17 | Ciba-Geigy Ag | Aliphatische Thioether |
US4889873A (en) * | 1984-07-18 | 1989-12-26 | Schering Corporation | Inhibitors of slow reacting substance of anaphylaxis |
US4758594A (en) * | 1984-07-18 | 1988-07-19 | Schering Corporation | Inhibitors of slow reacting substance of anaphylaxis |
US4798842A (en) * | 1984-07-18 | 1989-01-17 | Schering Corporation | Inhibitors of slow reacting substance of anaphylaxis |
US4988716A (en) * | 1984-07-18 | 1991-01-29 | Schering Corporation | Inhibitors of slow reacting substance of anaphylaxis |
GB8502258D0 (en) * | 1985-01-30 | 1985-02-27 | Lilly Industries Ltd | Organic compounds |
US4874792A (en) * | 1985-04-19 | 1989-10-17 | Smithkline Beckman Corporation | Thiophenyl Alkanoic acids useful as leukotriene antagonists |
US4937253A (en) * | 1985-04-19 | 1990-06-26 | Smithkline Beecham Corporation | Ester prodrugs |
AU595193B2 (en) * | 1985-04-19 | 1990-03-29 | Smithkline Beckman Corporation | Thio substituted acidic derivatives |
US4939279A (en) * | 1985-04-19 | 1990-07-03 | Smithkline Beecham Corporation | Leukotriene antagonists |
CA1309557C (en) | 1985-06-18 | 1992-10-27 | Robert N. Young | Leukotriene antagonists |
US4990526A (en) * | 1985-06-18 | 1991-02-05 | Merck Frosst Canada, Inc. | Leukotriene antagonists, compositions and methods of use thereof |
US4696946A (en) * | 1985-08-30 | 1987-09-29 | Schering Corporation | Topical Treatment of hyperproliferative skin diseases |
US4783483A (en) * | 1985-10-03 | 1988-11-08 | Ortho Pharmaceutical Corporation | Epoxides useful as antiallergic agents |
FI864901A (fi) * | 1985-12-06 | 1987-06-07 | Ciba Geigy Ag | Hydroxitioetrar. |
KR870011086A (ko) * | 1986-05-29 | 1987-12-19 | 벤자민 에프. 램버트 | 포스포리파제 a₂억제제 및 그의 합성방법 |
GB8709547D0 (en) * | 1987-04-22 | 1987-05-28 | Lilly Industries Ltd | Organic compounds |
DE3724669A1 (de) * | 1987-07-25 | 1989-02-02 | Hoechst Ag | Leukotrienantagonisten, verfahren zu ihrer herstellung und ihre anwendung zur behandlung von krankheiten |
DE3724735A1 (de) * | 1987-07-25 | 1989-02-02 | Hoechst Ag | Leukotrienantagonisten, verfahren zu ihrer herstellung, ihre anwendung zur behandlung von krankheiten, sowie vorprodukte |
GB8725260D0 (en) * | 1987-10-28 | 1987-12-02 | Lilly Industries Ltd | Organic compounds |
AU610528B2 (en) * | 1987-10-29 | 1991-05-23 | Smithkline Beckman Corporation | Leukotriene antagonists |
GB8807016D0 (en) * | 1988-03-24 | 1988-04-27 | Lilly Industries Ltd | Organic compounds & their pharmaceutical use |
US5073571A (en) * | 1988-06-16 | 1991-12-17 | Washington University | Method of inhibiting virus |
US4954513A (en) * | 1988-12-23 | 1990-09-04 | Smithkline Beecham Corporation | Leukotriene antagonists |
US5149835A (en) * | 1989-04-27 | 1992-09-22 | University Of New Mexico | Substituted mevalonolactones, and methods for stereoselective preparation thereof and desmethyl homologues thereof |
EP0410244A1 (en) * | 1989-07-27 | 1991-01-30 | Bayer Ag | Leukotriene antagonists |
US5238683A (en) * | 1989-11-24 | 1993-08-24 | The United States Of America As Represented By The Department Of Health And Human Services | Aerosol preparation of glutathione and a method for augmenting glutathione level in lungs |
WO1991017149A1 (en) * | 1990-05-01 | 1991-11-14 | Smithkline Beecham Corporation | 3-naphthyl-3-carboxyalkylthio or oxy substituted alkanoic acid leukotriene antagonists |
US8026280B2 (en) * | 2001-03-27 | 2011-09-27 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US7842727B2 (en) * | 2001-03-27 | 2010-11-30 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US7312247B2 (en) * | 2001-03-27 | 2007-12-25 | Errant Gene Therapeutics, Llc | Histone deacetylase inhibitors |
US20030212191A1 (en) * | 2002-04-15 | 2003-11-13 | Nippon Bee Chemical Co., Ltd. | Aqueous primer coating composition, process for formation of coating film using said composition, and coated article |
EP1511477A4 (en) * | 2002-05-22 | 2008-04-09 | Errant Gene Therapeutics Llc | HISTONE DEACETYLASE INHIBITORS BASED ON ALPHA-KETO-EPOXYDE COMPOUNDS |
CA2506504A1 (en) * | 2002-11-20 | 2004-06-03 | Errant Gene Therapeutics, Llc | Treatment of lung cells with histone deacetylase inhibitors |
JP5289707B2 (ja) * | 2004-08-31 | 2013-09-11 | 住友ベークライト株式会社 | オキシルアミノ基含有化合物 |
US20060160902A1 (en) * | 2004-11-08 | 2006-07-20 | Wiech Norbert L | Histone deacetylase inhibitors |
US7754838B2 (en) * | 2006-08-08 | 2010-07-13 | E.I. Du Pont De Nemours And Company | Poly(meth)acrylamides and poly(meth)acrylates containing fluorinated amide |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3177227A (en) * | 1963-01-30 | 1965-04-06 | Shell Oil Co | Lactone production |
DE2945497A1 (de) * | 1979-03-06 | 1980-10-09 | Degussa | Derivate der d-2-hydroxy-4-methylmercaptobuttersaeure, verfahren zu deren herstellung und deren verwendung |
US4311645A (en) * | 1980-03-24 | 1982-01-19 | Hoffmann-La Roche Inc. | Synthesis of SRS-active compounds |
FR2479213A1 (fr) * | 1980-03-28 | 1981-10-02 | Roussel Uclaf | Procede de preparation d'acide pentenoique possedant une fonction aldehyde |
JPS57118555A (en) * | 1981-01-13 | 1982-07-23 | Ono Pharmaceut Co Ltd | Leucotriene-analog compound, its preparation, and leucotriene-biosynthesis inhibiting agent containing said compound as active component |
US4352757A (en) * | 1981-02-02 | 1982-10-05 | Smithkline Beckman Corporation | Process for the preparation of esters of leukotriene A |
-
1982
- 1982-06-09 US US06/386,570 patent/US4513005A/en not_active Expired - Fee Related
- 1982-06-14 IL IL66056A patent/IL66056A0/xx not_active IP Right Cessation
- 1982-06-16 DK DK271682A patent/DK271682A/da not_active Application Discontinuation
- 1982-06-16 HU HU821941A patent/HU192105B/hu not_active IP Right Cessation
- 1982-06-16 NZ NZ200984A patent/NZ200984A/en unknown
- 1982-06-16 PT PT75058A patent/PT75058B/pt not_active IP Right Cessation
- 1982-06-16 PH PH27436A patent/PH23051A/en unknown
- 1982-06-17 GB GB08217589A patent/GB2101594B/en not_active Expired
- 1982-06-17 CA CA000405382A patent/CA1224795A/en not_active Expired
- 1982-06-17 RO RO107910A patent/RO83706B/ro unknown
- 1982-06-17 IE IE1443/82A patent/IE53522B1/en not_active IP Right Cessation
- 1982-06-17 BG BG057037A patent/BG37226A3/xx unknown
- 1982-06-17 DE DE8282303154T patent/DE3261237D1/de not_active Expired
- 1982-06-17 DD DD82240838A patent/DD202697A5/de not_active IP Right Cessation
- 1982-06-17 EP EP82303154A patent/EP0068739B1/en not_active Expired
- 1982-06-17 ES ES513221A patent/ES8307212A1/es not_active Expired
- 1982-06-17 ZA ZA824294A patent/ZA824294B/xx unknown
- 1982-06-18 PL PL1982240482A patent/PL137766B1/pl unknown
- 1982-06-18 CS CS824565A patent/CS241109B2/cs unknown
- 1982-06-18 GR GR68479A patent/GR76838B/el unknown
- 1982-06-18 PL PL24048382A patent/PL240483A1/xx unknown
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- 1982-06-18 FI FI822205A patent/FI77847C/fi not_active IP Right Cessation
- 1982-06-18 KR KR828202722A patent/KR890000622B1/ko active
- 1982-06-18 PL PL24048482A patent/PL240484A1/xx unknown
- 1982-06-18 AU AU85008/82A patent/AU549814B2/en not_active Ceased
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1983
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Owner name: LILLY INDUSTRIES LIMITED |