NO771926L - PROCEDURES FOR THE MANUFACTURE OF VERBENON, MYRTENAL AND PINOCARVEOL - Google Patents
PROCEDURES FOR THE MANUFACTURE OF VERBENON, MYRTENAL AND PINOCARVEOLInfo
- Publication number
- NO771926L NO771926L NO771926A NO771926A NO771926L NO 771926 L NO771926 L NO 771926L NO 771926 A NO771926 A NO 771926A NO 771926 A NO771926 A NO 771926A NO 771926 L NO771926 L NO 771926L
- Authority
- NO
- Norway
- Prior art keywords
- pinocarveol
- myrtenal
- verbenone
- treatment
- pharmaceutical composition
- Prior art date
Links
- 229930006721 pinocarveol Natural products 0.000 title claims description 31
- LCYXQUJDODZYIJ-UHFFFAOYSA-N pinocarveol Chemical compound C1C2C(C)(C)C1CC(O)C2=C LCYXQUJDODZYIJ-UHFFFAOYSA-N 0.000 title claims description 30
- KMRMUZKLFIEVAO-RKDXNWHRSA-N Myrtenal Natural products C1[C@H]2C(C)(C)[C@@H]1CC=C2C=O KMRMUZKLFIEVAO-RKDXNWHRSA-N 0.000 title claims description 29
- KMRMUZKLFIEVAO-UHFFFAOYSA-N 7,7-dimethylbicyclo[3.1.1]hept-3-ene-4-carbaldehyde Chemical compound C1C2C(C)(C)C1CC=C2C=O KMRMUZKLFIEVAO-UHFFFAOYSA-N 0.000 title claims description 28
- 238000000034 method Methods 0.000 title claims description 20
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- DCSCXTJOXBUFGB-JGVFFNPUSA-N (R)-(+)-Verbenone Natural products CC1=CC(=O)[C@@H]2C(C)(C)[C@H]1C2 DCSCXTJOXBUFGB-JGVFFNPUSA-N 0.000 claims description 29
- DCSCXTJOXBUFGB-SFYZADRCSA-N (R)-(+)-verbenone Chemical compound CC1=CC(=O)[C@H]2C(C)(C)[C@@H]1C2 DCSCXTJOXBUFGB-SFYZADRCSA-N 0.000 claims description 29
- DCSCXTJOXBUFGB-UHFFFAOYSA-N verbenone Natural products CC1=CC(=O)C2C(C)(C)C1C2 DCSCXTJOXBUFGB-UHFFFAOYSA-N 0.000 claims description 29
- 239000000203 mixture Substances 0.000 claims description 22
- 235000007586 terpenes Nutrition 0.000 claims description 19
- 150000001875 compounds Chemical class 0.000 claims description 17
- 150000003505 terpenes Chemical class 0.000 claims description 17
- RXBQNMWIQKOSCS-UHFFFAOYSA-N (7,7-dimethyl-4-bicyclo[3.1.1]hept-3-enyl)methanol Chemical compound C1C2C(C)(C)C1CC=C2CO RXBQNMWIQKOSCS-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 230000003647 oxidation Effects 0.000 claims description 9
- 238000007254 oxidation reaction Methods 0.000 claims description 9
- 239000013543 active substance Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- GRWFGVWFFZKLTI-IUCAKERBSA-N 1S,5S-(-)-alpha-Pinene Natural products CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 claims description 7
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 7
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 claims description 7
- 229910052753 mercury Inorganic materials 0.000 claims description 7
- 238000004508 fractional distillation Methods 0.000 claims description 6
- RXBQNMWIQKOSCS-RKDXNWHRSA-N Myrtenol Natural products C1[C@H]2C(C)(C)[C@@H]1CC=C2CO RXBQNMWIQKOSCS-RKDXNWHRSA-N 0.000 claims description 5
- 210000002345 respiratory system Anatomy 0.000 claims description 5
- GRWFGVWFFZKLTI-UHFFFAOYSA-N α-pinene Chemical compound CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 claims description 5
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 claims description 4
- 229940117975 chromium trioxide Drugs 0.000 claims description 4
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 claims description 4
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003242 anti bacterial agent Substances 0.000 claims description 3
- 230000002757 inflammatory effect Effects 0.000 claims description 3
- 230000001590 oxidative effect Effects 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 230000001580 bacterial effect Effects 0.000 claims description 2
- 230000003115 biocidal effect Effects 0.000 claims description 2
- WTARULDDTDQWMU-RKDXNWHRSA-N (+)-β-pinene Chemical compound C1[C@H]2C(C)(C)[C@@H]1CCC2=C WTARULDDTDQWMU-RKDXNWHRSA-N 0.000 claims 1
- WTARULDDTDQWMU-IUCAKERBSA-N (-)-Nopinene Natural products C1[C@@H]2C(C)(C)[C@H]1CCC2=C WTARULDDTDQWMU-IUCAKERBSA-N 0.000 claims 1
- WTARULDDTDQWMU-UHFFFAOYSA-N Pseudopinene Natural products C1C2C(C)(C)C1CCC2=C WTARULDDTDQWMU-UHFFFAOYSA-N 0.000 claims 1
- XCPQUQHBVVXMRQ-UHFFFAOYSA-N alpha-Fenchene Natural products C1CC2C(=C)CC1C2(C)C XCPQUQHBVVXMRQ-UHFFFAOYSA-N 0.000 claims 1
- 229930006722 beta-pinene Natural products 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- LCWMKIHBLJLORW-UHFFFAOYSA-N gamma-carene Natural products C1CC(=C)CC2C(C)(C)C21 LCWMKIHBLJLORW-UHFFFAOYSA-N 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- 230000002458 infectious effect Effects 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 230000001148 spastic effect Effects 0.000 claims 1
- OBROYCQXICMORW-UHFFFAOYSA-N tripropoxyalumane Chemical compound [Al+3].CCC[O-].CCC[O-].CCC[O-] OBROYCQXICMORW-UHFFFAOYSA-N 0.000 claims 1
- OMDMTHRBGUBUCO-IUCAKERBSA-N (1s,5s)-5-(2-hydroxypropan-2-yl)-2-methylcyclohex-2-en-1-ol Chemical compound CC1=CC[C@H](C(C)(C)O)C[C@@H]1O OMDMTHRBGUBUCO-IUCAKERBSA-N 0.000 description 38
- 229960000230 sobrerol Drugs 0.000 description 19
- OMDMTHRBGUBUCO-UHFFFAOYSA-N trans-sobrerol Natural products CC1=CCC(C(C)(C)O)CC1O OMDMTHRBGUBUCO-UHFFFAOYSA-N 0.000 description 19
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 238000000338 in vitro Methods 0.000 description 14
- 230000037396 body weight Effects 0.000 description 11
- 241000700159 Rattus Species 0.000 description 9
- WONIGEXYPVIKFS-UHFFFAOYSA-N Verbenol Chemical class CC1=CC(O)C2C(C)(C)C1C2 WONIGEXYPVIKFS-UHFFFAOYSA-N 0.000 description 9
- 230000000844 anti-bacterial effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
- 230000003182 bronchodilatating effect Effects 0.000 description 7
- 229960001340 histamine Drugs 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 230000001225 therapeutic effect Effects 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000002744 anti-aggregatory effect Effects 0.000 description 6
- 238000001727 in vivo Methods 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 241000700199 Cavia porcellus Species 0.000 description 4
- IRZWAJHUWGZMMT-UHFFFAOYSA-N Chrysanthenol Natural products CC1=CCC2C(C)(C)C1C2O IRZWAJHUWGZMMT-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 230000007059 acute toxicity Effects 0.000 description 4
- 231100000403 acute toxicity Toxicity 0.000 description 4
- 230000008588 hemolysis Effects 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 210000003437 trachea Anatomy 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 3
- 208000009079 Bronchial Spasm Diseases 0.000 description 3
- 208000014181 Bronchial disease Diseases 0.000 description 3
- 206010006482 Bronchospasm Diseases 0.000 description 3
- 206010030113 Oedema Diseases 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 3
- 125000003158 alcohol group Chemical group 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 230000002587 anti-hemolytic effect Effects 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- 235000010418 carrageenan Nutrition 0.000 description 3
- 229920001525 carrageenan Polymers 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000003743 erythrocyte Anatomy 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 150000002576 ketones Chemical class 0.000 description 3
- 238000002560 therapeutic procedure Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000021559 Dicerandra Species 0.000 description 2
- 241000588722 Escherichia Species 0.000 description 2
- 235000010654 Melissa officinalis Nutrition 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- NQFUSWIGRKFAHK-BDNRQGISSA-N alpha-Pinene epoxide Natural products C([C@@H]1O[C@@]11C)[C@@H]2C(C)(C)[C@H]1C2 NQFUSWIGRKFAHK-BDNRQGISSA-N 0.000 description 2
- 229930006723 alpha-pinene oxide Natural products 0.000 description 2
- 125000003425 alpha-pinene oxide group Chemical group 0.000 description 2
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 2
- 230000003555 analeptic effect Effects 0.000 description 2
- 230000002322 anti-exudative effect Effects 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 239000000865 liniment Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229910052759 nickel Inorganic materials 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 150000007659 semicarbazones Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- -1 terpene compounds Chemical class 0.000 description 2
- 230000002446 thrombocytic effect Effects 0.000 description 2
- 210000005090 tracheal smooth muscle Anatomy 0.000 description 2
- DCSCXTJOXBUFGB-MQWKRIRWSA-N (5r)-2,6,6-trimethylbicyclo[3.1.1]hept-2-en-4-one Chemical compound CC1=CC(=O)[C@H]2C(C)(C)C1C2 DCSCXTJOXBUFGB-MQWKRIRWSA-N 0.000 description 1
- FUFLCEKSBBHCMO-UHFFFAOYSA-N 11-dehydrocorticosterone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)C(=O)CO)C4C3CCC2=C1 FUFLCEKSBBHCMO-UHFFFAOYSA-N 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical class [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 description 1
- MFYSYFVPBJMHGN-ZPOLXVRWSA-N Cortisone Chemical compound O=C1CC[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 MFYSYFVPBJMHGN-ZPOLXVRWSA-N 0.000 description 1
- MFYSYFVPBJMHGN-UHFFFAOYSA-N Cortisone Natural products O=C1CCC2(C)C3C(=O)CC(C)(C(CC4)(O)C(=O)CO)C4C3CCC2=C1 MFYSYFVPBJMHGN-UHFFFAOYSA-N 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000007832 Na2SO4 Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 241000779819 Syncarpia glomulifera Species 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 230000001741 anti-phlogistic effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229940124630 bronchodilator Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000973 chemotherapeutic effect Effects 0.000 description 1
- KRVSOGSZCMJSLX-UHFFFAOYSA-L chromic acid Substances O[Cr](O)(=O)=O KRVSOGSZCMJSLX-UHFFFAOYSA-L 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 239000011651 chromium Substances 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Chemical class 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical class [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229960004544 cortisone Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 229910003460 diamond Inorganic materials 0.000 description 1
- 239000010432 diamond Substances 0.000 description 1
- 230000000001 effect on platelet aggregation Effects 0.000 description 1
- 150000002118 epoxides Chemical class 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
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- AWJWCTOOIBYHON-UHFFFAOYSA-N furo[3,4-b]pyrazine-5,7-dione Chemical compound C1=CN=C2C(=O)OC(=O)C2=N1 AWJWCTOOIBYHON-UHFFFAOYSA-N 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012678 infectious agent Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 125000000466 oxiranyl group Chemical group 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000001739 pinus spp. Substances 0.000 description 1
- 208000008423 pleurisy Diseases 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000007348 radical reaction Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 238000001256 steam distillation Methods 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000017105 transposition Effects 0.000 description 1
- 229940036248 turpentine Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- 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
- C07C45/27—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation
- C07C45/28—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by oxidation of CHx-moieties
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/78—Separation; Purification; Stabilisation; Use of additives
- C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation
- C07C45/82—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation by distillation
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Pulmonology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Steroid Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Description
Fremgangsmåte for fremstilling avMethod of manufacture of
verbenon, myrtenal og pinokarveol.verbenone, myrtenal and pinocarveol.
Oppfinnelsen vedrører fremstilling av verbenon, myrtenal og pinokarveol ved oksydering av terpenblandinger, The invention relates to the production of verbenone, myrtenal and pinocarveol by oxidizing terpene mixtures,
samt deres bruk i terapien for bronkopneumoniale sykdommer. as well as their use in the therapy of bronchopneumonic diseases.
Fremstillingen av verbenon og myrtenal, idet det gåes ut fra a-pinen ved oksyderén&e selvkatalyse i nærvær av salter av krom, kobolt og andre er gjentatt omtalt i utbytter fra 15 til 20%. En av grunnene for det lave reaksjonsutbytte er dannelsen av biprodukter av den homolyti ske reaksjon (radi-kal reaksjon) som verbenoler og myrtenoler, sistnevnte er alkoholer som ikke kan ytterligere oksyderes til ketoner i det spesifikke reaksjonsmedium. The production of verbenone and myrtenal, starting from α-pinene by oxyderene self-catalysis in the presence of salts of chromium, cobalt and others, has been repeatedly discussed in yields of 15 to 20%. One of the reasons for the low reaction yield is the formation of by-products of the homolytic reaction (radical reaction) such as verbenols and myrtenols, the latter being alcohols that cannot be further oxidized to ketones in the specific reaction medium.
I sveitsisk patent nr. 5^2.163 omtales en fremgangsmåte for fremstilling av terpenfraksjoner som er nyttige i behandling av bronkopneumonialsykdommer,•idet fremgangsmåten er basert på oksydering av blandinger som overveiende inneholder a-pinen. Mere spesielt oppnås med fremgangsmåten til overnevnte sveitsiske patent to terpenfraksjoner som destillerer resp. i temperaturområde fra 40°C til 60°C og fra 65°C til 103°C. Swiss patent no. 52,163 describes a method for the production of terpene fractions which are useful in the treatment of bronchopneumonic diseases, since the method is based on the oxidation of mixtures which predominantly contain α-pinene. More particularly, with the method of the above-mentioned Swiss patent, two terpene fractions are obtained which distill resp. in the temperature range from 40°C to 60°C and from 65°C to 103°C.
Det er nå funnet, hvilket er hovedgjenstanden for foreliggende oppfinnelse at slike oksydasjonsblandinger kan utsettes for en ekstra behandling, som i tilfelle fremstilling av verbenon og myrtenal er en ytterligere oksydasjonsbehandling som utføres med kromtrioksyd i svovelsyre, mens i tilfellet pinokarveol, den består i å åpne oksiranringen av a-pinenepok-sydet og etterfølgende transstilling av den resulterende forbindelse . It has now been found, which is the main object of the present invention, that such oxidation mixtures can be subjected to an additional treatment, which in the case of the production of verbenone and myrtenal is an additional oxidation treatment carried out with chromium trioxide in sulfuric acid, while in the case of pinocarveol, it consists in opening the oxiranation of the α-pinene epoxy side and subsequent transposition of the resulting compound.
Det er faktisk funnet at i tilfellet av verbenon og myrtenal i oksydasjonsbehandlingen med kromtrioksyd i svovelsyre av oksydasjonsblandingen ifølge det overnevnte sveitsiske patent foregår den oksydative metode med en total fjerning av alkoholene og en danning av karbonylforbindelser (ketoner og aldehyder). Ved behandling med kromtrioksyd i svovelsyre ut-føres en isolering av det dannede ketonlegeme ved hjelp av et bisulfitkompleks og fraksjonert destillering. It has actually been found that in the case of verbenone and myrtenal in the oxidation treatment with chromium trioxide in sulfuric acid of the oxidation mixture according to the above-mentioned Swiss patent, the oxidative method takes place with a total removal of the alcohols and a formation of carbonyl compounds (ketones and aldehydes). When treated with chromium trioxide in sulfuric acid, the ketone body formed is isolated using a bisulphite complex and fractional distillation.
I tilfellet pinokarveol utføres åpningen av oksiranringen fortrinnsvis med aluminiumisopropoksyd, hvoretter fjerningen av karbonylforbindelsen og den fraksjonelle destillering foretas for å isolere pinokarveol. •Med hensyn til den terapeutiske bruk av forbindelsene fremstillet ifølge oppfinnelsen omtales den terapeutiske bruk av terpenfraksjoner i sveitsisk patent nr. 5*12.163 og mere spesielt bruk av fraksjonen som destillerer i området 65°C - 103°C (i det følgende betegnet som "fraksjon 2"). In the case of pinocarveol, the opening of the oxirane ring is preferably carried out with aluminum isopropoxide, after which the removal of the carbonyl compound and the fractional distillation are carried out to isolate pinocarveol. •With regard to the therapeutic use of the compounds produced according to the invention, the therapeutic use of terpene fractions is mentioned in Swiss patent no. 5*12,163 and more particularly the use of the fraction that distills in the range 65°C - 103°C (hereinafter referred to as " fraction 2").
Den balsamiske og analeptiske virkning av slik fraksjon 2 er allerede kjent og den terapeutiske bruk skyldes nettopp slike virkninger. The balsamic and analeptic effect of such fraction 2 is already known and the therapeutic use is precisely due to such effects.
I tillegg til usikkerheten fra et vitenskapelig standpunkt med hensyn til den nøyaktige identifikasjon av de aktive prinsipper som er ansvarlige for den terapeutiske aktivitet av farmasøytiske sammensetninger, basert på slik fraksjon 2, er ulempen tydelig, fra et industrielt synspunkt, med å arbeide på en blanding av forbindelser som har en sammensetning som er foranderlig selv innen en viss grad. I tillegg er det verdt å nevne at den farmasøytiske sammensetning inneholdende fraksjon 2 har en generell indikasjon som et balsam, sammen med noen få biaktiviteter uten noen mulighet for å kunne utøve den ene av disse aktiviteter foretrukket i forhold til de andre eller med en forbedring av aktiviteten generelt. In addition to the uncertainty from a scientific point of view regarding the exact identification of the active principles responsible for the therapeutic activity of pharmaceutical compositions, based on such fraction 2, the disadvantage is clear, from an industrial point of view, of working on a mixture of compounds having a composition which is changeable even within a certain degree. In addition, it is worth mentioning that the pharmaceutical composition containing fraction 2 has a general indication as a conditioner, together with a few secondary activities without any possibility of being able to exercise one of these activities preferentially in relation to the others or with an improvement of the activity in general.
Det er nå funnet, hvilket er en gjenstand for oppfinnelsen at de aktuelle terpenforbindelser utøver i tillegg til noen allerede kjente aktiviteter, som som balsam og den analeptiske virkning også har god bronkodileterende, anti-flogistisk, antieksudativ og antiaggregative virkninger. It has now been found, which is an object of the invention, that the terpene compounds in question exert in addition to some already known activities, which as a balm and the analeptic effect also have good bronchodilating, anti-phlogistic, anti-exudative and anti-aggregative effects.
Påvisningen av den farmakologiske aktivitet av verbenon, pinokarveol og myrtenal er basert på følgende para-metre : The detection of the pharmacological activity of verbenone, pinocarveol and myrtenal is based on the following parameters:
1. Akutt toksisitet.1. Acute toxicity.
■ 2. Virkning på bronkial-muskulaturen.■ 2. Effect on the bronchial muscles.
3. Virkning på den inflammatoriske prosess.3. Effect on the inflammatory process.
4. Virkning på haemolyse.4. Effect on haemolysis.
5. Virkning på trombocytaggregasjonen.5. Effect on platelet aggregation.
6. Antibakteriell virkning.6. Antibacterial action.
I alle disse prøver er aktiviteten av forskjellige forbindelser sammenlignet med aktiviteten av fraksjon 2 nevnt ovenfor og med de terapeutiske preparater basert på terpen-alkoholer, mere spesielt sobrerol. In all these samples, the activity of different compounds is compared with the activity of fraction 2 mentioned above and with the therapeutic preparations based on terpene alcohols, more particularly sobrerol.
De individuelle forbindelser ifølge oppfinnelsen skal nå behandles: The individual compounds according to the invention will now be treated:
A - . verbenon.A - . verbenone.
1. Akutt toksisitet.1. Acute toxicity.
Tabell 1 viser LD^q (og de godtagbare grenser 95%) som bestemt ifølge Litchfield og Wilcoxon-metoden (J. Pharmacol. Exp. Ther., 96, 99, 19^9)} ved administrering av verbenon både intraperitonealt (i.p.) og oralt (p.o) til grupper på Table 1 shows the LD^q (and the acceptable limits 95%) as determined according to the Litchfield and Wilcoxon method (J. Pharmacol. Exp. Ther., 96, 99, 19^9)} when administering verbenone both intraperitoneally (i.p.) and orally (p.o) to groups of
10 mus og 6 kaniner pr. dose.10 mice and 6 rabbits per dose.
På basis av disse data fremtrer berbenon som en On the basis of these data, berbenone appears as a
god tolerert forbindelse, sa dens toksisitet er svak eller dårlig ifølge Gleason klassifikasjonen, referert til dyretype og ad-ministreringsmåte. well tolerated compound, said its toxicity is weak or poor according to the Gleason classification, referred to animal type and administration method.
2. Bronkodilaterende aktivitet.2. Bronchodilating activity.
Verbenon har utøvet, både in vitro og in vivo en uttalt bronkodilaterende aktivitet, hvorved det adskiller på Verbenone has exerted, both in vitro and in vivo, a pronounced bronchodilating activity, whereby it differs on
en statistisk klar måte både over de andre medisinske stoffer som er tilstede i fraksjon 2 ifølge sveitsisk patent 5^2.163 a statistically clear way both over the other medicinal substances present in fraction 2 according to Swiss patent 5^2.163
og i forhold til-referanseterpenet, dvs. sobrerol.and relative to the reference terpene, i.e. sobrerol.
a - in vitroa - in vitro
På marsvin trachea, isolert ifølge teknikken av Costantine (J. Pharm. Pharmacol., 17, 384, 1965), verbenon bevirker avslapning av den glatte trachealmuskulatur i konsentrasjoner fra 125 til 2000 mikrogram pr. milliliter med en intensitet som er klart høyere enn for terpener i fraksjon 2 og også i forhold til sobrerol (tabell 2). I tillegg, ved konsentrasjoner i området på 10 -3 M til 5.10 - XM, hindres en histamin-indusert kontraksjon av isolert marsvin trachea (Histamine 10~^M, se"tabell 3). On guinea pig trachea, isolated according to the technique of Costantine (J. Pharm. Pharmacol., 17, 384, 1965), verbenone causes relaxation of the smooth tracheal muscles in concentrations from 125 to 2000 micrograms per milliliters with an intensity that is clearly higher than for terpenes in fraction 2 and also in relation to sobrerol (Table 2). In addition, at concentrations in the range of 10 -3 M to 5.10 - XM, a histamine-induced contraction of isolated guinea pig trachea is prevented (Histamine 10 -3 M, see Table 3).
b.- in vivo , b.- in vivo,
Verbenoninjisert intravenøst anesteserte hunder i doser fra 0,6 mg pr. kg legemsvekt til 4,8 mg/kg legemsvekt bevirker en utpreget reduksjon av lungemotstanden som bestemt ifølge teknikken av Diamond (Arch. Int. Pharmacodyn., 168, 239, 1967) (se tabell 4). I tillegg hindrer verbenon, gitt intravenøst på kaniner i doseenhet på 2,5 ml pr. kg legemsvekt pr. minutt , histaminindusert eksperimentell bronkospasme (histamin 100 mikrogram pr. kg legemsvekt intravenøst) til en grad som er statistisk høyere enn for terpenet fra fraksjon 2 og også den for sobrerol (tabell 5)« Verbenone injected intravenously in anesthetized dogs in doses from 0.6 mg per kg body weight to 4.8 mg/kg body weight causes a marked reduction in pulmonary resistance as determined according to the technique of Diamond (Arch. Int. Pharmacodyn., 168, 239, 1967) (see Table 4). In addition, verbenone, given intravenously to rabbits in a dosage unit of 2.5 ml per kg body weight per minute , histamine-induced experimental bronchospasm (histamine 100 micrograms per kg body weight intravenously) to a degree statistically higher than that of the terpene from fraction 2 and also that of sobrerol (Table 5)'
3 » Anti- inflammatorisk aktivitet. 3 » Anti-inflammatory activity.
På albine rotter av COBS (Charles River)-familien administreres verbenon intraperitonealt i doser på 30 mg pr. In albino rats of the COBS (Charles River) family, verbenone is administered intraperitoneally in doses of 30 mg per
kg legemsvekt, hindrer eksperimentell ødema i poten indusert av carrageenin (Winter, C.A. et al., Proe. Soc. Exp. Biol. Med., 111, 5^4, 1962) både hos normale rotter og suprarenalektomiserte rotter til en grad som, fra et statistisk synspunkt er tydelig forbedret i forhold til fraksjon 2 og sobrerol (tabell 6). kg body weight, prevents experimental paw edema induced by carrageenin (Winter, C.A. et al., Proe. Soc. Exp. Biol. Med., 111, 5^4, 1962) in both normal and suprarenalectomized rats to a degree that, from a statistical point of view is clearly improved compared to fraction 2 and sobrerol (Table 6).
Når det administreres intraperitonealt på rotter i doser på 36 og 120 mg pr. kg legemsvekt utøver verbenon en intens antieksudativ aktivitet på eksperimentell, terpentinindusert pleurit (Hurley, J.V. et al., J. Path. 91, 575, 1966) til en grad som kan sammenlignes med aspirin (tabell 7). When administered intraperitoneally to rats in doses of 36 and 120 mg per kg body weight, verbenone exerts an intense antiexudative activity on experimental turpentine-induced pleurisy (Hurley, J.V. et al., J. Path. 91, 575, 1966) to a degree comparable to aspirin (Table 7).
4. Hemolytisk aktivitet, in vitro. 4. Haemolytic activity, in vitro.
Verbenon beskytter in vitro de røde blodceller på rotter fra hemolysis indusert av kapillaraktive stoffer (Tween 80) med en effektiv konsentrasjon 50% (EC 50) på 639,5 mikrogram pr. kg legemsvekt (toleransegrenser 95%'- 518.0 - 760.11). Verbenone protects in vitro the red blood cells of rats from hemolysis induced by capillary active substances (Tween 80) with an effective concentration 50% (EC 50) of 639.5 micrograms per kg body weight (tolerance limits 95%'- 518.0 - 760.11).
5. Antiaggregativ aktivitet, in vitro.5. Antiaggregative activity, in vitro.
Verbenon, i konsentrasjoner fra l6'0 til 1280 mikrogram/ml hindrer trombocytaggregasj'on fra ADP in vitro, utviklet ifølge metoden av Born og Cross (J. Physiol., London, 168, 178, 1963) til en grad som er høyere enn for terpener fra fraksjon 2 og sobrerol (tabell 8). Verbenone, in concentrations from 16'0 to 1280 micrograms/ml inhibits platelet aggregation from ADP in vitro, developed according to the method of Born and Cross (J. Physiol., London, 168, 178, 1963) to a degree higher than for terpenes from fraction 2 and sobrerol (Table 8).
6. Antibakteriell aktivitet. 6. Antibacterial activity.
Verbenon utøver en dårlig antibakteriell aktivitet på gram-positive og gram-negative bakterier, med en MIC (Minimum Inhiberingskonsentrasjon) på 800 mikrogram/ml på Staphylococcus aureus og Escherichia cpli (tabell 9) og er like aktiv som fraksjon 2 og mere aktiv enn sobrerol. Verbenone exerts a poor antibacterial activity on gram-positive and gram-negative bacteria, with an MIC (Minimum Inhibitory Concentration) of 800 micrograms/ml on Staphylococcus aureus and Escherichia cpli (table 9) and is as active as fraction 2 and more active than sobrerol .
Som konklusjon har forbindelsen vist å utøve en tydelig bronkodilaterende aktivitet, hvorved den adskiller seg statistisk tydelig både over andre medikamenter tilstede i fraksjon 2 ifølge sveitsisk patent 542.163 og referanseterpenet (sobrerol). In conclusion, the compound has shown to exert a clear bronchodilator activity, whereby it differs statistically clearly both over other drugs present in fraction 2 according to Swiss patent 542,163 and the reference terpene (sobrerol).
På grunn av disse spesielle egenskaper er verbenon effektiv som den aktive bestanddel av et farmasøytisk preparat som spesielt er beregnet- for behandling av bronkopneumoniale .. sykdommer som er fulgt av en obstruksjon av respiratorkanalen på grunn av inflammasjon og infektiøst bevirkende stoffer. Dosen som er egnet for terapeutisk applikasjon er fra 10 til 100 mg daglig. Because of these special properties, verbenone is effective as the active ingredient of a pharmaceutical preparation which is especially intended for the treatment of bronchopneumonic diseases which are followed by an obstruction of the respiratory tract due to inflammation and infectious agents. The dose suitable for therapeutic application is from 10 to 100 mg daily.
B. - Myrtenal.B. - Myrtenal.
1. Akutt - toksisitet.1. Acute - toxicity.
LD^q bestemt ifølge metoden av Litchfield og Wilcoxon (J. Pharmacol. Exp. Ther., 96, 99, 1949) ved administrering av myrtenal intravenøst til grupper på 10 mus var 17 0 mg pr. kg legemsvekt. LD^q determined according to the method of Litchfield and Wilcoxon (J. Pharmacol. Exp. Ther., 96, 99, 1949) when administering myrtenal intravenously to groups of 10 mice was 170 mg per kg body weight.
2. Bronkodilatorisk aktivitet.2. Bronchodilatory activity.
Myrtenal har både in vitro og in vivo vist en god bronkodilaterende aktivitet, Myrtenal has both in vitro and in vivo shown a good bronchodilating activity,
a - in vitro -a - in vitro -
På isolert marsvin-trachea ifølge teknikken av Costantine (J. Parm. Pharmacol., 17, 384, 1965) bevirker myrtenal relaksjon av trakeal glattmusklene i konsentrasjoner på 125-200 mikrogram/ml med en intensitet som er statistisk høyere enn for fraksjon-2.og sobrerol (tabell 10). On isolated guinea pig trachea according to the technique of Costantine (J. Parm. Pharmacol., 17, 384, 1965) myrtenal causes relaxation of the tracheal smooth muscles in concentrations of 125-200 micrograms/ml with an intensity that is statistically higher than for fraction-2 .and sobrerol (Table 10).
b - in vivo - b - in vivo -
Myrtenal perfusert intravenøst på kaniner i doser på 2,5 ml pr. kg legemsvekt pr. minutt inhiberer den eksperimentelle histamininduserte bronkospasme (histamin 100 mikrogram/kg legemsvekt intravenøst) på en måte som er klart høyere enn for sobrerol og noe lavere enn for fraksjon 2 (tabell 11). Myrtenal perfused intravenously on rabbits in doses of 2.5 ml per kg body weight per minute inhibits the experimental histamine-induced bronchospasm (histamine 100 micrograms/kg body weight intravenously) in a way that is clearly higher than for sobrerol and somewhat lower than for fraction 2 (Table 11).
3~Antiinflammatorisk aktivitet - 3~Anti-inflammatory activity -
På albinorotter av slekten COBS (Charles River) administreres myrtenal intraperitonealt i doserpå 30 mg pr. kg legemsvekt og hindrer eksperimentell podeødem fra injeksjon av carrageenin (Winter, A.C. et al.. Proe. Soc. Exp. Biol. Med. 111, 544 , 1962) i en grad som er mere intens enn for fraksjon 2 og også for sobrerol (tabell 12). In albino rats of the genus COBS (Charles River), myrtenal is administered intraperitoneally in doses of 30 mg per kg body weight and prevents experimental graft edema from injection of carrageenin (Winter, A.C. et al.. Proe. Soc. Exp. Biol. Med. 111, 544 , 1962) to a degree more intense than for fraction 2 and also for sobrerol ( table 12).
4. Antihemolytisk aktivitet, in vitro - 4. Antihemolytic activity, in vitro -
Myrtenal i konsentrasjoner fra 80.. til 500 mikrogram pr. ml beskytter de røde blodceller fra rotter for hemolyse indusert av kapillaraktive stoffer (Tween 80) med en effektiv konsentrasjon 50% tilsvarende 157,09 .mikrogram/ml (grenser 95% = 112,3 189,9) • Myrtenal in concentrations from 80 to 500 micrograms per ml protects the red blood cells from rats against hemolysis induced by capillary-active substances (Tween 80) with an effective concentration 50% corresponding to 157.09 micrograms/ml (limits 95% = 112.3 189.9) •
5. Antiaggregativ aktivitet -5. Antiaggregative activity -
Myrtenal hindrer i konsentrasjoner fra l60 tilMyrtenal prevents in concentrations from l60 to
1280 mikrogram/ml in vitro trombocytisk aggregasjon fra ADP, utviklet ifølge metoden av Born og Cross (J. Physiol., London, 168, 178, 1963) i en grad som er høyere enn for fraksjon 2 og sobrerol. 1280 micrograms/ml in vitro thrombocytic aggregation from ADP, developed according to the method of Born and Cross (J. Physiol., London, 168, 178, 1963) to an extent higher than that of fraction 2 and sobrerol.
6 . Ar. tib akt e ri e<1>1 a<k>ti<v>i<t>e<t>"' - 6. Year. tib act e ri e<1>1 a<k>ti<v>i<t>e<t>"' -
Myrtenal utøver en utpreget antibakteriell aktivitet på grampositive bakterier, mindre intens på gram-negative med en minimum inhiberingskonsentrasjon (MIC) på 200 mikrogram/ml på Staphylococcus aureus, og på 800 mikrogram/ml på Escherichia coli og er mere effektiv enn fraksjon 2 og sobrerol. (Tabell 14). Myrtenal exerts a pronounced antibacterial activity on gram-positive bacteria, less intense on gram-negative with a minimum inhibitory concentration (MIC) of 200 micrograms/ml on Staphylococcus aureus, and of 800 micrograms/ml on Escherichia coli and is more effective than fraction 2 and sobrerol . (Table 14).
Myrtenal har vist, som konklusjon, at den utøver en markert antibakteriell virkning ved hjelp av hvilket det adskiller seg tydelig fra bådé terpenblandingene av fraksjon 2 ifølge det sveitsiske patent og de andre medisinske referansestoffer. Myrtenal har en antiinflammatorisk virkning som er dårlig, det utøver en antihemolytisk aktivitet og endelig har det også en brohko-dilaterende lignende virkning og en antiaggregativ virkning sam-tidig. Myrtenal has shown, in conclusion, that it exerts a marked antibacterial effect by means of which it differs clearly from both the terpene mixtures of fraction 2 according to the Swiss patent and the other medicinal reference substances. Myrtenal has an anti-inflammatory effect which is poor, it exerts an anti-haemolytic activity and finally it also has a brohco-dilating similar effect and an anti-aggregative effect at the same time.
På grunn av disse spesielle trekk indikeres myrtenal som et aktivt stoff av medisinske sammensetninger som er spesielt egnet for terapi av bronkopneumoniale sykdommer når en viktig bakteriell komponent er tilstede eller når, til en viss grad, Because of these special features, myrtenal is indicated as an active substance of medicinal compositions particularly suitable for the therapy of bronchopneumonic diseases when an important bacterial component is present or when, to some extent,
en antibiotisk-basert terapi er nødvendig. I forbindelse med slike indikasjoner antas administrering av en daglig dose på an antibiotic-based therapy is necessary. In connection with such indications, administration of a daily dose of
fra 10 til 100 mg.from 10 to 100 mg.
C - Pinokarveol.C - Pinocarveol.
1. Akutt toksisitet.1. Acute toxicity.
LD^q som bestemt ifølge metoden av Litchfield og Wilcoxon (J. Pharm. Exp. Ther. 96, 98, 1949) ved administrering pinokarveol intravenøst i grupper på 10 rotter pr. dose var tilsvarende til 140 mg pr. kg. LD^q as determined according to the method of Litchfield and Wilcoxon (J. Pharm. Exp. Ther. 96, 98, 1949) by administering pinocarveol intravenously in groups of 10 rats per dose was equivalent to 140 mg per kg.
2. BronkodlTaterehde aktivitet.2. BronchodlTaterehde activity.
Pinokarveol har utøvet, både in vitro og in vivo,Pinocarveol has exerted, both in vitro and in vivo,
en god bronkodilaterende virkning.a good bronchodilating effect.
a - in vitro -a - in vitro -
På marsvin trakea isolert ifølge teknikken av Costantine (J. Pharm. Pharmacol., 17, 384, 1965) avslutter pinokarveol relaksjonen av de glatte trakealmuskler ved konsentrasjoner på 125-2000 mikrogram/ml med en intensitet som er klart høyere enn for sobrerol og som kan sammenlignes med fraksjon 2. On guinea pig trachea isolated according to the technique of Costantine (J. Pharm. Pharmacol., 17, 384, 1965) pinocarveol terminates the relaxation of the tracheal smooth muscles at concentrations of 125-2000 micrograms/ml with an intensity clearly higher than that of sobrerol and which can be compared to fraction 2.
b - in vivo -b - in vivo -
Pinokarveol perfusert intravenøst på kaniner i en dose på 2,5 mg pr. kg og pr. minutt åhhiberer den eksperimentelle bronkospasme indusert av histamin (100 mikrogram pr. kg intra-venøst) på en måte som er statistisk høyere enn for fraksjon 2 Pinocarveol perfused intravenously in rabbits at a dose of 2.5 mg per kg and per minute inhibits the experimental bronchospasm induced by histamine (100 micrograms per kg intravenously) in a manner that is statistically higher than for fraction 2
og sobrerol.and sobrerol.
3. Antiinflammatorisk aktivitet.3. Anti-inflammatory activity.
På albinorotter av slekten COBS (Charles River) inhiberer pinokarveol administrert intravenøst i en dose på 30 mg pr. kg det eksperimentelle podeødem fra injeksjoner av carrageenin (Winter, CA. et al., Proe. Soc. Exp. Biol. Med-., In albino rats of the genus COBS (Charles River), pinocarveol administered intravenously in a dose of 30 mg per kg the experimental graft edema from injections of carrageenin (Winter, CA. et al., Proe. Soc. Exp. Biol. Med-.,
111, 5^4, 1962) i en grad som er mer åntens enn for fraksjon 2111, 5^4, 1962) to a degree more similar to that of fraction 2
og sobrerol.and sobrerol.
4 - Antihemolytisk aktivitet, in vitro.4 - Antihemolytic activity, in vitro.
Pinokarveol i konsentrasjoner fra 20 til 200 mikrogram pr. ml beskytter de rød blodlegemer fra rotter fra hemolyse bevirket av kapillaraktive stoffer (Tween 20) med en effektiv konsentrasjon 50% (EC 50) på 132,29 mikrogram/ml (grenser 95% = 111,5 - 153,04). Pinocarveol in concentrations from 20 to 200 micrograms per ml protects the red blood cells from rats from hemolysis caused by capillary-active substances (Tween 20) with an effective concentration 50% (EC 50) of 132.29 micrograms/ml (limits 95% = 111.5 - 153.04).
5- - Antiaggregativ aktivitet.5- - Antiaggregative activity.
Pinokarveol inhiberer konsentrasjoner fra l60 til 1280 mikrogram pr. ml in vitro, den trombocytiske aggregasjon som skyldes ADP, utviklet ifølge metoden av Born og Cross (J. Physiol., London, 168, 178, 1963) til en grad som overskrider dette for terpenet fra fraksjon 2 og sobrerol. Pinocarveol inhibits concentrations from 160 to 1280 micrograms per ml in vitro, the thrombocytic aggregation due to ADP, developed according to the method of Born and Cross (J. Physiol., London, 168, 178, 1963) to an extent exceeding that for the terpene from fraction 2 and sobrerol.
6. - Antibakteriell aktivitet.6. - Antibacterial activity.
Pinokarveol er i besittelse av en dårlig antibakteriell aktivitet både overfor gram-positive og gram-negative bakterier med en MIC (Minimum inhiberingskonsentrasjon) på 800 mikrogram/ml på Staphylococcus aureus og Escherichia.coli og er således mere aktive enn sobrerol og likeså aktive som fraksjon 2. Pinocarveol has poor antibacterial activity against both gram-positive and gram-negative bacteria with an MIC (Minimum Inhibitory Concentration) of 800 micrograms/ml on Staphylococcus aureus and Escherichia.coli and is thus more active than sobrerol and equally active as a fraction 2.
Som konklusjon har forbindelsen pinokarveol vist seg å ha en uttalt antiinflammatorisk virkning, hvorved den adskiller seg tydelig fra andre medisinske stoffer som blandingen av fraksjon 2 ifølge det sveitsiske patent ovenfor og referanseterpenet (sobrerol). In conclusion, the compound pinocarveol has been shown to have a pronounced anti-inflammatory action, whereby it clearly differs from other medicinal substances such as the mixture of fraction 2 according to the Swiss patent above and the reference terpene (sobrerol).
Pinokarveol utøver en svak bronkodilaterende virkning og også utstyrt med en uttalt antihemolytisk aktivitet, hvorved det er mulig å tildele en slik forbindelse en stabiliser-ende virkning på cellemembrannivået. Pinocarveol exerts a weak bronchodilating effect and is also equipped with a pronounced antihemolytic activity, whereby it is possible to assign such a compound a stabilizing effect at the cell membrane level.
Pinokarveol utøver en svak antibakteriell virkningPinocarveol exerts a weak antibacterial effect
og også utøver en tydelig antiaggregativ virkning.and also exerts a clear antiaggregative effect.
På grunn av dets spesielle egenskaper kan pinokarveol være det aktive stoff av et medikament som er spesielt egnet for behandling av bronkopneumoniale sykdommer som er fulgt av sterkt inflammatorisk mønster i luftkanalene. Due to its special properties, pinocarveol can be the active substance of a drug that is particularly suitable for the treatment of bronchopneumonic diseases that are followed by a strong inflammatory pattern in the air passages.
Dosen som anbefales for denne terapeutiske anvend-else er fra 10 til 100 mg daglig. The dose recommended for this therapeutic use is from 10 to 100 mg daily.
De farmasøytiske sammensetninger ifølge oppfinnelsen kan foreligge i form av preparatet for.oral administrering, The pharmaceutical compositions according to the invention can be in the form of a preparation for oral administration,
normalt eller forsinket virkende, som bløte kapsler, eller inji-serbare ampuller, suppositorier, sprays i forskjellige oppløs-ningsformer, linjementer og balsamer med vanlige media, fyll-stoffer som vanligvis anvendes i farmasien, både som individuelle forbindelser og i forbindelse med medikamenter indikert i syk-dommene referert til ovenfor, dvs. antibiotika, antibakterielle stoffer, kjemoterapeutiske stoffer- sulfonamidmidler, antiin-flammatoriske midler, kortisonpreparater og analgetika. normal or delayed-acting, such as soft capsules, or injectable ampoules, suppositories, sprays in different solution forms, liners and balms with common media, fillers that are usually used in pharmacy, both as individual compounds and in connection with drugs indicated in the diseases referred to above, i.e. antibiotics, antibacterial substances, chemotherapeutic substances - sulfonamide agents, anti-inflammatory agents, cortisone preparations and analgesics.
Oppfinnelsen skal forklares nærmere ved hjelp avThe invention shall be explained in more detail by means of
noen eksempler.some examples.
Eksempel 1.Example 1.
a - AHoholoksydasjon.a - AHoloxidation.
100 gram av terpenblandingen ifølge fraksjon 2 i sveitsisk patent 542.163, hvorav 20-30% omfatter forbindelsene som har en karbonyldel (overveiende verbenon .og myrtenal), mens 50-60% omfatter forbindelser som har en alkoholdel (hovedsakelig verbenol og myrtenol) oppløses i 20.00 ml . tørr aceton. 100 grams of the terpene mixture according to fraction 2 in Swiss patent 542,163, of which 20-30% comprise the compounds that have a carbonyl part (mainly verbenone and myrtenal), while 50-60% comprise compounds that have an alcohol part (mainly verbenol and myrtenol) are dissolved in 20.00 ml. dry acetone.
Separat fremstilles oksydasjonsoppløsningen ved å blande forsiktig 37,41 gram CrO^med 32,2 ml konsentrert R^SO^Separately, the oxidation solution is prepared by carefully mixing 37.41 grams of CrO^ with 32.2 ml of concentrated R^SO^
i en vannmengde som er tilstrekkelig til å danne et sluttvolum nøyaktig tilsvarende 140 ml. in a quantity of water sufficient to form a final volume exactly corresponding to 140 ml.
Kromsyren settes deretter sakte og dråpevis til ace-tonoppløsningen under omrøring, avkjøling på et isbad for således å opprettholde temperaturen konstant under 30°C. Ved avslutning av tilsetningen utføres filtrering på en "Celite" og filtratet taes opp ved avdampning av aceton under nedtrykk ved 40°C. The chromic acid is then added slowly and dropwise to the acetone solution while stirring, cooling in an ice bath so as to maintain the temperature constantly below 30°C. At the end of the addition, filtration is carried out on a "Celite" and the filtrate is taken up by evaporation of acetone under reduced pressure at 40°C.
Residuet fortynnes deretter med vann, nøytraliseres kaldt medThe residue is then diluted with water, neutralized cold with
10% NaOH og ekstraheres med CHCl^inntil utarmingen av moderluten. De kombinerte organiske ekstrakter tørkes over vannfri Na2S0i|og fordampes til tørrhet under nedsatt trykk ved 40°C. 10% NaOH and extracted with CHCl^ until depletion of the mother liquor. The combined organic extracts are dried over anhydrous Na 2 SO 1 and evaporated to dryness under reduced pressure at 40°C.
Det oppnås således ca. 100 gram av et råprodukt somThus, approx. 100 grams of a raw product which
er sammensatt til 50-^60% av forbindelser som har en karbonyldel (overveiende verbenon og myrtenal). is composed to 50-^60% of compounds having a carbonyl part (predominantly verbenone and myrtenal).
b - Separering av karbonylforbindelsene fra råmaterialet oppnåddb - Separation of the carbonyl compounds from the raw material obtained
fra oksydasjonen.from the oxidation.
Et egnet kar fylles med 100 g av en råblandingA suitable vessel is filled with 100 g of a raw mixture
oppnådd fra trinn a, oppløst i 500 ml eter og en oppløsning dannet av 120 gram NaHSO^og72 gram NaHCO-j i 2000 ml vann. obtained from step a, dissolved in 500 ml of ether and a solution formed of 120 grams of NaHSO^ and 72 grams of NaHCO-j in 2000 ml of water.
Blandingen rystes kraftig i 20 timer ved værelsestemperatur og overføres deretter til en skilletrakt og den organiske fase adskilles. Den vandige fase vaskes toganger med 500 ml eter hver gang, hvoretter den vandige bisulfitoppløsning opptas og utsettes for dampdestillering. Behandling av destillatet gir 50-55 gram av en blanding som hovedsakelig omfatter rent verbenon og myrtenal. The mixture is shaken vigorously for 20 hours at room temperature and is then transferred to a separatory funnel and the organic phase is separated. The aqueous phase is washed twice with 500 ml of ether each time, after which the aqueous bisulphite solution is taken up and subjected to steam distillation. Treatment of the distillate yields 50-55 grams of a mixture which mainly comprises pure verbenone and myrtenal.
c - Fremstilling av rent verbenon og myrtenal.c - Preparation of pure verbenone and myrtenal.
50 gram av produktet fra tidligere trinn utsettes50 grams of the product from the previous step is set aside
for fraksjonering i vakuum ved 20 mm kvikksølv, idet det benyttes en tilbakeløpskolonne fylt med nikkelspon. Destilleringen utføres langsomt (5 til 8 ml/time) ved å opprettholde et tilbakeløpsforhold på ca. 40 til 1 gjennom hele destilleringen. Fraksjonen som destillerer ved 90-95°C er sammensatt av myrtenal (19 gram) og har følgende fysikalsk-kj;emiske egenskaper: = 1,50d2Q= 0,98. for fractionation in vacuum at 20 mm of mercury, using a reflux column filled with nickel shavings. The distillation is carried out slowly (5 to 8 ml/hour) by maintaining a reflux ratio of approx. 40 to 1 throughout the distillation. The fraction which distills at 90-95°C is composed of myrtenal (19 grams) and has the following physico-chemical properties: = 1.50d2Q= 0.98.
Infrarød analyse: bånd ved 1684 cm ^ yC=0 (konjugert) Infrared analysis: band at 1684 cm ^ yC=0 (conjugated)
1623 cm ^~ yC = C (konjugert) 1623 cm ^~ yC = C (conjugated)
1471 cm<_1>YC-H 1423-1387-1372 1471 cm<_1>YC-H 1423-1387-1372
Ultrafiolett analyse<A>maks(EtOH) = 246 nm (e ca. 8400). Ultraviolet analysis<A>max(EtOH) = 246 nm (e approx. 8400).
Semikarbazonet smelter ved 210-215°C.The semicarbazone melts at 210-215°C.
Fraksjonen som destillerer etterpå ved 110-113°C vedThe fraction which distills afterwards at 110-113°C at
20 mm kvikksølv er sammensatt av verbenon (28,5 gram) og har følgende fysikalsk-kjemiske egenskaper: n^°<=>1,49 d2Q= 0,97 20 mm of mercury is composed of verbenone (28.5 grams) and has the following physico-chemical properties: n^°<=>1.49 d2Q= 0.97
Infrarøde bånd ved 1670 cm 1yC=0 (konjugert)Infrared bands at 1670 cm 1yC=0 (conjugated)
l6l5 cm ^ yC = 0 (konjugert) l6l5 cm ^ yC = 0 (conjugate)
1650-1435-1370. 1650-1435-1370.
Ultrafiolett ^maks(EtOH) = 250 nm e = 7300. Semikarbazon: smeltepunkt l88-190°C. Ultraviolet ^max(EtOH) = 250 nm e = 7300. Semicarbazone: melting point l88-190°C.
Eksempel 2.Example 2.
a - Overføring av alfa- pinen epoksyd i pinokarveol.a - Transfer of alpha-pinene epoxide in pinocarveol.
60 gram av terpenblandingen fra fraksjon 2 ifølge det sveitsiske patent nr. 542.163, hvorav 10-15% omfatter alfa-pinen epoksyd, mens 20-30% består av en forbindelse med en karbonyldel og 50-60% består av en forbindelse som har en alkoholdel (verbenol, pinokarveol og myrtenol), oppløses i 60 ml vannfri toluen. Til oppløsningen settes et overskudd av aluminiumisopropoksyd (ca. 2-3 gram) og blandingen kokes i 10 minutter. Blandingen avkjøles forsiktig og surgjøres langsomt ved forsiktig tilsetning av fortynnet svovelsyre under opprettholdelse av en temperatur på 0°C eller lavere. Pasene adskilles, væsken ut-tømmes med toluen, den organiske oppløsning kombineres, vaskes med vann og tørkes over vannfri Na2S0jj. Filtrering utføres og fordampes ved 60°C under nedsatt trykk inntil det er dannet et fast stoff. Det er oppnådd ca. 60 gram av et råprodukt som er uttømt for epoksyd og anriket med forbindelser som har en alkohol-funksjon (pinokarveol, verbenol og myrtenol). 60 grams of the terpene mixture from fraction 2 according to Swiss patent no. 542,163, of which 10-15% comprises alpha-pinene epoxide, while 20-30% consists of a compound with a carbonyl moiety and 50-60% consists of a compound having a alcohol part (verbenol, pinocarveol and myrtenol), dissolve in 60 ml anhydrous toluene. An excess of aluminum isopropoxide (approx. 2-3 grams) is added to the solution and the mixture is boiled for 10 minutes. The mixture is carefully cooled and slowly acidified by careful addition of dilute sulfuric acid while maintaining a temperature of 0°C or lower. The phases are separated, the liquid is exhausted with toluene, the organic solution is combined, washed with water and dried over anhydrous Na 2 SO 4 . Filtration is carried out and evaporated at 60°C under reduced pressure until a solid is formed. It has been achieved approx. 60 grams of a raw product depleted of epoxide and enriched with compounds that have an alcohol function (pinocarveol, verbenol and myrtenol).
b - Separering. av karbonylforbindelser.b - Separation. of carbonyl compounds.
Residuet som er oppnådd fra det foregående trinn opptas med 300 ml dietyleter og den resulterende oppløsning utsettes for kraftig omrøring med en blanding dannet av 60 gram NaHSOj, 36 gram NaHCO^ og 1000 ml vann,.idet behandlingen utføres i 20 timer ved.værelsestemperatur. Blandingen overføres i en skilletrakt og fasene adskilles.. Den vandige .fase inneholder myrtenal og verbenon i form av oppløselige bisulfittaddukter, hvorfra de kan utvinnes i form,av rene produkter.ved opparbeidelse ifølge det.som .er angitt tidligere. Den organiske.fase som inneholder alkoholforbindeIsene vaskes til nøytralitet med vann, tørkes over Na2S0j|, filtreres og fordampes til tørrhet under nedsatt trykk. Det oppnås 40-50 gram residu som overveiende er sammensatt av pinokarveol, verbenol og myrtenol. The residue obtained from the previous step is taken up with 300 ml of diethyl ether and the resulting solution is subjected to vigorous stirring with a mixture formed of 60 grams of NaHSO 3 , 36 grams of NaHCO 3 and 1000 ml of water, the treatment being carried out for 20 hours at room temperature. The mixture is transferred into a separatory funnel and the phases are separated. The aqueous phase contains myrtenal and verbenone in the form of soluble bisulphite adducts, from which they can be recovered in the form of pure products by processing according to what has been stated previously. The organic phase containing the alcohol compounds is washed to neutrality with water, dried over Na2SO4, filtered and evaporated to dryness under reduced pressure. 40-50 grams of residue is obtained which is mainly composed of pinocarveol, verbenol and myrtenol.
c - Utvinning av ren pinokarveol.c - Extraction of pure pinocarveol.
Residuet som kommer fra foregående trinn utsettes for en serie fraksjonerte destilleringer under vakuum ved 20 mm kvikksølv, idet det benyttes tilbakeløpskolonne fylt med nikkelspon. Destilleringen utføres langsomt (5~6 ml/time) ved å opprettholde et tilbakeløpsforhold på ca. 40:1 under hele destiller ingen. Fraksjonen som går over ved 100-106°C under 20 mm kvikk-sølv og som er sterkt anriket på pinokarveol, samles og utsettes for redestillering under samme betingelse. Det oppnås 15-18 gram omtrent med 95~98% ren pinokarveol. som har følgende fysikalsk-kjemiske data: Kokepunkt 103-104°C under 20 mm Hg The residue from the previous step is subjected to a series of fractional distillations under vacuum at 20 mm of mercury, using a reflux column filled with nickel shavings. The distillation is carried out slowly (5~6 ml/hour) by maintaining a reflux ratio of approx. 40:1 under the whole distills no one. The fraction which passes at 100-106°C below 20 mm of mercury and which is highly enriched in pinocarveol, is collected and subjected to redistillation under the same conditions. Approximately 15-18 grams are obtained with 95~98% pure pinocarveol. which has the following physico-chemical data: Boiling point 103-104°C under 20 mm Hg
hp° = 1,4988; d^° = 0,98. hp° = 1.4988; d^° = 0.98.
Infrarød analyse: Karakteristiske bånd av terminale dobbeltbindinger ved 6,00 mikron og ved 11,20 mikron. Infrared analysis: Characteristic bands of terminal double bonds at 6.00 microns and at 11.20 microns.
Claims (8)
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH704276A CH625197A5 (en) | 1976-06-03 | 1976-06-03 | Process for preparing verbenone, myrtenal and pinocarveol |
Publications (1)
Publication Number | Publication Date |
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NO771926L true NO771926L (en) | 1977-12-06 |
Family
ID=4319020
Family Applications (1)
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NO771926A NO771926L (en) | 1976-06-03 | 1977-06-01 | PROCEDURES FOR THE MANUFACTURE OF VERBENON, MYRTENAL AND PINOCARVEOL |
Country Status (25)
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JP (1) | JPS52151156A (en) |
AR (1) | AR214200A1 (en) |
AT (1) | AT351520B (en) |
AU (1) | AU519521B2 (en) |
BE (1) | BE855297A (en) |
CA (1) | CA1099214A (en) |
CH (1) | CH625197A5 (en) |
CS (1) | CS251755B2 (en) |
DD (1) | DD130475A1 (en) |
DE (2) | DE2725247A1 (en) |
DK (1) | DK244277A (en) |
ES (1) | ES459425A1 (en) |
FI (1) | FI771765A (en) |
FR (2) | FR2416878A1 (en) |
GB (2) | GB1585832A (en) |
HU (1) | HU178205B (en) |
IT (1) | IT1074511B (en) |
NL (1) | NL7705934A (en) |
NO (1) | NO771926L (en) |
OA (1) | OA05678A (en) |
PL (1) | PL116550B1 (en) |
PT (1) | PT66619B (en) |
SE (2) | SE424723B (en) |
SU (1) | SU816396A3 (en) |
ZA (1) | ZA773345B (en) |
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JPH04239414A (en) * | 1991-01-24 | 1992-08-27 | Sekisui Chem Co Ltd | Device and method for banding with adhesive tape |
IT1251615B (en) * | 1991-10-04 | 1995-05-17 | Golgi Sa | ANTIELASTASIC ACTIVITY MEDICATION. |
IT1312537B1 (en) * | 1999-04-16 | 2002-04-22 | Euphar Group Srl | DERIVATIVES OF (-) - VERBENONE. |
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FR1103814A (en) * | 1953-04-30 | 1955-11-07 | Glidden Co | Improvements relating to the treatment of mixtures and autoxidation products of the terpene |
US2911442A (en) * | 1953-04-30 | 1959-11-03 | Glidden Co | Production of oxygenated terpenes from alpha-pinene |
FR1377525A (en) * | 1963-09-25 | 1964-11-06 | Centre Nat Rech Scient | Process for preparing terpene ketones |
FR1572146A (en) * | 1967-05-10 | 1969-06-27 | ||
US3673066A (en) * | 1969-02-14 | 1972-06-27 | Lab De L Ozothine | Process for the accelerated obtaining of terpenic oxides using ultraviolet light |
CH523962A (en) * | 1969-08-18 | 1972-06-15 | Int Flavors & Fragrances Inc | Use of indane derivatives as odorous principles |
CH542163A (en) * | 1971-06-14 | 1973-09-30 | Buskine Sa | Process for the production of a terpene mixture |
FR2267296A1 (en) * | 1974-04-12 | 1975-11-07 | Anvar | Myrtenol synthesis - by isomerisation of beta-pinene epoxide |
-
1976
- 1976-06-03 CH CH704276A patent/CH625197A5/en not_active IP Right Cessation
-
1977
- 1977-05-25 GB GB1504/80A patent/GB1585832A/en not_active Expired
- 1977-05-25 GB GB22089/77A patent/GB1585831A/en not_active Expired
- 1977-05-31 NL NL7705934A patent/NL7705934A/en not_active Application Discontinuation
- 1977-05-31 PT PT66619A patent/PT66619B/en unknown
- 1977-05-31 CS CS773586A patent/CS251755B2/en unknown
- 1977-06-01 NO NO771926A patent/NO771926L/en unknown
- 1977-06-01 AU AU25732/77A patent/AU519521B2/en not_active Expired
- 1977-06-01 SE SE7706385A patent/SE424723B/en unknown
- 1977-06-01 BE BE178116A patent/BE855297A/en unknown
- 1977-06-01 CA CA279,610A patent/CA1099214A/en not_active Expired
- 1977-06-02 PL PL1977198600A patent/PL116550B1/en unknown
- 1977-06-02 SU SU772494040A patent/SU816396A3/en active
- 1977-06-02 ES ES459425A patent/ES459425A1/en not_active Expired
- 1977-06-02 DK DK244277A patent/DK244277A/en not_active Application Discontinuation
- 1977-06-02 JP JP6404177A patent/JPS52151156A/en active Pending
- 1977-06-02 HU HU77CO341A patent/HU178205B/en unknown
- 1977-06-02 FI FI771765A patent/FI771765A/fi not_active Application Discontinuation
- 1977-06-03 DD DD7700199291A patent/DD130475A1/en unknown
- 1977-06-03 DE DE19772725247 patent/DE2725247A1/en active Granted
- 1977-06-03 AT AT394077A patent/AT351520B/en not_active IP Right Cessation
- 1977-06-03 IT IT24385/77A patent/IT1074511B/en active Protection Beyond IP Right Term
- 1977-06-03 OA OA56187A patent/OA05678A/en unknown
- 1977-06-03 DE DE2760410A patent/DE2760410C2/de not_active Expired - Fee Related
- 1977-06-03 FR FR7717088A patent/FR2416878A1/en not_active Withdrawn
- 1977-06-03 ZA ZA00773345A patent/ZA773345B/en unknown
- 1977-06-08 AR AR267933A patent/AR214200A1/en active
-
1981
- 1981-05-06 FR FR8108999A patent/FR2479804A1/en not_active Withdrawn
- 1981-09-25 SE SE8105687A patent/SE8105687L/en not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
FR2479804A1 (en) | 1981-10-09 |
PL116550B1 (en) | 1981-06-30 |
DK244277A (en) | 1977-12-04 |
PT66619A (en) | 1977-06-01 |
AR214200A1 (en) | 1979-05-15 |
GB1585832A (en) | 1981-03-11 |
DD130475A1 (en) | 1978-04-05 |
CH625197A5 (en) | 1981-09-15 |
CA1099214A (en) | 1981-04-14 |
SE8105687L (en) | 1981-09-25 |
DE2760410C2 (en) | 1990-08-16 |
SE7706385L (en) | 1977-12-04 |
AT351520B (en) | 1979-07-25 |
GB1585831A (en) | 1981-03-11 |
SU816396A3 (en) | 1981-03-23 |
DE2725247C2 (en) | 1987-02-12 |
ZA773345B (en) | 1978-04-26 |
BE855297A (en) | 1977-10-03 |
ATA394077A (en) | 1979-01-15 |
CS251755B2 (en) | 1987-08-13 |
AU2573277A (en) | 1978-12-07 |
JPS52151156A (en) | 1977-12-15 |
DE2725247A1 (en) | 1977-12-22 |
AU519521B2 (en) | 1981-12-10 |
PL198600A1 (en) | 1978-06-19 |
IT1074511B (en) | 1985-04-20 |
NL7705934A (en) | 1977-12-06 |
PT66619B (en) | 1978-10-27 |
FI771765A (en) | 1977-12-04 |
ES459425A1 (en) | 1978-04-01 |
SE424723B (en) | 1982-08-09 |
HU178205B (en) | 1982-03-28 |
OA05678A (en) | 1981-05-31 |
FR2416878A1 (en) | 1979-09-07 |
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