Vincamine V 2171 combination with glucose I-phosphate: BE 874 154 (E. Corvi Mora; appl. 14.2.1979). quaternary ammonium salts: DE 1 244 794 (Richter Gedeon; appl. 16.12.1963; H-prior. 19.12.1962). Formulation(s): amp. 15 mg/l ml, 20 mg; cps. 20 mg, 60 mg Trade Name(s): F: Cervoxan (SmithKline 1: Eburnal (Chiesi) Beecham) Scleramin (Ibirn) Tensiplex (Francia Farm.) Vincamine ATC: C04AX07 Use: vasodilator, antihypertensive, cerebrotonic RN: 1617-90-9 MF: C2,H2,N203 MW: 354.45 EINECS: 216-576-3 LD,,,: 47.74 mgtkg (M, i.v.); 460 mg/kg (M, p.0.); 1200 mgkg (R, p.0.) CN: (3a,14~,16a)-14,15-dihydro-l4-hydroxyebumamenine- 14-carboxylic acid methyl ester @ by extraction of pulverized and NH3-solution treated plant material of Vinca minor L. (myrtle) with toluene and column chramatographic separation of numerous (c. 30 biogenetic related) by-alkaloids (indole alkaloids) @ partial synthesis (Omnium process) (-)-tabersanine (from Voacanga grains) 0 CI 0 3-chloroper- 0/CH3 benzoic acid (-)-vincadifformine 9-oxide (I) (-)-3-hydroxy-3-methoxy- carbonyl-l,2-didehydro- aspidospermidine 9-oxide (11) (CgH5)3P. CHJCOOH I1 + triphenyl- phasphine HOW, apovincamine (-)-I 4-epivincamine (111) (+)-Gncamine 2172 V Vincamine (in the product mixture) @ total synthesis @ Richter Gedeon synthesis: NoOC2H5 H3C7 NoOH + B~-CI HOOC 0 0 k~, diethyl ethyl- 1 -brorno-3- diethyl 2-ethyl-2- 2-ethyl-2-(3- rnolonate chloropropane (3-chloropropyl)- hydroxypropy1)- rnolonate rnalonic ocid (IV) perchlorote 1. CH,OH. HCI H2/Pd-C or NoBH4 2. NoZCO, VII HCIO, 0 di~~clohexylcorbodiimide, H,P04. DMSO VlIl .%+% H,C' O hi3 I 0 'CH~ H3C (+)-epivincornine (M) (2)-vincomine (X) Vincamine V 2173 racernate resolution with (+)-tartaric acid or (+)-0.0'-dibenz~~ltartoric ocid or Aq2CO3/celite or Pt/Rh (+)-carnphorsulfonic acid M -X (in the mixture of racernotes) @ Roussel-Uclof synthesis: 1. H3C/0v'~~2 butyr- pyrrolidine aldehyde 1 -pyrrolidino- ocrylate 1-butene dimethyl 4-ethyl-4- formylpimelote (XI) (2)-trans-1 -ethyl-1-(2- (f)-cis-1 -ethyl-1-(2- methoxycarb0nylethyl)- methoxycarbonylethyl)- 4-0x0- I .2.3.4.6.7.12.12b- 4-0x0-1.2,3.4.6.7.12.12b- octahydraindolo[2.3-01- octohydroindolo[2.3-a]- quinolizine quinolirine (XU) 1. NoOH 2. (-)-ephedrine (racernate resolution) 3. CH,OH, H2S04 XI1 b ___, phosphorus pentosulfide H3C Raney-Ni No terl-amylote, toluene XlII - . (-)-la-ethyl-1-(2- rnethoxycarbonylethyl)- 1.2.3,4,6,7,12.12ba- octohydroindolo- [2,3-o]quinolizine tert-butyl nitrite CHpO. HCI, H20 xm. . (3a.16a)-14,15-di- hydro-14-oxo-D- homoeburnomenine (XIV) % o \CH~ (3a.16a)-14.154- hydro-14.15-dioxo- D-hornoeburnornenine (XV) 2174 V Vincamine Referencefs): a Schlittler, E. et al.: Helv. Chim. Acta (HCACAV) 36, 2017 (1953). HU 147 282 (Richter Gedeon; appl. 30.7.1960). Trojanek, J. et al.: Collect. Czech. Chem. Commun. (CCCCAK) 26, 867 (1961); 27,2801 (1962). b DAS 2 201 795 (Omnium Chimique; appl. 14.1.1972; B-prior. 15.1.1971,3.3.1971). DOS 2 652 165 (Omnium Chimique; appl. 16.1 1.1976; F-prior. 20.1 1.1975). similar processes from (-)-vincadifformine: GB 1 514 337 (Buskine S.A.; appl. 22.7.1975; CH-prior. 9.8.1974). US 4 145 552 (Parcor; 20.3.1979; F-prior. 13.7.1976). DOS 2 731 480 (Parcor; appl. 12.7.1977; F-prior. 13.7.1976). DOS 2 745 415 (Boehringer Mannh.; appl. 8.10.1977). synthesis of vincadifformine: DOS 2 758 896 (M. E. Kuehne; appl. 30.12.1977). cl DAS 2 222 186 (Richter Gedeon; appl. 5.5.1972; H-prior. 7.5.1971). US 3 755 333 (Richter Gedeon; 28.8.1973; H-prior. 7.5.1971). Sziintay, Cs. et al.: Tetrahedron Lett. (TELEAY) 1973, (3), 191. precursors: DOS 2 345 068 (Richter Gedeon; appl. 6.9.1973; H-prior. 6.9.1972). rearrangement epi-vincamine + vincamine: DAS 2 203 655 (Richter Gedeon; appl. 26.1.1972; H-prior. 29.1.1971). DOS 2 807 912 (Boehringer Mannh.; appl. 24.2.1978). c2 DAS 2 115 718 (Roussel-Uclaf; appl. 31.3.1971; F-prior. 31.3.1970, 10.9.1970). further synfheses: Kuehne, E.: J. Am. Chem. Soc. (JACSAT) 86,2946 (1964). US 3 454 583 (US-Secret. of Health; 8.7.1969; prior. 19.7.1965). Gibson, K.H.; Saxton, J.E.: Chem. Commun. (CCOMA8) 1969, 1490. Pfaffli, P. et al.: Helv. Chim. Acta (HCACAV) 58, 1131 (1975). DOS 2 314 876 (Sandoz; appl. 26.3.1973; CH-prior. 29.3.1972, 20.4.1972, 17.5.1972, 2.2.1973). DOS 2 330 990 (Anvar; appl. 18.6.1973; F-prior. 19.6.1972). GB 1 450 198 (Synthelabo; appl. 14.12.1973; F-prior. 15.12.1972). LJS 3 925 392 (Synthclabo; 9.12.1975; F-prior. 15.12.1972). US 4 001 251 (Synthelabo; 4.1.1977; F-prior. 15.12.1972). DOS 2 752 776 (ELMU; appl. 25.1 1.1977; E-prior. 27.4.1977). lyophilisate of vincamine with glycine: FR-M 7 222 (L. 0. Olivier; appl. 6.2.1968). vincamine pamoate: NL-appl. 7 304 654 (Merrell-Toraude; appl. 4.4.1973; F-prior. 1 1.4.1972). con~bination with ergot alkaloids: GB 1 494 625 (Unilever; appl. 4.2.1 974; valid from 4.2.1975) ronibitintion with rutin, hesperidin, eriodxtin or esculoside: DOS 2 337 202 (Centrc dlEtudes pour 1'Industrie Pharmaceutique; appl. 21.7.1973; F-prior. 24.7.1972). 5-bronionicofinafe of vincamine: DOS 2 714 486 (Ferrer Internat.; appl. 3 1.3.1977; F-prior. 31.3.1976). vincamine 5-pyridoxalphosphate: DAS 2 721 171 (Soc. &Etudes de Produits Chimiques; appl. 11 S.1977; GB-prior. 11.5.1976). diverse salts: US 4 122 179 (E. Corvi Mora; 24.10.1979; CH-prior. 3.6.1976). Fomulation(s): amp. 15 mg; cps. 30 mg; s. r. cps. 30 mg, 60 mg; tabl. 10 mg Vincristine V 2175 Trade Name(s): D: Cetal (Parke Davis) Vincafor (Pharmafarm) Vincari (Alfa Intes; as Vincamin-retard- Vincarutine (Pharbiol) hydrochloride) ratiopharm (ratiopharm) I: Anasclerol (Stallergenes; as Vincatreis (Ecobi) F: Pe~incamine (SynthClabo) hydrochloride) Vinsal (Salus Research) RhCobal (Niverpharm) Vasonett (Alfa Intes) Vraap (Inverni della Beffa) Vinca (Substipharm) Vincadar (Hoechst Marion generics Vinca Retard Roussel) (Substipharm) Vincristine (Leurocristine) ATC: LOICA02 Use: antineoplastic RN: 57-22-7 MF: C,6HS6N4010 MW: 824.97 EINECS: 200-3 18-1 LD,,,: 3990 kg/kg (M, i.v.); 1 mglkg (R, i.v.) CN: 22-oxovincaleukoblastine sulfate (1:l) RN: 2068-78-2 MF: C4,H5,N401,, . H,SO, MW: 923.05 EINECS: 218-190-0 LD,,,: 1700 pg/kg (M, i.v.); 1010 pgkg (R, i.v.) Vincristine By extraction from leaves of Vinca rosea. Reference(s): BE 867 670 (Richter Gedeon; appl. 31 S.1978; H-prior. 31.5.1977). FR 2 2103'12 (Richter Gedeon; appl. 19.12.1972). DOS 2 259 388 (Richter Gedeon; appl. 5.12.1972). DOS 2 124 023 (Richter Gedeon; appl. 14.5.1971 ; H-prior. 27.5.1970). DAS 1 445 689 (Eli Lilly; appl. 23.10.1962). GB 1 382 460 (Richter Gedeon; valid from prior. 4.12.1972). purification: DOS 2 442 245 (Eli Lilly; appl. 4.9.1974; USA-prior. 24.10.1973). total synthesis: DOS 2 614 863 (A. Rahman; appl. 6.4.1976). DOS 2 622 894 (United States Dep. of Commerce; appl. 21.5.1976; USA-prior. 30.5.1975). 7 2176 V Vindesine semisynthetic preparation: DOS 2 259 447 (Richter Gedeon; appl. 5.12.1972). CA 989 829 (Richter Gedeon; appl. 4.12.1972). BE 823 560 (Richter Gedeon; appl. 19.12.1 974; H-prior. 20.12.1973). US 3 899 493 (Richter Gedeon; 12.8.1975; prior. 22.12.1972). FR 2 210 392 (Richter Gedeon; appl. 19.1 2.1972). ZA 7 208 535 (Richter Gedeon; appl. 1.12.1972). complex formation with tubulin for treatment of leucemia: BE 854 053 (Inst. Intern. de Pathologic Cell. et Mol.; appl. 18.4.1977; F-prior. 28.4.1976). use for treatment of psoriasis: US 3 749 784 (Eli Lilly; 31.7.1973; prior. 26.10.1970, 3.5.1972). Formulation(s): vial 1 mglml, 1 mgIlO ml, 2 mglml, 5 mglml (as sulfate) Trade Name(s): D: cellcristine (cell pharm) Vincristin liquid Lilly GB: Oncovin (Lilly) FARMISTIN (Pharmacia & (Lilly) I: Vincristina (Lilly) Upjohn) Vincristinsulfat-GRY (Gry) Vincristina Tera (Tera) Vincristin (biosyn) F: Oncovin (Lilly) . J: Oncovin (Shionogi) Vincristin Bristol (Bristol- Vincristine Pierre Fabre USA: Oncovin (Lilly) Myers Squibb) (Pierre Fabre Oncologie) Vindesine A'K: LOICAO~ Use: antineoplastic RN: 53643-48-4 MF: C,3HssNs07 MW: 753.94 EINECS: 258-682-2 LD,,,: 13.8 mglkg (M, i.v.) CN: 3-(aminocarbonyl)-@-deacetyl-3-de(methoxycarbonyl)vincaleukoblastine NH,, CH,OH, 100 OC - 0 vinblastine Vindesine (9. v.1 Reference(s): US 4 203 898 (Lilly, 20.5.1980; prior. 29.8.1977). US 4 479 957 (Lilly; 30.10.1984; prior. 2.4.1973). DOS 2 415 980 (Eli Lilly; appl. 2.4.1974; USA-prior. 2.4.1973). Formulation(s): amp. 5 mg15 ml, 1 mg, 4 mg, 5 mg Trade Name(s): D: Eldisine (Lilly; 1980) GB: Eldisine (Lilly; 1980) J: Fildesin (Shionogi; 1985) F: Eldisine (Lilly) I: Eldisine (Lilly) r Vinorelbine V 2177 Vinorelbine (5'-Noranhydrovinblastine; PM259) ATC: LOlCA04 Use: antineoplastic (non small cell lung cancer) RN: 71486-22-1 MF: C,,H,,N,O, MW: 778.95 LD,,,: 26 mgkg (M, i.p.) CN: 3',4'-didehydro-4'-deoxy-C'-norvincaleukoblastine hydrogen tartrate (1:l) RN: 105661 -07-2 MF: C45H54N408 . C4H6O6 MW: 929.03 tartrate RN: 1253 17-39-7 MF: C45H54N108 . 2C4Hh06 MW: 1079.12 anhydrovinblastine (1) V _* trifluoroocetic K onhydride 0 CH3 2178 V Vinuocetine THF, H20 111 b Reference(s): EP 10 458 (ANVAR Agence Nat. Valorisation; F-prior. 24.8.1978,6.2.1979). Andriamialisoa, R.Z. et al.: Tetrahedron (TETRAB) 36, 20 (1980). Mangeney, P. et a].: Tetrahedron (TETRAB) 35,2175 (1979); J. Org. Chem. (JOCEAH) 44,3765 (1979). Gueritte, F. et al.: Eur. J. Med. Chem. (EJMCAS) 18,419 (1983). Potier, P.: Semin. Oncol. (SOLGAV) 16, (2. Suppl. 4), 2 (1989); J. Nat. Prod. (JNPRDF) 43,72 (1980). pharmaceutical formulation for parenteral administration: EP 31 7 401 (PierreFabre; appl. 10.1 1.1988; F-prior. 13.1 1.1987). synthesis of anhydrovinblastine: EP 354 778 (Mitsui Petrochem.; appl. 9.8.1989; J-prior. 11.8.1988). DOS 3 826 412 (Univ. of British Columbia; appl. 6.8.1988; CND-prior. 6.8.1987). FR 2 544 319 (Pierre Fabre; appl. 14.4.1983). HU 20 601 (Richter Gedeon; appl. 17.3.1977). WO 8 802 002 (Mitsui Petrochem.; appl. 16.9.1987; USA-prior. 18.9.1986). JP 63 119 690 (Mitsui Petrochem.; appl. 4.8.1987; USA-prior. 4.8.1986). Kutney, J.P. et al.: Helv. Chim. Acta (HCACAV) 58, 1690, 171 1 (1975); 59, 2858 (1976). Raucher, S. et al.: J. Am. Chem. Soc. (JACSAT) 109,442 (1987). Kutney, J.P. et a].: Heterocycles (HTCYAM) 27,621, 1845 (1988). Goodbody, A.E. et al.: Planta Med. (PLMEAA) 54, 136, 210 (1988). Vokovic, J. et al.: Tetrahedron (TETRAB) 44, 325 (1988). Atta-Ur-Rahman, P.S.: J. Nat. Prod. (JNPRDF) 51, 1275 (1988). Bray, B.L.: Dissertation Univ. Washington (Seattle), Diss. Abstr. Int. B 1988,48 (12), Pt. 1, 3567. Formulation(s): amp. 10 mglml, 50 mg15 ml (as base); vial 10 mglml, 50 mg15 ml (as tartrate) Trade Name(s): F: Navelbine (Pierre Fabre; GB: Navelbine (Pierre Fabre; as USA: Navelbine (Glaxo 1988) tartrate) Wellcome; as tartrate) 1: Navelbine (Pierre Fabre) Vinpocetine ATC: N06BX18 Use: vasodilator, cerebrostimulant RN: 42971-09-5 MF: C22H26N202 MW: 350.46 EINECS: 256-028-0 LD,,,: 45 mgkg (M, i.v.); 534 mgkg (M, p.0.); 32 mgkg (R, i.v.); 503 mgkg (R, p.0.) CN: (3a, l6a)-eburnamenine-14-carboxylic acid ethyl ester Vinvlbital V 2179 1. KOH, CHJOH 2. CH3COOH 3. H&-OH , H,SO, _________+ Vinpocetine 1 1. KOH 2. w-6 , KOH, C2H50H 0 tH,, Reference(s): US 4 035 370 (Richter Gedeon; 12.7.1977; prior. 11.10.1972). DAS 2 253 750 (Richter Ccdeon; appl. 2.1 1.1972; H-prior. 3.11.1971). Lorincz, C. et al.: Arzneim Forsch. (ARZNAD) 26, 1907 (1976). citrate phosphate: EP 154 756 (Covex; appl. 21.3.1984; E-prior. 29.2.1984). Formulation(s): tabl. 5 mg Trade Nume(s): D. Cavinton (Thiemann) J: Calan (Takeda; 1984) Vinylbital (Butylvinal) ATC: N05CA08 Use: hypnotic RN: 2430-49-1 MF: C,,H,,N,O, MW: 224.26 EINECS: 219-395-8 CN: 5-ethenyl-5-(k-methylbutyl)-2,4,6(1H,3H,5H)-pyrimidinetrione 1-methyl-2-pyrrolidane/zinc stearate, H3cd," + HC'CH 25 atrn + CH,O 5-(1 -methylbutyl)- acetylene barbituric acid Reference(s): FR 11 825 256 (BASF; appl. 9.9.1957). FR-M 896 (BASF; appl. 4.1.196 1 ). Fomulution(s): tabl. 150 mg 2180 V Viomycin Trade Name(s): D: Speda (Byk Gulden); wfm Optanox (Valpan); wfm Suppoptanox (Valpan); F: Optanox (Delagrange); Suppoptanox (Delagrange); wfm wfm wfm Viomycin ATC: JO~A Use: antibiotic RN: 32988-50-4 MF: C2sH43N,3010 MW: 685.70 EINECS: 251-323-0 CN: stereoisomer of 3,6-diamino-N-[6-[[(aminocarbonyl)amino]methylene]-3-(2-amino-1,4,5,6-tetrahydro-6- hydroxy-4-pyrimidinyl)-9,12-bis(hydroxymethyl)-2,5,8,11,1 Cpentaoxo-1,4,7,10,13- pentaazacyclohexadec- 15-yllhexanamide sulfate RN: 37883-00-4 MF: C,,H43Nl,0,, . xH2S04 MW: unspecified LD,,,: 1 12 mglkg (M, i.v.); 340 mg/kg (R, i.v.) I \OH Viomycin From fermentation solutions of Srreptomycesfloridae or Streptomyces puniceus. Reference(s): US 2 633 445 (Ciba; 1953; prior. 1947). US 2 828 245 (Commerc Solvents; 1958; prior. 1954). Forniulation(s): amp. 1 g Trade Name(s): D: Viocin (Pfizer); wfm J: Viomicin (Parke Davis- Viomycin Pfizer (Taito F: Panto-Viocine (Pfizer); Sankyo) Pfizer) wfm USA: Viocin (Pfizer); wfm Visnadine ATC: C04AX24 Use: coronary vasodilator RN: 477-32-7 MF: C2,H,,0, MW: 388.42 EINECS: 207-515-1 LD&: 2240 mglkg (M, p.0.); 12 13 mglkg (R, p.0.) CN: [9R-[9a(R*),1Oa]]-2-methylbutanoic acid 10-(acetyloxy)-9,10-dihydro-8,8-dimethy1-2-oxo-2H,8H- benzo[l,2-b:3,4-b']dipyran-9-yl ester . H3C/0v'~~2 butyr- pyrrolidine aldehyde 1 -pyrrolidino- ocrylate 1-butene dimethyl 4-ethyl- 4- formylpimelote (XI) (2)-trans-1 -ethyl- 1-( 2- (f)-cis-1 -ethyl- 1-( 2- methoxycarb0nylethyl )- methoxycarbonylethyl )-. 3298 8-5 0-4 MF: C2sH43N,3010 MW: 685.70 EINECS: 25 1-3 2 3-0 CN: stereoisomer of 3,6-diamino-N-[ 6-[ [(aminocarbonyl)amino]methylene ]-3 -( 2-amino-1,4,5,6-tetrahydro- 6- hydroxy-4-pyrimidinyl )-9 ,12-bis(hydroxymethyl )-2 ,5,8,11,1. EINECS: 20 7-5 1 5-1 LD&: 2240 mglkg (M, p.0.); 12 13 mglkg (R, p.0.) CN: [9R-[9a(R*),1Oa] ]-2 -methylbutanoic acid 1 0-( acetyloxy )-9 ,10-dihydro-8,8-dimethy 1-2 -oxo-2H,8H- benzo[l,2-b:3,4-b']dipyran-9-yl