Mezlocillin M 1321 Reference(s): US 3 954 872 (Boehringer Ing.; 4.5.1976; D-prior. 16.9.1966, 17.8.1967). DE 1 543 369 (Boehringer Ing.; prior. 16.9.1966). composition and use: US 4 031 244 (Boehringer Ing.; 21.6.1977; D-prior. 17.8.1967). Formulation(s): amp. 25 mglml, 250 mgllO ml; cps. I00 mg. 150 mg, 200 mg; s. r. cps. 360 mg (as hydrochloride) Trade Name(s): D: Mexitil (Boehringer Ing.; GB: Mexitil (Boehringer Ing.; 1: Mexitil (Boehringer Ing.; 1979) 1976) 1985) F: Mexitil (Boehringer Ing.; I: Mexitil (Boehringer Ing.; USA: Mexitil (Boehringer lng.; 1980) 1982) 1986) generics Mezlocillin ATC: JOICA~O Use: antibiotic RN: 51481-65-3 MF: C,,H,,N50,S2 MW: 539.59 EINECS: 257-233-8 CN: [2S-[2a,5a,6~(S*)]]-3,3-dimethyl-6-[[[[[3-(methylsulfonyl)-2-0~0-1- imida~olidinyl]carbonyl]amino]phenylacetyl]amino]-7-oxo-4-thia-l-azabicyclo[3.2.0]heptane-2- carboxylic acid monosodium salt RN: 42057-22-7 ME C,,H,N5Na0,S2 MW: 561.57 EINECS: 255-640-5 LD,: 6329 mgikg (M, i.v.); >16 glkg (M, p.0.); 2636 mgikg (R, i.v.); >20 glkg (R, p.0.) 1. (cH~)~s~cI. N(c~H~)~ 0 I I n n 2. COCI, H3C-S-CI f NH b K O\x ,N NH -b I I I H3C'S,' 1. tr~methylchlorostlane. 0 0 0 O triethylamine methanesulfonyl 2-imida- 1 -methanesulfonyl- 2 phosgene chloride zolidinone 2-imidazalidinone Reference(s): DOS 2 152 967 (Bayer; appl. 23.10.1971). DOS 2 152 968 (Bayer; appl. 23.10.1971). DOS 2 3 18 955 (Bayer; appl. 14.4.1973). US 3 974 142 (Bayer; 10.8.1976; appl. 3.9.1974; D-prior. 23.10.1971). COOH N(C2H,), combination with e. g. oxacillin: DOS 2 737 673 (Bayer; appl. 20.8.1977). 3-chloroformyl- ampicillin Mezlocillin 1 -methonesulfonyl- (9. v.) - 2-imidozolidinone (I) 1322 M Mianserin Formulation(s): vial 0.5g15 ml, 1 gI10 ml, 2 gl20 ml, 5 gI50 ml Trade Nanze(sj: D: Baypen (Bayer Vital; 1977) F: Baypen (Bayer-Pharma) J: Baypen (Yoshitomi; 1982) Melocin (curasan) GB: Baypen (Bayer; 1980); USA: Mezlin (Bayer; 1981) Optocillin (Bayer Vital; wfm 1979)-comb. with oxacillin I: Baypen (Bayer; 1983) Mianserin ATC: N06AX03 Use: antidepressant RN: 24219-97-4 MF: C,,H2,N2 MW: 264.37 EINECS: 246-088-6 LDsn: 365 mglkg (M, p.0.) CN: 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[cflpyrazino[l ,2-alazepine monohydrochloride RN: 21 535-47-7 MF: C,,HZnN2 . HCl MW: 300.83 EINECS: 244-426-7 LD,,,: 3 1 mglkg (M, i.v.); 224 mglkg (M, p.0.); 3 1 .X5 mglkg (R, i.v.); 780 mglkg (R, p.0.) styrene 2-methylomino- oxide ethanol (1) 2-amino- benzyl olcahol 7'43 H3C\ N PPA C+ "NP 5 dlp po~yphos- , 0 H 0 H phoric acid Mianserin I H3C\ & Reference(s): DOS 2 505 239 (Akzo; appl. 7.2.1975; NL-prior. 9.2.1974). medical use: US 4 128 641 (HZJ Research Center; 5.12.1978; prior. 31.7.1975, 28.2.1977). older methods: DOS 1 695 556 (Organon; appl. 9.3.1967; NL-prior. 12.3.1966). US 3 534 041 (Organon; 13.10.1970; NL-prior. 12.3.1966). Burg, W.J. Van der et al.: J. Med. Chem. (JMCMAR) 13, 35 (1970). Fornmlation(s): f. c. tabl. 10 mg, 30 mg, 60 mg (as hydrochloride) Trade Name(s): D: Tolvin (Organon; 1975) F: Athymil (Organon; 1979) GB: generics Bolvidon (Organon; 1976); wfm Mibefradil hydrochloride M 1323 Norval (Bencard; 1976); I: Lantanon (Organon ltalia; J: Tetramide (Sankyo; 1983) wfm 1979) Mibefradil hydrochloride (Ro-40-5967; Ro-40-59671001) ATC: CO8CXOl Use: anlihypertensivc, calcium channel blocker RN: 116666-63-8 MF: C,,H38FN303 .2HC1 MW: 568.56 CN: (1s-cis)-methoxyacetic acid 2-[2-[[3-(I H-benzimidazol-2-yl)propyl]methylamino]ethyl]-6-fluoro-1,2,3,4- tetrahydro-1-(1 -methylethyl)-2-naphthalenyl ester dihydrochloride base RN: 116644-53-2 MF: C2,H3,FN3O3 MW: 495.64 synthesis of intermediate 11: 4-[N-(benzyloxycorbonyl)- methylomino]butyric ocid CH3 N(C2H5)3. 15 OC 2. H2Nn H2N + 1. isobutyryl chloride 2. o-phenylenediamine 1. Tos-OH, to1uene.A pH3 HN 2. Hz. Pd-C, CH30H I 1. p-toluenesulfonic ocid b -k!~ 2. hydrogen 2-13-(methylomino). U' NH2 benzyl [3-[(2-amino- phenyl)carbamoyl]propyi]- methylcarbamate (I) synthesis of intermediate VII: - 1. S0Cll (RS)-2-(p-fluoropheny1)- 3-methylbutyric acid F (RS)-6-fluoro-3,4-di- hydro- 1 -isopropyl- 2(1 H) naphtholenone (111) o CH 1 "H34c& "go '"' 2. LiAIH,, THF 3. separation b 1. tert-butyl bromoacetate (N) F 2. lithium aluminum hydride (V) 1324 M Mibefradil hydrochloride p-toluene- sulfonyl chloride (V)) (IS.2S)-2-(6-fluoro- 1,2,3,4-tetrahydro-2- hydroxy-2-isopropyl- 2-naphthyl)ethyl p-toluenesulfonate (VII) asymmetric synthesis of intermediate VII: CH30H. HI (Amberlyst 15) A) or 0) - 22H A VIII F Ru[(R)-BIPHEMP](OAC)~ or 2-(4-fluorophenyl)- 3-hydroxy-3-methyl- butyric acid 2-(+-fluoropt,eny+ RU[(R)-M~O~IPHEPI(OA~)~ 3-methylcrotonic acid 1. IV, THF 2. LiAIH,, THF H3CyCH3 ~COOH VII 1. tert-bulyl bromoacetate 2, lithium aluminum hydride 2(S)-(4-fluorophenyl)- 3. p-toluenesulfonyl chloride 3-methylbutyric acid (Vln) synthesis of the finol product: Refemm(s): - - - - - - - - - - - - - - - - EP 268 148 (Hoffmann-La Roche AG; appl. 25.5.1988; CH-prior. 14.1 1.1986); p'3 1. H,C~N~CH~ 720 Q~ CH,CH, M. CHCI, 3. HCI , VII + I1 1. ethyldiisopropylamine 2. methoxyacetyl chloride 2 HCI F Mibefradil hydrochloride Mibolerone M 1325 synthesis of intermediate VII: EP 177 960 (Hoffmann-La Roche AG; appl. 16.4.1986; CH-prior. 1 l.lO.1984). asymmetric synthesis of 2(S)-(4-fluoropheny1)-3-methylbutyric acid: Crameri, Y. et al.: Chimia (CHIMAD) 51 (6), 303 (1997). synthesis of 2-(4-fluoropheny1)-3-methylcrotonic acid: Noyori, R. et al.: I. Org. Chem. (JOCEAH) 52,3176 (1987). Takaya, H. et al.: J. Org. Chem. (JOCEAH) 61,5510 (1996). Schmid, R. et al.: Helv. Chim. Acta (HCACAV) 71, 897 (1988). Heiser, B. et al.: Tetrahedron: Asymmetry (TASYE3) 2,51 (1991). EP 787 7 1 1 (Hoffmann-La Roche AG; appl. 6.8.1997; CH-prior. 3 1.1.1996) Formulation(s): f. c. tabl. 50 mg, 100 mg Trade Name(s): D: Cerate (ASTA Medica Posicor (Roche); wfm AWD); wfm USA: Posicor (Roche); wfm Mibolerone ATC: GO3 Use: oral contraceptive, anabolic RN: 3704-09-4 MF: C2,H,,O2 MW: 302.46 EINECS: 223-046-5 CN: (7a, 170)- 17-hydroxy-7,17-dimethylestr-4-en-3-one 1. H3C-MgBr 2. NoOH - 1. methylmognesium bromide 7a-methyl-3-pyrrolidino-19- norondrosta-3,5-dien-17-one (from 3.17-dioxo-7a-methyl- 19-nor-4-ondrostene) I Mibolerone Reference(s): US 3 341 557 (Upjohn; 12.9.1967; prior. 5.6.1961,6.11.1960,6.6.1958). FR-M 4 521 (Upjohn; appl. 4.6.1962; USA-prior. 5.6.1961). alternative synthesis: Campbell, J.A.; Babcock, J.C.: J. Am. Chem. Soc. (JACSAT) 81,4069 (1959). separation of the 7a-, 70-isomers: NL 6 601 855 (Ciba; appl. 14.2.1966; CH-prior. 15.2.1965). Trade Name(s): GB: Matenon (Upjohn); wfm USA: Cheque (Upjohn); wfm Micinicate (Nicotinyl cyclandelate) ATC: C04A Use: vasodilator (for treatment of chromic obliterating peripheral arteriopathy and microcircular disorders) RN: 39537-99-0 MF: C2,H,NO4 MW: 381.47 CN: (*)-cis-3-pyridinecarboxylic acid 2-oxo-l-phenyl-2-[(3,3,5-trimethylcyclohexyl)oxy]ethy1 ester 1326 M Miconazole 1. KOH 2. (COCI), 0 0 HO $2 COOH DCooH N -@%- 2. oxalyl chloride acid carboxylic acid onhydride carboxylic acid carboxyphenylrnethyl ester (I) SOCI,. DMF I + thionyl chloride cis-3.3.5-trimethyl- cyclohexanol pyridine-3- cis-3,3,5-trimethyl- corbonyl cyclohexyl (2)-rnandelate chloride Reference (s): a EP 157 151 (Ravizza; appl. 22.2.1985; I-prior. 3.7.1984). b JP 47 034 365 (Milsui; appl. 12.4.1971). DOS 2 461 909 (Gaver; appl. 3 1.12.1974; CH-prior. 3.1.1974). synthesis of cis-3,3,5-trimethylcyclohexyl mandelate: Funcke, A.B.H. et al.: Arzneim Forsch. (ARZNAD) 3,505 (1953). Forinula~ion(s): tabl. 400 mg Trade Narne(s): I: Micivas (Ravizza; IT); wfm Miconazole ATC: A01 AB09; A07ACOI; DO1 AC02; GOlAFO4; J02AB01; S02AA13 Use: topical antifungal RN: 22916-47-8 MF: C1RH,4CI,N20 MW: 416.14 EINECS: 245-324-5 LD,,,: 90.57 mglkg (M, i.v.); 872 mglkg (M, p.0.); 105 mglkg (R, i.v.); >3 gkg (R, p.0.); 60 mgkg (dog, i.v.) CN: l-[2-(2,4-dichlorophenyl)-2-[(2,4-dichlorophenyl)methoxy]ethyl]-lH-imidazole Micronomicin M 1327 mononitrate RN: 22832-87-7 MF: C,~H,,CI,N,O~HNO, MW: 479.15 EINECS: 245-256-6 LD,,: 28 mgkg (M, i.v.); 578 mgkg (M, p.0.); 14.7 mglkg (R, i.v.); 920 mg/kg (R, p.0.); >I60 mg/kg (dog, p.0.) imidazole 2-brorno- 2',4'-dichloro- ocetophenone 1. sodium hydride 2. 2,4-dichlorobenzyl bromide $0 boranate 1 -(2,4-dichloro- benzoylmethy1)- imidozole CI c,R, \ Q c I Miconozole 4 1 -(2,4-dichloro- phenyl)-2-(1 H- imidozol-1 -yl)- ethanol (1) DAS 1 940 388 (Janssen; appl. 8.8.1969; USA-prior. 19.8.1968,23.7.1969) US 3 717 655 (Janssen; 20.2.1973; appl. 19.8.1968). US 3 839 574 (Janssen; 1.10.1974; prior. 23.7.1969). Formulation(s): cream 2 g1100 g, 20 mg/g; vaginal cream 20 mglg; powder 2 g1100 g, 20 mglg (as mononitrate); sol. 20 mg/rnl; tabl. 250 mg (as free base) Trade Name(s): D: Acnidazil (Janssen-Ci1ag)- comb. Daktar (Janssen-Cilag; 1974) Epi-Monistat (Janssen- Cilag; 1974) Gyno-Daktar (Janssen- Cilag; 1974) Gyno-Monistat (Janssen- Cilag; 1974) F: Britane (M. Johnson & Johnson-MSD) Daktarin (Janssen-Cilag SA; 1974) Gyno-Daktarin (Janssen- Cilag SA) Miconazole GNR (GNR- pharma) GB: Acnidazil (Janssen-Ci1ag)- comb. Daktacort (Janssen-Ci1ag)- comb. Daktarin (Janssen-Cilag; 1974) Gyno-Daktarin (Janssen- Cilag) I: Andergin (Pierrel) Daktacort (Jamsen)-comb. Daktarin (Janssen; 1975) Micoderm (Kemyos) Miconal (Ecobi) Micotef (LPB) Prilagin (Gambar) J: Florid (Mochida; 1980) USA: Monistat (Ortho) Micronomicin ATC: S01AA22 Use: antibiotic, antibacterial RN: 52093-21-7 MF: C,,H,,N,O, MW: 463.58 CN: 0-2-amino-2,3,4,6-tetradeoxy-6-(methylamino)-a-~-e~osyl-(l+4)-0-[3-deoxy-4-C- methyl-3-(methylamino)-~-~-arabinopyranosyl(1+6)]-2-deoxy-~-streptamine 1328 M Midazolam sulfate RN: 66803- 19-8 MF: C,,H4,N,0, . xH,S04 MW: unspecified I Micronomicin Preparation by fermentation of Micromonospora sagamiensis var: nonreductans nov. sp. MK-65, ATCC 21 826. Reference (s): Okachi, R. et al.: J. Antibiot. (JANTAJ) 27,793 (1974). Nara, T. et al.: J. Antibiot. (JANTAJ) 28, 21 (1975). DOS 2 326 781 (Kyowa Ferm.; appl. 25.5.1973; J-prior. 27.5.1972). US 4 045 298 (Kyowa Ferm.; 30.8.1977; J-prior. 27.5.1972). structure: Egan, R.S. et al.: J. Antibiot. (JANTAJ) 28, 29 (1975). total synthesis,from gentamicin C,,: JP 50 126 639 (appl. 25.3.1974). JP 50 149 647 (appl. 28.5.1974). JP 50 149 646 (appl. 28.5.1974). JP 50 13 1 949 (appl. 9.4.1974). JP 50 123 640 (appl. 15.5.1974). JP 50 129 531 (appl. 29.3.1974). Formulation(s): amp. 60 mg, 120 mg; eye drops 0.3 %; ointment 0.3 % (as sulfate) Trade Name(s): F: Microphta (Europhta) J: Sagamicin (Kyowa Hakko) Santemycin (Santen) Midazolam ATC: N05CD08 Use: hypnotic RN: 59467-70-8 MF: C,,HI3ClFN3 MW: 325.77 EINECS: 261-774-5 LD,,,: 50 mgkg (M, i.v.); 75 mgkg (R, i.v.); 215 mgkg (R, p.0.) CN: 8-chloro-6-(2-fluoropheny1)- 1 -methy1-4H-imidazo[1,5-a][1,4]benzodiazepine monohydrochloride RN: 59467-96-8 MF: C,,HI3ClFN3. HC1 MW: 362.24 EINECS: 261-776-6 maleate (1:l) RN: 59467-94-6 MF: C,,Hl,ClFN3 . C4H404 MW: 441.85 EINECS: 261 -775-0 Midecamycin M 1329 clJx&F + 0 pyridine \ 2-omino-5-chloro- glycine ethyl estel 2'-fluorobenzo- hydrochloride phenone (cf. flunitrozepom synthesis) 7-chloro-5-(2- fluoropheny1)-1.3- dihydro-2H-1.4- benzodiozepin- 2-one (1) H NO I N , TiCI, 1 + H2N-CH3 - CH3 NoN02. CH,COOH titomum sodium tetrochloride \ / nitrite methyl- (n) ornine - 1, Hz. Roney-Ni KOC(CHd3 $02 2. -;0fH3 11 + H3C-NO2 + CI -, 111 potassium tert-butylote \ / nitro- methane HC N polyphosphoric acid "- CI CI manganese - dioxide (111) ( Midozolom 1 Reference (s): DOS 2 540 522 (Hoffmann-La Roche; appl. 11.9.1975; USA-prior. 11.9.1974). US 4 280 957 (Hoffmann-La Roche; 28.7.1981; prior. 8.2.1977). Formulation(s): amp. 5 mg15 ml, 15mg13 ml; f. c. tabl. 7.5 mg (as hydrochloride) Trade Name(s): D: Dormicum (Roche; 1984) GB: Hypnovel (Hoffmann-La J: Dormicum (Roche) F: Hypnovel (Produits Roche) Roche; 1983) USA: Versed (Roche; 1986) Midecamycin ATC: JOIFAO~ (Espinomycin; Midecamicin; Mydecamycin) Use: macrolide antibiotic RN: 35457-80-8 ME C,,H,,NO,, MW: 813.98 EINECS: 252-578-0 LD,,: 1 glkg (M, i.v.); 5800 mg/kg (M, p.0.); 9600 mglkg (R, p.0.) CN: leucomycin V 3,4B-dipropanoate 1330 M Midecamycin acetate Midecomycin Macrolide antibiotic from cultures of Streptomyces mycarofaciens. Midecamycin A,, A, and A, exist also in small amounts in the complex beside main component Midecamycin. Reference(s): US 3 761 588 (Meiji Seika; 25.9.1973; J-prior. 6.2.1969, 25.9.1969). Niida, T. et al.: J. Antibiot. (JANTAJ) 24, 319 (1971). Tsuruoka, T. et al.: J. Antibiot. (JANTAJ) 24,452 (1971). Inouye, S. et al.: J. Antibiot. (JANTAJ) 24,460 (1917). Formulution(s): cps. 50 mg, I00 mg, 200 mg; tabl. 400 mg Trade Name(s): F: MidCcacine (Clin-Midy); I: Midecin (Farmaka) wfm J: Medemycin (Meiji) Rubimycin (Nikken) Midecamycin acetate ATC: JO 1 F~03 Use: antibiotic (Miokamycin) RN: 55881-07-7 MF: C4,H7,N0,, MW: 898.05 EINECS: 259-879-6 LD,,,: 75 glkg (M, p.0.) CN: leucomycin V 3',9-diacetate 3,4B-dipropanoate . RN: 5209 3-2 1-7 MF: C,,H,,N,O, MW: 463.58 CN: 0-2 -amino-2,3,4,6-tetradeoxy- 6-( methylamino)-a-~-e~osyl-(l+4 )-0 -[ 3-deoxy-4-C- methyl- 3-( methylamino )-~ -~ -arabinopyranosyl(1+6) ]-2 -deoxy-~-streptamine. 2(S )-( 4-fluorophenyl )- 3. p-toluenesulfonyl chloride 3-methylbutyric acid (Vln) synthesis of the finol product: Refemm(s): - - - - - - - - - - - - - - - - EP 268 148 (Hoffmann-La. 370 4-0 9-4 MF: C2,H,,O2 MW: 302.46 EINECS: 22 3-0 4 6-5 CN: (7a, 170 )- 17-hydroxy-7,17-dimethylestr-4-en-3-one 1. H3C-MgBr 2. NoOH - 1. methylmognesium bromide 7a-methyl-3-pyrrolidino-19-