Pharmaceutical Substances Syntheses, Patents, Applications - Part 37 doc

Carticaine C 361 synthesis of intermediate 5-hydroxy-1,2,3,4-tetrahydroquinolin-2-one: Shono, T. et al.: J. Org. Chem. (JOCEAH) 46, 3719 (1981). Formulation(s): eye drops 1 %, 2 %, tabl. 2.5 mg, 5 mg, 20 mg (as hydrochloride) Trade Name(s): D: Arteoptic (CIBA Vision; CartCol (Chauvin; 1985) I: Carte01 (SIFI; 1987) 1984) Mikelan (Lipha SantC) J: Mikelan (Otsuka; 1980) Endak (Madaus; 1982) GB: Teoptic (CIBA Vision; USA: Cartrol (Abbott) F: Carpilo (Chauvin)-comb. 1986) Cartkahe ATC: NOIB; NOlBB08; N01BB58 Use: local anesthetic RN: 23964-58-1 MF: C,,H2,N20,S MW: 284.38 CN: 4-methyl-3-[[1-oxo-2-(propylamino)propyl]amino]-2-thiophenecarboxylic acid methyl ester monohydrochloride RN: 23964-57-0 MF: C,,H,,N,O,S . HC1 MW: 320.84 EINECS: 245-957-7 LD,,: 37 mgkg (M, i.v.) H3C NH, CH3 methyl 3-amino- P-bromo- 4-methylthiophene- propionyl 2-carboxylote chloride Reference(s): DAS 1 643 325 (Hoechst; appl. 7.7.1967). US 3 855 243 (Hoechst; 17.12.1974; D-prior. 7.7.1967). Fomulation(s): amp. lOmg/ml, 20 mglml, 40 mg/ml, 50 mglml Corticoine I Trade Name(s): D: Ultracain (Hoechst) F: Alphacai'ne (SPAD)-comb. Carurnonam (AMA-1080; Ro-17-2301) ATC: SOlAA Use: antibacterial (monobactam antibiotic) RN: 87638-04-8 MF: C,,H,,N,O,,S, MW: 466.41 CN: [2S-[2a,3a(2)]]-[[[2-[[2-[[(aminocarbonyl)oxy]methyl]-4-oxo-l-sulfo-3-azetidinyl]amino]-l-(2-amino-4- thiazoly1)-2-oxoethylidene]amino]oxy]acetic acid disodium salt RN: 86832-68-0 MF: C,,HI2N,Na2Ol,S, MW: 510.37 362 C Carumonam @ aretidinone intermediate: 1. HBr. CH,COOH 2. H,C-OH Br OH hydragen 0- 0-CH, H0 OH peroxide ascorbic ocid 0) KO%, DMF. Kl methyl (2R.3S)-4- acetoxy-2.3-epaxy- butanoote 1 CH,OH. HCI H N OH OXOH ONa 2. NH,, CH,OH 3. NaHCO,, 2-12 Z-NH OH c'/hCI , DMM 11 . _ * 111 3. benzyl chlorofarrnote OicoH ch10ro:cetyl chloride, NH2 dimethylacetarnide (111) methanesulfo- nyl chlaride IV _, 1. sulfur trioxide-2-picoline complex 3 tetrabutylammonium hydrogen sulfate Carurnonam C 363 fi 1. CI-8-NCO 0 I I FNH, 2 NoHC03 M- 1 chlorosulfonyl isocyonote tetrobutylamrnoniurn (3S.4S)-3-(benzyloxy- corbonylamino)-4- hydroxymethyl-2-0x0- ozetidine-1 -sulfonate (28-cis)-3-(benzyloxy- carbony1arnino)-2-(corb- ornoyloxymethyl)-4-0x0- azetidine-1-sulfonic ocid (VI) eids choin: DMF, KZCO, OHC IIZN4'?ffvcH3 + ~,a~yH3 * 0 CH, ethyl 2-(2-amino-4- tert-butyl lhiazolyl)-2(Z)- bromoacetate hydmxyiminwcetote 0 H3C CHFN, r-, N ,031 ~~~3 0 CH3 Od-CH3 , P(OC2H5)3 Vlll + o&4yD S' triethyl H2N<fis~b - phosphite 2,2'-dithiobis- ox) (benzothiozole) fino1 oroduct: Corumonam Referencefs): Kishimoto, S. et al.: J. Antibiot. (JANTAJ) 36, 1421 (1983) Sendai, M. eta].: J. Antibiot. (JANTAJ) 38, 346 (1985). special route according to a for VI: Manchand, P.S. el al.: J. Org. Chem. (JOCEAH) 53, 5507 (1988). 364 C Carvedilol alternative route for VI: Hashigushi, S. et al.: Heterocycles (HTCYAM) 24,2273 (1986). firther synthetic routes for carumonam and its intermediates: US 4 673 739 (Takeda; 16.6.1987; PCT-prior. 5.12.1980, 30.4.1981, 21.8.198l.24.9.1981; J-prior. 30.4.1982, 31.5.1982; USA-appl. 3.12.1981,5.8.1982, 31.5.1983, 18.9.1985). US 4 675 397 (Takeda 23.6.1987; PCT-prior. 5.12.1980, 30.4.1981, 21.8.1981, 24.9.1981; J-prior. 30.4.1982; USA-appl. 3.12.1981, 5.8.1982) - 446 pages. US 4 782 147 (Takeda; 1.11.1988; PCT-prior. 5.12.1980,30.4.1981, 21.8.1981, 24.9.1981; J-prior. 31.5.1982; USA-appl. 3.12.1981, 31.5.1983) - 504 pages. US 4 502 994 (Hoffmann-La Roche; 5.3.1985; appl. 9.12.1982). US 4 652 65 1 (Hoffmann-La Roche; 24.3.1987; prior. 31.5.1983, 14.4.1986). US 4 663 469 (Hoffmann-La Roche; 5.5.1987; prior. 9.12.1982, 10.12.1984). EP 96 297 (Hoffmann-La Roche; appl. 25.5.1983; CH-prior. 3.6.1982, 25.4.1983). EP 185 221 (Hoffmann-La Roche; appl. 25.1 1.1985; CH-prior. 19.12.1984). Formulation(s): (disodium salt) vial 0.5 g (i.m. and i.v. inj.), 1 g (i.v. inj.) Trade Name(s): D: Amasulin (Takeda); wfm Carvedilol (BM-14190) ATC: C07AG02; C07EA Use: non-selective PI-adrenoceptor blocker with vasodilating activity RN: 72956-09-3 MF: C,H,,N,O, MW: 406.48 LD,,,: 364 mglkg (M, i.p.); 27 mgkg (M, i.v.); 769 mglkg (R, i.p.); 25 mgflcg (R, i.v.); >1 glkg (dog, p.0.) CN: I-(9H-carbazol-4-yloxy)-3-[[2-(2-methoxyphenoxy)ethyl]amino]-2-propanol 4-hydroxy- epichloro- carbazole hydrin . Reference(s): DOS 2 815 926 (Boehringer Mannh.; appl. 13.4.1978). EP 4 920 (Boehringer Mannh.; appl. 4-7-1979; D-prior. 13.4.1978). synthesis of enantiomers: EP 127 099 (Boehringer Mannh.; appl. 19.5.1984; D-prior. 26.5.1983). Formulation(s): tabl. 6.25 mg, 12.5 mg, 25 mg, 50 mg F Carzenide C 365 Trade Name(s): D: Dilalrend (Boehringer F: Kredex (Boehringer Dilatrend (Boehringer Mannh.; SmithKline Mannh.; SmithKline Mannh.) Beecham; 199 1) Beecham) J: Artist (Daiichi Seiyaku) Querto (B yk Gulden) GB: Eucardic (Boehringer USA: Coreg (SmithKline Mannh. VK) Beecham) I: Carvipress (Gentili) Carzenide ATC: MOlAEOl Use: antispasmodic, diuretic (carboanhydrase inhibitor) RN: 138-41-0 MF: C,H7N04S MW: 201.20 EINECS: 205-327-4 LD,,: >I glkg (M, i.p.); 350 mglkg (R, i.p.) CN: 4-(arninosu1fonyl)benzoic acid monosodium salt RN: 6101-29-7 MF: C7H,NNa04S MW: 223.18 p-toluene- p-toluene- suifonyl chloride sulfonamide By-product of saccharin production. Reference(s): DRP 64 624 (Dr. C. Fahlberg; appl. 1891). Formulation(s): f. c. tabl. 200 mg Trade Name(s): D: Dismenol (Simons)-Comb. ( Correnide I Cefacetrile (Cephacetrile) ATC: J01DA34 Use: antibiotic RN: 10206-21-0 MF: C,3H,3N306S MW: 339.33 EINECS: 233-508-8 CN: (6R-trans)-3-[(acetyloxy)methyl]-7-[(cyanoacetyl)amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid monosodium salt RN: 23239-41-0 MF: C,,H,,N,NaO$ MW: 361.31 EINECS: 245-513-2 LD,,: 3700 mgkg (M, i.v.); 19 g/kg (M, p.0.); 3100 mgkg (R, i.v.); 15.1 g/kg (R, p.0.) 366 C Cefaclor COOH 0 I COOH ulr H-L cyanaacetyl 7-aminacephalo- chloride sporanic acid Cefocstrile Re,ference(s): DAS 1 670 324 (Ciba-Geigy; appl. 8.1.1966; CH-prior. 18.1.1965, 1.4.1965, 10.5.1965, 20.10.1965). US 3 483 197 (Ciba: 9.12.1969; CH-prior. 18.1.1965, 1.4.1965, IOS.l965,2O.lO.l96~). NL-appl. 6 600 586 (Ciba; appl. 17.1.1966; CH-prior. 18.1.1965, 1.4.1965, 10.5.1965, 20.10.1965). acylation with mixed anhydrides qf cyar~oacetic acid: DOS 2 730 580 (Pierre1 S.p.A.; appl. 6.7.1977; GB-prior. 10.7.1976). acylation via 1,3,2-dioxaboranyl-derivafives: DOS 2 755 902 (Dobfar; appl. 15.12.1977; I-prior. 16.12.1976). sodium salt: US 4 061 853 (Ciba-Geigy; 6.12.1977; CH-prior. 9.12.1975). Formulation(s): vial 1 g/5 ml Trade Name(s): D: Celospor (Cibat I: Celospor (Novartis; as Celtol (Takeda) Griinenthal); wfm sodium salt) F: Celospor (Ciba); wfm J: Celospor (Novartis) Cefaclor ATC: JOIDA08 Use: antibiotic RN: 53994-73-3 MF: C1SH14CIN,04S MW: 367.81 EINECS: 258-909-5 LD,,: >20 glkg (M, p.0.); >20 gkg (R, p.0.) CN: [6R-[6a,7~(R*)]]-7-[(aminophenylacetyl)amino]-3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid 4-nitrobenzyl 7-(2- potassium ethyl- (1) thienylocetamido)- xonthogenate R1: 4 cephalosporanote (from cephalotin) R2: QN02 Cefaclor C 367 Ln, nwun 2. HCI I OH L II R' H R' H 4-nitrobenzyl 4-nitrobenzyl 3- 3-methylane-7-(2- hydroxy-7-(2-thienyl thienylocetomido)- ocetornido)-3- cephom-4-corb- cephem-4-corb- oxylote oxylote 1. pyridine, PC\, 2. isobutonol 4-nitrobenzyl 7-omino-3-chloro- 3-cephem-4-corboxylote hydrochloride (111) &OoH N-ethoxycorbonyl-2-ethoxy- 1.2-dihydroquinoline, THF UI + HNy0k~~3 , El O H,C CH, COOH OMF, HCI, Zn I Cefoclor I Referencefs): US 3 925 372 (Lilly; 9.12.1975; prior. 23.2.1973, 1.4.1974). DOS 2 408 698 (Lilly; appl. 22.2.1974; USA-prior. 23.2.1973). Chauvette, R.R.; Pennington, P.A.: J. Med. Chem. (JMCMAR) 18,403 (1975). 3-halogenocephem precursors: DOS 2 408 686 (Lilly; appl. 22.2.1974; USA-prior. 23.2.1973). US 4 115 643 (Lilly; 19.9.1978; prior. 16.8.1976, 8.8.1977). 3-hydroxycephetn intermediates: US 3 917 587 (Lilly; 4.11.1975; appl. 28.11.1972). 7 368 C Cefadroxil 3-methylenecephem intermediates: US 3 932 393 (Lilly; 13.1.1976; appl. 25.2.1971). US 4 075 203 (Lilly; 21.2.1978; appl. 16.6.1976). 3-chlorocephem intermediates: US 3 962 227 (Lilly; 8.6.1976; prior. 23.2.1973, 1.4.1974). US 4 064 343 (Lilly; 20.12.1977; prior. 23.2.1973, 1.4.1974,9.2.1976). Formulation(s): cps. 250 mg, 500 mg; gran. 125 mg, 250 mg; s. r. tabl. 375 mg, 500 mg; syrup 125 mglml, 250 mglml Trade Name(s): D: Kefspor (ASTA Medica Sigacefal (Kytta-Siegfried) J: Kefral (Shionogi; 1982) AWD) F: Alfatil (Lilly; 1981) USA: Ceclor (Lilly; 1979) Muco Panoral (Lil1y)- GB: Distaclor MR (Lilly; 1979) Ceclor CD (Dura) comb. Keftid (Galen) Panoral (Lilly; 1979) I: Panacef (Lilly) Cefadroxil ATC: JOIDA09 Use: antibiotic RN: 50370-12-2 MF: C,,H,,N30sS MW: 363.39 EINECS: 256-555-6 LD,,,: >1.5gIkg(M,i.v.);>lOg/kg(M,p.o.); >I glkg (R, i.v.); >10 g/kg (R, p.0.); >2 gkg (dog, p.0.) CN: [6R-[6a,7~(R*)]]-7-[[amino(4-hydroxyphenyl)acetyl]amino]-3-methyl-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2. 7-amino-3-deacetoxy- cepholosporonic acid D(-)-4-hydroxy-N-(2-meth- oxycorbonyl- 1 -methyl- etheny1)phenylglycine I Cefodroxil I Reference(s): DE 1 795 292 (Bristol-Myers; appl. 5.9.1968; USA-prior. 5.9.1967). US 3 489 752 (Bristol-Myers; 13.1.1970; appl. 5.9.1967). GB 1 240 687 (Bristol-Myers; appl. 5.9.1968; USA-prior. 5.9.1967). US 3 985 741 (Bristol-Myers; 12.10.1976; prior. 15.9.1972, 18.10.1974). GB 1 532 682 (Bristol-Myers; appl. 27.4.1976; valid from 7.3.1977). crystalline monohydrate: US 4 160 863 (Bristol-Myers; 10.7.1979; prior. 7.4.1977, 2.2.1978). DOS 2 718 741 (Bristol-Myers; appl. 27.4.1977; GB-prior. 27.4.1976,7.3.1977). Formulation(s): cps. 500 mg; oral susp. 125 mg/5 ml, 250 mg/5 ml, 500 mgl5 ml; tabl. 1 g Trade Name(s): D: Bidocef (Bristol-Myers Cedrox (Hexal) Squibb; 1980) Griincef (Bristol-Myers Squibb; Griinenthal) Cefalexin C 369 F: Oracefal (Bristol-Myers Cephos (CT) Sumacef (Bristol Banyu; Squibb; 1977) Crenodyn (1st. Italiano 1982) GB: Baxan (Bristol-Myers Ferm.) USA: Duricef (Bristol-Myers Squibb; 1982) Oradroxil (Lampugnani) Squibb; 1978) I: Cefadril (AGIPS) J: Sedral (Banyu; 1982) Ultracef (Bristol; 198 1) Ceoxil (Magis) Cefalexin (Cephalexin) ATC: JOlDAOl Use: antibiotic RN: 15686-71-2 MF: C,,H,7N,0,S MW: 347.40 EINECS: 239-773-6 LD,,: 1495 mglkg (M, p.o.1; >20 gkg (R, p.0.) CN: [6R-[6a,7~(R*)]]-7-[(aminophenylacetyl)amino]-3-methyl-8-oxo-S-thia-l-azabicyclo[4.2.0]oct-2-ene-2- carboxylic acid monohydrate RN: 23325-78-2 MF: C,,HI7N,O4S . H,O MW: 365.41 COOH 0 COOH Pd-bSOt cefologlycine (I) Cefolexin tert-butyl chlaroforrnote (Boc-CI) N,O-bis(trirnethylsilyl)- 7-ornino-3- acetomide deocetoxy- cephalosporonic acid 370 C Cefalexin 1. CH,CN, (H,C)2N-CH2-C6H5, CI-COOCH, 111 + 2. CH30H [-I HN*O-CH3 1. benzyldimethylarnine CH30 D(-)-methyl 3-(a- corboxybenzylamino)- crotonate sodium salt Reference(s): DE 1 670 625 (Lilly; appl. 28.3.1967; USA-prior. 14.9.1966). US 3 507 86 1 (Lilly; 2 1.4.1970; prior. 3 1.7.1962, 14.9.1966). a,b Ryan, C.W. et al.: J. Med. Chem. (JMCMAR) 12, 310 (1968). FR 1 524 225 (Eli Lilly; appl. 23.3.1967; USA-prior. 14.9.1966). GB 1 174 335 (Eli Lilly; appl. 7.3.1967). c DOS 1 942 454 (Lilly; appl. 20.8.1969; USA-prior. 23.8.1968). GB 1 459 807 (Proter S.p.A.; appl. 27.5.1975). pur$cation: US 3 634 41 6 (Glaxo; 1 1 .l. 1972; GB-prior. 26.3.1969). US 3 676 437 (Glaxo; 11.7.1972, GB-prior. 26.9.1969). alternulive syntheses (also ring extension of penicillin sulfoxide esters): GB 1 204 394 (Eli Lilly; appl. 8.5.1968; USA-prior. 8.5.1967). US 3 502 663 (Eli Lilly; 24.3.1970; appl. 21.4.1969). US 3 671 449 (Lilly; 20.6.1972; prior. 23.8.1968, 19.8.1970). DAS 2 012 955 (Eli Lilly; appl. 18.3.1970; 1JSA-prior. 18.3.1969). DOS 2 117 377 (Bristol-Myers; appl. 8.4.1971; USA-prior. 10.4.1970, 5.10.1970). DOS 2 127 225 (Yamanouchi; appl. 2.6.1971; J-prior. 12.6.1970, 15.6.1970). DAS 2 241 091 (Toyo Jozo; appl. 21.8.1972; J-prior. 20.8.1971, 14.1.1972). DAS 2 242 684 (Lilly; appl. 30.8.1972; GB-prior. ll.9.l97l). US 3 946 002 (Eli Lilly; 23.3.1976; appl. 11.7.1974). DOS 2 728 578 (Lilly; appl. 24.6.1977; USA-pnor. 1.7.1976). Chauvette, R.R. et al.: J. Org. Chem. (JOCEAH) 36, 1259 (1971). ucylation via 1,3,2-dioxaboranyl-derivatives: DOS 2 755 902 (Dobfar; appl. 15. 12.1977; I-prior. 16.12.1976). tnicrobiological acvlation: US 4 073 687 (Shionogi; 14.2.1978; J,prior. 14.5.1975). crystalline rnonohydrute: US 3 531 481 (Lilly; 29.9.1970; prior. 21.4.1969). US 3 655 656 (Lilly; 11.4.1972; prior. 21.4.1969,4.6.1970). salts with sulfonic acids: US 3 676 434 (Lilly; 1 1.7.1972; prior. 29.7.1970). retard preparation: GB 1 543 543 (Shionogi; appl. 11.5.1 977; J-prior. 13.5.1976). Forrnulation(s): cps. 500 mg; f. c. tabl. 500 mg, 1000 mg; gran. 125 mg, 250 mg; vial 1 g/4 ml; susp. 250 mg/5 ml; syrup 50 mglml, 250 mglml Trade Name(s): D: Ceporexin (Glaxo Wellcome; Hoechst; 1973) GB: Oracef (Lilly; 1971) F: CeEacet (Norginc) Ceporexine (Glaxo I: Wellcome) Keforal (Lilly; 1970) Cefalexina (Marco Viti) Ceporex (Glaxo Wellcome; Ceporex (Glaxo) 1969) Foce (Medici)-comb. Keflex (Lilly; 1985) Fosfolexin (Lifepharma)- Cefalexi (Formulario Naz.; comb. Lifepharma) Lafarin (Lafarc) . [6R-[6a,7~(R*)] ]-7 -[ [amino(4-hydroxyphenyl)acetyl]amino ]-3 -methyl-8-oxo-5-thia-l- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 2. 7-amino-3-deacetoxy- cepholosporonic acid D (-) -4 -hydroxy-N-(2-meth- oxycorbonyl- 1 -methyl- etheny1)phenylglycine. tetrobutylamrnoniurn (3S.4S )-3 -( benzyloxy- corbonylamino )-4 - hydroxymethyl- 2-0 x 0- ozetidine-1 -sulfonate (28-cis )-3 -( benzyloxy- carbony1arnino )-2 -( corb- ornoyloxymethyl )-4 -0 x 0- azetidine-1-sulfonic ocid. II R' H R' H 4-nitrobenzyl 4-nitrobenzyl 3- 3-methylane- 7-( 2- hydroxy- 7-( 2-thienyl thienylocetomido )- ocetornido )-3 - cephom-4-corb- cephem-4-corb- oxylote oxylote 1. pyridine,