Formulations: disodium salt vial 0.5 g i.m.. synthesis of enantiomers: EP 127 099 Boehringer Mannh.; appl... CN: 4-arninosu1fonylbenzoic acid monosodium salt RN: 6101-29-7 MF: C7H,NNa
Trang 1Carticaine 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)
Endak (Madaus; 1982) GB: Teoptic (CIBA Vision; USA: Cartrol (Abbott)
F: Carpilo (Chauvin)-comb 1986)
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
Trang 2362 C Carumonam
@ aretidinone intermediate:
1 HBr CH,COOH
0-CH, H0 OH peroxide
KO%,
DMF Kl
methyl (2R.3S)-4-
acetoxy-2.3-epaxy- butanoote
1 CH,OH HCI
H N OH
ONa
2 NH,, CH,OH
3 NaHCO,, 2-12 Z-NH OH c ' / h C I , D M M
3 benzyl chlorofarrnote H c O i ch10ro:cetyl chloride,
NH2 dimethylacetarnide
(111) methanesulfo-
nyl chlaride
1 sulfur trioxide-2-picoline
complex
3 tetrabutylammonium
hydrogen sulfate
Trang 3Carurnonam C 363
fi
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,
O H C
IIZN4'?ffvcH3
+ ~ , a ~ y H -* 3
0 CH, ethyl 2-(2-amino-4- tert-butyl
hydmxyiminwcetote
0 H3C
C H F N ,
0 CH3
O d - C H 3 , P(OC2H5)3
- phosphite
(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)
Trang 43 6 4 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 m g k g (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-
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
Trang 5F
Carzenide C 365
Trade Name(s):
D: Dilalrend (Boehringer F: Kredex (Boehringer Dilatrend (Boehringer
Querto (B yk Gulden) GB: Eucardic (Boehringer USA: Coreg (SmithKline
I: Carvipress (Gentili)
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.)
Trang 6366 C Cefaclor
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)
F: Celospor (Ciba); wfm J: Celospor (Novartis)
Use: antibiotic RN: 53994-73-3 MF: C1SH14CIN,04S MW: 367.81 EINECS: 258-909-5
LD,,: >20 glkg (M, p.0.);
>20 g k g (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
cephalosporanote
(from cephalotin)
Trang 7Cefaclor C 367
Ln, nwun
2 HCI
R'
4-nitrobenzyl 4-nitrobenzyl 3-
3-methylane-7-(2- hydroxy-7-(2-thienyl
thienylocetomido)- ocetornido)-3-
cephom-4-corb- cephem-4-corb-
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
O H,C CH,
C O O H 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)
Trang 87
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)
Muco Panoral (Lil1y)- GB: Distaclor MR (Lilly; 1979) Ceclor CD (Dura)
Panoral (Lilly; 1979) I: Panacef (Lilly)
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 g k g (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
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)
Trang 9Cefalexin C 369
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 g k g (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
P d - b S O t
tert-butyl
chlaroforrnote
(Boc-CI)
N,O-bis(trirnethylsilyl)- 7-ornino-3-
acetomide deocetoxy-
cephalosporonic acid
Trang 10370 C Cefalexin
1 CH,CN, (H,C)2N-CH2-C6H5, CI-COOCH,
[-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)
Keflex (Lilly; 1985) Fosfolexin (Lifepharma)- Cefalexi (Formulario Naz.; comb