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)