Pharmaceutical Substances Syntheses, Patents, Applications - Part 133 doc

lithium aluminum hydride... 1324 M Mibefradil hydrochloride p-toluene- sulfonyl chloride V IS.2S-2-6-fluoro- 1,2,3,4-tetrahydro-2- hydroxy-2-isopropyl- 2-naphthylethyl p-toluenesulfo

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:

U S 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.;

F: Mexitil (Boehringer Ing.; I: Mexitil (Boehringer Ing.; USA: Mexitil (Boehringer lng.;

generics

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

LD,: 6329 mgikg (M, i.v.); >16 glkg (M, p.0.);

2636 mgikg (R, i.v.); >20 glkg (R, p.0.)

1 ( c H ~ ) ~ s ~ c I N ( c ~ H ~ ) ~

0

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

2-imidozolidinone (I)

1322 M Mianserin

Formulation(s): vial 0.5g15 ml, 1 gI10 ml, 2 gl20 ml, 5 gI50 ml

Trade Nanze(sj:

1979)-comb with oxacillin I: Baypen (Bayer; 1983)

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

N

PPA

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):

generics

Bolvidon (Organon; 1976);

wfm

Mibefradil hydrochloride M 1323

Mibefradil hydrochloride

(Ro-40-5967; Ro-40-59671001)

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 1 5 O C

2 H2Nn

H2N +

1 isobutyryl chloride

2 o-phenylenediamine

1 Tos-OH, to1uene.A

p H 3

HN

2 Hz Pd-C, CH30H

I

1 p-toluenesulfonic ocid b - k ! ~

2 hydrogen 2-13-(methylomino)

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

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

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

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:

R e f e m m ( s ) : - - - - - - - - - - - -

p ' 3

1 H , C ~ N ~ C H ~ 720 Q~

CH,CH,

M CHCI,

VII + I 1

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):

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

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):

Micinicate

(Nicotinyl cyclandelate)

Use: vasodilator (for treatment of chromic obliterating peripheral arteriopathy and microcircular disorders)

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

carboxylic acid onhydride carboxylic acid

carboxyphenylrnethyl ester (I)

SOCI, DMF

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

GOlAFO4; J02AB01; S02AA13 Use: topical antifungal

LD,,,: 90.57 mglkg (M, i.v.); 872 mglkg (M, p.0.);

105 mglkg (R, i.v.); >3 g k g (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

LD,,: 28 m g k g (M, i.v.); 578 m g k g (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

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)

Use: antibiotic, antibacterial

CN: 0 - 2 - a m i n o - 2 , 3 , 4 , 6 - t e t r a d e o x y - 6 - ( m e t h y l a m i n o ) - a - ~ - e ~ o s y l - ( l + 4 ) - 0 - [ 3 - d e o x y - 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):

Use: hypnotic

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

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 N O I

N ,

TiCI,

1 + H2N-CH3 - CH3 NoN02 CH,COOH

titomum sodium tetrochloride

ornine

- 1 , Hz Roney-Ni

11 + H3C-NO2 + CI - , 111

potassium tert-butylote

\ /

nitro-

methane

H C 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):

RN: 35457-80-8 M E 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):

Rubimycin (Nikken)

Use: antibiotic (Miokamycin)

LD,,,: 7 5 glkg (M, p.0.)

CN: leucomycin V 3',9-diacetate 3,4B-dipropanoate