Pharmaceutical Substances Syntheses, Patents, Applications - Part 64 pps

500 mg as sodium salt Trade Narnes: D: Dichlor-Stapenor Bayer F: Cefaplus Labif-comb.; Diclocil Bristol; wfm... 632 D Dicvcloverine Diclocil Bristol; wfrn Diclocillin Aristochimica; wf

Dicloxacillin D 631 GB: Daranide (Merck Sharp & 1: Antidrasi (SmithKline Glaumid (SIFI)

Fenamide (Farmigea) USA: Daranide (Merck)

Use: antibiotic RN: 31 16-76-5 MF: C,9Hl,CIZN30sS MW: 470.33 EINECS: 221 -488-3

CN: [2S-(2a,5a,6~)]-6-[[[3-(2,6-dichlorophenyl)-5-methyl-4-isoxazolyl]carbonyl]amino]-3,3-dimethyl-7- oxo-4-thia-l-azabicyclo[3.2.0]heptane-2-carboxylic acid

monosodium salt monohydrate

RN: 13412-64-1 MF: C,,H16C12N,Na0,S H 2 0 MW: 5 10.33

LD,,: 875 mglkg (M, i.v.); 4560 mglkg (M, p.0.);

520 m g k g (R, i.v.); 3579 mglkg (R, p.0.);

>3 glkg (dog, p.o.1

H2N-OH

amine

2,6-dichloro-

benzaldehyde

6-aminopeni-

cillonic acid

0 H 4 'OH ocetoacetote

3-(2.6-dichloro- phenyl)-5-methyl- isoxozole-4- carbaxylic acid

Reference (s):

NoOH

+

US 3 239 507 (Beecham; 8.3.1966; GB-prior 17.10.1962)

COOH

H

Dicloxocillin

GB 978 299 (Beecham; appl 17.10.1962; addition to GB 905 778 from 14.3.1961)

BE 657 504 (Bayer; appl 23.12.1964; D-prior 24.1 2.1963)

Formulation(s): cps 500 mg (as sodium salt)

Trade Narne(s):

D: Dichlor-Stapenor (Bayer) F: Cefaplus (Labif-comb.; Diclocil (Bristol); wfm

632 D Dicvcloverine

Diclocil (Bristol); wfrn

Diclocillin (Aristochimica);

wfrn

Diclocillin (Lagap); wfrn

Diclocta (Lusofarmaco)-

comb.; wfm

Dicloeta (Lusofarmaco)-

comb.; wfrn

Diclomax (Pulitzer); wfrn

Dicloxapen (Magis); wfm Diflor (Coli); wfm Etadipen (Chimas)-comb.;

wfrn Novapen (IBP); wfrn Versaclox (Bristo1)-comb.;

wfrn numerous combination preparations

J: Clocil (Bristre-Banyu) Combipenix (Toyo Jozo)- comb

Diclex (Meiji) Staphcillin (Banyu) USA: Dycill (Beecham); wfm Dynapen (Bristol); wfm Pathocil (Wyeth); wfm Veracillin (Ayerst); wfm

Dic ycloverine

(Dicyclomine)

ATC: A03AA07 Use: antispasmodic, anticholinergic RN: 77-19-0 MF: C,,H,,NO, MW: 309.49 EINECS: 201-009-4

CN: [I,]'-bicyclohexyl]-1-carboxylic acid 2-(diethy1amino)ethyl ester

hydrochloride

RN: 67-92-5 MF: C,,H,,NO, HCI MW: 345.96 EINECS: 200-671-1

LD,,: 3 1.5 mg/kg (M, i.v.); 625 mg/kg (M, p.0.);

1290 m g k g (R, p.0.)

benzyl cyanide 1.5-dibromo- 1 -cyano- 1

hexone

ethyl 1 -phenyl- cyclohexane-1 -

carboxylate (I)

I Dicycloverine

1 NaNH

0-CH,

1 sodium amide

2 cyclohexyl

cyano-

oxylote (Ill)

Rcrfcrrence(s):

US 2 474 796 (Merrell Comp.; 1949; prior 1946)

Tilford, C.H et al.: J Am Chem Soc (JACSAT) 69,2903 (1947)

Rmularion(s): cps 10 mg

Tmde Name(s):

D: Atumin (Merrell); wfm I: Bentyl (Merrell) Mamiesan (Kyowa

Spasrno-Rhoival (Tosse)- Merankol (Lepetit)-comb Yakuhln- hoe^)

comb.; wfm J: Bentyl (Shionogi) USA: Bentyl (Hoechst Marion

GB; Diarrcst (Galen)-comb BentylIPhenobarbital Roussel; as hydrochloride)

Kolanticon (Hoechst)- (Shionogi)-comb generics

Merbentyl (Florizel) Kolantyl (Shionogi)

ATC:

Use:

J05AF02 anti-AIDS therapeutic, symptomatic oral treatment

2',3'-didsoxy-

odonosina

Didonosine

I

Reference(s):

US4970 148 (Ajinomoto; 13.1 1.1990; appl 7.10.1988; J-prior 24.12.1987,7.10.1987, 13.9.1988)

Plunkett, W.; Cohen, S.S.: Cancer Res (CNREAS) 35, 1547 (1975)

alternative synthesis:

US 5 01 1 774 (Bristol-Mycrs Squibb; 30.4.1991; appl 28.2.1990; prior 17.7.1987)

Prisbe, E.J.; Martin, J.C.: Synth Commun (SYNCAV) 15,401 (1985)

Horwitz, J.P et al.: J Org Chem (JOCEAH) 32, 8 17 (1 967)

purification:

US 4 962 193 (Ajinomoto; 9.10.1990; appl 28.1 2.1988; J-prior 22.12.1987)

JP 1 175 991 (Ajinomoto; appl 29.12.1987)

JP 1 165 390 (Ajinomoto; appl 22.12.1987)

medical use for treatment of AIDS:

EP 206 497 (Wellcome; appl 14.5.1986; GB-prior 15.5.1985, 20.2.1986)

EP216 510 (US Department of Health; appl 21.8.1986; USA-prior 26.8.1985)

US4861 759 (US Department of Health; 29.8.1989; appl 15.5.1989; prior 11.8.1987,26.8.1985,4.12.1986)

US 5 026 687 (National Institute of Health; 25.6.199 1 ; appl 3.1.1990)

medical use for treatment of hepatitis B virus infections:

WO9 014 091 (US Department of Health; appl 15.5.1990; USA-prior 15.5.1989,4.12.1986, 11.8.1987)

synthesis of dideoxy adenosine:

The Merck Index, 3091 (Rahway 1989)

Formulation(s): chewable tabl 10 mg, 25 mg, 50 mg, 100 mg, 150 mg; powder 2 g, 4 g

634 D Dienestrol

Trade Name(s):

D: Videx (Bristol-Myers GB: Videx (Bristol-Myers USA: Videx (Bristol-Myers

F: Videx (Bristol-Myers J: Videx (Bristol-Myers

Dienestrol

(Dienoestrol)

ATC: G03CBOl; G03CC02 Use: estrogen

RN: 84-17-3 MF: CIp,H,,O2 MW: 266.34 EINECS: 201-519-7

CN: 4,4'-( 1,2-diethylidene-l,2-ethanediyl)bis[phenol]

4'-hydroxy-

propiophenone

I Nu-Hq

+

1 sodium omolgome

2 benzoyl chloride

(1)

2 KOH C2H50H

I

Reference(s):

GB 566 881 (Boots Pure Drug; appl 1943)

US 2 464 203 (Boots; 1949; GB-prior 1943)

US 2 465 505 (Roche; 1949; CH-prior 1944)

c;!ternative synthesis:

Hobday, G.I.; Short, W.F.: J Chem Soc (JCSOA9) 1943,609

review:

Ehrhart, Ruschig 111, 330

Dodds, E.C et al.: Proc R Soc London, Ser B (PRLBA4) 127, 162 (1939)

Formulation(s): cream 0.01 %; tabl 5 mg, 25 mg

Trade Narne(s):

D: Sanoprostal GB: Orho Dienoestrol (Janssen- Sebohormal (Bruschettini)-

wfm I: Sebohermal (Bruschettini)- USA: Ortho Dienestrol (Ortho-

Diethylcarbamazine D 635

Use: anthelmintic RN: 90-89-1 MF: CloH21N30 MW: 199.30 EINECS: 202-023-3

CN: N,N-diethyl-4-methyl-I-piperazinecarboxam~de

RN: 1642-54-2 MF: C,oH2,N30 C6H807 MW: 39 1.42 EINECS: 216-696-6

LD,: 180 m a g (M, i.v.); 660 mglkg (M, p a ) ;

1400 mg/kg (R, p.0.)

piperozine

S 2467 895 (American Cyanamid; 1949; prior 1946)

Formularion(s): tabl 50 mg

D: Hetrazan (Lederle); wfm GB: Banocide (Wellcome); wfm USA: Hetrazan (Lcdcrle); wfm

F: Notbine (Specia); wfnl J: Hetrazan (Lederle)

ATC: G03CB02; G03CC05; L02AAO1 Use: formerly in estrogenic hormone therapy, listed as a known carcinogen RN; 56-53-1 MF: C,,H,,O, MW: 268.36 EINECS: 200-2784

LDSO: 300 mgkg (M, i.v.); >3 glkg (M, p.0.);

>3 g/kg (R, p.o.1

CN: (0-4,4'-(1,2-diethyl-1,2-ethenediyl)bis[phenol]

I NoNH? NH3, - 80 OC

636 D Diethylstilbestrol

iodide

KOH, 2 2 0 OC

11

HO

4'-hydroxy-

propiaphenone

111 -* Diethylstilbestrol

Reference(s):

a US 2 392 852 (Lilly; 1946; prior 1941)

US 2 402 054 (Lilly; 1946; prior 1941)

b Dodds, E.C.: Nature (London) (NATUAS) 141,247 (1938)

c US 2 421 401 (Hoffmann-La Roche; 1947; S-prior 1943)

DRP 715 542 (Schering AG; appl 1939)

alternative syntheses:

Ullmanns Encykl Tech Chem., 3 AuB., Vol 8, 327

GB 526 927 (Richter Gedcon; appl 1939; H-prior 1938)

BE 665 818 (Miles Lab.; appl 23.6.1965; USA-prior 24.6.1964)

review:

Solmssen, U.V.: Chem Rev (Washington, D C.) (CHREAY) 37,481 (1945)

Ehrhart, Ruschig, 111,327

Formulation(s): tabl 1 mg, 5 mg

Trade Name(s):

D: Cyren A (Bayer); wfm Stilboestrol and Lactid USA: Diethylstilbestrol (Lilly);

Diethylstilbestrol dipropionate D 637

Diethylstilbestrol dipropionate ATC: G O ~ C B

@iethylstilboestrol-dipropionat; Diathylstilboestrol- Use: estrogen

dipropionat)

RN: 13C-80-3 MF: C24H2804 MW: 380.48 EINECS: 204-995-4

CN: (4-4,4'-(1,2-diethyl-l,2-ethenediyl)bis[phcnol] dipropanoate

pyridine

wH + H ~0 0 c ~ -, ~ ~ c H ~

Reference (s):

Dodds, E.C et al.: Proc K Soc London, Ser B (PRLBA4) 127, 140 (1939)

H 3 c J 0

diethylstilbestrol pmpianic anhydride

Formulation(s): amp

Diethylstilbeetroi dipropionate

Trade Name(s):

D: Klimax "Taeschner" USA: Dibestil (Breon); wfm

(Taeschner); wfm

Diethylstilbestrol disulfate ATC: G03CB

@iethylstilboestroldisulfat; Diiithylstilboestroldisulfat) Use: estrogen

RN: 316-23-4 MF: C18H2008S2 MW: 428.48 EINECS: 206-257-7

CN: (E)-4,4'-(1,2-diethyl-l,2-ethenediyl)bis[phenol]bis(hydrogen sulfate)

diethylstilbestrol

KOH

Diethylstilbestrol disulfate (1)

Diethylstilbestrol disulfate dipotassiurn salt

Reference(s):

US 2 234 31 1 (Ciba; 1941; CH-prior 1938)

Formulation(s): ointment

638 D Difenidol

Trade Name(s):

1: ldroestril (Maggioni); wfm Pappy (Kanto)

J: Estiol (Hokuriku)

Stilbestohormon (Tokyo Hosei)

Difenidol

(Diphenidol)

ATC: A04; DO4 Use: anti-emetic, antihistaminic RN: 972-02-1 MF: C2,H,,N0 MW: 309.45 EINECS: 213-540-9

LD,,,: 32 mglkg (M, i.v.); 450 mglkg (M, p.0.);

815 mglkg (R, p.0.)

CN: a,a-diphenyl-1-piperidinebutanol

hydrochloride

RN: 3254-89-5 MF: C,,H,,NO HCl MW: 345.91 EINECS: 221-850-0

LD,,: 37mg/kg(M,i.v.);400mg/kg(M,p.o.);

29 mglkg (R, i.v.); 5 15 mglkg (R, p.0.)

pamoate (2:l)

RN: 26363-46-2 MF: C,,H2,N0 1/2C,,H1,0, MW: 1007.28

Rqference(s):

US 2 41 1 664 (Ciba; 1946; CH-prior 1941)

Formulation(s): tabl 25 mg, 50 mg

Trade Name(s):

J : Ansumin (SS Seiyaku)

Antiul (Tokyo Hosei)

Cephadol (Nippon S.)

Cerachidol (Ono)

Cerrosa (Toyo Pharmar)

Degidole (Nihon Yakuhin)

Gipsydol (Nihon Yakuhin)

Maniol (Morishita)

Mecalmin (Yoshitomi-

Takeda)

benzophenone

Difenidol

Meniedolin (Toyo Shinyaku) Meranom (Hokuriku) Midnighton (Takata) Pineroro (Maruko) Promodor (Torii) Satanolon (Tatsumi) Sofalead (Nikken) Solnomin (Zensei) Tatimil (Mohan)

Verterge (Nippon Chemiphar) Wansar (Hoei) Yophadol (Yoshindol Horita)

USA: Vontrol (Smith Kline French); wfm

Use: antidiarrheal, antiperistaltic RN: 28782-42-5 MF: C2,H,,N20, MW: 424.54

CN: 1-(3-cyano-3,3-diphenylpropyl)-4-phenyl-4-piperidinecarboxylic acid

monohydrochloride

RN: 35607-36-4 MF: C,8H2xN202 HCI MW: 461.01 EINECS: 252-640-7

LD,,,: 149 mglkg (R, p.0.)

Diflorasone diacetate D

Reference(s):

DAS 1 953 342 (Janssen; appl 23.10.1969; USA-pnor 4.11.1968)

US 3 646 207 (Janssen; 29.2.1972; appl 4.1 1.1968)

rmulation(s): tabl 0.5 mg

D: Lyspafena (Cilag-Chemie)- I: Motofen (Ci1ag)-comb.; USA: Motofen (Carnrick; as

Use: topical glucocorticoid RN: 33564-31-7 MF: C26H32F20, MW: 494.53 EINECS: 251-575-1

LD5,: >3 g/kg (M, p.0.);

>3 g/kg (R, p.o.1

CN: (6a,ll~,16~)-17,21-bis(acetyloxy)-6,9-d1fluoro-11-hydroxy-16-methy1pregna-1,4-diene-3,20-dione

ditlorasone

RN: 2557-49-5 MF: C22H2,F20, MW: 410.46 EINECS: 219-875-7

1 (F3C-CO),O CH3COOH,

H3C

H 1 trifluoroocetic anhydride

0 ' , 2 N-brornoocetornide

F 3 potossiurn ocetote

21 -ocetoxy-3,20-d~oxo-

6a-fluoro- 17-hydroxy -

16p-methyl-4,9(1 1)-

prsgnadiene

1 H2F2 THF

" I J dioxone ~ ~

CI CI

I b

1 hydrogen fluoride

2 2,3-dichloro-5,6-

dicyano-l,4-benzoquinone

Diflorosone diocetote

!

640 D Diflucortolone valerate

6a,9a-difluoro-3,20- trimethyl

dioxo- 168-methyl- orthoocetote

1 l p , l 7 , 2 l -trihydroxy-

1,4-pregnodiene

2 1 1 , pyridine

H3C 0 CH3

Rejerence(s):

DE 2 308 73 1 (Upjohn; appl 22.2.1973; USA-prior 9.3.1972)

US 3 980 778 (Upjohn; 14.9.1976; appl 20.5.1975; prior 25.10.1973,20.12.1972,9.3.1972)

NL 7 303 262 (Upjohn; appl 8.3.1973; USA-prior 9.3.1972, 20.12.1972)

starting material:

US 3 557 158 (Upjohn; 19.1.1971; prior 22.1.1962, 18.3.1959.4.8.1958)

Formdation(s): cream 0.05 %; ointment 0.05 %

Trade Name(s):

D: Florone (Galderma; 1982) S terodelta crema Dlflal (Yamanouchi; 1985) I: Dermaflor (Brocchieri) (Gibipharma) USA: Florone (Decmik; 1978)

Sterodelta (Metapharma) J: Diacort (Upjohn- Maxiflor (Allergan; 1981)

Sumitomo; 1985)

Use: glucocorticoid RN: 59198-70-8 MF: C2,H,,F20s MW: 478.58 EINECS: 261-655-8

LD,,,: 450 mg/kg (M, i.p.); >4 g/kg (M, p.0.); 180 mgkg (M, s.c.);

98 m g k g (R, i.p.); 3.1 g/kg (R, p.0.); 13 mgkg (R, s.c.)

CN: (6a, 1 1 P,16a)-6,9-difluoro- 1 1-hydroxy- 16-methyl-21-[(1-oxopentyl)oxy]pregna-1,4-diene-3,20-dione diflucortolone

RN: 2607-06-9 MF: C22H2RF204 MW: 394.46 EINECS: 220-022-6

H3C-S02CI, pyridine, DMF

21 -0cetoxy-3.20-dioxo-6a-

fluoro- 118-hydroxy-16a-

methyl-4-pregnene

(cf fluocoriolone synthesis)