Pharmaceutical Substances Syntheses, Patents, Applications - Part 44 doc

2 mg, 5 mg Trade Names: D: Chlormadinon Jenapharm Menova Merck-comb.. Muskel Trancopal camp.. with codeine phosphate; wfm 0 Chlormezanone Supotran Winthrop; wfrn TrancogCsic W1nthrop

Chlormadinone acetate C 43 1 Peridex (Procter & Periogard (Colgate Oral; as

Gamble; as gluconate) gluconate)

Use: progestogen RN: 302-22-7 MF: C,,H,,ClO, MW: 404.93 EINECS: 206- 1 18-0

LD,,: >2 glkg (M, i.v.); >15 glkg (M, p.0.);

>I0 g k g (R, p.0.)

CN: 17-(acetyloxy)-6-chloropregna-4,6-diene-3,20-dione

_*

p-chloranil

acid

17-hydraxy-

progesterone

C I ( n o t isolated)

CI

Chlorrnadinone ocetote

Reference(s1:

DE 1 075 114 (E Merck AG; appl 29.4.1958)

Briickner, K et al.; Chem Ber (CHBEAM) 94, 1225 (1961)

Fortnulation(s): tabl 2 mg, 5 mg

Trade Name(s):

D: Chlormadinon (Jenapharm) Menova (Merck)-comb 1: Fisiosequil (Recordati);

Gestamestrol (Hermal- (Griinentha1)-comb J; Lutoral (Shionogi) Chemie)-comb F: Lutkran (SolymCs)

432 C Chlormerodrin

Use: diuretic RN: 62-37-3 MF: C5H,1CIHgN,02 MW: 367.20 EINECS: 200-530-4

LD,,: 215 mglkg (M, p.0.);

150 mglkg (R, p.0.)

CN: [3-[(aminocarbonyl)amino]-2-rnethoxypropyl-C1,03]chlor~mercury

Reference(s):

US 2 635 982 (Lakeside Labs.; 1953; prior 1951)

Formulafion(s): amp.; tabl 18 rng

Trade Name(s):

USA: Neohydrin (Lakeslde); wfm

Use: muscle relaxant RN: 80-77-3 MF: C,,H&INO,S MW: 273.74 EINECS: 201-307-4

LD,,: 600 mgfkg (M, p.0.);

605 m g k g (R, p.0.);

500 mg/kg (dog, p.0.)

CN: 2-(4-chlorophenyl)tetrahydro-3-methyl-4H-l,3-thiazin-4-one 1, I-dioxide

3-mercapto- methyl- 4-chloro- 2-(4-chloropheny1)-

propionic amine benzoldehyde 3-methyltetm-

4-one

Rejierence(s):

G B 815 203 (Sterling Drug; appl 3.7.1957; USA-prior 20.7.1956)

Surrey, A.R et al.: J Am Chern Soc (JACSAT) 80,3469,3471 (1958)

Formulation(sj: suppos 200 mg; tabl 100 mg, 200 mg, 400 mg

Trade Name(s):

(Winthrop); wfm codeino (Winthrop)-comb

Muskel Trancopal camp with paracetamol and

(Winthrop)-comb with codeine phosphate; wfm

0

Chlormezanone

Supotran (Winthrop); wfrn TrancogCsic (W1nthrop)- comb with aspirine; wfm

Trancopal (Winthrop); wfrn

paracetamol; wfm F: Alinam (Lucien); wfm GB: Trancopal (Winthrop); wfm

Chlormidazole C 4 3 3 Trancoprin (Winthrop)- Eblimon (Guidotti)-comb Transanate (Teikoku comb with aspirine; wfm numerous combination Hormone)

I: Clormetadone (Nuovo preparations USA: Trancopal (Sanofi)

Cons Sanit Naz.)-comb J: Myolespen (Dojin Iyaku)

Condo1 (Maggioni- Relizon (Mochida)

Winthrop)-comb Trancopal (Daiichi)

Chlormidazole

(Clornidazolum)

ATC: DO1 AC Use: fungistatic, antifungal RN: 3689-76-7 MF: C,,H,,CIN, MW: 256.74 EINECS: 222-998-9

CN: 1-[(4-chlorophenyl)methyl]-2-methyl-1H-benzimidazole

hydrochloride

RN: 54118-67-1 MF: C,,H,,ClN, HC1 MW: 293.20

Chlorrnidozole N-(chl0robenzyl)- acetic acid

o-phenylenediamine

2 4-chlorabenzyl bromide

2-methyl-

benzirnidozale

Referencefs):

Formulation(s): cream 5 %; ointment 5 % (as hydrochloride)

Trade Name(s):

D: Myco-Jellin (Griinentha1)- Polycid N (Griinentha1)-

comb with fluocinolone comb.; wfm

acetonide; wfm

Use: hypnotic, anesthetic

RN: 57-15-8 MF: C,H,C1,0 MW: 177.46 EINECS: 200-317-6

CN: 1 ,l, 1 -trichloro-2-methyl-2-propanol

434 C Chloroprednisone acetate

KOH

H 3 C ~ C H 3 + HCCI, +

0

acetone chloroform ( Chlorobutonol (

Rqfcrcnce(s):

Budesinsky-Protiva, 235

Willgerodt, C,: Bes Dtsch Chem Ges (BDCGAS) 14, 2451 (1881)

US 2 462 389 (Socony-Vac Oil; 1949; prior 1946)

Formzclation(s): sol 250 mgI100 ml

Trade Narne(s):

D: Givalex (Norgine)

F: Alodont (Warner-Lambeft)-

comb

Angispray (Monot)-comb

Balsamorhinol (Jamsen)-

comb

Ciella (RPR Cooper)-comb

Eludril (1nava)-comb

Givalex (Nagine Pharma)-

comb

Liquifilm (Allergan)-comb

Optrex (Etris)-comb

GB: Cerumol (L.A.B.)-comb

Eludril (Chefam)-comb

Monphytol (L.A.B.)-comb

I: Abiostil (Deca)-comb

Antipulmina (Lisapharma) Cerumenex (ASTA Medics)-comb

Clorobutanolo (Tariff Integrative)

Corizzina (SIT)-comb Desalfa (1ntes)-comb Fialetta odontalg Knapp (Montefannac0)-comb Oftalzina (SIT)-comb Respiru (Pierrel)-comb Rinoleina (Grane1li)-comb

Use: topical glucocorticoid RN: 14066-79-6 MF: C,,H,CIO, MW: 434.92 EINECS: 237-919-3

CN: (6a)-2 1-(acetyloxy)-6-chloro-17-hydroxypregna-l,4-diene-3,11,20-trione

Chloroprednisone ocetate

Reference(s):

DE 1 079 042 (Syntex; appl 1958; MEX-prior 1957)

FF-M 666 (Syntex; appl 20.9.1960)

alternative synthesis:

US 3 130 21 1 (Upjohn; 21.4.1964; prior 1957, 1958)

pharmace~ctical,formulation:

GB 955 89 1 (Organon; valid from 1962; NL-prior 196 1)

Formulation(s): cream; ointment

Chloroprocaine C 435

Trade Narnefs):

USA: Adremycin (Organon); Topilan (Syntex); wfm

wfm

Use: local anesthetic RN: 133-16-4 MF: C13Hl,C1N202 MW: 270.76

CN: 4-amino-2-chlorobenzoic acid 2-(diethy1amino)ethyl ester

monohydrochloride

RN: 3858-89-7 MF: C13HI,C1N,0, HCl MW: 307.22 EINECS: 223-371-2

LD,,: 266 mglkg (M, i.p.); 700 mglkg (M, LC.)

0 CI

2-diethylamino- ethonol N " 2

Chloroprocaine 4-amino-2- 4-amino-2- hydrochloride

chlorobenzoic chlorobenzoyl

acid chloride

hydrochloride

Reference (s):

US 2460 139 (Wallace & Tiernan; 1949; appl 1945)

Formulation(s): multiple-dose vial 1 %, 2 %; single-dose vial 2 %, 3 % (as hydrochloride)

Trade Narne(s):

.I: Piocaine (Teikoku Kagaku- USA: Nesacaine (Astra)

Chloropyramine

(Halopyramine; Chlortripelennamine)

ATC: D04AA09; R06AC03 Use: antihistaminic RN: 59-32-5 MF: CI6H2,CIN3 MW: 289.81 EINECS: 200-421-1

LD,,: 24.1 mglkg (M, i.v.); 354 m g k g (M, p.0.);

32.5 mglkg (R, i.v.); 920 mglkg (R, p.0.)

CN: N-[(4-chlorophenyl)methyl]-hr,hr-dimethyl-N-2-pyridinyl-1,2-ethanediamine

monohy drochloride

RN: 6170-42-9 MF: C,,H2,C1N3 HCl MW: 326.27 EINECS: 228-216-2

o c I + H ~ N - ~ / ~ ~ ~ Hz Raney-Ni b Pc1

N.N-dimethyl- N'-(4-chlorobenzyl) aldehyde ethylenediamine N,N-dimethyl-

436 C Chloropyrilene

Reference(s):

US 2 569 3 14 (American Cyanamid; 195 1 ; appl 1947)

Vaughan, J.R et al.: J Org Chem (JOCEAH) 14,228 (1949)

2-bromo-

Formulation(s): amp 20 mg; cream 1 %; tabl 25 mg

Chloropyramine

Trade Name(s):

D: Synpen (Geigy); wfm I: Sinopen (Geigy); wfm

pyridine

Chloropyrilene

(Chlorthenylpyramine)

ATC: R06AC Use: antihistaminic

RN: 148-65-2 MF: C,,H,,ClN,S MW: 295.84

LD,,,: 105 mg/kg (M, i.p.)

CN: N-[(5-chloro-2-thienyl)methyl]-A~,h~-dimethyl-N-2-pydinyl-1,2-ethanediamine

citrate (1:l)

RN: 148-64-1 MF: C,4H,,ClN3S C6H,07 MW: 487.96 EINECS: 205-720-0

monohy drochloride

RN: 135-35-3 MF: C,,H,,ClN,S HCl MW: 332.30

LD,,,: 438 mg/kg (M, p.0.)

5-chloro-2- N.N-dimethy1-N'-

chloromethyl- (2-pyridyl)ethylene-

thiophene diarnine

I Chloropyrilene I

Reference(s):

(cf thenyldiamine, methapyrilene)

US 2 581 868 (Monsanto; 1952; prior 1946)

Clapp, R.C et al.: J Org Chem (JOCEAH) 14,216 (1949)

Clapp, R.C et al.: J Am Chem Soc (JACSAT) 69, 1549 (1947)

Formulation(s): tabl 25 mg

Trade Name(s):

comb.; wfm USA: Tagathen (Lederle); wfm citrate); wfm

Chloroquine C 437

Use: antirheumatic, antimalarial RN: 54-05-7 MF: CI8H2,C1N3 MW: 319.88 EINECS: 200-191-2

LD,,: 21.6 mglkg (M, i.v.); 3 1 1 mglkg (M, p.0.);

60 rnglkg (R, i.v.); 330 mg/kg (R, p.0.)

CN: N4-(7-chloro-4-quinolinyl)-~1,~'-diethyl-l,4-pentanediamine

diphosphate

RN: 50-63-5 MF: C18H2hC1N3 2H3P04 MW: 515.87 EINECS: 200-055-2

LD,: 500 mg/kg (M, p.0.)

sulfate (1: 1)

RN: 132-73-0 MF: C18H&lN3 H2S04 MW: 417.96 EINECS: 205-077-6

sulfate (1:l) monohydrate

RN: 6823-83-2 MF: C,8H26CIN, H204S H20 MW: 435.97

dihydrochloride

RN: 3545-67-3 MF: C,8H2,CIN3 2HCl MW: 392.80 EINECS: 222-592-1

2,s-dihydroxybenzoate

RN: 16510-14-8 MF: C,,H,CIN, xC,H,O, MW: unspecified EINECS: 240-578-3

diorotate

RN: 16301-30-7 MF: C18H2,CIN, 2C,H,N2O4 MW: 632.07 EINECS: 240-389-6

LDS,: 1130 mg/kg (M, p.0.)

atorting products:

1 4.7-Dichloroquinoline

H

O C

'loNH2 + H 3 c v o A o , c H 3 + 250 oc

H3Cv0 0

3-chlorooniline (1) diethyl ethaxymethylene-

molonate

CI

m 0 , C H 3

P0CI3

CI

4.7-dichloro-

quinoline (N)

438 C Chloroquine

I ethyl 5-chloro-4- ethyl 7-chloro-4-

hydroxy-2-quinoline- hydroxy-2-quinoline-

carboxylate (V) carboxylate (VI)

(removal by crystallization

from acetic acid)

270 OC mineral ail POCI,

W I b Ill b N

I + H3c-od - c ' ~ ] mineral ail

POCI,

-b 111 -+ N

ethyl farmyl-

acetate

2 Navaldiamine

ethylene diethyl

oxide (VIII) amine (K)

2-diethylamina- ethanol

Z-diethylamino- ethyl chloride (X)

ethyl

ocetoacetote (XI)

- C 0 2 H NH Raney-Ni

.

navaldiarnine (XIV)

I -brama- 4-pentanane (XV)

H, NH3, Raney-Ni

XV + I X + XI11 -4 XIV

Chlorothiazide C 439

final product:

Chloroquine

I

Chloroquine

Reference(s):

US 2233 970 (Winthrop; 1941; D-prior 1937)

DRP 683 692 (I G Farben; appl 1937)

Drake, N.L et al.: J Am Chem Soc (JACSAT) 68, 1214 (1946)

l a Price, C.C.; Roberts, R.M.: J Am Chem Soc (JACSAT) 68, 1204 (1946)

DD 53 065 (S Schwarz et al.; appl 1966)

b Surrey, A.R.; Hammer, H.F.: J Am Chem Soc (JACSAT) 68, 113 (1946)

c US 2 478 125 (American Cyanamid; 1949; appl 1944)

2a DRP 486 079 (1 G Farben; appl 1924)

b Elderfield, R.C et al.: J Am Chem Soc (JACSAT) 68, 1579 (1946)

alternative syntheses ofnovoldiamine:

US 2 365 825 (Monsanto; 1944; appl 1942)

GB 1 157 637 (Sterling Drug; appl 1966; USA-prior 1965)

arninating hydrogenation of novolketone, continuous method:

DOS 2 923 472 (Bayer; appl 9.6.1979)

alternative synthesis of 4.7-dichloroquinoline from 3-chloroaniline and acrylic acid ester:

FR 1 514 280 (Roussel-Uclaf; appl 10.1.1967)

EP 56 765 (RhGne-Poulenc; appl 15.1.1982; F-prior 16.1.1981)

alternative synthesis of chloroquine from 7-chloro-4-0x0-l,2,3,4-tetrahydroquinoline and novoldiamine:

EP 56 766 (RhGne-Poulenc; appl 15.1.1982; F-prior 16.1.1981)

chlorination of 7-chloro-4-hydroxyquinoline with benzotrichloride:

DOS 3 112415 (Dynamit Nobel; appl 28.3.1981)

Formulation(s): amp 250 mgl5 ml; syrup 15 mg; tabl 50 mg, 155 mg, 300 mg (as phosphate)

Trade Name(s):

D: Resochin (Bayer Vital) GB: Avloclor (Zeneca) USA: Aralen (Sanofi; as

F: Nivaquine (RhGne-Poulenc Nivaquine (RhGne-Poulenc hydrochloride)

Savarine (Zeneca Pharma)- I: Cloroc (Formulario Naz.) phosphate)

Use: diuretic RN: 58-94-6 MF: C7H6C1N304S2 MW: 295.73 EINECS: 200-404-9

LD,,: 940 mg/kg (M, i.v.); 8 g/kg (M, p.0.);

200 mgkg (R, i.v.); 10 glkg (R, p.0.);

1 g k g (dog, i.v.)

CN: 6-chloro-2H- 1,2,4-benzothiadiazine-7-sulfonamide I, 1 -dioxide

sodium salt

RN: 7085-44-1 MF: C7H,C1N3Na0,S2 MW 317.71

440 C Chlorotrianisene :

i

forrnornide Chlorothiozide

4-omino-6-chloro- 1.3-berizenedisulfarnide (I)

Reference(.r):

US 2 809 194 (Merck & Co.; 8.10.1957; prior 2.5.1956)

US 2 937 169 (Merck & Co.; 17.5.1960; prior 25.9.1958)

Novello, E.C.; Sprague, J.M.: J Am Chem Soc (JACSAT) 79,2028 (1957)

alternatwe synthesis of 4-amino-6-chloro- 1,3-benzenedlsulfamide (chlorosu&onation of 1,3-dichlorobenzeneand

t

Formulatton(s): amp 500 mgl20 ml (as sodium salt); tabl 250 mg, 500 mg

Trade Name(s):

D: Chlotride (Sharp & I:

Dohme); wfm

F: Diupreskal (Th6raplix)-

comb.; wfm

Diurilix (Thtrap1ix)-comb.; J:

wfm

GB: Saluric (Merck Sharp &

Dohme)

Clotride (Merck Sharp & USA: Aldochlor (Merck)

Saluren (Croce Bianca); Diuril (Merck)

Aldoclor (Merck Sharp & salt)

methyldopa Chlotride (Merck-Banyu)

Use: synthetic cstrogen RN: 569-57-3 MF: C23H21C103 MW: 380.87 EINECS: 209-318-6

CN: 1, I',lU-(1-chloro- 1-ethenyl-2-ylidene)tris[4-methoxybcnzene]

4.4'-dimethoxybenrophenone 4-methaxybenzy-

rnognesium chloride