Pharmaceutical Substances Syntheses, Patents, Applications - Part 103 pdf

numerous combination 1: Dicodid Knoll; wfm Tussend Monarch-comb... 1 0 2 4 H Hydrocortisone acetate Trade Names1: D: Dermallerg-ratiopharm ratiopharm Dcrm Posterisan Kade Ficortril Pfi

Hydrocortisonc H 102 1

Trade Name(s):

D: Dicodid (Knoll) USA: Hycotuss (Endo)-comb numerous combination 1: Dicodid (Knoll); wfm Tussend (Monarch)-comb preparations

COSAAO I ; DO7XAO 1 ; H02AB09; S01BA02; S01CB03; S02BA01 Use: glucocorticoid, anti-inflammatory RN: 50-23-7 MF: C,,H,,O, MW: 362.47 EINECS: 200-020-1

LD,,:' >500 mglkg (M, s.c.);

150 mgkg (R, i.p.); 449 mg/kg (R, s.c.)

CN: (1 1 P)-11,17,21-trihydroxypregn-4-ene-3,20-dione

1 Hz Pd-C

2 HCOOH

1

B r ~ r

1 1

H3C OK

2 3 3 , Tos-OH

HJC 0 CH,

,

AI[OCH(CH,),I, microbiologicol hydroxylation

lil -*

Reichstein's substance S

1022 H Hydrocortisone

cortisone 2 1 -acetate semicorbazide

hydrochloride

KBH4

boro-

3.3:20.20-bis(ethy1enedioxy)-

11p,17,21 -trihydroxy-5-pregnene

(from cortisone)

rnicrobiologicol hydroxylation

CH3 [Rhiiopua arrhims Archer (ATCC-1 1 145)

H H

I Hydrocortisone I

progesterone (V)

0

Cr03, CH3COOH

v

diethyl oxalate

Hydrocortisone H 1023

1 H 2 0 , H+

FH3

H3C 0 CH3

+

morpholine

hydrocortisone

21 o c e t a t e (IX)

Reference(s):

a US 2 649 401 (Upjohn; 1953; appl 1950)

US 2 658 023 (Pfizer; 1953; appl 1952)

US 2 794 816 (Upjohn; 1957 appl 1954)

synthesis of cortexolon:

Julian, PL.: J Am Chem Soc (JACSAT) 72, 5145 (1950)

Sondheimer, F et al.: J Am Chem Soc (JACSAT) 78, 816 (1956)

The Merck Index, 289 1 (Rahway 1976)

b Oliveto, E et al.: J Am Chem Soc (JACSAT) 78, 1736 ('

c US 2 666 069 (American Cyanamid; 1954; appl 195 1)

synthesis of starting inaterial:

US 2 622 081 (American Cyanamid; 1952; appl 1951)

US 2700 666 (American Cyanamid; 1955; appl 1953)

d Hogg, J.A et al.: J Am Chcm Soc (JACSAT) 77,4436 (

US 2 769 823 (Upjohn; 1956; appl 1954)

alternative syntheses:

US 2 541 104 (Merck & Co.; 195 1; appl 1947)

GB 800 797 (Pfizer; appl 1956; USA-prior 1955)

US 4 041 055 (Upjohn; 9.8.1977; appl 17.1 1.1975)

DOS 2 803 660 (Schering AG; appl 25.1.1978)

DOS 2 803 661 (Schering AG; appl 25.1.1978)

review:

Fieser, L.F.; Fieser, M.: Steroide, 7 10,737 (Weinheim 1961)

Ullmanns Encykl Tech Chem., 4 Aufl., Vol 13.52

pharmaceurical fortnulation:

DOS 2 606 516 (Dermal; appl 18.2.1976; GB-prior 19.2.1975)

Formulation(s): cream 0.5 %; lotion 0.5 %: ointment 1 76, 2.5 %; tabl 10 mg

1 0 2 4 H Hydrocortisone acetate

Trade Name(s1:

D: Dermallerg-ratiopharm

(ratiopharm)

Dcrm Posterisan (Kade)

Ficortril (Pfizer; as acetate)

Hydrocort (Pharmagalen)

Hydrocortison Hoechst

(Hoechst)

H ydroderm (Karrcr)

Hydrogalen (Pharmagalen)

Munitren H (Rohugen)

Sanatison (Parke Davis)

generics and several

combination preparations

F: Daktacort (Janssen-Ci1ag)-

comb

Hydracort (Galderma)

numerous gcnerics and

combination preparations

GB: Cobadex (Cox)-comb

Corlan (Evans) Efcortelan (Glaxo Wellcome) Eurax Hydrocortisone (Novartis Consumer)- comb

Hydrocortistab (Knoll) Hydrocortisyl (Hoechst) Hydrocortone (Merck Sharp & Dohme) several combination preparations 1: Algicortis (Vaillant) Daktacort crema (Janssen)- comb

Dermocortal (Purophanna) Molidex (C1intec)-comb

Nasomixin (Pierrel)-comb Sintotrat (Edrnond) Vasosterone (Angelhi)- comb

several combination preparations J: Cortril (Taito Plizer) Solu-cortef (Sumitomo Chern.)

USA: Cortenema (Solvay) Hydrocortone (Merck Sharp & Dohme)

Hy tone (Dermik) Protocort (Monarch) several combination preparations

Use: glucocorticoid

RN: 50-03-3 MF: C,,H,,O, MW: 404.50 EINECS: 200-004-4

LD,,,: 2300 m g k g (M, i.p.); 45.05 m d k g (M, s.c.)

CN: ( I 1 ~)-21-(acetyloxy)-11,17-dihydroxypregn-4-ene-3,2O-dione

hydrocortisone

(9 v.)

ocetic onhydride

Hydrocortisone acetate

Rqference(s):

US 2 183 589 (Roche-Organon; 1939; CH-prior 1936)

alterilative syntheses:

US 2 541 104 (Merck & Co.; 1% 1 ; appl 1947)

US 2 769 823 (Upjohn; 1956; appl 1954)

Formulation(s): cream 3.3 mg; ointment (0.5 %, I %, 2 %); suppos 3.3 mg

Trade Name(s):

D: Colifoam (Trommsdorff)

Cortisol Thilo (Thilo)

Ebcnol (Strathrnann) F:

Ficortril Augensalbe

(Pfizer)

H ydrocortison-POS

(Ursapharm)

Litraderm (Desitin)

numerous combination preparations and generics Colofoam (Norgine Pharma)

Hydrocortisone Rousscl GB:

Susp Inj (Roussel) Onctose hydrocortisone (Monot)-comb

Proctocort (Boehringer Ing.1

numerous combination preparations and generics Actinac (Hoechst)-comb Anugesic HC (Parke Davis)-comb

Anus01 HC (Parke Davis)- comb

Hydrocortisone 17-butyratc H 1025

Colifoam (Stafford-Miller) Cortison-Chernicetina Xyloproct (Byk Gulden)- Fucidin H (Leo)-comb (Carlo Erbai-comb comb

Neo-cortef (Dominion)- Emorril (Po1i)-comb J: Dortizon Oint (Kobayashi comb Idrocet (Lusofarmaco)- Kako)

Proctofoam (Stafford- comb Hydrocortisone (Banyu) Miller)-comb Idrocortisone Roussel Hydrocortone (Merck- Xyloproct (Astra)-comb (Roussel) Banyu)

numcrous combination Idroneomicil (Poli)-comb KC Oint (Hokuriku) preparations Lenirit (Bonomelli Farm.) Manosil (Surnitomo

I: Antiacne Samil (Sarni1)- Mictasone (Zoja)-comb Kagaku)

comb Proctosedyl (Rousse1)- Otozon Babe (Nakano) Antiemorroidale comb Scheroson F (Nihon Milanfarma (Milanfarma)- Reumacort (Teofarmai- Schering)

comb comb USA: Anusol-HC (Parke Davis) Argisone (Teofarrna)-comb Urecortyn (Roussel) Cortifoam (Schwarz) Cortidro (Salus Research) Vasosterone antib Pramosone (Femdale) Cortinal (Teofarma)-comb (Angelhi)-comb numerous combination

preparations and gcncric

Use: glucocorticoid

RN: 13609-67-1 MF: C,,H,,O, MW: 432.56 EINECS: 237-093-4

LD,,: >3 glkg (M, p.0.);

>3 glkg (R, p.0.)

CN: (1 1 P)-11,21 -dihydroxy- 17-(I-oxobutoxy)pregn-4-ene-3,20-dione

hydrocortisone N,N-dimethyl-

1 (H,CO),SO*

NaOCH3

2 CH3COOH

1 dimethyl sulfate

Hydrocortisone 17-butyrote I

Referencefs):

DAS 2 644 556 (Beiersdorf AG; appl 2.10.1976)

alternative syntheses:

DAS 2 441 284 (Schering AG; appl 16.9.1974)

JP 52 010 489 (Taisho; appl 15.7.1975)

JP 52 136 157 (Taisho; appl 14.4.1976)

JP 53 015 360 (Taisho; appl 26.7.1976)

DOS 2 055 221 (Lab Chimico Farma Untico; appl 10.11.1970)

DOS 2 204 366 (Dermal; appl 27.1.1962)

Formulation(si: cream 1 mg/g; emulsion 1 mglg; lotion 1 mglg; ointment 1 mglg

Trade Name(s):

D: Alfason (Yamanouchi) GB: Locoid (Yamanouchi) Molidex (Clintec)-comb Laticort (medphano) I: Daktacort crema (Jamsen)- Nasomixin (Pierrel)-comb

E Locoid (Yamanouchi comb J: Locoid (Torii)

Pharma) Locoidon (Brocades) USA: Locoid (Ferndale)

1026 H Hydrocortisone sodium phosphate

Usc: glucocorticoid RN: 6000-74-4 MF: C,,H,,Na20,P MW: 486.41 EINECS: 227-843-9

LD,,,: 746 mglkg (M, i.v.); 3950 mgkg (M, p.0.);

632 mg/kg (R, i.v.); 6100 mgtkg (R, p.0.)

CN: ( 1 10)- 1 1,17-dihydroxy-21-(phosphonooxy)pregn-4-ene-3,20-dione disodium salt

free acid

RN: 3863-59-0 MF: C2,H3,08P MW: 442.45 EINECS: 223-382-2

pyridine

_,

\\ ,LH3

Nol, DMF

hydrocortisone methone

chloride

Hydrocortisone sodium phosphote

Kejerence (s):

US 2 936 313 (Glaxo; lO.S.1960; appl 18 11.1958; GB-prior 19.1 1 l957)

US 2 932 657 (Merck & Co.; 12.4.1960; appl 30:6.1957)

alternative syntheses:

US 2 870 177 (Merck & Co.; 20.1.1959; appl 4.8.1954)

US 3 068 223 (Merck & Co.; 11.12.1962; appl 18.1 1.1958; prior 4.8.1954)

DE 1 134 075 (Merck AG; appl 26.11.1959)

Formularion(s); amp 100 mg; drops 0.335 %

Trude Name(s):

D: Pantocrinale (Simons)- I: Idracemi coll (Farmigea) USA: Hydrocortone Phosphate comb Idracemi eparina Inj (Merck Sharp &

GB: Efcortesol (Glaxo (Farrnigea)-comb Dohme)

Wellcome) J: Gleiton (Sankyo Zoki)

LJse: diuretic, antihypertensive RN: 135-09-1 MF: C,H,F3N304S, MW: 331.30 EINECS: 205-1 73-8

LD,,,: 750mg/kg(M,i.v.);>10g/kg(M,p.o.)

CN: 3,4-dihydro-6-(trifluoromethyl)-2H-1,2,4-benzothiadiazine-7-sullunamide 1,1 -dioxide

Hydromorphone H 1027

3-lrilluaromethyl

aniline

4-amino-6-trifluoromethyl-

benzene-1.3-disulfomide (I)

paraform- Hydroflumethiazide

oldehyde

Reference(s1:

US 3 254 076 (Lovens Kemiske Fabrik; 31.5.1966; GB-prior 13.8.1958)

Holdrege, C.T et al.: J Am Chem Soc (JACSAT) 81,4807 (1959)

Formulation(s): tabl 25 mg, 50 mg

Trade Name(s):

F: Eusod (Leo)-comb.; wfm Hydrenox (Knoll) Robezon (Mitsu)

Leodrine (Leo); wfm I: Diuritens (Biotrading) Rontyl (Leo-Sankyo) Plurine (Leo)-comb, with comb.; wfm USA: Diucardin (Wyeth-Ayerst) KC]; wfm Rivosil (Benvegna); wfm

GB: Aldactide 50 (Sear1e)- J: Di-Ademil (Squibb-Showa)

comb Enjit (Meiji)

Use: analgesic RN: 466-99-9 MF: C,,HI,NO, MW: 285.34 EINECS: 207-383-5

LD,: 104 mglkg (M, i.v.)

CN: (5cl)-4,5-epoxy-3-hydroxy-I7-methylmorphinan-6-one

monohydrochloride

RN: 71-68-1 MF: C,,H,,NO, HCI MW: 321.80 CINECS: 200-762-6

LD,: 55 mglkg (M, i.v.)

Pd or Pt A isornerizotion

Reference(s):

Ehrhart, Ruschig I , 120

DRP 365 683 (Knoll; 1922)

DRP 607 93 1 (Knoll; 1935)

DRP 617 238 (Knoll; 1935)

DRP 623 821 (Knoll; 1935)

1028 H Hydroxocobalamin

Forrnulation(s): amp 1 mglml, 2 mglml, 10 mglml, 50 mgl5 ml; tabl 2 mg, 4 mg, 8 mg; vial 500 mg15 ml (as

hydrochloride)

Trade Narne(s):

D: Dilaudid (Knoll; as GB: Palladone (Napp; as

hydrochloride) hydrochloride)

Dilaudid-Atropin (Knoll; as USA: Dilaudid (Knoll; as

hydrochloride)-comb hydrochloride)

generics

(Aquocobalamin; Hydroxycobalamin; Vitamin BIZa) Use: antipernicious vitamin (depot form:

acetate) RN: 13422-5 1-0 MF: C,2H,,CoNl,0,5P MW: 1346.38 EINECS: 236-533-2

LD,,: >50 mglkg (M, i.v.)

CN: cobinamide dihydroxide dihydrogen phosphate (ester) mono(inner salt) 3'-ester with 5,6-dimethyl-1-a-D- ribofuranosyl- 1 H-benzimidazole

hydrate

RN: 13422-52- 1 MF: C,2H,,CoNl,0,5P~ H 2 0 MW: 1364.39 EINECS: 236-534-8

acetate

RN: 22465-48- 1 MF: C,H,lCoN,301,P MW: 1388.41 EINECS: 245-019-7

LD,,,: 2 glkg (M, i.v.)

cyanocobalamin

I Hydroxocobalarnin

Reference(s):

US 2 738 301 (Merck & Co.; 1956; appl 1950)

US 2 738 302 (Merck & Co.; 1956; appl 1950)

Hydroxycarbamide H 1029

stabilized solutions:

FR 1336 671 (Merck & Co.; appl 28.2.1962; USA-prior 13.3.1961)

Formulation(s): amp 0.5 mgll ml; cps 460 mg; vial 5 mg, 10 mg (as hydrochloride)

Trade Name(s):

D: Aquo-Cy tobion (Merck)

Lophakomp-B 12 Depot

(Lomapharm)

Novidroxin (Fatol; as

acetate)

numerous comhination

preparations

F: Arginotri-B (Bouchara)-

comb

DodCcavit (L'Arguenon; as

acetate)

Hydroxo 5000 (Lipha SantC

Division Aron-MCdica)

Inadrox (Logeais; as

acetate)-comb

Nbparyl B I 2 (CIBA

Vision Ophthalmics; as

acetate)-comb

Tcrncurine H 5000 (Bristol-

Myers Squibb; Labs

Al1ard)-comb

Vibalgan (Doms-Adrian; as

acetate)-comb

generic and numerous

combination preparations

GB: Cobalin-H (Link) Neo-Cytamen (Evans) numerous combination preparations

I: Idroxoc (Formulario Naz.) Idroxoc (Biologici Italia) Neocytamen (Teofarma) numerous combination preparations

J: Anemisol (Tobishi) Aquo B'av (Nippon Zoki) Bistin (Yamanouchi) B-Red S (Kyorin) B-Valet B I Z (Tokyo Tanabe) Cobalamin H (Otsuka) Colsamine (Kanto) USA:

Dasvit H (Tanabe) Docelan (Nippon Roussel- Chugai)

Dolevern (Seiko) Fresmin-S (Takeda; as

acetate) Funacomin-F (Funai) Hicobala (Mitaka) Hicobalan (Maruko)

Hydocobamin (Hishiyama) Hydocomin (Sanwa) Hydroxomin (Tokyo Hosei) Laseramin (Choseido) Masblon H (Fuso) Nichicoba (Nichiiko) OH-B,, (Morishita) Rasedon (Sawai) Red-B (Kowa) Redisol H (Merck-Banyu) Runova (Squibb-Sankyo) Solco H (Tobishi) Tsuerumin S (Mohan) Twelvmin (Mohan) Vigolatin (Kowa) Bevitamel (Westlake)- comb

Chromagen (Savage)- comb

Mega-B (Arco)-comb numerous combination preparations

Hydrox ycarbamide

(Hydroxyurea)

ATC: LOIXX05 Use: antineoplastic

RN: 127-07-1 MF: CH4N202 MW: 76.06 EINECS: 204-821-7

4730 mgkg (R, i.v.); 5760 m g k g (R, p.0.);

> I g/kg (dog, i.v.); >2 glkg (dog, p.0.)

CN: hydroxyurea

Amberlite IRA-41 0

Hydroxycarbamide

u

Rejerence(s):

U S 2 705 727 (Du Pont; 1955; prior 1952)

1030 H Hydroxychloroquine

Trade Name(s):

D: Litalir (Bristol-Myers GB: Hydrea (Bristol-Myers USA: Hydrea (Bristol-Myers

Syrea (medac) I: Onco-Carbide (Astra-

F: HydrCa (Bristol-Myers Simes)

Squibb) I: Hydrea (Bristol)

Use: antirheumatic, antimalarial RN: 1 18-42-3 MF: C,,H,,ClN,O MW: 335.88 EINECS: 204-249-8

LD,,,: 1240 mglkg (M, p a )

CN: 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]ethanol

sulfate (1:l)

RN: 747-36-4 MF: C,,H,,ClN,O H,SO, MW: 433.96 EINECS: 212-019-3

phosphate (1:2)

RN: 6168-85-0 MF: C,,H,,ClN,O 2H,P04 MW: 531.87

NH3, Hz, Raney-Ni

C H 3

5-chloro- 2-ethylamino-

2-oentanone ethanol

H 2 N w N " d ) H

C H 3 b H 3

CI

q u i d h e

Refermce(s):

US 2 546 658 (Sterling Drug; 195 1 ; prior 1949)

Formulation(s): drg 200 mg (as hydrochloride)

Trade Name(s):

D: Quensyl (Sanofi Winthrop) I: Plaquenil (Maggioni-

F: PlaquCnil (Sanofi Winthrop)

Rhyurnapirine S:Q (Nichiiko) Toremonil (Iwaki) winthrop) J: Eroquin (Shionogi)

GB: Plaquenil (Sanofi Plaquenil (Yamanouchi) USA: Plaquenil (Sanofi

Hydroxyethyl salicylate

(Glycol salicylate)

ATC: M02AC Use: anti-inflammatory, analgesic RN: 87-28-5 MF: C9H,,,0, MW: 182.18 EINECS: 201-737-2

CN: 2-hydroxybenzoic acid 2-hydroxyethyl ester