Pharmaceutical Substances Syntheses, Patents, Applications - Part 100 pot

pharmaceuticnl preparations: JP02009 816 Nippon Kayaku Co.; Takara Skuzo Co.; appl.. 100 mg as trihydrochloride Tmde Names: 1: Spanidin Nippon Kayaku... USA: Halog Westwood-Squibb Hal

Gusperimus trihydrochloride G

2 Pd-C, NiCI2 NaBHq

x -+ H 2 N ) p J - - 4 V N NH2

carbodiimide

7-guanidinoheptonarnide hydrochloride (XI)

final product:

H20 60 ' C

2 ch.ornatoqraphy

a n sephodex LH-20

X I t v -+

1 glutaric acid

3 HCI

I Gusperimus trihydrochloride I

Reference(s):

DE 3 626 306 (Microbiochemical Research Found.; appl 11.2.1988; D-prior 2.8.1986)

BE 894 651 (Microbiochemical Research Found.; appl 31.1.1983, J-prior 8.10.198 1)

JP08 020 533 (Nippon Kayaku; appl 23.1.1996; J-prior 7.7.1994)

DE 3 506 330 (Takara Skuzo Co.; Nippon Kayaku Co.; appl 29.8.1985; J-prior 29.2.1984)

purification:

IP59 029 652 (Nippon Kayaku Co.; appl 16.2.1984; J-prior 10.8.1982)

pharmaceuticnl preparations:

JP02009 816 (Nippon Kayaku Co.; Takara Skuzo Co.; appl 12.1.1990; J-prior 29.6.1988)

EP 188 821 (Microbial Chemistry Research Found.; appl 30.7.1986; J-prior 14.1.1985)

use of gusperimus hydrochloride:

C A 2 142 376 (Bristol-Myers Squlbb Co.; appl 26.8.1995; USA-prior 25.2.1994)

W 0 9 405 323 (Jekus Hopkins Univ., School of Medicine; appl 17.3.1994; WO-prior 4.9.1982)

DE 3 626 306 (Behringwerke A.G.; appl 11.2.1988; D-prior 2.8.1986)

synthesis of 0-tert-butyl S-(4,6-dimethyl-2-pyrimidinyl)thiocarbonate and 0-benzyl S(4.6-dimethyl-2- pyrimidiny1)thiocarbonate:

Nagasawaet al.: Bull Chem Soc Jpn (BCSJAB) 46, 1269, 1271 (1973)

DE 2 245 392 (Nitto Boseki; appl 12.4.1973; J-prior 17.9.1971, 27.9.1971, 30.9.1971, 10.1.1972)

US 3 936 452 (Nitto Boseki; appl 3.2.1976; J-prior 8.9.1972)

Fomulation(s): vial (inj.) 100 mg (as trihydrochloride)

Tmde Name(s):

1: Spanidin (Nippon Kayaku)

992 H Halazone

Halazone

(Aseptamide)

ATC: D08A Use: antiseptic, chemotherapeutic RN: 80-1 3-7 MF: C,HSCI2NO4S MW: 270.09 EINECS: 201-253- 1

CN: 4-[(dichloroamino)suIfonyl]benzoic acid

sodium salt

RN: 5698-56-6 MF: C,H4C1,NNa04S MW: 292.07 EINECS: 227-176-3

NoOCl

I

NH2

4-sulfomoyl- Holozone

benzoic acid

Reference(s):

DE 3 18 899 (M Claass; appl 19 18)

Formulation(s): tabl 4 mg

Trade Name(s):

F: Gynamide (Merminod); ThCragynes (Theragynes);

Halcinonide ATC: D07AD02

Use: glucocorticoid RN: 3093-35-4 MF: C24H32ClFOS MW: 454.97 EINECS: 221-439-6

LD,,: >I0 g k g (M, p.0.);

>5 glkg (R, pa.)

CN: (1 1 P, 16a)-2 1 -chloro-9-fluoro-l l -hydroxy- 16,17-[(I -methylethylidene)bis(oxy)]pregn-4-ene-3,2O-dione

8

0

rnethanesulfonyl chlor~de

hydrocortisone

(cf triomcinolone synthesis)

Halofantrine H 993

Referencers):

Bernstein, S.; Lenhard, R.H.: J Am Chem Soc (JACSAT) 82, 3680 (1960)

Bernstein, S et al.: J Org Chem (JOCEAH) 27, 690 (1 962)

use:

DE 2 355 710 (Squibb; appl 7.11.1973; USA-prior 24.11.1972)

Formularion(s): cream 0.1 %; ointment 0.1 %; sol 0.1 %

Trade Name(s):

D: Halog (Bristol-Myers GB: ~ a l c i c o m ~ ~ ( ~ ~ ~ ~ ) - J: Adcortin (Sankyo)

Myers Squibb) Halcort (F.A.I.R.) USA: Halog (Westwood-Squibb) Halog nComycine (Bristol- I: Ancofort (Squibb)-comb

Myers Squibb)-comb Halciderm (Squibb)

Halofantrine

(WR- 171669)

ATC: POlBXOl Use: antimalarial RN: 69756-53-2 MF: C2,H,,C1,F,N0 MW: 500.43 EINECS: 274-104-1

CN: 1,3-dichloro-cr-[2-(dibutylamino)ethyl]-6-(trifluoromethyl)-9-phenanthrenemethano1

hydrochloride

RN: 36167-63-2 MF: C2,H,,Cl2F,NO HCl MW: 536.89 EINECS: 252-895-4

LD,,: 2050 mgkg (R, i.p.); 3400 mglkg (R p.0.)

(-)-enantiomer

RN: 6605 1-76-1 MF: C,,H,,C12F,N0 MW: 500.43

(+)-enantiomer

RN: 66051-74-9 MF: C26H,oCI,F?N0 MW: 500.43

1 FeSO, NH,

2 NaOH

3 H3CY-0,No

HOOC

AcZO KZC03 H O O c ~ c 4 ,Cu, NoH,PO, CH3

, 1

3, isoomyl nitrite

CI

trifluorornethyl- benzaldehyde fluoromethylphenyl)-

994 H Halometasone

1 B2H6

2 Pb(OCOCH,),

1 diborane

/

2 lead tetra-

1,3-dichloro-

6-trifluorornethyl-

phenanthrene-9-

carboxylic acid (I)

1,3-dichloro- 6-trifluorornethyl- phenanthrene-9- carboxaldehyde (11)

H 3 C

C F 3 Halofantrine

Reference(s):

Colwell, W.T et al.: J Med Chem (JMCMAR) 15, 771 (1972)

preparation of 2-nitro-4-trifluoromethylphenylacetic acid:

Simet, L.: J Org Chem (JOCEAH) 28,358a (1963)

preparation of I:

Nodiff, E.A et al.: J Med Chem (JMCMAR) 14,921 (1971); 15,775 (1972)

resolution o f the racemate:

Carroll, F.I et al.: J Med Chem (JMCMAR) 21, 326 (1978)

glycero-phosphate, tartrate a t ~ d biquinate salts:

US 4 507 288 (Smith Kline & Beckman; 20.3.1985; prior 16.9.1983, 2.11.1983)

EP 138 374 (Smith Kline & Beckman; appl 11.9.1984; USA-prior 2.1 1.1983, 16.9.1983)

Fortnulation(s): drinking amp 2 %, 30 ml; susp 100 mgl5 ml; tabl 250 mg (as hydrochloride)

Trade Name(s):

D: Halfan (SmithKline F: Halfan (SmithKline GB: Halfan (SmithKline

hydrochloride)

Halometasone ATC: D07AB; D07AC12

Use: topical corticosteroid, anti- inflammatory

RN: 50629-82-8 MF: C,2H27C1F,0, MW: 444.90 EINECS: 256-664-9

CN: (6a, 11 P, 16a)-2-chloro-6.9-difluoro- 11,17,21 -trihydroxy-l6-methylpregna-l,4-diene-3,20-dione

I,+-diene-3,20-dime (I)

Halometasone I

Reference(s):

DE 1 807 980 (Ciba-Geigy; appl 9.1 1.1968; CH-prior 17.1 1.1967)

CH 551 399 (Ciba-Geigy; appl 17.10.1968)

US 3 652 554 (Ciba-Geigy; 28.3.1972; appl 15.1 1.1968; CH-prior 17.11.1967)

topical combination with triclosan:

GB 2 148 116 (Ciba-Geigy; appl 27.10.1983)

US 4 512 987 (Ciba-Geigy; 23.4.1985; appl 13.10.1982; GB-prior lS.7.lY82)

Formulation(s): cream 0.5 mglg (0.05 %),; ointment 0.5 mglg (0.05 %)

Trade Name(s):

D: Sicorlen (Novartis; 1986) Sicorten Plus (Novartis;

1986)-comb with triclosan

Haloperidol ATC: NOSADO1

Use: neuroleptic, antidyskinetic, antipsychotic

RN: 52-86-8 MF: C21H23C1FN0, M W 375.87 EINECS: 200- 155-6

LD,,: 13 mgkg (M, i.v.); 71 mg/kg (M, p.0.);

15 mgkg (R, i.v.); 128 mglkg (R, p.0.);

18 mgkg (dog, i.v.); 90 mglkg (dog, p.0.)

CN: 4-[4-~4-chlorophenyl)-4-hydroxy-1-piperidinyl]-l-(4-fluorophenyl)-1-butanone

4-chlorobutyryl fluoro-

chloride benzene

4-chloro-4'-fluoro- buryrophenone (I)

996 H Halopredone diacetate

2-(4-chloropheny1)-

propene

L J 4-(4-chloropheny1)-

1,2.3,6-tetrohydro- pyridine (11)

1 HBr CH3COOH

2 NoOH

I1 -b

4-(4-chloropheny1)- Holoperidol 4-hydroxypiperidine

Reference(s):

Janssen, P.A.J et al.: J Med Pharm Chem (JMPCAS) 1,281 (1959)

DE 1 289 845 (Janssen; appl 18.4.1959; GB-prior 22.4.1958)

US 3 438 991 (Janssen; 15.4.1969; GB-prior l8.ll.1959)

alternative syntheses:

GB 1 141 664 (Janssen; valid from 7.12.1966; prior 8.12.1965, 23.9.1966)

US 4 086 234 (Searle; 25.4.1978; appl 7.11.1975)

Formulation(s): amp 5 mg/ml, 100 mglml, 50 mg/ml; drops 2 mg, 20 mgfml, 2 mglml, 0.5 mgnd; sol 10 rng;

oral liquid 2 mglml, 10 mglml; tabl 1 mg, 2 mg, 5 mg, 10 mg, 20 mg

Trade Name(s):

D: Buteridol (Promonta

Lundbeck)

Haldol-Janssen (Janssen-

Cilag)

Sigaperidol (Kytta-

Siegfried)

generic

F: Haldol (Janssen-Cilag)

Vksadol (Janssen-Ci1ag)-

comb

GB: Dozic (Rosemont)

Haldol (Janssen-Cilag; as

decanoate)

Serenace (Baker Norton) I: Aloper (Sifra)

Aloperid (Formulario Naz.) Aloperid (Biologici Italia) Bioperidolo (Firma) Haldol (Janssen) Haldol Decanoas (Janssen;

as decanoate) Serenase (Lusofarmaco) J: Brotopon (Taito Pfizer) Einalon S (Maruko) Halojust (Horita)

Halomonth (Dainippon; as decanoate)

Halosten (Shionogi) Keselan (Sumtorno) Linton (Yoshitomi) Neoperidol (Kyowa Hakko:

as decanoate) Peluces (Isei) Serenace (Dainippon) USA: Haldol (Ortho-McNeil Pharmaceutical)

Halopredone diacetate ATC: H02AB

Use: glucocorticoid, top~cal anti- inflammatory

RN: 57781-14-3 MF: C2,H2,BrF,0, MW: 559.40 EINECS: 260-951-4

LDS,: >5 glkg (M, p.0.);

>5 glkg (R, p.0.)

CN: (6P, 1 1 P)- 17,2 1-bis(acety1oxy)-2-bromo-6,9-difluoro-l l -hydroxypregna- l,4-diene-3,20-dione

halopredone

RN: 57781 - 15-4 MF: C,,H,,BrF,O, MW: 475.33 EINECS: 260-953-5

Halovredone diacetate H 997

isoollospirostone-

38.1 1 a-diol

1 A

2 Cr03

2 NoHC03

*

2 chromium(Vl) oxide

1 HBr, Br,

H202 NoOH

2 sodium iodide

3 potassium acetate

1 HBr

ocetamide

COOH

H H 2 monoperphtholic O

2 I

_,

1 rnethonesulfonyl chloride

Li2C03 LiBr

_*

lithium carbonate lithium bromide

1 sodium ocetote

2 bromine

1.3-dibromo- 5.5-dimethyl- hydontoin

998 H Haloprogin

fluoride

I Halopredone ocetote

-b

B r

1 potassium corbonote

R&rence(s):

Bianchetti, A,; Riva, M.: J Med Chem (JMCMAR) 20, 213 (1977)

Br

F

BE 826 030 (Pierrel; appl 26.2.1975; GB-prior 27.2.1974, 5.7.1974, 25.7.1974, 19.1 1.1974)

synthesis of 2 1 -acetoxy- 1 1 a,l7-dihydroxypregn-4-ene-3,20-dione:

Djerassi, C et al.: J Am Chem Soc (JACSAT) 74, 1712, 3634 (1952); 75, 1277 (1953)

Formulation(s): amp 12.5 mglrnl, 25 mglml

Trade Name(s):

J: Haloart (Dainippon Ink-

Taiho)

Haloprogin ATC: DOlAEll

Use: antifungal, antiseptic RN: 777- 1 1-7 MF: C,H,Cl,IO MW: 361.39 EINECS: 212-286-6

LD,,: >5.6 glkg (R, p.0.);

>3 g/kg (dog, p.0.)

CN: 1,2,4-trichloro-5-[(3-iodo-2-propynyl)oxy]benzene

2.4.5-trichloro- P ~ O P O ~ ~ Y ~

2.4.5-trichlorophenyl proporgyl ether (I)

Rej'erence(s):

US 3 322 813 (Meiji Seika; 30.5.1967)

Formulation(s): cream 1 %; ointment 1 %; sol 1 %

Halothane H 999

Trade Nante(s):

D: Mycanden (Asche); wfm F: Mycilan (ThCraplix); wfm USA: Halotex (Westwood); wfrn Mycandcn (Schering); wfrn I: Polik (Meiji Seika)

Halothane ATC: NOlABOl

Use: inhalation anesthetic RN: 15 1-67-7 MF: C,HBrClF, MW: 197.38 EINECS: 205-796-5

LD,: 5680 mgikg (R p.0.)

CN: 2-bromo-2-chloro- I, 1, l -trifluoroethane

trichloroethylene 2-chloro-

1 1 1 -tritluoro- ethane

Reference(s):

GB 767 779 (ICI; appl 20.10.1954; valid from 11.10.1955)

US 2 921 098 (ICI; 12.1 l96O; GB-prior 20.10.1954)

GB 805 764 (ICI; appl 1956; valid from 1957)

alternative syntheses:

DE 1 039 503 (Bayer; appl 1953)

DE 1 041 937 (Hoechst; appl 1957)

US 2 959 624 (Hoechst; 8.1 1.1960; D-prior 18.7.1957)

US 3 082 263 (ICI; 19.3.1963; GB-prior 19.9.1959)

DAS 1 161 249 (Hoechst; appl 23.9.1960)

DAS 1 285 989 (Hoechst; appl 9.3.1963)

DOS 2 245 372 (Biocontrol; appl 15.9.1972)

Formulation(s): inhalation sol 125 ml, 250 ml

Trade Name(s):

D: Fluothane (Zeneca) F: Fluotane (Zeneca) I: Halothane (Hoechst) Halothan ASID (Riisch GB: Fluothane (ICI; 1957); wfm USA: Fluothane (Wyeth-Ayerst)

Haloxazolam ATC: NOSBA

Use: tranquilizer, benzodiazepine anxiolytic, hypnotic, sedative RN: 59128-97-1 MF: C17H14BrFNZ02 MW: 377.21

LD,,,: 1850 mglkg (M, p.0.)

CN: 10-bromo-l l b-(2-fluoropheny1)-2,3,7,1 lb-tetrahydrooxazolo[3,2-dl[l,4]benzodiazepin-6(5H)-one

1000 H Halquinol

2-amino-5-bromo- bromoocetyl

2'-fluorobenzo- bromide

phenone

~ i ~ a d e r a , T et al.: J Med Chem (JMCMAR) 14, 520 (1971)

JP 4 941 439 (Sankyo; appl 21.12.1970)

Formulation(s): tabl 5 mg, 10 mg

Trade Name(s):

J : Somelin (Sankyo)

Halquinol

(Chlorquinol)

ATC: A07 Use: intestinal antiseptic, topical anti- infective

RN: 8067-69-4 MF: unspecified MW: unspecified

CN: halquinols

Reference(s):

FR 1 372 414 ( O h Mathieson; appl 2.8.1961; GB-prior 24.6.1960, 28.2.1961)

Forntulation(s): cream, ointment, sol

oxyquinoline

Trade Nanze(s):

D: Combiase (Luitpo1d)- Dignoquine (Luitpo1d)- Hyalokombun (Merck1e)-

Diaront (Chephasaar)- Flarnutil (Voigt)-comb.; Mexaform plus (Ciba)-

Holquinol