Gusperimus trihydrochloride G 2. Pd-C, NiCI2. NaBHq 3. HCI H x + H2N)pJ 4VN NH2 1. dicyclohexyl- K 0 HCI 0 NH carbodiimide 7-guanidinoheptonarnide hydrochloride (XI) final product: H20. 60 'C 2. ch.ornatoqraphy an sephodex LH-20 XItv + 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: CA 2 142 376 (Bristol-Myers Squlbb Co.; appl. 26.8.1995; USA-prior. 25.2.1994). W09 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 o=s=o o=s=o 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); wfm wfm Halcinonide ATC: D07AD02 Use: glucocorticoid RN: 3093-35-4 MF: C24H32ClFOS MW: 454.97 EINECS: 221-439-6 LD,,: >I0 gkg (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 ocetone Halcinonide 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: ~alcicom~~(~.~.~.~.)- J: Adcortin (Sankyo) Squibb) comb. Simaderm (Bristol-Myers F: Halog crkme (Bristol- Halciderm (Squibb) Squibb) 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 HOOc~c, 4. Cu, NoH,PO, CH3 ,1 3, isoomyl nitrite CI trifluorornethyl- benzaldehyde fluoromethylphenyl)- phenylocetic 2.4-dichlora- acid cinnamic ocid 994 H Halometasone 1. B2H6 2. Pb(OCOCH,), "'pc , 1. diborane / 2. lead tetra- CF3 acetate CF3 1,3-dichloro- 6-trifluorornethyl- phenanthrene-9- carboxylic acid (I) 1,3-dichloro- 6-trifluorornethyl- phenanthrene-9- carboxaldehyde (11) H3cwtv CI H3C CF3 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 of the racemate: Carroll, F.I. et al.: J. Med. Chem. (JMCMAR) 21, 326 (1978). glycero-phosphate, tartrate at~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 Beecham; 1991) Beecham; 1988 as Beecham; 1991) 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 1 16.17-dihydroxy-21 -ocetoxypregna- 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, MW 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 nd - , ID hydrogen 1. bromine 2. sodium iodide 3. potassium acetate 1. HBr ocetamide COOH 1. ethylene glycol 1. hydrogen H H 2. monoperphtholic O 0 ' fluoride acid 2. bromine 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 F 2. hydrogen 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~OPO~~Y~ phenol bromide 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 % P 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) Hospital) I: Fluothane (Zeneca) 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~adera, 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 (Oh Mathieson; appl. 2.8.1961; GB-prior. 24.6.1960, 28.2.1961). OH OH Forntulation(s): cream, ointment, sol. oxyquinoline Trade Nanze(s): D: Combiase (Luitpo1d)- Dignoquine (Luitpo1d)- Hyalokombun (Merck1e)- comb.; wfm comb.; wfm comb.; wfm Diaront (Chephasaar)- Flarnutil (Voigt)-comb.; Mexaform plus (Ciba)- comb.; wfm wfm comb.; wfm CI CI Holquinol . 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. corticosteroid, anti- inflammatory RN: 5062 9-8 2-8 MF: C,2H27C1F,0, MW: 444.90 EINECS: 25 6-6 6 4-9 CN: (6a, 11 P, 16a )-2 -chloro-6.9-difluoro- 11,17,21 -trihydroxy-l6-methylpregna-l,4-diene-3,20-dione. (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 - 1 5-4 MF: C,,H,,BrF,O, MW: 475.33 EINECS: 26 0-9 5 3-5 Halovredone