Hydroxyprogesterone H 103 1 salicylic ethylene acid (I) glycol ethylene oxide Hydroxyethyl solicylote I Kaufmann, H.P.: Arzneimittel-Synthese, Springer Verlag 1953, p. 79. DD 218 616 (VEB Chem Pharmaz. Werk Oranienburg; app1. 18.4.1983). Formulation(s): cream 10.55 gI100 g, 12.5 gI100 g; gel 10.55 g1100 g, 12.5 gI100 g; ointment 10.55 gI100 g, 12.5 gI100 g Trade Name(s): D: Dolo-Arthrosonex (Brenner-Efeka) Kytta-Gel (Merck Produkte) Lumbinon (Lichtenstein) Phlogont Salbe (Azupharma) Traumasenex (Brenner- Efeka; LAW) ca. 100 combination I: preparations GB: Cremalgin (Berk)-comb.; wfm Dubam (Norma)-comb.; wfm Salonair (Salonpas)-comb.; wfm combination preparations on1 y : Balsamo Sifcamina (Midy) Disalgil (Also) Lasoreum Crema (Bayer) Mobilisin (Luitpold) Salonpas (Farmila) Sloan balsam0 (Parke Davis) Hydroxyprogesterone ATC: G03DA03 Use: progestogen RN: 68-96-2 MF: C2,H3003 MW: 330.47 EINECS: 200-699-4 CN: 17-hydroxypregn-4-ene-3,20-dione acetate RN: 302-23-8 MF: C23H3204 MW: 372.51 EINECS: 206-119-6 16-dehydropregnenolone (cf. pregnenolone synthesis) 1032 H Hydroxyprogesterone acetic anhydride Hydroxyprogesterone acetate ethisterone phenyls~lfin~l (4. v.) chloride (N) ( Hydroxyprogesterone 1 Referenceis): a Ringold, H.J. et al.: J. Am. Chem. Soc. (JACSAT) 78, 816 (1956). US 2 802 839 (Syntex; 1957; appl. 1953; MEX-prior. 1953). b US 4 041 055 (Upjohn; 9.8.1977; appl. 17.1 1.1975). alternative syntheses: US 2 648 662 (Glidden; 1953; appl. 1949). US 2 777 843 (Merck & Co.; 1957; appl. 1954). US 2 786 857 (Merck & Co.; 1957; appl. 1954; prior. 1952). US 2 813 060 (Upjohn; 1957; appl. 1955). US 3 000 883 (Upjohn; 1961; appl. 1957). Cutler, F.A. et al.: J. Org. Chem. (JOCEAH) 24, 1629 (1959). Formulation(s): amp. 250 mglml Hydroxyprogesterone caproate H 1033 Trade Name(s): F: Tocogestan (ThCramex; as GB: Proluton Depot (Schering; 17a-heptanoate)-comb. as hexanoate) Trophobolbne (ThCramex; USA: Prodox (Upjohn; as as heptanoate)-comb. acetate); wfm Hydroxyprogesterone caproate ATC: G03D Use: depot progestogen RN: 630-56-8 MF: C27H4004 MW: 428.61 EINECS: 211-138-8 CN: 17-[(I-oxohexyl)oxy]pregn-4-ene-3,20-dionc Reference(s): US 2 753 360 (Schering AG; 1956; D-prior. 1953). 17-hydroyprogesterone caproic anhydride altemarive synthesis: Babcock, J.C. et al.: J. Am. Chem. Soc. (JACSAT) 80,2904 (1958). Hydroxyprogesterone coproate Formulation(s): amp. 250 mgtml, 500 mglml (q 4 Trade Name(s): D: Gravibinon (Schering)- GB: Primolut Depot (Schering comb. Chemicals); wfm Progesteron-Depot I: Gravibinan (Schering)- (Jenapharm) comb. Proluton Depot (Schering) Lentogest (Amsa) F: ProgestCrone-Retard- Proluton Depot (Schering) Pharlon (Schering) J: Caprogen Depot (Kanto) Depot-Progen (Hokuriku) Oophormin Luteum Depot (Teikoku Zoki) Proluton-Depot (Nichidoku) USA: Delalutin (Squibb); wfm Dcluteval (Squibb)-comb ; wfm Prodrox (Legere); wfm Hydroxystilbamidine isethionate ATC: Polc Use: antiprotozoal (Leishmania) RN: 533-22-2 MF: CI,H,6N40 . 2C2H,0,S MW: 532.60 EINECS: 208-557-3 CN: 4-[2-[4-(aminoiminomethyl)phenyl]ethenyl]-3-hydroxybenzenecarboximidam1de compd. wlth 2- hydroxyethanesulfonic acld (1:2) 4 hydroxystiIbamidine RN 495-99-8 MF: C16H,,N40 MW: 280.33 EINECS: 207-811-0 LD,,: 27 mgikg (M, I.v.) 1034 H Hydroxyzine I SnCI2. HCI, piperidine. A WCN CH3COOH , I tin(ll) OHC NC ' chloride 4-cyano-2- 4-cyano- nitrotoluene benzaldehyde 4,4'-dicyono-2-nitro- stilbene 1. NoNO,. H2S04. HCI b Reference(s): US 2 510 047 (May & Raker; 1950; GB-prior. 1941). I. C2H50H. HCI Fortnultr~ion(s): vial 53.6 mg 2. NH3, C2H50H 3. K2C03 4. HO&S03H 11 + 4. isethionic acid Trade Name(s): GB: Hydroxystilbamide (May & USA: Hydroxystilbamidine generic Baker); wfm Isethionate (Merrell- National); wfm fl 2 H0-s03H H2N NH Hydroxystilbomidine isethionote Hydroxyzine ATC: NOSBBOI Use: tranquilizer RN: 68-88-2 MF: C,IH,7CIN,02 MW: 374.91 EINECS: 200-693-1 LD,,: 137 mglkg (M, 1.v.); 400 mgkg (M, p.0.); . 45 mgkg (R, i.v.); 840 rnglkg (R, p.0.) CW: 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]ethanol dihydrochloride RN: 2192-20-3 MF: C,,H2,ClN202 . 2HCI MW: 447.83 EINECS: 21 8-586-3 LD,,,: 48.9 mglkg (M, i.v.); 45 mgkg (R, i.v.); 950 mglkg (R, p.0.) pamoate RN: 10246-75-0 MF: C2,HI,O6. C2,H2,C1N202 MW: 763.29 EINECS: 233-582-1 1-(4-chlorobenz- 2-(2-hydroxyethoxy)- Hydronyzine hydry1)piperazine ethyl chloride Hymecromone H 1035 Reference(s): US 2 899 436 (UCB; 11.8.1959; B-prior. 30.10.1953). DE 1 049 383 (UCB; appl. 1954; B-prior. 1953). DE 1 061 786 (UCB; appl. 1954; B-prior. 1953). DE 1 068 262 (UCB; appl. 1954; B-prior. 1953). DE 1 072 624 (UCB; appl. 1954; B-prior. 1953). DE I 075 I 16 (UCB; appl. 1954; B-prior. 1953). Fomulation(s): f. c. tabl. 10 mg, 25 mg; inj. sol. 100 mg/2 ml; syrup 10 mg/5 ml; tabl. 10 mg, 25 mg, 100 mg (as dihydrochloride) Trade Name(s): D: AH3 (Rodleben)-comb. Atarax (Rodleben; UCB; Vedim; as hydrochloridc) Beta-lntensain (Cassel1a)- comb. Diligan (Rodleben; Vedim; as hydrochloride)-comb, Elroquil (Rodleben; as hydrochloride) F: Atarax (UCB; as dihydrochloride) GB: Atarax (Pfizer) Ucerax (UCB) I: Atarax (UCB) J: Atarax (Lederle-Pfizer Taito; as hydrochloride) Atarax P (Pfizer Taito; as pamoate) USA: Atarax (Pfizer; as hydrochloride) Marax (Pfizer; as hydrochloride) Vistaril (Pfizer; as hydrochloride) Vistaril (Pfizer; as pamoate) generic Hymecromone ATC: AOSAXOZ Use: choleretic RN: 90-33-5 MF: C,,,H,O, MW: 176.17 EINECS: 201-986-7 LD,,: 2850 mgtkg (M, p.0.); 15 mgkg (R, i.p.); 3850 mg/kg (R, p.0.) CN: 7-hydroxy-4-methyl-2H-I -benzopyran-2-one CH3 resorcinol ethyl 1 Hymecrornone acetoacetate L Reference(s): Pechmann, H. v.; Duisberg, C.: Ber. Dtsch. Chem. Ges. (BDCGAS) 16,2119 (1883). FR-M 1 430 (Lipha; appl. 13.7.1961). Woods, L.L.; Sapp, J.: J. Org. Chem. (JOCEAH) 27, 3703 (1962). Formulation(s): amp. 200 mg; cps. 200 mg, 400 mg; tabl. 400 mg (as sodium salt) Trade Name(s): D: Cholspasmin (Lipha) F: Cantabiline (Lipha SantC Cumarote CD (Towa) Cholspasmoletten Division Aron-MCdica) Himecol (Kissei) (Dolorgiet) I: Cantabilin (Formenti) Himecromon (Sawai) Gallo Merz Spasmo (Merz 1: Croamon (Torii) Paroamin (Zensei) & Co.) Crodimon (Roussel) generic 1036 1 Ibandronate sodium monohvdrate Ibandronate sodium monohydrate ATC: ~0.5~~06 (BM-21.0955; Ibandronic acid monosodium salt) Use: bone resorption inhibitor RN: 138926-19-9 MF: CyH22NNa07P2~ H20 MW: 359.23 CN: [1-hydroxy-3-(methylpentylamino)propylidene]bisphosphonic acid monosodium salt monohydrate anhydrous RN: 138844-81-2 MF: CYHz2NNaO7P2 MW: 341.21 free acid RN: 114084-78-5 MF: CyH2,N07P2 MW: 319.23 3-(methylpentylomino)- I lbondronote sodium 1. PCI3, chlorobenzene,lOO "C H~C-~P ,COOH 2. NOOH b I + H3P0, CH3 propionic acid I monohydrote HOP H~c-~~~~~ I p/ONo CH~HO; \\ 0 H,O Rejerence(s): EP 252 504 (Boehringer Mannh.; appl. 9.7.1987; D-prior. 11.7.1986) topical preparation: EP 407 344 (Ciba-Geigy; appl. 28.6.1990; CH-prior. 7.7.1989). oral fbrntulation: EP 566 535 (Ciba-Geigy; appl. 6.4.1993; CH-prior. 15.4.1992). stable injection solution: DE 4 228 552 (Boehringer Mannh.; appl. 27.8.1992; D-prior. 27.8.1992). drymixforntulation: WO 9 412 200 (Merck & Co.; appl. 17.1 1.1993; USA-prior. 2.12.1992). treatment of osteoporosis: US 5 366 965 (Boehringer Mannh.; appl. 19.1.1993; USA-~~~O~. 29.1.1993). combination with growth hormone secretagones: WO 9 51 1 029 (Merck & Co.; appl. 18.10.1994; USA-prior. 19.10.1993). Formulation(s): amp. 1 mglml, 2 mglml Trade Name(s): D: Bondronat (Boehringer Mannh.) Ibopamine ATC: COlCA16 Use: cardiotonic RN: 66195-31-1 MF: C,7H25N04 MW: 307.39 EINECS: 266-229-5 CN: 2-methylpropanoic acid 4-[2-(methylamino)ethyl]-1,2-phenylene ester Ibudilast I 1037 epinine isobutyryl chloride I Ibopamine I Reference(s): US 4 218 470 (Hal. Med. Sint. Sim; 19.8.1980; appl. 28.7.1977; I-prior. 5.8.1976). US 4 302 471 (Hal. Med. Sint. Sim; 19.8.1980; appl. 28.7.1977; I-prior. 5.8.1976). DOS 2 734 678 (Shes; appl. 1.8.1977; J-prior. 5.8.1976). Casagrande, C. et al.: Arzneim Forsch. (ARZNAD) 36 (I), 291 (1986). Formulation(s): tabl. 50 mg, 100 mg, 200 mg (as hydrochloride) Trade Name(s): I: Inopamil (Astra-Simes; Scandine (Zambon; 1984) 1984) Ibudilast (KC-404) ATC: R03DX04 Use: antiallergic, leukotriene antagonist RN: LDSo: CN: 50847-1 1-5 MF: C,4H,HN,0 MW: 230.31 146 mglkg (M, i.v.); 1860 mgkg (M, p.0.); 42.5 mgkg (R, i.v.); 1340 mgkg (R, p.0.) 2-methyl-1 -[2-(1 -methylethyl)pyrazolo[l,5-alpyridin-3-yl]- I-propanone acH H,N-0-S03K. HI 3 potassium hydroxylomine 0-su~fonate CH3 2-methyl- pyridine 1-amino-2- methyl- pyridinium iodide Reference(s): DE 2 315 801 (Kyorin; appl. 29.3.1973; J-prior. 30.3.1972). US 3 850 941 (Kyorin; 26.1 1 .l974; J-prior. 30.3.1972). synthesis of I -amino-2-methylpyridinium iodide: Gosl, R.; Meuwsen, A.: Chem. Ber. (CHBEAM) 92,2521 (1959). medical me for treatment of rheumutism: EP 215 438 (Kyorin; appl. 10.9.1986; J-prior. 14.9.1985). medicul usefor treatment of bronchial asthma, allergic rhinitis, urticaria: JP9 167 516 (Kyorin; appl. 21.9.1984; prior. 14.3.1983). inhalant: EP 320 002 (Kyorin; appl. 9.1 2.1988; J-prior. 10.12.1987). 1038 1 Ibuprofen trunsdermal ,formulation: EP 3 19 902 (Kyorin; appl. 6.12.1 988; J-prior. 10.12.1987). controlled-release formulation: EP 156 243 (Kyorin; appl. 12.3.1985; J-prior. 14.3.1984). synthesis of potassium hydroxylamine 0-sulfonate: Cosl, R.; Meuwsen, A,: Chem. Ber. (CHBEAM) 92,2521 (1959). Formulation(s): cps. 1 0 mg Trade Name(s): J: Ketas (Kyorin; 1989) Ibuprofen ATC: G02CCOl; MOl AEOl ; M02AA 13 Use: anti-inflammatory, antirheumatic RN: 15687-27-1 MF: C,,H,,O, MW: 206.29 EINECS: 239-784-6 LD,,,: 740 mg/kg (M, p.0.); 636 mg/kg (R, p.0.) CN: a-methyl-4-(2-methy1propyl)benzeneacetic acid 8 N'K (eutect" ___, H3C isobutene benzene isobutylbenzene (I) Boots process (industrial process) Cl/h0~CH3 0 ethyl chloro- HJC H3C ocetote ' ocetyl 4'4sobutyl- chloride acetophenone (11) I. NOOH I. (NH,OH),SO, 2. HCI 2. NaOH H3C / 2-(4-isobutylpheny1)- propionoldehyde Ibuprofen u 1. NaOH H+ 2. HCI IV + H3C H3C Ibuprofen I 1039 11 t HCN -4 H3C 4-isobutylbenzyl chloride 2-(4-isobutylphenyl)- ocetonitrile (V1) 1. NoNH2 1. NoOH 2. H3C-I 2. HCI VI + &k TI Ibuprofen H3C @ thy^ process triethyloluminum 1. NoOH 2. HCI &o-CI-I, - "3C H3C-OH % HCN V EL + VI1 [buprofen r-7 ibuprofen methyl ester (WI) @ BHC (Boots-Hoechst-Celonese) process (industrial) HF. 80°C H1, Raney-Ni I + + 11 b H3C acetic anhydride 1 -(4-isobutylpheny1)- ethanol (M) 0 P~CI,. P(c,H,),. COCI,. HCI, H,C&~~, Ibuprofen 1 1040 1 Ibuprofen Reference(s): DE 1 443 429 (Boots; appl. 26.1.1962; GB-prior. 2.2.1961). a,b GB 97 1700 (Boots; appl. 2.2.196 1). US 3 228 831 (Boots; 11.1.1966; GB-prior. 2.2.1961). US 3 385 886 (Boots; 28.5.1968; GB-prior. 2.2.1961). c GB 1 514 812 (Boots; appl. 4.4.1975; valid from 31.3.1976). similar method: US 3 959 364 (Boots; 25.5.1976; GB-prior. 24.5.1973). ,from 4'-isobutylacetophenone: GB 1 160 725 (Boots; appl. 25.11.1966; valid from 20.11.1967). US 4 021 478 (Upjohn; 3.5.1977; prior. 13.7.1972). fiom 4'-isobutylpropiophenone by oxidation with thallium(II1) nitrate: GB 1 535 690 (Upjohn; appl. 20.5.1977; USA-prior. 16.6.1976). Walker, J.A.; Pillai, M.D.: Tetrahedron Lett. (TELEAY) 42,3707 (1977). from vinyl isobutyl ketone and diethyl2-acetyl-3-methylsuccinate: GB 1 265 800 (Boots; appl. 5.1 1.1968 and 15.11.1968; valid from 16.10.1969). DOS 2 719 304 (Upjohn; appl. 29.4.1977; USA-prior. 24.5.1976, 15.3.1977). DOS 2 806 424 (Upjohn; appl. 15.2.1978; USA-prior. 17.3.1977). US 4 096 177 (L. Baiocchi; 20.6.1978; I-prior. 11.4.1974). ,from 1-(4-isobutylpheny1)ethyl chloride via the Grignard compound: DOS 2 605 650 (Ind. Chim. Prodotti Francis; appl. 12.2.1976; I-prior. 22.5.1975). alternative syntheses: DOS 2 404 159 (Nisshin Flour Milling; appl. 29.1.1974; J-prior. 29.1.1973). DOS 2 646 792 (Mitsubishi Petrochemical; appl. 16.10.1976; J-prior. 23.10.1975, 3 1.7.1976). DAS 2 709 504 (Sagami; appl. 4.3.1977; J-prior. 4.3.1976, 27.12.1976). DOS 2 724 702 (Valles Chimica; appl. 1.6.1977; E-prior. 2.6.1976). US 4 01 6 196 (Nisshin Flour Milling; 5.4.1977; J-prior. 27.7.1974,29.7.1974). US 4 13 1 747 (Ono Pharmaceutical; 26.12.1978; J-prior. 19.1 1.1975). BE 859 846 (Sagami; appl. 27.12.1976; J-prior. 18.10.1976). DOS 2 824 856 (Upjohn; appl. 6.6.1978; USA-prior. 16.6.1977). (S)-ibuprofen: Cleij, M. et al.: J. Org. Chem. (JOCEAH) 64, 5029-5035 (1999) Formulation(s): amp. 400 mg; drg. 200 mg, 400 mg; eff. gran. 200 mg; f. c. tabl. 200 mg, 400 mg, 600 mg; s. r tabl. 800 mg; suppos. 600 mg; syrup 100 mg/5 ml Trade Name(s): D: Aktren (Bayer Vital) Anco (Kanoldt) Brufen (Kanoldt; 1971) Dignoflex (Sankyo) Dolgit (Dolorgiet) DOLO PUREN (Isis Puren) Dolormin (Woelm) Duralbuprofen (durachemie) Esprenit (Hennig) Exneural (BASF Generics) Ibu (AbZ-Pharma) F: Ibu Beta (betapharm) Ibufug (Wolff) Ibuhexal (Hexal) Ibumerck (Merck Generika) Imbn (Merckle) Jenaprofen (Jenapharm) Novogent (Temmler) Opturem (Kade) Parsal (Brenner-Efeka) Tempi1 (Temmler) Toga1 (Togal) Urem (Kade) Advil (Whitehall) Algifene (Lab. Nicolas, Division de LRN SA) Antalibe (Bouchara SantC Active) Brufen (Lab. Knoll; 1972) Dolgit (Lab. Merck- ClCvenot) Ergix (Murat) GClufkne (Lab. CPF) Nurofen (Lab. Boots Healthcare) Oralfene (Pierre Fabre MCdicament) Rhinadvil (Whitehall)- comb. . p.0.) 2-methyl-1 -[ 2-( 1 -methylethyl)pyrazolo[l,5-alpyridin-3-yl ]- I-propanone acH H,N-0-S03K. HI 3 potassium hydroxylomine 0-su~fonate CH3 2-methyl- pyridine 1-amino- 2- methyl- pyridinium. progestogen RN: 6 8-9 6-2 MF: C2,H3003 MW: 330.47 EINECS: 20 0-6 9 9-4 CN: 17-hydroxypregn-4-ene-3,20-dione acetate RN: 30 2-2 3-8 MF: C23H3204 MW: 372.51 EINECS: 20 6-1 1 9-6 16-dehydropregnenolone. choleretic RN: 9 0-3 3-5 MF: C,,,H,O, MW: 176.17 EINECS: 20 1-9 8 6-7 LD,,: 2850 mgtkg (M, p.0.); 15 mgkg (R, i.p.); 3850 mg/kg (R, p.0.) CN: 7-hydroxy-4-methyl-2H-I -benzopyran-2-one CH3 resorcinol