Sevoflurane S 1871 ethyl acrylate polyphosphoric acid - ethyl 3-(2-benzylphenyl)- 1 -methyl-4-oxopiperidine- 5-carboxylate (111) DE 2 503 407 (Akzo; appl. 28.1.1975; NL-prior. 3 1.1.1974). US 4 002 632 (Akzo; 11 .l.l977; appl. 22.1 ,1975; NL-prior. 3 1.1.1974). preparation of ethyl (2-benzylpheny1)acetate: Kenyon, W.G. et al.: J. Org. Chem. (JOCEAH) 28,3108 (1963). Yoshioka, M.; Osawa, H.; Fukuzawa, S.: Bull. Chern. Soc. Jpn. (BCSJA8) 55 (3), 877 (1982). Weizmann et al.: J. Org. Chern. (JOCEAH) 15,918,920,926 (1950). McElvaln; Kent; Stevens: J. Am. Chem. Soc. (JACSAT) 68, 1922 (1946). Meyer: Ber. Dtsch. Chern. Ges. (BDCGAS) 21, 1313 (1888). medical use for treutment of gastric ulcers: US 4 447 437 (Mochida; 8.5.1984; appl. 24.5.1982; J-prior. 3.6.1981). Formulation(s): tabl. 1 rng Trade Name(s): J: Tecipul (Mochida; 1989) Sevoflurane ATC: NOIAB08 Use: anesthetic (inhalation) RN: 28523-86-6 MF: C,H,F,O MW: 200.05 LD,,,: 18.2 g/kg (M, p.0.); 28300 ppd3H (M, inhal.); 10.8 gkg (R, p.0.); 28800 ppd3H (R, inhal.) CN: 1,1,1,3,3,3-hexafluoro-2-(fluorornethoxy)propane - - 1872 S Sibutramine hydrochloride 1.1 .I J.3.3-hexo- 1.1.1.3.3.3-hexa- fluoro-2-methoxy- fluoro-2-(chloro- propone rnethoxy)propone (I) BrF3 or CIF3 I Sevoflurone Reference(s): a DE 1 954 268 (Baxter; appl. 28.10.1969; USA-prior. 29.10.1968). US 3 683 092 (Baxter; 8.8.1972; appl. 3 1.7.1970; prior. 28.10.1968). EP 341 005 (BOC; appl. 28.4.1989; USA-prior. 6.5.1988). US 4 874 901 (BOC; 17.10.1989; appl. 6.5.1988). b US 4 874 902 (BOC; 17.10.1989; appl. 20.5.1988). alternative synthesis: EP 42 41 2 (Baxter Travenol; appl. lO.l2.l98O; USA-prior. 26.12.1979). Formulation(s): inhalation sol. 1 ml Trade Name(s): D: Sevorane (Abbott) J: Sevofrane (Maruishi; 1990) Ultane (Abbott) I: Sevorane (Abbott) USA: Sevorane (Abbott) Sibutramine hydrochloride (BTS-54524) ATC: A08AA Use: antidepressant, anorexic RN: 125494-59-9 MF: CI ,H2,C1N . HC1. H20 MW: 334.33 CN: (+)-1-(4-chlorophenyl)-N,N-dimethyl-a-(2-methylpropyl)cyclobutanemethanamine hydrochloride monohydrate (&I- base RN: 106650-56-0 MF: C1,H2,C1N MW: 279.86 (*)-anhydrous hydrochloride RN: 84485-00-7 MF: Cl ,H2,C1N . HCl MW: 3 16.32 (+)-base RN: 154752-44-0 MF: CI7H2,ClN MW: 279.86 (+)-hydrochloride RN: 154752-45-1 MF: C,,H2,C1N . HC1 MW: 3 16.32 (-)-base RN: 153341-22-1 MF: C,,H,,CIN MW: 279.86 (-)-hydrochloride RN: 153341-23-2 MF: CI7H2,C1N . HC1 MW: 316.32 Sildenafil S 1873 4-chlarobenzyl 1,J-dibromo- cyanide propane 1 -(4-chlarophenyl)- cyclobutyl cyonide (I) a) NoBH, ,M~B~ or b) 1. OHC-NH2. HCOOH 2. H+, HZO Ir CH3 2-methylpropyl- rnognesiurn bromide Referencefs): DE 3 212682 (Boots; appl. 21.10.1982; GB-prior. 6.4.1981). WO 9 720 810 (Knoll AG; appl. 12.6.1997; GB-prior. 2.12.1996) US 4 929 629 (Boots; 29.5.1990; GR-prior. 17.12.1985). 1. HCHO . HCOOH c'v:H3 2. HCI , synthesis of 1 -(4-chlorophenyl)cyclobutyl cyanide: Butler. D.E.; Pollatz, J.C.: J. Org. Chem. (JOCEAH) 36, 1308 (1971). H3C\ P3 . HC - tip use for treating depression: GB 2 184 122 (Boots; appl. 17.6.1987; GB-prior. 17.12.1985). (n) i Sibutramine hydrochloride use for treatment of Parkinson's disease: WO 8 806 444 (Boots; appl. 7.9.1988; GB-prior. 28.2.1987). use,for treatment of obesity: WO 9 006 110 (Boots; appl. 14.6.1990; USA-prior. 29.1 1.1988). use to lower lipid levels: WO 9 813 034 (Knoll AG; appl. 2.4.1998; GB-prior. 25.9.1996). Formularion(s): cps. 5 mg, 10 mg, 15 mg Trade Name(s): D: Reductil (Knoll; 1999) USA: Meridia (Knoll; 1998) Sildenafil (UK-92480) ATC: G04C LJse: male erectile dysfunction, PDE 5- inhibitor RN: 139755-83-2 MF: C2,H3,,N60,S MW: 474.59 CN: 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-djpyrimidin-5-y1)-4- ethoxyphenyl]suIfonyl]-4-methylpiperazine 1874 S Sildenafil citrate RN: 171 599-83-0 MF: C,2H,,,N,0,S , C,H,O, MW: 666.71 O\\ /o\ "3% /S\ '33 1. o\O p3 2. NoOH ,OoCq ethyl 3-propyl- (11) pyrozole-5- corboxylote (I) 1. HN03 2. S0Cl2 SnCI2 3. NH40H "i;:' C2HSOH, reflux 11 - . 1. nitric acid OzN 2. thionyi chloride CH3 2-ethoxybenzayl chloride 4-(2-ethoxybenzamido)- 1 -methyl-3-propyl- pyrazole-5-carboxamide (IV) NoOH, 30% H20Z C2H50H, reflux CiS03H IV - - v chlorosulfonic acid 1 -methyl- Sildenofil piperazine (VI) Sildenafil S 1875 @ COOH SOC12. CIS0,H Cl, 2 ooAcH ___, thionyl chloride. chlorosulfonic acid 2-ethoxy- 5-chlorosulfonyl- benzoic acid 2-ethaxybenzaic acid (VU) 2-ethoxy-5-(4-methyl- piperazin-1 -ylsulfonyl)- benzoic ocid (VIII) K+O c(cH,),, HO-C(CH~)~, A M b Sildenafil potassium tert-butoxide preparation of ethyl 3-propylpyrazole-5-corboxylate 2-pentanone diethyl oxalate ethyl 2.4-dioxo- heptanoate Reference(7): a EP463 756 (Pfizer Inc.; appl. 7.6.1991; GB-prior. 20.6.1990). Terrett, N.K. eta].: Bioorg. Med. Chem. Lett. (BMCLES) 6, 1819-1824 (1996). Palmer, E.: Chem. Brit (CHMBAY) 1999, 24 b EP 812 845 (Pfizer Corp.; appl. 4.6.1997: GB-prior. 14.6.1996). Dale, D.J. et al.: Org. Process Res. Dev. (OPRDFK) 4, 17-22 (2000). preparation of ethyl 3-propylpyrazole-5-carboxylate: Terrett, N.K; Bell, AS.; Brown, D., Ellis, P.: Bioorg. Med. Chem. Lett. (BMCLEII) 6 (15), 1819 (1996). preparation of ethyl 2,4-dioxoheptanoate: Lapworth: Hann: J. Chem. Soc. (JCSOA9) 81, 1490 (1902). Libermann et al.: Bull. Soc. Chim. Fr. (BSCFAS) 1958,687, 690. Burch, H.A.; Gray, J.E.: J. Med. Chem. (JMCMAK) 15.429 (1972) use for treatment of impotence: WO 9 428 902 (Pfizer Inc; appl. 13.5.1994; GB-prior. 9.6.1993). Formulation(s): f. c. tabl. 25 mg, 50 mg, 100 mg (as citrate) 1876 S Silibinin Trade Natne(s): D: Viagra (Pfizer; 1999) GB: Viagra (Pfizer; 1999) USA: Viagra (Pfizer; 1998) F: Viagra (Pfizer; 1999) I: Viagra (Pfizer; 1999) Silibinin ATC: A05 Use: liver therapeutic RN: 22888-70-6 MF: C25H22010 MW: 482.44 EINECS: 245-302-5 LD,,,: 1056 mgkg (M, i.v.) CN: [2R-[2a,3~.6(2R*,3R*)]j-2-[2,3-dihydro-3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-1,4- henzodioxin-6-ylj-2,3-dihydro-3,5,7-trihydroxy-4H- I-benzopyran-Cone 0 H 0 H OH 0 Silibinin By extraction uf the fruits of Silyburn tnarianutn Gaertn. (milk thistle) and column chromatographic purification Reference(s): Wagner, H. et al.: Arzneim Forsch. (ARZNAD) 18,688 (1968); 24,466 (1974). DOS 1 767 666 (Madaus; appl. 1.6.1968) DAS 1 923 082 (Madaus; appl. 6.5.1969) DOS 3 537 656 (Madaus; appl. 23.10.1985; D-prior. 22.1 1.1984). derivatives and salts: DRP 1 963 3 1 8 (AT0 Investment; appl. 17.12.1969). DAS 2 302 593 (Madaus; appl. 19.1.1973). Forrnulation(s): cps. 35 mg, 70 mg, 140 mg, 150 mg, 200 mg; f. c. tabl. 70 mg, 140 mg; gran. 200 mg; susp. 0.43 gf100 g Trade Narne(s): D: durasilymarin (durachemie) F: . Ugalon (Madaus) Legalon (Madaus) 1: Eparsil (Pulitzer) Silymarin (Ziethen; ct- Legalon (IBI) Arzneimi ttel) Silepar (Ibirn) Silimarin R (Benedetti) comb. Silirex (Lampugnani) Silliver (Abbott) Simfibrate ATC: COlAB06 Use: antiarteriosclerotic (hypollpemic) RN: 14929-1 1-4 MF: C,,H,,Cl,O, MW: 469.36 EINECS: 238-998-7 LD,,,: 3300 mglkg (M, p.0.); 7300 mg/kg (R, p.0.) CN: 2-(4-ch1orophenoxy)-2-methylpropanoic acid 1,3-propanediyl ester Simvastatin S 1877 L TosOH + HO "OH + HOOC CH3 2-(4-ch1orophenoxy)- 1.3-proponediol isobutyric acid (cf. clofibrate synthesis) Sirnfibrote I Reference(s): US 3 494 957 (Yoshitomi; 10.2.1970; J-prior. 5.1.1965). Formulation(s): cps. 250 mg Trade Name(s): I: Cholesolvin (Cyanamid); Liposolvin (Tosi-Novara); Sinfibrex (Isnardi); wfrn wfm wfm - J: Cholesorbin (Takeda) Simvastatin ATC: ClOAAOl (MK-733; Synvinolin) Use: antihyperlipidemic cholesterol synthesis inhibitor, HMG-CoA- reductase inhibitor RN: 79902-63-9 MF: C25H3R05 MW: 418.57 LD,,,: 3 g/kg (M, p.0.); 4438 mglkg (R, p.0.); >5 g/kg (dog, p.0.) CN: [lS-[la,3a,7P,8~(2S*,4S*),8aP]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)eyl]-I-naphthalenyl ester 0 CH ~3~3 + CIxeH, 4-pyrrolidino- H3C pyridine 2,2-dirnethyl- butyryl chloride 1878 S Sisomicin R~ference(s): US 4 444 784 (Merck & Co.; 24.4.1984; prior. 5.8.1980,4.2.1980). (10 US 4 450 171 (Merck & Co.; 22.5.1984; prior. 14.6.1982, 18.12.1980,5.8.1980,4.2.1980). Hoffmann, W.F. et al.: J. Med. Chem. (JMCMAR) 29, 849 (1986). Simvastatin alternative syntheses: US 5 159 104 (Merck &L Co.; 27.10.1992; appl. 1.5.1991). GB 2 255 974 (Merck & Co.; 25.11.1992; USA-prior. 24.5.1991). WO 9 81 2 188 (Brantford; 5.9.1996; CA-prior. 19.9.1996). US 5 763 653 (Ranbaxy; 9.6.1998; appl. 13.3.1997). US 5 763 646 (Ranbaxy; 9.6.1998; appl. 13.3.1997). US 5 393 893 (Apotex; 28.2.1995; appl. 8.11.1993). EP 33 538 (Merck & Co.; appl. 2.2.1981; USA-prior. 4.2.1980, 5.8.1980). Thaper, R.K. et al.: Org. Process Res. Dev. (OPRDFK) 3,476-479 (1999). controlled-release formulation: EP 302 693 (Merck & Co.; appl. 1.8.1988; USA-prior. 3.8.1987,31.8.1987). Formulation(s): f. c. tabl. 5 mg, 10 rng, 20 mg, 40 rng; tabl. 5 mg, 10 mg, 20 mg, 40 mg Trade Nurne(s). D: Denan (Boehringer Ing.; GB: Zocor (Merck Sharp & Sivastln (Sigma-Tau) 1990) Dohme; 1989) Zucor (Neopharmed) Zocor (D~eckmann; 1990) 1: Liporiorm (Gentili) J: Llpovas (Banyu) F: Lodalks (Sanofi Winthrop) Medipo (Mediolanum) USA: Zocor (Merck) Zocor (MSD-Chibret; Sinvacor (Merck Sharp & 1989) Dohme) Sisomicin ATC: JOIGBOR Use: antibiotic RN: 32385-1 1-8 MF: C,,H3,NSO7 MW: 447.53 EINECS: 2.5 1-018-2 LD,,,: 34 mg/kg (M, i.v.); >5 glkg (M, p.0.); 32 mgkg (R, i.v.); >5 glkg (R, p.0.) CN: 0-3-deoxy-4-C-methyl-3-(methylamino)-~-~-arabinopyrasoyl-(1+6)-0-[2,6-diamino-2,3,4,6-tetradeoxy- a-11-glycero-hex-4-enopyranosyl-( I +4)]-2-deoxy-D-streptamine sulfate (25) RN: 53 179-09-2 MF: C,,H3,NS0, . 5/2H,SO, MW: 1385.46 EINECS: 258-414-4 LD,,,: 34 mglkg (M, i.v.); >5 g/kg (M, p.0.); 49 mg/kg (R, i.v.); >5 g/kg (R, p.0.) From fermentation solutions of Micromonospora inyoensis (NRRL 3292). Reference(s): DOS 1 932 309 (Scherico; appl. 26.6.1969; USA-prior. 27.6.1968, 16.12.1968). US 3 832 286 (Schering Corp.; 27.8.1974; prior. 16.12.1968,27.6.1968, 26.6.1973). US 3 907 771 (Schering Corp.; 23.9.1975; prior. 3.2.1971, 16.12.1968, 27.6.1968). US 4 009 328 (Scherico; 22.2.1977; prior. 2.5.1975). Wagman, G.H. et al.: J. Antibiot. (JANTAJ) 23, 55 1, 555 (1 970). Schmidt-Kastner, G.; Reimann, H.: Infection (Munich) (IFTNAL) 4, (Suppl. 4), 292 (1976). Structure: Reimann, H. et al.: 1. Org. Chem. (JOCEAH) 39, 1451 (1974). Cleophax, J. et al.: I. Chem. Soc., Chem. Commun. (JCCCAT) 1975, 11. synthesis: Davis, D.H. et al.: J. Med. Chem. (JMCMAR) 21, 189 (1978): Formulation(s): amp. 20 mg12 ml, 100 mg12 ml, 75 mg11.5 ml (as sulfate) Trade Name(s): D: Extramycin (Bayer; 1976); F: Sisolline (Schering I: Mensiso (Menarini) wfrn Plough); wfm Sisomin (Max) Pathomycin (Byk Essex; Sisolline (Unilabo- USA: Siseptin (Schering); wfm 1976); wfm CCtrane); wfm p-Sitosterin (p-Sitosterol; a-Phy tosterol) RN: 83-46-5 MF: C2&,0 CN: (3P)-stigmast-5-en-3-01 ATC: ClOAX; G04C Use: prostata adenoma therapeutic (benign prostate hypertrophy, BPH), antihypercholesterolemic MW: 414.72 EINECS: 201-480-6 1880 S Sizofiran From whcat seeds, soybeans etc Rcference(s): The Merck Index, 12th Ed., 1467 (1996). US 4 153 622 (Medipolar Oy; 8.5.1979; prior. 18.5.1978) use in combinatiorl with chenodeoxycholic ac~d,for disintegrution of gallstones: DOS 2 61 8 854 (Frescnius; appl. 29.4.1976). Formulntion(s): cps. 10 mg, 65 mg; gran. 1.76 g12 g; tabl. 75 mg, 100 mg Trade Nutne(s): D: Azuprostat Kapseln Liposit Merz (Merz & CO.) Triaslonal (Intermuti) (Azuchemie)-comb. LP-Truw (Tmw) F: Sitosterol Delalande Cinchol Kapseln (Evers); Prostasal Kapseln (TAD) (Delalande); wfm w fm Sito-Lande (Synthelabo) USA: Cytellin (Lilly): wfm Flemun (Intermuti) Sitosterin Prostata Kapseln Harzol (Hoyer) (Intennuti) Sizofiran (Schizophyllan) ATC: A06A; L03A Use: antineoplastic, imrnunomodulator RN: 9050-67-3 MF: [C,,H4,0,0]x MW: unspecified LD,,,: >300 mglkg (M, i.v.); >1 g/kg (M, p.0.); >300 rnglkg (R, i.v.); >SO0 mg/kg (K, p.o.), >I 00 rnglkg (dog, i.v.1 CN: poly~3+[O-~-~-gluco~yranosyl-(I+3)-O-[~-~-glucopyranosyl-(1+6)-0-~-~-glucopyranosy~-(1-13)]- Sizofiran Preparation by fermentation of Schizopl~yllwn commune. Reference(s): JP 71137 873 (Taito; appl. 20.7.1968). Kozima, T. et al.: Int. 1. Immunophar~nacol. (IJIMDS) 2 (3), 49 (1980). For~wululion(s): amp. 40 mg . 0-3 -deoxy-4-C-methyl- 3-( methylamino )-~ -~ -arabinopyrasoyl-(1+6 )-0 -[ 2,6-diamino-2,3,4,6-tetradeoxy- a-11-glycero-hex-4-enopyranosyl-( I +4) ]-2 -deoxy-D-streptamine sulfate (25) RN: 53 17 9-0 9-2 . 1,2,3,7,8,8a-hexahydro-3,7-dimethyl- 8-[ 2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)eyl]-I-naphthalenyl ester 0 CH ~3~3 + CIxeH, 4-pyrrolidino- H3C pyridine 2,2-dirnethyl- butyryl chloride. 2288 8-7 0-6 MF: C25H22010 MW: 482.44 EINECS: 24 5-3 0 2-5 LD,,,: 1056 mgkg (M, i.v.) CN: [2R-[2a,3~.6(2R*,3R*)]j- 2-[ 2,3-dihydro- 3-( 4-hydroxy-3-methoxyphenyl )-2 -( hydroxymethyl )-1 , 4- henzodioxin-6-ylj-2,3-dihydro-3,5,7-trihydroxy-4H-