Rofecoxib R 1831 H202, 5 mo1Z No2W04. 0 Aliquot 336, 0:: dCH3 8r2. C*BOO* 1- O\\ b Ill hydrogen peroxide, H~c-", bromine in o-dichlorobenzene acetic acid 4'-(methylsulfonyl)- acetophenone (11) DMF __* phenylocetic ocid sodium salt H H3CyyCH3 , DMF CH3CH3 IV Rofecoxib I W ~r,. AICI~, CHCI, I 11 -+ In magnesium monoperoxyphtholote (MMPP) OBU (1 ,a-diozobicyclo- phenylocetic [5.4.0]undec-7-ene) ocid (N) Rofecoxib 1 1832 R Rofecoxib 4-brorno- thioonisole (V) 2(5H)- furonone 1. pollodium(1l) acetote 2. iodine, pyridine r 1. tert-butyllithium 2. trirnethylsilyl chloride 4-[4-(rnethylthi0)- phenyl]-2(5~)- furanone (Vl) 2. Rofecoxib 2. monoperoxyphtholic acid phenylboronic ethyl brornoacetote ethyl 2-(phenylocetoxy)- ocetote (VllI) P Rolitetracycline R 1833 1. LiBr or LiCl 2.x, NO,CO,, P~(PP~,), b 0 4-(rnethylthi~)~henylboronic ocid (X) H3C-S 2 KHSO, - KHSO, . K,SO, XI - Rofecoxib "oxone- synthesis of 4-(rnethylthio)phenylboronic ocid triisopropyl borate Reference (s): a WO 9 800416 (Merck & Co.; appl. 27.6.1997; GB-prior. 29.7.1996). b WO 9 613 483 (Merck Frosst Canada; appl. 2.10.1994; USA-pr~or. 27.10.1994) e WO 9 608 482 (Merck & Co.; appl. 12.9.1995; USA-prior. 16.9.1994). a-e WO 9 500 501 (Merck Frosst Canada Inc.; appl. 15.5.1995; USA-prior. 24.6.1993, 10.1.1994) The discovery of rofecoxib: Prasit, P. et al.: Bioorg. Med. Chem. Lett. (BMCLES) 9 (13), 1773 (1999). alternative syntheses: WO 9 636 623 (Merck Frosst Canada; appl. 15.5.1996; USA-prior. 18.5.1995). GB 2 294 879 (Merck & Co.; appl. 9.10.1995; USA-prior. 19.10.1994). W09 619 469 (Merck Frosst Canada; appl. 18.12.1995; USA-prior. 21.12.1994). Formulation(s): susp. 25 mg; tabl. 12.5 mg Trade Name(s): D: Vioxx (Merck Sharp & GB: Vioxx (Merck Sharp & USA: Vioxx (Merck Sharp & Dohme) Dohme; 1999) Dohme) Rolitetrac ycline ATC: JOlAA09 Use: antibiotic, antibacterial RN: 751-97-3 MF: C,H,,N,O, MW: 527.57 EINECS: 212-031-9 LD,,: 75 mgkg (M, i.v.); 1320 mgkg (M, p.0.); 93 mglkg (dog, i.v.) CN: [4S-(4a,4aa,5aa,6P,12aa)]-4-(dimethylamino)-l,4,4a,5,5a,6,11,12a-octahydro-3,6,10,12,12a- pentahydroxy-6-methyl-l,11-dioxo-N-(l-pyrrolidinylmethyl)-2-naphthacenecarboxamide 1834 R Romurtide Reference(s): DE 1 044 806 (Hoechst; appl. 3.10.1956). DE 1 063 598 (Hoechst; appl. 14.2.1957). 1JS 3 104 240 (Bristol-Myers; 17.9.1963; prior. 18.8.1958). Gottstein, W.J. eta].: J. Am. Chem. Soc. (JACSAT) 81, 1198 (1959). tetracycline paraform- pyrrolidine aldehyde Trade Name(s): D: Reverin (Hoechst); wfm I: Colbiocin (SIF1)-comb. Hostacyclin-PRM F: Transcycline (Hoechst); Iducol (SIF1)-comb. (Hoechst) wfm Vitecaf (SIF1)-comb. Velacycline (Squibb) GB: Tetrex PMT (Bristo1)- J: Bristacin (Rristre-Banyu) IJSA: Syntetrin (Bristol); wfm comb.; wfm Ralitetracycline Romurtide ATC: L03AX (Muroctasin; Nomurtide) Use: immunostimulant, muramyldipeptide denvative, treatment of leukopenia associated with cancer radiotherapy RN: 781 13-36-7 MF: C43H7RN6013 MW: 887.13 LD,,,: >600 mglkg (M, p.0.); 436 mgkg (Mm, s.c.); 625 mglkg (Mf, s.c.); >90 mglkg (R, I.v.); >600 mglkg (R, p.0.); 761 mg/kg (Rm, s.c.); 801 mgkg (Rf, s.c.): >200 mglkg (dog, s.c.) CN: @-[@-[N-(N-acetylmuramoyl)-~-alanyl]-~-a-glutaminyl]-~-(l-oxooctadecyl)-~-lysine H H3C 0 N COOH + XKY H3C CH30 CH3 0 N-hydroxy- succinimide N-tert-butoxycarbonyl- benzyl D-iso- L-alonine glulorninote 0 . cIcocc,H,. N(~~H~)~ Hz. Pd-C I CO~H N6-(benzylaxycarbonyl)- ethyl b 11 H3C CH,~ CH, L-lysine benzyl ester chloroformate F Romurtide R 1835 0 L-olonyl-D-isoglutaminyl-Nz-(benzyl- oryc0rbonyl)-L-lysine benzyl ester (Ill) X O H3C COOH 1 -0-benzyl-4.6-0-benzylidene N-ocetylmuramic acid 1836 R Ronifibrate Rornurtide Keference(s): EP 21 367 (Daiichi; appl. 20.6.1980; J-prior. 21.6.1979). US 4 317 771 (Daiichi; 2.3.1982; appl. 23.6.1980; J-prior. 21.6.1979) medical use for treatment of thromboperiia: EP 331 756 (Daiichi; appl. 2.9.1988; J-prior. 2.9.1987). medical use as analgcsic/anti-inflammatory: JP 63 093 724 (Daiichi; appl. 9.10.1986). Formulation(s): vial 200 pg Trade Name(s): J: Nopia (Daiich~; 1991) Ronifibrate ATC: ClOAB07 Use: antihyperlipoproteinemic, fibrate serum antihyperlipidemic RN: 42597-57-9 MF: C19H,oClN05 MW: 377.82 LD,,: 3100-4080 mgkg (M, p.0.) . CN: 3-pyridinecarboxylic acid 3-[2-(4-ch1orophenoxy)-2-methyl-1 -oxopropoxy]propyl ester hydrochloride RN: 42749-78-0 MI;: C19HmCIN0,. HCI MW: 414.29 sodium 2-(4-chloro- phenoxy)-Emethyl- propionate nicotinoyl Ronifibrote chloride B Ropinirole R 1837 Reference (s): JP49 030 377 (Kowa; appl. 19.7.1972); C.A. (CHABA8) 81,135984s. JP 4 840 777 (Yamanouchi; appl. 5.10.1971); C.A. (CHABA8) 79,66180~ (1973). Fomulation(s): cps. 250 mg, 500 mg Trade Name(s): I: Cloprane (Sankyo Pharma) Ropinirole (SK&F-101468; SK & F-101468A) ATC: N04BC04 Use: dopamine-D,-agonist, antiparkinsonian RN: 91374-21-9 MF: C,,H,N,O MW: 260.38 CN: 4-[2-(dipropy1amino)ethyll-I ,3-dihydro-2-indol-2-one hydrochloride RN: 91374-20-8 MF: C,6H,N,0 . HCI MW: 296.84 bsnzayl isochrornon chloride 2-chlorornethylphenethyl benzoote (I) 2. HsC-COOH 3. Na2S,0, I 1. hexornethylene- tetmrnine 0 2-forrnylphenethyl benzoate (Il) 1. NaOCHs. CH30H 2. H20. HCI + H3C-NO2 - q0pN02 0 0 pyridine 1838 R Ropivacaine hydrochloride dipropylornine Ropinirole synthesis of ropinirole: WO 9 116 306 (Smith Kline & French; appl. 15.4.1991; GB-prior. 17.4.1990). EP 113 964 (Smith Kline & French; appl. 30.11.1983; USA-prior. 7.12.1982). Hayler, J.D. et al.: Org. Process Res. Dev. (OPRDFK) 2, 3 (1998). synthesis of 2-formylphenethyl benzoate: Hayler, H.D.; Howie, S.L.B.; Negus, A.; Oxley, P.W.: J. Heterocycl. Chem. (JHTCAD) 32 (3), 875 (1995). dihydroindolinones as cardiovascular agents: US 4 997 954 (Smith Kline & French; 25.1.1989; GB-prior. 19.6.1987). EP 300 6 14 (Smith Kline & French; appl. 16.6.1988; GB-prior. 19.6.1987). AU 8 777 61 5 (Smith Kline & French; appl. 25.1.1989; GB-prior. 30.8.1986). US 4 452 808 (Smith Kline & French; appl. 5.6.1984; USA-prior. 7.12.1982). WO 9 415 918 (Smith Kline & French; appl. 21.7.1994; GB-prior. 8.1.1993). use for treatment of Parkinson k disease: EP 299 602 (Smith Kline & French; appl. 18.1.1989; GB-prior. 21.5.1987). WO 9 71 1 696 (Cygnus Inc.; appl. 6.9.1996; USA-prior. 29.9.1995,4.9.1996). WO 9 639 136 (SmithKline Beecham; appl. 12.12.1996; GB-prior. 6.6.1995). WO 9 323 035 (SmithKline Beecham; appl. 25.11.1993; GB-prior. 18.5.1992). WO 9 200 735 (SmithKline Beecham; appl. 8.7.199 1 ; GB-prior. 9.7.1990). WO 9 706 786 (Scherer Ltd.; appl. 16.8.1996; GB-prior. 18.18.1995). Formulation(s): tabl. 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg (as hydrochloride) Trade Name(s): D: Requib (SmithKllne GB: ReQuip (SmithKline USA: Requib (SmithKline Beecham) Bcecham; 1996) Beecham) F: Requib (SmlthKline I: Requib (SmithKline Beecham) Beecham) Ropivacaine hydrochloride (LEA- 103) ATC: NOlBBOS) Use: local anesthetic RN: 98717-15-8 MF: C17H,N20 . HCI MW: 310.87 CN: (S)-N-(2.6-dimethylpheny1)- I-propyl-2-pipendinecarboxamide monohydrochloride monohydrate RN: 1321 12-35-7 MF: C,,H,,N,O. HCI . H20 MW: 328.88 base RN: 84057-95-4 MF: C,,H,,N,O MW: 274.41 Rosiglitazone R 1839 L-pipecolic acid L-pipecoloyl chloride Ropivocoine hydrochloride Reference(s): WO 8 500 599 (Apothekemes Lab., Astra; WO-prior. 1.8.1983). preparation of optically-enriched pipecolic acid: WO 9 61 1 185 (Chiroscience; appl. 9.10.1995; GB-prior. 7.10.1994). slorage stable optically pure hydrochloride monohydrate: AU 8 666 449 (Astra, Nissan; appl. 12.12.1986; S-prior. 3.1.1986). WO 9 636 606 (Astra; appl. 30.4.1996; S-prior. 16.5.1995). composition with long/medium chain triglycerides: EP 770 387 (Braun Melsungen; prior. 28.10.1995). sustained release formulation: WO 9 641 616 (Euroceltique; USA-prior. 9.6.1996). combination with P-blocker: WO 9 527 51 1 (Astra; appl. 24.3.1995; S-prior. 7.4.1994). composition containing hydroxypropyl-P-cyclodextrin: WO 9 505 198 (F. M. Borgbjerg; appl. 16.8.1994; DK-prior. 17.8.1993). injection suspension: WO 9 401 087 (Astra; appl. 24.6.1993; S-prior. 9.7.1992). Formulation(s): amp. 2 mglml, 5 mglml, 7.5 mglml, 10 mg/ml (as monohydrate) Trade Name(s): D: Naropin (Astra) GB: Naropin (Astra) USA: Naropin (Astra) F: Naropeine (Astra) I: Naropina (Astra) Rosiglitazone (BRL 49653) ATC: AlOBG02 Use: antidiabetic, insulin enhancer RN: 122320-73-4 MF: C,,H,,N,O,S MW: 357.43 CN: 5-[[4-[2-(Methyl-2-pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione (R)-(+)-form RN: 163860-1 6-0 MF: CI8H,,N,O3S MW: 357.43 maleate RN: 155141-29-0 MF: C,,H,,N3O3S . C4H40 MW: 425.51 1840 R Rosiglitazone F 120°C ncnO fJC' + NaH, DMF 4 ,N NeOH + 1 HNe~~ W 4-fluoro- benzoldehyde 2-chloro- 2-(methylamino)- 2-(methyl-2-pyri- pyridine ethanol 4-[2-(methyl-2-pyridlnyl- arnino)ethoxy]benzoldehyde (I) (52)-5-[[4-[2-(methyl-2 pyridinylamlno)ethoxy]- phenyl]methylene]-2.4- thiazolidinedione (11) 0 2.4-thiozo- lidinedione Mg. I*. CHJOH ___) Rosiglitozone @ alternative biocatolytic reduction of 11 ond synthesis of the (R)-(+)-enontiomcr Rosiglitazone El Rhodotorulo rubro CBS 6969, dioxone 11 b w Li+ HJC/YH~CH,. 1HF CHJ CH, 11 b FH3 msgO o Rosiglitozone 1 lithium tri-sec-butylborohydride . @-[ @-[ N-(N-acetylmuramoyl )-~ -alanyl ]-~ -a-glutaminyl ]-~ -( l-oxooctadecyl )-~ -lysine H H3C 0 N COOH + XKY H3C CH30 CH3 0 N-hydroxy- succinimide N-tert-butoxycarbonyl- benzyl D-iso-. 2-( methylamino )- 2-( methyl-2-pyri- pyridine ethanol 4-[ 2-( methyl-2-pyridlnyl- arnino)ethoxy]benzoldehyde (I) (52 )-5 -[ [ 4-[ 2-( methyl-2 pyridinylamlno)ethoxy ]- phenyl]methylene ]-2 . 4- thiazolidinedione. insulin enhancer RN: 12232 0-7 3-4 MF: C,,H,,N,O,S MW: 357.43 CN: 5-[ [ 4-[ 2-( Methyl-2-pyridinylamino)ethoxy]phenyl]methyl ]-2 ,4-thiazolidinedione (R )-( +)-form RN: 16386 0-1 6-0 MF: CI8H,,N,O3S MW: