4-tluorobenz- ethyl aldehyde isobutyrylacetate ethyl 3-amino- 4-methyl-2- pentenoate 1. DDO, CH2C12 2. Red-Al, THF 11 - 1. 2,3-dichloro- 5.6-dicyano-p- benzoquinone 2. sadium bis(2- methoxyethoxy)- dihydridoaluminate 2.6-diisopropyl- 4-(4-fluoropheny1)- 5-methoxymethyl- 3-pyridine- carboxaldehyde (111) ethyl 2-isobutyryl- 3-(4-fluoropheny1)- acrylate (I) CH3~ CH3 H3c~~~cH3 F diethyl 1,4-dihydro-2,S- diisopropyl-4-(4-fluoropheny1)- pyridine-3.5-dicarboxylate (11) F ethyl 2,6-diisopropyl-4- (4-fluorophenyl)-5-hydroxy- methylpyridine-3-carboxylate H~C' diethyl 2- (cyclohexylamino)- vinylphosphonate 1. H3C-I, NOH, THF 2. LiAlk. THF 1. methyl iodide 2. lithium aluminum hydride 3. pyridinium chlorochromate NOH. THF. 25 OC d N 0 0 THF, -65 OC + , v H3C u~/CH3 2. triethylborane methyl acetoacetote 412 C Cerivastatin sodium 1. THF, 50 "C 2. chromotogrophic separation of O, diosteromers CH3 + H2N OH F methyl erythro-(E)-7-[2,6-diisopropyl- (+)-(~)-~hen~l- 4-(4-fluorophenyl)-5-methoxymethyl- glycinol 3-pyridyll-3,5-dihydroxy-hept-6-enoote (V) 1 Cerivostotin sodium 1. NoOH chrornotogrophicseparotion of enontiomers 2. HCI with chirol phase "Boychirol PM' v -+ H,C' b (+)-VII OH F Cerivostotin sodium u Reference(s): a DE 4 040 026 (Bayer; appl. 14.12.1990). EP 325 130 (Bayer AG; appl. 9.1.1989; D-prior. 20.1.1988). EP 491 226 (Bayer AG; appl. 3.12.1991; D-prior. 14.12.1990). AU 9 189 615 (Bayer AG; appl. 11.12.1991; D-prior. 14.12.1990). (R)-(+)-a-phenethylamine can be used instead ofS-(+)-phenylglycinol. b Drugs Future (DRFUD4) 19,537-541 (1994). Formulation(s): tabl. 0.1 mg, 0.2 mg, 0.3 mg Trade Name(s): D: Lipobay (Bayer) GB: Lipobay (Bayer) USA: Baycol (Bayer) Ceruletide C 413 Ceruletide (Caerulein) ATC: V04CC04; V04CK Use: diagnostic (for pancreatic function), stimulant of gastric secretory RN: 17650-98-5 MF: C5RH73N1302LS2 MW: 1352.42 LD,,: 1012 mgkg (M, i.v.) CN: 5-oxo-~-prolyl-~-glutaminyl-~-a-asparty-O-sulfo-~-tyrosyl-~-threonylglycyl-~-tryptophyl-~-methionyl- L-a-aspartyl-L-pheny lalanin amide Boc-Tyr Boc-Tyr-NH-NH-Z Tyr-NH-NH-Z . HCI (I) 0 Boc: 40&?H, CH3 H N COOH , + Boc' - 4 -ifO\Bzl 0 1. HCI ______, 2. Boc-Gln 1. HCI Boc, 2. Z-Pyr Pyr-Gln-Asp-Tyr-N, (N) 414 C Ceruletide 1. HCI 3. HCI v ______* Tcp: bCl CI HCI COOH CH3 Ac-Thr-Gly-Trp-Met-Asp-Phe-NH . HCI (VI) H Pyr-Gln-kp -Tyr(s03H)-Thr(Ac)-~ly-Trp-Met-Asp-Phe-NH (W) Ceruletide DE 1 643 504 (Soc. Farmaceutici Italia; appl. 6.4.1972; I-prior. 9.8.1966). US 3 472 832 (Soc. Farmaceutici Italia; I-prior. 9.8.1966). Bernardi, L. et al.: Experientia (EXPEAM) 23, 700 (1967). structure and isolation from Hyla caeruleu: Anastasi, A. et al.: Experientia (EXPEAM) 23, 699 (1967). Cetalkonium chloride C 4 15 Formulation(s): amp. 5 ~glml, 40 pgl2 ml; vial 20 kg, 30 kg, 40 kg Trade Name(s): D: Takus (Pharmacia & J: Ceosunin (Kyowa Hakko) Upjohn) Cetalkonium chloride ATC: SOlAA Use: antiseptic, bactericide RN: 122-18-9 MF: C2,H4,C1N MW: 396.10 EINECS: 204-526-3 CN: N-hexadecyl-N,N-dimethylbenzenemethanaminium chloride cetyl chloride dimethyl- omine N-cetyl-N,N- dimethylomine (I) Reference(s): FR 77 1 746 (I. G. Farben; 1934). Formulation(s): sol. 13 g/100 g, 130 mg Trade Narne(s): benzyl chloride D: Baktonium (Bode) F: Pansoral (Pierre Fabre GB: Bonjela (Reckitt & Mundisal (Mundipharma)- SantC)-comb. Co1man)-comb. comb. J: Lazal (Shionogi) Cetalkonium chloride Cethexonium bromide ATC: DOSAX; R02AA20 Use: antiseptic RN: 1794-74-7 MF: C2,H,,BrN0 MW: 448.57 CN: N-hexadecyl-2-hydroxy-N,N-dimethylcyclohexanaminium bromide chloride RN: 58703-78-9 MF: CxHSoCINO MW: 404.12 2-amino- cetyl cyclohexanol bromide (1) 416 C Cetiedil (yH2)15-CH3 1. anion exchanger. ,- (OH- form) Nap, 2. HCI 11 + I-CH, b cethexonium iodide cethexonium chloride Keference(s): Winternitz, F. et al.: Bull. Soc. Chim. Biol. (BSCIA3) 33, 369 (1951). cyclohexane dimethyl- 2-dimethyl- Formulation(s): collutorium 0.025 g1100 ml, 0.1 mgI0.4 ml, 0.3 gI100 ml; eye.drops 0.025 % (bromide); ointment 1 dl00 g; powder 1.5 gllOO g; sol 50 rng/100 ml Cethexoniurn bromide Trade Name(s): F: Biocidan (Menarini) oxide amine aminocyclo- hexanol Cetiedil ATC: C04AX26 Use: vasodilator (peripheral) RN: 141 76- 10-4 MF: C,,,H3,N0,S MW: 349.54 EINECS: 238-028-2 LD,,,: 1726 mg/kg (M, p.0.) CN: a-cyclohexyl-3-thiopheneacetic acid 2-(hexahydro-IH-atepin-1-y1)ethyl ester citrate (1:l) RN: 16286-69-4 MF: C2,,H3,N02S . C6HR0, MW: 541.66 EINECS: 240-381-2 (C2~5)20. -70 OC COOH 3 cyclohexyl- 3-thienyl- glyoxylic ocid lithium (from 3-bromo- thiophene and butyllithiurn) cyclohexyl- cyclohexyl- (3-thienyl)- (3-thieny1)- glycolic acid acetic acid (1) 1-(2-chloroethy1)- Cetiedil hexohydro- 1H- ozepine Cetirizine C 417 Referencefs): FR 1 460 571 (InnothCra; appl. 10.6.1965). FR-M 5 504 (Innothefa; appl. 10.6.1965). Robba, M.; Guen, Y. Le: Chim. Ther. (CHTPBA) 1967 (No. 2), 120. synthesis of starting materials: Robba, M.; Guen, Y. Le: Chim. Ther. (CHTPBA) 1966 (No. 4), 238. FR-appl. 2 260 575 (Innothefa; appl. 11.2.1974). FR-appl. 2 260 576 (ImothQa; appl. 11.2.1974). synthesisfrom 3-thienylacetonitrile: US 4 108 865 (Labaz; 22.8.1978; prior. 29.8.1974, 1.3.1976). Formulation(s): cps. 100 mg (as citrate) Trade Name(s): F: Stratene (Gerda) Vasocet (Cipharm) I: Stratene (Sigma-Tau); wfm Cetirizine ATC: R06AE07 Use: non-sedative antihistaminic RN: 83881-51-0 MF: C21H25C1N203 MW: 388.90 CN: (~)-[2-[4-[(4-chlorophenyl)phenylmethyl]-I-piperazinyl]ethoxy]acetic acid dihydrochloride RN: 83881-52-1 MF: C21H25CIN203 .2HCI MW: 461.82 LD,: 365 mg/kg (R, p.0.); >320 mgkg (dog, p.0.) Q+-CH~ H 0+LCH3 & + (;I No2COJ HCI ___, (;I ___, [;I CI H cfoC, dnc, 4-chlorobenzhydryl N-corbethaxy- ethyl 4-(4-chlorabenzhydryI)- 1 -(4-chl~radi~henyl- chlo"de piperorinc piperazine- 1 -carbarylate methyl)piperozine (I) 0 0 Cl-~JoA+3 9 Na2C03 I b methyl 2-(2-chloroethoxy)- acetate . sodium carbonate methyl 2-[Z-[4-(4- Cetiririne chlarodiphenylmcthyl)- 1 -piperazinyl]ethoxy]ocetate Referencefs): EP 58 146 (UCB; appl. 5.2.1982; GB-prior. 6.2.1981, 8.4.1981). alternative synthesis (also enantiomers): GB 2 225 321 (UCB; appl. 23.11.1988). EP 801 064 (UCB; appl. 9.4.1997; BE-prior. 10.4.1996). WO 9 737 982 (UCB;-~~~I. 28.3.1997; ~~-~rior. 4.10.1996). WO 9 802 425 (Apotex; appl. 1 1.7.1997; CA-prior. 11.7.1996). 418 C Cetrimonium bromide synthesis of 1-(4-chlorodipheny1methyl)piperazine: US 2 8 19 269 (Abbott; 1958). HU 17 343 (Richter Gedeon; appl. 26.5.1977). US 2 709 169 (UCB; 1952). 4 Formulatlon(s). drops 10 mg, sol 0 1 %, tab1 10 mg (as dihydrochloride) 1 4 Trade Name(s) D. Zyrtec (UCB, Rodleben, GB Zlrtek (UCB) USA. Zyrtec (Pfizer, as Vedim) I. Formlstln (Formenti, 1990) h ydrochlonde) F Vlrllx (SynthClabo) Vlrllx (Chemil) Zyrtec (UCB) Z~rtec (UCB; 1990) Cetrimonium bromide (Cetrimide) ATC: R02AA17 Use: antiseptic RN: 57-09-0 MF: C,,H,,BrN MW: 364.46 EINECS: 200-311-3 LD,,,: 32mgkg(M,i.v.); 44 mgkg (R, i.v.); 410 mgkg (R, p.0.) CN: N, N, N-trimethyl- 1 -hexadecanaminium bromide hydroxide RN: 505-86-2 MF: C,,H,,NO MW: 301.56 EINECS: 208-022-4 cetyl bromide trimethylamine Cetrirnonium bromide I Shelton, R.S. et al.: J. Am. Chem. Soc. (JACSAT) 68,753 (1946). Formulation(s): sol. 117 mg1100 g; tabl. 4 mg Trade Name(s): D: Lemocin (Novartis Buccawalter (SmithKline GB: Consumer Health) Beecham)-comb. Xylastesin (Espe) CCtavlon (Zeneca) numerous combination DCrinox (ThCrabel Lucien)- I: preparations comb. F: Aseptit (Riom) Rectoquotane (Evans J: Medical)-comb. Ceanel Conc. (Quinodem)- comb. Cetavlex (Zeneca) Cetavlon (Zeneca) Xylonor (0gna)-comb. Cetavlon (Sumitorno Chem.) Cetrorelix (SB-75; D-20761) ATC: HOlCC02 Use: LHRH-antagonist RN: 120287-85-6 MF: C,,H,,ClN,,O,, MW: 143 1 .O6 CN: N-Acetyl-3-(2-naphthalenyl)-~-alanyl-4-choro-~-phenyaanyl-3-(3-pyridinyl)-~-alanyl-~-seryl-~- tyrosyl-~-(aminocarbonyl)-~-ornithyl-~-leucyl-~-arginy~-~-prolyl-~-alaninamide Cetrorelix C 419 acetate RN: 145672-81-7 MF: C70Hy2ClN,7014 . xC2H402 MW: unspecified diacetate RN: 130143-01-0 MF: C70Hy2ClN,70,4~2C2H402 MW: 1551.17 trifluoroacetate RN: 130289-71-3 MF: C70Hy2ClN17014 . C2HF,0, MW: 1545.09 pamoate RN: 132741 -85-6 MF: C70Hy2ClN170,4 . C2,H,,0, MW: 1819.44 @ solid-phom synthesis: 0-(p-C1)Phe 0-Pol Ssr TY~ 0-Cit Leu Pro 0-Ala Cit: Pal: Nal: (p-CI)Phe: Boc: BZL: 2-Br-2: Ac: Tos: LBZL '- Boc OH H- 7p BZL BZL citrulline (N~-~arbamo~lornithine) 3-pyridylalanine 2-naphthylalanine 4-chlarophenylolonine tert-butoxycarbonyl benzyl 2-bromabenzyloxycarbonyl acetyl tosyl Bos NH-R Boc NH-R NH-A ,2-Br-Z ,2-Br-Z .2-Br-Z NH-R ,2-Br-Z NH-R ,2-Br-2 I I v I I NH-R ,2-Br-Z To* , NH-R ,2-Br-Z To* NH-R NH2 polystyrene- divinylbenzene CH3 (MBHA-resin) After cleovoge from the resin the crude peptide is dissolved in aqueous acetic acid and purified via prep. HPLC. 420 C Cetrorelix Cetrorelix @ clossicol, liquid-phose synthesis: Cetrorelix u obbreviotions see method a Reference(s): a Bajusz, S. et al.: Int J. Pept. Protein Res. (IJPPC3) 32,425 (1988). EP 299 402 (ASTA Medica; appl. 11.7.1988; USA-prior. 17.7.1987). a,b Kleemann, A. et al.: Proc. Akabori Conf.: Ger Jpn. Symp. Pept. Chem., 4th, 1991,96-101. b Kunz, F.R. et al.: Proc. Akabori Conf.: Ger Jpn. Symp. Pept. Chem., Sth, 1994, 15-16. long-acting injection suspension with pamoate salt: US 773 032 (ASTA Medica; 10.6.1996; ~-~rior. 9.12.1993). sterile acetate formulation: EP 61 1 572 (ASTA Medica; D-prior. 19.2.1993). use in fertility control: EP 788 799 (ASTA Medica; USA-prior. 7.2.1996). use for BPH or prostate cancer: WO 9 810 781 (ASTA Medica; USA-prior. 12.9.1996). Formulation(s): vial 0.25 mg, 3 mg (as acetate) . 143 1 .O6 CN: N-Acetyl- 3-( 2-naphthalenyl )-~ -alanyl-4-choro-~-phenyaanyl- 3-( 3-pyridinyl )-~ -alanyl-~-seryl- ~- tyrosyl- ~-( aminocarbonyl )-~ -ornithyl-~-leucyl-~-arginy ~-~ -prolyl-~-alaninamide Cetrorelix. 1765 0-9 8-5 MF: C5RH73N1302LS2 MW: 1352 .42 LD,,: 1012 mgkg (M, i.v.) CN: 5-oxo-~-prolyl-~-glutaminyl-~-a-asparty-O-sulfo-~-tyrosyl-~-threonylglycyl-~-tryptophyl-~-methionyl- L-a-aspartyl-L-pheny. NH-R Boc NH-R NH-A ,2-Br-Z ,2-Br-Z .2-Br-Z NH-R ,2-Br-Z NH-R ,2-Br-2 I I v I I NH-R ,2-Br-Z To* , NH-R ,2-Br-Z To* NH-R NH2 polystyrene- divinylbenzene CH3 (MBHA-resin)