Pharmaceutical Substances Syntheses, Patents, Applications - Part 53 ppt

Clomocycline C 521 FH3 H~~N\ + COCI, , C"3 CI 3-d~methylom~no- 0 CI 1 -propano1 3-chloro-10.11 -di- phosgene hydro-5H-dibenz- [b,f]azepine (I) I Clomipramine cl-N\ CH3 I b 1. sodium omide 2. 3-dimethylamino- propyl chloride Reference (s). US 3 515 785 (Geigy; 2.6.1970; CH-prior. 6.12.1958; 12.1.1959). DE 1 161 278 (Geigy; appl. 5.12.1959; CH-prior. 6.12.1958, 12.1.1959). CH 371 799 (Geigy; appl. 6.12.1958). Craig, P.N. et al.: J. Org. Chem. (JOCEAH) 26, 135 (1961). starting material: DE 1 166 200 (Geigy; appl. 1959; CH-prior. 1958, 1959). US 3 056 774 (Geigy; 1962; CH-prior. 1958). US 3 056 776 (Geigy; 1962; CH-prior. 1959). Formulation(s): amp. 25 mg/2 ml; drg. 25 mg; f. c. tabl. 10 mg, 25 mg; s. r. tabl. 75 mg Trade Name(& D: Anafranil (Novartis) F: Anafranil (Novartis) J: Anafranil (Fujisawa) Hydiphen (ASTA Medica GB: Anafranil (Novartis) USA: Anafranil (Novartis; as AWD) I: Anafranil (Geigy) hydrochloride) Clomocycline (Chlormethylencycline; Clomociclina) ATC: JOIAAII Use: antibiotic RN: 1181-54-0 MF: C2,H,,C1N,0, MW. 508.91 LD,,: 115mg/kg(M,i.v.); 2830mglkg(M,p.o.) CN: [4S-(4a,4aa,5aa,6W 2aa)]-7-chloro-4-(dimeihylamino)-l,4,4a,5,5a,6,11 ,I 2a-octahydro-3,6,10,12,12a- pentahydroxy-N-(hydroxymethyl)-6-methyl-1,11-dioxo-2-naphthacenecarboxamide sodium salt RN: 68-20-2 MF: C,3H,CIN2Na09 MW: 530.89 522 C Clonazepam chlortetracycline hydrochloride Reference(s): BE 628 142 (Leo Ind. Chim. Farm. S.p.A.; appl. 7.2.1963). form- Formulation(s): cps. 170 mg (as sodium salt) Clornocycline Trade Name(s): GB: Megaclor (Pharmax); wfm I: Megaclor (Pharmax); wfm aldehyde Clonazepam ATC: N03AEOI Use: anticonvulsant RN: 1622-6 1-3 MF: C15HloC1N,03 MW: 3 15.72 EINECS: 21 6-596-2 CN: 5-(2-chloropheny1)- 1,3-dihydro-7-nitro-2H- l,4-benzodiazepin-2-one H Hz, Raney-Ni ":-Ic, 'XBr %rBr b A / brornoacetyl / \ \ brorn~de \ 2-chloro-2'- 2-amino-2'- (1) n~trobenzo- chlorobenzo- phenone phenone liq NH3 NVNH~ pyridine KNOJ, H2S0, I F ___* -N + / \ Cl \ - - phenyl)-2-oxo- j 2.3-dihydro- 1 H-1,4-benzo- diozepine Refe rence(s): Sternbach, L.H. et al.: J. Med. Chem. (JMCMAR) 6,261 (1963). US 3 116 203 (Hoffmann-La Roche; 31.12.1963; prior. 14.3.1962). US 3 123 529 (Hoffmann-La Roche; 3.3.1964; prior. 9.3.1962). US 3 121 1 14 (Roche; 1 1.2.1964; CH-prior. 2.12.1960). US 3 203 990 (Roche; 31.8.1965; prior. 27.6.1960,20.4.1961, 21.3.1962). US 3 335 181 (Roche; 8.8.1967; appl. 17.4.1964). Fonnulation(s): amp. 1 mglml; sol. 2.5 mg/ml; tabl. 0.25 mg, 0.5 mg, 1 mg, 2 mg C Clonidine C 523 Trade Name(s): D: Antalepsin (ASTA Medica F: Rivotril (Roche) USA: Klonopin (Koche Labs.) AWD) GB: Rivotril (Roche) Rivotril (Roche) I: Rivotril (Roche) Clonidine ATC: C02ACOI; N02CX02; SOIEA04 Use: antihypertensive RN: 4205-90-7 MF: CYHyCl2N, MW: 230.10 EINECS: 224-1 19-4 CN: N-(2,6-dichloropheny1)-4,s-dihydro- 1 H-imidazol-2-amine monohydrochloride RN: 4205-91-8 MF: CYHyCl2N, . HC1 MW: 266.56 EINECS: 224-121-5 LD,,: 17.6 mglkg (M, i.v.); 135 mg/kg (M, p.0.); 29 mglkg (R, i.v.); 126 mg/kg (R, p.0.); 6 mag (dog, i.v.); 30 mg/kg (dog, p.0.) C I H,C-I ~~'5 + NH; SCN - H~NYN~ 4 methyl ''Y'd . CI CI S \ iodide '3'' 2,S-dichloro- ammonium N-(2.6-di- aniline rhodanide chloropheny1)- thiourea ethylene- Clonidine diamine Reference(s): DE 1303 141 (Boehringer Ing.; appl. 9.10.1961). US 3 202 660 (Boehringer Ing.; 24.8.1965; D-prior. 9.10.1961). US 3 236 857 (Boehringer Ing.; 22.2.1966; D-prior. 9.10.1961,4.10.1963). BE 653 933 (Boehringer Ing.; appl. 2.10.1964; D-prior. 4.10.1963; 3 I .7.1964). GB 1 016 514 (Boehringer Ing.; appl. 2.10.1962; D-prior. 9.10.1961). GB 1 034 938 (Boehringer Ing.; appl. 28.9.1964; D-prior. 4.10.1963; addition to GB 1 016 514). alternative syntheses: DAS 1 770 874 (VEB Arzneimittelwerke Dresden; appl. 12.7.1968). DAS 2 505 297 (Lentia; appl. 7.2.1975; A-prior. 5.4.1974). Forrnulation(s): eye drops 0.625 mglml, 1.25 mglml; inj. sol. 0.15 mgll ml, 0.75 mglml; s. r. cps. 0.25 mg; , tabl. 0.075 mg, 0.15 mg, 0.3 mg Trade Name(s): D: Aruclonin (Chauvin ankerpharm) Catapresan (Boehringer Ing.) Combipresan (Boehringer 1ng.)-comb. Dispaclonidin (CIBA Vision) Dixarit (Boehringer Ing.) F: Catapressan (Boehringer Haemiton (ASTA Medica Ing.) AWD) GB: Catapres (Boehringer Ing.) Haemiton (ASTA Medica Dixarit (Boehringer Ing.) AWD)-comb. I: Adesipress (Carlo Erba) Isoglaucon (Alcon) Catapresan (Boehringer Mirfat (Merckle) 1ng.)-comb. Paracefan (Boehringer lng.) 524 C Clopamide Combipresan (Boehringer Isoglaucon (Boehringer J: Catapres (Tanabe) Ing.) Ing.; as hydrochloride) USA: Catapres (Boehringer Ing.) ; Clopamide ATC: C03BA03 Use: diuretic RN: 636-54-4 MF: C,,H,,CIN303S MW: 345.85 EINECS: 211-261-7 CN: cis-3-(aminosulfonyl)-4-chloro-N-(2,6-dimethyl-l-piperidinyl)benzamide COOH ClS03H QCooH Nt13 qCooH + CI CI chlorosul- O=SZ0 o=S=o i - o=s=o NH2 chloride I -NH, fonic acid CI 4-chlorobenzoic acid 1 -amino-cis- 2.6-dimethyl- piperidine acid H CH, CI Clopamide Jucker, E.; Lindenmann, A.: Helv. Chim. Acta (HCACAV) 45,2316 (1962). CH 412 891 (Sandoz; appl. 6.6.1961; addition to CH 396 905). CH 396 905 (Sandoz; appl. 9.11.1960). CH 436 288 (Sandoz; appl. 11.6.1963). combination with dihydroergocristine and reserpine: US 3 567 828 (Sandoz; 2.3.1971; appl. 12.8.1968; CH-prior. 17.8.1967). DAS 1 792 271 (Sandoz; appl. 13.8.1968; CH-prior. 17.8.1967). Formulation(s): drg. 2.5 mg, 5 mg (comb. with reserpine); tabl. 20 mg Trade Name(s): D: Brinaldix (Novartis Viskaldix (Novartis I: Brinerdina (Sandoz)-comb. Pharma) Pharma)-comb. USA: Brinaldix (Sandoz); wfm Briseridmite (Novartis F: Viskaldix (Sandoz)-comb. Pharma)-comb. GB: Viskaldix (Novartis)-comb. Clopenthixol ATC: N05AF02 Use: neuroleptic RN: 982-24-1 MF: C22H2sCIN20S MW: 400.97 EINECS: 213-566-0 LD,,: 226 mglkg (M, i.p.) CN: 4-[3-(2-chloro-9H-thioxanthen-9-ylidene)propyl]-l-piperazineethmol F Cloperastine C 525 dihydrochloride RN: 633-59-0 Ml? C22H2sClN20S . 2HCl MW: 473.90 EINECS: 21 1-194-3 LD,,: 11 1 mfig (M, i.v.); 560 mglkg (M, p.0.); 125 mglkg (R, i.v.); 660 mglkg (R, p.0.) FH3 130 "C, 48h PN-OH , &" + HN~ I '/ chlwprothixen 1 -(2-hydroxyethy1)- piperazine Clopenthixol Reference(s): US 3 116 291 (Kefalas; 31.12.1963; DK-prior. 4.12.1958). DE 1 231 254 (Kefalas; appl. 1960; DK-prior. 1959). US 3 149 103 (Kefalas A/s; 15.9.1964; ~~-~rior. 14.7.1 959). GB 932 494 (Kefalas; appl. 3.12.1959; DK-prior; 4.12.1958, 14.8.1 959). alternative syntheses: DE 1 443 983 (Roche; appl. 16.1.1962; CH-prior. 8.2.1961, 30.3.1961). DE 1 795 506 (Kefalas; appl. 3.12.1959; DK-prior. 4.12.1958, 14.8.1959). DOS 1 918 739 (Egyesiilt; appl. 12.4.1969; H-prior. l2.4,1968). separation of isomers: DAS 2 429 101 (Kefalas; appl. 18.6.1974; GB-prior. 25.6.1973). Formula~ion(s): amp. 10 mglml, 25 mglml; drg. 10 mg, 25 mg; tabl. 25 mg (as dihydrochloride) Trade Name(s): D: Ciatyl (Bayer Vital) GB: Clopixol (Lundbeck) I: Sordinol (Pierrel) Cloperastine ATC: R05DB21 Use: antitussive RN: 3703-76-2 MF: C,,HxCINO MW: 329.87 EINECS: 223-042-3 LD,,: 439 mgkg (g.p., route unreported) CN: 1-[2-[(4-chlorophenyl)phenylmethoxy]ethyl]piperidine I 1. sodium amide OH 2. 1 -(2-ch1oroethyl)- 4-chloro- piperidine poperastinfl benzhydrol Reference(s): GB 670 622 (Parke Davis; appl. 1948; CH-prior. 1947). sall wifh 2-[(6-hydroxy[ 1 ,l'-biphenyl]-3-yl)carbonyI]benzoic acid: GB 1 179 945 (Yoshitomi; appl. 7.7.1967; J-prior. 7.7.1966; 16.8.1966, 15.1 1.1966 and 1.3.1967). Formulalion(s): syrup 0.2 %; tabl. 5 mg, 10 mg, 20 mg 526 C Clopidogrel hydrogensulfate Trade Name(s): I: Nitossil (Zyma) Seki (Astra-Simes) Risoltuss (Magis) J: Hustazol (Yoshitomi) Clopidogrel hydrogensulfate (SR-25990C) ATC: BOIAC04 Use: platelet anti-aggregatory RN: 120202-66-6 MF: C,,HI6ClNO2S H2S04 MW: 419.91 CN: (S) ol-(2-Chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetic acid methyl ester sulfate (1:l) (f )-base RN: 90055-48-4 MF: CI6HI6ClNO2S MW: 321.83 (+)-base RN: 113665-84-2 MF: Cl6HI6ClNO2S MW: 321.83 o-chloro- benzoldehyde 5-(2-chloro- (+)-2-(2-chloro- pheny1)- phenyl)glycine (I) irnidozolidine- 2.4-dione optical resolution with goseous HCI O'CH, (+)-tartaric acid I + H,C-OH _______, CI C I (2)-2-(2-chloro- (+)-2-(2-chloro- pheny1)glycine pheny1)glycine methyl ester ((f)-11) methyl ester ((+)-I]) 1. optical resolution with (+)-10-comphorsulfonic acid 2. H3C-OH, gaseous HCI I b (+)-I1 111 (cf. ticlopidine) I. aq. (HCH0)n (V) , HCOOH or Oq. HCHO. DMF, gaseous HCI 2. H2S04 IV b (+)-2-(2-chloropheny1)- N-[2-(2-thienyl)ethyI]- glycine methyl ester (N) O~O\CH, gyp . H2S04 Clopidogrel hydrogensulfate Clopidogrel hydrogcnsulfate C 527 " alternative route 1, (?)-E 2 optical resolution with (+)-10-comphor;ulfon~c acld 3 (HCHO), (V) /HCOOH 4 H2S0, nl + Clap~dagrel hydrogensulfote Z-thiophene- mrboxoldehyde 2-thienyl- ocetoldehyde (VI) 1. H,N-OH ' HCI 1. (HCHO). (V), 70°C 2-(2-thieny1)- ethylornine 1. CI 2. opticol resolution with 10-cornphorsulfonic acid 3.H2S04, H20 M Clopidogrel hydrogensulfote 1. methyl chloro(2-chlorophenyI)ocetate Reference(s): a EP 99 802 (Sanofi; appl. 5.7.1983; F-prior. 13.7.1982). optical resolution of (*)-clopidogre1 with (+)-10-camphorsulfonic acid: EP281 459 (Elf Sanofi; appl. 16.2.1988; F-prior. 17.2.1987). b EP465 358 (Sanofi; appl. 3.7.1991; F-prior. 4.7.1990). alremative route for preparing 2-tlti~nylethylamine derivativesfiom thienylglycidic acid derivatives: WO 9 839 322 (Sanofi; appl. 5.3.1998; F-prior. 5.3.1997). pharmaceutical compositions: WO 9 729 753 (Sanofi; appl. 17.2.1997; F-prior. 19.2.1996). W09 717 064 (Sanofi; appl. 30.10.1996; F-prior. 3.1 1.1995). synthesis of optical pure (2-ch1orophenyl)glycine: Garcia, M.J.; Azerad, R: Tetrahedron: Asymmetry (TASYE3) 8 (I), 85 (1997) synthesis of (2-chlorophenyl)glycine: Hayashi: Chem. Pharm. Bull. (CPBTAL) 7, 912, 1914 (1959). Kobow, M.; Sprung, W D.; Schulz, E.: Pharmazie (PHARAT) 45 (7), 529 (1990). 528 C Cloprednol Formulation(s): f. c. tabl. 75 mg (as hydrogen sulfate) Trade Name(s): D: Iscover (Bristol-Myers Plavix (Sanofi-Synthelabo; USA: Plavix (Sanofi Pharm; Squibb) 1988) Bristol-Myers Squibb; GB: Plavix (Sanofi Winthrop) 1998) Cloprednol ATC: H02AB14 Use: glucocorticoid RN: 5251-34-3 MF: C,,H,,CIO, MW: 392.88 EINECS: 226-052-6 CN: (1 1 P)-6-chloro-1 l ,l7,21-trihydroxypregna- 1.4.6-triene-3,20-dione hydrocortisone (4. v.) perbenzoic ocid HCI d O HO 1. NaOH 2. CH,COOH ___, Ga-chloro- hydrocorlisone (11) cloprednol I Cloprednol I Reference(s): US 3 232 965 (Syntex; 1.2.1966; prior. 8.7.1957, 20.6.1958). GB 890 835 (Syntex; appl. 20.6.1958; Mex prior. 22.6.1957, 20.7.1957). Cloral betaine C 529 alternative synthesis: US 3 264 332 (Schering Corp.; 2.8.1966; prior. 7.1.1959). Fomulation(s): tabl. 2.5 mg, 5 mg, 10 mg Tmde Name(s): D: Syntestan (Syntex/Roche) I: Cloradryn (Recordati) Cloral betaine (Betainchloralum; Chloral Betaine) ATC: N05C Use: hypnotic, sedative RN: LDso: CN: 2218-68-0 MF: C2H3CI3O2 MW: 165.40 EINECS: 218-722-1 800 mgkg (M, p.0.) 1-carboxy-N,N, N-trimethylmethanaminium inner salt compd, with 2,2,2-trichloro-1.1 -ethanediol (1 :I ) OH H3C\ PCOOH CI$~ + N + OH OH- H,C' 'CH, Referencefs): US 3 028 420 (British Drug Houses; 3.4.1962). GB 874 246 (British Drug Houses; appl. 26.6.1959; valid from 27.5.1960). chloral hydrate betaine hydrate Trade Name(s): USA: Beta-Chlor (Mead Johnson); wfrn Clorol betoine Quinamm (Merrell- National); wfm Quinine sulfate (Perepac); wfm Clorexolone ATC: C03BA12 Use: diuretic RN: 2127-01-7 MF: CI,H,,C1N203S MW: 328.82 EINECS: 218-342-6 LD50: 230 mg/kg (M, i.v.); >6 glkg (M, p.0.); 120 mg/kg (R, i.v.); 6 gkg (R, p.0.) CN: 6-chloro-2-cyclohexy1-2,3-dihydro-3-oxo-lH-isoindole-5-sulfonamide HCI. NoBH,, GIG:,, + H2Na c~"2 la:^ C1ma sodium 0 0 boro- 0 4-chloro- cyclohexyl- 4-chloro-N- hydride 5-chloro-2- phthalimide amine cyclohexyl- cyclohexy- phthalimide soindolinone (1) 530 C Cloricromen 1. NoN02. HCI CI, - I I Clorexolone I Reference(s): BE 620 654 (May & Baker; appl. 25.7.1962; GB-prior. 28.7.1961). Formulation(s): tabl. 10 mg, 25 mg Trade Name(s): F: Flonatril (Specia); wfm GB: Nefrolan (May & Baker); Speciatensol (Seecia)- wfm comb.; wfm J: Nefrolan (Teikoku Zoki) Cloricromen ATC: BOlAC02; CO1 (AD-6) Use: c oronary vasodilator, antithrombotic RN: 68206-94-0 MF: C2,H2,C1NOS MW: 395.88 LD,,,: 10 mglkg (R, i.v.); 1250 mglkg (R, p.0.) CN: [[8-chloro-3-[2-(diethylamino)ethyl]-4-methy1-2-oxo-2H-1-benzopyran-7-yl]oxy]acetic acid ethyl ester hydrochloride RN: 74697-28-2 MF: C20H26C1NOs. HCI MW: 432.34 ethyl ocetoocetote 2-diethylomino- ethyl chloride ethyl 2-(2-diethyl- ominoethyl)oceto- ocetote (1) I + Ho&oH H3C p-toluenesullonic acid, polyphosphoric acid , 2-chloro- 8-chloro-3-(2-diethyl- resorcinol aminoethy1)-4-methyl- 7-hydroxycoumorin (11) 0 I1 + __* ethyl chloroacetote Cloricromen . anticonvulsant RN: 162 2-6 1-3 MF: C15HloC1N,03 MW: 3 15.72 EINECS: 21 6-5 9 6-2 CN: 5-( 2-chloropheny1 )- 1,3-dihydro-7-nitro-2H- l,4-benzodiazepin-2-one H Hz, Raney-Ni ":-Ic, 'XBr %rBr. 2-chloro-2&apos ;- 2-amino-2&apos ;- (1) n~trobenzo- chlorobenzo- phenone phenone liq NH3 NVNH~ pyridine KNOJ, H2S0, I F ___* -N + / Cl - - phenyl )-2 -oxo- j 2.3-dihydro-. antihypertensive RN: 420 5-9 0-7 MF: CYHyCl2N, MW: 230.10 EINECS: 22 4-1 1 9-4 CN: N-(2,6-dichloropheny1 )-4 ,s-dihydro- 1 H-imidazol-2-amine monohydrochloride RN: 420 5-9 1-8 MF: CYHyCl2N, . HC1