Pharmaceutical Substances Syntheses, Patents, Applications - Part 68 ppsx

Dinoprost D 671 KOH. CuBF4 OMSO -1 0 hc! C N 2,4-cyclopenta- 2-chloro- dienylrnethyl ocrylonitr~le 1 I benzyl ether 1. H20. H+ 2. resolution with (+)-ephedrine - 11 1. NaOH HOOCh 1. (C4H&SnH. NBN 2. Hz. Pd-C , 111 OH 1 tr~butylstannone chloride 1. Collins' reagent :o 2. dimethyl 2-oxoheptylphosphonate sodium salt. dimethoxyethone (-)-Corey lactone (111) 1. reagent from limonen and thexylborane. tert-butyllithium 672 D Dinoprost HO OH 2. diisobutylolurninurn hydride ('4 ' No+ 1. -cHZ/S\cH3 9'2,- 2. CH,COOH. H,, THF 1. dirnethylsulfoxide sodium salt 5-triphenylphosphonio- pentonecorboxylote Dinoprost Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 91,5675 (1969). Corey, E.J. et a].: J. Am. Chem. Soc. (JACSAT) 92, 397 (1970). Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 92,2586 (1970). Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 93, 1491 (1971). alternative syntheses: Fried, J. et al.: J. Am. Chem. Soc. (JACSAT) 94,4342,4343 (1972). Corey, E.J. et a].: Tetrahedron Lett. (TELEAY) 1970,307. Bundy, G.L. et al.: J. Am. Chem. Soc. (JACSAT) 94,2123 (1972). Corey, E.J.; Varma, R.K.: J. Am. Chem. Soc. (JACSAT) 93,73 19 (1971). Schneider, W.P.; Murray, H.C.: J. Org. Chem. (JOCEAH) 38,397 (1973). Tanouchi, T. et al.: Chem. Lett. (CMLTAG) 1976,739. NL 6 505 799 (Unilever; 6.5.1965). DOS 2 145 125 (Upjohn; 9.9.1971 ; USA-prior. 11.9.1970, 2.7.1971). DOS 2 328 13 1 (Schering AG; 30.5.1973). US 3 933 892 (Hoffmann-La Roche; 20.1.1976; prior. 18.1.1974, 12.2.1973). isolation: GB 1 040 544 (Karolinska Inst.ivalid from 21.2.1963; prior. 19.3.1962). racemic prostaglandin Fla: US 3 933 891 (Upjohn; 20.1.1976; prior. 8.7.1974, 3.10.1973, 17.6.1975, 2.7.1971, 11.11.1970). US 3 987 083 (Upjohn; 19.10.1976; prior. 6.12.1974, 14.3.1969). US 3 983 155 (Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969). US 3 983 154 (Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969). US 3 983 153 (Upjohn; 28.9.1976; prior. 6.12.1974, 14.3.1969). US 3 981 880 (Upjohn; 21.9.1976; prior. 6.12.1974, 14.3.1969). US 3 980 69 1 (Upjohn; 14.9.1976; prior. 6.12.1974, 14.3.1969). US 3 959 346 (Upjohn; 25.5.1976; prior. 6.12.1974, 14.3.1969). tron~etharnine salt: US 3 657 327 (Upjohn; 18.4.1972; prior. 1.6.1970). rise for control of conception cyclus: DOS 1 943 492 (Upjohn; appl. 27.8.1969; USA-prior. 29.8.1968). review: Prostaglandin Research (Ed. P. CrabbC) p. 1, 121 New York, San Francisco, London 1977. Dinoprostone D 673 Formulation(s): amp. 5 mglml Trade Name(s): D: Minprostin F2, (Pharmacia I: Prostin F2, (Upjohn); wfm Prostarmon-F (Ono) & Upjohn) J: Glandinon (Mochida) Zinoprost (Ono) F: Prostine F,, (Pharmacia & Penacelan-F (Glaxo-Fuji) USA: Prostin F,, (Upjohn); wfm Upjohn SA) Pronalgon (Upjohn) GB: Prostin F2 (Pharmacia & Prosmon (Fuji) Upjohn) Pros tamodin (Kanebo) Dinoprostone (Prostaglandin E,) ATC: G02AD02 Use: oxytocic, abortifacient RN: 363-24-6 MF: C20H320s MW: 352.47 EINECS: 206-656-6 LD,: 23.2 mglkg (M, i.v.); 750 mgkg (M, p.0.); 59.5 mglkg (R, i.v.); 500 mglkg (R, p.0.) CN: (5Z,l la,13E,15S)-11,15-dihydroxy-9-oxoprosta-5,13-dien-l-oic acid 1. Jones ox~dot~on (Cr03, H2SO4. acetone. -1 0 OC) 2. CH3COOH, H20 b 3 6 0 OH 1. chrorniurn(Vl) oxide Y 'I pmsloglondin Fq 9.1 1 -bis (tetrahydropyranyl ether) (cf. dinoprost synthesis) I Dinoprostone Reference(s j: Corey, E.J. et al.: J. Am. Chem. Soc. (JACSAT) 92, 397 (1970). alternative syntheses: US 3 948 981 (Upjohn; 6.4.1976; prior. 18.12.1974, 3.10.1973,2.7.1971, 11.9.1970). Schneider, W.P. et al.: J. Chem. Soc., Chem. Commun. (JCCCAT) 1973, 254. Heather, J.B. et a].: Tetrahedron Lett. (TELEAY) 1973, 231 3. isolation: GB 1 040 544 (Karlinska Inst.; valid from 21.2.1963; prior. 29.3.1962). further literature: cf. dinoprost synthesis medical use as broncholytic: ZA 681 055 (American Home Products; appl. 31.1.1968; USA-prior. 20.2.1967). review: Prostaglandin Research (Ed. P. CrabbC) p. 1, 121, New York, San Francisco, London 1977. Formulation(sj: amp. 0.5 gI0.5 ml, 0.75 mg10.75 ml; rectangular tabl. 0.5 mg; syringe with gel 0.5 mg; vaginal gel 0.5 mg13 g, 1 mgI3 g, 2 mgI3 g; vaginal tabl. 3 mg Trade Name(s): D: Minprostin E2 (Pharmacia F: PrCpidil gel (Pharmacia & GB: Prepidil (Pharmacia & & Upjohn) Upjohn SA) Upjohn) Prepidil Gel (Pharmacia & Prostine E, (Pharmacia & Propress RS (Ferring) Upjohn) Upjohn SA) 674 D Diodone \ 3 Prostm E2 (Pharmac~a & J: Prostadiel-E (Taiyo) Prepidll (Pharmacia & Up~ohn) Prostaglandin E, (Kaken) Upjohn) f I: Prepidil gel (Upjohn) Prostarmon-E (Ono) Prostin E, (Pharmacia & Prostin E, (Upjohn) USA: Cervid~l (Forest) UPJO~~) : Diodone ATC: ~08~~10 (Jodopyracet) Use: X-ray contrast medium RN: 101 -29-1 MF: C7H512N03 MW: 404.93 EINECS: 202-932-5 CN: 3,5-diiodo-4-0x0-l(4H)-pyridineacetic acid meglumine salt RN: 3736-90-1 MF: C7Hs12N03. C7H17N05 MW: 600.14 LD,,,: 5900 mgkg (R, i.v.) diethanolamine salt (1:l) RN: 300-37-8 MF: C7H,12N0, . C4HIlNO2 MW: 510.07 EINECS: 206-089-4 \ LD,,,: 6400 mgkg (M, i.v.); 5400 mgkg (R, i.v.) morpholine salt (1:l) RN: 3737-08-4 MF: C,Hs12N0,. C4H,N0 MW: 492.05 ClvCOOH " j50 OC, 0 I+ ,f& NaOH _____, lodlne I chlamocetic chloride CI- 0 mono- 0 acid chloride pyridine 1 -(4-pyridy1)- 4(1H)- $5-diiado- pyridinium pyridonc 4(1H)-pyddone chloride Reft'rence(s): DRP 554 702 (E. Koenigs, H. Greiner; 1929). DRP 579 224 (1. G. Farben; 1930). US 1 993 039 (I. G. Farben; 1935; D-prior. 1931). GB 517 382 (ICI; appl. 1938). Formulation(s): amp. 35 %, 50 %, 70 % Trade Name(s): D: Broncho-Abrodil GB: Umbradil (Astra)-comb.; I: Joduron (Bracco); wfm (Schering); wfm wfm J: Pyraceton (Daiichi) Diosmin ATC: C05CA03 Use: antihemorrhagic, vein tonic RN: 520-27-4 MF: C2,H,,OI5 MW: 608.55 EINECS: 208-289-7 CN: 7-[[6-O-(6-deoxy-a-~-mannopyranosyl)-~-~-glucopyranosyl]oxy]-5-hydroxy-2-(3-hydroxy-4- methoxypheny1)-4H-1 -benzopyran-4-one Reference(s): Zemplkn, G.; BognAr, R.: Ber. Dtsch. Chem. Ges. (BDCGAS) 76,452 (1943). Lorette, N.B. et al.: J. Org. Chem. (JOCEAH) 16,930 (1951). Horowitz, R.M.: J. Org. Chem. (JOCEAH) 21, 1184 (1956). S 2602 314 (Hommel; appl. 22.1.1976; CH-prior. 16.5.1975). Fonnulation(s): cps. 300 mg; cream 4 g/100 g; tabl. 150 mg Endium (Labs. Europhta) Daflon (Servier) Flebosmil (Socopharm) Diosven (CT) F: Daflon (Servier) Litosrnil (Evans Medical) Doven (Prophin) Dio (Labs. Scienex) MCdiveine (ElertC) Venosmine (Geymonat) Diosmil (RhBne-Poulenc Preparation H Veinotonic (Whitehall) Diovenor (InnothCra) I: Arvenum (Strqder) ATC: D04AB Use: local anesthetic RN: 101-08-6 MF: CzZHz7N3O4 MW: 397.48 EINECS: 202-913-1 CN: 3-(1-piperidiny1)-l,2-propanediol bis(pheny1carbamate) (cster) monohydrochloride RN: 537-12-2 MF: CZ2H2,N3O4 . HC1 MW: 433.94 EINECS: 208-659-8 LD,: 890 mglkg (M, s.c.) OCN phenyl isocyanate N-(2,J-dihydroxy- Diperodon propyl)pipendine US 2 004 132 0: H. Rider; 1935; prior. 1931). Fonnulation(s): ointment (comb.) Rider, T.H.: J. Am. Chem. Soc. (JACSAT) 52, 1528, 21 15 (1930). 676 D Diphemanil metilsulfate Trade Narnefs): USA: Diothane (Merrell); wfm Prnctodon (Rowell); wfm Diphemanil metilsulfate ATC: D11AA Use: anticholinergic, antispasmodic RN: 62-97-5 MF: C2,,HxN . CH4O3S MW: 374.53 EINECS: 200-552-4 LD,,,: 4012 pglkg (M, i.v.); 3 17 mglkg (M, p.0.); 5 mg/kg (R, i.v.); 1107 mglkg (R, p.0.) CN: 4-diphenylmethylene-1,l-dimethylpiperidinium methyl sulfate 4-benzoyl- phenylmognesiurn I -methyl- ' bromide (I) piperidine H3C, ,CH3 0 /? 111 + H~C' ),s,~,cH, + 0 dimethyl sulfate (1V) Diphernonil rnetilsulfote ethyl 4-pyridyl- isonicotinate diphenyl- corbinol H . PtO IV V 2b 11 . 111 - 1 Diphernonil rnetilsulfote 1 Reference(s): US 2 739 968 (Schering Corp.; 1956; prior, 1951). Fornulation(s): cream 2 %; tabl. 50 mg, 100 mg Trade Nanre(s): F: ~rantal (CCtrane); wfm I: Prantal (Schering-Plough) Diphenadione D 677 J: Prantal (Schering- USA: Prantal (Schering); wfm Shionogi) Diphenadione ATC: BOlAAlO Use: anticoagulant, rodenticide RN: 82-66-6 MF: C23Hlh03 MW: 340.38 EINECS: 201-434-5 LD,,: 28.3 mgkg (M, pa); 1500 p@g (R, p.0.); 3 mglkg (dog, p.0.) CN: 2-(diphenylacety1)-1 H-indene- 1,3(2H)-dione dimethyl phtholate 1,l -diphenyl- acetone 2. diphenylacetyi chloride Referencers): US 2 672 483 (Upjohn; 1954; prior. 1951) 1 Fonnulafion(s): tabl. 20 mg, 50 mg 1 Trade Narne(s): USA: Dipaxin (Upjohn); wfm Diphenadione u Oiphenodione 1 Diphenhydramine 1 ATC: D04AA32; R06AA02 Use: antihistaminic, anti-emetic, sedative, antitussive B % RN: 58-73-1 MF: CI7H2,NO MW: 255.36 EINECS: 200-396-7 1 LD,: 29mgkg(M,i.v.);l6Omgkg(M,p.o.); 42 mgkg (R, i.v.); 390 mglkg (R, p.0.) t CN: 2-(dipheny1methoxy)-N,N-dimethylethanamine k hydrochloride RN: 147-24-0 MF: C17H2,N0. HCI MW: 291.82 EINECS: 205-687-2 LD,,: 20 mgkg (M, i.v.); 64 mglkg (M, p.0.); 35 mgkg (R, i.v.); 500 mglkg (R, p.0.); 24 mgkg (dog, i.v.) 678 D Diphenhydramine 3 benzhydryl Z-dimethylamina- bromide ethanol Reference(s): US 2 421 71 4 (Parke Davis & Co.; 1947; prior. 1944). US 2 427 878 (Parke Davis; 1947; appl. 1947). Diphenhydramine alternative synthesis: US 2 397 799 (Geigy; 1946; CH-prior. 1942). Formulation(s): drops 12.5 mg; s. r. cps. 30 mg; suppos. 10 mg, 20 mg, 50 mg; syrup 2.67 mglml, 12.5 mglrnl; tabl. 25 mg, 50 mg (as hydrochloride) Trade Name(s): D: Anaestecomp (Ritsert)- comb. Benadryl (Warner- Lambert) Betadorm (Woelm)-comb. Dibenzyl-Rhenix (Pharma Wernigerode)-comb. F: Dolestan (Whitehall-Much) Dolestan (Whitehall- Much)-comb. Dormigoa (Scheurich) Dormutil (Isis Pharma) Emesan (Lindopharm) Halbmond-Tabletten (Whitehall-Much) Hevert-Dorm (Hevert) Lupovalin (Pharma Selz) GB: Moradorm (Bouhon)-comb. nervo OPT (Optimed) Nytol (Block Drug Company) I: Palacril (Warner-Lambelt)- comb. Palmicol (RIAM) Pheramin (Kanoldt) Praesidin (Medoeharm)- comb. Reisegold (Whitehall- Much)-comb. Reisegold tabs (Whitehall- Much) J: S.8 Tabletten (Chefaro) Sediat (Pfleger) Sedopretten (Schoning- Berlin) Sedovegan (Wolff) Valeriana comb. Hevert (Hevest)-comb. Visano Cor (Kade)-comb. Actifed Jour et unit (Warner-Lambert; as hydrochloride)-comb. Butix gel (Labs. Pierre Fabre SantC; as hydrochloride) Nautamine (SynthClabo) Onctose hydrocortisone (Monot; as methyl sulfate)- comb. Medinex (Whitehall) Nytol (Stafford-Miller) 'numerous combination preparations Allergan (Bouty) Asmarectal (Serpero)- comb. Benadryl (Parke Davis)- comb. Benylin (Parke Davis)- comb. Difeni (Formulario Naz.) Fluvaleas (Valeas)-comb. combination preparations Benadin Salicylate (Kongo; as salicylate) Benadol (Taisho) USA: Benadozol (Hokuriku; as tannate) Benadozol-S (Hokunku; as salicylate) Benapon (Danippon) Benasin (Kanto) Neo-Restar (Ohta; as maleate) Restamin (Kowa) Restar (Ohta; as salicylate) Restin (Mohan; as salicylate) Reston (Kowa Yakuhin) Salibena (Fuso; as salicylate) Vena (Tanabe) Venerlon (Sanwa; as tannate) Zeresmin (Juzen- Yarnanouchi; as salicylate) Actifed (Warner-Lambert; as hydrochloride) Benadryl (Parke Davis; as hydrochloride) Dytuss (Lunsco; as hydrochloride) Maximum (Pfizer Consumer; as hydrochloride) Tylenol (McNeil; as hydrochloride) Unisom (Pfizer Consumer; as hydrochloride) generics Diphenoxylate D 679 Diphenoxylate ATC: AO~DAOI Use: antidiarrheal, antiperistaltic RN: 915-30-0 MF: C30H32N202 MW: 452.60 EINECS: 213-020-1 LD,: 337 mg/kg (M, p.0.); 221 mg/kg (R, p.0.) CN: 1-(3-cyano-3,3-diphenylpropyl)-4-phenylpiperidine-4-carboxy1ic acid ethyl ester hydrochloride RN: 3810-80-8 MF: C3,H3,N2O2. HCI MW: 489.06 EINECS: 223-287-6 LD,: 221 mg/kg (R, p.0.) 4-bromo-2.2- diphenylbutyronitrile (from diphenyiaceto- nitrile and 1,2- dibromoethane) ethyl 4-phenyl- piperidine-4- carboxylote Diphenoxylate 2 1. sodium amide 2. ethyl 1 -(2-chioroethy1)- 4-phenyl-piperidine- 4-carboxylate Reference(s): US 2 898 340 (Janssen; 4.8.1959; NL-prior. 5.7.1957). US 4 086 234 (Searle; 25.4.1978; appl. 7.1 1.1975). Fomulation(s): tabl. 2.5 mg (comb. with 0.025 mg atropine sulfate) Tmde Narne(s): D: Reasec (Janssen-Ci1ag)- GB: Lomotil (Sear1e)-comb. USA: Lomotil (Searle; as comb, with atropine sulfate Tropergen (Norgine)-comb. hydrochloride) F: Diarsed (Sanofi Winthrop; I: Reasec (Cilag)-comb. Lonox (Geneva; as as hydrochloride) hydrochloride) 680 D Diphenylpyraline Diphenylp yraline ATC: R06AA07 Use: antiallergic, antihistaminic RN: 147-20-6 MF: C,,H,,NO MW: 281.40 EINECS: 205-686-7 LD,,,: 42 mgkg (M, i.v.); 250 mgkg (M, p.0.) CN: 4-(dipheny1methoxy)-1-methylpiperidine hydrochloride RN: 132-18-3 MF: C,,H,,NO. HCl MW: 317.86 EINECS: 205-049-3 LD,,,: 52 mgkg (M, i.v.); 210 mglkg (M, p.0.); 28.8 mglkg (R, i.v.); 698 mglkg (R, p.0.) 4-hydroxy- benzhydryl 1 -methyl- bromide piperidine Diphenylpyroline (cf. piprinhydrinate) Referencers): US 2 479 843 (Nopco Chem. Comp.; 1949; prior. 1948). DE 934 890 (Promonta; appl. 1951). Formulation(s): gel 15 mglg Trade Namefs): , , D: Arbid (Bayer Vital)-comb. Perdiphen (Schwabe; spitzner)-comb. Proctospre (Hennig) Tempi1 N (Temm1er)-comb. Topoderm (gepepharm)- comb. F: Belfkne (Roger Bellon); w fm GB: Escornade Spansule (Smith Kline & French)-comb.; wfrn Histryl (Smith Kline & French); wfrn Lergoban (Riker); wfrn I: lpercron (Maggioni)- comb.; wfm Pirazone Smit (UCB- Smith); wfrn J: Plokon (Nippon Shinyaku) USA: Diafen (Riker); wfrn Hispril (Smith Kline & French); wfrn Dipivefrine ATC: SOlEA02 Use: antiglaucoma RN: 52365-63-6 MF: C,,H,,NO, MW: 351.44 CN: (+)-2,2-dimethylpropanoic acid 4-11-hydroxy-2-(methy1amino)ethyll- 1,2-phenylene ester hydrochloride RN: 64019-93-8 MF: C,,H2,NOS~ HCI MW: 387.90 . RN: 52 0-2 7-4 MF: C2,H,,OI5 MW: 608.55 EINECS: 20 8-2 8 9-7 CN: 7-[ [6-O-(6-deoxy-a-~-mannopyranosyl )-~ -~ -glucopyranosyl]oxy ]-5 -hydroxy- 2-( 3-hydroxy- 4- methoxypheny1 )-4 H-1 -benzopyran-4-one Reference(s):. (Jodopyracet) Use: X-ray contrast medium RN: 101 -2 9-1 MF: C7H512N03 MW: 404.93 EINECS: 20 2-9 3 2-5 CN: 3,5-diiodo- 4-0 x0-l(4H)-pyridineacetic acid meglumine salt RN: 373 6-9 0-1 MF: C7Hs12N03 antiperistaltic RN: 91 5-3 0-0 MF: C30H32N202 MW: 452.60 EINECS: 21 3-0 2 0-1 LD,: 337 mg/kg (M, p.0.); 221 mg/kg (R, p.0.) CN: 1-( 3-cyano-3,3-diphenylpropyl )-4 -phenylpiperidine-4-carboxy1ic acid