Pharmaceutical Substances Syntheses, Patents, Applications - Part 186 potx

Salicylamide S 1851 alteruative synthesis: DAS 2 340 189 (Polfa; appl. 8.8.1973), R(-)-enantiomer: DE 2 128 258 (Allen & Hanburys; appl. 7.6.1971; GB-prior. 17.6.1970) Effenberger, F., Jager, J.: J. Org. Chem. (JOCEAH) 62, 3867 (1997). stable aqueous,formulation: DOS 3 319 356 (Glaxo; appl. 27.5.1983; GB-prior. 27.5.1982). Formulation(s): amp. 0.6 mglml, 1.5 mg12.5 ml, 3 mgl2.5 ml, 6 mg15 ml; metered-dose aerosol 0.1 mg; metered-dose aerosol 0.12 mg; powder 0.12 mg, 0.24 mg; sol. 6 mglg, 6 mglml; s. r. tabl. 4.82 mg, 9.64 mg; syrup 2.4 mg15 ml (as su1fate)tabl. 2.4 mg, 4.8 mg Trade Narne(s): D: Apsomol (Farmasan) Arubendol (Farmasan) Bronchospray (Klinge) Epaq (ASTA Medica AWD; 3M Medica) Loftan (Glaxo Wellcome1 Cascan) Salbulair (ASTA Medica AWD; 3M Medica) Sultanol (Glaxo; 197 1) Volmac (Glaxo Wellcome) F: Combivent (Boehringer 1ng.)-comb. Salbumol (Glaxo Wellcome) Sprtor (Inava) Ventodisks (Glaxo Wellcome) Ventoline (Glaxo Wellcome; 1971) GB: Asmasal (Evans) Combivent (Boehringer J: 1ng.)-comb. . Salamol Steri-Neb (Baker) Ventide (A. & H.)-comb. USA: Ventolin (Allen & Hanburys; 1969) Volmax (Allen & Hanburys) I: Breva (Valeas)-comb. Broncovaleas (Valeas) Clenil (Chiesi)- comb. Perventil (Malesci)-comb. Salbutard (Lusofarmaco) Ventolin (Glaxo Wellcome) Volmax (Glaxo Allen) Asmidon (Dainippon) Sultanol (Nippon Glaxo) Ventoli (Sankyo) Proventil (Schering; 1981) Ventolin (Glaxo Wellcome; 1981) Volumax (Muro) Salicylamide ATC: N02BA05 Use: analgesic, antipyret~c, antirheumatic RN: 65-45-2 MF: C,H7N02 MW: 137.14 EINECS: 200-609-3 LD,,,: 313 mgkg (M,.i.v.); 300 mglkg (M, p.0.); 980 mglkg (R, p.0.) CN: 2-hydroxybenzamide methyl salicylate Salicylarnide I Reference(s): Ullmanns Encykl. Tech. Chem., 3. Aufl., Vol. 13, 91. Formulation(s): gel 4 g1100 g; tabl. 200 mg, 400 mg Trade Name(s): D: Coffalon (Stark, Konstanz)- Glutisal (Ravensberg)- numerous combination comb. comb. preparations Girheulit (Pfliiger)-comb. Salistoperm (Ursapharm)- F: Percutalginc (Besins- comb. 1scovesco)-comh. 1852 S Salicylic acid GB: lntralgin (3M Health Care) J: Sahanun (Yosh~toml) USA: Lobac (Seatrace)-comb. I: Azerodol (Edmond) Salimtd (Yoshitoml) Tuscalman Berna (Berm)- numerous comblnatlon comb. preparations Salicylic acid ATC: DOIAE12 (Acidum salicylicum; Spiroylsaure; Spirsiure) Use: keratolytic, antipyretic, antirheumatic RN: 69-72-7 MF: C,H,O, MW: 138.12 EINECS: 200-712-3 LD,,,: 184 mglkg (M, i.v.); 480 mglkg (M, p.0.); 891 mglkg (R, p.0.) CN: 2-hydroxybenzoic acid monosodium salt KN: 54-21-7 MF: C,H,NaO, MW: 160.10 EINECS: 200-198-0 LD,,,: 560 mglkg (M, i.v.); 540 mglkg (M, p.0.); 930 mglkg (R, p.0.); 562 mglkg (dog, i.v.) calcium salt (2:l) RN: 824-35-1 MF: C,,HloCaO, MW: 314.31 EINECS: 212-525-4 magnesium salt RN: 18917-89-0 MF: C,,H,,,MgO, MW: 298.53 EINECS: 242-669-3 150-160 OC, 5 bar OH H,So, b (Kalbe-Schrnitt phenolate Salicylic acid I Rcference(s): Ullmanns Encykl. Tech. Chem., 4. Aufl., Vol. 20, 300. juid bed process: EP 89 565 (Bayer; appl. 11.3.1983; D-prior. 23.3.1982). Fornudariorz(s): cream 40 gIl00 g; eye drops 1 mglml; gel 10 g1100 g; ointment 3 g1100 g, 2 dl00 g; plaster 4 mg, 23 mg, 32 mg, 0.81 g, 1.39 g; sol. 0.1 glg, 10 g1100 g Trade Nnme(s): D: Gehwol (Gerlach) Guttaplast (Beiersdoro Hansaplast Footcare (Reiersdorf) Mobilat (Sankyo) Squamasol Gel (Ichthyol) Urgo Hiihneraugenpflastcr (Fournier Pharma) numerous combination preparations F: Algipan (Darcy) Betnesalic (Glaxo Wellcome) Coricide Le Diable (Sodia) Diprosalic (Schering- Plough) Eau PrCcieuse (Phygibne) GCntstrine (Amido) Pansoral (Pierre Fahre) Verrucosal (Novartis) numerous combination preparations GB: Acnisal (Euroderma) Aserbine (Goldshield)- comb. Capasal (Dermal) Cocois (Evans) Cuplex (S & N)-comb. Diprosalic (Schering- Plough)-comb. Duofilm (Stiefe1)-comb. Gelcosal (Quinoderm)- comb. Ionil T (Galderma)-comb. Meted (Euroderma) Monphytol (L.A.B.)-comb. Movelat (Sankyo)-comb. Occlusal (Euroderma) Phytcx (Pharmax)-comb. Posalfilm (Norgine)-comb. Pragmatar (Biog1an)-comb. Pyralvex (Norgine)-comb. Salactol (Dermal)-comb. Salmeterol S 1853 Verrugon (Pickles) I: Apsor (ID1 Farmaceutici)- comb. Collodio All'acido Salicilico (Afom)-comb. Dermatar (ID1 Farmaceutici)-comb. Diprosalic (Schering- Plough) Donalg (Dynacren)-comb. Giovanardi bruciaporri (Giovanardi)-comb. Halciderm (Bristol-Myers Squibb)-comb. Locorten-(Novartis) Losalen (Novartis) Mobilat (Sankyo Pharma)- comb. Pyralvex (Norgine 1talia)- comb. numerous preparations J: Salicylic acid-Vaseline (Iwaki; Maruishi; Ono; Toho-Sankyo; Tsukishima; Yoshida) Speel Plaster (Nichiban) USA: DHS Sal (Person & Covey)-comb. Hydrisalic Gel (Pedinol) Occlusal-HP (GenDerm)- comb. SalAc (GenDerm) Sal-Acid (Pedinol) Salactic Film (Pedino1)- comb. Sal-Plant (Pedinol) Salmeterol (Salmaterol) ATC: R03AC12 Use: long acting b2-adrenoceptor agonist RN: 89365-50-4 MF: C,,H37N04 MW: 415.57 CN: (f)-4-hydroxy-a'-[[[6-(4-phenylbutoxy)hexyl]aminomethyl]-1,3-benzenedimethanol xinafoate (1-hydroxy-2-naphthoate) RN: 94749-08-3 MF: C2sH,7N04 , C, ,H80, MW: 603.76 4-phenyl-1- 1,6-dibromo- butanol hexane [4 (6-bromohexyloxy)- butyllbenzene (I) DOS 3 414 752 (Glaxo; appl. 23.8.1989; GB-prior. 18.4.1983, 23.6.1983,4.11.1983, 25.1.1984). US 4 992 474 (Glaxo; 12.2.1991; appl. 23.8.1989; GB-prior. 18.4.1984, 19.1 1.1986; GB-prior. 18.4.1983. 23.6.1983, 4.11.1983, 25.1.1984). n1-(aminomethyl)- medical use for treatment of itflarnnlation: EP41h 925 (Glaxo; appl. 6.9.1990; GB-prior. 7.9.1989). Solrneterol combination with beclometasone: EP 416 950 (Glaxo; appl. 7.9.1990; GB-prior. 8.9.1989; 20.10.1989). 4-hydroxy-l.3- benzenedimethanol combination with fluticasone: EP 416 951 (Glaxo; appl. 7.9.1990; GB-prior. 8.9.1989, 20.10.1989). Formulation(s): dose aerosol 0.025 mgB5 mg; powder for inhalation 0.05 mgl12.5 mg (as xinafoate) Trade Name(s): D: aeromax (Glaxo Wellcomel Serevent (Glaxo Wellcome) GB: Serevent (Allen & Cascan) F: Serevent (Glaxo Wellcome) Hanburys) 4 1854 S Salsalate I: Aria1 (Dompe) Serevent (Glaxo Wellcome) Salmetedur (Menarini) USA: Serevent (Glaxo Wellcome) Salsalate ATC: N02BA Use: analgesic, antirheumatic, urinary antiseptic RN: 552-94-3 MF: C,,H,,OS MW: 258.23 EINECS: 209-027-4 LD,,,: 1020 mgkg (M, s.c.) CN: 2-hydroxybenzoic acid 2-carboxyphenyl ester 1, dimethylaniline, PCI, 2. 12% HCI . salicylic acid Reference(s): DRP 21 1 403 (C. F. Boehringer Mannh.; appl. 1907). Formulation(s): cps. 500 mg; tabl. 500 mg, 750 mg Trade Name(s): D: Disalgesic (Kettelhack- USA: Disalcid (3M) generic R~ker); wfm Mono-Gesic (Schwarz) GB: Disalcid (Riker); wfm Salflex (Carnrick) Saquinavir (Ro-3 1-8959) ATC: JOSAEOI Use: antlvlral, HIV-I -protease inhibitor RN: 127779-20-8 MF: C,,HsoN,Os MW: 670.86 CN: [3S-[2[1 R*(R*),~S*],~CC,~~B,~~P]]-N1-[3-[3[[( ,I -dimethylethyl)amino]carbonyl]octahydro-2(lH)- isoquinolinyl]-2-hydroxy- l-(phenylmethyl)propyl]-2-[(2-quinolinylcarbonyl)amino]butanediamide monomesylate RN: 149845-06-7 MF: C,,H,,N,O,. CH,O,S MW: 766.96 1. HCI, H20 COOH 2. HO a , J3"03'" + 0=C2 H3C b 2. benzyl alcohol L-phenyl- olonine (I) Saquinavir S 1855 N-tert-butyldecahydro- (4aS.BaS)-isoquinoline- 3(S)-corboxomide (IV) 0 Si, CH3 , 95 OC 1 + @! - & 1 oxalyl chloride b VI 0 2. tris(trirnethylsilyloxy)- phthalic (v) ethylene anhydride 1. TosOH 2. NaBH4, THF &, & O O 1. CH3S02CI, pyridine 2. TosOH, C2H50H 3. I-BuOK. THF N OMF, 120 OC VII 4 L VIIl 1. CH3NH2. C2H,0H 2. HCI. ethyl ocetate r 1856 S Saquinavir N-benzyloxycarbonyl- diazo- L-phenylalanine methane ~~-(2-~uinoiin~l- 3(S)-benzylaxycarbanyl- amino-1,2(S)-epoxy- 4-phenylbutane (X) Saquinavir 2-[3(S)-(L-asparaginylamino)- 2(R)-hydroxy-4-phenylbutyl]- ~-tert-butyldecahydro-(4aS,8aS)- isoquinaline-3(S)-carboxamide (XII) carbony1)-L- asparagine OCC, THF, HOBt XI1 + N COOH quinaldic acid Saquinavir S 1857 1 Al(iPr)3, 50 OC isopropanol . 1. (COCI)2, toluene 2. HZ, Pd-C 3. NaCN . H20 v + . Xv 1. No2C03. 80 OC 2. HCI, H20 3 NaOH, C2H50H. 80 "C + lv 'nosylate" (XVI) Reference(s): a Parkes, K.E.B. et al.: J. Org. Chem. (JOCEAH) 59, 3656 (1994). EP 346 847 (Hoffmann-La Roche; appl. 13.6.1989; GB-prior. 13.6.1988, 10.4.1989). EP 432 694 (Hoffmann-La Roche; appl. 10.12.1992; GB-pnor. 1 1.12.1989). b EP 432 695 (Hoffmann-La Roche; appl. 10.12.1990; GB-prior. 11.12.1989, 10.12.1990). combinations: WO 9 41 9 008 (Merrell Dow Pharm.; appl. 18.1.1994; GB-prior. 22.2.1 993). EP513 917 (Glaxo; appl. 11.5.1992; GB-prior. 16.5.1991,8.10.1991, 6.11.1991). EP 691 345 (Bristol-Myers Squibb; appl. 5.7.1995; USA-prior. 17.51995, 5.7.1994). WO 9 533 464 (Searle & Co.; appl. 2.6.1995; USA-prior. 3.6.1994). Formulation(s): cps. 200 mg (as mesylate) 1858 S Saralasin acetate Trade Narm(s): D: FORTOVASE (Roche) GB: Fortovase (Roche) USA: Invirase (Roche) Invirase (Roche) Invirase (Roche; 1996) F: Invirase (Roche; 1996) I: Invirase (Roche) Saralasin acetate ATC: C09 Use: antihypertensive, diagnostic (renin- dependent hypertension) RN: 39698-78-7 MF: C,,H,N,,O,, . xC2H402 . xH20 MW: unspecified LD,,,: 1171 mg/kg(M,i.v.) CN: I-(N-methylglycine)-5-~ valine-8-~-alanineangiotensin 11 acetate (salt) hydrate saralasin RN: 34273-10-4 MF: C,,H,SN,,O,o MW: 9 12.06 monoacetate RN: 60173-70-8 MF: C,,H,sN,30,,, . C2H40, MW: 972.12 1. HCI 1. Boc-~is(~'~-Bzl) 2. Boc-Pro 3. HCI 2. HCI Boc-Ala-Res -b H-Pro-Ala-Res H-His(~~~-~zl)-~ro-~la-Res 1. Boc-Val 1. Boc-Tyr(OBz1) 2. HCI 2. HCI H-~al-His(~~~-~zl)-~ro-~la-~es - 1. Boc-Val 2. HCI ~-T~r(~Brl)-~al-~is(~'~-~zl)-~ro-~la-Res -b H-V~I-Tyr(0Bzl)-Val-His(~'~-021)-Pro-Ala-Res 1. Boc-Arg(N02) 1. H,C-Gly 2. HCI 2. HBr, CF3COOH -b ~-~r~(~~~)-~al-~~r(~~zl)-~al-~is(~~~-~rl)-~ro-~la-~es -b I Sarolasin acetate Nlm-Bzl: N-benzylation in the imidazole ring Res: resin ester Scopolamine S 1859 Referenceis): DOS 2 127 393 (Norwich; appl. 2.6.1971; USA-prior. 12.2.1971). GB 1 320 104 (Norwich; valid from 20.5.1971). ZA 7 103 182 (Norwich; appl. 29.9.1971). subcutaneously applicable pharmaceutical ,formulation: US 3 932 624 (Morton-Norwich; 13.1.1976; prior. 17.6.1974). Trade Name( s): D: Sarenin (R6hm Pharma); USA: Sarenin (Norwich Pharm.); wfm wfm Scopolamine (Hyoscine) ATC: A04ADO1; N05CM05; S01FA02 Use: mydriatic, parasympatholytic, sedative, antispasmodic RN: 51-34-3 MF: CI7H2,NO4 MW: 303.36 EINECS: 200-090-3 LD,,,: 100mgIkg (M,i.v.); 1275 mglkg (M, p.0.); 2650 mglkg (R, p.0.) CN: [7(S)-(la,2P,4P,5a,7P)]-a-(hydroxymethyl)benzeneacetic acid 9-methyl-3-oxa-9- azatricyclo[3.3.1 .02,4]non-7-yl ester hydrobromide RN: 1 14-49-8 MF: C17H2,N04 . HBr MW: 384.27 EINECS: 204-050-6 LD,,: 203 mgIkg (M, i.v.); 1880 mglkg (M, p.0.); 1270 mglkg (R, p.0.) hydrobromide trihydrate RN: 6533-68-2 MF: C,7H2,N04. HBr . 3H20 MW: 438.32 a From mother liquors of hyoscyamine production (atropine, q. v.). h By extraction of Scopolia drugs, as Datura metel and Duboisia. Reference(s): Ullmanns Encykl. Tech. Chem., 3. Aufl., Vol. 3, 204. Formulation(s): amp. 0.3 mglml, 0.5 mglml, 1 mglml; eye drops 0.25 % (as hydrobromide trihydrate); eye drops 2.5 mglg (as borate); plaster 1.5 mgl2.5 cm2 Trade Nameis): D: Boro-Scopol (Winzer) Neurovegetalin (Ver1a)- comb. Scopoderm TTS (Novartis Pharma) Scopolamin. hydrobromic. Dispersa (Dispersa); wfm Scopolamin. hydrobromic. Dispersa Baeschlin (Baeschlin); wfm F: GCnoseopolamine (Amido) Scopoderm TTS (Novartis) GB: Buscopan (Boehringer Ing.) Hypal2 (S & N) I: Buscopan (Boehringer Ing.) Scopolamina Bromidrato (Biologici Italia) Spasmeridan (UCB) Transcop 4 sistemi transderm (Recordati) combination preparations J: numerous generic preparations 1860 S Secbutabarbital USA: Atrohist Plus (Medeva; as Bellatal (Richwood; as Donnatal (Robins; as hydrobromide) hydrobromide) hy drobromide) Transderm Scop (Novartis) Secbutabarbital ATC: NOSCA (Butabarbital; Secbutobarbitone; Sodium Butabarbital; Use: sedative, "ypnotic Butethal) RN: 125-40-6 MF: C,,,H,,N,O, MW: 212.25 EINECS: 204-738-6 LD,,,: 175 mglkg (M, i.v.) CN: 5-ethyl-5-(1-methylpropy1)-2,4,6(1 H,3H,SH)-pyrimidinetrione monosodium salt RN: 143-81-7 MF: C,,H,,N,NaO, MW: 234.23 EINECS: 205-611-8 LDS,,: 70 mgkg (R, i.v.); 78 mglkg (R, p.0.); 90 mglkg (dog, i.v.) 1. NaOCZH, O 0vCH3 2, H3CvBr 0 0 CH3 H3cJcj , N~OC,H, &o,CH3 H3C&x-CH3 - 1 0 2. ethyl 0 sec-butyl bromide bromide diethyl diethyl malonate ethylmolonate d~ethyl ethyl-sec- ureo butylmoonote (I) I Secbutabarbital R@rence(s): US 1 856 792 (Eli Lilly ; 1932; prior. 1929). Formulaiian(s): tahl. 15 mg, 30 mg, 50 mg, 100 mg (as sodium salt) Trade Nanle(s): D: Dormilfo (Wachter)-comb.; Resedorm (Lappe)-comb. w fni with aprobarbital; wfm Nervolitan (Kette1hack)- F: Butobarbital Dipharma comb.; wfm ( Amido) Hypnasmine (~lert6)-comb. GB: Soneryl (Concord) USA: Barbased (Major) Butisol Sodium (Wallace) Secnidazole ATC: POlAB07 Use: chemotherapeutic, amoebicide RN: 3366-95-8 MF: C,Hl ,N,O, MW: 185.18 EINECS: 222-1 34-0 CN: a,2-dimethyl-5-nitro-1 H-imidazolc-1-cthanol . H-Pro-Ala-Res H-His(~~ ~-~ zl )-~ ro-~la-Res 1. Boc-Val 1. Boc-Tyr(OBz1) 2. HCI 2. HCI H-~al-His(~~ ~-~ zl )-~ ro-~la-~es - 1. Boc-Val 2. HCI ~-T~r(~Brl )-~ al-~is(~' ~-~ zl )-~ ro-~la-Res. ~-T~r(~Brl )-~ al-~is(~' ~-~ zl )-~ ro-~la-Res -b H-V~I-Tyr(0Bzl)-Val-His(~' ~-0 21)-Pro-Ala-Res 1. Boc-Arg(N02) 1. H,C-Gly 2. HCI 2. HBr, CF3COOH -b ~-~ r~(~~~ )-~ al-~~r(~~zl )-~ al-~is(~~ ~-~ rl )-~ ro-~la-~es -b I Sarolasin. Saquinavir N-benzyloxycarbonyl- diazo- L-phenylalanine methane ~ ~-( 2-~ uinoiin~l- 3(S)-benzylaxycarbanyl- amino-1,2(S)-epoxy- 4-phenylbutane (X) Saquinavir 2-[ 3(S )-( L-asparaginylamino )- 2(R)-hydroxy-4-phenylbutyl]-