Pharmaceutical Substances Syntheses, Patents, Applications - Part 23 pot

Betacarotene B 221 KOC(CHJ3 CI r XIII patasslum tert-butylate retinyl chloride KOH. C2H,0H Rejerence(s): review: Ullmams Encykl. Tech. Chem., 4. Aufl., Vol. 23, 633 ff. 1 Isler, 0. et a].: Helv. Chim. Acta (HCACAV) 39, 249 (1956). Isler, 0.: Angew. Chem. (ANCEAD) 68,547 (1956). DE 855 399 (Roche; appl. 26.5.1950). DE 858 095 (Roche; appl. 1.10.1950). DE953 073 (Roche; appl. 23.5.1954; CH-prior. 29.6.1953). DE 953 074 (Roche; appl. 5.6.1954; CH-prior. 1.7.1953). isomerization to all-tmns-form: US 3 367 985 (Roche; 6.2.1968; appl. 18.4.1966). DE 2 440 747 (Roche; appl. 26.8.1974; USA-prior. 29.8.1973). 2 review: Pommer, H.: Angew. Chem. (ANCEAD) 72,911 (1960). Pommer, H.: Angew. Chem. (ANCEAD) 89,437 (1977). a DE 2 505 869 (BASF; appl. 12.2.1975). b DE 1 068 709 (BASF; appl. 6.6.1958). DE 1 158 505 (BASF; appl. 23.5.1962). c DE 954 247 (BASF; appl. 20.10.1954). DE 1068 705 (BASF; appl. 22.3.1958). DE 1 068 703 (BASF; appl. 14.3.1958). "C,,-dialdehyde ": DE 1 092 472 (BASF; appl. 2.10.1958). - 3 DE 2 224 606 (RhBne-Poulenc; appl. 19.5.1972; F-prior. 19.5.1971). isolation from carrots and similar material: US 2 848 508 (H. M. Harnett et al.; 1958; appl. 1954). fermentative production: US 2 959 521 (Grain Processing Corp.; 1960; appl. 1959). US 2 959 522 (Grain Processing Corp.; 1960; appl. 1959). US 3 001 912 (Commercial Solvents Corp.; 1961; appl. 1958). US 3 128 236 (Grain Processing Corp.; 1964; appl. 1961). Formulation(s): cps. 25 mg Trade Name(s): D: Bella Carotin (3M Medica) BCtasellen (Arkopharma) PhCnoro Roche (Roche)- Carotaben (Hermal) comb. comb. combination preparations Dijrarel 100 (Leurquin)- I: Fotoretin (Farmila)-comb. F: Azinc complexe comb. Mirtilene (SIFT)-comb. (Arkopharma)-comb. USA: Aces (Carlson) 222 B Betahistine Betahistine ATC: C04AX; N07CA0 1 Use: diaminooxydase inhibitor RN: 5638-76-6 MF: C8H12N2 MW: 136.20 EINECS: 227-086-4 LD,,,: 2920 mgkg (M, p.0.); 61 10 mgkg (R, p.0.) CN: N-methyl-2-pyridineethanamine dihydrochloride RN: 5579-84-0 MF: C8H,,N2 .2HCl MW: 209.12 EINECS: 226-966-5 dimesylate RN: 54856-23-4 MF: C8H12N2. 2CH403S MW: 328.41 EINECS: 259-377-7 LD,,,: 505 mglkg (M, i.v.); 500 mglkg (M, p.0.); 604 mglkg (R, i.v.); 3030 mglkg (R, p.0.) 2-picoline poroform- 2-(2-pyridyl)- 2-(2-brornoethy1)- Betohistine oldehyde ethanol pyridine Reference(s): Loffler, K.: Ber. Dtsch. Chcm. Ges. (BDCGAS) 37, 161 (1904). Walter, L.A. et al.: J. Am. Chem. Soc. (JACSAT) 63,2771 (1941). Formulation(s): drops 1.25 % (as dihydrochloride); s. r. tabl. 20 mg; tabl. 6 mg, 12 mg (as dimesylate), 8 mg, 16 mg (as dihydrochloride) Trade Narne(s). D: Aequamen (Promonta Vasornotal (Solvay GB Serc (Solvay; as Lundbeck) Arzneimittel) hydrochloride) Betavert (Henning) F: Extovyl (Marion Merrell) 1: Microser (Formenti) Melopat (Pharrnasal) Lectil (Bouchara) J: Menslon (Eisai) Ribrain (Searle- Serc (Solvay Pharma) USA: Serc (Unimed); wfm Endopharm; Yamanouchi) Betaine aspartate ATC: AOSBA; A09AB; A12BA Use: liver therapeutic, stomach therapeutic RN: 5292 1-08-1 MF: CSH, ,NO2. C4H,NO4 MW: 249.24 EINECS: 258-258-7 CN: I-carboxy-N,N,N-trimethylmethanaminium hydrogen L-aspartate betoine L-ospartic acid I Betoine aspartote I Reference(s): FR 1 356 945 (M. R. Cote; appl. 5.12.1962; MC-prior. 14.12.1961). FR-M 2 462 (Albert Rolland: appl. 9.10.1962). Betaine hydrate B 223 Formulation(s): amp. 2 g/dose;sol, 10 ml Trade Natne(s): F: Somatyl (Anphar-Rolland); wfm Somatyl (L'HCpatrol); wfm I: Betaina Manzoni (Manzoni)-comb. Betascor (Manetti Roberts)-comb. Bios Liver (Ausonia). comb. Ciatox (1birn)-comb. Glution (Boniscontro & Citroepatina (Roussel- Gazzone)-comb. Maestretti)-comb. Inobetin (Boniscontro & Eparbolic (Carlo Erba)- Gazzone)-comb. comb. Kloref (Sami1)-comb. Equipar (Lampugnani)- Somatyl (Prophin)-comb. comb. Glicobil (Medici Domus)- comb. Betaine hydrate ATC: A09AB02 Use: liver therapeutic, gastric therapeutic RN: 590-47-6 MF: C,H,,NO, MW: 135.16 EINECS: 209-684-7 CN: 1-carboxy-N,N,N-trimethylmethanaminium hydroxide inner salt hydrochloride RN: 590-46-5 MF: CSH ,,ClNO, MW: 153.61 EINECS: 209-683-1 dihydrogen citrate (1 : 1) RN: 17671-50-0 MF: C6H707 . CSH12N02 MW: 309.27 EINECS: 241-648-6 trimethyl- sodium ornine chloroacetate betaine chloride (1) I Betaine hydrate basic ion exchanger (e. g. IRA-410) I b by-praduct of beet-sugar production; isolation by acidic precipitation or by ion-exchange methods from the mash H,C, FH3 ,N<COOH OH- H3C Reference(s): Stoltzenberg, H.: Z. Physiol. Chem. (ZPCHAS) 92, 445 (1914). a DRP 269 701 (AG fiir Anilin-Fabrikation; appl. 1912). US 2 800 502 (Internat. Minerals & Chem. Corp.; 1957; appl. 1953). b US 1 685 758 (D. K. Tressler; 1928; appl. 1925). Formulation(s): gran. 400 mg Trade Name(s): D: Flacar (Schwabe)-comb. F: Citrarginine (Lapha1)- comb. Citrate de bCtai'ne Beaufour (Beau four) 224 B Betamethasone Citrate de GB: Kloref (Cox; as Somatyl (Teofarma; as bCtai'neeffervescent Upsa hydrochloride)-comb. aspartate) (UPSA)-comb. I: Betaina Manzoni J: Apellet-BT (0no)-comb. Gastrobul (Guerbet)-comb. (Gaymonat; as citrate) Molmagen (Toa Yakuhin- HCpagrume (SynthC1abo)- Citroepatina (Rousse1)- Torii)-comb. comb. comb. Ornitalne (Schwarz)-comb. Betamethasone ATC: A07EA04; D07ACO1; C05AA05; D07XCO 1 ; H02ABO I ; RO 1 ADO6; R03BA04; SO1 BAO6; SO 1 CBO4; S03CA06 Use: glucocorticoid RN: 378-44-9 MF: C22H29F05 MW: 392.47 EINECS: 206-825-4 LD,,: >4.5 glkg (M, p.0.) CN: (1 1 P, 16P)-9-fluoro- 11 ,l7,2l -trihydroxy-16-methylpregna- 1.4-diene-3,20-dione 3a-acetoxy-16-pregnene- diazo- 3a-acetoxy-16-methyl- 1 1.20-dione (I) methane 16-pregnene-11.20-dime (fram deoxycholic acid) 0 Tos-OH + N 1. peroxoocetic 2. sodium 3a-acetoxy-16p-methyl- acetic 3a.20-diacetoxy-16p- hydroxide pregnone-1 l,20-dione (11) anhydride @I) methylpregn-l7(20)- ene-ll-one 16j-methyI-3m.l7a,21- 17m.21 -dihydroxy-168- trihydroxypregnone-11.20- rncthylpregnane-3.11.2D- dionc 21 -acetate trionc 21-occtate (V) Betamethasone B 225 48-bromo-l7a.21 -di- hydroxy- 168-rnethyl- pregnane-3.1 1.20-trione 21 -ocetate 16g-methylcortisone 21-ocetote (VI) Bacillus s~haericus WH~ 1. semicarbazide H H 2. potassium 0 . 0- borohydride 16p-methylcartisone '' 'Odium nitrite 166-methylhydrocortisone go-brorno-168-msthyl- prednisolone 21 -0cetate (M) 98.1 18-apory-17n.21 -dihydmry- 1 S#-mcthyI-l,4-pregnadiene- 320-diono 21-acetate (X) betomethasone acetate (XI) Betamethasane 1. Na, CH3CH2CW,0H 2. CH3COOH, H20 ethylene glycol (xu) 3a.17~-dihydroxy-168- methyl-58-pregnane- 11,20- dione 20-ethylene acetal 226 B Betamethasone 0 1. Br2 CH3CONHBr, H20. acetone , XN 2. potassium N-bromo- HO.$ ocetate ocetamide 168-methyl-3a,l la,l7a- trihydroxy-58-pregnon- 20-one (XIII) 1. Tos-CI XV 2. OMF b w1 0 2. KOAc 3. H2F2 HCI, CH30H + 1. N-brorno- succinirnide r' I H202, NaOH XI , 0s-OH , 3a-acetoxy-16a.17a-epoxy- 58-pregnane-11.20-dione 21 -ethylene acetal (XVI) r' r' NaBHI. THF, H20 XVI &:H3 e H + :;;idin= &:3 Me H HO.'" H H H K HH H3C 0" 3a-acetoxy-20.20- ethylenedioxy-l6a,17o- apoxy-5~-pregnon-l18-ol (XW) H,C-SO2-CI . OMF XW , methonesulfonyl 1. methylmogne- chloride sium bromide ~0"' H Betamethasone l3 227~ CdJ. HPO,, acetone Br,. CH,COOH XVl'l chmmiurn(W) ' CH3 bromine ' axids Li2C03. LiBr. DMF Me ,,OH m lithium lithium ' dCH3 corbonate bromide 0 WH I H3C-COOK dCH3 + CH~COOH, acetone VIII H 0' 17a-hydroxy-21 -iodo-168- methylpregno-1.4,9(11)- triene-320-dione (XX) 1. CH3COONa. CH30H 2. CH,COOH, pyridine HZF,. THF, CHCI, M.X XI hydrogen fluoride 12. CO(OH)~. CaCl iodine 0 b N-bromo- succinirnide a US 3 164 618 (Schering Corp.; 5.1.1965; prior. 23.7.1957, 8.5.1958). b Oliveto, E.P. et al.: J. Am. Chem. Soc. (JACSAT) 80,4428 (1958). Olivelo, E.P. et al.: J. Am. Chem. Soc. (JACSAT) 80, 6687 (1958). c US 3 104 246 (Roussel-Uclaf; 17.9.1963; appl. 26.7.1962; F-prior. 18.8.1961). Julian, P.L. et al.: J. Am. Chem. Soc. (JACSAT) 77,4601 (1955). alternative syntheses: US 3 053 865 (Merck & Co.; 11.9.1962; prior. 19.3.1958, 1.3.1960). Taub, D. et al.: J. Am. Chem. Soc. (JACSAT) 80,4435 (1958); 28,4012 (1960). US 4 041 055 (Upjohn; 9.8.1977; appl. 17.1.1975). Formulation(s): syrup 0.6 mgl5 ml; tabl. 0.5 mg, 0.6 mg, 1 mg Trade Name(s): D: Beta-Creme (Lichtenstein) Betagalen (Pharmagalen) Betam-Ophtal (Winzer) Beta-Stulln (Pharma Stulln) F: Betnesol (Glaxo Wellcome) Betnesol-V (Glaxo WellcomeICascan) Celestamine N (Essex Pharma) Celestan (Essex Pharma) Cordes Beta (Ichthyol) Diprosis (Essex Pharma) Diprosone (Essex Pharma) Euvaderm (Parke Davis) Betnesalic (Glaxo Wellcome)-comb. Betnesol (Glaxo Wellcome) Betneval (Glaxo Wellcome) Betneval ntomycine (Glaxo Wellcome)-comb. CClestamine (Schering- Plough)-comb. Ctlesttne (Schering- Plough) Ctlestoderm (Schering- Plough) Diprolkne (Schering- Plough) Diprosalic (Schering- Plough)-comb. Diprosept (Schering- Plough)-comb. 1 228 B Betamethasone acetate Diprosone ntomycine Brumeton coll. Micutrin Beta crema (Schering-Plough)-comb. (Bruschettini)-comb. (Schiapparelli Searle)- Gentasone (Schering- Celestoderm (Schering- comb. Plough)-comb. Plough; as valerate) Minisone (IDI) GB: Betnelan (Evans) Celestone (Schering- Stranoval pom. derm. Betnesol (Evans) Plough) (Teofarma) Vista-Metasone Deltavagin (Farma- Viobeta (ID1)-comb. (Martindale) Biagini)-comb. Visublefarite sosp. oft. I: Alfaflor (1ntes)-comb. Dermatar (ID1)-comb. (Merck Sharp & Dohme)- Apsor pom. derm. (ID1)- Diproform (Schering- comb. comb. Plough)-comb. Visumetazone Antib. Beben (Parke Davis; as Diprogenta (Sca)-comb. (Merck Sharp & Dohme)- benzoate) Bentelan (Glaxo; as phosphate) Beta (IDI; as valeroacetate) Betabioptal (Farmila)- comb. Betameta (Formulario Naz.; as &propionate)- comb. Biorinil (Farmila)-comb. Diprorecto (Schering- comb. Plough)-comb. several combination Diprosalic (Schering- Plough)-comb. Diprosone (Schering- Plough; as dipropionate) Ecoval (Glaxo; as valerate) Eubetal (SIF1)-comb. Fluororinil (Farmila)-comb. Gentalyn Beta (Schering- Plough)-comb. preparations J: Betamamallet (Showa Yakuhin) Betametha (Dojin) Betnelan (Daiichi) Dabbeta (Zenyaku) Rinderon (Shionogi) Rinesteron (Fuso) USA: Celestone (Schering) Betamethasone acetate ATC: H02AB Use: glucocorticoid RN: 987-24-6 MF: C,H3,F06 MW: 434.50 EINECS: 213-578-6 CN: (1 1 ~,16~)-21-(acetyloxy)-9-fluoro-l1,17-dihydroxy-16-methylpregna-l,4-diene-3,20-dione 1. CH3-SO2-CI, pyridine 0 2. CH3-CO-NH-Br, dioxane 3. KO-COCH3. CH,OH 4. H2Fp CHC13 _______* 1. rnethanesulfonyl chloride 0 2. N-bromaacetarnide 3. potassium ocetate 168-rnethylprednisolone 4. hydrogen fluoride 21 -ocetote (from rneprednisone acetate) 1 Betarnethasme acetote Reference (s): US 3 164 618 (Schering Corp., 5.1.1965; prior. 8.5.1958, 23.7.1957). additional literature: betamethasone, q. v. Formulation(s): amp. 3 mglml, 3 mglml (in combination with betamethasone dihydrogen phosphate) Trade Name(s): D: Celestan Depot (Essex Ctlesthne chronodose I: Celestone Cronodose Pharma)-comb. (Schering-Plough)-comb.; (Schering-Plough)-comb. F: Betafluorene (Lepetit); wfm USA: Celestone Soluspan wfm (Schering)-comb. Betamethasone adamantoate B 229 Betamethasone adamantoate ATC: H02AB Use: glucocorticoid RN: 40242-27-1 MF: C3,Hd3F06 MW: 554.70 EINECS: 254-855-1 CN: (I lp,I6a)-9-fluoro-1 l,17-dihydroxy-16-methyl-21-[(tricyclo[3.3.1 .13~7]dec-l-ylcarbonyl)oxy]pregna-l ,4- Me ,,%.OH &H3+ F H HOOC~ triethylamine N(C2H5),, acetone b 0 11~,17-dihydroxy-3,20-dioxa- 1 -adornantone- 9a-fluom-21 -iodo-168- corboxylic acid methyl- 1,4-pregnodiene (from betarnethasone) Reference(s): DOS 2 232 827 (Glaxo; appl. 4.7.1972; GB-prior. 5.7.1971). (also alternative syntheses). Trade Name(s): GB: Betsovet (Claxo); wfm Bethomethasone odornantoote - Betamethasone benzoate ATC: D07AC Use: glucocorticoid RN: 22298-29-9 MF: C29H33F06 MW: 496.58 EINECS: 244-897-9 CN: (1 1 P,16P)- 17-(benzoy1oxy)-9-fluoro-11,21 -dihydroxy-16-methylpregna- l,4-diene-3,20-dione betomethosone (9. v.) 17,21-0-(a-methoxy- benzylidene)betomethosone (I) trimethyl orthobenzoate (COOH)2. CH,OH. H20 oxolic ocid 1 Betamethosone benzoate I 230 B Betamethasone butyrate propionate Reference(s): US 3 529 060 (Warner-Lambert; 15.9.1970; I-prior. 1.3.1967). Ercoli, A. et al.: J. Med. Chem. (JMCMAR) 15, 783 (1972). alternative synthesis: DOS 2 340 591 (Glaxo; appl. 10.8.1973; GB-prior. 11.8.1972). pharmaceutical formulation: US 3 749 773 (Warner-Lambert; 31.7.1973; prior. 25.2.1971). Formulation(s): cream 1 gl0.25 mg, 1 gll mg; gel 1 gll mg; lotion 0.1 %; ointment 0.1 % Trade Name(s): D: Euvaderm (Parke Davis) I: Beben crema derm. (Parke combination preparations GB: Bebate (Warner); wfm Davis) J: Asakin (Mikasa) Beben Sid (Parke Davis) Betamethasone butyrate propionate Use: topical anti-inflammatory, steroidal (BBP; TO- I 86) agent RN: 5534-02-1 MF: C,,H,,F07 MW: 518.62 CN: (1 1 P, 16P)-9-fluoro-1 I-hydroxy- 16-methyl- 17-(1 -oxobutoxy)-21-(l-oxopropoxy)pregna-l,4-diene-3,20- dione 1. triethyl orthobutyrate, p-toluenesulfonic ocid rnonohydrate betornethosone 2. butyric acid Reference(s): Imai, S. et al.: Clin. Rep. 24(1 l), 113 (1990). Shue, H J. et al.: J. Med. Chem. (JMCMAR) 23(4), 430 (1980) propionyl Trade Name(s): J: Antebate (Torii) Betarnethasone butyrale propionate chloride . 98 7-2 4-6 MF: C,H3,F06 MW: 434.50 EINECS: 21 3-5 7 8-6 CN: (1 1 ~,16~ )-2 1-( acetyloxy )-9 -fluoro-l1,17-dihydroxy-16-methylpregna-l,4-diene-3,20-dione 1. CH3-SO2-CI, pyridine 0 2. CH3-CO-NH-Br,. 3a.20-diacetoxy-16p- hydroxide pregnone-1 l,20-dione (11) anhydride @I) methylpregn-l7(20 )- ene-ll-one 16j-methyI-3m.l7a,2 1- 17m.21 -dihydroxy-16 8- trihydroxypregnone-11.2 0- rncthylpregnane-3.11.2D-. anti-inflammatory, steroidal (BBP; TO- I 86) agent RN: 553 4-0 2-1 MF: C,,H,,F07 MW: 518.62 CN: (1 1 P, 16P )-9 -fluoro-1 I-hydroxy- 16-methyl- 1 7-( 1 -oxobutoxy )-2 1-( l-oxopropoxy)pregna-l,4-diene-3,20-