Paramethasone P 1561 1. m,. H~SO, 1. HCI. CH3COOH 2. CH3COOK. 2. KOH. C2H50H CH,OH, N2 VI b _____, 1. chrornium(\rl) oxide F F 21 -0cetoxy-6p-fluoro-17-hydroxy- 6a-fluoro-17.21 -dihydroxy- 16o-methylpregn-4-ene-3.20-dione 16a-methylpregn-4-ene- 3.20-dione (M) 1. microbiological hydroxylation 2. 111 w1 + disodium phosphate: SeOz Xs dioxide 1 Paromethosone acetate Reference(s): US 2 671 752 (Syntex; 1954; appl. 1951). Djerassi, C. et al.: J. Am. Chem. Soc. (JACSAT) 82, 2318 (1960). - '? r-7 1 .Od-\-LO , o pyridine 2. acidic ion exchanger, & 3. ::Ep;H 8 "'CH3 pb H H 1. dimorpholino- 0 '= phosphinic chloride F paramethasone starling material: Marker, R.E.; Crooks, H.M.: J. Am. Chem. Soc. (JACSAT) 64, 1280 (1942). NaO F Paramethosone 21-disodium phosphate alternative syntheses: US 3 557 158 (Upjohn; 19.1.1971; appl. 22.1.1962; prior. 4.8.1958). Schneider, P. et al.: J. Am. Chem. Soc. (JACSAT) 81,3167 (1959). GB 850 263 (Organon; appl. 30.4.1959; NL-prior. 12.5.1958). US 4 041 055 (Upjohn; 9.8.1977; appl. 17.1 1.1975). disodiwn phosphate: DE 1 134 075 (Merck AG; appl. 26.1 1.1959). Fom~dation(s): amp 20 mglml (as acetate); tabl. 2 mg, 6 mg (as acetate) Trade Name(s): D: Monocortin (Griinenthal); GB: Haldrate (Lilly); wfm Paramezone (Recordati) wfm Metilar (Syntex); wfm J: Haldron (Dainippon) Monocortin S 1: Alfa-6 (Sam) Parame A (Syntex-Tanabe)- (Griinenthal); wfm Luxazone XP (Allergan)- comb. F: Dilar (Cassenne); wfm comb. 1562 P Parethoxycaine Para~nesone (Syntex- USA: Haldrone (Lilly); wfm Stero-Darvon (Li1ly)- Tanabe) Stemex (Syntex); wfm comb.; wfm Parethoxycaine ATC: NOIBC Use: local anesthetic RN: 94-23-5 MF: C,,H,,NO, MW: 265.35 CN: 4-ethoxybenzoic acid 2-(diethy1amino)ethyl ester hydrochloride RN: 136-46-9 MF: C,,H,NO,. HCI MW: 301.81 EINECS: 205-246-4 LD,,: 300 mglkg (M, i.p.); 430 mglkg (M, s.c.) 4-ethoxybenzoic 4-ethoxybenzoyl acid chloride reference!^): US 2 404 691 (Squibb; 1946; prior. 1937, 1944) Formulation(s): tabl. 0.75 mg (as hydrochloridc) Trade Nan~e(s): F: Maxicaine (Synthtlabo) OJH3 Porethoxycaine Pargyline ATC: C02KC01 Use: MAO-inhibitor, antihypertensive RN: 555-57-7 MF: CllH,3N MW: 159.23 EINECS: 209-101-6 LD,,: 56 mgkg (M, i.v.); 680 mglkg (M, p.0.); 300 mg/kg (R, p.o.) CN: N-methyl-N-2-propynylbenzenemethanamine hydrochloride RN: 306-07-0 MF: C,,H,,N . HC1 MW: 195.69 EINECS: 206-175-1 LD,,: YY mgkg (M, i.v.); 680 mgkg (M, p.0.): 175 mglkg (R, i.v.); 250 mglkg (R, p.0.); 175 mglkg (dog, p.0.) N-benzylmethyl- pro~argyl amine bromide Reference(s): US 3 155 584 (Abbott; 3.11.1964; prior. 3.12.1962). Paricalcitol P 1563 Formulation(s): tabl. 10 mg, 25 mg (as hydrochloride) Trade Name(s): F: Euditron (Abbott)-comb.; GB: Eutonyl (Abbott); wfm Eutron (Abbott)-comb.; wfm USA: Eutonyl (Abbott) wfm Paricalcitol (Paracalcin) Use: vitamin D-analog, treatment for hyperparathyroidism RN: 131918-61-1 MF: C,,H,O, MW: 416.65 CN: (1(r,3~,7E,22~-19-Nor-9,IO-secoergosta-5,7,22-triene-1,3,25-triol 25-hydroxyvitamin D2 (isolation from pig blood) oso,, pyridrne __+ osmium tetroxide 1. Tos-CI 2. H3C-OH 0 0 3. H~c~o~~H,. pyridine b la:25-dihydroxy-3,5-cydo- vitamin D2 1-acetate &methyl ether (1) No104 ____, sodium metaperiodate 111 + isomer 1564 P Paromomycin KOH. CH30H ___, I Poricolcitol EP 387 077 (Wisconsin Alumni Res. Found.; 12.9.1990; appl. 9.3.1990; USA-prior. 16.2.1990). WO 9 729 740 (Wisconsin Alumni Res. Found.; appl. 5.9.1996; USA-prior. 13.2.1996). Paaren, H.E. et al.: J. Org. Chem. (JOCEAH) 45,3253-3258 (1980). Paaren, H.E. et al.: J. Org. Chem. (JOCEAH) 48, 3819-3820 (1983). treatment of osteoporosis in comb. with growth hormone secretagogue: WO 9 853 827 (Ramoz Univ.; appl. 22.5.1998; IL-prior. 30.5.1997). . Formulation(s): amp. 5 pg/ml; 1 ml, 2 ml, 5 ml Trade Name(s): USA: Zemplar (Abbott; 1998) Paromomycin (Aminosidine) ATC: A07AA06 Use: antibiotic RN: 7542-37-2 MF: C23H4SN50L4 MW: 61 5.63 EINECS: 23 1-423-0 LD,,,: 2.275 glkg (M, p.0.); 21.62 g/kg (R, p.0.) CN: 0-2-amino-2-deoxy-a-~-glucopyranosyl-(1+4)-0-[0-2,6-diamino-2,6-dideoxy-~-l-idopyranosyl(l+3)- P-D-ribofuranosyl-(1+5)]-2-deoxy-D-streptamine sulfate RN: 1263-89-4 MF: C,,H4,N,0,4~ xH,S04 MW: unspecified EINECS: 215-031-7 LD,,,: 90 mgkg (M, i.v.); 23.5 glkg (M, p.0.); 181 rng/kg (R, i.v.); 21.62 g/kg (R, p.0.) Paroxetine P 1565 From fermentation solutions of Streptomyces rimosus forma paromomycinus or Streptomyces krestomyceticus N.C.I.B. 8995. Reference(s): US 2 916 485 (Parke Davis; 8.12.1959; prior. 12.1.1959). GB 880 035 (Soc. Farmaceutici Italia; appl. 31.3.1959; valid from 18.2.1960). Formulation(s): cps. 250 mg; powder 1 g; syrup 125 mg15 ml Trude Name(s): D: Humatin (Parke Davis) GB: Humatin (Parke Davis); Paramicina (Ragiomeri) F: Humagel (Parke Davis); wfm Sinosid (SIR) w fm I: Aminoxidin (Farmalabor) J: Humatin (Parke Davis- Humatin (Parkc Davis); Gabbroral (Carlo Erba) Sankyo) wfm Gabbroral (Farmalabor) USA: Humatin (Parke Davis); Humatin (Parke Davis) wtm Paroxetine (BRL 29060; FG 705 1) ATC: N06ABOS; N06AE Use: antidepressant, selective 5-HT-uptake inhibitor RN: 61869-08-7 MF: C,,H,,FN03 MW: 329.37 LD,,: 374 mglkg (R, p.0.) CN: (3S-trans)-(-)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl)piperidine hydrochloride RN: 78246-49-8 MF: C,9H2,FN03. HCI MW: 365.83 LD,,: 42 mgkg (M, i.v.); 378mgkg(M, p.0.); 30 mgkg (R, i.v.); 415 mdkg (R, p.0.) hydrochloride hydrate (2:l) RN: 110429-35-1 MF: C,,HzoFNO,. HCl . 112H20 MW: 749.68 maleate RN: 64006-44-6 MF: ClyH,,FN03 . xC4H,0, MW: unspecified LD,,: 500 mglkg (M, p.0.); 845 mglkg (M. s.c.) acetate RN: 72471-80-8 MF: Cl9HzOFNO3, C2H40z MW: 389.42 1566 P Paroxetine arecoline methylnipecotayl chloride (11) y"' 1. NaOCH, 2. SOCI, + U F 4-fluorophenyl- rnognesium bromide (I) F methyl &/trans-4- (4-fluoropheny1)-N- methylnipecotate OH H,cd,,,'b . distillotion CH3 7H3 2. HBr 3. UAIH4 , 1. (-)-menthol 3. lithium aluminum hydride CI S, decolin. A 0 ethyl pH3 chloroformate, / cuprous chloride F f methyl 1,4-dihydra-1-ethoxy- 4-(4-fluoropheny1)- nlcotinate carbanyl-4-(4-fluora- 3-methoxycarbonyl- phenyl]-3-methoxy- pyridine (N) carbonylpyridine 7H3 I. NOOCH, N 2. LiAlH, 3. racemate resolution with H2. Pt o""f~0~CH3 (-)-di-p-toluoyltartaric acid , IV + H3C Rr m F methyl bromide piperidine Paroxetine P 1567 6;" + F 4-fluora- benz- aldehyde y3 1. LiAlH, 2. rocernate resolution with (-)-di-p-toluoyl- H ,N*O-CH, NaoCH, , tartaric acid H3C 0 O ethyl N-methyl- malanomate 1. S0CI2 H 2. KOH 2. sodium 3.4- Q 1. phcnyl (methylenedioxy)- chloroformate phenolate (V) F F (-)-trons-4-(4-fluoro- Paroxetine pheny1)-3-((1.3-benzo- dioxol-5-yloxy)methyI]-1- rnethylpiparidine ethyl p-fluorocinnomote ethyl cyono- ocetote 1568 P Paroxetine J-pyridine- carbaraldehyde Reference(s): US 3 912 743 (Ferrosan, 14.10.1975; GB-prior. 30.1.1973). a,d US 4 007 196 (AIS Ferrosan; 8.2.1977; appl. 23.7.1975; prior. 21.1.1974; GB-prior. 30.1.1973). DE 2 404 1 13 (AIS Ferrosan; appl. 29.1.1974; GB-prior. 30.1.1973). GB 1 422 263 (AIS Ferrosan; appl. 30.1.1973). b EP 219 934 (Beecham; appl. 6.8.1986; GB-prior. 10.8.1985). c EP 223 334 (Beecham; appl. 6.8.1986; GB-prior. 10.8.1985, 23.5.1986). e WO 9 853 824 (SmithKline Beecham; appl. 29.5.1998; GB-prior. 29.5.1997). f WO 9 852 920 (Knoll; appl. 1351998; GB-prior. 17.5.1997). g WO 9 724 323 (Chiroscience; appl. 30.12.1996; GB-prior. 29.12.1995). alternative synthesis of 111: EP 300 617 (Beecham; appl. 17.6.1988; GB-prior. 23.6.1987). synthesis of arecoline: The Merck Index, 1 lth Ed., 803 (Rahway 1989). optically pure precursors: US 52 582 5 17 (Sepracor; 2.11.1993; appl. 6.8.1992). ctys!alline hydrochloride hemihydrate: EP 223 403 (Beecham; appl. 14.10.1986; GB-prior. 25.10.1985). US 4 721 723 (Beecham; 26.1.1988; appl. 23.10.1986; GB-prior. 25.10.1985). medical use for treatment of pain: EP 269 303 (Beecham; appl. 9.1 1.1986; GB-prior. 11.1 1.1985). medical use for treatment of obesity: EP 188 08 1 (Ferrosan; appl. 2.12.1985; GB-prior. 4.12.1984). preparation of easily soluble paroxetine: WO 9 831 365 (SmithKline Beecham; appl. 12.1.1998; GB-prior. 15.1 .l997). new polymorph of anhydrous paroxetine: CA 2 187 128 (Brabtfort Chem.; appl. 4.10.1996). method of producing amorphous paroxetine: EP 810 224 (Asahi Glass; appl. 30.5.1997; J-prior. 30.5.1996). US 5 672 612 (Pentech Pharm; USA-prior. 9.9.1996). controlled-release pharmaceutical compositions: WO 9 703 670 (SmithKline Beecham; appl. 19.7.1996; GB-prior. 20.7.1995). Formulation(s): tabl., 20 mg, 30 mg (as hydrochloride) Trade Name(s): D: Seroxat (SmithKline F: Dexorat (SmithKline GB: Seroxat (SmithKline Beecham) Beecham) Beecham; 1991) Tagonis (Janssen-Cilag) Parsalmide f' 1569 1: Sereupin (Ravizza) Seroxat (SmithKline USA: Paxil (SmilhKline Beecham) Beecham) Parsalmide ATC: NO2 Use: anti-inflammatory RN: 30653-83-9 MF: Cl,H1,N202 MW: 246.3 1 EINECS: 250-274-2 LDS,,: 148 mglkg (M, i.v.); 428 mgtkg (M, p.o.); 864 mg/kg (R, p.0.) CN: 5-amino-N-butyl-2-(2-propyny1oxy)benzamide COOH 1. H2N-CH3 2. NoOH thionyl 1. butylornine chloride 5-ocetamido-0-ocetyl- 5-ocetomido-0-ocetyl- salicylic ocid solicyloyl chloride 5-acetomido-N-butyl- proparw salicylamide (I) bromide Porsolmide Reference(s): DOS 2 029 991 (E.R.A.S.M.E.; appl. 18.6.1970; GB-prior. 20.6.1969). US 3 739 030(E.R.A.S.M.E.; 12.6.1973; GB-prior. 20.6.1969). Pedrazzoli, A. et al.: Chim. Ther. (CHTPBA) 3, 200 (1968). ulternative synthesis: GB 1 539 007 (C. M. Ind.; valid from 26.10.1977; F-prior. 8.11.1976). Fortnulution(s): drg. 200 mg, 400 mg; f. c. tabl. 600 mg; s. r. tabl. 800 mg Trade Name(s): 1: Parsal (Midy); wfm Pasiniazid ATC: J04AA Use: tuberculostatic. antibacterial RN: 2066-89-9 MF: C7H,N0,. C,H,N,O MW: 290.28 EINECS: 218-183-2 CN: 4-pyridinecarboxylic acid hydrazide mono(4-amino-2-hydroxybenzoate) 1570 P Pecazine $ + CII OH 60 "C _F__, ,NH2 0 N H NH2 isoniozid p-aminosalicylic Posiniozid (9. v.) acid (9. v.) Reference(s): CH 303 085 (Roche; appl. 1952) Fonnulation(s): tabl. 100 mg Trade Name(s): 1): Dipasic (Gewo); wfm Pasiniazide Rolland F: Paraniazide (L'HCpatrol); (L'HCpatrol); wfm wfm I: Dipasic (Farmerid); wfrn Pecazine (Mepazine) ATC: .N05A IJse: neuroleptic RN: 60-89-9 MF: C,,H,N,S MW: 310.47 EINECS: 200-490-8 LD,,: 70 mgkg (M, i.v.) CN: 10-[(1-methy1-3-piperidinyl)methy1]-10H-phenothiazine monoacetate RN: 24360-97-2 MF: Cl9HZ2N2S . C2H40, MW: 370.52 EINECS: 246-207-1 monohydrochloride RN: 2975-36-2 MF: C19H2zN2S . HCl MW: 346.93 EINECS: 221-020-8 LD,,,: 62mg/kg(M,i.v.); 155mg/kg(M,p.o.); 20 mgkg (R, i.v.); 1 glkg (R, p.0.) FH3 + 0 NoNH2 sodium Br ornide Reference(s): US 2 784 185 (Promonta; 1957; D-prior. 1953). Forrnulafion(s): tabl. 50 rng, 400 mg (as hydrochloride) Trade Name(s): D: Pacatal (Promonta); wfrn . 754 2-3 7-2 MF: C23H4SN50L4 MW: 61 5.63 EINECS: 23 1-4 2 3-0 LD,,,: 2.275 glkg (M, p.0.); 21.62 g/kg (R, p.0.) CN: 0-2 -amino-2-deoxy-a-~-glucopyranosyl-(1+4 )-0 -[ 0-2 ,6-diamino-2,6-dideoxy-~-l-idopyranosyl(l+3 )-. 1. chrornium( l) oxide F F 21 -0 cetoxy-6p-fluoro-17-hydroxy- 6a-fluoro-17.21 -dihydroxy- 16o-methylpregn-4-ene-3.20-dione 16a-methylpregn-4-ene- 3.20-dione (M) 1. microbiological hydroxylation. F (-) -trons- 4-( 4-fluoro- Paroxetine pheny1 )-3 -( (1.3-benzo- dioxol-5-yloxy)methyI ]-1 - rnethylpiparidine ethyl p-fluorocinnomote ethyl cyono- ocetote 1568 P Paroxetine J-pyridine- carbaraldehyde