Pharmaceutical Substances Syntheses, Patents, Applications - Part 155 potx

Oxytetracycline 0 1541 Formulafions: vaginal jelly 0.025 % as sulfate Trade Names: D: Antimycoticum Stulln Stu1ln-comb.; wfrn Aperisan Gel Dentinox- comb.; wfm Brand-u.. Wundgel Herit

Oxytetracycline 0 1541

Formulafion(s): vaginal jelly 0.025 % (as sulfate)

Trade Name(s):

D: Antimycoticum Stulln

(Stu1ln)-comb.; wfrn

Aperisan Gel (Dentinox)-

comb.; wfm

Brand-u Wundgel Herit

(Engelhard)-comb.; wfrn

Chinomint Plus

(Chinoso1fabrik)-comb.;

wfm

Chinosol (Chinoso1fabrik)-

comb.; wfm

Fungiderm (Terra-Bio)-

comb.; wfrn

Nasalgon (Labophama)- comb.; wfrn

Onychofissan (Fink)- comb.; wfrn

Ovis (Warner)-comb.; wfrn Robumycon (Robugen)- comb.; wfrn

Semori (Luitpold); wfrn Trachi form-V (Starke)- comb.; wfrn

F: Chromargon (Richard)- comb

Dermacide (Labs CS)- comb

Quinocarbine (GNR- pharma)-comb

UvCline (Crinex) GB: Aci-jel (Ortho-Cilag)- comb.; wfrn

I: Anticolitico Roberts (Manetti Roberts); wfrn Cortanol (Schiapparelli Farm.)-comb.; wfrn Foille (1snardi)-comb.; wfrn Leucorsan (Zil1iken)-comb Viderm (Gerassini)-comb USA: Aci-jel (Ortho-McNei1)- comb

SO 1 AA04 Use: antibiotic RN: 79-57-2 MF: C,,H,N,O, MW: 460.44 EJNECS: 201-212-8

LDo,: 140 mglkg (M, i.v.); 2240 mglkg (M, p.0.);

260 mglkg (R, i.v.); 4800 mglkg (R, p.0.)

CN: [4S-(4a,4aa,5a,5aa,6(3,12aa)]-4-(dimethylamino)- l,4,4a7S,5a,6,1 1,12a-octahydro-3,5,6,10,12,12a-

hexahydroxy-6-methyl- 1,11 -dioxo-2-naphthacenecarboxamide

monohydrochIoride

RN: 2058-46-0 MF: C2,H2,N209 HC1 MW: 496.90 EINECS: 218-161-2

LD,,,: 100mg/kg(M,i.v.);6696mglkg(M,p.o.);

302 mglkg (R, i.v.)

Oxytetracycline

From fermentation solutions of Streptomyces rimosus

Reference(s):

U S 2 51 h 080 (Pfizer; 1950; prior 1949)

Finlay, A.C et al.: Science (Washington, D.C.) (SCIEAS) 111,85 (1950)

stabilized formulations:

US 3 017 323 (Pfizer; 16.1.1962; prior 1952)

US 3 026 248 (Pfizer; 20.3.1962; prior 11.9.1959)

BE 861 855 (Philips; appl 14.12.1977; GB-prior 16.12.1976)

Formulation(s): cps 250 mg, 500 mg; eye ointment 10 mglg; ointment 10 mglg; vial 5 ml (as hydrochloride)

1542 0 Oxytocin

Trade Narne(s):

D: Bisolvomycin (Boehringer

1ng.)-comb with

bromhexine

Corti Biciron (S & K

Pharma)-comb with

tramazoline

Corti Biciron Augensalbe

(S & K Pharma)-comb

with dexamethasone 21-

isonicotinate

Dura Tetracyclin

(durachemie)

Oxytetracyclin Augensalbe

Jenapharm (Alcon;

Jenapharm)

Oxytetracyclinsalbe (Leyh)

Terracortil (Pfizer)-comb

with hydrocortisone

Terramycin (Pfizer)-comb

TerramycinIDepot (Pfizer) Terravenos (Pfizer) Tetracycletten (Voigt) GB :

Tetra-Gelomyrtol (Poh1)- comb

Tetra-Tablinen (Beiersdorf- Tablinen)

Tetra-Tablinen (Sanorania) I:

Vendarcin (Schering) numerous combination J:

preparations Auricularum (SCro1am)-

Posicycline (Alcon) Primyxine (Thera France)- comb

Ster-Dex (CIBA Vision 0phthalmics)-comb

Terramycine (Pfizer) Tetranase (Rottapharm) comb

Stecsolin (Squibb) Terra-cortril (Pfizer)-comb

Terramycin (Pfizer)-comb

Trimovate (Glaxo Wellcome)-comb

Cosmiciclina (Alfa 1ntes)- comb

Geomycin (Otsuka) Oxeten (Mochida) Terramycin (Taito F'fizer) Terra-Cortril (Pfizer) Terramycin (Pfizer) Urobiotic-250 (Pfizer)

Use: posterior lobe of pituitary gland hormone

RN: 50-56-6 MF: C,,H,,N,2012S2 MW: 1007.21 EINECS: 200-048:4

LD,,: 5800 pglkg (M, i.v.); >514 mglkg (M, p.0.);

2275 p g k g (R, i.v.); >20.52 mglkg (R, p.0.)

CN: L-~ysteinyl-~-tyrosyl-~-isoleucyl-~-glutaminyl-~-asparaginyl-~-cystein~l-~-prolyl-~-leuc~l~l~cinamide

cycllc (136)-disulfide

oxidation

,

L-C 6 L Tyr L Ilo-L-Glu-L-Asp-L-Cys-L-Pro-L-Leu-Gly-NH2

f - - - -

(only schematic)

In each case by use of S- and N-trityl groups

Ozagrel 0 1543

Reference(s):

US 2 938 891 (Roussel-Uclaf; 31.5 1960; F-prior 30.3.1956)

US 3 076 797 (Roussel-Uclaf; 5.2.1963; F-prior 22.7.1957)

Formulation(s): amp 3 iulml, 5 iulml, 10 iu/ml; spray 40 iulml

Trade Name(s):

D: Orasthin (Hoechst) F:

Oxytocin Hexal (Hexal) GB:

Oxytocin-Noury

(Nourypharma)

Syntocinon (Novartis I:

Pharma)

Syntometrin (Novartis J:

Pharma)-comb

Synthocinon (Novartis) Pitocin (Sankyo) Syntocinon (Novartis) Pituitan (Nippon Zoki) Syntometrine (Novartis)- Syntocinon (Sandoz-

Syntocinon (Novartis USA: Pitocin (Parke Davis) Farma)

Atonin-0 (Teikoku Zoki) Orasthin (Hoechst)

Ozagrel

(OKY-046)

ATC: BOlAC Use: thromboxane synthetase inhibitor, platelet aggregation inhibitor RN: 82571-53-7 MF: C,,H,2N202 MW: 228.25

LD,,: 1940 mgikg (Mm, i.v.); 1580 mgikg (Mf, i.v.); 3800 mgikg (M, p.0.);

1150 mgikg (Rm, i.v.); 1300 mglkg (Rf, i.v.); 5900 mglkg (R, p.0.)

CN: (E)-3-[4-(1H-imidazol-l-ylmethyl)phenyl]-2-propenoic acid

monohydrochloride monohydrate

RN: 83993-01-5 MF: C13H,2N202 HCI H 2 0 MW: 282.73

monohydrochloride

RN: 7871 2-43-3 MF: C,,H12N202 HCI MW: 264.71

2 benzayl peroxide

f l 0 ^ C H 3 - -,

succinimide ethyl 4-methylcinnamote

imidazole ethyl 4-(1 -imidozolylmethyl)-

cinnamote

ethyl 4-(bromomethy1)- cinnamate (1)

NoOH

Ozagrel

Reference(s):

US 4 226 878 (Kissei, Ono; 7.10.1980; J-prior 13.6.1978)

DOS 2 923 815 (Ono; appl 12.6.1979; J-prior 13.6.1978)

Iizuka, K et al.: J Med Chem (JMCMAR) 24, 1139 (1981)

1544 0 Ozagrcl

synthesis of ethyl 4-(bromomethy1)cinnamate:

DOS 2 755 759 (Merck & Co.; appl 14.12.1977; USA-prior 17.12.1976)

Fomulution(s): amp 20 mg

Trade Name(s):

J : Cataclot (Ono; 1988) Xanbon (Kissei; 1988)

Paclitaxel P 1545

Paclitaxel

(BMS-181339; NSC- 125973)

ATC: L O l C D O l Use: antineoplastic

R N : 33069-62-4 MF: C47H51N014 MW: 853.92

C N : [2aR-[2aa,4P,4aP,6fl,9a(aR*,@S*), 1 la, 12a, l2aa,l2ba]]-P-(benzoy1amino)-a-

hydroxybenzenepropanoic acid 6,12b-bis(acetyloxy)-12-(ben~~lo~y)-2a,3,4,4a,5,6,9,10,11,12,12a,l2b- dodecahydro-4,11-dihydroxy-4a,8,13,13-tetramethyl-5-oxo-7,1 l -methano- 1 H-cyclodeca[3,4]benz[1.2- cloxet-9-yl ester

0

pyridine

2 3 OC

10-deocetylboccotin In (I) triethyl-

(isolated from the leaves sily l

of Taxus boccota L.) chloride

pyridine,

0 O C

*

ocetyl

chloride

7-0-triethylsilyl- baccatin I11 (UI)

1 BuLi, hexone,

THF -45 OC

2 separation of epimers

by chromatography ond recrystallization

cis- 1 -benzoyl- 2',7-bis(triethylsily1)-

oxy)-4-phenyl-

1546 P Paclitaxel

0

aq HF, acetonitrile

pyridine 0 O C

v

I Paclitaxel

@ synthesis of IV:

ethyl glycolate triethyl-

silyl chloride (VI)

H C N CH,

"I1 + p""' -+ N

aldehyde imine

benzaldehyde p-methoxy-

aniline

2 ceric ammonium nitrate H

CH3CN, -10 OC

b

0

2-ocetoxyacetyl chloride (X)

cis-3-ocetyloxy- 4-phenyl-2-

Paclitaxel P 1547

(3R.45)-3- hydroxy-4- phenyl-2- ozetidinone (XU)

1 KOH

2 KOtBu

2 BuLi, ether,

1 BuLi, THF, -45 OC

2 HCI C,H,OH, 0 OC

1 u s

C Y toluene, 73 OC

0 CH3

0 ,

pyridine (2R.3S)-N-benzoyl-

0 - 0 -ethoxyethyl)-

3-phenylisoserine (XV)

@ synthesis of intermediote XV (or unprotected onologues)

(for more 3-phenylisoserine syntheses see Docetoxel)

1 NoN3 C2H50H

3 Hz Pd-C CzH50H

O H threo-ethyl 2-hydroxy-3- amino-3-phenyl- propionote (XVI)

1548 P Paclitaxel

2 XllI

3 LIOH, C2H50H

u

tert-butanol

DHQ-PHAL

morpholine oxide trons-methyl

cinnamote

1 NoN,, DMF 50 OC

2 HZ, Pd-C

3 10% oq HCI

4 VIII, 2N NaOH

/ OH

rCooH

(2R.3S)-N-benzoyl-

3-phenylisoserine (XIX)

THF CH2CI,

-35 OC

Tos-OH CH,CN

2 RuCI, NolO,,

CH,CN NaHCO,

3 (+)-ephedrine,

acetone

(-)-(lS.2S)-N-(2- hydroxy-1 -phenyl- 3-butenyl)benz- omide (XX)

Paclitaxel P 1549

1 KOH, THF

2 HCI, CH OH

3 q o 3 f l

3 benzoic onhydride b

methyl (2R,3S)-benzoylomino~

2- hydroxy-3-phenylpropionate

microbial reduction

*

O/"CH,

(?)-ethyl 2-oxo-3-

benzoylamino-3-

phenylpropionate

(2R,3S)-N-benzoyl- 3-phenylisoserine ethyl ester

Lipase PS-30 (from Pseudomonos cepacia) 0

29 "C, pH 7.0

0'

1550 P Paclitaxel

Reference(s):

a Denis, J.N et al.: J Am Chem Soc (JACSAT) 110, 5917-5919 (1988)

WO 9 306 094 (Florida State Univ.; appl 22.9.1992; USA-prior 3.4.1992, 23.9.1991) George, G.I et al.: J Med Chem (JMCMAR) 35,4230-4237 (1992)

aa US 5 01 5 744 (Florida State Univ.; appl 14.11.1989)

Georg, G.I et al.: Bioorg Med Chem Lett (BMCLEB) 3,2467-2470 (1993)

ab WO 9 418 164 ( Univ New York State; appl 28.1.1994; USA-prior 1.2.1993) Ojima, I et al.: J Org Chem (JOCEAH) 56, 1681-1683 (1991)

Holton, R.A et al.: Bioorg Med Chem Lett (BMCLEE) 3, 2475 (1993)

b US 5 254 703 (Florida State Univ.; appl 6.4.1992; USA-prior 6.4.1992)

EP 428 376 (Florida State Univ.; appl 13.1 1.1990; USA-prior 14.1 1.1989)

c Denis, J.N et al.: J Am Chem Soc (JACSAT) 110,5917-5919 (1988)

cb Sharpless, B et al.: J Org Chem (JOCEAH) 59,5104 (1994)

cc Denis, J.N et al.: J Org Chem (JOCEAH) 56,6939 (1991)

EP 528 729 (RhGne-Poulenc Rorer; appl 17.8.1992; F-prior 19.8.1991)

Denis, J.N et al.: J Org Chem (JOCEAH) 55, 1957 (1990)

ce WO 9 3 17 997 (RhGne-Poulenc Rorer; appl 16.9.1993; F-prior 10.3.1992)

WO 9 422 813 (RhGne-Poulenc Rorer; appl 25.3.1994; F-prior 29.3.1993)

cf Pabel, R.N et al.: Tetrahedron: Asymmetry (TASYE3) 33, 5185-5188 (1993)

cg Pabel, R.N et al.: Biotechnol Appl Biochem (BABIBC) 20,23-33 (1994)

further chemoenzymalic resolutions:

Hoenig, H el al.: Tetrahedron (TETRAB) 46,3841-50 (1990)

Gonet, D.-M et al.: J Org Chem (JOCEAH) 58, 1287-1289 (1993)

Brieva, R et al.: J Org Chem (JOCEAH) 58, 1068 (1993)

ester~fication:

Commercon, A et al.: Tetrahedron Lett (TELCAY) 33,5185 (1992)

reviews:

Hepperle, M.; Georg, G.1.: Drugs Future (DRFUD4) 19,573-584 (1994)

Georg, G.I et al.: Expert Opin Ther Pat (EOTPEG) 4, 109-120 (1994)

Nicolaou, K.C et al.: Angew Chem (ANCEAD) 107,2247-2259 (1995)

total synthesis of faxanes:

Holton, R.A et al.: J Am Chcm Soc (JACSAT) 116, 1599-1600 (1994)

Masters, J.J et al.: Angew Chcm (ANCEAD) 107, 1883 (1995)

Nicolaou, K.C et al.: Nature (London) (NATUAS) 367,630-634 (1994)

US 5 274 137 (K C Nicolaou et a].; appl 23.6.1992; USA-prior 23.6.1992)

Wessjohann, L.: Angew Chem (ANCEAD) 106, 1011 (1994)

purijcation of 10-deacetylbaccatin 111:

WO 9 421 622 (RhGne-Poulenc Rorer; appl 18.3.1994; F-prior 22.3.1993)

production of taxanesfrom explant tissue:

EP 568 821 (Squibb; appl 6.4.1993; USA-prior 7.4.1992)

liposome formulation:

US 5 415 869 (Univ New York State; appl 12.1 1.1993; USA-prior 12.1 1.1993)

cyclodextrine complexes:

WO 9 426 728 (Chinoin; appl 9.5.1994; HU-prior 12.5.1993)

use ugainst protozoa:

WO 9 41 2 172 (Th Jefferson Univ.; appl 2.12.1993; USA-prior 2.12.1992, 26.1.1993)

Formulation(s): vial 30 mgI5 ml