Scientific Publications

The present list of publications gives an outline of Hovione's Expertise and know-how in Process Chemistry. This list does not constitute a complete reference to all of Hovione publications and patents.

AN 2007:1336973 CAPLUS
TI A simple inhaler
IN Villax, Peter; Mcderment, Lain; Bunce, Martin
PA Hovione Inter AG, Switz.
SO PCT Int. Appl.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- -------------------- --------
PI WO 2007132217 A1 20071122 WO 2007-GB1756 20070511
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW
RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, MT, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
PRAI PT 2006-103481 A 20060516
AB A dry powder inhaler for pulmonary or nasal use, comprising at least an inhaler body (100) and a cartridge (110) with one or two compartments (121) each containing one dose of a drug. The compartment (121) has holes (123) to admit air and holes (120) to deliver powder, which, in use, communicate with an inhalation (102) channel in the inhaler body (100). To prevent the powder from leaking through the compartment holes before use, the air admission holes (123) are of reduced dimension, thereby blocking or hindering powder exit under the force of gravity. When the cartridge 110 is inserted inside the inhaler body (100), all its holes (120, 123) are blocked. By sliding the cartridge (110) in relation to the body (100) until the inhalation position is reached, the holes (120, 123) come into in fluid communication with one another and with the inhalation channel (103), thereby allowing a flow of air to disperse and entrain the dose through the mouthpiece (103). Five embodiments of the invention are disclosed.


AN 2007:592092 CAPLUS
TI Process for the manufacture of iohexol by the alkylation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with 1-chloro-2,3-propanediol using 2-(2-methoxyethoxy)ethanol as the reaction solvent
IN Galindro, Jose; Marto, Susana; Bandarra, Joao Antonio Moinho; Heggie, William
PA Hovione Inter Ltd., Switz.; Turner, Craig Robert
SO PCT Int. Appl., 13pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- -------------------- --------
PI WO 2007060380 A1 20070531 WO 2006-GB768 20060303
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW
RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
PRAI PT 2005-103391 A 20051124
AB A process for the prodn. of iohexol comprises alkylating 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with 1-chloro-2,3-propanediol using 2-(2-methoxyethoxy)ethanol as the reaction solvent in the presence of a base (e.g., sodium hydroxide).


AN 2006:558321 CAPLUS
TI Process for the preparation of tamsulosin and intermediates thereof starting from chiral phenylethylamine and using catalytic hydrogenation as the key step
IN Mendes, Zita; Baptista, Joana; Martin, Dionisio; Heggie, William
PA Hovione Inter Ltd., Switz.; Turner, Craig Robert
SO PCT Int. Appl., 25 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
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PI WO 2006061549 A1 20060615 WO 2005-GB155 20050118
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SM, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
PT 103216 A 20060630 PT 2004-103216 20041206
PRAI PT 2004-103216 A 20041206
AB A process for producing tamsulosin of formula I and pharmaceutically acceptable addn. salts, thereof is disclosed. The process comprises the following steps: reacting (R,R)-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-(1- phenyl-ethyl)-amine or a salt thereof with chlorosulfonic acid with or without an org. solvent, to obtain (R,R)-2-methoxy-5-[2-(1-phenyl-ethylamino)-propyl]-benzenesulfonic acid. Hydrogenolysis of (R,R)-2-methoxy-5-[2-(1-phenyl-ethylamino)-propyl]- benzenesulfonic acid or a salt thereof carried out in an alc. in the presence of a palladium catalyst using hydrogen or a source of hydrogen, to obtain (R)-(-)-5-(2-amino-propyl)-2-methoxy-benzenesulfonic acid. Reacting primary amine (R)-(-)-5-(2-amino-propyl)-2-methoxy-benzenesulfonic acid or a salt thereof, with a 2-(2-ethoxyphenoxy)ethyl halide to obtain 5-[(2R)-2-[2-(2-ethoxy-phenoxy)-ethylamino]-propyl]-2-methoxy-benzenesulfonic acid, which reacted with an halogenating agent, to obtain the corresponding sulfonyl chloride, which underwent amidation with ammonia to to give compd. I.


AN 2006:381179 CAPLUS
TI Process for preparation of fluticasone analogs via esterification of a carbothioic acid
IN Sobral, Luis; Martin, Dionisio; Heggie, William; Leitaeo, Emilia
PA Hovione Inter Ltd., Switz.; Turner, Craig Robert
SO PCT Int. Appl., 18 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
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PI WO 2006043015 A1 20060427 WO 2004-GB5052 20041202
WO 2006043015 B1 20061109
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM, ZW RW: AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT, LU, MC, NL, PL, PT, RO, SE, SI, SK, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG, BW, GH, GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
PRAI PT 2004-103202 A 20041019
OS CASREACT 144:412741
AB A process for prepg. esters, such as I (R = CO(CH2)n, COCHMe2, n = 1, 2), was disclosed and comprised esterification of the C-17 hydroxyl group of 6?,9?-difluoro-11?,17?-dihydroxy-16?-methyl-3-oxoandrosta-1,4-diene-17?-carbothioic acid I (R = H) with a slight excess of a corresponding acyl chloride, RCOCl, in an inert solvent in the presence of a tertiary amine.


AN 2004:1043516 CAPLUS
TI Selecting lactose for a capsule-based dry powder inhaler
AU Steckel, Hartwig; Borowski, Malte; Eskandar, Fadi; Villax, Peter
CS Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University Kiel, Kiel, D-24118, Germany
SO Pharmaceutical Technology Europe (2004), 16(4), 23-24,27-28,31-32,34-35
PB Advanstar Communications Inc.
DT Journal
LA English
AB Dry powder inhalers are a well-accepted dosage form for pulmonary drug delivery and a wide variety are either currently available or in development. This article examines a premetered, capsule-based multidose inhaler for which different qualities of _-lactose monohydrate were screened.

AN 2003:358112 CAPLUS
TI In vitro characterization of jet-milled and in-situ-micronized fluticasone-17-propionate
AU Steckel, Hartwig; Rasenack, Norbert; Villax, Peter; Muller, Bernd W.
CS Department of Pharmaceutics and Biopharmaceutics, Christian Albrecht University, Kiel, 24118, Germany
SO International Journal of Pharmaceutics (2003), 258(1-2), 65-75
DT Journal
LA English
AB Particle properties are decisive for therapeutic efficiency of an inhaled pulmonary drug. Jet-milling as the common way for micronization of inhaled powder drugs shows several disadvantages such as a non-homogeneous particle size distribution and unnatural, thermodynamically-activated particle surfaces causing a high agglomeration behavior. For pulmonary use in a dry powder inhaler (DPI) beside a small particle size, a good de-agglomeration activity is required. In this study, fluticasone-17-propionate (FP) is in-situ prepd. in a respirable particle size by a controlled crystn. technique. First, the drug is dissolved in acetone and pptd. by a solvent change method in the presence of a cellulose ether (HPMC) as stabilizing hydrocolloid. By rapidly pouring the drug soln. into the polymer-rich water phase, the previously molecularly dispersed drug is assocd. to small particles and stabilized against crystal growth simultaneously by the presence of the hydrophilic polymer. This dispersion was then spray-dried. The mean particle size of the drug was around 2 mm and consequently in the respirable range. The physico-chem. properties of the in-situ-micronized drug were compared to those of an unmilled and a jet-milled quality. Differences in the X-ray patterns and amorphous parts could be detected for the jet-milled but not for the in-situ-micronized drug. In addn., the aerodynamic behavior of the engineered and the jet-milled FP was analyzed using the FlowCaps inhaler as delivery device and compared to the com. product Flutide Diskus.. The fine particle fraction (FPF) (<5 mm) was increased four-fold from approx. 9% for the jet-milled drug to approx. 40% for the in-situ-micronized drug when the pure drug powder was dispersed with the FlowCaps device.

AN 2002:964374 CAPLUS
DN 138:24881
TI Process for the preparation of flumethasone and its 17-carboxyl-androstene analog
IN Villax, Ivan; Mendes, Zita
PA Hovione Limited, Peop. Rep. China; Wain, Christopher Paul
SO PCT Int. Appl., 20 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
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PI WO 2002100878 A1 20021219 WO 2002-GB2644 20020611
W: AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
RW: GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW, AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG
US 6528666 B1 20030304 US 2002-162862 20020606
PRAI PT 2001-102628 A 20010612
AB A process was disclosed for prepg. Flumethasone, Flumethasone 21-acetate, or its 17-carboxyl-androstene analog via fluorination of I (X = H) with an electrophilic fluorination agent to form intermediate I (X = F). Thus, (9b,11b,16b)-21-(acetyloxy)-9,11-epoxy-17-hydroxy-16-methylpregna-1,4-diene-3,20-dione was reacted with benzoyl chloride by heating at 80-85° in pyridine and N,N-dimethylacetamide (DMA) to form benzoate I (X = H) in situ which was fluorinated in situ using Selectfluor to form the unisolated intermediate I (X = F) which was subsequently treated with sodium metabisulfite and ammonia in CH2Cl2 to give II (RR1 = 9b,11b-epoxide, R2 = CH2OAc). The epoxide thus formed was converted to Flumethasone 21-acetate II (R = OH, R1 = a-F, R2 = CH2OAc) using HF in DMF which was in turn hydrolyzed using KOH/MeOH to give Flumethasone II (R = OH, R1 = a-F, R2 = CH2OH). Flumethasone 21-acetate was also converted to its 17b-carboxy analog II (R = OH, R1 = a-F, R2 = OH) with 91.3% yield by treatment with KOH/MeOH followed with aq. H2O2.

AN 2002:808463 CAPLUS
DN 137:312706
TI Crystallization process for the preparation of crystalline and solvent-free iohexol
IN Du Boulay Villax, Guido; Ganchas de Carvalho, Alexandre Jose; Alvarez Perez, Carlos Manuel
PA Hovione Inter Ltd., Switz.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI US 6469208 B1 20021022 US 1997-964339 19971104
AB An industrial process for the purifn. and removal of residual solvents from iohexol, is presented which is based on the suspension of cryst. iohexol, eventually contg. residual solvents above 100 ppm, in a fluid wherein it has a low soly., followed by heating, filtration, and drying. This process enables the formation of cryst. iohexol with no residual org. residual solvent above 100 ppm and with an increased purity level.

AN 2001:565063 CAPLUS
DN 135:153002
TI Process for preparing mometasone from icomethasone
IN Villax, Ivan; Bandarra, Joao; Bin, Cao Zhon; Heggie, William
PA Hovione Limited, Peop. Rep. China
SO PCT Int. Appl., 13 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
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PI WO 2001055171 A1 20010802 WO 2001-GB183 20010118
W: AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW, AM, AZ, BY, KG, KZ, MD, RU, TJ, TM
RW: GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW, AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR, BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG
PRAI PT 2000-102405 A 20000120
AB Mometasone [I; 9a,21-dichloro-1b,17a-dihydroxy-16a-methyl-pregna-1,4-dine-3,20-dione] was prepd. from icomethasone [II; 9a-chloro-11b,17a,21-trihydroxy-16a-methyl-pregna-1,4-diene-3,20-dione] by reaction with a sulfonyl chloride such as methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a tertiary amine and solvent, and the 21-sulfonate so obtained was reacted with a source of chloride ions. Thus, icomethasone 21-sulfonate, obtained by the reaction of methanesulfonyl chloride and II, was reacted with sodium chloride to afford I. I, thus obtained, is a potent anti-inflammatory agent.

AN 2001:58595 CAPLUS
DN 134:86424
TI Process for the preparation of mometasone furoate
IN Heggie, William; Bandarra, Joao
PA Hovione Inter Ltd., Switz.
SO U.S., 3 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
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US 6177560 B1 20010123 US 1999-476004 19991229
AU 9956024 A1 20010208 AU 1999-56024 19991022
EP 1074558 A1 20010207 EP 1999-308380 19991025
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI, LT, LV, FI, RO
NO 9905225 A 20010205 NO 1999-5225 19991026
JP 2001048897 A2 20010220 JP 1999-315236 19991105
CN 1282744 A 20010207 CN 1999-124380 19991126
PRAI PT 1999-102343 A 19990802
AB The invention provides a new process for the prepn. of mometasone 17-furoate (I), a steroid deriv. useful in the treatment of inflammatory disease, by direct esterification of the 17 hydroxyl group without prior protection of the free 11 hydroxy function.


AN 2000:600016 CAPLUS
DN 134:120812
TI Photostability studies of drug substances and products
AU Sequeira, Fernanda; Vozone, Carla
CS Hovione Sete Casas, Loures, 2674-506, Port.
SO Pharm. Technol. (2000), 24(8), 30, 32, 34-35
PB Advanstar Communications, Inc.
DT Journal
LA English
AB The authors studied the photostability characteristics of a drug substance and its formulated product according to the conditions proposed in ICH's guideline on photostability. Two photostability apparatuses were designed on the basis of Option 2 recommendations. The results indicate that the conditions provide insufficient details to ensure reproducibility. The current ICH recommendations are subject to different interpretations and therefore need further improvements and better standardization.


AN 2000:175540 CAPLUS
DN 132:207018
TI A process for the purification of roxithromycin by crystallization of methanol
IN Heggie, William; Sobral, Luis; Carvalho, Alexandre
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 985680 A1 20000315 EP 1999-305553 19990713
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI, LT, LV, FI, RO
AU 9940169 A1 20000316 AU 1999-40169 19990716
JP 2000086690 A2 20000328 JP 1999-216819 19990730
PRAI PT 1998-102202 19980910
AB A process for the purifn. of roxithromycin, an antibiotic for therapeutic purposes, in which the purifn. is carried out by the dissoln. or suspension of the product in methanol followed by cooling. Purifn. may also be obtained by addn. of a non-solvent and/or by concn. of the mixt., thus obtaining a purified product.


AN 1999:783805 CAPLUS
DN 132:7050
TI A process for the preparation of 4-(des-dimethylamino)-tetracyclines
IN Heggie, William; Santos, Pedro; Galindro, Jose; De Carvalho, Luis
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 6 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 962552 A1 19991208 EP 1999-302600 19990401
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI, LT, LV, FI, RO
AU 9922444 A1 19991202 AU 1999-22444 19990326
JP 2000034264 A2 20000202 JP 1999-105105 19990413
CN 1236775 A 19991201 CN 1999-105154 19990421
NO 9902072 A 19991129 NO 1999-2072 19990429
US 6143161 A 20001107 US 1999-317396 19990524
PRAI PT 1998-102160 19980526
AB The present invention refers to a process for the prepn. of 4-(desdimethylamino)tetracyclines, which compds. have a therapeutical application. The starting tetracyclines are treated with a methylating agent and the resulting trimethylammonium salts are reduced by electrolysis in an aq. soln. at acidic pH, in the presence of an adequate electrolyte. A direct elec. current with a potential of 0.5-1.5 V is applied between two convenient electrodes until the reaction is complete.
The 4-(desdimethylamino)tetracyclines are isolated by extn. with an org. solvent.

AN 1999:597477 CAPLUS
DN 131:219156
TI Preparation of azithromycin dihydrate
IN Heggie, William; Mendez, Zita; Bandarra, Joao
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 7 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 941999 A2 19990915 EP 1999-301788 19990310
EP 941999 A3 19991013
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT,
IE, SI, LT, LV, FI, RO
NO 9901204 A 19990914 NO 1999-1204 19990311
JP 11322776 A2 19991124 JP 1999-65443 19990311
CN 1232037 A 19991020 CN 1999-105538 19990312
PRAI PT 1998-102130 19980313
AB Azithromycin dihydrate is prepd. from azithromycin by adding a base to an aq. soln. of azithromycin to crystallize the dihydrate, the aq. soln. having a pH of from 1 to 5 and contg. acetone. Azithromycin 5 g was dissolved in 22.6 mL water and 2.4 mL HCl (6 N) and to this soln. was added 25 mL acetone and 2.8 mL of 20 % aq. NaOH soln. to adjust the pH to 9.8. After stirring for 5 h at 20-25.degree., the suspension was cooled to 0-5.degree.. The resulting solid was collected by filtration, washed with water, and dried at 35-40.degree. to give 3.3 g azithromycin dihydrate.

AN 1999:355612 CAPLUS
DN 130:352089
TI Process for the preparation of purified crystalline iohexol by crystallization using ethanol
IN Du Boulay Villax, Guido; Alvarez Perez, Carlos Manuel; Ganchas de Carvalho, Alexandre Jose
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 919540 A1 19990602 EP 1997-308629 19971029
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI, LT, LV, FI, RO
JP 11158136 A2 19990615 JP 1997-302830 19971105
PRAI EP 1997-308629 19971029
AB Hydrophobic contaminants (e.g., O-alkylated derivs.) and residual org. solvents are removed from the X-ray contrast agent iohexol by the use of a solvent such as ethanol in which the iohexol is insol. In one procedure, ethanol is added to an aq. soln. of iohexol. In another procedure, the iohexol is suspended in ethanol and then allowed to crystallize. Cryst. iohexol having a residual solvent content <100 ppm is prepd. in this way.

AN 1999:294110 CAPLUS
DN 130:293354
TI Process for the preparation of crystalline and solvent-free iohexol
IN Villax, Guido du Boulay ; Ganchas de Carvalho, Alexandre Jose; Perez, Carlos Manuel Alvarez
PA Hovione Inter Ltd., Switz.
SO Pat. Specif. (Aust.), 10 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
AU 696647 B1 19980917 AU 1997-42807 19971021
AB An industrial-scale process for the purifn. and removal of residual solvents from the X-ray contrast agent iohexol is presented which is based on the suspension of cryst. iohexol, eventually contg. residual solvents above 100 ppm, in a fluid where it has a low soly. (e.g., EtOH), followed by heating, filtration, and drying. The process allows the formation of cryst. iohexol with a residual org. solvent content of .ltoreq.100 ppm and with an increased purity level.

AN 1998:764191 CAPLUS
DN 130:25264
TI One-pot preparation of azithromycin
IN Heggie, William; De Mouro Vaz Azevedo Mendes, Zita Maria
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 879823 A1 19981125 EP 1998-303945 19980519
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL, SE, MC, PT, IE, SI, LT, LV, FI, RO
AU 9861938 A1 19981119 AU 1998-61938 19980417
CA 2237747 AA 19981119 CA 1998-2237747 19980515
CN 1199736 A 19981125 CN 1998-108489 19980518
PRAI PT 1997-102006 19970519
AB In prepg. azithromycin from erythromycin A by forming its oxime, Beckmann rearrangement of the oxime into the imino ether, redn. of the imino ether to 9-deoxo-9a-aza-9a-homo-erythromycin and reductive methylation of the latter, the last 2 steps are carried out in 1-pot sequentially, using a noble metal (Rh, Pt, Pd, Ru) catalyst and H in the presence of HCHO or a HCHO source, e.g., paraformaldehyde, in AcOH as solvent.

AN 1998:277948 CAPLUS
DN 128:317409
TI Pharmacokinetics, protein binding, and metabolic profile of 3H-icometasone enbutate following intravenous, oral, and intratracheal administrations to Sprague-Dawley rats
AU Duchene, Patrick; Giudicelli, Marie Dominique; Neau, Bernard; Gronfier, Agnes; Firmin, Yves; Villax, Peter ; Saivin, Sylvie; Houin, Georges
CS ADME Bioanalyses, Mougins, F-06250, Fr.
SO Arzneim.-Forsch. (1998), 48(4), 371-378
PB Editio Cantor Verlag
DT Journal
LA English
AB Absorption, distribution, and excretion of 3H-icometasone enbutate (9.alpha.-chloro-11.beta.,17.alpha.,21-trihydroxy-16.alpha.-methylpregna- 1,4-diene-3,20-dione, 17-butyrate, 21-acetate, CAS 103466-73-5 CL09) were studied in male and female Sprague-Dawley rats after a single dose administration by i.v. (1 mg/kg), oral, and intratracheal (2 mg/kg) routes. The metabolic profile after the different routes and protein binding were also detd. Independent of the route, the radioactivity was mainly excreted in feces. Less than 10% of the dose were excreted in urine. The majority of the administered doses was recovered within 24 h postdose, and the total recovery of the doses administered was obtained. After oral and i.v. administration to bile-duct cannulated rats, most of the radioactivity was excreted in the bile (80% of the administered dose) and some radioactivity was found in the feces. It can thus be concluded that some intestinal secretion occurred. After oral administration, mean max. blood concns. were obtained about 0.75 h postdose. For the intratracheal route, the radioactive dose administered was too low to det. precise blood pharmacokinetic parameters. However, the distribution study results allowed us to conclude that the drug was absorbed 1st from the lungs and then from the gastrointestinal tract. Immediately after the i.v. injection, the liver, the kidneys, the small intestine and its contents, and the carcass presented the highest levels of radioactivity. 168 H postdose, low radioactivity was still measurable in these organs. In other tissues, the radioactivity decreased reaching the limit of quantification 72 h postdose. After oral administration, the max. concns. were obsd. 1 h after administration in the liver, the small intestine and its contents. Then the radioactivity decreased in most of the tissues but a slight increase at 72 and/or 120 h postdose was noted in large intestine contents, carcass, lungs, eyes. After intratracheal administration, the max. radioactivity was obsd. in lungs and trachea. A few minutes later the radioactivity reached the gastrointestinal tract. The protein binding study showed a saturable binding in rat and human blood plasma without notable differences between the 2 species. The binding on human serum albumin was not saturable with a total binding capacity of 7.48 .mu.mol/L, suggesting that other proteins were involved in CL09 binding. This binding was reversible. CL09 was extensively metabolized since no unchanged CL09 was recovered in bile or urine and at least 9 metabolites were detected. The profiles were different according to the route of administration.

AN 1997:61241 CAPLUS
DN 126:74602
TI Process for the purification and crystallization of iopamidol using propanols
IN Heggie, William; De Mouro, Vaz Azevedo Mendes, Zita Maria; De Lacerda e Oliveira Santos, Pedro Paulo
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 6 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 747344 A1 19961211 EP 1996-304106 19960605
EP 747344 B1 19980114
R: AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LI, LU, NL, PT, SE
AU 9654512 A1 19961219 AU 1996-54512 19960527
AU 695662 B2 19980820
JP 08333319 A2 19961217 JP 1996-140103 19960603
JP 2835313 B2 19981214
AT 162180 E 19980115 AT 1996-304106 19960605
ES 2114336 T3 19980516 ES 1996-304106 19960605
CA 2178369 AA 19961209 CA 1996-2178369 19960606
PRAI PT 1995-101720 19950608
AB The purifn. and crystn. of iopamidol (I) is achieved by adding 1-propanol or 2-propanol to an aq. soln. of I followed, if necessary, by azeotropic distn. to reduce the quantity of water in relation to the quantity of propanol, and thereby ensure a high I yield. The aq. soln. can be prepd. either by the dissoln. of crude I in water or directly from the reaction in which the I is formed. This process presents advantages to the routine prodn. of I since the crystn. is straightforward to perform, can be easily controlled, and is reproducible at an industrial scale.

AN 1996:292698 CAPLUS
DN 125:10394
TI Aspects of the stereospecific hydrogenation of the exocyclic double-bond of methacycline
AU Heggie, William; Page, Philip Ronald; Villax, Ivan
CS Hovione Soc. Quimica, Port.
SO Actas Encontro Nac. Catal. Basica Apl. (Ind. Ambiental), 3rd (1995), 271-82. Editor(s): Portela, Manuel Farinha; Freire, Filipe Gama; Castillo, Maria do Pilar. Publisher: Sociedade Portuguesa de Catalise, Lisbon, Port.
DT Conference; General Review
LA English
AB Review with 12 refs.

AN 1996:55161 CAPLUS
DN 124:192324
TI Preparation, crystal structure and mechanism of formation of a novel dinuclear carbopentazane complex, [Rh2(PPh3)4{(NH2NH)2CH2}][NO3]2
AU Heaton, Brian T.; Jacob, Chacko; Monks, Gary L.; Hursthouse, Michael B.; Ghatak, Indira; Somerville, Richard G.; Heggie, William; Page, Philip R.; Villax, Ivan
CS Dep. Chem., Univ. Liverpool, Liverpool, L69 3BX, UK
SO J. Chem. Soc., Dalton Trans. (1996), (1), 61-7
DT Journal
LA English
AB The reaction of Rh(NO3)3.cntdot.2H2O with PPh3 and N2H4.cntdot.H2O in MeOH gave the dinuclear carbopentazane complex [Rh2(PPh3)4{(NH2NH)2CH2}](NO3)2 (I), which was characterized by multinuclear NMR measurements and x-ray diffraction (monoclinic, space group P21/n, R = 0.041). It has a dipos., dinuclear cation in which the two bis(triphenylphosphine)rhodium units are bridged by the tetradentate carbopentazane ligand. The Rh atoms have the expected square-planar geometry, with Rh-P and Rh-N distances of 2.225(3)-2.253(3) and 2.130(6)-2.166(6) .ANG., resp. Expts. aimed at elucidating the mechanism of formation of I indicated that the formation of the NCH2N linkage occurs via acid-catalyzed nucleophilic addn. of free N2H4 to the CH2 group of an NH2N:CH2 ligand coordinated to RhI, and unambiguous multinuclear NMR (13C, 15N and 31P) and mass spectrometric evidence was obtained for monomeric [cyclic] [Rh(PPh3)2(NH2NHCH2NHNH2)]+ (II), which readily rearranges to form I. Related expts. also provided evidence for the formation of [cyclic] [Rh(PPh3)2(NH2NHCHMeNHNH2)]+, which also rearranges to give a dinuclear complex, [Rh2(PPh3)4{(NH2NH)2CHMe}]2+.

AN 1995-276448 WPINDEX DERWENT INFORMATION LTD
TI Medicament inhaler and method.
IN Villax, Peter; Peres, Rui; Treneman, William Richard; McDerment, Iain Grierson; Bunce, Martin
PA (PLUR-N) PLURICHEMIE ANSTALT; (HOVI-N) HOVIONE PROD FARM SA
EP 666085 A1 19950809 EN
R: AT BE CH DE DK ES FR GB GR IE IT LI NL SE
PT 101450 A 19950809
AU 9511407 A 19950810
NO 9500368 A 19950803
SK 9500119 A3 19950809
CA 2141465 A 19950803
FI 9500444 A 19950803
ZA 9500356 A 19960228
CZ 9500210 A3 19960911
BR 9500536 A 19970325
HU 71287 T 19951128
CN 1111160 A 19951108
US 5673686 A 19971007
NZ 270403 A 19980325
AU 698047 B 19981022
PRAI PT 1994-101450 19940202
AB EP 666085 A UPAB: 19950921
Fluidising powdered medicament for inhalation comprises drawing air through an inhalation tube (1) closed by a chamber contg. the medicament and with air passage holes causing the air to fluidise and entrain the powder. Air is admitted to the tube downstream (6) of the chamber. Also claimed is a powdered medicament inhaler comprising an inhaler tube, chamber receiving means to receive a capsule or other chamber to close the tube and an air inlet downstream of the receiving means.
The tube end is pref. sized to receive a medicament capsule (4) in close fit. The capsule has air entry and exit holes (8,10). Alternatively, capsules are supplied successively from a magazine to the chamber, moving w.r.t. a knife which forms the holes. The exit hole area is larger than the inlet hole area. Movement of powder in the capsule is visible to the user through the capsule wall.
ADVANTAGE - Is simple and efficient to use can give the user clear evidence of capsule content release during inhalation.
Dwg.2/8

AN 1994:59231 CAPLUS
DN 120:59231
TI Process for simultaneous recovery of precious metals and tertiary phosphine from spent catalysts using tellurium
IN De Oliveira, Bandarra Joao J.; De Carvalho, Alexandre J. G.; Heggie, William
PA Plurichemie Anstalt, Liechtenstein
SO Can. Pat. Appl., 9 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
CA 2086384 AA 19930701 CA 1992-2086384 19921229
EP 565800 A2 19931020 EP 1992-311700 19921222
EP 565800 A3 19940209
R: AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LI, LU, NL, SE
AU 9230410 A1 19930708 AU 1992-30410 19921223
AU 653306 B2 19940922
ZA 9210085 A 19930803 ZA 1992-10085 19921229
CN 1073986 A 19930707 CN 1992-115022 19921230
CN 1035888 B 19970917
RU 2083280 C1 19970710 RU 1992-16226 19921230
US 5282884 A 19940201 US 1992-999319 19921231
HU 66996 A2 19950130 HU 1992-4188 19921231
HU 212481 B 19960729
JP 05263161 A2 19931012 JP 1993-46 19930104
PRAI PT 1991-99958 19911231
PT 1991-99959 19911231
AB The org. or inorg. wastes are contacted with a solvent >120.degree., distd. to remove the lower-b.p. solvents and water, and then are contacted with Te (or a reducing Te compd.) with heating an refluxing to react with the precious metal for recovery. The high-b.p. solvent is preferably DMF suitable for fractional distn. at .ltoreq.150.degree.. After the sepn. of metal-Te complexes, the residual soln. is heated to recover the high-b.p. solvent, followed by sepn. of the tertiary phosphine as oxide by pptn. with water. The process is suitable for recovery of catalyst metals from spent hydrogenation catalyst typically contg. tris(triphenylphosphine)chlorerhodium or similar Rh compds.

AN 1993:109031 CAPLUS
DN 118:109031
TI Waste minimization - a case study
AU Macleod, Fiona
CS Hovione , Loures, 2670, Port.
SO Chem. Eng. (Rugby, Engl.) (1992), 530, 21-4
DT Journal
LA English
AB The waste minimization in Hovione Co., Portuguese, was achieved by an efficient communication, economics and technol. evaluation, and recycling.

AN 1991:693314 CAPLUS
DN 115:293314
TI Structure of [RhH2(PPh3)2(bipy)]Cl (bipy = 2,2'-bipyridyl) from multinuclear NMR studies
AU Heaton, B. T.; Jacob, C.; Heggie, W.; Page, P. R.; Villax, I.
CS Dep. Chem., Univ. Liverpool, Liverpool, L69 3BX, UK
SO Magn. Reson. Chem. (1991), 29(Spec. Issue), S21-S24
DT Journal
LA English
AB By the use of the INEPT pulse sequence it has been possible to obtain 15N and 103Rh NMR data on [RhH2(PPh3)2(bipy)]Cl (bipy = 2,2'-bipyridyl) contg. natural abundance 15N and prove the stereochem.; 1H and 31P NMR data are also reported for [RhH2(PPh3)2(bipy)]Cl which can be easily prepd. in the pure state by the reaction of [RhCl(PPh3)3] or [Rh2Cl2(PPh3)4] with bipy ([Rh]:[bipy] = 1:1) under an H2 atmosphere.

AN 1991:220199 CAPLUS
DN 114:220199
TI Process for the preparation of a rhodium complex
IN Heggie, William; Page, Philip Ronald; Villax, Ivan ; Ghatak, Indira; Hursthouse, Michael Barry
PA Plurichemie Anstalt, Liechtenstein
SO Eur. Pat. Appl., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 411854 A1 19910206 EP 1990-308327 19900730
EP 411854 B1 19940907
R: AT, BE, CH, DE, ES, FR, GB, GR, IT, LI, LU, NL, SE
US 5075470 A 19911224 US 1990-558058 19900726
ES 2064647 T3 19950201 ES 1990-308327 19900730
PRAI PT 1989-91333 19890731
AB A process for the prepn. of .mu.-3-carbopentazane-N1,N4:N2,N5- bis[bis(triphenylphosphine)rhodium(I)] dinitrate, claimed as a stereospecific hydrogenation catalyst, involves reaction of tris(triphenylphosphine)nitratorhodium(I) with hydrazine in degassed MeOH under an inert atm.

¬ back to top


AN 1989:212494 CAPLUS
DN 110:212494
TI Homogeneous catalytic system for hydrogenation of methylenetetracyclines and a process for the preparation of same
IN Page, Philip R.; Villax, Ivan
PA Plurichemie Anstalt, Liechtenstein
SO U.S., 8 pp. Cont.-in-part of U.S. 4,550,096.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 4743699 A 19880510 US 1985-732952 19850513
US 4550096 A 19851029 US 1983-458068 19830114
CA 1218058 A1 19870217 CA 1983-425254 19830405
HU 34375 A2 19850328 HU 1983-2127 19830615
HU 196143 B 19881028
IN 160450 A 19870711 IN 1983-DE843 19831216
AT 8304452 A 19901215 AT 1983-4452 19831220
AT 392922 B 19910710
AT 51626 E 19900415 AT 1985-305045 19850715
US 32535 E 19871027 US 1986-858660 19860501
IN 164810 A 19890603 IN 1986-DE554 19860625
US 4877559 A 19891031 US 1986-925109 19861027
PRAI PT 1982-74303 19820119
PT 1982-76061 19821230
US 1983-458068 19830114
PT 1984-79774 19841228
US 1983-458067 19830114
IN 1983-DE843 19831216
US 1985-732952 19850513
EP 1985-305045 19850715
AB A process for the prepn. of a homogeneous stereospecific Rh complex hydrogenation catalyst for methylenetetracyclines, of a uniform and well defined compn., contg. Rh, a hydrazine and PPh3, as well as an anion, comprising reacting a Rh salt with R1R2NNR3R4 (I; R1, R2, R3, R4 = lower alkyl, H) or a salt thereof in the presence of PPh3, or by reacting a complex of Rh and PPh3 with I or salt thereof, if necessary in the presence of excess PPh3, was characterized by the fact that the reaction is carried out in a mixt. of a degassed org. solvent, miscible in the reaction, and possibly H2O, at a temp. between 0.degree. and reflux of the reaction medium for between 20 min and 5 h, under an inert atm., and the isolation of the catalyst is carried out by cooling when the complex so formed is little sol. in the cold reaction mixt., or by slow addn. of a degassed inert non-solvent and by cooling when the complex prepd. is sol. in the reaction mixt., followed by filtration and drying under an inert atom. (PPh3)3RhCl and N2H4.H2O in 95% EtOH were refluxed 25 min to give an orange product contg. 16.95% Rh and 4.25% N. This in MeOH was stirred with 6-methylene-5-hydroxytetracycline-HCl and PPh3 in MeOH under 8 kg/cm2 H2 6 h 30 min and the product treated with 4-MeC6H4SO3H to give an .alpha.-6-deoxyoxytetracycline p-tofluenesulfonate in 98.4% yield and 99.8% purity.

AN 1989:78059 CAPLUS
DN 110:78059
TI Rhodium-containing hydrogenation catalysts for the conversion of methacycline to doxycycline
IN Heggie, William; Hursthouse, Michael Barry; Page, Philip Ronald; Somerville, Richard Gerard; Villax, Ivan
PA Plurichemie Anstalt, Liechtenstein
SO Eur. Pat. Appl., 10 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 283615 A1 19880928 EP 1987-304278 19870514
EP 283615 B1 19910508
R: AT, BE, CH, DE, ES, FR, GB, GR, IT, LI, LU, NL, SE
AT 63312 E 19910515 AT 1987-304278 19870514
US 4863639 A 19890905 US 1987-50931 19870515
ZA 8703543 A 19881130 ZA 1987-3543 19870518
AU 8773432 A1 19880929 AU 1987-73432 19870527
AU 595606 B2 19900405
BE 1000435 A3 19881206 BE 1987-900 19870812
FR 2612802 A1 19880930 FR 1988-205 19880111
FR 2612802 B1 19921002
US 4968654 A 19901106 US 1989-325445 19890320
PRAI PT 1987-74303 19870325
EP 1987-304278 19870514
US 1987-50931 19870515
AB (.mu.-Hydrazine-N1:N2)-bis[bis(triphenylphosphine)chlororhodium (I)] (I) and di(.mu.-hydrazine-N1:N2)-bis[bis(triphenylphosphine)rhodium (I)]dichloride (II), useful as stereospecific hydrogenation catalysts for the conversion of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (methacycline) (III) to .alpha.-6-deoxy-5-hydroxytetracycline (doxycycline) (IV), are prepd. by reacting tris(triphenylphosphine)chlororhodium (V) with hydrazine hydrate in MeOH under an inert atm. in the absence of O using degassed MeOH. I is produced when each mol of V is reacted with .ltoreq.1 mol of hydrazine, and II is formed when the reaction is conducted with .gtoreq.1 mol of hydrazine. The reaction mixt. is stirred at room temp. or refluxed, followed by standing at room temp. for .gtoreq.12 h, forming crystals of the resp. complex catalyst. V (15.0 mg) and 124 mL of a 0.4 M methanolic hydrazine soln. were added to 60 mL MeOH under N, and 7.38 g III hydrochloride added. The mixt. was charged into a reactor and hydrogenated at 88.degree. and 8 kg/cm2. p-Toluenesulfonic acid (3.3 g) was added and the mixt. stirred at 0.degree. for 2 h, producing 8.84 g of 98.9% pure IV p-toluenesulfonate.

AN 1989:68575 CAPLUS
DN 110:68575
TI Isolation and x-ray crystal structure analysis of a hydrazine-containing rhodium catalyst, [(MeOH)2H]+[RhCl4(PPh3)(NHMeNHMe)]-
AU Hursthouse, Michael B.; Newton, Joy; Page, Philip R.; Villax, Ivan
CS Dep. Chem., Queen Mary Coll., London, E1 4NS, UK
SO Polyhedron (1988), 7(19-20), 2087-9
DT Journal
LA English
AB Reaction of RhCl(PPh3)3 with [MeH2NNH2Me]Cl in MeOH gives [(MeOH)2H][RhCl4(PPh3)(NHMeNHMe)], which was characterized by x-ray crystallog. [triclinic space group P.hivin.1, a 16.430(3), b 9.848(2), c 9.850(2) .ANG., .alpha. 117.79(2), .beta. 75.99(2), .gamma. 45.15(2).degree., Z = 2; R = 0.0393 for refinement of 3491 data with I > 1.5.sigma. (I)]. The complex anion has an octahedral structure with the phosphine and hydrazine ligands mutually trans and is formulated as a Rh(III) species on the basis of the bond lengths in the structure and its diamagnetism. The compensating cation is a proton which, although not unequivocally identified in the structure, is presumed to be present as a dimethanolium unit, in which the O...O distance is 2.67 .ANG..

AN 1989:64523 CAPLUS
DN 110:64523
TI Rhodium hydrogenation catalysts particularly for stereoselective hydrogenation of methacycline to doxycycline
IN Heggie, William; Page, Philip Ronald; Villax, Ivan ; Ghatak, Indira; Hursthouse, Michael Barry
PA Plurichemie Anstalt, Liechtenstein
SO Eur. Pat. Appl., 11 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 283616 A1 19880928 EP 1987-304279 19870514
EP 283616 B1 19910724
R: AT, BE, CH, DE, ES, FR, GB, GR, IT, LI, LU, NL, SE
AT 65429 E 19910815 AT 1987-304279 19870514
US 4857235 A 19890815 US 1987-50932 19870515
ZA 8703545 A 19881130 ZA 1987-3545 19870518
AU 8773431 A1 19880929 AU 1987-73431 19870527
AU 595319 B2 19900329
CA 1296327 A1 19920225 CA 1987-539016 19870605
BE 1000671 A3 19890307 BE 1987-710 19870625
FR 2612803 A1 19880930 FR 1987-9869 19870710
FR 2612803 B1 19890616
IL 84196 A1 19910816 IL 1987-84196 19871018
FI 8705168 A 19880926 FI 1987-5168 19871123
FI 86305 B 19920430
FI 86305 C 19920710
HU 47065 A2 19890130 HU 1988-1489 19880323
HU 200150 B 19900428
NO 8801313 A 19880926 NO 1988-1313 19880324
NO 169342 B 19920302
NO 169342 C 19920610
US 4911865 A 19900327 US 1989-322176 19890313
PRAI PT 1987-76061 19870325
EP 1987-304279 19870514
US 1987-50932 19870515
AB Homogeneous catalyst systems including I and II are prepd. for use in stereoselective hydrogenation of methacycline to the bactericide doxycycline. Rh(NO3)3.2H2O 1.18, PPh3 4.27, and hydrazine 3.36 mmol in MeOH (10 mL of a 10.77 mg/mL soln) were refluxed overnight under N in MeOH and large orange crystals of II obtained, for which the crystal structure was detd. (parameters given). Methacycline 21.7 mmol was suspended in MeOH 84.5 mL in a stainless steel high-pressure reaction vessel to which II 0.017 mmol was added. The vessel was purged under N and pressurized to 8 kg/cm2 with H. The reaction was performed at 88.degree. for 6.5 h with stirring. The H was discharged and p-toluenesulfonic acid 24.2 mmol was added; after stirring for 2 h, the resulting doxycycline p-toluenesulfonate 12.0 g was obtained by filtering, washing with MeOH and drying at 35.degree.; the product yield was 89.8% and the product, as shown by HPLC, was 99.2% pure.

AN 1988:204881 CAPLUS
DN 108:204881
TI Novel process for the preparation of steroidal esters
IN Page, Philip R.; Heggie, William
PA Plurichemie Anstalt, Liechtenstein
SO U.S., 13 pp. Cont.-in-part of U.S. Ser. No. 402,548, abandoned.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 4655971 A 19870407 US 1984-641267 19840816
ZA 8205551 A 19830629 ZA 1982-5551 19820802
PRAI PT 1981-73479 19810804
PT 1981-73864 19811022
US 1982-402548 19820728
AB Title compds. I [X = H, Cl, F; R1 = H, F, Cl, Me; R2 = halo, oxo, hydroxy; R3 = H, .alpha.- or .beta.-Me; R2X = O; R4 = RCO (R = alkyl, aralkyl, Ph); R5 = OH, R6 (R6 = H, R7CO2 where R7 = alkyl, aralkyl, Ph) a dashed line may be a double bond (II)], useful as drugs, are prepd. from I (R2 = trihaloacetoxy, H, oxo; R2X = O R4 = H) (III). Treatment of a mixt. of dexamethasone 11-trifuloacetate 21-acetate and MeSO3H with a mixt. of CF3CO2H and (Me2CHCO)2O at 60.degree. for 3 h gave dexamethasone 11-trifluoroacetate 17-isobutyrate 21-acetate, which in MeOH was treated with Et3N at 25.degree. for 1 h to afford dexamethasone 17-isobutyrate 21-acetate, whose vasoconstriction activity was 1280, vs. 100 for fluocinolone acetamide. An ointment was formulated contg. dexamethasone 17,21-dipropionate 0.1 (as dexamethasone), liq. paraffin 8.1, and solid vaseline 91.8%.

AN 1986:626200 CAPLUS
DN 105:226200
TI Rhodium hydrogenation catalyst
IN Villax, Joao Emerico ; Page, Philip Ronald
PA Hovione Inter Ltd., Switz.
SO Belg., 9 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
BE 903700 A1 19860314 BE 1985-215904 19851122
AU 8545010 A1 19860703 AU 1985-45010 19850715
AU 569164 B2 19880121
EP 187436 A1 19860716 EP 1985-305045 19850715
EP 187436 B1 19900404
R: AT, BE, CH, DE, FR, GB, LI
AT 51626 E 19900415 AT 1985-305045 19850715
CA 1245643 A1 19881129 CA 1985-486869 19850716
GB 2168979 A1 19860702 GB 1985-26784 19851030
GB 2168979 B2 19880622
DK 8505331 A 19860629 DK 1985-5331 19851119
DK 164815 B 19920824
DK 164815 C 19930104
NL 8503207 A 19860716 NL 1985-3207 19851121
FR 2575473 A1 19860704 FR 1985-17511 19851127
FR 2575473 B1 19891201
SE 8505766 A 19860629 SE 1985-5766 19851206
SE 460581 B 19891030
SE 460581 C 19900222
NO 8504972 A 19860630 NO 1985-4972 19851211
CH 668427 A 19881230 CH 1985-5365 19851217
DE 3545395 A1 19860703 DE 1985-3545395 19851220
ZA 8509760 A 19860924 ZA 1985-9760 19851220
JP 61161296 A2 19860721 JP 1985-293376 19851227
JP 03080149 B4 19911224
US 32535 E 19871027 US 1986-858660 19860501
PRAI PT 1984-79774 19841228
US 1983-458067 19830114
EP 1985-305045 19850715
AB (Ph3P)2Rh(OMe)NHNH2 is prepd. as a stereospecific catalyst for the hydrogenation of 6-demethyl-6-deoxy-6-methylene-5-hydroxytetracycline (I) into doxycycline. Thus, the catalyst was prepd. by refluxing .48 g (Ph3P)3RdCl with 76 .mu.L H2NNH2 in 20 mL MeOH for 90 min. I.HCl (7.38 g), 25 mg catalyst, and 0.1 g Ph3P in 40 mL MeOH were hydrogenated at 89.degree. and 8 kg/cm2, for 5.5 h to give doxycycline, isolated as the p-toluenesulfonate, in 99.5% purity.

AN 1986:479228 CAPLUS
DN 105:79228
TI Preparation and use of new solvates of beclomethasone 17,21-dipropionate
IN Page, Philip Ronald; Heggie, William
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 9 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 172672 A1 19860226 EP 1985-305303 19850725
EP 172672 B1 19880107
R: AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE
DK 8503364 A 19860126 DK 1985-3364 19850724
NO 8502948 A 19860127 NO 1985-2948 19850724
NO 163899 B 19900430
NO 163899 C 19900808
AU 8545305 A1 19860130 AU 1985-45305 19850724
AU 566318 B2 19871015
IL 75903 A1 19891031 IL 1985-75903 19850724
US 4913892 A 19900403 US 1985-758287 19850724
ZA 8505620 A 19860326 ZA 1985-5620 19850725
JP 61083197 A2 19860426 JP 1985-163086 19850725
JP 01029199 B4 19890608
AT 31721 E 19880115 AT 1985-305303 19850725
CA 1274503 A1 19900925 CA 1985-487542 19850725
ES 550595 A1 19870401 ES 1985-550595 19851231
PRAI PT 1984-78972 19840725
PT 1985-80796 19850711
EP 1985-305303 19850725
AB Diisopropyl ether solvates of beclomethasone 17,21-dipropionate (I), useful in aerosol inhalers (formulation given), are prepd. by dissoln. of I in an org. solvent, and pptn. by addn. of diisopropyl ether (II). Thus, 100 g I in 1 L CHCl3 was filtered and treated with 4 L II under stirring for 1 h. The pptd. solid was filtered, washed with II, and dried at 35.degree. to give 104.9 g I.cntdot.II solvate, m. 210-2.degree., which lost 10.8% wt. on drying, and showed 6.9% II and 3.0% CHCl3 by gas chromatog. Solvates of I and II also contg. THF or dioxane were similarly prepd. The solvates are stable in bulk or micronized forms, with the latter showing no significant crystal growth or agglomeration in aerosol formulations (no data).

AN 1986:460819 CAPLUS
DN 105:60819
TI 9.alpha.-Fluoro or 9.alpha.-chloro corticosteroid esters
IN Villax, Ivan ; Page, Philip Ronald; Heggie, William
PA Hovione Inter Ltd., Switz.
SO Eur. Pat. Appl., 17 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 170500 A2 19860205 EP 1985-305302 19850725
EP 170500 A3 19860611
EP 170500 B1 19901010
R: AT, BE, CH, DE, FR, GB, IT, LI, NL, SE
IL 75871 A1 19890515 IL 1985-75871 19850722
DK 8503345 A 19860126 DK 1985-3345 19850723
DK 167617 B1 19931129
AU 8545306 A1 19860130 AU 1985-45306 19850724
AU 571986 B2 19880428
JP 61053297 A2 19860317 JP 1985-162156 19850724
JP 02015559 B4 19900412
ES 545560 A1 19860601 ES 1985-545560 19850724
ZA 8505621 A 19860326 ZA 1985-5621 19850725
AT 57384 E 19901015 AT 1985-305302 19850725
CA 1307257 A1 19920908 CA 1985-487535 19850725
CN 85106388 A 19870311 CN 1985-106388 19850824
CN 1006070 B 19891213
JP 63054392 A2 19880308 JP 1987-162522 19870701
JP 03007679 B4 19910204
US 5026693 A 19910625 US 1990-527718 19900521
PRAI PT 1984-78973 19840725
US 1985-758289 19850724
EP 1985-305302 19850725
AB Title esters I (R = Cl, OR1; R1, R2 = C2-6 acyl, benzoyl; R3 = .alpha.- or .beta.-Me or -F; X = Cl, F; .DELTA.1 may be present or absent) were prepd. by reacting the epoxides II with HCl or HF. Thus, II (R = O2CPh, R2 = COEt, R3 = .alpha.-Me, .DELTA.1 present) was added slowly to 50% HCl in DMF at -5.degree. to 0.degree., followed by stirring for 2.5 h and pptn. in aq. NH3 and ice to give 96% I (X = Cl, others as above). Twenty-seven other I were similarly prepd., many (esp. with X = Cl) being novel antiinflammatories, and most of these having activities comparable to or greater than betamethasone 17-valerate in the rat-paw edema test. I (R = O2CPr, R2 = COPr, COEt, R3 = .alpha.-Me, X = Cl, .DELTA.1 present) were particularly active.

AN 1985:534233 CAPLUS
DN 103:134233
TI Semisynthetic tetracyclines. From molecular anatomy to clinical pharmacology
AU Bernardo, Mario; Page, Philip
CS Dep. Med. Hovione , Soc. Quim., Lda., Port.
SO Medico (Oporto, Port.) (1985), 112(1736), 593-4, 596, 599, 601
DT Journal; General Review
LA Portuguese
AB A review with 15 refs. on the pharmacokinetics and clin. applications of tetracyclines.

AN 1985:523270 CAPLUS
DN 103:123270
TI .alpha.-Deoxytetracyclines
IN Page, Philip Ronald
PA Hovione Inter Ltd., Switz.
SO Fr. Demande, 24 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2550788 A1 19850222 FR 1984-12815 19840814
FR 2550788 B1 19891117
DK 8403867 A 19850218 DK 1984-3867 19840810
AU 8431979 A1 19850221 AU 1984-31979 19840816
AU 548771 B2 19860102
ES 535223 A1 19851101 ES 1984-535223 19840816
ZA 8406423 A 19850327 ZA 1984-6423 19840817
EP 137661 A2 19850417 EP 1984-305623 19840817
EP 137661 A3 19870819
EP 137661 B1 19891102
R: AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE
JP 60126255 A2 19850705 JP 1984-170516 19840817
JP 63063539 B4 19881207
US 4597904 A 19860701 US 1984-641607 19840817
CA 1242704 A1 19881004 CA 1984-461264 19840817
AT 47710 E 19891115 AT 1984-305623 19840817
PRAI PT 1983-77210 19830817
PT 1984-78334 19840329
EP 1984-305623 19840817
AB .alpha.-Deoxytetracyclines I (R = H, OH) were prepd. stereoselectively by reducing methylenetetracyclines II (R = H, OH; R1 = Br, Cl) and III on an aminopropylsilsesquioxane-supported Rh catalyst in the presence of a triarylphosphine. Thus, III (R = OH) was hydrogenated on RhCl3[N[(CH2)3SiO3/2]3]10 in the presence of PPh3 to give 87.4% doxycycline 99.6% pure.

AN 1985:184881 CAPLUS
DN 102:184881
TI New nitrogen-containing rhodium catalysts
AU Villax, Ivan ; Page, Philip
CS Hovione -Soc. Quim., Lda., Lisbon, 1113, Port.
SO Actas Simp. Iberoam. Catal., 9th (1984), Volume 1, 446-52 Publisher: Soc. Iberoam. Catal., Lisbon, Port.
DT Conference
LA English
AB The reaction of (Ph3P)3RhCl with MeNHNHMe.2HCl, in an inert atm., produced the N-contg. Rh complex Ph3PRhCl4NHMeNHMe (I). The use of I in the homogeneous hydrogenation of the exocyclic methylene group of methacycline-HCl allowed virtually asym. synthesis of the required clin. active enantiomer of doxocycline. Further, the amt. of Rh necessary for the complete hydrogenation was considerably less than the amts. indicated in the literature.

AN 1984:22516 CAPLUS
DN 100:22516
TI Rhodium-containing catalysts and their application
IN Page, Philip Ronald; Villax, Ivan
PA Plurichemie Anstalt, Liechtenstein
SO Eur. Pat. Appl., 27 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 86046 A1 19830817 EP 1983-300254 19830119
EP 86046 B1 19870624
R: BE, CH, DE, FR, GB, IT, LI, NL
US 4500458 A 19850219 US 1983-458067 19830114
FR 2530490 A1 19840127 FR 1983-679 19830118
FR 2530490 B1 19871224
JP 58159851 A2 19830922 JP 1983-5971 19830119
JP 02058976 B4 19901211
JP 58164559 A2 19830929 JP 1983-5972 19830119
JP 62051946 B4 19871102
CA 1218058 A1 19870217 CA 1983-425254 19830405
HU 34375 A2 19850328 HU 1983-2127 19830615
HU 196143 B 19881028
IN 160450 A 19870711 IN 1983-DE843 19831216
AT 8304452 A 19901215 AT 1983-4452 19831220
AT 392922 B 19910710
US 32535 E 19871027 US 1986-858660 19860501
IN 164810 A 19890603 IN 1986-DE554 19860625
PRAI PT 1982-74303 19820119
PT 1982-76061 19821230
US 1983-458067 19830114
IN 1983-DE843 19831216
AB A catalyst for hydrogenating tetracycline intermediates was prepd. by treating a Rh phosphine complex with a hydrazine. Thus (Ph3P)3RhCl was treated with N2H4 to give a catalyst contg. 16.95% Rh which was used together with PPh3 to hydrogenate I (RR1 = CH2) to give I (R = Me, R1 = H) free from epimer.

AN 1983:422764 CAPLUS
DN 99:22764
TI Steroidal esters
IN Page, Philip Ronald; Heggie, William
PA Plurichemie Anstalt, Liechtenstein
SO Eur. Pat. Appl., 32 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
EP 72200 A2 19830216 EP 1982-304116 19820804
EP 72200 A3 19830601
EP 72200 B1 19851121
R: AT, BE, CH, DE, FR, GB, LI, LU, NL, SE
IL 66432 A1 19851129 IL 1982-66432 19820801
ZA 8205551 A 19830629 ZA 1982-5551 19820802
ES 514708 A1 19840616 ES 1982-514708 19820803
JP 58069899 A2 19830426 JP 1982-135285 19820804
JP 01011039 B4 19890223
AT 16601 E 19851215 AT 1982-304116 19820804
PRAI PT 1981-73479 19810804
PT 1981-73864 19811022
EP 1982-304116 19820804
AB Corticosteroid esters I and II (R = H, F, Cl; R1 = H, F, Cl, Me; R2 = halo, HO, oxo; R3 = H, Me; R4 = acyl; R5 = HO, H, halo, acyloxy) were prepd. as topical inflammation inhibitors and as agents in the treatment of psoriasis, eczema, neurodermatitis, seborrhea, contact dermatitis, and atopic dermatitis. Thus, 9.alpha.-fluoro-17-hydroxy-16.beta.-methyl- 11.beta.-(trifluoroacetoxy)pregna-1,4-diene-3,20-dione and 4-MeC6H4SO3H were added to a mixt. of [Me(CH2)5CO]2O and Cl3CCO2H at 0.degree. and reacted for 4 h at 40-50.degree. and then treated with 50% aq. Me2CHNH2 to give 21-deoxybetamethasone 17-heptanoate [II; R1 = R5 = H; R = F; R2 = HO; R3 = .beta.-Me; R4 = heptanoyl]. In the Mckenzie vasoconstriction test in humans, beclomethasone 17,21-diacetate possessed topical inflammation inhibiting activity equal to that of betamethasone 17-valerate and dexamethasone 17,21-dipropionate.

AN 1982:533572 CAPLUS
DN 97:133572
TI Water-soluble complexes of .alpha.-6-deoxy-5-hydroxytetracycline and sodium tetrametaphosphate and their use
IN Villax, Ivan
PA Port.
SO Belg., 13 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
BE 891236 A1 19820524 BE 1981-206644 19811124
ZA 8107804 A 19821229 ZA 1981-7804 19811111
AU 8177612 A1 19820603 AU 1981-77612 19811118
AU 543041 B2 19850328
ES 507293 A1 19830201 ES 1981-507293 19811119
DE 3146279 A1 19820819 DE 1981-3146279 19811121
FR 2494685 A1 19820528 FR 1981-21887 19811123
FR 2494685 B1 19850201
NL 8105309 A 19820616 NL 1981-5309 19811124
NL 190067 B 19930517
NL 190067 C 19931018
JP 57116033 A2 19820719 JP 1981-187068 19811124
GB 2088864 A 19820616 GB 1981-35611 19811125
GB 2088864 B2 19840912
PRAI PT 1980-72107 19801125
AB A water sol. complex of .alpha.-6-deoxy-5-hydroxytetracycline (I) and Na tetrametaphosphate has good bioavailability, broad spectrum antibacterial properties, excellent stability in gastric juice as well as in cryst. form and does not the disadvantages of I. However, the major advantage of using this complex is its decreased interference in the action in human serum of natural bactericides. The complex was prepd. by the treatment of freshly prepd. HPO3 with I and later with NaOH in MeOH. After addn. of iso-PrOH, the cryst. compd. was filtered, washed and dried. The increased bioavailability of the complex was demonstrated in humans after 100 and 200 mg capsule administration.

AN 1982:406656 CAPLUS
DN 97:6656
TI Selective solvolysis
PA Plurichemie Anstalt, Liechtenstein
SO Neth. Appl., 34 pp.
DT Patent
LA Dutch
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
NL 8102602 A 19811216 NL 1981-2602 19810527
NL 182963 B 19880118
NL 182963 C 19880616
GB 2079754 A 19820127 GB 1981-15317 19810519
GB 2079754 B2 19841107
IL 62948 A1 19840831 IL 1981-62948 19810525
JP 57067598 A2 19820424 JP 1981-78794 19810526
JP 01011038 B4 19890223
CH 655320 A 19860415 CH 1981-3452 19810526
US 4343739 A 19820810 US 1981-267553 19810527
PRAI PT 1980-71309 19800527
AB Corticosteroid esters I (R = H, F; R1 = H, trihaloacetyl; R2 = acyl; R3 = H, acyl; R2R3 = cyclic ortho ester group) underwent regioselective solvolysis-deacylation reactions. Thus, treatment of betamethasone 21-acetate 11-trifluoroacetate 17-valerate (20.0 g) with MeSO3H in abs. MeOH at 18.degree. for 24.5 h and then at 25.degree. for 2.75 h followed by hydrolysis with cold H2O gave 17.98 g betamethasone 11-trifluoroacetate 17-valerate. HCl and 4-MeC6H4SO3H were also effective catalysts for this deacetylation. Treatment of betamethasone 17,21-diacetete 11-trifluoroacetate (2.0 g) with NaOMe in water-free NaOH at 10.degree. for 5 min and then neutralization with 50% aq. HOac and hydrolysis with cold H2O gave 1.58 g betamethasone 17,21-diacetate.

¬ back to top



AN 1978:105018 CAPLUS
DN 88:105018
TI Recovery of doxycycline and products
IN Villax, Ivan
PA Port.
SO U.S., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 4061676 A 19771206 US 1976-669655 19760323
JP 56032303 B4 19810727 JP 1971-48699 19710702
PRAI PT 1970-54109 19700703
PT 1971-54109 19710609
US 1971-159462 19710702
AB Doxycyline, prepd., e.g., by hydrogenation of 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline, was purified by heating the reaction mixt. with concd. HCl, pptn. with 5-sulfosalicylic acid, neutralization, salt formation with HCl, then pptn. as the complex with PhCH2NHCH2CH2NHCH2Ph and Ca ion.

AN 1978:94819 CAPLUS
DN 88:94819
TI Antibiotic derivatives
IN Villax, Ivan
PA Port.
SO Can., 32 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
CA 1014552 A1 19770726 CA 1974-203732 19740628
FI 7401919 A 19741231 FI 1974-1919 19740624
FI 59789 B 19810630
FI 59789 C 19811012
DK 7403372 A 19750224 DK 1974-3372 19740624
DK 152119 B 19880201
DK 152119 C 19881024
AU 7470520 A1 19760108 AU 1974-70520 19740626
AU 497158 B2 19781207
ES 427715 A2 19770216 ES 1974-427715 19740627
AT 7405400 A 19760215 AT 1974-5400 19740628
AT 332970 B 19761025
FR 2282865 A2 19760326 FR 1974-22640 19740628
FR 2282865 B2 19790810
GB 1463726 A 19770209 GB 1974-28773 19740628
CH 611875 A 19790629 CH 1974-8952 19740628
SE 7408685 A 19750102 SE 1974-8685 19740701
SE 389333 B 19761101
PRAI PT 1973-54708 19730630
AB Alkali-metal polymetaphosphate complexes of doxycycline (I) were prepd. while not only having improved clin. activity but also increasing the clin. usefulness of I by increasing its blood-level concn. Also, blocking of I-functional groups considerably diminished chelation of Ca2+ and Mg2+ with I. Thus, to a freshly prepd. soln. of 4.74 g metaphosphoric acid in 100 mL CHCl3 and 150 mL MeOH. After keeping the clear soln. at 35.degree. for 1 h, 0.4 g NaOH dissolved in 4.4 mL MeOH was added. The product, I.cntdot.1/5 NaPO3.cntdot.1/5 (HPO3)5 [56648-96-5], was crystd. by adding 400 mL iso-PrOH.

AN 1978:23270 CAPLUS
DN 88:23270
TI Esters of 16.alpha.- or 16.beta.-methyl-9.alpha.-chloro- or -fluorosteroids with high topical activity
PA Plurichemie Anstalt, Liechtenstein
SO Span., 47 pp.
DT Patent
LA Spanish
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ES 435527 A1 19770316 ES 1975-435527 19750312
SE 7503356 A 19750929 SE 1975-3356 19750324
SE 418294 B 19810518
US 4024131 A 19770517 US 1975-561948 19750325
GB 1511820 A 19780524 GB 1975-47940 19750326
DK 7601967 A 19760503 DK 1976-1967 19760503
DK 146909 B 19840206
DK 146909 C 19841217
CH 625254 A 19810915 CH 1979-9468 19791022
PRAI PT 1974-61636 19740327
PT 1974-61637 19740327
PT 1975-61638 19750310
PT 1975-61636 19750310
CH 1975-3924 19750326
DK 1975-1295 19750326
GB 1975-12608 19750326
AB Pregnadienedione derivs. I (R = H, OH, OAc; R1 = H, COBu, COEt; R2 = H, COEt; R3 = Cl, F) (9 compds.) were prepd. Thus 16.beta.-methyl-9,11-epoxy- 17.alpha.-hydroxy-1,4-pregnadiene-3,20-dione was hydrochlorinated, I (R-R2 = H, R3 = Cl) trifluoroacetylated, I (R = R1 = H, R2 = CF3CO, R3 = Cl) treated with BuCO2H, I (R = H, R1 = COBu, R2 = CF3CO, R3 = Cl) hydrolyzed to give I (R = R2 = H, R1 = COBu, R3 = Cl) which had a topical vasoconstrictor potency of 180 relative to fluocinolone 100.

AN 1978:11915 CAPLUS
DN 88:11915
TI Alkali metal polymetaphosphate complexes of .alpha.-6-deoxy-5-
hydroxytetracycline
IN Villax, Ivan
PA Portugal
SO Span., 27 pp. Addn. to Span. 396,132.
DT Patent
LA Spanish
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ES 427715 A1 19770216 ES 1975-427715 19740627
ES 396132 A1 19721201 ES 1971-396132 19711019
PRAI ES 1971-396132 19711019
PT 1973-54708 19730630
PT 1970-54708 19701030
AB Improvements are described for a previously patented procedure for prepn. of alkali metal salts of .alpha.-6-deoxy-5-hydroxytetracycline (doxycycline) [564-25-0] metaphosphate complexes, which have a water soly. at 20.degree. >4.5 mg/mL. According to the previous procedure, 1 mol of metaphosphoric acid (H6P6O18) was first reacted with 1-5 mol Na or K hydroxide, and then with 1-5 mol doxycycline. In the present procedure, metaphosphoric acid is first reacted, in an org. medium, with 1-5 mol doxycycline, the residual metaphosphate is neutralized by addn. of MeOH or EtOH solns. of K or Na hydroxide, and the doxycycline complex is subsequently pptd. by addn. of EtOH, iso-PrOH, Et2O, or isopropyl ether. Blood levels of doxycycline in human subjects following administration of a gelatin capsule contg. doxycycline monosodium polyphosphate [64716-93-4] (100 mg doxycycline) were 50% higher than after administration of a capsule contg. doxycycline hyclate (100 mg doxycycline). The newly described preparative method is compared to other patented procedures.

AN 1977:139705 CAPLUS
DN 86:139705
TI Polyphosphate complexes of 6-demethyl-6-deoxy-6-methylenetetracycline and
its 11a-halo derivatives
IN Villax, Ivan
PA Port.
SO Span., 12 pp.
DT Patent
LA Spanish
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ES 420504 A3 19760501 ES 1973-420504 19731113
AB 5-Hydroxytetracycline 6,12-hemiacetal 12-phosphite was dehydrated by P2O5 to give 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline polymetaphosphate. Similarly prepd. was 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline metaphosphate.

AN 1976:524239 CAPLUS
DN 85:124239
TI Esters and ethers of 16-methyl-9.alpha.-halocorticosteroids
IN Villax, Joao E.
PA Plurichemie Anstalt, Liechtenstein
SO Fr. Demande, 40 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2274309 A1 19760109 FR 1975-9621 19750327
FR 2274309 B1 19781124
SE 7503356 A 19750929 SE 1975-3356 19750324
SE 418294 B 19810518
US 4024131 A 19770517 US 1975-561948 19750325
DK 7501295 A 19750928 DK 1975-1295 19750326
DK 153556 B 19880725
DK 153556 C 19881205
GB 1510617 A 19780510 GB 1975-12608 19750326
GB 1511820 A 19780524 GB 1975-47940 19750326
CA 1065848 A1 19791106 CA 1975-223091 19750326
AT 357696 B 19800725 AT 1975-2330 19750326
AT 7502330 A 19791215
CH 622811 A 19810430 CH 1975-3924 19750326
AU 7579603 A1 19760930 AU 1975-79603 19750327
AU 500060 B2 19790510
JP 51115457 A2 19761012 JP 1976-25985 19760310
JP 59022719 B4 19840528
DK 7601967 A 19760503 DK 1976-1967 19760503
DK 146909 B 19840206
DK 146909 C 19841217
AT 7903344 A 19900515 AT 1979-3344 19790504
AT 391703 B 19901126
CH 625254 A 19810915 CH 1979-9468 19791022
JP 58189200 A2 19831104 JP 1983-69325 19830421
JP 62041680 B4 19870903
PRAI PT 1974-61636 19740327
PT 1974-61637 19740327
PT 1975-61636 19750310
AT 1975-2330 19750326
CH 1975-3924 19750326
DK 1975-1295 19750326
GB 1975-12608 19750326
AB Pregnadienediones I [R = Cl, F; R1 = H, EtCO, F3CCO, (tetrahydropyran-2-yl)oxy; R2 = H, EtCO, BuCO; R3 = H, OAc, O2CEt] (16 compds.) were prepd. Thus, 20 g I (R = Cl, R1-R3 = H), was treated with (F3CCO)2O in pyridine to give 24.1 g I (R = Cl, R1 = F3CCO, R2 = R3 = H) (II). Heating 20 g II with BuCO2H-(F3CCO2)2O at 80.degree. gave 18.1 g I (R = Cl, R1 = F3CCO, R2 = BuCO, R3 = H), which (7.9 g) was partially deacylated and then esterified using EtCO2H - (F3CCO)2O to give 22.2 g I (R = Cl, R1 = EtCO, R2 = BuCO, R3 = H). I (R = Cl, R1 = EtCO, R2 = R3 = H) had 4.48 times the antiinflammatory activity of fluocinolone acetonide in the McKenzie assay.

AN 1976:499177 CAPLUS
DN 85:99177
TI Antibiotic derivatives
IN Villax, Ivan
PA Port.
SO Can., 17 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
CA 988081 A1 19760427 CA 1971-126250 19711027
PRAI PT 1970-54708 19701030
CA 1973-126250 19731219
AB Alkali polyphosphate complexes of doxycycline, (C22H24N2O8)z.(MPO3)x.(HPO3)y where M = Na or K, z = 1-5, x = 1-5, y = 1-5, x + y .ltoreq.6, and z .ltoreq. y, were prepd. and had water soly. >4.5 mg/ml. E.g., NaOH (0.5 g) dissolved in 10 ml MeOH was added to a soln. contg. metaphosphoric acid (8 g) in 200 ml 1:1 MeOH-CHCl3 and to this, doxycycline (23.1 g) in 100 ml EtOH was added. The resultant soln. was stirred for 1 hr and 350 ml iso-PrOH was added to ppt. (C22H24N2O8)3.(HPO3)5.NaPO3 [60022-06-2], m.p. 185-9.degree.

AN 1976:494616 CAPLUS
DN 85:94616
TI Preparation of steroids
IN Villax, Ivan
PA Plurichemie Anstalt, Liechtenstein
SO Can., 18 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
CA 987306 A1 19760413 CA 1972-143454 19720530
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB 17-Hydroxy-16.beta.-methylpregna-1,4,9(11)-triene-3,20-dione (I) was prepd. from epoxypregnanetrione II. Thus, II was ketalized using HOCH2CH2OH followed by KBH4 redn., the 11.beta.-hydroxy deriv. was mesylated-demesyloxylated, the 9(11)-unsatd. deriv. was condensed with MeMgBr and then hydrolyzed to give 17-hydroxy-16.beta.-methyl-5.beta.-pregn-9(11)-ene-3,20-dione (III). Bromination-dehydrobromination of III with subsequent dehydrogenation gave I.

AN 1976:446949 CAPLUS
DN 85:46949
TI Preparation of pharmacologically active 16-methyl-9.alpha.-halo steroid esters and ethers
PA Plurichemie Anstalt, Liechtenstein
SO Neth. Appl., 39 pp.
DT Patent
LA Dutch
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
NL 7503788 A 19750930 NL 1975-3788 19750327
NL 184321 B 19890116
NL 184321 C 19890616
GB 1511820 A 19780524 GB 1975-47940 19750326
DK 7601967 A 19760503 DK 1976-1967 19760503
DK 146909 B 19840206
DK 146909 C 19841217
CH 625254 A 19810915 CH 1979-9468 19791022
PRAI PT 1974-61636 19740327
PT 1975-61637 19750310
PT 1974-61637 19740327
PT 1975-61636 19750310
CH 1975-3924 19750326
DK 1975-1295 19750326
GB 1975-12608 19750326
AB Halopregnadienediones I [R = Cl, F; R1 = OH, O2CEt, (tetrahydropyran-2-yl)oxy; R2 = H, OH, O2CEt, O2CBu; R3 = OH, OAc, O2CEt] (15 compds.) were prepd. by selective acylation and solvolysis. Thus, I (R = Cl, R1 = O2CCF3, R2 = H, R3 = O2CBu) (II) was hydrolyzed using NaHCO3-H2O to give I (R = Cl, R1 = OH, R2 = H, R3 = O2CBu) which was acylated with EtCO2H in the presence of (F3CCO)2O to give I (R = Cl, R1 = O2CEt, R2 = H, R3 = O2CBu). Iodination of II followed by acetoxylation gave I (R = Cl, R1 = O2CCF3, R2 = OAc, R3 = O2CBu). Acylation of I (R = Cl, R1 = R3 = OH, R2 = H) by (F3CCO)2O gave I (R = Cl, R1 = O2CCF3, R2 = H, R3 = OH) which after treatment with BuCO2H-(F3CCO)2O gave II. I (R = F, R1 = O2CEt, R2 = H, R3 = O2CBu) had 7 times the topical antiinflammatory activity of fluocinolone acetonide in the McKenzie vasoconstrictor topical test.

AN 1976:421721 CAPLUS
DN 85:21721
TI 16.beta.-Methyl-17-hydroxypregna-1,4,9(11)-triene-3,20-dione
PA Plurichemie Anstalt, Liechtenstein
SO Austrian, 8 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
AT 327411 B 19760126 AT 1972-4719 19720531
AT 7204719 A 19750415
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB The title compd. I was prepd. from pregnanetrione II. Thus, ketalization of II using HOCH2CH2OH followed by redn. using KBH4 and then dehydration gave pregnene III. The Grignard reaction of III and MeMgBr followed by acid hydrolysis and bromination-dehydrobromination gave I.

AN 1976:165120 CAPLUS
DN 84:165120
TI Esters and ethers of 16-methyl-9.alpha.-halocorticosteroids
IN Villax, J. E.
PA Plurichemie Anstalt, Liechtenstein
SO Belg., 57 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
BE 827275 A1 19750716 BE 1975-154849 19750327
ZA 7501599 A 19760225 ZA 1975-1599 19750314
GB 1511820 A 19780524 GB 1975-47940 19750326
DK 7601967 A 19760503 DK 1976-1967 19760503
DK 146909 B 19840206
DK 146909 C 19841217
SE 7803041 A 19780316 SE 1978-3041 19780316
SE 440656 B 19850812
SE 440656 C 19851121
CH 625254 A 19810915 CH 1979-9468 19791022
AU 568510 B2 19880107 AU 1983-20002 19831005
AU 8320002 A1 19840315
PRAI PT 1974-61636 19740327
PT 1974-61637 19740327
PT 1975-61636 19750310
CH 1975-3924 19750326
DK 1975-1295 19750326
GB 1975-12608 19750326
AB Pregnadienediones I (R = Cl, F; R1 = H, COCF3, COEt, Ac; R2 = H, OH, OAc; R3 = H, COBu) (18 compds.) were prepd. Thus, acylation of I (R = Cl, R1-R3 = H) using (F3CCO)2O followed by BuCO2H gave I (R = Cl, R1 = COCF3, R2 = H, R3 = COBu) (II). Iodination of II and subsequent acetolysis gave I (R = Cl, R1 = COCF3, R2 = OAc, R3 = COBu) which was partially deacylated to I (R = Cl, R1 = H, R2 = OAc, R3 = COBu) (III). The antiinflammatory activity of III was 4.5 times that of fluocinolone acetonide.

AN 1976:164537 CAPLUS
DN 84:164537
TI Alkali metal polymetaphosphate complexes of doxycycline
IN Villax, Ivan
PA Port.
SO U.S., 7 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3927094 A 19751216 US 1973-376149 19730703
PRAI PT 1970-54708 19701030
US 1971-194049 19711029
US 1973-353528 19730423
AB Nine doxycycline-metaphosphate complexes (C22H24N2O8)n.bul.(NaPO3)m.bul.(HPO3)p (n = 3, 4, 5; m = 0, 1, 2; p = 4, 5, 6; m + p = .ltoreq.6) were prepd.

AN 1976:65260 CAPLUS
DN 84:65260
TI Alkali methal polymetaphate complexes of doxycycline
IN Villax, Ivan
PA Port.
SO S. African, 25 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7404181 A 19750730 ZA 1974-4181 19740628
FI 7401919 A 19741231 FI 1974-1919 19740624
FI 59789 B 19810630
FI 59789 C 19811012
DK 7403372 A 19750224 DK 1974-3372 19740624
DK 152119 B 19880201
DK 152119 C 19881024
AU 7470520 A1 19760108 AU 1974-70520 19740626
AU 497158 B2 19781207
ES 427715 A2 19770216 ES 1974-427715 19740627
AT 7405400 A 19760215 AT 1974-5400 19740628
AT 332970 B 19761025
FR 2282865 A2 19760326 FR 1974-22640 19740628
FR 2282865 B2 19790810
GB 1463726 A 19770209 GB 1974-28773 19740628
CH 611875 A 19790629 CH 1974-8952 19740628
SE 7408685 A 19750102 SE 1974-8685 19740701
SE 389333 B 19761101
PRAI PT 1973-54708 19730630
AB Alkali metal polymetaphosphate complexes of doxycycline (I) were prepd. to increase I blood levels and counteract pharmacol. disadvantages due to chelation of tetracyclines. Thus, metaphosphoric acid in CHCl3 and MeOH was treated with I to give a soln. which was treated with NaOH in MeOH. After washup I polyphosphate mono-Na complex (II) [56648-96-5], m. 184-8.degree., was obtained. Administration of II gave an av. overall increase of nearly 50% serum levels compared to I hyclate.

AN 1976:31309 CAPLUS
DN 84:31309
TI 16-Methyl-9.alpha.-halogen steroid esters and ethers
IN Villax, Joao E.
PA Plurichemie Anstalt, Liechtenstein
SO Ger. Offen., 54 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2512915 A1 19751009 DE 1975-2512915 19750324
DE 2512915 C2 19870910
SE 7503356 A 19750929 SE 1975-3356 19750324
SE 418294 B 19810518
US 4024131 A 19770517 US 1975-561948 19750325
DK 7501295 A 19750928 DK 1975-1295 19750326
DK 153556 B 19880725
DK 153556 C 19881205
GB 1510617 A 19780510 GB 1975-12608 19750326
GB 1511820 A 19780524 GB 1975-47940 19750326
CA 1065848 A1 19791106 CA 1975-223091 19750326
AT 357696 B 19800725 AT 1975-2330 19750326
AT 7502330 A 19791215
CH 622811 A 19810430 CH 1975-3924 19750326
AU 7579603 A1 19760930 AU 1975-79603 19750327
AU 500060 B2 19790510
JP 51115457 A2 19761012 JP 1976-25985 19760310
JP 59022719 B4 19840528
DK 7601967 A 19760503 DK 1976-1967 19760503
DK 146909 B 19840206
DK 146909 C 19841217
AT 7903344 A 19900515 AT 1979-3344 19790504
AT 391703 B 19901126
CH 625254 A 19810915 CH 1979-9468 19791022
JP 58189200 A2 19831104 JP 1983-69325 19830421
JP 62041680 B4 19870903
PRAI PT 1974-61636 19740327
PT 1974-61637 19740327
PT 1975-61636 19750310
AT 1975-2330 19750326
CH 1975-3924 19750326
DK 1975-1295 19750326
GB 1975-12608 19750326
AB Prednisolone mixed esters I (R = Cl, F; R1 = H, EtCO, F3CCO; R2 = H, AcO, EtCO2; R3 = H, BuCO, EtCO) (18 compds.) were prepd. Thus, acylation of I(R = Cl, F; R1 = H, R2 = H, AcO) with (F3CCO)2O gave I (R1 = F3CCO) which was acylated with (BuCO)2O. Solvolysis of I (R1 = F3CCO, tetrahydropyran-2-yl; R2 = H; R3 = BuCO) gave I (R1 = H, R2 = H, R3 = BuCO) which was acylated with (EtCO)2O to I (R1 = EtCO, R2 = H, R3 = BuCO). Treatment of I (R1 = F3CCO, R2 = H, R3 = BuCO) with iodine and CaO followed by KOAc gave I (R1 = F3CCO, R2 = AcO, R3 = BuCO) which underwent solvolysis and addnl. acylation. I (R = F, R1 = EtCO, R2 = H, R3 = BuCO) had 7 times the antiinflammatory activity as fluocinolone acetonide.

AN 1976:31305 CAPLUS
DN 84:31305
TI Sulfate and phosphate 21-esters of corticosteroids
IN Villax, Ivan
PA Port.
SO Span., 8 pp.
DT Patent
LA Spanish
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ES 403399 A1 19750416 ES 1972-403399 19720531
GB 1395820 A 19750529 GB 1972-22412 19720512
DK 135379 B 19770418 DK 1972-2408 19720515
CA 983019 A1 19760203 CA 1972-142424 19720517
AU 7242585 A1 19731129 AU 1972-42585 19720523
US 3773803 A 19731120 US 1972-257321 19720526
JP 54006553 B4 19790329 JP 1972-52406 19720526
AT 347052 B 19781211 AT 1972-4718 19720531
CH 578015 A 19760730 CH 1972-8214 19720602
BE 784409 A1 19721205 BE 1972-118289 19720605
NL 7207617 A 19721207 NL 1972-7617 19720605
PRAI PT 1971-55887 19710605
AB Betametasone (I) 21-phosphate (II) was prepd. in 96.7% yield by refluxing III (R = I) in 40 ml acetone with 1.2 g H3PO4 and 5.8 ml Et3N for 3.5 hr. Salts of I 21-sulfate and II with PhCH2NHCH2CH2NHCH2Ph also were prepd.

AN 1975:592945 CAPLUS
DN 83:192945
TI Separation of .alpha.-6-deoxytetracyclines from reaction mixtures
IN Villax, Ivan
PA Port.
SO Austrian, 8 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
AT 318803 B 19741125 AT 1971-5802 19710705
GB 1360998 A 19740724 GB 1971-30121 19710628
CH 588445 A 19770615 CH 1971-9612 19710630
JP 56032303 B4 19810727 JP 1971-48699 19710702
PRAI PT 1970-54109 19700703
PT 1971-54109 19710609
AB .alpha.-6-Deoxytetracyclines were sepd. from their mixts. with by-products or decompn. products by adding 5,2-(HO3S)(HO)C6H3CO2H to the soln., crystg. and sepg. the .alpha.-6-deoxytetracycline salt and treating it with Et3N to obtain the free base, or by adding (PhCH2NHCH2)2 or (PhCH2N:CH)2 and Ca(OH)2 to the soln. to form an insol. complex with the desired tetracycline, sepg. the complex, and decompg. it with a strong inorg. acid.

AN 1975:578652 CAPLUS
DN 83:178652
TI Doxycycline alkali metal polyphosphate complex with improved
pharmacological properties
IN Villax, Ivan
PA Port.
SO Neth. Appl., 24 pp. Addn. to Neth. Appl. 71 14,749.
DT Patent
LA Dutch
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
NL 7408875 A 19750102 NL 1974-8875 19740701
FI 7401919 A 19741231 FI 1974-1919 19740624
FI 59789 B 19810630
FI 59789 C 19811012
DK 7403372 A 19750224 DK 1974-3372 19740624
DK 152119 B 19880201
DK 152119 C 19881024
AU 7470520 A1 19760108 AU 1974-70520 19740626
AU 497158 B2 19781207
ES 427715 A2 19770216 ES 1974-427715 19740627
AT 7405400 A 19760215 AT 1974-5400 19740628
AT 332970 B 19761025
FR 2282865 A2 19760326 FR 1974-22640 19740628
FR 2282865 B2 19790810
GB 1463726 A 19770209 GB 1974-28773 19740628
CH 611875 A 19790629 CH 1974-8952 19740628
SE 7408685 A 19750102 SE 1974-8685 19740701
SE 389333 B 19761101
PRAI PT 1973-54708 19730630
AB Complexes of doxycycline (I) with HPO3 and NaPO3 or KPO3, prepd. by adding I base to predetd. excess of HPO3 in CHCl3-MeOH, then neutralizing the excess HPO3 with NaOH or KOH, had improved soly. [comparable to doxycline hyclate (II)], gave better retention and higher levels in the blood stream than II or other known I salts, had a better taste than II, and the metaphosphate groups blocked inactivation of I by chelation with Ca2+ or Mg2+. Complexes thus prepd., solns. of which had high stability, were: I.1/5NaPO3.HPO3; I.1/2NaPO3.HPO3; and I.1/5KPO3.HPO3.

AN 1975:514092 CAPLUS
DN 83:114092
TI Doxycycline alkali metaphosphate complexes
IN Villax, Ivan
PA Port.
SO Ger. Offen., 25 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2430550 A1 19750410 DE 1974-2430550 19740626
DE 2430550 C2 19820819
FI 7401919 A 19741231 FI 1974-1919 19740624
FI 59789 B 19810630
FI 59789 C 19811012
DK 7403372 A 19750224 DK 1974-3372 19740624
DK 152119 B 19880201
DK 152119 C 19881024
AU 7470520 A1 19760108 AU 1974-70520 19740626
AU 497158 B2 19781207
ES 427715 A2 19770216 ES 1974-427715 19740627
AT 7405400 A 19760215 AT 1974-5400 19740628
AT 332970 B 19761025
FR 2282865 A2 19760326 FR 1974-22640 19740628
FR 2282865 B2 19790810
GB 1463726 A 19770209 GB 1974-28773 19740628
CH 611875 A 19790629 CH 1974-8952 19740628
SE 7408685 A 19750102 SE 1974-8685 19740701
SE 389333 B 19761101
PRAI PT 1973-54708 19730630
AB Treatment of doxycycline (I, .alpha.-6-desoxy-5-hydroxytetracycline) with HPO3 (mole ratio I-HPO3 = 1-5:1) in an inert medium (e.g., CHCl3 or MeOH), then treating the excess HPO3 with methanolic or ethanolic NaOH or KOH gave a doxycycline alkali polyphosphate complex x I.y MPO3.z HPO3 [M = Na or K, x = 1-5, y = 1-5, z = 1-5 (y+z = 6, x .ltoreq. z], the soly. of which is such that, when taken internally, it maintains a more even and higher oxycycline concn. in blood than the known doxycycline hyclate.

AN 1975:443108 CAPLUS
DN 83:43108
TI Tetracycline derivatives
IN Villax, Ivan
PA Port.
SO Belg., 27 pp. Addn. to Belg. 774,717.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
BE 817063 A4 19741016 BE 1974-146061 19740628
FI 7401919 A 19741231 FI 1974-1919 19740624
FI 59789 B 19810630
FI 59789 C 19811012
DK 7403372 A 19750224 DK 1974-3372 19740624
DK 152119 B 19880201
DK 152119 C 19881024
AU 7470520 A1 19760108 AU 1974-70520 19740626
AU 497158 B2 19781207
ES 427715 A2 19770216 ES 1974-427715 19740627
AT 7405400 A 19760215 AT 1974-5400 19740628
AT 332970 B 19761025
FR 2282865 A2 19760326 FR 1974-22640 19740628
FR 2282865 B2 19790810
GB 1463726 A 19770209 GB 1974-28773 19740628
CH 611875 A 19790629 CH 1974-8952 19740628
SE 7408685 A 19750102 SE 1974-8685 19740701
SE 389333 B 19761101
PRAI PT 1973-54708 19730630
AB Doxycycline and alkali hydroxides were added to freshly prepd. metaphosphoric acid to give the following complexes (C22H24N2O8)n.(MPO3)m.(HPO3)p (M, n, m, and p given): Na, 5, 1, 5; Na, 4, 2, 4; K, 5, 1, 5. The polymetaphosphate complexes prepd. are useful as bactericides.

AN 1974:448543 CAPLUS
DN 81:48543
TI Biological transformation of anhydrotetracyclines to 6-deoxytetracyclines
IN Villax, Ivan
SO Fr. Demande, 11 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2187301 A1 19740118 FR 1973-20691 19730607
JP 49030592 A2 19740319 JP 1973-34425 19730326
NL 7307603 A 19731211 NL 1973-7603 19730530
PRAI PT 1972-57951 19720608
AB .alpha.-6-Deoxy-5-hydroxytetracycline (doxycycline) is obtained by adding, at the beginning or during aerobic fermn., anhydro-5-hydroxytetracycline to a culture of Streptomyces alboflavus (NCIB 10588 or NCIB 10589) in an aq. medium. After the transformation is complete, the fermented broth is acidified to pH 0.1-1.5 and the doxycycline sepd. by forming insol. derivs. with 3-hydroxy-2-naphthylates or with methylene-5,5-disalicylates. The crude ppt. is purified by transformation into the derivs. of .alpha.-6-deoxytetracycline with a purity sufficient for therapeutical use.

AN 1974:94266 CAPLUS
DN 80:94266
TI .alpha.-6-Deoxytetracyclines from anhydrotetracyclines
IN Villax, Ivan
SO Ger. Offen., 16 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2327990 A1 19731220 DE 1973-2327990 19730601
JP 49030592 A2 19740319 JP 1973-34425 19730326
NL 7307603 A 19731211 NL 1973-7603 19730530
PRAI PT 1972-57951 19720608
AB Deoxycycline (I, R = OH) and 6-deoxytetracycline (I, R = H) were manufd. by fermn. of common media contg. the anhydrotetracyclines II by Streptomyces alboflavus NCIB 10,588 or S. lusitanus. I (R = OH) was isolated as hydrochloride hemihydrate hemiethanolate.

AN 1974:60086 CAPLUS
DN 80:60086
TI Corticosteroid 21-sulfate and phosphate esters
IN Villax, Ivan
SO S. African, 11 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7203373 A 19730228 ZA 1972-3373 19720517
PRAI PL 1971-55887 19710605
AB Betamethasone phosphate (I; R = H, R1 = OPO3H) was prepd. in 92.5% yield by treating diiodopregnadienedione I (R = R1 = iodo) with K2HPO4-H3PO4. The sulfate ester I (R = H, R1 = OSO3H) was obtained similarly.

AN 1974:3715 CAPLUS
DN 80:3715
TI Betamethasone
IN Villax, Ivan
SO Brit., 7 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
GB 1328998 A 19730905 GB 1970-56961 19701201
DK 130991 B 19750512 DK 1970-6136 19701202
NL 7017904 A 19710615 NL 1970-17904 19701208
NL 166694 B 19810415
NL 166694 C 19810915
CH 551395 A 19740715 CH 1970-18282 19701210
IL 35823 A1 19770831 IL 1970-35823 19701210
ZA 7008393 A 19720726 ZA 1970-8393 19701211
AT 304774 B 19730125 AT 1970-11194 19701211
JP 50008080 B4 19750401 JP 1970-109617 19701211
NO 136049 B 19770404 NO 1970-4780 19701211
ES 386385 A1 19730316 ES 1970-386385 19701212
US 3792046 A 19740212 US 1972-278394 19720807
JP 57021280 B4 19820506 JP 1978-136836 19781108
JP 57021279 B4 19820506 JP 1978-136837 19781108
PRAI PT 1969-52923 19691213
AB Betamethasone (I, R = OH, R1 = H) was prepd. in high yield from 16.beta.-methyl-17-hydroxypregna-1,4,9(11)-triene-3,20-dione (II). Dehydrobromination of 16.beta.-methyl-9-bromo-11.beta.,17-dihydroxypregna-1,4-diene-3,20-dione, prepd. from the reaction of II with AcNHBrHClO3, gave the corresponding 9.alpha.,11.alpha.-epoxy steroid which with HF-DMF gave I (R = R1 = H). Diiodination of I (R = R1 = H) with iodine in the presence of CaO and CaCl2 gave I (R = R1 = I). The diiodo steroid was treated with KOAc to give betamethasone acetate (I, R = OAc, R1 = H) which was hydrolyzed to I (R = OH, R1 = H).

AN 1973:537390 CAPLUS
DN 79:137390
TI 16.beta.-Methyl-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione and
analogs
IN Villax, Ivan
PA Plurichemie Anstalt
SO S. African, 17 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7203782 A 19730328 ZA 1972-3782 19720602
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB Pregnatrienedione I was prepd. from epoxypregnanetrione II in 7 steps. Thus, II underwent ketalization with HOCH2CH2OH, KBH4 redn., dehydration, Grignard reaction with MeMgBr, and deketalization to give pregnenedione III. III was treated with Br2-HOAc and then debrominated to I.

AN 1973:537389 CAPLUS
DN 79:137389
TI 16.beta.-Methyl-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione
IN Villax, Ivan
PA Plurichemie Anstalt
SO U.S., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3761498 A 19730925 US 1972-257358 19720526
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB Pregnatrienedione I was prepd. from pregnanone II by KBH4 redn. followed by successive dehydration, methylation, bromination, and debromination.

AN 1973:526712 CAPLUS
DN 79:126712
TI 21-Sulfuric acid or 21-orthophosphoric acid ester sodium salts of prednisolone or 9.alpha.-fluoro-16.beta.-methylprednisolone
IN Villax, Ivan
SO Ger., 3 pp. Division of Ger. 1,200,822.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 1793707 A 19721228 DE 1967-1793707 19630614
DE 1793707 B2 19730719
DE 1793707 C3 19740221
AB Prednisolone esters I [R = (HO)2PO, (HO)SO2; R1 = H, Me; R2 = H, F]. (4 compds.) were prepd. Thus, prednisolone (I; R = R1 = R2 = H) was treated with EtO2COCl-H3PO4 in Et3N-MeCN and then with NaOMe to give 66% I [R = (HO)2PO].

AN 1973:453675 CAPLUS
DN 79:53675
TI Corticosteroid 21-sulfates and 21-phosphates
IN Villax, Ivan
SO Fr. Demande, 7 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2143690 A1 19730209 FR 1972-20152 19720605
FR 2143690 B1 19760305
GB 1395820 A 19750529 GB 1972-22412 19720512
DK 135379 B 19770418 DK 1972-2408 19720515
CA 983019 A1 19760203 CA 1972-142424 19720517
AU 7242585 A1 19731129 AU 1972-42585 19720523
US 3773803 A 19731120 US 1972-257321 19720526
JP 54006553 B4 19790329 JP 1972-52406 19720526
AT 347052 B 19781211 AT 1972-4718 19720531
CH 578015 A 19760730 CH 1972-8214 19720602
BE 784409 A1 19721205 BE 1972-118289 19720605
NL 7207617 A 19721207 NL 1972-7617 19720605
PRAI PT 1971-55887 19710605
AB Diidopregnadienedione I (R = R1 = I) (II) was treated with Me2CO contg. K2HPO4 and H3PO4 or MeCN-Me2CO contg. Et3N.H3PO4 to give betamethasone phosphate (I; R = H, R1 = OPO3H2), which yielded 1:1 and 2:1 salts with PhCH2NHCH2CH2NHCH2Ph. Treatment of II with K2SO4 and H2SO4 yielded betamethasone sulfate (I, R = H, R1 = OSO3H).

AN 1973:453675 CAPLUS
DN 79:53675
TI Corticosteroid 21-sulfates and 21-phosphates
IN Villax, Ivan
SO Fr. Demande, 7 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2143690 A1 19730209 FR 1972-20152 19720605
FR 2143690 B1 19760305
GB 1395820 A 19750529 GB 1972-22412 19720512
DK 135379 B 19770418 DK 1972-2408 19720515
CA 983019 A1 19760203 CA 1972-142424 19720517
AU 7242585 A1 19731129 AU 1972-42585 19720523
US 3773803 A 19731120 US 1972-257321 19720526
JP 54006553 B4 19790329 JP 1972-52406 19720526
AT 347052 B 19781211 AT 1972-4718 19720531
CH 578015 A 19760730 CH 1972-8214 19720602
BE 784409 A1 19721205 BE 1972-118289 19720605
NL 7207617 A 19721207 NL 1972-7617 19720605
PRAI PT 1971-55887 19710605
AB Diidopregnadienedione I (R = R1 = I) (II) was treated with Me2CO contg. K2HPO4 and H3PO4 or MeCN-Me2CO contg. Et3N.H3PO4 to give betamethasone phosphate (I; R = H, R1 = OPO3H2), which yielded 1:1 and 2:1 salts with PhCH2NHCH2CH2NHCH2Ph. Treatment of II with K2SO4 and H2SO4 yielded betamethasone sulfate (I, R = H, R1 = OSO3H).

AN 1973:442765 CAPLUS
DN 79:42765
TI 16.beta.-Methyl-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione
PA Plurichemie Anstalt
SO Fr., 12 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2141191 A5 19730119 FR 1972-20177 19720605
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB 16.alpha.,-17-Epoxypregnane-3,11,20-trione was ketalized with HOCH2CH2- OH and then reduced by KBH4 to give the bis(ethylenedioxy) pregnanediol I, which reacted with MeMgBr to give pregnenedione II, after hydrolysis. The 2,4-dibromo deriv. of II was debrominated in DMF contg. Li2- CO3 and LiBr to give the title compd. III.

AN 1973:89089 CAPLUS
DN 78:89089
TI Gently and selectively acting palladium on carbon supports as hydrogenation catalysts
IN Villax, Ivan
SO Fr. Demande, 8 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2120114 A5 19720811 FR 1971-47317 19711229
FR 2120114 B1 19751226
ES 398083 A1 19720816 ES 1971-398083 19711217
PRAI PT 1970-55008 19701229
AB PdCl2 soln. is stirred at 40-60.degree. with active charcoal while passing in coal gas, optionally dild. with up to 99 parts of H, until all the Pd is deposited as metal on the charcoal, which is then filtered, washed and dried. The product is a selective hydrogenation and (or) dehalogenation catalyst. In an example, 5 g of PdCl2 was dissolved in the min. amt. of H2O and the soln. poured into a stirred suspension of 54 g of active charcoal in 100 ml of H2O at 50.degree.. The mixt. was stirred for 2 hr at 50.degree. while passing in a rapid stream of a mixt. of H 96 and coal gas 4% until gas absorption ceased. The cooled mixt. was filtered, washed and dried to give a catalyst contg. 5% Pd. 6-Chloro-16-methylene-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione, 85 g, dissolved in 900 ml of AcOH was hydrogenated in presence of 12 g of Pd supported on charcoal, at 20-30.degree. and a pressure of 1,000 mm of H2O until 2 equivs. of H were consumed. The catalyst is filtered off and 16.beta.-methyl-17.alpha.-hydroxypregna-1,4,-9(11)-triene-3,20-dione is pptd. in 96% yield by addn. of 5 l. of H2O to the filtrate. Similar treatment of 9.alpha.-bromo-11.beta.,17.alpha.-dihydroxy-16-methylene-1,-4-pregnadiene-3,20-dione gives a 93.4% yield of a new compd., 11.beta.,17.alpha.-dihydroxy-16.beta.-methyl-1,4-pregnadiene-3,20-dione.

AN 1973:84652 CAPLUS
DN 78:84652
TI 16.beta.-Methyl-17-hydroxypregna-1,4,9(11)-triene-3,20-dione
PA Plurichemie Anstalt
SO Ger. Offen., 18 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2226067 A1 19730104 DE 1972-2226067 19720529
DE 2226067 B2 19760205
DE 2226067 C3 19760923
GB 1397267 A 19750611 GB 1972-25264 19720530
AU 7242949 A1 19731206 AU 1972-42949 19720531
CH 579590 A 19760915 CH 1972-8215 19720602
NL 7207616 A 19721207 NL 1972-7616 19720605
PRAI PT 1971-55886 19710605
AB The title compd. (I), useful as intermediate for the manuf. of betametasone, was prepd. Partial ketalization of the trioxo compd. (II), KBH4 redn. of the resulting oxo compd. (III), and subsequent dehydration by MeSO2Cl contg. SO3 gave the epoxypregnene (IV). Grignard reaction of IV with MeMgBr gave the methylhydroxy deriv. (V) and subsequent deketalization the dione (VI), which on 2-step bromination-dehydrobromination or 1-step dehydrogenation by dichlorodicyanobenzoquinone led to I.

AN 1973:75886 CAPLUS
DN 78:75886
TI Polymetaphosphate complexes of .alpha.-deoxy-5-hydroxytetracycline
IN Villax, Ivan
SO S. African, 21 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7107214 A 19720726 ZA 1971-7214 19711028
DK 152118 B 19880201 DK 1971-5166 19711025
DK 152118 C 19880620
NL 7114749 A 19720503 NL 1971-14749 19711026
IL 38014 A1 19750625 IL 1971-38014 19711026
SE 380518 B 19751110 SE 1971-13551 19711026
CH 593239 A 19771130 CH 1971-15580 19711026
FI 54799 C 19790312 FI 1971-3060 19711027
FI 54799 B 19781130
NO 140718 C 19791024 NO 1971-3985 19711027
NO 140718 B 19790716
BE 774717 A1 19720214 BE 1971-109964 19711029
AU 7135209 A1 19730510 AU 1971-35209 19711101
AT 312166 B 19731227 AT 1971-9439 19711102
PRAI PT 1970-54708 19701030
AB Poly(metaphosphoric acid) (PMA) and alkali metaphosphate complexes of .alpha.-6-deoxy-5-hydroxytetracycline (doxycycline) (I) were prepd. by reacting, I with PMA or its Na or K salt, resp. I derivs. such as its acid addn. salt may be substituted in the reaction. The 2 groups of complexes were distinguished by characteristic solubilities and ir peaks. Thus, 23.1 g I in 65 ml MeOH was added to 4.8 g PMA in 130 ml 1:1 CHCl3-MeOH. After stirring 2 g NaOH in 25 ml MeOH was added and pptn. was induced by adding Me2CHOH to give 21 g (C22H24N2O8)5(NaPO3).(HPO3)5 m.p. 187-92.degree.. Ten addnl. prepns. including phys. consts. and some comparative clin. blood level studies were described.

AN 1973:72449 CAPLUS
DN 78:72449
TI 16.beta.-Methyl-9.alpha.-fluoro steroids
IN Villax, Ivan
SO S. African, 19 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7008393 19720612
PRAI PT 1969-52923 19691213
AB 16.beta.-Methyl-17.alpha.-hydroxy-1,4,9(11)-pregnatriene-3,20-dione was treated with AcNHBr in dil. HClO4-THF to yield pregnadienedione I (R = Br, R1 = H), which underwent successive epoxidn. by NaOH and ring opening by HF in DMF to give I (R = F, R1 = H). The latter was treated with iodine, CaCl2, and CaO in MeOH at 25.degree. to give I (R = F, R1 = iodo), which was refluxed with KOAc in Me2Co to give betamethasone acetate in 63.3% overall yield.

AN 1973:58680 CAPLUS
DN 78:58680
TI Betamethasone 21-sulfate and 21-phosphate
IN Villax, Ivan
SO Ger. Offen., 10 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2225658 A 19721214 DE 1972-2225658 19720526
DE 2225658 B2 19760408
DE 2225658 C3 19761118
GB 1395820 A 19750529 GB 1972-22412 19720512
DK 135379 B 19770418 DK 1972-2408 19720515
CA 983019 A1 19760203 CA 1972-142424 19720517
AU 7242585 A1 19731129 AU 1972-42585 19720523
US 3773803 A 19731120 US 1972-257321 19720526
JP 54006553 B4 19790329 JP 1972-52406 19720526
AT 347052 B 19781211 AT 1972-4718 19720531
CH 578015 A 19760730 CH 1972-8214 19720602
BE 784409 A1 19721205 BE 1972-118289 19720605
NL 7207617 A 19721207 NL 1972-7617 19720605
PRAI PT 1971-55887 19710605
AB The title esters were prepd. by reaction of the 21,21-diiodo deriv. with H3PO4 or H2SO4 or their salts in acid soln. Thus, 21,21-diiodo-16.beta.-methyl-9.alpha.-fluoro-11.beta.,17.alpha.-dihydroxypregna-1,4-diene-3,20-dione was refluxed in aq. Me2CO contg. K2HPO4 and 85% H3PO4 for 3 hr to give 92.5% betamethasone 21-phosphate (I). Treating I with NaOH-MeOH (pH 10.5) led to the easily sol. di-Na salt.

AN 1973:43154 CAPLUS
DN 78:43154
TI Antibiotic tetracycline complexes
IN Villax, Ivan
SO Fr. Demande, 13 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2111952 A5 19720609 FR 1971-38787 19711028
FR 2111952 B1 19751226
DK 152118 B 19880201 DK 1971-5166 19711025
DK 152118 C 19880620
NL 7114749 A 19720503 NL 1971-14749 19711026
IL 38014 A1 19750625 IL 1971-38014 19711026
SE 380518 B 19751110 SE 1971-13551 19711026
CH 593239 A 19771130 CH 1971-15580 19711026
FI 54799 C 19790312 FI 1971-3060 19711027
FI 54799 B 19781130
NO 140718 C 19791024 NO 1971-3985 19711027
NO 140718 B 19790716
BE 774717 A1 19720214 BE 1971-109964 19711029
AU 7135209 A1 19730510 AU 1971-35209 19711101
AT 312166 B 19731227 AT 1971-9439 19711102
PRAI PT 1970-54708 19701030
AB Complexes of doxycycline and its salts with metaphosphoric acid were prepd. that gave higher blood antibiotic levels faster than doxycycline hydrochloride hemiethanolate hemihydrate. Thus 23.1 g doxycycline was treated with 4 g metaphosphoric acid to give 24.9 g of a 1:1-complex.

AN 1973:43153 CAPLUS
DN 78:43153
TI Catalytic dehalogenation, alone or with simultaneous reduction, of
11a-halo-6-deoxy-6-demethyl, 6-methylenetetracyclines by hydrazine
IN Villax, Ivan
SO Fr. Demande, 11 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2108191 A5 19720519 FR 1971-24328 19710702
FR 2108191 B1 19730629
ES 392576 A1 19721201 ES 1971-392576 19710623
GB 1360006 A 19740717 GB 1971-30120 19710628
DK 153393 B 19880711 DK 1971-3182 19710629
DK 153393 C 19881128
CH 582132 A 19761130 CH 1971-9613 19710630
PRAI PT 1970-54106 19700703
PT 1970-54107 19700703
PT 1970-54108 19700703
PT 1971-54108 19710503
AB Methacycline and .alpha.- and .beta.-doxycycline sulfosalicylates were prepd. by dehalogenating 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrofluoride or p-toluenesulfonate with N2H4.H2O-Pd-C and treating with 5-sulfosalicylic acid.

AN 1972:539669 CAPLUS
DN 77:139669
TI Recovery of .alpha.-6-deoxytetracyclines from reaction mixtures
IN Villax, Ivan
SO S. African, 19 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
ZA 7104323 A 19720329 ZA 1971-4323 19710701
CA 945546 A1 19740416 CA 1971-116691 19710625
NL 7109000 A 19720105 NL 1971-9000 19710629
FR 2148660 A5 19730323 FR 1971-24329 19710702
JP 56032303 B4 19810727 JP 1971-48699 19710702
ES 392575 A1 19730101 ES 1972-392575 19720623
PRAI PT 1970-54109 19700703
PT 1971-54109 19710609
AB .alpha.-6-Deoxytetracyclines were recovered from the reaction mixts. by treating the mixt. with aq. acid at 60-90.degree. for 15-90 min. This treatment destroyed the byproducts but did not interfere with the subsequent selective pptn. of the deoxytetracyclines. Terra-silica was added to crude 11a-chloro-6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline (I) in 70% aq. DMF and the resulting cake was washed with 50% aq. DMF. Concd. HCl was added, and the mixt. heated at 68-72.degree. for 30 min. After cooling 5-sulfosalicylic acid was added and the mixt. was stirred for 2 hr at 15.degree. to give the cryst. sulfosalicylate of I.

AN 1972:514704 CAPLUS
DN 77:114704
TI Palladium-active carbon hydrogenation catalyst
IN Villax, Ivan
SO Ger. Offen., 11 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2163362 A 19720720 DE 1971-2163362 19711221
ES 398083 A1 19720816 ES 1971-398083 19711217
PRAI PT 1970-55008 19701229
AB A Pd/C catalyst was made by redn. of Pd chloride in aq. suspension of active C with H-coal gas mixts. at 50.degree. and used for the redn. of .beta.-naphthoyl chloride to .beta.-naphthaldehyde or for the simultaneous dehalogenation and selective redn. of exocyclic methylene double bonds in pregnatriene, pregnadiene, and tetracycline derivs. Thus, 5 g Pd chloride in H2O was added to a suspension of 54 g active carbon in 100 ml H2O and a 96% H-4% coal gas mixt. passed through the suspension 2 hr at 50.degree. to give a 5% Pd/C catalyst. 9.alpha.-Bromo-11.beta.,17.alpha.-dihydroxy-16-methylenepregna-1,4-diene-3,20-dione was hydrogenated in AcOH in the presence of this catalyst at 20-30.degree. and 1000 mbar to give 93.4% 16.beta.-methyl-11.beta.,17.alpha.-dihydroxypregna-1,4-diene-3,20-dione of high cortisone activity.

AN 1972:502036 CAPLUS
DN 77:102036
TI 9-Fluoro-16.beta.-methyl steroids
IN Villax, Ivan
SO Fr. Demande, 11 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 2081356 A5 19711203 FR 1970-44641 19701211
FR 2081356 B1 19760917
DK 130991 B 19750512 DK 1970-6136 19701202
NL 7017904 A 19710615 NL 1970-17904 19701208
NL 166694 B 19810415
NL 166694 C 19810915
CH 551395 A 19740715 CH 1970-18282 19701210
IL 35823 A1 19770831 IL 1970-35823 19701210
ZA 7008393 A 19720726 ZA 1970-8393 19701211
AT 304774 B 19730125 AT 1970-11194 19701211
JP 50008080 B4 19750401 JP 1970-109617 19701211
NO 136049 B 19770404 NO 1970-4780 19701211
ES 386385 A1 19730316 ES 1970-386385 19701212
US 3792046 A 19740212 US 1972-278394 19720807
JP 57021280 B4 19820506 JP 1978-136836 19781108
JP 57021279 B4 19820506 JP 1978-136837 19781108
PRAI PT 1969-52923 19691213
AB The title compds. (I) were prepd. from pregnatriene (II) by treatment with MeCONHBr and aq. HClO4 to give the 9.alpha.-bromo-11.beta.-hydroxy deriv., treatment with NaOH to give the 9,11-epoxy deriv. which was treated with aq. HF to give I (R = H) which could be treated with I-MeOH in the presence of CaO to give the 21-diiodo deriv. which was treated with KOAc, giving I (R = OAc).

AN 1972:475076 CAPLUS
DN 77:75076
TI Polymetaphosphate complexes of .alpha.-6-deoxy-5-hydroxy tetracyclines
IN Villax, Ivan
SO Ger. Offen., 18 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2152476 A 19720510 DE 1971-2152476 19711021
DK 152118 B 19880201 DK 1971-5166 19711025
DK 152118 C 19880620
NL 7114749 A 19720503 NL 1971-14749 19711026
IL 38014 A1 19750625 IL 1971-38014 19711026
SE 380518 B 19751110 SE 1971-13551 19711026
CH 593239 A 19771130 CH 1971-15580 19711026
FI 54799 C 19790312 FI 1971-3060 19711027
FI 54799 B 19781130
NO 140718 C 19791024 NO 1971-3985 19711027
NO 140718 B 19790716
BE 774717 A1 19720214 BE 1971-109964 19711029
AU 7135209 A1 19730510 AU 1971-35209 19711101
AT 312166 B 19731227 AT 1971-9439 19711102
PRAI PT 1970-54708 19701030
AB The title Na phosphate complexes, useful as antibiotics and more sol. in water than the corresponding acid complexes, were prepd. by reaction of the tetracycline with Na hexametaphosphate or HPO3 then NaOH in an inert org. solvent, e.g., DMF, EtOH, MeOH, or CHCl3.

AN 1972:419891 CAPLUS
DN 77:19891
TI Betamethasone
IN Villax, Ivan
SO Ger. Offen., 17 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2059050 A 19720406 DE 1970-2059050 19701201
DK 130991 B 19750512 DK 1970-6136 19701202
NL 7017904 A 19710615 NL 1970-17904 19701208
NL 166694 B 19810415
NL 166694 C 19810915
CH 551395 A 19740715 CH 1970-18282 19701210
IL 35823 A1 19770831 IL 1970-35823 19701210
ZA 7008393 A 19720726 ZA 1970-8393 19701211
AT 304774 B 19730125 AT 1970-11194 19701211
JP 50008080 B4 19750401 JP 1970-109617 19701211
NO 136049 B 19770404 NO 1970-4780 19701211
ES 386385 A1 19730316 ES 1970-386385 19701212
US 3792046 A 19740212 US 1972-278394 19720807
JP 57021280 B4 19820506 JP 1978-136836 19781108
JP 57021279 B4 19820506 JP 1978-136837 19781108
PRAI PT 1969-52923 19691213
AB The title compd. (I, R = H) was prepd. Thus, bromination of 16.beta.-methyl-17.alpha.-hydroxypregna-1,4,9(11)-triene-3,20-dione with AcNHBr in THF-HClO4-H2O at 25-30.degree. gave 96% II (R = Br, Br1 = R2 = H), which was epoxidized with aq. NaOH in MeOH-CHCl3 under N at 0-3.degree. to give 92.6% 16.beta.-methyl-9,11-epoxy-17.alpha.-hydroxypregna-1,4-diene-3,20-dione (III). Fluorination of III with HF in DMF at 16-18.degree. gave 82.4% II (R = F, R1 = R2 = H), which was iodinated with iodine in the presence of CaCl2-CaO in MeOH at -10.degree. to -12.degree. under N in the dark to give 100% II (R = F, R1 = R2 = iodine) (IV). Refluxing IV with KOAc-HOAc for 1.5 hr in aq. Me2CO gave 86.6% I (R = Ac), which was hydrolyzed with 2N methanolic NaOMe to give 96.4% I (R = H).

AN 1972:152033 CAPLUS
DN 76:152033
TI Production of oxytetracycline using Streptomyces alboflavus (ATCC 15388)
IN Villax, Ivan
PA International Rectifier Corp.
SO U.S., 6 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3637463 A 19720125 US 1967-660936 19670816
BR 6353837 A0 19730614 BR 1963-153837 19631018
PRAI PT 1962-40140 19621019
AB Oxytetracycline is produced by cultivating a mutant of Streptomyces alboflavus under aerobic conditions at 22-30.degree.. Thus, sterile medium contg. corn steep liquor 10, sugar 10, CaCO3 1, (NH4)2HPO4 2, KH2PO4 2, and MgSO4.7H2O 0.25 g with tap H2O 1 l. was inoculated with 1 ml of a spore suspension of S. alboflavus mutant M-108-OX (ATCC 15388) and incubated in a rotary shaker at 25.degree. for 36 hr. One l. of the above culture was used to inoculate medium contg. tap H2O 120 l.; starch 6, corn steep liquor (50%) 2.7, CaCO3 0.72, (NH4)2SO4 0.8, NH4Cl 0.2, and sunflower oil 0.2 kg; CoCl2 0.18, CuSO4.5H2O 0.6, ZnSO4.7H2O 6, and FeSO4 0.18 g. Submerged fermentation was carried on at 26.degree. with stirring and sterile aeration. The pH dropped from 7.2 to 6.35 and the concn. of oxytetracycline was 6.6 g/l. after 150 hr of fermentation. Repeating the above but adding 8.4 g of N,.nu.'-dibenzylethylenediamine diacetate (NBED) before inoculation, after 50 and 120 hr increased the yield of oxytetracycline to 8.1 g/l. after 140 hr of fermentation. The broth from the 150 hr of fermentation was acidified to pH 1.5 with 25% H2SO4, filtered, and the mycelium was washed with H2O. To the 240 l. of combined filtrate and washings was added 2 g/l. of EDTA Na. The pH was adjusted to 6 with 12% NH4OH; 150 g of NBED was added and the pH was increased to 9.5 with 12% NH4OH. After stirring 3 hr the formed ppt. was filtered off and washed until the pH of the washings reached 7. The ppt. was dried at 50.degree. under vacuum. The dry ppt. was ground and then suspended in twice its wt. of MeOH. After stirring 0.5 hr it was acidified to pH 2 with gaseous HCl and then to pH 1.5 with 36% HCl. The mass was filtered, washed with MeOH, and dried for 6 hr under vacuum. Yield of oxytetracycline.HCl was 81%.

AN 1972:85602 CAPLUS
DN 76:85602
TI Methacycline and doxycycline from 11a-chloro-6-deoxy-6-demethyl-6-
methylenetetracycline
IN Villax, Ivan
SO Ger. Offen., 15 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2131944 A 19720120 DE 1971-2131944 19710626
DE 2131944 B2 19730510
ES 392576 A1 19721201 ES 1971-392576 19710623
CA 942743 A1 19740226 CA 1971-116690 19710625
GB 1360006 A 19740717 GB 1971-30120 19710628
DK 153393 B 19880711 DK 1971-3182 19710629
DK 153393 C 19881128
CH 582132 A 19761130 CH 1971-9613 19710630
US 3849491 A 19741119 US 1971-159458 19710702
PRAI PT 1970-54106 19700703
PT 1970-54107 19700703
PT 1970-54108 19700703
PT 1971-54108 19710503
AB Methacycline (I) was prepd. by dechlorination of 11a-chloro-6-deoxy-6-demethyl-6-methylenetetracycline (II) with 1 mole H2NNH2 over Pd/C. With excess H2NNH2 and a Pt catalyst, II was dechlorinated and the methylene bond simultaneously reduced to give both I and doxycycline (II). II was used as, e.g., II.HF, II sulfosalicylate, or as II mol. complexes with N,N'-dibenzylethylenediamine or N,N'-dibenzyl-ethylenediimine. Thus, 10% Pd/C and 2 ml 15% H2NNH2.H2O were added to II.HF in EtOH. After 15 min 2.7 ml 15% H2NNH2.H2O was added. The mixt. was filtered and 5 g sulfosalicylic acid in H2O added to give 5.5 g I sulfosalicylate. Addn. of 2 ml 15% H2NNH2.H2O and 10% Pt/C to 5 g II.HF, further addn. of 6 ml H2NNH2.H2O at intervals, stirring the mixt. 3 hr, and addn. of 5 g sulfosalicylic acid and H2O gave 3.8 g crude sulfosalicylate contg. I 41, III 53, and III .beta.-isomer 4%.

AN 1972:72318 CAPLUS
DN 76:72318
TI Purification of 6-.alpha.-deoxy-5-hydroxytetracycline
IN Villax, Ivan
SO Ger. Offen., 17 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 2131945 A 19720120 DE 1971-2131945 19710626
DE 2131945 B2 19730607
CA 945546 A1 19740416 CA 1971-116691 19710625
NL 7109000 A 19720105 NL 1971-9000 19710629
FR 2148660 A5 19730323 FR 1971-24329 19710702
JP 56032303 B4 19810727 JP 1971-48699 19710702
ES 392575 A1 19730101 ES 1972-392575 19720623
PRAI PT 1970-54109 19700703
PT 1971-54109 19710609
AB The title antibiotic (I) prepd. by stereospecific hydrogenation of 11.alpha.-chloro-6-deoxy-6-demethyl-6-methylenetetracycline (II) or redn. of II with H2NNH2 in the presence of Pt or Pd/C catalysts was sepd. from the crude reaction mixts. by decompn. of the by-products with HCl at 68-75.degree., selective pptn. of I as the 5-sulfosalicylate, and treatment of the sulfosalicylate in EtOH with Et3N [or pptn. as mol. complex compd. with N,N'-dibenzylethylene-diamine or N,N'-dibenzylethylenediimine and sepn. of I from the complexes by suspension in EtOH and addn. of HCl]. Thus, the filtered hydrogenation product of 12,500 g II in DMF was washed with 50% aq. DMF, heated with 27.5 l. HCl at 68-72.degree., cooled to 50.degree., aq. 5-sulfosalicylic acid added and the mixt. kept 2 hr at 15.degree. to give 8,360 g I sulfosalicylate, a suspension of which in aq. EtOH was treated with Et3N-EtOH to give 95% I.

AN 1971:420797 CAPLUS
DN 75:20797
TI Mineral hydroxy acid esters of 9.alpha.-fluoro-16-methylprednisolone
IN Villax, Joao
SO U.S., 4 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3564028 A 19710216 US 1969-871736 19691006
AB Prepn. of the title compds., useful for the remission of pain, bleeding tendency, and fever, is described. Orthophosphoric acid (85%) is dehydrated; MeCN and Et3N added and the mixt. cooled to -20.degree. and ClCO2Et in MeCN added. The mixt. is stirred 0.5 hr followed by the addn. of prednisolone in MeCN and Et3N. The mixt. is refluxed 1 hr, and 2N NaOMe in MeOH added to yield Na salt of prednisolone 21-phosphate, m. 200.degree.. Similarly are prepd. 6 addnl. analogs.

AN 1969:118109 CAPLUS
DN 70:118109
TI Complexes of chloramphenicol palmitate with calcium pantothenate
IN Villax, Ivan
SO Fr. M., 5 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 5815 19680401
PRAI PT 19640306
AB Complexes of chloramphenicol palmitate (I) with Ca pantothenate (II) in the mol. proportions of 4:1, 2:1, and 1:1 were prepd. They are free of bitter taste, and produce persistent and higher blood levels than I alone. A mixt. of 2246 g. I and 476 g. II (molar ratio 4:1) was heated to 110.degree. under N, slowly stirred 30 min., then cooled, powdered and sifted.

AN 1969:113856 CAPLUS
DN 70:113856
TI Fermentation production of tetracycline
IN Villax, Ivan
PA International Rectifier Corp.
SO U.S., 5 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3432394 A 19690311 US 1967-661497 19670815
AB Streptomyces lusitanus var tetracyclini 106-T NCIB9500 is cultivated in an aq. nutrient medium contg. cornsteep liquor, CaCO3, starch or semi-hydrolyzate, ammonium salts, trace elements, peanut meal, and lard oil at a pH 6.7-6.8 for 140 hrs. at 26-8.degree. with aeration to obtain tetracycline in very high yields. There is no chlortetracycline produced. Thus, a prefermentor contg. 150 l. of medium is inoculated with starter culture and fermented at 26.degree. with agitation for 24 hrs. Then, a fermentor having a useful capacity of 6000 l. and contg. a medium of the following compn./l. of tap water: cornsteep liquor, CaCO3, starch, (NH4)2SO4, NH4Cl, MnSO4.bul.4H2O, CoCl2.bul.6H2O, ZnSO4, peanut meal, and lard oil 28, 14, 38, 5.7, 1.5, 0.05, 0.002, 0.05, 25, and 35 g., resp., is inoculated with the 24-hr. culture and fermented at 30.degree. for an addnl. 24 hrs., with aeration of 1.5 l./min./l. of broth. Then, the temp. is lowered to 26.degree. and the aeration increased to 4 l./min./l. of broth. After 140 hrs. of fermentation, 11.1 g. tetracycline/l. was obtained.

AN 1969:60812 CAPLUS
DN 70:60812
TI Complex from chloramphenicol palmitate and calcium pantothenate
IN Villax, Ivan
SO Ger., 4 pp.
DT Patent
LA German
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
DE 1283246 19681121
PRAI PT 19640306
AB A tasteless complex (I) composed of 4 moles chloramphenicol palmitate (II) and 1 mole Ca pantothenate (III) is described. Thus, a mixt. of 2246 g. II and 476 g. III was stirred at 110.degree. under N for 30 min., cooled, and ground to yield I, m. .apprx.92-106.degree., insol. in H2O. I suspended in H2O changes to a complex (IV), m. 195-202.degree., [.alpha.] 40.degree. (c 1, MeOH), soly. in H2O 79 mg./l cc. IV is the form present in a syrup contg. I.

AN 1967:464116 CAPLUS
DN 67:64116
TI Tetracycline hexametaphosphate
IN Villax, Ivan
SO Fr., 2 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 1439818 19660527
PRAI PT 19610707
AB To a suspension of 2 kg. dibenzylethylenediamine-tetracycline complex (activity 680 .gamma./mg.) in 2 l. H2O, HCl was added to pH 2.9, a soln. of 300 g. Na hexametaphosphate (I) in 3 l. H2O was added with stirring and the pH adjusted to 2.2, the supernatant layer, removed and treated with a soln. of 250 g. I in 2500 ml. H2O, the title compd., RC22H24N2O8.NaPO3.5HPO3 (II), was pptd. at pH 1.7, the mixt. stirred 1 hr., and II filtered, washed with H2O followed by MeOH, and dried. The K salt of II was also prepd. Activity of II was 808.gamma./mg.

AN 1967:27709 CAPLUS
DN 66:27709
TI Preparation of N,N'-dibenzylethylenediamine tetracyclines
IN Villax, Ivan
SO Fr., 3 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 1439819 19660527
PRAI PT 19610710
AB Addn. of 0.1-0.4 g. of N,N'-dibenzylethylenediamine (I)/l. as a sol. salt to fermentations of tetracycline or its homologs results in formation of complexes (II) of I with the tetracyclines. As a result, fermentation liquors show greater activities, and isolation of the antibiotics is facilitated. I is maintained at a level of 20-33% by wt. of that of the antibiotic in the mixt. throughout the fermentation. II are extd. with H2SO4 or (COOH)2, pptd. at pH 8-10, and crystd., either as the base or as a salt. These II consist of I and a tetracycline in ratios of 1:1 or 1:2 or of these and an alk. earth metal in a ratio of 1:4:3. Extn. yields are 65-80%.

AN 1967:2771 CAPLUS
DN 66:2771
TI Addition compounds of chloramphenicol palmitate and calcium pantothenate
IN Villax, Ivan
SO Fr., 4 pp.
DT Patent
LA French
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 1438328 19660513
PRAI PT 19640306
AB Addn. compds. of chloramphenicol palmitate (I) and Ca pantothenate (II) are prepd. by melting together stoichiometric amts. of I and II. Thus, 2246g. I and 476g. II are heated at 110.degree. under N with stirring 30 min. The obtained cold mass is then crushed and sieved to yield 4:1 adduct (III), 96%, m. 92-106.degree. (.alpha.) 35.degree. (MeOH), 25.degree. (EtOH 80%-H2O 20%). The antibiotic activity of III is that of the I contained. The ir spectrum of III is given and is different from the spectrum of an intimate mixt. of 4 moles of I and 1 mole of II. III is stable in nonpolar solvents (32 g./l. ether) and gives polymorphic crystals, m. 195-202.degree. (H2O). Other complexes (2:1 and 1:1) are obtained by the same method.

AN 1967:1588 CAPLUS
DN 66:1588
TI Tetracycline-N,N'-dibenzylideneethylenediamine complexes for use in isolating tetracyclines
IN Villax, Ivan
SO U.S., 3 pp.
DT Patent
LA English
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
US 3280188 19661018
PRAI US 19640319
AB Tetracycline, oxytetracycline, chlortetracycline, and dimethylchlortetracycline are prepd. and isolated by adding PhCH:NCH2N:CHPh (I) to the culture medium during fermentation by a streptomyces tetracycline-producing microorganism, and then acidifying at a pH of 0.5-1.8 with an acid. The broth is filtered and the pH adjusted to 5 with NH3 in the event it contains enough alk. earth metal ions to form the I complex, or if not the pH is adjusted with an alk. earth metal hydroxide. I is added in the amt. of 0.5 mole per mole of the tetra-, oxy- or chlorotetracycline present and at least 1.5 moles per mole of demethylchlortetracycline. The addn. of the base is made until a pH of 8.0 to 9.5. The I complex is then pptd. The complexes can be used as such for pharmaceutical purposes or as feed supplements for animals, or by adjusting the pH of the suspension to the isoelec. point of the tetracycline with an acid, the pure base is crystd. The following example illustrates the process: 300 l. of a sterile culture medium of the compn.; corn steep liquor (50%) 28, CaCO3 12, starch 38, (NH4Cl) 1.5, MnSO4.4H2O 0.05, ZnCl2 0.02, CoCl2.6H2O 0.005, peanut meal 25, and lard oil 25 g./l. of tap water (pH 6.7 after sterilization) are inoculated with a spore suspension of Streptomyces aureofaciens. To the medium are added 100 mg./l. at the beginning and 200 mg./l. of I after 56 and 112 hrs. of fermentation. After 130 hrs. of fermentation, 2.8g./l. of demethylchlortetracycline are obtained. To the acidified filtrate 170 g. of I are added, NH4OH to pH 5.0, and 170 g. of I 1.5g./l. EDTA and 0.3g./l. of Na2SO3 (antioxidant). Upon raising the pH to 8.7, the complex precipitates and is further washed and purified. The final product is composed of: 52.8% of demethylchlortetracycline as anhydrous base (the remainder I, Ca, and water), and corresponds to the formula: demethylchlortetracycline2I Ca3 in the anhydrous state. The yield is 79%; sp. rotation, [.alpha.]D = -180 (c = 1 in 0.1 N HCl); uv spectrum max. 232 m.mu. (E 1% 1 cm. = 503), 366/368 m.mu. (E 1% 1 cm. = 171).

AN 1966:63043 CAPLUS
DN 64:63043
OREF 64:11824g-h
TI Biosynthesis of tetracycline
PA Ivan Villax
SO 17 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI NL 65000482 19650719 NL
PRAI PT 19640118
AB Streptomyces lusitanus is known to produce chlortetracycline in the presence of Cl- and tetracycline in a medium without Cl- (Neth. 266,725). A new strain has been isolated which produces only tetracycline, even in the presence of Cl-. It has been named S. luistanus var tetracyclini, and by careful selection a mutant 106-T NCIB 9500 has been obtained. By fermentation this strain produces 9-12 g. tetracycline/l. medium. Details of growth and culture properties are given. The strain does not grow if only inorg. N is given. By addn. of up to 65 g. starch hydrolyzate/l. of medium, the yield is enhanced. Another promotor is N,N'-dibenzylethylenediamine in a quantity of 0.1-1 g./l. Fermentation and isolation of the antibiotic are carried out in the usual manner.

AN 1966:39239 CAPLUS
DN 64:39239
OREF 64:7328f
TI Tetracycline process
PA Ivan Villax
SO 25 pp.; Addn. to Belg. 605,734
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI BE 658387 19650430 BE
PRAI PT 19640117
AB A newly isolated strain of Streptomyces lusitanus var tetracyclini NCIB 9500 produces tetracycline with no co-production of chlortetracycline in the presence of Cl-. Thus, in a 6000-1. fermentor, with corn-steep medium contg. 1.5 g. NH4Cl/l. the strain produces 11.1 g. tetracycline/l. and no detectable amt. of chlortetracycline.

AN 1966:27358 CAPLUS
DN 64:27358
OREF 64:5022c-d
TI Tetracycline phosphate complexes
IN Villax, Joao
SO 2 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI GB 1010634 19651124 GB
PRAI PT 19610707
AB Dried, crude tetracycline dibenzylethylenediamine (2 kg.) activity 680 .gamma./mg. (Brit. 936,314) was suspended in 20 1. H2O, dil. HCl added to pH 2.9, 300 g. Na or K hexametaphosphate (I) in 31.H2O added with stirring, pH adjusted to 2.2 and the supernatant decanted. The soln. was treated with 250 g. in 2.5 l. H2O, and pH adjusted to 1.7 to give the Na or K hexametaphosphate tetracycline complex (83%), with microbiological activity 808 .gamma./mg.

AN 1965:480911 CAPLUS
DN 63:80911
OREF 63:14948h,14949a-c
TI Esterification of temperature- or acid-sensitive compounds
IN Villax, Ivan
SO 3 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI DE 1200822 19650916 DE
PRAI PT 19610303
AB Treatment of salts of carboxylic acids or of inorganic oxyacids with alkyl chloroformates at low temps. yielded the mixed anhydride which on addn. of the appropriate alc. gave the ester. To a suspension of 37.2 g. Penicillin G K-salt in 100 g. Me2CO (I), 13 ml. ClCOOEt in 25 ml. I was added; then 13.5 ml. Et2NCH2CH2OH in 25 ml. I was added under ice cooling. After 20 min. 2.71 g. 47.3% HIO3 in 50 ml. I was added to bring the pH to 4.5-5. The ppt. was filtered off, washed with I and Et2O, dried, and then washed twice with H2O to give 74% the iodate of diethylaminoethyl ester of Penicillin G, m. 170-8.degree.. In a similar manner the following compds. were prepd.: chloramphenicol pantothenate; Iodate of diethylamino ethyl 6-aminopenicillanate; chloramphenicol palmitate, m. 89-90.degree., [.alpha.]D 25.degree. (2% in EtOH); methyl gibberellinate, m. 208-9.degree., [.alpha.]D 76deg;; Na prednisolone 21-phosphate, [.alpha.]D 105.degree., .lambda. 239 m.mu., E1%1cm. 306 (MeOH); Na prednisolone 21-sulfate, [.alpha.]D 110.degree., .lambda.max. 239 m.mu. E1%1cm. 312. Na 9.alpha.-fluoro-16.alpha.-methylprednisolone 21-sulfate, [.alpha.[D 80-5.degree. (1% in H2O), .lambda., 238 m.mu., E1%1cm. 292; Na 9.alpha.-fluoro-16.beta.-methylprednisolone 21-sulfate, [.alpha.]D 90-5.degree. (1% in H2O), .lambda. 238, E1%1cm. 291; testosterone propionate, m. 117-22.degree.; N-acetylpenicillamine ethyl ester, m. 91-8.degree.; methandriol diacetate, m. 145-7.degree.; ethyl ester of cholic acid diacetate, m. 183.degree. (decompn.); ethyl phenaceturate, m. 88-90.degree.; estradiol benzoate, m. 227-9.degree.

AN 1965:466725 CAPLUS
DN 63:66725
OREF 63:12283a-d
TI Complexes of tetracyclines with N,N'-dibenzylideneethylenediimine and alkaline earth ions
IN Villax, Joao
SO 13 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI BE 645682 19640716 BE
FR 1404469 FR
PRAI PT 19630328
AB In the production of tetracyclines it is possible to eliminate the org. solvents, increase the yields, and shorten the manufg. process by formation of complexes including tetracyclines, alk.-earth ions and N,N'-dibenzylideneethylenediamine (I). The sp. rotations and uv and ir data for these complexes are reported. The addn. of I to the culture medium during the fermentation is followed by the adjustment of pH at the end of fermentation; the broth is then filtered and pH corrected again with NH4OH or alk. earth hydroxides. Further amts. of I are added up to 0.5 mole per mole of tetracycline, oxytetracycline, chlortetracycline, and 1.5 mole per mole of demethylchlortetracycline. The broth is then treated with addnl. base until the pH is 8-9.5 and the complex (II) ppts. By acidification with HCl of an aq. suspension of II, it is possible to obtain the pure base of the tetracycline involved when its isolelec. point is reached. For example, a fermentation medium contg. starch, corn steep liquor, CaCO3, (NH4)2SO4, NH4Cl, and Cu, Fe, or Zn sulfates is inoculated with Streptomyces alboflavus and then 400 mg. of I/l. is added after 0, 36, 72, and 96 hrs. of fermentation. After 150 hrs., fermentation is stopped when the concn. of oxytetracycline is 7.6 g./l., H2SO4 (25%) is added to the broth until the pH is 1.5, and then mycelium removed by filtration; by treatment with 12% NH4OH, the pH is adjusted to 6, then 140 g. I is added and more 12% NH4OH until the pH reaches 9.5. After stirring for 3 hrs. and filtering, the solid complex, I-tetra-Ca oxytetracycline, is washed several times and then suspended in H2O. The suspension is treated with 10% oxalic acid until the pH is 1.5. Then the soln. is filtered and, when its pH is adjusted to 5, the pure oxytetracycline base is sepd. by crystn. The yield is 87%.

AN 1965:46962 CAPLUS
DN 62:46962
OREF 62:8355c-e
TI Preparation of oxytetracycline
PA Ivan Villax
SO 17 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
PI BE 638881 19640217 BE
DE 1195904 DE
DE 1201513 DE
FR 1379067 FR
GB 1018667 GB
PRAI PT 19621019
AB A mutant strain, CBS M-108-OX, of Streptomyces alboflavus, which gave increased yields of oxytetracycline (I), was obtained by uv irradiation. It differed in colonial morphology and in pigmentation from the parent strain and from S. rimosus. When grown in submerged culture on a production medium contg. starch 6 kg., corn-steep liquor 2.7 kg., CaCO3 0.72 kg., (NH4)2SO4 0.8 kg., NH4Cl 0.2 kg., CoCl2 0.18 g., CuSO4.5H2O 0.6 g., ZnSO4.7H2O 6.0 g., FeSO4.7H2O 0.18 g., sunflower oil 0.2 kg., and H2O 120 1., at 26.degree., starting pH 7.2, for 150 hrs., the yield of I was 6.6 g./l. Addn. of 3 aliquots of N,N'-dibenzylethylenediamine (II) increased the yield to 8.1 g./l. Recovery was by acidification of the broth to pH 1.5 with H2SO4, filtration, washing of the mycelium with H2O, addn. of 2 g./l. of EDTA, raising the pH to 6 with NH4OH, addn. of 150 g. (in 240 l.) of II, and raising the pH to 9.5. After 3 hrs. stirring, the ppt. was filtered, washed, and dried. It was resuspended in twice its wt. of MeOH, stirred 30 min., adjusted to pH 2(HCl gas), then to pH 1.5 with 36% HCl, and stirred. The ppt. was filtered, washed with MeOH, and dried. The yield of I, as hydrochloride, was 81%. It could be further purified and converted into the free base.

AN 1964:16415 CAPLUS
DN 60:16415
OREF 60:2849g-h,2850a
TI .alpha.-Ketols
PA Instituto Pasteur de Lisboa-Virginio Leitao Vieira dos Santos & Filhos and Ivan Villax
SO 6 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 1336654 19630906 FR
PRAI PT 19560802
AB Substituted .alpha.-ketols (I) with cortico-adrenal activity were prepd. by the reaction of substituted phenylbromopropanes with .alpha.-phenylacetol (II). Thus, I (R1 = OH, R2 = OMe, R3 = H) was obtained by treating 15 g. II in 80 ml. abs. Et2O with 5.4 g. NaOMe 3 hrs. at -5 to 0.degree., 24.5 g. bromoeugenol in 80 ml. Et2O added, the mixt. stirred 6 hrs. at ambient temp. then refluxed 2 3 hrs., pH adjusted with H3PO4 to 6-6.5, NaBr filtered off, the Et2O evapd., and the product isolated by dissolving in hot HOAc and pptg. with H2O. Other I were similarly prepd. by reaction of II with bromoanethole (R1 = OMe, R2 = H, R3 = H), with bromoisosafrol [(R1R2 =) OCH2O2, R3 = H], and with bromocinnamyl alc. (R1 = H, R2 = H, R3 = OH).

AN 1964:6009 CAPLUS
DN 60:6009
OREF 60:1078c-d
TI Fermentative production of tetracycline or chlortetracycline
IN Villax, Ivan
SO 5 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
GB 936313 19630911 GB
DE 1185771 DE
DE 1194097 DE
PRAI PT 19600723
AB A sterilized medium (300 1) contg. starch 60, peanut meal 3, CaCO3 4, (NH4)2SO4 4.5, corn steep liquor 4, dibenzylethylenediaminediacetate (I) 2.5 g. and lard oil 1.8% by vol./l. was inoculated with suspended spores of Streptomyces lusitanus, and fermented under submerged aerobic conditions, with stirring at 26.degree. for 120 hrs. The mycelium is sepd. from the broth (acidified with dil. H2SO4) by filtration. I (0.3 g./l.) is added, and the pH adjusted to 8.2 with 10% NH4OH. The ppt. of the I complex of chlortetracycline (II) thus obtained is removed by filtration, suspended in 6300 cc. of 2-ethoxy- or 2-methoxyethanol, and 864 g. NaCl and coned. HCl are added with strong stirring until the pH is 0.45. After 12 hrs. of the stirring the crystals are filtered, washed with 2-ethoxyethanol, iso-PrOH, and then H2O. The dried II-HCl thus obtained weighs 1753 g., m.p. 223-31, [.alpha.]20 -220 (c 1.5, 1: 1 HCONMe2-MeOH). A similar fermentation in a broth previously freed from Cl- yielded the I-tetracycline complex-HCl salt. Brit. 936,314; 5 pp. See preceding abstract.

AN 1963:53033 CAPLUS
DN 58:53033
OREF 58:8984d-e
TI Chloramphenicol esters
PA Instituto Pasteur de Lisboa-Virginio Leitao Vieira dos Santos & Filhos and Ivan Villax
SO 17 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
FR 1306601 19621019 FR
PRAI PT 19560802
AB Chloramphenicol is treated with various carboxylic acids to give esters which can be used as low-toxicity antibiotics. Ca pantothenate (24.1 g.) is suspended in 75 ml. abs. HCONMe2 9.6 ml. ClCO2Et is added dropwise at -5.degree., the mixt. is agitated for 30 min., and the soln. is mixed with 28 g. chloramphenicol in 45 ml. abs. HCONMe2. The mixt. is agitated for 1 hr. at room temp., HCONMe2 is distd. in vacuo, the warm residue is dissolved in iso-PrOH, the soln. is cooled, and the solid material that forms is filtered off. Et2O is added to the filtrate to give the pantothenate deriv., m. 93.degree. (decompn. begins). Also prepd. is 4-(O2N)C6H4CH(OH)CH[NHCOCH(O2CR)Cl]CH2OH in which RCO2 is the pantothenate group.

AN 1963:8383 CAPLUS
DN 58:8383
OREF 58:1322a-c
TI Esterification
PA Joao Emerico Villax
SO 10 pp.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
BE 614636 19620330 BE
PRAI PT 19610303
AB The use of chloroformate esters, carboxylic salt or acid, and the alc. was claimed to give an improved esterification process. Thus, to 14.5 g. BzONa in 100 cc. Me2CO at 0.degree. 10.9 g. ClCO2Et in 10 cc. Me2CO was added, stirred 1/2 hr., then 18 g. MeOH and 2 cc. pyridine stirred in until gas evolution stopped, reflux continued 2 hrs., then distd. to yield 43.6% BzOMe, b. 198-200.degree.. Similarly were prepd.: BzOEt, b. 210-13.degree., 92% yield; AcOEt (at -20.degree. with 1.4 cc. Et3N instead of pyridine), b. 75-7.degree., 88%; iso-Pr palmitate, m. 42-3.degree., 44%; diethylaminoethyl benzoate, in Me2CO 48%, in dimethyl formamide 89%; Et malonate, b. 192-200.degree. in tetrahydrofuran 87%; hydriodide of diethylamino ester of penicillin G, m. 170-8.degree., 74%; hydriodide of the diethyl amino ester of penicillic acid, 40%; Me ester of gibberellic acid, m. 208-10.degree. (C6H6-MeOH); Me ester of indoleacetic acid, 87%. In MeCN solvent: Na salt of 21-prednisolone phosphate, 66% yield; Na salt of 9.alpha.-fluoro-16.beta.-methylprednisolone, 75%; Na salt of 21-prednisolone sulfate; Na salt of 9.alpha.-fluoro-16.alpha.-methyl- prednisolone sulfate, 79%. In Me2CO solvent: testosterone propionate, 46%; Me ester of N-acetylpenicillamine, 23%, methandriol diacetate, 39%; Et ester of the diacetate of cholic acid, 63%; ethyl phenaceturate 81%, benzoate of estradiol. Similar reaction with Ca pantothenate and chloramphenicol (I) gave a cryst. product not further identified. K palmitate and I gave a product, m. 89-90.degree.

AN 1957:36662 CAPLUS
DN 51:36662
OREF 51:6957b-c
TI Esters of penicillin
IN Villax, Yvan
PA Instituto Pasteur de Lisboa; Virginio Leitao Vieira dos Santos & Filhos S.a r.l.
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
GB 759603 19561024 GB
AB Penicillin esters are prepd. by reaction of acid halides of penicillin (I) with an alkali in an inert org. solvent. PCl3 mixed with CHCl3 is added to I suspended in CHCl3, and pyridine is added at -2.degree.. After addn. of Et2O and recrystn. from CHCl3, the HCl of the diethylaminoethyl ester of I, m. 146-8.degree., is obtained. The HI of the diethylaminoethyl ester of I, m. 168-71.degree., the Me ester of I, and the cyclohexyl ester of I can be prepd. in a similar manner.

AN 1957:36661 CAPLUS
DN 51:36661
OREF 51:6957a-b
TI Acid halides of penicillin
IN Villax, Yvan
DT Patent
PATENT NO. KIND DATE APPLICATION NO. DATE
--------------- ---- -------- --------------- --------
GB 758653 19561010 GB
AB Pure penicillin acid (I) is made to react with a P halide to form an acid halide of I. Thus, 5.4 g. PCl3 and 27 g. CHCl3 were mixed with K penicillin G, dry pyridine added, kept at 5.degree. for 48 hrs., pptd. with abs. Et2O, filtered, and the filtrate treated with petr. ether. The acid chloride of I thus obtained can be recrystd. to give a white, nonhygroscopic powder, sol. in org. solvents and insol. in aliphatic hydrocarbons. It loses its activity slowly. The acid bromide and acid iodide of I are prepd. in a similar manner.