US3907779A - 5,6 Dihydro-5-azathymidine and derivatives - Google Patents

5,6 Dihydro-5-azathymidine and derivatives Download PDF

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Publication number
US3907779A
US3907779A US471322A US47132274A US3907779A US 3907779 A US3907779 A US 3907779A US 471322 A US471322 A US 471322A US 47132274 A US47132274 A US 47132274A US 3907779 A US3907779 A US 3907779A
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antibiotic
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Clarence Deboer
Brian Bannister
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Pharmacia and Upjohn Co
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Upjohn Co
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Priority to US471322A priority Critical patent/US3907779A/en
Priority to US541346A priority patent/US3907643A/en
Priority to ZA00752598A priority patent/ZA752598B/xx
Priority to CA225,567A priority patent/CA1037889A/en
Priority to GB1720675A priority patent/GB1472667A/en
Priority to AU80579/75A priority patent/AU482760B2/en
Priority to JP50052100A priority patent/JPS5851759B2/ja
Priority to DE2521197A priority patent/DE2521197C2/de
Priority to NL7505708A priority patent/NL7505708A/xx
Priority to FR7515539A priority patent/FR2271838B1/fr
Priority to BE156516A priority patent/BE829268A/xx
Application granted granted Critical
Publication of US3907779A publication Critical patent/US3907779A/en
Priority to CA303,945A priority patent/CA1056822A/en
Priority to JP58127066A priority patent/JPS5948072A/ja
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Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/12—Triazine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S435/00—Chemistry: molecular biology and microbiology
    • Y10S435/8215—Microorganisms
    • Y10S435/822—Microorganisms using bacteria or actinomycetales
    • Y10S435/886—Streptomyces
    • Y10S435/903—Streptomyces platensis

Definitions

  • U-44,590 is obtained by culturing Streplomyces platensis var. clarensis, NRRL 8035, in an aqueous nutrient medium under aerobic conditions.
  • Various derivatives of U-44,590 can be made as disclosed infra.
  • U-44,590 and its derivatives have the property of adversely affecting'the growth of Gram-negative and Gram-positive bacteria, for example, Streptococcus hemolyticus, Klebsiella pneumonia, Salmonella Sp., Serratia marcescens,.PasteureIla multocida, Hemophilus Sp., Proteus morgani and Proteus rettgeri. Accordingly, U-44,590 and its derivatives can be used alone or in combination with other antibiotic agents to prevent the growth of or reduce the number of bacteria, as disclosed above, in various environments.
  • U44,590 and its derivatives are also active against DNA viruses, for example, the Herpes virus and, thus, can be used to control such virus where its presence is not desired. 1
  • sh means a shoulder band.
  • band Frequency (Wave Numbers) Intensity 1510 1482 1461 1437 1420 1406 I396 1349 1310 129s 1290 1 1275 sh. 1263 1243 1 19.5 v 1 16s I085 1060 1010 98s 97I 942 883 870 347 827 791 754 733 Note: sh means a shoulder band.
  • Infrared band intensities throughout this disclosure, are indicated as S, M, and W respectively and are approximated in terms of the backgrounds in the vicinity of the bands.
  • An 8" band is of the same order of intensity as the strongest in the spectrum; M bands are between A and as intense as the strongest band; and, W bands are less than V3 as intense as the strongest band.
  • U-44,590 can be referred to by the trivial name 5,6-dihydro--azathymidine, or by its chemical name I 2-deoxy-B-D-erythro-pentofuranosyI )-5 ,o-dihydro- 5-methyl-s-triazine-2,4( lH,3H)-dione.
  • Difco Brain Heart Infusion Medium was used for all test bacteria except P. multocida and Hemoph ilus species which were grown in Difco Blood Agar Base with 5% defibrinated rabbit blood. All were grown aerobically at 37 C. (except Hemophilus species, grown anaerobically) 16-18 hours. lnocula were grown ovemite (16-18 hours) at 37 C. and used to seed agar at the rate of 0.025 ml. of 10 dilution (approximately 2500 to 25,000 bacteria per drop of inoculum).
  • antibiotic U-44,590 The following is an example of the antiviral activity of antibiotic U-44,590.
  • the antibiotic is administered subcutaneouslyto mice which are inoculated intravenously with Herpes simplex virus. Treatment. is initiated two hours prior to viral infection and is followed by treatment four times daily for five consecutive days.
  • Treatment. is initiated two hours prior to viral infection and is followed by treatment four times daily for five consecutive days.
  • mice Male mice, weighing approximately 20 gm. each, are divided into 4 groups of 20. Group I is treated with saline, Group 2 with 400 mg./kg./dose (mkd) U-44,590, Group 3 with 200 mkd U-44,590, and Group 4 with mkd U-44,590.
  • the antibiotic is dissolved in saline and administered subcutaneously in the nape of the neck at 8 a.m., 12 noon, 4 p.m., and 8 pm. on days 0, l, 2, 3, and 4.
  • the microorganism used for the production of U- 44,590 is Streptomyces platensis var. clarensis, NRRL 8035. A subculture of this'microorganism can be obtained from the permanent collection of the Northern Regional Research Laboratory, US. Department of Agriculture, Peoria, Ill.
  • the microorganism of this invention was studied and characterized by Alma Dietz of the Upjohn Research Laboratories.
  • Antibiotic-producing properties See Table 7, infra.
  • Soil Type culture Streptomyces platensis Pittenger and Gottling NRRL 2364.
  • Type variety Streptomyces platensis var. platensis NRRL 2364.
  • mist brown Xtlm irayish yellowish hrown
  • 3li l5ea ⁇ er Xllm irayish yellowish brown 95g Moderate olive brown 'Jacohson. l-. I t. (iramille. and L. loss, lI-tts'. (olor harmony manuaL 3rd ed. (ontaiuer Corporation otAmeriea.
  • Lactose l l. ('ellobiose l2. Raffinose l3. Dextrin 14. lnulin ("l 15. Soluble starch lo. (ilycerol I7. Dulcitol l K. D-Mannitol l). D-Sorhitol It). lnositol 2 l.
  • the new compound of the invention is produced when the elaborating organism is grown in an aqueous nutrient medium under submerged aerobic conditions.
  • Preferred nitrogen sources include comsteep liquor, yeast, autolyzed brewers yeast with milk solids, soybean meal, cottonseed meal, cornmeal, milk solids, pancreatic digest of casein, fish meal, distillers solids, animal peptone liquors, meat and bone scraps, and the like. Combinations of these carbon and nitrogen sources can be used advantageously.
  • Trace metals for example, zinc, magnesium, manganese, cobalt, iron, and the like, need not be added to the fermentation media since tap water and unpurified ingredients are used as components of the effected at any temperature conductive to satisfactory growth of the microorganism, for example, between about 1 8 and 40 C., and preferably between about 20 and 32 C. Ordinarily, optimum production of the compound is obtained in about to 'days.
  • the medium normally remains neutral during the fermentation.
  • the final pH is dependent,'in part, on the buffers present,
  • the vegetative form, rather than the spore form, of the microorganism for inoculation to avoid a pronounced lag in the production of the new compound and the attendant inefficient utilization of the equipment. Accordingly, it is desirable to produce a vegetative inoculum in a nutrient broth culture by inoculating this broth culture with an aliquot from a soil, liquid N agar plug, or a slant culture. When a young, active vegetative inoculum has thus been secured, it is transferred aseptically to large vessels or tanks.
  • the medium in which the vegetative inoculum is produced can be the same as, or different from, that utilized for the production of the new compound, so long as a good growth of the microorganism is obtained.
  • a variety of procedures can be employed in the isolation and purification of the compound of the subject invention, for example, solvent extraction, partition chromatography, silica gel chromatography, liquidliquid distribution in a Craig apparatus, absorption on resins, and crystallization from solvents.
  • the compound of the subject invention is recovered from the culture medium by separation of the mycelia and undissolved solids by conventional means, such as by filtration or centrifugation.
  • the antibiotic is recovered from the filtered or centrifuged broth by adsorption on activated carbon.
  • The'activated carbon is then washed with water to remove some impurities.
  • This is followed by elutions with acetone: water solutions which remove the antibiotic from the activated carbon.
  • the acetone in the eluates is removed, advantageously by evaporation, and the remaining aqueous residue is lyophilized to afford a crude preparation of antibiotic U-44,590.
  • a preferred purification procedure is to subject a crude preparation of U-44,590, as described above, to chromatography on silica gel from which U-44,590 is eluted. Fractions which show activity against the bacterium Klebsiella pneumoniae on a standard agar plate test, are pooled and taken to dryness to yield a relatively pure preparation of U-44,590. Further purification is achieved by acetylation to a crystalline diacetate derivative of U-44,590. Zemplen [G. Zemplen and E.
  • Antibiotic U-44,59O is active against Streptococcus hemolyticus and, thus, can be used to disinfect instruments, utensils or surfaces when contaminated with this microorganism, where the inactivation of this microorganism is desirable. Also, U-44,590 is active against Escherichia coli and can be used to reduce, arrest,,and-
  • Antibiotic U-44,590 can also be used to prolong the life of cultures of Trichomonas foetus, Trichomonas hominis, and Trichomonas vaginalis by freeing them of Escherichia coli contamination. Further, U-44,59O can 'be used to inhibit the growth of E. coli in hospital flower vases where it has been reported to exist and present a hazard to hospital patients. See Clinical Medicine, February, 1974, Page 9.
  • Novel acyl derivatives of U-44,590 can be used for the same antibiotic purposes as U-44,59O in environments possessing means to deacylate the compound to U-44,590.
  • the acyl derivatives of U-44,590 can be used to treat laboratory mice infected with a Gram-negative bacteria, for example E. coli, as disclosed herein.
  • acyl derivatives of U- 44,59O can be used, advantageously, to upgrade U- 44,590. This is accomplished by acylating U-44,590, recovering the acylated compound relatively free of impurities, then deacylating the acylated U-44,590 to give U-44,590 in a more purified form.
  • EXAMPLE I Part A Fermentation A soil stock of Streptomyces platensis var. clarensis, NRRL 8035 is used to inoculate a series of 500-ml. Er-
  • the antibiotic titer of the fermentation beer can be monitored by an agar plate disc assay using the bacterium Klebsiella pneumoniae.
  • This bacterium is inoculated into the assay agar (Streptomycin Assay Agar, BBL, Cockeysville, Md., 21030) of the following composition:
  • Deionized water 1 adjust 'pH to 7.9 with Sterilize at 121 C. lbs. steam pressure) for 15 minutes.
  • Phosphate buffer (0.1N pH 6.0) is used as the diluent.
  • the agar plates are incubated at 37 C.-for 16-18 hours. Presence of antibiotic U-44,590 is evidenced by the zone of inhibition around a paper disc to which a fermentation sample was previously applied. The diameter of the zone of inhibition reflects the potency of the 20 antibiotic sample. Thus, a 20 mm. zone of inhibition using a 12.7 mm. paper disc to which 0.08 ml. of antibiotic sample has been applied is expressed as one bio unit per m1. (1 BU/ml.).
  • the column is then eluted with 1 liter each of a 10%, and 50% acetone:water concentration. These eluates, which contain antibiotic U-44,590, are pooled and the acetone is removed on a rotatory evaporator at C./ 15 mm. Hg. The resulting acetone-free preparation is shell-frozen to an aqueous residue and then lyophilized, yield, 3.55 grams assaying 2 BU/mg. of U-44,590 against K. pneumoniae. This preparation, labeled for convenience as Solid A, is then subjected to further recovery procedures as follows.
  • a silica gel (Merck-Darmstadt Cat. 7734) column is prepared from 420 grams of silica gel packed in methanol: chloroform (1:1 v/v). The column measures 3.8 X 88 mm. Solid A, obtained as described above, is added on the top of the column and the column is then eluted with methanol: chloroform (1:1 v/v). Active fractions, as determined by the abovedescribed K. pneumoniae assay, are pooled and the solvent is removed from said pooled fractions by use of a rotary evaporator at 30 C./l5 mm. Hg; yield, 830 mg. assaying 7.5 BU/mg. of antibiotic U-44,590.
  • the procedure for this purification step is as follows: 65
  • a column of silica gel (Merck-Darmstadt, 1 15 grams/gram of the U-44,590 preparation being chromatographed) in ethyl acetate: methanol (6:1 v/v) is prepared by pouring a slurry of silica in the solvent into the column to give a height-diameter ratio of 10:1 after being packed.
  • the U-44,590 preparation obtained as described above in Part B, is dissolved in methanol, silica is added (three times the weight of the U-44,590 preparation used), and this is then taken down to a dry powder on a rotatory evaporator at 40/15 mm. Hg.
  • Fraction Zone of Wt. 'of solid Number 1 Inhibition in Fraction (using 12.7 (rnqm) mm. discs)
  • Fractions 120-180, incl. are pooled and taken to dryness on a rotatory evaporator at 40/7 mm. Hg. to give a syrup, wt. 2.66g, assaying 54 K.p. BU/mg
  • Fractions 181-240, incl. give a syrup, 830 mg; 32 BU/mg., and fractions 241-300, incl. give a syrup, wt. 710 mg., assaying 11 BU/mg.).
  • the tlc is conducted on silica gel plates using the solvent system MeOH-CI-I Cl (1:9 v/v). Zones of the antibiotic are detected by spraying the plates with 10f/M- n spray, and with 50% aq. H 80 followed by heating at 1 C. for ca 10 min.
  • the Rf of the active material in this solvent system is 0.1 1.
  • the preparation of antibiotic U-44,590 obtained in Part D can be further purified by acetylation of the preparation followed by deacetylation and crystallization.
  • the procedure for acetylation is as follows:
  • This syrup is stirred with CH CI (200 ml), and a colorless, flocculent precipitate is removed by filtration and washed with CH Cl until the washings are colorless. The precipitate is discarded.
  • the combined filtrate and washings are washed with aqueous HCl (N/20, 100 ml) twice, the aqueous layer being acidic after the second wash. The aqueous layers are discarded.
  • the organic phase is then washed with water (100 ml), saturated aqueous NaHCO (100 ml), again with water (100 ml), and dried (Na SO The aqueous layers are discarded.
  • the crystalline diacetate U-44,474 (24.90 g) is stirred magnetically in methanol (400 ml), and methanolic sodium methoxide (Stauffer Chem. Co. 25%, 5 drops) is added. Stirring is continued till the solid has dissolved (Drierite tube), and the solution allowed to stand at room temperature for about 2 hours. Solid carbon dioxide, in small pieces, is then added cautiously, with stirring, to neutralize the methoxide, and the solvent is removed on a rotatory evaporator at 40 and 15 mm. Hg., giving a colorless oil.
  • Part E can be substituted by acylating U-44,590 with any readily-available acylating agent to give acylated U-44,590.
  • This acylated U-44,590 product can then be deacylated by methods well known in the art to yield a purified preparationof U-44,590.
  • Readily-available I EXAMPLE 3 As disclosed in Example 2, various acylates of U- 44,950 can be made, and these acylates areuseful to upgrade U 44,590.
  • the 3,5'-di-esters of U-44,590 are formed.
  • the 5'-mono-esters can be formed by standard procedures using a minimum amount of acylating agent.
  • the 3-mono-esters and phosphate can be formed by tritylating U-44,590 to give the 5-'-trity1 derivative, acylating this compound with the desired acylating agent, selected from those disclosed above, to give the 3'- mono-ester 5 '-trityl derivative, which then can be converted to the 3'-mono-ester by removal of the trityl group.
  • the tritylationprocedure disclosed in U.S. Pat. No. 3,426,012, Columns 4 and 5, or other standard tritylation procedures can be employed.
  • the trityl group can be removed by using the procedure disclosed in U.S. Pat. No. 3,426,012, Column 6.
  • EXAMPLE 4 The 5-phosphate of U-44,590 can be prepared by procedures as disclosed in the work of D. Mitsunobu, K. Kato, and J. Kimura [J. Amer. Chem. Soc., 91, 6510 (1969)]. This compound can be used for the same purposes as U-44,590.
  • R and R are Selected from the group consist- Band Frequency ing of a carboxylic acid acyl radical of from 2 to 18 car- (wave Numb) bon atoms, inclusive; or a halo-, nitro-, hydroxy-, 328 W amino-, cyano-, thiocyano-, and lower alkoxy- 2930 a substituted hydrocarbon carboxylic acid acyl radical of 5 2880 w from 2 to 18 carbon atoms, inclusive; R is hydrogen gig and R is as defined above or phosphate; or R is hydro- 1732 5 gen and R is a carboxylic acid acyl radical of from 2 to 18 carbon atoms, inclusive; or a'halo nitro-, hydroxy-, 14 3 s aminocyano-, thiocyano-, and lower alkoxy- Egg M substituted hydrocarbon carboxylic acid acyl radical
  • Antibiotic U-44,590 havmg the structure 1750 s 1732 S 0 1702' 5 I520 S I468 (oil) 8 1411 M 1379 (oil) 5 H CH3 1358 w 1327 w 1318 w 1310 w 1298 w 1280 M I 1250 s 40 1227 s H88 M 1148 w 1113 w 1097 s 1057 M 1030 S 1011 M 1000 M 987 M OH 964 M 957 M 322 $3 2.
  • Band Frequency 5 (Wave Numbers) Intensity 3420 (water) W H 210 M 3 OR 18 carbon atoms, inclusive; or a halo-, nitro-, hydroxy-,
  • O-Xyiose read D-Xyiose for O-Fructose
  • Q read D-Fructose for "5.
  • O-Gaiactose read D-Gaiactose for "7.
  • O-Mannose read D-Mannose Column 18, line 21 for (mqm)” read (mgm) Column 21, line 15, for "date' read data Q Signed and Scaled this eighth Day of Junel976 [SEAL] Arrest:

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US471322A 1974-05-20 1974-05-20 5,6 Dihydro-5-azathymidine and derivatives Expired - Lifetime US3907779A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US471322A US3907779A (en) 1974-05-20 1974-05-20 5,6 Dihydro-5-azathymidine and derivatives
US541346A US3907643A (en) 1974-05-20 1975-01-15 Process for producing the antibiotic U-44,590
ZA00752598A ZA752598B (en) 1974-05-20 1975-04-22 Antibiotic 334a
CA225,567A CA1037889A (en) 1974-05-20 1975-04-24 Antibiotic 5,6-dihydro-5-azathymidine from streptomyces platensis
GB1720675A GB1472667A (en) 1974-05-20 1975-04-25 Nucleosidic antibiotic and derivatives thereof
AU80579/75A AU482760B2 (en) 1974-05-20 1975-04-28 Composition of matter and process
JP50052100A JPS5851759B2 (ja) 1974-05-20 1975-05-01 抗生物質の微生物による製法
DE2521197A DE2521197C2 (de) 1974-05-20 1975-05-13 1-(2-Deoxy-β-D-erythro-pentofuranosyl)-5,6-dihydro-5-methyl-s-triazin-2,4(1H,3H)-dion und Derivate
NL7505708A NL7505708A (nl) 1974-05-20 1975-05-15 Werkwijze ter bereiding van een nieuw antibioticum.
FR7515539A FR2271838B1 (it) 1974-05-20 1975-05-16
BE156516A BE829268A (fr) 1974-05-20 1975-05-20 Nouveaux antibiotiques et leur preparation
CA303,945A CA1056822A (en) 1974-05-20 1978-05-24 Acyl and phosphate derivatives of 5,6-dihydro-5-azathymidine
JP58127066A JPS5948072A (ja) 1974-05-20 1983-07-14 新規な微生物ストレプトミセスプラテンシスバラエテイクラレンシス

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JP (2) JPS5851759B2 (it)
BE (1) BE829268A (it)
CA (1) CA1037889A (it)
DE (1) DE2521197C2 (it)
FR (1) FR2271838B1 (it)
GB (1) GB1472667A (it)
NL (1) NL7505708A (it)
ZA (1) ZA752598B (it)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3988314A (en) * 1975-10-10 1976-10-26 The Upjohn Company Compound U-50,228, derivatives thereof, and processes for preparation
US4022889A (en) * 1974-05-20 1977-05-10 The Upjohn Company Therapeutic compositions of antibiotic U-44,590 and methods for using the same
DE2735378A1 (de) * 1976-08-19 1978-02-23 Upjohn Co 5,6-dihydro-syn(s)-triazinnukleoside und -nukleotide sowie verfahren zu ihrer herstellung
US4140850A (en) * 1977-08-29 1979-02-20 The Upjohn Company 2,2'-Anhydrotriazine nucleosides and process for preparing the same
US4239753A (en) * 1978-12-12 1980-12-16 The Upjohn Company Composition of matter and process
US4423212A (en) * 1980-12-18 1983-12-27 The Upjohn Company Nucleosides and process
US4477442A (en) * 1978-12-12 1984-10-16 The Upjohn Company Composition of matter and process
US5443972A (en) * 1991-03-27 1995-08-22 Sankyo Company, Limited Process to prepare leustroducsins
US5647957A (en) * 1993-06-16 1997-07-15 Ranpak Corporation Method of preparing paper strengthened with solubilized collagen
US5686262A (en) * 1993-06-16 1997-11-11 Ranpak Corporation Recycle process for the production of low-cost soluble collagen
US5700354A (en) * 1993-06-16 1997-12-23 Ranpak Corp. Paper strengthened with solubilized collagen and method
US5711853A (en) * 1993-06-16 1998-01-27 Ranpak Corp. Paper strengthened with solubilized collagen and method
US20040127436A1 (en) * 2002-09-24 2004-07-01 Koronis Pharmaceuticals, Inc. 1,3,5-Triazines for treatment of viral diseases
US20070207973A1 (en) * 2002-09-24 2007-09-06 Koronis Pharmaceuticals, Incorporated 1,3,5-Triazines for Treatment of Viral Diseases

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0411748Y2 (it) * 1984-11-20 1992-03-24
JPH04150878A (ja) * 1990-10-16 1992-05-25 Goerling George ゴルフスイング教習装置

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3300478A (en) * 1965-06-01 1967-01-24 Upjohn Co Arabinofuranosyl 2', 5'-and 3'-5'-dinucleoside phosphates and process therefor
US3457253A (en) * 1965-06-01 1969-07-22 Upjohn Co 5',5'-di-(ara)-nucleoside phosphates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3300478A (en) * 1965-06-01 1967-01-24 Upjohn Co Arabinofuranosyl 2', 5'-and 3'-5'-dinucleoside phosphates and process therefor
US3457253A (en) * 1965-06-01 1969-07-22 Upjohn Co 5',5'-di-(ara)-nucleoside phosphates

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4022889A (en) * 1974-05-20 1977-05-10 The Upjohn Company Therapeutic compositions of antibiotic U-44,590 and methods for using the same
US3988314A (en) * 1975-10-10 1976-10-26 The Upjohn Company Compound U-50,228, derivatives thereof, and processes for preparation
DE2735378A1 (de) * 1976-08-19 1978-02-23 Upjohn Co 5,6-dihydro-syn(s)-triazinnukleoside und -nukleotide sowie verfahren zu ihrer herstellung
US4171431A (en) * 1976-08-19 1979-10-16 The Upjohn Company Nucleosides and process
US4140850A (en) * 1977-08-29 1979-02-20 The Upjohn Company 2,2'-Anhydrotriazine nucleosides and process for preparing the same
US4239753A (en) * 1978-12-12 1980-12-16 The Upjohn Company Composition of matter and process
US4477442A (en) * 1978-12-12 1984-10-16 The Upjohn Company Composition of matter and process
US4423212A (en) * 1980-12-18 1983-12-27 The Upjohn Company Nucleosides and process
US5443972A (en) * 1991-03-27 1995-08-22 Sankyo Company, Limited Process to prepare leustroducsins
US5686262A (en) * 1993-06-16 1997-11-11 Ranpak Corporation Recycle process for the production of low-cost soluble collagen
US5647957A (en) * 1993-06-16 1997-07-15 Ranpak Corporation Method of preparing paper strengthened with solubilized collagen
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US5700353A (en) * 1993-06-16 1997-12-23 Ranpak Corporation Paper strengthened with solubilized collagen and method
US5707491A (en) * 1993-06-16 1998-01-13 Ranpak Corporation Paper strengthened with solubilized collagen and method
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Also Published As

Publication number Publication date
FR2271838A1 (it) 1975-12-19
JPS5948072A (ja) 1984-03-19
AU8057975A (en) 1976-11-04
JPS50148590A (it) 1975-11-28
NL7505708A (nl) 1975-11-24
DE2521197A1 (de) 1975-12-11
DE2521197C2 (de) 1984-09-13
FR2271838B1 (it) 1978-10-06
BE829268A (fr) 1975-11-20
JPS5851759B2 (ja) 1983-11-18
GB1472667A (en) 1977-05-04
ZA752598B (en) 1976-03-31
CA1037889A (en) 1978-09-05

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