IL45741A - Water-soluble derivative of 6-deoxytetracycline and proceswater-soluble derivative of 6-deoxy-tetracycline and process for the preparation thereof s for the preparation thereof - Google Patents
Water-soluble derivative of 6-deoxytetracycline and proceswater-soluble derivative of 6-deoxy-tetracycline and process for the preparation thereof s for the preparation thereofInfo
- Publication number
- IL45741A IL45741A IL45741A IL4574174A IL45741A IL 45741 A IL45741 A IL 45741A IL 45741 A IL45741 A IL 45741A IL 4574174 A IL4574174 A IL 4574174A IL 45741 A IL45741 A IL 45741A
- Authority
- IL
- Israel
- Prior art keywords
- preparation
- water
- soluble derivative
- minutes
- product
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 7
- 239000004098 Tetracycline Substances 0.000 title description 5
- 229960002180 tetracycline Drugs 0.000 title description 4
- 238000001990 intravenous administration Methods 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 7
- 150000003839 salts Chemical class 0.000 claims description 7
- 230000003115 biocidal effect Effects 0.000 claims description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 239000002798 polar solvent Substances 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- 150000001298 alcohols Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 229940043265 methyl isobutyl ketone Drugs 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical class O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 11
- 229960003722 doxycycline Drugs 0.000 description 11
- 150000001875 compounds Chemical class 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000007920 subcutaneous administration Methods 0.000 description 4
- 241000588724 Escherichia coli Species 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000036765 blood level Effects 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229930101283 tetracycline Natural products 0.000 description 3
- 235000019364 tetracycline Nutrition 0.000 description 3
- 150000003522 tetracyclines Chemical class 0.000 description 3
- 101000713585 Homo sapiens Tubulin beta-4A chain Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 241000193996 Streptococcus pyogenes Species 0.000 description 2
- 102100036788 Tubulin beta-4A chain Human genes 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 244000307700 Fragaria vesca Species 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- -1 N-methioninomethyl Chemical group 0.000 description 1
- 244000038458 Nepenthes mirabilis Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 244000127759 Spondias lutea Species 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004174 erythrosine Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- JTJMJGYZQZDUJJ-UHFFFAOYSA-N phencyclidine Chemical compound C1CCCCN1C1(C=2C=CC=CC=2)CCCCC1 JTJMJGYZQZDUJJ-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
»j»p»SRiee*»opi«»'r«i€ © o*03 nooan iVin nnaanV i»Vani A water-soluble derivative of 6-deoxy-tetracycli&eft and process or the preparation thereof The present invention has for subject matter a novel antibiotic product having the general formula; its pharmaceutically acceptable soluble salts of organic or inorganic acids and its pharmaceutically acceptable soluble mono- or poly-valent metal salts.
In U.S. Patent 3,637,471 and Belgian Patent !)615425 there are described aminoacid methylene derivatives of tetracycline. In British Patent 1,098,566 there is described methio- derivatives nineamide methyl adduoto of tetracycline and in the article whose abstract appears in CA 55, 21074e there is disclosed r' derivfttiv.fis N-methioninomethyl adducfe or tetracycline, however, none of said publications teach or suggest the present doxycycline or the advantageous properties thereof as described hereinafter.
The new derivative forming subject matter of the invention is characterized by great solubility in water at neutral pH, and it can therefore be administered both per os and intramuscularly or intravenously and, in addition, preserves unaltered the antibiotic activity of deoxycycline.
The new derivative has improved patient-toleration, stability and higher blood levels as compared with both the 6-deoxy-tetracyclines and with their water soluble derivatives; furthermore, its toxicity is lower while it maintains The product having the general formula I can be prepared by placing doxycycline into contact with an eguimolecular quantity of methionine, in the presence of formaldehyde, in a polar solvent, at the temperatures and for the periods of time necessary to obtain a complete reaction.
The formaldehyde should for preference be added in the proportion of one mole per mole of starting doxycycline and can be in the form of aqueous solution, gas or even in solid form. - la - Suitable solvents are mono- or poly-bydroxylated alcohols containing from 1 to 4 C atoms, water, dioxane, tetrahydrofurane, ^ methylisobutylketone, Ν,Ν' dimeth lformamide.
The reaction temperatures are comprised between 10° and 80°C , o but the most favourable range is 3 -40 C.
The reaction times vary from 20 minutes to 240 minutes.
The product is isolated by means of precipitation from the same solvent in which its formation takes place, or it can be precipitated with a second solvent in which it is insoluble, or it can be obtained by freeze-drying.
The product can be utilized as is or in the form of one of its pharmaceutically acceptable soluble salts of organic or Inorganic acids or in the form of one of its pharmaceutically acceptable soluble mono- or poly-valent salts.
While the invention will now be described in connection with certain preferred embodiments in the following examples it will be understood that these examples are illustrative and not restrictive and that e.g., equivalent salts other than those exemplified can also readily be produced and used.
Example 1 At 65°C, 4.44 g of doxyoycllne anhydrous base was dissolved under agitation in 140 ml of absolute ethanol. o At 35 C, addition was made of 1 .5 g of methionine dissolved with 1 .2 ml of 3 # NaOH and 1 .1 ml of 3 # formic aldehyde.
The agitation was continued for 30 minutes at 35°C and for a further o 30 minutes at 3 C, filtration was performed on the product obtained and washing performed with ethanol. o After vacuum drying at 40 C, there was obtained 4.85 g of product o in the form of a light yellow powder, m.p. 208 C.
The pH of a 5% aqueous solution was 7»! .
The solubility of the product was more than 1 g per ml „ Compositions Co0H N 0 S (mol. wt „ 605 - 6) , 2o 3 5 3 10 Calculated values s Cs 55*5%; Hs 5o%%; 0% 26*4%; Ss 5 .3 ; N's 7.0%, Values founds Cs 54 ° 6$ ; Hs 5.9%; Os 27 · 156 Ss 5. 456; s 6 . 5$ » There are now given the results of a few pharmacological, chemical and chemotherapeutic tests in order to illustrate the principal properties and characteristics of the product of the Example I„ A) - The product is soluble in water at pH values close to neutrality; 1 g of derivative will dissolve in 0 <, 7 ml of water „ B) - The stability of the product in aqueous solution is equal or superior to that of doxycycline in analogous conditions. This is confirmed by the spectrophotometric tests „ C) The Minimal Inhibitory Concentration (MIC) of the compound of the Example I, as compared with that of doxycycline, in respect of standard bacterial strains as listed hereunder demonstrates that, the content of doxycycline being equal, the activity of the derivative is almost identical _ M„I-C, • Compound Doxycycline of Ex „ I aureus 209P 0.2 0.25 s. aureus 171G 0.05 0.07 s. pyrogenes ATCC 8663 0,05 O.O7 s. fa ecalis ATCC 8043 Ο.25 0,35 B, a culans ATCC 9961 0,05 O.04 B, subtilis ATCC 6633 0.05 O.04 S. lutea ATCC 10054 0,05 O.07 D. pneumoniae 0,01 0,02 E. coli 11.3-3 1.5 2,0 E. coli 266 0.75 1.0 E, coli ATCC 8739 2,0 2.75 E. coli ATCC 10530 1.25 1.75 K. pneumoniae 132 1.5 2,25 P. vulgaris ATCC 9920 >50 50 P. ettgerii ATCC 9250 1.75 2.5 P. mirabilis ATCC 9921 9> 100 100 D) - Chemotherapeutic activity of the compound of the Example I expressed as mi°e infected with various bacterial strains.
Compound of Doxy- Infection ' Route (a) Dose (b) S. aureus (d) oral S. intravenous S, 7.11 78.6 subcutaneous M, 1,67 16.2 2,21 S, pyrogenes 8668 oral S. 7.55 - 5.74 S. pyrogenes 8668 intravenous S, 5.41 71.6 S, pyrogenes (d) oral S. 0,64 - 0.51 intravenous S, 0.47 73.3 Infection Route (a) Dos PD50 Doxy- \ mg/kg cycline Eo.coli 266 oral 52 o l 38.Ο intravenous 36. 7 70.4 E, coli (d) oral 20,4 16 , 2 intravenous 14.6 71 = 5 K, pneumoniae subcutaneous 1 .32 intravenous l o03 78.Ο a) = Route of administrations oral, intravenous, subcutaneous b) = Doses s single (S) or multiple (M) c) = decrease in percentage of oral PD, 50 d) = Strains of clinical origin e) = Decrease in percentage of subcutaneous PD( 50 E) - The blood level of the product of the Example I in mice, rats and rabbits after a single oral dose of 12.5 mg/kg is equal or superior, in the various time intervals, to the blood level of doxycycline in the same conditions „ F) - Acute toxicity (LD^) of the compound of the Example 1 in mice and rats „ Data compared with data for Doxycycline (in brackets) Animal species Route LD mg/kg Mouse oral 2000* ( -» 2000)* intravenous 394 ( 257) 67Ο ( 425) Rat oral 3000·* (ss-3000)* 582 (370) *) Tests limited to a maximum dose of 2.0 g/kg or 3 -0 g/kg, thereafter suspended inasmuch as not of great significance „ The following are some specific Examples of the preparation of formulations suitable for pharmaceutical use.
Example II Injectable preparation, ISO mg, of the compound prepared in the Example I, equivalent to 100 mg of doxycycline base, are admixed with 20 mg of solid NaCl, From this mixture a $% dextrose solution for slow intravenous perfusion is prepared.
Example III Capsules for oral administration Compound of Example I 150 mg Mg stea ate 3 mg Lactose 50 Talc 5 mg Corn starch, q„s, to 300 mg .
Example IV Powder for extemporaneous solution for oral administration.
Compound of Example I 1.5 g (equivalent to 1,0 g of doxycycline base) Na benzoate 0„06 g Na carboxymethyl cellulose 0.l6 g Sugar 35 g Strawberry spirit 0,05 g Colorant E 127 0.005 g.
Claims (8)
1. 45741/2 A novel antibiotic product having the general formula: its pharmaceutically acceptable soluble salts of organic or inorganic acids and ite pharmaceutically acceptable soluble mono- or poly-valent metal salts. ' . . ( ■
2. A process for the preparation of the product of claim 1 , wherein doxycycllne is placed into contact with an equimolecular quantity of methionine in the presence of formaldehyde in a polar solvent at .a o temperature of 10 to 80 C. J.
3. Process according to claim 2, characterized by that the polar solvent is selected in the group consisting of mono or polyhydroxylated alcohols containing from 1 to
4. C atoms, water, dioxane, tetrahydrofurane, methyl-isobutylketone and Ν,Ν' dimethylformamide. 4..: . Process according to. claim 2, characterized by that, the reaction o o temperature is comprised between 30 C and 40 C.
5. Process according to claim 2, characterized in that the reaction times are comprised between 20 minutes and 240 minutes, preferably between 30 and 120 minutes. 45741/2
6. Process for the preparation of a water soluble derivative of doxycycline according to the Example 1.
7. Novel antibiotic product according to claim 1 , associated with a therapeutically acceptable vehicle according to the Example 2, 3 and 4·
8. Novel antibiotic product according to claim 1 in water soluble form adapted for oral, intravenous, parenteral administration. Attorney for Applicants - 8 -
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2948673 | 1973-09-28 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IL45741A0 IL45741A0 (en) | 1974-11-29 |
| IL45741A true IL45741A (en) | 1977-12-30 |
Family
ID=11227072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL45741A IL45741A (en) | 1973-09-28 | 1974-09-25 | Water-soluble derivative of 6-deoxytetracycline and proceswater-soluble derivative of 6-deoxy-tetracycline and process for the preparation thereof s for the preparation thereof |
Country Status (15)
| Country | Link |
|---|---|
| JP (1) | JPS6044293B2 (en) |
| AT (1) | AT337359B (en) |
| BE (1) | BE820474A (en) |
| CA (1) | CA1031774A (en) |
| CH (1) | CH614190A5 (en) |
| DE (1) | DE2446586A1 (en) |
| DK (1) | DK153784C (en) |
| ES (1) | ES430512A1 (en) |
| FR (1) | FR2246275B1 (en) |
| GB (1) | GB1484345A (en) |
| IL (1) | IL45741A (en) |
| NL (1) | NL7412764A (en) |
| NO (1) | NO140345C (en) |
| SE (1) | SE398875B (en) |
| ZA (1) | ZA746147B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6442586U (en) * | 1987-09-07 | 1989-03-14 | ||
| KR20090122994A (en) * | 2007-03-23 | 2009-12-01 | 몰레큘러 리서치 센터, 인크. | Anti-Inflammatory Compositions Containing Tetracyclines and Their Uses |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES262241A1 (en) * | 1959-11-23 | 1961-02-01 | Erba Carlo Spa | Procedure for preparing new derivatives of tetracycline antibiotics (Machine-translation by Google Translate, not legally binding) |
| BE615425A (en) * | 1961-03-24 | 1962-07-16 | Erba Carlo Spa | New salts of derivatives of tetracycline antibiotics |
-
1974
- 1974-09-24 DK DK501674A patent/DK153784C/en active
- 1974-09-25 IL IL45741A patent/IL45741A/en unknown
- 1974-09-25 CA CA210,080A patent/CA1031774A/en not_active Expired
- 1974-09-26 AT AT776274A patent/AT337359B/en not_active IP Right Cessation
- 1974-09-26 NO NO743489A patent/NO140345C/en unknown
- 1974-09-26 GB GB41918/74A patent/GB1484345A/en not_active Expired
- 1974-09-27 SE SE7412215A patent/SE398875B/en not_active IP Right Cessation
- 1974-09-27 BE BE149013A patent/BE820474A/en not_active IP Right Cessation
- 1974-09-27 ZA ZA00746147A patent/ZA746147B/en unknown
- 1974-09-27 NL NL7412764A patent/NL7412764A/en not_active Application Discontinuation
- 1974-09-27 CH CH1305774A patent/CH614190A5/en not_active IP Right Cessation
- 1974-09-28 ES ES430512A patent/ES430512A1/en not_active Expired
- 1974-09-28 JP JP49112212A patent/JPS6044293B2/en not_active Expired
- 1974-09-30 DE DE19742446586 patent/DE2446586A1/en not_active Withdrawn
- 1974-09-30 FR FR7432896A patent/FR2246275B1/fr not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CH614190A5 (en) | 1979-11-15 |
| NL7412764A (en) | 1975-04-02 |
| SE7412215L (en) | 1975-04-01 |
| ZA746147B (en) | 1975-11-26 |
| SE398875B (en) | 1978-01-23 |
| DK153784B (en) | 1988-09-05 |
| JPS6044293B2 (en) | 1985-10-02 |
| JPS5062970A (en) | 1975-05-29 |
| AT337359B (en) | 1977-06-27 |
| AU7381274A (en) | 1976-04-01 |
| ES430512A1 (en) | 1977-01-16 |
| DE2446586A1 (en) | 1975-04-03 |
| BE820474A (en) | 1975-01-16 |
| NO743489L (en) | 1975-04-28 |
| FR2246275A1 (en) | 1975-05-02 |
| FR2246275B1 (en) | 1978-07-21 |
| ATA776274A (en) | 1976-10-15 |
| DK153784C (en) | 1989-01-23 |
| GB1484345A (en) | 1977-09-01 |
| IL45741A0 (en) | 1974-11-29 |
| NO140345B (en) | 1979-05-07 |
| DK501674A (en) | 1975-05-26 |
| CA1031774A (en) | 1978-05-23 |
| NO140345C (en) | 1979-08-15 |
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