NO140345B - ANALOGICAL PROCEDURE FOR PREPARATION OF WATER-SOLUBLE DERIVATIVES OF 6-DEOXY-TETRACYCLINES - Google Patents
ANALOGICAL PROCEDURE FOR PREPARATION OF WATER-SOLUBLE DERIVATIVES OF 6-DEOXY-TETRACYCLINES Download PDFInfo
- Publication number
- NO140345B NO140345B NO743489A NO743489A NO140345B NO 140345 B NO140345 B NO 140345B NO 743489 A NO743489 A NO 743489A NO 743489 A NO743489 A NO 743489A NO 140345 B NO140345 B NO 140345B
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- NO
- Norway
- Prior art keywords
- deoxy
- tetracyclines
- water
- preparation
- soluble derivatives
- Prior art date
Links
- 239000004098 Tetracycline Substances 0.000 title claims description 9
- 229940040944 tetracyclines Drugs 0.000 title claims description 6
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 3
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 12
- 150000001875 compounds Chemical class 0.000 claims description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 claims description 3
- 229930182817 methionine Natural products 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims description 2
- 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 class 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 8
- 229960003722 doxycycline Drugs 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241000699670 Mus sp. 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
- 150000003839 salts Chemical class 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 229960002180 tetracycline Drugs 0.000 description 3
- 241000700159 Rattus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000001580 bacterial effect Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 230000000973 chemotherapeutic effect Effects 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229960004672 doxycycline anhydrous Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 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
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
Foreliggende oppfinnelse angår en analogifremgangsmåte The present invention relates to an analog method
til fremstilling av 6-deoksy-tetracykliner, og som har følgende generelle formel: for the production of 6-deoxy-tetracyclines, and which have the following general formula:
hvor X er en tetracyklinkjerne, Y er en gruppe where X is a tetracycline nucleus, Y is a group
De nye derivater som fremstilles ifølge foreliggende oppfinnelse er karakterisert ved stor oppløselighet i vann ved nøytral pH, og kan derfor tilføres både pr. os og intramuskulært og intravenøst, og bevarer dessuten uendret den antibiotiske aktiviteten til deoksycyklin. The new derivatives produced according to the present invention are characterized by high solubility in water at neutral pH, and can therefore be supplied both per os and intramuscularly and intravenously, and also preserves unchanged the antibiotic activity of deoxycycline.
Derivatene har bedret pasient-toleranse, stabilitet og The derivatives have improved patient tolerance, stability and
høyere blodnivå sammenlignet med både 6-deoksy-tetracykliner og deres vannoppløselige derivater. Videre er deres toksisitet lavere selv om man bevarer uendret de antibiotiske egenskaper man finner i 6-deoksy-tetracyklinet. higher blood levels compared to both 6-deoxy-tetracyclines and their water-soluble derivatives. Furthermore, their toxicity is lower even if the antibiotic properties found in 6-deoxy-tetracycline are preserved unchanged.
Forbindelser med generell formel I kan fremstilles ved å plassere en forbindelse av gruppen 6-deoksy-tetracykliner i kontakt med en ekvimolekylar mengde av metionin, i nærvær av formaldehyd i et polart oppløsningsmiddel og ved temperaturer og i tidsrom som er tilstrekkelige til at man får en fullstendig reaksjon. Compounds of general formula I can be prepared by placing a compound of the group of 6-deoxy-tetracyclines in contact with an equimolar amount of methionine, in the presence of formaldehyde in a polar solvent and at temperatures and for times sufficient to obtain a complete reaction.
Formaldehydet bør fortrinnsvis tilsettes i mengder på The formaldehyde should preferably be added in amounts of
1 mol pr. mol av nevnte 6-deoksy-tetracyklin, og kan være i form av en vandig oppløsning, en gass eller i fast form. 1 mole per moles of said 6-deoxy-tetracycline, and can be in the form of an aqueous solution, a gas or in solid form.
Egnede oppløsningsmidler er mono- eller polyhydroksylerte alkoholer med fra 1 til 4 C-atomer, vann, dioksan, tetrahydro-furan, metylisobutylketon, N,N'-dimetylformamid osv. Suitable solvents are mono- or polyhydroxylated alcohols with from 1 to 4 C atoms, water, dioxane, tetrahydrofuran, methyl isobutyl ketone, N,N'-dimethylformamide, etc.
Reaksjonstemperaturene ligger mellom 10 og 80°C, fortrinnsvis mellom 30 og 40°C. The reaction temperatures are between 10 and 80°C, preferably between 30 and 40°C.
Reaksjonstiden kan variere fra 20 til 240 minutter. The reaction time can vary from 20 to 240 minutes.
Produktet kan isoleres ved at det utfelles fra samme opp-løsningsmiddel hvori det dannes, eller det kan utfelles ved hjelp av et annet oppløsningsmiddel i hvilket det er uoppløselig, The product can be isolated by being precipitated from the same solvent in which it is formed, or it can be precipitated using another solvent in which it is insoluble,
eller det kan oppnås ved hjelp av frysetørking. or it can be achieved by freeze-drying.
Produktet kan brukes som sådant eller som dets mineral-syresalt eller som et organisk syreoppløselig salt hvis dette er terapeutisk akseptabelt, og dessuten som mono- eller polyvalente metallsalter. The product can be used as such or as its mineral acid salt or as an organic acid-soluble salt if this is therapeutically acceptable, and also as mono- or polyvalent metal salts.
Det er i det etterfølgende gitt et eksempel på en fremstilling av et derivat av doksycyklin, men dette er ikke ment som en begrensning, idet fremgangsmåten rent prinsipielt kan brukes også for fremstilling av derivater av andre 6-deoksy-tetracykliner. An example of a preparation of a derivative of doxycycline is given below, but this is not intended as a limitation, as the method can in principle also be used for the preparation of derivatives of other 6-deoxy-tetracyclines.
Eksempel I Example I
Ved 65°C ble 4,44 g doksycyklin-vannfri base oppløst under omrøring i 140 ml absolutt etanol. At 65°C, 4.44 g of doxycycline anhydrous base was dissolved with stirring in 140 ml of absolute ethanol.
Ved 35°C tilsatte man så 1,5 g metionin oppløst i 1,2 ml 30% NaOH og 1,1 ml 35% formaldehyd. At 35°C, 1.5 g of methionine dissolved in 1.2 ml of 30% NaOH and 1.1 ml of 35% formaldehyde were then added.
Omrøringen ble fortsatt i 30 minutter ved 35°C og ytter-ligere 30 minutter ved 30°C, hvoretter man frafiltrerte det fremstilte produkt og vasket dette med etanol. Stirring was continued for 30 minutes at 35°C and a further 30 minutes at 30°C, after which the produced product was filtered off and washed with ethanol.
Etter vakuumtørking ved 40°C fikk man 4,85 g av produktet After vacuum drying at 40°C, 4.85 g of the product was obtained
i form av et lysegult pulver, smeltepunkt 208°C. in the form of a light yellow powder, melting point 208°C.
pH for en 5%'s vandig oppløsning var 7,1. The pH of a 5% aqueous solution was 7.1.
Oppløseligheten av produktet var mer enn 1 g pr. ml. Sammensetning: C2<gH>35<N>3<O>10<S> (Mol-vekt 605,6). The solubility of the product was more than 1 g per ml. Composition: C2<gH>35<N>3<O>10<S> (Mol weight 605.6).
Beregnede verdier: C 55,5%; H 5,8%; O 26,4%; S 5,3%; N 7,0%. Funnede verdier: C 54,6%; H 5,9%; O 27,1%; S 5,4%; N 6,5%. Calculated values: C 55.5%; H 5.8%; O 26.4%; S 5.3%; N 7.0%. Values found: C 54.6%; H 5.9%; O 27.1%; S 5.4%; N 6.5%.
Det er i det etterfølgende gitt resultater av en del farmakologiske, kjemiske og kemoterapeutiske prøver for å illustrere de vesentlige egenskaper og karakteristika for produktet fra eksempel I. A) Produktet er oppløselig i vann ved pH-verdier nær nøy-tralitet: 1 g av derivatet vil oppløse seg i 0,7 ml vann. B) Stabiliteten for produktet i vandig oppløsning er tilsvarende eller bedre enn den man finner for doksycyklin under analoge betingelser. Dette ble bekreftet ved hjelp av spektro-fotometriske prøver. C) Den minimalt inhiberende konsentrasjon (MIC) for forbindelsen fra eksempel I, sammenlignet med den tilsvarende for doksycyklin med hensyn til standard bakterielle raser, slik disse er gitt i det etterfølgende, viser at når innholdet av doksycyklin er likt, så er derivatets aktivitet nesten identisk med den man finner for doksycyklin. D) Kemoterapeutisk aktivitet for forbindelsen fra eksempel I uttrykt som PD^q i mus infisert med forskjellige bakterieraser. tabell forts. The results of a number of pharmacological, chemical and chemotherapeutic tests are subsequently given to illustrate the essential properties and characteristics of the product from example I. A) The product is soluble in water at pH values close to neutrality: 1 g of the derivative will dissolve in 0.7 ml of water. B) The stability of the product in aqueous solution is equivalent or better than that found for doxycycline below analogous conditions. This was confirmed using spectrophotometric tests. C) The minimal inhibitory concentration (MIC) of the compound from Example I, compared to the corresponding one for doxycycline with respect to standard bacterial races, as given below, shows that when the content of doxycycline is equal, the activity of the derivative is almost identical to that found for doxycycline. D) Chemotherapeutic activity of the compound from Example I expressed as PD^q in mice infected with different bacterial races. table cont.
a) = Tilførselsmåte: oralt, intravenøst, subkutant. a) = Method of administration: oral, intravenous, subcutaneous.
b) = Doser: enkle (S) eller flere (M). b) = Doses: single (S) or multiple (M).
c) = Senkning i prosent for oralt PD5q- c) = Decrease in percentage for oral PD5q-
d) = Raser av klinisk opprinnelse. d) = Breeds of clinical origin.
E) Innholdet i blodet av produktet fra eksempel I hos mus, rotter og kaniner etter en enkelt oral dose på 12,5 mg/kg er lik eller bedre, tatt på forskjellige tidsintervaller, enn det tilsvarende innhold for doksycyklin under samme betingelser. F) Akutt toksisitet (LD^^) for forbindelsen fra eksempel I hos mus og rotter. E) The content in the blood of the product from Example I in mice, rats and rabbits after a single oral dose of 12.5 mg/kg is equal to or better, taken at different time intervals, than the corresponding content for doxycycline under the same conditions. F) Acute toxicity (LD^^) of the compound from Example I in mice and rats.
Data sammenlignet med data for doksycyklin (i parentes). Data compared with data for doxycycline (in parentheses).
eller 3,0 g/kg kroppsvekt, og ble deretter avsluttet ettersom disse prøver ikke var av særlig stor betydning. or 3.0 g/kg body weight, and was then terminated as these samples were not of particular importance.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2948673 | 1973-09-28 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO743489L NO743489L (en) | 1975-04-28 |
| NO140345B true NO140345B (en) | 1979-05-07 |
| NO140345C NO140345C (en) | 1979-08-15 |
Family
ID=11227072
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO743489A NO140345C (en) | 1973-09-28 | 1974-09-26 | ANALOGICAL PROCEDURE FOR PREPARATION OF WATER-SOLUBLE DERIVATIVES OF 6-DEOXY-TETRACYCLINES |
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 | ||
| EP2125018A1 (en) * | 2007-03-23 | 2009-12-02 | Molecular Research Center, Inc. | Compositions and methods for anti-inflammatory treatments |
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 GB GB41918/74A patent/GB1484345A/en not_active Expired
- 1974-09-26 NO NO743489A patent/NO140345C/en unknown
- 1974-09-27 NL NL7412764A patent/NL7412764A/en not_active Application Discontinuation
- 1974-09-27 SE SE7412215A patent/SE398875B/en not_active IP Right Cessation
- 1974-09-27 CH CH1305774A patent/CH614190A5/en not_active IP Right Cessation
- 1974-09-27 ZA ZA00746147A patent/ZA746147B/en unknown
- 1974-09-27 BE BE149013A patent/BE820474A/en not_active IP Right Cessation
- 1974-09-28 JP JP49112212A patent/JPS6044293B2/en not_active Expired
- 1974-09-28 ES ES430512A patent/ES430512A1/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 |
|---|---|
| JPS6044293B2 (en) | 1985-10-02 |
| ZA746147B (en) | 1975-11-26 |
| FR2246275A1 (en) | 1975-05-02 |
| IL45741A0 (en) | 1974-11-29 |
| ES430512A1 (en) | 1977-01-16 |
| NL7412764A (en) | 1975-04-02 |
| AT337359B (en) | 1977-06-27 |
| DK153784B (en) | 1988-09-05 |
| BE820474A (en) | 1975-01-16 |
| GB1484345A (en) | 1977-09-01 |
| CA1031774A (en) | 1978-05-23 |
| NO140345C (en) | 1979-08-15 |
| ATA776274A (en) | 1976-10-15 |
| FR2246275B1 (en) | 1978-07-21 |
| DK153784C (en) | 1989-01-23 |
| DE2446586A1 (en) | 1975-04-03 |
| SE7412215L (en) | 1975-04-01 |
| DK501674A (en) | 1975-05-26 |
| CH614190A5 (en) | 1979-11-15 |
| NO743489L (en) | 1975-04-28 |
| SE398875B (en) | 1978-01-23 |
| IL45741A (en) | 1977-12-30 |
| AU7381274A (en) | 1976-04-01 |
| JPS5062970A (en) | 1975-05-29 |
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