CA1070675A - Polymyxin methyl tetracycline - Google Patents
Polymyxin methyl tetracyclineInfo
- Publication number
- CA1070675A CA1070675A CA222,417A CA222417A CA1070675A CA 1070675 A CA1070675 A CA 1070675A CA 222417 A CA222417 A CA 222417A CA 1070675 A CA1070675 A CA 1070675A
- Authority
- CA
- Canada
- Prior art keywords
- antibiotic
- formula
- salts
- colistine
- family
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
The present invention relates to the new antibiotic polymyxine methyl tetracycline wide spectrum salts of the general formula [TH+-CO-NH-CH2-NH)n-P, nA=], m HB-in which m and n represent positive integers of less than 6, A= and B- represent mineral or organic anions, T represents an antibiotic residue of the tetracycline family having a primary amide function and the formula T-CONH2, P represents a polypeptidic antibiotic residue of the polymyxine family of the formula P-(NH2)n, and particularly tri-(oxytetra-cycline methyl) colistine trichloride-sulfate. The present invention also relates to the methods of preparing antibiotic salts by preparing the methylols of tetracycline salts by the addition of formol to the treacycline salts, then, with or without isolation of this intermediate product, condens-ing it with an antibiotic of the polymyxine family. The present invention also relates to medications and pharma-ceutical forms containing the products of the invention.
The present invention relates to the new antibiotic polymyxine methyl tetracycline wide spectrum salts of the general formula [TH+-CO-NH-CH2-NH)n-P, nA=], m HB-in which m and n represent positive integers of less than 6, A= and B- represent mineral or organic anions, T represents an antibiotic residue of the tetracycline family having a primary amide function and the formula T-CONH2, P represents a polypeptidic antibiotic residue of the polymyxine family of the formula P-(NH2)n, and particularly tri-(oxytetra-cycline methyl) colistine trichloride-sulfate. The present invention also relates to the methods of preparing antibiotic salts by preparing the methylols of tetracycline salts by the addition of formol to the treacycline salts, then, with or without isolation of this intermediate product, condens-ing it with an antibiotic of the polymyxine family. The present invention also relates to medications and pharma-ceutical forms containing the products of the invention.
Description
~ ~ - 1070675 The present inventlon relates to-salts of polymyxine methyl tetracyclines having the characteristic formula:
- .... : .- ,, ~ .' - : . , [(TH - C0 - NH - CH2 - NH)n - P, nA ], mHB (A) in which~
; m and n represent positive integers less than 6, -A and B represent mineral or organic anions,~
`T represents a tetracyclical antibiotic residue of the tetra-cycline family having a prlmary amide function, the formula of - which is T - C0 - NH2, such as tetracycline, oxytetracycline, dimethylchlorotetracycline, methacycline, rolitetracycline, doxycycline, minocycline, P represents the residue of a colistine molecule, the formula of whlch is P - (~H2)n.
The tritetracycline methyl polymyxine trichloro-; hydrates have previously been described, but they are not usable industrially because of their instabillty both~in dry-condition and in solution.
The salts of this invention are remarkable in that they are stable in dry condition and even in neutral or slightly alkaline solution, for example at pH 8.5.
The present invention also relates to products respond-ing to the above formula (A) to trioxytetracycline methyl coli-stine trichlorohydrate, hereinafter called Negafongine.
~ The present invention also relates to the methods for the preparation of new salts of the invention, characterized by initially reacting formol and an antibiotic of the tetracycline family in the form of its salt, and then reacting the product with colistine sulfate.
-~ According to the invention, a reaction medium is sel-ected both for the initial addition and for the final ~$
condensation which does not react with formol, and although this temperature is not characteristic of the invention, gen-erally the opexation is carried out between room temperature and 60C. ~n fact, above this temperature, the antibiotic substrata co~mence to degrade.
The present invention moreover relates to medica-tions usable in human or veterinary medicine, characterized by containing, as primary or secondary active principal, one or more salts of the invention of the above formula (A). In ;~ 10 fact, at variable doses, these compounds are bacteristatic, ;~ bacteriocides on the Gram+ and Gram- bacteria, and on the large viruses, the protozaires and certain flagellates.
The interest in the salts of formula (A) of the in-vention resides particularly in the fact that the toxicity of the polymyxines is considerably reduced in this type of com-pound and that the anti-bacterial activity of the new com-pounds of the invention is higher, in vitro and in vovo, than the simple mixture of antibiotics from substrates for the syn-thesis of the new salts of the invention. In vivo, in particu-~0 lar, it is surprising to note that the new salts of the in-vention completely pass the gastro-intestinal barrier, thus pass into the interior medium and thus make it possible to treat Gram- a~fections outside the digestive tract, such as urinary affections, while it is well known that tetrac~clines, which pass the gastro-intestinal barrier, although poorly, are inactive and that the polymyxines do not pass this barrier and thus cannot act outside the digestive tract when they are administered orally.
The present invention relates in particular to med-3 ications for human or veterinaxy medicine, characterized by . : ~
:; ~
the fact that their activity is antibiotic and that they con-tain at least one salt of this invention of fo~ula (A) above as primary or secondary active principal.
Moreover, the present invention relates to the phar-maceutical compounds containing at least one salt of the in-vention of above formula (A).
In addition, the present invention relates to the pharmaceutical forms, such as wafers, powders, gellules, compresses, lozenges, syrup for oral administration, to the form for administration in ophthalmology, otorhinolaryngology, such as drops, pommades, cones, to the forms of rectal admin-istrations, suppositories, enemas, to ready to use injectable forms or those to be prepared at the time of use.
i The invention will be better understood from the following example ~iven as a non-limitative case and describ-ing the preparation and properties of one of the sales of the invention, defined above under the name of Negafongine.
PREPARATION OF NEGAFONGINE
56 grams oxytetracycline chlorohydrate is put into suspension in 6 liters of pure anhydrous alcohol. Heat to 50C and introduce, under agitation, 20 cc formol, previously concentrated by one third and filtered to eliminate the insol-ubles. The dissolution is complete in 15-20 minutes. Then ~ -evaporate to dryness under vacuum.
The crystals obtained are taken up with 50 cc abso-lute methanol after expansion in the air for a few hours to eliminate the formol odor. Add directly to this solution, 50 grams colistine sulfate to avoid the formation of lumps.
Heat to 45-50C under agitation. The dissolution is complete in 10~15 minutes. Some insoluble flakes are filtered and the ~070675 filtrate is left to stand overnight at -10C. The Nega0ngin2 obtaine~ is dried cold. 15-20% of product is still found in the mother liquors.
The Negafongine is water-soluble in stable form but has no clearly determined melting point because it decomposes when hot.
Spectroscopic-Analyses, performed essentially in comparison with those of the substrate having been used dur-ing the synthesis, that is to say oxytetracycline chloro-hydrate and colistine sulfate.
Infrared Analysis by dispersion in Nujol.
Considerable differences exist between Negafongine and oxytetracycline chlorohydrate in the area of 3500-3000 cm-l. Particularly the tetracyclinical band at 3400 cm~l no longer appears in Negafongine, which proves that the -NH2 group of the oxytetracycline amide function has reacted, which is still confirmed, although this area is charged by differences observed in the region of 17U0-1600 cm~l.
Analysis by Nuclear Magnetic Resonance: by dissolu-tion in deuterized dimethyl sulfoxide.
The spectrum of Negafongine has a mass in the strong fields which is absent in each of the starting substrata. It corresponds to the alcoyl radical hydrogens, proving the real-ity of the new Negafongine structure. In the region of the aromatic process, Negafongine maintains unchanged the oxy-tetracycline phenolhydroxyl, which implies that the addition of formol was not made in this area.
TOXICITY OF NEGAFONGINE
DL 50 per os male mice: 1900 mg/kg DL 50 intravenously male mice: 22.5 mg/kg aa/æmar4 DL 50 intramuscular male mice: 125 mg/kg These toxicological studies w~re completed by worX
on different galenic forms: "dry-fill" by intramuscular in-jection, "dry-fill" by intravenous injection, ready to use injectable solution, gelatin-coated pill for oral use, going from acute toxicity to chronic toxicity in mice, rats, rab-:
bits and dogs. At doses 2.5 times higher than those provid-ed in man, the tolerance always has been perfect, but at doses still 10 times higher, that is 25 times higher than those pro- -;~ 10 vided in man, a high mortality rate is observed (40/0 in rats i 63 days after treatment), a relatively high reduction of the number of red blood corpuscles and rather severe gastric seizures also were noted.
~ ACTIVE ANTI-MICROBIAN ACTIVITY IN VITRO OF NEGAFONGINE
'd` ~ 15 On Gram+ and Gram- bacteria of hospital origin, tests were conducted according to the known technique and the disc (gelatin-coated medium). The activities of the colistine and of oxyte~racycline are found with a synergizing activity which manifests itself particularly on the Aeruginose ~Gram-) '~ 20 P.S.
Results of the Clinical Tests The first clinical tests regarding Negafongine were -cQnducted by oral administration (gelatin-coated pills at 250 mg), ~y intramuscular ready to use injection or "dry-fill", by intravenous injection. These results are perfectly satis-factory, particularly as far as oral administration is con-cerned, where it is known that the colistine cannot pass the gastro-intestinal barrier. In fact, negafongine proved to be active orally on Gram- affection of the respiratory, the 3 urinary and the gynecological tracts, and of course the di-gestive tract.
- .... : .- ,, ~ .' - : . , [(TH - C0 - NH - CH2 - NH)n - P, nA ], mHB (A) in which~
; m and n represent positive integers less than 6, -A and B represent mineral or organic anions,~
`T represents a tetracyclical antibiotic residue of the tetra-cycline family having a prlmary amide function, the formula of - which is T - C0 - NH2, such as tetracycline, oxytetracycline, dimethylchlorotetracycline, methacycline, rolitetracycline, doxycycline, minocycline, P represents the residue of a colistine molecule, the formula of whlch is P - (~H2)n.
The tritetracycline methyl polymyxine trichloro-; hydrates have previously been described, but they are not usable industrially because of their instabillty both~in dry-condition and in solution.
The salts of this invention are remarkable in that they are stable in dry condition and even in neutral or slightly alkaline solution, for example at pH 8.5.
The present invention also relates to products respond-ing to the above formula (A) to trioxytetracycline methyl coli-stine trichlorohydrate, hereinafter called Negafongine.
~ The present invention also relates to the methods for the preparation of new salts of the invention, characterized by initially reacting formol and an antibiotic of the tetracycline family in the form of its salt, and then reacting the product with colistine sulfate.
-~ According to the invention, a reaction medium is sel-ected both for the initial addition and for the final ~$
condensation which does not react with formol, and although this temperature is not characteristic of the invention, gen-erally the opexation is carried out between room temperature and 60C. ~n fact, above this temperature, the antibiotic substrata co~mence to degrade.
The present invention moreover relates to medica-tions usable in human or veterinary medicine, characterized by containing, as primary or secondary active principal, one or more salts of the invention of the above formula (A). In ;~ 10 fact, at variable doses, these compounds are bacteristatic, ;~ bacteriocides on the Gram+ and Gram- bacteria, and on the large viruses, the protozaires and certain flagellates.
The interest in the salts of formula (A) of the in-vention resides particularly in the fact that the toxicity of the polymyxines is considerably reduced in this type of com-pound and that the anti-bacterial activity of the new com-pounds of the invention is higher, in vitro and in vovo, than the simple mixture of antibiotics from substrates for the syn-thesis of the new salts of the invention. In vivo, in particu-~0 lar, it is surprising to note that the new salts of the in-vention completely pass the gastro-intestinal barrier, thus pass into the interior medium and thus make it possible to treat Gram- a~fections outside the digestive tract, such as urinary affections, while it is well known that tetrac~clines, which pass the gastro-intestinal barrier, although poorly, are inactive and that the polymyxines do not pass this barrier and thus cannot act outside the digestive tract when they are administered orally.
The present invention relates in particular to med-3 ications for human or veterinaxy medicine, characterized by . : ~
:; ~
the fact that their activity is antibiotic and that they con-tain at least one salt of this invention of fo~ula (A) above as primary or secondary active principal.
Moreover, the present invention relates to the phar-maceutical compounds containing at least one salt of the in-vention of above formula (A).
In addition, the present invention relates to the pharmaceutical forms, such as wafers, powders, gellules, compresses, lozenges, syrup for oral administration, to the form for administration in ophthalmology, otorhinolaryngology, such as drops, pommades, cones, to the forms of rectal admin-istrations, suppositories, enemas, to ready to use injectable forms or those to be prepared at the time of use.
i The invention will be better understood from the following example ~iven as a non-limitative case and describ-ing the preparation and properties of one of the sales of the invention, defined above under the name of Negafongine.
PREPARATION OF NEGAFONGINE
56 grams oxytetracycline chlorohydrate is put into suspension in 6 liters of pure anhydrous alcohol. Heat to 50C and introduce, under agitation, 20 cc formol, previously concentrated by one third and filtered to eliminate the insol-ubles. The dissolution is complete in 15-20 minutes. Then ~ -evaporate to dryness under vacuum.
The crystals obtained are taken up with 50 cc abso-lute methanol after expansion in the air for a few hours to eliminate the formol odor. Add directly to this solution, 50 grams colistine sulfate to avoid the formation of lumps.
Heat to 45-50C under agitation. The dissolution is complete in 10~15 minutes. Some insoluble flakes are filtered and the ~070675 filtrate is left to stand overnight at -10C. The Nega0ngin2 obtaine~ is dried cold. 15-20% of product is still found in the mother liquors.
The Negafongine is water-soluble in stable form but has no clearly determined melting point because it decomposes when hot.
Spectroscopic-Analyses, performed essentially in comparison with those of the substrate having been used dur-ing the synthesis, that is to say oxytetracycline chloro-hydrate and colistine sulfate.
Infrared Analysis by dispersion in Nujol.
Considerable differences exist between Negafongine and oxytetracycline chlorohydrate in the area of 3500-3000 cm-l. Particularly the tetracyclinical band at 3400 cm~l no longer appears in Negafongine, which proves that the -NH2 group of the oxytetracycline amide function has reacted, which is still confirmed, although this area is charged by differences observed in the region of 17U0-1600 cm~l.
Analysis by Nuclear Magnetic Resonance: by dissolu-tion in deuterized dimethyl sulfoxide.
The spectrum of Negafongine has a mass in the strong fields which is absent in each of the starting substrata. It corresponds to the alcoyl radical hydrogens, proving the real-ity of the new Negafongine structure. In the region of the aromatic process, Negafongine maintains unchanged the oxy-tetracycline phenolhydroxyl, which implies that the addition of formol was not made in this area.
TOXICITY OF NEGAFONGINE
DL 50 per os male mice: 1900 mg/kg DL 50 intravenously male mice: 22.5 mg/kg aa/æmar4 DL 50 intramuscular male mice: 125 mg/kg These toxicological studies w~re completed by worX
on different galenic forms: "dry-fill" by intramuscular in-jection, "dry-fill" by intravenous injection, ready to use injectable solution, gelatin-coated pill for oral use, going from acute toxicity to chronic toxicity in mice, rats, rab-:
bits and dogs. At doses 2.5 times higher than those provid-ed in man, the tolerance always has been perfect, but at doses still 10 times higher, that is 25 times higher than those pro- -;~ 10 vided in man, a high mortality rate is observed (40/0 in rats i 63 days after treatment), a relatively high reduction of the number of red blood corpuscles and rather severe gastric seizures also were noted.
~ ACTIVE ANTI-MICROBIAN ACTIVITY IN VITRO OF NEGAFONGINE
'd` ~ 15 On Gram+ and Gram- bacteria of hospital origin, tests were conducted according to the known technique and the disc (gelatin-coated medium). The activities of the colistine and of oxyte~racycline are found with a synergizing activity which manifests itself particularly on the Aeruginose ~Gram-) '~ 20 P.S.
Results of the Clinical Tests The first clinical tests regarding Negafongine were -cQnducted by oral administration (gelatin-coated pills at 250 mg), ~y intramuscular ready to use injection or "dry-fill", by intravenous injection. These results are perfectly satis-factory, particularly as far as oral administration is con-cerned, where it is known that the colistine cannot pass the gastro-intestinal barrier. In fact, negafongine proved to be active orally on Gram- affection of the respiratory, the 3 urinary and the gynecological tracts, and of course the di-gestive tract.
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method of preparing salts of polymyxine methyltetracyclines having the formula [(TH+-CO-NH-CH2-NH)n-P, nA=] mHB-in which m and n represent integers less than 6, A= and B- represent mineral or organic anions, T represents the residue of an antibiotic of the tetra-cycline family having a primary amide function, the formula of which is T-CONH2, and P represents the residue of a colistine molecule, the formula of which is P-(NH2)n, which comprises initially reacting formol and an antibiotic of the tetracycline family in the form of its salt, and then reacting the product with colistine sulfate.
2. A method as claimed in claim 1 in which the reaction product of the formol and the antibiotic is isolated before reaction with the colistine sulfate
3. A method as claimed in claim 1 in which the reaction product of the formol and antibiotic is not isolated before reaction with the colistine sulfate.
4. A method as claimed in claim 1, in which T represents an oxytetra-cycline residue and m and n are each three.
5. Tri-(oxytetracycline methyl) colistine trichlorohydrate-sulfate, whenever prepared by the process claimed in claim 4, or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR7409510A FR2264558A1 (en) | 1974-03-20 | 1974-03-20 | Polymixin-methyl tetracycline salt antibiotics - active against Gram positive and negative bacteria, viruses and protozoa |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1070675A true CA1070675A (en) | 1980-01-29 |
Family
ID=9136607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA222,417A Expired CA1070675A (en) | 1974-03-20 | 1975-03-18 | Polymyxin methyl tetracycline |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS51125715A (en) |
| CA (1) | CA1070675A (en) |
| DE (1) | DE2511852A1 (en) |
| FR (1) | FR2264558A1 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2148255A1 (en) * | 1992-10-29 | 1994-05-11 | Rainer Denecke | Preparation for therapeutic and especially prophylactic treatment of digestive tract disorders |
| DE4307352A1 (en) * | 1992-10-29 | 1994-05-05 | Denecke Rainer Dr Med Vet | Preparation for therapy and especially prophylaxis of diseases of the digestive tract |
| JP4917210B2 (en) * | 2001-04-11 | 2012-04-18 | ロンシール工業株式会社 | Parting material |
| JP4917214B2 (en) * | 2001-05-14 | 2012-04-18 | ロンシール工業株式会社 | Waist wall baseboard and its construction method |
-
1974
- 1974-03-20 FR FR7409510A patent/FR2264558A1/en active Granted
-
1975
- 1975-03-18 DE DE19752511852 patent/DE2511852A1/en active Pending
- 1975-03-18 CA CA222,417A patent/CA1070675A/en not_active Expired
- 1975-03-19 JP JP50034211A patent/JPS51125715A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE2511852A1 (en) | 1975-10-09 |
| JPS51125715A (en) | 1976-11-02 |
| FR2264558A1 (en) | 1975-10-17 |
| FR2264558B1 (en) | 1979-07-13 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |