JPS6338037B2 - - Google Patents

Description

[Detailed description of the invention]

The properties and preparation of the antibiotic lincomycin are disclosed in US Pat. No. 3,086,912. Clindamycin is disclosed in US Pat. No. 3,496,163. These antibiotics are used extensively in human and veterinary medicine. A large number of patents worldwide have been issued for these antibiotics and their various derivatives. Lincomycin has the following structural formula. Clindamycin has the following structural formula. This application is based on the formula or a pharmaceutically acceptable acid addition salt thereof. [In the formula, R ₁ can be substituted one or more times at any position of the pyridine ring that is not already substituted with R ₂ , and is hydrogen, alkyl, substituted alkyl (substituted alkyl) (alkyl The part is 1
~8 carbon atoms) or its isomeric forms, cycloalkyl, substituted cycloalkyl (substituted cycloalkyl), substituted oxygen (substituted oxygen), substituted nitrogen (substituted nitrogen), halogen, phenyl, substituted Phenyl (substituted phenyl), -(CH ₂ ) _o
--OH, --(CH ₂ ) _o --NR ₄ R ₅ , or its isomeric form (where n is an integer from 1 to 8, and R ₄ and
R ₅ is H or alkyl of 1 to 8 carbon atoms or its isomeric form), R ₂ can be substituted once at any position of the pyridine ring that is not already substituted with R ₁ ;

[Formula], where X is 7 (R)-hydroxy-methyl 1-thio-α-lincosaminide, 7(S)-hydroxy-methyl 1-
Thio-α-lincosaminide, 7(S)-halo-methyl 1-thio-α-lincosaminide, 7(R)-
Halo-methyl 1-thio-α-lincosaminide, 7
(S)-methoxy-methyl 1-thio-α-lincosaminide, 7-deoxy-7(S)-(methylthio)-methyl 1-thio-α-lincosaminide, 7
-Deoxy-7(S)-(2-hydroxyethylthio)methyl 1-thio-α-lincosaminide and 7-deoxy-7(S)-(3-hydroxypropylthio)-methyl 1-thio-α-lincosaminide The amino functional group of a compound selected from the group consisting of: The present invention is a precursor to a compound of the following formula. In the formula, R ₁ can be substituted one or more times on the same carbon or different carbons in the ring, and R ₂
can be in the 2, 3, 4, 5, 6, 7, 8 or 9 position of the ring and are as defined above, R ₃ is H, CH ₃ , C ₂ H ₅ and -CH ₂ -CH ₂ -OH, and n is an integer from 1 to 4. The synthesis of the novel analogues described herein can be illustrated in the following exemplary form. Wavy lines indicate either the D-cis or L-cis isomer. Wavy lines indicate D-cis, L-cis, D-trans or L-trans structures. L-cis structure produced from the compound of the present invention For experimental purposes, Staphylococcus aureus (S.
It was shown to be 5 to 10 times more active than clindamycin against S. aureus and S. hemolyticus. From the above reaction an isomer of V can be isolated, which appears to be the D-cis compound VA. . D-cis structures are not as potent antimicrobial agents as L-cis compounds. MTL is the formula methyl 1-thio-α-lincosaminide. Epi-MTL is the formula methyl 7(S)-7-deoxy-7-hydroxy-1-thio-α-lincosaminide. 7-Cl-MTL is the formula Methyl 7(S)-7-deoxy-7-chloro-
1-thio-α-lincosaminide. Epi-7-Cl-MTL is the formula Methyl 7(R)-7-deoxy-7-chloro-
1-thio-α-lincosaminide. 7(S)-methoxy-methyl 1-thio-α-lincosaminide can be shown as follows.
(US Pat. No. 3,702,322, Example 1, Part B-1) Referring to the following formula, when R is CH ₃ 7-deoxy-7(S)-(methylthio)-methyl 1-thio-α-lincosaminide is present. R is - CH ₂ -
When CH ₂ -OH, 7-deoxy-7(S)-
(2-hydroxyethylthio)-methyl 1-thio-α-lincosaminide is present. Also, R-
When CH ₂ -CH ₂ -CH ₂ -OH, 7-deoxy-7(S)-(3-hydroxypropylthio)-
Methyl 1-thio-α-lincosaminide is present. (Examples 1 and 10 of U.S. Pat. No. 3,915,954 and
31) The hydroxy and halo group at the 7-position in the above formula can be represented as follows. In the formula, Y is selected from the group consisting of 7(R)-hydroxy, 7(S)-hydroxy, 7(S)-halo, and 7(R)-halo. carrying out said preparation using a pyridine acyl group,
The resulting analogs of the invention are reduced to yield the corresponding mixture of saturated compounds, one of which is the L-cis isomer. Other compounds that may be present are L-trans, D-cis, and D-trans isomers. Generally, for any of the compounds described herein, the reduced form has greater antimicrobial activity than the unsaturated precursor of the invention. The use of piperidine acyl group is
- gives analogs that exist as cis, L-cis, D-trans and L-trans isomers. Again, the L-cis isomer was found to have more potent antibacterial activity. The general method used herein to make the novel analogs is a well known method which involves coupling the appropriate acid with the appropriate sugar amine. (“Mixed Carboxylic Anhydride Procedure”
"Acid Anbydride Procednre" Chemistry of The Amino Acids Volume 2 970
Page, John Willey & Sons, 1961
Year). When the acid is unsaturated, the resulting unsaturated analog can be catalytically reduced under standard conditions to create a saturated analog. For example, reduction can be performed using the following conditions. H ₂ - 0.352 to 3.52 Kg/cm ² (5 to 50 psi) Catalyst - Platinum oxide (PtO ₂ ) Solvent - _{H 2} O or H ₂ O + MeOH, or H ₂ O +
EtOH HCl - 10% excess. Time - 24 to 48 hours As used herein, alkyl of 1 to 8 carbon atoms and its isomeric forms include methyl, ethyl,
Includes propyl, butyl, pentyl, hexyl, heptyl, octyl, and branched chain isomers thereof. Substituted alkyl is a substituted alkyl in which one or more of the hydrogen atoms is halogen, i.e. Cl, Br, F and I, oxygen,
Hydroxyl, amine (primary), amine (secondary - alkyl substituted with alkyl as above), amine (tertiary - alkyl substituted with alkyl as above), sulfur, - SH, and the above alkyl compound replaced by phenyl. Examples of compounds are 1-fluoroethyl, 1
-Chloroethyl, 2-fluoroethyl, 2-chloroethyl, 1-bromopropyl, 2-iodopropyl, 1-chlorobutyl, 4-fluorobutyl,
and 4-chlorobutyl. Cycloalkyl means cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Substituted cycloalkyl means cycloalkyl substituted as described above for substituted alkyl. Examples of compounds are 2-cyclopropylethyl, 3-cyclobutylpropyl, 4-cyclopentylbutyl, and 4-cyclohexylbutyl. Aromatics include phenyl, halogen, hydroxyl, amine (primary, secondary, and tertiary, where one or more of the hydrogen atoms are as above, but the latter two are as above) (substituted with alkyl), -SH, and substituted phenyl when replaced with phenyl. Examples of compounds are p-bromophenyl, m-iodophenyl, o-chlorophenyl, p-ethylphenyl, m-propylphenyl, o-methylphenyl, and p-octylphenyl. As detailed below, phosphorylation of the compounds of the invention produces 2-phosphate, and acylation produces 2-palmitate, both of which have antimicrobial activity in vivo. Substituted oxygen means oxygen substituted with alkyl, aryl and substituted aryl of 1 to 8 carbons. Substituted nitrogens are acyl of 2 to 18 carbons, 1 to 8
refers to nitrogen substituted with monoalkyl and dialkyl of 1 to 8 carbons (alkyl is 1 to 8 carbons, and both acyl and alkyl groups include isomeric forms). Halo means chloro, bromo, iodo, or fluoro. Exemplary sources of amino acids used as starting materials herein are as follows. 1 “Heterocyclic compounds”
Compounds), Volume 1, John Willey & Sons, 1950. This document describes the production of halogen and alkyl substituted amino acids. 2 Chemical Abstracts 81-105223A-Alkyl and cycloalkyl. 81-152243S-Alkyl and halogen substitution. 82-170746-Halogen substitution. 85-46322Q-dihalo substitution. 85-177258W-Dihalo substitution. 84-116928X-dihalo substitution. 81-3737d-phenyl substitution. 78-58201t-phenyl substitution. 76―126800y―Tetrahalo substitution. 82-11036K-bromo substitution. 83-27119W-Bromo substitution. 84-16613X-bromo substitution. 78-123494G-Bromo substitution. This compound can be hydrolyzed to an acid by means well known in the art, and the acid can be reduced by means also well known in the art. This compound can be hydrolyzed to the acid by means well known in the art. The resulting acid can then be N-demethylated by the procedure described in US Pat. No. 3,583,972. This compound can be hydrolyzed to the acid by means well known in the art. This compound can be hydrolyzed to the acid by means well known in the art. Also, one or both of the N-CH ₃ groups can be removed from the resulting acid by the procedure disclosed in US Pat. No. 3,583,972. This compound can be hydrolyzed to the acid by means well known in the art. The resulting acid is described in U.S. Patent No.
It can be converted into the following compound by the method disclosed in No. 3583972. Compounds with free NH ₂ or OH groups must have these groups protected before condensation with the amino sugar. Protection of such groups is well known in the art. “Protective Groups in Organic Chemistry”
Chemistry), JFW, JFWMcomie, Plenum Publishers,
See 1973. 3 Journal of Chemical Society (Jour.Chem.Soc.) 1969, p. 2134. Various H-alkyl substituted pyridines. (Commercially available) R = alkyl, branched alkyl, and cycloalkyl. 4 Joar.Chem.Soc.1969 934 pages The following examples are illustrative of the methods and products of the invention, but should not be considered limiting. Unless otherwise noted, all percentages are by weight and all proportions of solvent mixtures are by volume. Example 1 4-cis-ethyl of 7-Cl-MTL
L-hexahydropicolinic acid HCl (U-57930E
-Compound V) Amino acid HCl dissolved in 2.5 liters of acetonitrile (Chemical Abstracts Vol. 51)
1643a, 1957) and 71.5 g (0.714 mol) of triethylamine were cooled to 10°C and 47.6 g of isobutyl chloroformate
(0.354 mol) is added all at once. This mixture (solution A) is stirred at 10°C for 1 hour. Acetone 1500ml
7-Cl- in a warm mixture of and 1500 ml of H ₂ O
MTL (J.Med.Chem. Vol. 12, p. 780, 1969.
Solution B is prepared by dissolving 97.7 g (0.357 mol) of BJ Megerlein and F. Kagan. Solution B
Cool to 30°C and add to solution A all at once. reaction solution
Stir at 25° C. for 18 hours and remove acetone and acetonitrile under vacuum. The white, mushy residue is filtered and the crystalline material is collected and dried to yield 95 g of pure product. Workup of the filtrate (chromatography) yielded another 10 g of product. Overall yield 73% Analysis: For _{C17H25ClN2O5S} Calculated _: C, 50.42; H, 6.22; N, 6.92; _S , 7.92; _Cl , 8.76 Found: C, 50.67; H , 6.40; N, 6.64; S, 7.90; Cl, 8.70 α ^CHCl3 _D (C, 1.0) + 293° A mixture of 4.05 g (0.01 mol) of starting material, 40 ml of water, 60 ml of methanol, 1.0 ml of 37% HCl and 8.0 g of PtO ₂ was heated to 3.52 Kg/cm ² (50 p.si) using a parhydrogenator.
I returned it for 3 hours. CHCl ₃ : Methanol (6:
Analysis of the reaction mixture by TLC on a silica gel plate in the system consisting of 1) showed the disappearance of all the starting material and the presence of the two more polar materials in a ratio of approximately 1:1. The reaction was filtered to remove the catalyst and the filtrate was concentrated in vacuo to yield a white crystalline mass. This was filtered and the filtrate was stored. This white solid, the most polar of the two products observed by TLC of the reaction mixture, gives the desired product U-57930E in 25-35% yield when recrystallized from water, mp. 222-224°C was produced. Analysis: For C ₁₇ H ₃₂ Cl ₂ N ₂ O ₅ S Calculated: C, 45.63; H, 7.21; N, 6.26; S, 7.17; Cl, 15.85 Measured: C, 45.77; H, 7.44; N , 6.39; S, 7.21; Cl, 16.17 α ^H2O _D (C, 1.0) + 176° The absolute configuration and stereochemistry of V were determined by X-ray crystallography. In comparison with clindamycin, the tested U-57930E has the following antibacterial spectrum:

【table】

[Table] The procedure for the above test is as follows. The minimum inhibitory concentration (TIC) of both compounds against aerobic bacteria is determined using a standard microplate broth dilution method. Using brain heart infusion (BHI - manufactured by Difco) broth medium, the plate was incubated at 37°C.
Incubate for 20 hours. Staphylococcus aureus UC6685-6696 is a clinical isolate that is resistant to one or more commercially available antibiotics. ``UC is a registered trademark of Upziyon Co., Ltd.'s preservation culture media. These culture methods are available upon request from Upziyon Co., Kalamazoo, Michigan.

【table】

【table】

[Front] Tukas Anaerobi
Us
(Peptostreptococcus
anaerobius)
The procedure for the above test is as follows. Serial 2-fold dilutions of the drug were made in 1 ml volumes of Schaedler Broth, and 9.0 ml of molten (47°C) Wilkens-Chalgren agar (described below) was added to the antibiotic-supplemented broth. Add. Mix with the antibiotic and then pour the agar into a 100 mm x 20 mm Petri dish. The dishes are left on the bench overnight prior to inoculation. Cultures are streaked onto Wilkens-Chiangren agar and grown for 48 hours at 37°C in BBL anaerobic jars. The growth from the plate is taken and a cell suspension equal to a turbidity of 0.5 McFaeland Standard (10 ⁸ cells per ml) is made in Schiedler broth. Pipette the suspension into the well of a Steers replicator and distribute approximately 1-2 microns onto the surface of the agar plate. After allowing the inoculum to dry for 2-3 minutes, add a BBL anaerobic jar (85% N 10% H 5
Place the plate in an atmosphere of 72% _CO2 at 37 °C.
Incubate for hours. The minimum inhibitory concentration (MIC) is read as the minimum amount of the drug that inhibits growth. Very thin film-like growth or less than 3 colonies are considered negative. Wilkins Chalgren Agar Medium Prepare the following ingredients and dissolve in 1000ml of distilled water.
The pH should be between 7.0 and 7.2. Trypticase 10g Gelysate 10g Yeast extract 5g Dextrose 1g NaCl 5g L-arginine - free base 1g Pyruvate sodium salt 1g Agar 15g Add a solution of heme (ferroprotoprophyllin) and + vitamin K ₁ , hemin (chlorohemin)
Final concentration of 5 μg/ml and K ₁ 0.5 g/ml. Autoclave aerobically at 121°C for 10 minutes. Hemstock - Hemin 0.5g + 1N NaOH 10ml +
_H2O990ml . Autoclave at 121°C for 12 minutes. Add 10 ml of stock per medium. +Vitamin K stock - Vitamin K ₁ solution 0.05ml
+20ml of 95% ethanol. Sterilize and filter. Add 0.2 ml of stock per medium. Intraperitoneal administration of U-57930E in rats (I.
P.) LD ₅₀ was found to be 592mg/Kg. This value is the average of two separate similar LD ₅₀ measurements.
This value is approximately 2 times the LD ₅₀ of clindamycin HCl.
It's double. The LD ₅₀ value should be interpreted as indicating that the acute intraperitoneal toxicity of U-57930E is approximately half that of clindamycin HCl.

[Table] The procedure for the above test is as follows. Rat protection test: Groups of 10 standard laboratory rats (CF-1 rats) weighing 18-20 g were incubated at -170°C.
A standard bacterial suspension kept frozen at approx.
Infected with 100LD ₅₀ . Immediately before use, the suspension was quickly thawed and diluted appropriately. Infection is by the intraperitoneal route. Treatment of infected groups began immediately and continued once a day for 4 days (first 24 hours = 1 day). A group of untreated infected mice was used as a toxicity control for the culture medium. Seven days after treatment management began, surviving animals were sacrificed and the mean protective dose of antibiotic was calculated based on the mortality rate of the rats in the treatment group. The average protective dose and its
A 95% confidence interval was calculated. Compound A is also isolated from Part 1 of Example 1. This material is obtained as follows. The filtrate saved from the first part was concentrated to dryness under vacuum. The residue was converted to its free base and CHCl ₃ :methanol (6:
1) was used for chromatography on silica gel. In this way, the least polar materials mentioned in part were obtained. This was converted to its HCl salt and recrystallized from acetone and water. This isomer is tentatively designated as structure A. Epimerization of the carbonyl functionality attached to the piperidine ring of and A can be achieved by methods well known to those skilled in the art. The trans isomers B and C produced in this epimerization can be isolated by conventional procedures such as crystallization or chromatography. Hydrolysis of and A instead yields the amino acids D and E, which are then epimerized to F and G, respectively, by methods well known to those skilled in the art. Amino acids F and G can be coupled to any of the previously mentioned lincosaminides. The D-cis isomer (A) of U-57930E has the following antibacterial spectrum when tested in the BHI broth described above in Table 1.

[Table] Example 2 Other analogs of 7Cl-MTL Following the procedure of Example 1 but substituting the following amino acids for that amino acid, the corresponding novel antibacterial active analogs were prepared based on their free base or acid Made as an addition salt. The latter can be made by methods well known to those skilled in the art.

【table】

[Table] Example 3 Analogs of MTL The procedure of Example 1 was followed, but the amino acids were replaced with amino acids, and 7-Cl-MTL was replaced with MTL (J.Am.Chem.Soc.89 Volume 2448 pages,
In 1967, Davrieux Schroeder (W.
Schroeder), B. Bannister
and H. Hoeksema), the corresponding new antibacterial active analogs are created.

[Table] Example 4 Analogs of Epi-MTL Following the procedure of Example 1, but using the following amino acids in place of that amino acid, and 7-Cl-MTL
Epi-MTL (J.Chem.Soc. Parkin) instead of
Corresponding novel antibacterial active analogues are created using Perkin I., 1974, p. 360-B, Bannister).

[Table] Example 5 Analogs of Epi-7-Cl-MTL Following the procedure of Example 1, but replacing that amino acid with the following amino acids and replacing 7-Cl-MTL with Epi-7- Using Cl-MTL, corresponding new antibacterial active analogs are created.

Table: The procedure used to make 7-Cl-MTL produces epi-7-Cl-MTl, except that the starting material is epi-MTL instead of MTL. The chemical and physical properties of most of the compounds of Examples 2-5 are as follows.

[Table] Example 6 Fusaric acid amide of 7-chloro-MTL Following the procedure of Example 1 but substituting the following fusaric acid for that amino acid, U-55581 is obtained. Analysis: Calculated _{for C19H29ClN2O5S :} C, 52.70; H, 6.75; N, 6.47; S, 7.41; _Cl , 9.19 Measured: C, 52.15; H, 6.65; N, 6.36 ; S, 7.21; Cl, 7.94 Reference Example 1 4-cis-n-butyl-L-hexahydropicolinic acid amide or U of 7-Cl-MTL
-60970E A mixture of 4.0 g (0.0093 mol) of starting material, 40 ml of water, 40 ml of methanol, 2 ml of 37% HCl, and 8.0 g of Pto ₂ catalyst was heated to 3.52 Kg/cm ² using a par hydrogenation apparatus.
(50 psi) for 18 hours. The reaction was filtered to remove the catalyst and the filtrate was concentrated under vacuum to yield an amber oil. CHCl ₃ - methanol (2:
1) Dissolve the oil in 20 ml of solution and add enough triethylamine to neutralize the hydrochloric acid present. _CHCl3
The solution was chromatographed on silica gel using a solvent system consisting of -methanol (2:1). Two fractions of the main product are obtained. The fractions containing the faster moving material are combined and evaporated under vacuum to yield fraction A, a white solid. The fractions containing the slow-moving material are combined and evaporated under vacuum to yield fraction B, a white solid. Dissolve fraction B in a small amount of H ₂ O and adjust the pH to 2.
Add enough 37% HCl to Crystallization has occurred. When the solid is collected and recrystallized from _H2O ,
White crystals of the desired product U-60970E, (melting point
224-226°C) in 25-35% yield. Analysis: _{Calculated for C17H32Cl2N2O5S :} C, 47.99; H, 7.63; N, 5.89; S, 6.75; _Cl , 14.92 Measured: C, 47.97; H, 7.42; N , 6.23; S, 6.90; Cl, 14.87 α ^MeOH _D +178° (C, 1.0) CMR analysis supports the proposed structure. The minimum inhibitory concentrations (MIC) of U-60970E against various bacteria are as follows in μg/ml: Microorganism UC# MIC Staphylococcus aureus 6 0.125 Staphylococcus aureus 570 0.25 746 0.062 Enterococcus 694 0.25 Streptococcus pyogenes 152 0.008 Diplococcus pneumoniae 41 0.016 Escherichia coli 45 31.2 Klebsiella pneumoniae 58 7.8 M. schizophrenia 126 31.2 Pseudomonas aeruginosa 95 ＞125 The test procedure is This is as revealed in Example 1. U-60970E was also tested in vitro on standard laboratory rats that were experimentally infected with the bacteria. Tests were conducted while comparing with U-57930E. The following results show that U-60970E has significantly stronger activity than U-57930E in a living test against type and type pneumococci. For Staphylococcus aureus and Streptococcus hemolyticus, U-60970E
shows essentially the same activity as U-57930E.

[Table] Reference Example 2 4-cis-n-butyl-D-hexahydropicolinic acid amide or U of 7-Cl-MTL
―61734E Fraction A from the previous experiment was treated with its HCl in the same manner as described for fraction B.
Converted to salt. A yield of 25-35% of the product was obtained,
The CMR spectrum was essentially the same as that obtained from fraction B. Example 7 2-Phosphate Analogs 2-Phosphate analogs of the compounds made in Examples 1-6 are made by procedures well known to those skilled in the art. With obvious and suitable modifications, the procedure disclosed in US Pat. No. 3,487,068 can be used. Basically, any procedure involves first protecting the susceptible group by procedures well known to those skilled in the art. These are then removed after the phosphorylation is complete. Example 8 2-Palmitate Analogs 2-Palmitate analogs of the compounds made in Examples 1-6 are made by procedures well known to those skilled in the art. With obvious and suitable modifications, the procedure disclosed in US Pat. No. 3,580,904 can be used. Basically, any procedure involves first protecting the susceptible group by procedures well known to those skilled in the art. These are then removed after completion of the acylation with palmitoyl chloride. The minimum inhibitory concentrations (MICs) of some representative compounds prepared in Examples 2-6 are described below.
The test procedure is as described above.

【table】
‖ ‖ ‖
X
=C−7−Cl−MTL Y=C−MTL Z=C−epi−MTL
R _{= C2H5-}

The compounds of the present invention are active against a variety of Gram-positive and Gram-negative microorganisms and can therefore be used in a variety of environments to inhibit such microorganisms. For example, it can be used as a disinfectant on washed and stacked dishes contaminated with Staphylococcus aureus to inhibit this bacterium. It can also be used as a disinfectant for dental and medical equipment contaminated with Staphylococcus aureus. Additionally, the compounds of the invention can be used as bacteriostatic rinse agents for laundered clothing and for impregnating paper and textiles. They are also useful in inhibiting the growth of susceptible bacteria in plate assay media and other microbiological media. The compounds of the invention exist in protonated or unprotonated form depending on the environmental PH. When intended in the protonated form, the compound exists as a pharmaceutically acceptable acid addition salt; when intended in the unprotonated form, the compound exists as the free base. The free base is prepared by adjusting it with a suitable acid to a pH of approximately 7.0.
It can be converted into a stable acid addition salt by neutralization, preferably to a pH of about 2 to 6. Acids suitable for this purpose are hydrochloric acid, sulfuric acid, phosphoric acid, thiocyanic acid, fluorosilicic acid, hexafluoroarsenic acid, hexafluorophosphoric acid, acetic acid, succinic acid, citric acid, lactic acid, maleic acid, fumaric acid, pamoic acid, cholic acid. , palmitic acid, mucilage acid, camphoric acid, glutaric acid, glycolic acid, phthalic acid, tartaric acid,
Lauric acid, stearic acid, salicylic acid, 3-phenylsalicylic acid, 5-phenylsalicylic acid, 3
-Methylglutaric acid, orthosulfobenzoic acid,
Cyclohexanesulfamic acid, cyclopentanepropionic acid, 1,2-cyclohexanedicarboxylic acid, 4-cyclohexanecarboxylic acid, octadecenylsuccinic acid, octenylsuccinic acid, methanesulfonic acid, helianthinic acid, Reinetschic acid, dimethyldithiocarbamic acid, hexadecylsulfuric acid These include famic acid, octadecylsulfamic acid, sorbic acid, monochloroacetic acid, undecylenic acid, 4'-hydroxyazobenzene-4-sulfonic acid, octadecylsulfuric acid, picric acid, benzoic acid, cinnamic acid, and the like. Acid addition salts can be used for the same purpose as the free base, but can also be used to improve the quality of the base.
For example, the free base is converted to a water-insoluble salt such as picrate, which is subjected to purification procedures such as solvent extraction and washing, chromatography, fractional liquid-liquid extraction, and crystallization, followed by alkaline treatment. to regenerate the free base form or to make other salts by metathesis. or converting the free base to a water-soluble salt, such as a hydrochloride or sulfate, and extracting the aqueous solution of the salt with various water-immiscible solvents;
The free base form is regenerated by treatment of the extraction solution or converted to another salt by metathesis. In addition to the antimicrobial uses identified above, the free base can be used as a buffer or as an antacid. According to US Pat. Nos. 2,425,320 and 2,606,155, thiocyanate addition salts form resinous materials useful as acid wash inhibitors when condensed with formaldehyde. Free bases also make good excipients for toxic acids. For example, according to US Pat. Nos. 1,915,334 and 2,075,359, fluorosilicic acid addition salts are useful as moth repellents, and
According to Nos. 3,122,536 and 3,122,552, addition salts of hexafluoroarsenic acid and hexafluorophosphoric acid are useful as antiparasitic agents. The compounds of this invention are useful as antimicrobial agents in the form of suitable compositions. These compositions include tablets, capsules, pills, etc. containing appropriate amounts of the active compound in the form of the free base or pharmaceutically acceptable salts thereof.
They are provided for administration to humans and animals in unit dosage forms such as powders, granules, sterile parenteral solutions or suspensions, and oral solutions or suspensions, and oil-water emulsions. preferable. For oral administration, solid or fluid unit dosage forms can be made. For making solid compositions such as tablets, the basic active ingredient may be combined with talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, papilla, gum arabic, as a pharmaceutical diluent or carrier. Mix with conventional ingredients such as methylcellulose and functionally similar materials. Tablets can be stacked or otherwise compounded to provide a dosage unit with the advantage of prolonging or delaying action, or having the encapsulated drugs act in a predetermined order. . For example, a tablet can be made up of an inner ingredient and an outer ingredient, with the latter surrounding the former. The two components can also be separated by an enteric coat layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or to delay its release. Such enteric skins and coatings may contain a number of polymeric acids or polymeric acids and shellacs, cetyl alcohol, cellulose acetate phthalate, styrene, etc.
A variety of materials can be used, including mixtures with materials such as maleic acid copolymers, etc. Alternatively, two-component systems can be utilized to produce tablets containing two or more incompatible active ingredients. Wafers are made in the same way as tablets, except for their shape and the inclusion of sucrose and other sweeteners and flavorings. In its simplest embodiment, capsules, like tablets, are made by mixing the formulated compound with an inert pharmaceutical diluent and filling the mixture into hard gelatin capsules of suitable size. In another embodiment, capsules are made by filling coated beads of polymeric acid containing the active compound into hard gelatin capsules. Soft gelatin capsules are made by mechanical encapsulation of a slurry of the active ingredient with a suitable vegetable oil, light liquid petrolactam, or other inert oil. Fluid unit dosage forms for oral administration such as syrups, elixirs and suspensions can be made. The water-soluble form of the active compound is sugar,
A syrup is formed when dissolved in an aqueous vehicle with aromatic flavoring and preservatives. Eliquisils are made using a water-alcoholic (ethanol) vehicle along with aromatic flavoring and a suitable sweetener such as sugar. Suspensions can be made in insoluble form with syrup excipients with the aid of suspending agents such as gum arabic, gum tragacanth, methyl cellulose and the like. Topical ointments are made by dispersing the active compound in a suitable ointment base such as petrolatum, lanolin, polyethylene glycols, or mixtures thereof. It is advantageous to mill the compound by means of a colloid mill using soft liquid petrolatum as milling material before dispersing it in the ointment matrix. Topical creams and lotions are made by dispersing the compound in an oil phase before emulsifying the oil phase in water. For parenteral administration, fluid unit dosage forms are prepared utilizing the active compound and a sterile vehicle, water being preferred. The active compound, depending on the mode of use and concentration, can be suspended or dissolved in the excipient. To prepare solutions, a water-soluble form of the active compound is dissolved in water for injection and filter sterilized before filling and sealing in a suitable vial or ampoule.
Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents are dissolved in the excipient. To increase stability, the composition is frozen after filling into vials and the water is removed under vacuum. The lyophilized powder is sealed in a vial and refilled with an accompanying vial of water for injection to reconstitute the solution immediately before use. Parenteral suspensions are made in substantially the same manner, except that the active compound is suspended in the excipient instead of being dissolved and sterilization cannot be accomplished by filtration. Prior to suspension in a sterile vehicle, the active compound is sterilized by exposure to ethylene oxide. To facilitate homogeneous distribution of the active compound,
It may be advantageous to include surfactants or wetting agents in the composition. As used herein and in the claims, the term unit dosage form refers to physically discrete units that are suitable as unit doses for human patients and animals, and each A unit contains a predetermined amount of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier, or excipient. The specification of the novel unit dosage form of the present invention is based on (a) the remarkable properties of the active materials and the particular therapeutic effect sought to be achieved; and (b) as set forth in detail herein. Although dictated by and directly due to the limitations inherent in the art of compounding such active materials for human and animal therapy, these specifications are a feature of the present invention. Examples of suitable unit dosage forms according to the invention are tablets, capsules, pills, troches, suppositories, powder sachets, granules, wafers, casseroles, teaspoonfuls, sachets, drops, ampoules, vials,
Separate multiple uses of any of the above, and other forms described herein. In addition to administering the active compound as the main active ingredient of a composition for the treatment of the conditions described herein, other types of compounds can be included in the compound to obtain advantageous combinations of properties. Such combinations include, with the active compounds, spectinomycin, chloramphenicol, novobiocin, dihydrobobiocin, tetracyclines (e.g., tetracycline, oxytetracycline, and chlortetracycline), penicillins, erythromycin, kanamycin, streptomycin, neomycin. Antibiotics that broaden the antibacterial spectrum of the composition and have a synergistic action against specific bacteria, such as , polymyxin, bacitracin, nystatin, filipin, fumagillin and endomycin; hydrocortisone, prednisolone, 6α-methylprednisolone, 6α-fluoro Steroids with anti-inflammatory activity such as prednisolone; analgesics such as aspirin, sodium salicylate (acetylsalicylic acid) anhydride, N-acetyl-p-aminophenyl and salicylamide; chloropheniramine maleate, diphenylhydramine Antihistamines such as , promethazine, pyratiazine etc.; sulfadiazine,
Including sulfur drugs such as rufuamethazine, sulfamerazine, sulfacetamide, sulfadimethyloxazole, sulfamethizole, etc.; fungicides such as undecylenic acid, sodium propionate, salicylanilide, sodium caprylate and hexetidine; and vitamin preparations. do. The therapeutic appropriate amount of the active compound depends on the route of administration,
It depends on the patient's age, weight, symptoms, and the specific disease being treated. A dosage regimen of about 15-500 mg 1-4 times daily (every 6 hours) encompasses the effective range for the treatment of most conditions for which the composition is effective. Children are given a dose calculated on the basis of 15-30 mg per Kg per day every 6 hours. For convenient and effective administration, the active compound is compounded with a suitable pharmaceutical carrier in unit dosage form. In a preferred embodiment of the invention, the dosage units are 15, 30, 50, 125, 250 and
500mg and 0.25, 0.5, 1, 2 for topical treatment
and 5% amount, and for parenteral administration 5-65
% (w/v) of the compound. Dosages of compositions containing the active compound and one or more other active ingredients should be determined with reference to the usual dosages of each such ingredient. The following examples are illustrative of the best mode contemplated by the inventors for carrying out the invention, but should not be considered limiting. Composition Example 1 Capsules 1000 hard, two-shell gelatin capsules for oral use, each containing 250 mg of the active compound of the invention, are made from the following types and amounts of materials. Active compound of the invention 250 g Corn starch 100 g Talcum 75 g Magnesium stearate 25 g The ingredients are mixed thoroughly and encapsulated in the usual manner. The above capsules are effective in treating systemic infections in adults by oral administration of 1 capsule every 4 hours. Using the steps above, instead of the 250g above
Using 15, 30, 50, 125 and 500 g of active compound according to the invention, capsules containing 15, 30, 50, 125 and 500 mg of active compound according to the invention are made analogously. Composition Example 2 Capsules 1000 hard, two-shell gelatin capsules for oral use, each containing 200 mg of the active compound of the invention and 250 mg of tetracycline hydrochloride, are prepared from the following types and amounts of ingredients. Active compound of the invention 200 g Tetracycline hydrochloride 250 g Talc 75 g Magnesium stearate 25 g The ingredients are thoroughly mixed and then encapsulated in the usual manner. The above capsules are useful for treating systemic infections in adults by oral administration of 1 capsule every 6 hours. Using the above procedure, substituting 250 g of chloramphenicol, oxytetracycline, chlortetracycline, fumagillin, exthromycin, streptomycin, dihydronovobiocin, and novobiocin for tetracycline.
Capsules containing the active compounds of the invention and each of these antibiotics are similarly prepared. When using a penicillin such as potassium penicillin G instead of tetracycline, 250,000 units are used per capsule. Such a combination product is useful for the systemic treatment of mixed infections in adults by oral administration of one capsule every six hours. Composition Example 3 Tablets 1000 oral tablets containing 500 mg of the active compound of the invention per tablet are made from the following types and amounts of materials. Active compound of the invention 500 g Lactose 125 g Corn starch 65 g Magnesium stearate 25 g Light liquid petrolactam 3 g The ingredients are thoroughly mixed and slugged. Slatsug forces his way through sieve number 16 and destroys it. The resulting granules are compressed into tablets containing 500 mg of the active compound of the invention per tablet. The above tablets are useful for treating systemic infections in adults by oral administration of one tablet every four hours. Using the above procedure except reducing the amount of active compound of the invention to 250 g,
Tablets are made containing mg. Composition Example 4 Tablets 1000 oral tablets each containing 250 mg of the active compound of the invention and a total of 250 mg of sulfadiazine, sulfamerazine and sulfamethazine (83.3 mg each)
Tablets are made from the following types and amounts of materials: Active Compounds of the Invention 250 g Sulfadiazine 83.3 g Sulfamerazine 83.3 g Sulfamethazine 83.3 g Lactose 50 g Corn starch 50 g Calcium stearate 25 g Light liquid petrolatum 5 g The ingredients are thoroughly mixed and slugged. Slatsug forces it through sieve 16 and destroys it. The resulting granules are compressed into tablets containing 250 mg of the active compound of the invention and a total of 250 mg of sulfadiazine, sulfamerazine, and sulfamethazine (83.3 mg each). The above tablets are useful for treating systemic infections by first administering 4 tablets orally and then 1 tablet every 6 hours. For the treatment of urinary infections, it is advantageous to use 250 g of sulfur methylthiadiazole or 250 g of sulfacetamide instead of the three sulfur drugs in the above formulation. Composition Example 5 Oral Syrup 1000 c.c. of an oral aqueous suspension containing a total of 0.5 g of sulfur drug and 250 mg of the active compound of the invention in each 5 c.c. dose of the following types and amounts: Made from ingredients. Active compounds of the invention 50 g Sulfadiazine 33.3 g Sulfamerazine 33.3 g Sulfamethazine 33.3 g Citric acid 2 g Benzoic acid 1 g Sucrose 700 g Tragacanth 5 g Lemon oil 2 c.c. Deionized water Amount to make 1000 c.c. To solution 850 c.c. Disperse citric acid, benzoic acid, sucrose, tragacanth, and lemon oil in a sufficient amount of water. The active compound of the invention and the finely divided sulfur agent are stirred into the syrup until uniformly distributed. Add enough water to bring the total volume to 1000c.c. The composition thus produced is useful for the systemic treatment of pneumonia in adults at a dosage of one teaspoon four times a day. Composition Example 6 Parenteral Solution A sterile aqueous solution for intramuscular use containing 200 mg of the active compound of the invention in 1 c.c. is prepared from the following types and amounts of materials. Active compound of the invention 200 g Lidocaine hydrochloride 4 g Methylparaben 2.5 g Water for injection Amount to make 1000 c.c. The ingredients are dissolved in water and the solution is sterilized by filtration. Fill the vial with the sterile solution and seal the vial. Composition Example 7 Parenteral Preparation A sterile aqueous solution for intramuscular use containing 200 mg of the active compound of the invention and 400 mg of spectinomycin sulfate in 1 c.c. is prepared from the following types and amounts of ingredients. Active compound of the invention 200 g Spectinomycin sulphate 400 g Teat 50 g Water for injection Amount to make 1000 c.c. The active compound of the invention, spectinomycin sulphate and teat are dissolved in water and the solution is sterilized by filtration. do. Aseptically fill 2 c.c. of the sterile solution into sterile vials and freeze. The water is removed under high vacuum and the vial containing the lyophilized powder is sealed. Immediately before use, add enough sterile water for injection to the vial to make 2 c.c. of solution. Composition Example 8 Topical Ointment 1000 g of 0.25% ointment is made from the following types and amounts of ingredients. Active compound of the invention 2.5 g Zinc oxide 50 g Calamine 50 g Liquid petrolatum (weight) 250 g Sheep tallow 200 g White petrolatum Amount to make 1000 g Melt the white petrolatum and mutton tallow and add 100 g of liquid petrolatum to it. The active compound of the invention, zinc oxide and calamine are added to the remaining liquid petrolatum and the mixture is ground until the powder is finely divided and evenly distributed. Stir the powder mixture into the white petrolatum mixture and continue stirring until the ointment hardens. The above ointments are useful when applied topically to mammalian skin for the treatment of infections. The above composition can be made by omitting the zinc oxide and calamine. Following the above procedure, using 5, 10, 20 and 50 g of the active compound of the invention in place of the 25 g used above, amounts of 0.5, 1, 2, and 5% of the active compound of the invention An ointment containing is made in the same way. Composition Example 9 Cream 1000 g of vaginal cream is prepared from the following types and amounts of ingredients. Active Compounds of the Invention 50g Degassed Regular1 ⁾ 150g spermaceti 100g propylene glycol 50g polysorbate 80 5g methylparaben 1g deionized water 1 to 1000g self-emulsifying glyceryl from Goldschmidt Chemical Corporation, New York, NY・Monostearate. Melt the degassing and spermaceti together at a temperature of 70-80°C. Dissolve methylparaben in about 500g of water,
Propylene glycol, polysorbate 80, and the active compound of the invention are added in sequence, maintaining a temperature of 75-80°C. Gradually add the methylparaben mixture to the tegasid and spermaceti melt with constant stirring. While stirring constantly, bring the temperature to 40-45.
Continue the addition for at least 30 minutes until the temperature has decreased to 100°C. By mixing 2.5 g of citric acid and 0.2 g of dibasic sodium phosphate dissolved in about 50 g of water,
Adjust the final cream PH to 3.5. lastly,
Add enough water to bring the final weight to 1000 g and stir to keep it homogeneous until the preparation cools and solidifies. The above compositions are useful for treating vaginal infections in humans. Composition Example 10 Ophthalmic Ointment 1000 g of an ophthalmic ointment containing 0.5% of the active compound of the invention is prepared from the following types and amounts of ingredients. Active compound of the invention 5g Bacitracin 12.2g Polymyxin B sulfate (10000 units/mg)
1g Light liquid petrolatum 250g Sheep tallow 200g White petrolatum Quantity to make 1000g Finely grind the solid components using a pneumatic ultrafine grinder and add to the light liquid petrolatum. The mixture is colloid milled to uniformly distribute the finely ground particles. Melt the mutton tallow and white petrolatum together, stir and adjust the temperature to 45-50°C. Add the liquid petrolatum slurry and stir the ointment until set. It is suitable to package the ointment in 1 dram (3.9 g) ophthalmic tubes. The above ointments are usefully applied to the eye for the treatment of local infections in humans and other animals. Advantageously, the above composition contains 5 g (0.5%) of methylprednisolone for the treatment of inflammation,
Alternatively, bacitracin and polymyxin B sulfate can be omitted. Composition Example 11 Eye Drops/Ear Drops 1000 c.c. of a sterile aqueous eye or ear solution containing 10 mg of the active compound of the invention and 5 mg of methylprednisolone per c.c. of the following types and amounts of ingredients: Make from. Active compounds of the invention 10 g Methylprednisolone sodium phosphate 5 g Sodium citrate 4.5 g Sodium bisulfite 1 g Polyethylene glycol 4000 120 g Myristyl-γ-picolinium chloride
0.2 g polyvinylpyrrolidone 1 g deionized water Amount to make 1000 c.c. Dissolve the ingredients in water and sterilize the resulting solution by filtration. Aseptically fill the solution into a sterile dropper container. The compositions thus produced are useful for the topical treatment of inflammation and infection of the eyes and ears, as well as other sensitive tissues of the animal's body. Composition Example 12 Lozenges 10,000 lozenges are made from the following types and amounts of ingredients. Active compound of the invention 100g Neomycin sulfate 50g Polymyxin B sulfate (10000 units/mg)
1 g Ethyl aminobenzoate 50 g Calcium stearate 150 g Powdered sucrose Amount to make 5000 g The powdered materials are thoroughly mixed and compressed into 0.5 g troches according to conventional compressed tablet manufacturing techniques. The lozenge is held in a person's oral cavity and allowed to gradually dissolve so that it can be used to treat the person's mouth and throat. Composition Example 13 Suppositories for rectal use, each weighing 2.5 g, containing 100 mg of the active compound of the invention
Make 1000 suppositories containing the following types and amounts of ingredients: Active compound of the invention 100g Polymyxin B sulfate (10000 units/mg)
1.25 g Methylprednisolone 1 g Ethyl aminobenzoate 75 g Zinc oxide 62.5 g Propylene glycol 162.5 g Polyethylene glycol 4000 Amount to make 2500 g Active compound of the invention, polymyxin B sulfate,
Add methylprednisolone, ethyl aminobenzoate and zinc oxide to the propylene glycol and knead the mixture until the powder is finely divided and evenly distributed. Melt polyethylene glycol 4000 and gradually add to the propylene glycol dispersion while stirring. Pour the suspension at 40 °C into an uncooled mold. The composition is allowed to cool and solidify, removed from the mold, and each suppository is wrapped in foil. The suppository above is inserted into the rectum for local treatment of inflammation and infection. Alternatively, the steroid can be omitted to make the above composition. Composition Example 14 Mastitis Ointment 1000 g of ointment for the treatment of mastitis in dairy cows is prepared from the following types and amounts of ingredients. Active compound of the invention 25 g Methylprednisolone acetate 0.5 g Light liquid petrolactam 300 g Anhydrous chlorobutanol 5 g Polysorbate 80 5 g 2% aluminum monostearate-peanut oil gel 400 g White petrolactam Amounts to make 1000 g Active compound of the invention and methylprednisolone acetate is mixed with light liquid petrolatum until finely ground and uniformly distributed. Chlorobutanol, polysorbate 80, peanut oil gel and white petrolatum are heated to 48.9°C (120°C) to form a melt and the liquid petrolatum dispersion is mixed into it. With constant stirring, the dispersion is allowed to cool to room temperature, solidify, and is filled into disposable mastitis syringes at a dosage of 10 g. Composition Example 15 Animal Feed 1000 g of feed mix from the following types and amounts of ingredients:
Create. Active compound of the invention 10 g Soy flour 400 g Fish meal 400 g Wheat germ oil 50 g Sorghum molasses 140 g The ingredients are mixed together and compressed into pellets. This composition can be fed to laboratory animals, ie rats, mice, guinea pigs, hamsters, for prophylaxis during transport. For other animals such as poultry, eg chickens, ducks, turkeys, geese, an amount of the composition calculated to give the desired dose of the active compound of the invention may be added to the animal's normal feed. Composition Example 16 In accordance with the procedure of each of the above Composition Examples 1-15, each antimicrobially active compound of the invention was added to the composition of the invention shown in the Examples to provide therapeutic properties. An equivalent amount is substituted for the active compound. Similarly, each of the above free base compounds may be substituted with a pharmaceutically acceptable acid addition salt, such as hydrochloride, sulfate, nitrate, phosphate, citrate, lactate, acetic acid salt. Available in salt, tartrate, and succinate forms. Furthermore, the substitution of the 2-phosphate and/or 2-palmitate of each of the above antimicrobially active compounds of the invention as an active ingredient provides compositions with therapeutic properties.

Claims (1)

[Claims] 1 formula compound, its 2-phosphate, 2-palmitate, or a pharmaceutically acceptable acid addition salt thereof [R ₁ is one or more substituted at any position of the pyridine ring that is not already substituted with R ₂ hydrogen, alkyl, substituted alkyl (the alkyl moiety has 1 to 8 carbon atoms) or its isomeric forms, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen , halogen, phenyl, substituted phenyl,
-( _CH2 ) _o -OH, -( _CH2 ) _{o - NR4R5} , or its isomeric form (where n is an integer from 1 to 8,
R ₄ and R ₅ are H or alkyl of 1 to 8 carbon atoms or isomeric forms _thereof ), and R ₂ is selected from the group consisting of One can be replaced,
[Formula], where X is 7(R)-hydroxy-methyl 1-thio-α-lincosaminide,
7(S)-hydroxy-methyl 1-thio-α-lincosaminide, 7(S)-halo-methyl 1-thio-α-lincosaminide, 7(R)-halo-methyl 1-thio-α-lincosaminide, 7( S)-Methoxy-methyl 1-thio-α-lincosaminide, 7
-deoxy-7(S)-(methylthio)-methyl1-thio-α-lincosaminide, 7-deoxy-
7(S)-(2-hydroxyethylthio)-methyl 1-thio-α-lincosaminide and 7-deoxy-7(S)-(3-hydroxypropylthio)
- methyl 1-thio-α-lincosaminide]. 2. A compound according to claim 1, or a pharmaceutical compound, in which R ₁ is alkyl of 1 to 8 carbon atoms in the 4-position or an isomeric form thereof, and R ₂ is in the 2- or 3-position. Its acid addition salts are acceptable. 3 formulas [R ₁ can be substituted one or more at any position of the pyridine ring that is not already substituted with R ₂ , and is hydrogen, alkyl, substituted alkyl (the alkyl moiety is 1 to 8 ) or its isomeric forms, cycloalkyl, substituted cycloalkyl, substituted oxygen, substituted nitrogen, halogen, phenyl, substituted phenyl,
--(CH ₂ ) _o --OH, --(CH ₂ ) _o --NR ₄ R ₅ , or its isomeric form (where n is an integer from 1 to 8, R ₄ and R ₅ are H or 1 7(R) _-hydroxy- Methyl 1-thio-
α-lincosaminide, 7(S)-hydroxy-methyl 1-thio-α-lincosaminide, 7(S)-
Halo-methyl 1-thio-α-lincosaminide, 7
(R)-halo-methyl 1-thio-α-lincosaminide, 7(S)-methoxy-methyl 1-thio-α
-Lincosaminide, 7-deoxy-7(S)-
(Methylthio)-methyl 1-thio-α-lincosaminide, 7-deoxy-7(S)-(2-hydroxyethylthio)-methyl 1-thio-α-lincosaminide and 7-deoxy-7(S)-(3 -Hydroxypropylthio)-methyl 1-thio-α-
by reacting with a sugar amine compound selected from the group consisting of lincosaminides, the formula [wherein R ₁ is as defined above and R ₂
can be substituted once at any position of the pyridine ring that is not already substituted with R ₁ ,
[Formula], where X is 7(R)-hydroxy-methyl 1-thio-α-lincosaminide,
7(S)-hydroxy-methyl 1-thio-α-lincosaminide, 7(S)-halo-methyl 1-thio-α-lincosaminide, 7(R)-halo-methyl 1-thio-α-lincosaminide, 7( S)-Methoxy-methyl 1-thio-α-lincosaminide, 7
-deoxy-7(S)-(methylthio)-methyl1-thio-α-lincosaminide, 7-deoxy-
7(S)-(2-hydroxyethylthio)-methyl 1-thio-α-lincosaminide and 7-deoxy-7(S)-(3-hydroxypropylthio)
- an amino functional group of a compound selected from the group consisting of methyl 1-thio-α-lincosaminide].