JPH0114238B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel rifamycin compounds with high antibiotic activity. JP-A-52-36683 discloses compounds obtained by reacting 3-amino-desoxo-4-imino-lifamycin S with ketones. The rifamycin compounds according to the invention have an antibacterial effect in vitro against Gram-positive, Gram-negative and especially K. tuberculosis bacteria. The compound claimed in JP-A-52-36683 is obtained by reacting a rifamycin compound with the structural formula with N-substituted 4-piperidones, but in this case, the substitution on the nitrogen atom in the structural formula of the piperidone is When the group is alkyl, the number of carbon atoms is 1 to 3, and when the group is arylalkyl, the number of carbon atoms is up to 8.
In the case of an acyl group, the number of carbon atoms was up to 4. No other 4-substituted-piperidones were used. Furthermore, in JP-A-53-50199, the applicant proposed a new rifamycin compound. This is a compound that has a group selected from an alkyl group, a cycloalkyl group, or a phenyl group on the nitrogen atom bonded to the 3rd carbon of the rifamycin skeleton.
Subsequent research by the applicant revealed that the bioabsorbability in biological tests was poor, and therefore the biological activity was low. The present inventors have conducted intensive research to overcome the drawbacks of conventional rifamycin compounds and obtain rifamycin compounds with excellent biological activity. The carbon chain length of the substituent R on N of the piperidylidene group greatly influences the improvement of its antibacterial activity, especially when the R is It has been discovered that the antibacterial activity of rifamycin can be significantly enhanced by selecting a 4 or 5 alkyl group, and based on this finding, the present invention has been completed. (In the formula, R represents a linear alkyl or branched alkyl group having 4 or 5 carbon atoms, and Y is -
COCH ₃ . ) To compare the "in vivo" therapeutic efficacy of the compound of formula () with other compounds, white mice CD ₁ were infected with a culture of K. tuberculosis H ₃₇ RV by intravenous course. 2
It contained twice the LD ₅₀ . Each mouse was injected with 0.2 ml of the above culture. Three days after injection, they were treated orally with rifamycin compound at a dose of 20-1.25 mg/Kg. Groups of 15 mice were treated with each rifamycin compound once daily for 5 consecutive days for 6 weeks. Post-treatment death was registered and PD ₅₀ was calculated. Mice were observed for approximately 2 months. Table 1 shows the results of experiments conducted with the "ethyl derivative" and some of the other novel compounds.

[Table] As is clear from the above table, the compound of formula () (where R is a linear alkyl or branched alkyl group having 4 or 5 carbon atoms) has a surprisingly low concentration compared to the compound where R is an ethyl group. Has PD ₅₀ . Therefore, the new compounds of the present invention are more effective than the "ethyl derivatives" and therefore more effective than any of the compounds of JP-A-52-36683. The present invention will be explained below with reference to Examples. Example 1 8 g of 3-amino-4-deoxo-4-imino-rifamycin S was dissolved in 40 ml of dichloromethane and reacted with 2.6 g of 1-n-hexyl-4-piperidone at +5°C for 48 hours. The solution was diluted with 600 ml of ethyl ether, filtered and washed with water.
The organic layer was dried over sodium sulfate and then evaporated to dryness. The residue was extracted with ligroin and the violet solution was evaporated to dryness. Yield: Y - COCH ₃ ;
R is an n-hexyl residue. The electronic absorption spectrum of the product of structural formula () in 2.4 g methanol shows peaks at 497, 314, 278 and 239 nm. The same procedure was carried out except that 1-n-pentyl-4-piperidone was used as the reagent, and Y was -COCH ₃
Thus, a compound in which R is an n-pentyl residue was obtained.
The electronic absorption spectrum in methanol is 500,
Shows peaks at 316, 278 and 240nm. Example 2 8 g of 3-amino-4-deoxo-4-imino-rifamycin S was dissolved in 40 ml of tetrahydrofuran. 4 g of 1-(1',3'-dimethyl)-butyl-4-piperidone, 0.5 g of zinc and 0.5 g of ammonia acetate were added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was worked up as in Example 1, with Y being -COCH ₃ and R being 1,3-dimethyl-butyl. Product of structural formula () 3.5
I got g. The electronic absorption spectrum in methanol shows peaks at 500, 315, 277 and 240 nm. 1-(1-ethyl)-propyl-4 as a reagent
The above procedure was followed except that -piperidone was used to obtain a compound in which Y is -COCH ₃ and R is a 3-pentyl residue. The electronic absorption spectrum in methanol shows peaks at 500, 315, 276 and 240 nm. Example 3 The procedure was repeated in the same manner as in Example 1 except that 1-n-butyl-4-piperidone was used as the reagent, and Y
was -COCH ₃ and R was an n-butyl residue, a compound of formula () was obtained. The electronic absorption spectrum in methanol shows peaks at 496, 317, 276 and 240 nm. In a similar manner, Y is -COCH ₃ and R
is the formula of i-butyl or sec-butyl residue ()
The compound was obtained. In the case of R=i-butyl, the electronic absorption spectrum in methanol is 493, 315, 274
and shows a peak at 238 nm. For R=sec-butyl, the peaks are at 500, 315, 275 and 240 nm. Example 4 The procedure was the same as in Example 1 except that 1-(1,2-dimethyl)-propyl-4-piperidone was used as a reagent, Y was _-COCH3 , R was 1,
A compound of formula (), which is a 2-dimethyl-propyl residue, was obtained. Test Example 1 The antibacterial effect of the compound of the present invention was evaluated in Japanese Patent Application Laid-Open No. 52-36683.
Comparison was made with the compound described in No. Details and results of the test compounds are shown in Table A (comparative compounds) and Table B (compounds of the present invention) below. Unexamined Japanese Patent Application Publication No. 1983-1989 expressed by the following general formula ()
In the compound of No. 36683, X and Z together with the C atom to which they are bonded are on the N atom as shown in Table A below.
forms a piperidine ring having the group specified in as a substituent.

[Table] (Note) Compounds described in JP-A-52-36683 Formula () In the compound of the present invention represented by the above formula (), Y is -COCH ₃ and R has the meaning specified in Table B below.

【table】

[Table] The test method is as follows. The MIC against K. tuberculosis H ₃₇ R _v was determined by a 2-fold serial dilution method of Duvos-albumin broth (Difco) inoculated with approximately 2×10 ⁵ cells/ml. After culturing at 37°C for 8 days, the minimum concentration capable of inhibiting growth without any visible growth was defined as the MIC. PD ₅₀ is experimentally calculated as K. tuberculosis H ₃₇ R _v (2LD ₅₀ equivalent)
We followed mice infected with Medication was started 3 days after infection. Dosing is administered orally once a day, 1
I went there 5 days a week for 7 weeks. PD ₅₀ was calculated as the dose that could prevent the death of 50% of infected animals at the end of the experiment (90 days). AUC (area under the plasma curve) was calculated based on plasma levels obtained from mice administered orally at a dose of 50 mg/Kg. Plasma levels were determined microbiologically at 1/2, 1, 2, 4 and 7 hours after treatment with Sarcina lutea (agar plate diffusion). From the results in Tables A and B above, it is recognized that the compounds in Table B (groups having 4 to 5 carbon atoms) are substantially superior to those in Table A having 3 or less carbon atoms. The MICs of the compounds of Table B are lower than those of the compounds of Table A, ranging up to 1/100 of the values of the compounds of Table A. Furthermore, the PD ₅₀ of the compounds in Table B is 1/4 that of the compounds in Table A. Finally, the plasma curve AUC of the compounds in Table B is shown in Table A.
significantly higher than that of the compound. Test Example 2 The compound of the present invention represented by the above formula (), in which R has the meaning specified in the table below, was tested with various atypical bacterial species
The in vitro antibacterial activity against Mycobacteria was investigated. The results are shown in Table C. Furthermore, compound No. 8
are comparative examples, and compounds No. 1 to 7 are of the present invention. It can be seen that the compounds of the present invention exhibit significantly superior antibacterial activity compared to the comparative examples.

【table】

Claims (1)

[Claims] 1 Formula () (wherein R is a residue selected from the group consisting of linear or branched alkyl groups having 4 or 5 carbon atoms, and Y is -COCH ₃ ).