FI63238C - FOERFARANDE FROSTAELLNING AV ANTIBIOTISKA SPIROPIPERIDYLRIFAMYCINER - Google Patents

Description

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C ^ Paten tt L nySnnc tty 10 05 1933 Patent rceddelnt ^ T ^ (S1) K * .ik? /Inta.3 C 07 D 498/20 FINLAND — FINLAND (ii) Λ · -Μ ** · «·· - Λ * · β · «· Μ · * 781710. (22) HtkMil ^ Uvt-AMetotoiAg 3O.O5.78 '* (23) Alkupllvt — GIMgk «<a4ag 3Q 05 78

(41) Interpreters JulklMkai —MvM offartJIg _ _Q

Patent and Registry Administrators .... ......... ,. ..... υχ, χ * 'y _' (44) Nlhtivikslptnon Etc. moon monthDate. -

Patents and registration certificates 7 AmMu utiagd och utUkmtM pubUcwwi 31 Q1 g3 (32) (33) (31) Fyydttty Muoiksut — teglrd prtorttat (Tl) Farmitalia Carlo Erba SpA, Via Imbonati 2k, Milan, Italy-Italy (72) ) Leonardo Marsili, Milan, Vittorio Rossetti, Milan, Carmine Pasqualucci, Milan, Italy-Italy (IT) (7 * 0 Leitzinger Oy (5 ^) Method for the preparation of antibiotic spiro-piperidyl rifamycins

The present invention relates to a process for the preparation of antibiotic spiro-piperidylrifamycins of formula I

32 31 ch3 ch3 »33H3CvJ oh l | l | CH3C '° (I)

17¾¾. OH O p 5 J

H, Cv I CH3 i II 1

34 3 \ | 26 JL JUL NH

wherein R is straight or branched C4-C8 alkyl, C3-C4 alkenyl or 2-methylfuryl.

Finnish Patent No. 60208 to Archifar Industrie Chimiche del Trentino S.p.A. discloses compounds obtained by reacting 3-amino-4-deoxo-4-imino-rifamycin S with ketones. The rifamycin compounds according to the above-mentioned patent application are antibacterially active in vitro against gram-positive, gram-negative and in particular Mycobacterium Tuberculosis bacteria.

The process according to the invention is characterized in that the compound of general formula (II) 32 31 ch3 ch3 HO J. 21 Jv 19 y \ \ i7

»• 33 H, Cv ^ | 2« * λ Ml6 -A

CH., 00 ^ 3> OH O Λ 30 J28 e I J <Π> .sr o__ΐή nh

CH- O

13 J

wherein Y is the same as above, reacting 4-piperidone of general formula (III)

O

0

R

wherein R is the same as in formula (I).

3 63238

In vitro activity tests in mice infected intravenously with Mycobacterium Tuberculosis showed that the rifamycin compounds of formula I obtained by the method of the invention already differ from the derivatives obtained by introducing 3-amino-4-deoxo-4-imino- rifamycin S to react with ketones other than 4-piperidones so that their therapeutic activity is much higher.

The compounds disclosed in Patent No. 60208 were obtained by reacting a rifamycin compound of formula II with 4-piperidones having up to three carbon atoms in the group R = alkyl, up to eight carbon atoms in the group R = arylalkyl and up to four carbon atoms in the group R = acyl.

No other 4-substituted piperidones were used. Applicants have now used 4-substituted piperidones of formula III. The rifamycin compounds of formula I thus obtained were found to have surprisingly much higher therapeutic activity than the rifamycin compounds obtained using the 4-piperidones described in the aforementioned patent 60,208.

To demonstrate these "in vivo" differences in therapeutic activity, white CD1 mice were infected intravenously with Mycobacterium Tuberculosis H 2 RV culture. Each mouse was injected with 0.2 ml of the above culture at twice the LD50 value.

Three days after infection, mice were orally administered rifamycin compounds at doses ranging from 20 to 1.25 mg / kg. Groups of fifteen mice were treated with each rifamycin compound once daily, for five consecutive days, and for six weeks.

At the end of the treatment, the number of dead animals was recorded and the PD5Q value was calculated.

The animals were kept under observation for approximately 2 months.

The PD2 Q value of the "ethyl derivative" was 20 mg / kg.

Table I Activity

In vitro In vivo _R_MIC uq / ml_PP50 mg / kg_ n-butyl 0.0005 5 n-hexyl 0.005 10 allyl 0.0012 5 1-butyl 0.0012 2.6 methyl-allyl 0.005 5 sec-butyl 0.005 3.7 2 - methylfuryl 0,0012 --- 1,2-dimethylpropyl 0.005 2.5 n-pentyl 0.0012 5 1.3-dimethylbutyl 0.0012 2.5 3-pentyl 0.0012 2.5 ethyl 0.01 20

Table I shows the results obtained in these experiments with the "ethyl derivative" and some new compounds. The results show that the PD50 value of the new derivatives of general formula I in which R is as defined above is surprisingly much lower than that of the corresponding ethyl derivative or the compounds described in Finnish patent 60208.

The following non-limiting embodiments of the invention are provided in the following examples.

Example 1 8 g of 3-amino-4-deoxo-4-iminorifamycin S were dissolved in 40 g 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 5,63238,600 ml of ethyl ether, filtered and washed with water. The organic phase was dried over sodium sulfate and then evaporated to dryness. The residue was extracted with naphtha and the purple solution was evaporated to dryness.

Yield 2.5 g of a compound of formula (I) wherein Y is -COCH 3 and R is an n-hexyl radical.

The electron absorption spectrum in methanol shows peaks at 497, 314, 278 and 239 nm.

By acting in exactly the same manner but utilizing 1-n-pentyl-4-piperidone as a reactant, a compound of formula (I) wherein Y is -COCH 3 and R is an n-pentyl radical is obtained. The electron absorption spectrum in methanol shows peaks at 500, 316, 278 and 240 nm.

Example 2 8 g of 3-amino-4-deoxo-4-iminorifamycin S were 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 ammonium acetate were added and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was treated in the same manner as in Example 1 to give 3.5 g of the product of formula (I) wherein Y is -COCH 3 and R is a 1,3-dimethylbutyl radical.

The electron absorption spectrum in methanol shows peaks at 500, 315, 277 and 240 nm.

By acting exactly according to the above procedure, but using 1- (1-ethyl) -propyl-4-piperidone as the reactant, a compound is obtained in which Y is -COCH 3 and R is a 3-pentyl radical. The electron absorption spectrum in methanol shows peaks at 500, 315, 276 and 240 nm.

Example 3 8 g of 3-amino-4-deoxo-4-iminorifamycin S were dissolved in 40 ml of tetrahydrofuran. 1.8 g of 1-methallyl-4-piperidone were added.

6 63238 0. 2 g of zinc and 0.2 g of anunium acetate and the mixture was allowed to stand at + 5 ° C overnight. The reaction mixture was treated as in Example 1 to give 5.5 g of the product of formula (I) wherein Y is -COCH 3 and R is a methallyl radical.

The electron absorption spectrum in methanol shows peaks at 498, 313, 275 and 238 nm.

By proceeding as above, but using 1-allyl-4-piperidone as the reactant, a compound of formula (I) wherein Y is -COCH 3 and R is allyl is obtained.

The electron absorption spectrum of this compound shows peaks at 491, 314, 276 and 235 nm.

Example 4 8 g of 3-amino-4-deoxo-4-irino-rifamycin S were dissolved in 40 ml of tetrahydrofuran. 0.5 g of zinc, 0.5 g of ammonium acetate and 5.5 g of 1- (2-methylfuryl) -4-piperidone were added, and the mixture was stirred for 24 hours at room temperature. The reaction mixture was filtered, diluted with 500 mL of diethyl ether and washed with water. The organic phase was concentrated to 250 ml and then extracted with aqueous dilute acetic acid. The purple aqueous solution was extracted with dichloromethane and the organic phase was washed with water and dried over sodium sulfate and then evaporated to dryness.

Yield: 3.3 g of a product of formula (I) in which Y is -COCH 3 and R is a 2-methylfuryl radical.

The electron absorption spectrum in methanol shows peaks at 497, 316, 276 and 240 nm.

Following the procedure described above, but using 1-n-butyl-4-piperidone as the reactant, a compound of formula (I) wherein Y is -COCH 3 and R is an n-butyl radical is obtained. The electron absorption spectrum in methanol shows peaks at 496, 317, 276 and 240 nm. Similarly, compounds of formula (I) are obtained in which Y is -COCH 3 and R is i-butyl or a sec-butyl radical. When R * i-butyl shows peaks in the electron absorption spectrum in methanol at 493, 315, 274 and 238 nm. When R sec-butyl peaks are 500, 315, 275 and 240 nm.

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Example 5 8 g of 3-amino-4-deoxo-4-iminorifamycin S was dissolved in 40 ml of tetrahydrofuran and the mixture was added dropwise at 50 ° C to a mixture of 15 ml of tetrahydrofuran, 5 ml of acetic acid, 1 g of zinc and 4 g of - (l, 2-dimethyl) propyl-4-piperidone.

Heating of the mixture was continued for 30 minutes and then treatment of the mixture was continued as described in Example 4.

Yield: 3.7 g of the product of formula 1 in which R = 1,2-dimethylpropyl.

The electron absorption spectrum in methanol shows peaks at 496, 315, 277 and 240 nm.

Claims (2)

A process for the preparation of antibiotic spiro-piperidyl rifamycins of the formula I 32 31 ch3 ch3 ^ 0 H..C. L · Il 16 «i 3 3 ^ oi. OH <x äo -3 15¾ 0H 0 r5, I NH ch30Nt5; wherein R is straight or branched C 1 -C 6 alkyl, C 1 -C 4 alkenyl or 2-methylfuryl, R 1 (i) e I 3 <IJ 2Θ0 NH ° ”-f 2 Ί" / Λ ”3 ° V. characterized in that the compound of general formula (II) 32 31 CH3 ch3 ho II 18 H0.2 3 21 19 N2N22fVr \ 17 "33 H-, Cl2. Li * I I 16 CH-, ΟΟ ^ 3 y OH O ^ * s! .30 hcN f 9> Och3 “τ'- v · CH3 ° \ / ^ 26 9 ^ TV. NH <H>. 28 6 jf J f 0 '^ γάγ ^ - ™ 2 o_11_Li | NH CH 3 O 13 -3 9 63238 wherein Y is the same as above is reacted with 4-piperidone of general formula (III) φ R wherein R is the same as in formula (I). For the preparation of an antibiotic spiro-piperidylripha-myciner with the formula (I) 32 31 CH3 CH2?, 33H3C \ 2U OH o-CH-C-0 H, C J „CH3 I II 'CH 0 f. i I I 12 11 -Q% ·? ·