GB2088361A

GB2088361A - Rifamycin derivatives

Info

Publication number: GB2088361A
Application number: GB8131202A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1980-11-28
Filing date: 1981-10-16
Publication date: 1982-06-09
Also published as: GB2088361B

Abstract

There are provided rifamycin S derivatives of the formula <IMAGE> in which Z is a 5, 6 or 7 membered heterocyclic ring containing a ring N atom through which it is bonded to the rifamycin nucleus and a ring C atom to which is bonded a group =NX, X being H, OH, NH2, NH2CONH, NH2CSNH, NH2C(=NH).NH, R, OR, NHR', or NRR''; R=C1-C8 alkyl, C3 or C4 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, C7-C9 aralkyl, C6-C10 aryl or heterocyclic (5 or 6 membered ring; at least one ring atom is O, S or N); R'= any of the values of R or acyl or sulphonyl; R''=C1-C5 alkyl, C3 or C4 alkenyl, acyl or sulphonyl; or NRR'' = piperazinyl, 4-aralkyl-piperazinyl, 4- (C1-C8 alkyl)-piperazinyl and the ketone from which they are derived The corresponding rifamycin SV compounds are also provided, as are pharmaceutically acceptable salts, pharmaceutical compositions and preparative methods.

Description

SPECIFICATION Rifamycin derivatives The invention relates to rifamycin derivatives, to processes for their preparation, and to pharmaceutical compositions containing them.

The invention provides rifamycin derivatives of the general formula I

wherein Z represents a 5,6 or 7 membered heterocyclic ring containing a ring nitrogen atom through which it is bonded to the rifamycin nucleus and a ring carbon atom to which is bonded an imino group of the general formula =NX wherein X represents a hydrogen atom, a hydroxy, amino, ureido, thioureido or guanidino group or a group of the formula R, OR, NHR' or NRR" wherein R represents an alkyl group having from 1 to 8 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, a cycloalkyl group having from 3 to 6 ring carbon atoms, a cycloalkenyl group having from 3 to 6 ring carbon atoms, an aralkyl group having from 7 to 9 carbon atoms, an aryl group having from 6 to 10 carbon atoms or a heterocyclic ring having 5 or 6 ring atoms or which at least one is an oxygen sulphur or nitrogen atom, R' represents any of the groups which R may represent or an acyl or sulphonyl group, and R" represents an alkyl group having rrom 1 to 5 carbon atoms, an alkenyl group having 3 or 4 carbon atoms, an acyl group or a sulphonyl group or together with the nitrogen atom to which it is attached and the group R attached to that nitrogen atom represents a piperazinyl group, a 4-aralkyl-piperazinyl group or a 4-alkylpiperazinyl group, the 4-alkyl substituent of which has from 1 to 8 carbon atoms; and further provides pharmaceutically acceptable salts of such rifamycin derivatives.The invention also provides their reduction products o; the general formula II

wherein Z is as hereinbefore defined, and further provides pharmaceutically acceptable salts of such reduction products.

According to the invention the rifamycin derivatives of the general formula I and II may be prepared by reacting a 3-halo-rifamycin S with a 5, 6 or 7 membered heterocyclic ring compound containing a ring nitrogen atom to which a hydrogen atom is bonded and a ring carbon atom to which an oxo group is bonded to give a rifamycin derivative of the general formula III

wherein Z' represents a 5, 6 or 7 membered heterocyclic ring containing a ring nitrogen atom through which it is bonded to the rifamycin nucleus and a ring carbon atom to which an oxo group is bonded, the reaction being carried out in a dipolar aprotic solvent at from 1 0 C to 40CC in the presence of triethylamine, optionally reducing the rifamycin derivative of the general formula Ill to a rifamycin derivative of the general formula IV

wherein Z' is as hereinbefore defined, and condensing the rifamycin derivative of the general formula III or IV with a compound of the general formula NH2X wherein X is as hereinabove defined, the configuration (S or SV, general formula I or II respectively) of the rifamycin derivative obtained being dependent upon the configuration (S or SV, general formula III or IV respectively) of the rifamycin derivative employed and/or upon the nature of the compound NH2X employed; and, if the configuration of the rifamycin derivative obtained is not that desired, converting the rifamycin derivative obtained to that desired by reduction (S to SV) or oxidation (SV to S).

As stated, the S or SV configuration of the rifamycin derivative obtained depends upon the nature of the compound NH2X employed and/or upon the S or SV configuration of the compound of the general formula Ill or IV. In general, when the rifamycin derivative of the general formula Ill is condensed with ammonia, hydroxylamine or one of the compounds of the general formula RNH2 or RONH2, a rifamycin derivative of the general formula I is obtained. On the contrary, when the rifamycin derivative of the general formula Ill or IV is condensed with hydrazine, semicarbazide, thiosemicarbazide, iminosemicarbazide or one of the compounds of the general formula H2N.NR' or H2N.NRR", a rifamycin derivative of the general formula II is obtained, due to the reducing properties of such compounds.This is, however a generalisation and at least one exception exists in that condensation with tosylhydrazine leads predominantly to a rifamycin S derivative. Other exceptions may exist. The easy interconversion of the S and SV derivatives nevertheless enables all the compounds I and II to be obtained, and makes it a matter of little concern whether the S or SV derivative is obtained by the condensation.

The reduction of the rifamycin S derivatives of the general formula I into the corresponding rifamycin SV derivatives of the general formula II may easily be effected by treatment with ascorbic acid or with zinc and acetic acid. In the same way, the rifamycin SV derivatives of the general formula II can be easily transformed into the corresponding rifamycin S derivatives of the general formula I by treatment with an oxidizing agent such as manganese dioxide according to usual techniques.

The rifamycin derivatives of the general formulae ill and IV are included within the scope of the invention.

An alternative process for the preparation of rifamycin derivatives of the general formula I and II has also been developed. This alternative process, which is within the scope of the invention, comprises condensing a 3-halo-rifamycin S in a dipolar aprotic solvent at from 0 C to 400C with a compound of the general formula HZ wherein Z is as hereinbefore defined; and, if the desired rifamycin derivative is of the general formula II, reducing the rifamycin derivative I obtained.

The 3-halo rifamycins S are compounds well known per se, described for example in German Offenlegungsschrift No. 2548128, in J. Am. Chem. Soc. 97, (21), 6254/6231 and in J. Am. Chem. Soc.

98 (22), 7064.

The rifamycin derivatives I and II of the invention have high antibacterial activity both on Grampositive and Gram-negative bacteria and on Mycobacterium Tuberculosis. Accordingly, the invention further provides a pharmaceutical composition comprising a rifamycin derivative of the general formula I or II or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

The invention is illustrated by the following Examples, in which the C atoms in the PMR spectra are numbered according to IUPAC rules.

EXAMPLE 1 3-(4'-oxo-piperidino)-rifamycin S 7 g of 3-bromo-rifamycin S were dissolved in 20 ml of dimethylformamide, 1.7 ml of triethylamine and 1.8 g of 4-piperidone monohydrate hydrochloride were added at room temperature under stirring.

After 30 minutes the reaction mixture was diluted with 300 ml of diethyl ether, washed with a phosphate buffer solution at pH 7.5 and then with water. The organic phase was dried on anhydrous sodium sulphate and concentrated to 50 ml. 20 ml of petroleum ether were added, the solution was filtered and the filtrate was evaporated to dryness. 4.2 g of the title compound were obtained. This compound was dark violet.

PMR (CDCl3): 0.23 6 [d,CH3-C(22)]; 0.73 US [d,CH3-C(20)]; 0.91 # [d,CH3-C(16)]; 1.06 # [d,CH3-C(18)]; 1.78 6 [1,CH3-C(12)]; 2.11 a [s,CH3-COO-C(21 )J; 2.15 # [s,CH3-C(12)]; 2.32 #(s,CH3-C(4)]; 3.14 b [s,CH3O-C(23)].

Ms: 792 (M+) EXAMPLE 2 3-(4'-hydroxyimino-piperidino)-rifamycin SV 3.0 g of 3-bromo-rifamycin S were added to a solution of 0.75 g of 4-hydroxyimino-piperidine in 25 ml of dimethylformamide at room temperature. The solution was stirred for 2 hours, 100 ml of chloroform were added and the mixture was washed with dilute acetic acid and then with water. After drying with anhydrous sodium sulphate the solvent was evaporated off under vacuum.

The crude residue was dissolved in 50 ml of methanol and treated with ascorbic acid 150 ml of ethyl acetate were added and the organic phase was washed with a phosphate buffer solution at pH 7.5. The organic layer was dried and then evaporated under vacuum. The residue was crystallized from dichloromethane. Yield 1.5 g of the title compound.

PMR (CDCl3): -0.11 b [d,CH3-C(22)]; 0.63 S [d,CH3-C(20)]; 0.86 # [d,CH3-C(16)]; 1.03 # [d,CH3-C(18)]; 1.78 CS [s,CH3-C(2)]; 2.08 #[s,CH3COO-C(21) and CH3-C(1 2)]; 2.23 #(1,CH3-C(4)]; 3.09 #[s,CH3O-C(23)].

MS: 809 (Mt) EXAMPLE 3 3-(4'-methoxyimino-piperidino)-rifamycin SV 0.7 g of 3-(4'-oxo-piperidino)-rifamycin S, prepared as described in Example 1, were dissolved in 10 ml of tetrahydrofuran. 0.25 g of anhydrous sodium acetate and 0.1 5 of methoxylamine hydrochloride were added under stirring. The mixture was stirred for 60 minutes at 400 C, 3 ml of methanol and 1 g of ascorbic acid were added, the stirring was continued for 10 minutes and then the solution was added dropwise to 100 ml of water. The precipitate was filtered off, washed with water and dried at 400C under vacuum. 0.50 g of the title compound were obtained. This compound was yellow.

PMR (CDCl3): -0.10 b [d,CH3-C(22)]; 0.62 6 [d,CH3-C(20)]; 0.88 # [d,CH3-C(16)]; 1.03 # [d,CH3-C(18)]; 1.78 b [s,CH3-C(2)]; 2.07 b [s,CH3-COO-C(21) and CH3-C(12)]; 2.22 # [s,CH3-C(4)]; 3.08 # [s,CH3O-C(23)]; 3.87 b [s,CH30N=].

Ms 823(M+) EXAMPLE 4 3-[4'-(4"-methyl- 1 "-piperazinyl-imino)-piperidino]-rifamycin S.

0.7 g of 3-(4'-oxo-piperidino)-rifamycin S, prepared as described in Example 1, were dissolved in 10 ml of tetrahydrofuran. 0.48 ml of 1 -amino-4-methylpiperazine were added and the solution was stirred at 40 C for 30 minutes. 30 ml of dichloromethane were added, and the solution was washed with dilute acetic acid and then with water. After drying on anhydrous sodium sulphate, the solvent was evaporated off and the residue was crystallized from acetone. The product was dissolved in 20 ml of dichloromethane and oxidized with MnO2. The mixture was filtered and the solvent evaporated off under vacuum.

Yield: 0.380 g of the title compound.

PMR (CDCl3): 0.20 S [d,CH3-C(22)]; 0.72 S [d,CH3-C(20)]; 0.88 #[d,CH3-C(16)]; 1.03 # [d,CH3-C(18)]; 1.75 # [s,CH3-C(2)]; 2.08 # [s,CH3-COO-C(21)]; 2.12 S [s,CH3-C(12)]; 2.30 S [s,CH3-C(4) and CH3-N < ]; 3.12 S [s.CH3O-C(23)].

Ms: 889 (M+) By reacting 3-(4'-oxo-piperidino)-rifamycin S with benzoylhydrazine according to the method described above, but omitting the oxidation step, there is obtained 3-(4'-benzoylhydrazono-piperidino)rifamycin SV.

Ms: 912 (M+).

EXAMPLE 5 3-(4'-oxo-piperidino)rifamycin SV thiosemicarbazone 1 g of 3-(4'-oxo-piperidino)-rifamycin SV were dissolved in 10 ml of tetrahydrofuran and 0.5 g of thiosemicarbazide were added. The mixture was stirred at 30 C for 60 minutes, 50 ml of dichloromethane were added and the solution was washed with water. The organic phase was dried on anhydrous sodium sulphate and the solvent was evaporated off. The crude residue was purified by column chromatography on silica gel, eluting with 98:2 by volume dichloromethane:methanol.

Yield: 0.6 g of the title compound.

PMR (CDCl3): -0.10 S [d,CH3C(22)3; 0.65 S [d,CH3-C(20)]; 0.88 a [d,CH3-C(16)J; 1.04a [d,CH3-C(18)]; 1.80 S [s,CH3-C(2)]; 2.08 S [s,CH3-COO-C(2 1) and CH3-C(1 2)]; 2.22 S [s,CH3-C(4)]; 3.08 S [s,CH3O-C(23)j.

Ms: 867 (M+) EXAMPLE 6 3-(4'-oxo-piperidino)-rifa mycin S semicarbazone 1 g of 3-(4'-oxo-pipendino)-rifamycin SV were dissolved in 10 ml of tetrahydrofuran. 0.5 g of semicarbazide hydrochloride and 0.5 g of anhydrous sodium acetate were added. The mixture was stirred at 300C for 60 minutes, 50 ml of dichloromethane were added and the solution was washed with water. The organic phase was dried on anhydrous sodium sulphate and concentrated to 50 ml, and manganese dioxide was added and, after 60 minutes stirring, filtered off. The solvent was evaporated off and the crude product was purified by column chromatography on silica gel, eluting with 98:2 by volume dichloromethane:methanol.

Yield: 0.5 g of the title compound.

MS: 849 (M+).

EXAMPLE 7 3-(4'-tosylhydrazono-piperidino)-rifamycin S.

1 g of 3-(4'-oxo-piperidino)-rifamycin S, prepared as described in Example 1 , were dissolved in 10 ml of tetrahydrofuran and 1 g of tosylhydrazine were added. The mixture was stirred at 350C for 3 hours, 50 ml of dichloromethane were added and the solution was washed with water. The organic phase was dried on anhydrous sodium sulphate and the solvent was evaporated off. The crude residue was purified by column chromatography on silica gel, eluting with 98:2 by volume dichloromethane:methanol.

Yield: 0.5 g of the title compound.

MS: 960 (M+) The compound above obtained was dissolved in methanol and treated with ascorbic acid at 300C.

The reaction mixture was diluted with dichloromethane and washed with water. After drying, the organic phase was evaporated off and the residue was collected.

Yield: 0.4 g of 3-(4'-tosylhydrazono-piperidino-rifamycin SV MS: 962 (M+) The compounds prepared in the Examples have the following formulae:

Example Formula Z (Z' if formula is ill) Example Formula I III -N'4O =N-OH 2 II -NN-OH N-OCH3 m n -N 1J - CH3 U 4 and ll - Nt92= N- NH I I N-NH-CS-NH2 5 11 --N i N= N NH~S02 4 CH3 7 and ii - N NH~S02 9 CH3 The antibacterial activity of the compounds according to the invention was tested in vitro by the twofold dilution technique in nutrient medium.

The Mick were recorded after incubation at 370C for 24 hrs (7 days for Mycobacteríum Tuberculosis).

Compounds obtained as described in Examples 1, 2 and 3 are antibacterial antibiotics whose spectrum of activity is similar to that of Rifampicin.

The compound described in Example 3 is superior to Rifampicin on Mycobacterium Tuberculosis (4 times higher activity) and on Staphylococcus aureus Rifampicin resistant.

Compounds obtained as described in Examples 4, 5 and 6 are wide spectrum antibiotics with characteristics of activity in vitro comparable to those of Rifampicin.

TABLE Microorganisms Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Staphylococcus aureus 209P 0.009 0.0022 0.009 0.0011 0.009 0.0022 Streptococcus faecalis 5 5 2.5 0.6 0.6 1.25 Streptococcus pyogenes - - - 2.5 2.5 5 Sarcina lutea 0.009 0.0022 0.009 0.018 0.037 0.075 Staphylococcus aureus 209P > 20 < 200 > 20 < 200 20 200 > 200 200 (Rifampicin resistant) Escherichia coli B 10 10 10 10 10 20 Klebsiella pneumoniae 10 10 10 5 10 10 Proteus vulgaris 5 5 5 10 10 10 Escherichia coli Ginetta 10 10 10 10 10 20 Escherichia coli C1 > 200 > 200 > 200 > 200 > 200 > 200 (Rifampicin resistant) Pseudomonas aeruginosa 10 5 10 10 10 10 Salmonella abortivoequina 10 5 5 10 10 10 Mycobacterium tuberculosis H37Rv 0.0025 0.0025 0.0012 0.01 > 0.02 0.01

Claims

1. A rifamycin derivative of the general formula I or II as herein defined or a pharmaceutically acceptable salt of such a rifamycin derivative.

2. 3-(4'-Hydroxyimino-piperidino)-rifamycin SV.

3. 3-(4'-Methoxyimino-piperidino)-rifamycin SV.

4. 3-[4'-(4"-Methyl-1 "-piperazino-imino)-piperidino]-rifamycin S.

5. 3-(4'-Benzoylhydrazono-piperidino)-rifamycin SV.

6. 3-(4'-Oxo-piperidino)-rifamycin SV thiosemicarbazone.

7. 3-(4'-Oxo-piperidino)-rifamycin S semicarbazone.

8. 3-(4'-Tosylhydrazono-piperidino)-rifamycin S.

9. 3-(4'-Tosylhydrazono-piperidino)-rifamycin SV.

10. A method for the preparation of a rifamycin derivative of the general formula I or II as herein defined, the method comprising reacting a 3-halo-rifamycin S with a 5, 6 or 7 membered heterocyclic ring compound containing a ring nitrogen atom to which a hydrogen atom is bonded and a ring carbon atom to which an oxo group is bonded to give a rifamycin derivative of the general formula III as herein defined, the reaction being carried out in a dipolar aprotic solvent at from 100C to 400C in the presence of triethylamine, optionally reducing the rifamycin derivative of the general formula Ill to a rifamycin derivative of the general formula IV as herein defined, and condensing the rifamycin derivative of the general formula Ill or IV with a compoud of the general formula NH2X wherein X is as herein defined, the configuration (S or SV, general formula I or II respectively of the rifamycin derivative obtained being dependent upon the configuration (S or SV, general formula Ill or IV respectively) of the rifamycin derivative employed and/or upon the nature of the compound NH2X employed; and, if the configuration of the rifamycin derivative obtained is not that desired, converting the rifamycin derivative obtained to that desired by reduction (S to SV) or oxidation (SV to S).

11. A method according to claim 10 in which the condensation gives a compound of the general formula I which is converted to the corresponding compound of the general formuia II by treatment with ascorbic acid or with zinc and acetic acid.

1 2. A method according to claim 10 in which the condensation gives a compound of the general formula II which is converted to the corresponding compound of the general formula by treatment with manganese dioxide.

1 3. A method for the preparation of a rifamycin derivative of the general formula I or II as herein defined, the method condensing a 3-halo-rifamycin S in a dipolar aprotic solvent at from OOC to 400C with a compound of the general formula HZ wherein Z is as herein defined; and, if the desired rifamycin derivative is of the general formula II, reducing the rifamycin derivative I obtained.

14. A method according to claim 1 3 in which the reduction is effected by treatment with ascorbic acid or with zinc and acetic acid.

1 5. A method according to claim 10, the method being substantially as described herein with reference to Examples 3 to 7.

1 6. A method according to claim 13, the method being substantially as described herein with reference to Example 2.

1 7. A pharmaceutical composition comprising a rifamycin derivative according to any of claims 1 to 9 or a rifamycin derivative prepared according to any of claims 10 to 1 6 or a pharmaceutically acceptable salt of such a rifamycin derivative in admixture with a pharmaceutically acceptable diluent or carrier, 1 8. A rifamycin derivative of the general formula Ill or IV as herein defined.

1 9. 3-(4'-Oxo-piperidino)-rifamycin S.