GB2082169A

GB2082169A - Hydrazono rifamycins

Info

Publication number: GB2082169A
Application number: GB8118411A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1980-08-14
Filing date: 1981-06-16
Publication date: 1982-03-03
Also published as: GB2082169B

Abstract

Hydrazono rifamycins of the formula:- <IMAGE> wherein R1=H, C1-C5 alkyl or aryl, R2=C1-C5 alkyl, C3-C6 cycloalkyl, C6-C10 aryl, substituted aryl or heterocyclic or CR1R2= a cycloaliphatic or heterocyclic ring including an N atom R3=H, alkyl, cycloalkyl, aryl or substituted aryl, and their reduced derivatives in which a hydroquinone moiety replaces the quinone moiety, have antibacterial activity and may be formulated as pharmaceutical compositions. Also disclosed are hydroquinone derivatives as above but in which the CR<1>R<2> moiety is replaced by two hydrogen atoms.

Description

SPECIFICATION Hydrazono rifamycins Description The invention relates to rifamycin derivatives having high antibacterial activity both on Gram-positive and Gram-negative bacteria and on Mycobacterium Tuberculosis.

The invention provides hydrazono-rifamycins having the general formula I

wherein R1 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, or an aryl group, R2 represents an alkyl group having from 1 to 5 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, an aryl group having from 6 to 10 carbon atoms, or a substituted aryl or heterocyclic group, or R1 and R2 together with the carbon atom to which they are bonded represent a cycloalkyl ring or a heterocyclic ring containing a nitrogen atom, and R3 represents a hydrogen atom or an alkyl, cycloalkyl, aryl or substituted aryl group and further provides their reduced derivatives having the general formula II.

The invention further provides a method for the preparation of hydrazono-rifamycins of the general formula I, according to which a compound having the general formula Ill

in which X represents a halogen or hydrogen atom is reacted in a dipolar aprotic solvent at a temperature of from 0 C to 50"C with a hydrozone of the general formula IV

in which R1, R2 and Rs are as above defined.

The hydrazono-rifamycin derivatives of the general formula Il are obtained according to the invention by reducing the quinone moiety of the hydrazono-rifamycin derivatives of the general formula I with ascorbic acid or its salts or with zinc and acetic acid.

The starting compound of the general formula Ill in which X represents a hydrogen atom is well known under the name "rifamycin S". The starting compounds of the general formula Ill in which X represents a halogen atom and their preparation are well known and are described in the German Offenlegungsschrift No.2548128, in J. Am. Chem. Soc. 97, (21), 6254,6231, and in J. Am. Chem. Soc. 98(22), 7064.

The invention further provides a pharmaceutical composition comprising a hydrazono-derivative I or II according to the invention in admixture with a pharmaceutically acceptable diluent or carrier.

The compounds of the general formulae I and II may be also hydrolysed to the corresponding free hydrazino-rifamycins SV of the general formula ll under suitable conditions. More particularly a hydrazono-rifamycin S of the general formula I may be reacted with hydrazine hydrate in a solvent such as dichloromethane or chloroform at from-10 C to +1 00C to give the corresponding hydrazino rifamycin SV (II, =CR1R2 replaced by 2 H atoms). These hydrazino-rifamycins SV are suitable intermediates for the preparation of other rifamycin derivatives.

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

EXAMPLE 1 3-[p-nitro-benzylidene-hydrazono]-rifamycinSV 7 g of 3-bromo-rifamycin S were dissolved in 25 ml of dimethylformamide and 2 g of p-nitrobenzylidenehydrazine was added at room temperature.

The solution was stirred for 30 minutes and then diluted with 200 ml of ethyl acetate. After washing with water the organic phase was dried on anhydrous sodium sulphate, filtered and evaporated to dryness.

The crude product thus obtained was purified by column chromatography on silica gel, eluting with chloroform: methanol 97:3 by volume. The solution of the pure 3-[p-nitro-benzylidene-hydroazono]-rifamycin S thus obtained was evaporated to dryness, the residue was treated with a methanolic solution of ascorbic acid and the red solution extracted with dichloromethane; after washing with water the organic phase was dried, filtered and evaporated to dryness.

Yield: 1.0 g of a compound of the general formula II wherein R1 = H, R2 = p-nitro-benzylidene and R3 = H.

P. M. R. (CDCl3): -0.2o b [d, CH3-C(22)1; 0.45 6 [d, CH3-C (20)]; 0.70 6 [d, CH3-.C(16)]; 0.96 ä[d, CH3-C(18)]; 1.80 8[s, CH3-C(2)]; 2.08 #[s, CH3-COO-C(21)]; 2.20 8[s, CH3-C)12) + CH3-C(4)]; 3.07 8[s, CH3 O-C(23)j; 3.40-4.00 b[m, C(23) H and 0(1 9)H1; 4.80-5.406[m, C(21)H and C(24)H]; 6.10-6.80 #[m, C(13)H, C(14)H, C(15)H, C(25)H]; 7.59 b[d, 2HNO2]; 7.80 8[s, N=CH-]; 8.17 8[d, 2H a NO2]; 8.90 8[s, C(9)OH]; 11.25 8[s, NH-CO-]; 12.05 and 12.62 #[s and bs, C(5)OH and C(6)OH].

MS: 860(M+) EXAMPLE 2 3-[Isopropylidene-N'-methyl-hydrazono]-rifamycin S 7 g of 3-bromo-rifamycin S was dissolved in 25 ml of dimethylformamide and 1.7 g of N'-methylisopropylidene-hydrazine was added to the solution. After stirring for 30 minutes at room temperature the reaction mixture was diluted with 100 ml of dichloromethane and washed with water. The organic solution was dried on anhydrous sodium sulphate, filtered and evaporated to dryness.

Yield: 3.5 of a compound of the general formula I wherein R1=R2=R3=CH3 MS = 779 (M+) EXAMPLE 3 3-[o-chlorobenzylidene-N'-methyl-hydrazono]-rifamycin SV 7 g of 3-bromo-rifamycin S was dissolved in 25 ml of dimethylformamide and 1.7 g of N'methylisopropylidene-hydrazine was added to the solution. After 30 minutes stirring at room temperature, 2.2 ml of o-chlorobenzaldehyde, 0.2 g of Zn powder and 4 ml of acetic acid were added. The mixture was warmed to 40 C and stirred for 30 minutes, 200 ml of dichloromethane was added and the solution was washed with water. After drying over anydrous sodium sulphate, the organic phase was filtered and evaporated to dryness; the crude residue was dissolved in 400 ml ethyl acetate, washed with phosphate buffer solution at pH 7.5 and then with water.The ethyl acetate solution was dried and evaporated; the residue was dissolved in dichloromethane and allowed to crystallize.

Yield: 1.5 g of a compound of the general formula ll wherein R1 =H, R2 = o-chloro-benzylidene and R3 = CH3.

P.M.R. (CDCl3)-0.07 #[d, CH3-C(22)]; 0.59 #[d, CH3-C(20)]; 0.86 #[d, CH3-C(16)]; 1.01 #[d, CH3-C(18)]; 1.80 #[s, CH3-C(2)]; 1.93 #[s, CH3-COO-C(21)]; 2.05 #[s, CH3-CH3-C(12)]; 2.23 #[s, CH3-C(4)]; 3.08 #[s, CH3 O-C(23)]; 3.44 5[s, CH3-N-]; 4.7-5.4#[m, C(21)H and C(24)H]; 5.9-6.8 5(m, C(13)H, C(14)H, O(15)H, C(25)H]; 7.0-8.0 #[m, four aromatic protons]; 7.63 #[s, -N=CH-]; 8.83 #[s, C(9)OH]; 11.56 #[s, O(5)OH and C(6)OH] MS: 863 (M+).

EXAMPLE 4 3-[Furfurylidene-N'-methyl-hydrazono]-rifamycin SV Operating as in Example 3, but using furfuraldehyde in place of o-chlorobenzaldehyde, a compound of the general formula II wherein R1 = H, R2 = furfurylidene and R3 = CH3 was obtained.

P.M.R. (CDCI3): -0.01 #[d, CH3-C(22)]; 0.65 Sid, CH3-C(20)]; 0.89 stud, 0H3-C(16)]; 1.06 #[d, OH3-C(18)]; 1.82 #[s, CH3-C(2)]; 2.02 #(s, CH3-COO-C(21)]; 2.10 #(s, CH3-C(12)]; 2.26 #[s, CH3-C(4)]; 2.12 #[s, CH30-C(23)]; 3.46 #[s, -N-CH3]; 4.90-5.40 #[m, O(21)H and Ct24)H]; 5.9-6.8 #[m, O(13)H, O(14)H, O(15)H, C(25)H, NH-CO-, 2 OH furan]; 7.085; 7.43 ô; 8.80 #[s, C(9)OH]; 11.65 #[s, C(5)OH and C(6)OH].

MS: 819 (M+).

EXAMPLE 5 3-[p-toluylidene-N'-methyl-hydrazono]-rifamycin SV Operating as in Example 3, but using p-toluylaldehyde instead of o-chlorobenzaldehyde, a compound of the general formula II wherein R1 = H, R2 = p-toluylidene and R3 = CH3 was obtained.

P.M.R. (CDCl3): - 0.06 #[d, CH3-C(22)]; 0.61 #[d, CH3-C(20]; 0.88 #[d, CH3-C(16)]; 1.03 #[d, CH3-C(18)]; 1.78 #[s, CH3-C(2)]; 1.07 #[s, CH3-COO-C(21)]; 2.07 #[s, CH3-C(12)]; 2.25 #[s, CH3-C(4)]; 2.33 #[s, CH3-#; 3.085 [s, CH3O-C(23)]; 3.43 #[s, CH3-N-]; 4.08-5.40 #[m, 0(21 )H and C(24)H]; 5.7-6.6 #[m, O(13)H, C(14)H, C(15)H, C(25)H]; 7.1 #[d, two aromatlc protons]; 7.43 #[d, two aromatic protons]; 7.18 #[s, -N=CH=-# 8.98 #[s, C(9)OH]; 11.48 and 12.52 5 [s and bs, C(5)OH and C(6)OH].

MS: 843 (M+).

EXAMPLE 6 3-(N'-methyl-hydrazino)-rifamycin SV.

5 g of 3-(isopropylidene-N'-methyl-hydrazono)-rifamycin S, prepared as described in Example 2, was dissolved in 40 ml of dichloromethane. The solution was cooled to 0 C and 0.4 ml of hydrazine hydrate was added dropwise under stirring. The orange solution obtained was stirred for a further 30 minutes at 0 C, washed with dilute acetic acid and then with water. The organic solution was dried on anhydrous sodium sulphate, filtered and concentrated under reduced pressure. After diluting with petroleum ether, the title compound precipitated and was collected by filtration. Yield: 3.7 g.

MS: 741 (M+).

Claims

1. A hydrazono-rifamycin derivative of the general formula I or Il as herein defined.

2. 3-(p-Nitro-benzylidene-hydrazono)-rifamycin S or SV.

3. 3-(lsopropylidene-N '-methyl-hydrazono)-rifamycin S.

4. 3-(o-Chlorobenzylidene-N '-methyl-hydrazono-rifamycin S or SV.

5. 3-(Furfurylidene-N'-methyl-hydrazono)-rifamycin S or SV.

6. 3-(p-Toluyl idene-N '-methyl-hydrazono)-rifamycin S or SV.

7. A method for the preparation of a hydrazono-rifamycin derivative of the general formula I as herein defined, the method comprising reacting a rifamycin derivative of the general formula Ill as herein defined with a hydrazone of the general formula IV as herein defined in a dipolar aprotic solvent at a temperature of from 0 C to 50 c.

8. A method according to claim 7 in which the dipolar aprotic solvent is dimethylformamide.

9. A method for the preparation of a hydrazono-rifamycin derivative of the general formula II as herein defined, the method comprising reducing of the quinone moiety of a hydrazono-rifamycin derivative prepared according to claim 8 or claim 9 by treatment with ascorbic acid or a salt thereof or with zinc and acetic acid.

10. A process for the preparation ofa hydrazono-rifamycin derivative of the general formula I or II as herein defined, the process being substantially as described herein with reference to any of Examples 1 to 5.

11. A pharmaceutical composition comprising a hydrazono-rifamycin derivative according to any of claims 1 to 6 or a hydrazono-rifamycin derivative prepared according to any of claims 7 to 10 in admixture with a pharmaceutically acceptable diluent or carrier.

12. A hydrazino-rifamycin derivative of the general formula II wherein R3 is as herein defined and the group =CUR2 is replaced by two hydrogen atoms.

13. 3-(N'-methyl-hydrazino)-rifamycin SV.

14. A method for the preparation of a hydrazino-rifamycin derivative according to claim 12, the method comprising reacting a hydrazono-rifamycin derivative according to claim 1 with hydrazine hydrate in a solventatfrom -1000to +10 C.

15. A method for the preparation of a hydrazino-rifamycin derivative according to claim 12, the method being substantially as described herein with reference to Example 6.