GB2084997A - Triazino Rifamycins - Google Patents

Abstract

Triazino-rifamycins of the general formula I: <IMAGE> wherein R1 and R2=H, C1-C5 alkyl, C3-C6 cycloalkyl, aryl, or 5- or 6-membered heterocyclyl ring with 1 or more N, O and/or S atoms or R1+R2+the C atom to which they are attached=5- or 6- membered ring; R3=H, alkyl, cycloalkyl, aryl or substituted aryl, and the corresponding reduced derivatives in which the quinone moiety is replaced by a hydroquinone moiety have antibacterial activity on gram + and - bacteria and on Mycobacterium Tuberculosis. They may be formulated as pharmaceutical compositions.

Description

SPECIFICATION Triazino Rifamycins The invention relates to rifamycin derivatives having high antibacterial activity both on Grampositive and Gram-negative bacteria and on Mycobacterium Tuberculosis.

The invention provides triazino-rifamycins having the general formula I

wherein each of R1 and R2 independently represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms, a cycloalkyl group having from 3 to 6 carbon atoms, an aryl group or a 5 or 6 membered heterocyclic ring having one or more nitrogen and/or oxygen and/or sulphur heteroatoms, or R, and R2 together with the carbon atom to which they are attached form a 5 or 6 membered ring, R3 represents hydrogen atom, an alkyl, cycloalkyl, aryl or substituted aryl group and further provides their reduced derivatives having the general formula II.

If R1 and R2 together with the carbon atom to which they are attached form a 5 or 6 membered ring, this ring is preferably a carbocyclic ring such as a cyclohexyl ring or a heterocyclic ring containing a nitrogen atom, such as a piperidine ring.

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

in which R3 is as above defined R4 represents a hydrogen atom, an alkyl group having from 1 to 5 carbon atoms or an aryl group and R5 represents an alkyl group having from 1 to 5 carbon atoms, a cycloaikyl 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 R4 and R5 together with the carbon atom to which they are attached represent a cycloalkyl ring or a heterocyclic ring containing a nitrogen atom, described in our British Patent Appiication Number 8026587) is reacted in a dipolar aprotic solvent at a temperature from 200C to 800C with a carbonyl compound of the general formula R1 . COR2 in which R1 and R2 are as above defined.

The invention also provides another method for the preparation of triazino-rifamycins of the general formula 1, according to which a compound having the general formula V

in which X represents a hydrogen or halogen atom is reacted in a dipolar aprotic solvent at a temperature from 200C to 800C with a hydrazone of the general formula IV

in which Fl1, R2 and R3 are as above defined.

The compounds of the general formula II are obtained according to the invention by reducing the quinone moiety of the compounds of the general formula I with a suitable reducing agent such as ascorbic acid or its salts or zinc and acetic acid.

The starting compound of the general formula V in which X represents a hydrogen atom is well known under the name "rifamycin S". The starting compound of the general formula V 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, J.Am. Chem. Soc. 97, 6254 and J. Am. Chem. Soc. 98(22)7064.

The invention is illustrated by the following Examples.

Example 1 II(R1=H, R2=cyclohexyl, R3=CH3) 3.5 g of 3-bromorifamycin S and 0.85 g of N'-methylisopropylidene-hydrazine were dissolved in 20 ml of dimethylformamide and allowed to react at room temperature for 30 minutes. 1.2 ml of cyclohexanecarboxaldehyde, 0.1 g of zinc and 2 mlof acetic acid were added and the mixture was stirred at 400C for 20 minutes. 100 ml of dichloromethane was added, and the solution was washed with aqueous sodium bisulphite and then with water. After drying with anhydrous sodium sulphate and filtering, the dichloromethane solution was evaporated to dryness. The crude residue was dissolved in 30 ml of methanol, 300 ml of diethyl ether was added and the solution was extracted with 5% sodium bicarbonate solution.The aqueous phase was washed with diethyl ether and then extracted with ethyl acetate. The organic phase was washed with water, dried with anhydrous sodium sulphate, filtered and evaporated to dryness.

Yield: 1.5 g.

P.M.R. (CEl3): 0.02 a [d, CH3-C(22)]; 0.65 a [d, CH3-C(20)]; 0.91 d[d, CH3-C(1 6)]; 1.06 # [d, CH3-C( 18)]; 1.82 ô [s, CH3-C(2)]; 2.08 a [s, CH3-C00-C(2 1). CH3-C( 12) and CH3- C(4)]; 1.0-2.3 a [m, aromatic protons]; 3.15 a [s, CH30-C(23)j; 3.22 a [s, CH3-N]; 4.90-5.30 a [m, C(21) H and C(24) H)]; 5.90-6.80 a [m, C(13) H, C(14) H, C(1 5)H. and C(25)H]; 8.37 # [s,HO-C(9)]; 11.79 # (s, HO-C(5) and HO-C(6)].

MS: 835 (M+).

Example 2 II (R1=H, R2=n-propyl, R3=CH3) Following the method described in Example 1, but using n-butyraldehyde in place of cyclohexanecarboxaldehyde. 1.7 g of the title compound was obtained.

P.M.R. (CDCl3): 0.07 # [d, CH3-C(22)]: 0.64 # [d, CH3-C(20)]; 0.90 # [d, CH3-C(16)]; 0.04 # [t, CH3-C(H2)]; 1.07 # [d, CH3-C(18)]; 1.83 # [s, CH3-C-(2)]; 2.08 # [s, CH3-COO C(21) and CH3-C(12)]; 2.23 # (s, CH3-C(4)]; 3.13 # [s, CH3O-C(23)]; 3.30 # [s, CH3

0-5.30 S [m, 0(21 )H and C(24)H]; 5.90-6.80 S [m, 0(1 3)H, 0(1 4)H, 0(1 5FH and 9.07 # [s, HO-C(9)]: 11.47 # [s, HO-C(5) and HO-C(6)].

MS: 795 (M+).

Example 3 11 (R1=H,R2'=i-propyl, R3=CH3) Following the method described in Example 1, but using isobutyraldehyde instead of cyclohexanecarboxaldehyde, the title compound was obtained.

P.M.R. (CDCl3):-0.12 # [d, CH3-C(22)]; 0.61 # [d, CH3-C(20)]; 0.86 # [d, CH3-C(16)]; 1.02 S [s, CH3-C(18) and

1.80 # [s, CH3-C(2)]; 2.05 # [s, -CH3-COO-C(21) and CH3-C(12)]; 2.22 # [s, CH3 C(4)]; 3.08 # [s, CH3O-C(23)]; 3.25 # [s, CH3-N]; 4.90-5.30 # [m, C(21) H and C(24) H]; 5.90-6.60 # [m, C(13)H, C(14)H, C(15)H and C(25)H]; 9.30 # [s, HO-C(9)]; 11.40 and 11.67-1267 # [s and bs, HO-C(5) and HO-C(6)].

MS: 795 (M+).

Example 4 11 (R1=H, R2=n-pentyl. R3=CH3) Following the method described in Example 1, but using hexanal instead of cyclohexanecarboxaldehyde, the title compound was obtained.

The title compound was also obtained by reacting 3-bromo-rifamycin S with hexanal methylhydrazone.

P.M.R.(CDCl3):-0.10 # [d, CH3-C(22)]; 0.62 # [d, CH3-C(20)]; 0.87 # [d, CH3-C(16)]; 0.98 # [t, CH3-C(H2)-]; 1.04 # [d, CH3-C(18)]; 1.80 # [s CH3-C(2)]; 2.07 # [s, -CH3 COO-C(21) and CH3-C(12)]; 2.24 # [s, CH3-C(4)]; 3.08 # [s, CH3O-C(23)]; 3.27 # [s, CH3-N#]; 4.90-5.30 # [m. C(21) H and C(24) H]; 5.90-6.80 # [m, C(13)H, C(14)H C(15)H and C(25)H]; 9.l9 # [s, HO-C(9)]; 11.44 and 12.55 # [s and bs, HO-C(5) and HO-C(6)].

MS: 823 (M+).

The compounds obtained according to Examples 1 and 3 have been tested for their antibacterial activity and it has been found that they are wide spectrum ansamycin antibiotics. Their antibacterial activity in vitro, measured as MIC in solid medium (twofold dilution technique) was comparable to that of rifampicin on mild strains of G+ and G- bacteria and on Mycobacterium tuberculosis H37Rv. Their inhibiting activity on two mutant strains (S. aureus and E. coli) resistant to Rifampicin (MIC > 200 mcg/ml) was higher than that of the reference compound 20-200 mcg/ml).

Claims (11)

Claims

1. A triazino-rifamycin having the general formula I as defined herein, or a reduced derivative thereof having the general formula II as defined herein.

2. A triazino-rifamycin or reduced derivative thereof wherein R1 and R2 together with the carbon atom to which they are bound represent a 5 or 6 membered heterocyclic ring containing a nitrogen atom.

3. The compound of the general formula II wherein R1 represents a hydrogen atom, R2 represents a cyclohexyl group and R3 represents a methyl group.

4. The compound of the general formula ll wherein R1 represents a hydrogen atom, R2 represents a u-propyl group and R3 represents a methyl group.

5. The compound of the general formula II wherein R1 represents a hydrogen atom, R2 represents an i-propyl group and R3 represents a methyl group.

6. The compound of the general formula II wherein R1 represents a hydrogen atom, R2 represents an n-pentyl group and R3 represents a methyl group.

7. A method for the preparation of a triazino-rifamycin of the general formula I as herein defined, the method comprising reacting a hydrazono-rifamycin of the general formula Ill as herein defined in a dipolar aprotic solvent at a temperature of from 200C to 800C with a carbonyl compound of the general formula R.COR2 wherein R1 and R2 are as herein defined.

8. A method for the preparation of a triazino-rifamycin of the general formula I as herein defined, the method comprising reacting rifamycin S or a 3-halo-rifamycin S of the general formula V as herein defined in a dipolar aprotic solvent at a temperature of from 200C to 800C with a hydrazone of the general formula IV as herein defined.

9. A method for the preparation of a triazino-rifamycin of the general formula II as herein defined, the method comprising reducing a triazino-rifamycin of the general formula I as herein defined with ascorbic acid, with a salt thereof, or with zinc and acetic acid.

10. A method for the preparation of a triazino-rifamycin of the general formula II as herein defined, the method being substantially as described herein with reference to any of the Examples.

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