DE1695384B - Rifamycin SV derivatives and a process for their preparation - Google Patents

Description

in which R is a hydrogen atom, a lower alkyl or hydroxyalkyl radical, benzyl or phenyl ^, radical. R 'a lower alkyl radical, R "a lower alkyl or alkoxy radical. an amino group, a lower alkylamino or dialkylamino group or a Is phenylamine.

2.1 '.2' - Dimethyl - 3 '- carbomethoxypyrrolo [3.2-c] -4-deoxyrifamycin SV.

3. 2 '- methyl - 3' - carba'thoxypyrrolo [3,2 - c] 4-dcoxyrifamycin SV.

4.1 '^' - Dimethyl-S'-dimethylcarbamylpyrrolo- [3,2-c] -4-deoxyrifamycin SV.

5. r, 2'-Dimethyl-3'-carbäthoxypyn-olo [3,2-c] ·· 4-deoxyrifamycin.

6. Process for the preparation of the rifamycin SV derivatives according to claim 1, characterized in that that one rifamycin S of the formula

HO

H ₃ C CH ₃

CH ₃ O

H ₃ CO

with an at least equimolecular amount of a compound of the general formula

R '

R - NH - C = CH - COR "

reacted in an organic inert solvent at room temperature for 7 to 70 hours.

The invention relates to rifamycin SV derivatives of the general formula

H ₃ C CH ₃

CH ₃ O

H ₁ C

in which R is a hydrogen atom, a lower alkyl or alkylamino or dialkylamino group or a

Hydroxyalkyl radical. a henzyl or phenyl radical. R 'is phenylamino, and a process for their

a lower alkyl radical and R "a lower alkyl production, or alkoxy, an amino group, a lower one

The process of making the new compounds consists in having rifamycin S of the formula

HO

CH

CH ₃ O

Compound of the general formula
R '

R - NH - C = CH - COR "

II

with an at least equimole'.cular amount of one in an organic inert solvent 7
Reacts 70 hours at room temperature.

The new rifamycins are usually well crystallized substances; they are more stable than the other rifamycins and have a much lighter color - straw-colored to amber - than the stem compounds. As a rule, they do not have a well-defined melting point and decompose above 150 ^° C.

They are in chloroform, methanol, ethanol, and many other common organic solvents soluble; they are sparingly soluble in water at a pH value close to neutral. The invention Compounds have a high bactericidal effect.

Comparative experiments which were carried out on mice infected with Staphylococcus aureus gave the following ED ₅₀ values. Tetracycline, which is widely used in Staphylococcus infections, was used as a comparison substance.

connection vclin R " ED _5n . I. orally ^ lousy LD ₅₀ . orally mouse i. p. R. R- OCH ₃ 1.63 subcutaneous 1800 950 CH ₃ CH ₃ OC ₂ H ₅ 1.62 0.81 1450 680 H CH ₃ N (CH ₃ ), 13.00 1.42 > 3000 1050 CH ₃ CH ₃ OC ₂ H ₅ 3.25 3.9 1475 660 CH ₃ CH ₃ OC (CH ₃ ), 10 2.14 > 3000 960 HC ₃ H ₇ CH ₃ OC (CH ₃ ), 2.32 8th 2450 690 CH ₃ CH ₃ OCH, 0.76 4.92 "630 985 H CH ₃ OC ₂ H ₅ 5.66 0.61 > 3000 970 CH ₃ n-C, H ~ OCH ₃ 3.25 4.93 1890 860 CH ₅ CH, NHC ₁₁ H ₅ 11.8 2.83 > 3000 1300 CH ₃ CH ₃ CH ₃ 4th 12th 1760 760 Q ₁ H ₅ CH, CH, 8.3 2.3 2210 923 Q ₁ H ₅ CH ₂ CH, CH, 5.2 6.1 1660 740 HOC ₂ H ₄ CH, 9.3 3.25 1950 250 Tctrac 2.6

The substances can be used for therapeutic purposes administered both parenterally and locally.

The diseases successfully treated with the compounds according to the invention are such. caused by pathogenic microorganisms. / .. B. Infectious diseases, such as pneumonia. Abscesses, phlegmon. Boil. Ear infection. Inflammation of the bone marrow. Bladder catarrh. Inflammation of the gallbladder and infections.

The invention is illustrated by the following examples.

At s ρ i e I 1 <*>

r ^ '- Dimethyl-S'-carbomylhoxypyrrolo- [3,2-c] -4-deoxyrifamycin SV

A suspension of 1.4 g (0.0020 mol) rifamycin S in 16 ecm methanol gives 0.300 g (0.0023 mol) f> 5 Methyl 3-methyl-amino-crotonate, which is dissolved in 4 ecm of methanol is dissolved, added. The suspension is stirred for a few minutes until it is completely dissolved.

After the solution 15 hours at room temperature stand, it is concentrated in a vacuum to half the volume. Large crystals will soon set up away; after the solution has been cooled at 4 to 5 ° C for 24 hours, the precipitation is complete. the Lemon yellow crystals of the final compound are filtered off with a small amount of cold methanol washed and dried at 45 C in a vacuum; Yield: 1.23 g (75%); M.p. 210 to 212 "C (decomposition).

Analysis: C ₄₃ H ₅₄ N ₂ Oi ₃ (molecular weight: 806.92). Calculated .. C 64.00. H 6.75, N 3.47%;
found ... C 63.60, H 6.81. N 3.39%.

Adsorption spectrum:

?. _max = 238 mix. E !? "= 488

/. = 270 ma. E | "= 377

L = 31ImJx. Eli = 390

;., "" = 425 mix. E ¹ , * = 147

Thin layer chromatography on silica level + 3% citric acid; Acetone: chloroform = 1: 1; Rf = 0.7 (yellow spot),

Example 2

2'-methyl-3'-carbethoxypyrrolo [3,2-c] -4-deoxyrifamycin SV

, S is the ECM 125 in methanol is suspended an amount of 7.0 g (0,010MoI) rifamycin, a solution of 2.0 g (0.015 mol) is ethyl 3-amino-crotonate added in 20 cc of methanol under stirring until the complete resolution is achieved. After standing at 20 to 22 ° C for 70 hours, the solution is concentrated to a quarter of its volume. The liquid is poured into 350 ecm of a 2% aqueous ascorbic acid solution with stirring in order to convert any rifamycin S that may still be present into the corresponding reduced form, ie into rifamycin SV. The pH is adjusted to 2 to 3 and the rifamycins are extracted with 400 ecm of ethyl acetate. The organic phase is dried with powdered sodium sulfate, concentrated to dryness in vacuo and the residue is taken up in 10 ecm chloroform. The solution is chromatographed on a silica gel and eluted with a chloroform-ethanol mixture in a ratio of 9: 1. The first 100 ecm of the colored fraction are discarded, while the next three fractions of 100 ecm each are combined and evaporated to dryness. The residue is dissolved in 30 to 35 ecm of methanol. From this solution, which is cooled for 2 to 3 hours at 0 to 5 C, the end compound precipitates in the form of pale amber-colored crystals, which are separated off, washed with methanol and dried in vacuo at 40 to 45 C; Yield: 4.2g (52%); F. 162 to 166 C (decomposition).

35

Analysis: ^ 4th, H ₅₄ N ₂ O ₁₃ (molecular weight 806.92). Thin-layer chromitography on silica gel; Acetone-chloroform 1: 1; Rf ~ 0.4 (yellow spot).

Calculated .. C 64.00. H 6.75. N 3.47%: found ... C 63.38. H 6.66, N 3.60%.

Absorption spectrum:

>, "," = 232 ma, i: \\ = 559
,. "," = 310 ma, El '; = 334
/. _m " _r = 422 ma. E '" I = 147

45

Example 3

1,2'-Dimethyl-3'-dimethylcarbarnylpyrrolo- [3,2-c] -4-deoxyrifamycin SV

To a suspension of 1.6 g (0.002 mol) of rifamycin S in 25 ecm of methanol, 0.370 g (0.0028 mol) of S-methylaminocrotonic acid dimethylamide, dissolved in 5 ecm of methanol, are added with stirring until complete dissolution is achieved. The solution is allowed to stand for 26 hours at 20 to 22 "C and then concentrated ecm in vacuo to about 20. After standing overnight at about 5 ^a C light yellow crystals of the final compound settle out. The crystals are separated, gewaschtn with methanol and dried in vacuo dried at 40 to 45 ° C; yield: 1.58 g (80.0%); mp 183 to 188 ° C (decomposition).

Analysis: C ₄₄ H ₅₇ N ₃ O ₁₂ (molecular weight 819.96).

Calculated. C 64.45, H 7.01, N 5.12%; found ... C 63.93, H 7.10, N 5.20%.

Absorption spectrum:

_ai = 242 mil, egg ^ = 445

'• ma.

'■ max = 310

m l = 344 /. "," = 425 ma, ElX = 151

Thin layer chromatography on silica gel + 3% citric acid; Acetone + chloroform = 1: 1; Rf ~ 0.55 (lemon colored spot).

40 Examples 4 to 5

Following the procedures outlined in Examples I through 3, those listed in Table II were made Compounds prepared whose UV absorption spectra are given in Table III:

Table II

Ikpiel

CH,

n-CjH,

CH ₃

CH,

C ₂ H,

CH,

n-CjH,

CH,

C ₆ H,

CJ) ₅ CH,

IK) C ₂ H ₄

connection

R '

CH,

CH,

CH,

CH,

nC, H ₇

CH,

CH.,

CFI,

CH,

CH,

CH.,

CH,

R "

OC ₂ H ₅

OC ₂ H ₅

OC (CH,),

OCH,

OC ₂ H ₅

OCH,

NHCJI,

CH,

CH,

CH,

CH,

CH,

I ormcl

C ₄ Ji ₆₀ N ₂ O ₁ , C ₄ Ji ₆₀ N ₂ O ₁ , C ₄₂ H ₅₂ N ₂ O ₁ , C ₄₆ H _6n N ₂ O ₁ , C ₄₄ H ₅₆ N ₂ O ₁ , C ₄ JI ₅₇ N ₃ O ₁₂ C ₄₅ H ₅ ^ N ₂ O ₁₂ C ₄ JI ₅₄ N ₂ O ₁₂ C ₄ JI ₅₆ N ₂ O ₁₂ CH ₅₁₁ N ₂ O ₁₂ C ₄₄ H ₅₆ N ₂ O ₁ , melting point, C.
l / .erse'znng

i () 9 to 172
202 to 205
225 to 228
179 to 181
200 to ΙΓ4
204 to 210
190 to 200
186 to 188
255 to 256
210 to 215
183 to 185
214 to 218

calculated ' C. Il N found % C. H 64.37 6.88 3.41 64.60 6.S4 65.08. 7.12 3.30 64. ΊΟ 6.99 65.08 7.12 3.3G 64.63 7.18 63.62 6.61 3.53 62.40 6.8H 65.08 7.12 3.30 64.80 7.40 64.37 6.87 3.41 63.68 7.17 66.42 6.62 4.84 65.78 6.78 66.00 7.14 3.42 65.69 7.28 65.29 6.89 3.54 65.22 6.92 67.59 6.61 3.28 67.51 6.52 67.88 6.74 3.23 67.79 6.36 64.37 6.88 3.41 64.49 6.80

3.2 (1 3.50 3.36 3.68 3.27 3.07 4.49 3.60 3.70 3.60 3.59 3.30

7th ) 1 695 384 S. Table II! IV-Ahsorpli MKspecs example 238 B. IO 4th 270 487 310 358 425 282 150 238 15th 5 270 479 310 356 425 378 20th 240 151 310 452 6th 425 352 233 139 25th 7th 310 565 423 364 269 135 8th 309 347 425 375 141

example

10

14th

15th

I Λ -AhsnrptH misspectra

310 390 425 157 310 362 425 139 240 450 270 362 307 360 428 157 240 153 278 301 311 370 428 153 240 495 276 312 311 397 428 165

2333

Claims (1)

Patent claims:
1. Rifamycin SV derivatives of the general formula H ₃ C CH ₃ CH ₃ O H ₃ CO