PL184862B1 - Novel derivatives of riphamycin with enlarged chromophore system and method of obtaining them - Google Patents

Abstract

1. New rifamycin derivatives with enlarged ohromoyor system Formula I wherein R is a group aoethyl or hydrogen and X is hydrogen or element I of group of the periodic table. 2. The method of obtaining new ryfamyoyn with an enlarged chromophore system Formula I wherein R is acetyl or hydrogen and X is hydrogen or an element of group I of the system periodic in the reaction of 3-yormylrifamycin SV or 3-yormclh-25-O-dnsaoethyloryyamcocdc SV with ammonia, against acid catalyst in a solvent organic, characterized in that the reaction is carried out with gaseous ammonia, preferably used in excess molar, at a temperature of 10 ° C to the boiling point of the solvent.

Description

The subject of the invention is new rifamycin derivatives with an enlarged chromophore system of the formula I, in which R is an acetyl group or hydrogen, and X is hydrogen or an element of group I of the periodic table, and the method of their preparation.

Rifamycins are a known group of macrocyclic antibiotics that are particularly active against gram-positive bacteria and mycobacteria, including Mycobacterium tuberculosis (tuberculosis) and Mycobacterinm Laprae (leprosy). The essence of the anti-bacterial action of rifamycins is the selective inhibition of the bacterial DNA enzyme - RNA-dependent polymerase (DDRP). In addition, some rifamycin derivatives have been found to have antiviral properties, and others have demonstrated the ability to lower cholesterol levels in the body, so the interest in medicine in this group of compounds is high.

Rifamycins have a unique ansamycin structure. A characteristic feature of their structure is the presence of an aliphatic bridge, called ansa, connecting the two positions of the aromatic chromophore system that is part of the molecule. In the structure of one of the basic rifamycins - SV rifamycin (formula 2), the chromophore is present in the typical form of a flat naphthohydroquinone system and a fused heterocyclic five-membered 4-ketooxolane ring and a multi-membered ansa chain linking C2 in the naphthohydroquinone system with C12 in the 4-ketoxolane system.

One of the directions of chemical modification of the structure of rifamycins is the synthesis of derivatives with an enlarged chromophore system. This category of compounds includes, inter alia, derivatives in which the new cyclic system, added to the original chromophore, has been formed in such a way that the introduced sequence of atoms spins the C15 carbon atom with the C3 carbon atom.

This group of compounds includes substances of formula 3, with the 1,6-dihydropyrimidine system attached to the chromophore, obtained by reductive animation of 3-formylrifamycin SV with ammonia or appropriate amines in the presence of sodium cyanoborohydride and hydrogen chloride in methanol (JL Moore, JR McCarthy, Tetrahedron Lett., 50, 4541, 1976: JR McCarthy, JL Moore. DV Wysong. CD Aldrich. J. Med. Chem., 20, 10, 1227., 1977).

In the process of oxidation of compounds of formula 3, where R = H, a quinone derivative was obtained with the 1,6-dihydropyrimidine system (formula 4) and a quinone derivative with the new system

184 862 of pyrimidine, attached to the chromophore (formula 5). Reduction of the substance of formula 5 with ascorbic acid gave the derivative of formula 6 with the 1,6-dihydro-6-hydroxypyrimidine system and not, as would be expected, the hydroquinone form of the substance of formula 5.

The novel rifamycin SV derivatives according to the invention have the structure of formula I, wherein R is acetyl or hydrogen and X is hydrogen or an element of group I of the periodic table.

The novel rifamycin SV derivatives of formula I are obtained by reacting 3-formyl rifamycin SV or 3-formyl-25-O-desacetyl rifamycin sV with gaseous ammonia, preferably used in molar excess, in the presence of a catalytic amount of an acid catalyst, preferably acetic acid. The reaction is carried out in inert organic solvents at a temperature between 10 ° C and the boiling point of the solvent. The solvents used are preferably lower aliphatic alcohols with a chain length of 1 to 5 carbon atoms, aliphatic halogenated hydrocarbons, tetrahydrofuran.

The structure of the new rifamycin SV derivative of the formula 1 wherein R is acetyl and X is Na was examined using spectroscopy and ^{1H- l3} C-NMR. In addition, a mass spectrum and an IR spectrum were made.

The chemical shifts and signal assignments in the 11- and ^B C-NMR spectra are presented in the table.

For NMR studies, samples of this substance crystallized from chloroform were used. The sample was dried under vacuum at about 50 ° C. DMSO-d6 was used as the solvent for NMR analyzes.

The assignments of proton and carbon atoms signals were made on the basis of the registered basic (1D) Ή-NMR and ^B C-NMR- (decoupled) spectra and 2D-NMR correlation spectra: Ή, 'H COZY and ^b C, * H COZY (optimized for coupling constant through one bond), as well as the correlation spectrum 1 ³ C, Ή COLOC (optimized for long-range interactions). In addition, DEPT 45, 90 and 135 spectra were performed, as well as the1 H-NMR spectrum after sample deuteration.

The spectrum of the 1 ³ C-NMR of the test compound in DMSO-d _(, signals are present on all 38 carbon atoms.

In the ^B C, 1 H COZY spectrum of this substance, the correlation signals of the following CH couplings through one bond were identified: C13-H13, C14-H14, C17-H17, C18-H18, C19-H19, C20-H20, C21-H21, C22- H22, C23-H23, C24-H24, C25-H25, C26-H26, C27-H27, C28-H28, C29-H29, C30-H30, C31-H31, C32-H32, C33-H33, C34-H34, C36-H36, C37-H37 and C6'-H6 '(the hydrogen atoms are numbered with the number of the carbon atom to which they are attached).

In the spectrum 1h, 'Η COZY, the following correlation signals of conjugated vicinal protons were found: H17-H18, H18-H19, H20-H31, H22-H23, H22-H32, H23-C23-OH, H24-H33, H25-H26, H27 -H28, H28-H29, and also the correlation signal from the long range coupling: C21-OH - C23-OH.

Correlation signals from the following long-range CH interactions were identified in the 1h COLOC spectrum of sodium salt: C1-C1-OH, C1-H6 ', C2-H6', C3-C4-OH, C3-H6 ', C4-C4- OH, C4-H6 ', C6-H14, C7-H14, C8-H14, C9-C1-OH, C10-C4-OH, C11-H13, C12-H13, C12-H29, C16-C1-OH, C16 -H30, C22-H23, C35-H36, C37-H27, as well as coupling correlation signals through one bond: C14-H14, C29-H29, C30-H30, C36-H36 and C6'-H6 '.

DEPT 135 spectrum was found and identified as the signals from all the carbon atoms in (CH) and (CH3) present in the molecule (the groups (CH ₂₎ - no). In the DEPT 45 spectrum, signals of the carbon atoms of the CH ₂ groups were not observed, which is consistent with the structure of formula 1.

The signals of the quaternary carbon atoms (C5 and C15) in the1C-NMR spectrum for which no linkages were found were assigned based on comparative data.

At 155.3, a signal for a C6 '(sp2) carbon not belonging to the aldehyde group is observed (the chemical shift of the carbon of the aldehyde group in SV 3-formylrifamycin is approximately 193.9). The spectrum ¹ H-NMR in DMSO-d6, the signal of the proton bonded to the

184,862 of the C6 'carbon appears as a singlet at 9.57 which does not disappear when the sample is deuterated. Proton H6 'in the COLOC spectrum shows a long range coupling with the following carbon atoms: C1 (150.4), C2 (134.8), C3 (113.1) and C4 (141.1).

The C15 carbon signal appears at 160.2. It is shifted by about 8-10 ppm towards the high fields with respect to the C15 signal in various rifamycin derivatives with a secondary or tertiary amide group. The shift of the C15 carbon atom signal is interpreted as a result of the formation of a new aromatic pyrimidine ring in which the C15 carbon atom is bonded with two nitrogen atoms.

The spectrum ¹ H-NMR is two singlets of low-(13.16; 16.38) of the two mobile protons (these signals disappear after deuteracji). The proton signal (13.16) shows a long-range coupling with the carbon atoms: C4 (141.1) and C3 (113.1). It is therefore the signal of the C4-OH proton. The proton signal (16.38) shows a long range coupling with the carbon atoms: C1 (150.4), C2 (134.8) and c9 (115.2). So it is the signal of the C1-OH proton. The lack of the C8-OH proton signal is due to the formation of the sodium salt.

In the mass spectrum of the sodium salt (FAB) there is an intense signal at m / e 728, corresponding to the molecular ion of the sodium salt (compound of formula 1 + Na-H) +.

The IR (KBr) spectrum of the sodium salt shows the following absorption bands: 3432 (sharp), 1712 (sharp), 1648, 1622, 1584, 1546, 1522, 1482, 1456, 1443 cm ⁴

The new rifamycin derivatives according to the invention are obtained in the following manner.

Example. A solution of 5.8 g of 3-formyl rifamycin SV (about 0.008 mol) in a mixture of chloroform (50 ml) and acetic acid (2 ml) was saturated for two minutes with ammonia gas at 40-45 ° C and stirred for about one hour. After this time, the post-reaction system was first washed with 150 ml of water, the pH of the aqueous phase was adjusted during the washing to about 7.0 with 5% sulfuric acid, and then washed with 150 ml of 5% Na2HPO4. The resulting chloroform solution of the product was dried over anhydrous sodium sulfate and, after the desiccant had been separated off, concentrated to a small volume (about 30 ml) and placed in the refrigerator for 8 hours. The purple crystalline product was filtered off, washed with cold chloroform (10 ° C) and dried under vacuum. Yield: 3.7 g of the sodium salt of the product.

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14

Chemical shifts and signal assignments in the H-NMR and C-NMR spectra of the substance of formula I, where R is acetyl and X is Na (analysis solvent: DMSO-d6)

Atom H. &, ppm Atom C &, ppm Ν3Ή (amide) - 1 150.4 OH-1 16.38 2 134.8 OH-4 13.16 3 113.1 OH-8 - 4 141.1 H-13 1.67 5 98.1 H-14 1.95 6 173.0 H-17 6.28 7 100.1 H-18 6.35 8 185.5 H-19 5.83 9 115.2 H-20 2.12 10 113.6 H-21 3.50 11 183.4 OH-21 4.47 12 108.8 H-22 1.13 13 22.2 H-23 2.79 14 7.4 OH-23 4.32 15 160.2 H-24 1.51 16 135.5 H-25 5.04 17 130.0 H-26 1.13 18 126.4 H-27 3.23 19 137.1 H-28 4.92 twenty 38.1 H-29 6.20 21 72.2 H-30 1.98 22 37.4 H-31 0.85 23 75.8 H-32 0.30 24 32.9 H-33 0.81 25 73.0 H-34 -0.37 26 40.2 H-36 2.28 27 76.4 H-37 2.91 28 29 thirty 31 32 33 34 35 36 37 116.8 142.4 22.1 18.2 7.7 11.6 8.4 169.7 20.6 55.8 H-6 ' 9.57 6 ' 155.3

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W2ÓR 1

CARRIAGE 2

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W + ÓR M

U-Ζόβ. 5

Pattern. 6

Publishing Department of the UP RP. Circulation of 50 copies

Price PLN 2.00.

Claims (4)

Patent claims 1. New derivatives of rifamycins with an enlarged chromophore system of formula I, in which R is an acetyl group or hydrogen, and X is hydrogen or an element of group I of the periodic table. 2. The method of obtaining new rifamycins with an enlarged chromophore system of formula 1, in which R is an acetyl group or hydrogen, and X is hydrogen or an element of group I of the periodic table, by the reaction of 3-formyl rifamycin SV or 3-formyl-25-O-desacetyl rifamycin SV with ammonia, in the presence of an acid catalyst, in an organic solvent, characterized in that the reaction is carried out with gaseous ammonia, preferably used in molar excess, at a temperature from 10 ° C to the reflux temperature of the solvent. 3. The method according to p. A process as claimed in claim 2, characterized in that acetic acid is used as the catalyst. 4. The method according to p. The process of claim 2, characterized in that aliphatic alcohols with a chain length of 1 to 5 carbon atoms, aliphatic halogenated hydrocarbons, tetrahydrofuran are used as the solvent.