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DE1795736C3 - Rifamycin SV derivatives and processes for their preparation - Google Patents

Rifamycin SV derivatives and processes for their preparation

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Publication number
DE1795736C3
DE1795736C3 DE19651795736 DE1795736A DE1795736C3 DE 1795736 C3 DE1795736 C3 DE 1795736C3 DE 19651795736 DE19651795736 DE 19651795736 DE 1795736 A DE1795736 A DE 1795736A DE 1795736 C3 DE1795736 C3 DE 1795736C3
Authority
DE
Germany
Prior art keywords
rifamycin
preparation
derivatives
processes
formylrifamycin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
DE19651795736
Other languages
German (de)
Other versions
DE1795736B2 (en
DE1795736A1 (en
Inventor
Nicola Cusano Milanino; Sensi Piero; Mailand Maggi (Italien)
Original Assignee
Ausscheidung aus: 17 95 567 Gruppo Lepetit S.p.A., Mailand (Italien)
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB30327/64A external-priority patent/GB1109631A/en
Application filed by Ausscheidung aus: 17 95 567 Gruppo Lepetit S.p.A., Mailand (Italien) filed Critical Ausscheidung aus: 17 95 567 Gruppo Lepetit S.p.A., Mailand (Italien)
Priority claimed from DE1795567A external-priority patent/DE1795567C3/en
Priority claimed from FR63914A external-priority patent/FR5518M/fr
Publication of DE1795736A1 publication Critical patent/DE1795736A1/en
Publication of DE1795736B2 publication Critical patent/DE1795736B2/en
Application granted granted Critical
Publication of DE1795736C3 publication Critical patent/DE1795736C3/en
Expired legal-status Critical Current

Links

Description

C22H36O5 C 22 H 36 O 5

-CO-CO

(D(D

1515th

CH = NORCH = NOR

in der R Wasserstoff, die Methyl- oder die 2-Morpholinoäthylgruppe darstellt.in which R represents hydrogen, the methyl or the 2-morpholinoethyl group.

2. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man 3-Formylrifamycin-SV der Formel Il
C22H311O5 CO
2. Process for the preparation of the compounds according to claim 1, characterized in that 3-formylrifamycin SV of the formula II
C 22 H 311 O 5 CO

NHNH

CH = OCH = O

nach an sich bekannten Methoden mit einer Verbindung der allgemeinen Formel IIIby methods known per se with a compound of the general formula III

H2NOR (III)H 2 NOR (III)

umsetzt, in der R die oben angegebene Bedeutung hat.converts, in which R has the meaning given above.

3. Therapeutische Zubereitung, bestehend aus einer oder mehreren Verbindungen nach Anspruch 1 und üblichen Hilfs- und/oder Trägerstoffen. 3. Therapeutic preparation consisting of one or more compounds according to claim 1 and customary auxiliaries and / or carriers.

Gegenstand der Erfindung sind
Derivate der allgemeinen Formel I
The subject of the invention are
Derivatives of the general formula I

Rifamycin-SV- 30 dung der allgemeinen Formel IIIRifamycin-SV- 30 preparation of the general formula III

H1NORH 1 NOR

C22H36O5 C 22 H 36 O 5

COCO

(D(D

CH = NORCH = NOR

in der R Wasserstoff, die Methyl- oder die 2-Morpholino-äthylgruppe darstellt.in which R is hydrogen, the methyl or the 2-morpholino-ethyl group represents.

Die Erfindung betrifft auch ein Verfahren zur Herstellung dieser neuen Antibiotika, das darin besteht, daß man 3-Formylrifamycin-SV der Formel IIThe invention also relates to a process for the preparation of these new antibiotics, which consists in that 3-formylrifamycin-SV of the formula II

C22H36O5 COC 22 H 36 O 5 CO

NHNH

CH = OCH = O

(II)(II)

nach an sich bekannten Methoden mit einer Verbinumsetzt, in der R die oben angegebene Bedeutung hat. In der deutschen Patentschrift 10 89 513 ist diereacted by methods known per se with a compound in which R has the meaning given above. In the German patent 10 89 513 is the

Herstellung des Antibiotikums Rifamycin durch Züchtung von Streptomyces mediterranei ATCC 13 685 beschrieben. In diesem Patent ist auch angegeben, daß Rifamycin aus einem Gemisch antibiotisch wirksamer Substanzen besteht. Eine dieser Substanzen, Rifa-Production of the antibiotic rifamycin by cultivating Streptomyces mediterranei ATCC 13 685 described. This patent also states that rifamycin is more antibiotically effective from a mixture Substances. One of these substances, Rifa-

mycin-B mit der Summenformel C39H49NO14, stellt eine zweibasische Säure (pH l'/2 = 2,8; pH 2'/2 = 6,7) dar, wobei eine der Säuregruppen eine Carboxylgruppe ist. Eine der besonderen Eigenschaften dieses Antibiotikums besteht darin, daß seine Wirksamkeitmycin-B with the empirical formula C 39 H 49 NO 14 , represents a dibasic acid (pH 1 '/ 2 = 2.8; pH 2' / 2 = 6.7), one of the acid groups being a carboxyl group. One of the special properties of this antibiotic is that its effectiveness

zunimmt, wenn es in Wasser gelöst wird, d. h., es wandelt sich in eine andere Substanz mit höherer antibakterieller Wirksamkeit um. Das aktivere, als Rifamycin-S bezeichnete Produkt hat die Summenformel C37H45NO12. Es kann durch milde Reduktion in einincreases when it is dissolved in water, that is, it turns into another substance with higher antibacterial effectiveness. The more active product, known as rifamycin-S, has the empirical formula C 37 H 45 NO 12 . It can be turned into one by mild reduction

weiteres Antibiotikum der Rifamycinklasse, das Rifamycin-SV (C37H47NO12), umgewandelt werden. Das Verfahren zur Herstellung von Rifamycin-SV besteht in der Oxydation von Rifamycin-B zu Rifamycin-O, der Hydrolyse von Rifamycin-0 unter AbspaltungAnother antibiotic of the rifamycin class, the rifamycin-SV (C 37 H 47 NO 12 ), can be converted. The process for the production of rifamycin-SV consists in the oxidation of rifamycin-B to rifamycin-O, the hydrolysis of rifamycin-0 with cleavage

von Glykolsäure zu Rifamycin-S und der Reduktion von Rifamycin-S zu Rifamycin-SV. Sowohl Rifamycin-S als auch Rifamycin-SV weisen keine Carboxylgruppe auf. Sie wird während der Aktivierungsstufe in Form von Glykolsäure abgespalten.from glycolic acid to rifamycin-S and the reduction of rifamycin-S to rifamycin-SV. Both rifamycin-S as well as rifamycin-SV do not have a carboxyl group. It will be used during the activation stage split off in the form of glycolic acid.

Die Struktur der Rifamycine ist in Experientia. Bd. 20 (1964), S. 336,veröffentlicht.The structure of the rifamycins is in experientia. Vol. 20 (1964), p. 336.

Die neuen Derivate des Rifamycins-SV zeichnen sich durch eine ausgeprägte antibakterielle Wirkung in vitro aus, wie aus der nachfolgenden Tabelle 1 hervor-The new derivatives of Rifamycins-SV are characterized by a pronounced antibacterial effect in in vitro, as shown in Table 1 below.

geht, in der die kleinsten Hemmkonzentrationen gegenüber pathogenen Mikroorganismen in ;Vccm angegeben sind. R hat dabei die oben angegebene Bedeutung. in which the smallest inhibitory concentrations against pathogenic microorganisms are given in; Vccm are. R has the meaning given above.

Tabelle 1Table 1

Verbin dung Nr.Connect manure No.

M. aureusM. aureus

S.S.

pyog.pyog.

S.S.

face.face.

B.B.

subt.subt.

Pro- Eicoli Kleb, teus pneuPro-Eicoli adhesive, teus pneu

Pseudom. H37R aereataPseudom. H 37 R aereata

—H
-CH3
-H
-CH 3

0,02 0,01 0,0005 0,010.02 0.01 0.0005 0.01

0,1 0,10.1 0.1

0,005 0,010.005 0.01

-CH2CH2-N O 0,005 0,02 0,05 0,2-CH 2 CH 2 -NO 0.005 0.02 0.05 0.2

10 5
2 5
10 5
2 5

10 510 5

20
10
20th
10

10
10
10
10

2020th

5
0,05
5
0.05

0,50.5

Die ausgezeichnete antibiotische Wirksamkeit der in vitro untersuchten Verbindungen wurde durch In-vivo-Versuche an mit Staphylococcus aureus infkierten Mäusen bestätigt, wobei diese Versuche gemäß dem von Arioli et ai. in Arzneimittel-Forschung Bd. 17, 1967, S. 523, beschriebenen Verfahren durchgeführt wurden. Diese Versuche zeigen, daß die erfindungsgemäßen Verbindungen dem Rifamycin-SV überlegen sind und nur geringe Toxizität besitzen.The excellent antibiotic activity of the compounds examined in vitro was confirmed by in vivo tests on mice infected with Staphylococcus aureus, these experiments according to the method of Arioli et ai. in Arzneimittel -forschung Vol. 17, 1967, p. 523, methods described were carried out. These experiments show that the compounds according to the invention are superior to rifamycin-SV and only have low toxicity.

Tabelle 2Table 2

Verbindung
XI1.
connection
XI 1 .
R = R = Λ
O
y
Λ
O
y
ED50, oralED 50 , oral ED50, s. c.ED 50 , sc LD50, i.p.LD 50 , ip LD50, oralLD 50 , oral
(mg/kg)(mg / kg) (mg/kg)(mg / kg) (mg/kg)(mg / kg) (mg;kg)(mg; kg) 11 HH 5,665.66 2,462.46 365365 - 22 CH3 CH 3 0,530.53 0,870.87 152152 · —- 33 CH2-CH2-N^CH 2 -CH 2 -N ^ 44th 44th 378378 - Rifamycin-SVRifamycin SV 260260 17,717.7 625625 21202120

Die erfindungsgemäßen Verbindungen haben auch antituberkulöse Wirkung, wie bei Versuchen, die gemäß dem von P a 11 a η g a et al. in Arzneimittel-Forschung, Bd. 17, 1967, S. 529, beschriebenen Verfahren durchgeführt wurden, festgestellt wurde.The compounds according to the invention also have an antitubercular effect, as in experiments according to that of P a 11 a η g a et al. in drug research, Vol. 17, 1967, p. 529, was carried out.

Das folgende Beispiel erläutert das erfindungsgemäße Verfahren.The following example explains the method according to the invention.

45 Beispiel 45 example

3-Formylrifamycin-SV-oxim3-formylrifamycin SV oxime

Ein Gemisch aus 7,3 g 3-Formylrifamycin-SV, 200 ecm Tetrahydrofuran, 27 ecm Pyridin und 0,75 g Hydroxylaminhydrochlorid wird 3 Stunden bei Raumtemperatur gerührt. Dann wird es in etwa 21 Eiswasser gegossen, mit Salzsäure angesäuert und mit Äthylacetat extrahiert. Der organische Extrakt wird auf etwa 50 ecm eingeengt und gekühlt. Die ausgefallenen orangefarbenen Kristalle werden gesammelt und getrocknet. A mixture of 7.3 g of 3-formylrifamycin SV, 200 ecm of tetrahydrofuran, 27 ecm of pyridine and 0.75 g of hydroxylamine hydrochloride are used for 3 hours at room temperature touched. Then it is poured into about 21 ice water, acidified with hydrochloric acid and with ethyl acetate extracted. The organic extract is concentrated to about 50 ecm and cooled. The unusual orange crystals are collected and dried.

Ausbeute 5,7g (76%); F. = 190 bis 1930C. Das UV- und das sichtbare Spektrum zeigen Maxima bei 323ΐημ(Ε!* = 273,9) und 468 πΐμ (E1,* = 179,4).Yield 5.7g (76%); F. = 190 to 193 0 C. The UV and the visible spectrum show maxima at 323ΐημ (Ε! * = 273.9) and 468 πΐμ (E 1 , * = 179.4).

In gleicher Weise wurde das O-Methyloxim erhalten; Fp. = 240bis250°C(Zers.);AmnJt = 325(EJl = 298); 470(Ej* = 198); ferner das O-[2-Morpholinoäthyl]-oxim; Fp. = 157 bis 162° C (Zers.); ληαχ = 325 (EJ* = 253,2); 465 bis 470 (EJ *m = 164,3).The O-methyl oxime was obtained in the same way; Mp = 240-250 ° C (dec.); A mnJt = 325 (EJl = 298); 470 (Ej * = 198); also the O- [2-morpholinoethyl] oxime; M.p. = 157-162 ° C (dec.); λ ηαχ = 325 (EJ * = 253.2); 465 to 470 (EJ * m = 164.3).

Claims (1)

17951795 ftft 736736 Patentansprüche:
1. Rifamycin-SV-Derivate der allgemeinen
Patent claims:
1. Rifamycin SV derivatives of the general
Formel IFormula I.
DE19651795736 1964-07-31 1965-07-28 Rifamycin SV derivatives and processes for their preparation Expired DE1795736C3 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB3032764 1964-07-31
GB30327/64A GB1109631A (en) 1964-07-31 1964-07-31 Derivatives of rifamycin sv
DE1795567A DE1795567C3 (en) 1964-07-31 1965-07-28 Rifamycin SV derivatives and processes for their preparation
FR63914A FR5518M (en) 1964-07-31 1966-06-02

Publications (3)

Publication Number Publication Date
DE1795736A1 DE1795736A1 (en) 1974-05-30
DE1795736B2 DE1795736B2 (en) 1976-04-01
DE1795736C3 true DE1795736C3 (en) 1976-11-25

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