Method of producing derivatives of azinoriphamycin

专利摘要:
There are provided azino rifamycin compounds of the formula (I): <IMAGE> (I) Y=H or CH3CO; R1 linear or branched C1-C7 alkyl or C3-C4 alkenyl- R2=linear or branched C1-C7 alkyl, C2-C4 chloroalkyl, C3-C4 alkenyl, Cycloalkyl having 3 to 7 C atoms in the ring, cycloalkyl alkyl having 3 to 6 C atoms in the ring, phenyl, or C7-C8 aralkyl, unsubstituted or mono-substituted by a halogen atom in the aryl group; or NR1R2=a cyclic moiety having 5 to 8 C atoms, unsubstituted or substituted by 1 or 2 CH3 groups, morpholino. The compounds inhibit the growth of gram positive bacteria and Mycobacterium tuberculosis. Oxidized compounds, preparative methods and pharmaceutical compositions are also described and claimed.
公开号:SU1378783A3
申请号:SU823511202
申请日:1982-11-12
公开日:1988-02-28
发明作者:Франчески Джованни；Марсили Леонардо；Санфилиппо Аврора；Виоглио Серджио
申请人:Фармиталия Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:

 CN
The invention {does not relate to a method for producing new azinrifamycins of the general formula
CHj CH,
..CH NRR 0 CHr-cnJ; i, 79 5 S CH (13); 2.06S
 Gn 9 inS G with pti. - PCT
Is, CH (36); 2.10S S, CH3 (30);
Where
At R,
R
ace til |
linear or branched
C alkyl |
linear or branched C-alkyl, phenyl or benzylJ or R and R together with the nitrogen atom,
to which they are associated. are morpholinyl, piperidinyl D per hydroazepinyl or pyrrolidinyl group, possess antibacterial activity against gram-positive and gram-negative bacteria, as well as against Mycobacterium tubercalosis,
The purpose of the invention is the creeping up of new rifamycin derivatives, possessing improved properties, or of a structural analogue, rifampin,
In the examples given, the NMR spectra were determined using the internal standard TMSj and the S values are given in parts per million.
Example K 3 (N-piperidino-methyl-azino) methylrifamycin. 5 g of 3 formyl ™ of rifamycin SV is dissolved in 250 ml of tetrahydrofuran and added dropwise to a solution of EZZ3 ml of hydrazine hydrate in 50 ml of tetrahydrofuran for 15 minutes with stirring, at which the temperature is equal to -20 ° C. thin layer chromatography (g) was then added 2 ml of triethylamine while maintaining the temperature of the solution at -20 ° C. 5 g of chloropyperylformamide chloride 5 was added in portions, and the mixture was slowly heated to room temperature with stirring. 350 ml of ethyl acetate are added to the mixture, after which the resulting solution is washed with water. After drying on anhydrous sodium sulfate, the solvent is distilled off and
the crude product is crystallized from methanol and then from acetone. Get 2.3 g of the target product is red,
NMR (CDCl); 0 ,, CH, (34) J; 0 ,, CH3 (33); 0 ,, (31) J; 0 ,, CH (32); I ,, CH,
CHr-cnJ; i, 79 5 S CH (13); 2.06S
Mr GN. 9 inS G with pti. - PCT
Is, CH (36); 2.10S S, CH3 (30);

2.23 G S, CHj (14);
Ch. (37); 7.73 and 9.03 2S, -CH
3.04 5
N
N
; 11.935 G S,
N ch o
 -NH C 13.27 and 13.87 & S, OH-C (1), (8), OH-C (4).
Example 2. 3- (N-morpholinomethyl "azido) methylrifamycin. The procedure described above, in Example I5, subjected to the interaction of 3 forkyl-rifamycin SV with chloromorpholinoforminimine chloride, is obtained, the compound corresponding to the general formula ( I) where U COCH, and NR, Ra - morfolino, t, pl. (with different).
NMR (CDClg): - 0.28 5 Id, CH3 (34); 0.65 S Id, CE, (33): 0.7b S {d, CH3 (31); 0.99 I d, CHj (32); 1.78 § S, CHj (3); 2.06 5 S, CHj (36) 31 2.10S s, CHj (30); 2.23 Sis, CHj (14); 3.04 S,
CH,
five
0
five
f5, OH — C (1), OH — C (4), OH — C (8) MS; 836 M).
Example 3. 3 - (K-dimitylamino-nomethyl azino) methylpiphmycin-SV. Similar to the method described in
 Example 1 5 and carrying out the reaction of 3-formyl-rifamycin SV with chlordimethylformamine chloride, receive the compound described by formula I, where
Y COCH, and R ,, m. Pl. 2681: (with different) "
NMR (CDCl,); 0.26 S d,. CH3 (34); 0.68 STd SNd (33); .0.77. d, SNZ. (SG); 1.045 d, CH3 (32); 1.85 S Is, CH3 (13); 2.10 with s,, (36); 2.17 f S, CH 3 (30); 2.27 E S, CHj (14);
3.09 S S,
9.05 S 2S,
ABOUT
-CH N - NX, Jl, 96, -NH-C-; 13.29 and 13.92 (IOH-C (91), OH-C (8) OH-C (4).
MS: 794 (M).
Example 4. 3- (L-gee-hydroazapinement-azino) methylrifamine. 3 g of 3 formyl-rifamycin SV is dissolved in 50 ml of dichloroethane and added dropwise to a solution of 0.2 ml of hydrazine hydrate in 24 dichloroethane over 15 minutes with stirring, the temperature being -20 ° C. After 15 minutes, the resulting solution of 3-hydrazinomethyl-rifamycin is kept until the temperature reaches + 5 ° C, after which 3 g of chlorohexhydroazepiphylaminimine chloride is added to it. The mixture was stirred for 15 minutes, at room temperature, and then diluted with 100 ml of dichloroethane and washed with water. After drying on anhydrous sodium sulphate, the solvent is distilled off and the resulting crude product is purified on a silica gel chromatography column using ethyl peptide-methanol as elution solution. The purified product thus obtained is crystallized from acetone. 0.70 g of a red compound is obtained, corresponding. the general formula (I), where Y. is COCH3, and hexahydroazepiryl, t. pl. 258-260 ° C. MS: 848 (M).
Example 5. 3- (H-di-p-propyl-aminomethyl-azino) methylrifamycin SV. A solution of 3 g of 3-formirrifamycin SV in tetrahydrofuran (150 ml) is added to 0.2 ml of hydrazine hydrate dissolved in tetrahydrofuran (50 ml) cooled to -20 ° C. After 15 minutes, the resulting solution of 3-hydronomonomethyl-rifamycin SV is left until it is heated to 0 ° C, and then 1.2 ml of triethylamine and 3 g of chloro-di-p-propyl are added to it. - formimine chloride. After 15 minutes at room temperature, the reaction mixture was diluted with 200 ml of ethyl acetate, washed with 3% aqueous sodium bicarbonate solution, and then with water. The organic phase is dried over anhydrous sulphate.
0
5 0 5 O g Q

0
five
sodium, then the solution is concentrated and then diluted with ethyl ether, to give 0.8 g of a red substance, which is described by the general formula (I), where Y is COCH, and R2 is CjH, m.p. 173-.
NMR (CDCl1): -0.25 Sid, CH (34); 0 ,, CH (33); 0.73 cTCd, CH3 31); 0 ,, SND (32); 1.5-1 ,, N (CH CH2CH) J; 1.78 (S, CH3 OZ); 2 ,, CH, (36); 2.09 cTfS, CHj (30); 2 ,, CHj O4); 3.04 LS, OCHj; 4.9 Id d, H, (25); 5 ,, H (28); 5.80, H (19); 6.1-6.8 (, H (17), H (18), H (29); 7.18 Sts, CH N - N - CH - N -); 9.00 s, CH N - N CH - Nj; 12.03 and 13.4
Sis, OH and NH.
MS: 850 (M).
Example 6. 3 (N-methyl-p-butylaminomethyl-azino) methyl trifamycin SV.
Using the procedure described in Example 5 and ensuring the reaction of 3-formyl-rifamycin SV hydrazone with chloromethyl-p-butylforminimide chloride, a compound is obtained which is described by the general formula (I), where Y is COCHd, RI is CH 3 and Rj is C. Hg, m.p. 218- 220 ° C (with decomp.).
NMR (CDCb): - 0 ,, CHj (34); 0.64 (ha, CH3 (33); 0.73 Sid, CH3 (31); 0 ,, CH3 (32); I ,, N-CHgCH CHj; 1, CHj (13); 2.04, S , CHj (36); 2.07S s, CH (30); 2 ,, CHg (14); 2.9351s, (N-CHj); 3.04S, OCHj-; 4.07-5.2, H (25), H (28); 5.5-6.6 (m, H (17), H (29); 7.78 SS, CH N - N CH - 9.01 (CS, CH N - N - -CH - 12.035 S, NHJ.
MS: 836 (M +).
P p and M ep 7. 3- (H-di-sec-butyl-aminomethyl-azino) methylrifamycin SV, Following the procedure described in Example 5, and conducting the reaction of 3-formyl-rimecine SV of hydrozone with chloro-di- sec-butylformin chloride, a compound is obtained which is described by the general formula (I), where Y is COCHj, and R and Rj are each ceK-C4Hj, t. pl. 178-180 ° C.
NMR (CBCI): - 0.25 ha, CHj (34); 0 ,, CH, (33) 1; 0.75 Sid, CH3 (31) 1; 1.01 Sid, CH3 (32); l ,, NCHCHgl; one,,
5137
1 ,, СНз (13); 2 ,, CHj (36); 2.09 Sis, CHj (30) J; 2 ,, CHj (14); 3.03 S s, 4.20 I m, (N-CH-) 7; 4.9, H (25) 5 ,, H (28) 1; 5.38, H (19) 1; 6, l-6 ,, H (17), H (18); H (29); 7.89 &amp; s, CH N - N CH - 8,99 Sis, CH N - N CH - NJ; 11.90: 13.25: 13.82 and 14.01 S, NH, three OH,
MS: (878 (M).
Example 8. 3- (M-methyl-benzylaminomethyl-azino) methylrifamycin SV. Following the procedure described in ™ 5, and the reaction of 3-formyl-triamycin SV hydrazone with chloromethylbenzyl-forminimine chloride, a compound is obtained having the general formula (I), where Y is COCHj, R is CHj and R is CHgCjHs. -.
NMR (CDCl 3): 0.235 Ga, CH 3 (34); 0 ,, CH3 (33); 0 ,, CHj (3); 0.96 SHY, CHj (32); l, 77cfCs, CH (13); 2,045 С s, CHj. (36) 3; 2 ,, CHj (14); 2.90, S, 3.02, OCH. 4 ,, СНгСбНу; 4.7-5., H (25), H (28); 5.5-6.7 (Cm, H (17) H (18), H (29); 7 ,,; 7, CH N - N - CH - 9.035 C S, CH N - N - CH - 12, .3, NH. MS: 870 (M).
Example 9, 3- (M-diethylamino-methyl-azino) methylrifamycin SV. A solution of 3 g of 3-formyl-rifamycin SV in tetrahydrofuran (150 ml) is added to Of 2 MP of hydrazine hydrate dissolved in tetrahydrofuran (50 ml) cooled to 20 ° C. After 15 minutes the resulting solution of 3-hydrazonomethyl α -riphamycin SV is allowed to heat until it reaches 0 ° C, after which 3 g of chlorodiethylformamine chloride is added to it, and the reaction proceeds for 15 minutes at room temperature. Ethyl acetate (150 ml) is then added. The resulting solution is washed with dilute acetic acid and water, and at the end of the process the organic phase is dried over anhydrous sodium sulfate. The solvent is distilled off, after which the precipitate is crystallized from ethanol and then from acetone. 1.5 g of the red compound described by the general formula (I) are obtained, where Y is COCHj, and R-, and RS are each separately, t. Pl. (with different).
NMR (CDCl 3): -0.23, CHj (34); 0.66 j- d, CHj (33); 0.74 (5Ud, CHj (31); 0.99 Sid, CH3 (32); l ,, l, 79 (rs, CH3 - (13) 3; 2, CH3 (36) 1; 2, CHj - (30) 1; 2.23, CH3 (1) 1 5 3.04, 3.40J m, NCHjCHjl; 4.91, H (25); 5, m, H (28); 5.84, i tdd, H (19); 6, l-6 ,, H C29); H (17), H (15); 7.77 S, CH N - N CH - 9, CH 1 - N - N CH - Nl; ll, 95; 13.26: 13.80 and 13.89 S, N, H, three OH.
M.S: 822. ().
Example 10. 3- (N-pyrrodinomethyl-azino) methylrifamycin SV. Following the procedure described in Example 9 and the reaction of 3-hydrazonomethyl rifamycin SVc chloropyrrolino fermimine chloride, a compound is obtained having the general formula (I), where Y COCHj, a - pyrrolidino, t. Pl. 260 ° C (with decomp.).
NMR (CBC1): - 0 ,, CH (34) 0 ,, CH3 (33); 0.74S d, CHj (31); 0.99 Sid, Cie (32); 1.79 Sis, SI 3 (13); l ,, N (-CH2-CH -); 2.06 Sis, (36) 1; 2 ,, CHj (30) I 2.23S S, CH-, (14); 3.04 S, 3.45S |; m, N (CH2CH2) J; 4 ,, H (25); 5.07 cfCdd, H (28); 5 ,, H (19) 1; 6, -6 ,, H (7), H (18), H (29) j; 7.95 Sis, CH N - N —CH. 9.08 S, CH N - N CH - 11.94: 13.44 and 13.86 S Is, NH, three OH.
MS: 820 ().
Similarly, the following compounds were obtained, described by formula (I), where Y is COH3, a.
NMR (CDCl1): -0, d, CHj (34) J; 0 ,, CHj (33); 0.76 Sid, CH3 (31); 0 ,, SNS (32); 1.2-1.3, 1 ,, CH j (13); 2.06 f Is, CHj (36); 2.11 Sis, CHj (30); 2.22, CHj (4) j; 3.03 S, OCHgl; 3 ,, H (21); 3.72
SIL bd H (27) 1; 4.57 Sim, C} 1
C ..
4 ,, H (25) 3; 5 ,, H (28) 5,89 cStdd, H (19); 6.28, H (29) J 6 ,, H (17); 6.555Ctn, H (18); 6.89 S, CH N - N CH -
CH,
9.02 Sis, CH N - N CH - N 11.92: 13.28: 13.95 and 14.06 s, NH, three OH. MS: 850 (M).
Kg
С4Нэ, т. Пл, 168-170 С.
h
NMR (CDCU): - 0.25 jffd,); 0 ,, CHj (33); 0.74 ild, CHj (31); l ,, СНз (32) j; 1,3-l ,, Ы (СН2СН2СН СНз) 1.79
S, CHj (13) J; 2.07 S, CH 3 (36) J; 2.11 S,% (30) 1; 2 ,, CHj (14); 3 ,, OSS; 4.91 4a, H (25); 5 ,, H (28) J; . 5 ,, H (19); 6, l-6 ,, H (17), H (16), H (29); 7.77 S, CH N - N CH - NJ; 9 ,, CH N - N CH - 11.97: 1; 3.28 :.
, 13.81 and 13.93 S Is, three. MS: 878 (M).
T, submarine
i CHj, (c).
R,
,
NMR (CDCl1): -0.2 V, CH (34); 0.58cfCd, CH3 (33); 0.66, CE (31) 1; 0.95 Sid, SN3 Q2) I
1.80 (US5, CH3 03); 2.06, CH (36) 3; 2.11S is, CHj (30); 2 ,, СНз (1) 3; 3 ,, OCHN1; 3 ,, nch; 3.77 bd, H (27); 4 ,, H. (25); 5.14 dd, H (28); 5 ,, H (19) 1; 6.26 5 d, H (29); 6.34.5 d, H (17); 6.59iStbdd, H (18) 1; 7.1-7 ,, NCgH5; 8.37 {S, CH N - N CH - Nj; 9.17 fCs, CH - N - N CH - 12.07; 13.25: 13.78 and 13.87 S, UN, three OH. MS: 856 (M).
 CH,
g
T. PL 2272
23l C (c decomp.). Rf 0.38 in CH, C. MeOH 20: 1.
MS: 862 (I).
The in vitro activity of the new azinrifamycin derivatives obtained in accordance with the examples was tested by their effect on some gram-positive and gram-negative microorganisms, in addition, on Hycobacterium tuberculosis (the method of sequential dilution).
The results are shown in the table in which new compounds are compared with rifampicin, with the digital data corresponding to the values of the minimum inhibitory concentrations (MIC) indicated in µg / ml. The newly obtained compounds have low toxicity.

rmula
eight.
the invention
1. A method for preparing azinrifamycin derivatives of the general formula CHjCHj
ten
  CH-NR, R,
where -Y is acetyl;
R is linear or branched C-C4 alkyl;
 R 2 linear or branched C-C-alkyl, cyclohexyl, phenyl or benzyl, or R, and Rj together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl, perhydroazepinyl or pyrrolidinyl group, characterized in that 3- formylrifamycin SV of general formula
CH3 9%
thirty
35
about
about
where Y has the indicated value, dissolved in an aprotic solvent, such as tetrahydrofuran or 1,2-dichloroethane, is reacted with an equivalent amount of hydrazine hydrate to obtain an intermediate hydrazonomethyl rifamycin intermediate, of the formula
SNS SNZ
BUT
50
Nzo
NZSO
55
CH N-T "H2
HE
ABOUT
where Y is an acetyl group, which is in situ in the presence of a tertiary amine is treated with chloroformine chloride of the general formula
where R and Rj have the indicated values, the first stage of the process is carried out at (-20) C, followed by a gradual increase in temperature and the end of the process at room
eleven
1378783
12
Table continuation

24 -12

权利要求:
Claims (2)
[1]
Claim
1. The method of obtaining derivatives of azinorifamycin of the General formula where - ¥ - acetyl;
R ^ is a linear or branched C ₁ -C 4 -alkyl;
• R ₂ “linear or branched C ^ -C ^ -alkyl, cyclohexyl, phenyl or benzyl, or R, and R ₂ together with the nitrogen atom to which they are attached form a morpholinyl, piperidinyl, perhydroazepinyl or pyrrolidinyl group, characterized in that that 3-formylrifamycin SV of the general formula where Y has the indicated meaning, dissolved in an aprotic solvent such as tetrahydrofuran or 1,2-dichloroethane, is reacted with an equivalent amount of hydrazine hydrate to give an intermediate hydrazonomethylrifamycin SV of the formula Y - acetyl group, which in situ in the presence of a tertiary amine is treated with chloride of general formula hlorformimina
SNS1
K II / X ⁺ cr where R ₄ and R ₂ have the indicated meanings, the first stage of the process being carried out at (-20) ° C followed by
5 by a gradual increase in temperature and completion of the process at room temperature.
[2]
2. The method according to claim 1, characterized in that triethylamine is used as a tertiary amine.
.-I.
Example
Microorganism
K. pneumoniae 10 ²⁶ 20 20 20 10 ²⁰ P, vulgaris 10 20 10 10 0 10 20 E. coll B 10 · 20 10 20 . 10 10 20 E, Coli ginetta 10 20 10 10 10 10 20 E. Coll ri Rifr > 200 200 200 200 > 200 > 200 •> 200 P, aeruginosa 5 20 10 10 10 »0 10 So _o abortivoeguina 5 20 10 10 10 5 10 S, aureus 209p 0,037 0.009 0.018 0.009 0.0022 0.18 ’ 0,037 foecalie 0.6. 0.6 0.6 0.6 1.25 0.6 1.85 So pyogenes 1.25 1.25 2,5 1.25 2,5 1, 25 10 S <, lutea 0,037 0.18 0,087 0.009 0.009 • 0.18 0,037 So aureus 2O9P Rif <200 > 200 > 200 > 20-200 20 > 20-200 10 So tuberculosis H 37 RV 0.01 0.02 0.02 0.04 0.02 0.04 0.04 Half life T 1/2 for mice after application of 10 mg / kg by mouth, h * 19-20 * 17 -24-30 * 18 * 24 ______________
L. ·
Table continuation
Microorganism zm
Example
Rifam- RICIN r ₄ "ch,
10
> 200 20 • 10 , Vulgaris * 20-200 20
eleven
Table continuation
-U.
L.
x
Example
Microorganism to • (R, -R ₄ -nC ₄ H,) TfR.-R "[1C, N _T >
Tr, -CH, n ---- Rifampicin
8. coll B 20 10 10 E, Coli ginetEa 20 10". 10 E. Coli el Rifr > 200 > 200 > 200 P, aeruginosa 10 5 10 S, abortivoeguina 10 5 5 S, aureus 209p 0.018 0.0045 0.0045 S. foecalis '0.6 0.6 0.6 S. pyogenes 1.25. 1.25 2,5 S, lutea 0.0045 0.0045 0.0045 S, aureus 209P Rif > 20-200> 20-200 > 200 S. tuberculosis H 37 RV 0.04 0.02 0.01 Half life T 1/2 for mice after application of 10 mg / kg by mouth, h ~ 24 -12
-> 200 10 > 20-200 10 10 > 20-200 10 > 20-200 10 10 > 200 > 200 > 2Q0 200 > 200 > 20-200 20 20 20 10 10 5 20 10 10 ' 0.18 0.009 0,039 0,075 0.018 2.5 ‘ 0.6 0.6 1.25 0.6 20 2,5 - 2,5 2,5 0.018 0.018 0,075 0,075 0,037 10 > 20-200 > 20-200 20-200 > 200 0.04 0.01 0.02 0.01 0.01

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

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FR208F|1964-07-31|

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GB1336399A|1971-06-24|1973-11-07|Lepetit Spa|3-formylrifamycin sv derivatives|

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BE794298A|1972-01-19|1973-05-16|Lepetit Spa|RIFAMYCIN IMIDAZOLE DERIVATIVES AND THEIR PREPARATION|

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AR205434A1|1972-03-27|1976-05-07|Lepetit Spa|PROCESS FOR THE PREPARATION OF 3-ACILHIDRAZONOMETIL RIFAMICINAS SV|

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CH605974A5|1973-09-28|1978-10-13|Ciba Geigy Ag|3- rifamycin S and SV derivs|

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JPS5128640A|1974-09-03|1976-03-11|Matsushita Electric Ind Co Ltd|

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GB1478563A|1975-03-05|1977-07-06|Lepetit Spa|Rifamycin derivatives|

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IT1135270B|1980-04-12|1986-08-20|Erba Farmitalia|3-amidino-ANSAMICINE|GB8308166D0|1983-03-24|1983-05-05|Erba Farmitalia|Preparation of azinomethyl-rifamycins|

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IT1201963B|1983-03-24|1989-02-02|Prodotti Antibiotici Spa|DERIVATIVES OF THE REFAMICINE AND PROCEDURE FOR THEIR PREPARATION|

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US4560509A|1983-11-16|1985-12-24|Eli Lilly And Company|Antibiotic A39079 factor S-1|

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GB8408924D0|1984-04-06|1984-05-16|Dobfar Spa|3-azinomethyl rifamycins|

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US4956373A|1989-01-31|1990-09-11|Farmitalia Carlo Erba S.R.L|Pharmaceutical composition comprising 3- methylrifamycin S as active ingredient|

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JPH02215716A|1989-02-08|1990-08-28|Farmitalia Carlo Erba Spa|Pharmaceutical composition containing 3-methylrifamycin s as active component|

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JP3202960B2|1998-02-17|2001-08-27|大塚化学株式会社|Halogenating agent and method for halogenating hydroxyl group|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8134549|1981-11-17|

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