Method of preparing derivatives of beta-lactams

专利摘要:
There are provided compounds of the formula Ia and Ib <CHEM> wherein A is hydrogen atom or an organic residue, R<1> is halogen atom, or an organic group, R<2> is hydrogen or halogen atom, C1-C4 alkyl or alkoxy group R<3> is hydrogen atom, C1-C4 alkyl or alkoxy group, benzyl or a methylene group and R4 is an organic residue. Said derivatives (Ia) and (Ib) are endowed with elastase inhibitory activity. A two-step process for their preparation starting from the corresponding 4-carboxy cephem or 3-carboxy penam is also provided.
公开号:SU1750430A3
申请号:SU894613926
申请日:1989-04-12
公开日:1992-07-23
发明作者:Биссолино Пьерлуиджи；Альпеджани Марко；Перроне Этторе；Орецци Пьерджузеппе；Франчески Джованни
申请人:Фармиталиа Карло Эрба С.Р.Л. (Фирма)；
IPC主号:

专利说明:

The invention relates to a method for producing new beta-lactam derivatives of the formula
R
H Oh

4n I TYCD
SOA
where R is chlorine or methoxy;
A is C-C4 alkyl, phenyl or 4-ter. Butylphenyl; X is a group of formula:
Y
sn
one
SI} or Ig
XS
ate about
4 GO
about

00
where R2 is methyl, bromomethyl, acetoxy methyl, methoxymethyl, (1-methyl-1, 2,3,4-tetrazol-5-yl)
thiomethyl or (2-methyl-5 oxo 6-hydroxy-2,5-dihydro-1,2, A-triazin-3 yl) thiomethyl, which have the property to inhibit human leukocyte elastase and can be used in medicine. Beta-lactam derivatives are known to inhibit ft-lactamase or elastase.
The purpose of the invention is to obtain new beta-lactam derivatives, which have the property of inhibiting human leukocyte elastase with increased stability.
The objective is achieved in that according to a multistep process for the preparation of beta-lactam derivatives of the formula (I), comprising the fact that a compound of the formula

but
with
where RJ - has the values indicated for X under the condition that RОВ
methyl,
treated with a halogenating agent in an organic solvent to form a compound of formula
(W)
where k
and a
BUT
X have the indicated meanings
- halogen, treated with the compound of the formula
AMgHal, (IV) where A has the indicated meanings; Hal - halogen, in the presence of Cul A1C1 in an organic solvent at a temperature of from -78 to -50 ° C, the resulting compound of the formula
  -g
l
n o
i
/ ml
SOA
n
where R., A and X
H
peracid tour from
0 ° C
have the indicated meanings
or its salt at room temperature to room temperature and, if necessary, the target product in which R is methyl is treated with N-bromo succinimide in the presence of &amp; i, (y-azo-bis-isobutyronitrile in an organic solvent at reflux temperature and in if necessary, the resulting target
s x
), e
e
Yu )
;
and)
15
20
25
thirty
35
40
45
50
55
product in which,
R2brommethyl
treated with acetic acid or its salt, methanol or base and 5 mercapto-1-methyl-1,2,3,4-tetraz &amp;, or 3 mercapto-2-methyl-5-oxo-6-benzhydroloxy-2,5- Dihydro-1, 2, -triazine and, if necessary, remove the benzhydryl group with trifluoroacetic acid in the presence of anisole to give the desired product, where K is acetoxymethyl, methoxymethyl (1-methyl-1,2,3,4- tetrazol-) thiomethyl or (2-methyl-5 oxo 6-hydroxy-2,5-dihydro-1,2, -tri-) thiomethyl.
Example 1. (7схО-Chloro-4-ethylcarbonyl-3-methyl-3 Jfem-1,1-dioxide (compound 33).
A solution of () -chloro-3-methyl-3-tsefem-A-carboxylic acid (515 mg) in 30 ml of dry benzene is stirred at 7 ° C for 5 minutes in the presence of saline chloride (0.38 ml).
After removal of the volatiles in vacuo, crude (700-chloro-chloro-carbonyl-3-methyl-3-cephem) is obtained.
IR (KVg) MAX: 1780 br., 1750 cm.
This material is mixed with dry ether and treated under aluminum at -70 ° C with aluminum trichloride (195 mgU and 2M ether solution of ethyl magnesium bromide (1.5 ml). After 5 min, the reaction mixture is poured into ice water and washed successively with an aqueous solution of NaHCO and a strong salt solution. The organic layer is dried with NaЈS04 and concentrated under vacuum to give (7 ° O chloro-4-ethylcarbonyl-3 methyl cephamate) as a mixture of D5 and D2 isomers (210 mg).
This mixture is dissolved in a mixture of 0.05 and a pH of 7 phosphate buffer and ethyl acetate 1: 2, the total volume is 9 ml and treated at 0-5 ° C with m-chlorinated perbenzoic acid (385 mg)
one
five
After stirring at room temperature for 1 h, the reaction mixture was poured into ice-cold water and washed successively with an aqueous solution of sodium metabisulfite, an aqueous solution of sodium hydrogencarbonate and a strong salt solution. After drying with the aid of, the solvent was removed and the strength was subjected to chromatography on a residue gel to give the pure objective compound (90 mg) as a syrup.
IR (СНС13) ax 1780, 1690
And pm. 2. p. 4-tert-lutylcarboyl nyl- (7ob) -methoxy-3-methyl-3-cephem-1, dioxide (compound 49).
A solution of (7 &) - methoxy-3-methyl-3-cephem-4-carboxylic acid (1.68 g) in dry benzene (100 ml) is processed at 7 ° C with dry DMF (a few drops) and oxalyl chloride (1, 26 ml). After stirring for 45 hours of removal of volatile materials under vacuum, crude 4-chlorocarbonyl- (7ob) -methoxy-3-methyl-3-cephem was obtained.
This material is mixed with dry THF (50 ml) and treated at -70 ° C. under nitrogen atmosphere with aluminum trichloride (195 mg) and 1.43 M ether solution with tert-butyl magnesium chloride (5.13 ml). After stirring for 13 minutes at -30 ° C, the reaction mixture is poured into ice water, successively washed with an aqueous solution of NaHCOj and strong salt solution and evaporated to dryness, resulting in a crude 4-tert-butylcarbonyl- (7ob) -methoxy -3-methyl-cephem.
A portion (.300 mg / of this material was dissolved in ztilacetate (70 ml) and treated at room temperature with m-chloroperbenzoic acid (570 mg). After 1.5 hours, the reaction mixture was successively washed with an aqueous solution of NaHSO, an aqueous solution of NaH60 and a strong solution salt. After drying with Na2SO4, removal of the solvent and chromatography on the silica gel of the residue, pure objective compound (114 mg) is obtained in
iO
white powder, m.p. 128 ° C. IR (CHClj)) MQKC: 1783, 1685 NMR (200 MHz, CDC13): 1.2b (9H, S9), 1.70 (3H.S), 3, 31, 3.93 (2H, each d, I G / Hz), 3.56 (3H, S), 4.66 and 5.16 (each 1H, d 1, b Hz) ppm. MS (FD) 301 m / z (M).






ten
20
PRI me R 3. 3 Bromomethyl-4-tert-butylcarbonyl- (7) -methoxy-3-cephem-1,1-dioxide (compound 50).
A solution of 4-tert-butylcarbonyl- (7cd) -methoxy-3-methyl-3-cephem-1,1-dioxide (Example 2.130 mg), N-bromo-succinimide (NBS, 100 mg) or Ј, c1-azo-bis isobutyronitrile (AIBN, 5 mg) in carbon tetrachloride (20 ml) and dichloromethane (15 ml) is boiled for 2 hours. After removal of the solvent and chromatography on silica gel, the indicated compound (PO 15 mg) is obtained in the form of a white powder.
IR (CHCU)}
31v ma ks
1790, 1690 cm
.... h. . /, N.-and
NMR (200 MHz, OC13): 1.31 (9H, S), 3.56 (3H, S), 3.53 (1H, d, 1 14.6 Hz), 3.79 and 3.91 ( 2H, each d, I 11, 4 Hz), 4.28 (1H, dd, T, 6 and 1.4 Hz), 4.76 (iH.dd.l 1.9 and 1.4 Hz), 5 , 20 (1H, d, I 1.9 Hz) MS (FD) 379 m / (M +).
EXAMPLE 4 3-Acetoxymethyl-5 4-tert-butylcarbonyl- (70 $ -methoxy-3-cephem-1,1-dioxide (compound 5T). Solution 3-bromomethyl-4-tert-butyl carbonyl- (7 xO-methoxy-3 cefem-1,1-, dioxide (example 3.93 mg; dry 0 acetonitrile (5 ml) is stirred at
room temperature for 1 h in the presence of acetic acid (0.15 ml) and silver acetate (lt8 mg).
The reaction mixture is mixed with 5 EtOAc and successively washed with an aqueous solution of NaHCOE and brine. After drying with. and removing the solvent, followed by chromatography on silica gel, the title compound (45 mg) was obtained as a white powder, mp. 134 ° C.
IR (KVG) Zmax: 1780, 1732, 1687 cm 1.
NMR (200 MHz, gas quantization) Y: 1.28 (9H S), 2.08 (3H, S), 3.37 (3H.S), 3.83 (IH.dI 18.5 Hz), 4, 00 (iH.dd.I 18.5 and 1.5 Hz), 4.43 (2H, ABq ,, splitting the internal lines of 1.9 Hz), 4.73 dH.dd.I 1.9 and 1.5 Hz) -3.20 (1H, dd, I 1.9 Hz) ppm. MS (DG) 339 m / (Mf) EXAMPLE 5. 4-tert-Vutylcarbonyl - () - chlorine-3 netil-3-cephem-1, 1- c dioxide (compound 1).
A solution of (7OB) -chloro-4-chloroclontonyl-Zmethyl-3-cephem (example |., 2.32 g): in dry THF (80 ml) is sequentially treated with copper iodide (I)
0
five
0
71
(2.076 g) and 2M ethereal solution of re-butyl magnesium chloride (4.59 ml) at -70 ° C under a nitrogen atmosphere.
The reaction mixture is left at -50 ° C, then poured into ice water. After 10 minutes of stirring, extraction with ethyl acetate, washing the organic layer with an aqueous solution of aHCOg, drying by means of and removing the solvent, a crude 4-tert-butylcarbonyl (7-4) chloro-3-methylcepham is obtained.
This material is passed through a short silica gel column and then treated with m-chloroperbenzoic acid (2.5 g) in ethyl acetate at 105 ° C. overnight. The reaction mixture is diluted with ethyl acetate, then orally washed with an aqueous solution of NaH03, an aqueous solution of NaHCO, an aqueous solution of NaCl, dried (), concentrated under vacuum and purified by column chromatography
silica gel, resulting in the indicated compound (550 mg) as a white powder, m.p. 218 ° C.4
IR (KBG Yamax: 1773, 168 cm.
NMR (200 MHz, CDCl1) Ј: 1.6 (9H.S), 1.72 (3N,), 3.60 (1H, d, 1 Hz), 3.96 (1H, dd, I 18, 1 and 1.3 Hz), 4.76 (1H, dd ,, 3 and 1.7 Hz) 5.32 (1H, d ,, 7 Hz) ppm.
Example 60 60 3-Bromomethyl-4-tert-butylcarbonyl- (7oi) -chloro-3 cephem-1,1-dioxide (compound 2).
A solution of 4-tert-butylcarbonyl- (7c /) - chloro-3-methyl-cephem -1, 1-dioxide (Example 5, 150 mg) in carbon tetrachloride (40 ml) is boiled for 4 hours in the presence of NBS (114 mg) and AIBN (2 mg).
After removal of the solvent and chromatography, the indicated compound (112 mg, plus 40 mg of starting material) is obtained as a white powder. M.p. 155 C.
IR (kBr) OWQlcc: G / 95, 1x90 cm.
ms (FD) zv m / z (m +).
NMR (200 MHz, CDCH): 1.31 (9H, S), 3.65 (1H, d ,, 1 Hz), 3.85 (2H, Abg ,, 4 Hz), D.32 (lH, dd , l 11.4 and 1.3 Hz), 4.88 (iH.dd ,, 8 and 1.3 Hz), 5.37 (1H, d ,, 5 Hz / million, shares.
-one
504308
Example/. (BvЈ) -lrom-3-ethylcarbonylpenam-1,1-dioxide (compound 146).
A solution of 6,6-dibromopenicillic acid (7.18 g) in dichloromethane is treated at -20 ° C with 2-pyridyl disulfide (4.41 g) and triphenylphosphine (5.24 g). Reaction mixture
JQ is heated to room temperature, the solvent is removed under vacuum and the residue (consisting of the crude 2-pyridyl ester of the starting material) is used to react
i5 at 75 ° C with a 2M ethereal solution of ethylmagnesium bromide (15.5 ml) in THF (110 ml). After 35 min, the reaction is treated with a saturated aqueous solution and extracted
20 with 1: 2 ethyl acetate / isopropyl ether. The organic extracts are washed twice with water, dried and concentrated. After chromatography on silica gel, (6 ° /) - bromo-325 ethylcarbonylpenes (1.3 g) are obtained in the form of a white powder, m.p. 8e - 69 ° C. IR (СНС13) Zma) 4С: 1780, 1710 cm NMR (90 MHz, CDCl 3): 1.10 (3N, t ,, 5 Hz), 1.37 and 1.70 (each
30 ZN, S), 2.62 and 2.67 (2H, each q, I 7.5 Hz), 4.40 (1H, S), 4.85 and 5.41 (each lM, d, Hz) million shares.
This material (100 mg) in dichloromethane (5 ml) is stirred for
35 5 hours at 25 ° C in the presence of m-chloroperbenzoic acid (293 mg).
The reaction mixture is sequentially washed with an aqueous solution of NaHS03 and
NaHCCb aqueous solution. After removal of the solvent, under a vacuum, 40
flash chromatography yields the title compound as a yellowish product (80 mg). M.p. 117 - Н8 С.
IR (KBr)} Mqkc: 1793, 1712 cm. . 4E NMR (90 MHz, 1.10 (3N, s, I 7.5 Hz), 1.38 and 1.62 (each 3H, S), 2.70 (2H, q, 5 Hz), 4, 20 (1H.S), 4.70 and 5.2T (each 1H, d, I 1.7 Hz) ppm.
50 EXAMPLE 8 (bsb) -chloro-3-ethylcarbonylpenam-1,1-dioxide (compound 116 /.
A solution of (6iX.) - chloropenam-3-carbocarb 55 of sodium silate (543 mg) in dry THF is used to carry out the reaction at 5 ° C for 1 h with oxalyl chloride (0.18 ml) in the presence of
9
DMF (1 drop). The reaction mixture is evaporated to dryness, treated with dry THF (10 ml), cooled under nitrogen atmosphere to -78 ° C and treated with copper (I) iodide (402 mg) and 2M ether solution of ethyl magnesium bromide (1.06 ml).
After stirring for 15 minutes, the reaction mixture was poured into ice-water and extracted with ether. The extracts are washed with an aqueous solution of NaHCO, dried and evaporated. After chromatography on silica gel, I get (6ЈЈ) chloro-3-ethylcarbonylpenes (50 mg) as a syrup. .
IR (СНС1, НМакс: 1778Г 17 ° 5 cm
NMR (200 MHz, CDC1,): 1.05 (3N, t ,, 1 Hz), 1.41 and 1.62 (each 3N, S), 2.58 and 2.62 (2H, each q, I 7.1 Hz), 4.36 (1H.S), 4.77 and 5.29 (each 1, d, 3 Hz) ppm.
The resulting material (20 f) was dissolved in ethyl acetate (1 ml) 4 and reacted with m-chloric benzoic acid (81 mg) for 6 hours at room temperature. After washing with a 1M aqueous solution of NaHS03, a saturated aqueous solution of NaHCO3 and a saline solution, followed by removal of the solvent and chromatography on silica gel, the title compound is obtained as foamy material (17 mg).
IR (SCHN) E
"one
  1fcUb, 1715 cm
NMR (200 MHz, CDC1): 1.08 (3N, t ,, 1 Hz), 1.39 and 1, b2 (each 3H, S), 2.66 and 2.71 (2H, each q, 1 7.1 Hz), 4.19 (1H.S), 4, 55 and 5.19 (each 1H, d ,, 7 Hz) ppm.
PRI me R 9. 4-Ethylcarbonyl-7yЈ methoxy-3-methyl-3 cephem-1,1-dioxide (compound 147).
A solution of 7fЈ-methoxy-3-methyl-3 cefem-4-carbonyl chloride (0.7 g) obtained in example 2 in dry distilled ethyl ether (20 ml) is treated at -70 ° C under a nitrogen atmosphere with copper iodide (I) (0.54
After 10 minutes of stirring, a 2M ethyl magnesium bromide ethereal solution (2 ml) was added to the reaction mixture. The reaction mixture was allowed to stand until the temperature rose to -50 ° C, and then poured into ice water. After extraction with ethyl acetate, washing with an aqueous solution of NaHC03




ten
and removing the solvents, a residue remains, which is purified by flash chromatography (siU2, EtOAc /) hexane, and then treated with m-chloradienzoic acid (1.5 g) in cold / O L / ethyl acetate. The reaction mixture is stirred at 10-15 ° C for 1 hour, then 10
15


-25
20
40
,

 ) "50

washed thoroughly with an aqueous solution of NaHCOj, aqueous solutions of NaHCOi, Nad. After drying and removing the solvent and subsequent flash chromatography, the title compound (150 mg) is obtained as a pale yellow oil.
IR (CHC13) MA) c6: 1780, 1685 cm.
NMR (200 MHz, COCl3): 1.13 (jH.c, 1 Hz), 1.96 (3H, S), 2.66, and 2.90 (2H, each, and 7.1 Hz), 3.59 (3H, S), 3.60 OH, d, I 17.6 Hz), 3.85 (1H, dc ,, 6 and 1.2 Hz), 4.65 (lH, d, d, , 4 and 1.2 Hz), 5.14 (lH, d I, 1.4 Hz) ppm.
PRI me R 10. 4-tert-butylcarbonyl-7-chloro-3- (1-methyl-1, 2,3,4-tetrazol-5-yl) thiomethyl 3 cephem-1,1-dioxide (compound 150).
A solution of 3-bromomethyl-4-tert-6uti-30 carbonyl-7o6-chloro-3 cephem-1,1-dioxide (65 mg) prepared in Example 6 is treated with dry acetone (5 ml) and triethylamine (0.025 ml) and 5-mercapto-1-methyl-1,2,3,4-tetrazol 35 (26 mg). There is an immediate response (TLC control). The solvent was removed in vacuo and the residue was purified by flash chromatography, whereby the title compound was obtained as a white powder (35 mg). M.p. 162 - 164 ° C.
IR (KBG) Rd, ohm: 1790, 1690.
NMR (200 MHz, CDC13): 1.26 (9H, S), 3.76 and 4.08 (2H, each d, I 45 14.3 Hz), 3.93 (3H, S), 4, 01 (1H, d, 9 Hz), 4.26 (1H, dd ,, 9 and 0.9 Hz), 4.85 (1H, dd ,, 7 and 0.9 Hz), 5.33 (1H , d ,, 7 Hz) ml. ndol.
Pr and m-e p 11. 4-tert-butylcarbonyl- (7 &amp; b) methoxy-3-O-methyl-1,2, 3,4-tetrazol-5 yl) thiomethyl-3-cephem-1 , 1-dioxide (compound 151).
A solution of 3-bromomethyl-4-tert-butyl-55 carbonyl- (7 &amp; 0-methoxy-3 cephem-1,1-dioxide (52 mg) obtained in example 3, in dimethylformamide (1 ml) is treated with 1 methyl-1 2,3,4-tethos-l
Zolyl-5-mercaptide sodium (mg mg). After 10 minutes, the reaction mixture was diluted with ethyl acetate and washed with a strong salt solution. After removal of the solvent and flash chromatography, the title compound (30 mg) is obtained as a white powder. M.p. 60 - 62 ° C.
IR (KBr) 3woll: e: 1790, 1690 cm
NMR (200 MHz, CDC13): 1.2 (JH, S), 3.78 and 4.05 (2H, each d, I 14.2 Hz) X, 56 (3H, S), 3.92 ( iH.d, 1 17.8 Hz), 4.20 (1H, d ,, 8 Hz), 4.75 (1H, br, s), 5.17 (1H, d, I 1.7 Hz) million „Share about
EXAMPLE 12 4-tert-butylcarbonyl- (7o-) -methoxy-3- (2-methyl-5 oxo-6-hydroxy-2.5 Dihydro-1,2,4-tri-azine -3-yl) thiomethyl-3 Cephem-1, 1-dioxide (compound 153).
A solution of 3-bromomethyl-4-tert-butylcarbonyl- (7oЈ) methoxy-3-cephem-1,1-dioxide (230 mg) obtained in example 3 in dry acetonitrile (50 ml) is treated with triethylamine (0.1 ml) and 3 mercapto-2-methyl-5 oxo-6-benzhydryloxy-2,5-dihydro 1,2,4-triazine (2.75 mg). After 20 minutes, the solvent is removed and the protected compound is purified on a silica gel chromatography column. It is dissolved in dichloromethane (2 ml) and then (anisole (U, 025 ml) and trifluoroacetic acid (1 ml) are added. After 15 minutes, the TNPA was completely removed under vacuum and the residue was treated with dichloromethane (1 mlK. After adding isopropyl ether, the title compound (175 mg) was obtained as a white powder. Mp. 148-150 ° C.
IR (KBr)} MQKO: 1790, 1690, 1640 (wide)
NMR (200 MHz, CDCl1) 1.28 (9H, S), 3.63 and 4.19 (2H, each d, I 14.1 Hz), 3.56 (3N), 3.74 (3N), 3.83 (1H, d ,, 8 Hz), 4.09 OH.d, I, 17.8 Hz), 4.76 (1H, Li, 5), 4.17 (1H, d, I G / Hz) million, shares.
EXAMPLE 13 4-Tert-butylcarbonyl- (7) -chloro-3-methoxymethyl-3 cephem-1,1-dioxide (compound 6).
Starting from 1,1-dioxide 3-bromomethyl-4- (tert-butylcarbonyl) - (7oi) - chlorine 3 cephem obtained in Example 6 and heating in a methanol solution, the desired
product as white powder, IR (KBr)) MQ) c: 1788, 1690.
NMR (200 MHz, CDC33) Ј: |, 2b (9H, s.), 3.28 (3N, s.), 3.75 (2H, cJ, 3.81 (1H, d, 2 Hz) , 4.04 (1H,
DD, T 1 and 18.2 Hz), 4.82 (1H, m „), 5.35 (1N.De, 8 Hz).
Example 14. 4- (4-Tert-butyl-0-nyl) carbonyl- (7) -methoxy-3-methyl-3 cephem-1,1-dioxide (compound 169). Following the procedure described in Example 2, and using 4-tert-butylphenyl magnesium chloride as
5 Grignard reagents, the title compound is obtained as a white powder.
IR (KBGL: 1780, 1675, 1608.
NMR (200 MHz, CDC13): 1.34 (9H,
0 s.), 1.66 (ZN, s.), 3.53 (ZN, s.), 3.58 (1H, d., Hz), 3.99 (1H, dm., 1 18 Hz) , 4.80 (1H, m), 5.19 OH, d, 1 1.7 Hz), 7.50 and 8.86 (4H, two d., 1 8.6 Hz) „
5 EXAMPLE 15 7-Methoxy-3 0-methyl-1,2,3,4-tetrazol-5-yl) thiolmethyl-4-phenylcarbonyl-3 Cephem-1,1-dioxide.
0 Following the procedure described in Examples 2, 3 and 11, and using phenyl magnesium chloride as the Grignard reagent, the desired product is obtained as a white powder.
5 IR (KVg) Omaks: 1798, 1665. NMR (200 MHz, CDC13): 3.49 (ZN, s.) 3.80 (1H, To), 4 Hz), 3.85 (ZN, s.), 3.97 OH, Dv,, 1 Hz), 4.09 (1H, d., 4 Hz), 4.38 (1H,
0 dd., 3 and 18.1 Hz), 4.88 (1H, m.), 5.17 OH, d., 7 Hz, 7.4 - 7.9 (5H, m).

The potential for therapeutic action of a protease inhibitor in the treatment of diseases; associated with the destruction of connective tissue, recently attracted wider attention. Significant
0 the number of papers devoted to the study of inhibitors of human leukocyte elastase (HLE), which is the main destructive agent in pulmonary emphysema and, probably, is involved
5 in the processes of rheumatoid arthritis
It turned out that low molecular weight inhibitors possess a number of
properties as compared to natural high-molecular-weight and proteolytic proteases of plant or animal origin: they can be obtained in sufficient quantities, they can be given a rational or optimal structure, they do not have antigenic effect, and they can be used orally or in aerosols. Many of the established low molecular weight elastase inhibitors contain reactive functional groups (chloromethyl ketones, isocyanates), they can interact with functional groups of proteins and therefore can be quite toxic. In this respect, p-lactam compounds are of potential interest, because that being reactive with the serine protease, they are not toxic at very high concentrations,
The proposed method compounds are characterized by a high inhibitory effect on HLE. When tested in vitro, they have advantages over the known inhibitors of y-lactams. In addition, they have surprisingly good chemical stability at physiological pH values, which provides additional advantages when tested in in vivo conditions. Thus, for example, compound b1 (example k), when compared, compares the corresponding cephalosporan ether complex (standard) in improved chemical stability (with 1/2), a higher rate of formation of the HLE complex (), a lower dissociation rate (KQЈ | ) and better efficacy (smaller constant of apparent dissociation of the HLE inhibitor complex in the steady state, K; 53)
The chemical stability at 37 C, 0.05 M phosphate buffer pH 7, k (5% DISO as a solubilizing agent) is determined by the time dependence of the flow rate of the starting material (pseudo-fast kinetics, 10 mM initial concentration) by HPLC ( stationary phase Wliacman Parcisphere 5C18, 110x, 7 mm cond., mobile phase A, pH 2.5 0.1 M phosphate buffer, mobile phase B, phase A / MeCN, UV detection at fl 2b nM)
The kinetic parameters of HI, G, (biochem. L, cp. 702738) are determined at 37 ° C, 0.027 M pH 7, L phosphate tank, U DMSO, U MeCN, NnCl (I 0.25), by excretion 7 amino-A-methyl coumarin (fluorescence detection) from N-methoxy-succinyl-aryl-prolyl-valyl-7-amido-β-methylcoumarin as a substrate according to the following equations
five
0 5 0
0 5 0 5
0
 +
K K., + Oil
(Yz:%) 5 i, j
KQn CO
HsJ / Kb, 1 ± W / K1a.
W -i +
where r, l, s - concentration
product, inhibitor and substrate;
V is the steady-state velocity;
V is the speed at zero time; V0 - speed at
DJ - 0;
K is the Michaelis constant for an enzyme-substrate pair (independently determined under the same experimental conditions)
Due to their high inhibitory activity towards elastase and negligible toxicity, the proposed compounds can be used to treat inflammatory and degenerative diseases caused by proteolytic enzymes in mammals, including humans. The compounds of this invention can be used to produce drugs used to prevent or stop the spread of diseases caused by proteolytic breakdown of the lungs and connective tissues to reduce inflammation and heat and relieve pain. Such diseases include emphysema, syndrome of acute respiratory disease, inflammation of the bronchi, rheumatoid arthritis, osteoarthritis, infectious arthritis, rheumatic fever
fever, spindlesis, gout, lupus, psoriasis.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining oet-lactam derivatives of the general formula
R1 A
X is chlorine or methoxed group; Cf-Sgalkyl, phenyl or 4-tert. butylphenyl; formula group
Y
CHj
CH3 or R2
where R2 is methyl, bromomethyl, acetoxymethyl, methoxymethyl (1-methyl-1,2,3,4-tetrazole) thiomethyl or (2-methyl-5-oxo-6-hydroxy-2,5-dihydro-ro- 1,2,4-triazin-3 yl) thio-methyl,
characterized in that
compound of general formula
RI,
i (
Nh-f oiuH
C02H
where C has the indicated meanings; X is as defined in X, provided that R.2 is methyl,
treated with a halogenating agent in an organic solvent, forming a compound of the general formula
where is r,
and X is as defined;
Aq - halogen, treated with compound of formula
AMgHal where A has the indicated meanings;
Hal - halogen,
in the presence of Cul or A1C19 in an organic solvent at a temperature of from -78 to -OH ° C, the resulting compound of the general formula is oxidized
where R, A and X
have the indicated meanings
peracid or its salt at a temperature
from О С to room temperature and, if necessary, the target product, in which Rg is methyl, is treated with N-bromosuccinimide in the presence of od, oi
azo bis bisobutyronitrile in an organic solvent at reflux temperature and, if necessary, the resulting product in which
R - bromomethyl, treated with acetic acid or its salt, methanol or base and 5-mercapto-1-methyl-1,2,3 tetrazole, or 3 mercapto-2-methyl-5-oxo-6-benzhydryloxy 2, 5 Dihydro-1 , 2,4-triazine and, if necessary, remove the benzhydryl group with trifluoroacetic acid in the presence of anisole to obtain the desired product, in which R2 is acetoxymethyl, methoxymethyl (1-methyl-1,2,3,4-tetrazole-5 yl) thiomethyl or (2-methyl-5 oxo-6-hydroxy-2,5-dihydro-1,2,4-tria) -thiomethyl.
w
Compound
hell V V-rS
oL Well OOSNz Q-X-mpem ScN9
Compound 51 (HSB H) 19.3
Reference () 3.2
1750 3018
Chemical Kinetic Stability Parameters Inhibition (a) of HLE (a) s 1/2, h () (KG3 S) K ™ K0Ј
2.6 3.5
eleven
18, k

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同族专利:

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公开号 | 公开日

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CN1037151A|1989-11-15|

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NO891516L|1989-10-16|

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FI93731B|1995-02-15|

---

ES2075850T3|1995-10-16|

---

DK175689A|1989-10-14|

---

DK175689D0|1989-04-12|

---

FI891700A0|1989-04-11|

---

KR0138771B1|1998-05-15|

---

IL89929D0|1989-12-15|

---

SU1766261A3|1992-09-30|

---

EP0337704B1|1995-06-14|

---

DE68923033D1|1995-07-20|

---

FI891700A|1989-10-14|

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HU206118B|1992-08-28|

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YU47481B|1995-10-03|

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US5077286A|1991-12-31|

---

EP0337704A2|1989-10-18|

---

AU615048B2|1991-09-19|

---

FI93731C|1995-05-26|

---

HUT50348A|1990-01-29|

---

NO173016C|1993-10-13|

---

AT123778T|1995-06-15|

---

NO891516D0|1989-04-12|

---

MY104428A|1994-03-31|

---

NZ228681A|1991-07-26|

---

NO173016B|1993-07-05|

---

JP2840286B2|1998-12-24|

---

EP0337704A3|1991-09-25|

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GB8808701D0|1988-05-18|

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JPH0228183A|1990-01-30|

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YU74489A|1991-02-28|

---

IE891132L|1989-10-13|

---

AU3276289A|1989-10-19|

---

IE67549B1|1996-04-17|

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KR890016048A|1989-11-28|

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GR3017081T3|1995-11-30|

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DE68923033T2|1995-10-26|

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CA1325077C|1993-12-07|

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ZA892629B|1989-12-27|

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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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GB888808701A|GB8808701D0|1988-04-13|1988-04-13|Beta-lactam derivatives|

---