专利摘要:
An oral antibacterial, 7beta-[(Z)-2-(2-aminothiazol-4-yl)-2-alkenoylamino]-3-cephem-4-carboxylic acid pharmaceutically acceptable ester represented by the following formula: <IMAGE> (wherein R is amino or protected amino, R1 is straight, branched, or cyclic alkyl optionally substituted by alkoxy, R2 is hydrogen or a 3-substitutent of cephalosporins, R3 is a pharmaceutically acceptable ester group, and X is sulfur or sulfinyl).
公开号:SU1556541A3
申请号:SU874203251
申请日:1987-09-08
公开日:1990-04-07
发明作者:Хамасима Есио;Исикура Кодзи;Минами Киодзи;Кубота Тадатоси;Есида Тадаси
申请人:Сионоги Энд Компани, Лтд (Фирма);
IPC主号:
专利说明:

This invention relates to a process for the preparation of new 3-cephem-4-carboxylic acid derivatives, namely to a process for the preparation of pharmaceutically acceptable esters of (2-substituted amino-thiazolyl) -alkenoylamino-fem-4-carboxylic acid, intermediate products for the preparation of new cephalosporin antibiotics - pharmaceutically acceptable esters of .2- (2-amino-thiazolyl) -alkenoyl-amino3-3 cephem-carboxylic acid
The purpose of the invention is to increase new 3-cephem-A-carboxylic acid derivatives of intermediates for the synthesis of new derivatives of the cephalosporin antibiotics with improved antibacterial activity with less toxicity and administered orally.
The isolation is carried out in the usual way (if necessary, after adding a solvent, for example, water, dichloromethane acid) and the separated organic layer is washed with water, dried and distilled in vacuum to obtain a residue, which can then be purified in the traditional way (for example, by chromatography on silica gel, recrystallization., precipitation).
Example 1. Esterification of Pivaloyloxymethyl ether „
Iodomethyl pivalate (1-2 eq.) Is added to a solution of the potassium salt of the carboxylic acid in M, N-dimethylformamide (2–5 h) at a temperature from -50 ° C to room temperature. After stirring for 15 minutes to 2 hours, the mixture is diluted with ethyl acetate, washed with ice water and aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue is recrystallized from ethyl acetate and get pivaloyloxymethyl ether
Similarly, beer-lloxymethyl esters are prepared as shown in board 1.
PRI mme R 2. Acetoxymethyl ether.
Instead of the pivalate used in Example 1, bromomethyl acetate is used under the same conditions to obtain the corresponding acetoxymethyl ester.
Acetoxymethyl esters are obtained in a similar manner (Table 1).
PRI me R 3 "Acetoxyethyl ether"
Instead of the iodomethyl pivalate used in Example 1, bromo ethyl acetate is used under the same conditions to obtain the corresponding acetoxy ethyl ester.
five
0
five
0
five
0
five
0
five
Acetoxyethyl ethers are prepared in a similar manner (Table 1).
Example. 1-Pivaloyloxyethyl ether.
To a solution of 2 (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoyl-amino-3-cephem-C-carboxylic acid, g) in M, 1Н-dimethylformamide (2, ml), at 25 - ZO C is added 138 mg of potassium carbonate and the mixture is stirred for a few minutes. "Pivaloyloxyethyl iodide (480 µl) is added to the mixture and the mixture is stirred for 60 minutes. The reaction mixture is diluted with ethyl acetate, washed with brine, sodium bicarbonate solution and water, dried and concentrated. The residue is chromatographed on silica gel to give the corresponding pivaloyloxyethyl ether (161 mg). Yield 53%.
In a similar way, beer-yloxyethyl ethers are prepared (GBgl. 1).
PRI me R 5. Ethoxycarbonyloxyethyl ether.
To a solution of 7-f 2- (2-tert-butoxycarbonylamino-thiazolyl) -2-pentenoyl-amino-3-cePhem -carboxylic acid (mg) in H, M-dimethylformamide (2, ml) with potassium carbonate (138 mg) and 150 mg of 1-ethoxycarbonyloxyethyl bromide. After stirring for 36 minutes, the mixture was diluted with ethyl acetate, washed with salt water and sodium bicarbonate, water, dried, and concentrated. The residue is chromatographed on silica gel to give the corresponding ethoxycarbonyl oxyethyl ether (191 mg).
64.1%.
In a similar way, ethoxycarbonyloxyethyl esters are obtained (Table 1).
PRI me R 6. 5-Methyl-2-oxo-1, -3-dioxol-4-en-methyl methyl ether. A mixture of (I) -2- (2-tert-butoxycarbonylaminothiazol-4-yl) -2-pentenoyl-α-amino-3-cephem-carboxylic acid (mg), potassium carbonate (83 mg) and dimethylformamide ( 3 ml) is stirred at room temperature for kQ min and mixed with a solution of 4-bromomethyl-5-methyl-1, 3-dioxol-en-2-one (102 mg) in dimethylformamide (1 ml). After stirring at 0 ° C for 30 minutes, the mixture was diluted with an aqueous solution of hydrochloric acid and extracted with ethyl acetate. The extract is purified by chromatography on silica gel to give 5 methyl 2-oxo-1,
3-dioxol-4-en-4-ylmethyl ester of 7-bf (Z) -2- (2-tert-butoxycarbonylamino-HOI and azol-4-yl) -2-pentenoyl 1 amino-3- -cepheme-4-carboxylic acid ( 83 mg) as a pale yellow powder.
PRI me R 7 “Cyclohexylacetoxyethyl ether.
To a solution of (2-tert-butoxycarbonylamino-4-thiazolyl) -2-pentenoyl-MHHoJ 3 cephem-4-carboxylic acid (240 mg) in H, N-dimethylformamide (2.4 ml) is added 138 mg of carbonate
sodium bicarbonate solution and extruded with ethyl acetate. The extract is purified by chromatography on a silica gel column to obtain L-2-loyloxymethyl ester L (Z) -2- (2-α-aminothiazol-4-yl) -2-pentenoyl-amino-3-cephem-4-carboxylic acid (5 250 Mr). The latter is dissolved in dichloromethane, mixed with a solution of hydrochloric acid in ethyl acetate and concentrated. The crystalline residue is washed with ether and the hydrochloride is obtained. PRI me R 9 "K suspension G2kali and 1-cyclohexylacetoxyethyl iodide
(355 mg) at -10 ° C. After stirring for 15 min. (15-2-tert-butoxy-carbonylethylamine) for 45 minutes, the mixture is diluted with sol-4-yl) -pent-2-enoyl-amino-3 with ethyl acetate, washed with saline water.
and sodium bicarbonate and water, dried and concentrated. After chromatography of 4-carboxylic acid (572 mg) in dimethylformamide (5 ml) while cooling (30 ° C), a solution of carboxylation of the residue on silica gel of potassium pentate 20 (329 mg) in dimethylforma- tion is obtained, the corresponding cyclohexyl acetoxide (3 ml) and then iodomethyl pivalate ethylethyl eLir (152 mg). (223 ml). After stirring in a similar manner, cyclohexyloxyethyl esters are obtained (Table 1).
1 h at the same temperature, the mixture is diluted with ethyl acetate, washed

 . Q
sodium bicarbonate solution and extracted with ethyl acetate. The extract is purified by chromatography on a silica gel column to obtain L-2-loyloxymethyl ester L (Z) -2- (2-α-aminothiazol-4-yl) -2-pentenoyl-amino-3-cephem-4-carboxylic acid (5 250 Mr). The latter is dissolved in dichloromethane, mixed with a solution of hydrochloric acid in ethyl acetate and concentrated. The crystalline residue is washed with ether and the hydrochloride is obtained. PRI me R 9 "K suspension G2
15 - (2-tert-butoxycarbonylethylamine azol-4-yl) -pent-2-enoyl-amino-3 cephem-4-carboxylic acid (572 mg) in dimethylformamide (5 ml) with cooling (30 ° C) by adding carbonium solution for 1 h at the same temperature, the mixture is diluted with ethyl acetate, washed
PRI me R 8. Acid salts with ice-water and aqueous bidinen solution.
1. Trifluoroacetate. A solution of C (2) -2- (2-tert-butoxycarbonylaminothiazol-4- -yl) -2-pentenoyl 7 emino-carbamoyl-methylsimethyl-3 cephem-carboxylic acid (50 mg) piperovalone ester (50 mg) in trifluoroacetic acid (5 ml) stirred at room temperature for 120 minutes and then concentrated. The residue is diluted with an aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract is purified by chromatography on silica gel to obtain the corresponding free amine. The latter is dissolved in dichloromethane (4 ml), mixed with trifluoroacetic acid (1 ml), and concentrated in vacuo. The crystalline residue is triturated in a mixture of ether and petroleum ether to give pivalloxymethyl trifluoroacetate - Lovoy ester G (2) -2- (2-aminothiazol-4-yl) -2-pentenoyl-amino 3 carbaimoyloxymethyl-3-cephem-carboxylic acid (290 mg) „
2) Hydrochloride. A solution of j (Z) -2- (2-TpeT-β-butoxycarbonylaminothiazol-4-yl) 2-β-pentenoyl 3-amino-3-cephem-carboxylic acid (360 mg) pivaloylsimethyl ether and trifluoroacetic acid (2 ml) was stirred at room temperature for 150 minutes and concentrated. The residue is dissolved in aqueous
0
five
0
five
0
five
sodium carbonate, dried and concentrated under vacuum. The residue is purified by chromatography on silica gel (0 g) using a mixture of benzene and ethyl acetate (1: 5) as eluent, the fraction containing the ether is collected and concentrated.
The residue is crystallized from ethyl acetate to obtain pivaloyloxymethyl 7 (2-tert-butoxycarbonylamino-azol-A-yl) -pent-2-enoyl 1 amino-3 cephem-carboxylate (485 mg), yield 68%.
NMR (CDClb) ppm: 1.06 (t, J = 8 Hz, 3N); 1.19 (C, 9H); 1.52 (C, 9H); 2, d (quintet, J 8 Hz, 2H); 3.3 (DD, A part ABH, J 7 Hz, J 19.8 Hz, 1H); 3.61 (dd, part ABX, J k Hz, J 19.8 Hz, 1H); 5.03 (d, J 5 Hz, 1H); 5.83, 5.90 (AB, J i, 5 Hz, 2H); 5.97 (dd, J 5 Hz, J 8 Hz, 1H); 6.45 (t, J 8 Hz, 1H); 6.58 (dd, X part ABH, J 4 Hz, J 7 Hz, 1H); 6.73 (s. 1H); 7, (d, J 8 Hz, 1H); 8.94 (bs, 1H).
Similarly, compounds are obtained whose physical constants are listed in Table 1. All compounds have the radical Re and the amido group in cis positions.
The proposed compounds are intermediate products for the synthesis of drugs for oral administration, in contrast to the known drugs manufactured by Bayer

715
and / or Glaxo, which are free acids, which makes it possible to use them only as injections. In addition, the proposed compounds derived from intermediates show high urinary excretion, high blood levels, prolonged blood levels and high integral blood levels depending on the duration of action compared with oral cephalosporins, such as cefuroxime (UK) , SCE 21 Ik (Japan) and T-2588 and CS-807 (Japan). Compounds derived from intermediates show an excellent in vivo i of 2.88 mg / kg compared with T-2588 (10.8 mg / kg) and CS-807 (7.8 mg / kg), which is a significant advantage of the proposed compounds in comparison with the known.
Biological testing of new cephalosporin antibiotics obtained from the proposed compounds by removing the protective amino groups in the thiazole ring.
Male rats weighing 20-25 g are abundantly fed with an aqueous solution of kQ% glucose and vitamins for one day instead of a diet. The next day, the rats were orally administered a suspension of amoxicillin (compounds for comparison) or one of the esters (test compounds) in an aqueous 5% emergency gum with a concentration of 2 mg / ml, the dose administered is 0 mg / kg for each compound used either as a reference or as a test. Then every 15 minutes, blood is taken for analysis to determine plasma activity. The determination is carried out by planting on aha


pe, Escherichia coli is used for esters, and for amoxicillin, Micrococcus luteus.
The test results are shown in Table. 2
The proposed compounds in the tested doses show no signs of toxicity and belong to the category of low-toxic compounds.
Thus, the proposed compounds are intermediate compounds that allow to synthesize new antibiotics of the cephalosporin series, possessing an improved antibacterial .5
activity and injected oralrial but.
权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining pharmaceutically acceptable esters of (2-amino-4-β-thiazolyl) -alkenoylamino-3 cephem-4-carboxylic acid of the formula

sn
Rl
CONH Oh
X
COOFU
Rn rial but. 0 5 0
five
0 40 IU 45
50
where RJ is a t-butoxycarbonyl, benzyloxycarbonyl, formyl, chloroacetyl or nitrobenzylidene protected amino group;
unbranched or branched Cd-C-alkyl, optionally substituted by a methoxy group, C-Cd-cycloalkyl, cyclopentylmethyl, cyclopropylmethyl, hydrogen or chlorine, methoxymethyl, acetoxymethyl, carbomoyloxymethyl, 2-propenyloxymethyl, 2-fluoroethoxymethyl, 2 -methyl, -1, 3, -thiadiazol-5- -thythiomethyl, 2-amino-1,2, -thiazole 5 ylthiomethyl, 1- (2- -hydroxyethyl) -tetrazol 5 -thythiomethyl, 1,2,3-thiadia gold-5thylthiomethyl or isopropoximethyl;
acetoxymethyl, acetoxyethyl pivaloyloxymethyl, pivalo-yloxyethyl, 1- (ethoxycarbonyloxy) ethyl, 4-methyl-2 oxy-1,3 dioxyl-5 enylmethyl, cyclohexylacetoxyethyl; sulfur or X - -SO-, when tert-butoxycarbonylamino, ethyl,
hydrogen or chlorine, R4 - pivaloyloxymethyl, characterized in that (2-substituted amino) thiazol - - - yl-alkenoylamino-3-cephem-4-carboxylic acid of formula
R4 X RIV
R35
N
Biy sn
X
hgO
Yaz Soon
where R ;, Rt, R and X have the indicated values, or its reactive compounds are esterified with a reagent of the formula YR, where R has the specified values, Y is a chlorine, bromine or iodine atom, in an inert solvent, such as dimethylacetamide, dimethylformamide, in the case of neobon
BOONI1
POI
CHjS (1,2,
3-tialiazol-5-yl)
PSN
Ethyl
BOCNH
Ethyl
ACE
Ethyl
BOCNH
Ethyl
POI
eight;
Ethyl
POS
BOCNH
Ethyl
ECE
in the presence of a base, such as alkali metal carbonate, alkali metal ethyl hexanoate at temperatures from 0 to 0 ° C for 0 hours.
ZUO, 1786, 1.20 (s, 9H); 1.5 (p. 9U; 2.04 (d, 1 - 1725, 1678. 7 Hz, 3), 3.42 (dd, D of AVH, J - S Hz, 1280, 1155 J - 9.9 Hz, IH); 3.61 (DP, B from ABC, J -3 Hz, J. 0.9 Hz, G); 5.02 (d, J -5 Hz, 1H); 5.65 (s, 2H); 5.91) (dd, J -5 Hz), J - 8 Hz, 1H); 6.42-6.62 (m, 2H); 6.69 (s, 1H); 8.0 (, J - 8 Hz, 1H); 9.62 (ws, 1H)
ZM5, 1787, 1.21 (s, 9H); 1.51 (s, 9U; 2.02 (d, J - 1678, 1545, - 7 Hz, ZN); 3.39 (4.13 (ABq, J -1 Hz, 11552Н); 4.81, 5 , 05 (AVQ, J - 13.5 Hz, 2H);
5.02 (d, J "4.5 Hz, IH); 5.05 (s, 2H);
5.87 (s, 2H); 5.91 (d, J - 45 Hz, J -8, 5 Hz, IH); 6.52 (q, J - 7 Hz, 1H)}
6.73 (s, 1H); 7.90 (d, J - 8.5 Hz, 1H) | 8.47 (bs, 1H)
2975, 1795. 1.20 (s, 9H); 1.50 (s. 9H); 2.06 (n, J - 1730, 1680, - 7 Hz, 3N); 3.54 (bs, 2H); 3.96, i, 8 1375, 1300, (AVQ, J - 13 Hz, 2H); 5.03 (d, J - 1115, 995-5 Hz, 1H); 5.80 (s, 2H); 5.86 (ld, J -5 Hz, J 8 Hz, F); 6.52 (KB, J - 7 Hz, 1H); 6.72 (s, 1H); 8.15 (d, J - 8 Hz, IH);
8.52 (s, 1H); 9.05 (ws, 1 n).
2960, 1785, 1.07 (t, J 8 Hz, 3N); 1.53 (s, 9H); 2.10
1670, 1540, (s, 3N), 2.45 (quintet, J - 8 Hz, 2H);
1285, 1156, 3.20-3.76 (m, 2H), 4.99 (d, J - 5 Hz, IH);
5.82, 5.88 (L8ka, J - 6 Hz, 2H); 5.95 (dd,
J 5 Hz, 1–9 Hz, IH); 6.1) 3 (t, J -. 8 Hz, IH), 6.53-6.63 (n. 1H); 6.75 (s, F); 7.75 (n, J - 9 Hz, IH); 8.76 (w.SH)
o1.07 (t, J - 7.5 Hz, 3N); 1.53 (s, 9H);
1.53 (d, J - 6.0 Hz, 3N); 2.0 {s, 3N}; 2, li8 (kaintet, J - 7.5 Hz, 2 / 2H); 2.50 (quintet, J - 7.5 Hz, 2 / 2H); 3.21-3.75 (m, 2H); 4.94 (d, J - 45 Hz, I / 2H); 499 (d, J - 4.5 Hz, I / 2H); 5.79-6.02 (m, 1H); 6.42 (t, J - 7.5 Hz, F); 6.1) 9-6.61 (m, 1H); b, 1 (c. F); 6.93 (KB, J - 6 Hz, 1 / 2H); 6.99 (KB, J- 6 Hz, 1 / 2H); 7.70 (d, J -8, 5 Hz, I / 2H); 7.74 (d, J 8.5 Hz, 1 / 2H); 8.60 (ws, 1 / 2H); 9.55 (ws, 1 / 2Y)
o1.06 (t, J - Hz, ZN); 1.19 (s, 9H) | 1.52
(s, 9H); 2.1 | 1 | (quintet, J - 8 Hz, 2H); 3.3 (DD, L of ABX, J - 7 Hz, J - 19.8 Hz, 1H); 3.61 (dd, b and L8X, JH Hz, J 19 H, 8 H, F); 5.03 (d, J - 5 Hz, 1H) j 5.83; 5.90 (ABq, J 4.5 Hz, 2H); 5.97 (dd, J - 5 Hz, J - 8 Hz, F); 6.45 (t,
J - 8 Hz, 1H); 6.58 (dd, X of ABX, J -4 Hz, J - 7 Hz, 1H); 6.73 (s, 1H);
7.88 (d, J - 8 Hz, 1H); 8.94 (ws, IH)
3186, 1802, G, 08 (t, J - 7.5 Hz, 3N); 1.21 (s, 9H) i 1720, 1670, 2.52 (quintet, J - 7.5 Hz, 2H); 3.28 455 (dd, A from AVH, J - 1.5 Hz, J - 19.8 Hz,
F); 3.82 (dd, V of AVH, J - 6 Hz, J -19, 8 Hz, F); 459 (dd., J - 1.5 Hz, J - 4.5 Hz, 1H); 5.84, 5.96 (ABq, J -7 Hz, 2H); 6.23 (dd, J - 45 Hz, J -9 Hz, F); 6.38 (dd, X of DI, J -1, 5 Hz, J - 6 Hz, IH); 6.47 (t, j.
-7.5 Hz, F); 6.72 (s, F); 8.81 (her, F); 8.94 (d, J - 9 Hz, 1H)
1785, 1740, 1.08 St, J - 8 Hz, ЗН); 1.20 (s, 9H);
1675, 1545, 1.53 (s, 9H); 1.53 U, J - 5 Hz, ЗН);
II55, U70 2.25-2.65 (m, 2H); 3.20-3.80 (m, 2H) j 497; 5.02 (2Xd, J - 5 Hz, F); 5.95 (dl, J - 5 Hz, J - 9 Hz, G); 6.40 (t, J 8 Hz, F); 6.49-6.59 (m, W);
6.74 (s, 1H); 6.90 6.96 (2Khka, J. 7 Hz, 1H); 7.40; 7.45 (2X, d, J - 9 Hz, F)
2960, 1785, 1.07 (t, J = 7 Hz. 3N); 1.30 (t, J. 1730, 1675, - 7 Hz, 3N); 1.53 (s, 9H); 1.56 (d. J- 1370, 1290, - 5 Hz, 3N); 2.30-2.66 (m, 2H); 3.10 - 10803.80 (m, 4.20 (KB, J - 7 Hz, 2H);
4.34, 5.00 (2Xn, J - 5 Hz, G); 5.85;
5.95 (2 Chdv. D, J - 5 Hz, J - 9 Hz, 1H) |
nzirzi
stab
Type
LLP
BOCNH
Ethyl
COAE
BOCNH
Ethyl
C1
1IOM
13
BOCNII
Ethyl
UN
Ethyl
CH, 0 (isopropyl)
MON
BOCNH
Ethyl
snao (2lrlpenil)
POI
BOCNH
Ethyl
CH, 0 (2-fluoro-POI ethyl)
BOCNH
Ethyl
SN.OSOM
POM
1B
BOCNH
CH.OCONH,
ACE
BOCNH
Ethyl
CH.OCONH,
IPM
Continuing iaCn. I
08.3220.1818,
83,1725,1722,
70,1523,1288, 53
10.2930.1790,
755, 730,1680,
540,1290,1160, 075
395, 3180, 1802, 753, 179, 1668, 547, 52, 985
120, 2980, 1790, 750, 730, 1680, 5050, 375, 1160
410.2960.1780,
/ 50.1720.1670
540.1365,1150,
120.10E5
410, 1785, 1750, 1725, 1675
3420, 1792, 1755, 1726, 1678, 1548, 1156
3570 W, 3415, 3240 W, 1790, 1752, 1730, 1679, 1546, 1159
3520, 3405, 1778, 1722, 1633, 1540, 1148, 1070
Not given
6.43 (J - 7 Hz, 1I), 6.46-6.63 (and
I), 6.73 (s, G); 6.84; 6.90 (. J - 5 Hz, software; 7.72 (, 1 9 Hz, 1M)
1.07 (t, I 7.5 Hz, ЗН); 1.52 (s, 9H); 2.17 (C, 5H); 2.96 (qiiteg, J 7.5 Hz, (2H); 3.40 (dd, A from AVH, I 7.Hz, I
-19.0 Hz, 1H), 3.62 (d, B from ABX, .1 -3 Hz, J - 19 Hz. 1H), 4.97 (s, 2H); 5.00 (d, J - 5.0 Hz, 1H); 5.94 (dl, J -5 Hz, J - 9 Hz, 1H); 6.43 (t, I
-7.5 Hz, 1H); 6.56 (hell, X of AVH, J
-3 Hz, J 7 Hz, IH); 6.74 (s, 1H), 6.74 (n, J 9 Hz, 1H); 8.7 (those 111)
0.85-1.95 (m, 14n); 1.07 (, J - 8 Hz, 3 Hz, 3N); 1.53 (s, 9H); 2.15-2.65 (m, 4H); 3.20-3.80 (m, 2H); 4.92; 5.00 (2Xd, J - 5 Hz, 1H); 5.82, 5.95 (2Hd d, J - 5 Hz, J - 9 Hz, W); 6.43 (t, .1-8 Hz, IH), 6.48-6.58 (m, 1h); 6.73 (s, 1H); 6.92, 6.98 (2Kvc, J 5 Hz, N); 6.72; 7.74 (2Xd, J - 9 Hz, IH)
1.08 (t, J 7.5 Hz, 3N); 1.22 (s, 9H);
1.52 (s, 94); 2.51 (quintet, I - 7.5 Hz, 2M); 3.64, 3.93 (ABcke, J 16.2 Hz, 2H); 4.76 (, J - 5 Hz, F); 5.89, 6.00 (ABe, J - 5.4 Hz, 2H); 6.19 (dvd, J 5 Hz,
J - 10 Hz, 1H), 6.1 (8 (g, J - 7.5 Hz, IK); 6.73 (s, IH); 8.94 (d, J 10 Hz, 1H); 8, 96 (bs, 1H)
1.07 (t, J - 8 Hz, ZN); 1.20 (s, 9H);
1.53 (s, 9H); 2.45 (quintet) 8 Hz, 2H); 3.31 (s, 3N); 3.53 (s, 2I); 4.28 (s, 2H); 5.03 (d, J - 5 Hz, IH); 5.86 (s, 2H); 5.90 (dd, J - 5 Hz, J - 9 Hz, 1H); 6.43 (t, J - 8 Hz, 1H); 6.73 (s, 1H); 7.77 (d, J 9 Hz. 1H); 8.53 (W, 1H)
1.0 (t, J 8 Hz, 3N); 1.15 (d, J -6 Hz, 6n); 1.22 (s, 9H); 1.53 (s, 9H); 2.46 {quintet, J 8 Hz, 2H); 3.58 (s, 2H); 3.60 (septet, J - 6 Hz, 1H); 4.36 (s, 2H); 5.05 (d, T - 5 Hz, 1H); 5.88 (s, 2H); 5.90 (dd, J - 5 Hz, J 9 Hz, W); 6.45 (t, J 8 Hz, 1H); 6.75 (s, 1H); 7.80 (d, J. 9 Hz, IH)
1.08 (t, J 7 Hz ZN); 1.23 (s, 9H); 1.53 (s, YO); 2.27-2.60 (m, 2H); 3.58 (s, 2H); 3.97 (m, 2H); 4.36 (s, 2H); 5.04 (d, J 5 Hz, 111); 5.13-5.33 (m, 2H); 5.67-6.10 (m, 1 (H); 6.41 (g, J.
-7 Hz, IH); 6.73 (s, IH); 7.64 (d, J 8 Hz, 1H)
1.07 IT, J. 8 Hz, ZN); 1.22 (s, 9H);
1.52 (s, 9H); 2.47 (dd, J - 8 (c, J «« 8 Hz, 2H); 3.58 (s, 2H); 3.68 (dt, J 2.5 Hz, J 30 Hz, 2H) ; 5.1 (2 (s, 2H); 4.5i | (dt, J 4.5 Hz, 2H); 5.04 (d, J 1 |, 5 Hz, IH); 5.87 ( s, 2H); 5.94 (dd, J - 4.5 Hz, W); 6, Vi (T, J.
-8 Hz, IH); 6.73 (s, 1H); 7.81 (fl, j
-8 Hz, IH); 8.56 (UK, IH)
1.06 (t, J - 8 Hz, 3N); 1.21 (s, 9H);
1.53 (s, 9H); 2.05 (s, 3N); 2.41 ((quintet, J - 8 Hz, 2H); 3.36, 3.55 (Avka,
J 18 Hz, 2H); 4.78, 5.07 (AVka, J
-13.5 Hz, 2H); 5.02 (d, J. 5 Hz, 1H); 5.86 (s, 2H); 5.89 (dd. J 5 Hz, J
 8 Hz, IH), 6.1 (1 (t, t.) - 8- Hz, III); 6.71 (s, 1H); 7.82 (n, J - 8 Hz, 1H); 8.78 (ws, 1H)
1.06 (t, J - 7.5 Hz, 3N); 1.46 (d, J
-6 Hz, ЗН); 1.51 (s, 9H); 2.06 (s, 3N); 2.45 (quintet, J - 7.5 Hz, 2 / 2H); 2.50 (quintet, J 7.5 Hz. 2 / 2H); 3.4 ((Ws, 2H); 4.12-5.31 (m, 5H); 5.63-5.92 (m, 1H); 6.38 (t, J - 7.5 Hz, IH); 6.72 (s, 1H); 6.89 (q. J 6 Hz, 1 / 2H); 7.04 (KB, J 6 Hz, I / 2H); 7.76 (d, J 8 Hz, 1H)
1.07 (t, J 7.5 Hz, 3N); 1.23 (s, 9H); 1.54 (s, 9H); 2.47 (quintet, J 7.5 Hz, 2H), 3.40, 3.56 (AVke, J 18 Hz, 2H); 4.79, 5.07 (ABq, J - 13.5 Hz, 2H); 5.02 (d, J. 5 Hz, 1H); 5.03 (s, 2H); 5.B7 (s, 2H); 5.90 (dd, J - 5 Hz, J. 8.5 Hz, IH); 6.41 (t, J = 7.5 Hz, H); 6.76 (s, 1H); 7.74 (d, J 8.5 Hz, 111); 9, P (s, 1H)
Note AC is acetyl; ACE - acetoxyethyl, LOM - ecetoxymethyl BOC - tert-butoxycarbonyl, w - broad, BOC - benzioipoxycarbonyl; COAE - “iclohexylmethoxyethyl, CP5K - chloroperbenzoic acid; DHM - dichloromethane; DND - dinetraladamide; DMF - dimethylformamide; DOL is 1-methyl-2-oxo-1,3-dioxol-5-ylmethyl; ECE is ethoxycarbonyloxyethyl; POS - liapoxyloxyethm; Non-methyl; TFA - trifluoroacetic acid.
Note. R (- amino group, R - pivalo-yloxymethyl (after oral administration to mice).
table 2
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同族专利:
公开号 | 公开日
ES8801922A1|1988-03-16|
IT8667257D0|1986-03-28|
BR1100475A|1999-10-05|
GB8607855D0|1986-04-30|
GR860838B|1986-07-29|
ES557640A0|1988-03-16|
DE3610581A1|1986-10-02|
ATA82386A|1990-09-15|
JPS6289A|1987-01-06|
AU5520486A|1986-10-02|
CH669600A5|1989-03-31|
CA1269655A|1990-05-29|
KR860007266A|1986-10-10|
DE3610581C2|1993-04-01|
FR2579597B1|1991-04-12|
HK47993A|1993-05-27|
GB2173194B|1989-06-28|
NL192926B|1998-01-05|
NL192926C|1998-05-07|
ES8800237A1|1987-11-01|
SU1581223A3|1990-07-23|
KR870001983B1|1987-10-24|
AT392471B|1991-04-10|
JPH0588715B2|1993-12-24|
GB2173194A|1986-10-08|
IL78301A|1991-07-18|
US4731361A|1988-03-15|
SU1575941A3|1990-06-30|
IT1191997B|1988-03-31|
AU580855B2|1989-02-02|
IL78301D0|1986-07-31|
NL8600804A|1986-10-16|
FR2579597A1|1986-10-03|
BE904517A|1986-07-16|
ES553426A0|1987-11-01|
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法律状态:
优先权:
申请号 | 申请日 | 专利标题
JP6728085|1985-03-29|
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