Method for synthesis

专利摘要:
Simple amides and derivatives thereof useful for inhibiting the angiotensinogen-cleaving action of the enzyme renin of the formula: <CHEM> wherein R1 is (C6-C8)cycloalkyl or i-propyl; R2 is (C3-C5)alkyl, phenyl, methylvinyl, dimethylvinyl, halovinyl, hydroxy(C1-C3)alkyl or amino(C1-C4)alkyl; R3 is (C1-C6)alkyl or morpholinoethyl; and Het is defined to include certain mono and bicyclic nitrogen-containing heterocyclic rings or heterocyclylalkyl groups.
公开号:SU1651786A3
申请号:SU884613032
申请日:1988-12-14
公开日:1991-05-23
发明作者:Луис Росати Роберт
申请人:Пфайзер Инк. (Фирма)；
IPC主号:

专利说明:

S)) - CHj-- CH (NH-C / 0 / -Het) ... CH2-0-C (O)
with amine III NH2R3 gDe Het, K, Kg cm, above, in the environment of lower al canola at room temperature and isolation of the target product in its scope. The invention relates to a method for producing new simple amidov indols that exhibit hypotensive activity in mammals, including including humans, associated with their ability to inhibit angiotensinogen splitting under the influence of renn.
The purpose of the invention is the synthesis of new amide derivatives of indole, showing a more effective inhibition
CH2. CH - "- R2
free form. New compounds show more efficient inhibition of renin than polypeptides. And table.
WITH
reninosis compared with polypeptides
Example I. 2R, 4S, logex-5 (5 chlorindol -2 -yl-carbonylamino) 4-hydroxy-2- (2-chloro-2 / -propenyl) -N methylhexamide (Het-5-chloroindol-2- yl; R - cyclohexyl; R2 - C (C1) CH2 and Kg - CH3.
A. 2K, 48,58-6-Cyclohexyl-5- (5-chloro-indole) -21 -yl-carbonylamino) 0
ate
V
oo
O5

s
3
-2- (2-chloro-2 propenyl) -) hexacolacton.
165.5 mg (0.5 mmol) of 2R, 48.53-b-cyclohexyl-5-amino-2- (2-chloro-2-propenzho Uteksanoloktona hydrochloride, 50 , 6 mgt
(0.5 mmol) N-methylmorphonic, 97.8 mg (0.5 mmol) of 5-chloroindole-2-carboxylic acid, 67.5 mg (0.5 mmol) of Thydroxybenzotriazole, and 103 mg (0.5 mmol) of dicyclohexyl - carbodiimide, and then the resulting reaction mixture is stirred at room temperature for a night. The reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is redissolved in ethyl acetate, washing the agate successively with water, using sodium bicarbonate and sodium bicarbonate and brine, and then dried with n-magnesium sulfate. The solvent is removed and the residue, 280 mg, is chromatographed on silica gel using chloroform as eluent, and 226 mg of the expected product is obtained.
B. 2K, 48.53 6-Cyclohexyl-5- - (5-chloroindol-2, or carbonylamino) -4thydroxy 2 (2-- chloro-2-prolenyl) N-methyl g e cs anamide
A solution containing 226. Mg of the product obtained in Example A in 10 ml of methanol is saturated with methane type gas, followed by keeping the reaction mixture at room temperature for 1.5 h. The reaction mixture is evaporated to dryness and the residue is triturated with ether 155 g yield of the desired product
NMR analysis (CDjOD) ft, ppm: 2.7 (ZN, s); 5.15 (2H, m); 7.0-8.0 (4, N, m
Example 2. The procedure of Example Au B is used. The result of the interaction of the corresponding initial reagents is the compounds listed in Table.
To 10 ml of methylene chloride at 0 ° C, 20 mg (0.1 mmol) of 3-chloro-indole-3-carboxylic acid, 30 mg (0.1 mmol) of 2R, 48.58-6-cyclohexyl-5- amino-2- (2 methylpropyl) - -H hexanolactone hydrochloride, 15 µl (0.1 mmol) of cytophosphoric acid diethyl ester and 42 µl (0.3 mmol) of triethylamine0 Dimethylformamide (1 ml) are added to the reaction
0 "j 0 5
Q
0
five
7864
stirring at room temperature overnight. The reaction mixture is evaporated to dryness and dissolved in ethyl acetate, followed by washing successively with water (2 times), saturated sodium bicarbonate (2 times) and brine. The resulting solution was dried with sodium sulfate and evaporated to an oil, 51 mg.
B. 2E, 48.53-6-Cyclohexyl-5- (5- -chloroindol-3-yl-carbonylamino) -4-tyroxy-2- (2 methylpropyl) -Y-methylhexanamide
The solution containing the product of Example A in 10 ml of methanol is saturated with methylamine at room temperature, and then the resulting reaction mixture is stirred at room temperature for 2: hours. The mixture is then evaporated to obtain 61 mg of foam, which is chromatographed on silica gel using as eluent a mixture methanol: chloroform The fractions containing the desired product are combined and concentrated to yield 14 mg of the desired product.
NMR spectrum (CD3OD),, ppm: 0.95 (6H, d, J 5 Hz); 2.7 (3N, s); 7.0-8 (4H, m).
Example 4. Using the procedure of Example 3, the following compounds are obtained as a result of the interaction of the corresponding starting reagents, which are listed in Table 2. 2
Example 3. 2K, 48.58-6-Cyclohexyl-5 (5-chloroindol-3 -yl-carbonylamino) -4-hydroxy-2- (2-methyl-propyl) - N-methylhexanamide (Het - 5 chloro-indol-3-yl; R, - cyclohexyl; RЈ - isopropyl; R CH.
A. 2R, 48,58-6-Cyclohexyl-5- - (3-ChlorindOl-3 -yl-carbonylamino) -2 -2 (2-methylpropyl) -hexanolactone.
The ability of the proposed compounds to act as antihypertensive agents in inhibiting renin can be seen from the following in vitro test.
Inhibition of angiotensinogen-splitting renin activity in vitro.
Blood plasma is collected from healthy laboratory personnel, which is then combined and stored until needed in a frozen fish.
Before use, a portion of plasma No. 1 is thawed and centrifuged, and the resulting supernatant is mixed with protease inhibitors and buffered to pH 7.4. Renin inhibitors, taken at various concentrations, are then added to individual aliquots of plasma supernatant. The resulting mixtures (310 L mbda) are incubated for 3 hours at 37 ° C together with control mixtures that do not contain renin inhibitors. After incubation, the mixtures are rapidly cooled in ice water, and each of the samples is analyzed for angiotensin 1 yield using angiotensin antibody. The yield of angiotensin obtained in the presence of renin inhibitors is compared with that obtained without it, and then the degree of inhibition is calculated. Using data obtained from double incubations of each of the tested inhibitors taken in different concentrations, calculate the concentration of inhibitor in the incubation mixture necessary to obtain 50% inhibition of renin angiotensinogen cleavage for each of the tested inhibitors.
Angiotensin 1 in refrigerated incubations is tested by radioimmunoassay using components from the renin radioimmunoassay kit supplied by hecton Dickinson and Co. (Orangeburg, N.Y.).
Table 4 presents the data characterizing the inhibition by compounds of human renin, expressed as the values of the preparation’s preparation, inhibition by 50%.
The standard used for comparison is pepstatin, which has a size of 1 ° C of 10 µM. Compounds produced according to the invention and which are simple, targeted amino acid derivatives, in contrast to polypeptides, show a significant improvement.
1C50, i.e. required for

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining the amide of the general formula
.R,
Hei- 00
m
COHWR,
ten
HE
(I)
where Het means a group of general formula
15
five
0
where X is hydrogen or 5-chloro;
Cl. - hydrogen or C -C V al kil;
Cg-Cd cycloalkyl;
C-C-alkyl, methylvinyl, halo-vinyl or hydroxy-
S C} -al kil;
C.-Cg-alkyl or morpholinoethyl,
h. y u and with the fact that
synthesis of new amide derivatives of indole, showing a more effective inhibition of renin in comparison with polypeptides, a compound of the general formula
R4 - R2
R3
about tl and with a view
35
Het-C ON H
40
about-
about
where Het has the indicated meanings;
K.- C-Cj-alkyl, methylvinyl, haloidvinyl or hydroxy-C-Sdil,
subjected to interaction with the amine of the General formula
R61%
where R-J is as defined, in a lower alkanol at room temperature, with the desired product being isolated in free form.
Table

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引用文献:

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EP0181110A3|1984-10-22|1988-05-11|Kissei Pharmaceutical Co. Ltd.|Histidine derivatives as renin inhibitors|

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US4727060A|1984-11-13|1988-02-23|Ciba-Geigy Corporation|Novel 5-amino-4-hydroxyvaleryl derivatives|FR2638747B1|1988-11-08|1993-12-24|Synthelabo|PHENYLOXYPROPANOLAMINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION|

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AU622330B2|1989-06-23|1992-04-02|Takeda Chemical Industries Ltd.|Condensed heterocyclic compounds having a nitrogen atom in the bridgehead for use as fungicides|

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ID23789A|1997-02-26|2000-05-11|Pfizer|HETEROARIL-HEXANOAT AMIDES, AMERICANS, AND THE USE AS SELECTIVE OBSERVATIONS OF MIP-1, ALFA THAT BINDED TO CCR1-HIS RECEPTORS|

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US7405210B2|2003-05-21|2008-07-29|Osi Pharmaceuticals, Inc.|Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase|

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CN108218865B|2018-03-31|2020-06-26|济南市儿童医院|Amide derivative and application thereof in cardiovascular and cerebrovascular aspects|

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CN108456207B|2018-03-31|2020-11-20|浙江药苑生物科技有限公司|Amide derivative and application thereof in cardiovascular and cerebrovascular aspects|

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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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US13237387A| true| 1987-12-15|1987-12-15|

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