前苏联专利SU1364237A3 Method of obtaining derivatives of 1,4 dihydropyridine or their hydrochlorides

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专利摘要:
1,4-Dihydropyridine derivatives of the formula:- and their pharmaceutically acceptable acid addition salts; where R is aryl or heteroaryl; R1 and R2 are each independently C1-C4 alkyl or 2-methoxyethyl; Y is -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(CH3)2-; R3 is hydrogen or a group selected from:- where R4 is H, C1-C4 alkyl, C3-C6 cycloalkyl, -COO(C1-C4 alkyl), -CH2COO(C1-C4 alkyl), aryl, -S02.aryl, or heteroaryl, and X is 0 or S; where R5 is 1-pyrrolidinyl, -NH2, -NH(C1-C4 alkyl), -N/C1-C4 alkyl)2, or -NH(CH2)2N(C1-C4 alkyl)2; where R6 is C1-C4 alkyl or aryl; where R7 is -CONH(C1-C4 alkyl) or -COO(C1-C4 alkyl); where R8 is -CN, -SO2(C1-C4 alkyl) or -SO2 aryl; (h) -CH2CO.R9 where R9 is -NH2, -NH(C1-C4 alkyl), -NH.aryl or C1-C4 alkoxy; (i) -SO2.R10 where R10 is -NH2, -N(C1-C4 alkyl)2 or C1-C4 alkyl; and (j) -CO.R" where R" is H, halomethyl, -COO(C1-C4 alkyl), -CH2O(C1-C4 alkyl), -CH2CO(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkoxy, aryl, heteroaryl, morpholino or 5-oxo-pyrrolidin-2-yl. The compounds have utility as anti-ischaemic and antihypertensive agents.
公开号:SU1364237A3
申请号:SU833641411
申请日:1983-09-02
公开日:1987-12-30
发明作者:Фразер Кемпбэлл Симон；Эдвард Кросс Питер；Кендрик Стаббс Джон
申请人:Пфайзер Корпорейшн (Фирма) (Ра)；
IPC主号:

专利说明:

11364237
The invention relates to the field of production of new 1,4-dihydropyridine derivatives of the general formula
RI n
HjCOOCOx COOCzHs, i,
NsSLg SNg-OCHjCHj-N ir-C-NHRz H
where R is mono- or disubstituted chlorine phenyl; 10 R, is hydrogen, (C, -C) -alkk-sh, or their hydrochlorides, has a hypotensive effect.
The purpose of the invention is the development of a new method for obtaining new 154-15 dihydropyridine derivatives with valuable pharmacological properties. Example 1 4- (2 5 3-Dichlorophenyl) n
For Compound 1a, effective dosages are 3-10 mg / kg, while the levels of normal blood pressure of dos3-ethoxycarbonyl-5-methoxycarbonyl-6methyl-2-C2- (4- {H-methylcarbamoyl} pipo-20 are burned 1 h after receiving razin-1-yl) ethoxymetsh1 -1,4-dihydroPi Dose. Duration of action of pre-idine (Compound 1a).
higher than 6h
4- (2,3-Dichlorophenyl) -3-ethoxy-arbonyl-5-methoxycarbonyl-b-methyl-2- 2- (piperazin-1-yl) -ethoxymethyl 1,4-dihydropyridine (2.55 g) was dissolved in dry methylene chloride. (50 ml) and methylisodia was added with stirring. The toxicity of the compound was investigated. When administered into the mouth one time per day, 45 rats were used for 14 consecutive days at dose levels of 20 and 40 mg. / kg It has been found that compound 1a does not cause any visible j harmful effects. At higher donates (Oj3 g). After stirring at 30 times, a decrease in the room temperature for 16 hours is observed, the solvent is removed by evaporation. The residue is suspended in aqueous sodium carbonate (50 ml), extracted with ether (2 x 50 ml) and then with methylene chloride (3 x 50 ml). The methylene chloride extracts were combined, dried over magnesium sulfate, filtered, and evaporated to give a dark brown oil. (1.82 g). After stirring in ether, a solid crystallized out, which was recrystallized from ethyl acetate, and 167 g of the title compound were obtained, mp 72-74 ° C.
Calculated,%: C 54.84 | H 6.02; N 9.84.
Cij Hj N OtCli.
Found%: C 54.18 | H 5.96; N 9.93.
Analogously to Example 1, 4- (2-chlorophenyl) -3-ethoxycarbrash1-5-methoxycarbonyl-6-methyl-2-2 (methylcarbamoyl piperazin-1-yl) ethoxymethyl-1.4-dihydropyridine (compound 16) is obtained. hydrochloride, m.p., 165-1b7 ° C.
Calculated,%: C 54.64; H 6.35; N 9.80.
CitH jjN40tCl-NS
Found,%: C 54.49; H 6.31; N 9.67.
In analogy to Example 1, but using potassium dtanate and aqueous acetic acid instead of methyl isocyanate, 4- (2,3-dichlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- 2- (4-carbamoyl-piperazin-1-yl ) -ethoxymethane1 1,4-dihydropyridine (compound 1c) as a hemihydrate, so pl. 168-170 C.
Calculated,%: C 53.19; H 5.89; N 9.78.
.
Found,%: C 53.10; H 5.73; N 9.93.
For Compound 1a, dosages of 3-10 mg / kg are effective, while normal blood pressure levels are reached 1 hour after administration of the Dose. Duration of action is
Fail 1 h after administration of the Dose. Duration of action is
higher than 6h
The toxicity of the compound was studied. When administered to the mouth one time a day, in 45 rats for 14 consecutive days at dose levels of 20 and 40 mg / kg. It has been found that compound 1a does not cause any visible adverse effects. At higher values up to 5
laziness of food, but it does not affect body weight. On the 7th-8th day, an increase in water consumption is observed depending on the dose, but this is absent at the end of the experiment. No animals died during the 14-day study period. No hematologic evidence of toxicity, and histopathological studies
0 t end of the experience did not reveal any deviations from the norm.
In order to estimate the duration of action of the compounds of general formula I, they were administered intravenously (selecting the dose
5 in such a way as to cause approximately 60% of the maximum coronary dilatation) and recorded the time required to reduce the peak effect on the coronary vasculature by 50%. The following results were obtained, h :. Nifedipine
0
five
0.5 7
1.2. 5.5
Compound 1a
Compound 16.
Compound 1c
Thus, the compounds obtained are characterized by a longer clearance time compared with nifedipine. .
31364237

权利要求:
Claims (1)
[1]
The invention of the invention R N
The method of obtaining derivatives 1,4-G1G
digchropyridine general formula NzS N CHjOCH2CHj,
RI nN
H3COOCO CCOoCiHj where R has the indicated values,
n, sLLSn, o-CH, Ckg-O - - gpodverzhdayut interaction with cyanate
Jj potassium in the presence of acid or with
where R, is mono- or disubstituted by chloisocyanat of the general formula:
rum phenyl; .- RjNCO,
Rj is hydrogen or C, -C -papil, where R C, -C is alkyl,
or their hydrochlorides, differ-
u and with the fact that the compound total1product in free veed or in the form
hydrochloride formula.
Compiled by And, Bocharova Editor I. Rybchenko Tehred L. Serdyukovz Proofreader V. Butt ha
Order 6387/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Project, 4

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法律状态:

优先权:

申请号 | 申请日 | 专利标题

GB8225246|1982-09-04|

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