Method of producing derivatives of hydantoin

专利摘要:
1-Substituted-spiro[chroman-4,4'-imidazolidine]-2',5'-dione compounds are useful for treating arrhythmia.
公开号:SU1445559A3
申请号:SU864027225
申请日:1986-04-02
公开日:1988-12-15
发明作者:Минами Норио；Матукура Масаюки；Уеда Коитиро；Танака Сатору；Игараси Тосидзи
申请人:Эйсай Ко.Лтд. (Фирма)；
IPC主号:

专利说明:


s
This invention relates to a process for the preparation of novel hydantoin derivatives having an antiarrhythmic effect with very low toxicity.
The purpose of the invention is to obtain new derivatives of hydantoin, which have an activity that is not characteristic of this range of compounds.
Example 1, 2,2-Dimethyl-6-fluoro (4-hydroxyperidine) propyl (spiro) chroman-4,4-imidazolidin3-2, 5 is a dione. .
 but. 2,2-Dimethyl-6-fluoro-1 - 3-bromopropyl (spiro) chroman-4,4-imidazol-, 5-dione.
1.0 g (25 mM) of sodium hydride (60% suspension in mineral oil) was added to a solution of 6.6 g (25 mM) of 2,2-dimethyl-6-fluorospiro (chroman-4,4 - imidazolidine) - 2, 5 -dione and to a solution of 10.1 g (50 mm) of 1,3-dibromopropane 5 to 70 ml of dimethylformamide at 15-30 C. The mixture was stirred at room temperature for 5 hours. The reaction liquid was poured into ice / water. After extraction with ethyl acetate, the resulting ethyl acetate layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off at low pressure, 12.7 g of the residue was purified using silica gel column chromatography (developed, dichloromethane / ethanol) to obtain 6.95 g (72.2%) of the desired product. M.p. 190-192 ° C.
Calculated,%: C 49.87; H 4.71; N 7.27.
C fiH eBrFNjOj.
Found,%: C 49.63; H 4.59; N 7.15.
NMR (CDCl1) 5: 1.32 (3H, s); 1.50 (ЗН, s); 2.02 (1H, d Hz); 2.24 (2H, k, Hz); 2.60 (1H, d Hz) 3.40 (2H, tons Hz); 3.74 (2I, t, Hz); 6.36 (1H, s); 6.45-7.10 (ЗН, m).
B. 2,2-Dimethyl-6-fluoro-1 (4-hydroxypiperidino) propyl (spiro) chroman-4 4 -imidazolidine -2, 5 -dione,
 6.0 g (15.6 mm) of the methyl compound obtained in Example 1a, 3.15 g (31.2 mm) of 4-hydroxypiperidine, 4.31 g (31.2 mm) of calcium carbonate and a solution of a small amount Potassium iodide in 70 ml of dimethylforma-MIDA was stirred for 5 hours at 90 ° C. The reaction liquid was poured into water and extracted with ethyl acetate. Semi
five

0

oh oh

50 55
35
45
The ethyl acetate layer was washed with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ethanol-ethyl acetate. 5.85 g (92.6%) of the desired product was obtained, which was then converted to its hydrochloride salt in the usual way. M.p. hydrochloride salt 211-2J3 C (free form 195-197 C).
Calculated,%: C, 62.20; H 6.96;
N 10.36.
C2, H, gFN, 04.
Found,%: C 61.92; H 7.01; N 10.25,
NMR (CDCl 2): 1.32 (3H, s); 1.52 (ЗН, s); 1.60-300 (14H, m); 3.62 (2H, t, Hz); 3.45-3.80 (1H, m); 6.50 - 7.10 (ЗН, m).
EXAMPLE 2-76. Using the procedure of Example 1 (a-b), target compounds I were obtained, given in t-abl. 3 and 4.
The intermediates obtained in Example la are shown in Table. 1 and 2.
The results of the following pharmacological tests show the effectiveness of the proposed compounds.
Experimental example.
1. Caused by chloroform arrhythmias (mice).
Mice were placed in a device filled with chloroform gas. After death, ventricular pulses were counted by an electrocardiogram. The antiarrhythmic activity of the tested compound was determined on the basis of the effect of alleviating tachycardia. The lethal, toxic, and minimal effective doses of each compound were determined by administering experimental doses at a typical ratio of 2. Compounds were tested by administration in two ways, i.e. orally and intravenously. From the obtained results, it was concluded that the relative oral exposure of these compounds. The hold time was obtained from the observed medical effects when the time interval between the administration of the compound and the treatment of the mice with chloroform was reduced.
In tab. 6 shows the results (effective dose for arrhythmias and lethal dose) of experiments where the test compound was administered to mice.
31445559
orally one hour prior to treatment, 3, acute toxicity (rats),
chloroform (as cf. Acute toxicity test
For example, the standard medical drugs used in rats (oral administration) of the drugs were quinidine, and they were used with typical pyramids and phenytoin. Compounds according to the invention, - 6From table. 6 shows that the antiarrhythmichloro-2,2-dimethyl-1 - s- (4-hydroxypiperidic activity of the compounds on isobidically) propyl (spiro) chroman-A-A-imidenerateny significantly exceeds active-polidine -2 -3-dione (compound I) of comparative compounds, and co-and 2,2-dimethyl-6-fluoro-1 - 3- (4-hydroxy-safety ratio proposed by piperidine) propyl (spiro) chroman-4- 4 - compounds (the ratio of lethal and epimidazolidine) -2, 5-dione (compound doses) are higher than the beating coefficient 2).
safety of comparative compounds. The test results are summarized in the impact of the proposed compounds g table, 5.
It lasts from 3 to 6 hours after oral administration. The results of the described trials of this administration prove that the proposed compound 2, caused by aconitine arrhythmias, does not have a remarkable anti- (mouse) length. Rhythmic activity, low toxicity I-IbiraaM introduced a toxic dose - aconitine and investigated caused by this pasnes and they can be used to dose the ventricular extastole. They are preferred antiarrhythmics by intraperitoneal administration.
 0.1 μg / kg of aconitine was administered, the antiarrhythmic mechanism of the compound in the general case, the ventricular tachi-25 of the invention was investigated on cardi in 20 minutes. In the basis of the effects on the potential of the actual experiment, the tested soy beings and the resting potential of the extracted in doses in example 1 were injected with the myocardium of guinea pigs and pigs with mice orally and after definitively using microelectro clothes. It was established that aconitine injection was administered by injection, which suggested that the compounds were reduced. The occurrence of arrhythmia was used and the rate of increase of the potential of the real-ventricular extrasisteal was calculated from vi, although they do not have any electrocardiogram to determine the effect of the peco potential. In particular, the antiarrhythmic activity. When electrical stimulation is strong, the inhibitory effect on
In tab. 7 summarizes the results of the action also stronger. torture in which a verifiable compound is a property of antiarrhythmidine or a comparative standard class 2 agent (quinidine, a medicine (quinidine i-shea disopyramide) disopyramide). This fact indicates that the mechanism and diseases, for which an abdominal injection of 0.1 mg / kg of aconitin, were administered orally one hour before the intravenous mechanism. The compounds of the invention are an effective dose given in effectives (i.e., supraGlobe table. 7 is the dose that is non-patient and ventricular arrhythmias), is the same for treating aconitine-induced For these compounds and antiarrhythmic-ventricular tachycardia so that class 2. to provide the ratio of normal sinu-one. One of the pharmacological properties of the sovioge rhythm to the ventricular pulse of the compounds of the invention is 1: 1. Most of the tested compounds do not manifest their effectiveness. effect in myocardial colicration. These properties, which are much smaller than ke-are used when using these amounts of quinidine or dispyramide. ® ° Compounds as antiarrhythmic. When these compounds are used agents. For example, quinidine and diolium in quantities greater than ephesiramide reduce the ability of the relative amount (see, Table 2), myocardial shrinkage several times that caused by aconitine ventricular more than what is needed for recovery. - lizirovaniya antiarrhythmic ubiquitous normal sinus rhythm. vii However, these compounds do not. This effect lasts almost 6 hours after affecting the ability of co-oral administration of myocardial withdrawal, even in the amount
which is 10 times the effective dose for antiarrhythmia.
The described compounds are effective for the treatment and prevention of various types of arrhythmias, such as ventricular arrhythmias and atrial (supraventricular) arrhythmias. When used as antiarrhythmic agents, they are administered orally or parenterally (intramuscularly, subcutaneously or intravenously). The dosage varies depending on the patient, the symptoms and the age, and is not strictly limited. In general, the dosage should be 1-1000 mg / day, preferably 100-300 mg / day, for adults. Effective doses of the compounds obtained are given in table. 6 and 7.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining dantoin derivatives of the general formula
OS - N-CCH V HN.
G .so
 Ri,
de X and Xj are different and each is a water.
genus or halogen;
R 4 and Rj are the same or different and each is a hydrogen atom or a lower alkyl group,
n is an integer from 2. to 7; Z is either a group of formula
-NC
Of R
where R and R; are the same and mean lower alkyl.
together with the nitrogen atom to which they are bound form a group, the formulas
where iij- is a phenyl or a group of the formula
ORg.
where Rg is hydrogen or lower alkyl, characterized in that the compound of the formula
Xj go co
20
25
thirty
.RI
where X ,, X, R, are specified
meanings
subjected to interaction with the compound. by formula
y- (CH2) f, -y, where Y. is halogen;
p - has the indicated values, in the presence of an alkali metal hydride in an organic solvent, and the resulting compound of the formula
OS-N-tCHx n-Y
where is x
one
R "Ri
2 n Y have the indicated meanings
is reacted with a compound of the form 0 lu HZ, where Z has the indicated meanings,;
in the presence of calcium carbonate in the medium of an organic solvent with the separation of the target product.
Table 1
ten
Table 2
The top column is calculated, the bottom one is found.
"about
" but . h y «1 n
c
Oj
g
(
g
g
6
I
 X
Sh
Sh
tt,
i
Cx i
vO
S
o "
i
about m
sc ”h
6
her
g
at
n
Bt
nu
J
and
A
about
J
1-4r "S
oh
S

SIt
Cf
 “H O
m n
Compound I
OC-N (CH2) n-7
.Ri X,
6-F - H. C, H
Cjh
LD
50
mg / kg
930 858 860 780
Table
25
400
6-F
H
CH.
sn.
Quinidinsulfonate
Disopyramide Phosphate
Phenytoin sodium
OS-K- (SNO) and -HHO IIi
-Shz
about sns
OS-Y No. 2) 3- (3} HNv CO
{about Shz
General Formula (A)
2 3 4 5 6 7
General formula (B)
-NQ-OSS
25
400
200
800
50
600
Table
(BUT)
(AT)
 ,
N N N N
80 5
ten
40
40
40
five
five
10 80
Hinndsin sulfate Disopyramide phosphate
6-C1
8-C1
10 80 40

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JPH0276882A|1988-06-20|1990-03-16|Eisai Co Ltd|Optically active hydantion derivative|

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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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JP59013442A|JPH0441149B2|1984-01-30|1984-01-30|

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