Method of producing derivatives of pyridazine

专利摘要:
The invention relates to pyridazine derivatives, in particular the preparation of compounds of the general formula R 4NH-ci NN CR j-CRz-CR ;, where R is lower alkyl or Rj is H or R, + P.2 f-CH CH-CH CH- 7; Rj - - H or R - - (CH2) 4 -CH, where n is an integer l, 2,3,7; Rs-H or CH ,; R-H, OH OR,; R7 - lower alkyl, which have activity against convulsions, strychnine, bicuculline, electroshock. The purpose of the invention is the creation of new, more active and low-toxic substances of the specified class. Synthesis is carried out from the chlorine derivative of pyridazine and an excess of the corresponding amine in the solvent medium (aliphatic alcohol at the boiling of the reaction mixture in the presence of copper. New substances have a toxicity of 250 mg / kg L0gr and a better activity than the known analogues in action. Table 3 SAAE O ) soa
公开号:SU1356960A3
申请号:SU823475703
申请日:1982-08-10
公开日:1987-11-30
发明作者:Вермут Камиль-Жорж；Шамбон Жан-Пьер
申请人:Санофи (Фирма)；
IPC主号:

专利说明:

This invention relates to a process for the preparation of new pyridase derivatives on the general formula
%
RCF / VNHBL;
Th -n
where RI is lower alkyl or phenyl; , R ,, - hydrogen,
or R and R. together form a group
-CH CH-CH CH- to form a benzene ring attached to a pyridazim ring;
hydrogen or phenyl; group of general formula
CH - R6
 - R. (.
Where
7,
five
p - integer 1,2,3 or
RJ is hydrogen or methyl;
R is hydrogen, hydroxyl, group
ether common ffiopmuly OR ,,
where R is lower alkyl with valuable pharmacological properties.
The purpose of the invention is to obtain new pyridazine derivatives, which have a pharmacological advantage over known analogues of this effect.
Example 1. 3-Butylamino-4-methyl-6-phenyl-pyridazine tartrate (CM 30 434).
g
RR, - CH3; R, - H; R, - - (CK) A mixture of 10.3 g of 3-chloro-4-methyl-b-phenyl-pyridazine and 7.5 g of butylamine in 100 ml of butanol is boiled under reflux for 48 hours. The mixture, a chlorinated derivative, is obtained, is poured into 200 ml of water and the compounds (I) shown in Table 1 are extracted. ethyl acetate. The organic phase is separated and its extract is aqueous 5N. sulfuric acid solution. Acidic extract pap1: hydrate with sodium bicarbonate, then extracted with chloroform. The solution is washed with water, dried and the solvent is evaporated. An oily product is obtained.
This oil is dissolved in hot isopropanol, an equivalent amount of tartaric acid is added and the mixture is heated until dissolved. After cooling, solid colorless primer is suctioned out. Example 7. 3- (2-Propionyloxyethylamino) -4-methyl-6-phenyl-pyridazin 50 (maleate) (CM 30 098).
CH CH OOSN OH.
16 g of the compound CM 30 094 (base prepared in example 2) dissolve
55
r yut. in 250 ml of pyridine by stirring at room temperature. Then, drop by drop, while stirring, 6.3 ml of propionyl chloride is added. At the end of the addition, the further substance that is recrystallized from isopropanol, mp 184-186 ° C, yield 12.5 g,
Tartrate crystallizes with two water molecules.
Following the same method of operation, but replacing butylamine with an equivalent amount of 1 octylamine, get 3-oxylamino-4-methyl-6-fencp-pyridazine tartrate (30,435), R., 64-166 C (isopropanol-ether), yield 54%.
PRI mme R 2. 3- (2-Oxy-ethyl-5 amino) -4-methyl-6-phenyl-pyridazine hydrochloride (CM 30 094).
I, - CW,
- H; R,
four .
A mixture of 30.6 g of 3-chloro-4-methyl-6-phenyl-pyridazine, 36.6 g of 2-amino-ethanol and O, 1 g of copper powder in 400 ml of benzene is refluxed for three days.
The mixture is poured into 500 ml of water and the solution is filtered through a Büchner funnel. Extracted with ethyl acetate and the solution is dried with magnesium sulfate. The solvent is evaporated to dryness. The residue crystallizes. Recrystallize from ethyl acetate - isopropanol (2: 1 but by volume). Colorless crystals (20 g) are obtained, mp.151 C. Chlorohydrate.
11.45 g of base is dissolved in 100 ml of isopropanol, heating until dissolved. 4.7 g of concentrated hydrochloric acid is added and the mixture is allowed to crystallize on cooling. Recrystallize two times from methanol.
A colorless solution (7 g) is obtained. m.p. 200 ° C.
EXAMPLE 3-6. Following the same procedure using amino alcohol or
5, a chlorinated derivative, the compounds (I) obtained are shown in Table 1.
Example 7. 3- (2-Propionyloxyethylamino) -4-methyl-6-phenyl-pyridazine 50 (maleate) (CM 30 098).
chlorinated derivative, receive the compound (I) shown in table 1.
CH CH OOSN OH.
16 g of the compound CM 30 094 (base prepared in example 2) dissolve
55
r yut. in 250 ml of pyridine by stirring at room temperature. Then, drop by drop, while stirring, 6.3 ml of propionyl chloride is added. When the addition is complete, continue: iI
They are stirred for 2 hours at room temperature, the sateM is allowed to dry. The residue, dissolved in a minimum amount of chloroform, is chromatographed on a silica column. Eluted with ethyl acetate-hexane (50:50 by volume), a colorless solid was obtained after replacing the solvent.
After recrystallization from a small volume of ethyl acetate so pl. 02 ° C, weight 8 g
Maleat.
8 g of the obtained base is dissolved in 100 ml of hot isopropanol, then a hot solution of 4.02 g of malic acid in 10 ml of isopropanol is added. After cooling and adding a small amount of ether, a colorless solid is isolated which is recrystallized twice from acetonitrile. M.p. 110 ° C, weight 6.5 g. In the same way, replacing propionyl chloride with an equivalent amount of acetyl chloride, 3- (2-acetoxy) -ethyl-amino-4-methyl-6-phenyl-pyridazine was isolated. Mp pl.127 ° C
Maleate: m.p. 102-105 ° C (acetonitrile).
PRI me R 8. 3- (2-Methoxy-ethyl-amino) -4-methyl-6-phenyl-pyridazine (hydrochloride) (CM 30 310).
R1 3
R, - H; R
- CH, jCH20CHj.
3 - /
A mixture of 7 g of 3-chloro-4-methyl-6-phenyl-pyridazine and 7 g of 2-methoxy-ethylamine in 50 ml of butanol is boiled under reflux for four days. The hot solution is poured into 200 ml of water and extracted with ethyl acetate. The organic solution is dried over magnesium sulfate, then evaporated to dryness. The residue is distilled under high vacuum. M.p. 208-210 C, weight 6.8 g
Hydrochloride.
6.8 g of the base is dissolved in hot isopropanol, then 2.5 ml of concentrated hydrochloric acid is added and left to crystallize. M.p. 194 ° C, weight: 6.5 g. Crystallizes with 1/2 water molecule.
Working in the same way, 3- (2-methoxy-ethylamino) -4,6-diphenylpyridazine (CM 30 340) is obtained from 3-chloro-4,6-diphenyl-pyridazine (CM 30 340). 92 s (diisopropyl ether).
Hydrochloride, so pl. iol)
193 s (isoprop
569604
PRI me R 9. 3- (2-Methoxy-ethyl 1-amino) phthalazine (hydrochloride) (CM 30320).
R and R, —CH — CH — CH — CH—; Rg - H; R CHjCH OCHg.
A mixture of IO g 3-chloro-phta-lasine and 80 g 2-methoxy-ethylamine in 10 80 ml of ethanol is refluxed for 1 hour with reflux condenser. The solvent was stripped and the residue poured into 500 ml of water. Alkalinize with concentrated sodium hydroxide solution and extragigate with ethyl acetate. The organic phase 15 is separated, dried and the solvent is evaporated to dryness. The residue crystallizes and is recrystallized from isopropanol-diisopropyl ether (50:50 by volume). Obtain 2Q crystals of pale yellow color (10 g) so pl. . Hydrochloride.
5 g of the base obtained is dissolved in isopropanol and 25 2.6 ml of concentrated hydrochloric acid are added. The solid is evaporated off and recrystallized from isopropanol - weight 5 g, m.p. 170 ° C. The hydrochloride crystallizes with one molecule of water. The proposed products were investigated in relation to their pharmacological activity.
1. Anticonvulsant activity.
The anticonvulsant activity of the derivatives was evaluated in relation to two chemical agents: strychnine and bicuculline, and in relation to electroshock. In various experiments, products were compared with minaprine, 4Q Products were also compared with sodium salt of valproic acid (1 acide valprouque), the anticonvulsant activity of which is well known and used in human therapy.
Antistrikinny activity.
35
45
Products were administered orally 30 minutes before strychnine in the amount of 0.9 mg / kg intraperitoneally. The occurrence of tetanus seizures, as well as mortality, was noted within 60 minutes following the administration of strychnine.
Anti-bicukullinova activity.
Products were administered orally 30 minutes before the introduction of bicuculline in the amount of 0.9 mg / kg intravenously. The appearance of convulsive seizures, pillar-like seizures, and mortality
five
were observed within 60 minutes following the administration of bicuculline.
A11 thielectroshock activity.
Products were administered orally 30 minutes before the electric shock (12.5 V for 0.5 s). The electric shock of the animal is ejected by the horn electrodes. Immediate clinical appearance of convulsions in control animals was noted. Animals without extension of the hind limbs were considered protected:.
In three cases, the products are administered in a range of doses of 10 out of 10 doses per dose.
For each product, the effective dose (50 / EC) or the dose that antagonizes the convulsive effect of the agent used in 50% of the treated animals is determined.
Table 2 presents the results obtained with the various typical products of the invention.
The proposed products exhibit significant anticonvulsant activity. In relation to strychnine, this activity is especially strong for CM compounds 30,096, 30,310, and 30339. In relation to bicuculline and electroshock, anticonvulsant activity is less strong, but noticeable, especially for derivatives, cm 30,096 and 30,370.
As for standard products, minaprine is generally inactive in these tests up to the maximum tolerated dose, and sodium valproate, administered orally, has an effective dose of 50, under the same experimental conditions, which is higher than the products of the invention.
Accepted designations:
CM 30 094: 3- (2-hydroxyethylamine) -4-methyl-6-phenyl-pyridazine hydrochloride;
CM 30 310: 3- (2-methoxyethylamine) -4-methyl-6-phenyl-pyridazine hydrochloride
CM 30 320: 3- (2-methoxyzthylamine) - phthalazine chlorohrchrate.
2. Remaining toxicity.
The studied products were administered orally in doses of 250, 500 and 1000 mg / kg in batches of 5 mg each. Derivatives caused by mortality were determined within 24 hours following the administration of the product.
Results expressed in percentage of animals that died.
after the introduction of the various products of the invention, are noted in Table 3. All test products lack toxicity at a dose of 250 mg / kg orally. At a dose of 500 mg / kg orally, only derivatives CM 30 096, CM 30 320, CM 30 339 have a toxic effect. Minaprin causes a much more significant toxic effect, it causes 220% mortality, starting with a dose of 100 mg / kg orally in mice.
Thus, the conducted studies show that the proposed products have enhanced pharmacological properties and low toxicity.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining pyridazine derivatives of general formula I
% PI
RZCH / XlslHRit;
Nn
where R is lower alkyl or phenyl;
Kj is hydrogen, or
 together form an -CH-CH-CH-CH- group to form a benzene ring attached to the pyridazine ring;
Ks is hydrogen or phenyl; R4 is a group of general formula
(CH2) y-CH-KB
RS
where n is an integer of 1,2,3 or 7;
RJ is hydrogen or methyl;
R is hydrogen, gneroxyl, an ether group of the general formula,
OR ,,
de R- ;, lower alkyl, which consists in the fact that chlorine derived general Formula II
% one
50
Kccs / hCl
Nn
where r
one
H, and R
the values indicated are, g is reacted with an amine.
General formula III
- (CHP - R,
Hjn
I R,
where Rj and n are as defined,
boiling round of the reaction mass and
R — hydrogen, hydroxyl, or cadaver — in the presence of an acid acceptor — from ether, an excess of amine of general formula III, and a solvent medium, such as a lower catalyst, a wider aliphatic alcohol, at a tempera
C7-4 / NH- (CH2) p-CH-KB
cm 30 095 -CHj 2 NON
CM 30 096 -CHj 1 CHj OH
CM 30 097 -CH 3 N OH
CM 30 -339
1 N bN
72,134 (isoprop-209/95 (ethanol) iol)
72 PA (ethylacetate- 193/95 (edetate) nol)
93 (ethylace-196/95 (etatat) nol)
Hygroscopic-I82 (izprokoprok (solid-enol) substance)
T a b l and yes 2
135696010
Table 3

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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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FR8115546A|FR2511366B1|1981-08-11|1981-08-11|

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