DE958562C - Process for the production of new pyridazines - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

ISSUED FEBRUARY 21, 1957

GERMAN PATENT OFFICE

PATENT LETTERING

CLASS 12 p GROUP 10 INTERNAT. CLASS C07d

C II020 IVb / 12p

Dr. Jean Druey, Riehen, and Dr. Paul Schmidt, Therwil (Switzerland)

have been named as inventors

CIBA Aktiengesellschaft, Basel (Switzerland)

Process for the production of new pyridazines

Patented in the territory of the Federal Republic of Germany from April 1, 1955 Patent application known since August 23, 1956

Grant of patent announced on January 31, 1957 The priority of the application in Switzerland of May 11, 1954 has been claimed

The invention relates to the preparation of pyridazines, which are etherified in the 6-position Oxy or an etherified mercapto group, especially an aliphatically etherified oxy group, preferably have a lower alkoxy group and a cyano group in the 5-position. The invention relates in particular to those pyridazines which have lower alkyl and methyl radicals in the 3- and 4-positions wear, e.g. B. o-methoxy-S-cyano-s, 4-dimethyl-pyridazine the formula

CH,

OCH,

(I)

The new compounds can be used as remedies or as intermediates, so

They have an analgesic effect. The 5-cyanopyridazines, which are particularly valuable in this regard have a methoxy group in the 6-position.

British Patent 656 228, among other things, describes the preparation of 5-amino-i> phenylpyridazone (6) compounds described, which are to be used as analgesics. The 5-dimethylaminoiphenyl-pyridazon- (6) which can be prepared by this process the formula

(II)

and o-methoxy-S-cyano-s, 4-dimethyl-pyridazine (I), their similarity from the presence of the oxo or methoxy group in 6-S division and the nitrogen-containing functional group in the 5-position of the two pyridazines emerges tested for their analgesic effect and compared with each other.

A modification of the Wolff-HaMy method was used for this test (F. Gross, HeIv. Physiol. Acta, 5 [1947], C 31). It will in mice a heat stimulus is applied to the tip of the tail and the latency period from the moment of Beginning of the irritation up to the reaction, which consists of reflexively pulling the tail away, measured. In the unaffected animal, this latency period is 4 ± 0.3 seconds. By analgesic active compounds, the latency period is typically extended. To the individual To largely eliminate scatter, the investigations are carried out simultaneously on ten mice each carried out, with two successive measurements of the latency period being taken every 15 minutes. The mean value is determined in each case from the twenty values obtained in this way.

The abovementioned compounds (I) and (II) were given in a single dose of 100 mg per kg Body weight administered orally. The table below is the mean latency extension given as a percentage of the latency period of untreated animals.

Analgesic effect (100 mg per kg body weight, orally)

after Minutes
administration ° / ₀ extension
Connection (I) ' the latency
Connection (II) 40
50
40
20th 0
0
0
0 30th
45 -
60 2O
20th 0
0 90
120.

6 - methoxy - 5 - cyano - 3, 4 - dimethylpyridazine (I) thus clearly shows a strong analgesic Effect, while 5 - dimethylamino -1 - phenylpyridazon- (6) (II) is analgesic ineffective.

The new pyridazines are produced by converting into 5-cyanopyridazines, which are in the 6-position have free oxy or mercapto group or a halogen atom, these substituents in known Way converted into an etherified oxy or etherified mercapto group. In these implementations one works under customary conditions, preferably in the presence of organic solvents.

The starting materials can be known from siclP Methods win. So you get z. B. 6-halopyridazines by reacting 6-oxypyridazines with halogenating agents, preferably with phosphoric acid halides, such as phosphorus oxychloride, Phosphorus pentachloride or phosphorus pentabromide. 6-mercapto-pyridazines can, for example by reacting 6-halopyridazines with thiourea in very good yield getting produced.

The invention is described in the following examples. Between part by weight and part by volume exists the same relationship as between grams and cubic centimeters. The temperatures are in Degrees Celsius.

example 1

16 parts by weight of 6-chloro-5-cyano-3,4-dimethyl-pyridazine are introduced into a sodium methylate solution, prepared from 2.6 parts by weight of sodium and 150 parts by volume of methyl alcohol, and the mixture is stirred at room temperature for 3 hours. The reaction solution is then evaporated to dryness in vacuo, the residue is taken up in 100 parts by volume of water and the aqueous solution is extracted with chloroform. After evaporating the chloroform, the residue is recrystallized from ligroin. This gives 6-methoxy-S-cyano-3, 4-dimethylpyridazine in white crystals with a melting point of 93 to 94 ^° . Yield 52%.

The 6-chloro-5-cyano-3, 4-dimethyl-pyridazine used as starting material can be obtained as follows: 20 parts by weight of 6-oxy-5-cyano-3, 4-dimethyl-pyridazine are for 1 hour in a bath of 100 ° heated together with 90 parts by volume of phosphorus oxychloride. Evaporate "o in vacuo from the excess phosphorus oxychloride and the residue is mixed with ice water. The aqueous solution is adjusted with 2 N sodium hydroxide solution to p _H = 7, extracted with chloroform, and the chloroform residue from ligroin recrystallized. O-chloro-S-cyano -s, 4-dimethyl-pyridazin is thus obtained in white crystals melting at 81 to 82 ^0. 90 ⁰ A yield).

Example 2

2.6 parts by weight of sodium are dissolved in 150 parts by volume Ethyl alcohol and, as soon as the formation of sodium alcoholate has ended, add 16 parts by weight of δ-chloro-s-cyano-S, 4-dimethyl-pyridazine. The mixture is stirred for 3 hours at room temperature, in a vacuum

evaporated, the residue taken up in 100 parts by volume of water and the aqueous solution extracted with chloroform. By recrystallizing the chloroform residue from petroleum ether, o-ethoxy-S-cyano-s, 4-dimethyl-pyridazine is obtained in white crystals with a melting point of 77 to 79 °. Yield 63%.

Example 3

17 parts by weight of o-mercapto-s-cyano-s, 4-dimethylpyridazine are dissolved in 50 parts by volume of 2η sodium hydroxide solution and slowly add 13 parts by weight of dimethyl sulfate in three portions. It will Left to stand for V2 hours at room temperature, then made alkaline with 2η sodium hydroxide solution and extracted with chloroform. After evaporation of the chloroform, the residue becomes ligroin recrystallized and so o-methylmercapto-s-cyan-3, 4-dimethyl-pyridazine in yellow crystals from

Melting point 66 to 67 ° . Yield 41%.

The 6-MercaptO "5-cyano-3,4-dimethyl-pyridazine used as starting material can be obtained as follows: 16.7 parts by weight 6-chloro-5-cyano-3, 4-dimethyl-pyridazine, 8.5 parts by weight

The thiourea and 100 parts by volume of ethyl alcohol are heated to the boil for 12 hours while stirring. It is allowed to cool and the yellow crystals which have precipitated are filtered off with suction. After recrystallization from boiling ethyl alcohol, the o-mercapto-S-cyano ^, 4-dimethyl-pyridazine is obtained in yellow crystals with a melting point of 213 to 214 ⁰ . Yield 74%.

Example 4

1.3 parts by weight of sodium are added to 150 parts by volume of isopropyl alcohol. If everything Sodium is reacted, one gives a solution of parts by weight 6 - chloro-s-cyano-3, 4-dimethyl-pyridazine in 300 parts by volume of benzene and stir for 10 hours at room temperature. It is then evaporated to dryness in vacuo and the residue is extracted with petroleum ether. After the petroleum ether has been distilled off, the oil obtained is distilled in vacuo. 6-isopropoxy-5-cyano-3,4-dimethyl-pyridazine the formula

CH,

NC

H ₃ CT _N

Y / CH.

oh;

passes below 0.1 mm Hg pressure at 138 to 140 ⁰ . Yield 30%.

Claims (2)

Patent claims: 1. A process for the preparation of new pyridazines, characterized in that in 5-cyanopyridazines which have a free oxy or mercapto group or a halogen atom in the 6-position have these substituents in a known manner in an etherified oxy or etherified mercapto group transferred. 2. The method according to claim 1, characterized in that that in 5-cyano-6-halopyridazines, the 3- and 4-positions are lower Carry alkyl radicals, the halogen atom is converted into an aliphatically etherified oxy group. © 609 580/470 8.56 (609 802 2.57)