Method of producing derivatives of dihydropyridazinone

专利摘要:
Compounds of the formula (I): …<CHEM>… and pharmaceutically acceptable salts are described, wherein R<1> is hydrogon or methyl and R<2> is hydrogen or C1-4alkyl. These compounds have inotropic, vasodilator, bronchodilating and platelet aggregation inhibiting properties. Pharmaceutical compositions are described as are methods of use. Intermediates and processes for the preparation of the compounds of the formula (I) are described.
公开号:SU1396963A3
申请号:SU853958649
申请日:1985-09-12
公开日:1988-05-15
发明作者:Энтони Слэтер Роберт
申请人:Смит Клайн Энд Фрэнч Лабораториз Лимитед (Фирма)；
IPC主号:

专利说明:


The invention relates to a method for the preparation of new biologically active chemical compounds, specifically to a method for the preparation of new dihydropyridyainone derivatives exhibiting inotropic, vasodilating and bronchodilatory activity and having the ability to inhibit platelet aggregation. These properties suggest the possibility of using these compounds in medicine.
The aim of the invention is semi
anhydrous pyridine (25 ml) is added dimethyl cyanodithioiminocarbonate (5.75 g) and the mixture is stirred at reflux for 3 hours. The reaction mixture is evaporated under reduced pressure to about half the volume, diluted with ethanol and left to give a solid substances (3.85 g). After settling and grinding, the filtrate gives an additional amount of solid (1.42 g). The solid is combined and dissolved in
The preparation of new dihydropyrivir derivatives is boiling pyridine (60 ml) containing dazinone with a new kind of water. The solution is filtered and
a number of pyridazinone derivatives of the biological activity of inotropic.
Example 1. (N-methyl-N-cyanoguanidino) -phenyl-5-methyl-4,5-dihydro-3 (2H) -pyridazinone.
A. The solution of 6- (4-amikophenyl) 5-me; thyl-4,5-dihydro-3- (2H) -pyridazinone
(2.0 g, 0.0098 mol) and diphenyl cyano-imine carbonate (2.4 g, 0.01 mol) in anhydrous dimethylformamide (15 mp) are stirred at 115-120 ° C for 6 hours. Then add additional
The amount of diphenylcyanoiminocarbonate is heated at boiling with reverse hot water (0.6 g, 0.0025 mol) and the solution is kept in a –30 bath for 2 hours. Then the mixture is heated for another 2 hours. The reaction mixture is allowed to cool.
Distillation of the solvent under reduced pressure yielded a brown residue, which was washed with boiling ethanol and then recrystallized from water and dimethylformamide to give (N-cyanophenoxyformamidino) phenyl-5-methyl-4,5-dihydro 3 (2H) - Pyridazinone, 1.5 g, so pl. 164-165 ° C.
and filtered to obtain the target compound (32 g), which after recrystallization from aqueous dimethylformamide gives the target compound, so pl. 270-272 s, identical according to thin layer chromatography and NMR spectroscopy, to the product of example 1.
Example 3. 6-t4- (N3-Ethyl-N2Compound t-ivjAer can also be overwritten by cyanoguanidino) phenyl-5-metsh-4,5-dihydro-3 (2H) -pyridazinone.
(N-Cyanophenoxyformamidino) -phenyl-5-methyl-4,5-dihydro-3 (2H) -pididazine (2.0 g) and a solution of ethylamine (33% in ethanol, 75 ml) are mixed and heated at reflux for 3 hours. An additional amount of ethylamine (33% in ethanol, 75 ml) was added and stirred at reflux for an additional 3 hours. The mixture was evaporated under reduced pressure to obtain a brown oil. It is triturated under chloroform to obtain a cream solid (1.15 g), which is subjected to column chromatography on silica gel (eluant-chloroform) to obtain citalylated from acetonitrile.
B. A mixture of the indicated formamidine (1.5 g, 0.0043 mol) and a solution of methylamine (33% in ethanol, 50 mp) is transferred and heated at reflux for 3.5 h. The solution is evaporated to a small volume. under reduced pressure and the residue is dissolved in hot ethanol. After treatment with charcoal, the solution is treated with water and allowed to cool to obtain the target compound (1.0 g), m.p. 264-265 ° C.
Example 2. (K-Methyl-. N-cyanoguanidino) phenyl-5-methyl-4,5-dihydro-3 (2) -pyridazinone.
A. K 6- (4-aminophenyl) -5-methyl-4,5-dihydro-3 (2H) -pyridazinone (4 g) in
50
55
reduced in volume to obtain a suspension, which is diluted with acetone and left. This gives crystals of 6 ((M-cyano-B-methylisothioureido) -phenip-5-methyl-4,5-dihydro-3 (2H) -pyridazinone (4.02 g), mp. 231-232 C (different).
B. (N-Cyano-8-methipisothioureido) phenyl-5-methyl-4,5-dihydro-3 (2H) pyridazinone (48 g) is added to a solution of methylamine (33% in ethanol, 600 mp) with transfer and mixture
and filtered to obtain the target compound (32 g), which after recrystallization from aqueous dimethylformamide gives the target compound, so pl. 270-272 s, identical according to thin layer chromatography and NMR spectroscopy, to the product of example 1.
Example 3. 6-t4- (NЗ-Ethyl-N2-left compound (O, AO g), mp. 208-209 C.
Example 4. 6-fA- (N - Isopropyl-No-cyano-guanidino) phenyl-5-methyl-4,5-dihydro-3 (2H) -pyridazinone,
Isopropylamine (7.4 ml) is added to (N-cyano) phenoxyformamidino) phenyl-5-methyl-4,5-dihydro-3 (2H) -pyridazinone (1.5 g) in ethanol (100 ml) and the mixture is stirred 4 hours at reflux (additional isopropyl-amine 3 ml, added after 2 hours). The mixture is evaporated under reduced pressure to obtain a pale green solid. Rubbing under ethanol gives a cream solid (0.94 g), which is subjected to flash column chromatography on silica gel (gradient from chloroform to chloroform: methanol 40: 1) to give the title compound as a solid (0.65 g ), so pl. 255 ° C.
Example 5. (M-Buttsh-N-cyanoguanidino) phenyl 3-5-methyl-4,5-dihydro-3- (2H) -pyridazinone.
A mixture of n-butylamine (0.7 g) and 6-4- (K-cyanophenoxyformamidino) phenyl | 5-metsh-4,5-dihydro-3 (2H) -pyridazinone (2.0 g) in ethanol (100 ml) is stirred for 4 hours at boiling under reflux. The mixture is evaporated under reduced pressure to give a pale yellow oil, which, when triturated with diethyl ether, gives an off-white solid. It is subjected to flash chromatography on silica gel (elution
a gradient from chloroform to., chloroform of the compound (1.1 g), mp, methanol 40: 1) to give the desired
(different).
Compounds as a white solid (0.75 g), m.p. 184-186 ° C.
Example 6. (N-Cyanoguanidino) Phenyl J-5-methyl-4,5-dihydro-3 (2H) pyridazinone.
6-C4- (N-Cyanofenyxiformamidino) -phenyl-5-methyl-4,5-dihydro-3 (2H) -pyridazinone (2.0 g) in ethanol (100 ml) is stirred for 3 hours at reflux in the process ammonia gas bubble through solution. The reaction mixture is left overnight and then evaporated under reduced pressure to give a sticky solid, which is treated with boiling ethanol, to give a white solid (1.1 g). Recrystallization from meta 0
nola gives the target compound (0.8 g), so pl. 258-260 C (decomp.).
Example 7. (N-Methyl-N-cyanoguanidino) phenyl-4,5-dihydro-3 (2H) -pyridazinone.
A. 6- (4-Aminophenyl) -4, L-dihydro-3 (2H) -pyridazinone (5.0 g) and diphenylcyanoimino carbonate (0.9 g) are stirred in anhydrous dimethylformamide (20 ml) for 4 hours at 120 ° C. The reaction mixture is cooled, filtered and evaporated under reduced pressure. with oil. This oil is extracted into boiling ethanol (1 l), which is reduced in volume (to 3D ml) and filtered to obtain (cyanophenoxyformamidino) phenyl-4.5-dihydro-3 (2H) -pyridazinone (3.5 g),
Further extraction of the oil with boiling ethanol gives an additional product (2.2 g).
B. A mixture of the specified formamidine (3.2 g) and a solution of methylamine (33%
5 in ethanol, 100 ml) is stirred and heated for 3 hours at reflux and refluxed. The mixture is filtered hot and the solid is washed with ethanol and diethyl fiber. The impurities are extracted from this solid while stirring in boiling ethanol. The solid is then dissolved in hot dimethylformamide, the wood is processed. charcoal, filtered through diatomite, and the filtrate is evaporated to a small volume (about 5 ml). It is then triturated with hot ethanol (100 ml) and filtered to obtain the desired
o compound (1.1 g), m.p.
267 ° C
compounds (1.1 g), m.p.
(different).
Example 8. (K2-Cyano) - ethoxyformamidino) phenyl-5-methyl-4,5-dihydro-3 (2H) -pyridazinone.
6- (4-Aminophenyl) -5-methyl-4,5-dihydro-3 (H) -pyridazinone and diethyl cyanoimino carbonate in dimethylformamide are heated to give the desired compound. This compound is reacted with methylamine to give the compound of Example 1.
The novel dihydropyridazinol derivatives are subjected to biological tests for the following activities.
Cardiac stimulating activity.
The compounds and their pharmaceutically acceptable salts are tested for the purpose of determining cardiac stimulating activity.
Guinea pigs (500-700 g) of both sexes are killed, hearts are quickly removed and transferred to an anatomical cuvette containing an oxygenated medium. When in the bath-forming medium, the right ventricle is cut into two lanes. Each strip is suspended in a 50 ml bath containing Krebs-Henseleite solution at 37 ° C
and the bath is bubbled with 9-5% oxygen and 5% carbon dioxide. Ventricular strips are subjected to electrical stimulation with a frequency of 1.0 Hz at twice the threshold voltage. A voltage of 1.0 g is created on the strips and the voltage is kept constant by re-adjusting during the equilibration period (60 min). The bath-forming environment is often replaced during this period. After the stationary reference line has been reached, the compound to be tested is added to the Bottom-forming medium and the response curve is drawn for cumulative concentration. The compounds tested according to the invention give a 50% increase in the force of contraction of the ventricular band at concentrations in a bath-forming medium that are less than 10 molar, which demonstrates their activity as
positive inotropic drugs.
In the above test procedure, the compounds according to the examples are characterized by the following indicators (cardiac stimulating activity in vitro).
In vivo cardiostimulating activity (anesthetized cats).
In anesthetized cats, pred0
Having been treated with a ganglioblocator (with mecamylamine or pempidine) and propranolol, the compounds according to the examples cause a steady increase in dp / dt for the left ventricle (which is an index of contractility of the left ventricle) when administered intravenously. The dose required to increase the dp / dt j, c dp of the left ventricle by 50%, is indicated as EDU |,.
Amrinon
0.2 0.2 0.2
0.31
0.7
1.6
5.6
Lasting effect
Medium duration effect
Prolonged effect Average duration of effect
Short effect
0
five
0
five
Minimal changes in blood pressure or heart rate are observed.
In vivo cardiostimulating activity (dogs in normal condition).
The compound of Example 1 increases the dp / dt value for the left one. in the normal state of the dogs after intravenous administration at a dosage below 0.1 mg / kg. Oral administration induces a positive inotropic reaction at a dosage of 0.25 mg / kg and below. This positive inotropic response is maintained for 9-12 hours without a change in blood pressure or heart rate. Therefore, this compound is particularly beneficial for strength - heart rate. In contrast, amrinone is less active and its duration of action is shorter.
Vasodilating activity. The compound of Example 1 causes a dosing-dependent dilation of the posterior torso vessels of anesthetized rats (autoperfused at a constant blood pressure) within the dosage range of 1-10 μmol / kg (intravenously). The dose required for a 50% increase in blood flow in the back of the body is 4.6 µmol / c. A significant duration of effect is observed.
The compounds of Examples 3, 4, 5, and 7 test on the back of the body, autoperfused anesthetized rats (autoperfusion at constant blood flow). The doses required for a 15% reduction in perfusion pressure in the posterior part of the body (expansion of the vessels) are given below.
Enlarged bronchus in vivo.
Guinea pigs - male Dun-kin-Hortley races (530 g 1 6 g) are anaesthetized with sagatal (pentobarbital sodium, 90 mg / kg intraperitoneally). Airborne airway resistance is measured using a variation of the classic Concett-Rossler method.
For intravenous injection of a dose of 2-pyridine ethylamine, which gives an approximately 100% increase in airway resistance, a bolus dose of the compound of Example 1 is administered g- (intravenously) 1 minute prior to the administration of 2-pyridylethylamine. . .
The compound of example 1 reduces 2-pyridylethylamine-induced bronchospasm. The threshold dose for this compound is 3.16-10 mol / kg. The dose of the compound of Example 1, which reduces 2-pyridylethylamine bronchospasm by 50% (ED5o), is 3.9
“10 mol / kg, which demonstrates anti-, bronchospasmic activity.
5 10 g
15 20
25
thirty

35
40
45
50
55
Inhibition of platelet aggregation in vitro.
Plasma is prepared as follows. Blood from 6 normal healthy volunteers is mixed with 3.8 wt.% (Vol.) Trisodium citrate (9 ch. Blood: 1 ch. Citrate). Samples were centrifuged at 150 g for 10 minutes and the supernatant platelet-rich plasma (RNTP) was separated. The platelet concentration in the RHTP was adjusted to 300 ± 50 x 10 L of platelets by addition of autologous platelet-poor plasma.
25 µl aliquot samples of the 40 µg / ml solution of the compound of Example 1 are incubated with 225 µl OTPP aliquots in the Peyton Aggregometer for 3 min. Control solutions are also studied, one of which is similar to the test solution in terms of the pH of the solution and its tonicity, and the other is a solution of 0.9 May,% (about) NaCl. After 3 minutes, aliquots of 25 lcp of adenosine diphosphate solution are added to each solution at a concentration of 20 µmol. Record the aggregation reaction data to its completion with a maximum of 3 minutes. The procedure is repeated using different aggregating agents: 100 µg of collagen; 100 μmol adrenaline or 5 ml / ml arachidonic acid instead of adenosine diphosphate.
Aggregation reactions induced by different and aggregating agents are measured for platelets from each donor. The results are evaluated by visual observation of the aggregation indication carried out by the Peyton aggregate-meter, and semi-quantitatively determined by measuring the light transmission 3 minutes after the addition of the indone means.
The compound of example 1 at a final concentration of 5 μg / ml inhibits platelet aggregation induced by solutions of adenosine diphosphate, arachidonic acid, collagen or adrenaline. Sequential dilutions of this compound should be prepared and tested to inhibit the aggregation induced by adenosine diphosphate. The second wave of aggregation was completely inhibited by the compound of Example 1 at 0.5 μg / ml or more.
9
Derivatives of dihydropyridazinone exhibit a new type of biological activity for a given range of compounds, since the closest compounds of the similar structure of dialkylguanine dinophenylpyridazinones do not exhibit inotropic activity.

权利要求:
Claims (1)
[1]
New dihydropyridaznone derivatives show no signs of toxicity at doses that reach a 100-fold estimated therapeutic dose when orally administered to dogs in a normal state. Invention Formula
A process for the preparation of dihydropyridazinone derivatives of the general formula. Foot
II
HH-C-NHRj
3
10 where R, is hydrogen or methyl,
R {is hydrogen or C -C-alkyl, characterized in that the compound of the general formula
NH-C
.15 CN
where R has the indicated values L — a removable group selected from the group consisting of C, -C alkylthio groups, Cj-C alkoxy groups or phenoxy groups, is reacted with an amine of total NHjR, where R is of the indicated values.

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同族专利:

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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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GB848400863A|GB8400863D0|1984-01-13|1984-01-13|Chemical compounds|

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