KR810000426B1 - Preparation for 2-substituted-1.3-diazacyclic compounds - Google Patents

Abstract

Title compds. (I; R1 = H, halogen, lower alkyl or lower alkoxy; R3 = H, lower alkyl, lower hydroxy alkyl or aralkyl; R4 = H, lower alkyl or allyl; R6 = cyclohexyl or pyridyl; n = 2 -4; T = amidino, aminoether or nitrile) were prepd. by reaction of II and III. I had hypotensive and blood platelet aggregation inhibiting activities; the data were given in rats in comparison with tolbutamide and phenformin.

Description

Method for preparing 2-substituted-1,3-diazacyclic compound

The present invention relates to a method for preparing a 2-substituted-1,3-diazacyclic compound having an effect on treating diabetes.

To date, as a representative antidiabetic agent, benzhydryl lactamamides having the following chemical chambers structurally similar to the compounds of the present invention are known.

This is described in the Journal of Medical Chemstry vol. 16 P. 885-892 (1973).

라 칭함]은 부작용과 충분치 못한 효과 때문에 치료용으로 만족스럽지 못했다.However, these compounds [hereinafter referred to as compounds

Is not satisfactory for treatment because of side effects and insufficient effects.

It is an object of the present invention to make compounds which have excellent hypoglycemic and platelet aggregation inhibitory effects and which can be used safely without clinically harmful side effects.

In particular, the present invention is a novel 2-substituted-1,3-diazacyclic compound represented by the general formula (I) below.

Wherein R ₁ is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.

R ₂ is a hydrogen atom, a lower alkoxycarbonyl group, an aliphatic acyl group or an aromatic ring (wherein the aromatic ring refers to a ring substituted with a halogen atom, a lower alkyl group, a lower alkoxy group acyl group or an acyloxy group). R ₃ is a hydrogen atom, a lower alkyl group, a lower hydroxyalkyl group or an aralkyl group. R ₄ is a hydrogen atom, a lower alkyl group or an aryl group. R ₆ is a chlorohexyl group, a pyridyl group or a phenyl group substituted with a halogen atom, a lower alkyl group or a lower alkoxy.

A is -N =, -N (loweralkyl)-group or methylene group. n is an integer of 2-4. The dashed line indicates that the double bond is arbitrary. The compound of this invention is manufactured by the method shown by the following reaction schemes (A)-(D).

General symbols in the reaction schemes (A)-(D) have the following meanings.

X is halogen. Y is a halogen, an alkyl group or a nitroamino group. Z is a halogen, an alkyl sulfate group or an acyloxy group. T is an amidino group, an amino ether group, or a nitrile group. R ₇ is halogen or lower alkyl group. R ₈ is hydrogen or a lower alkyl group. R ₁ , R ₂ , R ₃ , R ₄ , R ₆ and n are as described above.

Each of the methods is described in detail below.

[Method A]

The desired compound according to the invention is produced by reacting compound (II) with compound (III) and / or compound (IV). Alkylation is superior to acylation in this synthesis. Alkylation is carried out in a suitable solvent with a base such as alkali hydride or alkoxide at a temperature between the boiling point of the solvent at room temperature.

Acylation is carried out with a suitable solvent between 0 ° -100 ° C. The solvent is used as an inert solvent such as diethyl ether, chloroform, benzene, pyridine, dimethyl formamide. Furthermore, bases such as amine (triethylamine) alkali hydrides (eg sodium hydride) or alkaline carboates can be used.

[Method B]

The compound according to the invention is produced by reacting isochiurenium compound (V) with diamine (VII) without solvent or at a suitable solvent such as methanol, tetramethylenediamine and the like at 0 ° -200 ° C.

Isocyanide dihalide (VI) instead of isochiurenium (V) may react with diamine (VII) under the same conditions.

[Method C]

The compounds of the present invention are produced by reacting diamine (VII) with structural formula (IX) in a suitable solvent such as toluene or xylene at the boiling point of the system. More preferably by heating without solvent at a temperature between 100 ° -200 ° C.

[Method D]

The compounds of the present invention are also produced by reacting compound (XI) with compound (XII) in a suitable solvent at room temperature for several hours or tens of hours at about 50 ° C.

Suitable solvents are chloroform, diethylethyl, dioxane or benzene. The compounds of the present invention obtained can be converted into pharmaceutically possible acid addition salts, i.e. hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, oxalate, malonate, maleinate, humate or methanesulfonate.

As described in the above description, various preparation methods have been applied to produce compounds belonging to the 2-substituted-1,3-diazacyclic.

The compounds of the present invention have specific diabetic therapeutic actions that are not made from known typical drugs such as tolubutamide.

의 특성과 비교하였다.To demonstrate the superiority of the present compounds, the pharmacological properties of the representative compounds of the present invention are tolubutamide, phenformin or known compounds.

Compared with the characteristics of.

1. Action in hypoglycemia

1) Relationship between Dose Effects in Normal Rats

Five male Wister rats, each weighing about 170 grams, were used as dose criteria. Rats starved for 24 hours prior to the administration of feed solution or suspension were administered 25 milligrams per body weight directly through the tube. After 2, 3 and 5 hours of administration, blood is taken from the tail vein of the rat and glucose is quantified by the glucose oxidase method. The obtained results are shown in Table 1.

TABLE 1

Dose = 100 mg / kg

2) Glucose Tolerance Test in Normal Rats

혈당이 증가함에 따라 산출된다. 수득한 결과 표 2에 나타냈다.Five male Wister rats weighing about 200 grams each were used as the dose criteria. A solution or suspension of the sample is administered in the stomach through a tube to a starved rat for 24 hours prior to administration. One hour after administration, each mouse received an intraperitoneal injection of glucose solution (1 gram per kilogram of body weight). After 15,30,60 and 90 minutes, blood was drawn from the tail sperm to quantify blood glucose. Glucose tolerance in rats was 90 minutes after glocose injection

Calculated as blood glucose increases. The obtained results are shown in Table 2.

TABLE 2

* Obtained 30 minutes before glucose injection.

Compounds A-F in Tables 2-8 are representative compounds of the present invention. Details are as follows.

Compound A = 1-Methyl-2-benzhydrylaminoimidazolidine

Compound B = 2- (2,2-diphenylethyl) -2-imidazoline

Compound C = 1-methyl-2- (2,2-diphenylethyl) -2-amidazolin

Compound D = 1-Methyl-2-benzhydrylimino-3-benzoyl imidazolidine

Compound E = 1-Methyl-2-benzhydrylimino-3-chienoyl imidazolidine

Compound F = 1-Methyl-2-benzhydrylimino-3-nicotinoyl-imidazolidine

3) Glucose Tolerance Test in Diabetic Rats Induced by Streptochotocin.

A single intraperitoneal administration of streptochotocin (20 mg / kg body weight) of the sample solution or suspension is starved and orally administered 24 hours prior to the administration of a male Weister rat with diabetes for about two months.

에 의해 산출된다. 수득된 결과는 표 3에 나타나 있다.Control diabetic rats receive water. The blood glucose levels of hungry and hungry rats were 89 ± 1-103 ± 4mg / dl and 123 ± 2-189 ± 11mg / dl, respectively. One hour after sample administration, each rat is administered a glucose solution by intraperitoneal injection (1 g of glucose per kg of body weight). 15,30,60 and 90 minutes after glucose injection, blood is drawn from the tail vein to quantify blood glucose. Glucose tolerance in rats is associated with an increase in blood glucose for 90 minutes after glucose injection.

Calculated by The results obtained are shown in Table 3.

TABLE 3

II. Insulin sustained release action

The physiological saline containing the sample is injected into the femoral vein of an outgoing normal Wister male rat weighing about 200 grams under pentobarbital anesthesia. 10,20,30 and 40 minutes after injection of the sample, blood is drawn from the tail vein and quantified by immunoreactive insulin (lRl) by the method of C.R.Morgan et al. (Diabetes 12,115,1963). The results are shown in Table 4.

TABLE 4

Increase in serum immunized insulin for 40 minutes after sample injection

III. Inhibitory effect on platelet aggregation

Sufficient plasma platelets are made by centrifuging (1000 rpm, 5 min) the blood of rats with fresh citrate. 50 microliters of a solution containing different concentrations of the sample is added to a platelet containing 0.4 milliliters of plasma and stirred at 1100 rpm for 1 minute at 30 ° C. Then 50 milliliters of the collagen suspension is added to the platelets and begins to aggregate. This method is a measure of turbidity according to GVR Borm (Nature, 194, 927, 1962). ID ₅₀ refers to the concentration of compound (mM) with 50% inhibition of the response ratio of regulated lysed platelets. The results are shown in Table 5 below.

TABLE 5

IV. Effective on serum lactate standards.

Samples or suspensions of the sample are orally administered daily to 200 milligrams of body weight, such as kilograms of body weight, for 4 days in normal Wyster male rats weighing approximately 200 grams. (5 / group) The tail vein is collected and quantified with lactate serum according to the method of Hans-Jurgens Hohorst (Methods of Enzymatic Analysis, ed, by Hans URrich Bergmayer, Aca. Pro. NY, 1965). The results obtained are shown in Table 6.

TABLE 6

(Base compound) * immediately after the second administration

** 3 hours after last dose

*** 3 dead in this experiment

V. Long-term Effect of Compound A on Diabetic Mice Induced by Strepchocin

Streptochotocin is injected once intraperitoneally (60mg / kg) or intravenously (35mg / kg) in a Wyster male rat weighing about 170 grams to cause diabetes. These mice show typical symptoms of diabetes. That is, multiphagia, next plethora, polyuria, and hypoglycemia over 400 milligrams of glucose / dl.

These mice were treated with daily administration of 25, 50, and 10 mg of Compound A, toluburamide, or phenformin per kilogram of body weight, respectively. Control diabetic rats were not treated. Treatment started one month after streptochotocin injection and continued for four months (tolubutamide and phenformin) or five months (Compound A).

The blood glucose levels of the fed rats were 485 ± 18mg / dl at the beginning of treatment and 415 ± 27 (control), 423 ± 17 (compound A group), 447 ± 15 (tolubutamide group) and 425 ± 29mg / dl at the expiration of the experiment. (Penformin).

At the end of the experiment, rats were used to test history of kidney and liver and to quantify blood fat. The results are shown in Table 7 below.

TABLE 7

* Confidence limit, P <0.05 (about control diabetes)

VI. Poison castle

Toxicity studies are performed by oral administration to rats. Each LD ₅₀ is calculated at the 7th day lethality according to the Litchfield Wilcoxon method. Ten male Donryu rats were used. The results obtained are shown in Table 8.

TABLE 8

As shown in the test of the above results, the 2-substituted-1,3-azacyclic compound of the present invention exhibits an inhibitory effect on the aggregated platelets of a clear and effective diabetes treatment effect and does not exhibit unwanted side effects on humans and animals. .

More specifically, tolubutamide and phenformin decrease significantly with increasing blood triglycerides of the present invention as compared to a tendency to increase hyperlipidemia. Furthermore, the compound does not affect the amount of lactate in the blood which is the cause of lactic acid. Severe acidosis results from diffuse intravenous aggregation, cardiac palpation and lowering blood pressure, ventricular contractility, and blood dynamic imbalances of cardiac output.

Furthermore, according to histopathologic examination of the kidney, the compound of the present invention does not cause glomerulosclerosis and urinary tubular degeneration in diabetic rats similar to human diabetes. In turn, these lesions are exacerbated by tolubutamide treatment.

Appropriate dosage, i.e., oral administration, suitable pharmaceutically acceptable carriers, such as lactose, sucrose, sorbitol, starch, gelatin and magnesium stearate, and polyethylene glycol with diluents such as tablets, capsules, powders, and about 60 kilograms in single or multiple doses. Administer 2-15 milligrams per kilogram of weight of grams.

Synthesis Example 1

A mixture of 7.3 grams of benzhydrylamine, 4.88 grams of 2-methylmelcapto-imidazoline hydroiodide and 10 milliliters of methanol is refluxed for 3 hours. After cooling the methanol is distilled off and 10% of sodium hydroxide is added to the resulting residue. This solution is extracted with 200 milliliters of chloroform. The chloroform solution is washed with water and dehydrated. Benzhydrylamine not reacted with chloroform is distilled off and a small amount of acetone is added to the residue to obtain 3.2 grams of crystalline 2-benzhydrylamino-amidazolidine at a melting point of 189-191 ° C.

Elemental Analysis: C ₁₆ H ₁₇ N ₃

Calculated Value: C 76.46, H6.82, N16.72

Found: 76.69, 6.88, 16.96

Synthesis Example 2

A mixture of 22 grams of benzhydrylamine and 5.2 grams of 2-nitroamino-2-imidazoline is heated at 180 ° -200 ° C. for 30 minutes. The reaction mixture was treated in the same manner as in Synthesis Example 1 to obtain crystalline 2-benzhydrylimino imidazolidine.

Synthesis Example 3

A mixture of 30 milliliters of ethyl ether containing 2.26 grams of benzhydrylamine and 2.5 grams of 2-chloro-2-imidazoline are left at room temperature for 2 days. The reaction mixture was treated in the same manner as in Synthesis Example 1 to give crystalline 2-benzhydrylimino imidazolidine. This crystal is dissolved in methanol and added to the same amount of hydrochloric acid solution. This solution was distilled under vacuum to yield 3.2 grams of 2-benzhydrylimino imidazolidine having a melting point of 207-209 ° C.

Elemental Analysis: C ₁₆ H ₁₈ N ₃ Cl

Calculated Value: C66.7, H6.30, N14.60

Found: 66.81, 6.31, 14.63

Synthesis Example 4

A mixture of 1.8 grams of benzhydrylamine and 3.4 grams of 1-methyl-2-methylmelcapto-2-imidazoline hydroiodide is left for 2 days at room temperature. At this time, chloroform distillation yields 1.2 grams of 1-methyl-2-benzhydryl iminoimidazoline hydro iodide having a melting point of 254-256 占 폚.

Elemental analysis: C ₁₇ H ₂₀ N ₃ l

Calculation: C67.65, H6.68, N13.92

Found: 67.91, 6.84, 13.94

Synthesis Example 5

-(P-클로로페닐)벤질아민과 4.54그람의 2-메틸멜캅토-2-이미다졸린 하이드로 아이오다이드의 혼합물을 150-160℃에서 20분간 가열한다. 냉각시킨 후 반응혼합물을 메타놀에 녹이고 이 용액을 수산화나트륨으로 염기성으로 하면 융점 187-189℃의 2(

-(P-클로로페닐)벤질)이미노이미다졸리딘을 수득한다.3.37 grams

A mixture of-(P-chlorophenyl) benzylamine and 4.54 grams of 2-methylmelcapto-2-imidazoline hydro iodide is heated at 150-160 ° C. for 20 minutes. After cooling, the reaction mixture is dissolved in methanol and the solution is made basic with sodium hydroxide.

-(P-chlorophenyl) benzyl) iminoimidazolidine is obtained.

Synthesis Example 6-9

Practically repeating in the same manner as in Example 5 (with the exception of starting materials only), the following derivatives shown in Table 9 were prepared.

TABLE 9

Synthesis Example 10

3.6 grams of sodium hydroxide is dissolved in 20 milliliters of water and cooled in an ice bath. 6.0 grams of 2-chloroimidazoline sulfate is added to this solution. The solution is extracted three times with chloroform and the chloroform layer is dehydrated. 3.0 g of methylbenzhydrylamine was added to the chloroform solution and left to stand for 2 days. This solution is evaporated. The residue is taken up in 50 milliliters of water and washed with ethyl ether. The aqueous solution is based on sodium hydroxide. The resulting crystals were collected by filtration, washed with water and dried to afford 2- (N-methyl, N-benzohydryl) -amino-2-amidazolin at melting point 161-162 ° C.

Elemental Analysis: C ₁₇ H ₁₉ N ₃

Calculated Value: C76.94, H7.22, N15.92

Found: 76.96, 7.23, 15.89

Synthesis Example 11

2- (N-ethyl N-benzhydryl) amino-2-imidazoline having a melting point of 141-142 ° C. was prepared in the same manner as in Example 10 except for the starting material.

Synthesis Example 12

A mixture of 5.46 grams of N-benzhydryl-S-methylisochiuronium iodide, 8.53 grams of ethylenediamine and 40 milliliters of methanol is refluxed for 15 hours. After cooling, ethylene diamine not reacted with methanol is distilled off under reduced pressure. The resulting residue is dissolved in 30 milliliters of ethanol, made basic with sodium hydroxide and extracted with chloroform. The chloroform solution is washed with water, dehydrated and evaporated to form crystalline material and recrystallized with isopropyl alcohol to give 2.7 grams of pure 2-benzhydryl aminoimidazolidine (melting point: 189-190 ° C).

Synthesis Example 13

3.84 grams of N-benzhydryl-S-methyl isochiuronium iodide, 7.5 grams of 1,3-propanediamine and 25 milliliters of methanol are refluxed for 16 hours. The reaction mixture is actually treated as in Example 6 to give crude 2-benzhydryl imino-1,3-diazacyclohexane.

The crude product is added to methanol containing hydrochloric acid to yield 3.3 grams of 2-benzhydrylamino-1,3-diazacyclohexane.

Elemental Analysis: C ₁₇ H ₂₀ N ₃ Cl

Calculated Value: C66.65, H6.68, N13.92

Found: 66.77, 6.67, 13.70

Synthesis Example 14-25

Various other 1,3-diazacycloalkane derivatives are prepared by repeating in the same manner as in Example 13 except for the starting material. The obtained product is shown in Table 10 below.

TABLE 10

Synthesis Example 26

A mixture of 2.07 grams of 2,2-diphenylpropionitrile and 2.78 grams of ethylenediamine tosylate is heated at 200 ° C. for 3 hours. After cooling it is made basic with alkali hydroxide (metal) and extracted with chloroform. The chloroform layer is washed with water and dehydrated. After evaporating chloroform, the resulting residue was recrystallized from a mixture of benzene and hexane to obtain 1.4 grams of 2- (2,2-diphenylethyl) -2-imidazoline having a melting point of 98-101 ° C. Its hydrochloride has a melting point of 173-175 ° C.

Elemental Analysis: C ₁₇ H ₁₈ N ₂ ㆍ HCl

Calculated Value: C71.20, H6.68, N9.77

Found: 70.84, 6.72, 9.98

Synthesis Example 27-29

Except for the starting material, in practically the same manner as in Example 26, the following compounds were obtained.

[Synthesis Example 27]

1-methyl-2- (2,2-diphenylethyl) -2-imidazoline sulfate melt: 108-110 ° C

Elemental analysis: C ₁₈ H ₂₀ N ₂ ㆍ H ₂ SO ₄

Calculated Value: C59.65, H6.12, N7.73

Found: 59.58, 6.08, 7.64

Synthesis Example 28

2- (2,2-diphenylethyl) -1,4,5,6-tetrahydropyrimidine-hydrochloride Melting point: 173-175 ° C

Synthesis Example 29

2- (2,2-diphenylethyl) -1,5,6,7-tetrahydro-1,3-diazepine hydrochloride Melting Point: 190-195 ° C

Synthesis Example 30

6.9 grams of 2-phenyl-2-cyclohexyl propionitrile and 8.0 grams of ethylenediamine tosylate are heated at about 200-210 ° C. for 3 hours. The reaction mixture was treated in the same manner as in Example 26 to yield 5.7 grams of 2- (2-phenyl-2-cyclohexylethyl) -2-imidazolidine at a melting point of 75-77 ° C.

Synthesis Example 31

A mixture of 2.6 grams of ethyl 2- (4-pyridyl) -propionate and 10 grams of ethylenediamine was refluxed for 10 hours. After the unreacted ethylene diamine was distilled off, the resulting residue was heated at 210-230 ° C. for 3 hours. The reaction mixture was treated in the same manner as in Example 26 to yield 2- [2-phenyl-2- (4-pyridyl) ethyl] -2-imidazoline having a melting point of 105-107 ° C.

Synthesis Example 32

A mixture of 5.06 grams of ethyl 2,2-diphenylpropioiminoether and 1.8 grams of 1,2-propanediamine is heated at 140-150 ° C. for 1 hour. After cooling, the reaction mixture was put into alumina column chromatography and eluted with a mixture of benzene and ethyl acetate. The eluted solvent was distilled off to obtain 2- (2,2-diphenyl-ethyl) -4-methyl-2-imidazoline having a melting point of 55-57 占 폚.

[Synthesis Example 33]

A mixture of 1.25 grams of 2-benzhydriminoimidazolidine 0.16 grams of sodium hydroxide and 7 milliliters of anhydrous dimethylformamide is stirred at room temperature for 20 minutes. Then 1.0 gram of methyl iodide is added to this solution and stirred for another 2 hours. After completion of the reaction, dimethylformamide was evaporated in vacuo, a small amount of water was added and extracted with chloroform. The chloroform layer is washed with water and dehydrated. After evaporating the chloroform layer, the residue is dissolved in a small amount of methanol and hydrochloric acid is added to this solution. Evaporation of the methanol yields 0.95 grams of 1-methyl-2-benzhydryliminoimidazoline hydrochloride. Melting point 254-256 ℃

Synthesis Example 34-38

Except for the starting material, in practice it was repeated in the same manner as in Example 33 to prepare various other 1,3-diazacycloalkane derivatives. The products obtained are summarized in Table 11.

TABLE 11

Calculated Value: C74.27, H6.89, N13.67

Found: 74.54, 6.93, 13.58

Synthesis Example 42-51

Repeating in the same manner as in Example 41, except for the starting material, produced various other 1,3-diazacyclic compounds. The results obtained are summarized in Table 12 below.

TABLE 12

Synthesis Example 52

A mixture of 2.5 grams of 2- (2,2-diphenylethyl) -2-imidazoline and 50 milliliters of ethyl formate was refluxed for 5 hours. After the reaction, unreacted ethyl formate is distilled off. The resulting residue was put into silica gel column chromatography and eluted with methylene chloride. Removal of the solvent yields 1-formyl-2- (2,2-diphenylethyl) -2-imidazoline having a melting point of 105-107 ° C.

Synthesis Example 53

To a mixture of 5.0 grams of 2- (2,2-diphenylethyl) -2-imidazoline and 50 milliliters of pyridine are added 1.1 grams of acetyl chloride dropwise and stirred at room temperature for 2 hours. After the reaction, pyridine is distilled off. Add 100 milliliters of benzene and the same amount of water to the resulting residue and mix the solution well. The benzene layer is separated, washed with water and dehydrated with sodium sulfate. Recrystallization of the resulting residue with ether after removal of benzene yields 1-acetyl-2- (2,2-difeethylethyl) -2-imidazoline. Melting point 104-106 ℃

Synthesis Example 54

In Example 53, when 2- (2,2-diphenylethyl) -2-imidazoline was reacted with ethyl chlorocarbonate instead of acetyl chloride, 1-ethoxycarbonyl-2- (2, 2-diphenylethyl) -2-imidazoline is obtained.

Synthesis Example 55

A mixture of 0.75 grams of 2- (2,2-diphenylethyl) -2-imidazoline, 0.3 grams of paraformaldehyde and 5 milliliters of benzene was refluxed for about 2 hours to yield 1-hydroxy having a melting point of 161-163 占 폚. Methyl-2- (2,2-diphenylethyl) -2-imidazoline is obtained.

Synthesis Example 56

To a mixture of 1.0 grams of 2- (N-methyl, N-benzhydryl) amino-2-imidazoline, 10 milliliters of chloroform and 0.42 grams of triethylamine, 0.33 grams of acetyl chloride was added to the mixture for 1 hour. Stir at room temperature. The aqueous solution was washed with water, dehydrated with sodium sulfate, and chloroform was distilled to obtain 0.8 grams of 1-acetyl-2- (N-methyl, N-benzhydryl) amino-2-imidazole having a melting point of 99-101 ° C.

Although the present invention has been described in detail with reference to it, various changes and technical changes can be made without departing from the scope of the present invention.

Claims (1)

A process for preparing the compound of formula (X) by reacting a compound of the general formula (VII) with a compound (IX).

In the above formula, R ₁ is hydrogen, halogen, lower alkyl group or lower alkoxy group, R ₃ is hydrogen, lower alkyl group, lower hydroxyalkyl group or aralkyl, R ₄ is hydrogen, lower alkyl group or aryl group, R ₆ Is a cyclohexyl group, a pyridyl group or a phenyl group (which may be substituted with a halogen, lower alkyl group or lower alkoxy group), n is an integer from 2 to 4, T is an amidino group, an iminoether group or a nitrile group.