JPH08291173A - Imidazoquinoline analog - Google Patents

Abstract

PURPOSE: To obtain a new imidazoquinoline analog which is a specific imidazoquinoline analog, having excellent vasodilator, antistenocardiac, cardiotonic actions, etc., causing less side effects and useful as a synthetically effective therapeutic agent, etc., for diseases in the circulatory system. CONSTITUTION: This new imidazoquinoline analog is expressed by formula I (either of A and B is carbon atom when the other is nitrogen atom; either of R<1> and R<2> is a mono- or a di-lower alkyl-substituted amino when the other is formyl or hydroxymethyl; R<3> to R<6> are each H, a halogen or a lower alkyl; the dotted line indicates the presence of an aromatic double bond). The analog has vasodilator, antistenocardiac, cardiotonic actions, etc., and is useful as an effective therapeutic agent, etc., for diseases, etc., in the circulatory system. The imidazoquinoline analog is obtained by reacting 2-cyanoguinolines of formula II with a Vilsmeier reagent prepared by stirring a mixture of anhydrous N,N-dimethylformamide with phosphorus oxychloride under conditions for cooling with ice and, as necessary, further reducing the formyl group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to imidazoquinoline analogs, and more particularly to novel imidazoquinoline derivatives and imidazoisoquinoline derivatives which are expected to be useful therapeutic agents in the medical field of cardiovascular diseases and the like. .

[0002]

2. Description of the Related Art It is a well known fact that cardiovascular diseases have increased with the increase of the aging population, and have become a major problem along with malignant tumors. Therefore, although it is desired to develop drugs that are comprehensively effective against cardiovascular diseases, the main drugs currently used for therapeutic purposes are β-receptor stimulants, and others. Has only theophylline drugs. However, both of these drugs have many side effects and a large number of administrations, and are currently considerably restricted in drug treatment. Therefore, there has been a demand for the development of a therapeutic drug having fewer side effects and being comprehensively effective for cardiovascular diseases such as vasodilatory action, antianginal action and cardiotonic action.

[0003]

In view of such circumstances, the inventors of the present invention have conducted diligent research, and as a result, the imidazoquinoline analog represented by the general formula (I) described below can be an excellent therapeutic drug for cardiovascular disease. That is, they have a vasodilatory action, an antianginal action and a cardiotonic action, and have completed the present invention. That is, the present invention provides the following general formula (I):

[0004]

[Chemical 6]

In the formula, A and B are carbon atoms when one is a nitrogen atom, and R ¹ and R ² are mono- or di-lower alkyl substituted when one is a formyl group or a hydroxymethyl group. Represents an amino group, R ³ , R ⁴ , R
^{And 5} and R ⁶ each independently represent a hydrogen atom, a halogen atom or a lower alkyl group, and the dotted line represents the presence of an aromatic double bond, or a pharmacologically acceptable salt thereof. Is. Further, the present invention, in a specific embodiment of the above definition, has the following general formula (I-1a):

[0006]

[Chemical 7]

In the formula, R ⁷ represents a mono- or di-lower alkyl-substituted amino group, and R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, or an imidazoquinoline derivative or a drug thereof. A physically acceptable salt, and a general formula (I
-1b):

[0008]

Embedded image

Where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are
As defined above, the present invention provides an imidazoquinoline derivative represented by or a pharmaceutically acceptable salt thereof. Furthermore, the present invention, in another embodiment of the above definition, has the general formula (I-2a):

[0010]

[Chemical 9]

Where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are
As defined above, an imidazoisoquinoline derivative represented by: or a pharmaceutically acceptable salt thereof, and a general formula (I-2b):

[0012]

[Chemical 10]

Where R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are
It also provides an imidazoisoquinoline derivative represented by: or a pharmaceutically acceptable salt thereof as defined above. Since these compounds of the present invention have strong vasodilatory action, antianginal action or cardiotonic action, they are expected to be applied as excellent therapeutic agents for cardiovascular diseases.

The present invention will be described in more detail below. The "lower alkyl group" used in the present specification may be any linear or branched alkyl group, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,
Examples thereof include n-hexyl, isohexyl, n-heptyl, isoheptyl and the like, with preference given to methyl, ethyl and n.
-Propyl, isopropyl, n-butyl, isobutyl,
sec-butyl and tert-butyl. Further, the “halogen atom” or “halogen” means a chloro atom,
It means a bromine atom, a fluorine atom or an iodine atom.

The "mono- or di-lower alkyl-substituted amino group" means a mono- or di-lower alkyl-substituted amino group in which the lower alkyl group has the above-mentioned meaning, for example, mono (or di) methylamino, mono ( Or, di) ethylamino, mono (or di) n-propylamino, methylethylamino, methyl n-propylamino, ethyl n-propylamino and the like can be mentioned, preferably methylamino,
Dimethylamino, ethylamino and diethylamino.

The method for producing the compound (I) of the present invention is described in detail below. (A) The imidazoquinoline derivative which is one of the specific embodiments of the compound (I) of the present invention can be synthesized, for example, according to the method shown in the following reaction formula A.

[0017]

[Chemical 11]

In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ to R ⁷ are as defined above. The step (1) is prepared by mixing a 2-cyanoquinoline derivative represented by the formula (II-1), which is a synthetic raw material, with N-mono or N, N-di-lower alkyl-substituted formamide and phosphorus oxyhalide. Is a step of reacting the so-called Vilsmeier reagent described above to obtain a compound represented by the formula (I-1a) which is one of the compounds of the present invention.

The reaction is carried out without solvent or in an organic solvent inert to the reaction, for example, alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, diethyl ether and dioxane, halogenated hydrocarbons such as dichloromethane and chloroform, In a benzene-based solvent such as benzene, toluene or xylene, the compound of formula (II-1)
In a mixture of the synthetic raw material and the Vilsmeier reagent, and heated at room temperature or a temperature near the boiling point of the solvent used,
It is performed by stirring.

The reaction time cannot be unconditionally limited depending on the solvent used, the type of reagent and the amount used, but it is 0.5 to 36.
The reaction can be completed in about 2 to 25 hours, and the intended compound of the present invention represented by the formula (I-1a) can be obtained. The obtained compound (I-1a) of the present invention can also be isolated as a crystal from the reaction mixture by a method known per se (concentration, extraction, liquid conversion, chromatography, etc.).

The Vilsmeier reagent used in this step is, for example, 1 to 2 equivalents of phosphorus oxyhalide is added to 1 equivalent of N-mono or N, N-di-lower alkyl-substituted formamide, preferably Under ice cooling 0.1
It can be prepared by stirring for ~ 2 hours.

Step (2) is a step of converting the formyl group of the compound represented by the formula (I-1a) obtained in the above step (1) into a hydroxymethyl group. The reaction can be carried out under various conditions capable of reducing the formyl group substituted on the aromatic ring, and for example, a compound represented by the formula (I-1a) can be prepared by
It can be easily carried out by treating with sodium borohydride or the like in an organic solvent appropriately selected from the examples given above. The obtained compound of the present invention (I-1
b) is a method known per se from the reaction mixture (concentration,
It can also be isolated as crystals by extraction, liquid conversion, chromatography and the like).

(B) The imidazoisoquinoline derivative which is another specific embodiment of the compound (I) of the present invention can be synthesized, for example, according to the method shown in the following reaction formula B.

[0024]

[Chemical 12]

In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ to R ⁷ are as defined above. Each step shown in the above reaction scheme B can be carried out under the same conditions as the method described in detail for each step of the above reaction scheme A, whereby the formula (I) which is a specific embodiment of the compound of the present invention can be easily carried out. -2a) and (I
-2b), the imidazoisoquinoline derivative can be obtained. The compounds (I-2a) and (I-2b) of the present invention obtained by the method shown in the reaction formula B are prepared from the reaction mixture by a method known per se (concentration, extraction, liquid conversion,
It can also be isolated as crystals by chromatography).

The compound of the present invention represented by the formula (I) obtained by the above method can be isolated as an arbitrary acid addition salt by further treating with an organic acid or an inorganic acid. Examples of the organic acid used here include lower fatty acids such as formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid and trichloroacetic acid; substituted or unsubstituted benzoic acid such as benzoic acid and p-nitrobenzoic acid; methanesulfone. Acids, (halo) lower alkyl sulfonic acids such as trifluoromethane sulfonic acid; benzene sulfonic acid, p-nitrobenzene sulfonic acid, p-bromobenzene sulfonic acid, toluene sulfonic acid, 2,4,6-triisopropylbenzene sulfonic acid, etc. Substituted or unsubstituted aryl sulfonic acid; organic phosphoric acid such as diphenyl phosphoric acid can be mentioned, and examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid, perchlorine. Acid, nitrous acid, etc. are mentioned.

The thus-produced compound of the present invention represented by the formula (I) was found to have a vasodilatory action, an antianginal action and a cardiotonic action. Above all, regarding cardiotonic action,
As is clear from the results of the pharmacological test described below, it was confirmed that it has an extremely excellent action. Therefore,
The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof is expected to be a useful drug in the field of cardiovascular diseases.

The compound of formula (I) or a pharmaceutically acceptable salt thereof of the present invention can be administered to mammals including human being in the form of a composition for oral administration. The dose can be varied over a wide range depending on the age, weight, condition of the patient to be treated, diagnosis by a doctor, etc.
Dosages in the range of up to 3,000 mg are standard and will usually be given once or several times a day.

Therefore, the above-mentioned composition for oral administration is a carrier or diluent for formulation which is commonly used in the field of medicine, such as starch, lactose, sucrose, crystalline cellulose,
Excipients such as calcium hydrogen phosphate; binders such as acacia, hydroxypropyl cellulose, alginic acid, gelatin, polyvinylpyrrolidone; lubricants such as stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated vegetable oils; processed starch. , Calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, and other disintegrants; nonionic surfactants, anionic surfactants, and other dissolution aids, and the like. Specific forms of the composition for oral administration include solid preparations such as tablets, coating agents, capsules, chewable agents, powders, fine granules, granules and dry syrups,
Alternatively, a liquid preparation such as a syrup may be mentioned.

The compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof can also be administered as an injection. In this case, for example, it may be previously dispersed or dissolved in an aqueous carrier such as physiological saline with a surfactant, a dispersant, or the like, or a crystal preparation for injection so that it can be dispersed or dissolved each time when necessary. Alternatively, it may be a freeze-dried preparation. In addition to the above-mentioned components, a pH adjuster and a stabilizer may be added to the aqueous carrier as optional components. The administration route of such an injection is not particularly limited, and can be selected from intravenous administration, intraarterial administration, subcutaneous administration, intraperitoneal administration and the like depending on the symptoms and the characteristics of the patient. These may be administered all at once or gradually by infusion or the like.

[0031]

EXAMPLES Next, the present invention will be described in more detail by showing Examples, pharmacological tests and toxicity tests of specific compounds of the present invention, but the present invention is not limited to the following description. Needless to say. The numbers in parentheses attached to the compound names below indicate the compound numbers.

Example 1 1.31 g (18 m) of anhydrous N, N-dimethylformamide
M) and phosphorus oxychloride 5.51 g (36 mM) are stirred under ice-cooling for 0.5 hours to prepare a Vilsmeier reagent. 2-cyanoquinoline 0.
Add 92 g (6 mM) and stir at 80 ° C for 1.5 hours. After completion of the reaction, excess phosphorus oxychloride is distilled off, 50 ml of water is added to the residue, the mixture is made basic with sodium carbonate, and then extracted with chloroform. The separated organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off.
The residue was subjected to silica gel column chromatography (eluting solvent: n-hexane-ethyl acetate) to obtain the following compound of the present invention.

(A) First elution section 4-chloro-1-dimethylamino-3-formylimidazo [1,5-a] quinoline (1-a) 1.04 g (yield: 64%) Melting point: 150- 153 °, yellow needle crystals (recrystallization solvent: n
-Hexane) IR (KBr) cm ^-1 : 1660 (carbonyl) H ¹ -NMR (CDCl ₃ ) δ: 2.94 (6H, s),
7.58 (1H, brt, J = 8Hz), 7.72 (1
H, brt, J = 8 Hz), 8.17 (1H, brd,
J = 8 Hz), 8.22 (1H, brs), 9.03
(1H, brd, J = 8Hz), 10.06 (1H,
s) Elemental analysis: C ₁₄ H ₁₂ ClN ₃ O Calculated: C, 61.43; H, 4.41 ; N, 15.3
5 Experimental value: C, 61.69; H, 4.68; N, 15.3
Two

(B) Second elution section 5-chloro-1-dimethylamino-3-formylimidazo [1,5-a] quinoline (1-b) 110 mg (yield: 6.8%) Melting point: 206- 207 °, yellow needle crystals (recrystallization solvent: cyclohexane) IR (KBr) cm ⁻¹ : 1660 H ¹ -NMR (CDCl ₃ ) δ: 2.97 (6H, s),
7.46 (1H, s), 7.52 (1H, brd, J =
7 Hz), 7.62-7.70 (2H, m), 8.99
(1H, brd, J = 9Hz), 10.74 (1H,
s) Elemental analysis: C ₁₄ H ₁₂ ClN ₃ O Calculated: C, 61.43; H, 4.41 ; N, 15.3
5 Experimental value: C, 61.38; H, 4.59; N, 15.1
7

Example 2 2.19 g (30 m) of anhydrous N, N-dimethylformamide
M) and phosphorus oxychloride 9.18 g (60 mM) are stirred under ice-cooling for 0.5 hours to prepare a Vilsmeier reagent. Next, 1.54 g (10 mM) of 1-cyanoisoquinoline is added to this reagent, and the mixture is stirred at 80 ° C. for 24 hours. After completion of the reaction, phosphorus oxychloride is distilled off, 100 ml of water is added to the residue, and the mixture is made basic with sodium carbonate and then extracted with chloroform. The separated organic layer is washed with water, dried over anhydrous sodium sulfate, and the solvent is distilled off.
The residue was subjected to silica gel column chromatography (eluting solvent: benzene-ethyl acetate) to give 0.90 g of 3-dimethylamino-1-formylimidazo [5,1-a] isoquinoline (2) (yield: 38%) was obtained. Melting point: 112-113 °, yellow needle crystal (recrystallization solvent: cyclohexane) IR (KBr) cm ⁻¹ : 1660 H ¹ -NMR (CDCl ₃ ) δ: 3.02 (6H, s),
7.09 (1H, brd, J = 7Hz), 7.66-
7.72 (3H, m), 7.77 (1H, d, J = 7H
z), 9.71 (1H, m), 10.24 (1H, s) Elemental analysis value: C ₁₄ H ₁₃ N ₃ O Calculated value: C, 70.27; H, 5.47; N, 17. 5
6 Experimental value: C, 70.04; H, 5.29; N, 17.3
Two

Example 3 The following compounds were obtained according to the method described in Example 1 above. (A) 5-chloro-1-dimethylamino-3-formyl-8-methylimidazo [1,5-a] quinoline (3-
a) Melting point: 180-181 °, yellow needle crystals (recrystallization solvent: n
-Hexane) H ¹ -NMR (CDCl ₃ ) δ: 2.60 (3H, s),
2.94 (6H, s), 7.39 (1H, brd, J =
8 Hz), 8.03 (1H, d, J = 8 Hz), 8.1
4 (1H, brs), 8.81 (1H, brs), 1
0.04 (1H, s)

(B) 5-chloro-1-dimethylamino-
3-Formyl-7-methylimidazo [1,5-a] quinoline (3-b) Melting point: 175-177 °, yellow needle crystals (recrystallization solvent: n
-Hexane-cyclohexane) H ¹ -NMR (CDCl ₃ ) δ: 2.55 (3H, s),
2.93 (6H, s), 7.52 (1H, brd, J =
8.8 Hz), 7.95 (1H, brs), 8.21
(1H, s), 8.90 (1H, d, J = 8.8H
z), 10.05 (1H, s)

Example 4 The following compound was obtained according to the method described in Example 2 above. (A) 3-Dimethylamino-1-formyl-4-methylimidazo [5,1-a] isoquinoline (4-a) Melting point: 118-119 °, pale yellow needle crystals (recrystallization solvent:
n-hexane / cyclohexane) H ¹ -NMR (CDCl ₃ ) δ: 2.87 (6H, s),
2.90 (3H, brs), 6.77 (1H, br)
s), 7.55-7.61 (3H, m), 9.74 (1)
H, m), 10.18 (1H, s)

(B) 1-Formyl-3-methylaminoimidazo [5,1-a] isoquinoline (4-b) Melting point: 257-259 °, yellow needle crystals (recrystallization solvent: ethyl acetate) H ^1- NMR (DMSO-d ₆ ) δ: 3.03 (3H,
s), 7.24 (1H, d, J = 7.5 Hz), 7.4
6 (disappeared at 1H, br, D ₂ O), 7.66 (2H,
m), 7.82 (1H, m), 8.06 (1H, d, J
= 7.5 Hz), 9.39 (1H, brs), 10.0
6 (1H, s)

Example 5 3-Dimethylamino-1-formylimidazo [5,1-a] isoquinoline (2) obtained in Example 2 above was treated with sodium borohydride to give 3-dimethylamino- 1-hydroxymethylimidazo [5,1-
a] Isoquinoline (5) was obtained. Melting point: 151-153 °, yellow columnar crystal (recrystallization solvent: ethyl acetate) H ¹ -NMR (CDCl ₃ ) δ: 2.89 (6H, s),
5.11 (2H, s), 6.71 (1H, d, J = 7.
5Hz), 7.39 (1H, m), 7.53 (3H,
m), 8.14 (1H, brd, J = 7.6Hz)

Pharmacological test 1: Cardiotonic effect The cardiotonic effect of the compounds of the present invention on the heart muscle of guinea pigs was investigated. The cardiotonic effect was a positive chronotropic effect, and the concentration of the test drug (EC ₃₀ ) required to increase the heart rate in the left atrium of the guinea pig at 30 beats / minute or more was examined. Also,
As a positive inotropic effect, the contraction pressure when stimulating the right ventricle of the guinea pig administered the test drug was measured, and the increase in the pressure reached 20% of the increase when the isoproterenol was administered. Concentration of the test drug required for
We examined the C _20). The compounds (2), (4-a) and (4-b) of the present invention obtained in the above Examples were used as test drugs. The results are shown in Table 1 below.

[0042]

[Table 1]

As shown in Table 1, the compounds of the present invention were found to have excellent cardiotonic action.

Pharmacological test 2: vasodilatory action The isolated thoracic aorta of the rat from which the endothelium has been peeled off is suspended in the Magnus tube and 1 g of the suspension is applied. After the resting tension is stabilized, phenylephrine is applied. The test drug was cumulatively applied when the strained state was stabilized, and the drug concentration that relaxed the strain by 25% (EC ₂₅ ) was examined. As a study drug,
The compounds (2) and (3-) of the present invention obtained in the above Examples
b) was used and amrinone was used as a control drug. The results are shown in Table 2 below.

[0045]

[Table 2]

As shown in Table 2, it was found that the compound of the present invention showed good smooth muscle relaxation and had a vasodilatory action.

Toxicity Test The acute toxicity test of the compound of the present invention was conducted by the following method.
ICR male mice were purchased at the age of 4 weeks, and subjected to an experiment after preliminary breeding for about 10 days. The test drug is mouse weight 10g
The suspension was suspended in a 1% carboxymethylcellulose solution at a volume of 0.1 ml, and was orally administered by force using a metal gastric tube. The mice were fasted for 16 hours from the day before the experiment. The observation period after the administration was set to 14 days, and the LD ₅₀ value was determined by the Richfield Wilcoxon method from the survival rate after 14 days. As test drugs, the above-mentioned Example compounds (2), (3-b), (4-a) and (4-b) were used. As a result, all the compounds of the present invention were 1.5 g / kg.
That was all.

Claims (5)

[Claims] 1. A compound represented by the general formula (I): In the formula, A and B represent a carbon atom when one is a nitrogen atom, and R ¹ and R ² represent a mono- or di-lower alkyl-substituted amino group when one is a formyl group or a hydroxymethyl group. Represents R ³ , R ⁴ , R ⁵ and R ⁶
Each independently represent a hydrogen atom, a halogen atom or a lower alkyl group, and the dotted line represents the presence of an aromatic double bond, or a pharmaceutically acceptable salt thereof. 2. General formula (I-1a): The imidazoquinoline derivative according to claim 1, wherein R ⁷ represents a mono- or di-lower alkyl-substituted amino group, and R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above. Or a pharmaceutically acceptable salt thereof. 3. A compound represented by the general formula (I-1b): In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and the imidazoquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1. 4. General formula (I-2a): In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and the imidazoisoquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1. 5. A compound represented by the general formula (I-2b): In the formula, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above, and the imidazoisoquinoline derivative or a pharmaceutically acceptable salt thereof according to claim 1.