JPH09227559A - Spiro-substituted tricyclic heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a spiro substituted tricyclic heterocyclic compound useful as a therapeutic agent for respiratory disease, having relaxant effect on muscularis of bronchus and antiasthmatic effect, slight in adverse effect, suitable in a medical field. SOLUTION: This new spiro-substituted tricyclic heterocyclic compound is shown by formula I (R is H, a halogen or a lower alkyl; X and Y are each CH or N; (n) is 0, 1 or 2), has relaxant effect on muscularis of bronchus and antiasthmatic effect, slight in adverse effect and is useful as a medicine for respiratory disease. The compound is obtained by esterifying 5-chlorosalicylic acid of formula II, reacting the esterified substance with 4-chlorobutyronitrile, amidating the resultant substance by treatment with ammonia, dehydrating the amidated substance to give a nitrile derivative of formula III, then subjecting the derivative to a ring formation reaction to give a compound of formula IV, treating the compound with a dihaloalkylene compound and simultaneously carrying out a ring formation reaction, ring opening of the furan ring and a rearrangement reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a tricyclic heterocyclic compound, and more particularly to a novel spiro-substituted tricyclic heterocyclic compound having bronchodilator action and anti-asthma action, and a pharmacologically acceptable compound thereof. Related to salt.

[0002]

2. Description of the Related Art With the remarkable changes in eating habits and living environment of modern people, the diseases in question are also changing. For example, allergic respiratory diseases represented by asthma attacks are regarded as typical diseases of modern people, and the number of patients is increasing. In particular, recently, hay fever associated with the scattering of cedar pollen and the like is becoming a serious problem, and a large number of therapeutic agents or symptomatic therapeutic agents for such diseases are provided and used in the medical field. However, no medicinal product that can be a specific medicine has yet to appear due to the occurrence of side effects or a weak effect, and it is the current situation that further excellent medicinal products are being energetically developed. In this case, in order to develop a new therapeutic drug for the above-mentioned diseases, it can be said that it is essential to develop a drug that further reduces the side effects that have been conventionally problematic and has a strong therapeutic effect.

[0003]

DISCLOSURE OF THE INVENTION The inventors of the present invention have been earnestly studying for the development of a drug having an excellent therapeutic effect, and a polycyclic heterocycle having a condensed ring, which has not been studied previously, has been studied. As a result of examining bronchodilator action, cholesterol lowering action and the like of cyclic compounds, it was found that various pharmacological activities were recognized, and some of them have already been applied for patents (JP-A-7-
316162). The compounds provided by the present inventors are
Side effects are reduced compared to conventional medicines,
In addition, it has a strong pharmacological activity, but this time it is an object to provide a better bronchodilator substance.

[0004]

In view of such circumstances, as a result of earnest research for development of an excellent drug, the present inventors have found that the spiro-substituted tricyclic heterocyclic compound represented by the following general formula (I). The compound was found to have a bronchodilator effect, and it was newly found that these compounds can be excellent drugs, and the present invention was completed. That is, the present invention provides the following general formula (I):

[0005]

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In the formula, R represents a hydrogen atom, a halogen atom or a lower alkyl group; X and Y represent the same or different CH or N; n represents an integer of 0, 1 or 2; The present invention provides a spiro-substituted tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof. The compound represented by the above formula (I) itself is a novel compound which has not been described in the literature so far, and thus it has never been known that the above-mentioned pharmacological activity is observed in these compound groups.

Further, according to the aspect defined above, the present invention specifically includes the following general formulas (Ia), (Ib) and general formula (Ic):

[0008]

[Chemical 6]

[0009]

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[0010]

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In the formula, R and n are as defined above, and a spiro-substituted tricyclic heterocyclic compound represented by and a pharmacologically acceptable salt thereof are provided. Further, in another aspect, the present invention provides the above formulas (I) and (I-
There is provided a bronchodilator having a compound represented by a), (Ib) or (Ic) or a pharmacologically acceptable salt thereof as an active ingredient, and an anti-asthma therapeutic agent. The compound provided by the present invention is expected to be practically commercialized as an excellent drug, as is clear from the results of the pharmacological action described below.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention will be described in detail below. In the present specification, the term "lower" means
It means that the substituent or compound to which this term is attached has 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms.
Therefore, in each of the above general formulas, the "lower alkyl group" in the definition of the substituent "R" has 1 to 10 carbon atoms.
7 means a chain or branched chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-hexyl, isohexyl, n-heptyl. , Isoheptyl, etc., but preferably 1 to 1 carbon atoms.
4 methyl, ethyl, n-propyl, isopropyl, n
-Butyl, isobutyl, sec-butyl, tert-butyl.

The "halogen atom" is chlorine, bromine, fluorine, iodine or the like, preferably chlorine atom.

The compound represented by the formula (I) provided by the present invention can be produced, for example, by the method shown in the following reaction formula A or reaction formula B.

[0015]

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In each of the above reaction formulas, R, X, Y and n are as defined above, m is an integer of 0, 1 or 2, and Hal represents a halogen atom. The production in the above reaction scheme will be described below.

Reaction formula A : That is, the compound of the formula (I) of the present invention is obtained by treating the compound of the formula (II) with phosphorus oxychloride to give an intramolecular ring-closing reaction of the compound of the formula (II) and the subsequent molecule. It is produced by allowing the internal rearrangement reaction to proceed simultaneously in one reaction system to lead to the specific spiro-substituted tricyclic heterocyclic compound represented by the formula (I) which is the object compound of the present invention. The reaction in this case is preferably carried out in an organic solvent, but as an organic solvent that can be used,
Any organic solvent that does not directly influence the reaction can be used, and examples of such a solvent include halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, trichloroethane, chloroform and carbon tetrachloride; Examples thereof include benzene-based solvents such as benzene, toluene and xylene; ether-based solvents such as ether, tetrahydrofuran and dioxane. Of these, halogenated hydrocarbon-based solvents are preferable, and chloroform is particularly preferable. Of course, the purpose can be achieved by using only phosphorus oxychloride without the presence of an organic solvent.

The amount of phosphorus oxychloride used in the reaction is
1 to 10 times by mol of the compound represented by the formula (II),
It is preferably 1 to 5 times by mole, more preferably 2 to 4 times by mole. The reaction temperature and the reaction time are appropriately changed depending on the compound (II) to be used and the organic solvent used, and thus cannot be unconditionally limited, but are 0 ° C. to 100 ° C., preferably 1 to 20 at room temperature or around the boiling point of the solvent used. It can be performed for about 1 to 10 hours. The compound represented by the formula (I) obtained by the method of this reaction scheme A is
A method known per se from the reaction mixture (concentration, extraction, filtration,
In many cases, the compound itself can be isolated as a crystal, or as a crystal in the form of a salt, by appropriately applying liquid conversion, chromatography, recrystallization, and the like.

Reaction formula B : Further, the compound of formula (I) of the present invention is prepared by treating the amino compound of formula (III) with a dihaloalkylene compound of formula (IV) in the presence of a base to form a ring. It is produced by leading to a specific spiro-substituted tricyclic heterocyclic compound represented by the formula (I), which is the object compound of the present invention, by ring-opening and rearrangement reaction of the furan ring simultaneously with the formation reaction. Examples of the base used include alkali metal hydrides such as sodium hydride and potassium hydride; alkali metal amides such as sodium amide and potassium amide; alkali metal alkoxides such as sodium methoxide, sodium ethoxide and sodium-
Examples thereof include t-butoxide, potassium methoxide, potassium ethoxide, potassium-t-butoxide; alkali metal oxides such as sodium oxide and potassium oxide; alkaline earth metal oxides such as calcium oxide, and among them, alkali metal hydrogen. Compounds and alkaline earth metal oxides are preferable, and sodium hydride and calcium oxide are particularly preferable.

The reaction in this case is preferably carried out in an organic solvent, but any organic solvent which does not directly affect the reaction can be used as the organic solvent. For example, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane, trichloroethane, chloroform and carbon tetrachloride; benzene solvents such as benzene, toluene and xylene; ether solvents such as ether, tetrahydrofuran and dioxane can be used. Among them, ethereal solvents are preferable, and dioxane is particularly preferable. Of course, the object can be achieved even if the reaction is carried out without the presence of an organic solvent.

The amount of the dihaloalkylene compound represented by the formula (IV) used in the reaction is 1 to 20 times, preferably 2 to 15 times, and more preferably the mole of the compound represented by the formula (III). It is about 5 to 10 times mol, and the amount of the base to be present is 1 to 10 times mol, preferably 1 to 8 times mol, more preferably 1 to 5 times mol, of the compound represented by the formula (III). It is a degree. The reaction temperature and the reaction time are the same as those of the compounds (III) and (I
V), a base and an organic solvent to be used are appropriately changed, and therefore there is no particular limitation, but it can be performed at 0 ° C. to 150 ° C., preferably in the vicinity of the boiling point of the solvent used for about 1 hour to several days. The compound represented by the formula (I) obtained by the method of the reaction formula B is appropriately applied by a method known per se (concentration, extraction, filtration, liquid conversion, chromatography, recrystallization, etc.) from the reaction mixture, Often the compound itself can be isolated as a crystal, or as a salt form of the crystal.

In the methods of reaction formulas A and B, the compounds represented by the formulas (II) and (III), which are the starting compounds, can be easily produced according to the methods described in the production examples described below. However, many of these compounds are the compounds listed in Tables 3 and 4; Tables 7 and 8 and Tables 11 and 12 of JP-A-7-316162 already proposed by the present inventor. Can be manufactured according to the examples described in the publication.

On the other hand, examples of the dihaloalkylene compound represented by the formula (IV) include the following depending on the kind of halogen atom and alkylene. 1,
2-dichloroethane, 1,2-dibromoethane, 1,3
-Dichloropropane, 1,3-dibromopropane, 1,
4-dichlorobutane, 1,4-dibromobutane.

By the above method, the compound of formula (I) which is the object compound of the present invention can be obtained. The compound represented by the formula (I) is optionally derived into a compound as a pharmaceutically acceptable salt, and the formation of such a salt is carried out by treating with an organic acid or an inorganic acid. . Examples of the organic acid used here include formic acid, acetic acid, propionic acid, butyric acid, trifluoroacetic acid,
Lower fatty acids such as trichloroacetic acid; substituted or unsubstituted benzoic acids such as benzoic acid and p-nitrobenzoic acid; (halo) lower alkyl sulfonic acids such as methanesulfonic acid and trifluoromethanesulfonic acid; benzenesulfonic acid and p-nitrobenzene Substituted or unsubstituted aryl sulfonic acids such as sulfonic acid, p-bromobenzene sulfonic acid, toluene sulfonic acid and 2,4,6-triisopropylbenzene sulfonic acid; and organic phosphoric acid such as diphenyl phosphoric acid can be mentioned. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, borofluoric acid, perchloric acid, nitrous acid and the like.

The compound of the formula (I) of the present invention obtained by the above-mentioned method has a bronchial muscle relaxant action, as is clear from the results of the pharmacological tests described below.
In particular, it can be used for alleviating asthma symptoms.
Therefore, the compound of formula (I) of the present invention is expected to be a useful drug in the field where these effects can be applied to therapy. Among them, particularly preferred embodiments of the present invention include the following formulas (V), (VI) and (VII):

[0026]

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[0027]

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[0028]

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In each formula, R and n are as defined above, and is a bronchial muscle relaxant agent containing the compound represented by and a pharmacologically acceptable salt thereof as an active ingredient.

When the compound of the present invention is used as the above-mentioned therapeutic agent, various dosage forms such as tablets, capsules, powders, troches, and the like can be prepared by a conventional formulation technique.
It may be an oral administration preparation such as a liquid preparation. The above-mentioned formulation can be carried out by a method known per se. That is,
The compound of formula (I) is converted into starch, mannitol,
Excipients such as lactose; binders such as sodium carboxymethyl cellulose and hydroxypropyl cellulose; disintegrators such as crystalline cellulose and carboxymethyl cellulose calcium; lubricants such as talc and magnesium stearate; improvement of fluidity such as plasma silicic acid Tablets, capsules, powders, granules or troches can be produced by appropriately combining and formulating the agents and the like. When such an orally administered drug is administered to humans, it varies depending on the age and symptoms of the patient, but its effective amount is usually 10 to 10 per day.
It is preferable to administer 00 mg orally in 1 to 3 divided doses.

Furthermore, the compound of the present invention can be administered by injection. In this case, for example, it may be previously dispersed or solubilized in a water carrier such as physiological saline with a surfactant or a dispersant, or for injection so that it can be dispersed or solubilized each time when necessary. It may be a crystal preparation or a freeze-dried preparation. In addition to the above-mentioned components, the above water carrier has
A regulator or stabilizer may be added as an optional component. The administration route of such an injection is not particularly limited, and intravenous administration, intraarterial administration, subcutaneous administration, intraperitoneal administration, etc. are appropriately selected according to the symptoms and the characteristics of the patient. These may be administered all at once, or may be administered gradually by infusion or the like.

[0032]

The present invention will be described in detail below by describing Production Examples and Examples of specific compounds of the present invention, and pharmacological effects and toxicity tests of those compounds. The numbers in parentheses indicate the compound numbers. Production Example 1 :

[0033]

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(A) 25 g (0.21 m) of compound (1)
ol) in 400 ml of anhydrous dimethylformamide,
43 g (0.32 mol) of 4-chlorobutyronitrile and 32 g (0.32 mol) of potassium carbonate were added, and the mixture was stirred and refluxed for 4 hours. After the reaction was completed, 400 ml of ice water was added, and the deposited precipitate was collected by filtration and recrystallized from ethanol to give compound (2) 37 as colorless plate crystals at mp 48-49 ° C.
g (95%) were obtained. ^{IRcm -1: 2230,2180 (CN) 1} H-NMR (CDCl 3) δ: 2.23 (2H, q,
J = 5.8 Hz), 2.70 (2H, t, J = 5.8H)
z), 4.23 (2H, t, J = 5.8Hz)

(B) Compound (2) obtained in (a) above 3.
7 g (20 mmol) of anhydrous dimethylformamide 10
Dissolved in 0 ml, potassium-t-butoxide 4.48 g
(40 mmol) was added and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, 1000 ml of ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried (sodium sulfate), and then the solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, eluted with a mixed solution of benzene-ethyl acetate (4: 1), and recrystallized from ethyl acetate to give mp19.
Compound (3) 0.52 as brown columnar crystals at 2-194 ° C
g (14%) was obtained. ^{IRcm -1: 3490,3330 (NH) 1} H-NMR (CDCl 3) δ: 3.33 (2H, t,
J = 8.7 Hz), 4.70 (2H, t, J = 8.7H)
z), 5.24 (2H, brs, NH ₂ ) Production Example 2 :

[0036]

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(A) 1.0 g of 5-chlorosalicylic acid
(5.8 mmol) was dissolved in 1 ml of anhydrous methanol, 0.6 g of concentrated sulfuric acid was added dropwise thereto, and ordinary esterification was carried out for 4 hours. After the reaction was completed, water was added to the mixture and extracted with ether.
Washing with water-washing with saturated aqueous solution of potassium hydrogen carbonate-washing with water, drying (sodium sulfate) and evaporation of the solvent. The obtained residue was recrystallized from n-hexane to give 0.9 g of a methyl ester compound of the compound (4) as crystals at mp 46-47 ° C.
(82%) was obtained. IRcm ^-1: 1660 (ester _{^{carbonyl) 1 H-NMR (CDCl 3}} ) δ: 3.96 (3H, s,
CH ₃ ) Then, this ester form 330 mg (1.77 mmol)
Was dissolved in 1 ml of anhydrous dimethylformamide, 274 mg (2.66 mmol) of 4-chlorobutyronitrile and 366 mg (2.66 mmol) of potassium carbonate were added,
The mixture was stirred and refluxed for 5 hours. After the reaction was completed, ice water was added, the mixture was extracted with ethyl acetate, washed with water, dried (sodium sulfate), and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, eluted with benzene, and recrystallized from a mixed solution of ethyl acetate-n-hexane to give mp56-57.
368 mg (82%) of methyl 5-chloro-2- (3-cyanopropoxy) benzoate was obtained as colorless needle crystals at ℃. ^{IRcm -1: 2235 (CN),} 1705 ( ester _{^{carbonyl) 1 H-NMR (CDCl 3}} ) δ: 2.23 (2H,
m), 2.72 (2H, t, J = 6Hz), 3.88
(3H, s, OCH ₃ ), 4.14 (2H, t, J = 6)
Hz)

Then, 5-chloro-2 thus obtained
1.0 g of methyl (3-cyanopropoxy) benzoate
(3.95 mmol) was dissolved in 20 ml of dioxane,
Hydrolysis was carried out by adding 20 ml of 1N-NaOH, followed by conventional treatment, and recrystallization from ethyl acetate-n-hexane to give mp.
Compound (5) was added as a colorless needle crystal at 94-95 ° C. to 0.9
g (95%) was obtained. IRcm ⁻¹ : 3430 (OH), 2245 (CN), 1
^{700 (CO) 1 H-NMR} (CDCl 3) δ: 2.28 (2H, b
q), 2.70 (2H, t, J = 6Hz), 4.24
(2H, t, J = 6Hz), 9.92 (1H, brs,
OH)

(B) Compound (5) obtained in (a) above 1.
0 g (4.18 mmol) of phosphorus oxychloride 6.4 g
It was dissolved in (41.8 mmol) and stirred under reflux for 4 hours.
After completion of the reaction, excess phosphorus oxychloride was distilled off under reduced pressure, 50 ml of liquid ammonia was added to the residue under cooling, and the mixture was left standing overnight. Saturated saline was added to this, and the precipitate was collected by filtration and recrystallized from ethanol-n-hexane to give mp120-1.
Compound (6) of 0.9 g (9
2%). IRcm- ¹ : 3385, 3190 (NH), 2250
(CN), 1635 (amidocarbonyl) ¹ H-NMR (CDCl ₃ ) δ: 2.10-2.71
(4H, m), 4.26 (2H, t), 6.46 (2
H, brs, NH ₂ )

(C) Compound (6) 20 obtained in the above (b)
0 mg (0.84 mmol) was dissolved in anhydrous chloroform, 1.29 g (8.4 mmol) of phosphorus oxychloride was added, and the mixture was stirred and refluxed for 2 hours. After the reaction was completed, the solvent and excess phosphorus oxychloride were distilled off, ice water was added to the residue, and the deposited precipitate was recrystallized from ether to give Compound (7) as colorless needle crystals at mp 57-58 ° C. 185 mg (quantitative)
Obtained. ^{IRcm -1: 2235,2245 (CN) 1} H-NMR (CDCl 3) δ: 2.17-2.42
(2H, m), 2.70 (2H, t, J = 5.6H
z), 4.21 (2H, t, J = 5.6Hz)

(D) Compound (7) 30 obtained in the above (c)
0 mg (1.36 mmol) was dissolved in 3 ml of anhydrous dioxane, and potassium tert-butoxide 305 mg (2.
72 mmol) was added and the reaction was carried out at 100 ° C. After completion of the reaction, the solvent was evaporated, ice water was added, and the deposited precipitate was recrystallized from ethyl acetate to obtain 250 mg (83%) of Compound (8) as brown needle crystals at mp 254 to 255 ° C. ^{IRcm -1: 3490,3395 (NH) 1} H-NMR (CDCl 3) δ: 3.32 (2H, t,
J = 8.8 Hz), 4.72 (2H, t, J = 8.8H)
z), 5.16 (2H, brs, NH ₂ ), 7.36
(1H, d, J = 8.9 Hz), 7.46 (1H, d
d, J = 8.9 Hz, 2.0 Hz), 7.70 (1H,
d, J = 2.0 Hz) Production Example 3 :

[0042]

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(A) Compound (9) 29 g (0.24 mo
1) was dissolved in 300 ml of dimethylformamide, and 107 g (0.73 mo) of 4-bromobutyronitrile was dissolved therein.
1) and 100 g (0.73 mol) of potassium carbonate were added, and the mixture was stirred and refluxed for 9 hours. After the reaction was completed, ice water was added to precipitate the deposited precipitate, which was recrystallized from ethyl acetate.
Compound (1
0) was obtained.

(B) Compound (10) 2 obtained in (a) above
00 mg (1.1 mmol) of dimethylformamide 5
dissolved in ml, potassium-t-butoxide 240 mg
(1.1 mmol) was added and the mixture was stirred at 60 ° C. for 30 minutes.
After the reaction was completed, ice water was added and the mixture was extracted with ethyl acetate, washed with water and dried (sodium sulfate), and the organic layer was evaporated.
The residue obtained is recrystallized from ethyl acetate, mp23
Compound (11) 90 as yellow needle crystals at 2-234 ° C.
Obtained mg (45%). ^{IRcm -1: 3450,3280 (NH) 1} H-NMR (CDCl 3) δ: 3.30 (2H, t,
J = 8.8 Hz), 4.73 (2H, t, J = 8.8H)
z), 5.92 (2H, brs, NH ₂ )

(C) Compound (11) 1 obtained in the above (b)
g (5.4 mmol) was dissolved in 15 ml of concentrated hydrochloric acid, and 0.74 g of NaNO ₂ (10.7 mmol-water 2.
(7 ml) aqueous solution was added dropwise, the end point was confirmed with potassium iodide-starch paper, and sodium hydrogen carbonate was added to neutralize. The deposited precipitate was collected by filtration, the filtrate was extracted with benzene, washed with water and dried (sodium sulfate), and then benzene was distilled off. The residue and the above precipitate were combined and recrystallized from dioxane to obtain 0.74 g (67%) of compound (12) as colorless granular crystals of mp196-198 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 3.51 (2H,
t, J = 9.0 Hz), 4.82 (2H, t, J = 9.
0Hz), 7.75 (1H, dd, J = 4.0Hz, J
= 8.5 Hz), 8.23 (1H, dd, J = 1.5H)
z, J = 8.5 Hz), 8.89 (1H, dd, J =
4.0Hz, J = 1.5Hz)

(D) Compound (12) obtained in the above (c)
To 1.0 g (4.8 mmol) of 2-aminoethanol, 5.9 g (96.9 mmol) was added, and the mixture was heated and stirred at 120 ° C. for 1 hour. Ice water was added to the reaction solution, and the deposited precipitate was collected by filtration, recrystallized from ethyl acetate, and mp171-
5- (2-hydroxyethylamino) -1,2-dihydrofuro [3,2-f] as yellow columnar crystals at 173 ° C.
0.76 of [1,7] naphthyridine [compound (13)]
g (68%). ^{IRcm -1: 3400,3250 (OH, NH} ) 1 H-NMR (CDCl 3) δ: 3.28 (2H, t,
J = 8.7 Hz), 4.72 (2H, t, J = 8.7H)
z), 7.32 (1H, brs, NH), 7.42 (1
H, dd, J = 4.1 Hz, J = 8.4 Hz), 7.6
9 (1H, dd, J = 1.8Hz, J = 8.4Hz),
8.45 (1H, dd, J = 4.1Hz, J = 1.8H
z)

In place of 2-aminoethanol, 3-amino
Amino-1-propanol was used for the same treatment and recrystallized from ethyl acetate to give 5- (3-hydroxypropylamino) -1,2 as yellow columnar crystals at mp 158-159 ° C.
-Dihydrofuro [3,2-f] [1,7] naphthyridine [compound (14)] was obtained in a yield of 64%. IRcm ^-1 : 3400,3350 (OH, NH) ¹ H-NMR (CDCl ₃ ) δ: 1.84 (2H, br
s, J = 5.7 Hz), 3.27 (2H, t, J = 8.
5 Hz), 3.62-3.83 (4 H.m), 4.46
(1H, brs, OH), 4.72 (2H, t, J =
8.5 Hz), 7.16 (1H, brs, NH) Production Example 4 :

[0048]

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(A) Compound (15) 25 g (0.19 m
ol) in 280 ml of dimethylformamide,
To this, 55 g of 4-bromobutyronitrile (0.37 mo
1) and 51 g (0.37 mol) of potassium carbonate were gradually added, and the mixture was stirred at 80 to 90 ° C for 2 hours. After the reaction was completed, ice water was added, and the obtained precipitate was collected by filtration and recrystallized from cyclohexane-benzene to obtain 28.5 g (76%) of compound (16) as colorless plate crystals at mp 85-87 ° C. ^{IRcm -1: 2220 (CN) 1} H-NMR (CDCl 3) δ: 2.19 (2H, q,
J = 7Hz), 2.50 (3H , s, CH 3), 2.6
1 (2H, t, J = 7Hz), 4.54 (2H, t, J
= 7 Hz), 6.85 (1H, d, J = 7.7 Hz),
7.76 (1H, d, J = 7.7Hz)

(B) Then, 3 g (14.9 mmol) of the compound (16) obtained in the above (a) was added to 60 m of dioxane.
2.5 g of potassium t-butoxide (2 g
2.3 mmol) was added and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, ice water was added, and the deposited precipitate was collected by filtration and recrystallized from ethanol to obtain 2.5 g (83%) of compound (17) as pale yellow prism crystals at mp 279-280 ° C. ^{IRcm -1: 3420,3140 (NH) 1} H-NMR (DMSO-d 6) δ: 2.53 (3H,
s, CH ₃ ), 3.24 (2H, t, J = 8.7H
z), 4.58 (2H, t, J = 8.7 Hz), 7.0
9 (2H, brs, NH ₂ )

(C) Compound (17) obtained in the above (b)
To a solution of 3.76 g (18.7 mmol) in 250 ml of concentrated hydrochloric acid, 25 g of sodium chloride was added, and 6.45 g (93.5 mmol) of sodium nitrite aqueous solution was gradually added dropwise at 0 to -5 ° C over 1 hour. After completion of the reaction, the solution was neutralized with a saturated aqueous solution of sodium hydrogen carbonate, the deposited precipitate was collected by filtration, and the filtrate was extracted with benzene. The benzene layer was washed with water, dried (magnesium sulfate), and then distilled off. The obtained residue and the above precipitate were combined and subjected to silica gel column chromatography, eluted with a chloroform-acetone mixed solution, and recrystallized from benzene to give Compound (18) as a pale yellow crystal at mp 128-130 ° C. 0.4 g (34%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 2.74 (3 H, s,
CH ₃ ), 3.61 (2H, t, J = 9 Hz), 4.8
4 (2H, t, J = 9Hz), 7.20 (1H, d, J
= 8.7 Hz), 8.35 (1H, d, J = 8.7H)
z)

(D) Compound (18) 2 obtained in the above (c)
20 mg (1.0 mmol), potassium carbonate 207 mg
(1.5 mmol) and 2-aminoethanol 1 ml
The mixture was heated at 60-70 ° C for 1 hour. After completion of the reaction, ice water was added and the mixture was neutralized with acetic acid, the precipitated crystals were collected by filtration, and the filtrate was extracted with benzene. The benzene layer was washed with water, dried (magnesium sulfate), and then distilled off. The obtained residue and the above crystals were combined and recrystallized from a cyclohexane-ethanol mixed solution to give 5- (2-hydroxyethylamino) -8-methyl-1,2-dihydrofuro as yellow plate crystals at mp178-181 ° C. [2,3-h] [1,6]
170 mg of naphthyridine [compound (19)] (69
%)Obtained. ^{IRcm -1: 3337 (OH),} 3152 (NH) 1 H-NMR (CDCl 3) δ: 2.65 (3H, s,
CH ₃ ), 3.45 (2H, t, J = 8.9Hz),
3.77 (1H, OH and 2H, t, J = 5Hz),
3.91 (2H, t, J = 5Hz), 4.73 (2H,
t, J = 8.9 Hz), 5.80 (1H, brs, N
H), 6.95 (1H, d, J = 8.5 Hz), 7.8
7 (1H, d, J = 8.5Hz)

It should be noted that instead of 2-aminoethanol, 3-amino
The same reaction treatment was carried out using amino-1-propanol, and recrystallized from a cyclohexane-ethanol mixed solution to give mp15.
5- (3-hydroxypropylamino) -8-methyl-1,2-dihydrofuro [2,3-h] [1,6] naphthyridine [compound (2
0)] was obtained in a yield of 200 mg (77%). ^{IRcm -1: 3390 (OH, NH} ) 1 H-NMR (CDCl 3) δ: 1.86 (2H, q,
J = 6Hz), 2.66 (3H , s, CH 3), 3.4
5 (2H, t, J = 8.9Hz), 4.72 (2H,
t, J = 8.9 Hz), 5.82 (1H, brs, N
H), 6.95 (1H, d, J = 8.5 Hz), 7.8
4 (1H, d, J = 8.5 Hz) Example 1 :

[0054]

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213 mg of the compound (3) obtained in Preparation Example 1
(1.15 mmol) of 1,2-dibromoethane 2.1
It was dissolved in 5 g (11.5 mmol), 110 mg (4.6 mmol) of sodium hydride was added, and the mixture was stirred and refluxed for 4 days. After the reaction was completed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (sodium sulfate), and the solvent was evaporated. The obtained residue was subjected to silica gel column chromatography, benzene-ethyl acetate (4: 1).
Elute with mixed solution, recrystallize from n-hexane, mp15
2 ′, 3′-dihydrospiro [cyclopropane-1,6 ′-(5′H) imidazo [2,1-a] isoquinolin] -5′-one [compound ( 21)] was obtained in an amount of 32 mg (13%). IRcm ^-1: 1665 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.43-1.49 &
2.00-2.06 (each 2H, m, spiro ring proton), 3.95-4.21 (4H, m), 6.77 (1
H, brd, J = 7.7 Hz), 7.32 (1H, t
d, J = 7.7 Hz, J = 1.4 Hz), 7.48 (1
H, td, J = 7.7 Hz, J = 1.4 Hz), 8.1
5 (1H, dd, J = 7.7 Hz, J = 1.4 Hz) In addition, 110 mg (0.59 mmol) of compound (3) was used in dioxane 5 ml solvent, 1,2-dibromoethane 1.10 g (5.9 mmol). ) And sodium hydride, calcium oxide 132 mg (2.36)
mmol), and treated in the same manner as above to obtain 79 mg (63%) of compound (21). The instrumental analysis data of the obtained compound was in agreement with the above data. Example 2 :

[0056]

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50 mg of the compound (3) obtained in Preparation Example 1
(0.27 mmol) was added to 1,3-dibromopropane 54
It was dissolved in 3 mg (2.70 mmol), 26 mg (1.08 mmol) of sodium hydride was added, and the mixture was stirred and refluxed for 12 hours. After the reaction was completed, ice water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried (sodium sulfate),
The solvent was distilled off. The obtained residue was subjected to silica gel column chromatography, and benzene-ethyl acetate (9:
1) Elute with mixed solution, recrystallize from n-hexane, mp
3 ', 4'-Dihydro-2'H-spiro [cyclopropane-1,7'-(6 'as colorless needle crystals at 97-98 ° C.
H) 32 mg (52%) of pyrimido [2,1-a] isoquinoline] -7′-one [compound (22)] was obtained. IRcm ^-1: 1665 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.43-1.49 &
1.99-2.05 (each 2H, m, spiro ring proton), 1.96 (2H, q, J = 5.8Hz), 3.7.
2 (2H, t, J = 5.8Hz), 3.91 (2H,
t, J = 5.8 Hz), 6.70 (1H, brd, J =
7.7 Hz), 7.27 (1 H, t, J = 7.7 Hz,
J = 1.5 Hz), 7.40 (1H, t, J = 7.7H
z, J = 1.5 Hz), 8.24 (1H, dd, J =
7.7 Hz, J = 1.5 Hz) In addition, using 100 mg (0.54 mmol) of the compound (3), 1.03 g (5.4 mmol) of 1,3-dibromopropane and sodium hydride in 5 ml of dioxane solvent. Instead, 121 mg of calcium oxide (2.1
6 mmol) and reacted for 6 days and treated in the same manner as above to obtain 76 mg (63%) of compound (22). The instrumental analysis data of the obtained compound was in agreement with the above data. Example 3 :

[0058]

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200 mg of the compound (8) obtained in Preparation Example 2
(0.91 mmol) was dissolved in 2 ml of anhydrous dioxane, and 1.70 g (9.1 mmo) of 1,2-dibromoethane.
l) and calcium oxide 204 mg (3.64)
(mmol) was added and the mixture was stirred and refluxed for 10 days. After completion of the reaction, the same treatment as in Example 1 was carried out, and recrystallization from n-hexane was performed to obtain 9'-chloro-2 ', 3'-dihydrospiro [cyclopropane-] as colorless needle crystals at mp182-183 ° C.
45 mg (2) of 1,6 ′-(5′H) imidazo [2,1-a] isoquinolin] -5′-one [compound (23)]
0%). IRcm ^-1: 1670 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.40-1.46 &
2.01 to 2.07 (each 2H, m, spiro ring proton), 3.94-4.20 (4H, m), 6.69 (1
H, d, J = 8.6 Hz), 7.42 (1H, dd, J
= 8.6 Hz, J = 2.3 Hz), 8.14 (1H,
d, J = 2.3 Hz) Example 4 :

[0060]

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200 mg of the compound (8) obtained in Preparation Example 2
(0.91 mmol) was dissolved in 2 ml of anhydrous dioxane, and 1.84 g (9.1 mm of 1,3-dibromopropane).
ol) and calcium oxide 204 mg (3.6
(4 mmol) was added and the mixture was stirred and refluxed for 4 days. After completion of the reaction, the same treatment as in Example 1 was carried out, and recrystallization from n-hexane was performed to obtain 10'- as colorless needle crystals at mp 151-152 ° C.
Chloro-3 ', 4'-dihydro-2'H-spiro [cyclopropane-1,7'-(6'H) pyrimido [2,1-
75 mg (32%) of a] isoquinoline] -6′-one [compound (24)] was obtained. IRcm ^-1: 1670 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.41-1.47 &
1.99-2.05 (2H, m, spiro ring protons each), 1.96 (2H, q, J = 5.9Hz), 3.7
2 (2H, t, J = 5.9Hz), 3.90 (2H,
t, J = 5.9 Hz), 6.63 (1H, d, J = 8.
4Hz), 7.34 (1H, dd, J = 8.4Hz, J
= 2.3 Hz), 8.25 (1H, d, J = 2.3H
z) Example 5 :

[0062]

[Chemical 21]

400 mg of the compound (13) obtained in Preparation Example 3
(1.73 mmol) was dissolved in 10 ml of chloroform, 795 mg (5.19 mmol) of phosphorus oxychloride was added, and the mixture was stirred and refluxed for 2 hours. After completion of the reaction, the solvent was distilled off, and the residue was made basic with a saturated aqueous sodium carbonate solution, extracted with chloroform, the organic layer was washed with water and dried (sodium sulfate), and then the solvent was distilled off. The obtained residue was recrystallized from acetone to give spiro [cyclopropane-1, as colorless needle crystals at mp 214-217 ° C (decomposition).
79 'of 6'-(5'H) imidazo [1,2-h] [1,7] naphthyridine] -5'-one [compound (25)]
g (21%) was obtained. IRcm ^-1: 1670 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.43 & 2.08
(Each 2H, dd, J = 8Hz, J = 4Hz, spiro ring proton), 3.99-4.29 (4H, m), 7.12
(1H, dd, J = 8.2Hz, J = 4.6Hz),
7.40 (1H, dd, J = 8.2Hz, J = 1.5H
z), 8.67 (1H, d, J = 1.5 Hz, J = 4.
6 Hz) Example 6 :

[0064]

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200 mg of the compound (19) obtained in Preparation Example 4
(0.82 mmol) is dissolved in 3 ml of chloroform,
0.15 ml (1.63 mmol) of phosphorus oxychloride was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the same treatment as in Example 5 was performed, and the obtained residue was subjected to silica gel column chromatography, eluted with chloroform, and recrystallized from benzene to give 2 ′, 3 as violet prism crystals at mp138-140 ° C. '-Dihydro-8'-methylspiro [cyclopropane-1,6'-(5'H) imidazo [2,1
50 mg (27%) of -f] [1,6] naphthyridine] -5'-one [compound (26)] was obtained. IRcm ^-1: 1670 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.89 (4H, m,
Spiro ring proton), 2.53 (3H, s, CH ₃ ),
4.00 & 4.14 (each 2H, m), 7.08 (1H,
d, J = 8 Hz), 8.20 (1H, d, J = 8 Hz) Example 7 :

[0066]

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200 mg of the compound (20) obtained in Preparation Example 4
(0.77 mmol) is dissolved in 1 ml of chloroform,
0.14 ml (1.54 mmol) of phosphorus oxychloride was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the same treatment as in Example 6 was carried out to recrystallize from benzene to give mp105-10.
3 ', 4'-dihydro-
9'-methylspiro [cyclopropane-1,7'-
(6′H)-[2H] -pyrimido [2,1-f] [1,
80 mg (43%) of 6] naphthyridine] -6′-one [compound (27)] was obtained. IRcm ^-1: 1670 _{^{(carbonyl) 1 H-NMR (CDCl 3}} ) δ: 1.89 (4H, S,
Spiro ring proton), 1.96 (2H, q, J = 5.7)
Hz), 2.50 (3H, s , CH 3), 3.70 &
3.90 (2H, t, J = 5.5Hz each), 7.03
(1H, d, J = 8.2 Hz), 8.29 (1H, d,
J = 8.2Hz)

Pharmacological test 1 : against guinea pig isolated tracheal contraction
Inhibitory effect : A trachea was extracted from a Hartley male guinea pig to prepare a ring-shaped specimen. This is Tyr
Suspend in a 37 ° C liquid tank filled with ode's liquid, and constantly ventilate a mixed gas of 95% carbon dioxide gas and 5% carbon dioxide gas,
A tension of 1 g was applied. Tracheal tension was measured using an isometric transducer. After the tension was stabilized, carbamoylcholine chloride (CCh) 10 ⁻⁶ M was added to induce contraction. After the contraction was stabilized, the test compound was cumulatively added, the relaxation reaction was recorded, and finally papaverine 10 ⁻⁵ M was added to induce the maximum relaxation. The relaxation rate was calculated assuming that the relaxation by papaverine was 100%, and the relaxation rate was 30% for each test compound.
The% relaxing concentration was calculated. As the test compounds, the compounds (21) to (24) and (2) obtained in the above Examples are used.
6) and (27) were used. The results are shown in Table 1.

[0069]

[Table 1]

As is clear from the results in the table, it is clear that the compounds of the present invention have a good bronchomuscular dilating effect.

Pharmacological test 2 : Toxicity test : An 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 compound to be tested was 0.
The suspension was suspended in 1% carboxymethylcellulose solution so as to be 1 ml, and was orally administered by force using a metal stomach tube.
The mice were fasted for 16 hours from the day before the experiment. The observation period after administration was set to 14 days, and the LD ₅₀ value was determined from the survival rate 14 days later by the Richfield Wilcoxon method. As a result, the compounds (21) to (2
7) was 1.5 g / Kg or more, and did not show remarkable toxicity.

[0072]

INDUSTRIAL APPLICABILITY The specific spiro-substituted tricyclic heterocyclic compound represented by the formula (I) of the present invention is a novel compound which has not been known so far and has a bronchial muscle relaxing action. , Useful as a medicine.

Claims (6)

[Claims] 1. A compound of the general formula (I): In the formula, R represents a hydrogen atom, a halogen atom or a lower alkyl group; X and Y represent the same or different CH or N; n represents an integer of 0, 1 or 2; A tricyclic heterocyclic compound or a pharmaceutically acceptable salt thereof. 2. A compound represented by the general formula (Ia): In the formula, R and n are as defined above; or a spiro-substituted tricyclic heterocyclic compound represented by: or a pharmaceutically acceptable salt thereof. 3. A compound represented by the general formula (Ib): In the formula, R and n are as defined above; or a spiro-substituted tricyclic heterocyclic compound represented by: or a pharmaceutically acceptable salt thereof. 4. A compound of the general formula (Ic): In the formula, R and n are as defined above; or a spiro-substituted tricyclic heterocyclic compound represented by: or a pharmaceutically acceptable salt thereof. 5. A bronchodilatory agent containing the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient. 6. An anti-asthma therapeutic agent comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.