JPH0971586A - New bicyclic condensed imidazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful for treating chronic cardiac insufficiency, myocard fibrosis, primary hyperaldosteronism, hypocalcemia, alkalosis, muscle hyposthenia, polyuria, polydispia, hypertension, congestive heart failure, edema, liver cirrhosis, cardiac hypertrophy, etc. SOLUTION: This compound of formula I [ring A is a 5- to a 6-membered unsaturated heterocyclic ring containing 1-4 N or S atoms; B is absent or a lower alkylene; R<1> and R<2> are each absent or H, a halogen, a lower alkyl, etc.; (n) is 1-3], e.g. 5-(3-pyridyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine. The compound of formula I is obtained by converting OH group in a compound of formula II (V is H, trityl, acetyl, etc.) into an eliminative group W and carrying out the cyclizing reaction of the resultant compound of formula III.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a medicine, in particular, a novel bicyclic fused imidazole derivative which inhibits aldosterone synthase cytochrome P-450C ₁₈ or a pharmaceutically acceptable salt thereof, and their active ingredients. To an aldosterone biosynthesis inhibitor.

[0002]

2. Description of the Related Art Aldosterone is produced in vivo from cholesterol in various stages, and is a cause of hyperaldosteronism and various diseases in which aldosterone is involved as an aversive factor. Regarding the production of aldosterone, it is known that an enzyme called cytochrome P-450C ₁₈ is involved in the final process of its biosynthetic pathway (Kawamoto T. et al., Proc. Natl. Acad.S.
ci. 89 , 1458, (1992)). This enzyme hydroxylates the 11-position of 11-deoxycorticosterone and also hydroxylates the methyl group of the 18-position to produce aldosterone.

Hyperaldosteronism includes primary aldosteronism caused by abnormalities of the adrenal cortex and secondary aldosteronism caused by extra-adrenal causes. Hyperaldosteronism often occurs with syndromes characterized by hypertension, electrolyte abnormalities, or metabolic alkalosis.

Further, in recent years, Weber KT et al., J. Hypertension 10 , has shown that aldosterone has an action of promoting fibrosis of heart tissue and behaves as an exacerbating factor in the pathological condition of heart failure (Weber KT et al., J. Hypertension 10 , S87-S9
4. (1992), WO95 / 15166). When myocardial fibrosis progresses,
The diastolic compliance of the ventricles decreases, leading to progression to chronic heart failure. Digitalis preparations and diuretics which are frequently used as therapeutic agents for heart failure are not effective for diastolic heart failure caused by such myocardial fibrosis. This is because digitalis originally improves only the contractile function as a cardiotonic drug, and the diuretic drug is only one of the coping therapy for heart failure.

Therefore, if it is possible to specifically inhibit the cytochrome P-450C ₁₈ which is an aldosterone biosynthetic enzyme, it is possible to effectively produce aldosterone without affecting other hormone producing systems such as aromatase. It is possible to prevent and treat various diseases in which aldosterone is involved as an aggravating factor. Specifically, primary and secondary hyperaldosteronism, renal hypertension, chronic heart failure, congestive heart failure,
It is useful for treating myocardial fibrosis, left ventricular dysfunction, edema, cirrhosis with ascites, cardiac hypertrophy, etc.

As an aldosterone synthesis inhibitor based on the cytochrome P-450C ₁₈ inhibitory action, a compound having a steroid skeleton has been disclosed in JP-A-3-31295. In addition, in recent years, JP-A-57-77698
Cytochrome P-450C ₁₈ in the disclosed compounds No.
Compounds with inhibitory action have been found (J. Steroi
d Biochem, Moles, Biol., 52 , 17 (1995)). Further, JP-A-2-169518 discloses a compound in which benzene having various substituents is bound to a bicyclic imidazole as a therapeutic agent for hyperaldosterone, but these compounds are later described as cytochrome P-450C. ₁₈ to inhibit shown (J.Clin.Endocrinol Metab. 70, 116
2 (1991)).

[0007]

Based on the above background, the inventors of the present invention have found that cytochrome P-450C ₁₈
As a result of advancing the screening of compounds having inhibitory activity against the above, it was found that a novel bicyclic fused imidazole derivative has the above-mentioned activity, and the present invention has been completed.

[0008]

The present invention relates to a bicyclic fused imidazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

[0009]

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(However, the symbols in the formulas have the following meanings: Ring A: 5- or 6-membered unsaturated heterocycle containing 1 to 4 nitrogen atoms or sulfur atoms. B: Absent or lower alkylene. And a lower alkylene group which may be substituted with a hydroxyl group R ¹ , R ^{2 are the} same or different and do not exist, or are hydrogen atoms,
A halogen atom, a lower alkyl group, a lower alkoxy group, a morpholinyl group, or -NR ³ R ⁴ or -S (O) _m N
A group represented by R ⁵ R ⁶ . Here, R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a lower alkyl group,
m is 1 or 2. n: an integer of 1 to 3. )

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the general formula (I) is further described as follows. Specific examples of the “5- or 6-membered unsaturated heterocycle containing 1 to 4 nitrogen atoms or sulfur atoms” include the following. Examples of the 5-membered ring group containing a nitrogen atom include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group,
Examples of the 6-membered ring group include a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a triazinyl group and a tetrazinyl group.

Examples of the 5-membered ring group containing a nitrogen atom and a sulfur atom include thiazolyl group, isothiazolyl group, thiadiazolyl group, thiatriazolyl group, and examples of the 6-membered ring group include thiazinyl group and thiatriazinyl group. Examples of the ring group containing a sulfur atom include a thienyl group and a thiopyranyl group. Among these groups, preferable groups include an imidazolyl group, a pyridyl group, a pyrimidinyl group, a pyridazinyl group, a pyrazinyl group, a thiazolyl group and a thienyl group.

In the present specification, the term "lower" has 1 carbon atom.
~ 6 straight or branched hydrocarbon chains.

Therefore, as the "lower alkyl group", specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, Isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methyl Pentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group , 1-ethylbutyl group, 2-ethylbutyl group,
Examples thereof include a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group.

Specific examples of the "lower alkylene group" include methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, methylmethylene group, propylene group and dimethylmethylene group. , Methylethylene group, methyltrimethylene group,
Examples thereof include a 1,1-dimethyltetramethylene group and a 1,2-dimethyltetramethylene group, but a methylene group is preferable.

Specific examples of the "lower alkoxy group" include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec.
-Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, t
ert-pentyloxy group, 1-methylbutoxy group, 2
-Methylbutoxy group, 1,2-dimethylpropoxy group,
Hexyloxy group, isohexyloxy group, 1-methylpentoxyoxy group, 2-methylpentoxyoxy group,
3-methylpentoxyoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-
Dimethyl butoxy group, 3,3-dimethyl butoxy group, 1
-Ethylbutoxy group, 2-ethylbutoxy group, 1,1,
2-trimethylpropoxy group, 1,2,2-trimethylpropoxy group, 1-ethyl-1-methylpropoxy group,
Examples thereof include a 1-ethyl-2-methylpropoxy group, and a methoxy group is particularly preferable.

"Halogen atom" means a fluorine atom,
Examples thereof include chlorine atom, bromine atom, and iodine atom.

Further, the compound of the present invention may be capable of forming a salt with an inorganic acid or an organic acid, and these salts also have a cytochrome P-450C ₁₈ inhibitory action like the free base. Suitable salts include, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, inorganic acid salts such as phosphoric acid,
Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, carbonic acid, glutamic acid, aspartic acid,
Examples thereof include organic acid salts such as methanesulfonic acid and ethanesulfonic acid.

The compound of the present invention has an asymmetric carbon atom depending on the type of the lower alkylene group of B or the type of substituent, and such a compound has optical isomers based on the asymmetric carbon atom and is 2 or more. When it has an asymmetric carbon atom of, diastereoisomers are further present. The present invention includes isolated forms of these various isomers and mixtures of these isomers.

Further, the compounds of the present invention include various hydrates, various solvates of methanol, ethanol and the like, crystalline polymorphs and the like. In the present invention, isolated compounds and mixtures of these compounds are present. Is included.

(Production Method) The compound of the present invention and a salt thereof can be produced by applying various synthetic methods by utilizing the characteristics based on the basic skeleton or the kind of the substituent. At that time, depending on the kind of the functional group, when it is effective in manufacturing technology to replace the functional group with an appropriate protecting group at the stage of the raw material or the intermediate, that is, a group which can be easily converted into the functional group. There is. After that, the protecting group can be removed by a usual operation, if necessary, to obtain the desired compound. Examples of such a functional group include a hydroxyl group and an amino group, and examples of the protective group thereof include Green and Wuts.
s), [Protective Groups in
Organic Synthesis ", 2nd edition can be mentioned, and these may be appropriately used depending on the reaction conditions.

The typical method for producing the compound of the present invention will be illustrated below. (First manufacturing method)

[0023]

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(In the formula, A, B, R ¹ , R ² and n have the above-mentioned meanings. Further, V represents hydrogen, trityl group, acetyl group, dimethylcarbamoyl group or dimethylsulfamoyl group, W represents a halogen atom such as a chlorine atom or a bromine atom, or a sulfoxy group such as a mesyloxy group or a tosyloxy group, etc. When R ¹ or R ² is an amino group, it is protected by the above-mentioned protecting group represented by V. Group, the same shall apply hereinafter.)

The compound (Ia) of the present invention has the general formula (II
The compound (IIIa) obtained by converting the OH group of the compound represented by a) into the leaving group W can be produced.

From compound (IIa) to compound (IIIa)
The reaction to, methylene chloride, chloroform, THF, in an organic solvent such as dioxane, hydrogen chloride, hydrogen bromide, phosphorus trichloride, phosphorus tribromide, halogenating reagents such as thionyl chloride or mesyl chloride, benzenesulfonyl chloride, The reaction is carried out in the presence of a sulfonyl reagent such as tosyl chloride and a base such as triethylamine or pyridine under ice cooling to reflux temperature.

When V is hydrogen, the reaction from the compound (IIIa) to the compound (Ia) of the present invention can be carried out using acetonitrile, D
It is carried out in an organic solvent such as MF at room temperature to reflux conditions. At that time, triethylamine, pyridine, as a reaction accelerator,
It is desirable to add a base such as sodium hydroxide or potassium hydroxide. On the other hand, when V is a protecting group, water, hydrochloric acid, acetic acid or a protic solvent such as methanol or ethanol is added, and the mixture is subjected to room temperature to reflux conditions to transform the intermediate (IVa) to the compound of the present invention (Ia). The reaction to is accelerated.

(Second manufacturing method)

[0029]

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Where A, B, R ¹ , R ² , V, W and n
Has the meaning given above. )

The compound (Ib) of the present invention has the general formula (II
It can be produced from the compound represented by b) by a method similar to the first production method.

(Third manufacturing method)

[0033]

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(In the formula, A, B, R ² , R ³ , R ⁴ and n have the above-mentioned meanings. R ⁷ represents a lower alkyl group and Y represents a leaving group.)

The compounds (Id, Ie) of the present invention can be produced by a nucleophilic substitution reaction of a compound represented by the general formula (Ic) with ammonia, a primary amine, a secondary amine or various alkoxides. . The leaving group for Y is preferably a halogen atom such as Br or Cl. In the N-alkylation, it may be a mesyloxy group, a trifluforomethanesulfonyloxy group or a tosyloxy group.
As the solvent, various alcohols such as methanol and ethanol, DMF, DMSO, benzene, toluene,
THF, methylene chloride and the like are preferably used, but it is also possible to carry out the reaction without using a solvent. Reaction is ice-cooled
It is carried out under the conditions of room temperature to heating and normal pressure to pressure.

(Fourth manufacturing method)

[0037]

[Chemical 6]

(In the formula, A, B, R ¹ and R ² have the above-mentioned meanings. B ′ does not exist or is a lower alkylene group having one carbon atom less than the lower alkylene group represented by B above. Show.)

The compound (If) of the present invention has the general formula (VI)
After selectively reducing the pyridine ring of the compound represented by
It can be produced through the formation of a double bond by a dehydration reaction and the reduction of the double bond.

The selective reduction reaction of only the pyridine ring is carried out by using 5 to 10% palladium carbon, palladium black, palladium hydroxide, palladium oxide, platinum oxide in a solvent such as methanol, ethanol or concentrated hydrochloric acid, acetic acid, trifluoroacetic acid. In the presence of a catalyst such as the above, the reaction is carried out at room temperature to reflux temperature under normal pressure to increased pressure in a hydrogen gas atmosphere.

The reaction for producing the compound (If) from the compound (VII) or the compound (If) directly from the compound (VI) is carried out by 5 to 10% palladium carbon, palladium black, palladium hydroxide, palladium oxide, platinum oxide, etc. In the presence of the catalyst, the reaction is carried out in an acidic solvent such as a mixed solution of concentrated hydrochloric acid and ethanol in a hydrogen gas atmosphere under pressure under heating and reflux.

(Fifth Production Method) The compound of the present invention is R ¹ or R ²
It can also be obtained by dehalogenating a compound of the present invention in which is a halogen atom. The dehalogenation reaction can be carried out at room temperature or with heating under reflux using Raney nickel in a solvent.

(Sixth manufacturing method)

[0044]

[Chemical 7]

(In the formula, Bu represents a butyl group, respectively.)

By reacting compound (VIII) with a formylating reagent such as DMF or 4-formylmorpholine in the presence of a base such as n-BuLi, a 5-formyl derivative (IX) is obtained regioselectively. You can Next, a hydroxylamine is allowed to act on the oxime compound (X).
Then, a cyano compound (XI) can be easily derived by performing a dehydration reaction in acetic anhydride. The compound (Ig) of the present invention can be produced by converting the cyano form (XI) into the tetrazole form (XII) with sodium azide, tributyltin azide or the like, and further performing a desulfurization reaction and a catalytic reduction reaction.

(Others) When the nitrogen atom of A ring is protected by a protecting group, it can be deprotected in the first production method under the same reaction conditions as in the case where V is a protecting group.

Raw material compound (IIa) in the first production method
Can be manufactured, for example, as follows.

[0049]

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(In the formula, A, R ¹ , R ² , V and n have the above-mentioned meanings. X represents a hydrogen atom or a bromine atom.)

The compound (IIa-1) can be produced by the coupling reaction of the aldehyde derivative (XIV) and the compound (XV). The reaction is carried out using n-butyllithium, lithium diisopropylamide, or lithium 2,2,6,6 in a solvent such as dry THF or dry ether.
-In the presence of a base such as tetramethylpiperidide, both compounds are reacted at a low temperature of -110 ° C to 50 ° C.

The starting compound (VI) in the fourth process is
For example, it can be manufactured as follows.

[0053]

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(In the formula, A, B ', R ¹ and R ² have the above-mentioned meanings.)

Imidazo [1,5-a] pyridine (XV
When I) is treated with a base such as n-butyllithium, lithiation at the 3-position proceeds regioselectively, and reaction with various electrophiles becomes possible. Therefore, in an organic solvent such as dry ether or dry THF. The compound (XVIII) can be obtained by reacting with the compound (XVII) under a low temperature condition of −78 to −50 ° C.

When only the 3-position carbon of imidazo [1,5-a] pyridine is bonded to a sulfur atom like the compound (XVIII), regioselection is carried out by treating with a base such as n-butyllithium. It is known that the lithiation at the 5-position progresses and the reaction with various electrophiles becomes possible (Tetrahedron Letters 1980, 21 , 2195-2196). Therefore, the compound (XVIII) is replaced with the above compound (XVI).
From the compound to the compound (XVIII) under the same conditions,
By reacting with the compound (XIX), the compound (X
X) can be obtained. Further, the compound (XX)
Compound (VI-1) can be produced by stirring and reacting in an alcohol solvent such as ethanol in the presence of a catalyst such as Raney nickel under isothermal or heating conditions.

The reaction products obtained by the above respective production methods are
It is isolated and purified as various solvates such as free compounds, salts or hydrates thereof. The salt can be produced by subjecting it to an ordinary salt-forming reaction. Isolation and purification are performed by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, and various types of chromatography.

[0058]

The compound of the present invention specifically inhibits cytochrome P-450C ₁₈ , which is an aldosterone synthase. Therefore, since it is possible to suppress the production of aldosterone with almost no inhibition of other enzyme systems such as aromatase which is an estrogen synthase, aldosterone is involved as an aversive factor without causing side effects on other hormone production systems. It can be used for the treatment of various diseases. Such diseases include, for example, chronic heart failure,
Symptoms such as myocardial fibrosis, primary and secondary hyperaldosteronism, accompanying hypokalemia, alkalosis, muscle weakness, polyuria and polydipsia, as well as renal and essential hypertension, and congestiveness. Examples include heart failure, left ventricular dysfunction, edema, cirrhosis with ascites, cardiac hypertrophy, skin or digestive tract wounds, and the like.

The pharmacological action of the compound of the present invention will be described below by posting experimental examples. (Experimental Method) In Vitro Cytochrome P-450C ₁₈ Inhibition Test Ogishima et al.'S method (J. Biol. Chem., 264 (19) 109).
35-10938 (1989)). Eight week old SD male rats were fed a low sodium and high potassium diet and 0.154M.
After feeding with potassium chloride-added water for 7 days and allowing water to enter, a mitochondrial fraction was obtained from the spherical layer of the adrenal cortex. The measurement of the enzyme activity was performed as follows. 20 μM at final concentration
Corticosterone, 60 nM ³ H-corticosterone, 4 mM magnesium chloride, 200 μM NADP
100 mM potassium phosphate containing H, 8 mM glucose-6-phosphate, 12IU glucose-6-phosphate dehydrogenase, 57 μM adrenodoxin, 2.6 μM adrenodoxin reductase, rat adrenal mitochondrial fraction 50 μg, and test compound Buffer solution (pH 7.
4) 500 μl was used as a reaction solution and incubated at 37 ° C. for 2 hours. Then, the reaction solution was extracted with ethyl acetate, and the aldosterone produced in the solution was quantified by high performance liquid chromatography (HPLC). The IC ₅₀ value was calculated based on the Probit method. As a result, the compound of the present invention effectively inhibited the production of aldosterone.

In vivo aldosterone production inhibition test method by Bhatnagnar et al. (J. Steroid Biochem. 3
4 , 567 (1989)). The ACTH depot (SYNACTHEN-DEPOT, Ciba-G) was added to 7-week-old male Wistar rats.
eigy Ltd, Basel) 1 mg / kg was subcutaneously administered. After 17 hours, the test compound (20% polyethylene glycol solution or suspension) was orally administered, and after 3 hours, blood was collected by decapitation and the amount of aldosterone in serum was measured by RIA to measure the aldosterone production inhibitory activity. As a result, the compound of the present invention effectively inhibited aldosterone production even at a concentration of 10 mg / kg or lower, or at a lower concentration.

A pharmaceutical composition containing one or more compounds such as the compound represented by the general formula (I) or a pharmaceutically acceptable salt or hydrate thereof as an active ingredient is usually used. Tablets, powders, fine granules, granules, capsules, pills, using carriers and excipients for formulation and other additives
It is prepared as a solution, injection, suppository or the like, and is orally or parenterally administered.

The dose is appropriately determined according to each case in consideration of symptoms, age of the subject, sex, body weight and the like.
Usually, the dose is 0.1 to 100 mg, preferably 0.1 to 10 mg per day for an adult, and is orally administered once to several times a day, or 0.1 to 100 m per day for an adult.
In the range of g, the drug is parenterally administered once to several times a day, or is continuously administered intravenously in the range of 1 hour to 24 hours a day. Of course, as described above, the dosage varies under various conditions, so that an amount smaller than the above dosage range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium aluminate and the like.

According to a conventional method, the composition comprises an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, and the like. It may contain a solubilizing agent such as glutamic acid or aspartic acid. If necessary, tablets or pills may be coated with sugar coating such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and generally used inert diluents. For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injections and physiological saline. Examples of the water-insoluble solution and suspension include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, alcohols such as ethanol, polysorbate 80.
There are surfactants such as (brand name). Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria-retaining filter, blending of a bactericide, or irradiation. They can also be used to produce sterile solid compositions which are dissolved in sterile water or sterile injectable solvents before use.

[0067]

EXAMPLES The present invention will be described in more detail below with reference to examples. Needless to say, the present invention is not limited to the compounds of Examples. Further, when the raw material used in the present invention is novel, it will be described as a reference example.

Reference Example 1 700 ml of anhydrous tetrahydrofuran containing 55 g of 2- (1,3-dioxolan-2-yl) ethyltriphenylphosphonium bromide
After cooling to 78 ° C., under an argon gas stream, 76 ml of n
-Butyllithium / hexane solution (1.68 M / l) was slowly added dropwise, and the mixture was stirred for about 1 hour. 4-formyl-1-
After adding 39.88 g of trityl-1H-imidazole to the reaction solution and raising the temperature to room temperature, stirring was continued for about 12 hours. A saturated ammonium chloride aqueous solution (500 ml) was poured, the mixture was extracted with an appropriate amount of ethyl acetate, and then the organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography, and 31.42 g of an olefin compound was obtained from the elution part of ethyl acetate-hexane (1: 2). Next, the obtained olefin compound was dissolved in 1000 ml of methanol, 3.0 g of 10% palladium carbon was added, and then the mixture was stirred at room temperature while replacing with hydrogen gas. The catalyst was filtered off and the obtained filtrate was distilled off under reduced pressure. To 28.75 g of the resulting residue, 600 ml of a mixed solution of tetrahydrofuran-1N hydrochloric acid (2: 1) was poured,
Heat at ℃ for about 4 hours. The reaction solution was concentrated to half volume, 100 ml of ethyl acetate and 1N hydrochloric acid were added, and the aqueous layer obtained by the liquid separation operation was distilled off under reduced pressure. To the resulting pale yellow crystals, 300 ml of methylene chloride and 23.6 ml of triethylamine were added, and 18.9 g of trityl chloride was added under cooling, and the mixture was stirred at room temperature for about 2 hours.
An appropriate amount of purified water and methylene chloride were poured into the reaction solution, and the obtained organic layer was washed successively with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The residue produced by evaporation of the solvent was purified by silica gel column chromatography,
23.3 from the elution part of ethyl acetate-hexane (10: 1)
4 g of 4- (1-tritylimidazol-4-yl) butanal was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 1.85 to 2.15 (2H, m), 2.30 to 2.
66 (4H, m), 6.54 (1H, br), 7.02
~ 7.56 (16H, m), 9.73 (1H, br).

Reference Example 2 3-bromopyridine 2.1 m
200 ml of anhydrous ether containing 1 was cooled to −78 ° C., and 13 ml (1.68 M / l) of n-butyllithium / n-hexane solution was gradually added dropwise under an argon gas stream,
It was stirred as it was for about 1 hour. This reaction solution is referred to as solution (A). Beforehand 4- (1-tritylimidazol-4-yl)
Anhydrous tetrahydrofuran 50 containing 6.8 g of butanal
The ml solution was cooled to −78 ° C. and added to this solution (A).
The liquid was quickly added under an argon gas stream, and the temperature was raised to room temperature. Pour an appropriate amount of saturated ammonium chloride solution,
After extraction with ethyl acetate several times, the organic layer was dried over anhydrous magnesium sulfate, and the residue produced by distilling off the solvent was purified by silica gel column chromatography, and then eluted with chloroform-methanol (100: 1) to give 3- [1-
Obtained 4.22 g of hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 1.66 to 1.89 (4H, m), 2.45 to 2.
70 (2H, m), 4.74 (1H, br), 7.50
(1H, br), 6.91 to 7.48 (18H, m),
8.35-8.56 (2H, m).

Reference Example 3 In the same manner as in Reference Example 2, 4-
From (1-tritylimidazol-4-yl) butanal and 3,5-dibromopyridine, 5-bromo-3- [1
-Hydroxy-4- (1-tritylimidazole-4-
Ill) butyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.55 to 1.88 (4H, m), 2.41-2.
70 (2H, m), 4.74 (1H, br), 6.52
(1H, br), 6.95 to 7.45 (17H, m),
7.87 (1H, br), 8.49 (1H, br).

Reference Example 4 In the same manner as in Reference Example 2,
Bromopyridine and 4- (1-tritylimidazole-4)
-Yl) butanal to 2- [1-hydroxy-4-
(1-Tritylimidazol-4-yl) butyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.71-1.87 (4H, m), 2.52-2.
66 (2H, m), 4.68 to 4.80 (1H, m),
6.52 (1H, s), 7.06 to 7.66 (19H,
m), 8.47 to 8.55 (1H, m).

Reference Example 5 In the same manner as in Reference Example 2,
From bromo-4-methylpyridine and 4- (1-tritylimidazol-4-yl) butanal, 2- [1-hydroxy-4- (1-tritylimidazol-4-yl)
Butyl] -4-methylpyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.70 to 1.84 (4H, m), 2.33 (3
H, s), 2.50 to 2.63 (2H, m), 4.69
(1H, brs), 6.52 (1H, d, J = 1.4H
z), 6.94 to 7.36 (18H, m), 8.36
(1H, d, J = 4.4 Hz).

Reference Example 6 In the same manner as in Reference Example 2, 4-
From (1-tritylimidazol-4-yl) butanal and 2- (trimethylsilyl) thiazole, 5- [1-
Hydroxy-4- (1-tritylimidazol-4-yl) butyl] thiazole was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.71-1.95 (4H, m), 2.48-2.
75 (2H, m), 5.03 (1H, br), 6.52
(1H, br), 7.00 to 7.39 (16H, m),
7.69 (1H, s), 8.67 (1H, d, J = 0.
7 Hz).

Reference Example 7 In the same manner as in Reference Example 2,
Bromothiazole and 4- (1-tritylimidazole-
4-yl) butanal to 2- [1-hydroxy-4
-(1-Tritylimidazol-4-yl) butyl] thiazole was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.72-1.96 (4H, m), 2.52-26
9 (2H, m), 4.98 to 5.10 (1H, m),
6.52 (1H, s), 7.05 to 7.35 (17H,
m), 7.66 (1H, d, J = 3.3Hz).

(Reference Example 8) In the same manner as in Reference Example 2, 1-
(N, N-dimethylsulfamoyl) imidazole and 4
2- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] -1- (N, N-dimethylsulfamoyl) imidazole from-(1-tritylimidazol-4-yl) butanal Obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.75 to 2.10 (4H, m), 2.52 to 2.
68 (2H, m), 2.89 (6H, s), 6.54
(1H, s), 6.96-7.36 (18H, m).

Reference Example 9 In the same manner as in Reference Example 2, 3-
3- [1-Hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine was obtained from (1-tritylimidazol-4-yl) propionaldehyde and 3-bromopyridine. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.95 to 2.20 (2H, m), 2.60 to 2.
85 (2H, m), 4.88 (1H, t, J = 5.0H
z), 6.55 (1H, d, J = 1.4 Hz), 6.9
6 to 7.52 (17H, m), 7.77 (1H, dt,
J = 1.8, 8.0 Hz), 8.46 (1H, dd, J
= 1.8, 4.9 Hz), 8.59 (1H, d, J =
1.4 Hz).

(Reference Example 10) In the same manner as in Reference Example 2, 3
From 5- (1-tritylimidazol-4-yl) propionaldehyde and 3,5-dibromopyridine, 5-bromo-3- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine was obtained. It was Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.75 to 2.16 (2H, m), 2.61 to 2.
85 (2H, m), 4.87 (1H, br), 6.56
(2H, br), 7.02 to 7.55 (16H, m),
7.94 (1H, br), 8.50 (2H, br).

(Reference Example 11) In the same manner as in Reference Example 2, 3
4- [3-Hydroxy-3- (3-thienyl) propyl] -1-trityl-1H-imidazole was obtained from-(1-tritylimidazol-4-yl) propionaldehyde and 3-bromothiophene. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.03 to 2.19 (2H, m), 2.60 to 2.
76 (2H, m), 4.89 (1H, t, J = 6.0H
z), 6.54 (1H, br), 6.91 to 7.37.
(19H, m).

Reference Example 12 In the same manner as in Reference Example 2, 4- [3-hydroxy-3- (thienyl) propyl] -1 was prepared from thiophene and 3- (1-tritylimidazol-4-yl) propionaldehyde. -Trityl imidazole was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.19 (2H, t, J = 6.4 Hz), 2.73
(2H, dd, J = 6.4, 6.1 Hz), 5.05
(1H, t, J = 6.1Hz), 6.54 (1H, d,
J = 1.4 Hz), 6.91 to 7.37 (19H,
m).

(Reference Example 13) In the same manner as in Reference Example 2, 5
5- [1-Hydroxy-5- (1-tritylimidazol-4-yl) pentyl] pyridine was obtained from-(1-tritylimidazol-4-yl) pentaldehyde and 3-bromopyridine. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.25 to 1.88 (6H, m), 2.40 to 2.
66 (2H, m), 4.74 (1H, br), 6.49
(1H, br), 7.04 to 7.73 (18H, m),
8.45 (1H, dd, J = 1.8, 4.9Hz),
8.54 (1H, d, J = 1.8Hz).

Reference Example 14 50 ml of an anhydrous tetrahydrofuran solution containing 5.1 ml of n-butyllithium / hexane solution (1.68 M / l) was cooled to −78 ° C., and 1.2 ml of diisopropylamine was added dropwise under an argon gas stream. After that, gently warm to -10 ° C. Again -78 ° C
The reaction solution was cooled to 0.8 ml of 2-chloropyridine, and stirred for about 2 hours as it was. This reaction solution is (A)
And 3- (1-tritylimidazol-4-yl)
After 2.57 g of propionaldehyde was dissolved in 10 ml of anhydrous tetrahydrofuran and cooled to -78 ° C, the reaction solution (A) was quickly poured under an argon gas stream and warmed to room temperature with stirring. After pouring an appropriate amount of saturated ammonium chloride aqueous solution into the reaction solution and extracting several times with ethyl acetate,
The organic layer was washed with water and subsequently dried over anhydrous magnesium sulfate. The solvent was evaporated, the resulting residue was purified by silica gel column chromatography, and chloroform-methanol-28% aqueous ammonia (100: 0.9: 0.1) solution was added to 2-chloro-3- [1-hydroxy. -3- (1-
2.02 g of tritylimidazol-4-yl) propyl)] pyridine was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 1.70 to 2.25 (2H, m), 2.63 to 2.
89 (2H, m), 5.14 (1H, br), 6.58
(1H, br), 7.05 to 7.50 (17H, m),
8.09 (1H, br), 8.25 (1H, dd, J =
2.0, 4.9 Hz).

Reference Example 15 In the same manner as in Reference Example 14,
From 3- (1-tritylimidazol-4-yl) propionaldehyde and 2,6-difluoropyridine, 2,
6-difluoro-3- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.80 to 2.20 (2H, m), 2.60 to 2.
88 (2H, m), 5.08 (1H, br), 6.56
(1H, br), 6.79 (1H, br), 7.00
7.55 (16H, m), 8.20 (1H, br).

Reference Example 16 In the same manner as in Reference Example 14,
From 2-fluoropyridine and 4- (1-tritylimidazol-4-yl) butanal, 2-fluoro-3-
[1-Hydroxy-4- (1-tritylimidazole-
4-yl) butyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.70 to 1.90 (4H, m), 2.56 to 2.
69 (2H, m), 4.90-4.98 (1H, m),
6.53 (1H, s), 7.05 to 7.36 (18H,
m), 7.98-8.02 (1H, m).

Reference Example 17 In the same manner as in Reference Example 14,
From 2-chloropyridine and 4- (1-tritylimidazol-4-yl) butanal, 2-chloro-3- [1-
Hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.56 to 1.94 (4H, m), 2.50 to 2.
70 (2H, m), 4.97-5.10 (1H, m),
6.52 (1H, s), 7.05 to 7.36 (18H,
m), 8.19-8.28 (1H, m).

(Reference Example 18) In the same manner as in Reference Example 14,
2,6-dichloro-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine from 2,6-dichloropyridine and 4- (1-tritylimidazol-4-yl) butanal Got Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.63 to 1.90 (4H, m), 2.50 to 2.
71 (2H, m), 4.93 to 5.07 (1H, m),
6.53 (1H, s), 7.04 to 7.36 (18H,
m).

Reference Example 19 In the same manner as in Reference Example 14,
From 4-chloropyridine and 4- (1-tritylimidazol-4-yl) butanal, 4-chloro-3- [1-
Hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.72-1.88 (4H, m), 2.57-2.
74 (2H, m), 5.06 to 5.14 (1H, m),
6.53 (1H, s), 7.11 to 7.37 (17H,
m), 8.38 (1H, d, J = 7.2 Hz), 8.8
1 (1H, s).

Reference Example 20 Dry tetrahydrofuran 2
N-butyllithium-n-hexane solution 1 in 00 ml
After adding 5 ml (1.65 M / l) and cooling to -78 ° C, 2,2,6,6-tetramethylpiperidine 4.2 m
1 was gradually added dropwise. The reaction solution was heated to 0 ° C., cooled to −78 ° C. again, 2.2 ml of chloropyrazine was added dropwise, and the mixture was stirred for about 30 minutes as it was. A solution prepared by dissolving 7.33 g of 3- (1-tritylimidazol-4-yl) propionaldehyde in a small amount of tetrahydrofuran was gradually added dropwise to the reaction solution, and the temperature was raised to room temperature. An appropriate amount of saturated ammonium chloride aqueous solution was poured, the mixture was extracted several times with ethyl acetate, dried over anhydrous magnesium sulfate, and the residue produced by evaporation of the solvent was purified by silica gel column chromatography.
2.57 g of 2- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyrazine was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 1.85 to 2.31 (2H, m), 2.68 to 2.
95 (2H, m), 5.13 (1H, dd, J = 4.
9, 8.5 Hz), 6.59 (1H, br), 7.01
~ 7.52 (16H, m), 8.27 (1H, d, J =
2.5Hz), 8.48 (1H, d, J = 2.5H
z).

(Reference Example 21) In the same manner as in Reference Example 20,
From 4- (1-tritylimidazol-4-yl) butanal and chloropyrazine, 3-chloro-2- [1-hydroxy-4- (1-tritylimidazol-4-yl)
Butyl] pyrazine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.66 to 2.10 (3H, m), 2.34 to 2.
70 (3H, m), 5.04 (1H, br), 6.54
(1H, br), 7.02 to 7.39 (16H, m),
8.28 (1H, d, J = 2.5Hz), 8.45 (1
H, d, J = 2.5 Hz).

(Reference Example 22) In the same manner as in Reference Example 20,
From 3,6-dimethoxypyridazine and 4- (1-tritylimidazol-4-yl) butanal, 4- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] -3,6-dimethoxypyridazine Got Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.62 to 1.77 (4H, m), 2.45 to 2.
66 (2H, m), 4.00 (3H, s), 4.01
(3H, s), 4.74-4.87 (1H, m), 6.
52 (1H, s), 7.05 to 7.36 (17H,
m).

Reference Example 23 100 ml of a dry tetrahydrofuran solution containing 2.5 g of 2,5-dibromopyridine
Was cooled to −100 ° C. under an argon gas stream, and then n−
Butyl lithium-hexane solution (1.68 M / l) 6.
2 ml was gradually added dropwise, and the mixture was stirred as it was for about 1 hour. Four
10 ml of a tetrahydrofuran solution containing 3.04 g of-(1-tritylimidazol-4-yl) butanal was gradually added dropwise to the reaction solution, then gradually warmed to room temperature, and further stirred at room temperature for 30 minutes. An appropriate amount of saturated aqueous ammonium chloride solution was poured, the mixture was extracted several times with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. A mixed solution of ethyl acetate-hexane (5: 1) was added to the residue obtained by distilling off the solvent, and the resulting crystals were collected by filtration and washed with diethyl ether to give 2-bromo-5- [1-hydroxy-4]. 2.20 g of-(1-tritylimidazol-4-yl) butyl] pyridine was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 1.65 to 1.88 (4H, m), 2.50 to 2.
70 (2H, m), 4.75 (1H, br), 6.53
(1H, br), 6.52 to 7.55 (18H, m),
8.31 (1H, d, J = 2.3 Hz).

(Reference Example 24) In the same manner as in Reference Example 23,
From 3- (1-tritylimidazol-4-yl) propionaldehyde and 5-bromopyrimidine, 5- [1-
Hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyrimidine was obtained. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.90 to 2.18 (2H, m), 2.60-2.
81 (2H, m), 4.91 (1H, t, J = 5.5H
z), 6.57 (1H, br), 7.06-7.38.
(16H, m), 8.77 (2H, s), 9.08 (1
H, s).

Reference Example 25 100 m of anhydrous tetrahydrofuran containing 4.9 g of imidazo [1.5-a] pyridine
1 solution was cooled to −78 ° C. under an argon gas stream, and n−
Butyllithium-n-hexane solution 25 ml (1.7 M
/ L) was gradually added dropwise, and the mixture was stirred as it was for about 1 hour. Diphenyl disulfide (9.07 g) was added to the reaction solution, the temperature was raised to room temperature, and the mixture was further stirred at room temperature for about 30 minutes. An appropriate amount of ethyl acetate and 3N hydrochloric acid were poured, the aqueous layer obtained by the liquid separation operation was neutralized with potassium carbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the oily substance obtained by distilling off the solvent was purified by silica gel column chromatography. 3-phenylthioimidazo [1] was obtained from the eluate of ethyl acetate-n-hexane (2: 1). ，
9.01 g of 5-a] pyridine was obtained.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 6.53 to 6.92 (2H, m), 6.98 to 7.
27 (5H, m), 7.50 (1H, dt, J = 1.
4, 8.8Hz), 7.64 (1H, d, J = 0.9H
z), 8.13 (1H, dq, J = 1.4, 8.8H
z).

(Reference Example 26) A solution of 250 g of anhydrous tetrahydrofuran containing 9.0 g of 3-phenylthioimidazo [1.5-a] pyridine in an argon gas stream at -78 ° C.
Cooled to n-butyllithium-n-hexane solution 2
6 ml (1.7 M / l) was gradually added dropwise, and about 1 as it was.
Stir for hours. After dropwise adding 4.1 ml of nicotinaldehyde, the temperature was raised to room temperature, and the mixture was further stirred at room temperature for about 30 minutes. An appropriate amount of saturated ammonium chloride aqueous solution and ethyl acetate were poured into the reaction solution, and the organic layer obtained by the liquid separation operation was washed with saturated saline and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the obtained oily substance was purified by silica gel column chromatography. From the eluate of ethyl acetate, (3-phenylthioimidazo [1.5-a] pyridine-
There was obtained 10.30 g of 5-yl) -3-pyridylmethanol.

Nuclear magnetic resonance spectrum (CDCl ₃ , TM
S internal standard) δ: 5.42 (1H, br), 6.57 to 6.88 (4
H, m), 7.00 to 7.20 (4H, m), 7.42
~ 7.55 (2H, m), 7.64 (1H, s), 8.
29-8.70 (2H, m).

Reference Example 27 An appropriate amount of Raney nickel was added to 300 ml of ethanol containing 10.3 g of (3-phenylthioimidazo [1.5-a] pyridin-5-yl) -3-pyridylmethanol to give about 8 Heated to reflux for hours. After cooling, the catalyst was filtered off and the resulting filtrate was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography, and the imidazo [1.5- a] Pyridin-5-yl-
3.72 g of 3-pyridylmethanol was obtained.

Nuclear magnetic resonance spectrum (DMSO-d ₆ ,
TMS internal standard) δ: 6.19 (1H, d, J = 4.9 Hz), 6.65
(1H, d, J = 4.9 Hz), 6.70 (1H, d,
J = 4.9 Hz), 6.84 to 6.88 (1H, m),
7.32 to 7.45 (2H, m), 7.56 (1H,
d, J = 8.8 Hz), 7.87 (1H, dt, J =
1.8, 8.0 Hz), 8.33 (1H, s), 8.5
1 (1H, dd, J = 1.8, 8.0 Hz), 8.72
(1H, d, J = 1.8 Hz).

(Example 1) 3- [1-hydroxy-4-]
A catalytic amount of N, N-dimethylformamide was added to 100 ml of methylene chloride containing 4.21 g of (1-tritylimidazol-4-yl) butyl] pyridine, and 0.8 ml of thionyl chloride was added dropwise, followed by stirring at room temperature for about 1 hour. did. After pouring an appropriate amount of saturated sodium hydrogen carbonate aqueous solution into the reaction solution for neutralization, the obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 200 ml of acetonitrile was poured into the resulting residue, and the mixture was heated under reflux for about 12 hours, 100 ml of methanol was added, and the mixture was further heated under reflux for 4 hours.
After allowing to cool, the residue generated by distilling off the solvent was neutralized by pouring an appropriate amount of saturated sodium hydrogen carbonate aqueous solution, and then extracted several times with ethyl acetate. The residue obtained by drying the obtained organic layer and then distilling off the solvent was purified by silica gel column chromatography, and chloroform-methanol (100:
1) From the elution part, 5- (3-pyridyl) -5,6,7,8
-Tetrahydroimidazo [1.5-a] pyridine 1.2
1 g was obtained.

Melting point 90-92 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.74-1.83 (1 H, m), 1.86-2.
01 (2H, m), 2.28 to 2.35 (1H, m),
2.83 to 2.94 (2H, m), 5.25 (1H, d
d, J = 5.0, 7.4 Hz), 6.86 (1H,
s), 7.13 (1H, s), 7.27 to 7.32 (2
H, m), 8.47 (1H, s), 8.58 (1H,
t, J = 2.5 Hz).

(Embodiment 2) In the same manner as in Embodiment 1, 2-
From fluoro-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine, 5-
(2-fluoropyridin-3-yl) -5,6,7,8
-Tetrahydroimidazo [1.5-a] pyridine was obtained. Mp 114-115 ℃ (iPr ₂ O) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.69~1.84 (2H, m ), 2.04~2.
10 (1H, m), 2.30 to 2.36 (1H, m),
2.81 to 2.94 (2H, m), 5.59 (1H,
t, J = 5.2 Hz), 6.87 (1H, s), 6.9
9 to 7.03 (1H, m), 7.12 to 7.15 (1
H, m), 7.22 (1H, s), 8.16 (1H,
d, J = 4.9 Hz).

(Embodiment 3) As in Embodiment 1, 2-
From chloro-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine to give 5-
(2-chloropyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1.5-a] pyridine was obtained. Mp 169-170 ° C. (AcOEt) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.67~1.84 (2H, m ), 2.04~2.
13 (1H, m), 2.33 to 2.39 (1H, m),
2.80 to 2.95 (2H, m), 5.70 (1H,
t, J = 5.2 Hz), 6.86 to 6.88 (2H,
m), 7.17 to 7.20 (1H, m), 7.20 (1
H, s), 8.34 (1H, dd, J = 4.9, 1.8)
Hz).

(Embodiment 4) In the same manner as in Embodiment 1,
From bromo-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine, 5-
(5-Bromopyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1.5-a] pyridine was obtained. Melting point 121-123 ° C. (AcOEt-Et ₂ O) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.75 to 1.99 (3H, m), 2.30 to 2.
34 (1H, m), 2.85 to 2.90 (2H, m),
5.25 (1H, dd, J = 5.5, 7.3Hz),
6.88 (1H, s), 7.16 (1H, s), 7.4
5 (1H, d, J = 1.9 Hz), 8.35 (1H,
d, J = 1.9 Hz), 8.65 (1H, d, J = 1.
9 Hz).

(Embodiment 5) As in Embodiment 1,
From bromo-5- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine, 5-
(6-Bromopyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1.5-a] pyridine • hydrochloride was obtained. Mp 206-209 ° C. Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.72~1.80 (1H, m ), 1.85~1.
93 (1H, m), 2.04 to 2.09 (1H, m),
2.29 to 2.32 (1H, m), 2.84 to 2.97
(2H, m), 5.65 (1H, dd, J = 5.0,
8.9 Hz), 7.52 (1 H, s), 7.67 to 7.
74 (2H, m), 8.39 (1H, d, J = 2.5H
z), 8.79 (1H, s).

(Embodiment 6) In the same manner as in Embodiment 1, 4-
From chloro-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine to give 5-
(4-chloropyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine was obtained. Melting point 133-134 ° C. (AcOEt) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.79 to 1.85 (2H, m), 2.06 to 2.
12 (1H, m), 2.29 to 2.35 (1H, m),
2.84 to 2.96 (2H, m), 5.69 (1H,
t, J = 5.8 Hz), 6.88 (1H, s), 7.1
9 (1H, s), 7.36 (1H, d, J = 5.5H
z), 7.90 (1H, s), 8.45 (1H, d, J
= 5.5 Hz).

(Embodiment 7) Similar to Embodiment 1,
From 6-dichloro-3- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyridine,
5- (2,6-dichloropyridin-3-yl) -5,
6,7,8-Tetrahydroimidazo [1,5-a] pyridine was obtained. Melting point 196-197 ° C. (AcOEt-hexane) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.65 to 1.73 (1 H, m), 1.79 to 1.
86 (1H, m), 2.04 to 2.10 (1H, m),
2.32 to 2.38 (1H, m), 2.80 to 2.95
(2H, m), 5.67 (1H, t, J = 5.2H
z), 6.81 (1H, d, J = 8.6 Hz), 6.8
8 (1H, s), 7.19 (1H, s), 7.20 (1
H, d, J = 8.6 Hz).

(Embodiment 8) In the same manner as in Embodiment 1, 2-
[1-Hydroxy-4- (1-tritylimidazole-
4-yl) butyl] pyridine to 5- (2-pyridyl) -5,6,7,8-tetrahydroimidazo [1,5
-A] Pyridine dihydrochloride was obtained. Melting point 195-197 ° C. (MeOH-AcOEt) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.71-1.79 (2H, m), 2.17-2.
22 (1H, m), 2.34 to 2.40 (1H, m),
2.89 (2H, t, J = 6.4Hz), 5.89 (1
H, t, J = 5.7 Hz), 7.46 to 7.51 (3
H, m), 7.99 (1H, dd, J = 9.1, 8.0
Hz), 8.58 (1H, d, J = 4.8 Hz), 8.
90 (1H, s), 10.17 (1H, brs), 1
4.97 (1H, brs).

(Embodiment 9) As in Embodiment 1,
[1-Hydroxy-4- (1-tritylimidazole-
4-yl) butyl] -4-methylpyridine to give 5-
(4-Methylpyridin-2-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine 1.5
A fumarate salt was obtained. Mp 146-147 ° C. (acetone) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.66~1.70 (2H, m ), 2.08~2.
14 (1H, m), 2.18 to 2.24 (1H, m),
2.29 (3H, s), 2.73 to 2.83 (2H,
m), 5.43 (1H, t, J = 5.8Hz), 6.6
2 (3H, s), 6.77 (1H, s), 6.78 (1
H, s), 7.16 (1H, d, J = 4.9 Hz),
7.39 (1H, s), 8.40 (1H, d, J = 4.
9 Hz).

(Embodiment 10) As in Embodiment 1, 5
From 5- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] thiazole to 5- (5-thiazolyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine. Obtained. Mp _{94-95 ℃ (AcOEt-Et 2 O} ) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.78~1.87 (1H, m ), 1.98~2.
09 (2H, m), 2.34 to 2.41 (1H, m),
2.79 to 2.93 (2H, m), 5.53 (1H, d
d, J = 4.9, 8.0 Hz), 6.82 (1H,
s), 7.24 (1H, s), 7.77 (1H, s),
8.81 (1H, s).

(Embodiment 11) Similar to Embodiment 1, 2
-[1-Hydroxy-4- (1-tritylimidazol-4-yl) butyl] thiazole to 5- (2-thiazolyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine 1 The hydrochloride salt was obtained. Mp _{187-189 ℃ (EtOH-iPr 2 O} ) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.71~1.74 (1H, m ), 1.88~1.
84 (1H, m), 2.30 to 2.33 (1H, m),
2.43 to 2.50 (1H, m), 2.81 to 2.94
(2H, m), 6.20 (1H, t, J = 5.2H
z), 7.50 (1H, s), 7.82 (1H, d, J
= 3.4 Hz), 7.86 (1H, d, J = 3.4H)
z), 9.09 (1H, s), 14.92 (1H, br
s).

(Embodiment 12) Similar to Embodiment 1, 2
From 5- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] -1- (N, N-dimethylsulfamoyl) imidazole to 5- [1- (N, N-dimethylsulfamoyl) ) Imidazol-2-yl]-
5,6,7,8-Tetrahydroimidazo [1,5-a]
Pyridine was obtained. Melting point 143-144 ° C. (AcOEt-hexane) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.75 to 1.83 (1 H, m), 2.05 to 2.
13 (1H, m), 2.20 to 2.36 (2H, m),
2.80 to 2.94 (2H, m), 2.97 (6H,
s), 5.81 (1H, t, J = 6.1Hz), 6.8
1 (1H, s), 7.04 (1H, s), 7.17 (1
H, s), 7.27 (1H, s).

(Embodiment 13) Similar to Embodiment 1, 4
-[1-Hydroxy-4- (1-tritylimidazol-4-yl) butyl] -3,6-dimethoxypyridazine to 5- (3,6-dimethoxypyridazin-4-yl) -5,6,7, 8-tetrahydroimidazo [1.5
-A] Pyridine was obtained. Mp 209-210 ° C. (AcOEt-hexane) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.61~1.63 (1H, m ), 1.77~1.
78 (1H, m), 2.07 to 2.10 (1H, m),
2.23 to 2.30 (1H, m), 2.73 to 2.79
(1H, m), 2.89 to 2.94 (1H, m), 4.
00 (3H, s), 4.14 (3H, s), 5.52
(1H, t, J = 4.9 Hz), 6.02 (1H,
s), 6.86 (1H, s), 7.24 (1H, s).

(Embodiment 14) Similar to Embodiment 1, 3
From -chloro-2- [1-hydroxy-4- (1-tritylimidazol-4-yl) butyl] pyrazine, 5-
(3-chloropyrazin-2-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine was obtained. Melting point 149-150 ° C (AcOEt-Et ₂ O) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.77 to 1.98 (2H, m), 2.16-2.
23 (1H, m), 2.34 to 2.41 (1H, m),
2.84 to 2.94 (2H, m), 5.80 (1H,
t, J = 6.1 Hz), 6.85 (1H, s), 7.0
9 (1H, s), 8.35 (1H, d, J = 2.5H
z), 8.46 (1H, d, J = 2.5Hz).

(Example 15) Similar to Example 1, 5
From 6- (3-pyridyl) -6,7,8,9-tetrahydro-5H-imidazo [1,5-a, from-[1-hydroxy-5- (1-tritylimidazol-4-yl) pentyl] pyridine. I got azepine. Melting point 77-78 ° C (AcOEt-Et ₂ O) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.50 to 1.58 (1H, m), 1.64 to 1.
72 (1H, m), 1.75 to 1.89 (2H, m),
2.11 to 2.18 (1H, m), 2.36 to 2.42
(1H, m), 2.55 to 2.62 (1H, m), 2.
84-2.90 (1H, m), 5.53 (1H, d, J
= 4.3 Hz), 6.87 (1 H, s), 7.20-
7.31 (3H, m), 8.39 (1H, d, J = 1.
8 Hz), 8.57 (1H, d, J = 4.9 Hz).

(Example 16) Similar to Example 1, 3
-[1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine to give 6,7-dihydro-5- (3-pyridyl) -5H-pyrrolo [1,2-
c] Imidazole 1.5 fumarate was obtained. Mp 149-150 ° C. Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.46~2.53 (1H, m ), 2.83~2.
96 (2H, m), 3.01 to 3.09 (1H, m),
5.57 (1H, dd, J = 5.5, 8.0Hz),
6.12 (3H, s), 6.78 (1H, s), 7.4
1 (1H, dd, J = 4.9, 8.0 Hz), 7.52
(1H, dt, J = 1.9, 8.0 Hz), 7.61
(1H, s), 8.46 (1H, d, J = 1.9H
z), 8.55 (1H, dd, J = 1.9, 8.0H
z).

(Embodiment 17) Similar to Embodiment 1, 2
From -chloro-3- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine, 5
-(2-chloropyridin-3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole was obtained. Melting point 120-121 ° C (Et ₂ O-AcOEt) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.48 to 2.54 (1 H, m), 2.80 to 2.
95 (2H, m), 3.17 to 3.26 (1H, m),
5.71 (1H, dd, J = 3.7, 8.6Hz).

(Embodiment 18) Similar to Embodiment 1, 2
-Chloro-3- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] -6-methoxypyridine to 5- (2-chloro-6-methoxypyridin-3-yl) -6, 7-dihydro-5H-pyrrolo [1,
2-c] imidazole hydrochloride was obtained. Mp 232 ° C. (decomposition) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.50 (1H, t , J = 2.0Hz), 2.54
~ 2.61 (1H, m), 3.00 to 3.07 (2H,
m), 3.89 (3H, s), 5.95 to 6.03 (1
H, m), 6.91 (1H, d, J = 8.5 Hz),
7.49 to 7.57 (2H, m), 8.99 (1H,
s).

(Embodiment 19) As in Embodiment 1, 5
-Bromo-3- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyridine from 5
-(5-Bromopyridin-3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole was obtained. Mp _{114-116 ℃ (AcOEt-Et 2 O} ) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 2.49~2.56 (1H, m ), 2.89~3.
02 (2H, m), 3.08 to 3.16 (1H, m),
5.33 (1H, dd, J = 5.5, 7.4Hz),
6.84 (1H, s), 7.31 (1H, s), 7.4
9 (1H, t, J = 1.8Hz), 8.39 (1H,
d, J = 1.8 Hz), 8.66 (1H, d, J = 1.
8 Hz).

(Embodiment 20) In the same manner as in Embodiment 1,
2,6-difluoro-3- [1-hydroxy-3- (1
-Tritylimidazol-4-yl) propyl] pyridine to 5- (2,6-difluoropyridin-3-yl) -6,7-dihydro-5H-pyrrolo [1,2-c]
I got imidazole. Melting point 107-108 ° C (Et ₂ O-AcOEt) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.48 to 2.55 (1H, m), 2.87 to 2.
97 (2H, m), 3.10 to 3.18 (1H, m),
5.58 (1H, dd, J = 4.9, 8.0Hz),
6.80 (1H, dd, J = 3.1, 8.0Hz),
6.83 (1H, s), 7.23 to 7.29 (1H,
m), 7.36 (1H, s).

(Embodiment 21) Similar to Embodiment 1, 4
-[3-Hydroxy-3- (3-thienyl) propyl]
From -1-trityl-1H-imidazole, 6,7-dihydro-5- (3-thienyl) -5H-pyrrolo [1,2
-C] Imidazole hydrochloride was obtained. Mp 141-143 ° C. Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.61~2.70 (1H, m ), 2.97~3.
15 (3H, m), 5.88 (1H, t, J = 7.0H
z), 7.19 (1H, dd, J = 1.8, 4.9H)
z), 7.45 (1H, s), 7.64 to 7.67 (2
H, m), 9.04 (1H, s).

(Embodiment 22) Similar to Embodiment 1, 4
From (3-hydroxy-3-thienylpropyl) -1-tritylimidazole, 6,7-dihydro-5- (2
-Thienyl) -5H-pyrrolo [1,2-c] imidazole fumarate was obtained. Mp 156-158 ℃ (MeOH-AcOEt) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.51~2.59 (1H, m ), 2.83~3.
00 (2H, m), 3.00 to 3.07 (1H, m),
5.77 (1 H, t, J = 6.4 Hz), 6.62 (2
H, s), 6.67 (1H, brs), 7.04 (1
H, dd, J = 5.2, 3.3 Hz), 7.12 (1
H, d, J = 3.0 Hz), 7.52 (2H, m).

(Embodiment 23) Similar to Embodiment 1, 5
-[1-Hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyrimidine to 6,7-dihydro-5- (5-pyrimidyl) -5H-pyrrolo [1,2
-C] Imidazole was obtained. Mp _{136-137 ℃ (Et 2 O-AcOEt} ) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 2.53~2.60 (1H, m ), 2.93~3.
04 (2H, m), 3.13 to 3.20 (1H, m),
5.36 (1H, dd, J = 5.5, 8.0Hz),
6.85 (1H, s), 7.33 (1H, s), 8.5
3 (2H, s), 9.22 (1H, s).

(Embodiment 24) Similar to Embodiment 1, 3
From 5-chloro-2- [1-hydroxy-3- (1-tritylimidazol-4-yl) propyl] pyrazine to 5
-(3-chloropyrazin-2-yl) -6,7-dihydro-5H-pyrrolo [1,2-c] imidazole was obtained. Mp _{126-127 ℃ (AcOEt-Et 2 O} ) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 2.77~2.84 (1H, m ), 2.91~2.
97 (1H, m), 3.01 to 3.08 (1H, m),
3.13 to 3.21 (1H, m), 5.85 (1H, d
d, J = 4.9, 8.5 Hz), 6.78 (1H,
s), 7.39 (1H, s), 8.35 (1H, d, J
= 2.5 Hz), 8.45 (1H, d, J = 2.5H
z).

Example 25 5- (3 obtained in Example 24
-Chloropyrazin-2-yl) -6,7-dihydro-5
80 ml of potassium hydroxide in 30 ml of a methanol solution containing 0.27 g of H-pyrrolo [1,2-c] imidazole
After adding g and a catalytic amount of 10% palladium carbon, the mixture was stirred at room temperature for about 30 minutes in the presence of hydrogen gas. The catalyst was filtered off and the obtained filtrate was evaporated under reduced pressure. An appropriate amount of saturated aqueous sodium hydrogen carbonate solution was poured into the resulting residue, and the mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate, and the residue obtained after distilling off the solvent was recrystallized from a mixed solution of ethyl acetate-n-hexane to give 6,7-dihydro-5- (2-pyrazyl)-.
0.11 g of 5H-pyrrolo [1,2-c] imidazole was obtained.

Melting point 108-109 ° C. (AcOEt-E
t ₂ O) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 2.73 to 2.80 (1H, m), 2.90 to 3.
40 (2H, m), 3.11 to 3.19 (1H, m),
5.48 (1H, dd, J = 4.9, 8.5Hz),
6.82 (1H, s), 7.40 (1H, s), 8.3
4 (1H, d, J = 1.2Hz), 8.56 (1H,
d, J = 2.5 Hz), 8.58 (1H, t, J = 2.
5 Hz).

Example 26 5- (6-) obtained in Example 5
Bromopyridin-3-yl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine (0.25 g) was added to 30 ml of a methanol solution containing 40% of methylamine and heated in a sealed tube for one day. Refluxed. After allowing to cool, an appropriate amount of saturated aqueous sodium hydrogen carbonate solution was poured into the oily substance produced by distilling off the solvent, and the mixture was extracted several times with ethyl. The organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated, and the obtained residue was purified by silica gel column chromatography. 5- [6- ( Methylamino) pyridin-3-yl]
-5,6,7,8-Tetrahydroimidazo [1,5-
a] 0.13 g of pyridine was obtained.

Melting point 142-143 ° C. (AcOEt-E
t ₂ O) Nuclear magnetic resonance spectrum (COCl ₃ , TMS internal standard) δ: 1.74-1.80 (2H, m), 1.86-2.
00 (2H, m), 2.18 to 2.21 (1H, m),
2.76 to 2.83 (1H, m), 2.94 (3H,
d, J = 5.0 Hz), 4.61 (1H, br), 4.
99 (1H, dd, J = 5.0, 9.0Hz), 6.3
8 (1H, d, J = 8.5 Hz), 6.81 (1H,
s), 7.12 (1H, s), 7.15 (1H, dd,
J = 2.5, 8.5 Hz), 7.97 (1H, d, J =
2.5 Hz).

(Example 27) 0.1 g of sodium metal was added to 10 ml of dry methanol, and the sodium methoxide obtained by distilling off the solvent was added to the solution obtained in Example 5-5-.
(6-Bromopyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine 0.21
After adding to an 8 ml solution of N, N-dimethylformamide containing g, the mixture was heated at 60 ° C. for 24 hours. An appropriate amount of purified water was poured into the residue obtained by distilling off the solvent and the mixture was extracted with ethyl acetate, then the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography, chloroform-methanol (20
0: 1) gave 0.14 g of pale yellow oil from the eluate,
To this was added an appropriate amount of 4N hydrochloric acid-ethyl acetate solution, and the resulting white crystals were collected by filtration to give 5- (6-methoxypyridin-3-yl) -5,6,7,8-tetrahydroimidazo [1, 5-a] pyridine dihydrochloride was obtained.

Melting point 141-145 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.77 to 2.26 (4H, m), 2.83 to 2.
98 (2H, m), 3.88 (3H, s), 5.53
(1H, dd, J = 4.0, 6.8Hz), 6.89
(1H, d, J = 6.8Hz), 7.50 (1H,
s), 7.67 (1H, dd, J = 2.0, 6.8H)
z), 8.16 (1H, d, J = 2.0 Hz), 8.6
9 (1H, s).

Example 28 5- [1 obtained in Example 12
-(N, N-dimethylsulfamoyl) imidazole-
200 mg of 2-yl] -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine was dissolved in 15 ml of a 1N aqueous hydrochloric acid solution, heated to 60 ° C and stirred for 1.5 hours. After pouring an appropriate amount of concentrated aqueous ammonia into the reaction solution for neutralization, it was extracted several times with chloroform. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue is purified by silica gel column chromatography, and chloroform-
40 mg of 5- (1H-imidazol-2-yl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine was obtained from the elution part of methanol (20: 1).

Melting point 228 ° C. (decomposition) (AcOEt-M
eOH) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.68 to 1.76 (1H, m), 1.95 to 2.
01 (1H, m), 2.14 to 2.20 (2H, m),
2.66 to 2.72 (1H, m), 2.77 to 2.83
(1H, m), 5.31 (1H, t, J = 6.7H
z), 6.63 (1H, s), 6.87 (1H, s),
7.13 (2H, s), 12.13 (1H, brs).

Example 29 A catalytic amount of 1 in an ethanol-concentrated hydrochloric acid (4: 1) solution containing 0.46 of imidazo [1,5-a] pyridin-5-yl-3-pyridylmethanol.
0% Palladium on carbon was added, heated to 60 ° C. in the presence of hydrogen gas at 3 atm, and heated for about 5 hours. The catalyst was filtered off and the obtained filtrate was evaporated under reduced pressure, neutralized with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resulting residue was isolated and purified by silica gel column chromatography to give a chloroform-methanol (100: 1) eluate.
25 g of colorless oil was obtained. An appropriate amount of 4N hydrochloric acid-
Ethyl acetate was added, the resulting white crystals were collected by filtration, and 5-
(3-Pyridylmethyl) -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine dihydrochloride was obtained.

Melting point 183-185 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.68 to 1.76 (2H, m), 1.87 to 1.
99 (2H, m), 2.75 to 2.83 (2H, m),
3.31 (1H, dd, J = 8.0, 10.8Hz),
3.72 (1H, d, J = 4.0, 8.0 Hz), 4.
79 to 4.82 (1H, m), 7.46 (1H, s),
8.02 (1H, dd, J = 4.4, 6.4Hz),
8.53 (1H, d, J = 6.4Hz), 8.86 (1
H, d, J = 4.4 Hz), 9.02 (1H, s),
9.41 (1H, s).

(Example 30) 0.23 g of imidazo [1,5-a] pyridin-5-yl-3-pyridinemethanol
A catalytic amount of platinum oxide was added to 5 ml of trifluoroacetic acid containing and was stirred at room temperature for about 30 minutes in the presence of hydrogen gas. The catalyst was filtered off, the obtained filtrate was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography, and the chloroform-methanol (50: 1) eluate was used to extract 5,6.
60 mg of 7,8-tetrahydroimidazo [1,5-a] pyridin-5-yl-3-pyridylmethanol was obtained.

Melting point 165-167 ° C. Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.25 to 2.10 (4H, m), 2.42 to 2.
82 (2H, m), 4.15 to 4.61 (2H, m),
5.32 (1H, d, J = 3.1Hz), 6.61 (1
H, br), 7.19 to 7.46 (2H, m), 7.6
5 to 7.88 (1H, m), 8.42 to 8.73 (2
H, m).

(Example 31) 5- obtained in Example 5
(6-Bromopyridin-3-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine 0.5
g was added to 20 ml of morpholine, and the mixture was heated under reflux for about 15 hours. The solvent was distilled off under reduced pressure, to the resulting residue was poured an appropriate amount of purified water and ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The resulting residue was purified by silica gel column chromatography, and a pale yellow oily matter 0.4 was obtained from the eluate of chloroform-methanol (100: 1).
After obtaining 3 g, by adding an appropriate amount of 4N hydrochloric acid-ethyl acetate solution, 5- [6-morpholinopyridine-3-
Il] -5,6,7,8-tetrahydroimidazo [1,
5-a] pyridine dihydrochloride was obtained.

Melting point 221-225 ° C. Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.76 to 2.21 (4H, m), 2.82 to 2.
99 (2H, m), 3.75 (8H, br), 5.53
(1H, t, J = 5.0 Hz), 7.33 (1H, d,
J = 8.0 Hz), 7.50 (1H, s), 7.92
(1H, d, J = 8.0 Hz), 8.15 (1H,
s), 8.73 (1H, s).

The chemical structural formulas of the compounds obtained in Examples 1 to 31 are listed in Tables 1 to 6 below.

[0143]

[Table 1]

[0144]

[Table 2]

[0145]

[Table 3]

[0146]

[Table 4]

[0147]

[Table 5]

[0148]

[Table 6]

The compounds shown below can be easily produced by substantially the same method as the above-mentioned production method and the method described in the Examples or by applying some modifications obvious to those skilled in the art to them. .

5- (5-methoxypyridin-3-yl)
-5,6,7,8-Tetrahydroimidazo [1,5-
a] pyridine. 5- (1H-tetrazol-5-yl)
-5,6,7,8-Tetrahydroimidazo [1,5-
a] pyridine. 5- (1H-pyrrol-3-yl)-
5,6,7,8-Tetrahydroimidazo [1,5-a]
Pyridine. 5- (1H-imidazol-4-yl)-
5,6,7,8-Tetrahydroimidazo [1,5-a]
Pyridine. 5- (5-isothiazolyl) -5,6,7,
8-Tetrahydroimidazo [1,5-a] pyridine. 5
-(1H-pyrazol-4-yl) -5,6,7,8-
Tetrahydroimidazo [1,5-a] pyridine. 5-
(1,2,4-triazin-3-yl) -5,6,7,
8-Tetrahydroimidazo [1,5-a] pyridine. 5
-[2- (Dimethylamino) pyridin-5-yl]-
5,6,7,8-Tetrahydroimidazo [1,5-a]
Pyridine. 5- (2-sulfamoylpyridin-5-yl) -5,6,7,8-tetrahydroimidazo [1,5
-A] pyridine. 5- [2- (isopropylamino) pyridin-3-yl] -5,6,7,8-tetrahydroimidazo [1,5-a] pyridine.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/495 A61K 31/495 31/50 31/50 31/505 31/505 31/535 31 / 535 31/55 ABN 31/55 ABN C07D 471/04 108 C07D 471/04 108X (72) Inventor Taiki Minatani 2-5-9 Ninomiya Ninomiya Tsukuba City, Ibaraki Prefecture 415 (72) Inventor Masafumi Kudo Ibaraki Prefecture 7-8-19 Yakushidai, Moriya-cho, Kitasoma-gun

Claims (3)

[Claims] 1. A bicyclic fused imidazole derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (However, the symbols in the formulas have the following meanings: Ring A: 5- or 6-membered unsaturated heterocycle containing 1 to 4 nitrogen atoms or sulfur atoms. B: Absent or lower alkylene group. In the case of an alkylene group, it may be substituted with a hydroxyl group R ¹ , R ² : the same or different, absent, a hydrogen atom,
A halogen atom, a lower alkyl group, a lower alkoxy group, a morpholinyl group, or -NR ³ R ⁴ or -S (O) _m N
A group represented by R ⁵ R ⁶ . Here, R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each is a hydrogen atom or a lower alkyl group,
m is 1 or 2. n: an integer of 1 to 3. ) 2. A medicament comprising the bicyclic fused imidazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof. 3. An aldosterone biosynthesis inhibitor comprising the bicyclic fused imidazole derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.