JPH10330377A - Piperidine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a potent inhibitory action for cell adhesion, and having excellent anti-inflammatory activity, antiallergic activity, suppressing activity of a rejection on an organ transplantation and suppressing activity of cancer metastasis. SOLUTION: This piperidine derivative is a compound of formula I [R<1> is a (non)substituted lower alkyl, hydroxy, etc.; R<2> is H, carboxyl, etc.; R<3> is H or a lower alkyl; R<4> is H, a lower alkoxy, etc.; X<1> -X<2> is N=N, N=C(R<5> ), (R<5> is H, amino, etc.), etc.; Y<1> -Y<2> -Y<3> is =N-C-(R<8> )=N, =N-N=C-(R<8> A), (R<8> , R<8> A are each H, a halogen, etc.), etc.; Z<1> , Z<2> are each H, nitro, etc.; (n) is 0-2] or a salt thereof, e.g. 1-[1-(4-chlroo-6,7-dimethoxy-1-phthaladinyl)-4- piperidinyl]-2,3-dihydro-5-methyl-1H-benzimidazol-2-one. The compound of the formula I is obtained by e.g. reacting a compound of formula II with a compound of formula III (Hal is chlorine, bromine or iodine) in a solvent such as methanol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an anti-inflammatory agent, an anti-allergic agent, a cancer metastasis inhibitor, which has an activity of inhibiting cell adhesion,
The present invention relates to piperidine derivatives useful as immunosuppressants and the like.

[0002]

2. Description of the Related Art In recent years, it is expressed on inflammatory cells and vascular endothelial cells in the stage related to the initiation of inflammation, that is, in the process in which inflammatory cells flowing in the blood vessel infiltrate outside the blood vessel and migrate to the inflammatory site. It has been clarified that it is essential that the in vivo molecules collectively referred to as adhesion molecules adhere to each other. Further, it has been suggested that this cell adhesion is strongly involved in immune reaction and cancer metastasis.
Therefore, THE HANDBOOK OF IMMUN
OPharmacology, ADHESIONMOL
ECULES, Academic Press: London (199
4), Experimental Medicine Series for Clinicians, Volume 18,
As disclosed in Cell Adhesion Molecules and Diseases, Yodosha (1994), compounds that inhibit cell adhesion can be used as therapeutic agents for inflammation, allergy, autoimmune diseases, cancer, etc., or at the time of organ transplantation. It is expected to be useful as a rejection inhibitor. Various publicly known documents including the above documents have revealed that monoclonal antibodies of each adhesion molecule are effective in various models of inflammation, allergy, organ transplantation and the like. However, an antibody is not always satisfactory as a drug because of its antigenicity and low oral absorbability. On the other hand, various low molecular adhesion inhibitors have been reported to overcome the drawbacks.
For example, Ann. Rep. Med. Chem. , 29th
Vol. 215-224 (1994), Exp. Opi
n. Invest. Drugs, Volume 3, 709-72
On page 4 (1994), saccharides that inhibit selectin / sugar chain adhesion are described. In addition, Exp. Opin.
Invest. Drugs, Vol. 3, pp. 861-869 (1994), Exp. Opin. Ther. Pat
ents, Vol. 5, pp. 35-40 (1995), describes low molecular weight compounds having various cell adhesion inhibitory effects.

[0003] West German Patent 2,530,894 (1976)
), JP-A-60-120,872, Chem.
Pharm. Bull. 38, 1591-159
5 (1990), Chem. Pharm. Bull
l. 38, 2179-2183 (1990).
In addition, there are formulas (E) having cardiotonic action

[0004]

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(Wherein R ^A represents hydrogen, lower alkyl, lower alkoxy, etc., X ^A -X ^B represents —N−CH
^2- , -NH-C (= O)-, -N = N- and the like,
Y ^A -Y ^B is, -CH = N -, - N = CH- represents like,
Z ^A and Z ^B represent lower alkoxy and the like) are disclosed. But,
No known compounds exhibiting an anti-inflammatory effect, an anti-allergic effect, an effect of suppressing rejection during organ transplantation, an effect of suppressing cancer metastasis, and the like.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to have a strong cell adhesion inhibitory effect, an excellent anti-inflammatory effect, an anti-allergic effect, an inhibitory effect on rejection during organ transplantation, an inhibitory effect on cancer metastasis and the like. To provide a novel compound having the following formula:

[0007]

[Means for Solving the Problems] The inventors of the present invention have conducted research for the purpose of creating a cell adhesion inhibitor, particularly a compound that suppresses adhesion between vascular endothelial cells and neutrophils. As a result, human umbilical vein endothelial cells ( human umbilical vein d
enhanced endothial cells,
We have found a compound that strongly inhibits the adhesion between HUVEC) and leukemia cells (HL60) and completed the present invention.

The present invention relates to a compound of the formula (I)

[0009]

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Where R¹Is substituted or unsubstituted low
Primary alkyl, hydroxy, lower alkoxy, carboxy
, Lower alkoxycarbonyl, lower alkyl carbonyl
, Substituted or unsubstituted aryl, substituted or unsubstituted
Substituted aryloxy, substituted or unsubstituted aryl
Xycarbonyl, substituted or unsubstituted arylcarbo
Nil, carbamoyl, mono- or di-lower alkylcarba
Moyl, mono- or diarylcarbamoyl, nitro
Or halogen, R²Is hydrogen, substituted or unsubstituted
Substituted lower alkyl, hydroxy, lower alkoxy, cal
Boxy, lower alkoxycarbonyl, lower alkyl carb
Bonyl, substituted or unsubstituted aryl, substituted or
Unsubstituted aryloxy, substituted or unsubstituted aryl
Ruoxycarbonyl, substituted or unsubstituted arylca
Rubonyl, carbamoyl, mono- or di-lower alkyl
Lubamoyl, mono- or diarylcarbamoyl, nitro
Represents b or halogen;^ThreeIs hydrogen or lower alcohol
Represents a kill, R^FourIs hydrogen, lower alkyl or lower
Represents ruboxy, X¹-X²Is -N = N-, -N = C
(R ^Five)-(Where R^FiveIs hydrogen, lower alkyl or
Mino), -N (R⁶) -W- (wherein, R⁶Is the water
Alkyl, substituted or unsubstituted lower alkyl or substituted
Or unsubstituted aryl, W represents C = O, C = S or
Or SO_Two) Or -OC (= R⁷)-(Wherein
R⁷Represents O or S), and Y represents¹-Y^Two-Y³Is
= NC (R⁸) = N- [where R⁸Is hydrogen, lower alcohol
Coxy, halogen, amino, mono or di (substituted or
Is unsubstituted lower alkyl) amino or substituted or non-substituted
Represents a substituted alicyclic heterocyclic group], = NN-C (R^8A)
-(Where R^8AIs the R⁸And = N-C
(R^8B) = CH- (wherein, R^8BIs the R⁸Synonymous with
) Or = C [C (= O) R⁹] -CH = N- [Formula
Medium, R⁹Is hydrogen, hydroxy, lower alkyl, lower alkyl
Lucoxy, substituted or unsubstituted aryl, substituted or unsubstituted
Is unsubstituted aryloxy, amino, mono- or di-lower
Alkylamino, mono or di (substituted or unsubstituted)
Aryl) amino or substituted or unsubstituted alicyclic compound
Represents a ring group];¹And Z^TwoAre the same or different
Hydrogen, substituted or unsubstituted lower alkyl, hydr
Roxy, lower alkoxy, carboxy, lower alkoxy
Carbonyl, lower alkylcarbonyl, carbamoyl,
Mono- or di-lower alkylcarbamoyl, halogen or
Represents nitro or Z¹And Z²Together-N
(R^Ten) C (= X) N (R¹¹)-(Where R ^TenAnd R
¹¹Are the same or different and represent hydrogen or lower alkyl.
X is O or S), and n is 0, 1 or
Piperidine derivative represented by｝ representing 2, or its pharmacology
It relates to a chemically acceptable salt.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by the formula (I) is hereinafter referred to as compound (I). The same applies to compounds of other formula numbers. In the definition of each group of compound (I), lower alkyl, lower alkoxy, lower alkylcarbonyl,
As the lower alkyl moiety of the lower alkoxycarbonyl, mono- or di-lower alkylamino and mono- or di-lower alkylcarbamoyl, straight-chain or branched one having 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Sec-butyl, ter
t-butyl, pentyl, isopentyl, hexyl and the like. As the aryl moiety of aryl, aryloxy, aryloxycarbonyl, arylcarbonyl, mono- or diarylcarbamoyl and mono- or diarylamino, an aromatic hydrocarbon group such as phenyl and naphthyl or an aromatic group such as pyrrolyl, furyl, thienyl, imidazolyl and pyridyl Group heterocyclic groups and the like. As the alicyclic heterocyclic group, for example, pyrrolidinyl,
Piperidino, morpholino, N-methylpiperazinyl and the like. Halogen means each atom of fluorine, chlorine, bromine or iodine.

Substituted aryl, substituted aryloxy, substituted aryloxycarbonyl, substituted arylcarbonyl,
The substituents of the mono- or di-substituted arylamino may be the same or different and have 1 to 3 substituents, for example, lower alkyl, lower alkoxy, hydroxy, amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl, carbamoyl, mono Or di-lower alkylcarbamoyl, nitro, halogen and the like, and lower alkyl, lower alkoxy, mono- or di-lower alkylamino, lower alkoxycarbonyl, mono- or di-lower alkylcarbamoyl and halogen have the same meanings as described above. Substituents of the substituted lower alkyl and the mono- or di-substituted lower alkylamino may be the same or different and have 1 to 3 substituents, such as hydroxy, lower alkoxy, halogen, amino, mono- or di-lower alkylamino, alicyclic heterocycle Group, substituted or unsubstituted aryl,
Substituted or unsubstituted arylcarbonyl and the like can be mentioned, and lower alkoxy, halogen, mono- or di-lower alkylamino, alicyclic heterocyclic group, aryl and arylcarbonyl have the same meanings as described above. Examples of the substituent for the substituted aryl and the substituted arylcarbonyl include the same groups as the substituents for the above-mentioned substituted aryl. Examples of the substituent of the substituted alicyclic heterocyclic group include lower alkyl, hydroxy, lower alkoxy, carboxy,
Lower alkoxycarbonyl, amino, carbamoyl and the like can be mentioned, and lower alkyl, lower alkoxy and lower alkoxycarbonyl have the same meanings as described above, respectively.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Acid addition salts include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, fumarate, maleate, tartrate, citrate, lactate, oxalate, methanesulfonic acid Salts, organic salts such as benzenesulfonate and p-toluenesulfonate. Examples of the metal salts include alkali metal salts such as lithium salt, sodium salt and potassium salt, and alkaline earth metals such as magnesium salt and calcium salt. Salts, aluminum salts, zinc salts, etc .; ammonium salts, such as ammonium and tetramethylammonium salts; organic amine addition salts, such as morpholine and piperidine; and amino acid addition salts. Addition salts of glycine, phenylalanine, aspartic acid, glutamic acid, lysine and the like can be mentioned.

Next, a method for producing the compound (I) will be described. In the production methods shown below, when the defined group changes under the conditions of the practice method or is unsuitable for carrying out the method, introduction and elimination of a protecting group commonly used in organic synthetic chemistry [ For example, Protective Groups in Organic Synthesis
pos in Organic Synthesis), Green (TWGreene)
Author, John Wiley & Sons Inc. (1981)] can be used to obtain the desired compound. Further, the order of the substituent introduction step can be changed as necessary.

Method 1 Compound (I) can be produced according to the following reaction steps.

[0016]

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(In the formula, Hal represents each atom of chlorine, bromine or iodine, and R ¹ , R ² , R ³ , R ⁴ , X ¹ -X ² and Y ^1-
Y ² -Y ³ , Z ¹ , Z ² and n have the same meanings as described above, respectively.) Compound (I) is equivalent to compound (A) and compound (B) in an equivalent amount.
In the presence or absence of a large excess of a base such as triethylamine, N, N-diisopropylethylamine, in the presence or absence of a catalytic amount to 1 equivalent of potassium iodide, methanol, ethanol, tetrahydrofuran,
It can be obtained by reacting in a solvent such as N, N-dimethylformamide at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours.

The following are representative starting compounds (II) to (XI) [specific examples of compound (B)] of compound (I).

[0019]

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(Wherein R ^9a represents lower alkoxy in the definition of R ⁹ , and R ¹ , R ² , R ³ , R ⁴ , R ¹⁰ , R ¹¹ ,
Z ¹ , Z ² and Hal have the same meanings as described above. The raw materials can be obtained by the methods described in the following Reference Examples, patents and literatures, or by methods analogous thereto. Compound (II): J. Med. Chem. , Volume 30,
Page 814 (1987) Compound (III): U.S. Patent 3,266,990 Compound (IV): Reference Example 3, Reference Example 4 or Reference Example 5 Compound (V): J. Chem. Soc. , Page 1756 (1948) Compound (VI): Reference Example 1 or Reference Example 2 Compound (VII): JP-A-58-227,347 Compound (VIII): Reference Example 6 Compound (IX): Chem. Ber. , Volume 102, 3
Page 666 (1969) Compound (X): J. Am. Med. Chem. , Volume 14, 1
Page 7 (1971) Compound (XI): JP-A-56-7784

Method 2 In the compound (I), the compound (Ia) in which X ¹ -X ² is —NH—W— (wherein W is as defined above) and n is 0 is as follows: It can also be produced by a reaction step.

[0022]

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Where R¹²Is benzyl or lower alcohol
Represents xycarbonyl, R¹, R^Two, R ^Three, R^Four, Y¹-Y^Two
-Y^Three, Z¹And Z^TwoIs as defined above. ) R¹²Lower alkoxycarbonyl in the definition of
Synonymous with lower alkoxycarbonyl. Compound (XII
I) comprises the process described in West German Patent 2,527,261 or
Converts the compound (XII) obtained according to the method into an ordinary compound
It can be obtained by deprotection by a method. For example, R
¹²When is benzyl, compound (XII) is converted to chloroformic acid
In the presence of vinyl, chloroform, methylene chloride, ether
Between 0 ° C and the boiling point of the solvent used in an inert solvent such as
After reacting for 1 to 24 hours at temperature, continue to add acid such as hydrochloric acid.
In the presence of, an inert solvent such as methanol or ethanol
Medium, at a temperature between room temperature and the boiling point of the solvent used for 1-24 hours.
It can be obtained by adapting. Also, R¹²Is low
In the case of a lower alkoxycarbonyl, the compound (XII) is
In the presence of a base such as potassium hydroxide,
Temperature in any inert solvent between 0 ° C. and the boiling point of the solvent used
Can be obtained by reacting for 1 to 24 hours.
You.

Compound (XIV) is compound (XIII)
Is reacted with the compound (B) according to Method 1, and then the nitro group is reduced. The reduction of the nitro group is carried out in the presence of a catalyst such as palladium-carbon, Raney nickel and platinum dioxide, if necessary, in the presence of a catalytic amount to a large excess of an acid such as hydrochloric acid and acetic acid, alcohols such as methanol and ethanol, and ethyl acetate. In an inert solvent such as an ester, under an atmosphere of hydrogen at normal pressure, at a temperature between 0 ° C. and the boiling point of the solvent used for 1 to 24 hours, or in the presence of stannous chloride, if necessary, In an inert solvent such as methanol or ethanol in the presence of a catalyst amount to a large excess of an acid such as hydrochloric acid, a temperature between 0 ° C. and the boiling point of the solvent used is 1 to 24.
Either reduce over time or in an inert solvent such as methanol or ethanol containing water in the presence of a catalytic amount to a large excess of reduced iron and ferric chloride at a temperature between 0 ° C. and the boiling point of the solvent used. It is carried out by reducing over 1 to 24 hours.

Compound (Ia) is prepared by converting compound (XIV) with urea, N, N'-carbonyldiimidazole, ethyl chloroformate, carbon disulfide, sulfamide and the like, if necessary, in a catalytic amount to a large excess of triethylamine, carbonate In the presence of a base such as potassium, a solvent such as methanol, ethanol, acetonitrile, tetrahydrofuran, N, N-dimethylformamide or pyridine or a reagent is also used as a solvent. It can be obtained by reacting for 24 hours.

Method 3 In compound (I), X ¹ -X ² is -N = N-,
Compound (Ib) wherein n is 0 can also be produced by the following reaction step.

[0027]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , Y ¹ -Y ^2-
Y ³ , Z ¹ and Z ² each have the same meaning as described above.) Compound (Ib) is obtained by converting compound (XIV) and a nitrite such as sodium nitrite into water, if necessary, in the presence of an acid such as hydrochloric acid. -20 in solvents such as methanol and ethanol
It can be obtained by reacting at a temperature between ℃ and the boiling point of the solvent used for 0.5 to 24 hours.

Method 4 In the compound (I), X ¹ -X ² is -N = C (R ⁵ )-.
(In the formula, R ⁵ has the same meaning as above), and the compound (Ic) in which n is 0 can also be produced by the following reaction step.

[0030]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , Y ¹ −
Y ² -Y ^3, Z ¹ and Z ² are the same meanings as defined above, respectively) Compound (Ic) is Compound (XIV) and cyanogen halide, such as ortho esters or cyanogen bromide, such as triethyl orthoformate , If necessary, in the presence of a catalytic amount to a large excess of acetic acid, acid such as trifluoroacetic acid, methanol,
It can be obtained by reacting in a solvent such as ethanol or using a reagent also as a solvent at a temperature between 0 ° C. and the boiling point of the solvent used for 1 to 24 hours.

Method 5 In the compound (I), X ¹ -X ² is -OC (= R ⁷ )
And the compound (Id) wherein n is 0 can also be produced by the following reaction step.

[0033]

[Chemical 9]

(Where R¹³Is benzyl or lower alcohol
Represents xycarbonyl, R¹, R^Two, R ^Three, R^Four, R⁷, Y¹
-Y^Two-Y^Three, Z¹And Z^TwoIs the same as above
R)¹³Lower alkoxycarbonyl in the definition of
Synonymous with lower alkoxycarbonyl. Compound (XVI
I) is based on J.I. Chem. Soc. 980, p.
Year) or a compound obtained according to it
(XV) and Helv. Chim. Acta. , Forty-first
Vol., P. 1184 (1958) or the method described therein.
Compound (XVI) obtained according to the following, methanol,
In a solvent such as ethanol, between 0 ° C and the boiling point of the solvent used
After reacting for 1 to 24 hours at a temperature of
Reduction of sodium hydrogen, sodium cyanoborohydride, etc.
At a temperature between -20 ° C and the boiling point of the solvent used in the presence of the base agent
It can be obtained by treating for 1 to 24 hours.

Compound (XVIII) is compound (XVI)
I) and urea, N, N'-carbonyldiimidazole,
Ethyl chloroformate, carbon disulfide and the like, if necessary, in a solvent such as methanol, ethanol, tetrahydrofuran, acetonitrile, N, N-dimethylformamide in the presence of a catalytic amount to a large excess of a base such as triethylamine or potassium carbonate or Room temperature ~
After reacting at a temperature between the boiling points of the used solvents for 1 to 24 hours, the compound (XII) shown in the method 2 is converted to the compound (XI)
II), or in the presence of a catalyst such as palladium-carbon, Raney nickel, platinum dioxide, etc., if necessary in the presence of a catalytic amount to a large excess of hydrochloric acid, an acid such as acetic acid, methanol,
Reduction is carried out in an inert solvent such as alcohols such as ethanol and esters such as ethyl acetate under a hydrogen atmosphere at normal pressure to medium pressure at a temperature between 0 ° C. and the boiling point of the solvent used for 1 to 24 hours. It can be obtained by deprotection by a method.

Compound (Id) is compound (XVIII)
With compound (B) according to method 1.

Method 6 In the compound (I), X ¹ -X ² is -N = N-, -N =
C (R ⁵ )-(wherein R ⁵ is as defined above) or-
NH-W- (W has the same meaning as above), and n
Is 1 or 2 can also be produced by the following reaction step.

[0038]

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(Where nA represents 1 or 2, X^1A−
X^2AIs X¹-X^Two-N = N-, -N = C in the definition of
(R^Five)-Or -NH-W-;¹, R^Two, R^Three,
R^Four, Y¹-Y ^Two-Y^Three, Z¹, Z^TwoAnd Hal respectively
Compound (XX) is as defined in J. Am. Org. Chem. , 27th
Volume, p. 284 (1962) or the method described therein.
Using compound (XIX) and compound (B) obtained according to
Aldehydes such as benzaldehyde
Obtained by reacting in the presence according to Method 1.
Can be.

Compound (XXII) is compound (XX)
And Bull. Soc. Sci. etetters
lodz, Class III, Volume 3, p. 10 (1
952) or the method described in U.S. Pat. No. 3,294,629 or the compound (XXI) obtained according to the method described above, if necessary in the presence of an equivalent to a large excess of a base such as potassium carbonate, tetrahydrofuran, N, N-. It can be obtained by reacting in an inert solvent such as dimethylformamide at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours.

Compound (Ie) can be obtained using compound (XXII) according to the method described in Method 2, Method 3 or Method 4.

Method 7 A part of the compound (I) obtained here can be used as a synthetic intermediate to further lead to a new derivative (I).

Method 7-1 R ¹⁴ NH or R ¹⁴ N as a substituent in compound (I)
(Wherein, R ¹⁴ represents substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl, and substituted or unsubstituted lower alkyl or substituted or unsubstituted aryl are as defined above, respectively) I
ga) is equivalent to the compound (Ifa) having NH ₂ or NH as a substituent in the compound (I) in an equivalent amount to a large excess of R ^14.
-Hal (wherein R ¹⁴ and Hal have the same meanings as above) in the presence of an equivalent to a large excess of a base such as sodium hydride in the presence of a tetrahydrofuran, N, N-dimethylformamide or the like. It can be obtained by reacting in an active solvent at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours.

Method 7-2 In compound (I), R ⁸ , R ^8A or R ^8B is lower alkoxy, amino, mono- or di (substituted or unsubstituted lower alkyl) amino or substituted or unsubstituted alicyclic. The compound (Igb) having a heterocyclic group is the same as the compound (Ifb) having a halogen as R ⁸ , R ^8A or R ^{8B in the} compound (I) with an equivalent to a large excess of a lower alkoxide such as sodium methoxide. , Methylamine, morpholine, and other amines, if necessary in equivalent
In the presence of a large excess of a base such as triethylamine or N, N-diisopropylethylamine, methanol, N, N-
In an inert solvent such as dimethylformamide or N-methyl-2-pyrrolidone, at a temperature between room temperature and the boiling point of the solvent used or, if necessary, the boiling point of the solvent used in a sealed tube to 300 ° C.
At a temperature between 1 and 72 hours.

Method 7-3 Compound (Igc) having hydrogen as R ¹ , R ² , R ⁸ , R ^8A , R ^8B , Z ¹ or Z ² in compound (I) is the same as compound (I). And a compound (Ifc) having a halogen as R ¹ , R ² , R ⁸ , R ^8A , R ^8B , Z ¹ or Z ^{2 in} the presence of a catalyst such as palladium-carbon, Raney nickel or platinum dioxide, if necessary in a catalytic amount. ~ In the presence of a large excess of acid such as hydrochloric acid and acetic acid, in an inert solvent such as alcohols such as methanol and ethanol, esters such as ethyl acetate, etc. It can be obtained by reducing at a temperature between 0 ° C. and the boiling point of the solvent used for 1 to 24 hours.

Method 7-4 Compound (Igd) having carboxy as a substituent in compound (I) is a compound (Ifd) having lower alkoxycarbonyl as a substituent in compound (I).
It can be obtained by hydrolysis in a solvent such as methanol or ethanol containing water at a temperature between room temperature and the boiling point of the solvent used for 1 to 24 hours in the presence of a base such as sodium hydroxide.

Process 7-5 Compound (Ige) having carbamoyl, mono- or di-lower alkylcarbamoyl or mono- or diarylcarbamoyl as a substituent in compound (I) is equivalent to compound (Ifd) in an equivalent to a large excess, for example. Ammonia, propylamine, amines such as aniline and the like in the presence of an equivalent to a large excess of a base such as n-butyllithium in an inert solvent such as tetrahydrofuran at a temperature between 0 ° C. and the boiling point of the solvent used. It can be obtained by reacting for ~ 72 hours.

Method 7-6 The compound (Ige) is a compound (Ife) having a carboxy as a substituent in the compound (I) and ammonia,
Methylamine, amines such as aniline, if necessary in the presence of an equivalent to excess of a base such as triethylamine,
If necessary, in the presence of an equivalent to a large excess of an additive such as N-hydroxybenzotriazole, for example, in the presence of a condensing agent such as 1,3-dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole, tetrahydrofuran, methylene chloride, It can be obtained by reacting in an inert solvent such as N, N-dimethylformamide at a temperature between 0 ° C. and the boiling point of the solvent used for 1 to 24 hours.

Method 7-7 Compound (Igf) having hydroxymethyl as a substituent in compound (I) can be obtained by converting compound (Ifd) in the presence of a reducing agent such as lithium aluminum hydride and diisobutyl aluminum hydride. , In an inert solvent such as tetrahydrofuran at a temperature between -78 ° C and the boiling point of the solvent used for 1 to 24 hours.

Process 7-8 The compound (Ifc) is prepared by combining the compound (Igc) and a halogenating agent such as bromine or N-bromosuccinimide with an inert solvent such as carbon tetrachloride, methylene chloride or 1,2-dichloroethane. Medium, at a temperature between 0 ° C. and the boiling point of the solvent used,
It can be obtained by reacting for 4 hours.

The intermediates and target compounds in the above-mentioned production methods are isolated and purified by purification methods commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like. You can do it. In addition, the intermediate can be subjected to the next reaction without purification. Compound (I) may exist as isomers such as positional isomers, geometric isomers or optical isomers, and the possible isomers and mixtures of the isomers in any ratio are included in the present invention.

When it is desired to obtain a salt of compound (I), compound (I) may be dissolved or suspended in an appropriate solvent, and a salt may be formed by adding an appropriate acid or base to isolate the compound. . The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.

Compound (I) obtained by the above production method
Table 1 shows specific examples. Note that Me, Et, Pr, ⁱ P
r, Bu, and Ph represent methyl, ethyl, propyl, isopropyl, butyl, and phenyl, respectively.

[0054]

[Table 1]

[0055]

[Table 2]

[0056]

[Table 3]

[0057]

[Table 4]

[0058]

[Table 5]

[0059]

[Table 6]

[0060]

[Table 7]

[0061]

[Table 8]

[0062]

[Table 9]

[0063]

[Table 10]

Next, the pharmacological action of the compound (I) will be specifically described with reference to test examples.

Test Example Cell Adhesion Inhibitory Activity Test Human umbilical vein endothelial cells (HUVEC) were prepared by adding 10% fetal bovine serum [FBS; Lifetech Oriental Co., Ltd.] and endothelial cell growth factor [En]
general cell grow sup
plant, ECGS; Cosmo Bio Co., Ltd.]
(30 μg / ml), heparin (Wako Pure Chemical) (100 μ
g / ml), penicillin (100 U / ml) and streptomycin (100 μg / ml). 10 human leukemia cells (HL60)
RPMI supplemented with% FBS, penicillin (100 U / ml) and streptomycin (100 μg / ml)
Culture was performed using -1640 medium. 3- in HL60 cells
(4,5-Dimethylthiazol-2-yl) -2,5-
Diphenyltetrazolium bromide (MTT; Sigma) (1 mg / ml) was added and reacted for 30 minutes for labeling. HUVECs were cultured in a collagen-coated 96-well microplate under the above conditions, and when they reached a confluent state, TNF (tumor necrosis factor) α (10 U
/ Ml). Various concentrations of drug were added during stimulation. After 4 hours, MTT-labeled HL60 cells were treated with 2 × 1.
0 ⁵ cells was added and incubated for another 30 minutes to adhere the cells. After washing the non-adherent cells, dimethyl sulfoxide was added to dissolve the MTT dye, and the absorption at 540 nm was measured with a microplate reader. The inhibition rate is
The amount of adhesion of HL60 cells to HUVEC stimulated with TNFα and the amount of adhesion of HL60 cells to non-stimulated HUVEC were calculated as the maximum adhesion amount and the minimum adhesion amount, respectively, from the adhesion amount of HL60 cells in the presence of a drug according to the following formula. .

Inhibition rate (%) = [1- (P ₂ −P ₀ ) /
(P ₁ −P ₀ )] × 100 P ₀ ; adhesion amount of HL60 cells to unstimulated HUVEC P ₁ ; HL60 to HUVEC stimulated with TNFα
Cell adhesion P ₂ ; Adhesion of HL60 cells in the presence of drug The test results are shown in Table 2.

[0067]

[Table 11]

As is apparent from Table 2, the compound (I) or a pharmaceutically acceptable salt thereof obtained according to the present invention has an excellent cell adhesion inhibitory action. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.

The pharmaceutical preparation according to the present invention contains compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. You can In addition, these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.

The route of administration is preferably the one that is most effective in the treatment, and is orally or, for example, rectal,
Parenteral, such as buccal, subcutaneous, intramuscular and intravenous, can be mentioned. Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections,
There are ointments and tapes.

Liquid preparations suitable for oral administration, such as emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. And oils such as, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor and peppermint, and the like. Capsules, tablets, powders, granules, etc. are lactose,
Excipients such as glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, lubricants such as magnesium stearate and talc, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, fatty acid esters, etc. It can be produced using a surfactant, a plasticizer such as glycerin, or the like.

Formulations suitable for parenteral administration comprise sterile aqueous preparations containing the active compounds which are preferably isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier composed of a salt solution, a glucose solution or a mixture of saline and a glucose solution. Formulations for enteral administration are prepared using a common carrier such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids and are provided as suppositories.

Topical formulations are prepared by dissolving or suspending the active compound in one or more vehicles, for example, mineral oils, petroleum, polyhydric alcohols, or other bases used in topical pharmaceutical formulations. Also, in these parenteral preparations,
Diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified for the oral preparation,
One or more auxiliary components selected from plasticizers and the like can be added.

The effective dose and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, age of the patient, body weight, and the nature or severity of the condition to be treated. The dosage is 0.1 to 1 per day.
The dose is 0000 mg / person, preferably 1 to 1000 mg, and the administration frequency is preferably once a day or divided.

Examples and reference examples will be shown below.

Example 1 1- [1- (3-chloro-6,6)
7-dimethoxy-1-isoquinolyl) -4-piperidini
] -2,3-dihydro-5-methyl-1H-benzoi
Midazol-2-one (Compound 52) 2.37 g of 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one
(8.84 mmol) and 2.00 g (7.74 mmol) of 1,3-dichloro-6,7-dimethoxyisoquinoline in 30 mL of N, N-dimethylformamide were added with 5.39 g of potassium carbonate (38.
9 mmol) and 250 mg (1.50 mmol) of potassium iodide, and the mixture was stirred at 130 ° C for 5 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
Purification by 1: 1) gave 2.58 g (74%) of compound 52 as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.82-8.74 (1H, br.-s), 7.34 (1H,
s), 7.22 (1H, s), 7.17 (1H, d, J = 8.2), 6.96 (1H,
s), 6.92 (1H, d, J = 8.2), 4.64-4.50 (1H, m), 4.02-
3.94 (8H, m), 3.24-3.14 (2H, br.-t), 2.81-2.62 (2
H, m), 2.39 (3H, s), 2.01-1.97 (2H, br.-d).

Example 2 1- [1- (4-chloro-6,6)
7-dimethoxy-1-phthalazinyl) -4-piperidinini
] -2,3-Dihydro-5-methyl-1H-benzoi
Midazol-2-one (Compound 47) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one
0,120,872 and 1,4-dichloro-6,7-dimethoxyphthalazine obtained by the method described in Example 1.
Compound 47 was obtained by reacting according to the method described in. ¹ H NMR (CDCl ₃ ): δ 8.92 (1H, s), 7.46 (1H, s), 7.35
(1H, s), 7.14 (1H, d, J = 8.4), 6.95 (1H, s), 6.91 (1
(H, d, J = 8.4), 4.67-4.49 (1H, m), 4.11 (3H, s), 4.0
9 (3H, s), 4.04-3.98 (2H, br.-d), 3.34-3.25 (2H, b
r.-t), 2.89-2.70 (2H, m), 2.38 (3H, s), 2.04-1.99
(2H, br.-d).

Example 3 8-chloro-1,3-diethyl
-2,3-dihydro-5- [4- (2,3-dihydro-
5-methyl-2-oxo-1H-benzimidazole-
1-yl) -1-piperidinyl] -1H-imidazo
[4,5-g] phthalazin-2-one (compound 49) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 6
Compound 49 obtained by reacting with compound f obtained in 1. according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ8.72 (1H, s), 7.68 (1H, s), 7.54
(1H, s), 7.15 (1H, d, J = 8.3), 6.95 (1H, s), 6.93 (1
H, d, J = 8.3), 4.64-4.49 (1H, m), 4.17-3.97 (6H, m),
3.40-3.25 (2H, br.-t), 2.96-2.77 (2H, m), 2.39 (3
H, s), 2.08-1.97 (2H, br.-d), 1.51-1.40 (6H, m).

Example 4 4- [4- (2,3-dihydro
-5-methyl-2-oxo-1H-benzimidazole
-1-yl) -1-piperidinyl] -6,7-dimethoxy
Ethyl shiquinoline-3-carboxylate (compound 53) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4-chloro-6,7-dimethoxyquinoline-3 -Compound 53 was obtained by reacting with ethyl carboxylate according to the method described in Example 1. ¹ H NMR (CDCl ₃ ): δ 9.56 (1H, s), 8.82 (1H, s), 7.56
(1H, s), 7.43 (1H, s), 7.16 (1H, d, J = 8.1), 6.95 (1
H, s), 6.91 (1H, d, J = 8.1), 4.63-4.43 (3H, m), 4.10
(3H, s), 4.06 (3H, s), 3.52-3.38 (4H, m), 2.90-2.
71 (2H, m), 2.40 (3H, s), 2.07-1.97 (2H, br.-d),
1.48 (3H, t, J = 7.1).

Example 5 4- [4- (2,3-dihydro
-5-methyl-2-oxo-1H-benzimidazole
-1-yl) -1-piperidinyl] -6,7-dimethyl
Ethyl quinoline-3-carboxylate (Compound 59) 2,3-Dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and the method described in French Patent 2,002,888. Compound 59 was obtained by reacting the obtained ethyl 4-chloro-6,7-dimethylquinoline-3-carboxylate according to the method described in Example 1. ¹ H NMR (CDCl ₃ ): δ 9.39 (1H, s), 8.85 (1H, s), 7.92
(1H, s), 7.85 (1H, s), 7.21 (1H, d, J = 8.4), 6.99 (1
H, s), 6.95 (1H, d, J = 8.4), 4.67-4.55 (1H, m), 4.48
(2H, q, J = 7.3), 3.59-3.37 (4H, m), 2.80-2.73 (2H,
m), 2.52 (3H, s), 2.49 (3H, s), 2.40 (3H, s), 2.05
-1.95 (2H, br.-d), 1.47 (3H, t, J = 7.3).

Example 6 4- [4- (2,3-dihydro
-5-methyl-2-oxo-1H-benzimidazole
-1-yl) -1-piperidinyl] -6-methoxyquino
Ethyl phosphorus-3-carboxylate (Compound 62) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and the method described in U.S. Pat. No. 4,343,804. The resulting ethyl 4-chloro-6-methoxyquinoline-3-carboxylate is
Compound 62 was obtained by reacting according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ10.02 (1H, s), 8.83 (1H, s), 8.02
(1H, d, J = 9.2), 7.57 (1H, d, J = 2.3), 7.43 (1H, dd,
J = 9.2, 2.3), 7.19 (1H, d, J = 7.9), 7.00 (1H, s),
6.91 (1H, d, J = 7.9), 4.73-4.53 (1H, m), 4.50 (2H,
q, J = 7.1), 4.02 (3H, s), 3.60-3.38 (4H, m), 2.93-2.
76 (2H, m), 2.40 (3H, s), 2.07-1.99 (2H, br.-d),
1.49 (3H, t, J = 7.1).

Example 7 4- [4- (2,3-dihydro
-5-methyl-2-oxo-1H-benzimidazole
-1-yl) -1-piperidinyl] -7-methoxyquino
Ethyl phosphorus-3-carboxylate (Compound 63) 2,3-Dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and the method described in U.S. Pat. No. 4,343,804. The resulting ethyl 4-chloro-7-methoxyquinoline-3-carboxylate is
Compound 63 was obtained by reacting according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.70-9.59 (1H, br.-s), 8.89 (1H,
s), 8.14 (1H, d, J = 9.2), 7.42 (1H, d, J = 2.3), 7.26
(1H, dd, J = 9.2, 2.3), 7.19 (1H, d, J = 8.1), 6.99 (1
H, s), 6.94 (1H, d, J = 8.1), 4.67-4.49 (1H, m), 4.
48 (2H, q, J = 7.3), 3.98 (3H, s), 3.53-3.40 (4H,
m), 2.89-2.68 (2H, m), 2.40 (3H, s), 2.03-1.95 (2
H, br.-d), 1.48 (3H, t, J = 7.3).

Embodiment 81,3-diethyl-2,3-di
Hydro-8- [4- (2,3-dihydro-5-methyl-
2-oxo-1H-benzimidazol-1-yl)-
1-piperidinyl] -2-oxo-1H-imidazo
[4,5-g] ethyl quinoline-7-carboxylate (compound
Thing 65) 2,3-dihydro-5-methyl-1- (4-piperidini
) -1H-benzimidazol-2-one and 8-chloro
B-1,3-Diethyl-2,3-dihydro-2-oxo
-1H-imidazo [4,5-g] quinoline-7-carbo
Reaction with ethyl acid according to the method described in Example 1
By doing so, compound 65 was obtained. ¹ H NMR (CDCl_Three): δ8.87 (1H, s), 8.64 (1H, s), 7.77
(1H, s), 7.61 (1H, s), 7.18 (1H, d, J = 7.7), 6.96 (1
H, s), 6.91 (1H, d, J = 7.7), 4.70-4.53 (1H, m), 4.49
 (2H, q, J = 7.1), 4.14-4.02 (4H, m), 3.54-3.43 (4H,
 m), 2.93-2.72 (2H, m), 2.41 (3H, s), 2.09-1.97 (2
H, br.-d), 1.58-1.39 (6H, m), 1.25 (3H, t, J = 7.1).

Embodiment 91- [1- (2-chloro-6,
7-dimethoxy-4-quinazolyl) -4-piperidini
] -2,3-dihydro-5-methyl-1H-benzoi
Midazol-2-one (Compound 27) 2,3-dihydro-5-methyl-1- (4-piperidini
L) -1H-benzimidazol-2-one and 2,4-
Dichloro-6,7-dimethoxyquinazoline and
By reacting according to the method described in 1, the compound
The product 27 was obtained. ¹ H NMR (DMSO-d₆): δ10.78 (1H, s), 7.21 (1H, s), 7.
19 (1H, d, J = 6.4), 7.15 (1H, s), 6.81 (1H, s), 6.7
9 (1H, d, J = 6.4), 4.58-4.33 (3H, m), 3.94 (3H, s),
 3.92 (3H, s), 3.41-3.21 (2H, br.-t), 2.62-2.41 (2
H, m), 2.30 (3H, s), 1.90-1.78 (2H, br.-d).

Example 10 1- [1- (6,7-dieto)
Xy-4-quinazolinyl) -4-piperidinyl] -2,
3-dihydro-5-methyl-1H-benzimidazole
-2-one (compound 33) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and WO94
/ 19,342.
Compound 33 was obtained by reacting with 6,7-diethoxyquinazoline according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.40 (1H, s), 8.72 (1H, s), 7.27
(1H, s), 7.18 (1H, s), 7.07 (1H, d, J = 7.9), 6.96 (1
H, s), 6.89 (1H, d, J = 7.9), 4.71-4.55 (1H, m), 4.41
-4.14 (6H, m), 3.32-3.18 (2H, br.-t), 2.79-2.60 (2
H, m), 2.38 (3H, s), 2.06-1.95 (2H, br.-d), 1.60-
1.49 (6H, m).

Example 11 2,3-Dihydro-5-methyi
Ru-1- [1- (6,7,8-trimethoxy-4-quina
Zolinyl) -4-piperidinyl] -1H-benzimidazole
Zol-2-one (compound 34) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one
Compound 34 was obtained by reacting 4-chloro-6,7,8-trimethoxyquinazoline obtained by the method described in -169,520 according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.12 (1H, s), 8.81 (1H, s), 7.04
(1H, d, J = 8.1), 7.00 (1H, s), 6.95 (1H, s), 6.88
(1H, d, J = 8.1), 4.72-4.59 (1H, m), 4.53-4.38 (2H, b
r.-d), 4.16 (3H, s), 4.08 (3H, s), 3.98 (3H, s),
3.37-3.23 (2H, br.-t), 2.80-2.62 (2H, m), 2.38 (3
H, s), 2.13-1.98 (2H, br.-d).

Example 12 2,3-Dihydro-1- [1
-(7,8-Dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-methyl-1H-benzimidazole
-2-one (compound 35) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4 obtained by the method described in Canadian Patent 2,086,968. Compound 35 was reacted with -chloro-7,8-dimethoxyquinazoline according to the method described in Example 1.
I got _{^{1 H NMR (CDCl 3):}} δ9.32 (1H, s), 8.81 (1H, s), 7.32
(1H, d, J = 9.4), 7.24 (1H, d, J = 9.4), 7.06 (1H, d,
J = 7.9), 6.96 (1H, s), 6.88 (1H, d, J = 7.9), 4.71-4.
58 (1H, m), 4.57-4.44 (2H, br.-d), 4.11 (3H, s),
4.04 (3H, s), 3.55-3.21 (2H, br.-t), 2.76-2.58 (2
H, m), 2.38 (3H, s), 2.06-1.97 (2H, br.-d).

Example 13 2,3-dihydro-1- [1
-(7-Methoxy-4-quinazolinyl) -4-piperidi
Nyl] -5-methyl-1H-benzimidazole-2-
On (compound 69) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and J.I. Ch
em. Soc. And 4-chloro-7-methoxyquinazoline obtained by the method described on page 890 (1947).
Compound 69 was obtained by reacting according to the method described in Example 1. ¹ H NMR (CDCl ₃ ): δ 9.22 (1H, s), 8.73 (1H, s), 7.85
(1H, d, J = 9.2), 7.26 (1H, d, J = 2.6), 7.12 (1H, dd,
J = 9.2, 2.6), 7.06 (1H, d, J = 8.1), 6.95 (1H, s), 6.
88 (1H, d, J = 8.1), 4.73-4.58 (1H, m), 4.57-4.42 (2
H, br.-d), 3.96 (3H, s), 3.36-3.21 (2H, br.-t), 2.7
8-2.57 (2H, m), 2.38 (3H, s), 2.09-1.96 (2H, br.-
d).

Example 14 2,3-Dihydro-1- [1
-(6-Methoxy-4-quinazolinyl) -4-piperidi
Nyl] -5-methyl-1H-benzimidazole-2-
On (compound 36) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and J.I. Ch
em. Soc. And 4-chloro-6-methoxyquinazoline obtained by the method described on page 890 (1947).
Compound 36 was obtained by reacting according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ8.78 (1H, s), 8.75 (1H, s), 7.94
(1H, d, J = 9.2), 7.46 (1H, dd, J = 9.2, 2.6), 7.23 (1
H, d, J = 2.6), 7.05 (1H, d, J = 8.1), 6.94 (1H, s), 6.
89 (1H, d, J = 8.1), 4.72-4.56 (1H, m), 4.53-4.42 (2
H, br.-d), 3.94 (3H, s), 3.37-3.21 (2H, br.-t), 2.7
7-2.59 (2H, m), 2.38 (3H, s), 2.08-1.95 (2H, br.-
d).

Example 15 2,3-Dihydro-5-methyl
Ru-1- [1- (6-methyl-4-quinazolinyl) -4
-Piperidinyl] -1H-benzimidazol-2-o
(Compound 37) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4-chloro- obtained by the method described in Canadian Patent 2,086,968. Compound 37 was obtained by reacting with 6-methylquinazoline according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.49 (1H, s), 8.77 (1H, d, J = 1.
7), 7.85 (1H, d, J = 8.6), 7.72 (1H, s), 7.61 (1H, d
d, J = 8.6, 1.7), 7.07 (1H, d, J = 7.9), 6.97 (1H, s),
6.89 (1H, d, J = 7.9), 4.72-4.59 (1H, m), 4.57-4.43
(2H, br.-d), 3.35-3.20 (2H, br.-t), 2.78-2.58 (2
H, m), 2.55 (3H, s), 2.38 (3H, s), 2.06-1.96 (2H,
br.-d).

Example 16 2,3-dihydro-5-methyl
Ru-1- [1- (4-quinazolinyl) -4-piperidini
1] -H-benzimidazol-2-one (compound 3
8) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Egyp
t. J. Pharm. Sci. 30, p. 429 (1989), and reacted with 4-chloroquinazoline according to the method described in Example 1 to obtain compound 38. _{^{1 H NMR (CDCl 3):}} δ9.32 (1H, s), 8.81 (1H, s), 7.99-
7.90 (2H, m), 7.74 (1H, d, J = 7.4), 7.51 (1H, t, J =
7.4), 7.05 (1H, d, J = 8.2), 6.93 (1H, s), 6.88 (1H,
d, J = 8.2), 4.71-4.46 (3H, m), 3.57-3.22 (2H, br.-
t), 2.77-2.59 (2H, m), 2.38 (3H, s), 2.08-1.97 (2
H, br.-d).

Example 17 2,3-Dihydro-8- [4
-(2,3-dihydro-5-methyl-2-oxo-1H
-Benzimidazol-1-yl) -1-piperidinini
] -1,3-dimethyl-1H-imidazo [4,5-
g] Quinazolin-2-one (compound 39) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 3
Was reacted according to the method described in Example 1 to give Compound 39. ¹ H NMR (CDCl ₃ ): δ 10.48 (1H, s), 8.72 (1H, s), 7.55
(1H, s), 7.40 (1H, s), 7.04 (1H, d, J = 8.1), 6.89
(1H, s), 6.84 (1H, d, J = 8.1), 4.63-4.49 (1H, m), 4.
42-4.32 (2H, br.-d), 3.52 (6H, s), 3.36-3.20 (2H,
br.-t), 2.80-2.61 (2H, m), 2.35 (3H, s), 2.03-1.93
(2H, br.-d).

Example 18 6-Chloro-2,3-dihydride
B-8- [4- (2,3-Dihydro-5-methyl-2-
Oxo-1H-benzimidazol-1-yl) -1-
Piperidinyl] -1,3-dimethyl-1H-imidazo
[4,5-g] quinazolin-2-one (compound 40) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 2
Compound 40 obtained by reacting with compound b obtained in 1. according to the method described in Example 1. ¹ H NMR (DMSO-d ₆ ): δ 10.78 (1H, s), 7.49 (1H, s), 7.
42 (1H, s), 7.15 (1H, s), 6.83-6.76 (2H, m), 4.60-
4.40 (3H, m), 3.49-3.27 (8H, m), 2.68-2.49 (2H,
m), 2.30 (3H, s), 1.95-1.81 (2H, br.-d).

Example 19 6-Chloro-1,3-diethyl
Le-2,3-dihydro-8- [4- (2,3-dihydro
-5-methyl-2-oxo-1H-benzimidazole
-1-yl) -1-piperidinyl] -1H-imidazo
[4,5-g] quinazolin-2-one (compound 42) 2,3-dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 1
Compound 42 was obtained by reacting with compound a obtained in 1. according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ8.00 (1H, s), 7.39 (1H, s), 7.30
(1H, s), 7.22 (1H, s), 7.04 (1H, d, J = 8.6), 6.90
(1H, d, J = 8.6), 4.67-4.38 (3H, m), 4.08-3.92 (4H,
m), 3.40-3.23 (2H, br.-t), 2.80-2.59 (2H, m), 2.38
(3H, s), 2.07-1.97 (2H, br.-d), 1.43-1.30 (6H,
m).

Example 20 2,3-dihydro-8- [4
-(2,3-dihydro-5-methyl-2-oxo-1H
-Benzimidazol-1-yl) -1-piperidini
] -1,3-dipropyl-1H-imidazo [4,5-
g] Quinazolin-2-one (Compound 44) 2,3-Dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 4
Was reacted according to the method described in Example 1 to obtain Compound 44. _{^{1 H NMR (CDCl 3):}} δ9.13 (1H, s), 8.76 (1H, s), 7.46
(1H, s), 7.35 (1H, s), 7.07 (1H, d, J = 8.1), 6.96
(1H, s), 6.89 (1H, d, J = 8.1), 4.72-4.58 (1H, m), 4.
43-4.32 (2H, br.-d), 4.00-3.89 (4H, m), 3.39-3.23
(2H, br.-t), 2.81-2.61 (2H, m), 2.38 (3H, s), 2.08
-1.97 (2H, br.-d), 1.98-1.78 (4H, m), 1.05-0.94 (6
H, m).

Example 21 1,3-Dibutyl-2,3-
Dihydro-8- [4- (2,3-dihydro-5-methyl
-2-oxo-1H-benzimidazol-1-yl)
-1-piperidinyl] -1H-imidazo [4,5-g]
Quinazolin-2-one (Compound 45) 2,3-Dihydro-5-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and Reference Example 5
Was reacted according to the method described in Example 1 to obtain a compound 45. _{^{1 H NMR (CDCl 3):}} δ8.76 (1H, s), 8.64 (1H, s), 7.46
(1H, s), 7.34 (1H, s), 7.06 (1H, d, J = 7.9), 6.94 (1
H, s), 6.88 (1H, d, J = 7.9), 4.75-4.56 (1H, m), 4.43
-4.32 (2H, br.-d), 4.03-3.91 (4H, br.-t), 3.38-3.2
2 (2H, br.-t), 2.80-2.61 (2H, m), 2.38 (3H, s), 2.0
9-1.97 (2H, br.-d), 1.89-1.72 (4H, m), 1.48-1.34 (4
H, m), 1.03-0.92 (6H, m).

Example 22 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -6-methyl-1H-benzimidazole
-2-one (compound 23) 2,3-dihydro-6-methyl-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4 obtained by the method described in West German Patent 3,124,366. Compound 23 was reacted with -chloro-6,7-dimethoxyquinazoline according to the method described in Example 1.
I got _{^{1 H NMR (CDCl 3):}} δ9.13 (1H, s), 8.72 (1H, s), 7.33
(1H, s), 7.18 (1H, s), 6.99 (1H, d, J = 7.9), 6.97 (1
H, s), 6.88 (1H, d, J = 7.9), 4.68-4.52 (1H, m), 4.47
-4.36 (2H, br.-d), 4.04 (3H, s), 4.00 (3H, s), 3.3
8-3.20 (2H, br.-t), 2.80-2.62 (2H, m), 2.39 (3H,
s), 2.06-1.95 (2H, br.-d).

Example 23 2,3-Dihydro-1- [1
-(6,7-Dimethoxy-4-quinazolinyl) -3-me
Tyl-4-piperidinyl] -5-methyl-1H-benzo
Imidazol-2-one (Compound 25: 3-position of piperidine
And a mixture of stereoisomers 1: 1 at the 4-position) Compound k obtained in Reference Example 11 and 4-chloro-6,7-
Compound 25 was obtained by reacting with dimethoxyquinazoline according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ11.02 (1H, s), 10.92 (1H, s), 8.7
6 (1H, s), 7.35-7.00 (4H, m), 6.88 (1H, d, J = 8.3),
4.71-2.02 (7H, m), 4.05 (3H, s), 4.03 (3H, s), 4.0
2 (3H, s), 2.37 (3H, s), 1.45-1.27 (1H, m), 1.39 (3
H, d, J = 6.4), 0.92 (3H, d, J = 6.4).

Example 24 2,3-dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -6-fluoro-1H-benzimidazo
Lu-2-one (Compound 14) Compound m obtained in Reference Example 12 and 4-chloro-6,7-
Compound 14 was obtained by reacting with dimethoxyquinazoline according to the method described in Example 1. _{^{1 H NMR (DMSO-d 6}} ): δ10.94 (1H, s), 8.58 (1H, s), 7.
27 (1H, dd, J = 9.9, 2.3), 7.24 (1H, s), 7.22 (1H,
s), 6.95 (1H, dd, J = 8.6, 5.0), 6.84-6.76 (1H, m),
4.53-4.39 (1H, m), 4.36-4.31 (2H, br.-d), 3.94 (3
H, s), 3.93 (3H, s), 3.26-3.18 (2H, br.-t), 2.64-
2.50 (2H, m), 1.86-1.82 (2H, br.-d).

Example 25 2,3-Dihydro-1- [1
-(6,7-Dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-fluoro-1H-benzimidazo
Ru-2-one (Compound 15) 2,3-Dihydro-5-fluoro-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4-chloro-6,7-dimethoxyquinazoline Compound 1 was obtained by reacting according to the method described in Example 1.
5 was obtained. ¹ H NMR (CDCl ₃ ): δ 9.68 (1H, s), 8.74 (1H, s), 7.30
(1H, s), 7.17 (1H, s), 7.06 (1H, dd, J = 8.6, 4.3),
6.88 (1H, dd, J = 8.3, 2.3), 6.83-6.77 (1H, m), 4.67
-4.58 (1H, m), 4.43-4.38 (2H, br.-d), 4.04 (3H,
s), 4.01 (3H, s), 3.34-3.24 (2H, br.-t), 2.74-2.65
(2H, m), 2.61-2.03 (2H, br.-d).

Example 26 5-Chloro-2,3-dihydride
B-1- [1- (6,7-dimethoxy-4-quinazolini
) -4-Piperidinyl] -1H-benzimidazole
2-one (Compound 16) 5-chloro-2,3-dihydro-1- (4-piperidinyl) -1H-benzimidazol-2-one and 4-chloro-6,7-dimethoxyquinazoline were prepared in the same manner as in Examples. Compound 16 is obtained by reacting according to the method described in 1.
Got _{^{1 H NMR (CDCl 3):}} δ9.56 (1H, s), 8.74 (1H, s), 7.30
(1H, s), 7.17 (1H, s), 7.13 (1H, s), 7.07 (1H, d, J
= 7.9), 7.05 (1H, d, J = 7.9), 4.66-4.57 (1H, m), 4.42
-4.37 (2H, br.-d), 4.04 (3H, s), 4.01 (3H, s), 3.3
3-3.24 (2H, br.-t), 2.73-2.61 (2H, m), 2.03-1.99
(2H, br.-d).

Example 27 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-trifluoromethyl-1H-benzo
Imidazol-2-one (Compound 17) 2,3-Dihydro-1- (4-piperidinyl) -5-trifluoromethyl-1H-benzimidazol-2-one and 4-chloro-6,7-dimethoxyquinazoline ,
The compound 17 was obtained by reacting according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.87 (1H, s), 8.75 (1H, s), 7.39
(1H, s), 7.37 (1H, d, J = 6.9), 7.30 (1H, s), 7.23 (1
(H, d, J = 6.9), 7.17 (1H, s), 4.72-4.63 (1H, m), 4.44
-4.39 (2H, br.-d), 4.05 (3H, s), 4.02 (3H, s), 3.3
5-3.26 (2H, br.-t), 2.77-2.65 (2H, m), 2.04-2.01
(2H, br.-d).

Example 28 2,3-Dihydro-1- [1
-(6,7-Dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -2-oxo-1H-benzimidazole
Methyl-5-carboxylate (Compound 20) Compound n obtained in Reference Example 13 and 4-chloro-6,7-
Compound 20 was obtained by reacting with dimethoxyquinazoline according to the method described in Example 1. ¹ H NMR (CDCl ₃ ): δ9.44-9.32 (1H, br.-s), 8.75 (1H,
s), 7.85 (1H, dd, J = 8.3, 1.7), 7.81 (1H, d, J = 1.
7), 7.30 (1H, s), 7.20 (1H, d, J = 8.3), 7.18 (1H,
s), 4.71-4.62 (1H, m), 4.43-4.38 (2H, br.-d), 4.05
(3H, s), 4.02 (3H, s), 3.92 (3H, s), 3.34-3.25 (2
H, br.-t), 2.80-2.65 (2H, m), 2.05-2.02 (2H, br.-
d).

Example 29 3- [1- (6,7-dimethoate)
[Xy-4-quinazolinyl) -4-piperidinyl] -6-
Methylbenzoxazol-2 (3H) -one (compound
21) Compound j obtained in Reference Example 10 and US Pat.
Compound 21 was obtained by reacting 4-chloro-6,7-dimethoxyquinazoline obtained by the method described in 990 according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ8.73 (1H, s), 7.28 (1H, s), 7.14
(1H, s), 7.07 (1H, s), 7.00 (1H, d, J = 7.9), 6.91 (1
H, d, J = 7.9), 4.53-4.31 (3H, m), 4.04 (3H, s), 4.01
(3H, s), 3.30-3.20 (2H, br.-t), 2.69-2.52 (2H,
m), 2.39 (3H, s), 2.06-1.99 (2H, br.-d).

Example 30 7-Ethoxy-4- [4-
(2,3-dihydro-5-methyl-2-oxo-1H-
Benzimidazol-1-yl) -1-piperidinyl]
Ethyl-6-methoxyquinoline-3-carboxylate (Compound
54) (1) 7-Ethoxy-1,4-dihydro-6-methoxy-4-obtained by the method described in European Patent 343,574
151 mg of ethyl oxoquinoline-3-carboxylate (0.518 m
mol) was dissolved in 1 mL of phosphorus oxychloride and stirred at 100 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, and washed with a saturated aqueous solution of sodium hydrogen carbonate. The solvent was distilled off under reduced pressure and then dried to give 4-chloro-
160 mg (100%) of ethyl 7-ethoxy-6-methoxyquinoline-3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
Compound 54 was obtained by reacting 2-one with the compound obtained in (1) according to the method described in Example 1.
Got ¹ H NMR (CDCl ₃ ): δ 8.81 (1H, s), 8.60 (1H, s), 7.54
(1H, s), 7.41 (1H, s), 7.15 (1H, d, J = 8.1), 6.94 (1
H, s), 6.90 (1H, d, J = 8.1), 4.66-4.43 (3H, m), 4.30
(2H, q, J = 7.1), 4.09 (3H, s), 3.57-3.40 (4H, m),
2.87-2.74 (2H, m), 2.40 (3H, s), 2.05-1.96 (2H, br.-
d), 1.58 (3H, t, J = 7.1), 1.47 (3H, t, J = 7.1).

Example 31 4- [4- (2,3-dihydride)
B-5-Methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -7-isopropo
Ethyl xy-6-methoxyquinoline-3-carboxylate
(Compound 55) (1) Using compound o obtained in Reference Example 14, Example 3
The reaction was carried out according to the method described in 0 (1) to obtain ethyl 4-chloro-7-isopropoxy-6-methoxyquinoline-3-carboxylate.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
Compound 55 was obtained by reacting 2-one with the compound obtained in (1) according to the method described in Example 1.
Got ¹ H NMR (CDCl ₃ ): δ8.96 (1H, s), 8.09 (1H, s), 7.54
(1H, s), 7.42 (1H, s), 7.16 (1H, d, J = 8.1), 6.95 (1
H, s), 6.89 (1H, d, J = 8.1), 4.87-4.74 (1H, m), 4.66
-4.43 (3H, m), 4.07 (3H, s), 3.52-3.41 (4H, m), 2.
90-2.74 (2H, m), 2.39 (3H, s), 2.07-1.96 (2H, br.-
d), 1.53-1.42 (9H, m).

Example 32 4- [4- (2,3-dihydrido)
B-5-Methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -6-methoxy-
Ethyl 7-methoxymethylquinoline-3-carboxylate
(Compound 56) (1) Using compound p obtained in Reference Example 15, Example 3
By reacting according to the method described in 0 (1), ethyl 4-chloro-6-methoxy-7-methoxymethylquinoline-3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
By reacting 2-one with the compound obtained in (1) according to the method described in Example 1, compound 56 was obtained.
I got _{^{1 H NMR (CDCl 3):}} δ8.84 (1H, s), 8.47 (1H, s), 8.08
(1H, s), 7.53 (1H, s), 7.15 (1H, d, J = 8.1), 6.94 (1
H, s), 6.90 (1H, d, J = 8.1), 4.72-4.42 (5H, m), 4.04
(3H, s), 3.57-3.36 (7H, m), 2.91-2.72 (2H, m), 2.
40 (3H, s), 2.08-1.95 (2H, br.-d), 1.48 (3H, t, J =
7.3).

Example 33 6,7-Diethoxy-4-
[4- (2,3-dihydro-5-methyl-2-oxo-
1H-benzimidazol-1-yl) -1-piperidi
Ethyl] quinoline-3-carboxylate (compound 57) (1) 6,7-diethoxy-1,4-dihydro-4- obtained by the method described in French Patent 2,002,888
Using ethyl oxoquinoline-3-carboxylate according to the method described in Example 30 (1), ethyl 4-chloro-6,7-diethoxyquinoline-3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
By reacting 2-one with the compound obtained in (1) according to the method described in Example 1, compound 57 was obtained.
Got _{^{1 H NMR (CDCl 3):}} δ8.80 (1H, s), 8.71 (1H, s), 7.53
(1H, s), 7.40 (1H, s), 7.16 (1H, d, J = 8.3), 6.95 (1
H, s), 6.89 (1H, d, J = 8.3), 4.64-4.49 (1H, m), 4.47
(2H, q, J = 7.1), 4.39-4.22 (4H, m), 3.51-3.36 (4H,
m), 2.89-2.68 (2H, m), 2.40 (3H, s), 2.06-1.95 (2
H, br.-d), 1.69-1.52 (6H, m), 1.47 (3H, t, J = 7.1).

Example 34 4- [4- (2,3-dihydrido)
B-5-Methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -6,7-diiso
Ethyl propoxyquinoline-3-carboxylate (compound 5
8) (1) Acta Chim. 1,4-dihydro-6,7-diisopropoxy-4- obtained by the method described in (Budapest), vol. 73, p. 469 (1972).
By using ethyl oxoquinoline-3-carboxylate and reacting according to the method described in Example 30 (1), 4-chloro-6,7-diisopropoxyquinoline-
Ethyl 3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
By reacting 2-one with the compound obtained in (1) according to the method described in Example 1, compound 58 was obtained.
I got _{^{1 H NMR (CDCl 3):}} δ8.78 (1H, s), 8.77-8.69 (1H, br.-
s), 7.58 (1H, s), 7.42 (1H, s), 7.17 (1H, d, J = 8.
3), 6.95 (1H, s), 6.88 (1H, d, J = 8.3), 4.84-4.52
(3H, m), 4.46 (2H, q, J = 7.3), 3.52-3.39 (4H, m),
2.82-2.63 (2H, m), 2.40 (3H, s), 2.03-1.95 (2H, br.
-d), 1.54-1.35 (15H, m).

Example 35 4- [4- (2,3-dihydride)
B-5-Methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -6,7,8-to
Ethyl rimethoxyquinoline-3-carboxylate (compound 6
0) (1) Example 3 using compound q obtained in Reference Example 16
0 (1) to give 4-chloro-6,7,8-trimethoxyquinoline-
Ethyl 3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
By reacting 2-one with the compound obtained in (1) according to the method described in Example 1, compound 60 was obtained.
I got _{^{1 H NMR (CDCl 3):}} δ9.33 (1H, s), 8.89 (1H, s), 7.38
(1H, s), 7.15 (1H, d, J = 8.3), 6.97 (1H, s), 6.91 (1
(H, d, J = 8.3), 4.67-4.41 (3H, m), 4.15 (3H, m), 4.09
(3H, s), 4.08 (3H, s), 3.57-3.38 (4H, m), 2.92-2.
72 (2H, m), 2.40 (3H, s), 2.07-1.96 (2H, br.-d),
1.47 (3H, t, J = 7.1).

Example 36 4- [4- (2,3-dihydride
B-5-Methyl-2-oxo-1H-benzimidazo
L-1-yl) -1-piperidinyl] -6,8-dimeth
Ethyl xyquinoline-3-carboxylate (Compound 61) (1) Using ethyl 1,4-dihydro-6,8-dimethoxy-4-oxoquinoline-3-carboxylate obtained by the method described in British Patent 942,524 Example 30
By reacting according to the method described in (1),
Ethyl 4-chloro-6,8-dimethoxyquinoline-3-carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
By reacting 2-one with the compound obtained in (1) according to the method described in Example 1, compound 61 was obtained.
Got _{^{1 H NMR (CDCl 3):}} δ9.17-9.01 (1H, s), 8.80 (1H, s),
7.17 (1H, d, J = 8.1), 7.17 (1H, d, J = 2.5), 6.96 (1
H, s), 6.90 (1H, d, J = 8.1), 6.78 (1H, d, J = 2.5),
4.63-4.50 (1H, m), 4.48 (2H, q, J = 7.1), 4.07 (3H,
s), 4.00 (3H, s), 3.61-3.47 (4H, m), 2.93-2.70 (2H,
m), 2.40 (3H, s), 2.04-1.78 (2H, br.-d), 1.47 (3
(H, t, J = 7.1).

Example 37 4- [4- (2,3-dihydrido)
Ro-5-methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -8-methyl-6
-Ethyl nitroquinoline-3-carboxylate (Compound 6
4) (1) Example 3 using compound r obtained in Reference Example 17
0 (1) to give 4-chloro-8-methyl-6-nitroquinoline-3
-Ethyl carboxylate was obtained.

(2) 2,3-dihydro-5-methyl-1
-(4-piperidinyl) -1H-benzimidazole-
Compound 64 was obtained by reacting 2-one with the compound obtained in (1) according to the method described in Example 1.
Got ¹ H NMR (CDCl ₃ ): δ 10.30-10.09 (1H, br.-s), 9.14 (1
H, s), 9.08 (1H, s), 8.37 (1H, s), 7.29 (1H, d, J =
8.1), 7.05 (1H, s), 6.98 (1H, d, J = 8.1), 4.81-4.62
(1H, m), 4.52 (2H, q, J = 7.1), 3.60-3.44 (4H, m),
2.94-2.82 (5H, m), 2.41 (3H, s), 2.10-2.01 (2H, b
r.-d), 1.49 (3H, t, J = 7.1).

Example 38 4- [4- (2,3-dihydrido)
B-6-Methyl-2-oxobenzoxazole-3-
Yl) -1-piperidinyl] -8-methyl-6-nitro
Ethyl quinoline-3-carboxylate (compound 22) Compound j obtained in Reference Example 10 and 4-chloro-8-methyl-6-nitroquinoline obtained in Example 37 (1)
Compound 22 was obtained by reacting with ethyl 3-carboxylate according to the method described in Example 1. _{^{1 H NMR (CDCl 3):}} δ9.09 (1H, s), 9.07 (1H, s), 8.37
(1H, s), 7.27 (1H, s), 7.25 (1H, d, J = 8.4), 7.09 (1
H, s), 7.07 (1H, d, J = 8.4), 4.59-4.42 (3H, m), 3.56
-3.46 (4H, m), 2.87 (3H, s), 2.85-2.68 (2H, m), 2.
41 (3H, s), 2.15-2.05 (2H, br.-d), 1.48 (3H, t, J =
7.1).

Example 39 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] methyl-5-methyl-1H-benzimidazole
Sol-2-one (Compound 24) (1) 4.31 g (10.0 mmo) of compound i obtained in Reference Example 9
To a solution of l) in 100 mL of ethanol were added 10 mL of water, 4 g of reduced iron, and 0.4 g of ferric chloride, and the mixture was stirred at room temperature for 12 hours. After the reaction solution was filtered using a filter aid, the filtrate was concentrated under reduced pressure to obtain 4- [4- (2-amino-4-methylanilino) methyl-1-piperidinyl] -6,7-dimethoxyquinazoline.

(2) 407 mg of the compound obtained in (1)
(1.00 mmol) in 5 mL of acetonitrile, N, N'-
195 mg (1.20 mmol) of carbonyldiimidazole was added, and the mixture was stirred at 50 ° C for 1 hour. After the reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 5).
0: 1) to give 154 mg (36%) of compound 24 as white crystals. ¹ H NMR (CDCl ₃ ): δ 9.49 (1H, s), 8.67 (1H, s), 7.26
(1H, d, J = 7.9), 7.25 (1H, s), 7.08 (1H, s), 6.93
(1H, d, J = 7.9), 6.91 (1H, s), 4.28-4.11 (2H, br.-
d), 4.02 (3H, s), 3.97 (3H, s), 3.85 (2H, d, J = 7.
3), 3.09-2.98 (2H, br.-t), 2.38 (3H, s), 2.33-2.17
(1H, m), 1.93-1.56 (4H, m).

Example 40 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-methyl-1H-benzimidazole
2-one (Compound 26) (1) Using the compound g obtained in Reference Example 7, Example 39
By reacting according to the method described in (1),
4- [4- (2-amino-4-methylanilino) -1-
Piperidinyl] -6,7-dimethoxyquinazoline was obtained.

(2) Compound 26 was obtained by reacting the compound obtained in (1) according to the method described in Example 39 (2). _{^{1 H NMR (CDCl 3):}} δ8.71 (1H, s), 8.48 (1H, s), 7.43
(1H, s), 7.16 (1H, s), 7.03 (1H, d, J = 8.1), 6.92 (1
H, s), 6.89 (1H, d, J = 8.1), 4.71-4.55 (1H, m), 4.54
-4.45 (2H, br.-d), 4.06 (3H, s), 4.00 (3H, s), 3.3
8-3.26 (2H, br.-t), 2.77-2.58 (2H, m), 2.38 (3H,
s), 2.08-1.99 (2H, br.-d).

Example 41 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-methyl-1H-benzimidazole
-2-thione (compound 8) 4- [4- (2-amino-) obtained in Example 40 (1)
4-methylanilino) -1-piperidinyl] -6,7-
Dimethoxyquinazoline 401 mg (1.00 mmol) in ethanol
0.5 ml carbon disulfide and triethylamine in 3 ml solution
0.5 ml was added, and the mixture was stirred at 80 ° C for 1 hour. After evaporating the reaction solution under reduced pressure, the residue was recrystallized from ethanol-water to obtain 308 mg (70%) of Compound 8 as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.77 (1H, s), 7.34 (1H, s), 7.30-
7.24 (2H, m), 7.17 (1H, s), 7.08 (1H, s), 6.99 (1
H, d, J = 8.4), 4.64-4.50 (1H, m), 4.48-4.39 (2H, b
r.-d), 4.05 (3H, s), 4.01 (3H, s), 3.46-3.36 (2H,
br.-t), 2.78-2.57 (2H, m), 2.41 (3H, s), 2.09-2.00
(2H, br.-d).

Example 42 6,7-Dimethoxy-4-
[4- (6-methyl-1H-benzotriazole-1-
Yl) -1-piperidinyl] quinazoline (compound 1) (1) Example 39 was carried out using compound h obtained in Reference Example 8.
By reacting according to the method described in (1),
4- [4- (2-amino-5-methylanilino) -1-
Piperidinyl] -6,7-dimethoxyquinazoline was obtained. (2) To 200 mg (0.499 mmol) of the compound obtained in (1),
A solution of 1 ml of concentrated hydrochloric acid and 34.5 mg of sodium nitrite in 1 ml of water was added, and the mixture was stirred at room temperature for 30 minutes. Ice water and 4
An aqueous solution of N sodium hydroxide was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give Compound 1.
Was obtained as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.73 (1H, s), 7.97 (1H, d, J = 8.
6), 7.36 (1H, s), 7.32 (1H, s), 7.23 (1H, d, J = 8.
4), 7.18 (1H, s), 4.99-4.83 (1H, m), 4.44-4.32 (2H,
br.-d), 4.05 (3H, s), 4.02 (3H, s), 3.46-3.34 (2
H, br.-t), 2.83-2.64 (2H, m), 2.56 (3H, s), 2.45-
2.33 (2H, br.-d).

Example 43 6,7-Dimethoxy-4-
[4- (5-methyl-1H-benzotriazole-1-
Yl) -1-piperidinyl] described quinazoline (Compound 2) Example 40 (1) 4- [4- (2-Amino -
4-Methylanilino) -1-piperidinyl] -6,7-
Compound 2 was obtained by reacting with dimethoxyquinazoline according to the method described in Example 42 (2). _{^{1 H NMR (CDCl 3):}} δ8.74 (1H, s), 7.85 (1H, s), 7.48
(1H, d, J = 8.6), 7.33 (1H, d, J = 8.6), 7.31 (1H, s),
7.17 (1H, s), 5.00-4.84 (1H, m), 4.43-4.30 (2H, b
r.-d), 4.04 (3H, s), 4.01 (3H, s), 3.47-3.29 (2H,
br.-t), 2.79-2.57 (2H, m), 2.53 (3H, s), 2.43-2.32
(2H, br.-d).

Example 44 6,7-Dimethoxy-4-
[4- (6-methyl-1H-benzimidazole-1-
Yl) -1-piperidinyl] quinazoline (compound 3) 4- [4- (2-amino-) described in Example 42 (1).
5-methylanilino) -1-piperidinyl] -6,7-
To 200 mg (0.499 mmol) of dimethoxyquinazoline, 1 ml of triethyl orthoformate was added, and the mixture was stirred at 120 ° C for 1 hour. The reaction solution was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 168 mg (82%) of compound 3 as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.73 (1H, s), 8.02 (1H, s), 7.71
(1H, d, J = 8.3), 7.33 (1H, s), 7.21 (1H, s), 7.16-
7.11 (2H, m), 4.58-4.38 (3H, m), 4.05 (3H, s), 4.0
1 (3H, s), 3.41-3.28 (2H, m), 2.52 (3H, s), 2.42-
2.31 (4H, m).

Example 45 6,7-Dimethoxy-4-
[4- (5-methyl-1H-benzimidazole-1-
Yl) -1-piperidinyl] quinazoline (compound 4) 4- [4- (2-amino-) described in Example 40 (1).
4-Methylanilino) -1-piperidinyl] -6,7-
Compound 4 was obtained by reacting with dimethoxyquinazoline according to the method described in Example 44. ¹ H NMR (CDCl ₃ ): δ8.74 (1H, s), 8.01 (1H, s), 7.62
(1H, s), 7.36 (1H, d, J = 8.4), 7.29 (1H, s), 7.15 (1
(H, d, J = 8.4), 7.13 (1H, s), 4.58-4.31 (3H, m), 4.04
(3H, s), 4.01 (3H, s), 3.39-3.24 (2H, m), 2.50 (3
H, s), 2.41-2.31 (4H, m).

Example 46 2-amino-1- [1-
(6,7-dimethoxy-4-quinazolinyl) -4-pipe
Lydinyl] -5-methyl-1H-benzimidazole
(Compound 5) 4- [4- (2-amino-) described in Example 40 (1)
4-methylanilino) -1-piperidinyl] -6,7-
Dimethoxyquinazoline 802 mg (2.00 mmol) in ethanol
To the 5 ml solution was added 233 mg (2.20 mmol) of cyanogen bromide, and the mixture was stirred at room temperature for 3 hours. After evaporating the reaction solution under reduced pressure, a saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 304 mg of compound 5 (36%).
Was obtained as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.34 (1H, s), 7.28 (1H, s), 7.24
(1H, s), 7.21 (1H, d, J = 8.2), 7.14 (1H, s), 6.90 (1
(H, d, J = 8.2), 4.51-4.32 (3H, m), 4.04 (3H, s), 4.00
(3H, s), 3.37-3.22 (2H, br.-t), 2.79-2.60 (2H,
m), 2.41 (3H, s), 2.12-2.00 (2H, br.-d).

Example 47 6,7-Dimethoxy-4-
[4- (5-methyl-2-propyl-1H-benzoimid
Dazol-1-yl) -1-piperidinyl] quinazoline
(Compound 6) 4- [4- (2-amino-) described in Example 40 (1)
4-methylanilino) -1-piperidinyl] -6,7-
Compound 6 was obtained by reacting dimethoxyquinazoline with trimethyl orthobutyrate according to the method described in Example 44. _{^{1 H NMR (CDCl 3):}} δ8.77 (1H, s), 7.53 (1H, s), 7.40
(1H, d, J = 8.3), 7.30 (1H, s), 7.17 (1H, s), 7.02
(1H, d, J = 8.3), 4.57-4.35 (3H, m), 4.05 (3H, s), 4.
00 (3H, s), 3.34-3.20 (2H, br.-t), 2.97-2.72 (4H,
m), 2.45 (3H, s), 2.07-1.94 (2H, br.-d), 1.89 (2H,
q, J = 7.6), 1.09 (3H, t, J = 7.6).

Example 48 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-methyl-2,1,3-benzothiadi
Azole-2,2-dioxide (compound 7) 4- [4- (2-amino-) described in Example 40 (1).
4-Methylanilino) -1-piperidinyl] -6,7-
Dimethoxyquinazoline 300 mg (0.748 mmol) pyridine 3
216 mg (2.25 mmol) of sulfamide were added to the
Heated to reflux for hours. Water was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 141 mg (41%) of compound 7 as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.57 (1H, s), 7.22 (1H, s), 7.14
(1H, s), 6.93 (1H, d, J = 7.9), 6.75 (1H, d, J = 7.9),
6.66 (1H, s), 4.38-4.12 (3H, m), 3.94 (3H, s), 3.92
(3H, s), 3.32-3.18 (2H, br.-t), 2.41-2.20 (5H, m)
2.17-2.04 (2H, br.-d).

Example 49 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -3,6-dimethyl-1H-benzimidida
Sol-2-one (Compound 9) 150 mg (0.350 mmo ) of Compound 23 obtained in Example 22
15.5 mg (0.385 mmol) of sodium hydride was added to a solution of l) in 3 mL of N, N-dimethylformamide under ice-cooling, and the mixture was stirred for 30 minutes. did. A saturated aqueous ammonium chloride solution was added to the reaction solution, the mixture was extracted with ethyl acetate, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 83.7 mg (54%) of compound 9 as white crystals. _{^{1 H NMR (CDCl 3):}} δ8.73 (1H, s), 7.30 (1H, s), 7.18
(1H, s), 6.96 (1H, s), 6.93 (1H, d, J = 8.1), 6.88 (1
H, d, J = 8.1), 4.68-4.53 (1H, m), 4.45-4.34 (2H, br.
-d), 4.04 (3H, s), 4.01 (3H, s), 3.40 (3H, s), 3.3
3-3.21 (2H, br.-t), 2.81-2.62 (2H, m), 2.40 (3H,
s), 2.03-1.92 (2H, br.-d).

Example 50 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -3,5-dimethyl-1H-benzimidazole
Sol-2-one (Compound 10) Compound 10 was obtained by reacting Compound 26 obtained in Example 40 with methyl iodide according to the method described in Example 49. _{^{1 H NMR (CDCl 3):}} δ8.72 (1H, s), 7.28 (1H, s), 7.16
(1H, s), 7.04 (1H, d, J = 7.9), 6.88 (1H, d, J = 7.9),
6.83 (1H, s), 4.67-4.53 (1H, m), 4.42-4.30 (2H, br.
-d), 4.03 (3H, s), 4.00 (3H, s), 3.41 (3H, s), 3.3
1-3.19 (2H, br.-t), 2.78-2.59 (2H, m), 2.41 (3H,
s), 2.03-1.94 (2H, br.-d).

Example 51 2,3-Dihydro-3-
(3,4-dimethoxyphenacyl) -1- [1- (6,
7-dimethoxy-4-quinazolinyl) -4-piperidini
] -5-Methyl-1H-benzimidazol-2-o
(Compound 11) Compound 26 obtained in Example 40 and 2-bromo-3 ′
Example 49 using 4'-dimethoxyacetophenone
Compound 11 was obtained by reacting according to the method described in (1). ¹ H NMR (CDCl ₃ ): δ 8.73 (1H, s), 7.76 (1H, dd, J = 8.
4, 1.7), 7.60 (1H, d, J = 1.7), 7.27 (1H, s), 7.17
(1H, s), 7.07 (1H, d, J = 8.4), 6.96 (1H, d, J = 8.4),
6.89 (1H, d, J = 8.4), 6.71 (1H, s), 5.24 (2H, s),
4.69-4.52 (1H, m), 4.41-4.29 (2H, br.-d), 4.04 (3H,
s), 4.00 (3H, s), 3.98 (3H, s), 3.94 (3H, s), 3.3
2-3.18 (2H, br.-t), 2.80-2.52 (2H, m), 2.35 (3H,
s), 2.08-1.98 (2H, br.-d).

Example 52 4- [4- (2,3-dihydride)
B-5-Methyl-2-oxo-1H-benzimidazo
1-yl) -1-piperidinyl] -6,7-dimet
Xyquinoline-3-carboxylic acid (Compound 66) 304 mg (0.619 mmol) of compound 53 obtained in Example 4
1N sodium hydroxide solution 4 in ethanol 5 mL solution
mL (4.00 mmol) was added, and the mixture was stirred at 80 ° C for 3 hours. The reaction solution was ice-cooled, a 1N aqueous hydrochloric acid solution was added and the mixture was stirred, and the resulting crystals were collected by filtration to obtain 249 mg (87%) of Compound 66 as white crystals. ¹ H NMR (CDCl ₃ -CD ₃ OD): δ 9.01 (1H, s), 7.66 (1H, s),
7.46 (1H, s), 7.14 (1H, d, J = 8.3), 6.93 (1H, s),
6.92 (1H, d, J = 8.3), 4.74-4.49 (1H, m), 4.11 (3H,
s), 4.09 (3H, s), 3.80-3.58 (4H, m), 2.95-2.57 (2
H, m), 2.39 (3H, s), 2.14-2.02 (2H, br.-d).

Example 53 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -2-oxo-1H-benzimidazole
-5-carboxylic acid (Compound 18) Compound 1 obtained by reacting compound 20 obtained in Example 28 according to the method described in Example 52.
8 was obtained. _{^{1 H NMR (DMSO-d 6}} ): δ11.22 (1H, s), 8.82 (1H, s), 7.
64 (1H, d, J = 8.3), 7.52 (1H, s), 7.43 (1H, d, J = 8.
3), 7.41 (1H, s), 7.38 (1H, s), 4.88-4.84 (1H, m),
4.78-4.73 (2H, br.-d), 3.99 (3H, s), 3.95 (3H,
s), 3.71-3.62 (2H, br.-t), 2.58-2.49 (2H, m), 2.00
-1.96 (2H, br.-d).

Example 54 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -2-oxo-1H-benzimidazole
-5-carboxamide (Compound 19) 400 mg (0.889 mmo ) of the compound 18 obtained in Example 53
180 mg (1.11 mmol) of N, N'-carbonyldiimidazole was added to a solution of l) in 5 mL of tetrahydrofuran, and the mixture was stirred with heating under reflux for 1 hour, the reaction solution was allowed to cool, and 1 mL of 28% aqueous ammonia was added, Stir for 20 minutes at room temperature. Saturated saline was added to the reaction solution, extracted with chloroform, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 23 of compound 19.
0 mg (58%) was obtained as white crystals. _{^{1 H NMR (DMSO-d 6}} ): δ11.17 (1H, s), 8.59 (1H, s), 7.
91 (1H, s), 7.63 (1H, s), 7.53 (1H, s), 7.34 (1H,
d, J = 8.3), 7.22 (1H, d, J = 8.3), 7.20 (1H, s), 7.00
(1H, s), 4.57-4.51 (1H, m), 4.35-4.29 (2H, br.-
d), 3.93 (6H, s), 3.30-3.18 (2H, br.-t), 2.62-2.54
(2H, m), 1.90-1.80 (2H, br.-d).

Example 55 2,3-Dihydro-1- [1
-(6,7-dimethoxy-4-quinazolinyl) -4-pi
Peridinyl] -5-hydroxymethyl-1H-benzoi
Midazol-2-one (Compound 12) 711 mg (1.53 mmol) of Compound 20 obtained in Example 28
10.7 mL of diisobutylaluminum hydride (1 M solution in tetrahydrofuran)
(10.7 mmol), and the mixture was stirred for 8 hours while heating under reflux. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was filtered using a filter aid. The filtrate was extracted with ethyl acetate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 30: 1). ) To give 230 mg (34%) of compound 12 as white crystals. _{^{1 H NMR (CDCl 3):}} δ10.45 (1H, s), 9.68 (1H, s), 7.27
(1H, s), 7.19 (1H, s), 7.14 (1H, s), 7.09 (1H, d,
J = 8.1), 7.04 (1H, d, J = 8.1), 4.68 (2H, s), 4.67-4.
51 (1H, m), 4.46-4.33 (2H, br.-d), 4.01 (3H, s),
3.98 (3H, s), 3.36-3.20 (2H, br.-t), 2.76-2.57 (2
H, m), 2.04-1.89 (2H, br.-d).

Example 56 6-Bromo-2,3-dihydride
B-1- [1- (6,7-Dimethoxy-4-quinazolini)
Ru) -4-piperidinyl] -5-methyl-1H-benzo
Imidazol-2-one (Compound 13) 750 mg (1.78 mmo ) of compound 26 obtained in Example 40
To a solution of l) in 1,2-dichloroethane (15 mL) was added N-bromosuccinimide (634 mg, 3.55 mmol), and the mixture was stirred under heating and reflux for 2 days. After the reaction solution was filtered, the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain 516 mg (58%) of compound 13 as white crystals. . _{^{1 H NMR (CDCl 3):}} δ8.74 (1H, s), 8.48 (1H, s), 7.46
(1H, s), 7.29 (1H, s), 7.25 (1H, s), 7.15 (1H, d, J
= 8.1), 4.62-4.41 (3H, m), 4.07 (3H, s), 4.02 (3H,
s), 3.38-3.25 (2H, br.-t), 2.76-2.56 (5H, m), 2.23
-1.98 (2H, br.-d).

Example 57 2,3-Dihydro-5-methyl
Ru-1- [1- (2,6,7-trimethoxy-4-quina)
Zolinyl) -4-piperidinyl] -1H-benzimida
Sol-2-one (Compound 28) 400 mg (0.881 mmol) of Compound 27 obtained in Example 9
0.5 mL (8.75 mmo) of sodium methoxide (28% methanol solution) was added to 5 mL of methanol solution of
Stir for 5 hours. Ethyl acetate was added to the reaction solution, washed with water,
Dry over anhydrous sodium sulfate. The solvent is distilled off under reduced pressure,
The residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give 21 of compound 28.
7 mg (53%) were obtained as white crystals. _{^{1 H NMR (CDCl 3):}} δ9.34 (1H, s), 7.17 (1H, s), 7.13
(1H, s), 7.07 (1H, d, J = 8.2), 6.96 (1H, s), 6.89 (1
H, d, J = 8.2), 4.75-4.56 (1H, m), 4.50-4.38 (2H, br.
-d), 4.07 (3H, s), 4.03 (3H, s), 3.97 (3H, s), 3.3
7-3.22 (2H, br.-t), 2.81-2.62 (2H, m), 2.38 (3H,
s), 2.11-1.98 (2H, br.-d).

Example 58 2,3-Dihydro-1- [1
-(6,7-dimethoxy-2-morpholino-4-quinazo
Linyl) -4-piperidinyl] -5-methyl-1H-be
Nzoimidazol-2-one (Compound 32) 300 mg (0.660 mmol) of Compound 27 obtained in Example 9
Morpholine in 5 mL of N-methyl-2-pyrrolidone
0.3 mL (3.44 mmol) was added, and the mixture was stirred at 130 ° C for 3 hours.
Water was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from ether to give 295 mg (89%) of Compound 32 as white crystals. _{^{1 H NMR (CDCl 3):}} δ9.66 (1H, s), 7.09-7.00 (3H, m),
6.97 (1H, s), 6.87 (1H, d, J = 7.9), 4.71-4.56 (1H,
m), 4.38-4.22 (2H, br.-d), 4.00 (3H, s), 3.94 (3H,
s), 3.90-3.77 (8H, m), 3.30-3.16 (2H, br.-t), 2.7
7-2.57 (2H, m), 2.38 (3H, s), 2.00-1.89 (2H, br.-
d). In the following Examples 59 to 65, the target compound was obtained in the same manner as in Example 58, using the corresponding halogenated aromatic heterocyclic compound and amine.

Example 59 1- {1- [2- (2-amido)
Noethyl) amino-6,7-dimethoxy-4-quinazoly
Nyl] -4-piperidinyl} -2,3-dihydro-5-
Methyl-1H-benzimidazol-2-one (compound
29) ¹ H NMR (CDCl ₃ ): δ 7.15 (1 H, d, J = 7.9), 7.05 (1 H,
s), 6.94 (1H, s), 6.91 (1H, s), 6.88 (1H, d, J = 7.
9), 4.66-4.50 (1H, m), 4.35-4.23 (2H, br.-d), 3.98
(3H, s), 3.93 (3H, s), 3.62-3.52 (8H, m), 3.24-3.
09 (2H, br.-t), 2.99 (2H, t, J = 5.9), 2.74-2.58 (2
H, m), 2.37 (3H, s), 2.02-1.89 (2H, br.-d).

Example 60 2,3-dihydro-1- {1
-[6,7-dimethoxy-2- (2-hydroxyethyl
Ru) amino-4-quinazolinyl] -4-piperidinyl}
-5-methyl-1H-benzimidazol-2-one
(Compound 30) ¹ H NMR (CDCl ₃ ): δ 8.20 (1 H, s), 7.06 (1 H, d, J = 8.
0), 7.04 (1H, s), 6.96 (1H, s), 6.92 (1H, s), 6.88
(1H, d, J = 8.0), 4.67-4.50 (1H, m), 4.40-4.26 (2H,
br.-d), 3.97 (3H, s), 3.92 (3H, s), 3.89 (2H, t, J
= 5.3), 3.78-3.59 (3H, m), 3.46 (2H, q, J = 5.3), 3.29
-3.12 (2H, br.-t), 2.78-2.54 (2H, m), 2.35 (3H, s),
2.04-1.97 (2H, br.-d).

Example 61 2,3-Dihydro-1- {1
-[6,7-dimethoxy-2- (3,4-dimethoxyphen
Ethenyl) amino-4-quinazolinyl] -4-piperidi
Nil} -5-methyl-1H-benzimidazole-2-
On (compound 31) ¹ H NMR (CDCl ₃ ): δ 10.29-10.14 (1H, br.-s), 7.09 (1
H, d, J = 8.3), 7.06 (1H, s), 6.98 (1H, s), 6.96 (1H,
s), 6.87 (1H, d, J = 7.6), 6.81-6.76 (3H, s), 5.46-
5.24 (1H, br.-s), 4.77-4.59 (1H, m), 4.42-4.30 (2
H, br.-d), 3.99 (3H, s), 3.94 (3H, s), 3.85 (3H,
s), 3.83 (3H, s), 3.76 (2H, q, J = 6.7), 3.30-3.16
(2H, br.-t), 2.92 (2H, t, J = 6.7), 2.79-2.61 (2H,
m), 2.37 (3H, s), 2.09-1.96 (2H, br.-d).

Example 62 2,3-Dihydro-8- [4
-(2,3-dihydro-5-methyl-2-oxo-1H
-Benzimidazol-1-yl) -1-piperidinini
1,3-dimethyl-6-morpholino-1H-imi
Dazo [4,5-g] quinazolin-2-one (Compound 4
1) ¹ H NMR (CDCl ₃ ): δ8.09-8.05 (1H, br.-s), 7.25 (1H,
s), 7.16 (1H, s), 7.03 (1H, d, J = 7.9), 6.91 (1H,
s), 6.89 (1H, d, J = 7.9), 4.68-4.54 (1H, m), 4.40-
4.22 (2H, br.-d), 3.96-3.80 (8H, m), 3.46 (6H, s),
3.33-3.17 (2H, br.-t), 2.78-2.59 (2H, m), 2.38 (3
H, s), 2.03-1.88 (2H, br.-d).

Example 63 1,3-Diethyl-2,3-
Dihydro-8- [4- (2,3-dihydro-5-methyl
-2-oxo-1H-benzimidazol-1-yl)
-1-piperidinyl] -6-morpholino-1H-imida
Zo [4,5-g] quinazolin-2-one (compound 43) ¹ H NMR (CDCl ₃ ): δ 9.07 (1H, s), 7.21 (1H, s), 7.13
(1H, s), 7.04 (1H, d, J = 8.1), 6.95 (1H, s), 6.88 (1
H, d, J = 8.1), 4.71-4.55 (1H, m), 4.40-4.23 (2H, br.
-d), 4.04-3.79 (12H, m), 3.34-3.20 (2H, br.-t), 2.
79-2.60 (2H, m), 2.38 (3H, s), 2.00-1.89 (2H, br.-
d), 1.48-1.30 (6H, m).

Example 64 1,3-diethyl-2,3-
Dihydro-5- [4- (2,3-dihydro-5-methyl
-2-oxo-1H-benzimidazol-1-yl)
-1-piperidinyl] -8-morpholino-1H-imida
Zo [4,5-g] phthalazin-2-one (compound 50) ¹ H NMR (CDCl ₃ ): δ 8.64 (1 H, s), 7.57 (1 H, s), 7.52
(1H, s), 7.19 (1H, d, J = 8.6), 6.95 (1H, s), 6.93
(1H, d, J = 8.6), 4.58-4.45 (1H, m), 4.17-3.88 (10H,
m), 3.54-3.42 (4H, m), 3.37-3.23 (2H, br.-t), 2.9
1-2.73 (2H, m), 2.40 (3H, s), 2.09-2.00 (2H, br.-
d), 1.50-1.37 (6H, m).

Example 65 1- {4- [4- (2,3-
Dihydro-5-methyl-2-oxo-1H-benzoimid
Dazol-1-yl) -1-piperidinyl] -6,7-
Dimethoxy-2-quinazolinyl dipiperidine-4-cal
Boxamide (Compound 70) ¹ H NMR (CDCl ₃ -CD ₃ OD): δ7.31 (1H, s), 7.07-6.98 (2H,
m), 6.92-6.83 (2H, m), 4.95-4.81 (2H, br.-d), 4.6
4-4.50 (1H, m), 4.43-4.28 (2H, br.-d), 4.00 (3H,
s), 3.93 (3H, s), 3.31-3.15 (2H, br.-t), 3.05-2.93
(2H, m), 2.75-2.57 (2H, m), 2.52-2.40 (1H, m), 2.
20 (3H, s), 2.06-1.88 (4H, m), 1.86-1.67 (2H, m).

Example 66 2,3-Dihydro-1- [1
-(6,7-dimethoxy-1-phthalazinyl) -4-pi
Peridinyl] -5-methyl-1H-benzimidazole
-2-one (compound 46) 226 mg (0.498 mmol) of compound 47 obtained in Example 2
To a solution of acetic acid (25 mL) was added 10% palladium-carbon (80 mg), and the mixture was stirred at room temperature for 8 hours under a hydrogen stream. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 20: 1).
To give 130 mg (63%) of compound 46 as white crystals. _{^{1 H NMR (CDCl 3):}} δ10.81-10.69 (1H, br.-s), 9.14 (1
H, s), 8.32 (1H, s), 7.52 (1H, s), 7.31 (1H, s),
7.21 (1H, d, J = 8.1), 7.09 (1H, d, J = 8.1), 4.51-4.2
6 (1H, m), 4.07-3.76 (8H, m), 3.25-3.06 (2H, br.-
t), 2.77-2.59 (2H, m), 2.30 (3H, s), 1.87-1.78 (2H,
br.-d). In the following Examples 67 to 68, the target compound was obtained by reacting according to the method described in Example 66 using the corresponding halogenated aromatic heterocyclic compound.

Example 67 1,3-Diethyl-2,3-
Dihydro-5- [4- (2,3-dihydro-5-methyl
-2-oxo-1H-benzimidazol-1-yl)
-1-piperidinyl] -1H-imidazo [4,5-g]
Phthalazin-2-one (compound 48) ¹ H NMR (CDCl ₃ ): δ 9.20 (1 H, s), 8.70 (1 H, s), 7.54
(1H, s), 7.36 (1H, s), 7.18 (1H, d, J = 8.3), 6.95
(1H, s), 6.92 (1H, d, J = 8.3), 4.68-4.50 (1H, m), 4.
14-3.98 (6H, m), 3.39-3.24 (2H, br.-t), 2.93-2.75
(2H, m), 2.39 (3H, s), 2.11-1.98 (2H, br.-d), 1.52
-1.40 (6H, m).

Example 68 2,3-Dihydro-1- [1
-(6,7-Dimethoxy-1-isoquinolyl) -4-pi
Peridinyl] -5-methyl-1H-benzimidazole
-2-one (compound 51) ¹ H NMR (CDCl ₃ ): δ 10.18-9.95 (1 H, br.-s), 8.11 (1 H,
d, J = 5.4), 7.45 (1H, s), 7.21 (1H, d, J = 8.1), 7.20
(1H, d, J = 5.4), 7.06 (1H, s), 7.00 (1H, s), 6.91
(1H, d, J = 8.1), 4.86-4.56 (1H, m), 4.05 (3H, s),
4.03 (3H, s), 3.97-3.92 (2H, br.-d), 3.22-3.13 (2
H, br.-t), 2.86-2.72 (2H, m), 2.38 (3H, s), 2.06-2.
02 (2H, br.-d).

Example 69 N-propyl-4- [4-
(2,3-dihydro-5-methyl-2-oxo-1H-
Benzimidazol-1-yl) -1-piperidinyl]
-6,7-Dimethoxyquinoline-3-carboxamide
(Compound 67) 253 mg (0.515 mmol) of compound 53 obtained in Example 4.
0.212 mL (2.57 mmol) of propylamine and 3.75 mL (6.32 mmol) of n-butyllithium (1.69 M hexane solution) were added to a solution of 10 mL of tetrahydrofuran under ice-cooling.
The mixture was stirred at room temperature under a nitrogen atmosphere for 25 hours. Water was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate. This was washed with a 1 N aqueous hydrochloric acid solution, saturated aqueous sodium hydrogen carbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from hexane: ethyl acetate = 1: 1 to give compound 67-1.
94 mg (75%) were obtained as white crystals. ¹ H NMR (CDCl ₃ -CD ₃ OD): δ 8.54 (1H, s), 7.64 (1H, s),
7.39 (1H, s), 7.35 (1H, d, J = 8.4), 7.04 (1H, d, J
= 8.4), 6.91 (1H, s), 4.52-4.48 (1H, m), 4.11 (3H,
s), 4.06 (3H, s), 3.84-3.63 (2H, m), 3.59-3.53 (2
H, br.-t), 3.45-3.38 (2H, m), 2.93-2.85 (2H, m),
2.39 (3H, s), 2.10-2.02 (2H, br.-d), 1.70 (2H, q,
J = 7.3), 1.03 (3H, t, J = 7.3).

Example 70 N-phenyl-4- [4-
(2,3-dihydro-5-methyl-2-oxo-1H-
Benzimidazol-1-yl) -1-piperidinyl]
-6,7-Dimethoxyquinoline-3-carboxamide
(Compound 68) Compound 68 was obtained by reacting with aniline according to the method described in Example 69. ¹ H NMR (CDCl ₃ -CD ₃ OD): δ 8.66 (1H, s), 7.79 (1H, s),
7.75 (1H, s), 7.53-7.37 (3H, m), 7.39-7.26 (2H,
m), 7.07 (1H, d, J = 8.4), 6.90 (1H, s), 6.86 (1H,
d, J = 8.4), 4.50-4.36 (1H, m), 4.06 (3H, s), 4.05
(3H, s), 3.64-3.35 (2H, m), 2.87-2.67 (2H, m), 2.38
(3H, s), 1.99-1.85 (2H, br.-d).

Reference Example 1 6,8-dichloro-1,3-di
Ethyl-2,3-dihydro-1H-imidazo [4,5-
g] Quinazolin-2-one (compound a) (1) 5.76 methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate obtained by the method described in JP-A-61-207388. g (30.0 mmo
To a solution of l) in 50 mL of N, N-dimethylformamide, 2.64 g (66.0 mmol) of sodium hydride was added, and after stirring at room temperature for 10 minutes, 4.8 mL (60.0 mmol) of ethyl iodide was added.
The mixture was stirred at room temperature for 1 hour. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
Methyl diethyl-2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate 5.02 g (68%)
I got (2) To a solution of 5.02 g (20.4 mmol) of the compound obtained in (1) in 10 mL of acetic anhydride was added 1.02 mL (25.5 mmol) of fuming nitric acid, and the mixture was stirred at 0 ° C for 20 minutes. Pour the reaction solution into ice water,
Extracted with ethyl acetate and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 1,3-diethyl-2,3-dihydro-6-nitro-2-oxo-1H-. 4.00 g (67%) of methyl benzimidazole-5-carboxylate was obtained. (3) To a solution of 4.00 g (13.5 mmol) of the compound obtained in (2) in 50 mL of ethanol was added 10% palladium / carbon 800
mg was added and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. After the catalyst was removed by filtration using a filter aid, the filtrate was concentrated under reduced pressure and recrystallized from ether to give 6-amino-1,3-diethyl-
3.28 g (91%) of methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate were obtained. (4) A mixture of 500 mg (1.90 mmol) of the compound obtained in (3) and 456 mg (7.60 mmol) of urea was stirred at 180 ° C. for 2 hours. Water was added to the reaction solution, and the resulting crystals were collected by filtration and 1,3-diethyl-1H-imidazo [4,5-g] quinazoline-2,6,8 (3H, 5H, 7H) -trione 46
0 mg (88%) was obtained. (5) Using the compound obtained in (4), Example 30
By reacting according to the method described in (1),
6,8-Dichloro-1,3-diethyl-2,3-dihydro-1H-imidazo [4,5-g] quinazolin-2-one was obtained.

Reference Example 2 6,8-Dichloro-2,3-di
Hydro-1,3-dimethyl-1H-imidazo [4,5-
g] Quinazolin-2-one (compound b) Methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate and methyl iodide obtained by the method described in JP-A-61-207388. And 8, 6-dichloro-2,3-dihydro-1, by sequentially reacting according to the method described in Reference Example 1.
3-Dimethyl-1H-imidazo [4,5-g] quinazolin-2-one was obtained.

Reference Example 3 8-chloro-2,3-dihydro
-1,3-Dimethyl-1H-imidazo [4,5-g] ki
Nazolin-2-one (compound c) (1) Methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate obtained by the method described in JP-A-61-207388 and iodide By reacting sequentially with methyl according to the method described in Reference Examples 1 (1) to (3), 6-amino-2,3-
Methyl dihydro-1,3-dimethyl-2-oxo-1H-benzimidazole-5-carboxylate was obtained. (2) Using the compound obtained in (1) and formamide,
8-Chloro-2,3-dihydro-1,3-dimethyl-1H-imidazo [4,5-g] was obtained by sequentially reacting according to the method described in Reference Example 1 (4) and (5).
Obtained quinazolin-2-one.

Reference Example 4 8-chloro-2,3-dihydro
-1,3-Dipropyl-1H-imidazo [4,5-g]
Quinazolin-2-one (Compound d) Methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate and propyl iodide obtained by the method described in JP-A-61-207388. The reaction was carried out sequentially according to the method described in Reference Example 3 to give 8-chloro-2,3-dihydro-1,3-dipropyl-1H-imidazo [4,5-g] quinazoline-
2-on was obtained.

Reference Example 5 8-chloro-1,3-dibutyl
-2,3-dihydro-1H-imidazo [4,5-g] ki
Nazolin-2-one (Compound e) Methyl 2,3-dihydro-2-oxo-1H-benzimidazole-5-carboxylate obtained by the method described in JP-A-61-207388 and butyl iodide The reaction was carried out sequentially according to the method described in Reference Example 3 to give 8-chloro-1,3-dibutyl-2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2.
-Got on.

Reference Example 6 5,8-Dichloro-1,3-di
Ethyl-2,3-dihydro-1H-imidazo [4,5-
g] phthalazin-2-one (compound f) (1) Tetrahedron Lett. , 28th
Vol., P. 1389 (1987), using 2,3-dihydro-5,6-dimethyl-1H-benzimidazol-2-one and ethyl iodide as reference example 1 (1). By reacting according to the method described, 1,3-diethyl-2,3-dihydro-5,6-dimethyl-1H-benzimidazol-2-one was obtained. (2) 1.00 g (4.58 mmol) of the compound obtained in (1) was added to 2
-Methyl-1-propanol Dissolve in 10 mL of water and 15 mL of water, and stir with heating at 110 ° C while stirring potassium permanganate.
3.62 g (22.9 mmol) was added slowly. After heating and stirring at 110 ° C for 1 hour, add 1.45 g of potassium permanganate
(9.16 mmol), and the mixture was heated and stirred at 110 ° C. for 1 hour. Thereafter, the mixture was filtered while hot using a filter aid, and the filtrate was concentrated.
The obtained residue was dissolved in water, a 2N aqueous hydrochloric acid solution was added dropwise thereto, and the precipitated crystals were collected by filtration to give 1,3-diethyl-dichloromethane.
779 g (61%) of 2,3-dihydro-2-oxo-1H-benzimidazole-5,6-dicarboxylic acid were obtained. (3) 300 mg (1.08 mmol) of the compound obtained in (2) was dissolved in 3 mL of acetic acid and 3 mL of water, and 0.26 mL of hydrazine monohydrate was dissolved.
(5.40 mmol) was added, and the mixture was heated under reflux for 1.5 hr. After cooling down,
The precipitated crystals were collected by filtration, and 1,3-diethyl-1H-imidazo [4,5-g] phthalazine-2,5,8 (3H,
6H, 7H) -trione 102 mg (34%) was obtained. (4) Example 30 using the compound obtained in (3)
By reacting according to the method described in (1),
5,8-Dichloro-1,3-diethyl-2,3-dihydro-1H-imidazo [4,5-g] phthalazin-2-one was obtained. ¹ H NMR (CDCl ₃ ): δ 7.70 (2H, s), 4.13 (4H, q, J = 7.
3), 1.47 (6H, d, J = 7.3).

Reference Example 7 4- [4- (4-methyl-2-
Nitroanilino) -1-piperidinyl] -6,7-dim
Toxiquinazoline (Compound g) (1) 3.10 g of commercially available 4-fluoro-3-nitrotoluene
(20.0 mmol) and 3.81 g (20.0 mmol) of 4-amino-1-benzylpiperidine in N, N-dimethylformamide
4.15 g (30.0 mmol) of potassium carbonate was added to the 20 mL solution, and the mixture was stirred at 120 ° C for 5 hours. The reaction solution was extracted with ether, washed with saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was dissolved in ether, 10 mL (40.0 mmol) of a 4N hydrochloric acid-ethyl acetate solution was added, and the mixture was stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to give 7.29 g (100%) of 4- (1-benzyl-4-piperidinyl) amino-3-nitrotoluene hydrochloride as orange crystals. (2) 3.62 g (10.0 mmol) of the compound obtained in (1) was dissolved in ether, and a 1N aqueous solution of sodium hydroxide was added thereto.
Extracted with ether. After drying over anhydrous magnesium sulfate, the mixture was filtered, and 1.35 mL (15.0 mmo) of vinyl chloroformate was added to the filtrate.
l) was added and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was triturated with ether-hexane to give 2.12 g (67%) of 4- (1-vinyloxycarbonyl-4-piperidinyl) amino-3-nitrotoluene as an orange color. Obtained as crystals. (3) Dissolve 1.98 g (6.25 mmol) of the compound obtained in (2) in 20 mL of methanol, and add 4N hydrochloric acid-ethyl acetate solution 5
mL (20.0 mmol) was added, and the mixture was stirred at 60 ° C for 5 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was recrystallized from ether-methanol to give 4- (4-piperidinyl) amino-3-.
1.74 g (100%) of nitrotoluene were obtained as yellow crystals. (4) The compound obtained in (3) and US Pat.
By reacting 4-chloro-6,7-dimethoxyquinazoline obtained by the method described in 990 according to the method described in Example 1, 4- [4- (4-methyl-
2-nitroanilino) -1-piperidinyl] -6,7-
Dimethoxyquinazoline was obtained as orange crystals. _{^{1 H NMR (CDCl 3):}} δ8.69 (1H, s), 8.10 (1H, d, J = 6.
9), 8.10 (1H, s), 7.30-7.20 (2H, m), 7.10 (1H, s),
6.86 (1H, d, J = 8.9), 4.23-4.09 (2H, br.-d), 4.03
(3H, s), 4.01 (3H, s), 3.92-3.77 (1H, m), 3.42-3.3
6 (2H, br.-t), 2.35-2.20 (5H, m), 1.97-1.78 (2H,
m).

Reference Example 8 4- [4- (5-methyl-2-)
Nitroanilino) -1-piperidinyl] -6,7-dime
Toxiquinazoline (Compound h) 4- [4- (5-Methyl-2-nitroanilino)-was obtained by sequentially reacting with commercially available 3-fluoro-4-nitrotoluene according to the method described in Reference Example 7.
[1-Piperidinyl] -6,7-dimethoxyquinazoline was obtained as yellow crystals. _{^{1 H NMR (CDCl 3):}} δ8.70 (1H, s), 8.26 (1H, d, J = 7.
3), 8.10 (1H, d, J = 8.6), 7.29 (1H, s), 7.11 (1H,
s), 6.70 (1H, s), 6.49 (1H, d, J = 8.6), 4.20-4.08
(2H, m), 4.04 (3H, s), 4.01 (3H, s), 3.93-3.79 (1
H, m), 3.43-3.31 (2H, br.-t), 2.39-2.24 (5H, m), 1.
98-1.79 (2H, m).

Reference Example 9 4- [4- (4-methyl-2-
Nitroanilino) methyl-1-piperidinyl] -6,7
-Dimethoxyquinazoline (compound i) (1) Org. Chem. Vol. 27, p. 284 (1962), to a solution of 1.00 g (5.00 mmol) of 4-aminomethylpiperidine in 10 mL of methanol, 1.4 mL (10.0 mmol) of triethylamine and 756 mg of 2-nitrobenzaldehyde ( After stirring at room temperature for 20 minutes, 1.12 g (5.00 mmol) of 4-chloro-6,7-dimethoxyquinazoline and triethylamine 1.4 obtained by the method described in U.S. Pat. No. 3,226,990.
mL (10.0 mmol) was added, and the mixture was stirred at 80 ° C for 2 hours. After the reaction solution was concentrated under reduced pressure, 10 mL of 6N hydrochloric acid (60.0 mL) was added to the residue.
mmol) and stirred at room temperature for 1 hour. 4N reaction solution
After neutralization with an aqueous sodium hydroxide solution, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 4- (4-aminomethyl-1-piperidinyl) -6,7-dimethoxyquinazoline as a brown oil. (2) Reference example 7 (1) using the compound obtained in (1)
By reacting according to the method described in
[4- (4-methyl-2-nitroanilino) methyl-1
-Piperidinyl] -6,7-dimethoxyquinazoline as orange crystals.

Reference Example 10 6-Methyl-3- (4-pipet)
(Ridinyl) benzoxazol-2 (3H) -one salt
Acid salt (compound j) (1) 5.00 g of commercially available 2-amino-5-methylphenol
1-benzyl- in a 60 mL solution of methanol (40.6 mmol)
Add 9.0 mL (48.5 mmol) of 4-piperidone and add
Stir for hours. Sodium borohydride (2.00 g, 52.8 mmol) was added to the reaction solution under ice cooling, and the mixture was stirred under ice cooling for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with chloroform. This was washed with saturated saline and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 2- (1
-Benzyl-4-piperidinyl) amino-5-methylphenol was obtained. (2) 3- (1-benzyl-4-piperidinyl) was obtained by reacting 12.0 g (40.6 mmol) of the compound obtained in (1) according to the method described in Example 39 (2).
-6-Methylbenzoxazol-2 (3H) -one 5.
14 g (2 steps: 63%) were obtained. ¹ H NMR (CDCl ₃ ): δ 7.40-7.28 (5H, m), 7.11 (1H, d, J
= 8.1), 7.02 (1H, s), 6.95 (1H, d, J = 8.1), 4.25-4.0
9 (1H, m), 3.56 (2H, s), 3.12-3.01 (2H, br.-d), 2.
49-2.32 (5H, m), 2.24-2.11 (2H, br.-t), 1.90-1.77
(2H, br.-d). (3) Dissolve 5.14 g (15.9 mmol) of the compound obtained in (2) in 100 mL of ethanol, and add 10% palladium-carbon 120%.
mg and 2 mL (2.00 mmol) of a 1N aqueous hydrochloric acid solution were added, and the mixture was stirred at room temperature under a hydrogen stream for 5 hours. After neutralizing with triethylamine, the catalyst was filtered off with a filter aid, and the filtrate was concentrated under reduced pressure. Chloroform-methanol (10: 1)
Dissolved in 4N hydrochloric acid-ethyl acetate solution 5 mL (20.0 mmol)
Was added and stirred at room temperature for 2 hours. The precipitated crystals were collected by filtration to give 6-methyl-3- (4-piperidinyl) benzoxazol-2 (3H) -one.hydrochloride 1.47 g.
(34%) was obtained as a white crystal. ¹ H NMR (CDCl ₃ ): δ9.43-9.25 (1H, br.-s), 7.54 (1H,
d, J = 7.9), 7.19 (1H, s), 7.03 (1H, d, J = 7.9), 4.57
-4.42 (1H, m), 3.46-3.33 (2H, br.-d), 3.17-3.02 (2
H, br.-t), 2.69-2.50 (2H, m), 2.33 (3H, s), 2.01-1.
89 (2H, br.-d).

Reference Example 11 2,3-dihydro-5-methyl
1- (3-methyl-4-piperidinyl) -1H-be
Nzoimidazol-2-one (Piperidine 3 and 4
Mixture of stereoisomers at position (compound k) (1) Obtained by the method described in European Patent 92,391 4
4- (1-benzyl-3-methyl-4-piperidinyl) amino-3- by reacting with -amino-1-benzyl-3-methylpiperidine according to the method described in Reference Example 7 (1). Nitrotoluene (piperidine 3
A mixture of stereoisomers at the 3rd and 4th positions). (2) Using the compound obtained in (1) and reacting according to the method described in Example 39, 2,3-dihydro-5-methyl-1- (1-benzyl-3-methyl-
4-piperidinyl) -1H-benzimidazole-2-
One (a mixture of stereoisomers at the 3- and 4-positions of piperidine) was obtained. (3) Reference Example 10 using the compound obtained in (2)
By reacting according to the method described in (3), 2,3-dihydro-5-methyl-1- (3-methyl-4)
-Piperidinyl) -1H-benzimidazol-2-one (mixture of stereoisomers at the 3- and 4-positions of piperidine) was obtained.

Reference Example 12 2,3-dihydro-6-fur
Oro-1- (4-piperidinyl) -1H-benzimidazole
Zol-2-one hydrochloride (Compound m) (1) 2- (1-benzyl-) by reacting with commercially available 2,4-difluoronitrobenzene according to the method described in Reference Example 7 (1). 4-Piperidinyl) amino-4-fluoronitrobenzene was obtained. (2) By using the compound obtained in (1) and sequentially reacting it according to the method described in Example 39, 1- (1
-Benzyl-4-piperidinyl) -2,3-dihydro-
6-Fluoro-1H-benzimidazol-2-one was obtained. _{^{1 H NMR (CDCl 3):}} δ9.46-9.23 (1H, br.-s), 7.43-7.27
(5H, m), 7.04 (1H, dd, J = 9.2, 2.3), 6.98 (1H, dd,
J = 8.6, 4.6), 6.81-6.73 (1H, m), 4.40-4.27 (1H,
m), 3.58 (2H, s), 3.08-3.03 (2H, br.-d), 2.45-2.39
(2H, m), 2.22-2.17 (2H, br.-t), 1.82-1.65 (2H, b
r.-d). (3) Reference Example 10 using the compound obtained in (2)
By reacting according to the method described in (3), 2,3-dihydro-6-fluoro-1- (4-piperidinyl) -1H-benzimidazol-2-one.hydrochloride was obtained.

Reference Example 132,3-dihydro-2-oxo
So-1- (4-piperidinyl) -1H-benzimidazo
Methyl 5-carboxylate (Compound n) (1) J. Am. Chem. Soc. , Volume 78, 60
4-fur obtained by the method described on page 34 (1956)
Reference Example 7 Using Methyl Oro-3-Nitrobenzoate
By reacting according to the method described in (1), 4
-(1-benzyl-4-piperidinyl) amino-3-ni
Methyl torobenzoate was obtained. (2) Using the compound obtained in (1), described in Example 39
1- (1
-Benzyl-4-piperidinyl) -2,3-dihydro-
2-oxo-1H-benzimidazole-5-carboxyl
Methyl acid was obtained. ¹ H NMR (CDCl_Three): δ9.83-9.51 (1H, br.-s), 7.83 (1H,
 d, J = 8.2), 7.79 (1H, s), 7.49-7.24 (6H, m), 4.49-
4.32 (1H, m), 3.92 (3H, s), 3.60 (2H, s), 3.16-3.0
1 (2H, m), 2.57-2.38 (2H, m), 2.28-2.14 (2H, m),
1.95-1.87 (2H, br.-d). (3) Reference Example 10 using the compound obtained in (2)
By reacting according to the method described in (3)
2,3-dihydro-2-oxo-1- (4-piperidini
M) -1H-benzimidazole-5-carboxylate
I got

Reference Example 14 1,4-dihydro-7-iso
Propoxy-6-methoxy-4-oxoquinoline-3-
Ethyl carboxylate (compound o) (1) To a solution of 5.25 g (27.4 mmol) of commercially available sodium 2-methoxy-5-nitrophenoxide in 50 mL of N, N-dimethylformamide, 3.25 mL (32.5 mL) of isopropyl iodide was added.
mmol) and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, it was extracted with ethyl acetate and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to obtain 3.60 g (62%) of 3-isopropoxy-4-methoxynitrobenzene. (2) 3-isopropoxy-4-methoxyaniline was obtained by reacting 3.60 g (17.0 mmol) of the compound obtained in (1) according to the method described in Reference Example 1 (3).
2.63 g (85%) were obtained. (3) 3.2 mL (15.8 mmol) of diethyl ethoxymethylenemalonate was added to 2.63 g (14.5 mmol) of the compound obtained in (2), and the mixture was stirred at 100 ° C. for 1 hour. The reaction solution was added to 10 mL of diphenyl ether heated to 250 ° C, and the mixture was stirred at 250 ° C for 50 minutes. The resulting crystals were collected by filtration and dried to give 3.09 g of ethyl 1,4-dihydro-7-isopropoxy-6-methoxy-4-oxoquinoline-3-carboxylate.
(70%) as brown crystals. _{^{1 H NMR (DMSO-d 6}} ): δ11.99 (1H, s), 8.44 (1H, s), 7.
50 (1H, s), 7.08 (1H, s), 4.73-4.60 (1H, m), 4.19
(2H, q, J = 7.1), 3.83 (3H, s), 1.35 (6H, d, J = 5.9),
1.27 (3H, t, J = 7.1).

Reference Example 15 1,4-dihydro-6-metho
Xy-7-methoxymethyl-4-oxoquinoline-3-
Ethyl carboxylate (compound p) (1) Commercially available 2-methoxy-5-nitrobenzyl bromide 5.
To a solution of 01 g (20.3 mmol) in 45 mL of methanol was added 1.65 g (30.5 mmol) of sodium methoxide, and the mixture was heated to reflux for 3.
Stir for 5 hours. The reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to give 2.41 g of 4-methoxy-3-methoxymethylnitrobenzene (60%).
%). (2) Using the compound obtained in (1), Reference Example 1 (3)
And by sequentially reacting according to the method described in Reference Example 14 (3), ethyl 1,4-dihydro-6-methoxy-7-methoxymethyl-4-oxoquinoline-3-carboxylate was obtained as brown crystals. Obtained.

Reference Example 16 1,4-dihydro-4-oxo
So-6,7,8-trimethoxyquinoline-3-carboxylic
Ethyl acid (compound q) (1) Commercially available 4-nitropyrogallol hemihydrate 1.
09 g (6.05 mmol) of N, N-dimethylformamide 25
1.09 g (12.1 mmol) of cesium carbonate was added to the mL solution, and the mixture was stirred under ice cooling for 30 minutes, and then methyl iodide 1.4 mL (22.5
mmol) and stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, it was extracted with ethyl acetate and washed with water. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1) to give 2,3,4-
790 mg (62%) of trimethoxynitrobenzene were obtained. (2) By using 790 mg (3.42 mmol) of the compound obtained in (1) and reacting sequentially according to the method described in Reference Example 1 (3) and Reference Example 14 (3), 1,4- 699 mg (67%) of ethyl dihydro-4-oxo-6,7,8-trimethoxyquinoline-3-carboxylate was obtained as brown crystals.

Reference Example 17 1,4-dihydro-8-methyl
Ru-6-nitro-4-oxoquinoline-3-carboxylic acid
Ethyl (compound r) Using commercially available 2-methyl-4-nitroaniline, the reaction was carried out according to the method described in Reference Example 14 (3) to give 1,4-dihydro-8-methyl-6-nitro- 4-
Ethyl oxoquinoline-3-carboxylate was obtained.

[0173]

Industrial Applicability According to the present invention, the present invention has a strong cell adhesion inhibitory activity, and has an anti-inflammatory agent, an anti-allergic agent, a cancer metastasis inhibitor,
A piperidine derivative useful as an immunosuppressant or the like is provided.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/505 AED A61K 31/505 AED 31/535 ABF 31/535 ABF C07D 413/14 211 C07D 413/14 211 417/14 211 417/14 211 487/04 144 487/04 144 (72) Inventor: Ichiro Miki 410-1, Naumeri, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Hiroshi Kase 3-35-18 Maeharacho, Koganei-shi, Tokyo

Claims (1)

[Claims] 1. A compound of the formula (I)中 where R¹Is a substituted or unsubstituted lower alkyl,
Hydroxy, lower alkoxy, carboxy, lower alcohol
Xycarbonyl, lower alkylcarbonyl, substituted or
Is unsubstituted aryl, substituted or unsubstituted aryl
Xy, substituted or unsubstituted aryloxycarboni
, Substituted or unsubstituted arylcarbonyl, carb
Moyl, mono- or di-lower alkylcarbamoyl, mono
Or diarylcarbamoyl, nitro or halogen
And R^TwoIs hydrogen, substituted or unsubstituted lower alkyl
Kill, hydroxy, lower alkoxy, carboxy, lower
Alkoxycarbonyl, lower alkylcarbonyl, substituted
Or unsubstituted aryl, substituted or unsubstituted ant
Oxy, substituted or unsubstituted aryloxycar
Bonyl, substituted or unsubstituted arylcarbonyl,
Rubamoyl, mono- or di-lower alkylcarbamoyl,
Mono- or diarylcarbamoyl, nitro or halo
Gen^ThreeRepresents hydrogen or lower alkyl,
R^FourRepresents hydrogen, lower alkyl or lower alkoxy.
Then X¹-X²Are -N = N-, -N = C (R ^Five)-(Expression
Medium, R^FiveRepresents hydrogen, lower alkyl or amino
), -N (R⁶) -W- (wherein, R⁶Is hydrogen, also substitution
Or unsubstituted lower alkyl or substituted or unsubstituted
W represents C = O, C = S or SO_Two
) Or -OC (= R⁷)-(Where R⁷Is O
Or S)), and Y¹-Y²-Y³Is: NC
(R⁸) = N- [where R⁸Is hydrogen, lower alkoxy,
Halogen, amino, mono or di (substituted or unsubstituted
Lower alkyl) amino or substituted or unsubstituted fats
Represents a cyclic heterocyclic group], = NN-C (R^8A)-(Expression
Medium, R^8AIs R⁸), = NC (R^8B)
ＣＨCH- (wherein, R^8BIs R⁸Is synonymous with) or
= C [C (= O) R⁹] -CH = N-, wherein R⁹Is the water
, Hydroxy, lower alkyl, lower alkoxy, substituted
Or unsubstituted aryl, substituted or unsubstituted ant
Oxy, amino, mono- or di-lower alkylamino
No, mono or di (substituted or unsubstituted aryl)
Mino or a substituted or unsubstituted alicyclic heterocyclic group
And Z¹And Z^TwoAre the same or different water
Alkyl, substituted or unsubstituted lower alkyl, hydroxy,
Lower alkoxy, carboxy, lower alkoxy carbonyl
, Lower alkylcarbonyl, carbamoyl, mono or
Is di-lower alkylcarbamoyl, halogen or nitro
Or Z¹And Z^TwoTogether form -N (R^Ten) C (=
X) N (R¹¹)-(Where R ^TenAnd R¹¹Are the same or
Represents differently hydrogen or lower alkyl, X is O or
Represents S) and n represents 0, 1 or 2
Piperidine derivatives or their pharmacologically acceptable
Salt.