WO1999043674A1 - Remedies for erectile dysfunction - Google Patents

Abstract

Remedies for erectile dysfunction containing as the active ingredient quinazoline derivatives represented by general formula (I) which have a potent and selective cGMP-specific phosphodiesterase (PDE) inhibitory effect and are useful in treating or relieving sexual impotence, etc., or pharmacologically acceptable salts thereof. In formula (I) Y represents N or CH; -X1-X2-X3- represents -N=N-NR7-, -NH-C(=N-CN)-NR7-, -NH-C(=N-CONH¿2)-NR?7-, -N=CR8-NR7-, -N=C(NHR9)-NR7-, -N=C(OR10)-NR7-, -NH-C(=O)-NR7- or -NH-C(=S)-NR7-.

Description

 Specification

 Erectile dysfunction drug

Technical field

 The present invention has a cyclic guanosine 3 ′, 5′-1 phosphate (cGMP) -specific phosphodiesterase (PDE) inhibitory effect, and is useful for treating erectile dysfunction and thrombosis, angina pectoris, hypertension, heart failure And a quinazoline derivative or a pharmaceutically acceptable salt thereof which is useful for treating or alleviating cardiovascular diseases such as arteriosclerosis and asthma.

Background art

 c GMP plays an important role as a secondary messenger of the intracellular signal transduction mechanism in living organisms.Inhibitors of cGMP-specific PDE, which is a degrading enzyme, increase intracellular cGMP concentration, Shows potentiating effects of derived relaxation factor (EDRF), nitro vasodilators or atrial sodium diuretic peptide, antiplatelet, antivasospasm, vasodilatory effects, etc., thrombosis, angina, hypertension, congestion Heart failure including congestive heart failure, revascularization after percutaneous coronary angioplasty or bypass surgery, peripheral vascular disease, cardiovascular diseases such as arteriosclerosis, bronchitis, chronic asthma, allergic asthma, allergic nasal catarrh, etc. It is useful for the treatment or alleviation of inflammatory allergic diseases of the digestive tract such as irritable bowel syndrome, glaucoma, or impotence.

 Journal 'Ob' Medical 'Chemistry (J. Med. Chem.), Vol. 29, p. 972 (1986), Vol. 32, p. 2247 (1989), Journal' Ob 'Organic · Chemistry (J. Org. Chem.), 51, 616 (1986) and references cited therein include the PDE inhibitory activity and adenosine receptor antagonistic activity of imidazo [4,5-g] quinazoline derivatives. Is described. However, these compounds are not particularly potent PDE inhibitors and are not selective cGMP-specific PDE inhibitors. WO95 / 06648 and

WO96 / 26940 discloses a 2,3-dihydro-1H-imidazo [4,5-g] quinazoline derivative having inhibitory activity against cGMP-specific PDEs. [4,5-g] quinoline derivative, imidazoquinazoline ring There is no description of a compound having a substituent such as an alkyl group, a cycloalkyl group, or an aralkyl group at the 6-position. The newly disclosed 2-substituted amino-2,3-dihydro-1H-imidazo [4,5- _g ] quinazoline derivative, 2-cyano imino-2,3-dihydrido-1H-imidazo There is no description about [4,5-g] quinazoline derivatives. WO95 / 19970 and USP 5,679,683 disclose 3H-imidazo [4,5-g] quinazoline derivatives having tyrosine kinase inhibitory activity, but there is no description on selective CGMP-specific PDE inhibitory activity. J. Med. Chem., 39, 918 (1996) and EP 0635507 A1 contain imidazo [4,5-g] quinazoline and triazo. Although oral [4,5-g] quinazoline is disclosed to have tyrosine kinase activity, there is no description of selective cGMP-specific PDE inhibitory activity.

 Many known PDE inhibitors inhibit not only cGMP-specific PDEs but also similar enzymes such as cyclic adenosine 3 ', 5'-1 phosphate (cAMP) -specific PDEs. This causes an increase in cAMP concentration as well as intracellular cGMP concentration, which is problematic in terms of side effects and the like. In addition, the inhibitory strength is still unsatisfactory, and compounds with higher activity and higher selectivity are expected and required.

Disclosure of the invention

 An object of the present invention is to provide a quinazoline derivative which has a potent and selective cGMP-specific PDE inhibitory action, raises intracellular cGMP concentration, and contains a novel compound useful for treating or alleviating erectile dysfunction. Or to provide a pharmaceutically acceptable salt thereof.

The present invention provides a compound represented by the general formula (I):

(I)

[Wherein, R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, Y represents N or CH, and — X ¹ — X ² — X ³ — is one N = N— NR ⁷ — (wherein R ⁷ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or Unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl Or a substituted or unsubstituted aryl), one NH—C (—N—CN) —NR ⁷ — (wherein R ⁷ is as defined above), —NH—C (= N -C ONH ₂ ) 1 NR ⁷ — (wherein, R ⁷ is as defined above), — N = CR ⁸ — NR ⁷ — (wherein, R ⁷ is as defined above, and R ⁸ is R ⁷ N = C (NHR ⁹ ) — NR ⁷ — (wherein R ⁷ is as defined above, and R ⁹ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Represents a substituted aryl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted heteroaryl, a substituted or unsubstituted aralkyl, a lower alkoxycarbonyl or a carbamoyl), — N = C ( OR ¹⁰⁾ one NR ⁷ - (wherein, R ⁷ is the same as the In and, R ¹ has the same meaning as ^{R 7), -. NH- C} (= O) -NR 7 - ( wherein R ⁷ has the same meaning as defined above) or one NH—C (—S) —NR ⁷ — (wherein, R ⁷ has the same meaning as defined above), and R ¹ and R ² are the same or different , Hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted trialkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted Represents an unsubstituted lower alkenyl, a substituted or unsubstituted heteroarylalkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aralkyl, or R ¹ and R ² together; Or a substituted or unsubstituted nitrogen-containing heterocyclic group formed by containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

 The general formula (I A)

 (IA)

[Wherein, R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl,

(i) When Y represents N, one X ^1A — X ^2A — X ^3A — is one N = N— NR ⁷ — (where R ⁷ is as defined above), — NH— C (= N - CN) - NR ⁷ i (wherein, R ⁷ has the same meaning as defined above) or a NH- C (= N - C 0 NH 2) one NR ⁷ - (in the formula, R ⁷ is a as defined above And R ^1A is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkyl, a substituted or unsubstituted trialkyl. Chloroalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl; R ^2A is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocyclo Alkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl;

R ^1A and R ^2A may together represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N,

(ii) When Y represents CH, — X ^1A — X ^2A — X ^3A — is — N = N— NR ⁷ — (wherein R ⁷ is as defined above), and one NH—C (= N - CN) - NR ⁷ - (wherein, R ⁷ is as defined above), single NH- C (= 0) - NR 7 i (wherein, R ⁷ is as defined above) or - NH- C (= S) - NR ⁷ i (wherein, R ⁷ has the same meaning as defined above) represents, R ^1A is unsubstituted or replacement of lower alkyl, substituted or unsubstituted cycloalkyl, substituted or is properly non Substituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted R ^2A represents a heteroaryl, substituted or unsubstituted aralkyl or substituted or unsubstituted aryl. R ⁷ and Ri synonymous der compound or a pharmacologically represented by R ^1A and R ^2A may represent a substituted or non-replacement of the nitrogen-containing heterocyclic group formed by including a together a connexion N] Permissible salts.

The general formula (IB)

 (m)

[Wherein, R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, Y represents N or CH, and X ^1B — X ^2B — X ^3B — is one N = CR ⁸ — NR ^7A — (wherein, R ⁸ is as defined above, and R ^7A is a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl, Substituted or unsubstituted bicycloalkyl, substituted or unsubstituted trialkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted Represents an unsubstituted heteroaryl or a substituted or unsubstituted aralkyl), one N = C (NH R ^9A ) —NR ^7A — (wherein, R ^7A is as defined above, R ^9A is hydrogen, Replace Or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, Substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl. Substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, lower alkoxycarbonyl Or N = C (OR ¹⁰ ) -NR ^7A- (wherein R ^7A and R ¹⁰ are as defined above), and R ^1B is a substituted or unsubstituted heteroarylalkyl or an substitution or unsubstituted Ararukiru, R ^2B is hydrogen, substituted or non-replacement of the heteroalkyl § reel alkyl or substituted or unsubstituted Represents Ararukiru of conversion, unsubstituted or is formed containing N becomes R ^1B and R ^2B gar cord May represent a substituted nitrogen-containing heterocyclic group] or a pharmaceutically acceptable salt thereof.

 Furthermore, the general formula (IC)

 (I C)

[Wherein, R ^3C represents hydrogen, Y ^c is N, and one X ^1C — X ^2C — X ^3C — is —NH—C (= 〇) one NR ⁷ — (wherein, R ⁷ is as defined above. synonymous) or - NH- C (= S) - NR 7 - ( wherein, R ⁷ represents the same meaning as defined above), R ^1C is include N number of substituted 1-4 same or different Heteroarylalkyl in which a substituted or unsubstituted nitrogen-containing heterocyclic group to be formed is substituted with a heteroaryl, or aralkyl {provided that the aralkyl part of the aralkyl is the same or different and has 1 to 5 substituents Z— (C HR ⁴ ) — (CH ₂ ) _m NR ⁵ R ⁶ (wherein Z represents S, and R ⁴ , m, R ⁵ and R ⁶ are as defined above) or, the same or different in NR HR ¹² (equation. 1 to 5, R ¹¹ and R ¹² are the same or different, hydrogen, a substituted or unsubstituted lower alkyl, substituted or unsubstituted Chloroalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted Represents an aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroarylalkyl, or a substituent formed by combining R ¹¹ and R ¹² to contain N. Or an unsubstituted nitrogen-containing heterocyclic group) and at least one or more N Represents a substituted or unsubstituted nitrogen-containing heterocyclic group which is formed, and R ^2C is hydrogen, substituted or unsubstituted formed containing the same or different N having 1 to 5 substituents Heteroarylalkyl or aralkyl in which a nitrogen-containing heterocyclic group is substituted with heteroaryl, provided that the aralkyl moiety of the aralkyl is the same or different and has 1 to 5 substituents Z— (CHR ⁴ ) — (CH ₂ ) _m NR ^S R ⁶ (wherein Z represents S, and R ⁴ , m, R ⁵ and R ⁶ are as defined above) or may be the same or different. Is different! NR HR ¹² (wherein the ~ 5, R ¹¹ and R ¹² are as defined above, a substituted or unsubstituted nitrogen-containing heterocyclic group and R ¹¹ and R ¹² are formed containing together a connexion N Which is substituted by at least one substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N) or a pharmaceutically acceptable compound thereof. It relates to a compound represented by a salt or a pharmaceutically acceptable salt thereof.

 Furthermore, the general formula (ID)

(ED)

[Wherein, R ^3D represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl;

^D ttN, and one X ^1D — X ^2D — X ^3D — is one NH— C (= 0) one NR ⁷ — (where R ⁷ is as defined above) or — NH— C (= S) - NR ⁷ - (wherein, R ⁷ has the same meaning as defined above) represents, R ^1D is table terrorism § reel alkyl or substituted or unsubstituted Ararukiru to the substituted or unsubstituted, R ^2D is hydrogen, substituted or Unsubstituted heteroarylalkyl or Or a substituted or unsubstituted nitrogen-containing heterocyclic group which is formed by containing N together with a scale and a scale ^2D . Permissible salts.

In the general formula (IA), a compound in which R ³ represents hydrogen and Y represents N is one of preferred embodiments of the present invention, and among them, —X ^1A —X ^2A —X ^3A— N-NR ⁷ - (wherein, R ⁷ is the and a is defined above) compounds and one X ^1A is represented by - X ^2A - X ^3A - is - NH- C (= N - CN ) - NR 7 one ( In the formula, R ⁷ has the same meaning as described above.

In the general formula (IA), a compound in which R ³ represents hydrogen and Y represents CH is a preferred embodiment of the present invention, in which one X ^1A —X ^2A —X ^3A — is —NH—C (= 0) — NR ⁷ — (wherein, R ⁷ is as defined above), and — X ^1A — X ^2A — X ^3A — is — NH— C (= S) — NR ⁷ — ( In the formula, R ⁷ has the same meaning as described above. In the general formula (IA), R ³ represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted aralkyl, and a compound in which Y represents N is a preferred embodiment of the present invention. This is an example.

In formula (IB), R ³ represents hydrogen, compound Y represents N, R ³ represents hydrogen, compound Y represents CH, R ³ is a substituted or unsubstituted lower alkyl, substituted or unsubstituted The compound which represents cycloalkyl or substituted or unsubstituted aralkyl, and Y represents N is one of preferred embodiments of the present invention. In the general formula (IB), among the compounds in which R ³ represents hydrogen and Y represents N, — X ^1B — X ^2B — X ^3B — is — N = CR ⁸ — NR ^7A- (wherein, R ⁸ and compounds you express in R ^7A are respectively the same as the aforementioned> one ^{X 1B - X 2B - X 3B} - is one ^{N = C (NHR 9A) -} NR 7 eight - (wherein, R ^7A and R ^9A compounds represented by the same meanings as defined above), and one X one _{chi 2B} one X _3B - Gar N = c (oR ¹⁰⁾ one NR ^7A - (wherein, R ^7A and R ^1Q is defined as above The compound represented by the following is one of preferred embodiments of the present invention. In the general formula (IC), — X ^1C — X ^2C — X ^3C — is —NH—C (= O) —NR ⁷ — (wherein, R ⁷ has the same meaning as described above) or A pharmaceutically acceptable salt thereof, and a compound represented by the formula: X ^1C — X ^2C — X ^3C — is —NH—C (= S) —NR ⁷ — (wherein, R ⁷ is as defined above) The compound or a pharmaceutically acceptable salt thereof is one of the preferred embodiments of the present invention.

In the general formula (ID), a compound represented by the formula: X ^1D — X ^2D — X ^3D — is —NH—C (= O) —NR ⁷ — (wherein, R ⁷ has the same meaning as described above) or A pharmaceutically acceptable salt thereof, and one X ^1D — X ^2D — X ^3D — is —NH—C (= S) —NR ⁷ — (wherein, R ⁷ is as defined above) The compound or a pharmaceutically acceptable salt thereof is one of the preferred embodiments of the present invention.

 Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

In the definition of each group of formula (I), lower alkyl includes straight-chain or branched-chain C 1-8, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. Such as butyl, pentyl, isopentyl, neopentyl, sec-pentyl, tert-pentyl, hexyl, isohexyl, heptyl, octyl, and isooctyl are included, and the lower alkyl portion of lower alkoxycarbonyl has the same meaning. Cycloalkyls include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc., and bicycloalkyls having 7 to 10 carbon atoms, such as bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.3.1] nonyl, etc., and the tricycloalkyl has 9 to 12 carbon atoms, for example, tricyclo [3.3.1.1]. ^{3 '7]} decyl, preparative Rishikuro [3.3.1.0 ^{3' 7]} nonyl, preparative _ Rishiku port [5.4.0.0 ^{2 '9]} Undeshiru like are included, as benzo cycloalkenylene Le, 8 carbon atoms 1 2 For example, benzocyclobutenyl, dihydric benzobutenyl, indanyl, benzocyclohexenyl, dihydrob Benzohexenyl, tetrahydrobenzohexenyl, benzocyclooctenyl and the like. Lower alkenyl includes straight-chain or branched-chain C 2 -C 6, such as vinyl, aryl, propenyl, methyl phenyl, butenyl, crotyl, pentenyl, hexenyl and the like. Aralkyl includes benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms, aryl includes phenyl and naphthyl, and heteroaryl includes pyridyl, pyrimidyl, virazyl and quinoyl. Ryl, isoquinolyl, phenyl, furyl, pyrrolyl, benzophenyl, benzofuryl, indolyl and the like are included. The alkylene moiety in the heteroarylalkyl is a group obtained by removing one hydrogen from the lower alkyl, and the heteroaryl moiety has the same meaning as the heteroaryl. Examples of the nitrogen-containing heterocyclic group formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperazinyl, imidazolyl, tetrahydroisoquinolyl and the like.

Substituents in the substituted lower alkyl, substituted cycloalkyl, substituted bicycloalkyl and substituted tricycloalkyl are the same or different and have 1 to 3 substitutions, for example, cycloalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxy. Examples include carbonyl, amino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amino, substituted or unsubstituted alicyclic complex, nitro, halogen and the like. Here, cycloalkyl has the same meaning as the above cycloalkyl. The alkyl moiety in lower alkoxy, lower alkoxylability luponyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino is as defined above for lower alkyl. Halogen means fluorine, chlorine, bromine and iodine atoms. Here, specific examples of the alicyclic heterocyclic group include tetrahydrofuryl, piperidino, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperazinyl, -tetrahydrodrobilanyl, pyrrolidinyl, imidazolyl, tetrahydrolysoquinolyl and the like. Examples of the substituent of the substituted alicyclic heterocyclic ring include lower alkyl, aralkyl, aralkyl, and heteroarylalkyl as defined above. And heteroaryl. Preferred examples of the substituted alicyclic heterocyclic group include N-methylbiperazinyl, N-ethylbiperazinyl, N-methylhomopiperazinyl, N-phenylbiperazinyl, and N-benzylpiperazinyl. is there. Specific examples of the lower alkyl having a hydroxy group include hydroxymethyl, 2-hydroxyl, 3-hydroxypropyl, 4-hydroxyl butyl, 3-hydroxybutyl, 2-hydroxylbutyl, 5-hydroxypentyl, etc. Are included as preferred examples.

Substituents in substituted benzocycloalkenyl, substituted lower alkenyl, substituted aralkyl aryl, substituted aryl, substituted heteroarylalkyl and substituted heteroaryl are the same or different and are the same or different, and have 1 to 5 substituents. Alkyl, hydroxy, lower alkyl with hydroxy, lower alkoxy, carboxy, lower alkoxyl propyl, amino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amino, nitro, sulfonamide, halogen, trifluoromethyl , substituted or nitrogen-containing heterocyclic group which is formed to include unsubstituted N is included, the Raney ^{Z- (CHR 4) - (CH} 2) m NR 5 R 6 { wherein, Z It is 0, S or a single bond, R ⁴ is hydrogen or substituted or unsubstituted lower alkyl (wherein the substituted lower a Substituents Kill represents the same meaning as defined above), m represents an integer of 0 to 3, R ⁵ and R ⁶ are the same or different and are hydrogen, substitution or unsubstituted lower alkyl, substituted or unsubstituted Substituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl (where the substituents of substituted lower alkyl, substituted cycloalkyl, substituted bicycloalkyl, and substituted tricycloalkyl are as defined above. Substituted or unsubstituted lower alkenyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl Or substituted or unsubstituted heteroaryl (wherein, substituted alkenyl, substituted benzocycloalkenyl) Aryl, substituted aryl, substituted aryl, substituted heteroarylalkylheteroaryl, substituted heteroaryl The substituents on the reel are the same or different, and have 1 to 5 substituents, lower alkyl, hydroxy, lower alkyl having hydroxy, lower alkoxy, ethoxy, lower alkoxycarbonyl, amino, mono-lower alkyl substituted amino. Or a di-lower alkyl-substituted amino, nitro, sulfonamide, halogen, trifluoromethyl, substituted or unsubstituted nitrogen-containing heterocyclic group formed with N) or R ⁵ and R ⁶ There being together such connexion represents a substituted or unsubstituted nitrogen-containing heterocyclic group are comprise forms a N} or other NRHR ^{1 2} {wherein, R ^{1 1} and R ^{1 2} are the same or different, hydrogen, Substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricyclo Alkyl (where the substituents of the substituted lower alkyl, the substituted cycloalkyl, the substituted bicycloalkyl, and the substituted tricycloalkyl are as defined above), substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted Lower alkenyl, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroarylalkyl (where substituted benzocycloalkenyl, Substituted alkenyl, substituted aralkyl aryl, substituted aryl, substituted heteroarylalkyl heteroaryl, substituted heteroaryl substituents may be the same or different and have 1 to 5 substituents, lower alkyl, hydroxy, hydroxy. Lower alkyl with droxy, lower alkoxy, ethoxylate, Lower alkoxycarbonyl, amino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amino, nitro, sulfonamide, halogen, trifluoromethyl, substituted or unsubstituted nitrogen-containing complex R ¹¹ and R ¹² together represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N}. You.

In the preceding paragraph, the alkyl moiety in lower alkyl, lower alkoxy, lower alkoxycarbonyl, mono-lower alkyl-substituted amino and di-lower alkyl-substituted amino has the same meaning as the above lower alkyl, and halogen is The nitrogen-containing heterocyclic group formed having a substituted or unsubstituted N has the same meaning as the above-mentioned halogen, and the substituent on the nitrogen-containing heterocyclic ring formed having N is as defined above. Lower alkyl as defined above, hydroxy, lower alkyl having the same meaning as defined above, lower alkoxy, lower alkoxy, lower alkoxy, lower amino, diamino, mono-lower alkyl-substituted amino, di-lower alkyl-substituted amino, nitro , Sulfonamide, norogen, trifluoromethyl and the like. In addition, benzocycloalkenyl, alkenyl, aralkyl, aryl, heteroarylalkyl, and heteroarylalkenyl have the same meanings as described above.

 Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, for example, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, sulfate Inorganic acid salts such as phosphate, formate, acetate, benzoate, tartrate, maleate, fumarate, succinate, oxalate, dalioxylate, aspartate, methanesulfonate And organic acid salts such as benzenesulfonate.

 Next, a method for producing the compound (I) will be described.

Manufacturing method 1 1 1

In compound (I), Y is N, and R ³ is a raw material of a compound represented by a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, or a substituted or unsubstituted aralkyl group Compound (VIII) can be synthesized according to the following production method.

 (m)

(V) (IV)

(Wherein, R ¹ RRR ⁷ has the same meaning as described above, and R ¹³ represents a substituted or unsubstituted aryl. However, R ³ is not H.)

The compound (IVa) in which R ³ is a methyl group in the compound (IV) can be prepared by a known method [Anal, Chim. (Rome)), Vol. 56 (8-9), p. 839 (1966), and references described in the literature].

When R ³ is a substituent other than a methyl group in the compound (IV), it can be obtained by the method described below. That is, the compound (II

I) is the same as the compound (II): 1 to 10 equivalents of a carboxylic acid represented by R ³ COOH and 1 to 10 equivalents of 1,3-dicyclohexylcarpoimide, N-ethyl-N- (3 Reaction in an inert solvent in the presence of an appropriate condensing agent such as 1-dimethylaminopropyl) carpoimide, 1-hydroxybenzotriazole, or compound (II) and R ³ C〇OH (where R ³ Is the same as defined above), a reactive derivative of a carboxylic acid represented by the formula (acid chloride represented by R ³ COC 1,

(R ³ C 0) ₂ ), and 1 to 5 equivalents, and if necessary, 0.05 to 1 equivalent of triethylamine, N, N-diisopropylethylamine, pyridine, In the presence of a base such as dimethylaminopyridine, in the absence of a solvent or in a solvent such as pyridine, dichloromethane, 1,2-dichloroethane or the like, the boiling point of the solvent used under ice-cooling. It can be obtained by reacting at the melting temperature of the material for 1 to 48 hours.

 Compound (IV) was prepared according to the method described in Japanese Patent Application Laid-Open No. 499-134697.

(III) and 1 to 10 equivalents of an alkali metal hydroxide such as lithium hydroxide, potassium hydroxide and sodium hydroxide or an alkaline earth metal hydroxide such as barium hydroxide and magnesium hydroxide. In water, methanol, ethanol, 1-propanol or a mixture thereof in the presence of 1 to 10 equivalents of an oxidizing agent such as hydrogen peroxide or chromic acid, from room temperature to 10 minutes at the boiling point of the solvent used. It can be obtained by reacting for 24 hours. Compound (V) is obtained by compounding compound (IV) with 1 to 1.5 equivalents of nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate, etc. in a solvent usually used for nitration such as sulfuric acid, fuming sulfuric acid, acetic acid and acetic anhydride. The reaction can be carried out at a temperature between -78 ° C and the boiling point of the solvent used for 1 to 24 hours. Compound (VI) is the compound (V) and 1 to 10 equivalents of the formula, (wherein, R ⁷ has the same meaning as defined above) R ⁷ NH ₂ and Amin or aqueous amine solution represented by In a solvent such as ethanol, butanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, etc., in a sealed container if necessary (in a sealed tube) at room temperature to 150 ° C for 1 to 24 hours. Can be done.

Compound (VII) may be used in the presence of 1 to 10 equivalents of a base such as triethylamine, N, N-diisopropylethylamine or pyridin, if necessary, without solvent or in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane or the like. Medium, if necessary, 0.05 to 2 equivalents of N, N-dimethylformamide, 4-dimethylaminopyridine, etc. may be added, but compound (VI) is converted to 1.2 to 10 at the boiling point of the solvent used from room temperature. Reaction for 1 to 96 hours with an equivalent amount of a sulfonating agent such as methanesulfonyl chloride, benzenesulfonyl chloride, para-toluenesulfonyl chloride or a chlorinating agent such as phosphorus oxychloride, thionyl chloride, or phosphorus pentachloride After 1 to: 10 equivalents of the formula, R ¹ R ² NH

(Wherein R ¹ and R ² are as defined above) in the presence of a base such as 1 to 10 equivalents of triethylamine, Ν, Ν-diisopropylethylamine or pyridine, if necessary. In a solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, 1,2-dichloroethane, etc. at -20 t: for 30 minutes to 24 hours at the boiling point of the solvent used. Obtainable.

 Compound (VIII) is obtained by converting compound (VII) to water, tetrahydrofuran, methanol, ethanol, N, N-dimethyl in the presence of a catalytic reduction catalyst such as palladium / carbon in a weight ratio of 1/100 to 1/10. In a solvent such as formamide, under a hydrogen atmosphere or a hydrogen stream, catalytically reduce at room temperature for 1 to 24 hours at the boiling point of the solvent used, or 2 to 8 equivalents of reducing agent such as iron Z ferric chloride It can be obtained by reduction in a solvent such as water-containing ethanol or water in the presence of water while stirring from room temperature to the boiling point of the solvent used for 1 to 24 hours.

On the other hand, for a compound (Vila) in which R ³ is a methyl group, 1 to 5 equivalents of R ¹³ CH〇 (in the formula, R ¹³ is used in a solvent such as formic acid or acetic acid or in a non-solvent). Is the boiling point of the solvent used from room temperature in the presence of 1 to 20 equivalents of sodium acetate, ammonium acetate, potassium acetate, etc. By reacting for 1 to 48 hours at the melting temperature of the substrate, it is possible to lead to the compound (IX) in which R ³ is CH = CHR ¹³ .

Compound (VIII) in which R ³ is CH ₂ CH ₂ R ¹³ can be prepared in the presence of a catalytic reduction catalyst such as palladium Z carbon in a weight ratio of 1/100 to 1/10 with respect to compound (IX). , Water, tetrahydrofuran, stanol. Catalytic reduction in a solvent such as ethanol, N, N-dimethylformamide, etc. under a hydrogen atmosphere or a hydrogen stream at room temperature for 1 to 24 hours at the boiling point of the solvent used. Obtainable.

Manufacturing method 1 1 2

In the compound (I), Y is CH, raw material comprising a compound of compounds wherein R ³ is hydrogen (XV II) may be obtained by the following production method.

(X )

(X)

(Wherein, RRR ⁷ is as defined above)

The starting compound (X) can be prepared by a known method [Journal of American, Michal's Society (J. Am. Chem. Soc.), Vol. 71, p. 1901 (1949) and references described in the literature].

Compound (XI) is prepared by using compound (X) and 1-5 equivalents of nitrating agent such as nitric acid, fuming nitric acid, potassium nitrate, etc. in the normal nitration of sulfuric acid, fuming sulfuric acid, acetic acid, acetic anhydride, etc. in is solvent - ₇ at a temperature between the boiling point of the solvent used from 8 ° C can be obtained by reacting 1 to 24 hours.

Compound (XII) is compound (XI) with 1 to 10 equivalents of an amine represented by the formula: R ⁷ NH ₂ (wherein R ⁷ has the same meaning as described above) or an aqueous solution thereof. It can be obtained by reacting in a solvent such as phenol, tetrahydrofuran, dioxane, or dimethylsulfoxide in a sealed container if necessary (in a sealed tube) at room temperature to 150 at room temperature for 1 to 24 hours.

 Compound (XIII) can be prepared by converting compound (XII) in a solvent such as dichloromethane, toluene, chloroform, dioxane, or a mixture of these solvents in an amount of 1 to 30 equivalents of manganese dioxide, chromic acid, pyridinium chlorochloride. It can be obtained by reacting in the presence of an oxidizing agent such as a lime under dehydration conditions using Dean Stark, molecular sieve, or the like, at room temperature to the boiling point of the solvent used for 1 to 24 hours.

 Compound (XIV) is prepared by converting compound (XIII) from 1 to 10 equivalents of an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or sodium or potassium alcoholate. 1 to 24 hours in the presence of an organic base such as methanol, ethanol, propanol, etc., in a solvent such as water, dioxane, tetrahydrofuran or a mixed solvent of the above solvents, from room temperature to the boiling point of the solvent used. It can be obtained by reacting.

Compound (XV) is optionally used in the presence of a base such as triethylamine, Ν, Ν-diisopropylethylamine, pyridine or the like without solvent or in a solvent such as dichloromethane, 1,2-dichloroethane or the like, if necessary, with Ν, Ν-dimethylformamide. When adding a solvent such as solvent and 4-dimethylaminopyridine Is the boiling point of the solvent used from room temperature to the boiling point of the solvent used, and from room temperature to the boiling point of the chlorinating agent used when no solvent is used. It can be obtained by reacting a chlorinating agent such as phosphorus chloride alone or in combination for 1 to 96 hours.

The compound (XVI) is a compound represented by the formula (XV) and 1 to 10 equivalents of an amine represented by the formula: R ¹ R ² NH (wherein R ¹ and R ² are as defined above); If necessary, in a solvent such as tetrahydrofuran, dioxane, methylene chloride, 1,2-dichloroethane or in the absence of a solvent in the presence of 10 equivalents of bases such as triethylamine, Ν, Ν-diisopropylethylamine, pyridine, etc. Add 0.05 to 1 equivalent of Ν, Ν-dimethylformamide, 4-dimethylaminopyridinine, etc., and add the boiling point of the solvent used from -78 ° C. It can be obtained by reacting between the boiling points for 30 minutes to 24 hours.

 Compound (XV II) is prepared by using compound (XVI) as a raw material, in the presence of a catalytic reduction catalyst such as palladium Z carbon in a weight ratio of 1/100 to 1/10, water, tetrahydrofuran, methanol, Catalytic reduction in a solvent such as ethanol, ethanol, dioxane, Ν, Ν-dimethylformamide, hydrogen atmosphere or hydrogen stream, from room temperature to the boiling point of the solvent used for 1 to 24 hours, or 2 ~ 8 equivalents of iron / ferric chloride in the presence of a reducing agent in a solvent such as aqueous ethanol, water, etc. Obtainable.

 Manufacturing method 1 1 3

In the compound (I), Υ is 、, R ³ is hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted aralkyl group, and X ¹ — The compound (Ia) in which X ² — X ³ — is 一 C— C (= 0) — NR ⁷ — (wherein R ⁷ has the same meaning as described above) is obtained by starting from the compound (VIII). It can be produced according to the following reaction steps.

(Wherein, R ¹ , RR ³ , and R ⁷ are as defined above)

 Compound (Ia) may be used in combination with compound (VIII) and 1 to: L0 equivalent of a carbonylation reagent such as Ν, Ν'-carbonyldiimidazole, phosgene, urea, black alkyl carbonate, black aryl carbonate if necessary. It can be obtained by cyclizing by reacting in an inert solvent in the presence of up to 10 equivalents of a base. Examples of the base include triethylamine, Ν, Ν-diisopropylethylamine, pyridine and the like. Examples of inert solvents include water, alcohols (e.g., methanol and ethanol), nonpolar solvents (e.g., ethyl acetate and ether), and nonprotonic polar solvents (acetonitrile, Ν, Ν-dimethylformamide, dimethylacetate). Tomide, dimethylsulfoxide, tetrahydrofuran, dioxane, etc.), and halogenated hydrocarbons (dichloromethane, chloroform, etc.). The reaction is completed in 10 minutes to 48 hours from 0 ° C. to the boiling point of the solvent used.

Manufacturing method 1 1 4

In the compound (I), Y is N, R ³ is hydrogen, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted cycloalkyl group or a substituted or unsubstituted aralkyl group, and — X ¹ — A compound (lb) in which X ² — X ³ — is —NH—C (= S) -NR ⁷ — (wherein R ⁷ has the same meaning as described above) is obtained by starting from the compound (VIII) It can be produced according to the reaction process.

(Wherein, R ¹ , R ² , R ³ and R ⁷ are as defined above)

 Compound (lb) is prepared by combining compound (VIII) with 1 to 10 equivalents of Ν, -'- thiocalponyldiimidazole, thiophosgene or 1 to 200 equivalents of a thiocarbonylating reagent such as carbon disulfide, if necessary. It can be obtained by cyclizing by reacting in an inert solvent in the presence of 200 equivalents of a base. The base and the inert solvent are the same as those used in production method 13 to produce compound (Ia). Is mentioned. The reaction is completed in 10 minutes to 120 hours from 0 ° C. to the boiling point of the solvent used.

Manufacturing method 1 1 5

In the compound (I), Y is N and R ³ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and — X ¹ — X ² — X ³ — is — N = N— NR ⁷ — (wherein R ⁷ is as defined above) (I c) is a compound

 (V I I) can be used as a starting material according to the following reaction steps.

R,

(Wherein, R ¹ , R ² , R ³ and R ⁷ are as defined above) Compound (I c) can be obtained by reacting compound (VIII) with 1-2 equivalents of a nitrous acid solubilizing agent such as sodium nitrite in an aqueous solution of hydrochloric acid, acetic acid, sulfuric acid or a mixed solvent thereof. it can. The reaction is performed between ice-cooling and the boiling point of the solvent used, and is completed in 10 minutes to 4 hours.

Manufacturing method 1 1 6

In the compound (I), Y is N, R ³ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and one X ¹ —X ² — X ³ — but — NH— C

(= N-CN) _NR ⁷ — (wherein R ⁷ is as defined above), can be produced from compound (VIII) as a starting material according to the following reaction steps. it can.

(Wherein, R ¹ R ² , R ³ and R ⁷ are as defined above)

 Compound (Id) may be prepared by adding i-io equivalents of dialkylcyanodithioiminocarbonate and diarylcyanodithioimino carbonyl compound to compound (VIII) in the presence of ~ ^ equivalents of base, if necessary. It can be obtained by cyclizing by reacting in an active solvent or without using a solvent. Examples of the base and the inert solvent include the same ones as in the production method 112 for producing the compound (Ia). The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used, or the temperature at which the substrate melts if no solvent is used.

The compound (Id) is obtained from the compound (lb) obtained by the production method 1-4. Can be obtained by the following two methods (a, b). That is, the compound (lb) is reacted with 1 to 6 equivalents of mercury oxide (II) Z sulfur in an inert solvent in the presence of 1 to 10 equivalents of a base, if necessary, and then 1 to 10 equivalents as necessary. The compound (Id) can be obtained by reacting 2-5 equivalents of cyanamide (H ₂ NCN) in the presence of the base (Method a). On the other hand, the compound (Ib) is reacted with: ~ 5 equivalents of a cyanamide lead salt (Pb = N-CN) in the presence of 1 to 10 equivalents of a base, if necessary, in an inert solvent to form a cyclized compound. The compound (Id) can also be obtained by carrying out (Method b). As the base and the inert solvent in the above reaction, those similar to Production methods 1-3 for producing compound (Ia) can be mentioned. The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.

Manufacturing method 1 1 7

In the compound (I), Y is N, R ³ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and X ¹ — X ² — X ³ — is one NH— CR ⁸ = NR ^7A — (wherein R ⁸ and R ^7A are as defined above). The compound (I e) is obtained by using the compound (VIII) as a starting material in the next reaction step. It can be manufactured according to

(Wherein, R ¹ R ² , R ³ , R ^7A and R ⁸ are as defined above)

Compound (I e) is 1 to 15 equivalents of compound (VIII) and 15 equivalents of ethyl orthoformate (CH (〇CH ₂ CH ₃ ) ₃ ) and ethyl acetate ortho (CH ₃ C (〇CH ₃ It can be obtained by reacting ortho acid esters such as ₂ CH ₃ ) ₃ ) and ethyl ethyl orthopropionate (CH ₃ CH ₂ C (〇CH ₂ CH ₃ ) ₃ ) in an inert solvent or without solvent. . Compound (VIII) and 1 to 10 equivalents of a carboxylic acid represented by R ⁸ C00H can be combined with 1 to 10 equivalents of 1,3-disc-hexylcarboximide, N-ethyl-N- (3- Dimethylaminopropyl) force The reaction is carried out in an inert solvent in the presence of a suitable condensing agent such as luposimid or hydroxybenzotriazole, or the reaction between compound (VIII) and a carboxylic acid represented by R ⁸ COOH. 1 to 10 equivalents of triethylamine, N, and the like, depending on the necessity of the acid derivative (an acid anhydride represented by R ⁸ C 0 C 1 or an acid anhydride represented by (R ⁸ CO) ₂₀ ). After reacting in an inert solvent in the presence of a suitable base such as N-diisopropylamine or pyridine, treat with 1 to 10 equivalents of a suitable base such as sodium hydroxide or potassium tert-butoxide. The compound (I e) can also be obtained by the method described above. As the base and the inert solvent in the above reaction, those similar to the production method 13 to produce the compound (Ia) can be mentioned. The reaction is completed in 10 minutes to 48 hours from 0 ° C to the boiling point of the solvent used.

Manufacturing method 1 1 8

In the compound (I), Y is N and R ³ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and X ¹ — X ^The compound (If) wherein ² — X ³ — is one of N = C (NH R ^9A ) — NR ^7A — (wherein R ^9A and R ^7A are as defined above) is a compound (VIII) In a well-known method using the starting material [ABSTRACTS 26th CONGRESS OF HETEROCYCLIC CHEMISTRY] C-19 (pp.241-244), Otsu (November 6-8, 1995) It can be manufactured according to it.

(Wherein, R ¹ R ² , R ³ , R ^7A and R ^9A are as defined above)

Compound (If) is reacted with compound (VIII) and 1-5 equivalents of R ^9A —N = C = S in the absence of solvent or in pyridine to obtain the corresponding thiourea derivative. Thereafter, the obtained thiourea derivative can be obtained by reacting the obtained thiourea derivative with an appropriate silver salt such as 1 to 5 equivalents of silver acetate, silver trifluoroacetate, or silver trifluorene acetate in an inert solvent. . As the inert solvent, those similar to the production method 13 of producing the compound (Ia) can be mentioned. The reaction is completed in 10 minutes to 48 hours from 0 ° C. to the boiling point of the solvent used.

Manufacturing method 1 1 9

In the compound (I), Y is N, R ³ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and X ¹ — X ² — X ³ — is — N = C (OR ¹⁰ ) -NR ^7A — (wherein R ¹⁰ and R ^7A have the same ^meanings as above). It can be produced according to the following reaction steps.

(式中、 R ¹ R ²、 R ³、 R ^7A、 R ^{1 C)}は前記と同義である） 化合物 （ I g ) は、 化合物 （V I I I ) をテトラメ トキシメタン、 テ トラエトキシメタン等の C (O R ¹⁰) ₄で表される化合物中、 1/1000〜5 当量の塩酸、 硫酸、 酢酸、 トリ フルォロ酢酸、 トリフルォロスタンスル ホン酸等の酸存在下に反応させることで得ることができる。 反応は、 無 溶媒で行われ、 0 °Cから使用されるテトラアルコキシメタンの沸点の間 で、 10 分〜 48 時間で終了する。

^{(Wherein, R 1 R 2, R 3} , R 7A, R 1 C) are the same as defined above) Compound (I g), the compound (VIII) with tetramethylene Tokishimetan, such as Te tiger diethoxymethane C (OR ¹⁰ ) It can be obtained by reacting the compound represented by ₄ in the presence of 1/1000 to 5 equivalents of an acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, and trifluorostansulfonic acid. The reaction is carried out without solvent and is completed between 0 minutes and the boiling point of the tetraalkoxymethane used in 10 minutes to 48 hours.

Manufacturing method 1 1 1 0

In the compound (I), Y is CH, R ³ is hydrogen, and one X ¹ — X ² — X ³ — is —NH—C (= O) —NR ⁷ — (wherein R ⁷ is The compound (Ih) having the same meaning as the above) can be produced by the same method as in Production method 13 using compound (XVII) as a raw material.

(Wherein, R ¹ RR ⁷ is as defined above)

Manufacturing method 1 — 1 1

In compound (I), Y is CH, R ³ is hydrogen, and —X ¹ —2-3 -——? ^^ ₁ - ○ ^{(= S) - NR 7 -} ( wherein, R ⁷ has the same meaning as defined above) compound is (I i) are have use compound (XV II) as a raw material, production method 1 one It can be manufactured by the same method as in 4.

(Wherein, RRR ⁷ is as defined above)

Manufacturing method 1 1 1 2

In the compound (I), Y is CH, R ³ is hydrogen, and — X ¹ — X ² — X ³ — is N = N—NR ⁷ — (wherein, R ⁷ has the same meaning as described above.) )) Can be produced in the same manner as in Production Methods 1 to 5, using Compound (XVII) as a raw material.

(Wherein, RRR ⁷ is as defined above)

Manufacturing method 1 1 1 3

In the compound (I), Y is CH, R ³ is hydrogen, and — X ¹ -X ² —X ³ — is —NH—C (= N—CN) —NR ⁷ — (wherein, R ⁷ Is the same as defined above), and can be produced by the same method as in Production Methods 1 to 6, using Compound (XVII) as a raw material. NC-N

(Wherein, RR ² and R ⁷ are as defined above)

Manufacturing method 1 1 1 4

In the compound (I), Y is CH, R ³ is hydrogen, and X ¹ — X ² — X ³ — is —NH—CR ⁸ = NR ^7A — (wherein R ⁸ and R ^7A are The compound (Im) is a compound (Xm) as a starting material, and can be produced by a method similar to the production method 117.

(Wherein, R ¹ RR ^7A and R ⁸ are as defined above)

Manufacturing method 1 1 1 5

In the compound (I), Y is CH, R ³ is hydrogen, and one X ¹ — X ² — X ³ — is — N = C (NHR ^9A ) _NR ^7A — (wherein, ⁹ and ¹⁷ (In is) as defined above, can be produced by using the compound (XVII) as a raw material in the same manner as in the production method 118.

(Wherein, R ¹ R ² , R ^7A and R ^9A are as defined above)

Manufacturing method 1 1 1 6

In the compound (I), Y is CH, R ³ is hydrogen, and —X ¹ —X ² —X ³ is one N = C (OR ¹⁰ ) -NR ^7A- (where R ¹⁰ and R ^7A are Compound (I p) having the same meaning as described above can be produced by the same method as in Production Methods 1 to 9 using compound (XVII) as a raw material.

(Wherein, R ¹ , R ² , R ^7A and R ¹⁰ are as defined above)

 Intermediates and target compounds in the above production methods can be isolated and purified by purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, and various types of chromatography. it can. In addition, the intermediate can be subjected to the next reaction without purification. Some of the compounds (I) may have positional isomers, geometric isomers, optical isomers or tautomers, but the present invention relates to all possible isomers, including these, Of mixtures.

When it is desired to obtain a salt of compound (I), compound (I) is obtained in the form of a salt. In the case where it is obtained in a free form, it may be isolated or purified by dissolving or suspending it in an appropriate solvent, adding an acid to form a salt, and purifying.

Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts of water or various solvents, and these adducts are also included in the present invention. Table 1 shows specific examples of the compound (I) obtained by the present invention.

zi-/ 66cevlcd> 9ε o

o

 (¾¾H) ()> KS: HN =-

(¾D)) KN (S: HN =-

()23(>NHCNCSHCH CH= --- (¾.Li). ) H. ¾) N) HM S =-

() 23 (> NHCNCSHCH CH = ---

雠 ^ 121 Table 1-3

Compound number -xLx ^ x ³ YR ¹

21 -NH-C (= S) -N (CH ₂ CH ₃ )-N CH ₂ ~ N NCH ₃ HH

26 -N = CN (CH ₂ CH ₃ )-N CH ₂ -N (CH ₃ ) ₂ HH

27 -N = C (NHC0 ₂ CH ₂ CH ₃ ) -N (CH ₂ CH ₃ )-NHH

28 -N = C (NH ₂ ) -N (CH ₂ CH ₃ )-N CH ₂ ~ i -N (CH ₃ ) ₂ HH

第 1表一 4

Table 1-4

Compound number-χ ^ χ χ ³ Υ R ¹

31 -N = C (NHCH,)-N (CH ₂ CH-N CH ₂ Η Η

32 -NH-Q = N-CN) -N (CH, CH ₃ )-Ν CH ₂ -<\ I Η Η

33 -NH-C (= N-CONH ₂ ) -N (CH ₂ CH ₃ )-Ν CH ₂

 Ν · I Η Η

34 -N = C (OCH ₂ CH ₃ ) -N (CH ₂ CH ₃ )-Ν CH 2 飞 -N (CH ₃ ) ₂ Η Η

35 -N = C (OCH ₃ ) -N (CH ₂ CH ₃ )-Ν Η Η

36 -N = C (OCH ₃ ) -N (CH ₂ CH ₃ )-Ν -CH ₂ CH ₂ -0-CH ₂ CH ₂ - _Η

38 -NH-C (= S) -N (CH ₂ CH ₃ )-CH HH

H ₃ CO

39 -NH-C (= S) -N (CH ₂ CH ₃ )-CH CH ₂ CH ₂ CH ₂ N ^ OHH

40 -NH-C (= S) -N (CH ₂ CH ₃ )-CH CH ₂ CH ₂ H /> HH

N-g Table 1-5

Compound number -X -X -X-YR ¹

41 -NH-Cf = S) -NfCH ₂ CH ₃ )-CH CH ₂ -(\ // HH

42 -NH-C (= 0) -N (CH ₂ CH ₃ )-CH CH.0 HH

,

43 -N = NN (CH ₂ CH ₃ )-N CH 2 / NO HH

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

Test Example 1. Inhibitory effect on PDE derived from canine tracheal smooth muscle

 (1) Purification of enzyme

 PDEV (cGMP-specific) from canine tracheal smooth muscle, mainly according to the method of Torphy et al. [Molecular 'Mol. Pharmacol., 37, 206 (1990)] PDE) was purified.

 (2) PDE activity measurement method

 The activity was determined by the method of Kincaid et al. [Methods in, Enzymol. (J. D. Corbin et al.), 159, 457].

(1988), Academic Press, New York]. That is, [ ³ H] c GMP (1.0 mol) was used as a substrate, and the reaction was carried out in a composition buffer as follows.

Noffer composition: 50 mM N, N-bis (2-hydroxyxetyl) -2-aminoethanesulfonic acid (pH 7.2), 1 mM MgCl 2, 0.1 mg / ml soybean trypsin inhibitor

3f Yuichi.

The reaction was started by addition of the enzyme, and the reaction was stopped by adding hydrochloric acid after reacting at 30 for 10 to 30 minutes. After neutralization with sodium hydroxide, 5'-GMP was converted to guanosine with 5'-nucleotidase, the reaction solution was applied to a DEAE-Sephadex A-25 column, and [ ³ H] guanosine was eluted with distilled water. Radioactivity was measured with a liquid scintillation counter. The inhibitor was dissolved in 1.7% dimethyl sulfoxide.

 Table 2 shows the PDE inhibitory activity. Table 2 Activity of P D EV

Compound number Inhibition rate (%)

 Compound concentration (1 nM)

1 86

 2 91

 3 89

4 84

42

13 89

17 97

21 83

22 90

23 87

24 79 Test example 2. Antihypertensive action in rat

After urethane anesthesia, a male Sprague-Dawley rat was fixed on the back, a forcepray was inserted into the trachea, and artificial respiration was performed at 10 ml / kg, 60 times / min. Was done. In addition, force neurons were introduced into the carotid artery and the duodenum, which were used for blood pressure measurement and drug administration, respectively. The drug was dissolved or suspended in distilled water and administered into the duodenum using the above-mentioned forcenula. Mean blood pressure up to 30 minutes after drug administration _(m BP) measured before drug administration value

The maximum decrease rate (in%) from (100%) was determined. When distilled water was administered, there was no change in mean blood pressure for 30 minutes.

Table 3 shows the results. Table 3 Antihypertensive activity

Compound number Rat, 10 mg / kg, i.d.N = 2

 Maximum decrease rate (%)

13 14

Test Example 3. Intra-cavernous pressure-increasing action and internal pressure-increasing duration in dogs

Male beagle dogs (body weight 9-13 kg, manufactured by Nippon Agriculture) were used in the experiment under anesthesia with bentovalpital. Fix the patient on the bench in the supine position, place the trachea in the trachea, and use a human respirator (SN-480-3, Shinano Seisakusho) to keep the respiratory volume constant (15-20 mL / kg, 15-20 times Z minutes) Kept. For intracavernous pressure (ICP), an 18-gauge winged needle (SV-18CLK, Terumo) was inserted into the corpus cavernosum, and the other end was connected to a pressure-strain sensor (TP-600DT, Nihon Kohden). Amplifier (AP-621G, Japan (Photoelectric). The pelvic nerve was detached and a bipolar stimulating electrode (UT-1530, Unique Medical) was attached, and stimulated with an electric stimulator (SEN-3201, Nippon Koden). First, excessive electrical stimulation (10 to 40 Hz,:! To 5 V, for 10 to 20 seconds) was applied to induce an increase in ICP, which was defined as the maximum response. Then, the stimulation conditions were adjusted to obtain a 30-50% response. The stimulation was repeated at 10-minute intervals, and the experiment was started after confirming that the reaction occurred reproducibly. The drug was dissolved in a 0.5% methylcellulose solution and administered in the duodenum (lmg / kg, 0.5mL / kg), and observed for 2 hours and 30 minutes.

 Table 4 shows the results.

Compound A: 3-Ethyl-8- (2-pyridylmethylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione · 2 hydrochloride (WO95 / Compound of Example 49 of 06648)

Compound B: 3-Ethyl-8- {2- [1- (1,2,3,6-tetrahydropyridyl) methyl] benzilamino} -2,3-dihydrido-1H-imidazo [4,5-g ] Quinazolin-2-thione dihydrochloride (Compound of Example 71 of WO96 / 26940)

Table 4 Activity of increasing intracavernous pressure

0.5 ¾ C 55 mmHg 55 mmHg ± 0% 3 Compound A 54 mmHg 71 mmHg + 25% 2 Compound B 50 mmHg 68 mmHg + 36% 3

 W095 / 06648 W096 / 26940

 Compound 49 Compound 71

From the above, it is apparent that the compound (I) or a pharmaceutically acceptable salt thereof described in claim 1 is useful as a therapeutic drug for erectile dysfunction. Compound (I) or a pharmacologically acceptable salt thereof includes, for example, commonly used preparations such as tablets, capsules, injections, drops, syrups, sublingual tablets, various creams, suppositories, etc. It can be prepared in a form that can be administered orally or by parenteral administration, such as intramuscular injection, intravenous injection, intraarterial injection, infusion, application, rectal administration with suppositories. For the preparation of such oral or parenteral dosage forms, generally known methods are applied, for example, various excipients, lubricants, binders, disintegrants, suspending agents, It may contain a tonicity agent, an emulsifier and the like.

Pharmaceutical carriers used include, for example, water, distilled water for injection, physiological saline, glucose, sucrose, mannite, lactose, starch, and cellulose. Methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glyceric acid ester, etc. Is raised.

Formulation Example 1 (tablet)

 A tablet having the following composition was prepared by a conventional method.

Compound 13 100 mg

Lactose 60 mg

Potato starch 30 mg

Polyvinyl alcohol 2 mg

Magnesium stearate 1 mg

Tar dye

Formulation Example 2 (powder)

 A powder having the following composition was prepared by a conventional method.

Compound 1 3 150 mg

280 mg of sugar

Formulation example 3 (syrup)

 A syrup having the following composition was prepared by a conventional method.

Compound 13 100 mg

40 g purified sugar

P-hydroxyethyl benzoate 40 mg

P-hydroxypropyl benzoate 10 mg

 Strawberry flavor 0.1 cc

 Add water to make the total volume 100 cc.

The dosage and frequency of administration vary depending on the dosage form, patient age, body weight, symptoms, etc., but usually 0.05 to 5 g / 60 kg / day is appropriate for oral administration, and 0.01 to 5 mg / day for infusion. It is preferred that the daily oral dose at kg / min not exceed the limit. BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples.

The proton nuclear magnetic resonance spectra ( ¹ H-NMR) used in Examples and Reference Examples were measured at 270 MHz unless otherwise indicated. The peak shape is expressed as follows. _s: singlet, d: doublet, t: triplet, m: multiplet, br: broad. Reference example 1

 7-Cu mouth- 2-methyl-6-nitro-2- 4 (3H) -quinazolinone

 Methods described in the literature [Anal 'Di' Kimika (Rome) (Ann. Chim.

(Rome)), vol. 56 (8-9), p. 839 (1996), etc.], and concentrated sulfuric acid was added to concentrated sulfuric acid (3.89 g, 20.0 mmol) obtained from 7-cloguchi-2-methyl-4 (3H) -quinazolinone. (20 ml), and fuming nitric acid (0.8 ml, 20.0 mmol) was added dropwise while maintaining the internal temperature at 10 ° C or lower. After completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred for 3.5 hours. The reaction solution was poured on ice, neutralized, and the precipitated crystals were collected, washed with water, methanol and ether in that order, and dried to obtain the title compound (2.74 g, 57%).

1 H-NMR (DMSO-d ₆ ) δ (ppm): 2.40 (3H, s), 7.89 (1H, s), 8.63 (1H, s),

12.65 (1H, br). Reference Example 2

 7-Ethylamino-2-methyl-6-nitro-2--4 (3H) -quinazolinone

 The compound (28.0 g, 117 mmol) obtained in Reference Example 1 and a 70% aqueous solution of ethylamine (120 ml) were stirred in dimethyl sulfoxide (200 ml) at 80 ° C for 2 hours. To complete the reaction, the above ethylamine solution (20 ml) was further added, and the mixture was stirred at the same temperature for 1 hour. After the completion of the reaction, a large amount of water was added, and the precipitated crystals were collected, washed with water, and dried to obtain the title compound (19.7 g, 68%).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.28 (3H, t, J = 7.1 Hz), 2.32 (3H, s), 3.36- 3.46 (2H, m), 6.82 (1H, s), 8.09 (1H, br), 8.74 (1H, s), 12.00 (1H, br). Reference example 3

 7-ethylamino-2-methyl-4- (4-dimethylamino) benzylamino-6-diquinoquinoline

 Compound obtained in Reference Example 2 (1.00 g, 4.03 mmoi), p-toluenesulfonyl chloride (1.15 g, 6.00 mmol), triethylamine (2.23 ml, 16.0 mmol)> 4-dimethylaminopyridine (0.024 g, 0.20 mmol) Was stirred in methylene chloride (10 ml) at room temperature overnight. Further, P-toluenesulfonyl chloride (1.15 g) and trieramine (2.23 ml) were added, and the mixture was stirred overnight at room temperature. After completion of the reaction, a saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted with a mouth-mouth form. The organic layer was dried (anhydrous sodium sulfate) and concentrated under reduced pressure to obtain an oily substance.

 The obtained oil was dissolved in tetrahydrofuran (30 ml), and triethylamine (2.80 ml, 20.0 mmol) 4-dimethylaminobenzylamine dihydrochloride (1.34 g, 6.00 mmol) was added. Stirred overnight. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added to the obtained oil, and the mixture was extracted with ethyl acetate. The organic layer was dried (magnesium sulfate) and concentrated under reduced pressure. The obtained oily substance (2.67 g) was subjected to gel chromatography on silica gel (eluted with chromatoform Z and ethyl acetate = 6) to give the title compound (1.19 g, 78%).

_{i H-NMR (CDC1 3)} δ (ppm): 1.37 (3H, t, J = 7.3Hz), 2.60 (3H, s), 2.94 (6H, s), 3.30-3.36 (2H, m), 4.72 ( 2H, d, J = 4.6Hz), 6.36 (1H, br), 6.71 (2H, d, J = 8.9Hz), 6.91 (1H, s), 7.28 (2H, d, J = 8.9Hz), 7.68 ( 1H, t, J = 4.6Hz), 8.69 (1H, s). Reference Example 4

 7-Ethylamino-2-methyl-6-dimethoxy-4- (2-pyridylmethyl) aminoquinazones

 The title compound was obtained in the same manner as in Reference Example 3 (yield 11%).

_{^ -NMR (CDC1 3) (3} (ppm): 1.39 (3H, t, J = 7.3Hz), 2.55 (3H, s), 3.33-3.40 (2H, m), 4.91 (2H, d, J = 4.6 Hz), 6.86 (1H, s), 7.26-7.31 (1H, m), 7.40 (1H, d, J = 7.9Hz), 7.68-7.77 (2H, m), 8.01 (1H, br), 8.65 (1H, d, J = 5.1Hz), 8.81 (1H, s).

 2-morpholine benzonitrile

 2-Fluorobenzonitrile (1.21 g, 1.00 mmol) was dissolved in acetonitrile (50 ml), morpholine (33 ml, 377 mmol) was added, and the mixture was stirred at 110 ° C under nitrogen. After completion of the reaction, the reaction solution was concentrated, and the obtained oily substance was purified by silica gel column chromatography (eluted with silica gel column chromatography) to obtain the title compound (1.80 g, 95%) as an oily substance.

_{^{1 H-NMR (CDC1 3)}} δ (ppm):. 3.15-3.23 (4H, m), 3.83-3.97 (4H, m), 7.01- 7.10 (2H, m), 7.48-7.60 (2H, m) Reference Example 6

 7-ethylano-2-methyl-4- (2-morpholino) benzylamino-6-nitroquinazoline

 Lithium aluminum hydride (2.43 g, 64.0 mmol) was suspended in tetrahydrofuran (100 ml) and stirred. Under ice cooling, a solution of the compound obtained in Reference Example 5 (4.00 g, 21.3 mmol) in tetrahydrofuran (100 ml) was added dropwise to the above suspension. After completion of the dropwise addition, the reaction solution was reacted at 80 for 3 hours. After completion of the reaction, the reaction solution was cooled, and sodium sulfate / 10-hydrate was added little by little until foaming stopped. The insoluble material was filtered, and the filtrate was concentrated to obtain an oily substance (about 3.8 g).

 The title compound (14% yield) was obtained by treating the oily substance obtained above and the compound obtained in Reference Example 2 with P-toluenesulfonyl chloride in the same manner as described in Reference Example 3. ).

^ -NMR (DMSO-d ₆ ) δ (ppm): 1.26 (3H, t, J = 7.1 Hz), 2.34 (3H, s), 2.83-2.92 (4H, m), 3.32-3.39 (2H, m) , 3.73-3.77 (4H, m), 4.86 (2H, d, J = 5.6Hz), 6.80 (1H, s), 7.06 (1H, dd, J = 7.3Hz, 8.6Hz), 7.17 (1H, d, J = 7.6Hz), 7.23- 7.29 (2H, m), 7.75 (1H, t, J = 5.6Hz), 9.03 (1H, t, J = 5.3Hz), 9.28 (1H, s). Reference Example 7

 4-propylaminobenzonitrile

 The title compound was obtained from 4-fluorobenzonitrile and n-propylamine in the same manner as in Reference Example 5 (yield: 45%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 0.99 (3H, t, J = 7.4Hz), 1.57-1.71 (2H, m), 3.06- 3.34 (2H, m), 4.50 (1H, br), 6.55 (2H, d, J = 8.7Hz), 7.38 (2H, d, J = 8.7Hz). Reference Example 8

 7-ethylamino-2-methyl-6-nitro-2--4- (4-pyruamino) benzylaminoquinazoline

 The title compound was obtained in the same manner as in Reference Example 6 using the compound obtained in Reference Example 7 and the compound obtained in Reference Example 2 (yield 79

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.91 (3H, t, J = 7.4 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.46-1.59 (2H, m), 2.38 ( 3H, s), 2.89-2.97 (2H, m), 3.30-3.40 (2H, m), 4.56 (2H, d, J = 5.6Hz), 5.51 (1H, t, J = 5.6Hz), 6.51 (2H , d, J = 8.6Hz), 6.76 (1H, s),

7.10 (2H, d, J = 8.6Hz), 7.72 (1H, t, J = 5.6Hz), 8.96 (1H, t, J = 5.6Hz), 9.22 (1H, s).

 4-chloro-2- (propionylamino) benzonitrile

 4-Chloroanthranilonitrile (1.53 g, 10.0 mmol) was dissolved in 5 ml of pyridine, and under ice cooling, 4-dimethylaminopyridine (0.12 g, 1.00 mmol) and propionic acid chloride (1.05 ml, After addition of water (500 ml), the precipitated crystals were collected, washed with a large amount of water, dried and dried to give the title compound (1.82 mmol). g, 87%).

_{1 H-NMR (CDC1 3)} (5 (ppm): 1.28 (3H, t, J = 7.6Hz), 2.51 (2H, q, J = 7.6Hz), 7.15 (1H, dd, J = 2.0Hz, 8.6 Hz), 7.50 (1H, d, J = 8.6Hz), 8.57 (1H, d, J = 2.0Hz). Reference example 10

 7-Black mouth-2-ethyl-4 (3H) -quinazolinone

 According to a known method (open patent publication, JP-A-4-19-134697), the compound obtained in Reference Example 9 was subjected to a hydroxylation power in the presence of hydrogen peroxide in a mixed solvent of ethanol and Z water. The title compound (83% yield) was obtained.

'H-NMR (DMSO-d ₆ ) δ (ppm): 1.28 (3H, t, J = 7.3 Hz), 2.66 (2H, q, J = 7.3 Hz), 7.51 (1H, d, J = 7.6 Hz) , 7.67 (1H, s), 8.09 (1H, d, J = 7.6Hz), 12.36 (1H, br). Reference Example 1 1

 7-Black mouth-2-Ethyl-6-6-2-mouth-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 10 as a raw material, the title compound was obtained in the same manner as in Reference Example 1 (yield, quantitative).

^X H-NMR (DMSO-d ₆ ) δ (ppm): 1.26 (3H, t, J = 7.6 Hz), 2.64 (2H, q, J = 7.6 Hz), 7.91 (1H, s), 8.63 (1H, s), 12.68 (1H, s). Reference Example 1 2

 2-Ethyl-7-ethylamino-6-two-mouth-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 11 as a raw material, the title compound was obtained in the same manner as in Reference Example 2 (57% yield).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.22-1.32 (6H, m), 2.58 (2H, q, J = 7.6 Hz), 3.37-3.47 (2H, m), 6.84 (1H, s ), 8.10 (1H, t, J = 5.3Hz), 8.75 (1H, s), 12.03 (1H, br).

 2-Ethyl-7-ethylamino-4- (2-pyridyl) methylamino-6-nitroquinoline

 Using the compound obtained in Reference Example 12 as a raw material, the title compound was obtained in the same manner as in Reference Example 3 (yield 33%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.30 (3H, t, J = 7.6Hz), 1.37 (3H, t, J = 7.3Hz), 2.76 (2H, q, J = 7.6Hz), 3.30-3.38 (2H, m), 5.15 (2H, br), 6.88 (1H, s), 7.28 (1H, dd, J = 4.3Hz, 7.9Hz), 7.45 (1H, d, J = 7.6Hz), 7.64 (1H, t, J = 5.0Hz), 7.76 (1H, dd, J = 7.6Hz, 7.9Hz), 8.45 (1H, br), 8.63 (1H, d, J = 4.3Hz), 8.71 (1H, s). Reference example 1 4

 4-chloro-2- (cyclopentylcarboxyamide) benzonitrile

 The title compound was obtained from 4-cyclomouth anthranilonitrile and cyclopentanecarbonyl chloride in the same manner as in Reference Example 9 (yield 79%).

_{L H-NMR (CDC1 3)} δ (ppm): 1.62-2.07 (8H, m), 2.74-2.86 (1Η, m), 7.13 (1H, dd, J = 2.0Hz, 8.6Hz), 7.49 (1H, d, J = 8.6Hz), 7.67 (1H, br), 8.58 (1H, d,

J = 2.0Hz). Reference example 1 5

 7-Cu mouth mouth 2- 2-neck mouth pentyl -4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 14, the title compound was synthesized in the same manner as in Reference Example 10 (82% yield).

'H-NMR (DMSO-d ₆ ) δ (ppm): 1.60-2.09 (8H, m), 2.97-3.09 (1Η, m), 7.47 (1H, d, J = 8.6 Hz), 7.63 (1H, s ), 8.06 (1H, d, J = 8.6 Hz), 12.27 (1H, br).

 7-Black mouth 2-Chick mouth pentyl-6-Nito mouth-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 15 as a raw material, the title compound was obtained in the same manner as in Reference Example 1 (yield, quantitative).

i fi-NMR (DMSO-d ₆ ) δ (ppm): 1.63-2.05 (8H, m), 3.02-3.14 (1Η, m), 7.85 (1H, s), 8.63 (1H, s), 12.67 (1H , S). Reference Example 1 7

 2-cyclopentyl -7-ethylamino -6-nitro-4-4 (3H) -quinazolinone

Using the compound obtained in Reference Example 16 as a raw material and labeling in the same manner as Reference Example 2 Compound was obtained (yield 91%)

¹ H-NMR (D SO-d ₆ ) δ (ppm): 127 (3Η, t, J = 6.9 Hz), 1.60-1.95 (8H, m), 2.92-3.01 (lH, m), 3.40- 3.46 (2H, m), 6.83 (1H, s), 8.10 (1H, br), 8.75 (1H, s), 12.03 (1H, br). Reference Example 1 8

 2-cyclopentyl-7-ethylamino-4- (4-dimethylaminobenzilamino) -6-nitroquinazoline

The title compound was obtained in the same manner as in Reference Example 3 using the compound obtained in Reference Example 17 and 4-dimethylaminobenzylamine dihydrochloride (yield 82%). _{1 H-NMR (CDC1 3)} δ (ppm): 1.34 (3H, t, J = 7.3Hz), 1.67- 1.72 (2H, m), 1.85- 1.89 (2H, m), 2.00-2.17 (4H, m ), 2.91 (6H, s), 3.17-3.30 (3H, m), 4.74 (2H, d, J = 5.0Hz), 6.57 (1H, br), 6.67 (2H, d, J = 8.6Hz), 6.88 (1H, s), 7.28 (2H, d, J = 8.6Hz), 7.63 (1H, t, J = 4.6Hz), 8.71 (1H, s).

 2-cyclopentyl-7-ethylamino-6-nitro-2--4- (2-pyridylmethylamino) quinazoline

 The title compound was obtained in the same manner as in Reference Example 3 using the compound obtained in Reference Example 17 and 2-pyridylmethylamine as raw materials (yield 59%).

_{i H-NMR (CDC1 3)} δ (ppm): 1.34 (3H, t, J = 7.3Hz), 1.64-2.02 (8H, m), 3.02- 3.14 (1H, m), 3.21-3.31 (2H, m ), 4.88 (2H, d, J = 4.6Hz), 6.74 (1H, s), 7.24- 7.29 (1H, ra), 7.47 (1H, d, J = 7.9Hz), 7.53 (1H, br), 7.71 -7.78 (1H, m), 8.62 (1H, d, J = 8.6Hz), 8.64 (1H, s), 8.90 (1H, br). Reference example 20

 2-cyclopentyl-7-ethylamino-4- (2-morpholinobenzylamino) -6-nitroquinazoline

Using the compound obtained in Reference Example 17 as a raw material, This gave the title compound (yield 64%).

_{^ -NMR (CDC1 3) δ (} ppm): 1.38 (3H, t, J = 7.3Hz), 1.66-1.79 (2H, m), 1.83- 2.18 (6H, m), 3.02-3.06 (4H, m) , 3.13-3.23 (1H, m), 3.31-3.38 (2H, m), 3.90-3.94 (4H, m), 4.96 (2H, d, J = 5.3Hz), 6.96 (1H, s), 7.12 (1H , dd, J = 7.3Hz, 7.3Hz), 7.23 (1H, dd, J = 7.3Hz, 8.3Hz), 7.30-7.37 (2H, m), 7.54 (1H, br), 7.69 (1H, t, J = 5.0Hz), 8.68 (1H, s). Reference Example 2 1

 2-cyclopentyl -7-ethylamino -6-nitro-2--4- (4-propylamino benzodiamino) quinazoline

 The title compound was obtained in the same manner as in Reference Example 6 using the compound obtained in Reference Example 17 as a starting material (yield 58%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 0.99 (3H, t, J = 7.4Hz), 1.36 (3H, t, J = 7.3Hz), 1.61- 1.67 (4H, m), 1.80-1.90 ( 2H, m), 1.95-2.07 (4H, m), 3.03-3.14 (2H, m), 3.17-3.35 (3H, m), 4.71 (2H, d, J = 5.3Hz), 4.90 (1H, br) , 6.31 (1H, br), 6.57 (2H, d, J = 8.6Hz), 6.92 (1H, s), 7.21 (2H, d, J = 8.6Hz), 7.65 (1H, t, J = 4.6Hz) , 8.67 (1H, s). Reference Example 2 2

 4-black mouth-2- (isobutyrylamino) benzonitrile

 The title compound was obtained from 4-closan anthranilonitrile and isobutyric acid chloride using the same method as in Reference Example 9 (96% yield).

_{1 H-NMR (CDC1 3)} (5 (ppm): 1.30 (6H, d, J = 6.9Hz), 2.56-2.68 (1Η, m), 7.15 (1H, dd, J = 2.0Hz, 8.6Hz), 7.50 (1H, d, J = 8.6Hz), 7.70 (1H, br), 8.58 (1H, d, J = 2.0Hz). Reference Example 2 3

 Fukuro-guchi-2-isopropyl-4 (3H) -quinazolinone

Using the compound obtained in Reference Example 22 and using the same method as in Reference Example 10 To give the title compound (yield quantitative).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.28 (6H, d, J = 6.9 Hz), 2.84-2.94 (1Η, m), 7.42 (1H, d, J = 8.6 Hz), 7.61 ( 1H, s), 8.07 (1H, d, J = 8.6Hz), 12.25 (1H, br).

 7-Cu mouth mouth 2- 2-isopropyl-6-nitro mouth-4 (3H) -quinazolinone

 The title compound was obtained in the same manner as in Reference Example 1 using the compound obtained in Reference Example 23 (yield: 95% ヽ.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 127 (6Η, d, J = 6.9 Hz), 2.87-2.98 (1Η, m), 7.94 (1H, s), 8.65 (1H, s ), 12.68 (1 H, s). Reference Example 2 5

 7-Ethylamino-2-isopropyl-6-nitro-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 24 and the same method as in Reference Example 2, the title compound was obtained (80% yield).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.24- 1.30 (9H, m), 2.90-2.98 (1Η, m), 3.41-3.49 (2H, m), 6.86 (1H, s), 8.09 (1H, s), 8.28 (1H, s), 11.95 (1H, s).

 7-ethylamino-2-isopropyl-6-nitro-2--4- (2-pyridylmethylamino) quinazoline

 The title compound was obtained in the same manner as in Reference Example 3 using the compound obtained in Reference Example 25 and 2-pyridylmethylamine as raw materials (yield 55%, yield: 55%).

_{1 H-NMR (CDC1 3)} δ (ppm): 1.26 (6H, d, J = 6.6Hz), 1.36 (3H, t, J = 7.1Hz), 2.92-2.98 (lH, m), 3.27-3.32 ( 2H, m), 4.91 (2H, d, J = 4.6Hz), 6.80 (1H, s), 7.24-7.29 (lH, m), 7.48 (1H, d, J = 7.9Hz), 7.53 (1H, br ), 7.71 -7.76 (1H, m), 8.61 (1H, d, J = 5.0Hz), 8.67 (1H, s), 8.68 (1H, br). 4-black mouth-2- (bivaloylamino) benzonitrile

 The title compound was obtained from 4-chloroanthranilonitrile and pivaloyl chloride in the same manner as in Reference Example 9 (yield 85).

 '' H-NMR (CDC13) δ (ppm): 1.37 (9Η, s), 7.17 (1Η, d, J = 8.3Hz), 7.50 (1H, d, J = 8.3Hz), 7.98 (1H, br) , 8.59 (1H, s). Reference Example 2 8

 2-ter butyl -7-butanol-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 27, the title compound was synthesized in the same manner as in Reference Example 10 (quantitative yield).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.48 (9H, s), 7.41 (1H, d, J = 8.6 Hz), 7.75 (1H, s), 8.20 (1H, d, J = 8.6 Hz), 11.17 (1H, s). Reference example 2 9

 2-tert-butyl -7-octopene-6-nitopen-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 28 as a raw material, the title compound was obtained in the same manner as in Reference Example 1 (yield 81%).

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.36 (9H, s), 7.93 (1H, s), 8.65 (1H, s), 12.43 (1H, s). Reference Example 30

 2-tert-butyl -7-ethylamino-4--4-butanol-4 (3H) -quinazolinone

 Using the compound obtained in Reference Example 29, the title compound was obtained in the same manner as in Reference Example 2 (93% yield).

'H-NMR (DMSO-d ₆ ) δ (ppm): 1.27-1.40 (12H, m), 3.40-3.46 (2H, m), 6.84 (1H, s), 8.07 (1H, br), 8.77 (1H , s), 11.58 (1H, br). Reference Example 3 1

2-tert-butyl-7-ethylamino-6-nitro-2--4- (2-pyridylmethylamino) quina Zolin

 The title compound was obtained in the same manner as in Reference Example 3 using the compound obtained in Reference Example 30 and 2-pyridylmethylamine as raw materials (yield 77%, yield: 77%).

_{1 H-NMR (CDC1 3)} δ (ppm): 1.35- 1.44 (12H, m), 3.32-3.37 (2H, m), 4.90 (2H, d, J = 5.0Hz), 6.88 (1H, br), 7.23-7.28 (1H, m), 7.45 (1H, d, J = 7.9Hz), 7.57 (1H, br), 7.70-7.78 (lH, m), 8.21 (1H, br), 8.60 (1H, d, J = 5.0Hz), 8.72 (1H, s). Reference Example 3 2

 2-tert-butyl-7-ethylamino -4-[(2-morpholino) benzylamino] -6-nitroquinazoline

 Using the compound obtained in Reference Example 30 as a raw material, the title compound was obtained in the same manner as in Reference Example 6 (yield: 78%).

'H-NMR (CDCl ₃ ) δ (ppm): 1.39 (3H, t, J = 7.3 Hz), 1.42 (9H, s), 3.01-3.05 (4H, m), 3.36-3.42 (2H, m), 3.91-3.95 (4H, m), 4.97 (2H, d, J = 5.3Hz), 7.04 (1H, br), 7.11 (1H, dd, J = 7.3Hz, 7.3Hz), 7.21 (1H, d, J = 6.9Hz), 7.26 (1H, s), 7.28- 7.38 (2H, m), 7.67 (1H, br), 8.69 (1H, s).

 4-benzylamino-7-ethylamino-2-methyl-6-nitroquinazoline

 Using the compound obtained in Reference Example 2 and benzylamine as raw materials, the title compound was obtained in the same manner as in Reference Example 3 (43% yield).

_{^{1 H-NMR (CDC1 3)}} (5 (ppm): 1.38 (3H, t, J = 7.2Hz), 2.58 (3H, s), 3.30-3.45 (2H, m), 4.85 (2H, d, J = 5.1Hz), 6.05-6.35 (lH, br), 6.96 (1H, s), 7.30-7.60 (5H, m), 7.65-7.75 (lH, m), 8.68 (1H, s).

4-Benzylamino-7-ethylamino-6-two-mouth-2-styrylquinazoline The compound obtained in Reference Example 33 (1.00 g, 2.97 mmol) benzaldehyde (0.90 ml, 8.91 mmol) and ammonium acetate (2.26 g, 29.3) mmol) in acetic acid : L 鹦 鹦 掣 ΐ ΐ ΐ 1 ΐ ΐ ΐ 缀. One tifi 绺 ^ ¾ ¾-! ¾氺01 * Ma Tsu Wei ^氺¾ Si ^, ¾ on one ^^^ ° #lf ¾ transliteration I丄^氺, ¾ on ^ Doaniyome soil ¾ :)逖慇'T¾ ^ ^m 0 (H) Ku Otsu mouth? ! ^ 1 4 O) (louiui _L - _Z f '§ 0 T) i ^> ¾l ¾ L 9 ε fi ^%. · ΖΠ ί¾ι Tsu ^^^ earth ^ Ku $ ^{Kage籙::) (ι ω ο (} η) Ku

^ Otsuguchi> | ^ 4 ¾ (IOUIUI s-Ll '§ 9'0) Ma 2 ^ Ma ^ fi ^ Mine 氺 Π "1 ェ (/ Γι

 9 S f (%

• (ΖΗ6 · n = JT 'Ρ' Ηΐ 6 · n '(ΖΗ9 "8 = Γ' ΖΗ £ · n = f 'PP" u tfL' (ΖΗ £ 'n = i' P 'HI) t ^''(zH9'8 = f' ΖΗ6 'Δ = Γ' PP 'Hl) 9l "A' (« 'Η £) 06 · ε' O 'HS ん ε-ε9'(zH9'L = f 'H 0 'ε' (ΖΗ9 · n = f ')' H) 89 '(™' H1 /) IS '0: (mdd) ρ Ιθαθ) N_H _t

 ° meeting) ¾ 畺 ¾¾ ^^^^ 鷇

Tsutsu! laXffj ^ ΟΟΠΓ— ^ / ma ^^ b) ichiichi ^! mouth ^ ma /! Then π, 鹦 觳 丄 缀 ^.つ Φ m wi a. Ooi-m -a ι χ, ¾ i¾ (I ^OUIUI ξ'ΐί 'S εΐίε) ¾ 邈 1¾ I · Γι f ΐero □ -a iW ^. Tsumi (^ ¾ (louiui z-iL '§ ^ Zl) (-i -6-^^

 ^ Ikiro '^ [^ （(, Γι ^ Λ (^:)-Ζ} -Ζ

 S ε Ρ ^ #

'ΗΖ)0Α·ん-ん 9'ん 'Hん） 6 ·Δ-εε·ん '(∞ 'ΗΙ)8Ζ·ん -£Γん '(zHS'Sl = f 'Ρ 'Ηΐ) Γ乙 ' 'Ηΐ)ん 8'9 '(ZH£-S=f 'Ρ 'ΗΖ)98·ャ'( ^J q' Hl) ^ f 6 '(s' ΗΙ) Γ6' (ZHS-Sl = f '' Η "θ96

'ΗΖ) 0Α-n- 9' n 'H-n) 6 · Δ-εε-n' (∞ 'ΗΙ) 8Ζ-n-£ Γn'(zHS'Sl = f 'Ρ' Ηΐ) ΓO ''Ηΐ) No 8'9' (ZH £ -S = f 'Ρ' ΗΖ) 98

'Ο Ήζ) εΐ7 · ε-εε'ε' (ΖΗΓΖΗΓ = r Ί Ήε) · ι ： Odd) ρ p-oswa) Η Η · Η _Τ

、つ つ ff?½ tW¾^ 丄 ^ ¾ ° つ ί¾¾Β ζ 2>。 οπ PI '§

One ff? ½ tW¾ ^ 丄 ^ ¾ ° One ζ ζ 2>. οπ

0Z600 / 66df / I3d L9 £ P / 660fA _{^{1 H-NMR (CDC1 3)}} (5 (ppm): 2.30-2.38 (4H, m), 2.44 (2H, t, J = 6.6Hz), 3.04 (2H, t, J = 6.6Hz), 3.59-3.67 (4H, m), 4.71 (2H, br), 7.22-7.31 (2H, m), 7.35-7.39 (lH, m), 7.43-7.48 (lH, m).

 2- [2- (morpholino) ethylthio] benzaldehyde

 The compound (8.24 g, 32.6 mmol) obtained in Reference Example 36 was dissolved in stomal form (60 ml), activated manganese dioxide (35 g, 403 mmol) was added, and the mixture was stirred for 16 hours under solvent reflux. After completion of the reaction, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure.The obtained residue was purified by silica gel column chromatography (eluted with chloroformumethanol = 200) to give the title compound (7.86 g, 96%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 2.45-2.52 (4H, m), 2.65 (2H, t, J = 7.3Hz), 3.09 (2H, t, J = 7.3Hz), 3.65-3.72 ( 4H, m), 7.32 (1H, dd, J = 7.6Hz, 7.9Hz), 7.43-7.56 (2H, m), 7.85 (1H, d, J = 7.6Hz), 10.44 (1H, s). 3 8

 7-Ethylamino -4- {2- [2- (morpholino) ethylthio] benzylamino} -6-Nitroquinazoline

 The compound (4.92 g, 19.6 mmoi) obtained in Reference Example 37 was suspended in ethanol (50 ml), and hydroxylamine hydrochloride (1.77 g, 25.5 mmol) and sodium carbonate (2.70 g, 25.5 mmol) were added. The mixture was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a white solid.

 The obtained white solid was suspended in ether (240 ml), lithium hydride (10.14 g, 266 mmol) was added, and the mixture was stirred under reflux of the solvent for 1.5 hours. After the completion of the reaction, sodium sulfate decahydrate was added little by little until the foaming was stopped while the reaction solution was cooled on ice. The insolubles were filtered and the filtrate was concentrated to give an oil (4.76 g).

The oily substance (4.76 g) and triethylamine (5.27 ml, 37.8 mmol) were added to the solution. 9S

' 'ΗΖ ん '(ΖΗΓΔ=Γ 'b 'Η17)8? '(ΖΗΓん =f 'ϊ 'Η9)£0Ί ： (uidd) ρ u D) HWN"H _τ • (s Ήΐ) ΐ1τ · 0Χ '(ΖΗ9 · = f' P 'HI)''O' HZ) Z «W '' (ΖΗ6 · 8 'ΖΗ6 ·

'' ΗΖ '(' Δ = Γ 'b' Η17) 8? '(ΖΗΓ ==''' 9) £ 0Ί: (uidd) ρ u D) HWN "H _τ

ι ε 、¾?^蕙 マ ニミ マ 6 n 挲氺 iつ：）對 fei 9 ε P^# ¾%^^¾; 9 t^ .6 ε r^## ° (% 9L ^ ¾ ^ ®) ¾¾¾ (# ^^ 5gm n¾

ι ε, ¾? ^ 蕙 Manimima 6 n 挲 氺 i :) vs fei 9 ε P ^ # ¾% ^^ ¾; 9 t ^ .6 ε r ^ ##

 H ^^ ΊΓ ί- ^ ΐ ^ ΐ, ^ d ^-b)

 0 r ^

"(ω 'Ηΐ) 96 · n -ΐ6' (tu 'Η 9' n -Ζε'Otsu 'Ηΐ) 9 n -80 · m' ( ^s 'H £) 68"£' (ΖΗ £ Ί 'ΗΖ) 0 0 ££ -86Ζ Ζ'(ζΗε'Δ = Γ 'ΗΖ) £ 8-乙' (ω 'Β ^ ί ^ Ζ-ζζ-Ζ' Ο 'Η9) Δ0 66 · 0: (mdd) ρ ια α) so-called Ν_Η _τ

 ° (06

* ¾ι) ¾¾ι¾ ^^^ 鷇 鷇 :) fe fei s ε r ^ ^? ¾ ¾ ^ mx · Ku erotic mouth -ε- ^ ^ ema Wei ^ Γι

 Assault ^ (Γ ΐ, ^ d ^)

 6 ε ίι ^ #

'Ρ 'Ηί)ひ'ん 'Ο 'Ηζ)8Γん -ZVL '(ΖΗε·8 'ΖΗ9"9 = Γ 'ΡΡ 'HI) ん ' Ήΐ)ΐ78'9 '(zH0'S=f 'Ρ ⁱUZ)9f 'Ο-(s' ΗΙ) 0ε6 '(ZH0'S = f' 5 'Ηΐ) 0Γ6'(s' ΗΤ) 83'8 '(zH £ "S

'Ρ' Ηί) Hi '' Ο 'Ηζ) 8Γ -ZVL' (ΖΗε8 'ΖΗ9 "9 = Γ' ΡΡ 'HI)''')ΐ78'9'(zH0'S = f' Ρ ⁱ UZ) 9f 'Ο

'H e ε-ο ・ ε' (™ Ήζ) 8ε ·-£ ε · ε '(ΖΗ £ · Δ = Γ Ί Ήζ) 60 · ε' (ζΗε · = Γ Ί 'H) 6t

'Ο' Ht SS'Z '(ΖΗΓOL = f Ή Ήε) ^ Ζ · Τ: (^ dd) ρ (9 p-〇S) ¾ N "H _t ' § 68) i¾ ^> 21 ^ Agata (ffl ^ i 0S〜00I = —, Nomaro

9 I '§ 8Ι·ε /#^-^0)»SI 8 990/S6OAV)く 「し、 ÷口 4二- 9_ Z Γ ェ-ん-ロ口

C! ) One ^ ^ 4 ロ ^ ^ "1 、 ¾¾¾ 鹦 鎩 鹦 鎩 鹦 鎩 soil

9 I '§ 8Ι · ε / # ^-^ 0) »SI 8 990 / S6OAV)

0Z600 / 66dT / X3d Ρί9 £ Ρ / 6β OAV Reference example 4 1

 7-ethylamino -4- [2- (2-ethylaminoethylthio) benzylamino] -6-ditroquinazoline

 The compound obtained in Reference Example 40 was treated with xylamine hydrochloride in the presence of sodium carbonate, reduced with lithium aluminum hydride, and further treated with 4-chloro-7-ethylethylamino-6-nitroquinazoline ( The compound was reacted with the compound described in WO95 / 06648) to give the title compound (yield 33%).

i H-NMR (DMSO-d ₆ ) δ (ppm): 0.95 (6H, t, J = 7.1 Hz), 1.30 (3H, t, J = 7.1 Hz), 2.48-2.60 (4H, m), 2.62- 2.75 (2H, br), 3.08 (2H, t, J = 7.3Hz), 3.34-3.42 (2H, m), 4.79 (2H, d, J = 5.3Hz), 6.87 (1H, s), 7.16 (1H , dd, J = 6.6Hz, 6.9Hz), 7.24- 7.29 (2H, m), 7.44 (1H, d, J = 7.3Hz), 7.76 (1H, t, J = 5.3Hz), 8.30 (1H, s ),

9.11 (1H, t, J = 5.5Hz), 9.35 (1H, s). Reference example 4 2

 Methyl nicotinate

 6-Chloronicotinic acid (5.00 g, 31.7 mmol) was dissolved in N, N-dimethylformamide (30 ml), and methyl bromide (2.37 ml, 38 · mInol), potassium carbonate (5.26 g) , 38.1 mmol) and stirred at room temperature overnight. After completion of the reaction, a large amount of water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluted with hexane Z-ethyl acetate = 5) to give the title compound (4.56 g, 83%) as white crystals.

_{'H-NMR (CDC1 3)} δ (ppm): 3.96 (3H, s), 7.43 (1H, d, J = 8.4Hz), 8.25 (1H, dd, J = 2.0Hz, 8.4Hz), 9.00 (1H , d, J = 2.0Hz). Reference Example 4 3

 Methyl 6- (4-methylpiperazinyl) nicotinate

The compound obtained in Reference Example 42 (2.00 g, 11.7 mmol) and 1-methylbiperazine (4.53 mml, 40.8 mmol) were stirred in acetonitrile (5 ml) at 80 ° C for 1 hour. Stirred. After completion of the reaction, the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure to obtain the title compound (2.20 g, 80%) as an oil.

'H-NMR (CDC1 ₃ ) d (ppm): 2.40 (3H, s), 2.56-2.63 (4H, m), 3.74-3.79 (4H, m), 3.87 (3H, s), 6.60 (1H, d , J = 9.2Hz), 8.03 (1H, dd, J = 2.0Hz, 9.2Hz), 8.79 (1H, d, J = 2.0Hz).

 5-hydroxymethyl-2- (4-methylpiperazinyl) pyridine

 Reference Example 43 The compound obtained in 3 (2.00 g, 8.51 mmol) was dissolved in tetrahydrofuran (20 ml), and lithium aluminum hydride (0.32 g, 8.51 mmol) was added under ice-cooling. Stirred for 0.5 hours. After the completion of the reaction, sodium sulfate decahydrate was added little by little until the foaming stopped while the reaction solution was cooled on ice. The insolubles were filtered off and the filtrate was concentrated to give the title compound as an oil (1.98 g, 92%).

_{^ -NMR (CDC1 3) δ (} ppm): 2.32 (3H, s), 2.42-2.57 (4H, m), 3.45-3.57 (4H, m), 3.67 (1H, br), 4.52 (2H, br) , 6.63 (1H, d, J = 8.6Hz), 7.52 (1H, dd, J = 2.3Hz, 8.6Hz), 8.10 (1H, d, J = 2.3Hz).

 5-formyl-2- (4-methylbiperazinyl) pyridine

 The compound obtained in Reference Example 4 (2.30 g, 11.1 mmol) and activated manganese dioxide (2.30 g, 26.4 mmol) were dissolved in toluene (25 ml) 120. (The oil was stirred at (oil bath temperature) for 2 hours. After the reaction was completed, the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl hexanenoacetate = 10). The title compound (2.05 g, 90%) was obtained.

_{1 H-NMR (CDC1 3)} δ (ppm): 2.36 (3H, s), 2.51-2.60 (4H, m), 3.76-3.87 (4H, m), 6.67 (1H, dd, J = 2.0Hz, 9.2 Hz), 7.92 (1H, d, J = 2.0Hz, 9.2Hz), 8.55 (1H, d, J = 2.0Hz), 9.78 (1H, s). Reference Example 4 6

 7-ethylamino-4-{[6- (4-methylpiperazinyl) -3-pyridyl] methylamino} -6-diquinoazoline

 The compound (2.00 g, 9.76 mmol) obtained in Reference Example 45 was suspended in ethanol (25 ml), and hydroxylamine hydrochloride (0.88 g, 12.7 mmol) and sodium carbonate (1.34 g, 12.7 mmol) were suspended. mmol) and stirred at room temperature. The reaction solution was concentrated under reduced pressure to obtain a white solid.

 The obtained white solid was suspended in a mixed solvent of methanol (50 ml) and Z tetrahydrofuran (25 ml), 10% palladium-carbon catalyst (0.8 g) was added, and the mixture was stirred at room temperature under a hydrogen stream for 24 hours. . After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to obtain an oily substance.

 The above oily substance, triethylamine (2.80 ml, 20.1 mmol) was suspended in tetrahydrofuran (70 ml) and stirred at room temperature. To the above solution was added 4-chloro-7-ethylamino-6-nitroquinazoline (compound described in WO95 / 06648, 1.00 g, 3.96 mmol), and the mixture was stirred at room temperature overnight. After the completion of the reaction, the solution was concentrated under reduced pressure, and the obtained residue was subjected to gel chromatography on silica gel (eluted with gel-form / methanol = 50) to obtain the title compound (0.76 g, 46%). Was.

1 H-NMR (DMSO-d ₆ ) (5 (ppm): 1.29 (3H, t, J = 6.9 Hz), 2.23 (3H, s), 2.39-2.50 (4H, m), 3.32-3.50 (6H, m), 4.59 (2H, d, J = 5.6Hz), 6.76 (1H, d, J = 8.6Hz), 6.84 (1H, s), 7.56 (1H, dd, J = 2.3Hz, 8.6Hz), 7.72 (1H, t, J = 5.6Hz), 8.15 (1H, d, J = 2.3Hz), 8.34 (1H, s), 9.06 (1H, t, J = 5.5Hz), 9.23 (1H, s). Reference Example 4 7

 6- (piperidino) methyl nicotinate

 The title compound was obtained from the compound obtained in Reference Example 42 and piperidine in the same manner as in Reference Example 43 (yield 57%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.60- 1.78 (6H, m), 3.66-3.78 (4H, m), 3.86 (3H, s), 6.59 (1H, d, J = 9.2Hz), 7.99 (1H, dd, J = 2.3Hz, 9.2Hz), 8.78 (1H, d, J = 2.3Hz). Reference Example 4 8

 5-formyl-2- (piperidino) pyridine

 The compound obtained in Reference Example 47 was used as a starting material, reduced with lithium aluminum hydride in the same manner as in Reference Example 44, and then oxidized with manganese dioxide in the same manner as in Reference Example 45 to obtain the title compound. 90%).

_{^{1 H-NMR (CDC1 3)}} <5 (ppm): 1.60-1.76 (6H, m), 3.70-3.76 (4H, m), 6.65 (1H, d, J = 9.2Hz), 7.88 (1H, dd, J = 2.3Hz, 9.2Hz), 8.53 (1H, d, J = 2.3Hz), 9.74 (1H, s).

 7-Ethylamino-6-nitro-2--4-[[6- (piridino) -3-pyridyl] methylamino] quinazoline

 The title compound was obtained in the same manner as in Reference Example 46 using the compound obtained in Reference Example 48 (yield 51%).

_{^{X H-NMR (CDC1 3)}} δ (ppm): 1.38 (3H, t, J = 7.3Hz), 1.60-1.75 (6H, m), 3.31- 3.41 (2H, m), 3.50-3.60 (4H, m ), 4.72 (2H, br), 6.66 (1H, d, J = 8.9Hz), 7.02 (1H, s), 7.50 (1H, br), 7.63 (1H, d, J = 8.9Hz), 7.69 (1H , br), 8.25 (1H, br), 8.50 (1H, s), 8.95 (1H, s). Reference Example 50

 2-morpholino-5-nitrobenzonitrile

 Dissolve benzonitrile (5.00 g, 27.4 mmol) in Ν, Ν-dimethylformamide (20 ml) and add morpholine (4.90 ml, 56.3 mmol). For 0.5 hour. After completion of the reaction, water was added, and the precipitated yellow crystals were washed with water and dried to obtain the title compound (6.30 g, 99% :).

_{1 H-NMR (CDC1 3)} δ (ppm): 3.48-3.52 (4H, m), 3.90-3.94 (4H, m), 7.01 (1H, d, J = 9.2Hz), 8.31 (1H, dd, J = 2.6Hz, 9.2Hz), 8.46 (1H, d, J = 2.6Hz). Reference Example 5 1 -Methoxybenzylamino-2-morpholinobenzonitrile

 The compound (1.00 g, 4.29 mmol) obtained in Reference Example 50 was dissolved in a mixed solvent of methanol (10 ml) and tetrahydrofuran (5 ml). A 10% -palladium carbon catalyst (0.20 g) was added, and the mixture was stirred at room temperature for 3 hours under a stream of ice. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to obtain an oily substance (0.87 g, quantitative). One half (2.15 mmol) of the obtained oil was dissolved in ethanol (5 ml), p-anisaldehyde (0.34 g, 2.50 mmol) was added, and the mixture was stirred overnight at room temperature under an argon atmosphere. The solvent was removed, and P-anisaldehyde (0.60 g, 4.40 mmol) was added, followed by stirring at 80 under an argon atmosphere for 3.5 hours. Ethanol (5 ml) was added, and sodium borohydride (0.30 g, 7.93 mmol) was added under ice cooling, followed by stirring for 0.5 hour. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluted with hexane Z ethyl acetate = 4) to give the title compound (0.75 g, 95%) as an oil.

_{i H-NMR (CDC1 3)} δ (ppm): 3.06-3.09 (4H, m), 3.80 (3H, s), 3.81-3.89 (4H, m), 4.22 (2H, br), 6.85-6.98 (5H , m), 7.25-7.28 (3H, s).

 7-ethylamino-4-{[5- (4-methoxybenzyl) amino-2-morpholino] benzylamino} -6-nitroquinazoline

 Reference Example 51 The compound obtained in Reference Example 1 (0.75 g, 2.32 mmol) was dissolved in tetrahydrofuran (10 ml), and lithium aluminum hydride (0.27 g, 7.11 mmol) was added under ice-cooling. Stirred for hours. After completion of the reaction, sodium sulfate decahydrate was added little by little until the foaming stopped while the reaction solution was cooled on ice. The insolubles were filtered and the filtrate was concentrated to give an oil.

The above oily substance, triethylamine (1.40 ml, 10.3 mmol) was suspended in tetrahydrofuran (10 ml) and stirred at room temperature. To the above solution was added 4-chloro-7-ethylamino-6-nitroquinazoline (the compound described in WO95 / 06648, 0.52 g, 2.06 mmol), and the mixture was stirred at room temperature overnight. After completion of the reaction, the solution is The residue obtained by concentration was subjected to column chromatography on silica gel (eluted with chloroform Z methanol: = 50), and triturated with ether / methanol to obtain the title compound (0.71 g, 63%).

'H-NMR (DMSO-d ₆ ) δ (ppm): 1.30 (3H, t, J = 6.9 Hz), 2.70-2.83 (4H, m), 3.34-3.43 (2H, m), 3.63 (3H, s ), 3.65-3.70 (4H, m), 4.02 (2H, br), 4.78 (2H, d, J = 5.3Hz), 6.00 (1H, br), 6.41-6.46 (2H, m), 6.63 (2H, d, J = 8.6Hz), 6.88-6.94 (2H, m), 7.05 (2H, d, J = 8.6Hz), 7.79 (1H, t, J = 5.3Hz), 8.28 (1H, s),

9.03 (1H, br), 9.26 (1H, s).

 5-Methylamino-2-morpholinobenzonitrile

 The compound (2.00 g, 8.58 mmol) obtained in Reference Example 50 was dissolved in a mixed solvent of methanol (20 ml) and Z-tetrahydrofuran (10 ml). A 10% -palladium Z carbon catalyst (0.40 g) was added, and the mixture was stirred overnight at room temperature under a hydrogen stream. After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to obtain an oily substance (quantitative).

 The obtained oily substance (0.60 g, 2.9 mmol) and a catalytic amount of trifluoroacetic acid were stirred at 150 ° C. in orthoarylethyl (18 ml, 108 mmol) for 5 hours. After that, the solution was concentrated under reduced pressure, the obtained residue was dissolved in ethanol (12 ml), sodium borohydride (0.30 g, 7.93 mmol) was added under ice-cooling, and the same temperature was maintained overnight. Stirred. After completion of the reaction, water was added, and the mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane / ethyl acetate = 4) to give the title compound (0.614 g, 96%) as an oil. Was.

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 2.82 (3H, s), 3.01-3.06 (4H, m), 3.80-3.89 (4H, m), 6.76-6.80 (2H, m), 6.95 (1H , dd, J = 2.0Hz, 7.3Hz).

7-ethylamino-4-[(5-methylamino-2-morpholino) benzylamino] -6-nitroquinazoline The compound obtained in Reference Example 53 was reduced with lithium hydride in the same manner as in Reference Example 52, and then treated with 4-chloro-7-ethylamino-6-nitroquinazoline (the compound described in WO95 / 06648). The reaction was performed to obtain the title compound (yield 67%). ^X H-NMR (DMSO-d ₆ ) δ (ppm): 1.41 (3H, t, J = 7.3 Hz), 2.82 (3H, s), 2.98-3.02 (4H, m), 3.35-3.45 (2H, m ), 3.89-3.93 (4H, m), 4.88 (2H, d, J = 4.6Hz), 6.56-6 · 60 (2Η, m), 7.04 (1H, s), 7.15 (1H, d, J = 9.2 Hz), 7.76 (1H, br), 8.22 (1H, br), 8.53 (1H, br), 8.69 (1H, s), 9.33 (1H, s).

 7-Ethylamino-6-dito-l- (p-toluenesulfonyl) -2,3-dihydroto-4 (1H) -quinolone

 7-Hokuguchi-l- (p-Toluenesulfonyl) -2,3-dihydrogen-4 (1H) -quinolone [Journal of the American American Chemical Society] (J. Am. Chem. Soc.), Volume 71, p. 1901 (1949)] (13.9 g, 41.4 mmol) was dissolved in acetic anhydride (140 ml), a catalytic amount of concentrated sulfuric acid was added, and the mixture was cooled to -30 and stirred. did. Fuming nitric acid (5.14 ml, 124 mmol) was dropped at such a rate that the internal temperature did not rise. After completion of the dropwise addition, the mixture was stirred for 1 hour under ice cooling and for 2 hours at room temperature. The reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with a saturated sodium hydrogen carbonate solution and a saturated saline solution, dried (magnesium sulfate;), and concentrated under reduced pressure. The obtained residue was dissolved in ethanol (280 ml), a 70% -ethylamine aqueous solution (26.6 ml, 413 mmol) was added, and the mixture was stirred under reflux of the solvent for 2 hours. After completion of the reaction, the solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with hexane Z-ethyl acetate = 2) to give the title compound (4.50 g, 28%) I got In addition, 7-ethylamino-8-nitro-2-l- (p-toluenesulfonyl) -2,3-dihydro-4 (1H) -quinopen (3.6 g, 22%) was obtained as a by-product. . The iH-NMR data are shown in the order of the title compound and by-product.

'H-NMR (title _{compound, CDC1 3) δ (ppm)} : 1 · 42 (3Η, t, J = 7.3Hz), 2.42 (2H, t, J = 6.4Hz), 2.43 (3H, s), 3.39 -3.42 (2H, m), 4.24 (2H, t, J = 6.4Hz), 7.21 (1H, s), 7.31 (2H, d, J = 8.4Hz), 7.67 (2H, d, J = 8.4Hz) , 8.31 (1H, br), 8.84 (1H, s). ^X H-NMR _{(byproduct, CDC1 3) δ (ppm)} : 1 · 39 (3Η, t, J = 7.3Hz), 2.21 (2H, t, J = 6.3Hz), 2.43 (3H, s), 3.30-3.50 (2H, m), 3.90-4.40 (2H, m), 6.80 (1H, d, J = 9.2Hz), 7.50 (1H, br), 7.28 (2H, d, J = 8.6Hz), 7.58 (2H, d, J = 8.6Hz), 7.97 (1H, d, J = 9.2Hz).

 7-Ethylamino-6- (2H) -4 (1H) -quinolone

 Reference Example 55 Water generated in a mixed solvent of toluene (110 ml) / dioxane (44 ml) containing the compound obtained in Step 5 (2.20 g, 5.65 imnol) and activated manganese dioxide (9.82 g, 113 mmol) was removed. The mixture was refluxed for 3 hours while heating. After completion of the reaction, the mixture was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance. The oily substance obtained above was dissolved in ethanol (27 ml), 10 N sodium hydroxide solution (0.7 ml, 7.00 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the pH of the reaction solution was adjusted to 6, and the precipitated crystals were collected by filtration and dried to obtain the title compound (0.88 g, 67%).

'' H-NMR (CDC1 g-DMSO-d ₆ ) δ (ppm): 1.42 (3H, t, J = 7.2 Hz), 3.27-3.40 (2H, m), 5.99 (1H, d, J = 7.4 Hz) , 6.64 (1H, s), 7.54 (1H, dd, J = 5.6Hz, 7.4Hz),

7.80 (1H, br), 9.05 (1H, s), 11.30 (1H, d, J = 5.6Hz).

 4-kuguchi- 7-ethylamino-6-ditroquinoline

 The compound (1.14 g, 4.89 mmol) obtained in Reference Example 56 was heated to reflux in phosphorus oxychloride (2.3 ml, 24.7 mmol) for 1 hour. After completion of the reaction, the residue obtained by concentration under reduced pressure (azeotropic azeotrope) was tritiated (ethyl acetate Z-isopropyl ether) to obtain red crystals (0.50 g, 41%).

_{^ -NMR (CDC1 3) δ (} ppm): 1.42 (3H, t, J = 7.1Hz), 3.34-3.46 (2H, m), 7.21 (1H, d, J = 4.8Hz), 7.30 (1H, s ), 7.40 (1H, br), 8.68 (1H, d, J = 4.8Hz), 9.08 (1H, s). 4_benzylamino-7-ethylamino-6-ditroquinoline

 The compound obtained in Reference Example 57 (1.00 g, 3.97 mmol) and benzylamine (4.0 ml, 36.6 rmnol) were stirred at 100 for 2 hours. After the completion of the reaction, the reaction solution was cooled to room temperature, a saturated sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated saline, dried (magnesium sulfate), and concentrated under reduced pressure. The resulting residue was triturated with isopropyl ether to give the title compound (0.70 g, 55%).

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.41 (3H, t, J = 7.2Hz), 3.29-3.45 (2H, m), 4.54 (2H, d, J = 5.3Hz), 5.56 (1H, br), 6.21 (1H, d, J = 5.4Hz), 7.17 (1H, s), 7.35-7.49 (6H, m), 8.43 (1H, d, J = 5.4Hz), 8.77 (1H, s) Reference Example 5 9

 7-ethylamino-4- (2-methoxybenzylamino) -6-nitroquinoline

 The title compound was obtained from the compound obtained in Reference Example 57 and 2-methoxybenzylamine (yield 64%) o

^ -NMR (CDC1 ₃ ) δ (ppm): 1.38 (3Η, t, J = 7.2 Hz), 3.26-3.42 (2H, m), 3.83 (3H, s), 4.56 (2H, br), 6.20 (1H , d, J = 5.6 Hz), 6.60-6.80 (lH, br), 6.83-7.00 (2H, m), 7.18 (1H, s), 7.18-7.30 (2H, m), 7.43 (1H, br), 8.26 (1H, d, J = 5.6Hz), 8.93 (1H, s). Reference example 60

 7-Ethylamino-4- (3-morpholinopropylamino) -6-ditroquinoline The title compound was obtained from the compound obtained in Reference Example 57 and 3-aminopropylmorpholine (yield 41%).ヽ.

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.40 (3H, t, J = 7.2Hz), 1.91-2.00 (2H, m), 2.45- 2.65 (6H, m), 3.33-3.43 (4H, m ), 3.68 (1H, br), 3.83-3.98 (4H, m), 6.12 (1H, d, J = 5.6Hz), 7.16 (1H, s), 7.41 (1H, br), 8.42 (1H, d, J = 5.6Hz), 8.83 (1H, s). Reference example 6 1 7-ethylamino-6-nitro-2--4- [2- (2-pyridyl) ethylamino] quinoline Reference Example 57 The title compound was obtained from the compound obtained in 7 and 2- (2-aminoaminoethyl) pyridine ( Yield 74

_{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.43 (3H, t, J = 7.2Hz), 3.23 (2H, t, J = 6.1Hz), 3.30-3.46 (2H, m), 3.64-3.72 ( 2H, m), 6.17 (1H, d, J = 5.6Hz), 7.18 (1H, s), 7.23-7.27 (2H, m), 7.44 (1H, br), 7.61-7.71 (1H, m), 7.72 -7.88 (lH, m),

8.38 (1H, d, J = 5.6Hz), 8.76 (1H, dd, J = 2.0Hz, 5.3Hz), 8.96 (1H, s). Reference example 6 2

 7-ethylamino-6-nitro-2--4- (2-pyridylmethylamino) quinoline

 The title compound was obtained from the compound obtained in Reference Example 57 and 2-aminomethylpyridine (yield 30

¹ H-NMR (CDC1 (5 (ppm): 1.38 (3H, t, J = 7.1 Hz), 3.28-3.40 (2H, m), 4.60 (2H, br), 6.12 (1H, d, J = 5.6 Hz ), 7.07 (1H, s), 7.26-7.36 (4H, m), 7.70-7.80 (lH, m), 8.35 (1H, d, J = 5.6Hz), 8.67 (1H, d, J = 4.9Hz) , 8.88 (1H, s). Reference example 6 3

 4-piperidinobenzonitrile

 The title compound was synthesized from 4-fluorobenzonitrile and piperidine in the same manner as in Reference Example 5 (yield: 99%).

_{^{X H-NMR (CDC1 3)}} (5 (ppm): 1.60-1.75 (6H, m), 3.30-3.38 (4H, m), 6.83 (2H, d, J = 8.9Hz), 7.45 (2H, d, J = 8.9Hz). Reference example 6 4

7-Ethylamino-6-dito-4- (4-piperidinobenzylamino) quinazoline Reference Example 63 The compound obtained in Reference Example 3 was reduced with lithium hydride in the same manner as Reference Example 6. The title compound was obtained from the obtained compound and 4-chloro-7-ethylamino-6-2-troquinazoline (compound described in WO95 / 06648) in the same manner as in Reference Example 3 (yield 74%). _{^{1 H-NMR (CDC1 3)}} δ (ppm): 1.41 (3H, t, J = 7.4Hz), 1.50- 1.80 (6H, m), 3.02- 3.19 (4H, m), 3.33-3.43 (2H, m ), 4.73 (2H, s), 6.20 (1H, br), 6.80-7.00 (2H, m), 7.21-7.30 (3H, m), 7.69 (1H, br), 8.54 (1H, s), 8.69 ( 1H, s). Reference example 6 5

 7-ethylamino-4-morpholino-6-nitroquinazoline

 Morpholine and 4-chloro-7-ethylamino-6-ditroquinazoline

(Compound described in WO95 / 06648) to give the title compound in the same manner as in Reference Example 3 (yield 50%).

_{'H-NMR (CDC1 3)} (5 (ppm): 1.42 (3H, t, J = 6.9Hz), 3.34-3.49 (2H, m), 3.85- 3.95 (8H, m), 7.02 (1H, s) , 7.65 (1H, br), 8.53 (1H, s), 8.85 (1H, s).

 3-Ethyl-6-methyl-8- (4-dimethylaminobenzylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione dihydrochloride (Compound 1)

 The compound (0.700 g, 1.84 mmol) obtained in Reference Example 3 was suspended in a mixed solvent of methanol (50 ml) and tetrahydrofuran (20 ml). To this suspension was added 10% -palladium / carbon catalyst (0.14 g), and the mixture was stirred at room temperature under a hydrogen gas atmosphere. After completion of the reaction, the catalyst was separated by filtration using a filter aid, and triethylamine (2.00 ml, 14.3 mmol) and carbon disulfide (10.0 ml, 166 mmol) were added to the obtained filtrate, followed by stirring at room temperature overnight. After the completion of the reaction, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with black-mouthed form Z medium = 100) to obtain the free base of the title compound (0.630 g, 87). Was.

 The obtained free base (0.50 g, 1.28 mmol) was suspended in methanol (10 ml), and an excess amount of 4N hydrogen chloride monoethyl acetate was added under ice cooling. The solution was concentrated to about half under reduced pressure, and the precipitated crystals were separated to obtain the title compound (0.53 g, 89%).

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.31 (3H, t, J = 7.3 Hz), 2.67 (3H, s), .06 (6H, s), 4.34 (2H, q, J = 7.3Hz), 4.91 (2H, d, J = 5.3Hz), 7.50-7.54 (4H, br), 7.67 (1H, s), 8.33 ( 1H, s), 10.62 (1H, t, J = 5.3Hz), 13.69 (1H, s).

 3-Ethyl-6-methyl-8- (2-pyridylmethylamino) -2,3-dihydrogen-1H-imidazo [4,5-g] quinazolin-2-thione dihydrochloride ( Compound 2)

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 4 (yield 47%).

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.32 (3H, t, J = 7.3 Hz), 2.62 (3H, s), 4.35 (2H, q, J = 7.3 Hz), 5.16 (2H, d, J = 5.3Hz), 7.63 (1H, dd, J = 6.3Hz, 6.6Hz), 7.76 (1H, d, J = 7.6Hz), 7.68 (1H, s), 8.14 (1H, dd, J = 6.3Hz, 7.6Hz), 8.37 (1H, s), 8.70 (1H, d, J = 6.6Hz), 10.75 (1H, t, J = 5.3Hz), 13.72 (1H, s). Example 3

 3-Ethyl-6-methyl-8- (2-morpholinobenzylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinazolin-2-thione dihydrochloride (Compound 3)

 Using the compound obtained in Reference Example 6, the title compound was obtained in the same manner as in Example 1 (yield 43%).

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.33 (3H, t, J = 6.9 Hz), 266 (3Η, s), 2.95 (4H, br), 3.79 (4H , br), 4.38 (2H, q, J = 6.9Hz), 5.07 (2H, d, J = 5.3Hz), 7.08 (1H, dd, J = 7.3Hz, 7.6Hz), 7.30-7.36 (3H, m ), 7.72 (1H, s), 8.37 (1H, s), 10.43 (1H, t, J = 5.3Hz), 13.67 (1H, s).

3-Ethyl-6-methyl-8- (4-propylaminobenzilamino) -2,3-dihydrido-1H-imidazo [4,5- _g ] quinazolin-2-thione · 2 hydrochloride (Compound 4 )

 Using the compound obtained in Reference Example 8, the title compound was obtained in the same manner as in Example 1 (yield: 12%).

¹ H-NMR (2 hydrochloride, DMSO-d ₆ ) δ (ppm): 0.93 (3H, t, J = 7.4 Hz), 1.31 (3H, t, J = 7.4Hz), 1.60-1.74 (2H, m), 2.68 (3H, s), 3.12-3.18 (2H, m), 3.80 (1H, br), 4.33 (2H, q, J = 7.4Hz), 4.92 (2H, d, J = 5.4Hz), 7.38-7.52 (4H, m), 7.65 (1H, s), 8.33 (1H, s), 10.60 (1H, s), 13.71 (1H, s). Example 5

 3,6-Jetyl -8- (2-pyridylmethylamino) -2,3-dihydrid-1H-imidazo

[4,5-g] quinazolin-2-thione · 2 hydrochloride (Compound 5)

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 13 (yield 36

'H-NMR (dihydrochloride, DMSO-d ₆ ) (5 (ppm): 1.10 (3H, t, J = 7.6 Hz), 1.30 (3H, t, J = 7.1 Hz), 2.88 (2H, q, J = 7.6Hz), 4.32 (2H, q, J = 7.1Hz), 5.24 (2H, d, J = 5.0Hz), 7.79-7.85 (2H, m), 7.94 (1H, d, J = 7.9Hz) , 8.35 (1H, dd, J = 7.6Hz, 7.9Hz), 8.43 (1H, s), 8.79 (1H, d, J = 5.3Hz), 11.05 (1H, t, J = 5.0Hz), 13.78 (1H , s). Example 6

 6-cyclopentyl-3-ethyl-8- (4-dimethylaminobenzylamino) -2,3-dihydrido-1H-imidazo [4,5-g] quinazoline-2-thione (compound 6)

 Using the compound obtained in Reference Example, the title compound was obtained in the same manner as in Example (yield 11% ヽ).

'H-NMR (free base, DMSO-d ₆ ) (5 (ppm): 1.27 (3H, t, J = 6.8 Hz), 1.55- 1.79 (4H, m), 1.90-1.98 (4H, m), 2.83 (6H, s), 3.10-3.19 (1H, m), 4.32 (2H, q, J = 6.8Hz), 4.64 (2H, d, J = 5.3Hz), 6.66 (2H, d, J = 8.3Hz) , 7.24 (2H, d, J = 8.3Hz), 7.59 (1H, s), 7.98 (1H, s), 8.60 (1H, br), 13.15 (1H, s).

 6-cyclopentyl-3-ethyl-8- (2-pyridylmethylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione · 2 hydrochloride (compound 7)

Using the compound obtained in Reference Example, the title compound was obtained in the same manner as in Example (yield 27 ¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.30 (3H, t, J = 6.6 Hz), 1.50-

I .65 (6H, m), 1.80-1.95 (2H, m), 3.40-3 ・ 45 (1Η, m), 4.32 (2H, q, J = 6.6Hz), 5.20 (2H, br), 7.80- 7.92 (3H, m), 8.33-8.38 (lH, m), 8.43 (1H, s), 8.77 (1H, s),

I I .04 (1H, br), 13.77 (1H, s).

 6-Cyclopentyl-3-ethyl-8- (2-morpholinobenzylamino) -2,3-dihydrido-1H-imidazo [4,5-g] quinazolin-2-thione-2 hydrochloride (Compound 8) Reference Using the compound obtained in Example 20, the title compound was obtained in the same manner as in Example 1 (yield 13% ヽ).

'H-NMR (dihydrochloride, DMSO-d ₆ ) (5 (ppm): 1.30 (3H, t, J = 7.3 Hz), 1.60-96 (8Η, m), 2.85-2.89 (4H, m ), 3.34-3.40 (lH, m), 3.73-3.77 (4H, m),

4.32 (2H, q, J = 7.3Hz), 4.99 (2H, d, J = 5.3Hz), 7.03 (1H, dd, J = 7.3Hz, 7.3Hz), 7.17-7.28 (3H, m), 7.83 ( 1H, s), 8.41 (1H, s), 10.64 (1H, br), 13.72 (1H, s).

 6-cyclohexyl pentyl-3-ethyl-8- (4-propylaminobenzylamino) -2,3-dihydric mouth-1H-imidazo [4,5-g] quinazoline-2-thione 2 Hydrochloride (Compound 9) Using the compound obtained in Reference Example 21, the title compound was obtained in the same manner as in Example 1 (yield: 25%).

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) 6 (ppm): 0.91 (3H, t, J = 7.4 Hz), 1.29 (3H, t, J = 7.1 Hz), 1.63-1.86 (8H, m ), 1.98-2.09 (2H, m), 3.11-3.18 (2H, m), 3.41- 3.45 (1H, m), 3.80 (1H, br), 4.32 (2H, q, J = 7.1Hz), 4.88 ( 2H, d, J = 5.3Hz), 7.39-7.51 (4H, m), 7.79 (1H, s), 8.35 (1H, s), 10.75 (1H, br), 13.72 (1H, s). Example 1 0

 3-Ethyl-6-isop-mouth pill-8- (2-pyridylmethylamino) -2,3-dihydro- mouth-1H-imidazo [4,5-g] quinazoline-2-thione (Compound 10 )

Using the compound obtained in Reference Example 26 and title in the same manner as in Example 1. Compound (yield 30

¹ H-NMR (free base, DMSO-d ₆ ) 6 (ppm): 1.15 (6H, d, J = 6.6 Hz), 1.29 (3H, t, J = 6.9 Hz), 2.81-2.92 (1H, m) , 4.32 (2H, q, J = 6.9Hz), 4.85 (2H, d, J = 5.6Hz), 7.24 (1H, dd, J = 5.3Hz, 6.6Hz), 7.34 (1H, d, J = 7.6Hz) ), 7.61 (1H, s), 7.68 (1H, dd, J = 6.6Hz, 7.6Hz), 8.07 (1H, s), 8.51 (1H, d, J = 5.3Hz), 8.86 (1H, t, J = 5.6Hz), 13.19 (1H, s).

 6-tert-butyl-3-ethyl-8- (2-pyridylmethylamino) -2,3-dihydrogen-1H-imidazo [4,5-g] quinazoline-2-thione. · 2 hydrochloride ( Compound 11 1)

 Using the compound obtained in Reference Example 31, the title compound was obtained in the same manner as in Example 1 (yield: 52%).

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.32- 1.35 (12H, m), 4.31 (2H, q, J = 6.9 Hz), 5.24 (2H, d, J = 5.3 Hz) ), 7.79 (1H, dd, J = 6.3Hz, 6.6Hz), 7.91 (1H, d, J = 8.3Hz), 8.33 (1H, dd, J = 6.6Hz, 8.3Hz), 8.43 (1H, s) , 8.48 (1H, s), 8.77 (1H, d, J = 6.3Hz), 11.11 (1H, br), 13.78 (1H, s).

 6-tert-butyl-3-ethyl-8- (2-morpholinobenzylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione.2 hydrochloride (Compound 1 2)

 Using the compound obtained in Reference Example 32, the title compound was obtained in the same manner as in Example 1 (yield 26

¹ H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.32 (3H, t, J = 6.8 Hz), 1.39 (9H, s), 2.89 (4H, br), 3.76 (4H, br ), 4.30 (2H, q, J = 6.8Hz), 5.04 (2H, d, J = 5.3Hz), 7.04 (1H, dd, J = 7.3Hz, 7.3Hz), 7.17-7.29 (3H, m), 8.39 (1H, s), 8.42 (1H, s), 10.77 (1H, br), 13.72 (1H, s).

8-benzylamino-3-ethyl-6-methyl-2,3-dihydrogen- 1H-imidazo [4,5-g] Quinazolin-2-thione monohydrochloride (Compound 13)

 Using the compound obtained in Reference Example 33 and the same method as in Example 1, the title compound was obtained (yield: 50%).

¹ H-NMR (1 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.29 (3H, t, J = 7.2 Hz), 2.66 (3H, s), 4.35 (2H, q, J = 7.2 Hz), 4.94 (2H, d, J = 3.5Hz), 7.25 -7.45 (5H, m), 7.61 (1H, s), 8.32 (1H, s), 10.45-10.55 (1H, br), 13.71 (1H, s Example 1 4

 8-Benzylamino-3-ethyl-6-methyl-2,3-dihydrogen-1H-imidazo [4,5-g] quinazolin-2-one / 1 hydrochloride (Compound 14)

 Reference Example 33 The compound obtained in 3 (1.00 g, 2.96 mmol) was dissolved in tetrahydrofuran (20 ml), and a 10% -palladium carbon catalyst (0.10 g) was added, followed by catalytic reduction under a hydrogen gas atmosphere. Was done. After completion of the reaction, the catalyst was filtered through celite, and the filtrate was concentrated under reduced pressure to obtain an oily substance. „

 Half (1.48 mmol) of the obtained oily substance was dissolved in acetonitrile (5 ml), and N, N-propanoldimidazole (CDI, 0.960 g, 5.92 mmol) was added. For 2 hours and at 100 for 2.5 hours. After completion of the reaction, water was added, and the precipitated crystals were collected by filtration, washed with a mixed solvent of acetonitrile water, and dried to obtain the free base of the title compound (0.394 g, 80%).

 The obtained free base (0.344 g) was suspended in a mixed solvent of chloroform (5 ml) / methanol (1 ml), and an excess amount of 4N hydrogen chloride-ethyl acetate was added under ice cooling. The solution was concentrated in half under reduced pressure, and the precipitated crystals were collected and triturated with chloroform to give the title compound (0.270 g, 71).

'H-NMR (monohydrochloride, DMSO-d ₆ ) δ (ppm): 1, 26 (3H, t, J = 7.2Hz), 2.63 (3H, s), 3.94 (2H, q, J = 7.2Hz) ), 4.91 (2H, d, J = 5.5Hz), 7.25 -7.45 (6H, m), 8.09 (1 H, s), 10.25 -10.35 (1H, br), 11.93 (1H, s). Five

8-Benzylamino-3-ethyl-6-phenethyl-2,3-dihydric mouth-1H-imidazo [4,5-g] quinazoline-2-thione monohydrochloride (Compound 15)

 Using the compound obtained in Reference Example 34, the title compound was obtained in the same manner as in Example 1 (yield 59

¹ H-NMR (monohydrochloride, DMSO-d ₆ ) δ (ppm): 1.29 (3H, t, J = 7.2 Hz), 3.05- 3,30 (4H, m), 4.34 (2H, q, J = 7.2Hz), 4.93 (2H, d, J = 5.0Hz), 7.10-7.45 (10H, m), 7.54 (1H, s), 8.28 (1H, s), 10.40-10.50 (1H, br), 13.68 ( 1H, s). Example 16

 8-Benzylamino-3-ethyl-6-phenethyl-2,3-dihydrogen-1H-imidazo

[4,5-g] quinazolin-2-one · 1 hydrochloride (Compound 16)

 The title compound was obtained in the same manner as in Example 14 using the compound obtained in Reference Example 34 (yield 28

¹ H-NMR (1 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.28 (3H, t, J = 7.2 Hz), 3.05- 3.25 (4H, m), 3.94 (2H, q, J = 7.2 Hz) ), 4.91 (2H, d, J = 4.5Hz), 7.10-7.45 (11H, m), 8.04 (1H, s), 10.20-10.30 (1H, br), 11.89 (1H, s).

 3-Ethyl-8- [2- (2-morpholinoethylthio) benzylamino] -2,3-dihydro-1H-imidazo [4, .5-g] quinazoline-2-thione · 2 hydrochloride (Compound 17 )

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 38 (yield 58%). '

^X H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.29 (3H, t, J = 7.1 Hz), 2.38-2.43 (4H, m), 2.54 (2H, t, J = 7.6 Hz) , 3.14 (2H, t, J = 7.6Hz), 3.53-3.59 (4H, m), 4.36 (2H, q, J = 7.1Hz), 4.84 (2H, d, J = 5.6Hz), 7.13 (1H, dd, J = 6.6Hz, 7.3Hz), 7.22-7.28 (2H, m), 7.44 (1H, d, J = 7.9Hz), 7.65 (1H, s), 8.13 (1H, s), 8.36 (1H, s), 8.77 (1H, t, J = 5.6Hz), 13.28 (1H, s).

3-Ethyl-8- [2- (2-morpholinoethylthio) benzylamino] -2,3-dihydro- 1H-imidazo [4,5-g] quinazolin-2-one.dihydrochloride (compound 18)

 The title compound was obtained in the same manner as in Example 14 using the compound obtained in Reference Example 38 (yield 27%).

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.25 (3H, t, J = 7.1 Hz), 2.38- 2.42 (4H, m), 2.57 (2H, t, J = 7.6 Hz) , 3.14 (2H, t, J = 7.6Hz), 3.53-3.58 (4H, m), 3.93 (2H, q, J = 7.1Hz), 4.79 (2H, d, J = 5.3Hz), 7.13 (1H, dd, J = 6.9Hz, 7.6Hz),

7.20- 7.27 (2H, m), 7.39 (1H, s), 7.43 (1H, d, J = 7.6Hz), 7.87 (1H, s), 8.31 (1H, s), 8.50 (1H, t, J = 5.3Hz), 11.43 (1H, s).

 3-Ethyl-8- [2- (2-getylaminoethylthio) benzylamino] -2,3-dihydrogen-1H-imidazo [4,5-g] quinazoline-2-thione · 2 hydrochloride ( Compound 19) The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example (yield 60

¹ H-NMR (free base, DMSO-d ₆ ) (ppm): 0.93 (6H, t, J = 7.1 Hz), 1.29 (3H, t, J = 7.1 Hz), 2.50 (4H, q, J = 7.1 Hz), 2.66 (2H, t, J = 7.4Hz), 3.07 (2H, t, J = 7.4Hz), 4.36 (2H, q, J = 7.1Hz), 4.80 (2H, d, J = 5.3Hz) , 7.12 (1H, dd, J = 7.3Hz, 7.6Hz),

7.21- 7.27 (2H, m), 7.42 (1H, d, J = 7.9Hz), 7.64 (1H, s), 8.13 (1H, s), 8.35 (1H, s), 8.75 (1H, t, J = 5.3Hz), 13.25 (1H, s).

 3-Ethyl-8- [2- (2-ethylethylaminothio) benzylamino] -2,3-dihydrido-1H-imidazo [4,5-g] quinazolin-2-one · 2 hydrochloric acid Salt (Compound 20) The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example (yield: 20).

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 0.96 (6H, t, J = 7.1 Hz), 1.28 (3H, t, J = 7.1 Hz), 2.53 (4H, q, J = 7.1Hz), 2.69 (2H, t, J = 7.3Hz), 3.07 (2H, t, J = 7.3Hz), 3.93 (2H, q, J = 7.1Hz), 4.80 (2H, d, J = 5.3Hz), 7.10 (1H, dd, J = 6.9Hz, 7.3Hz), 7.20-7.25 (2H, m), 7.33 (1H, s), 7.40 (1H, d, J = 7.3Hz), 7.86 (1H , s), 8.29 (1H, s), 8.46 (1H, t, J = 5.3Hz), 1 1.38 (1H, s).

 3-Ethyl-8- [6- (4-methylbiperazinyl) -3-pyridylmethylamino] -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione · 3 hydrochloride (Compound 21)

 Reference Example 46 The compound (0.60 g, 1.42 mmol) obtained in 6 was suspended in a mixed solvent of tetrahydrofuran (70 ml) and Z methanol (10 ml), and 10% palladium / carbon catalyst (0.20 g) was added. Then, the mixture was stirred for 6 hours under a hydrogen gas stream. After completion of the reaction, the catalyst was separated by filtration using a filter aid, and the obtained filtrate was concentrated under reduced pressure. The obtained concentrated residue was purified by silica gel column chromatography (eluted with a solvent in which 5% ammonia was absorbed in a mixed solvent of chloroform and methanol = 10) to give an oily substance (0.58 g). The oily substance after purification was dissolved in methanol (16 ml), and triethylamine (2.70 ml, 19.4 mmol) and carbon disulfide (2.68 ml, 44.6 mmol) were added, followed by stirring at room temperature. After completion of the reaction, the precipitated crystals were collected and washed with ethanol Z ether to obtain the free base of the title compound (0.21 g, 34%).

 The obtained free base (0.130 g, 0.300 mmol) was suspended in methanol (10 ml), and an excess amount of 4N hydrogen chloride-ethyl acetate was added under ice cooling. The reaction solution was concentrated to about half, and the precipitated crystals were separated and dried to obtain the title compound (0.150 g, 93%).

¹ H-NMR (3 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.30 (3H, t, J = 7.1 Hz), 2.77 (3H, s), 3.07-3.18 (2H, m), 3.38-3.55 (4H, m), 4.30-4.58 (4H, m), 4.87 (2H, d, J = 5.6Hz), 7.17 (1H, d, J = 8.9Hz), 7.75 (1H, s), 7.93 (1H, d, J = 8.9Hz), 8.23 (1H, s),

 8.38 (1H, s), 8.89 (1H, s), 10.84 (1H, t, J = 5.6Hz), 13.77 (1H, s).

3-Ethyl-8- [3- (6-piperidinopyridyl) methylamino] -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione · 2 hydrochloride (Compound 22 ) The title compound was obtained in the same manner as in Example 21 using the compound obtained in Reference Example 49 (yield 21%).

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.31 (3H, t, J = 6.9 Hz), 1 -51- 1.65 (6H, m), 3.44-3.48 (4H, m), 4.34 (2H, q, J = 6.9Hz), 4.62 (2H, d, J = 5.6Hz), 6.71 (1H, d, J = 8.6Hz), 7.54 (1H, dd, J = 2.3Hz, 8.6Hz) , 7.57 (1H, s), 8.03 (1H, s), 8.14 (1H, d, J = 2.3Hz), 8.42 (1H, s), 8.75 (1H, t, J = 5.6Hz), 13.50 (1H, s). Example 2 3

 3-Ethyl-8- [5- (4-methoxybenzylamino) -2-morpholinobenzylamino] -2,3-dihydro-1H-imidazo [4,5-g] quinazoline-2-thione · 3 hydrochloride (compound 23)

 Using the compound obtained in Reference Example 52, the title compound was obtained in the same manner as in Example 1 (yield: 22%) o

¹ H-NMR (free base, DMSO-d ₆ ) 6 (ppm): 1.34 (3H, t, J = 6.9 Hz), 2.70-2.85 (4H, m), 3.59 (3H, s), 3.65-3.75 ( 4H, m), 3.98 (2H, br), 4.37 (2H, q, J = 6.9 Hz), 4.83 (2H, d, J = 5.3 Hz), 5.92 (1H, br), 6.40 (1H, dd, J = 2.6Hz, 8.6Hz), 6.48 (1H, d, J = 2.6Hz), 6.55 (2H, d, J = 8.6Hz), 6.91 (1H, d, J = 8.6Hz), 6.98 (2H, d, J = 8.6Hz), 7.61 (1H, s), 8.07 (1H, s), 8.37 (1H, s), 8.62 (1H, t, J = 5.3Hz), 13.22 (1H, s).

 3-Ethyl-8- [5-methylamino-2-morpholinobenzylamino] -2,3-dihydro-1H-imidazo [4,5-g] quinazolin-2-thione · 3 hydrochloride (Compound 2 4) Using the compound obtained in Reference Example 54, the title compound was obtained in the same manner as in Example 1 (yield 41).

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.30 (3H, t, J = 6.9 Hz), 2.51 (3H, d, J = 5.3 Hz), 2.73-2.81 (4H, m) , 3.67-3.72 (4H, m), 4.35 (2H, q, J = 6.9Hz), 4.84 (2H, d, J = 5.6Hz), 5.40 (1H, br), 6.38 (1H, dd, J = 2.6 Hz, 8.6Hz), 6.48 (1H, d, J = 2.6Hz), 6.99 (1H, d, J = 8.6Hz), 7.61 (1H, s), 8.12 (1H, s), 8.37 (1H, s) , 8.63 (1H, t, J = 5.6Hz), 13.22 (1H, s).

 3-Ethyl-2-ethylamino-8- (4-dimethylaminobenzylamino) -3H-imidazo [4,5-g] quinazoline · 3 hydrochloride (Compound 25)

 7-Ethylamino-4- (4-dimethylaminobenzylamino) -6-dimethoxyquinazoline (compound described in WO95 / 06648, 30.0 g, 82.0 mmol) was added to methanol (800 ml) and Z tetrahydrofuran (500 ml). ), A 10% -palladium Z carbon catalyst (6.0 g) was added, and the mixture was subjected to catalytic reduction in a hydrogen stream for 9 hours. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated to obtain 6-amino-7-ethylamino-4- (4-dimethylaminobenzylamino) quinazoline (quantitative) as a brown solid. .

 The obtained brown solid (1.50 g, 4.46 mmol) was dissolved in pyridine (15 ml), and ethyl isothiosineate (0.97 ml, 11.0 mml) was slowly added dropwise under ice cooling. After completion of the dropwise addition, the temperature was raised to room temperature, and the mixture was stirred at the same temperature for 3 hours. After completion of the reaction, the solvent was concentrated under reduced pressure, and ethanol was added to the resulting concentrated residue, followed by trituration. The obtained solid was washed with ethanol to obtain a corresponding thiourea compound (0.60 g, 32%).

 The obtained thiourea compound (0.40 g, 0.946 mmol) was suspended in acetonitrilile (20 ml), silver trifluoroacetate (0.46 g, 2.08 mmol) was added, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, 4N hydrochloric acid was added to the concentrated residue obtained by concentrating the solution under reduced pressure, and the deposited precipitate was separated by filtration. Sodium bicarbonate solution was added to the filtrate to adjust the pH to 8-9. The precipitated crystals were collected, washed with water, and dried to give the free base of the title compound (0.21 g, 57%).

 To the obtained free base (0.21 g, 0.540 mmol) was added methanol (15 ml). Under ice-cooling, 4 mol / l ethyl acetate hydrochloride (0.68 ml, 2.72 mmol) was added. Stirred for hours. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were recrystallized from ethanol Z water to obtain the title compound (0.26 g, 98%).

'H-NMR (3 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.28-1.34 (6H, m), 3.00 (6H, s), 3,67 (2H, br), 4.33 (2H, br), 4.91 (2H, br), 7.20-7.50 (4H, m), 7.83 (1H, s), 8.72 (1H, s), 8.86 (1H, s), 9.82 (1H, br), 11.27 (1H, s).

 3-Ethyl-8- (4-dimethylaminobenzylamino) -2-phenylamino-3H-imidazo [4,5-g] quinazoline · 3 hydrochloride (Compound 26)

 The method described in Example 25 was repeated using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinazoline (compound described in WO95 / 06648) and phenylisothiocinnamate. The title compound was obtained in the same manner (yield

37

¹ H-NMR (3 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.38 (3H, t, J = 6.9 Hz), 3.05 (6H, s), 4.52 (2H, q, J = 6.9 Hz), 4.95 (2H, d, J = 5.3Hz), 7.18 (1H, t, J = 7.2Hz), 7.41- 7.47 (3H, m), 7.50-7.60 (4H, m), 7.80 (1H, s), 7.82 -7.90 (2H, m), 8.67 (1H, s), 8.83 (1H, s), 10.91 (1H, s).

 2-ethoxycarbonylamino-3-ethyl-8- (4-dimethylaminobenzylamino) -3H-imidazo [4,5-g] quinazolin dihydrochloride (Compound 27)

 Example 25 was carried out using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinoline (compound described in WO95 / 06648) and ethoxycarbonylisothiocinane. The title compound was obtained in the same manner as described (yield 16%).

'H-NMR (dihydrochloride, DMSO-d ₆ ) δ (ppm): 1.24- 1.32 (6H, m), 2.98 (6H, s), 4.08-4.23 (4H, m), 4.91 (2H, d, J = 5.3Hz), 7.10-7.42 (4H, m), 7.73 (1H, s), 8.41 (1H, s), 8.85 (1H, s), 10.68 (1H, br), 13.10 (1H, br). Example 2 8

2-Amino-3-ethyl-8- (4-dimethylaminobenzylamino) -3H-imidazo [4,5-g] quinazoline · 3 hydrochloride (Compound 28) The free base (0.770 g, 1.78 mmol) of the compound obtained in Example 27 was dissolved in methanol (77 ml) and water (23 ml), and then added with hydroxide hydroxide (0.696 g, 4.06 mmol). The mixture was stirred under reflux of the solvent for 5.5 hours. Further, barium hydroxide (1.30 g, 7.58 mmol) was added, and the mixture was stirred at the same temperature for 16 hours. After completion of the reaction, 4N hydrochloric acid was added to the concentrated residue obtained by concentrating the solution, the insolubles were filtered off, the filtrate was neutralized with an aqueous solution of sodium hydrogen carbonate, and the precipitated crystals were separated by silica gel chromatography. Purification by chromatography (eluting with black form Z methanol = 20) gave the free base of the title compound (0.23 g, 36%).

 The obtained free base (0.23 g, 0.637 mmol) was dissolved in ethanol (10 ml), and 4 mol / 1 hydrochloric acid-ethyl acetate (0.800 ml, 3.20 mmol) was added under ice-cooling, and the mixture was heated at room temperature for 2 hours. Stirred. The reaction solution was concentrated under reduced pressure, and the precipitated crystals were washed with ethanol to obtain the title compound (0.15 g, 50).

'H-NMR (3 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.32 (3H, t, J = 7.3 Hz), 2.97 (6H, s), 4.00 (2H, br), 4.30 (2H, q , J = 7.3Hz), 4.89 (2H, br), 7.10-7.50 (4H, m), 7.86 (1H, s), 8.67 (1H, s), 8.88 (1H, s), 9.38 (1H, br) Example 2 9

 3-Ethyl-2-methylamino-8- (4-dimethylbuminobenzylamino) -3H-imidazo [4,5-g] quinazoline · 3 hydrochloride (Compound 29)

As in the method described in Example 25 using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinazoline (compound described in WO95 / 06648) and methylisothiocinnamate To give the title compound (20% yield). '' H-NMR (3 hydrochloride, DMSO-d ₆ ) δ (ppm): 1.32 (3H, t, J = 6.9 Hz), 3.04 (6H, s), 3.20 (3H, d, J = 4.6 Hz), 4.35 (2H, q, J = 6.9 Hz), 4.94 (2H, d, J = 5.6 Hz), 7.45- 7.60 (4H, m), 7.89 (1H, s), 8.79 (1H, s), 8.87 (1 H, s), 10.18 (1H, t, J = 5.6Hz), 11.43 (1H, br).

2-arylamino-3-ethyl-8- (4-dimethylaminobenzylamino) -3H-imi Dazo [4,5-g] quinazoline (Compound 30)

Method described in Example 25 using 7-ethylamino-4- (4-dimethylaminobenzylamino) -6-ditroquinazoline (compound described in WO95 / 06648) and arylisothiocinane The title compound was obtained in the same manner as described above (yield: 12%). ¹ H-NMR (free _{base, CDC1 3) (5 (ppm} ): 1.37 (3H, t, J = 7.3Hz), 2.91 (6H, s), 3.96 (2H, q, J = 7.3Hz), 4.08 ( 2H, br), 4.70 (2H, br), 5.15-5.27 (2H, m), 5.92- 6.03 (1H, m), 6.64 (2H, d, J = 8.3Hz), 7.19 (2H, d, J = 8.3Hz), 7.38 (1H, s),

7.77 (1H, br), 8.58 (1H, s), 10.10 (1H, br), 13.10 (1H, br).

 3-Ethyl-2-methylamino-8- (2-pyridylmethylamino) -3H-imidazo [4,5-g] quinazoline (Compound 31)

 Using 7-ethylamino-6-nitro-2--4- (2-pyridylmethylamino) quinazoline (compound described in WO95 / 06648) and methylisothiocinnamate, the method described in Example 25 was followed. The title compound was obtained in the same manner (yield: 14%).

i H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.24 (3H, t, J = 7.2Hz), 3.00 (3H, d, J = 4.0Hz), 4.12 (2H, q, J = 7.2Hz), 4.90 (2H, d, J = 5.0Hz), 7.22-7.32 (3H, m), 7.40 (1H, s), 7.71 (1H, dd, J = 7.6Hz, 7.9Hz), 8.06 (1H , s), 8.33 (1H, s), 8.52 (1H, d, J = 7.6 Hz), 8.77 (1H, s).

 2-Cyanimino-3-ethyl-8- (2-pyridylmethylamino) -2,3-dihydrogen-1H-imidazo [4,5-g] quinazoline (Compound 32)

7-Ethylamino-6-dito-4- (2-pyridylmethylamino) quinazoline (compound described in WO95 / 06648, 10.0 g, 30.9 mmol) was added to methanol (300 ml) and Z tetrahydrofuran (180 ml). And a 10% -palladium / carbon catalyst (5.0 g) was added thereto, and catalytic reduction was carried out for 9 hours under a hydrogen stream. After completion of the reaction, the catalyst was filtered off, the filtrate was concentrated as a brown solid 6- Amino - 7-E Chiruamino 4- (2-pyridyl-methyl-amino) Kinazori emissions (8.78 g, 97%) was obtained _c Heat 6-amino-7-ethylamino-4- (2-pyridylmethylamino) quinazoline (1.00 g, 3.40 mmol) and dimethylcyanodithioiminocarbonate (5.00 g, 34.2 mmol) at 90 ° C for 13 hours Stirred. After the completion of the reaction, the reaction solution was purified by silica gel column chromatography (eluted with chromatoform Z methanol = 50) to obtain the title compound (0.43 g, 37%).

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.27 (3H, t, J = 6.9 Hz), 4.08 (2H, q, J = 6.9 Hz), 4.87 (2H, d, J = 5.3Hz), 7.22-7.33 (2H, m), 7.64-7.74 (2H, m), 8.05 (1H, s), 8.36 (1H, s), 8.51 (1H, br), 8.96 (1H, s), 13.17 (1H, br). Example 3 3

 3-Ethyl-8- (2-pyridylmethylamino) -2-perido-3H-imidazo [4,5-g] quinazoline dihydrochloride (Compound 33)

 The compound (0.400 g, 1.16 mmol) obtained in Example 32 was stirred in 50% sulfuric acid (6 ml) / acetic acid (3 ml) at room temperature for 1 hour. Further, 50% -sulfuric acid (12 ml) and Z acetic acid (4 ml) were added, and the mixture was stirred at room temperature for 3 hours. After the completion of the reaction, a saturated sodium hydrogen carbonate solution was added little by little to neutralize. The precipitated crystals were collected, dried and purified by silica gel gel chromatography (eluted with black form Z methanol = 50) to give the free base of the title compound (0.300 g, 71%).

 The obtained free base (0.290 g, 0.801 mmol) was dissolved in methanol (10 ml), and 4 mol / l ethyl acetate hydrochloride Z (1.00 ml, 4.00 mmol) was added under ice-cooling. Stir for 2 hours. The precipitated crystals were washed with methanol to obtain the title compound (quantitative).

¹ H-NMR (2 hydrochloride, DMSO-d ₆ ) (5 (ppm): 1.35 (3H, br), 4.53 (2H, br), 5.24 (2H, br), 6.50 (2H, br), 7.60- 7.82 (3H, m), 7.99 (1H, br), 8.20 (1H, br), 8.72-8.78 (2H, m), 8.88 (1H, s), 11.15 (1H, s).

2-ethoxy-3-ethyl-8- (4-dimethylaminobenzylamino) -3H-imidazo [4,5-g] quinazoline (Compound 34) 7-Ethylamino-4- (4-dimethylaminobenzylamino) -6-nitroquinoline (compound described in WO95 / 06648, 1.10 g, 3.00 mmol) was reduced in the same manner as in Example 25. The obtained 6-amino-7-ethylamino-4- (4-dimethylaminobenzylamino) quinazoline, tetraethoxymethane (7.00 ml, 33.5 mmol) and acetic acid (0.30 ml, 5.24 mmol) were added, and the mixture was refluxed under solvent. Stir for 1 hour. After completion of the reaction, the solution was concentrated, and the precipitated crystals were separated, dried, and purified by silica gel column chromatography (eluted with chloroform-formanol = 50) to give the title compound (0.220 g, 19%). .

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.26 (3H, t, J = 7.3 Hz), 1.40 (3H, t, J = 6.9 Hz), 2.79 (6H, s), 4.06 (2H, q, J = 6.9Hz), 4.56 (2H, q, J = 7.3Hz), 4.64 (2H, d, J = 5.6Hz), 6.61 (2H, d, J = 8.6Hz), 7.16 (2H , d, J = 8.6Hz), 7.52 (1H, s), 8.25 (1H, s), 8.29 (1H, s), 8.37 (1H, t, J = 5.6Hz).

 3-Ethyl-2-methoxy-8- (4-piperidinobenzylamino) -3H-imidazo [4,5-g] quinazoline (Compound 35)

 Using the compound obtained in Reference Example 64, the title compound was obtained in the same manner as in Example 34 (yield: 11% ヽ).

¹ H-NMR (free base, DMSO-d ₆ ) 6 (ppm): 1.30 (3H, t, J = 6.9 Hz), 1.48-1.65 (6H, m), 3.04-3.10 (4H, m), 4.12 ( 2H, q, J = 6.9Hz), 4.19 (3H, s), 4.71 (2H, d, J = 5.6Hz), 6.86 (2H, d, J = 8.3Hz), 7.22 (2H, d, J = 8.3) Hz), 7.63 (1H, s), 8.33 (1H, s), 8.36 (1H, s), 8.52 (1H, t, J = 5.6Hz).

 3-ethyl-2-methoxy-8-morpholino-3H-imidazo [4,5-g] quinazoline (Compound 36)

 Using the compound obtained in Reference Example 65, the title compound was obtained in the same manner as in Example 34 (yield 30

¹ H-NMR (free base, DMSO-d ₆ ) δ (ppm): 1.33 (3H, t, J = 7.3 Hz), 3.61- 3.66 (4H, m), 3.83-3.87 (4H, m), 4.15 (2H, q, J = 7.3 Hz), 4.21 (3H, s), 7.78 (1H, s), 8.29 (1H, s), 8.60 (1H, s). Example 3 7

 8-benzylamino-3-ethyl-2,3-dihydro-1H-imidazo [4,5-g] quinolin-

2-thione (compound 37)

 Reference Example 58 The compound obtained in Reference Example 8 (0.400 g, 1.24 mmoi) was dissolved in tetrahydrofuran (12 ml), and 10% -palladium carbon catalyst (0.12 g) was dissolved in ethanol (1.2 ml) and dioxane (2.4 ml). The solution suspended in was added, and the mixture was stirred at room temperature in a hydrogen gas atmosphere for 4 hours. After completion of the reaction, the catalyst was separated by filtration using a filter aid, and the filtrate was concentrated under reduced pressure. Ethanol (4.0 ml), triethylamine (0.32 ml, 2.48 mmol) and carbon disulfide (4.0 ml, 66.5 mmol) were added to the residue, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the precipitated crystals were collected by filtration, washed with isopropyl ether, and dried to obtain the title compound (0.15 g, 36).

'H-NMR (free _{base, DMSO-d 6 -CDC1 3)} δ (ppm): 1.32 (3H, t, J = 7.1Hz), 4.34 (2H, q, J = 7.1Hz), 4.53 (2H, d , J = 5.4Hz), 6.22 (1H, d, J = 5.3Hz), 7.17-7.38 (5H, m), 7.60 (1H, s), 7.87 (1H, t, J = 5.4Hz), 8.02 (1H , s), 8.22 (1H, d, J = 5.3Hz), 12.50 (1H, br).

 3-Ethyl-8- (2-methoxybenzylamino) -2,3-dihydro-1H-imidazo [4,5-g] quinolin-2-thione (Compound 38)

 Using the compound obtained in Reference Example 59, the title compound was obtained in the same manner as in Example 1 (yield 35%).

¹ H-NMR (free _{base, DMSO-d 6 -CDC1 3)} δ (ppm): 1.30 (3H, t, J = 7.0Hz), 3.87 (3H, s), 4.33 (2H, q, J = 7.0Hz ), 4.48 (2H, d, J = 5.4Hz), 6.13 (1H, d,

J = 5.3Hz), 7.11 -7.23 (4H, m), 7.62 (1H, s), 7.74 (1H, br), 8.02 (1H, s), 8.21 (1H, d, J = 5.3Hz), 12.50 ( 1H, br). Example 3 9

 3-Ethyl-8- (3-morpholinopropylamino) -2,3-dihydroxy-1H-imidazo [4,5-g] quinolin-2-thione (Compound 39)

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 60 (44% yield).

¹ HN R (free _{base, DMSO-d 6 -CDC1 3)} δ (ppm): 1.41 (3H, t, J = 7.3Hz), 1.90- 1.99 (2H, m), 2.50-2.59 (6H, m), 3.42-3.47 (2H, m), 3.66-3.82 (4H, m), 4.37 (2H, q, J = 7.3Hz), 6.38 (1H, d, J = 5.4Hz), 7.11 (1H, br), 7.56 (1H, s), 7.8- 7.81 (2H, m), 8.39 (1H, d, J = 5.4Hz).

 3-Ethyl-8- [2- (2-pyridyl) ethylamino] -2,3-dihydrogen-1H-imidazo [4,5-g] quinolin-2-thione (Compound 40)

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 61 (yield 33% ヽ).

¹ H-NMR (free _{base, DMSO-d 6 -CDC1 3)} δ (ppm): 1.40 (3H, t, J = 7.2Hz), 3.10-3.30 (2H, m), 3.65-3.74 (2H, m) , 4.37 (2H, q, J = 7.2Hz), 6.44 (1H, d, J = 5.3Hz), 7.20-7.35 (3H, ra), 7.56 (1H, s), 7.60-7.70 (lH, m), 7.88 (1 H, s), 8.39 (1 H, d, J = 5.3 Hz), 8.61 (1 H, d, J = 5.4 Hz), 12.30 (1 H, br).

 3-Ethyl-8- (2-pyridylmethylamino) -2,3-dihydrogen-1H-imidazo [4,5-g] quinolin-2-thione (Compound 41)

 The title compound was obtained in the same manner as in Example 1 using the compound obtained in Reference Example 62 (yield: 45%).

^ -NMR (free _{base, DMSO-d 6 -CDC1 3)} δ (ppm): 1.38 (3H, t, J = 7.1Hz), 4.37 (2H, q, J = 7.1Hz), 4.65 (2H, d, J = 5.6Hz), 6.26 (1H, d, J = 5.1Hz), 7.20- 7.25 (1H, m), 7.36 (1H, d, J = 7.6Hz), 7.59 (1H, s), 7.67 (1H, dd, J = 1.7Hz, 7.6Hz), 7.80 (1H, br), 8.03 (1H, s), 8.27 (1H, d, J = 5.1Hz), 8.56 (1H, d, J = 5.1Hz), 12.30 (1H, br).

 8-Benzylamino-3-ethyl-2,3-dihydrogen-1H-imidazo [4,5-g] quinolin-2-one (Compound 42)

 The title compound was obtained in the same manner as in Example 14 using the compound obtained in Reference Example 58 (44% yield).

¹ H-NMR (free _{base, DMSO-d 6 -CDC1 3)} 5 (ppm): 1.37 (3H, t, J = 7.1Hz), 3.95 (2H, q, J = 7.1Hz), 4.56 (2H, d , J = 5.3Hz), 6.23 (1H, d, J = 5.3Hz), 7.20-7.40 (7H, m), 7.78 (1H, s), 8.23 (1H, d, J = 5.3Hz), 11.00 (1H , br). Example 4 3

 8-benzylamino-3-ethyl-3H- 1,2,3-triazolo [4,5-g] quinazolin-2-thione-3 hydrochloride (compound 43)

 4-Benzylamino-7-ethylamino-6-nitroquinazoline (compound described in WO95 / 06648, 3.00 g, 9.28 mmol) was dissolved in N, N-dimethylformamide (100 ml), and 10% -palladium Z A carbon catalyst (0.3 g) was added, and catalytic reduction was performed for 9 hours under a hydrogen stream. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated to obtain 6-amino-4-benzylamino-7-ethylaminoquinazoline (2.59 g, 95%) as a brown solid.

 The obtained 6-amino-4-benzylamino-7-ethylaminoquinazoline (0.291 g, 1.00 mmol) was dissolved in 0.8N hydrochloric acid (4.8 ml), and acetic acid (2 ml) was added under ice cooling. Further, sodium nitrite (0.07 g, 1.00 mmol) was added. After stirring at the same temperature for 1 hour, water was added to the reaction solution to make the solution slightly alkaline. The precipitated crystals were separated and recrystallized from methanol-Z dioxane to obtain the title compound (0.167 g, 55%).

^X H-NMR (free base, 90MHz, DMSO-d ₆ ) <3 (ppm): 1.56 (3H, t, J = 7.1Hz), 4.70-4.90 (4H, m), 7.27-7.42 (5H, m) , 8.15 (1H, s), 8.46 (1H, s), 9.22 (1H, br), 9.25 (1H, s). Industrial applicability

 The present invention provides a therapeutic agent for erectile dysfunction, which has a potent and selective cGMP-specific PDE inhibitory action. In addition, it has a strong and selective cGMP-specific PDE inhibitory effect, and is used for treatment or alleviation of thrombosis, angina, hypertension, heart failure, cardiovascular disease such as arterial stiffness, asthma, erectile dysfunction, etc. Useful imidazo quinazoline derivatives or pharmacologically acceptable salts thereof are provided.

Claims

The scope of the claims  (1) General formula (I)

Wherein R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aralkyl, Y represents N or CH, and — X ¹ — X ² — X ³ — is — N = N— NR ⁷ — (wherein R ⁷ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted Substituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted A substituted aralkyl or a substituted or unsubstituted aryl), one NH—C (= N—CN) —NR ⁷ — (wherein R ⁷ is as defined above) NH—C (= N -C ON H _? ) One NR ⁷ — (where R ⁷ is as defined above), N = CR ⁸ — NR ⁷ — (wherein, R ⁷ has the same meaning as described above, and R ⁸ has the same meaning as R ⁷ ), — N = C (NHR ⁹ ) — NR ⁷ — (wherein R ⁷ is as defined above, and R ⁹ is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted Substituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroarylalkyl Teloaryl, if substituted Or an unsubstituted aralkyl, lower alkoxycarbonyl or carbamoyl), — N = C (OR ¹⁰ ) — NR ⁷ — (wherein, R ⁷ has the same meaning as described above, and R ¹⁰ has the same meaning as R ⁷ ), —NH—C (= O) —NR ⁷ — (wherein, R ⁷ is as defined above) or —NH—C (= S) —NR ⁷ — (wherein, R ⁷ is as defined above. Wherein R ¹ and R ² are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted Is unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted Show replacement aralkyl Or, R ¹ and R ² are together a connexion. The compound represented by a substituted or unsubstituted nitrogen-containing heterocyclic group formed by including a N] or an active ingredient a pharmaceutically acceptable salt thereof And erectile dysfunction drug.  (2) General formula (IA)

(IA) [Wherein, R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl, (i) When Y represents N, — X ^1A — X ^2A — X ^3A — is one N = N— NR ⁷ — (where R ⁷ is as defined above), — NH— C (= N - CN) - NR ⁷ i (wherein, R ⁷ is as defined above) or a NH- C (= N - C 0 N H ₂ ) — NR ⁷ — (wherein, R ⁷ is as defined above), and R ^1A is substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl Substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted heteroaryl Represents an unsubstituted aralkyl, wherein R ^2A is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, Is unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted Or substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl or substituted or unsubstituted aralkyl, and a substituted or unsubstituted nitrogen-containing nitrogen atom formed by combining R ^1A and R ^2A together with N May represent a heterocyclic group, (ii) When Y represents CH, — X ^1A — X ^2A — X ^3A — is — N = N— NR 7 — (wherein R ⁷ is as defined above), and one NH—C (= N - CN) - NR ⁷ - (wherein, R ⁷ is as defined above), single NH- C (= 〇) - NR ⁷ i (wherein, R ⁷ is as defined above) or - NH- C (= S) - NR ⁷ i (wherein, R ⁷ has the same meaning as defined above) represents, R ^1A is unsubstituted or replacement of lower alkyl, substituted or unsubstituted cycloalkyl, substituted or is properly non Substituted substituted alkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl Represents a substituted or unsubstituted aralkyl or a substituted or unsubstituted aryl, and R ^2A represents R ⁷ And a substituted or unsubstituted nitrogen-containing heterocyclic group formed by R and R ^2A being N and containing N may be represented by the formula: Acceptable salt. (3) The compound according to claim 2, wherein R ³ represents hydrogen and Y represents N. Is its pharmacologically acceptable salt. (4) The compound according to claim 2, wherein R ³ represents hydrogen and Y represents CH, or a pharmaceutically acceptable salt thereof. (5) The compound according to claim 2, wherein R ³ represents substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or substituted or unsubstituted aralkyl, and Y represents N, or a pharmaceutically acceptable compound thereof. Salt. (6) — X ^1A — X ^2A — X ^3A — is — NH— C (= N-CN) -NR ⁷ — (wherein, R ⁷ has the same meaning as described above). Or a pharmaceutically acceptable salt thereof. (7) — X ^1A — X ^2A — X ^3A — is — N = N— NR ⁷ — (wherein, R ⁷ has the same meaning as described above), or a pharmacological compound thereof. Acceptable salts. (8) The compound according to claim 4, wherein X ^1A — X ^2A — X ^3A — is —NH—C (= O) -NR ⁷ — (wherein R ⁷ has the same meaning as described above). Or a pharmacologically acceptable salt thereof. (9) — The compound according to claim 4, wherein X ^1A — X ^2A — X ^3A — is — NH— C (= S) -NR ⁷ — (wherein, R ⁷ has the same meaning as described above). Or a pharmacologically acceptable salt thereof.  (10) General formula (IB)

(IB) Wherein R ³ represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aralkyl. And Y represents N or CH, and X ^1B — X ^2B — X ^3B — is — N = CR ⁸ — NR ^7A- (wherein, R ⁸ has the same meaning as described above, and R ^7A is substituted or unsubstituted. Lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or Represents an unsubstituted heteroarylalkyl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aralkyl), one N = C (NHR ^9A ) one NR ^7A — (wherein R ^7A is as defined above) R ^9A is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricyclic Loalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Represents unsubstituted aralkyl, lower alkoxycarbonyl or carbamoyl) or one N = C (OR ¹⁰ ) —NR ^7A — (wherein R ⁷ A and R ^{1 Q} are as defined above); R ^1B represents Teroari one Ruarukiru or substitution or unsubstituted Ararukiru to the substituted or unsubstituted, R ^2B represents hydrogen, a hetero § reel alkyl or substituted or unsubstituted Ararukiru substituted or non-replacement, R ¹⁸ And R ^2B may be linked to represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N]. Or a pharmaceutically acceptable salt thereof. (11) The compound or the pharmaceutically acceptable salt thereof according to claim 10, wherein R ³ represents hydrogen and Y represents N. (12) The compound or the pharmaceutically acceptable salt thereof according to claim 10, wherein R ³ represents hydrogen and Y represents CH. (13) The compound according to the claim 10 or a pharmacologically active compound thereof, wherein R ³ represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted aralkyl, and Y represents N. Acceptable (1 4) — Claim 1 represented by the formula: X ^1B — X ^2B — X ^3B — — N = CR ⁸ — NR ^7A — (wherein R ⁸ and R ^7A are as defined above). 2. The compound according to 1 or a pharmaceutically acceptable salt thereof. (15) — X ^1B — X ^2B — X ^3B — — N = C (NHR ^9A ) — NR ^7A — (wherein, R ^7A and R ^9A are as defined above). 11. The compound according to 11 or a pharmacologically acceptable salt thereof. (1 6) Claims represented by the formula: X ^1B — X ^2B — X ^3B —— N = C (OR ¹⁰ ) —NR ^7A — (wherein, R ^7A and R ^1Q are as defined above). 11. The compound according to 1 or a pharmacologically acceptable salt thereof.  (17) General formula (IC)

 (I C) [Wherein, R ^3C represents hydrogen, Y ^c is N, and one X ^1C — X ^2C — X ^3C — is —NH—C (= 0) —NR ⁷ — (wherein, R ⁷ is as defined above. synonymous a is) or -NH- C (= S) one NR ⁷ - (wherein, R ⁷ represents the same meaning as defined above), R ^1C is include N number of substituted 1-4 same or different Heteroarylalkyl or aralkyl in which the formed substituted or unsubstituted nitrogen-containing heterocyclic group is substituted with heteroaryl, provided that the aralkyl part of the aralkyl is the same or different and has 1 to 5 —Z— (CHR ⁴ ) — (CH ₂ ) _m NR ⁵ R ⁶ (wherein Z represents S, and R ⁴ , m, R ⁵ and R ⁶ have the same meanings as defined above) 1 to 5 NR HR ¹² (where R ¹¹ and R ¹² are the same or different Substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted bicycloalkyl, substituted or unsubstituted tricycloalkyl, substituted or unsubstituted benzocycloalkenyl, substituted or unsubstituted Represents a substituted lower alkenyl, a substituted or unsubstituted aralkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl or a substituted or unsubstituted heteroarylalkyl; R ¹¹ and R ¹² may together represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N) and at least one or more substitutions formed containing N Or R ^2C represents hydrogen, a substituted or unsubstituted nitrogen-containing heterocyclic group formed from the same or different and containing N having 1 to 5 substituents. heteroarylalkyl to the substitution in Heteroariru or Ararukiru {However, Ariru portion of the Araruki Le is one Z- number of substituted 1-5 same or different ^{(C HR 4) - (CH} 2) m NR 5 R ⁶ (wherein, Z is represents S, R ^4, m, R ⁵及beauty R ⁶ has the same meaning as defined above) 1 or is substituted with a substituent represented by the same also is properly different 5 NR ¹² (wherein, R ¹¹ and R ¹² are as defined above, is formed to include N becomes R ¹¹ and R ¹² gar緖of Substituted or unsubstituted nitrogen-containing heterocyclic group) and at least one substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N. A compound represented or a pharmacologically acceptable salt thereof. ^{(1 8) - X IC -} X 2C - X 3C - Gar NH- C (= O) - NR 7 - ( wherein, R ⁷ has the same meaning as defined above) compound in the range 1 7, wherein according to a Or a pharmacologically acceptable salt thereof. The compound according to claim ¹⁷ , wherein (1 9) — X ^1C — X ^2C — X ^3C — is — NH— C (= S) — NR ⁷ — (wherein, R ⁷ has the same meaning as described above). Or a pharmacologically acceptable salt thereof. (20) — general formula (ID)

 (ID) [Wherein, R ^3D represents a substituted or unsubstituted lower alkyl, a substituted or unsubstituted cycloalkyl or a substituted or unsubstituted aralkyl, and is YN, and one X ^1D — X ^2D — X ^3D — is —NH — C (= O) i NR ⁷ — (wherein, R ⁷ is as defined above) or — NH— C (= S) — NR ⁷ — (wherein, R ⁷ is as defined above) R ^1D represents a substituted or unsubstituted heteroarylalkyl or a substituted or unsubstituted aralkyl, and R ^2D represents hydrogen, a substituted or unsubstituted heteroarylalkyl or a substituted or unsubstituted aralkyl. And R ^1D and R ^2D may together represent a substituted or unsubstituted nitrogen-containing heterocyclic group formed containing N] or a pharmaceutically acceptable compound thereof. salt. (21) The claim 20 represented by the formula: X ^1D — X ^2D — X ^3D — —— NH— C (= 〇) — NR ⁷ — (wherein, R ⁷ has the same meaning as described above). Or a pharmaceutically acceptable salt thereof. Claim 20 represented by the formula (2 2) — X ^1D — X ^2D — X ^3D — is — NH— C (= S) — NR ⁷ — (wherein, R ⁷ has the same meaning as described above). Or a pharmaceutically acceptable salt thereof.