JPH11152275A - Nitrogen-containing condensed ring compound, its production and agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound useful as a preventing and therapeutic agent for an allergic disease, atopic dermatitis, allergic rhinitis, asthma, allergic conjunctivitis, urticaria, etc. SOLUTION: This compound is represented by formula I ring A is a (substituted) cyclic hydrocarbon or a (substituted) nitrogen-containing heterocycle; D and E are each O or S; either one of R<1> and R<2> is a group of formula II [Ar<1> and Ar<2> are each a (substituted) aromatic or the like; ring B is a (substituted) nitrogen-containing heterocycle; X and Y are a direct bond, O, S(O)p (p is 0 to 2) or the like; R<3> is H, a (substituted)hydroxy or the like] and the other is H, cyano or the like}, e.g. 2,4-dioxo-1-[3-(4-diphenylmethoxy-1- piperidinyl)propyl]-1,2,3,4-tetrahydroquinazoline. The compound of formula I is obtained by reacting, e.g. a compound (salt) of formula III (Q<1> is a leaving group) with a compound (salt) of formula IV (Q<2> is a reactive group; R<2> ' is H, cyano or the like).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention has excellent antiallergic, antihistamine, antiinflammatory, and eosinophil chemotaxis inhibitory effects, and is useful for allergic diseases, atopic dermatitis, allergic rhinitis, and asthma. Novel nitrogen-containing fused ring compounds (preferably quinazoline derivatives) useful as prophylactic / therapeutic agents for (eg, bronchial asthma), allergic conjunctivitis, urticaria (eg, chronic urticaria), Agent and the like.

[0002]

2. Description of the Related Art At present, a large number of compounds having a nitrogen-containing fused ring (for example, quinazoline) skeleton have been synthesized as drugs against various diseases.
(1) JP-A-57-206665 describes the formula

Embedded image Wherein R ¹ and R ³ represent a lower alkyl group, R ² represents a linear or branched alkoxycarbonyl group, and R ¹ , R ² and R ³ represent a 5- or 6-position of a quinazoline nucleus. And 7- or 6-position, 7-position and 8-position, R ⁴ is a hydrogen atom, a halogen atom, an alkyl group, a trifluoromethyl group or a nitro group, and X is an alkylene which may have an alkyl side chain. A group, Y is a nitrogen atom or an atomic group CH, R ⁵ , R ⁶ and R
⁷ represents a hydrogen atom, a halogen atom, an alkyl group or an alkoxy group, R ⁸ and R ⁹ each represent a hydrogen atom or a lower alkyl group, and m is 0 to 3, and n is 0 or 1.
Is useful as a vasodilator, a blood flow improving agent, a hypotensive agent or an anti-atherosclerotic agent, (2) JP-A-60-152417.
The expression

Embedded image [Wherein, R represents a hydrogen atom or a fluorine atom. That the compound or salt thereof is useful as an anticancer effect enhancer, (3) EP-A-040793,
formula

Embedded image Wherein R ¹ and R ³ are an alkyl group, R ² is an alkoxycarbonyl group, B is an alkyl group or at least one halogen, alkyl, alkoxy, dialkylamino,
O-CH ₂ -O, CF ₃ or NO ₂ with an optionally substituted phenyl group, A is a hydrogen atom, an alkyl group, a carboxy - alkyl group, alkoxycarbonyl - alkyl group,
Hydroxyalkyl group, benzyl group optionally substituted by NO ₂ or lower alkoxy, pyridylmethyl, alkyl, alkoxy, benzyl, tetramethylene, pentamethylene, hexamethylene, heptamethylene, methylene optionally substituted by alkyl A substituted aminoalkyl group, a lower alkyl group substituted with piperidine or pyrrolidine, R ⁴ R ⁵ N—CO—X, R ⁶ R ⁷ N—X ¹
-O-CO-X,

Embedded image (X and X ¹ are lower alkylene group, R ⁴ is hydrogen atom or alkyl group, R ⁵ is hydrogen atom, alkyl group, dialkylamino-alkyl group, benzyl group, piperidino-morpholino, 1-piperazinyl, 4- (lower) Acyl-1-
Piperazinyl, 4-carbamoyl-1-piperazinyl-alkyl group in which carbamoyl group may be substituted with alkyl or phenyl or piperidino or 4-alkylpiperazino in NR ⁴ R ⁵ , R ⁶ is alkyl group, R ⁷ is alkyl group Group, benzyl group, piperidino-alkyl, morpholino-alkyl). The compound or a salt thereof is useful as an anti-atherosclerotic agent,
(4) U.S. Pat. No. 3,274,194 has the formula

Embedded image Wherein R ¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group or an amino group, and n is 0
And R ² represents a di-lower alkylamino or heterocyclic group. And the salts thereof are useful as anti-inflammatory and sedative agents, and (5) Japanese Patent Application Laid-Open No.

Embedded image [In the formula, any one of X, Y and Z represents a sulfur atom, the other represents a carbon atom, E and G are the same or different and represent an oxygen atom or a sulfur atom, and R ¹ is substituted. A piperidino group or a substituted 1-piperazinyl group (the substituent is an aralkyl group, an aralkyloxy group, an aralkylcarbonyl group, an aromatic acyl group or an aralkylidene group), and R ² and R ³ are the same Alternatively, R ⁴ represents a hydrogen atom, a lower alkyl group, an aryl group or a halogen atom, R ⁴ represents a hydrogen atom, a lower alkyl group or an acyl group, and A represents an alkylene group having 1 to 4 carbon atoms. Or a salt thereof has an antihistamine action, an anti-serotonin action, an anti-allergic action and an anti-asthmatic action. On the other hand, compounds having an anti-allergic action or an anti-histamine action include, for example, terfenadine [The Merck Index, 12th edition,
9307] and Ebastine [The Merck Index, 12th edition, 353]
4], which are used in clinical practice.

[0003]

There is a demand for the development of new compounds that are more satisfactory in terms of their effects, sustainability and safety as compared with conventional antiallergic agents, antihistamines, antiinflammatory agents and the like. .

[0004]

Means for Solving the Problems As a result of various studies, the present inventors have found that one of two nitrogen atoms on a nitrogen-containing fused ring (preferably quinazoline) skeleton contains a piperidine or piperazine. A compound having a great feature in chemical structure where two substituents are bonded through a spacer containing a nitrogen heterocycle.

Embedded image [In the formula, ring A represents a homocyclic ring which may have a substituent or a nitrogen-containing heterocyclic ring which may have a substituent, and D and E are the same or different and each represents an oxygen atom or a sulfur atom. And ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² be the have a substituent indicates an aromatic group, an Ar ¹ and Ar ² are adjacent optionally fused ring group which may have a substituent together with the carbon atoms Ring B may represent a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y may be the same or different and each may be a bond, an oxygen atom, S (O) p (p is 0 Or an integer of 2 or less), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group) or a divalent straight chain which may have a substituent and may have 1 to 3 heteroatoms. R ³ represents a hydrogen atom, a hydroxy group which may have a substituent or a carboxyl group which may be esterified.), And the other is a chain lower hydrocarbon group. It represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent. A novel nitrogen-containing condensed ring compound (preferably a quinazoline derivative) or a salt thereof is synthesized for the first time, and these compounds have unexpectedly excellent antiallergic activity based on their specific chemical structure Antihistamine action, anti-inflammatory action, eosinophil chemotaxis inhibitory action (especially having both antihistamine action and eosinophil chemotaxis inhibitory action)
And its excellent persistence and safety, and its extremely low transferability to the brain. The present inventors have found that they can be advantageously used as preventive and therapeutic agents, and have completed the present invention.

[0005] That is, the present invention provides the following [1]

Embedded image Wherein ring A represents a cyclic hydrocarbon which may have a substituent or a nitrogen-containing heterocyclic ring which may have a substituent,
D and E are the same or different and each represent an oxygen atom or a sulfur atom, and ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² be the have a substituent indicates an aromatic group, an Ar ¹ and Ar ² are adjacent optionally fused ring group which may have a substituent together with the carbon atoms Ring B may represent a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y may be the same or different and each represents a bond, an oxygen atom, S (O) p (p is 0 Or an integer of 2 to 2), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group) or a divalent straight chain which may have a substituent and may be via 1 to 3 heteroatoms. A chain lower hydrocarbon group, and R ³ represents a hydrogen atom, a hydroxy group which may have a substituent or a carboxyl group which may be esterified, or a group represented by the following formula: Represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent Or a salt thereof],

[2] ring A is (i) a halogen atom, (ii)
C _1-3 alkylenedioxy group, (iii) nitro group, (iv)
Cyano group, (v) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom in addition to carbon atoms,, A C _1-6 alkyl group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from an oxygen atom and a sulfur atom, or a benzo-fused ring group thereof, (Vi) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _2-6 alkenyl group which may be present, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or a C _1-6 aralkyl optionally having di -C _1-6 alkylamino A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atom, or a substituent selected from benzo-fused ring groups thereof. C _2-6 alkynyl group which may be present, (viii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) halogenated C _1-6 alkyl optionally, (f) C _2-6 alkenyl optionally halogenated, (g) C _2-6 alkynyl optionally halogenated, (h) C _3-6 cycloalkyl , (I) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_1-6 alkoxy, (j) optionally halogenated C
_1-6 alkylthio, (k) hydroxy, (l) amino,
(M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C
_1-6 alkyl-carbonyl, (q) carboxyl, (r)
C _1-6 alkoxy-carbonyl, (s) carbamoyl,
(T) mono-C _1-6 alkyl-carbamoyl, (u) di-
C _1-6 alkylcarbamoyl group, (v) C _6-10 aryl-
Carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo ,
(Cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) C _3-6 cycloalkyl optionally substituted by carboxyl-C _1-6 alkyl, (ix A) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1 -6} alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6
Alkyl-sulfonamide, and 1 to 3 selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom
A C _1-6 alkoxy group which may have a substituent selected from a 5- to 10-membered heterocyclic group containing two hetero atoms or a benzo-fused ring group thereof, and (x) an optionally halogenated C _1-6 alkylthio group, (xi) hydroxy group, (xi
i) amino group, (xiii) mono-C _1-6 alkylamino group,
(Xiv) di-C _1-6 alkylamino group, (xv) 5-6
Membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xvii) carboxyl group, (xviii) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6 Alkyl-carbamoyl group, (xxi) di-C
_1-6 alkyl carbamoyl group, (xxii) C _6-10 aryl-carbamoyl group, (xxiii) sulfo group, (xxiv) C _1-6
Alkylsulfonyl group, (xxv) (a) halogen atom,
(B) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) optionally halogenated C _{2- 6} alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) a halogen atom,
Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl,
Amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C ₁ optionally having mono- or di-C _1-6 alkylamino _-6 alkyl-sulfonamide, and 5 to 1 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _1-6 alkoxy optionally having a substituent selected from a 0-membered heterocyclic group or a benzo-fused ring group thereof, (j) an optionally halogenated C _1-6 alkylthio, and (k) hydroxy (1) amino, (m) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5-6
Membered cyclic amino, (p) C _1-6 alkyl-carbonyl,
(Q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C _1-6 alkyl-
Carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl Good C _6-10 aryl groups, (xxvi) (a) halogen atoms, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _{1 -6} alkyl, (f) optionally halogenated C
_2-6 alkenyl, (g) optionally halogenated C
_2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono _-Or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C _1-6 alkyl optionally having mono- or di-C _1-6 alkylamino Having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms or a benzo-fused ring thereof. Optionally, C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino, (m) mono-C _1-6
Alkylamino, (n) di-C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl - carbamoyl, (u) di -C _1-6 alkylcarbamoyl, (v) C _6-10 aryl - carbamoyl,
(W) sulfo, (x) C _1-6 alkylsulfonyl, (y) C
_6-10 aryl, (z) C _6-10 aryloxy, (aa) C
_7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl,
(Ff) C _6-10 aryl-thiocarbamoyl, (gg) C
_7-16 aralkyl, (hh) a C _7-15 aralkyl group which may be substituted by (C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl, (xx
vii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) halogenated _Optionally substituted C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl,
(I) halogen atom, hydroxy, carboxyl, C _1-6
Alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- Or di-C _1-6
C _1-6 alkyl-sulfonamide _{optionally having} alkylamino, and a 5- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms C _1-6 alkoxy optionally having a substituent selected from the group or a benzo-fused ring group thereof, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino (M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-carbonyl, (q) carboxyl , (R) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-
C _1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl, (v) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl,
(Y) C _6-10 aryl, (z) C _6-10 aryloxy,
(Aa) C _7-16 aralkyloxy, (bb) oxo, (cc)
Thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl,
(Gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-
C _6-10 aryloxy group optionally substituted with C _1-6 alkyl, (xxviii) (a) halogen atom, (b) C _1-3
Alkylenedioxy, (c) nitro, (d) cyano,
(E) an optionally halogenated C _1-6 alkyl,
(F) an optionally halogenated C _2-6 alkenyl,
(G) optionally halogenated C _2-6 alkynyl,
(H) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and In addition to the carbon atom, it may have a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a substituent selected from a benzo-fused ring group thereof. C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (1) amino, (m) mono-C _1-6 alkylamino,
(N) di-C _1-6 alkylamino, (o) 5- to 6-membered cyclic amino, (p) C _1-6 alkyl-carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl,
(S) carbamoyl, (t) mono-C _1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl good C _7-16 aralkyloxy group, (xxix)
Oxo group, (xxx) thiocarbamoyl group, (xxxi) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxii) di-
C _1-6 alkyl - thiocarbamoyl group, (xxxiii) C
_6-10 aryl-thiocarbamoyl group, (xxxiv) C _6-10
Aryl-carbonyloxy, (xxxv) (a) halogen atom, (b) optionally halogenated C _1-6 alkyl group, (c) optionally halogenated C _2-6 alkenyl, (d) Optionally halogenated C _2-6 alkynyl, (e) C _3-6 cycloalkyl, (f) halogen atom,
Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl,
Amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C ₁ optionally having mono- or di-C _1-6 alkylamino _-6 alkyl-sulfonamide, and 5 to 1 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
C _1-6 alkoxy optionally having a substituent selected from a zero-membered heterocyclic group or a benzo-fused ring group thereof, (g) optionally halogenated C _1-6 alkylthio, (h) hydroxy (I) amino, (j) mono-C _1-6 alkylamino, (k) di-C _1-6 alkylamino, (l) 5-6
Membered cyclic amino, (m) C _1-6 alkyl-carbonyl,
(N) carboxyl, (o) C _1-6 alkoxy-carbonyl, (p) carbamoyl, (q) mono-C _1-6 alkyl-
Carbamoyl, (r) di-C _1-6 alkylcarbamoyl,
(S) C _6-10 aryl-carbamoyl, (t) sulfo,
(U) C _1-6 alkylsulfonyl, (v) C _6-10 aryloxy, (w) C _6-10 aryloxy, (x) C _7-16 aralkyloxy, (y) thiocarbamoyl, (z) mono- C _1-6 alkyl-thiocarbamoyl, (aa) di-C _1-6 alkyl-thiocarbamoyl, (bb) C _6-10 aryl-thiocarbamoyl, (cc) C _7-16 aralkyl, (dd) C _{1- 6} alkoxy-carbonyl-C _1-6 alkyl or (ee) aminocarbonyl optionally having a carboxyl-C _1-6 alkyl group, (xxxvi) selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom A 5- or 6-membered heterocyclic group containing 1 to 4 one or two heteroatoms, (x
xxvii) C _1-6 alkoxy-carbonyl-C _1-6 alkoxy-carbonyl group, (xxxviii) C _1-6 alkoxy-carbonyl-C _1-6 alkyl-carbamoyl group, (xxxix) hydroxy-C _1-6 alkyl- Carbamoyl group, (xxxx)
A C _1-6 alkoxy-carbonyl-carbamoyl group, (xxx
xi) C _6-14 arylsulfonamide, (xxxxii) C _1-6
Alkylsulfonamide, (xxxxiii) carboxy-C
_1-6 alkyl-carbonyl-amino group, (xxxxiv) C _1-6
Alkoxy-carbonyl-C _1-6 alkyl-carbonyl-amino group, (xxxxv) C _1-6 alkyl-carbonyloxy-C _1-6 alkyl-carbonyl-amino group, (xxxxv
i) a hydroxy-C _1-6 alkyl-carbonyl-amino group, and (xxxxvii) hydroxy or (and) C
(1) a 3- to 10-membered group which may have a substituent selected from the group consisting of a C _6-14 aryl-C _2-6 alkenyl-carbonylamide group optionally substituted with _1-6 alkoxy; A cyclic hydrocarbon or (2) a 3- to 13-membered nitrogen-containing heterocyclic ring containing one nitrogen atom and optionally containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. And D and E are the same or different and each represent an oxygen atom or a sulfur atom,
One of R ¹ and R ² is a formula

Embedded image [Wherein R ³ represents (1) a hydrogen atom, (2) (i) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, (iv) a cyano group, or (v) a halogen atom. Atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _1-6 alkyl group which may have, (vi) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _2-6 alkenyl group which may have a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _{1- 6} alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_2-6 alkynyl group, (viii) C _3-6 cycloalkyl group,
(Ix) halogen atom, hydroxy, carboxyl, C
_1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_1-6 alkoxy group, (x) optionally halogenated C
_1-6 alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono-C _1-6 alkylamino group, (xiv)
Di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xv
ii) carboxyl group, (xviii) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6
Alkyl - carbamoyl group, (xxi) di -C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl - carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (xxv) C _6-10 aryl group, (xxvi) C _6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 A substituent selected from the group consisting of an alkyl-thiocarbamoyl group, (xxxi) di-C _1-6 alkyl-thiocarbamoyl group, (xxxii) C _6-10 aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group (I) a hydroxy group optionally having a C _1-16 chain or cyclic hydrocarbon group, (3) a carboxyl group, or (4) a hydrogen atom of a carboxyl group, halogen atom, (ii) C _1-3 alkylenedioxy Alkoxy group, (iii) nitro group, (iv) cyano group, (v)
Halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1- 6} alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen atom and a sulfur atom A C _1-6 alkyl group optionally having a substituent selected from a selected 5 to 10-membered heterocyclic group containing 1 to 3 hetero atoms or a benzo-fused ring group thereof, (vi) a halogen atom, Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_2-6 alkenyl group, (vii) halogen atom, hydroxy,
Carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C
_1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and nitrogen atom besides carbon atom, an oxygen atom and a sulfur 1 selected from atoms
A C _2-6 alkynyl group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing from 3 to 3 hetero atoms or a benzo-fused ring group thereof, (viii) a C _3-6 cycloalkyl Group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen A C _1-6 alkoxy group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms and sulfur atoms or a benzo-fused ring group thereof, x) an optionally halogenated C _1-6 alkylthio group, (xi) a hydroxy group, (xii)
An amino group, (xiii) a mono-C _1-6 alkylamino group, (x
iv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group,
(Xvii) carboxyl group, (xviii) C _1-6 alkoxy-
Carbonyl group, (xix) carbamoyl group, (xx) mono-
C _1-6 alkyl - carbamoyl group, (xxi) di -C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl - carbamoyl, (xxiii) sulfo group, (xxiv) C _{1 -6} alkylsulfonyl group, (Xxv) a C _6-10 aryl group, (xxvi) C
_6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di -C _1-6 alkyl - thiocarbamoyl group and (xxxii) C _6-10 aryl - thiocarbamoyl and (xxxiii) C _7-16 may have a substituent group selected from the group consisting of aralkyl groups C _1- A carboxyl group having a _16- chain or cyclic hydrocarbon group, wherein Ar ¹ and Ar ² are (i) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, and (iv) a cyano group, respectively. Group, (v) halogen atom, hydroxy, carboxyl,
C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_1-6 alkyl group, (vi) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy - carbonyl, C _1-6 alkyl - carbonyl, amino, mono -
Or di-C _1-6 alkylamino, mono- or di-C _1-6
Alkyl-carbonylamino, sulfonamide, mono-
Or C optionally having di-C _1-6 alkylamino
Selected from _1-6 alkyl-sulfonamides and 5- to 10-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms or benzo-fused ring groups thereof A C _2-6 alkenyl group which may have a substituent, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and 5 to 10 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _2-6 alkynyl group optionally having a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof, (viii)
C _3-6 cycloalkyl group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _{1- 6} alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and carbon atoms, nitrogen atom in addition, 1 to 5 to 10-membered heterocyclic group or a benzo-fused ring may have a substituent group selected from the group C ₁ containing 3 hetero atoms selected from oxygen atom and a sulfur atom _-6 alkoxy group, (x) optionally halogenated C _1-6 alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono-C _1-6 alkylamino group, (xiv) di -C _1-6 A Kiruamino group,
(Xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xvii) carboxyl group, (xvii
i) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6 alkyl-carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxi)
i) C _6-10 aryl-carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (xxv) C
_6-10 aryl group, (xxvi) C _6-10 aryloxy group,
(Xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) a thiocarbamoyl group, (xxx) mono- -C
_1-6 alkyl-thiocarbamoyl group, (xxxi) di-C _1-6
Alkyl-thiocarbamoyl group and (xxxii) C _6-10
(1) C _6-14 aryl group, (2) nitrogen atom other than carbon atom, which may have a substituent selected from the group consisting of aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group; 5 to 8 containing 1 to 4 one or two hetero atoms selected from a sulfur atom and an oxygen atom
A 3-membered aromatic heterocyclic group or (3) a condensed heterocyclic group of the 5- to 8-membered aromatic heterocyclic group and a C _6-14 aromatic cyclic hydrocarbon, wherein Ar ¹ and Ar ² represent adjacent carbon atoms Along with the atom, a substituent which may have the same substituent as the substituent of the aromatic group represented by Ar ¹ and Ar ² described above,

Embedded image [Wherein, R ³ has the same meaning as described above], and the ring B may be a (i) halogen atom, (i
i) C _1-3 alkylenedioxy group, (iii) nitro group, (i
v) cyano group, (v) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino , mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamide and nitrogen in addition to carbon atoms, C _1-6 alkyl optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms or a benzo-fused ring group thereof Group, (vi) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _2-6 alkenyl group which may be present, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or a C _1-6 aralkyl optionally having di -C _1-6 alkylamino A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atom, or a substituent selected from benzo-fused ring groups thereof. Optionally having a C _2-6 alkynyl group, (viii) a C _3-6 cycloalkyl group, (ix) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _1-6 alkoxy group optionally having a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (x) an optionally halogenated C _1-6 alkylthio group, (xi ) Hydroxy group, (xii) amino group, (xii
i) mono-C _1-6 alkylamino group, (xiv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group,
(Xvi) a C _1-6 alkyl-carbonyl group, (xvii) a carboxyl group, (xviii) a C _1-6 alkoxy-carbonyl group,
(Xix) carbamoyl group, (xx) mono-C _1-6 alkyl-
Carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl-carbamoyl, (xxii
i) a sulfo group, (xxiv) a C _1-6 alkylsulfonyl group,
(Xxv) a C _6-10 aryl group, (xxvi) a C _6-10 aryloxy group, (xxvii) a C _7-16 aralkyloxy group, (xxvii
i) an oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di-C _1-6 alkyl-thiocarbamoyl group and (xxxii)
C _6-10 aryl-thiocarbamoyl and (xxxiii) C
_7-16 optionally having a substituent selected from the group consisting of an aralkyl group, containing one nitrogen atom, and further containing one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom And X and Y are the same or different and each represents (1) a bond, (2) an oxygen atom, (3) S (O) p (p
Represents an integer of 0 to 2), (4) NR ⁴ (R ⁴ represents a hydrogen atom or a C _1-6 alkyl group), or (5)
(I) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, (iv) a cyano group, (v) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _1-6 alkyl group which may have a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (vi) a halogen atom, hydroxy, carboxyl,
C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_2-6 alkenyl group, (vii) halogen atom, hydroxy,
Carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C
_1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and nitrogen atom besides carbon atom, an oxygen atom and a sulfur 1 selected from atoms
A C _2-6 alkynyl group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing from 3 to 3 hetero atoms or a benzo-fused ring group thereof, (viii) a C _3-6 cycloalkyl Group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen A C _1-6 alkoxy group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms and sulfur atoms or a benzo-fused ring group thereof, x) an optionally halogenated C _1-6 alkylthio group, (xi) a hydroxy group, (xii)
An amino group, (xiii) a mono-C _1-6 alkylamino group, (x
iv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group,
(Xvii) carboxyl group, (xviii) C _1-6 alkoxy-
Carbonyl group, (xix) carbamoyl group, (xx) mono-
C _1-6 alkyl-carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl-carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (Xxv) a C _6-10 aryl group, (xxvi) C
_6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di An oxygen atom optionally having a substituent selected from the group consisting of —C _1-6 alkyl-thiocarbamoyl group and (xxxii) C _6-10 aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group A C _1-6 alkylene group which may contain 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom in the hydrocarbon chain,
A C _2-6 alkenylene group or a C _2-6 alkynylene group], the other being (1) a hydrogen atom,
(2) a cyano group, or (3) (i) a halogen atom, (i
i) C _1-3 alkylenedioxy group, (iii) nitro group, (i
v) cyano group, (v) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino , mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamide and nitrogen in addition to carbon atoms, C _1-6 alkyl optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms or a benzo-fused ring group thereof Group, (vi) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _2-6 alkenyl group which may be present, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or a C _1-6 aralkyl optionally having di -C _1-6 alkylamino A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atom, or a substituent selected from benzo-fused ring groups thereof. C _2-6 alkynyl group which may be present, (viii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) halogenated C _1-6 alkyl optionally, (f) C _2-6 alkenyl optionally halogenated, (g) C _2-6 alkynyl optionally halogenated, (h) C _3-6 cycloalkyl , (I) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_1-6 alkoxy, (j) optionally halogenated C
_1-6 alkylthio, (k) hydroxy, (l) amino,
(M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C _1-6
Alkyl-carbonyl, (q) carboxyl, (r) C
_1-6 alkoxy-carbonyl, (s) carbamoyl,
(T) mono-C _1-6 alkyl-carbamoyl, (u) di-
C _1-6 alkylcarbamoyl group, (v) C _6-10 aryl-
Carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo ,
(Cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) C _3-6 cycloalkyl optionally substituted by carboxyl-C _1-6 alkyl, (ix A) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1 -6} alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6
Alkyl-sulfonamide, and 1 to 3 selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom
A C _1-6 alkoxy group which may have a substituent selected from a 5- to 10-membered heterocyclic group containing two hetero atoms or a benzo-fused ring group thereof, and (x) an optionally halogenated C _1-6 alkylthio group, (xi) hydroxy group, (xi
i) amino group, (xiii) mono-C _1-6 alkylamino group,
(Xiv) di-C _1-6 alkylamino group, (xv) 5-6
Membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xvii) carboxyl group, (xviii) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6 Alkyl-carbamoyl group, (xxi) di-C
_1-6 alkyl carbamoyl group, (xxii) C _6-10 aryl-carbamoyl group, (xxiii) sulfo group, (xxiv) C _1-6
Alkylsulfonyl group, (xxv) (a) halogen atom,
(B) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) optionally halogenated C _{2- 6} alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) a halogen atom,
Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl,
Amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C ₁ optionally having mono- or di-C _1-6 alkylamino _-6 alkyl-sulfonamide, and 5 to 1 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _1-6 alkoxy optionally having a substituent selected from a 0-membered heterocyclic group or a benzo-fused ring group thereof, (j) an optionally halogenated C _1-6 alkylthio, and (k) hydroxy (1) amino, (m) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5-6
Membered cyclic amino, (p) C _1-6 alkyl-carbonyl,
(Q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C _1-6 alkyl-
Carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl Good C _6-10 aryl groups, (xxvi) (a) halogen atoms, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _{1 -6} alkyl, (f) optionally halogenated C
_2-6 alkenyl, (g) optionally halogenated C
_2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono _-Or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C _1-6 alkyl optionally having mono- or di-C _1-6 alkylamino Having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms or a benzo-fused ring thereof. Optionally, C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino, (m) mono-C _1-6
Alkylamino, (n) di-C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl - carbamoyl, (u) di -C _1-6 alkylcarbamoyl, (v) C _6-10 aryl - carbamoyl,
(W) sulfo, (x) C _1-6 alkylsulfonyl, (y) C
_6-10 aryl, (z) C _6-10 aryloxy, (aa) C
_7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl,
(Ff) C _6-10 aryl-thiocarbamoyl, (gg) C
_7-16 aralkyl, (hh) a C _7-15 aralkyl group which may be substituted by (C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl, (xx
vii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) halogenated _Optionally substituted C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl,
(I) halogen atom, hydroxy, carboxyl, C _1-6
Alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- Or di-C _1-6
C _1-6 alkyl-sulfonamide _{optionally having} alkylamino, and a 5- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms C _1-6 alkoxy optionally having a substituent selected from the group or a benzo-fused ring group thereof, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino (M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-carbonyl, (q) carboxyl , (R) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-
C _1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl, (v) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl,
(Y) C _6-10 aryl, (z) C _6-10 aryloxy,
(Aa) C _7-16 aralkyloxy, (bb) oxo, (cc)
Thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl,
(Gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-
C _6-10 aryloxy group optionally substituted with C _1-6 alkyl, (xxviii) (a) halogen atom, (b) C _1-3
Alkylenedioxy, (c) nitro, (d) cyano,
(E) an optionally halogenated C _1-6 alkyl,
(F) an optionally halogenated C _2-6 alkenyl,
(G) optionally halogenated C _2-6 alkynyl,
(H) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and In addition to the carbon atom, it may have a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a substituent selected from a benzo-fused ring group thereof. C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (1) amino, (m) mono-C _1-6 alkylamino,
(N) di-C _1-6 alkylamino, (o) 5- to 6-membered cyclic amino, (p) C _1-6 alkyl-carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl,
(S) carbamoyl, (t) mono-C _1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl good C _7-16 aralkyloxy group, (xxix)
Oxo group, (xxx) thiocarbamoyl group, (xxxi) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxii) di-
C _1-6 alkyl - thiocarbamoyl group, (xxxiii) C
_6-10 aryl-thiocarbamoyl group, (xxxiv) C _6-10
Aryl-carbonyloxy, (xxxv) (a) halogen atom, (b) optionally halogenated C _1-6 alkyl group, (c) optionally halogenated C _2-6 alkenyl, (d) Optionally halogenated C _2-6 alkynyl, (e) C _3-6 cycloalkyl, (f) halogen atom,
Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl,
Amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C ₁ optionally having mono- or di-C _1-6 alkylamino _-6 alkyl-sulfonamide, and 5 to 1 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
C _1-6 alkoxy optionally having a substituent selected from a zero-membered heterocyclic group or a benzo-fused ring group thereof, (g) optionally halogenated C _1-6 alkylthio, (h) hydroxy (I) amino, (j) mono-C _1-6 alkylamino, (k) di-C _1-6 alkylamino, (l) 5-6
Membered cyclic amino, (m) C _1-6 alkyl-carbonyl,
(N) carboxyl, (o) C _1-6 alkoxy-carbonyl, (p) carbamoyl, (q) mono-C _1-6 alkyl-
Carbamoyl, (r) di-C _1-6 alkylcarbamoyl,
(S) C _6-10 aryl-carbamoyl, (t) sulfo,
(U) C _1-6 alkylsulfonyl, (v) C _6-10 aryloxy, (w) C _6-10 aryloxy, (x) C _7-16 aralkyloxy, (y) thiocarbamoyl, (z) mono- C _1-6 alkyl-thiocarbamoyl, (aa) di-C _1-6 alkyl-thiocarbamoyl, (bb) C _6-10 aryl-thiocarbamoyl, (cc) C _7-16 aralkyl, (dd) C _{1- 6} alkoxy-carbonyl-C _1-6 alkyl or (ee) aminocarbonyl optionally having a carboxyl-C _1-6 alkyl group, (xxxvi) selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom A 5- or 6-membered heterocyclic group containing 1 to 4 one or two heteroatoms, (x
xxvii) C _1-6 alkoxy-carbonyl-C _1-6 alkoxy-carbonyl group, (xxxviii) C _1-6 alkoxy-carbonyl-C _1-6 alkyl-carbamoyl group, (xxxix) hydroxy-C _1-6 alkyl- Carbamoyl group, (xxxx)
A C _1-6 alkoxy-carbonyl-carbamoyl group, (xxx
xi) C _6-14 arylsulfonamide, (xxxxii) C _1-6
Alkylsulfonamide, (xxxxiii) carboxy-C
_1-6 alkyl-carbonyl-amino group, (xxxxiv) C _1-6
Alkoxy-carbonyl-C _1-6 alkyl-carbonyl-amino group, (xxxxv) C _1-6 alkyl-carbonyloxy-C _1-6 alkyl-carbonyl-amino group, (xxxxv
i) a hydroxy-C _1-6 alkyl-carbonyl-amino group, and (xxxxvii) hydroxy or (and) C
C _1-16 chain or cyclic carbon optionally having a substituent selected from the group consisting of C _6-14 aryl-C _2-6 alkenyl-carbonylamide group optionally substituted with _1-6 alkoxy The compound according to item (1), which represents a hydrogen group],

[3] The ring A is a benzene ring which may have a substituent, a pyridine ring which may have a substituent or a pyrazine ring which may have a substituent. [4] The compound according to [ ¹ ], wherein Ar ¹ and Ar ² are each a phenyl group which may have a substituent, and [5] X is a bond or a C _1-6 alkylene. The compound according to item [1], wherein [6] Y is a C _1-6 alkylene which may be substituted with a bond, an oxygen atom or a hydroxy group, and which may contain an oxygen atom in the alkylene chain. The compound according to item [1], wherein the ring [7] is a group represented by the formula:

Embedded image [In the formula, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² are the same or different, and each represents a straight-chain C _{1 which} may be substituted with a hydroxy group, an oxo group, or a C _1-6 alkyl group. _-6 represents an alkylene group], the compound according to item [1], wherein the ring [8] is

Embedded image The compound according to item [1], which is

[9] The compound according to [1], wherein R ³ is a hydrogen atom or a hydroxy group,
[10] One of R ¹ and R ² is a formula

Embedded image (Wherein each symbol has the same meaning as described in item [1]), and the other is a hydrogen atom, a cyano group, an optionally substituted C _1-6 alkyl group or a substituted A compound according to item [1], which represents a C _3-6 cycloalkyl group which may be _substituted ; [11] a compound according to item [1], wherein D and E are both oxygen atoms;

[12] ring A is (i) a halogen atom, (i
i) a nitro group, (iii) a C _1-6 alkyl group optionally having carboxyl or C _1-6 alkoxy-carbonyl, (iv) a C _1-6 alkoxy group, (v) a hydroxy group,
(Vi) amino group, (vii) mono- or di-C _1-6 alkylamino group, (viii) carboxyl group, (ix) C _1-6 alkoxy-carbonyl group, (x) carbon atom, nitrogen atom, One or two selected from an oxygen atom and a sulfur atom
A 5- or 6-membered heterocyclic group containing 1 to 4 heteroatoms, (xi) a C _1-6 alkylsulfonamide, (xii) a carboxy-C _1-6 alkyl-carbonyl-amino group, (x
iii) C _1-6 alkoxy-carbonyl-C _1-6 alkyl-
A carbonyl-amino group, (xiv) C _1-6 alkyl-carbonyl-oxy-C _1-6 alkyl-carbonyl-amino group and (xv) hydroxy optionally substituted with hydroxy or (and) C _1-6 alkoxy. _A C _6-14 aryl ring which may have a substituent selected from the group consisting of _6-14 aryl-C _2-6 alkenyl-carbonylamide group, D and E represent oxygen atoms, R ¹ and R ² Either is an expression

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents a bond or an oxygen atom, and R ³ represents a hydrogen atom or a hydroxy group), the other being (1) a hydrogen atom, (2) Cyano group, (3) (i) halogen atom, (ii) carboxyl group, (iii) C _1-6 alkoxy-carbonyl group, (iv)
A 5- or 6-membered nitrogen-containing heterocyclic group, (v) having a substituent selected from C _7-15 aralkyl, carboxyl-C _1-6 alkyl and C _1-6 alkoxycarbonyl-C _1-6 alkyl. Carbamoyl group, (vi) C _6-14 aryl-carbonyloxy group, (vii) sulfamoyl group, (v
iii) Substitution selected from the group consisting of mono or di-C _1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) C _1-6 alkoxy group optionally having carboxyl or carbamoyl and (x) cyano. A C _1-16 alkyl group optionally having a group, (4) a C _3-7 cycloalkyl group optionally having a carboxyl or C _1-6 alkoxycarbonyl, and (5) a C _6-14 aryl group Or (6) the compound of [1], which represents a C _7-15 aralkyl group which may have a substituent selected from C _1-6 alkoxy, carboxyl or C _1-6 alkoxy-carbonyl,

[0009] [13] A ring is (i) a halogen atom or (ii) C _1-6 alkoxy - a benzene ring which may have a C _1-6 alkyl optionally substituted with carbonyl, D and E is an oxygen atom, and ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B is

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, R ³ represents a hydrogen atom or a hydroxy group), and the other is (1) a hydrogen atom, (2) a cyano group, (3)
(I) a halogen atom, (ii) a C _1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) a C _1-6 alkyl group which may have a substituent selected from the group consisting of cyano, (4) The compound according to (1), which represents a C _3-7 cycloalkyl group optionally having C _1-6 alkoxycarbonyl,

[14] Ring A is a benzene ring which may have a halogen atom, D and E are oxygen atoms, and ^one of R ¹ and R ² has the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, and R ³ represents a hydrogen atom), and the other represents a C _1-6 alkyl group _optionally having carboxyl. The compound according to item [1], [15] 2,4-dioxo-1- [4- (4
-Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-valeric acid or a salt thereof, [16] 2
-[2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]
Isobutyric acid or a salt thereof, [17] 2- [2,4-dioxo-1- [4
-(4-diphenylmethoxypiperidino) butyl] -6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyric acid or a salt thereof,

[18] Equation

Embedded image [Wherein Q ¹ represents a leaving group, and other symbols have the same meanings as described in item [1].]

Embedded image [In the formula, Q ² represents a reactive group, R ² ′ represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent, and other symbols are as described in the item [1]. The method for producing a compound according to item [1], wherein the compound is represented by the following formula [1]:
9] Expression

Embedded image [Wherein each symbol has the same meaning as described in the item [1]] and a salt thereof and Q ³ —CO—Q ⁴ (Q ³ and Q ⁴ each represent a leaving group) Wherein the compound is subjected to a ring closure reaction.

[20] A pharmaceutical composition comprising the compound according to item [1] or a salt thereof, and [21] an antihistamine and / or an antihistamine comprising the compound according to item [1] or a salt thereof. Eosinophil chemotaxis inhibitor, [22] No. [1]
[23] An antiallergic agent comprising the compound according to item [1] or a salt thereof, and [23] asthma, allergic conjunctivitis, allergic rhinitis, urticaria or atopy comprising the compound according to item [1] or salt thereof. Provide a preventive / therapeutic agent for atopic dermatitis. Further, when the compound (I) or a salt thereof contains an asymmetric carbon in the structure, both the optically active form and the racemic form are included in the scope of the present invention, and the compound (I) or a salt thereof is a hydrate, Any of non-hydrates may be used.

In the above formula (I), ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² be the have a substituent indicates an aromatic group, an Ar ¹ and Ar ² are adjacent optionally fused ring group which may have a substituent together with the carbon atoms Ring B may represent a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y may be the same or different and each represents a bond, an oxygen atom, S (O) p (p is 0 Or an integer of 2), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group), or a divalent straight chain which may have a substituent and may have 1 to 3 heteroatoms. A chain lower hydrocarbon group, and R ³ represents a hydrogen atom, a hydroxy group which may have a substituent or a carboxyl group which may be esterified.) The other represents a hydrogen atom or a hydrocarbon group which may have a substituent.

[0014] In the above formula (II), Ar ¹ and Ar ² represents an "aromatic group which may be substituted", Ar ¹ and A
r ² may form a condensed ring group which may have a substituent together with an adjacent carbon atom. Examples of the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² include, for example, a monocyclic, condensed polycyclic or ring-assembled aromatic hydrocarbon group ,
More specifically, phenyl, biphenyl, 1-naphthyl,
2-naphthyl, 2-indenyl, 2-anthryl, 1-
C _6-14 aryl groups such as anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or 9-phenanthryl and the like (preferably phenyl, biphenyl, 1-naphthyl or 6- to 14-membered monocyclic, fused polycyclic or ring-assembled aromatic hydrocarbon groups of 2-naphthyl or the like, particularly preferably phenyl or the like, or selected from nitrogen, sulfur and oxygen other than carbon atoms Preferably one or two heteroatoms
Or more (for example, 1 to 4, preferably 1 to 3
(Including preferably 5 to 8 members) or a fused aromatic heterocyclic group thereof, more specifically, thiophene, benzo [b] thiophene, benzo [b] furan, benzimidazole, benzoxazole, benzoxazole, Thiazole,
Benzisothiazole, naphtho [2,3-b] thiophene, thianthrene, furan, isoindolizine, xanthrene, phenoxathiin, pyrrole, imidazole,
Triazole, thiazole, oxazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indole, isoindole, 1H-indazole, purine, 4H-quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline Aromatic heterocycles such as phenanthridine, acridine, phenazine, isothiazole, phenothiazine, isoxazole, furazane, phenoxazine or isochroman (preferably pyridine, thiophene or furan, more preferably pyridine, etc.), or One or more (preferably one or two, more preferably one) aromatic rings (preferably, the above-mentioned monocyclic heterocyclic ring) Such as aromatic hydrocarbon radicals, preferably such as a monovalent group formed by removing any hydrogen atom from a ring formed by condensing a benzene ring, etc.).
As the “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² , for example, phenyl is preferable.

The “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² includes, for example, (i) a halogen atom (for example, fluorine, chlorine, bromine, Iodine), (ii) lower alkylenedioxy group (for example, C _1-3 alkylenedioxy group such as methylenedioxy and ethylenedioxy), (iii) nitro group,
(Iv) a cyano group, (v) an optionally substituted lower alkyl group (for example, C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like) Alkyl group), (vi) optionally substituted lower alkenyl group (for example, vinyl, propenyl, isopropenyl, 2-
C _2-6 alkenyl groups such as buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like), (vi
i) an optionally substituted lower alkynyl group (for example,
2-butyn-1-yl, 4-pentyn-1-yl, 5-
A C _2-6 alkynyl group such as hexyn-1-yl, etc.),
(Viii) a lower cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.); (ix) a lower alkoxy group which may be substituted (eg, methoxy, ethoxy, propoxy) , Isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like
_1-6 alkoxy group), (x) lower alkylthio group which may be halogenated, (xi) hydroxy group, (xi
i) amino group, (xiii) mono-lower alkylamino group (for example, mono-C such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.)
_1-6 alkylamino group, etc.), (xiv) di-lower alkylamino group (for example, dimethylamino, diethylamino,
Di-C _1-6 alkylamino groups such as dipropylamino, dibutylamino, etc.), (xv) 5- to 6-membered cyclic amino groups (for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidine-1-yl) Yl), (xvi) a lower alkyl-carbonyl group (e.g.,
Carbonyl group), (xvii) carboxyl group, (xviii) lower alkoxy - - acetyl, C _1-6 alkyl, such as propionyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6, such as butoxycarbonyl (Xix) carbamoyl group, (xx) mono-lower alkyl-carbamoyl group (for example, mono-C _1-6 alkyl such as methylcarbamoyl, ethylcarbamoyl, etc.)
A carbamoyl group), (xxi) a di-lower alkyl-carbamoyl group (eg, a di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.), and (xxii) an aryl-carbamoyl group (eg, phenylcarbamoyl, (C _6-10 aryl-carbamoyl such as naphthylcarbamoyl), (xxiii) sulfo group, (xxiv) lower alkylsulfonyl group (for example,
A C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl, an (xxv) aryl group (eg, a C _6-10 aryl group such as phenyl and naphthyl), an (xxvi) aryloxy group (eg, phenoxy, such as C _6-10 aryloxy group such as naphthyloxy), (xxvii) an aralkyloxy group (e.g., a C _7-16 aralkyloxy group such as benzyloxy), (xx
viii) oxo group, (xxix) thiocarbamoyl group, (xx
x) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl and the like), (xxxi) di-lower alkyl-thiocarbamoyl group (for example, dimethyl (Xxx) di-C _1-6 alkyl-thiocarbamoyl groups such as thiocarbamoyl and diethylthiocarbamoyl, and (xxxii) aryl-thiocarbamoyl groups (for example, C _6-10 aryl-thiocarbamoyl such as phenylthiocarbamoyl and naphthylthiocarbamoyl). etc.), (xxxiii) an aralkyl group (e.g., benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, etc. C _7-16 aralkyl group such as 2-phenylpropyl), (xxxiv) a lower alkoxy - carbonyl - lower alkyl Group (for example, methylcarbonyl Le, C _1-6 alkoxy such as ethyl carbonyl methyl - carbonyl -
C _1-6 alkyl group) or (xxxv) carboxyl-
And lower alkyl groups (eg, carboxyl-C _1-6 alkyl groups such as carboxylmethyl and carboxylethyl).

The "optionally substituted lower alkyl group" represented by "substituent" of the "optionally substituted aromatic group" represented by Ar ¹ and Ar ² Examples of the “substituent” of the “optionally substituted lower alkenyl group”, “optionally substituted lower alkynyl group” and “optionally substituted lower alkoxy group” include (i) a halogen atom (eg, (Ii) mono- or di-lower alkylamino groups (for example, mono- or di-C ₁ such as methylamino, dimethylamino, ethylamino, dimethylamino, etc.); _-6 alkylamino group), (iii) lower alkoxy-carbonyl group (for example, methoxycarbonyl,
C _1-6 alkoxy-carbonyl group such as ethoxycarbonyl), (iv) aminocarbonyl group, (v) carboxyl group and (vi) one to three atoms selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom And 1 to 3 substituents selected from a 5- to 10-membered heterocyclic group containing a hetero atom and a benzo-fused ring group thereof. Among the above substituents, examples of the lower alkyl group which may be substituted with a halogen atom (the lower alkyl group which may be halogenated) include, for example, 1 to 3 halogen atoms (eg, a fluorine atom, chlorine Atom, bromine atom, iodine atom or the like, and a C _1-6 alkyl group (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2) 2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl, etc.). As a lower alkenyl group optionally substituted by a halogen atom (a lower alkenyl group optionally halogenated) and a lower alkynyl group optionally substituted by a halogen atom (lower alkynyl group optionally substituted by a halogen atom) Is a C _2-6 alkenyl group which may be substituted with 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, vinyl, propenyl, isopropenyl, 2- Buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like and a C _2-6 alkynyl group (eg, 2-butyn-1-yl, 4-pentyn-1-yl, 5-hexin-1-yl) is used.

The "optionally substituted lower alkylthio group" represented by "substituent" of the "optionally substituted aromatic group" represented by Ar ¹ and Ar ² is For example, a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (eg, methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, And C _1-6 alkylthio groups such as isobutylthio, sec-butylthio, tert-butylthio and the like. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4-trifluorobutylthio, pentylthio, hexylthio and the like can be mentioned. The substituent of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² is 1 to 5 (preferably 1 to 3) at a substitutable position on the aromatic group. , More preferably 1 or 2). When the “aromatic group” has two or more substituents, the respective substituents may be the same or different.

When Ar ¹ and Ar ² together with adjacent carbon atoms form a condensed ring group which may have a substituent, specific examples of the “condensed ring group” include:

Embedded image [Wherein, R ³ has the same meaning as described above. ] And the like.

Examples of the substituent on these condensed ring groups include those similar to the “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² described above. These condensed ring groups have the same or different 1 to 5, preferably 1 to 3, more preferably 1 or 2 substituents at substitutable positions on the condensed ring. You may. Ar ¹ and Ar ² are the same or different and are each preferably a monocyclic or condensed polycyclic aromatic hydrocarbon group which may have a substituent, and a phenyl group which may have a substituent And more preferably an unsubstituted phenyl group.

In the above formula (II), the ring B represents a “nitrogen-containing heterocycle optionally having substituent (s)”. The “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent (s)” represented by ring B includes, for example, one nitrogen atom, and further includes, for example, nitrogen atom, oxygen atom, sulfur 3 to 13 which may contain 1 to 3 (preferably 1 or 2 and more preferably 1) heteroatoms selected from atoms and the like.
And nitrogen-containing heterocycles, and particularly preferably those bonded to X in the above formula (II) via the nitrogen atom in the nitrogen-containing heterocycle. Preferred specific examples of the ring B include, for example,

Embedded image [In the formula, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² are the same or different and each is a linear C _1-6 alkylene which may be substituted with hydroxy, oxo or C _1-6 alkyl. (Preferably, the total number of carbon atoms of the linear C _1-6 alkylene group represented by Z ¹ and Z ² is 2
Above 11). (In the specific example of the ring B, it is described as a divalent group in order to clarify the bonding position between the ring B and X and Y in the above formula (II)).

The “linear C _1-6 ” represented by Z ¹ and Z ²
As the “alkylene group”, for example, a straight-chain C represented by methylene, ethylene, propylene, butylene,
_{1-6 represents an} alkylene group. The “C _1-6 alkyl” represented as a substituent of the “linear C _1-6 alkylene group” represented by Z ¹ and Z ² includes, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl , Se
Examples thereof include a linear or branched C _1-6 alkyl group such as c-butyl, tert-butyl, pentyl, and hexyl. Preferably the Z ¹ and Z represented by ² "hydroxy, oxo or C _1-6 alkyl optionally substituted linear C _1-6 alkylene group", an unsubstituted straight chain C _1-6
And an alkylene group.

More preferably, the ring B is piperidine,
And piperazine. Specifically, for example,

Embedded image 3 to 9 members (more preferably 3 to 6 members)
And the like. (Specific examples of the ring B include:
(In order to clarify the bonding position between the ring B and X and Y in the above formula (II), it is described as a divalent group.) In particular, those bonded to X in the above formula (II) via the nitrogen atom in the nitrogen-containing heterocycle are preferable. As the "substituent" of the "nitrogen-containing heterocycle optionally having substituent (s)" represented by ring B,
For example, those similar to the “substituent” of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² are used, and the substituent is on the nitrogen-containing heterocyclic ring. 1 to 3 identical or different, preferably 1
Alternatively, two, more preferably one, may be substituted.

In the above formula (II), X and Y are the same or different and each represents a bond, an oxygen atom, S (O) p
(P represents an integer of 0 to 2), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group), or may have a substituent, and may have 1 to 3 hetero atoms. Shows good divalent linear lower hydrocarbon groups. As the lower alkyl group represented by R ⁴ , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
Examples thereof include a linear or branched C _1-6 alkyl group such as c-butyl, tert-butyl, pentyl, and hexyl. "1 to 3 heteroatoms of a divalent linear lower hydrocarbon group which may have a substituent and may be via 1 to 3 heteroatoms" represented by X and Y As the divalent straight-chain lower hydrocarbon group which may be intervened, the hydrogen atom bonded to the same or different carbon atom of a lower (C _1-6 ) hydrocarbon is removed one by one (two in total). And a group that may contain a hetero atom selected from an oxygen atom, a sulfur atom, a nitrogen atom, and the like in the hydrocarbon chain. Specific examples of the “divalent linear lower hydrocarbon group” include (i) a C _1-6 alkylene group (for example, —CH ₂ —, — (CH ₂ ) ₂ —, — (CH ₂ ) ₃ — ,-(CH ₂ ) ₄ -,-(CH ₂ ) ₅ -,-(CH
₂ ) ₆ -etc.), (ii) C _2-6 alkenylene group (for example, -CH
= CH-,-CH = CH-CH ₂ -,-CH ₂ -CH = CH-CH ₂ -,-(CH ₂ ) ₂ -CH = CH-CH ₂
-,-(CH ₂ ) ₂ -CH = CH- (CH ₂ ) ₂ -,-(CH ₂ ) ₃ -CH = CH-CH _2-, etc.),
(Iii) C _2-6 alkynylene group (for example,

Embedded image And so on.

As the "substituent" of "a divalent linear lower hydrocarbon group optionally having a substituent and optionally having 1 to 3 heteroatoms" represented by X and Y. Is
For example, those similar to the “substituent” of the “aromatic group which may have a substituent” represented by the above Ar ¹ and Ar ² are used, and particularly, a hydroxy group or an oxo group is used. preferable. "A divalent linear lower hydrocarbon group optionally having a substituent and optionally having 1 to 3 heteroatoms interposed therebetween" represented by X and Y Specific examples of the case where the `` hydrocarbon group '' includes a hetero atom in the hydrocarbon chain include, for example,-(CH ₂ ) ₂ -O-,-(CH ₂ ) ₃ -O-,-
(CH ₂ ) ₄ -O-,-(CH ₂ ) ₆ -O-,-(CH ₂ ) ₂ -NH-,-(CH ₂ ) ₃ -NH-,-(C
_{H 2) 4 -NH -, -} (CH 2) 3 -S -, - CH 2 -CO-CH 2 -O -, - (CH 2) 2 -CO-NH-,
-CH ₂ -CO-NH-,-CO-O- (CH ₂ ) ₂ -O-,-CO-O- (CH ₂ ) ₃ -O-,-(CH ₂ )
₆ -NH-,-(CH ₂ ) ₆ -S-,-(CH ₂ ) ₂ -O- (CH ₂ ) ₂ -O-,-(CH ₂ ) ₂ -O- (CH
₂ ) ₂ -S- and the like. X represents a bond or C
_{A 1-6} alkylene group and the like are preferable, and a bond is particularly preferable. Y is preferably a C _1-6 alkylene group which may be substituted with a bond, an oxygen atom or a hydroxy group and may contain an oxygen atom in the alkylene chain, and is preferably a bond, an oxygen atom, -O -CH ₂ -, - CH ₂ - or -CH (OH) -, etc. are particularly preferred.

In the above formula (II), R ³ represents a hydrogen atom, a hydroxy group which may be substituted or a carboxyl group which may be esterified. The “optionally substituted hydroxy group” represented by R ³ includes, for example, “optionally substituted hydroxy group” in place of the hydrogen atom of (1) hydroxy group or (2) hydroxy group. A hydroxy group having one "good hydrocarbon group" and the like. Examples of the “hydrocarbon group” of the “hydrocarbon group optionally having a substituent” represented as the “hydroxy group having one hydrocarbon group optionally having a substituent” include, for example, And a group in which one hydrogen atom has been removed from a hydrocarbon compound. Examples thereof include a chain or cyclic hydrocarbon group such as an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Is raised. Of these, a chain (linear or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and specific examples include: a) an alkyl group [preferably a lower alkyl group (eg, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl, C _1-6 alkyl group such as hexyl)], b) alkenyl groups [preferably, lower alkenyl groups (e.g., vinyl, C2-6 alkenyl groups such as allyl, isopropenyl, butenyl, isobutenyl and sec-butenyl)], c) alkynyl group [preferably lower alkynyl group (for example, C _2-6 such as propargyl, ethynyl, butynyl, 1-hexynyl and the like) _2-6 an alkynyl group)], d) a cycloalkyl group [preferably, lower cycloalkyl group (e.g., Shikuropuropi , Cyclobutyl, cyclopentyl, 1 to 3 lower alkoxy groups (e.g.,
A C _1-6 alkoxy group such as methoxy, etc.) and a C _3-6 cycloalkyl group such as cyclohexyl which may be condensed with a benzene ring which may have, e) an aryl group (for example, phenyl, Biphenyl, 1-
Naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, such as 4-phenanthryl or 9-phenanthryl C _{6- 14} ) an aralkyl group [preferably a lower aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl,
A _C7-16 aralkyl group such as 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, and 5-phenylpentyl, and more preferably a benzyl group)]. Examples of the "substituent" of the "hydrocarbon group optionally having a substituent" represented as the "hydroxy group having one hydrocarbon group optionally having a substituent" include, for example, The same as the “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² are used. The “carboxyl group which may be esterified” represented by R ³ includes, for example, (1)
A carboxyl group having, for example, one "hydrocarbon group which may have a substituent (s)" in place of the carboxyl group or (2) a hydrogen atom of the carboxyl group. Examples of the "hydrocarbon group optionally having substituent (s)" represented as the "carboxyl group having one hydrocarbon group optionally having substituent (s)" include, for example, And the same as the "hydrocarbon group optionally having substituent (s)" in "hydroxy group having one hydrocarbon group which may be possessed". R ³ is preferably a hydrogen atom, a hydroxy group or a carboxyl group, more preferably a hydrogen atom or a hydroxy group, and particularly preferably a hydrogen atom.

In the formula (I), the other of R ¹ and R ² represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent. “Hydrocarbon group” of “hydrocarbon group optionally having substituent (s)” shown as the other of R ¹ and R ²
Represents, for example, a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include, for example, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and a chain such as an aralkyl group. And a cyclic hydrocarbon group. Among them, carbon number 1 to 16
Preferred are a chain (straight or branched) or cyclic hydrocarbon group, and specifically, a) an alkyl group [preferably a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl) , isobutyl, sec- butyl, tert- butyl, pentyl, C _1-6 alkyl group such as hexyl)], b) alkenyl groups [preferably, lower alkenyl groups (e.g., vinyl, allyl, isopropenyl, butenyl, isobutenyl , C _2-6 alkenyl group such as sec- butenyl)], c) alkynyl groups [preferably, lower alkynyl group (e.g., propargyl, ethynyl, butynyl, C _2-6 alkynyl groups such as 1-hexynyl)] D) a cycloalkyl group [preferably a lower cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentene) Le, 1 to 3 lower alkoxy groups (e.g.,
A C _1-6 alkoxy group such as methoxy, etc.) and a C _3-6 cycloalkyl group such as cyclohexyl which may be condensed with a benzene ring which may have, e) an aryl group (for example, phenyl, Biphenyl, 1-
Naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, such as 4-phenanthryl or 9-phenanthryl C _{6- 14} ) an aralkyl group [preferably a lower aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl,
A _C7-16 aralkyl group such as 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, and 5-phenylpentyl, and more preferably a benzyl group)].

The “substituent” of the “optionally substituted hydrocarbon group” represented as the other of R ¹ and R ² includes, for example, (i) a halogen atom (for example, fluorine,
(Ii) a lower alkylenedioxy group (eg, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (iii) a nitro group, and (iv) a cyano group. (V) a lower alkyl group which may be substituted, (vi) a lower alkenyl group which may be substituted, (vii) a lower alkynyl group which may be substituted, (viii) (a) a halogen atom (for example, , Fluorine, chlorine, bromine, iodine, etc.), (b) lower alkylenedioxy group (eg, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (c) nitro group, (d ) Cyano group, (e) lower alkyl group which may be halogenated, (f) lower alkenyl group which may be halogenated, (g) lower alkynyl group which may be halogenated, (h) lower Cycloa Kill group (e.g., cyclopropyl, cyclobutyl, cyclopentyl,
C _3-6 cycloalkyl groups such as cyclohexyl),
(I) an optionally substituted lower alkoxy group, (j) an optionally halogenated lower alkylthio group, (k)
Hydroxy groups, (l) amino group, (m) mono - lower alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, etc. mono -C _1-6 alkylamino groups such as butylamino), ( n) di-lower alkylamino group (for example, di-amino such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.)
C _1-6, such as alkylamino group), (o) 5 to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (p) lower alkyl - Carbonyl group (for example,
Carbonyl group), (q) a carboxyl group, (r) lower alkoxy - - acetyl, C _1-6 alkyl, such as propionyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6, such as butoxycarbonyl (S) carbamoyl group, (t) mono-lower alkyl-carbamoyl group (eg, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.), (u) di Lower alkyl-carbamoyl groups (for example di-C _1-6 alkylcarbamoyl groups such as dimethylcarbamoyl, diethylcarbamoyl and the like),
(V) aryl-carbamoyl group (for example, C _6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (w) sulfo group, (x) lower alkylsulfonyl group (for example, methylsulfonyl, ethylsulfonyl and the like) C _1-6, such as alkylsulfonyl group), (y) an aryl group (e.g., phenyl, C _6-10 aryl groups such as naphthyl), (z) aryloxy group (e.g., phenoxy, C, such as naphthyloxy _{6- Ten}
Aryloxy group), (aa) aralkyloxy group (for example, C _7-16 aralkyloxy group such as benzyloxy), (bb) oxo group, (cc) thiocarbamoyl group, (dd) mono-lower alkyl- Thiocarbamoyl group (eg, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee) di-lower alkyl-thiocarbamoyl group (eg, dimethylthiocarbamoyl, diethylthiocarbamoyl, etc.) di -C _1-6 alkyl - such as thiocarbamoyl group), (ff) aryl - thiocarbamoyl group (e.g., phenylthiocarbamoyl, C _6-10 aryl, such as naphthyl thio carbamoyl - thiocarbamoyl etc.), (gg) aralkyl Groups (e.g., benzyl, phenethyl, 2-phenylethyl, 1- Enirupuropiru, 2
-A _C7-16 aralkyl group such as phenylpropyl),
(Hh) a lower alkoxy-carbonyl-lower alkyl group (for example, a C _1-6 alkoxy-carbonyl-C _1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl and the like) or (ii) a carboxyl-lower alkyl group (for example, A lower cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) which may be substituted with a carboxyl-C _1-6 alkyl group such as carboxylmethyl and carboxylethyl. Such),

(Ix) a lower alkoxy group which may be substituted, (x) a lower alkylthio group which may be halogenated, (xi) a hydroxy group, (xii) an amino group, (xii
i) a mono-lower alkylamino group (eg, a mono-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.); (xiv) a di-lower alkylamino group (eg, ,
Dimethylamino, diethylamino, dipropylamino,
Di-C _1-6 alkylamino groups such as dibutylamino, etc.), (xv) 5- to 6-membered cyclic amino groups (eg, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl etc.), (Xvi) a lower alkyl-carbonyl group (for example, a C _1-6 alkyl-carbonyl group such as acetyl, propionyl and the like), (xvi
i) carboxyl group, (xviii) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xix) carbamoyl group, (xx) mono A lower alkyl-carbamoyl group (for example, a mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl and the like),
(Xxi) a di-lower alkyl-carbamoyl group (for example,
Di-C _1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl), (xxii) aryl-carbamoyl (for example, phenylcarbamoyl,
C _6-10 aryl, such naphthylcarbamoyl - such as carbamoyl), (xxiii) sulfo group, (xxiv) a lower alkylsulfonyl group (e.g., a C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl), (x
xv) (a) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (b) lower alkylenedioxy group (eg, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.) , (C) nitro group,
(D) a cyano group, (e) an optionally halogenated lower alkyl group, (f) an optionally halogenated lower alkenyl group, (g) an optionally halogenated lower alkynyl group, (h ) A lower cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy group, and (j) a halogenated group. Good lower alkylthio groups, (k) hydroxy groups, (l) amino groups, (m) mono-lower alkylamino groups (e.g., mono-C _1- such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.) ₆ including an alkylamino group), (n) di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, dibutyl Di-C such as ruamino
_1-6, such as an alkylamino group), (o) 5 to 6-membered cyclic amino group (e.g., morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl, etc.), (p) lower alkyl - carbonyl Groups (eg, C _1-6 alkyl-carbonyl groups such as acetyl and propionyl), (q) carboxyl group, (r) lower alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like) A C _1-6 alkoxy-carbonyl group),
(S) carbamoyl group, (t) mono-lower alkyl-carbamoyl group (for example, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl and the like), (u) di-lower alkyl-carbamoyl group ( (E.g., di-C _1-6 alkylcarbamoyl groups such as dimethylcarbamoyl and diethylcarbamoyl), (v) aryl-carbamoyl groups (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (w ) A sulfo group, (x) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), (y) an aryl group (eg, a C _6-10 aryl group such as phenyl and naphthyl) ), (Z) aryloxy group (for example, phenoxy, naphthyloxy Which C _6-10 aryloxy group such as), (aa) aralkyloxy group (e.g., a C _7-16 aralkyloxy group such as benzyloxy), (b
b) oxo group, (cc) thiocarbamoyl group, (dd) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.), (ee )
Di-lower alkyl-thiocarbamoyl groups (eg, di-C _1-6 alkyl-thiocarbamoyl groups such as dimethylthiocarbamoyl and diethylthiocarbamoyl), (f
f) aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.
_6-10 aryl-thiocarbamoyl, etc.), (gg) aralkyl group (eg, C _7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) A lower alkoxy-carbonyl-lower alkyl group (for example, a C _1-6 alkoxy-carbonyl-C _1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ii) a carboxyl-lower alkyl group (for example, carboxylmethyl And an aryl group which may be substituted with a carboxyl-C _1-6 alkyl group such as carboxylethyl (eg, C _6-10 such as phenyl and naphthyl).
Aryl group),

(Xxvi) (a) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); (b) a lower alkylenedioxy group (eg, C _1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.) Oxy group), (c)
Nitro group, (d) cyano group, (e) lower alkyl group which may be halogenated, (f) lower alkenyl group which may be halogenated, (g) lower alkynyl group which may be halogenated , (H) a lower cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy group,
(J) optionally halogenated lower alkylthio, (k) hydroxy, (l) amino, (m) mono-
Lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
(N) di-lower alkylamino group (for example, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) 5
A 6-membered cyclic amino group (for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl and the like), (p) a lower alkyl-carbonyl group (for example, C _1-6 such as acetyl and propionyl) Alkyl-carbonyl group), (q) carboxyl group,
(R) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) carbamoyl group, (t) mono-
Lower alkyl-carbamoyl groups (eg, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc.), (u) di-lower alkyl-
Carbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.); (v) aryl-carbamoyl group (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.) , (W) a sulfo group, (x) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), and (y) an aryl group (eg, a C _6- group such as phenyl and naphthyl). ₁₀ an aryl group), (z) aryloxy group (e.g., phenoxy, etc. C _6-10 aryloxy group such as naphthyloxy), (aa) aralkyloxy group (e.g., C _7-16 aralkyloxycarbonyl such as benzyloxycarbonyl Bb) oxo group, (cc) thiocarbamoyl group, (dd) mono-lower Kill - thiocarbamoyl group (e.g., methyl thiocarbamoyl, mono--C _1-6 alkyl such as ethyl thiocarbamoyl - such as thiocarbamoyl group), (ee) di - lower alkyl - thiocarbamoyl group (e.g., dimethylthiocarbamoyl, diethylthiourea Di-C _1-6 alkyl-thiocarbamoyl groups such as carbamoyl), (ff) aryl-thiocarbamoyl groups (eg, C _6-10 aryl-thiocarbamoyl such as phenylthiocarbamoyl and naphthylthiocarbamoyl), (gg Aralkyl groups (eg, benzyl,
C _7-16 aralkyl groups such as phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) lower alkoxy-carbonyl-lower alkyl groups (for example, methylcarbonylmethyl, ethylcarbonylmethyl and the like) C _1-6 alkoxy-carbonyl-C _1-6
An aralkyl group (eg, benzyl, phenethyl, etc.) which may be substituted with (ii) a carboxyl-lower alkyl group (eg, carboxyl-C _1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.) _C7-15 aralkyl groups such as 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, naphthylmethyl, etc.),

(Xxvii) (a) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.); (b) a lower alkylenedioxy group (eg, C _1-3 alkylenedioxy such as methylenedioxy, ethylenedioxy, etc.) Oxy group), (c)
Nitro group, (d) cyano group, (e) lower alkyl group which may be halogenated, (f) lower alkenyl group which may be halogenated, (g) lower alkynyl group which may be halogenated , (H) a lower cycloalkyl group (eg, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (i) an optionally substituted lower alkoxy group,
(J) optionally halogenated lower alkylthio, (k) hydroxy, (l) amino, (m) mono-
Lower alkylamino groups (eg, mono-C _1-6 alkylamino groups such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.),
(N) di-lower alkylamino group (for example, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.);
5- or 6-membered cyclic amino group (for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl and the like), (p) lower alkyl-carbonyl group (for example, C _1- such as acetyl and propionyl) ₆
Alkyl-carbonyl group), (q) carboxyl group, (r) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s A) carbamoyl group, (t) mono-lower alkyl-carbamoyl group (for example, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl and the like), (u) di-lower alkyl-carbamoyl group (for example, Dimethylcarbamoyl,
Di-C _1-6 alkylcarbamoyl groups such as diethylcarbamoyl, etc.), (v) aryl-carbamoyl groups (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (w) sulfo group, (w) x) lower alkylsulfonyl groups (eg, C _1-6 alkylsulfonyl groups such as methylsulfonyl and ethylsulfonyl), (y) aryl groups (eg, C _6-10 aryl groups such as phenyl and naphthyl), (z )
Aryloxy group (for example, C _6-10 aryloxy group such as phenoxy and naphthyloxy), (aa) aralkyloxy group (for example, C _7-16 aralkyloxy group such as benzyloxy), (bb) oxo group , (Cc) thiocarbamoyl group, (dd) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl and the like), (ee) di-lower Alkyl-thiocarbamoyl groups (eg, di-C _1-6 alkyl-thiocarbamoyl groups such as dimethylthiocarbamoyl and diethylthiocarbamoyl), (ff) aryl-thiocarbamoyl groups (eg, phenylthiocarbamoyl, naphthylthiocarbamoyl, etc.) _C6-10 aryl-thiocarbamoyl, etc.), (gg) arals Alkyl group (e.g., _C7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl); (hh) lower alkoxy-carbonyl-lower alkyl group (e.g., methylcarbonyl C _1-6 alkoxy-carbonyl- such as methyl and ethylcarbonylmethyl-
An aryloxy group (eg, a C _1-6 alkyl group) or (ii) a carboxyl-lower alkyl group (eg, a carboxyl-C _1-6 alkyl group such as carboxylmethyl, carboxylethyl, etc.) , C _6-10 aryloxy groups such as phenoxy, naphthyloxy, etc.),

(Xxviii) (a) a halogen atom (for example,
(B) a lower alkylenedioxy group (for example, a C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.),
(C) nitro group, (d) cyano group, (e) lower alkyl group optionally halogenated, (f) lower alkenyl group optionally halogenated, (g) optionally halogenated A lower alkynyl group, (h) a lower cycloalkyl group (for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like), (i) an optionally substituted lower alkoxy group, (j) Lower alkylthio group which may be halogenated, (k) hydroxy group, (l) amino group, (m) mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc. Mono-C _1-6 alkylamino group, etc.),
(N) di-lower alkylamino group (for example, di-C _1-6 alkylamino group such as dimethylamino, diethylamino, dipropylamino, dibutylamino, etc.), (o) 5
A 6-membered cyclic amino group (for example, morpholino, thiomorpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl and the like), (p) a lower alkyl-carbonyl group (for example, C _1-6 such as acetyl and propionyl) Alkyl-carbonyl group), (q) carboxyl group,
(R) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (s) carbamoyl group, (t) mono-
Lower alkyl-carbamoyl groups (eg, mono-C _1-6 alkyl-carbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, etc.), (u) di-lower alkyl-
Carbamoyl group (eg, di-C _1-6 alkylcarbamoyl group such as dimethylcarbamoyl, diethylcarbamoyl, etc.); (v) aryl-carbamoyl group (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.) , (W) a sulfo group, (x) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), and (y) an aryl group (eg, a C _6- group such as phenyl and naphthyl). ₁₀ an aryl group), (z) aryloxy group (e.g., phenoxy, etc. C _6-10 aryloxy group such as naphthyloxy), (aa) aralkyloxy group (e.g., C _7-16 aralkyloxycarbonyl such as benzyloxycarbonyl Bb) oxo group, (cc) thiocarbamoyl group, (dd) mono-lower Kill - thiocarbamoyl group (e.g., methyl thiocarbamoyl, mono--C _1-6 alkyl such as ethyl thiocarbamoyl - such as thiocarbamoyl group), (ee) di - lower alkyl - thiocarbamoyl group (e.g., dimethylthiocarbamoyl, diethylthiourea Di-C _1-6 alkyl-thiocarbamoyl groups such as carbamoyl), (ff) aryl-thiocarbamoyl groups (eg, C _6-10 aryl-thiocarbamoyl such as phenylthiocarbamoyl and naphthylthiocarbamoyl), (gg Aralkyl groups (eg, benzyl,
C _7-16 aralkyl groups such as phenethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, etc.), (hh) lower alkoxy-carbonyl-lower alkyl groups (for example, methylcarbonylmethyl, ethylcarbonylmethyl and the like) C _1-6 alkoxy-carbonyl-C _1-6
An aralkyloxy group (eg, an alkyl group) or (ii) a carboxyl-lower alkyl group (eg, a carboxyl-C _1-6 alkyl group such as carboxylmethyl and carboxylethyl);
_C7-16 aralkyloxy groups such as benzyloxy),

(Xxix) oxo group, (xxx) thiocarbamoyl group, (xxxi) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl, ethylthiocarbamoyl, etc.) ), (Xxxii) di-lower alkyl-thiocarbamoyl groups (eg, di-C _1-6 alkyl-thiocarbamoyl groups such as dimethylthiocarbamoyl and diethylthiocarbamoyl), (xxxiii) aryl-thiocarbamoyl (eg, phenyl) etc. thiocarbamoyl), (xxxiv) aryl - - thiocarbamoyl, C _6-10 aryl, such as naphthyl thio carbamoyloxy carbonyloxy (e.g., C _6-10 aryl such as phenyl carbonyloxy - carbonyl oxy) substituted (xxxv) Optionally aminocarbonyl, (xxxvi) 5 or 6-membered heterocyclic group, (xxxvii) a lower alkoxy - carbonyl - lower alkoxy - carbonyl (e.g., methoxycarbonyl methoxycarbonyl, C _1-6 alkoxy, such as ethoxycarbonyl ethoxycarbonyl - carbonyl - carbonyl -C _1-6 alkoxy) , (Xxxviii) lower alkoxy-carbonyl-lower alkyl-carbamoyl (e.g.,
C _1-6 alkoxyoxy such as methoxycarbonylmethylcarbamoyl and ethoxycarbonylethylcarbamoyl;
Carbonyl-C _1-6 alkyl-carbamoyl, etc.), (xx
xix) hydroxy-lower alkyl-carbamoyl (eg, hydroxy-C _1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl, hydroxyethylcarbamoyl, etc.); (xxxx) lower-alkoxy-carbonyl-carbamoyl group (eg, methoxycarbonylcarbamoyl, ethoxy) C _1-6 such as carbonylcarbamoyl
An alkoxy-carbonyl-carbamoyl group, etc.), (xx
xxi) arylsulfonamide group (C _6-14 arylsulfonamide group such as phenylsulfonamide), (xxxx
ii) alkylsulfonamide groups (C _1-6 alkylsulfonamide groups such as methylsulfonamide and ethylsulfonamide), (xxxxiii) carboxy-C _1-6 alkyl-carbonyl-amino groups (eg, carboxymethylcarbonylamino, carboxy Methylcarbonylamino), (xxxxiv) C _1-6 alkoxy-carbonyl-C _1-6
Alkyl-carbonyl-amino group (eg, methoxycarbonylmethylcarbonylamino, etc.), (xxxxv) C _1-6 alkyl-carbonyloxy-C _1-6 alkyl-carbonyl-amino group (eg, methylcarbonyloxymethylcarbonylamino, etc.) , (Xxxxvi) hydroxy-C _1-6 alkyl-carbonyl-amino group (eg, hydroxymethylcarbonylamino, etc.), (xxxxvii) hydroxy or (and) C _1-6 alkoxy (eg, methoxy, ethoxy, etc.) _{Optionally a} C _6-14 aryl-C
_{A 2-6} alkenyl-carbonylamide group (eg, (4-hydroxy-3,5-methoxy) phenyl-ethynylcarbonylamide) and the like are used.

The "substituent" of the "optionally substituted hydrocarbon group" represented as the other of the above R ¹ and R ²
As the “optionally substituted aminocarbonyl” represented by, for example, one or two (a) halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.),
(B) a lower alkyl group which may be halogenated,
(C) an optionally halogenated lower alkenyl group,
(D) an optionally halogenated lower alkynyl group,
(E) a lower cycloalkyl group (for example, a C _3-6 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (f) a lower alkoxy group which may be substituted, and (g) a halogenated group. A lower alkylthio group, (h) a hydroxy group,
(I) amino group, (j) mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino,
Mono-C _1-6 such as isopropylamino and butylamino
An alkyl amino group), (k) di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, and di -C _1-6 alkylamino group such as dibutylamino), (l) 5 to 6-membered Cyclic amino groups (eg, morpholino, thiomorpholino, piperazine-
1-yl, piperidino, pyrrolidin-1-yl and the like),
(M) a lower alkyl-carbonyl group (for example, a C _1-6 alkyl-carbonyl group such as acetyl, propionyl and the like), (n) a carboxyl group, and (o) a lower alkoxy-
Carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (p)
Carbamoyl group, (q) mono-lower alkyl-carbamoyl group (eg, mono-C _1-6 alkyl-carbamoyl group such as methylcarbamoyl, ethylcarbamoyl, etc.), (r) di-lower alkyl-carbamoyl group (eg, dimethyl Di-C _1-6 alkylcarbamoyl groups such as carbamoyl and diethylcarbamoyl), (s) aryl-carbamoyl groups (eg, C _6-10 aryl-carbamoyl such as phenylcarbamoyl and naphthylcarbamoyl), (t) sulfo group , (U) a lower alkylsulfonyl group (eg, a C _1-6 alkylsulfonyl group such as methylsulfonyl and ethylsulfonyl), (v) an aryl group (eg, a C _6-10 aryl group such as phenyl and naphthyl), (W) aryloxy groups (for example, phenoxy, naphthyloxy, etc. C such as _6-10 aryloxy group), (x) an aralkyl group (e.g., a C _7-16 aralkyloxy group such as benzyloxy), (y)
Thiocarbamoyl group, (z) mono-lower alkyl-thiocarbamoyl group (for example, mono-C _1-6 alkyl-thiocarbamoyl group such as methylthiocarbamoyl and ethylthiocarbamoyl), (aa) di-lower alkyl-thiocarbamoyl Groups (eg, di-C _1-6 alkyl-thiocarbamoyl groups such as dimethylthiocarbamoyl and diethylthiocarbamoyl), (bb) aryl-thiocarbamoyl groups (eg, phenylthiocarbamoyl,
C _6-10 aryl-thiocarbamoyl such as naphthylthiocarbamoyl and the like; (cc) aralkyl group (for example, C _7-16 aralkyl group such as benzyl, phenethyl, 2-phenylethyl, 1-phenylpropyl and 2-phenylpropyl) ), (Dd) lower alkoxy-carbonyl-lower alkyl group (for example, C _1-6 alkoxy-carbonyl-C _1-6 alkyl group such as methylcarbonylmethyl, ethylcarbonylmethyl, etc.) or (ee) carboxyl-lower alkyl. And aminocarbonyl which may have a group (for example, a carboxyl-C _1-6 alkyl group such as carboxylmethyl and carboxylethyl).

The "substituent" of the "optionally substituted hydrocarbon group" represented as the other of the above R ¹ and R ²
As the “5- or 6-membered heterocyclic group” represented by
For example, in addition to a carbon atom, a 5- or 6-membered heterocyclic group containing 1 to 4 kinds of one or two kinds of hetero atoms such as a nitrogen atom, an oxygen atom, and a sulfur atom is included. As the heterocyclic group, specifically, for example, furyl, thienyl,
Pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,
2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanil,
1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl,
Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,
Examples thereof include 5- or 6-membered aromatic monocyclic heterocyclic groups such as triazinyl, and among them, pyridyl and the like are preferable.
The “optionally substituted lower alkyl group” represented as the “substituent” of the “optionally substituted hydrocarbon group” represented as the other of the above R ¹ and R ² , `` Optionally substituted lower alkenyl group '', `` optionally substituted lower alkynyl group '', `` optionally substituted lower alkoxy group '' and `` optionally halogenated lower alkylthio group '' Ar ¹ and Ar ²
The same groups as those exemplified as the “substituent” of the “aromatic group which may have a substituent” represented by are used. Further, “optionally substituted lower alkyl group”
Examples of the “substituent” include a mono- or di-C _1-6 alkyl-amino-methyleneaminosulfonyl group (eg, dimethylaminomethyleneaminosulfonyl). A “optionally substituted lower cycloalkyl group” represented as a “substituent” of the “optionally substituted hydrocarbon group” represented as the other of R ¹ and R ² ,
The `` optionally substituted aryl group '', the `` optionally substituted aryloxy group '' and the `` optionally substituted aralkyloxy group '' represented by the `` substituted group '' Good lower alkyl group ",
"Optionally halogenated lower alkenyl group",
"Optionally halogenated lower alkynyl group" and "optionally halogenated lower alkylthio group"
The same as those exemplified as the “substituent” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² above are used.

As the “hydrocarbon group” of the “hydrocarbon group which may have a substituent” shown as the other of R ¹ and R ² , a lower alkyl group (eg, methyl, ethyl, propyl) And C _1-6 alkyl groups such as isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl). R ¹
Is and preferably as "substituent" of the "optionally substituted hydrocarbon group" represented as the other of R ^2, for example, (i) (a) a lower alkyl - group (e.g., acetyl, propionyl C _1-6 alkyl such as - carbonyl group), (b) a lower alkoxy - substituted with such carbonyl group) - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, C _1-6 alkoxy such as butoxycarbonyl Lower cycloalkyl groups (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like;
_3-6 cycloalkyl group), (ii) carboxyl group, (ii
i) lower alkoxy-carbonyl group (for example, C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like); (iv) (a) lower alkoxy group (for example,
Methoxy, ethoxy, propoxy, isopropoxy, n
- butoxy, isobutoxy, sec- butoxy, C _1-6 alkoxy group such as tert- butoxy), (b) a lower alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, such butoxycarbonyl C _{1- 6} alkoxy-carbonyl group etc.)
Or (c) an aryl group optionally substituted with a carboxyl group or the like (for example, C
_6-10 an aryl group), (v) aryl - carbonyloxy (e.g., C _6-10 aryl such as phenyl carbonyloxy - carbonyl oxy), (vi) optionally substituted aminocarbonyl, (vii) 5 Or a 6-membered heterocyclic group, (viii) a sulfonamide optionally substituted with lower alkyl which may be substituted with di-lower alkylamino (for example, di-C _{1 of} sulfonamide, dimethylaminomethylsulfonamide) _-6 alkylamino or the like which may sulfonamide -C also be _1-6 alkyl substituted with C _1-6 alkyl optionally substituted), (ix) lower alkoxy - carbonyl - lower alkoxy - carbonyl (e.g., methoxy carbonyl methoxycarbonyl, C _1-6 alkoxy, such as ethoxycarbonyl ethoxycarbonyl - carbonyl -C _1-6 alkoxy - Cal Sulfonyl, etc.),
(X) a lower alkoxy group optionally substituted by (a) aminocarbonyl or (b) carboxyl (for example, C _1- optionally substituted by aminocarbonyl such as methoxy, ethoxy, aminocarbonylmethoxy, carboxylmethoxy and the like) ₆ an alkoxy group), (xi) lower alkoxy - carbonyl - lower alkyl - carbamoyl group (for example, C, such as methylcarbonyl methylcarbamoyl
₆ alkoxy - carbonyl -C _1-6 alkyl - such as carbamoyl group), (xii) hydroxy - lower alkyl - carbamoyl group (e.g., hydroxy methylcarbamoyl, hydroxy, such as hydroxy ethylcarbamoyl -
C _1-6 alkyl - such as carbamoyl group), (xiii) lower alkoxy - carbonyl - carbamoyl group (e.g., methoxycarbonyl carbamoylmethyl, C _1-6 alkoxy such as ethoxy carbonylation carbamoyl - carbonyl - such as carbamoyl group) or (xiv) cyano And the like.

The other of R ¹ and R ² is preferably a hydrogen atom, a cyano group, a C _1-6 alkyl group which may have a substituent, or a C _3-6 group which may have a substituent. mentioned cycloalkyl group and the like, in particular, a hydrogen atom, a cyano group, methyl, tert- butyl, cyclohexyl, _{phenyl, -CH 2 CO 2 Me, -} (CH 2) 2 CO 2 Et, - (CH 2) 3 CO ₂ Et, -C (Me) ₂
CO ₂ Et, -C (Me) ₂ CO ₂ Me, -C (Me) ₂ CO ₂ H,-(CH ₂ ) ₄ CO ₂ Et, -C
H ₂ CO ₂ H,-(CH ₂ ) ₂ OCH ₂ CONH ₂ ,-(CH ₂ ) ₂ OCH ₂ CO ₂ H,-(CH ₂ ) ₂
CO ₂ H,-(CH ₂ ) ₄ CO ₂ H,-(CH ₂ ) ₂ OCOPh, -CH ₂ CONMeCH ₂ CH ₂ P
h, -CH ₂ Ph,-(CH ₂ ) ₂ Ph,-(CH ₂ ) ₃ Ph,-(CH ₂ ) ₂ C (Me) ₂ CO ₂ E
t, -CH ₂ C ₆ H ₄ (2-CO ₂ Me), -CH ₂ C ₆ H ₄ (3-CO ₂ Me), -CH ₂ C ₆ H
₄ (4-CO ₂ Me), -CH ₂ C ₆ H ₄ (2-CO ₂ H), -CH ₂ C ₆ H ₄ (3-CO ₂ H),-
(CH ₂ ) ₂ C (Me) ₂ SO ₂ NHCHNMe ₂ ,-(CH ₂ ) ₂ C (Me) ₂ SO ₂ NH ₂ , -CH ₂
CO ₂ CH ₂ CO ₂ Me, -CH ₂ CON (Me) CH ₂ CO ₂ Et, -CH ₂ CON (Me) CH ₂ CO
_{2 H, -CH 2 CONHC (Me} ) 2 CO 2 Et, -CH 2 CONHCH 2 CO 2 Me, -CH 2 CON
HCH ₂ CO ₂ H, -CH ₂ CONH (CH ₂ ) ₂ CO ₂ Et, -CH ₂ CONH (CH ₂ ) ₂ CO
₂ H,-(CH ₂ ) ₂ CONHCO ₂ Me,-(CH ₂ ) ₂ CONHCO ₂ H,-(CH ₂ ) ₄ CN,

Embedded image (Me represents methyl, Et represents ethyl, and Ph represents phenyl).

"C _1-6 alkyl group _optionally having substituent (s)" and "C _3-6 cycloalkyl _optionally having substituent (s)", which are preferred as the other of R ¹ and R ² , As the “substituent” of the “alkyl group”, the above R ¹ and R ²
The same as the "substituent" of the "hydrocarbon group which may have a substituent" shown as the other of the above, and the like,
"C _3-6 cycloalkyl group _optionally having substituent (s)"
As the “substituent”, the “substituent” of the “optionally substituted aromatic group” represented by the above Ar ¹ and Ar ²
And the like are preferred.

Among the above, ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents a bond or an oxygen atom, and R ³ represents a hydrogen atom or a hydroxy group), the other being (1) a hydrogen atom, (2) Cyano group, (3) (i) halogen atom, (ii) carboxyl group, (iii) C _1-6 alkoxy-carbonyl group, (iv)
A 5- or 6-membered nitrogen-containing heterocyclic group, (v) having a substituent selected from C _7-15 aralkyl, carboxyl-C _1-6 alkyl and C _1-6 alkoxycarbonyl-C _1-6 alkyl. Carbamoyl group, (vi) C _6-14 aryl-carbonyloxy group, (vii) sulfamoyl group, (v
iii) a substitution selected from the group consisting of a mono- or di-C _1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) a C _1-6 alkoxy group optionally having carboxyl or carbamoyl, and (x) cyano. A C _1-16 alkyl group optionally having a group, (4) a C _3-7 cycloalkyl group optionally having a carboxyl or C _1-6 alkoxycarbonyl, and (5) a C _6-14 aryl group Or (6)
C _1-6 optionally having a substituent selected from C _1-6 alkoxy, carboxyl and C _1-6 alkoxy-carbonyl
_It is preferable to show a _7-15 aralkyl group.

Further, as R ¹ and R ² , either one is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, R ³ represents a hydrogen atom or a hydroxy group), and the other is (1) a hydrogen atom, (2) a cyano group, (3)
(I) a halogen atom, (ii) a C _1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) a C _1-6 alkyl group optionally having a substituent selected from the group consisting of cyano or (4) It is preferable to show a C _3-7 cycloalkyl group which may have a C _1-6 alkoxycarbonyl.

In particular, ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, and R ³ represents a hydrogen atom), and the other represents a C _1-6 alkyl group _optionally having carboxyl. The case shown is preferred.

In the above formula (I), the ring A represents a homocyclic ring which may have a substituent or a nitrogen-containing heterocyclic ring which may have a substituent. The “homologous or (nitrogen-containing) heterocycle” represented as the ring A has an arbitrary number (preferably 1 to 5, more preferably 1 to 3) of substituents at substitutable positions, When the number of groups is two or more, the respective substituents may be the same or different, and two adjacent substituents may be bonded to each other to form a ring. Examples of the ring when two adjacent substituents are bonded to each other to form a ring include, for example, (1) a 3- to 10-membered cyclic hydrocarbon (preferably a 5- or 6-membered cyclic hydrocarbon), (2) One or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom and a nitrogen atom are one or more (for example, 1 to 4, preferably 1 to 3) A 3- to 9-membered aromatic nitrogen-containing heterocycle (preferably a 5- or 6-membered aromatic nitrogen-containing heterocycle), or (3) selected from nitrogen, sulfur and oxygen other than carbon and nitrogen One or two
One or more heteroatoms (e.g., one to four,
5 to 9-membered non-aromatic nitrogen-containing heterocyclic ring (preferably 5- or 6-membered non-aromatic nitrogen-containing heterocyclic ring) containing preferably 1 to 3). More specifically, examples of the “cyclic hydrocarbon” of the above (1) include, for example, C _6-10 aryl (eg, benzene), C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cycloheptene, Octene, etc.), C
_3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) and the like. Of these, a 5- or 6-membered homocyclic ring such as a benzene, cyclopentane, or cyclohexane ring is preferable, and a benzene ring is particularly preferable.
Examples of the “aromatic nitrogen-containing heterocycle” of the above (2) include, for example, carbon and nitrogen atoms such as pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiazole, isothiazole, oxazole and isoxazole rings. Other examples include a 5- to 9-membered (preferably 5- or 6-membered) aromatic nitrogen-containing heterocyclic ring containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples of the “non-aromatic nitrogen-containing heterocycle” in the above (3) include, for example,
Tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydro Pyridazine, tetrahydropyran, morpholine, thiomorpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydrooxazole, and the like other than carbon and nitrogen atoms, nitrogen atom, oxygen Selected from atoms and sulfur atoms 5 to include 3 to 1 with no heteroatoms 9-membered (preferably 5- or 6-membered) such as a non-aromatic nitrogen-containing heterocycle can be mentioned.

The "homocycle" of the "homocycle optionally having substituent (s)" represented by ring A means a cyclic hydrocarbon consisting of carbon atoms, for example, a 3- to 10-membered cyclic hydrocarbon. Hydrogen, preferably a 5- or 6-membered cyclic hydrocarbon, is included. Specifically, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C
_3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) and the like. Of these, a 5- or 6-membered homocyclic ring such as a benzene, cyclopentane, or cyclohexane ring is preferable, and a benzene ring is particularly preferable.
As the "substituent" of the "homocyclic ring optionally having substituent (s)" represented by ring A, the "hydrocarbon optionally having substituent (s)" shown as the other of the above R ¹ and R ² And the like as the "substituent" of the "group". Above all,
(I) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii) a nitro group, (iii) a lower alkyl group which may be halogenated, (iv) an amino group, (v)
Mono-lower alkylamino groups (e.g., methylamino,
Ethylamino, propylamino, isopropylamino,
Such as mono--C _1-6 alkylamino groups such as butylamino), (vi) di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, di -C _1-6 alkylamino group such as dibutylamino Such),
(Vii) a carboxyl group, (viii) a lower alkoxy-carbonyl group (for example, a C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), and (ix) a di-lower alkylamino. Sulfonamide optionally substituted with lower alkyl which may be substituted (for example,
C which may be substituted with di-C _1-6 alkylamino of sulfonamide or dimethylaminomethylsulfonamide
Sulfonamide optionally substituted with _1-6 alkyl
C _1-6 alkyl etc.), (x) lower alkoxy - carbonyl - lower alkyl (e.g., methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, C _1-6 alkoxy such as ethoxy carbonyl ethyl - carbonyl -C _1-6 Alkyl), (xi) hydroxy-lower alkyl-carbamoyl (eg, hydroxy-C _1-6 alkyl-carbamoyl such as hydroxymethylcarbamoyl, hydroxyethylcarbamoyl), (xii) phenylsulfonamide, (xiii) hydroxy group and (xiv) a lower alkoxy group which may have a substituent. The “optionally halogenated lower alkyl group” represented as the “substituent” of the “optionally substituted homocyclic ring” represented by the ring A includes the above Ar ¹ and Ar ² The same as the “lower alkyl group which may be halogenated” exemplified as the “substituent” of the “aromatic group optionally having substituent (s)” and the like are used.

As the "lower alkoxy group optionally having substituent (s)" shown as the "substituent" of the "homocyclic ring optionally having substituent (s)" represented by the ring A, A
The same as the “lower alkoxy group optionally having substituent (s)” exemplified as the “substituent” of the “aromatic group optionally having substituent (s)” represented by r ¹ and Ar ² Is used. As the “substituent” of the “optionally substituted lower alkoxy group” as a substituent of Ring A, for example, (i) a lower alkoxy-carbonyl group (for example,
C _1-6 such as methoxycarbonyl and ethoxycarbonyl
(Ii) an aromatic group (for example, an “aromatic group” of the “aromatic group which may have a substituent” represented by Ar ¹ and Ar ² ) and the like. A lower alkoxy group optionally having one or two substituents selected (for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, s
and C _1-6 alkoxy groups such as ec-butoxy and tert-butoxy.

The “nitrogen-containing heterocycle” of the “nitrogen-containing heterocycle optionally having substituent (s)” represented by ring A includes, for example, one nitrogen atom, and further includes, for example, a nitrogen atom, an oxygen atom And a 3- to 13-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms selected from sulfur atoms and the like. Specifically, for example,

Embedded image 3 to 9 members (more preferably 3 to 6 members)
And the like are preferred. Above all,

Embedded image Etc. are particularly preferred.

The "substituent" of the "nitrogen-containing heterocyclic ring optionally having substituent (s)" represented by ring A is, for example, the same as the "optionally substituted substituent" represented by ring A above. The same substituents as those exemplified as the "substituent" of the "element ring" are used. As the ring A, a benzene ring optionally having a substituent, a pyridine ring optionally having a substituent, a pyrazine ring optionally having a substituent, or the like is preferable. "Substitution of benzene ring optionally having substituent (s)", "pyridine ring optionally having substituent (s)" and "pyrazine ring optionally having substituent (s)" represented as preferred ring A Examples of the "group" include, for example, the "substituent" of the "homocyclic ring optionally having substituent (s)" or the "nitrogen-containing heterocyclic ring optionally having substituent (s)" shown in ring A above. The same ones as those described above are used. As the A ring,
(1) unsubstituted benzene ring or (2) (i) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (ii)
Nitro group, (iii) lower alkyl group which may be halogenated, (iv) amino group, (v) mono-lower alkylamino group (for example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc. such as mono--C _1-6 alkylamino group), (vi) di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, such as dibutylamino di -
C, such as _1-6 alkylamino group), (vii) carboxyl group, (viii) a lower alkoxy - carbonyl group (e.g.,
(C _1-6 alkoxy-carbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (ix) sulfonamide optionally substituted by lower alkyl which may be substituted by di-lower alkylamino (e.g., sulfonamides, dimethylaminomethyl sulfonamide di -C _1-6 good sulfonamide -C _1-6 alkyl optionally substituted by C _1-6 alkyl optionally substituted with alkylamino, etc.), (X) lower alkoxy-carbonyl-lower alkyl (for example, C _1-6 alkoxy-carbonyl such as methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, etc.)
C _1-6 alkyl etc.), (xi) hydroxy - lower alkyl - carbamoyl (e.g., hydroxy methylcarbamoyl, hydroxy, such as hydroxy ethylcarbamoyl -
C _1-6 alkyl - such as carbamoyl), (xii) phenyl sulfonamide, (xiii) a hydroxy group and (xix)
A benzene ring having 1 to 3 substituents selected from a lower alkoxy group which may have a substituent is particularly preferable. Examples of the “optionally halogenated lower alkyl group” and “optionally substituted lower alkoxy group” represented as the substituent of the ring A include the “Ar ¹ and Ar ² ” described above. Same as "optionally halogenated lower alkyl group" and "optionally substituted lower alkoxy group" exemplified as "substituent" of "optionally substituted aromatic group" And the like. In the above formula (I), D and E are the same or different and each represent an oxygen atom or a sulfur atom. It is preferred that D and E both represent an oxygen atom.

Preferred compounds (I) of the present invention include the following compounds. (I) Compound (Ia) wherein Ring A is (i) a halogen atom, (ii) a nitro group, (iii) a C _1-6 alkyl group optionally having a carboxyl or C _1-6 alkoxy-carbonyl, ) C _1-6 alkoxy, (v) hydroxy, (vi) amino, (vii) mono- or di-C _1-6 alkylamino, (viii) carboxyl, (ix) C _1-6 alkoxy- A carbonyl group, a (x) 5- or 6-membered heterocyclic group containing 1 to 4 one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, (xi) C _{1 -6} alkylsulfonamido, (xii) carboxy -C _1-6 alkyl - carbonyl - amino group, (xiii) C _1-6 alkoxy - carbonyl -C _1-6 alkyl - carbonyl - amino group, (xiv)
C _1-6 alkyl-carbonyl-oxy-C _1-6 alkyl-
C optionally substituted with a carbonyl-amino group and (xv) hydroxy or (and) C _1-6 alkoxy
_6-14 aryl-C _2-6 alkenyl-carbonylamido group _optionally having a substituent selected from the group consisting of
_{A 6-14} aryl ring, D and E each represent an oxygen atom, and ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents a bond or an oxygen atom, and R ³ represents a hydrogen atom or a hydroxy group), the other being (1) a hydrogen atom, (2) Cyano group, (3) (i) halogen atom, (ii) carboxyl group, (iii) C _1-6 alkoxy-carbonyl group, (iv)
A 5- or 6-membered nitrogen-containing heterocyclic group, (v) having a substituent selected from C _7-15 aralkyl, carboxyl-C _1-6 alkyl and C _1-6 alkoxycarbonyl-C _1-6 alkyl. Carbamoyl group, (vi) C _6-14 aryl-carbonyloxy group, (vii) sulfamoyl group, (v
iii) a substitution selected from the group consisting of a mono- or di-C _1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) a C _1-6 alkoxy group optionally having carboxyl or carbamoyl, and (x) cyano. A C _1-16 alkyl group optionally having a group, (4) a C _3-7 cycloalkyl group optionally having a carboxyl or C _1-6 alkoxycarbonyl, and (5) a C _6-14 aryl group Or (6)
C _1-6 optionally having a substituent selected from C _1-6 alkoxy, carboxyl and C _1-6 alkoxy-carbonyl
_7-15 A compound showing an aralkyl group.

(II) Compound (Ib) A benzene ring in which ring A may have (i) a halogen atom or (ii) C _1-6 alkyl which may be substituted by C _1-6 alkoxy-carbonyl. D and E are oxygen atoms, and ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B is

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, R ³ represents a hydrogen atom or a hydroxy group), and the other is (1) a hydrogen atom, (2) a cyano group, (3)
(I) a halogen atom, (ii) a C _1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) a C _1-6 alkyl group optionally having a substituent selected from the group consisting of cyano or (4) A compound showing a C _3-7 cycloalkyl group optionally having a C _1-6 alkoxycarbonyl.

(III) Compound (Ic) A ring may have a benzene ring which may have a halogen atom,
D and E each represent an oxygen atom, and ^one of R ¹ and R ² is a group represented by the formula

Embedded image (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents

Embedded image X represents a C _1-6 alkylene group, Y represents an oxygen atom, and R ³ represents a hydrogen atom), and the other represents a C _1-6 alkyl group _optionally having carboxyl. The compound shown. (IV) Compound (Id) 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-valeric acid or a salt thereof, -[2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyric acid or a salt thereof (particularly hydrochloride ), And 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyric acid Or a salt thereof (particularly, hydrochloride).

Next, a method for producing the compound (I) of the present invention or a salt thereof will be described. In the compound (I) of the present invention or a salt thereof, R ¹ is

Embedded image In the case of a group represented by, for example, the following (Method A)
Or it is manufactured by a method according to it.

(Method A) Formula

Embedded image [In the formula, Q ² represents a reactive group, R ² ′ represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent, and other symbols have the same meanings as described above. ] Or a salt thereof. As the leaving group represented by Q ^1, for example sodium, an alkali metal such as potassium is used. Further, Q ¹ may be a hydrogen atom. Examples of the reactive group represented by Q ² include halogen (eg, chlorine, bromine, iodine, etc.), C _6-10 arylsulfonyloxy (eg, benzenesulfonyloxy, p-tolylsulfonyloxy, etc.), C _1-4 Alkyl-sulfonyloxy (for example, methanesulfonyloxy and the like) and the like are used. R above
"Hydrocarbon group which may have a substituent" represented by ² '
For example, those similar to the “hydrocarbon group which may have a substituent” represented by the other of the above R ¹ and R ² are used.

In the above (Method A), about 1.1 to about 2.0 mol, preferably about 1.2 to about 1.5 mol of compound (IIa) or a salt thereof is used per 1 mol of compound (III) or a salt thereof. The reaction described in the above (Method A)
The reaction is preferably performed in the presence of a base.
(1) For example, methyl lithium, n-butyl lithium,
alkyl lithium reagents such as s-butyllithium and t-butyllithium; (2) for example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, cesium carbonate, sodium hydride, hydrogen Inorganic bases such as potassium iodide, (3)
For example, organic bases such as triethylamine, pyridine and diethylisopropylamine, (4) metal alcoholates such as sodium methoxide, sodium ethoxide and potassium t-butoxide are used. Instead, for example, an alkali metal such as metal lithium, metal potassium, and metal sodium is used. Among them, potassium carbonate and triethylamine are preferred.

The amount of the base used is usually the same as that of the compound [II
I] or about 1.1 mol to about 2.0 mol per 1 mol of the salt
And preferably Compound [III] or a salt thereof 1
It is about 1.2 mol to about 1.5 mol per mol. Further, the reaction described in the above (Method A) includes (1) alcohols such as methanol, ethanol and propanol, (2) ethers such as diethyl ether, dioxane and tetrahydrofuran, (3) pentane, hexane, benzene, toluene, Hydrocarbons such as xylene; (4) nitriles such as acetonitrile; (5) amides such as N, N-dimethylformamide, N, N-dimethylacetamide and hexamethylphosphoric triamide; (6) dimethyl sulfoxide and the like The reaction can also be performed in an inert solvent such as a sulfoxide or an aromatic amine such as (7) pyridine. Among them, acetonitrile and N, N-dimethylformamide are preferred. These solvents can be used alone, or, if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent used is about 5 to 1 g of the compound (IIa).
ml to about 50 ml, preferably about 20 ml to about 30 ml, per 1 g of compound (IIa). Also, Q
^{When the} reactive group represented by ² is chlorine or the like, it is preferable to add sodium iodide or the like to the solvent.

The base and the solvent used in the reaction described in the above (Method A) include, for example, (1) triethylamine as a base and acetonitrile as a solvent;
(2) Triethylamine as a base, N, N as a solvent
Or (3) potassium carbonate as a base and N, N-dimethylformamide as a solvent. The reaction temperature is usually about 10 ° C to about 150 ° C, preferably room temperature (about 10 ° C to about 30 ° C) to about 100 ° C. The reaction time is usually about 12 hours to about 3 hours.
6 hours, preferably about 15 hours to about 28 hours. Next, a method for producing the compounds (IIa) and (III) of the above (Method A) and salts thereof will be described. The compound (IIa) or a salt thereof is described in, for example, European Patent Publication No. 0399.
No. 414 (EP-A-0399414), Journal of Organic Chemistry, 26, 4084 (1961)
(J.Org.Chem., 26, 4084 (1961)), European Journal of Medicinal Chemistry, No. 26
Volume, p. 69 (1991) (Eur. J. Med. Chem., 26, 69 (199)
1)) or Journal of Medicinal Chemistry, 38, 2472 (1995) (J. Med. Chem., 38,
2472 (1995)) or a method analogous thereto. Compound (III) and a salt thereof are produced, for example, by the method described in the following (Scheme A) or a method analogous thereto.

(Scheme A)

Embedded image [Compounds [III] to [VII] in Scheme A above]
In the above, each symbol has the same meaning as described above. ]

In reaction step 1, compound [IV] or compound [V] or a salt thereof is converted to R ² ′ -NH ₂ (compound [VII
I]) (R ² ′ has the same meaning as described above) or a salt thereof, and shows the production process of compound [VI] or a salt thereof. However, when R ² ′ is a hydrogen atom or the like, in the above compound [VI], the group represented by —NHR ² ′ is, for example, 4-methoxybenzylamine, 4-methoxyphenylamine, 4- (4 It is preferably protected by a protecting group such as -methoxy) phenylamine or 2,4-dimethoxybenzylamine (especially, 4-methoxybenzylamine is preferably used). Known methods [TW Green and PGMWuts, "Protective Groups in Organic Chemistry", 2nd edition, John Wiley and Sands, Inc. (1991)
Groups in Organic Chemistry "2nd. Ed., John Willey
& Sons, Inc., (1991)] or a method analogous thereto. Compound [I] of the present invention
Alternatively, when producing a salt thereof, the protecting group is preferably deprotected in the reaction step described in the above reaction step 3. As a specific method for deprotection, for example, the compound [III] protected by the above protecting group or a salt thereof is mixed with acetonitrile and water (1 g of the protected compound, usually about 20 ml to about 40 ml, preferably In a mixed solvent of about 30 ml to about 35 ml (usually acetonitrile: water = 5: 1), cerium (IV) ammonium nitrate (typically about 1.2 to 1 mol of the protected compound) is used.
Mol to about 2.0 mol, preferably about 1.5 mol). In the above reaction step 1, compound [VIII] or a salt thereof is used usually in an amount of about 1.1 mol to about 1.5 mol, preferably about 1.2 mol, per 1 mol of compound [IV] and compound [V] or a salt thereof. As the compound [IV] and the compound [V] or a salt thereof, a commercially available compound can be used or, for example, synthesis, page 505 (1.
980) (Synthesis, 505 (1980)), Advansis in Heterocyclic Chemistry, Vol. 28, No. 127
Page (1981) (Adv. Heterocyclic Chem. 28, 127 (198
It can be synthesized by the method described in 1)) or a method similar thereto.

The reaction in the reaction step 1 is, for example,
(1) alcohols such as methanol, ethanol, and propanol; (2) ethers such as diethyl ether, dioxane, and tetrahydrofuran; (3) pentane;
Hydrocarbons such as hexane, benzene, toluene and xylene; (4) nitriles such as acetonitrile; (5)
In an inert solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, amides such as hexamethylphosphoric triamide, (6) sulfoxides such as dimethylsulfoxide, and (7) aromatic amines such as pyridine. In particular, tetrahydrofuran, N, N-dimethylformamide and the like can be mentioned as preferable solvents. Further, when compound [IV] or a salt thereof is used as a starting compound, it is preferable to use tetrahydrofuran or the like as a solvent, and when compound [V] or a salt thereof is used as a starting compound,
It is preferable to use N, N-dimethylformamide or the like as the solvent. These solvents can be used alone, or, if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent used is the compound (I
V) About 10 ml to about 50 ml per 1 g, preferably
About 10 ml to about 15 ml is used per 1 g of the compound [IV].

The reaction described in the above reaction step 1 may be carried out in the presence of a base, and particularly when compound [V] or a salt thereof is used as a starting compound, it is usually carried out in the presence of a base. preferable. Examples of the base include (1) an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium and t-butyllithium; (2) eg, sodium hydroxide, potassium hydroxide, sodium carbonate, and carbonate. Inorganic bases such as potassium, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydride and potassium hydride; (3) organic bases such as triethylamine, pyridine and diethylisopropylamine; (4) sodium methoxide, sodium Metal alcoholates such as ethoxide and potassium t-butoxide are used. In place of the bases described in (1) to (4), for example, alkali metals such as metal lithium, metal potassium and metal sodium are also used. Especially, triethylamine etc. are mentioned as a preferable base. The amount of the base to be used is generally about 1.2 mol to about 1 mol per 1 mol of compound [V] or a salt thereof.
3.0 mol, preferably compound [V] or a salt thereof 1
It is about 2.0 mol to about 2.5 mol per mol. When the compound [V] or a salt thereof is used as the starting compound in the above reaction step 1, for example, it is preferable to use about 1.2 equivalents of a condensing agent with respect to the compound [V] or a salt thereof. Are, for example, diethyl cyanophosphate (DEPC), diphenylphosphate azide (DPP)
A), N, N-carbonyldiimidazole, 1,3-dicyclohexylcarbodiimide, 2-bromo-1-iodide
Methylpyridinium, 2-chloro-1-methylpyridinium iodide, 2,2′-dithiopyridine and the like are used, and among them, DEPC is preferably used. The reaction time of the above reaction step is usually about 15 hours to about 36 hours, preferably about 15 hours to about 24 hours, and the reaction temperature is usually room temperature (about 10 ° C. to 30 ° C.) to about 100 ° C., preferably Room temperature to about 60 ° C. In reaction step 2, compound [VI] or a salt thereof is reacted with, for example, N, N
-A process for producing a compound [VII] or a salt thereof by subjecting it to a cyclization reaction by reacting with -carbonyldiimidazole (CDI) or ethyl chloroformate or the like.

In the above reaction step 2, Q ³ —CO—Q ⁴ (Q ³ and Q
⁴ each represents a leaving group) from about 1.0 mol to about 1.
5 moles, preferably about 1.2 moles are used. The leaving groups represented by Q ³ and Q ⁴ are the same or different
(1) a hydrogen atom, (2) a halogen atom (such as fluorine, chlorine, bromine or iodine), or (3) a lower alkyl group which may be substituted with a halogen atom (such as fluorine, chlorine, bromine or iodine) (for example, (4) lower alkoxy groups (eg, methoxy, ethoxy, etc.) which may be substituted with halogen atoms (eg, fluorine, chlorine, bromine, iodine) such as C _1-6 alkyl groups such as methyl, ethyl and propyl.
C _1-6 alkoxy group such as propoxy) or (5)
5- or 6-membered heterocyclic group (eg, imidazolyl)
Specific examples of Q ³ —CO—Q ⁴ (Q ³ and Q ⁴ have the same meanings as described above) include N, N-carbonyldiimidazole (CDI), ethyl chloroformate and triphosgene. (Preferably CDI or ethyl chloroformate and the like). The reaction in the above reaction step 2 includes, for example, (1) alcohols such as methanol, ethanol, and propanol; (2) diethyl ether;
Ethers such as dioxane and tetrahydrofuran,
(3) hydrocarbons such as pentane, hexane, benzene, toluene and xylene; (4) nitriles such as acetonitrile; (5) N, N-dimethylformamide;
The reaction can be carried out in an inert solvent such as amides such as N-dimethylacetamide and hexamethylphosphoric triamide, (6) sulfoxides such as dimethylsulfoxide, and (7) aromatic amines such as pyridine. Preferable solvents include ethanol, N, N-dimethylformamide, pyridine and the like. In addition, the compound [V
I] or a salt thereof and CDI, N,
N-dimethylformamide is preferred as a solvent, and when reacting compound [VI] or a salt thereof with ethyl chloroformate, pyridine is preferred as a solvent. These solvents can be used alone or, if necessary,
Two or more kinds may be mixed at an appropriate ratio or used as a mixed solvent with water.
The amount of the solvent used is about 3 ml to about 10 ml per 1 g of compound (VI), preferably about 3 m per 1 g of compound (VI).
From 1 to about 7 ml are used. In the reaction described in the above reaction step 2, when the compound [VI] or a salt thereof has a bulky substituent such as an isobutyrate group (—C (Me) ₂ CO ₂ Et) as R ² ′, The compound [VII] can be obtained by converting the carbamate into a carbamate by reaction with ethyl chloroformate or the like, and then subjecting the carbamate to a ring-closing reaction in the presence of a base, and more strictly neutralizing with an acid.

Examples of the base include (1) methyl lithium, n-butyl lithium, s-butyl lithium, t
-Alkyl lithium reagents such as butyl lithium, (2)
For example, inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydride, potassium hydride and the like; (3) for example, triethylamine, pyridine, diethylisopropyl Organic bases such as amines and (4) metal alcoholates such as sodium methoxide, sodium ethoxide and potassium t-butoxide are used. Instead of the bases described in (1) to (4), for example, metal lithium, Alkali metals such as metal potassium and metal sodium are also used. Among them, sodium ethoxide and the like are preferred. The amount of the base used is usually about 1.0 mol to about 2.0 mol per 1 mol of the compound [VI] or a salt thereof, preferably about 1 mol to 1 mol of the compound [VI] or a salt thereof.
1.0 mole to about 1.2 mole. The reaction described in the above reaction step 2 is usually performed at room temperature (about 10 ° C. to about 30 ° C.) to 180 ° C., preferably 120 ° C. to 150 ° C.,
The reaction time is generally 8 to 24 hours, preferably 1 hour.
5 to 24 hours. In the reaction described in the above reaction step 2, a carbamate compound wherein the compound [VI] or a salt thereof has a bulky substituent such as an isobutyrate group (—C (Me) ₂ CO ₂ Et) as R ² ′ Is usually carried out under reflux, and the reaction temperature is about 100 ° C. to about 120 ° C. The reaction time is generally about 8 hours to about 24 hours, preferably about 12 hours to about 18 hours. Also,
As the solvent,

(1) alcohols such as methanol, ethanol and propanol; (2) ethers such as diethyl ether, dioxane and tetrahydrofuran;
(3) hydrocarbons such as pentane, hexane, benzene, toluene and xylene; (4) nitriles such as acetonitrile; (5) N, N-dimethylformamide;
Inactive solvents such as amides such as N-dimethylacetamide and hexamethylphosphoric triamide, (6) sulfoxides such as dimethylsulfoxide, and (7) aromatic amines such as pyridine are used. ,
Usually about 10 ml to about 30 ml per 1 g of compound [VI],
Preferably, about 15 to 20 ml is used. Reaction step 3
Is obtained by reacting compound [VII] or a salt thereof with Q ² ′ -X—Q ² (Q ² and X have the same meanings as above, and Q ² ′ has the same meaning as Q ² ) or a salt thereof. Compound [II
I] or a process for producing a salt thereof. The reaction in the above reaction step 3 includes, for example, (1) alcohols such as methanol, ethanol, and propanol; (2) ethers such as diethyl ether, dioxane, and tetrahydrofuran; (3) pentane, hexane, benzene, toluene, xylene, and the like. Hydrocarbons, (4) nitriles such as acetonitrile, (5) amides such as N, N-dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide, and (6) sulfoxides such as dimethyl sulfoxide (7) The reaction can also be carried out in an inert solvent such as aromatic amines such as pyridine, and among them, N, N-dimethylformamide and the like are preferred. These solvents can be used alone, or, if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent used is about 5 ml to about 20 ml per 1 g of the compound (VII), preferably about 5 ml to about 15 ml per 1 g of the compound (VII).
1 is used.

The reaction described in the above reaction step 3 may be carried out in the presence of a base. Examples of the base include (1) methyllithium, n-butyllithium, s-butyllithium, t-butyllithium. Alkyl lithium reagents such as lithium; (2) inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, potassium hydride; 3) For example, organic bases such as triethylamine, pyridine and diethylisopropylamine, (4) metal alcoholates such as sodium methoxide, sodium ethoxide and potassium t-butoxide are used. Instead of base, for example, metal lithium, metal potassium, metal sodium, etc. Such as an alkali metal it can also be used. Especially, sodium hydride etc. are mentioned as a preferable base. The amount of the base to be used is generally about 1.1 mol to about 2.0 mol per 1 mol of compound [VII] or a salt thereof, preferably about 1.2 mol to about 2.0 mol per 1 mol of compound [VII] or a salt thereof. 1.5 moles. The reaction temperature in the above reaction step 3 is usually 10 ° C to 30 ° C.
° C, preferably 15 ° C to 25 ° C, and the reaction time is usually 8 hours to 24 hours, preferably 15 hours to 24 hours. In the above compound [III], when R ² ′ is a hydrogen atom (for example, in the above reaction step 3, a compound in which a 4-methoxybenzyl group is deprotected), the compound [I] of the present invention or a compound thereof The salt is prepared by subjecting compound [III] to a suitable solvent (preferably N, N-dimethylformamide or the like) in the presence of a suitable base (preferably potassium carbonate or the like) while coexisting with NaI or the like if necessary. , Formula R
² '-L ¹ [XI] (wherein, R ^2' have the same meanings as defined above (except hydrogen atom), L ¹ is a halogen atom (e.g., chlorine,
Bromine, iodine, etc.). ) (Reaction process)
4) can be manufactured by

Examples of the solvent used in the above reaction step 4 include (1) alcohols such as methanol, ethanol and propanol, (2) ethers such as diethyl ether, dioxane and tetrahydrofuran, (3) pentane, hexane and the like. Benzene, toluene,
Hydrocarbons such as xylene, (4) nitriles such as acetonitrile, (5) N, N-dimethylformamide,
Examples include inert solvents such as amides such as N, N-dimethylacetamide and hexamethylphosphoric triamide, among which N, N-dimethylformamide and the like are preferably used. These solvents can be used alone, or, if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent used is about 10 ml to about 30 ml per 1 g of the compound (I), preferably about 15 ml to about 20 ml per 1 g of the compound (I).
Is used. Examples of the base used in the above reaction step 4 include (1) an alkyllithium reagent such as methyllithium, n-butyllithium, s-butyllithium and t-butyllithium; Inorganic bases such as potassium, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydride and potassium hydride; (3) organic bases such as triethylamine, pyridine and diethylisopropylamine; ) Sodium methoxide, sodium ethoxide, potassium t-
A metal alcoholate such as butoxide is used. In place of the base described in (1) to (4), for example, an alkali metal such as metal lithium, metal potassium, and metal sodium is also used. The amount of the base to be used is generally about 1.1 mol to about 2.0 mol per 1 mol of compound [I] or a salt thereof, preferably about 1.1 mol to about 2.0 mol per 1 mol of compound [I] or a salt thereof. 1.5 moles. The reaction temperature in the above reaction step 4 is usually 10 ° C to 100 ° C, preferably 20 ° C to 60 ° C, and the reaction time is generally 12 hours to 36 hours, preferably 16 hours to
30 hours.

In the compound (I) of the present invention or a salt thereof, R ² is

Embedded image In the case of a group represented by formula (I), it is produced, for example, by the following (Method B) or a method analogous thereto. (Method B) Formula

Embedded image [Wherein the symbols have the same meanings as described above. Wherein Q ³ -CO-Q ⁴ (Q ³ and Q ⁴ each represent a leaving group) are reacted with the compound represented by the formula

As the leaving groups represented by Q ³ and Q ⁴ , the same as those described above can be used. The ring closure reaction in Method B can be carried out in the same manner as the ring closure reaction represented in Reaction Step 2 of Method A described above, except that Compound [IX] and CD
I (generally, about 1.1 mol to about 1.5 mol of CDI per mol of compound [IX], preferably about 1.2 mol of CDI per mol of compound [IX]) and N, N-dimethylformamide ( Usually, N, N-dimethylformamide is reacted in about 10 ml to about 20 ml with respect to 1 g of the compound [IX], preferably about 15 ml with N, N-dimethylformamide with respect to 1 g of the compound [IX]. Is preferred.

The compound [IX] can be prepared by reacting the compound [IV] described in Scheme A or a salt thereof with a compound of the formula

Embedded image [Wherein the symbols have the same meanings as described above. And a salt thereof (Method C).

The compound [X] or a salt thereof is described, for example, in Journal of Heterocyclic Chemistry, Vol. 22, p. 1035 (1985) (J. Heterocycl.
m., 22,1035 (1985)) or Chemical Pharmaceutical Britain, 37 (1), 100 (1989).
(Chem. Pharm. Bull., 37 (1), 100 (1989)) or a method analogous thereto. In the above (Method C), about 1.1 mol to about 1.5 mol, preferably about 1.2 mol, of compound (X) or a salt thereof is used per 1 mol of compound (IV) or a salt thereof. The reaction described in the above (Method C) may be carried out in the presence of a base, and as the base, (1) for example, methyl lithium,
alkyl lithium reagents such as n-butyllithium, s-butyllithium, t-butyllithium, (2)
Sodium hydroxide, potassium hydroxide, sodium carbonate,
Inorganic bases such as potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydride and potassium hydride; (3) organic bases such as, for example, triethylamine, pyridine and diethylisopropylamine;
(4) sodium methoxide, sodium ethoxide,
A metal alcoholate such as potassium t-butoxide is used. Instead of the base described in (1) to (4), for example, an alkali metal such as lithium metal, potassium metal, and sodium metal is used. Above all,
Preferred bases include potassium carbonate and triethylamine. The amount of the base used is usually about 1.1 mol to about 1.5 mol per 1 mol of the compound [IV] or a salt thereof, preferably about 1.2 mol per 1 mol of the compound [IV] or a salt thereof.

The reaction described in the above-mentioned (Method C) includes (1) alcohols such as methanol, ethanol and propanol, (2) ethers such as diethyl ether, dioxane and tetrahydrofuran, (3) pentane, hexane, benzene, Hydrocarbons such as toluene and xylene,
(4) nitriles such as acetonitrile, (5) N, N-
Amides such as dimethylformamide, N, N-dimethylacetamide, hexamethylphosphoric triamide,
(6) sulfoxides such as dimethyl sulfoxide,
(7) The reaction can also be performed in an inert solvent such as aromatic amines such as pyridine. Among them, tetrahydrofuran, N, N-dimethylformamide and the like are preferred. These solvents can be used alone, or, if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of solvent used depends on the compound
About 20 ml to about 40 ml per 1 g of (IV), preferably about 25 ml to about 30 ml per 1 g of compound (IV)
Is used. The reaction temperature is usually about 10 ° C. to about 100
° C, preferably from about 20 ° C to about 25 ° C. The reaction time is generally about 12 hours to about 36 hours, preferably about 16 hours to about 24 hours.

The compound (I) or a salt thereof thus obtained can be converted into a salt according to a conventional method in the case of a free form, and can be converted into a free form or another salt according to a conventional method when a salt is formed. Can be. The compound (I) or a salt thereof thus obtained can be obtained by known means, for example, solvent extraction, liquid conversion, phase transfer, salting out, and crystallization. It can be isolated and purified by recrystallization, chromatography and the like. When the compound (I) or a salt thereof contains an optical isomer, the compound (I) can be separated into an R-form and an S-form by a usual optical resolution means. In each of the reactions of the present invention and each of the reactions for synthesizing the starting material, when the starting compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, such a group is generally used in peptide chemistry or the like. The target compound may be obtained by removing the protecting group as needed after the reaction, if necessary. Examples of the amino-protecting group include formyl, optionally substituted C _1-6 alkylcarbonyl (eg, acetyl, ethylcarbonyl, etc.), phenylcarbonyl, optionally substituted C _1-6 alkyl-oxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.), phenyloxycarbonyl optionally having substituent (s), C _7-10 aralkyl-carbonyl _optionally having substituent (s) Benzylcarbonyl), optionally substituted trityl, optionally substituted phthaloyl or optionally substituted N, N-dimethylaminomethylene, optionally substituted 4-methoxybenzylamine, optionally substituted 4-methoxyphenylamine, optionally substituted 4- ( For example, 4-methoxy) phenylamine or 2,4-dimethoxybenzylamine which may have a substituent is used.
As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl-carbonyl (eg, methylcarbonyl, ethylcarbonyl, butylcarbonyl, etc.), nitro group and the like are used. The number of substituents is about 1 to 3.

Examples of the carboxyl-protecting group include, for example, optionally substituted C _1-6 alkyl (eg, methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl) And phenyl which may have a substituent, trityl which may have a substituent, and silyl which may have a substituent. As these substituents, a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), formyl, C _1-6 alkyl-
A carbonyl (for example, acetyl, ethylcarbonyl, butylcarbonyl, etc.), a nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the hydroxyl-protecting group include C _1-6 which may have a substituent.
Alkyl (eg, methyl, ethyl, n-propyl, i
-Propyl, n-butyl, tert-butyl, etc.), optionally substituted phenyl, optionally substituted C _7-10 aralkyl (eg, benzyl, etc.), formyl, Optionally substituted C _1-6 alkyl-carbonyl (eg, acetyl, ethylcarbonyl, etc.), optionally substituted phenyloxycarbonyl, optionally substituted benzoyl, substituted C _7-10 aralkyl-carbonyl (e.g., benzylcarbonyl and the like) which may be substituted, pyranyl which may have a substituent, furanyl which may have a substituent and Good silyl is used. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl (eg, methyl, ethyl, n-propyl, etc.), phenyl, C _7-10
Aralkyl (for example, benzyl and the like), a nitro group and the like are used, and the number of substituents is about 1 to 4. As a method for removing the protecting group, a method known per se or a method analogous thereto is used. For example, acid, base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride And a method of treating with palladium acetate or the like.

The compound (I) of the present invention or a salt thereof is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, or a salt with an organic acid. Salts, salts with basic or acidic amino acids and the like are used. Preferred examples of the salt with an inorganic base include an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), an aluminum salt, an ammonium salt and the like. Preferred examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N-dibenzylethylenediamine, and the like. Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-benzene -Salts with toluenesulfonic acid and the like are used. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, a salt with aspartic acid and glutamic acid. When the target product is obtained in a free state, it may be converted to a salt according to a conventional method, and when the target product is obtained as a salt, it may be converted to a free form according to a conventional method. Good. The compound (I) of the present invention or a salt thereof may be a hydrate or an anhydrate.

The compound (I) of the present invention or a salt thereof has excellent antiallergic action, antihistamine action, antiinflammatory action, anti-PAF (platelet activating factor) action, eosinophil chemotaxis inhibitory action and the like. And its toxicity is low (acute toxicity: LD ₅₀ > 2 g / kg), so that it can be used as a safe antiallergic agent for mammals (eg, human, mouse, dog, rat, cow, etc.). Further, the compound (I) or a salt thereof has an antihistamine effect and an eosinophil chemotaxis-inhibitory effect, so that urticaria (eg, chronic urticaria), atopic dermatitis, allergic rhinitis in the mammals , Allergic diseases such as allergic conjunctivitis, irritable pneumonitis, skin diseases such as eczema, herpetic dermatitis, psoriasis, respiratory diseases such as eosinophilic pneumonia (PIE syndrome), asthma (eg, bronchial asthma, etc.) ) Can be used for treatment or prevention. Among them, it is used as a prophylactic / therapeutic agent for allergic diseases, asthma (for example, bronchial asthma), allergic conjunctivitis, allergic rhinitis, urticaria (for example, chronic urticaria) or atopic dermatitis. The administration route may be oral or parenteral. Further, the preparation used in the present invention may contain other pharmaceutical ingredients other than the compound (I) or a salt thereof as an active ingredient. Examples of such pharmaceutically active ingredients include anti-asthmatic agents (eg, theophylline, procaterol, ketotifen, azelastine, seratrodast, etc.), anti-allergic agents (eg, ketotifen, terfenadine, azelastine, epinastine, etc.), anti-inflammatory agents (eg, , Diclofenac sodium, ibuprofen, indomethacin, etc.), antibacterial agents (eg, cefexime, cefdinir, ofloxacin, tosfloxacin, etc.), antifungal agents (eg, fluconazole, itraconazole, etc.). These components are not particularly limited as long as the object of the present invention is achieved, and can be used at an appropriate mixing ratio. When administering a compound or a salt thereof and the above-mentioned pharmaceutically active ingredient as an active ingredient, a plurality of pharmaceutically active ingredients may be formulated as a single preparation and administered separately. Alternatively, they may be administered with a time lag. Specific examples of dosage forms include tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, syrups, emulsions, suspensions, Injections, inhalants, ointments and the like are used. These preparations are prepared according to a conventional method (for example, a method described in Japanese Pharmacopoeia). In the preparation of the present invention, compound (I)
Alternatively, the content of the salt thereof varies depending on the form of the preparation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, more preferably about 0.5 to 100% by weight based on the whole preparation. It is about 20% by weight.

Specifically, a tablet is produced by adding the excipient, a binder, a disintegrant or other suitable additives and mixing the drug as it is, and uniformly mixing the resulting mixture with granules by an appropriate method. After that, add lubricants and compression-mold, or directly compress-mold the drug as it is, or mix evenly with excipients, binders, disintegrants or other appropriate additives. Alternatively, the granules can be produced by compressing and molding the granules prepared in advance as they are, or after adding an appropriate additive and mixing them evenly. In addition, the present agent can contain a coloring agent, a flavoring agent, and the like as needed. Further, the agent can be coated with an appropriate coating agent. In the method of manufacturing an injection, a certain amount of a drug is dissolved, suspended or emulsified in a vegetable oil or the like in the case of an aqueous solvent, water for injection, physiological saline, Ringer's solution, etc. in the case of an aqueous solvent, or a non-aqueous solvent, to a certain amount. Alternatively, a predetermined amount of a drug can be taken and sealed in a container for injection. As the carrier for oral preparations, for example, substances commonly used in the field of preparations such as starch, mannitol, crystalline cellulose and sodium carboxymethylcellulose are used. As an injection carrier,
For example, distilled water, physiological saline, glucose solution, infusion agent and the like are used. In addition, additives generally used in preparations can be appropriately added. The dosage of these preparations varies depending on age, body weight, symptoms, administration route, administration frequency, etc. For example, for an adult asthmatic patient, it is converted into the active ingredient (compound (I) or its salt) per day. Usually about 0.1 to 100 mg / kg, preferably about 1 to 50 mg / kg.
mg / kg, more preferably about 1 to 10 mg / kg once a day.
Oral administration is preferably performed in two divided doses.

[0073]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described below in more detail with reference to examples and reference examples. However, the present invention is not limited by the examples, and May be changed. Elution in column chromatography in Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography, thin layer chromatography) unless otherwise specified. In the TLC observation, Merck was used as a TLC plate.
The solvent used as the elution solvent in the column chromatography was used as the developing solvent using 60F ₂₅₄ manufactured by the company. A UV detector was used for detection. Silica gel 60 (70-230 mesh) manufactured by Merck was used as silica gel for column chromatography. Room temperature usually means a temperature of about 10 ° C to 35 ° C. Further, sodium sulfate or magnesium sulfate was used for drying the extract. The meanings of the abbreviations in Examples and Reference Examples are as follows. NMR: nuclear magnetic resonance spectrum, Hz: hertz, J: coupling constant, m: multiplet, q: quartet, t: triplet, d: doublet, s: singlet, b: broad, like: approximation.

[0074]

EXAMPLES Reference Example 1 2-Amino-N- (4-methoxybenzyl) benzamide isatoic anhydride (10.0 g) was added to tetrahydrofuran (150 ml).
In 4-methoxybenzylamine (9.61 ml)
Was added dropwise. After stirring the reaction mixture at room temperature for 20 hours,
The solvent was distilled off under reduced pressure to give crude crystals of the title compound (17.8 g,
About 100%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 104-105 ° C. IR (Nujor): 3450, 3350, 3300, 1625, 1600, 1580, 15
^{. 30, 1510 cm -1 1 H} -NMR (CDCl 3) δ: 3.81 (3H, s), 4.54 (2H, d, J = 5.
4 Hz), 5.56 (2H, bs), 6.25 (1H, bs), 6.58-6.73 (2H,
. m), 6.89 (2H, d, J = 8.2 Hz), 7.15-7.34 (4H, m) Elemental _{analysis: C 15 H 16 N 2 O} 2 Calculated (%): C, 70.29; H, 6.29 ; N, 10.93 Found (%): C, 70.19; H, 6.32; N, 11.08

Reference Example 2 2-Amino-N- (4-methoxybenzyl) nicotinamide 2-aminonicotinic acid (7.15 g) was suspended in N, N-dimethylformamide (100 ml), and stirred under ice-cooling. -Methoxybenzylamine (8.12 ml), diethyl cyanophosphate (9.9
2 ml) and triethylamine (8.66 ml) were sequentially added. After stirring the reaction mixture at room temperature for 15.5 hours, it was concentrated under reduced pressure and extracted with ethyl acetate. Wash the extract with water and dry (Na ₂ SO
₄ ) After that, the solvent was distilled off under reduced pressure to obtain the title compound (15.9 g, about 100%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 165-166 ° C. IR (Nujor): 3420, 3280, 3110, 1620, 1570, 1520, 15
^{. 10 cm -1 1 H-NMR} (CDCl 3) δ: 3.81 (3H, s), 4.54 (2H, d, J = 5.
2 Hz), 6.21 (1H, bs), 6.37 (2H, bs), 6.58 (1H, dd,
J = 7.6, 5.0 Hz), 6.90 (2H, d, J = 8.6 Hz), 7.28 (2H,
d, J = 8.2 Hz), 7.58 (1H, dd, J = 7.8, 1.8 Hz), 8.16
(1H, dd, J = 4.8,1.6 Hz). Elemental analysis: Calculated as C ₁₄ H ₁₅ N ₃ O ₂ (%): C, 65.36; H, 5.88; N, 16.33 Actual (%): C , 65.52; H, 5.93; N, 16.41

Reference Example 3 3-Amino-N- (4-methoxybenzyl) pyrazine-2-carboxamide In the same manner as in Reference Example 2, the title compound (5.57 g) was prepared from 3-aminopyrazine-2-carboxylic acid (4.90 g). g, 61%). Recrystallization from ethyl acetate-ethyl ether gave a melting point of 9
Colorless crystals at 3-95 ° C were obtained. IR (KBr):. 3320, 1659, 1595, 1510 cm -1 1 H-NMR (CDCl 3) δ: 3.80 (3H, s), 4.54 (2H, d, J = 5.
8 Hz), 6.88 (2H, d, J = 8.4 Hz), 7.28 (2H, d, J = 8.0
Hz), 7.76 (1H, d, J = 2.2 Hz), 8.13 (1H, d, J = 2.2 H
. z), 8.15 (1H, bs) Elemental _{analysis: C 13 H 14 N 4 O} 2 · 0.5H 2 O Calculated (%): C, 58.42; H, 5.66; N, 20.96 Found (%) : C, 58.31; H, 5.48; N, 21.26

Reference Example 4 2-Amino-4-chloro-N- (4-methoxybenzyl) benzamide In the same manner as in Reference Example 2, the title compound (8.86 g) was obtained from 2-amino-4-chlorobenzoic acid (5.00 g). g, 47%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 113-115 ° C. IR (KBr): 3452, 3340, 2933, 1633, 1612, 1575, 151
^{. 3, 1488 cm -1 1 H} -NMR (CDCl 3) δ: 3.81 (3H, s), 4.52 (2H, d, J = 5.
4 Hz), 6.19 (1H, bs), 6.58 (1H, dd, J = 8.4, 2.0 Hz),
6.68 (1H, d, J = 2.2 Hz), 6.89 (1H, d, J = 8.8Hz), 7.
21 (1H, d, J = 8.4 Hz), 7.27 (2H, d, J = 8.4 Hz). Elemental analysis: C ₁₅ H ₁₅ N ₂ O ₂ Cl ・ 0.7H ₂ O Calculated (%): C , 59.39; H, 5.45; N, 9.23 Found (%): C, 59.42; H, 5.53; N, 8.67

Reference Example 5 2-Amino-5-chloro-N- (4-methoxybenzyl) benzamide 5-chloroisatoic anhydride was obtained in the same manner as in Reference Example 1.
(5.00 g) to give the title compound (4.40 g, 60%). Recrystallization from ethyl acetate-ethyl ether, melting point 137-139 ℃
To obtain colorless crystals. IR (KBr): 3458, 3357, 3289, 1612, 1579, 1536, 151
^{. 5, 1484 cm -1 1 H} -NMR (CDCl 3) δ: 3.82 (3H, s), 4.52 (2H, d, J = 5.
4 Hz), 6.20 (1H, bs), 6.63 (1H, d, J = 8.8 Hz), 6.85-
6.96 (4H, m), 7.15 (1H, dd, J = 8.6, 2.4 Hz), 7.24-7.
34 (1H, m). Elemental analysis: C ₁₅ H ₁₅ N ₂ O ₂ Cl Calculated (%): C, 61.97; H, 5.20; N, 9.63 Found (%): C, 61.82; H, 5.07; N, 9.72

Reference Example 6 2-Amino-N- (4-methoxybenzyl) -4-nitrobenzamide In the same manner as in Reference Example 2, the title compound (8.03 g) was obtained from 2-amino-4-nitrobenzoic acid (5.00 g). g, 97%). Recrystallization from ethyl acetate-isopropyl ether gave yellow crystals having a melting point of 129-131 ° C. IR (KBr): 3469, 3344, 2935, 1644, 1571, 1513, 1492
^{. cm -1 1 H-NMR (} CDCl 3) δ: 3.81 (3H, s), 4.55 (2H, d, J = 5.
6 Hz), 5.85 (2H, bs), 6.29 (1H, bs), 6.90 (2H, d, J
= 8.4 Hz), 7.28 (2H, d, J = 8.4 Hz), 7.38-7.43 (2H,
. m), 7.51 (1H, s) Elemental analysis: Calculated _{C 15 H 15 N 3 O 4} (%): C, 59.80; H, 5.02; N, 13.95 Found (%): C, 59.70; H, 4.83; N, 13.59

Reference Example 7 2-Amino-N- (4-methoxybenzyl) -5-nitrobenzamide In the same manner as in Reference Example 2, the title compound (13.8 g) was obtained from 2-amino-5-nitrobenzoic acid (10.0 g). g, 84%). Recrystallization from ethyl acetate-isopropyl ether gave yellow crystals having a melting point of 189-191 ° C. IR (KBr): 3476, 3360, 3289, 2921, 1622, 1593, 153
^{. 7, 1514, 1501 cm -1} 1 H-NMR (CDCl 3) δ: 3.82 (3H, s), 4.55 (2H, d, J = 5.
4 Hz), 6.42 (1H, bs), 6.55 (2H, bs), 6.66 (1H, d, J
= 9.0 Hz), 6.91 (2H, d, J = 8.4 Hz), 7.29 (2H, d, J = 8.
4 Hz), 8.09 (1H, dd, J = 9.0, 2.2 Hz), 8.30 (1H, d,
J = 2.2 Hz). Elemental analysis: C ₁₅ H ₁₅ N ₃ O ₄ Calculated (%): C, 59.80; H, 5.02; N, 13.95 Found (%): C, 59.67; H, 5.01; N, 13.91

Reference Example 8 2-Amino-N- (4-methoxybenzyl) -5-methylbenzamide In the same manner as in Reference Example 2, the title compound (7.11) was prepared from 2-amino-5-methylbenzoic acid (5.00 g). g, 80%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 144-145 ° C. IR (KBr): 3415, 3294, 2914, 1631, 1587, 1513, 1498
^{. cm -1 1 H-NMR (} CDCl 3) δ: 2.21 (3H, s), 3.81 (3H, s), 4.5
3 (2H, d, J = 5.4 Hz), 6.24 (1H, bs), 6.62 (1H, d, J
= 8.4 Hz), 6.90 (2H, d, J = 8.8 Hz), 7.03 (1H, d, J = 8.
8 Hz), 7.09 (1H, s), 7.28 (2H, d, J = 9.4 Hz). Elemental analysis: C ₁₆ H ₁₈ N ₂ O ₂ Calculated (%): C, 71.09; H, 6.71; N, 10.36 found (%): C, 70.75; H, 6.78; N, 10.30

Reference Example 9 Methyl 2- (2-aminobenzamido) acetate It was synthesized according to the synthesis method described in JP-A-3-181469. Glycine methyl ester hydrochloride (10.0 g) was suspended in a mixture of tetrahydrofuran (450 ml) and water (10.0 ml),
While stirring, triethylamine (13.1 ml) was added thereto, followed by isatoic anhydride (11.8 g). After stirring the reaction mixture at room temperature for 16 hours, water was added, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure to obtain crude crystals of the title compound (14.0 g, 93%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 84.0-85.0 ° C. IR (Nujor): 3450, 3360, 3340, 1740, 1630, 1600, 15
^{. 70, 1530 cm -1 1 H} -NMR (CDCl 3) δ: 3.81 (3H, s), 4.21 (2H, d, J = 5.
0 Hz), 5.57 (2H, bs), 6.58 (1H, bs), 6.63-6.72 (2H,
m), 7.24 (1H, ddd, J = 9.0, 7.6, 1.4 Hz), 7.42 (1H,
dd, J = 8.0, 1.4 Hz). Elemental analysis: Calculated for C ₁₀ H ₁₂ N ₂ O ₃ (%): C, 57.69; H, 6.81; N, 13.45 Found (%): C, 57.97; H, 5.64; N, 13.57

Reference Example 10 Ethyl 3- (2-aminobenzamido) propionate In the same manner as in Reference Example 9, β-alanine ethyl hydrochloride (10.0 g) was used to give the title compound (14.5 g, about 100%) as an oil. As obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.27 (3H, t, J = 7.0 Hz), 2.63 (2
H, t, J = 6.2 Hz), 3.68 (2H, q, J = 5.8 Hz), 4.17 (2H,
q, J = 7.0 Hz), 5.53 (2H, bs), 6.60-6.70 (2H, m), 6.7
4 (1H, bs), 7.20 (1H, t, J = 7.0 Hz), 7.30 (1H, d, J
= 8.6 Hz).

Reference Example 11 Ethyl 4- (2-aminobenzamido) butyrate In the same manner as in Reference Example 9, the title compound (13.3 g, 98%) was obtained from 4-aminobutyric acid ethyl ester hydrochloride (10.0 g) as an oil. Obtained as a product. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 1.84-2.
02 (2H, m), 2.44 (2H, t, J = 7.0 Hz), 3.47 (2H, q, J =
6.0 Hz), 4.14 (2H, q, J = 7.2 Hz), 5.53 (2H, bs), 6.3
9 (1H, bs), 6.60-6.72 (2H, m), 7.35 (2H, m).

Reference Example 12 2-Amino-N-methylbenzamide isatoic anhydride (10.0 g) was added to tetrahydrofuran (200 ml).
And a 40% methanol solution of methylamine (10.0 ml) was added dropwise with stirring. After stirring at room temperature for 16 hours, the solvent was distilled off under reduced pressure to give the title compound (10.3 g, ca.
00%). 78.0-79.0 ° C (recrystallized from ethyl acetate-n-hexane). IR (KBr):. 3450, 3333, 1615, 1580, 1539 cm -1 1 H-NMR (CDCl 3) δ: 2.97 (3H, d, J = 5.0 Hz), 6.05 (1
H, bs), 6.60-6.72 (2H, m), 7.14-7.32 (2H, m). Elemental analysis: Calculated as C ₈ H ₁₀ N ₂ O Calculated (%): C, 63.98; H, 6.71; N , 18.65 Found (%): C, 63.44; H, 6.60; N, 18.58

Reference Example 13 2-amino-N- (1,1-dimethylethyl) benzamide In the same manner as in Reference Example 12, tert-butylamine (5.
Using 38 g), the title compound (13.2 g, about 100%) was synthesized. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 4.49 (1H, bs), 5.
86 (2H, bs), 6.60-6.70 (2H, m), 7.13-7.30 (2H, m).

Reference Example 14 2-Amino-N- (3-pyridylmethyl) benzamide The title compound (12.0 g, about 100%) was prepared in the same manner as in Reference Example 12 using 3-aminomethylpyridine (5.99 ml). Was synthesized. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 117-118 ° C. IR (KBr):. 3337, 1638, 1583, 1528, 1491 cm -1 1 H-NMR (CDCl 3) δ: 4.62 (2H, d, J = 5.8 Hz), 5.54 (2
H, bs), 6.50 (1H, bs), 6.58-6.74 (2H, m), 7.15-7.38
(3H, m), 7.71 (1H, d, J = 7.6 Hz), 8.54 (1H, d, J = 5.
2 Hz), 8.60 (1H, s). Elemental analysis: Calculated for C ₁₃ H ₁₃ N ₃ O Calculated (%): C, 68.71; H, 5.76; N, 18.49 Found (%): C, 68.45; H, 5.59; N, 18.45

Reference Example 15 2-Amino-N-phenylbenzamide In the same manner as in Reference Example 12, the title compound (12.6 g, about 100%) was obtained as crystals using aniline (5.36 ml).
This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 5.49 (2H, bs), 6.67-6.77 (2H,
m), 7.15 (1H, ddd, J = 8.2, 7.4, 0.8 Hz), 7.20-7.31
(1H, m), 7.32-7.42 (2H, m), 7.47 (1H, d, J = 7.6 H
z), 7.52-7.60 (2H, m), 7.75 (1H, bs).

Reference Example 16 2-amino-N-cyclohexylbenzamide Cyclohexylamine was prepared in the same manner as in Reference Example 12.
(6.73 ml) to give the title compound (11.7 g, about 100%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 152-154 ° C. IR (KBr): 3478, 3418, 3370, 2934, 2853, 1620, 158
. 8, 1568, 1537, 1489 cm - 1 1 H-NMR (CDCl 3) δ: 1.10-1.56 (5H, m), 1.56-1.82 (3
H, m), 1.94-2.10 (2H, m), 3.82-4.02 (1H, m), 5.89
(1H, bs), 6.60-6.71 (2H, m), 7.20 (1H, ddd, J = 8.6,
7.0, 1.6 Hz), 7.26-7.60 (1H, m). Elemental analysis: Calculated as C ₁₃ H ₁₈ N ₂ O ・ 0.1H ₂ O (%): C, 70.94; H, 8.33; N, 12.73 Values (%): C, 70.98; H, 8.37; N, 12.70

Reference Example 17 2-amino-N- [3- (4-diphenylmethoxypiperidino) propyl] benzamide In the same manner as in Reference Example 1, 4-methoxybenzylamine was used instead of 1- (3-aminobenzylamine). The title compound (6.19 g, 66%) was synthesized from isatoic anhydride (2.87 g) using (propyl) -4-diphenylmethoxypiperidine. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.54-1.98 (6H, m), 2.10-2.32 (2
H, m), 2.52 (2H, t, J = 5.6 Hz), 2.74-2.88 (2H, m),
3.40-3.56 (3H, m), 5.50 (1H, s), 5.61 (2H, bs), 6.
59-6.70 (2H, m), 7.12-7.42 (13H, m), 8.38 (1H, b
s).

Reference Example 18 2-amino-N- [4- (4-diphenylmethoxypiperidino) butyl] benzamide In the same manner as in the synthesis of Reference Example 1, 1-methoxybenzylamine was used instead of 4-methoxybenzylamine. Using (4-aminobutyl) -4-diphenylmethoxypiperidine, isatoic anhydride
(3.18 g) to give the title compound (9.14 g, about 100%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 74.0-75.0 ° C. IR (KBr): 3446, 3338, 2941, 1637, 1585, 1533, 1494
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.50-1.96 (8H, m), 2.04-2.10 (2
H, m), 2.30-2.40 (2H, m), 2.68-2.80 (2H, m), 3.32-
3.50 (3H, m), 5.46 (2H, bs), 5.50 (1H, s), 6.59-6.
70 (3H, m), 7.16-7.40 (11H, m). Elemental analysis: Calculated as C ₂₉ H ₃₅ N ₃ O ₂・ 0.3H ₂ O Calculated (%): C, 75.23; H, 7.75; N, 9.08 Found (%): C, 75.12; H, 7.65; N, 9.13

Reference Example 19 Ethyl 2- (2-aminobenzamido) isobutyrate Ethyl 2-aminoisobutyrate hydrochloride (9.22 g, 55.0 mmol) was suspended in tetrahydrofuran (250 ml) and water (25 ml), and triethylamine was stirred. (9.06 ml, 65.0 mmol) and isatoic anhydride (8.16 g, 50.0 mmol) were added sequentially.
The reaction mixture was stirred at room temperature for 15 hours, then at 60 ° C. for 24 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying (MgSO ₄ ),
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (2: 1,
v / v) to elute the title compound (5.26 g, 42%) with a melting point of 106 ° C
As crystals. IR (KBr):. 3471, 3356, 1726, 1644, 1617, 1585 cm -1 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.65 (6
H, s), 4.23 (2H, q, J = 7.2 Hz), 5.47 (2H, bs), 6.61
(1H, bs), 6.62-6.69 (2H, m), 7.16-7.25 (1H, m), 7.
36 (1H, dd, J = 1.4 Hz, 8.0 Hz). Elemental analysis: Calculated as C ₁₃ H ₁₈ N ₂ O ₃ (%): C, 62.38; H, 7.25; N, 11.19 Actual (%) : C, 62.23; H, 7.34; N, 11.38

Reference Example 20 Methyl 2- (2-aminobenzamide) isobutyrate In the same manner as in Reference Example 19, methyl 2-aminoisobutyrate hydrochloride (11.
8 g, 77.0 mmol) and isatoic anhydride (11.4 g, 70
mmol) to give the title compound (7.53 g, 46%) as an oil. IR (KBr): 3471, 3356, 1733, 1641, 1616, 1583, 1521
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.65 (6H, s), 3.77 (3H, s), 5.5
5 (2H, bs), 6.56 (1H, bs), 6.62-6.69 (2H, m), 7.17-
7.25 (1H, m), 7.36 (1H, dd, J = 8.3 Hz, 1.5 Hz).

Reference Example 21 Ethyl 2- (2-amino-5-methylbenzamide) isobutyrate Ethyl 2-aminoisobutyrate hydrochloride (6.04 g, 36.0 mmol)
It was dissolved in N, N-dimethylformamide (60 ml), and triethylamine (10.04 ml, 72.0 mmol) was added dropwise. 15 at room temperature
Stir in 2-amino-5-methylbenzoic acid (5.15 g, 30.0 g
mmol), and then ethyl cyanophosphate under ice-cooling.
(6.07 ml, 36.0 mmol) was added dropwise. The mixture was stirred at the same temperature for 1 hour and then at room temperature for 15 hours. Ice water was added to the reaction mixture,
Extracted with ethyl ether. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure.The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (3: 1, v / v) to give the title compound (7.48 g, 88%) as an oil. IR (KBr): 3465, 3358, 2984, 2838, 1725, 1642, 161
^{. 3, 1580, 1522 cm -1} 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.64 (6
H, s), 4.23 (2H, q, J = 7.2 Hz), 5.60 (2H, bs), 6.56
(1H, bs), 6.61 (1H, dd, J = 8.2 Hz, 2.0 Hz), 6.66 (1
H, d, J = 1.8 Hz), 7.28 (1H, d, J = 8.4 Hz). The compounds described in Reference Examples 22 to 24 below were synthesized in the same manner as described above.

Reference Example 22 Ethyl 2- (2-amino-5-nitrobenzamido) isobutyrate The title compound (7.05 g, 80%) was obtained from 2-amino-5-nitrobenzoic acid (5.75 g, 30.0 mmol) as an oil. As obtained. IR (KBr): 3453, 3343, 2986, 2940, 1725, 1651, 164
. 5, 1617, 1593, 1526 , 1505 cm -1 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.67 (6
H, s), 4.24 (2H, q, J = 7.2 Hz), 6.46 (2H, bs), 6.70
(1H, bs), 6.65 (1H, d, J = 9.2 Hz), 8.09 (1H, dd, J =
9.1 Hz, 2.5 Hz), 8.37 (1H, d, J = 2.6 Hz).

Reference Example 23 Ethyl 2- (2-amino-5-fluorobenzamido) isobutyrate The title compound (2.32 g, 87%) was obtained from 2-amino-5-fluorobenzoic acid (1.60 g, 10.0 mmol) as an oil. As obtained. IR (KBr): 3461, 3362, 2986, 2940, 1725, 1651, 159
^{. 3, 1564, 1526 cm -1} 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.65 (6
H, s), 4.24 (2H, q, J = 7.2 Hz), 5.24 (2H, bs), 6.59
(1H, bs), 6.62 (1H, dd, J = 8.9 Hz, 4.7 Hz), 6.96 (1
H, ddd, J = 9.0 Hz, 7.9 Hz, 2.9 Hz), 7.08 (1H, dd, J
= 9.2 Hz, 2.8 Hz).

Reference Example 24 Ethyl 2- (2-amino-4-chlorobenzamido) isobutyrate The title compound (7.48 g, 88%) was obtained from 2-amino-4-chlorobenzoic acid (5.15 g, 30.0 mmol) as an oil. As obtained. IR (KBr): 3465, 3358, 2984, 2938, 1725, 1642, 161
^{. 3, 1580, 1522 cm -1} 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.2 Hz), 1.64 (6
H, s), 4.23 (2H, q, J = 7.2 Hz), 5.60 (2H, bs), 6.56
(1H, bs), 6.61 (1H, dd, J = 8.2 Hz, 2.0 Hz), 6.66 (1
H, d, J = 1.8 Hz), 7.28 (1H, d, J = 8.4 Hz).

Reference Example 25 Ethyl 2- (2-amino-5-chlorobenzamido) isobutyrate By the same method as in Reference Example 19, 5-chloroisatoic anhydride (8.15 g, 40.0 mmol) and ethyl 2-aminoisobutyrate ( 7.
The title compound (4.65 g, 41%) was obtained as an oil from 38 g (44.0 mmol). IR (KBr): 3469, 3356, 2987, 2939, 1724, 1649, 161
. 7, 1581, 1523, 1508 cm -1 1 H-NMR (CDCl 3) δ: 1.28 (3H, t, J = 7.1 Hz), 1.65 (6
H, s), 4.23 (2H, q, J = 7.1 Hz), 5.60 (2H, bs), 6.54
(1H, bs), 6.61 (1H, d, J = 8.8 Hz), 7.15 (1H, dd, J =
8.7 Hz, 2.5 Hz), 7.32 (1H, d, J = 2.4 Hz).

Reference Example 26 2,4-Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (Method 1) 2-amino-N- (methoxy) obtained according to Reference Example 1 Benzyl) benzamide (17.8 g) and N, N-carbonyldiimidazole (14.9 g) were converted to N, N-dimethylformamide (1
(00 ml) at 150 ° C. for 15 hours. After cooling, the reaction mixture was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, methanol and ethyl ether in that order, and dried to give the title compound (17.0 g, 98%) as colorless crystals. (Method 2) 2-Amino-N- (methoxybenzyl) benzamide (23.6 g) was dissolved in pyridine (150 ml), and ethyl chloroformate (10.6 ml) was added dropwise with stirring under ice cooling. The reaction mixture was stirred at room temperature for 8 hours, and then heated to reflux for 18.5 hours. After cooling, the mixture was poured into ice water and treated in the same manner as in Method 1 to give the title compound (25.5 g, 98%) as colorless crystals. 229-230 ° C. IR (Nujor):. 1710, 1655, 1600, 1500, 1480 cm -1 1 H-NMR (CDCl 3) δ: 3.76 (3H, s), 5.21 (2H, s), 6.8
4 (2H, d, J = 8.8 Hz), 7.06 (1H, d, J = 8.0 Hz), 7.23
(1H, t, J = 7.6 Hz), 7.51 (2H, d, J = 8.8 Hz), 7.61 (1
H, ddd, J = 8.2, 6.6, 1.6 Hz), 8.14 (1H, dd, J = 7.0,
1.2 Hz), 9.77 (1H, bs). Elemental analysis: Calculated as C ₁₆ H ₁₄ N ₂ O ₃ (%): C, 68.08; H, 5.00; N, 9.92 Actual (%): C, 67.93 ; H, 4.83; N, 10.06

Reference Example 27 2,4-Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine The same method as in Reference Example 26 (Method 1) ), 2-amino-N-
The title compound (2.93 g, 88%) was synthesized from (4-methoxybenzyl) nicotinamide (3.00 g). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 272-273 ° C. IR (Nujor):. 1720, 1660, 1600, 1510 cm -1 1 H-NMR (CDCl 3) δ: 3.76 (3H, s), 5.14 (2H, s), 6.8
1 (2H, d, J = 8.6 Hz), 7.10-7.20 (1H, m), 7.46 (2H,
d, J = 7.4 Hz), 8.36 (1H, d, J = 7.6 Hz), 8.54-8.63 (1
. H, m), 11.49 ( 1H, bs) Elemental analysis: Calculated _{C 15 H 13 N 3 O 3} (%): C, 63.60; H, 4.63; N, 14.83 Found (%): C, 63.17; H, 4.43; N, 14.89

Reference Example 28 2,4-Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropteridine In the same manner as in Reference Example 26 (method 1), 2-amino-N-
(4-methoxybenzyl) pyrazine-2-carboxamide (1
1.0 g) to give the title compound (5.98 g, 49%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 233-234 ° C. IR (KBr):. 2971, 1732, 1682, 1611, 1582, 1510 cm -1 1 H-NMR (CDCl 3) δ: 3.78 (3H, s), 5.22 (2H, s), 6.8
4 (2H, d, J = 8.8 Hz), 7.54 (2H, d, J = 8.8 Hz), 8.58
(1H, d, J = 2.2 Hz), 8.63 (1H, d, J = 2.2 Hz), 8.95 (1
H, bs). Elemental analysis: C ₁₄ H ₁₂ N ₄ O ₃ Calculated (%): C, 59.15; H, 4.25; N, 19.71 Found (%): C, 59.07; H, 4.31; N , 19.51

Reference Example 29 7-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,
3,4-Tetrahydroquinazoline In the same manner as in Reference Example 26 (method 1), 2-amino-4-
Chloro-N- (4-methoxybenzyl) benzamide (8.00 g)
Was used to synthesize the title compound (7.13 g, 82%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 254-256 ° C. IR (KBr):. 2987, 1714, 1668, 1616, 1600, 1515 cm -1 1 H-NMR (CDCl 3) δ: 3.77 (3H, s), 5.19 (2H, s), 6.8
5 (2H, d, J = 8.8 Hz), 7.08 (1H, s), 7.20 (1H, d, J =
7.4 Hz), 7.50 (2H, d, J = 8.8 Hz), 8.07 (1H, d, J = 8.
8 Hz), 9.88 (1H, bs). Elemental analysis: C ₁₆ H ₁₃ N ₂ O ₃ Cl Calculated (%): C, 60.67; H, 4.14; N, 8.84 Found (%): C, 60.70; H, 4.05; N, 9.07

Reference Example 30 6-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,
3,4-tetrahydroquinazoline 2-amino-5-chloro-N- (4-methoxybenzyl) benzamide (Reference Example 5) by the same method (Method 1) as in Reference Example 26.
The title compound (7.14 g, 71%) was synthesized from (9.22 g). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 252-253 ° C. IR (KBr):. 1718, 1662, 1610, 1513, 1479 cm -1 1 H-NMR (CDCl 3) δ: 3.77 (3H, s), 5.18 (2H, s), 6.8
3 (2H, d, J = 8.4 Hz), 6.98 (1H, d, J = 8.6 Hz), 7.48
(2H, d, J = 8.8 Hz), 7.54 (1H, dd, J = 8.8, 2.2Hz), 8.
11 (1H, d, J = 2.6 Hz), 9.23 (1H, bs). Elemental analysis: Calculated as C ₁₆ H ₁₃ N ₂ O ₃ Cl (%): C, 60.67; H, 4.14; N, 8.84 Found (%): C, 60.65; H, 4.36; N, 9.07

Reference Example 31 2,4-dioxo-3- (4-methoxybenzyl) -7-nitro-1,2,
3,4-Tetrahydroquinazoline By the same method as in Reference Example 26 (method 2), 2-amino-N-
(4-Methoxybenzyl) -4-nitrobenzamide (Reference Example 6)
(5.00 g) to give the title compound (5.17 g, 95%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 244-246 ° C. IR (KBr): 1722, 1704, 1662, 1633, 1612, 1538, 1513
^{. cm -1 1 H-NMR (} CDCl 3) δ: 3.77 (3H, s), 5.22 (2H, s), 6.8
6 (2H, d, J = 8.8 Hz), 7.52 (2H, d, J = 8.8 Hz), 7.95
(1H, d, J = 2.0 Hz), 8.03 (1H, dd, J = 8.4, 2.2Hz), 8.
34 (1H, d, J = 8.4 Hz), 10.01 (1H, bs). Elemental analysis: Calculated as C ₁₆ H ₁₃ N ₃ O ₅・ 0.2H ₂ O (%): C, 58.08; H, 4.08 ; N, 12.70 found (%): C, 57.90; H, 4.02; N, 12.60

Reference Example 32 2,4-Dioxo-3- (4-methoxybenzyl) -6-nitro-1,2,
3,4-Tetrahydroquinazoline The title compound was obtained from 2-amino-N- (4-methoxybenzyl) -5-nitrobenzamide (10.0 g) obtained in Reference Example 7 by the same method (Method 1) as in Reference Example 26. (9.65 g, 89%)
Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 254-256 ° C. IR (KBr): 2880, 1721, 1651, 1609, 1541, 1514, 1487
^{. cm -1 1 H-NMR (} CDCl 3) δ: 3.77 (3H, s), 5.15 (2H, s), 6.8
3 (2H, d, J = 8.8 Hz), 7.32 (1H, d, J = 9.2 Hz), 7.47
(2H, d, J = 8.8 Hz), 8.34 (1H, dd, J = 8.8, 2.6Hz), 8.
94 (1H, d, J = 2.6 Hz), 11.82 (1H, bs). Elemental analysis: Calculated as C ₁₆ H ₁₃ N ₃ O ₅ (%): C, 58.72; H, 4.00; N, 12.84 Observed Values (%): C, 58.67; H, 3.96; N, 12.82

Reference Example 33 2,4-Dioxo-3- (4-methoxybenzyl) -6-methyl-1,2,
3,4-Tetrahydroquinazoline The title compound was obtained from 2-amino-N- (4-methoxybenzyl) -5-methylbenzamide (7.00 g) obtained in Reference Example 8 in the same manner as in Reference Example 26 (Method 2). (7.97 g, about 100
%) Were synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 263-265 ° C. IR (KBr):. 2901, 1705, 1661, 1609, 1581, 1512 cm -1 1 H-NMR (CDCl 3) δ: 2.39 (3H, s), 3.76 (3H, s), 5.2
0 (2H, s), 6.83 (2H, d, J = 8.8 Hz), 6.95 (1H, d, J =
8.2 Hz), 7.41 (1H, dd, J = 8.0, 1.8 Hz), 7.50 (2H, d,
. J = 8.8 Hz), 7.93 (1H, s), 9.65 (1H, bs) Elemental analysis: Calculated _{C 17 H 16 N 2 O 3} (%): C, 68.91; H, 5.44; N, 9.45 Found (%): C, 68.73; H, 5.31; N, 9.74

Reference Example 34 Methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate The same method as in Reference Example 26 (method 1) was used to obtain 2- ( Methyl 2-aminobenzamide) acetate (14.0
g) to give the title compound (13.0 g, 83%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 205-206 ° C. IR (Nujor): 1750, 1710, 1650, 1620, 1590, 1510, 14
^{. 80 cm -1 1 H-NMR} (CDCl 3) δ: 3.80 (3H, s), 4.86 (2H, s), 7.6
4 (1H, ddd, J = 8.8, 7.4, 1.4 Hz), 8.13 (1H, d, J = 7.
8 Hz), 9.75 (1H, bs). Elemental analysis: Calculated as C ₁₁ H ₁₀ N ₂ O ₄ (%): C, 56.41; H, 4.30; N, 11.96 Found (%): C, 56.38 ; H, 4.42; N, 11.99

Reference Example 35 Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate In the same manner as in Reference Example 26 (Method 1), 3- The title compound (14.0 g, 87%) was synthesized from ethyl (2-aminobenzamide) propionate (14.5 g). Recrystallized from ethyl acetate-ethyl ether, melting point 192
Colorless crystals at -194 ° C were obtained. IR (Nujor): 1725, 1715, 1655, 1620, 1600, 1490 cm
^{. -1 1 H-NMR (CDCl} 3) d: 1.25 (3H, t, J = 7.0 Hz), 2.75 (2
H, t, J = 7.8 Hz), 4.16 (2H, q, J = 7.4 Hz), 4.41 (2H,
t, J = 7.8 Hz), 7.10 (1H, d, J = 8.8 Hz), 7.63 (1H, d
dd, J = 8.8, 7.2, 1.6 Hz), 8.14 (1H, dd, J = 7.8, 1.4
Hz), 9.69 (1H, bs). Elemental analysis: Calculated as C ₁₃ H ₁₄ N ₂ O ₄ (%): C, 59.54; H, 5.38; N, 10.68 Found (%): C, 59.42; H, 5.23; N, 10.81

Reference Example 36 Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-butyrate By the same method as in Reference Example 26 (Method 1), 4- ( Ethyl 2-aminobenzamide) butyrate (13.
From 3 g), the title compound (13.8 g, 94%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 133-135 ° C. IR (KBr):. 3195, 3136, 2977, 1727, 1633, 1492 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.0 Hz), 2.00-2.
18 (2H, m), 2.44 (2H, t, J = 7.2 Hz), 4.04-4.22 (4H,
m), 7.11 (2H, d, J = 8.4 Hz), 7.24 (1H, t, J = 7.6 H
z), 7.62 (1H, ddd, J = 8.2, 7.0, 1.2 Hz), 8.13 (1H,
. dd, J = 7.8, 0.8 Hz), 9.89 (1H, bs) Elemental analysis: Calculated _{C 14 H 16 N 2 O 4} (%): C, 60.86; H, 5.84; N, 10.14 Found ( %): C, 60.86; H, 5.62; N, 10.21

Reference Example 37 2,4-Dioxo-3-methyl-1,2,3,4-tetrahydroquinazoline The 2-amino-amino compound obtained in Reference Example 12 was obtained in the same manner as in Reference Example 26 (Method 1). N-methylbenzamide (10.3 g)
From there, the title compound (5.34 g, 44%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 233-235 ° C. IR (KBr):. 1717, 1669, 1645, 1624, 1599, 1493 cm -1 1 H-NMR (CDCl 3) δ: 3.50 (3H, s), 7.11 (1H, d, J = 8.
0 Hz), 7.25 (1H, ddd, J = 8.2, 7.2, 1.0 Hz), 7.63 (1
H, ddd, J = 8.6, 7.2, 1.4 Hz), 8.15 (1H, d, J = 8.0 H
z), 9.66 (1H, bs). Elemental analysis: Calculated as C ₉ H ₈ N ₂ O ₂ (%): C, 61.36; H, 4.58; N, 15.90 found (%): C, 61.31; H, 4.49; N, 16.01

Reference Example 38 3- (1,1-Dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline In the same manner as in Reference Example 26 (Method 1), The title compound (8.73 g, 77%) was synthesized from the obtained 2-amino-N- (1,1-dimethylethyl) benzamide (10.0 g). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 218-220 ° C. IR (KBr):. 1715, 1651, 1609, 1489 cm -1 1 H-NMR (CDCl 3) δ: 1.79 (9H, s), 6.97 (1H, d, J = 7.
8 Hz), 7.17 (1H, t, J = 7.0 Hz), 7.55 (1H, ddd, J = 8.
8, 7.2, 1.6 Hz), 8.02 (1H, dd, J = 7.0, 1.0 Hz), 9.2
8 (1H, bs). Elemental analysis: C ₁₂ H ₁₄ N ₂ O ₂ Calculated (%): C, 66.04; H, 6.47; N, 12.84 Found (%): C, 66.02; H, 6.44 ; N, 12.96

Reference Example 39 2,4-Dioxo-3- (3-pyridinylmethyl) -1,2,3,4-tetrahydroquinazoline Obtained according to Reference Example 14 by the same method as in Reference Example 26 (Method 1). The title compound (9.50 g, 78%) was synthesized from 2-amino-N- (3-pyridylmethyl) benzamide (11.7 g). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 241-243 ° C. IR (KBr): 3059, 1715, 1669, 1618, 1516, 1508, 1491
^{. cm -1 1 H-NMR (} CDCl 3) δ: 5.27 (2H, s), 7.07 (1H, d, J = 7.
6 Hz), 7.20-7.32 (2H, m), 7.63 (1H, t, J = 7.6 Hz),
7.88 (1H, d, J = 8.4 Hz), 8.15 (1H, d, J = 8.0 Hz), 8.
53 (1H, d, J = 4.4 Hz), 8.84 (1H, s), 9.60 (1H, bs
. s) Elemental _{analysis: C 14 H 11 N 3 O} 2 Calculated (%): C, 66.40; H, 4.3
8; N, 16.59 found (%): C, 66.10; H, 4.3
2; N, 16.64

Reference Example 40 2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinazoline The 2-amino-amino compound obtained in Reference Example 15 was obtained in the same manner as in Reference Example 26 (Method 2). N-phenylbenzamide (12.5
g) to give the title compound (6.96 g, 50%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 287-289 ° C. IR (KBr):. 3200, 1732, 1649, 1607, 1493 cm -1 1 H-NMR (CDCl 3) δ: 6.95 (1H, d, J = 8.0 Hz), 7.18-7.
36 (2H, m), 7.46-7.64 (5H, m), 8.16 (1H, d, J = 7.4 H
. z), 9.46 (1H, bs) Elemental _{analysis: C 14 H 10 N 2 O} 2 · 0.1H 2 O Calculated (%): C, 70.05; H, 4.28; N, 11.67 Found (%) : C, 69.84; H, 4.25; N, 11.43

Reference Example 41 3-Cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline The 2-amino-amino compound obtained in Reference Example 16 was obtained in the same manner as in Reference Example 26 (Method 2). N-cyclohexylbenzamide
(11.7 g) to give the title compound (10.8 g, 84%). Recrystallized from ethyl acetate-ethyl ether, melting point 236-238 ℃
To obtain colorless crystals. IR (KBr): 3285, 2930, 2857, 1732, 1717, 1626, 159
^{. 7, 1526 cm -1 1 H} -NMR (CDCl 3) δ: 1.18-2.10 (8H, m), 2.40-2.62 (2
H, m), 4.80-5.00 (1H, m), 7.03 (1H, d, J = 8.2 Hz),
7.20-7.30 (2H, m), 7.60 (1H, t, J = 8.0 Hz), 8.12 (1
. H, d, J = 8.2 Hz), 9.39 (1H, bs) Elemental _{analysis: C 14 H 16 N 2 O} 2 · 0.2H 2 O Calculated (%): C, 67.83; H, 6.67; N , 11.30 Found (%): C, 67.81; H, 6.69; N, 11.26

Reference Example 42 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Ethyl) ethyl isobutyrate Ethyl 2- (2-aminobenzamido) isobutyrate obtained in Reference Example 19 by the same method (Method 1) as in Reference Example 26.
(5.01 g, 20.0 mmol) to give the title compound (2.52 g, 46%). 133-134 ° C. IR (KBr): 3265, 3213, 3141, 1720, 1668, 1621, 1610
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.89 (6
H, s), 4.20 (2H, q, J = 7.2 Hz), 7.04 (1H, d, J = 8.0
Hz), 7.18-7.26 (1H, m), 7.57-7.66 (1H, m), 8.04-8.0
9 (1H, m), 10.06 (1H, bs). Elemental analysis: Calculated as C ₁₄ H ₁₆ N ₂ O ₄ (%): C, 60.86; H, 5.84; N, 10.14 Found (%): C, 60.86; H, 5.64; N, 10.24 (Method 2) Ethyl 2- (2-aminobenzamido) isobutyrate (6.98 g, 27.9 mmol) obtained in Reference Example 19 was dissolved in pyridine (30 ml), and iced. Ethyl chloroformate (2.94 ml, 30.7 mmol) was added dropwise while stirring under cooling. After stirring the reaction mixture at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of potassium hydrogen sulfate and subsequently with a saturated saline solution, dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol (150 ml), sodium ethylate (2.09 g, 30.7 mmol) was added, and the mixture was heated under reflux for 15 hours. The solvent was distilled off under reduced pressure, and the residue was diluted with water and neutralized with 1N hydrochloric acid. The precipitated crystals were collected by filtration to give the title compound (6.57 g, 85%) as colorless crystals.

Reference Example 43 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Methyl 2- (2-aminobenzamido) isobutyrate (7.5) obtained in Reference Example 20 by the same method (Method 2) as Reference Example 26.
The title compound (1.65 g, 20%) was synthesized from 2 g, 31.8 mmol). 158-159 ° C. IR (KBr): 3280, 3210, 3138, 3072, 2997, 2949, 174
. 5, 1718, 1668, 1621 , 1610 cm -1 1 H-NMR (CDCl 3) δ: 1.89 (6H, s), 3.73 (3H, s), 7.0
4 (1H, d, J = 8.0 Hz), 7.18-7.26 (1H, m), 7.57-7.66
. (1H, m), 8.04-8.08 (1H, m), 10.01 (1H, bs) Elemental analysis: Calculated _{C 13 H 14 N 2 O 4} (%): C, 59.54; H, 5.38; N , 10.68 Found (%): C, 59.46; H, 5.30; N, 10.56

Reference Example 44 Ethyl 2- (2,4-dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (Method 3), The title compound (5.51 g) was obtained from ethyl 2- (2-amino-5-methylbenzamido) isobutyrate (6.33 g, 23.9 mmol) obtained in Reference Example 21.
g, 79%). 156-157 ℃ (recrystallized from ethanol). IR (KBr): 3196, 3169, 3071, 2986, 2938, 1742, 171
. 1, 1661, 1626, 1514 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.87 (6
H, s), 2.38 (3H, s), 4.19 (2H, q, J = 7.0 Hz), 6.93
(1H, d, J = 8.2 Hz), 7.40 (1H, dd, J = 1.9 Hz, 8.1 H
z), 7.84 (1H, s), 9.92 (1H, bs). Elemental analysis: C ₁₅ H ₁₈ N ₂ O ₄ Calculated (%): C, 62.06; H, 6.25; N, 9.65 found ( %): C, 61.92; H, 6.29; N, 9.73

Reference Example 45 Ethyl 2- (2,4-dioxo-6-nitro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (Method 3), The title compound (5.02 g, 66) was obtained from ethyl 2- (2-amino-5-nitrobenzamido) isobutyrate (7.04 g, 23.8 mmol) obtained in Reference Example 22.
%) Were synthesized. Melting point: 184-185 ° C (recrystallized from ethanol). IR (KBr): 3210, 3094, 2988, 2942, 1732, 1682, 162
. 8, 1609, 1537, 1510 cm -1 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.89 (6
H, s), 4.22 (2H, q, J = 7.2 Hz), 7.17 (1H, d, J = 9.0
Hz), 8.47 (1H, dd, J = 8.9 Hz, 2.5 Hz), 8.96 (1H, d,
J = 2.4 Hz), 10.32 (1H, bs). Elemental analysis: Calculated as C ₁₄ H ₁₅ N ₃ O ₆ (%): C, 52.34; H, 4.71; N, 13.08 Actual (%): C , 52.34; H, 4.60; N, 13.16

Reference Example 46 Ethyl 2- (2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (Method 3), From the ethyl 2- (2-amino-5-fluorobenzamido) isobutyrate (2.31 g, 8.6 mmol) obtained in Reference Example 23, the title compound (1.19 g,
47%). Melting point 167-169 ° C (recrystallized from ethanol). IR (KBr): 3280, 3240, 3204, 3129, 3083, 2990, 294
. 0, 1721, 1669, 1510 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.88 (6
H, s), 4.19 (2H, q, J = 7.1 Hz), 7.03 (1H, dd, J = 8.8
Hz, 4.2 Hz), 7.35 (1H, ddd, J = 8.8 Hz, 7.9 Hz, 2.9
Hz), 7.73 (1H, dd, J = 8.3 Hz, 2.9 Hz), 10.14 (1H,
bs). Elemental analysis: Calculated as C ₁₄ H ₁₅ N ₂ O ₄ F Calculated (%): C, 57.14; H, 5.14; N, 9.52 Found (%): C, 57.01; H, 5.01; N, 9.58

Reference Example 47 Ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (Method 3), From the ethyl 2- (2-amino-4-chlorobenzamido) isobutyrate (7.47 g, 26.2 mmol) obtained in Reference Example 24, the title compound (7.28 g, 8
9%). Melting point: 201-202 ° C (recrystallized from ethanol). IR (KBr): 3194, 3110, 3071, 2990, 2934, 2876, 173
. 4, 1715, 1663, 1620 , 1601 cm -1 1 H-NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.87 (6
H, s), 4.21 (2H, q, J = 7.2 Hz), 7.03 (1H, d, J = 1.8
Hz), 7.17 (1H, dd, J = 8.4 Hz, 1.8 Hz), 7.99 (1H, d,
J = 8.6 Hz), 9.77 (1H, bs). Elemental analysis: Calculated for C ₁₄ H ₁₅ N ₂ O ₄ Cl (%): C, 54.11; H, 4.87; N, 9.02 Actual (%): C, 54.06; H, 4.62; N, 9.13

Reference Example 48 Ethyl 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (Method 3), From the ethyl 2- (2-amino-5-chlorobenzamido) isobutyrate (3.12 g, 11.0 mmol) obtained in Reference Example 25, the title compound (1.88 g, 55
%) Were synthesized. 179-180 ° C (recrystallized from ethanol). IR (KBr): 3195, 3043, 2987, 2939, 1720, 1670, 161
^{. 7, 1500 cm -1 1 H} -NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.87 (6
H, s), 4.19 (2H, q, J = 7.1 Hz), 6.99 (1H, d, J = 8.6
Hz), 7.55 (1H, dd, J = 8.7 Hz, 2.5 Hz), 8.03 (1H, d,
J = 2.2 Hz), 10.08 (1H, bs). Elemental analysis: Calculated as C ₁₄ H ₁₅ N ₂ O ₄ Cl (%): C, 54.11; H, 4.87; N, 9.02 Observed (%): C, 53.99; H, 4.80; N, 9.06

Reference Example 49 1- (3-chloropropyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline sodium hydride (60% oily, 0.34 g ) Was obtained in Reference Example 26 in a suspension of N, N-dimethylformamide (30 ml).
2,4-Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (2.0 g) was added, and the mixture was stirred at room temperature for 30 minutes. To this was added 1-bromo-3-chloropropane (1.05 ml), and the mixture was further stirred for 13.5 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography,
Elution with n-hexane-ethyl acetate (5: 1, v / v) gave the title compound (1.58 g, 62%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 124-125 ° C. IR (Nujor):. 1700, 1645, 1600, 1500 cm -1 1 H-NMR (CDCl 3) δ: 2.14-2.30 (2H, m), 3.68 (2H, t,
J = 6.2 Hz), 3.77 (3H, s), 4.29 (2H, t, J = 7.6 Hz),
5.21 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.20-7.31 (2
H, m), 7.50 (2H, d, J = 8.8 Hz), 7.68 (1H, ddd, J = 8.
8, 7.0, 1.8 Hz), 8.26 (1H, dd, J = 8.4, 1.6 Hz). Elemental analysis: Calculated as C ₁₉ H ₁₉ N ₂ O ₃ Cl (%): C, 63.60; H, 5.34; N, 7.81 found (%): C, 63.52; H, 5.07; N, 7.90

Reference Example 50 1- (4-chlorobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline Obtained in 26
By reacting 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (4.84 g) with 4-bromo-1-chlorobutane, the title compound (4.54 g, 71 %) Were synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 123-124 ° C. IR (Nujor):. 1690, 1645, 1600, 1510, 1480 cm -1 1 H-NMR (CDCl 3) δ: 1.84-2.00 (4H, m), 3.61 (2H, t,
J = 5.8 Hz), 3.77 (3H, s), 4.16 (2H, t, J = 7.0 Hz),
5.21 (2H, s), 6.83 (2H, d, J = 8.8 Hz), 7.14-7.30 (2
H, m), 7.49 (2H, d, J = 8.8 Hz), 7.66 (1H, ddd, J = 8.
6, 7.0, 1.6 Hz), 8.25 (1H, dd, J = 7.8, 1.4 Hz). Elemental analysis: Calculated as C ₂₀ H ₂₁ N ₂ O ₃ Cl (%): C, 64.43; H, 5.68; N, 7.51 Found (%): C, 64.73; H, 5.80; N, 7.48

Reference Example 51 1- (5-chloropentyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline Obtained in Example 26
2,4-Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (5.00 g) was reacted with 5-bromo-1-chloropentane to give the title compound (7.54 g, ca. 100
%) Were synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 110-111 ° C. IR (KBr):. 1781, 1702, 1658, 1610, 1513, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.68 (2H, m), 1.68-1.94 (4
H, m), 3.55 (2H, t, J = 6.4 Hz), 3.77 (3H, s), 4.13
(2H, t, J = 7.8 Hz), 5.22 (2H, s), 6.84 (2H, d, J = 8.
6 Hz), 7.11 (1H, d, J = 8.4 Hz), 7.24 (1H, t, J = 8.0
Hz), 7.50 (2H, d, J = 8.8 Hz), 7.66 (1H, ddd, J = 8.6,
7.0, 1.6 Hz), 8.25 (1H, dd, J = 7.8, 1.4 Hz) Elemental analysis: Calculated as C ₂₁ H ₂₃ N ₂ O ₃ Cl (%): C, 65.20; H, 5.99; N, 7.24 Found (%): C, 64.86; H, 5.93; N, 7.26

Reference Example 52 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline sodium hydride (60% oily, 4.34 g) Was added to a suspension of N, N-dimethylformamide (100 ml) in 2,4-dioxo-3- (4-methoxybenzyl) -1,2,
Add 3,4-tetrahydroquinazoline (25.5 g) and add 2
Stir for hours. Add 1,4-dibromobutane (21.6
ml) of N, N-dimethylformamide (50 ml) was added dropwise, and the mixture was stirred at room temperature for 19 hours. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure to give the title compound (30.8 g, 82
%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 124-125 ° C. IR (KBr):. 2958, 1700, 1656, 1610, 1511, 1482 cm -1 1 H-NMR (CDCl 3) δ: 1.82-2.08 (4H, m), 3.48 (2H, t,
J = 6.2 Hz), 3.77 (3H, s), 4.16 (2H, t, J = 7.0 Hz),
5.21 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.16-7.30 (2
H, m), 7.50 (2H, d, J = 8.8 Hz), 7.67 (1H, ddd, J = 8.
8, 7.2, 1.6 Hz), 8.26 (1H, dd, J = 7.8, 1.4 Hz). Elemental analysis: Calculated as C ₂₀ H ₂₁ N ₂ O ₃ Br (%): C, 57.56; H, 5.07; N, 6.71 found (%): C, 57.52; H, 4.88; N, 6.76

Reference Example 53 1- (3-chloropropyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine In the same manner as in Example 49, obtained in Reference Example 27
Synthesis of the title compound (525 mg, 83%) from 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine (500 mg) did. Recrystallization from n-hexane-isopropyl ether gave colorless crystals having a melting point of 114-115 ° C. IR (Nujor):. 1700, 1660, 1590, 1510, 1480 cm -1 1 H-NMR (CDCl 3) δ: 2.16-2.32 (2H, m), 3.63 (2H, t,
J = 6.6 Hz), 3.77 (3H, s), 4.50 (2H, t, J = 7.4 Hz),
5.20 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.20 (1H, d
d, J = 7.8, 4.8 Hz), 7.50 (2H, d, J = 8.8 Hz), 8.46 (1
H, dd, J = 7.6, 1.8Hz), 8.64 (1H, dd, J = 4.8, 1.8 H
z). Elemental analysis: C ₁₈ H ₁₈ N ₃ O ₃ Cl Calculated (%): C, 60.09; H, 5.04; N, 11.68 Found (%): C, 59.81; H, 4.95; N, 11.47

Reference Example 54 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine Reference Example In the same manner as in Example 52, obtained in Reference Example 27
The title compound (12.8 g, about 100%) was obtained from 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine (8.00 g). Synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 80-82 ° C. IR (KBr):. 2962, 1714, 1668, 1600, 1515, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.80-2.02 (4H, m), 3.47 (2H, t,
J = 6.2 Hz), 3.77 (3H, s), 4.38 (2H, t, J = 6.8 Hz),
5.20 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.19 (1H, d
d, J = 7.8, 4.4 Hz), 7.49 (2H, d, J = 8.8 Hz), 8.46 (1
H, dd, J = 8.0, 1.8Hz), 8.63 (1H, dd, J = 4.8, 1.8 H
z). Elemental analysis: Calculated as C ₁₉ H ₂₀ N ₃ O ₃ Br (%): C, 54.56; H, 4.82; N, 10.05 Found (%): C, 54.49; H, 4.70; N, 10.08

Reference Example 55 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropteridine Obtained at 28
The title compound (3.92 g, 46 g) was obtained from 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropteridine (5.77 g).
%) Were synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 117-119 ° C. IR (KBr): 2961, 1721, 1672, 1611, 1582, 1547, 151
^{. 0, 1489 cm -1 1 H} -NMR (CDCl 3) δ: 1.80-2.04 (4H, m), 3.46 (2H, t,
J = 6.2 Hz), 3.77 (3H, s), 4.33 (2H, t, J = 7.0 Hz),
5.25 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.53 (2H, d,
J = 8.8 Hz), 8.58 (1H, d, J = 2.2 Hz), 8.61 (1H, d, J
= 2.2 Hz). Elemental analysis: Calculated for C ₁₈ H ₁₉ N ₄ O ₃ Br (%): C, 51.56; H, 4.57; N, 13.36 Found (%): C, 51.80; H, 4.44; N, 13.50

Reference Example 56 1- (4-bromobutyl) -7-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline A method similar to that in Reference Example 52. As a result, the product was obtained in Reference Example 29.
7-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,
The title compound from 3,4-tetrahydroquinazoline (5.00 g)
(8.32 g, about 100%) was synthesized. Recrystallization from ethyl acetate-n-hexane gave colorless crystals having a melting point of 107-109 ° C. IR (KBr): 2958, 1708, 1662, 1606, 1583, 1513, 1494
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.85-2.08 (4H, m), 3.49 (2H, t,
J = 6.4 Hz), 3.77 (3H, s), 4.11 (2H, t, J = 5.2 Hz),
5.19 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.17-7.24 (2
H, m), 7.48 (2H, d, J = 8.8 Hz), 8.18 (1H, d, J = 8.8
Elemental analysis: C ₂₀ H ₂₀ N ₂ O ₃ BrCl Calculated (%): C, 53.18; H, 4.46; N, 6.20 Found (%): C, 53.76; H, 4.45; N, 6.34

Reference Example 57 1- (4-Bromobutyl) -6-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline A method similar to that in Reference Example 52. Thus, obtained in Reference Example 30
6-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,
The title compound from 3,4-tetrahydroquinazoline (5.00 g)
(5.35 g, 75%) was synthesized. Recrystallization from ethyl acetate-n-hexane gave colorless crystals having a melting point of 146-147 ° C. IR (KBr): 2958, 1704, 1662, 1610, 1587. 1511, 149
^{. 0, 1463 cm -1 1 H} -NMR (CDCl 3) δ: 1.78-2.06 (4H, m), 3.47 (2H, t,
J = 6.2 Hz), 3.77 (3H, s), 4.13 (2H, t, J = 7.2 Hz),
5.19 (2H, s), 6.83 (2H, d, J = 8.8 Hz), 7.13 (1H, d,
J = 8.8Hz), 7.47 (2H, d, J = 8.4 Hz), 7.60 (1H, dd, J
= 9.2, 2.6 Hz), 8.21 (1H, d, J = 2.6 Hz) Elemental _{analysis: C 20 H 20 N 2 O} 3 BrCl · 0.5H 2 O Calculated (%):. C, 52.14 ; H, 4.59; N, 6.08 Found (%): C, 52.11; H, 4.24; N, 6.18

Reference Example 58 1- (4-Bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -7-nitro-1,2,3,4-tetrahydroquinazoline A method similar to that in Reference Example 52. Thus, obtained in Reference Example 31
2,4-dioxo-3- (4-methoxybenzyl) -7-nitro-1,2,
From 3,4-tetrahydroquinazoline (6.84 g), the title compound (1
1.1 g, about 100%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 122-123 ° C. IR (KBr): 2962, 1710, 1666, 1625, 1598, 1538, 151
^{. 3, 1469 cm -1 1 H} -NMR (CDCl 3) δ: 1.84-2.12 (4H, m), 3.49 (2H, t,
J = 6.2 Hz), 3.78 (3H, s), 4.22 (2H, t, J = 7.0 Hz),
5.21 (2H, s), 6.84 (2H, d, J = 8.8 Hz), 7.49 (2H, d,
J = 8.4 Hz), 8.00-8.09 (2H, m), 8.43 (1H, d, J = 9.2
. Hz) Elemental _{analysis: C 20 H 20 N 3 O} 5 Br Calculated (%): C, 51.96; H, 4.36; N, 9.09 Found (%): C, 51.72; H, 4.27; N, 8.96

Reference Example 59 1- (4-Bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -6-nitro-1,2,3,4-tetrahydroquinazoline A method similar to that in Reference Example 52. As a result, obtained in Reference Example 32
2,4-dioxo-3- (4-methoxybenzyl) -6-nitro-1,2,
The title compound from 3,4-tetrahydroquinazoline (4.68 g)
(6.05 g, 92%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave yellow crystals having a melting point of 143-144 ° C. IR (KBr):. 2961, 1715, 1667, 1615, 1514, 1497 cm -1 1 H-NMR (CDCl 3) δ: 1.82-2.10 (4H, m), 3.49 (2H, t,
J = 5.8 Hz), 3.78 (3H, s), 4.20 (2H, t, J = 7.0 Hz),
5.21 (2H, s), 6.85 (2H, d, J = 8.8 Hz), 7.32 (1H, d,
J = 9.6 Hz), 7.49 (2H, d, J = 8.8 Hz), 8.50 (1H, dd,
J = 9.0, 3.0 Hz), 9.12 (1H, d, J = 3.8 Hz). Elemental analysis: Calculated as C ₂₀ H ₂₀ N ₃ O ₅ Br (%): C, 51.96; H, 4.36; N, 9.09 found (%): C, 51.85; H, 4.11; N, 9.06

Reference Example 60 1- (4-Bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -6-methyl-1,2,3,4-tetrahydroquinazoline A method similar to that in Reference Example 52. As a result, the product was obtained in Reference Example 33.
2,4-dioxo-3- (4-methoxybenzyl) -6-methyl-1,2,
The title compound from 3,4-tetrahydroquinazoline (5.00 g)
(6.21 g, 85%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 164-165 ° C. IR (KBr):. 2959, 1698, 1659, 1590, 1510 cm -1 1 H-NMR (CDCl 3) δ: 1.80-2.04 (4H, m), 2.40 (3H,
s), 3.47 (2H, t, J = 6.2 Hz), 3.77 (3H, s), 4.13 (2
H, t, J = 7.4 Hz), 5.21 (2H, s), 6.83 (2H, d, J = 8.4
Hz), 7.08 (1H, d, J = 8.6 Hz), 7.44-7.53 (3H, m), 8.
04 (1H, s). Elemental analysis: Calculated as C ₂₁ H ₂₃ N ₂ O ₃ Br Calculated (%): C, 58.48; H, 5.37; N, 6.49 Found (%): C, 58.56; H, 5.30; N, 6.52

Reference Example 61 Methyl 1- (3-chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate Obtained in Reference Example 34 in the same manner as in Reference Example 49. Was
The title compound (1.81 g, 34%) was synthesized from methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate (4.08 g). Recrystallization from ethyl acetate-ethyl ether gave a melting point of 1.
Colorless crystals at 44-146 ° C were obtained. IR (Nujor):. 1750, 1700, 1660, 1610 cm -1 1 H-NMR (CDCl 3) δ: 2.16-2.32 (2H, m), 3.69 (2H, t,
J = 6.0 Hz), 3.78 (3H, s), 4.32 (2H, t, J = 7.6Hz), 4.
86 (2H, s), 7.24-7.38 (2H, m), 7.73 (1H, ddd, J = 8.
6, 7.2, 1.4 Hz), 8.26 (1H, dd, J = 7.6, 1.2 Hz). Elemental analysis: C ₁₄ H ₁₅ N ₂ O ₄ Cl Calculated (%): C, 54.11; H, 4.87; N, 9.02 found (%): C, 53.80; H, 4.75; N, 9.31

Reference Example 62 Methyl 1- (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate Obtained in Reference Example 34 in the same manner as in Reference Example 49. Was
The title compound (2.21 g, 53%) was synthesized from methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate (3.00 g). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 119-120 ° C. IR (KBr):. 1756, 1704, 1668, 1610, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.88-2.00 (4H, m), 3.62 (2H, t,
J = 5.8 Hz), 3.78 (3H, s), 4.19 (2H, t, J = 7.0 Hz),
4.86 (2H, s), 7.22-7.34 (2H, m), 7.72 (1H, ddd, J =
8.6, 7.0, 1.6 Hz), 8.26 (1H, dd, J = 7.8, 1.6 Hz). Elemental analysis: Calculated as C ₁₅ H ₁₇ N ₂ O ₄ Cl (%): C, 55.48; H, 5.28; N, 8.63 Found (%): C, 55.01; H, 5.01; N, 8.34

Reference Example 63 Ethyl 1- (3-chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate In the same manner as in Reference Example 49, Reference Example 35 was prepared. Got
Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate (3.00 g) to give the title compound (1.85 g, 48%)
Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 80-81 ° C. IR (Nujor):. 1720, 1690, 1660, 1600 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 2.13-2.
35 (2H, m), 2.72 (2H, t, J = 7.6 Hz), 3.70 (2H, t, J =
6.0 Hz), 4.14 (2H, q, J = 7.2 Hz), 4.31 (2H, t, J = 7.6
Hz), 4.41 (2H, t, J = 7.2 Hz), 7.22-7.36 (2H, m), 7.
70 (1H, ddd, J = 8.8, 7.2, 1.6 Hz), 8.25 (1H, dd, J =
8.0, 1.4 Hz). Elemental analysis: C ₁₆ H ₁₉ N ₂ O ₄ Cl ・ 0.2H ₂ O Calculated (%): C, 56.13; H, 5.71; N, 8.18 Actual (%): C, 55.91; H, 5.40; N, 8.17

Reference Example 64 Ethyl 1- (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate Obtained in Reference Example 35 in the same manner as in Reference Example 49. Was
The title compound (5.40 g, 80%) was obtained from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate (5.00 g).
Was synthesized. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 71-72 ° C. IR (KBr):. 1733, 1699, 1662, 1608, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.4 Hz), 1.86-1.
98 (4H, m), 2.71 (2H, t, J = 7.6 Hz), 3.60-3.66 (2H,
m), 4.14 (2H, q, J = 7.0 Hz), 4.10-4.23 (2H, m), 4.40
(2H, t, J = 7.4 Hz), 7.16-7.30 (2H, m), 7.69 (1H,
t, J = 7.0 Hz), 8.24 (1H, dd, J = 7.8, 1.4 Hz). Elemental analysis: Calculated as C ₁₇ H ₂₁ N ₂ O ₄ Cl (%): C, 56.43; H, 6.13; N, 7.74 Found (%): C, 56.39; H, 5.87; N, 7.70

Reference Example 65 Ethyl 1- (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-butyrate Obtained in Reference Example 36 by the same method as in Reference Example 49. Was
The title compound (13.8 g, about 100%) was obtained as an oil from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-butyrate (8.00 g). ¹ H-NMR (CDCl ₃ ) d: 1.23 (3H, t, J = 7.2 Hz), 1.88-2.1
4 (6H, m), 2.40 (2H, t, J = 7.6 Hz), 3.40-3.56 (2H,
m), 4.02-4.22 (6H, m), 7.18-7.30 (2H, m), 7.69 (1
H, ddd, J = 8.6, 6.8, 1.8 Hz), 8.24 (1H, dd, J = 8.0,
1.6 Hz).

Reference Example 66 1- (3-chloropropyl) -2,4-dioxo-3-methyl-1,2,3,4
-Tetrahydroquinazoline obtained in Reference Example 37 by a method similar to that of Reference Example 49.
The title compound (1.34 g, 28%) was synthesized from 2,4-dioxo-3-methyl-1,2,3,4-tetrahydroquinazoline (3.34 g). ¹ H-NMR (CDCl ₃ ) δ: 2.16-2.32 (2H, m), 3.49 (3H,
s), 3.70 (2H, t, J = 6.2 Hz), 4.32 (2H, t, J = 1.8 H
z), 7.24-7.36 (2H, m), 7.70 (1H, ddd, J = 8.6, 7.0,
1.6 Hz), 8.26 (1H, dd, J = 7.8, 1.4 Hz).

Reference Example 67 1- (4-chlorobutyl) -2,4-dioxo-3-methyl-1,2,3,4-
Tetrahydroquinazoline obtained in Reference Example 37 by a method similar to Reference Example 49.
The title compound (1.93 g, 43%) was synthesized from 2,4-dioxo-3-methyl-1,2,3,4-tetrahydroquinazoline (3.00 g).
Recrystallized from ethyl acetate-ethyl ether, melting point 99-100
C. Colorless crystals were obtained. IR (KBr):. 1699, 1652, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.88-2.00 (4H, m), 3.49 (3H,
s), 3.58-3.64 (2H, m), 4.14-4.26 (2H, m), 7.18-7.3
2 (2H, m), 7.69 (1H, ddd, J = 8.6, 7.0, 1.6 Hz), 8.25
. (1H, d, J = 7.6 Hz) Elemental _{analysis: C 13 H 15 N 2 O} 2 Calculated Cl (%): C, 58.54 ; H, 5.67; N, 10.50 Found (%): C, 58.07; H, 5.56; N, 10.39

Reference Example 68 1- (3-Chloropropyl) -3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline In the same manner as in Reference Example 49, Obtained in Reference Example 38.
From 3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (4.00 g), the title compound (3.20 g, 59
%) As an oil. ¹ H-NMR (CDCl ₃ ) d: 1.74 (9H, s), 2.12-2.28 (2H, m),
3.68 (2H, t, J = 6.2 Hz), 4.21 (2H, t, J = 7.4 Hz),
7.14-7.24 (2H, m), 7.62 (1H, ddd, J = 9.2, 7.4,1.8 H
z), 8.09 (1H, dd, J = 8.2, 1.6 Hz).

Reference Example 69 1- (4-chlorobutyl) -3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline In the same manner as in Reference Example 49, Obtained in Reference Example 38
From 3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (4.00 g), the title compound (7.05 g, about 100%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.74 (9H, s), 1.82-2.04 (4H,
m), 3.55-3.68 (2H, m), 4.03-4.12 (2H, m), 7.10 (1
H, d, J = 8.4 Hz), 7.18 (1H, t, J = 7.6 Hz), 7.60 (1H,
ddd, J = 8.4, 7.4, 1.0 Hz), 8.08 (1H, dd, J = 8.2, 1.
4 Hz).

Reference Example 70 1- (4-Bromobutyl) -2,4-dioxo-3- (3-pyridinylmethyl) -1,2,3,4-tetrahydroquinazoline A method similar to that of Reference Example 52 was synthesized. , Reference Example 3
2,4-dioxo-3- (3-pyridinylmethyl) -1, obtained in 9
The title compound from 2,3,4-tetrahydroquinazoline (4.00 g)
(1.57 g, 26%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.84-2.08 (4H, m), 3.48 (2H, t,
J = 6.4 Hz), 4.16 (2H, t, J = 7.0 Hz), 5.28 (2H, s),
7.18-7.32 (3H, m), 7.69 (1H, ddd, J = 8.4, 7.0, 1.4
Hz), 7.86 (1H, d, J = 8.0 Hz), 8.25 (1H, dd, J = 8.0,
1.2 Hz), 8.51 (1H, d, J = 3.4 Hz), 8.78 (1H, s).

Reference Example 71 1- (4-bromobutyl) -2,4-dioxo-3-phenyl-1,2,3,4
-Tetrahydroquinazoline obtained in Reference Example 40 by a method similar to Reference Example 52.
The title compound (8.20 g, about 100%) was obtained from 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazoline (4.00 g) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.84-2.16 (4H, m), 3.38-3.54 (2
H, m), 4.21 (2H, t, J = 7.0 Hz), 7.24-7.35 (4H, m),
7.44-7.59 (3H, m), 7.75 (1H, t, J = 8.0 Hz), 8.29 (1
(H, d, J = 7.4 Hz).

Reference Example 72 1- (4-bromobutyl) -3-cyclohexyl-2,4-dioxo-
1,2,3,4-tetrahydroquinazoline In the same manner as in Reference Example 52, obtained in Reference Example 41.
From 3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (4.00 g) to the title compound (6.84 g, about 100%)
Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.12 (12H, m), 2.46-2.60
(2H, m), 3.40-3.54 (2H, m), 4.13 (2H, t, J = 7.4 Hz),
4.82-5.02 (1H, m), 7.12-7.28 (2H, m), 7.65 (1H, dd
d, J = 8.8, 7.0, 1.8 Hz), 8.22 (1H, dd, J = 8.0, 1.4 H
z).

Reference Example 73 Ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate In the same manner as in Reference Example 52, Obtained in Reference Example 42
2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Yl) ethyl isobutyrate (2.21 g) to give the title compound (2.86 g,
87%). Recrystallization from ethyl acetate-n-hexane gave colorless crystals having a melting point of 113-114 ° C. IR (KBr):. 1741, 1708, 1664, 1608 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.85 (6
H, s), 1.87-2.04 (4H, m), 3.48 (2H, t, J = 6.2 Hz),
4.11 (2H, t, J = 7.2 Hz), 4.20 (2H, q, J = 7.1 Hz), 7.
16-7.28 (2H, m), 7.63-7.71 (1H, m), 8.16 (1H, dd,
J = 7.8 Hz, 1.6 Hz). Elemental analysis: Calculated as C ₁₈ H ₂₃ N ₂ O ₄ Br (%): C, 52.57; H, 5.64; N, 6.81 Found (%): C, 52.76; H, 5.52; N, 6.90

Reference Example 74 Methyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate In the same manner as in Reference Example 52, Obtained in Reference Example 43
2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Yl) methyl isobutyrate (1.31 g) from the title compound (1.37 g,
69%) as an oil. IR (KBr):. 1747, 1708, 1662, 1608 cm -1 1 H-NMR (CDCl 3) δ: 1.85 (6H, s), 1.89-2.02 (4H,
m), 3.48 (2H, t, J = 6.3 Hz), 3.72 (3H, s), 4.08-4.1
8 (2H, m), 7.16-7.29 (2H, m), 7.63-7.72 (1H, m),
8.16 (1H, dd, J = 7.9 Hz, 1.7 Hz).

Reference Example 75 2- [1- (4-bromobutyl) -2,4-dioxo-6-methyl-1,2,3,
Ethyl 4-tetrahydroquinazolin-3-yl] isobutyrate Obtained in Reference Example 44 by a method similar to Reference Example 52.
The title compound from ethyl 2- (2,4-dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (0.58 g)
(0.57 g, 67%) as an oil. IR (KBr): 2990, 2940, 1744, 1705, 1665, 1624, 159
^{. 5, 1508 cm -1 1 H} -NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.84 (6
H, s), 1.85-2.05 (4H, m), 3.40 (3H, s), 3.47 (2H,
t, J = 6.2 Hz), 4.04-4.11 (2H, m), 4.19 (2H, q, J = 7.
2 Hz), 7.07 (1H, d, J = 8.6 Hz), 7.47 (1H, dd, J = 8.4
Hz, 1.8 Hz), 7.95 (1H, d, J = 1.4 Hz).

Reference Example 76 2- [1- (4-bromobutyl) -2,4-dioxo-6-nitro-1,2,3,
Ethyl 4-tetrahydroquinazolin-3-yl] isobutyrate Obtained in Reference Example 45 by a method similar to Reference Example 52.
The title compound from ethyl 2- (2,4-dioxo-6-nitro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (0.64 g)
(0.30 g, 33%) was obtained as an oil. IR (KBr): 2984, 2942, 1742, 1717, 1674, 1615, 1530
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.85 (6
H, s), 1.86-2.05 (4H, m), 3.50 (2H, t, J = 6.0 Hz),
4.12-4.19 (2H, m), 4.21 (2H, q, J = 7.2 Hz), 7.31 (1
H, d, J = 9.2 Hz), 8.51 (1H, dd, J = 9.2 Hz, 2.6 Hz),
9.02 (1H, d, J = 2.6 Hz).

Reference Example 77 2- [1- (4-bromobutyl) -2,4-dioxo-6-fluoro-1,2,
Ethyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate Obtained in Reference Example 46 by a method similar to Reference Example 52.
The title compound (0.58 g, 68%) from ethyl 2- (2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (0.59 g). IR (KBr) : 2986, 2940, 1742, 1709, 1667, 1624, 1505
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.84 (6
H, s), 1.85-2.07 (4H, m), 3.48 (2H, t, J = 6.2 Hz),
4.05-4.12 (2H, m), 4.20 (2H, q, J = 7.2 Hz), 7.16 (1
H, dd, J = 4.0 Hz, 9.2 Hz), 7.40 (1H, ddd, J = 9.2 Hz,
7.6 Hz, 3.0 Hz), 7.83 (1H, dd, J = 8.2 Hz, 3.0 Hz).

Reference Example 78 2- [1- (4-bromobutyl) -7-chloro-2,4-dioxo-1,2,3,
Ethyl 4-tetrahydroquinazolin-3-yl] isobutyrate Obtained in Reference Example 47 by a method similar to Reference Example 52.
The title compound from ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (0.62 g)
. (0.50 g, 56%) IR (KBr):. 2984, 2940, 1744, 1713, 1667, 1605 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.83 (6
H, s), 1.85-2.06 (4H, m), 3.49 (2H, t, J = 6.2 Hz),
4.03-4.10 (2H, m), 4.19 (2H, q, J = 7.2 Hz), 7.17-7.
23 (2H, m, ArH), 8.08 (2H, d, J = 8.2 Hz).

Reference Example 79 2- [1- (4-bromobutyl) -6-chloro-2,4-dioxo-1,2,3,
Ethyl 4-tetrahydroquinazolin-3-yl] isobutyrate Obtained in Reference Example 48 by a method similar to Reference Example 52.
The title compound from ethyl 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (0.62 g)
(0.62 g, 70%) was obtained as an oil. IR (KBr): 2984, 2940, 1742, 1711, 1667, 1609, 1591
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.83 (6
H, s), 1.85-2.05 (4H, m), 3.48 (2H, t, J = 6.2 Hz),
4.08 (2H, t, J = 7.2 Hz), 4.19 (2H, q, J = 7.2 Hz), 7.
13 (1H, d, J = 8.8 Hz), 7.61 (1H, dd, J = 8.8 Hz, 2.6
Hz), 8.12 (1H, d, J = 2.6 Hz).

Reference Example 80 Ethyl 2- [1- (3-bromopropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate In the same manner as in Reference Example 52, Obtained in Reference Example 42.
The title compound was obtained from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.55 g, 2.0 mmol).
(0.53 g, 67%) as an oil. IR (KBr):. 2982, 2940, 1742, 1709, 1663, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.85 (6
H, s), 2.22-2.37 (2H, m), 3.52 (2H, t, J = 6.3 Hz),
4.16-4.27 (4H, m), 7.26-7.29 (2H, m, ArH), 7.64-7.
73 (1H, m, ArH), 8.16 (1H, dd, J = 8.2 Hz, 1.6 Hz).

Reference Example 81 Ethyl 2- [1- (5-bromopentyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Reference Example 52 was synthesized. In the same manner, Reference Example 4
The title compound (0.63 g, 74%) was obtained as an oil from the ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.55 g, 2.0 mmol) obtained in Step 2. Obtained. IR (KBr): 2990, 2938, 2867, 1742, 1707, 1665, 1609
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.53-2.
01 (6H, m), 1.85 (6H, s), 3.43 (2H, t, J = 6.7 Hz),
4.07 (2H, t, J = 8.6 Hz), 4.19 (2H, q, J = 7.2 Hz), 7.
12-7.27 (2H, m, ArH), 7.62-7.70 (1H, m, ArH), 8.16
(1H, dd, J = 7.9Hz, 1.7 Hz).

Reference Example 82 Ethyl 2- [1- (6-bromohexyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate The same method as in Reference Example 52 was used. Obtained in Reference Example 42.
The title compound was obtained from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.55 g, 2.0 mmol).
(0.66 g, 75%) was obtained as an oil. IR (KBr): 2984, 2936, 2863, 1744, 1709, 1663, 1609
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.40-1.
93 (8H, m), 1.84 (6H, s), 3.42 (2H, t, J = 6.6 Hz),
4.01-4.09 (2H, m), 4.19 (2H, q, J = 7.1 Hz), 7.12-7.
27 (2H, m, ArH), 7.61-7.70 (1H, m, ArH), 8.15 (1H,
(dd, J = 7.8 Hz, 1.6 Hz).

Reference Example 83 1- (3-chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline 1- (3-chloropropyl) -2,4 obtained in Reference Example 49 -Dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (3.02 g) was added to acetonitrile (80 ml) and water (16 m
The mixture was dissolved in the mixed solvent of l), and cerium (IV) ammonium nitrate (9.23 g) was added thereto little by little. Reaction mixture at room temperature
After stirring for 21 hours, the solvent was distilled off under reduced pressure. The residue was extracted with ethyl acetate, and the extract was washed with water and dried (Na ₂ SO ₄ )
Thereafter, the solvent was distilled off under reduced pressure to give the title compound (1.42 g, 71%).
I got Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 183-184 ° C. IR (Nujor):. 1690, 1600 cm -1 1 H-NMR (CDCl 3) d: 2.15-2.30 (2H, m), 3.70 (2H, t,
J = 6.2 Hz), 4.29 (2H, t, J = 7.6 Hz), 7.29-7.38 (2H,
m), 7.74 (1H, ddd, J = 9.0, 7.6, 1.4 Hz), 8.23 (1H, d
d, J = 7.8, 1.6 Hz). Elemental analysis: C ₁₁ H ₁₁ N ₂ O ₂ Cl Calculated (%): C, 55.36; H, 4.65; N, 11.74 Observed (%): C, 55.18 ; H, 4.47; N, 11.70

Reference Example 84 1- (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline Obtained in Reference Example 50 in the same manner as in Reference Example 83.
The title compound (2.28 g, 74%) was synthesized from 1- (4-chlorobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (4.54 g). . Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 127-128 ° C. IR (Nujor):. 1710, 1660, 1600 cm -1 1 H-NMR (CDCl 3) δ: 1.90-2.00 (4H, m), 3.63 (2H, t,
J = 6.0 Hz), 4.16 (2H, t, J = 7.0 Hz), 7.20-7.34 (2H,
m), 7.73 (1H, ddd, J = 8.6, 7.0, 1.6 Hz), 8.24 (1H,
dd, J = 7.8, 1.6 Hz). Elemental analysis: C ₁₂ H ₁₃ N ₂ O ₂ Cl Calculated (%): C, 57.04; H, 5.19; N, 11.09 Found (%): C, 56.97 ; H, 5.03; N, 11.26

Reference Example 85 1- (5-chloropentyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline Obtained in Reference Example 51 in the same manner as in Reference Example 83.
Synthesis of the title compound (2.37 g, 57%) from 1- (5-chloropentyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (6.00 g) did. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 162-163 ° C. IR (KBr): 3170, 3039, 2954, 2864, 1704, 1695, 161
^{. 0, 1500, 1484 cm -1} 1 H-NMR (CDCl 3) δ: 1.50-1.68 (2H, m), 1.68-1.92 (4
H, m), 3.57 (2H, t, J = 6.6 Hz), 4.12 (2H, t, J = 7.6
Hz), 7.21 (1H, d, J = 8.4 Hz), 7.28 (1H, t, J = 7.8 H
z), 7.71 (1H, ddd, J = 8.4, 6.6, 1.8 Hz), 8.23 (1H,
dd, J = 7.8, 1.8 Hz). Elemental analysis: Calculated as C ₁₃ H ₁₅ N ₂ O ₂ Cl ・ 0.1H ₂ O (%): C, 58.15; H, 5.71; N, 10.43 Actual (% ): C, 57.93; H, 5.73; N, 10.39

Reference Example 86 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline Obtained in Reference Example 52 by the same method as in Reference Example 83.
The title compound (5.11 g, 81%) was synthesized from 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (8.83 g). . Recrystallization from ethyl acetate gave colorless crystals having a melting point of 152-153 ° C. IR (KBr): 3176, 3043, 2842, 1704, 1683, 1608, 1482
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.84-2.10 (4H, m), 3.50 (2H, t,
J = 6.2 Hz), 4.16 (2H, t, J = 7.4 Hz), 7.25 (1H, d, J =
7.8 Hz), 7.29 (1H, t, J = 7.6 Hz), 7.72 (1H, ddd, J =
8.4, 7.2, 1.2 Hz), 8.24 (1H, dd, J = 8.2, 1.6 Hz). Elemental analysis: C ₁₂ H ₁₃ N ₂ O ₂ Br ・ 0.2H ₂ O Calculated (%): C, 47.92 ; H, 4.49; N, 9.31 Found (%): C, 47.94; H, 4.43; N, 9.37

Reference Example 87 1- (3-chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine In the same manner as in Reference Example 83, Obtained in Example 53
1- (3-chloropropyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine (1.72 g) to give the title compound (918 mg, 80%) was synthesized.
Recrystallized from ethyl acetate-isopropyl ether and melting point>
Colorless crystals at 300 ° C. were obtained. IR (Nujor): 3150, 1710, 1695, 1670, 1590, 1485 cm
^{. -1 1 H-NMR (CDCl} 3) δ: 2.28-2.34 (2H, m), 3.65 (2H, t,
J = 6.6 Hz), 4.49 (2H, t, J = 7.6 Hz), 7.20-7.30 (1H,
m), 8.46 (1H, dd, J = 8.0, 2.0 Hz), 8.70 (1H, dd, J =
4.8, 2.2 Hz). Elemental analysis: C ₁₀ H ₁₀ N ₃ O ₂ Cl Calculated (%): C, 50.12; H, 4.21; N, 17.53 Found (%): C, 50.62; H, 3.99 ; N, 17.38

Reference Example 88 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine In the same manner as in Reference Example 83, Obtained at 54
1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine
(15.0 g) to give the title compound (6.10 g, 57%). Recrystallized from ethyl acetate-ethyl ether, mp 139-141 ℃
To obtain colorless crystals. IR (KBr):. 3043, 1704, 1699, 1600, 1587, 1488 cm -1 1 H-NMR (CDCl 3) δ: 1.80-2.08 (4H, m), 3.48 (2H, t,
J = 6.6 Hz), 4.35 (2H, t, J = 7.0Hz), 7.19-7.26 (1H,
m), 8.45 (1H, dd, J = 7.8, 1.8 Hz), 8.69 (1H, dd, J =
4.68, 1.8 Hz). Elemental analysis: Calculated as C ₁₁ H ₁₂ N ₃ O ₂ Br (%): C, 44.32; H, 4.06; N, 14.09 Found (%): C, 44.44; H, 4.11 ; N, 14.03

Reference Example 89 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydropteridine Obtained in Reference Example 55 by a method similar to that in Reference Example 83.
The title compound (1.70 g, 62%) was synthesized from 1- (4-bromobutyl) -2.4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydropteridine (3.82 g). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 154-155 ° C. IR (KBr): 3196, 3075, 2965, 1715, 1578, 1547, 1489
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.84-2.04 (4H, m), 3.48 (2H, t,
J = 6.2 Hz), 4.34 (2H, t, J = 7.0 Hz), 8.63 (1H, d, J =
2.2 Hz), 8.68 (1H, d, J = 2.2 Hz), 9.06 (1H, bs). Elemental analysis: Calculated as C ₁₀ H ₁₁ N ₄ O ₂ Br (%): C, 40.15; H, 3.71 ; N, 18.73 Found (%): C, 40.33; H, 3.73; N, 18.55

Reference Example 90 1- (4-bromobutyl) -7-chloro-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline was obtained in Reference Example 56 in the same manner as in Reference Example 83.
1- (4-bromobutyl) -7-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (6.32
g) to give the title compound (1.94 g, 42%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 180-182 ° C. IR (KBr): 3163, 3041, 2842, 1699, 1579, 1498 cm ^-1 .
¹ H-NMR (CDCl ₃ ) δ: 1.87-2.10 (4H, m), 3.51 (2H,
t, J = 6.2 Hz), 4.12 (2H, t, J = 7.4 Hz), 7.22-7.30 (2
H, m), 8.16 (1H, d, J = 9.0 Hz), 8.71 (1H, bs). Elemental analysis: C ₁₂ H ₁₂ N ₂ O ₂ BrCl Calculated (%): C, 43.47; H, 3.65; N, 8.45 Found (%): C, 43.67; H, 3.67; N, 8.48

Reference Example 91 1- (4-bromobutyl) -6-chloro-2,4-dioxo-1,2,3,4-
Tetrahydroquinazoline was obtained in Reference Example 57 in the same manner as in Reference Example 83.
1- (4-bromobutyl) -6-chloro-2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (8.00
g) to give the title compound (3.39 g, 58%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 154-156 ° C. IR (KBr): 3055, 1699, 1683, 1610, 1583, 1488, 1471
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.82-2.10 (4H, m), 3.49 (2H, t,
J = 6.2 Hz), 4.14 (2H, t, J = 7.4 Hz), 7.20 (1H, d, J =
9.0 Hz), 7.67 (1H, dd, J = 9.0, 2.6 Hz), 8.20 (1H, d,
J = 2.4 Hz), 9.19 (1H, bs). Elemental analysis: C ₁₂ H ₁₂ N ₂ O ₂ BrCl Calculated (%): C, 43.47; H, 3.65; N, 8.45 Found (%): C, 43.17; H, 3.52; N, 8.27

Reference Example 92 1- (4-bromobutyl) -2,4-dioxo-7-nitro-1,2,3,4-
Tetrahydroquinazoline was obtained in Reference Example 58 in the same manner as in Reference Example 83.
1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -7-nitro-1,2,3,4-tetrahydroquinazoline (11.1
g) to give the title compound (4.14 g, 50%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 202-203 ° C. IR (KBr): 3047, 1720, 1699, 1623, 1594, 1538, 1478
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.88-2.16 (4H, m), 3.51 (2H, t,
J = 6.0 Hz), 4.23 (2H, t, J = 7.0 Hz), 8.06-8.14 (2H,
m), 8.42 (1H, d, J = 8.4 Hz), 8.81 (1H, bs) Elemental analysis: C ₁₂ H ₁₂ N ₃ O ₄ Br Calculated (%): C, 42.13; H, 3.54; N, 12.28 found (%): C, 42.35; H, 3.67; N, 12.23

Reference Example 93 1- (4-bromobutyl) -2,4-dioxo-6-nitro-1,2,3,4-
In the same manner as in Tetrahydroquinazoline Reference Example 83, 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -6-nitro-1,2,3 obtained in Reference Example 59 , 4-tetrahydroquinazoline (16.0 g) from the title compound (5.19
g, 44%) as crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.86-2.14 (4H, m), 3.51 (2H, t,
J = 5.8 Hz), 4.21 (2H, t, J = 7.4 Hz), 7.40 (1H, d, J =
9.2 Hz), 8.56 (1H, dd, J = 9.6, 2.6 Hz), 8.97 (1H, b
s), 9.09 (1H, d, J = 2.4 Hz).

Reference Example 94 1- (4-bromobutyl) -2,4-dioxo-6-methyl-1,2,3,4-
Tetrahydroquinazoline In the same manner as in Reference Example 83, 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -6-methyl-1,2,3 obtained in Reference Example 60 The title compound (940 m) was obtained from 2,4-tetrahydroquinazoline (2.53 g).
g, 52%) as crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.82-2.12 (4H, m), 2.42 (3H,
s), 3.49 (2H, t, J = 6.2 Hz), 4.14 (2H, t, J = 7.4 H
z), 7.14 (1H, d, J = 8.6 Hz), 7.53 (1H, dd, J = 8.4, 2.
2 Hz), 8.04 (1H, d, J = 1.4 Hz), 8.86 (1H, bs).

Reference Example 95 2,4-Dioxo-3- (2-hydroxyethyl) -1,2,3,4-tetrahydroquinazoline Lithium borohydride (1.12 g) was added to tetrahydrofuran (1
00 ml) and stirred under ice-cooling to give Reference Example 34.
The methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate (6.00 g) obtained in the above was added little by little. The reaction mixture was stirred at room temperature for 21 hours, and then acidified with 1N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, methanol and ethyl ether to give the title compound (4.41 g, 84%). Recrystallized from ethyl acetate-ethyl ether, melting point 240
Colorless crystals at -242 ° C were obtained. IR (Nujor): 3370, 1710, 1660, 1610, 1600, 1510, 14
^{. 85 cm -1 1 H-NMR} (CDCl 3) δ: 3.87 (2H, t, J = 5.8 Hz), 4.29 (2
H, t, J = 5.4 Hz), 7.10-7.24 (2H, m), 7.55 (1H, t, J
= 8.0 Hz), 8.07 (1H, d, J = 8.4 Hz), 11.05 (1H, bs) .Elemental analysis: C ₁₀ H ₁₀ N ₂ O ₃・ 0.1H ₂ O Calculated (%): C, 57.74; H, 4.94; N, 13.47 Found (%): C, 57.53; H, 5.20; N, 13.52

Reference Example 96 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
2,4-Dioxo-3- (2-hydroxyethyl) -1,2,3,4-tetrahydroquinazoline (2.50 g) obtained in Reference Example 95 was suspended in pyridine (50.0 ml). Then, benzoyl chloride (1.55 ml) was added dropwise. After stirring the reaction mixture at room temperature for 16 hours, the solvent was distilled off under reduced pressure and 1N
Neutralized with hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (3.27 g, 87%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 196-197 ° C. IR (KBr):. 3072, 1720, 1664, 1621, 1608, 1492 cm -1 1 H-NMR (CDCl 3) δ: 4.52-4.59 (2H, m), 4.61-4.69 (2
H, m), 7.00 (1H, d, J = 8.4 Hz), 7.18-7.34 (3H, m),
7.41 (1H, d, J = 7.0 Hz), 7.59 (1H, t, J = 8.4 Hz), 7.
97 (2H, d, J = 7.2 Hz), 8.13 (1H, d, J = 8.0 Hz) Elemental analysis: C ₁₇ H ₁₄ N Calculated _{2 O 4 (%):.} C, 65.80; H, 4.55 ; N, 9.03 found (%): C, 65.26; H, 4.59; N, 9.43

Reference Example 97 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] ethylbenzoate In the same manner as in Reference Example 52, Obtained in Reference Example 96.
The title compound (3.02 g) was obtained from 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazon-3-yl) ethylbenzoate (3.27 g).
g, 65%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 101-102 ° C. IR (KBr):. 2961, 1705, 1661, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.92-2.00 (4H, m), 3.40 (2H, t,
J = 6.2 Hz), 4.14 (2H, t, J = 6.8 Hz), 4.51-4.66 (4H,
m), 7.14-7.30 (2H, m), 7.34-7.45 (2H, m), 7.52 (1
H, d, J = 7.4 Hz), 7.69 (1H, t, J = 7.4 Hz), 7.99 (2H,
d, J = 8.4 Hz), 8.25 (1H, d, J = 8.0 Hz). Elemental analysis: Calculated as C ₂₁ H ₂₁ N ₂ O ₄ Br (%): C, 56.64; H, 4.75; N, 6.29 Found (%): C, 57.13; H, 4.68; N, 6.38

Reference Example 98 2,4-Dioxo-1,2,3,4-tetrahydroquinazoline-3-acetic acid Obtained in Reference Example 34 by a method similar to that in Example 47.
The title compound (3.04 g, 93%) was synthesized from methyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate (3.50 g). Recrystallized from ethyl acetate-ethyl ether, melting point 282
Colorless crystals at -284 ° C were obtained. IR (KBr): 3500-2200, 1717, 1659, 1626, 1510, 1495
^{. cm -1 1 H-NMR (} CDCl 3) δ: 4.76 (2H, s), 7.11-7.24 (2H,
m), 7.56 (1H, t, J = 7.2 Hz), 8.07 (1H, d, J = 7.8 H
z), 11.13 (1H, bs). Elemental analysis: Calculated as C ₁₀ H ₈ N ₂ O ₄ (%): C, 54.55; H, 3.66; N, 12.72 Found (%): C, 54.31; H, 3.60; N, 12.80

Reference Example 99 2,4-Dioxo-N-methyl-N- (2-phenethyl) -1,2,3,4-tetrahydroquinazoline-3-acetamide 2,4-dioxo obtained in Reference Example 98 -1,2,3,4-tetrahydroquinazoline-3-acetic acid (3.04 g) and N-methylphenethylamine (2.41 ml) were added to N, N-dimethylformamide (60.0 m
l), diethyl cyanophosphate (DEPC) (2.65 ml),
Subsequently, triethylamine (2.31 ml) was added dropwise. The reaction mixture was stirred at room temperature for 26 hours, poured into ice water, and extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (2.06 g, 45%). Recrystallization from ethyl acetate-ethyl ether gave a melting point of 210.
Colorless crystals at -212 ° C were obtained. IR (KBr):. 3198, 2932, 1723, 1667, 1493 cm -1 1 H-NMR (CDCl 3) δ: 2.90 (2H, t, J = 7.0 Hz, major),
3.00, (3H, s, minor), 3.02 (3H, s, major), 3.05 (2
H, t, J = 7.6 Hz, minor), 3.64 (2H, t, J = 7.4 Hz), 4.
82 (2H, s, minor), 4.87 (2H, s, major), 7.01 (1H,
d, J = 8.4 Hz), 7.06-7.54 (8H, m), 7.90-8.02 (1H,
m), 9.37 (1H, bs). Elemental analysis: Calculated as C ₁₉ H ₁₉ N ₃ O ₃ (%): C, 67.64; H, 5.68; N, 12.45 Found (%): C, 67.34; H, 5.74; N, 12.47

Reference Example 100 1- (4-bromobutyl) -2,4-dioxo-N-methyl-N- (2-phenethyl) -1,2,3,4-tetrahydroquinazoline-3-acetamide Reference Example 52 In a similar manner, obtained in Reference Example 99
2,4-Dioxo-N-methyl-N- (2-phenethyl) -1,2,3,4-tetrahydroquinazoline-3-acetamide (1.50 g) to give the title compound (1.55 g, 74%) as an oil Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.76-2.00 (4H, m), 2.76 (2H, t,
J = 8.0 Hz, major), 2.86, (3H, s, minor), 2.90 (3H,
s, major), 2.93 (2H, t, J = 7.6 Hz, minor), 3.39 (2
H, t, J = 6.2 Hz), 3.44-3.58 (2H, m), 4.04-4.15 (2H,
m), 4.75 (2H, s, minor), 4.79 (2H, s, major), 7.0
4-7.30 (7H, m), 7.60 (1H, t, J = 8.0 Hz), 8.10-8.20
(1H, m).

Reference Example 101 Dimethyl 3-nitrophthalate Dimethyl sulfate (27.4 g) was added to a suspension of 3-nitrophthalic acid (25.5 g, 0.120 mol) and potassium carbonate (40.1 g, 0.289 mol) in acetone (500 ml). ml, 0.2
89 mmol) was added dropwise and the reaction mixture was heated at reflux for 21 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (5: 1,
v / v) to give the title compound (18.0 g, 63%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 66.0-67.0 ° C. IR (KBr):. 2955, 1738, 1630, 1613, 1574, 1541 cm -1 1 H-NMR (CDCl 3) δ: 3.96 (3H, s), 4.03 (3H, s), 7.6
9 (1H, t, J = 8.2 Hz), 8.32-8.42 (2H, m). Elemental analysis: C ₁₀ H ₉ NO ₆ Calculated (%): C, 50.22; H, 3.79; N, 5.86. Found (%): C, 50.25; H, 3.71; N, 5.94.

Reference Example 102 Dimethyl 3-aminophthalate The dimethyl 3-nitrophthalate (18.0 g, 75.2 mmol) obtained in Reference Example 101 was concentrated hydrochloric acid (50.0 ml), water (250
ml) and methanol (25.0 ml), and an excess amount of zinc powder was added little by little. After completion of the reaction, the reaction mixture was filtered, the filtrate was made basic with 25% aqueous ammonia, and extracted with ethyl acetate. Wash the extract with water and dry (MgSO ₄ )
Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (13.1 g, 83%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.85 (3H, s), 3.86 (3H, s), 5.2
0 (2H, bs), 6.78 (1H, dd, J = 8.4, 1.2 Hz), 6.90 (1H,
dd, J = 7.4, 0.8 Hz), 7.24 (1H, d, J = 8.0 Hz).

Reference Example 103 1,3-Dimethyl-4-nitrobenzene 4-nitroisophthalate (10.0 g, 66.2 mmol)
Was dissolved in a mixture of pyridine (65.0 ml) and water (130 ml), and potassium permanganate (62.7 g, 0.39 g) was dissolved.
7 mol) was added little by little, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was filtered, and the filtrate was distilled off under reduced pressure. The residue was acidified with 1N hydrochloric acid and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (12.4 g, 89%) as yellow crystals. This product was used for the next reaction without further purification.

Reference Example 104 Dimethyl 4-nitroisophthalate In the same manner as in Reference Example 101, the title compound (17.0 g, 76%) was obtained from 4-nitroisophthalic acid (19.8 g, 93.9 mmol) obtained in Reference Example 103. Was synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 84.0-86.0 ° C. IR (KBr):. 3443, 3118, 2957, 1732, 1539 cm -1 1 H-NMR (CDCl 3) δ: 3.96 (3H, s), 4.00 (3H, s), 7.9
3 (1H, d, J = 8.4 Hz), 8.30 (1H, dd, J = 8.4, 1.8 Hz),
8.45 (1H, d, J = 1.8 Hz). Elemental analysis: C ₁₀ H ₉ NO ₆ Calculated (%): C, 50.22; H, 3.79; N, 5.86. Found (%): C, 50.32 ; H, 3.71; N, 5.95.

Reference Example 105 Dimethyl 4-aminoisophthalate The dimethyl 4-nitroisophthalate (17.0 g, 71.2 mmol) obtained in Reference Example 104, 10% palladium-carbon (5
0.32 water) (7.12 g), methanol (100 ml) and THF
(100 ml) was stirred under a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered, and the solvent was distilled off from the filtrate under reduced pressure to obtain the title compound (12.4 g, 83%). Recrystallized from ethyl acetate-isopropyl ether, melting point 125-126 ℃
To obtain colorless crystals. IR (KBr): 3461, 3355, 2953, 1694, 1620, 1590, 156
^{. 3, 1501 cm -1 1 H} -NMR (CDCl 3) δ: 3.88 (3H, s), 3.90 (3H, s), 6.4
0 (2H, bs), 6.65 (1H, d, J = 8.8 Hz), 7.91 (1H, dd, J
= 8.8, 2.2 Hz), 8.59 (1H, d, J = 1.8 Hz). Elemental analysis: C ₁₀ H ₁₁ NO ₄・ 1.2H ₂ O Calculated (%): C, 52.04; H, 5.85; N , 6.07. Found (%): C, 51.75; H, 5.47; N, 6.09.

Reference Example 106 5-Fluoro-2-nitrobenzoic acid In the same manner as in Reference Example 103, the title compound (5.12 g, 31%) was obtained from 4-fluoro-2-methylnitrobenzene (14.0 g, 90.2 mmol). Obtained as yellow crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 7.36 (1H, ddd, J = 9.0, 6.2, 2.8
Hz), 7.53 (1H, dd, J = 7.6, 2.8 Hz), 8.01 (1H, dd, J
= 8.8, 4.4 Hz).

Reference Example 107 Methyl 5-fluoro-2-nitrobenzoate thionyl chloride (2.41 ml) was added dropwise to methanol (30.0 ml) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. 5-fluoro-2-nitrobenzoic acid obtained in Reference Example 106 (5.12 g, 27.5 m
mol) was added to the reaction mixture under ice cooling, and the mixture was heated under reflux for 15.5 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (10:
1, v / v) to give the title compound (4.69 g, 96%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.95 (3H, s), 7.31 (1H, ddd, J =
8.8, 7.4, 1.4 Hz), 7.39 (1H, dd, J = 7.6, 3.0 Hz),
8.03 (1H, dd, J = 8.8, 4.4 Hz).

Reference Example 108 Diethyl 3-methoxycarbonyl-4-nitrophenylmalonate To a solution of diethyl malonate (8.04 ml, 52.9 mmol) in N, N-dimethylformamide (30.0 ml) was added potassium tert-butoxide (5.94 g, 52.9 mmol). mmol) was completely dissolved, and then methyl 5-fluoro-2-nitrobenzoate (4.69 g, 26.5 mmol) obtained in Reference Example 107 was added. After stirring the reaction mixture at 60 ° C. for 25 hours, it was poured into ice water, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound as an oil. This product was used for the next reaction without further purification.

Reference Example 109 3-carboxy-4-nitrophenylacetic acid A mixture of diethyl 3-methoxycarbonyl-4-nitrophenylmalonate obtained in Reference Example 108, concentrated hydrochloric acid (10.0 ml) and acetic acid (40.0 ml) was prepared. The mixture was heated under reflux for 17.5 hours.
The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound as white crystals. This product was used for the next reaction without further purification.

Reference Example 110 Methyl 3-methoxycarbonyl-4-nitrophenylacetic acid The title compound (4.49 g, 67) was obtained from 3-carboxy-4-nitrophenylacetic acid obtained in Reference Example 109 in the same manner as in Reference Example 101. %) As an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.93 (3H, s), 3.97 (3H, s), 3.9
7 (2H, s), 7.57 (1H, dd, J = 8.6, 2.2 Hz), 7.65 (1H,
d, J = 1.8 Hz), 7.91 (1H, d, J = 8.6 Hz).

Reference Example 111 Methyl 4-amino-3-methoxycarbonylphenylacetate Methyl 3-methoxycarbonyl-4-nitrophenylacetic acid obtained in Reference Example 110 (9.11 g, 36.0 mmol) in the same manner as in Reference Example 102. ) To the title compound (5.53 g, 69
%) As an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.65 (3H, s), 3.87 (3H, s), 3.8
7 (2H, s), 6.64 (1H, d, J = 8.4 Hz), 7.23 (1H, dd, J
= 8.4, 2.2 Hz), 7.77 (1H, d, J = 2.2 Hz).

Reference Example 112 Methyl 2-methyl-2- (3-methoxycarbonyl-4-nitrophenyl) propionate A suspension of sodium hydride (60% oil) in N, N-dimethylformamide obtained in Reference Example 101. Methyl 4-amino-3-methoxycarbonylphenyl acetate (4.49
g, 17.7 mmol) and stirred at room temperature for 2 hours. To this was added iodomethane and stirred for an additional 18.5 hours. The solvent was distilled off under reduced pressure, 1N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (10: 1, v
/ v) to give the title compound (4.25 g, 96%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.63 (6H, s), 3.68 (3H, s), 3.9
4 (3H, s), 7.58 (1H, dd, J = 8.4, 1.8 Hz), 7.67 (1H,
d, J = 2.2 Hz), 7.91 (1H, d, J = 8.4 Hz).

Reference Example 113 Methyl 2-methyl-2- (4-amino-3-methoxycarbonylphenyl) propionate In the same manner as in Reference Example 105, methyl 2-methyl-2- (3 The title compound (4.82 g, 75%) was synthesized from (-methoxycarbonyl-4-nitrophenyl) propionate (6.39 g, 25.6 mmol). Recrystallization from n-hexane gave colorless crystals having a melting point of 58.0-60.0 ° C. IR (KBr): 3482, 3372, 2951, 1730, 1694, 1626, 159
^{. 0, 1563, 1501 cm -1} 1 H-NMR (CDCl 3) δ: 1.55 (6H,
s), 3.64 (3H, s), 3.87 (3H, s), 5.69 (2H, bs), 6.6
4 (1H, d, J = 8.8 Hz), 7.27 (1H, dd, J = 8.8, 2.6 Hz),
7.84 (1H, d, J = 2.4 Hz) Elemental analysis: Calculated _{C 13 H 17 NO 4 (%} ):.. C, 62.14; H, 6.82; N, 5.57 Found (%): C, 62.08 ; H, 6.92; N, 5.60.

Reference Example 114 Methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4
-Tetrahydroquinazoline-5-carboxylate 4-methoxyphenylacetic acid (11.5 g, 69.4 mmol) was suspended in toluene (200 ml), and triethylamine (11.
6 ml, 85.2 mmol) and diphenylphosphate azide (17.9
ml, 85.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, and then heated under reflux for 3 hours. Reference Example 1
Dimethyl 3-aminophthalate (13.1)
g, 62.4 mmol) and further heated under reflux for 20 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (10: 1, v / v) to give the title compound (8.49 g, 40%) as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 3.77 (3H, s), 4.01 (3H, s), 5.1
4 (2H, s), 6.78-6.90 (3H, m), 7.09 (1H, d, J = 8.4 H
z), 7.46 (2H, d, J = 8.4 Hz), 7.60 (1H, d, J = 8.2 H
z), 9.52 (1H, bs).

Reference Example 115 Methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4
-Tetrahydroquinazoline-6-carboxylate In the same manner as in Reference Example 114, the dimethyl 4-aminoisophthalate obtained in Reference Example 105 (12.0 g, 57.4
mmol) to give the title compound (11.2 g, 57%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 235-237 ° C. IR (KBr): 3663, 2928, 1734, 1715, 1671, 1624, 160
^{. 7, 1512, 1489 cm -1} 1 H-NMR (CDCl 3) δ: 3.77 (3H, s), 3.95 (3H, s), 5.2
1 (2H, s), 6.84 (2H, d, J = 8.8Hz), 7.09 (1H, d, J =
8.6 Hz), 7.50 (2H, d, J = 8.8 Hz), 8.26 (1H, dd, J =
8.6, 2.0 Hz), 8.84 (1H, d, J = 1.4 Hz), 9.77 (1H, b
. s) Elemental _{analysis: C 18 H 16 N 2 O} 5 Calculated (%):. C, 63.52 ; H, 4.74; N, 8.23 Found (%): C, 63.29; H, 4.61; N, 8.19.

Reference Example 116 Methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4
-Tetrahydroquinazoline-7-carboxylate In the same manner as in Reference Example 114, the title compound (4.96 g, 48%) was synthesized from dimethylaminoterephthalate (6.29 g, 30.1 mmol). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 254-256 ° C. IR (KBr): 3279, 3007, 2965, 1732, 1709, 1651, 161
. 5, 1601, 1586, 1510 cm -1 1 H-NMR (CDCl 3) δ: 3.76 (3H, s), 3.98 (3H, s), 5.2
0 (2H, s), 6.84 (2H, d, J = 8.8Hz), 7.53 (2H, d, J =
8.8 Hz), 7.76 (1H, s), 7.84 (1H, d, J = 8.4 Hz), 8.2
1 (1H, d, J = 8.4 Hz), 9.39 (1H, bs). Elemental analysis: C ₁₈ H ₁₆ N ₂ O ₅ Calculated (%): C, 63.52; H, 4.74; N, 8.23. Found (%): C, 63.05; H, 4.65; N, 8.17.

Reference Example 117 Methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4
-Tetrahydroquinazoline-6-acetate In the same manner as in Reference Example 114, the title compound (5.96 g, 24.9 mmol) was obtained from the methyl 4-amino-3-methoxycarbonylphenylacetate (5.56 g, 24.9 mmol) obtained in Reference Example 111.
g, 68%) as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 3.66 (3H, s), 3.76 (3H, s), 3.7
9 (2H, s), 5.19 (2H, s), 6.88-6.90 (1H, m), 6.83
(2H, d, J = 8.8 Hz), 7.56 (1H, dd, J = 8.4, 2.2 Hz),
8.05 (1H, d, J = 2.2 Hz), 6.35 (1H, bs).

Reference Example 118 Methyl 2- [2,4-dioxo-3- (4-methoxybenzyl) -1,2,
3,4-Tetrahydroquinazolin-6-yl] -2-methylpropionate Methyl 2-methyl-2- (4-amino-3-methoxycarbonyl) obtained in Reference Example 113 in the same manner as in Reference Example 114. The title compound (4.85 g, 61%) was obtained as an oil from phenyl) propionate (4.70 g, 18.7 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.61 (6H, s), 3.65 (3H, s), 3.7
7 (3H, s), 5.19 (2H, s), 7.00 (1H, d, J = 8.4 Hz),
7.20 (2H, d, J = 8.8 Hz), 7.49 (2H, d, J = 8.6 Hz), 7.
57 (1H, dd, J = 8.6, 2.4 Hz), 8.13 (1H, d, J = 2.4 H
z), 9.28 (1H, bs).

Reference Example 119 Methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-5-carboxylate Same as Reference Example 52 By the method of methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2, obtained in Reference Example 114
3,4-tetrahydroquinazoline-5-carboxylate (4.7
The title compound (4.51 g, 68%) was obtained from 3 g (13.9 mol) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.80-2.08 (4H, m), 3.47 (2H, t,
J = 6.0 Hz), 3.77 (3H, s), 4.01 (3H, s), 4.16 (2H,
t, J = 7.2 Hz), 5.16 (2H, s), 6.76-6.90 (3H, m), 7.2
0 (1H, t, J = 7.4 Hz), 7.45 (2H, d, J = 8.8Hz), 7.68
(1H, t, J = 7.4 Hz).

Reference Example 120 Methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate Same as Reference Example 52 By the method of methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2, obtained in Reference Example 115
3,4-tetrahydroquinazoline-6-carboxylate (10.
9 g, 32.0 mmol) to give the title compound (12.4 g, 81%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.86-2.08 (4H, m), 3.48 (2H, t,
J = 5.8 Hz), 3.80 (3H, s), 3.94 (3H, s), 4.18 (2H,
t, J = 7.2 Hz), 5.21 (2H, s), 6.84 (2H, d, J = 8.8 H
z), 7.16-7.30 (1H, m), 7.50 (2H, d, J = 8.8 Hz) 8.31
(1H, d, J = 9.2 Hz), 8.91 (1H, d, J = 2.2 Hz).

Reference Example 121 Methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxylate Same as Reference Example 52 By the method of methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2, obtained in Reference Example 116
3,4-tetrahydroquinazoline-7-carboxylate (4.9
6 g, 14.6 mmol) to give the title compound (3.92 g, 56%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.87-2.08 (4H, m), 3.48 (2H, t,
J = 6.0 Hz), 3.77 (3H, s), 3.98 (3H, s), 4.21 (2H,
t, J = 6.2 Hz), 5.21 (2H, s), 6.84 (2H, d, J = 8.8 H
z), 7.50 (2H, d, J = 8.2 Hz), 7.82-7.90 (2H, m), 8.3
1 (1H, d, J = 8.6 Hz).

Reference Example 122 Methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6-acetate Same as in Reference Example 52. According to the method, methyl 2,4-dioxo-3- (4-methoxybenzyl) -1,2,2 obtained in Reference Example 117 was obtained.
3,4-tetrahydroquinazoline-6-acetate (5.86 g, 1
6.5 mmol) to give the title compound (6.61 g, 82%) as an oil. This product was used for the next reaction without further purification.

Reference Example 123 Methyl 2- [1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6-
Yl] -2-methylpropionate Methyl 2- [2,4-dioxo-3- (4-methoxybenzyl) -1, obtained in Reference Example 118, in the same manner as in Reference Example 52.
From the 2,3,4-tetrahydroquinazolin-6-yl] -2-methylpropionate (4.50 g, 11.8 mmol), the title compound (4.7
7 g, 78%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.62 (6H, s), 1.84-2.08 (4H,
m), 3.41-3.52 (2H, m), 3.65 (3H, s), 3.77 (3H, s),
4.14 (2H, t, J = 7.0 Hz), 5.21 (2H, s), 6.83 (2H,
d, J = 8.4 Hz), 7.15 (1H, d, J = 8.8 Hz), 7.48 (2H, d,
J = 8.8 Hz) 7.64 (1H, dd, J = 8.8, 2.6 Hz), 8.24 (1H,
d, J = 2.6 Hz).

Reference Example 124 Methyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-5-carboxylate Obtained in Reference Example 119 in the same manner as in Reference Example 83. Title from the obtained methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-5-carboxylate (4.51 g, 9.47 mmol) The compound (1.83 g, 54%) was obtained as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) d: 1.82-2.12 (4H, m), 3.49 (2H, t,
J = 6.2 Hz), 3.98 (3H, s), 4.16 (2H, t, J = 7.8 Hz),
7.21 (1H, d, J = 7.2 Hz), 7.32 (1H, d, J = 8.4 Hz), 7.
74 (1H, t, J = 7.2 Hz), 8.72 (1H, bs).

Reference Example 125 Methyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate Obtained in Reference Example 120 in the same manner as in Reference Example 83. Title from the obtained methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6-carboxylate (12.4 g, 26.0 mmol) The compound (2.71 g, 29%) was obtained as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.12 (4H, m), 3.49 (2H, t,
J = 6.2 Hz), 3.96 (3H, s), 4.18 (2H, t, J = 7.0 Hz),
7.24-7.32 (1H, m), 8.37 (1H, d, J = 8.6 Hz), 8.57 (1
H, bs), 8.88 (1H, s).

Reference Example 126 Methyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate Obtained in Reference Example 121 in the same manner as in Reference Example 83. Title from the obtained methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-7-carboxylate (3.92 g, 8.23 mmol) A compound (1.78 g, 61%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 184-185 ° C. IR (KBr): 3166, 3044, 1726, 1715, 1682, 1622, 1510
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.88-2.16 (4H, m), 3.50 (2H, t,
J = 6.2 Hz), 4.00 (3H, s), 4.21 (2H, t, J = 6.6 Hz),
7.86-7.95 (2H, m), 8.30 (1H, d, J = 8.0 Hz), 8.45 (1
H, bs). Anal.Calcd for C ₁₄ H ₁₅ N ₂ O ₄ Br ・ 0.6H ₂ O: C, 4
5.94; H, 4.46; N, 7.65. Found: C, 45.89; H, 4.18;
N, 7.71. Elemental analysis: C ₁₄ H ₁₅ N ₂ O ₄ Br · 0.6H ₂ O Calculated (%): C, 45.94; H, 4.46; N, 7.65. Found (%): C, 45.89 ; H, 4.18; N, 7.71.

Reference Example 127 Methyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-acetate Obtained in Reference Example 122 in the same manner as in Reference Example 83. Methyl 1- (4-bromobutyl) -2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6-acetate (6.61 g, 13.6 mmol) from the title compound ( 3.16
g, 63%) as an oil. This product was used for the next reaction without further purification.

Reference Example 128 Methyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-6-yl] -2-methylpropionate Methyl 2- [1- (4-bromobutyl) -2,4-dioxo-3- obtained in Reference Example 123 in the same manner as in Reference Example 52. (Four-
(Methoxybenzyl) -1,2,3,4-tetrahydroquinazoline-6
-Yl] -2-methylpropionate (4.77 g, 9.22 mmol)
The title compound (2.12 g, 58%) was synthesized from. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 164-165 ° C. IR (KBr): 3165, 3044, 2841, 1726, 1686, 1620, 158
^{. 4, 1507, 1474 cm -1} 1 H-NMR (CDCl 3) δ: 1.64 (6H, s), 1.84-2.08 (4H,
m), 3.49 (2H, t, J = 6.2 Hz), 3.67 (3H, s), 4.13 (2
H, t, J = 7.4 Hz), 7.21 (1H, d, J = 9.2 Hz), 7.70 (1H,
dd, J = 8.6, 2.6 Hz), 8.21 (1H, d, J = 2.6 Hz), 8.32
(1H, bs). Elemental analysis: C ₁₇ H ₂₁ N ₂ O ₄ Br Calculated (%): C, 51.40; H, 5.33; N, 7.05. Found (%): C, 51.16; H, 5.38; N, 6.85.

Reference Example 129 Ethyl 6-aminovalerate hydrochloride In the same manner as in Reference Example 107, 5-aminovaleric acid (2
The title compound (51.5 g, 86%) was synthesized from 5.0 g (0.216 mol). Recrystallized from ethyl ether, melting point 103-105
C. Colorless crystals were obtained. IR (KBr):. 3412, 2980, 1732, 1603, 1495, 1472 cm -1 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.64-1.
92 (4H, m), 2.37 (2H, t, J = 6.2 Hz), 2.94-3.16 (2H,
m), 4.13 (2H, q, J = 7.0 Hz), 8.30 (2H, bs). Elemental analysis: C ₇ H ₁₆ NO ₂ Cl · 0.1H ₂ O Calculated (%): C, 45.82; H , 8.90; N, 7.67. Found (%): C, 45.50; H, 8.52; N, 7.56.

Reference Example 130 Ethyl 6-aminohexanoate hydrochloride In the same manner as in Reference Example 107, 6-aminohexanoic acid (10.0 g, 76.2 mmol) was used to give the title compound (15.1 g, approximately 1: 1).
00%) as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.38-1.
58 (2H, m), 1.58-1.90 (4H, m), 2.32 (2H, t, J = 7.4 H
z), 2.90-3.12 (2H, m), 4.12 (2H, q, J = 7.4 Hz), 8.27
(2H, bs).

Reference Example 131 Ethyl 8-aminooctanoate hydrochloride In the same manner as in Reference Example 107, the title compound (7.21 g, almost 10%) was obtained from 8-aminooctanoic acid (5.0 g, 31.4 mmol).
0%) as white crystals. This product was used for the next reaction without further purification. IR (KBr):. 3374, 3300-2400, 2932, 1736, 1607 cm -1 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.26-1.
52 (6H, m), 1.61 (2H, t, J = 7.0 Hz), 1.72-1.84 (2H,
m), 2.29 (2H, t, J = 7.4 Hz), 2.90-3.08 (2H, m), 4.12
(2H, q, J = 7.4 Hz), 8.29 (2H, bs).

Reference Example 132 Methyl 1-amino-1-cyclopentylcarboxylate hydrochloride In the same manner as in Reference Example 107, 1-amino-1-cyclopentylcarboxylic acid (25.0 g, 0.216 mol) was used to give the title compound (7.21 g, Almost 100%). Recrystallization from ethyl ether gave colorless crystals having a melting point of 200-202 ° C. IR (KBr):. 3428, 2961, 1746, 1576, 1514 cm -1 1 H-NMR (CDCl 3) δ: 1.70-2.16 (8H, m), 3.83 (3H,
s), 8.96 (2H, bs). Elemental analysis: C ₇ H ₁₃ NO ₂ · HCl Calculated (%): C, 46.80; H, 7.85; N, 7.80. Found (%): C, 46.74 ; H, 7.76; N, 8.05.

Reference Example 133 Methyl 1-amino-1-cyclohexylcarboxylate hydrochloride The title compound (21.8 g, 0.16 mol) was obtained from 1-amino-1-cyclohexylcarboxylic acid (15.1 g, 0.106 mol) in the same manner as in Reference Example 107. Almost 100%). Recrystallization from ethyl ether gave colorless crystals having a melting point of 199-201 ° C. IR (KBr):. 3466, 3320-2350, 1744, 1590, 1522 cm -1 1 H-NMR (CDCl 3) δ: 1.30-1.50 (2H, m), 1.58-2.22 (8
H, m), 3.82 (3H, s), 8.98 (2H, bs). Elemental analysis: C ₈ H ₁₅ NO ₂ · HCl · 0.2H ₂ O Calculated (%): C, 48.71; H, 8.38 N, 7.10. Found (%): C, 48.50; H, 8.10; N, 7.39.

Reference Example 134 Ethyl 6- (2-aminobenzamide) hexanoate In the same manner as in Reference Example 9, ethyl 6-aminohexanoate hydrochloride (15.1 g, 77.2 mmol) was used instead of glycine methyl ester hydrochloride. The title compound (18.9
g, 97%). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.34-1.
54 (2H, m), 1.55-1.74 (4H, m), 2.32 (2H, t, J = 7.2 H
z), 3.42 (2H, q, J = 6.2 Hz), 4.13 (2H, q, J = 7.0 H
z), 5.49 (2H, bs), 6.12 (1H, bs), 6.60-6.71 (2H,
m), 7.20 (1H, ddd, J = 8.4, 7.0, 1.4 Hz), 7.31 (1H, d
d, J = 8.0, 1.2 Hz).

Reference Example 135 Ethyl 8- (2-aminobenzamide) octanoate In the same manner as in Reference Example 9, ethyl 8-aminooctanoate hydrochloride (7.00 g, 31.1 mmol) was used instead of glycine methyl ester hydrochloride. The title compound (9.82
g, almost 100%). ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.32-1.
44 (6H, m), 1.55-1.68 (4H, m), 2.29 (2H, t, J = 7.2 H
z), 3.40 (2H, q, J = 6.2 Hz), 4.12 (2H, q, J = 7.0 H
z), 5.49 (2H, bs), 6.06 (1H, bs), 6.58-6.70 (2H,
m), 7.20 (1H, ddd, J = 8.4, 7.0, 1.4 Hz), 7.30 (1H, d
d, J = 8.2, 1.6 Hz).

Reference Example 136 Methyl 1- (2-aminobenzamido) -1-cyclopentylcarboxylate In the same manner as in Reference Example 9, glycine methyl ester hydrochloride was replaced with methyl 1-amino-1-cyclopentylcarboxylate hydrochloride. (7.10 g, 39.5 mmol)
The title compound (3.05 g, 32%) was synthesized. Recrystallization from isopropyl ether gave colorless crystals having a melting point of 108-109 ° C. IR (KBr): 3465, 3362, 2953, 1728, 1645, 1614, 158
^{. 3, 1520 cm -1 1 H} -NMR (CDCl 3) δ: 1.74-1.94 (4H, m), 1.94-2.12 (2
H, m), 2.28-2.46 (2H, m), 3.74 (3H, s), 5.47 (2H, b
s), 6.40 (1H, bs), 6.60-6.70 (2H, m), 7.21 (1H, t,
. J = 7.6 Hz), 7.35 (1H, d, J = 7.4 Hz) Elemental _{analysis: C 14 H 18 N 2 O} 3 Calculated (%):. C, 64.11 ; H, 6.92; N, 10.68 Found Values (%): C, 64.19; H, 6.77; N, 10.70.

Reference Example 137 Methyl 1- (2-aminobenzamido) -1-cyclohexylcarboxylate In the same manner as in Reference Example 9, methyl 1-amino-1-cyclohexylcarboxylate hydrochloride was used instead of glycine methyl ester hydrochloride. (10.0 g, 51.6 mmol) was used to synthesize the title compound (5.88 g, 45%). Recrystallization from isopropyl ether gave colorless crystals having a melting point of 123-124 ° C. IR (KBr): 3465, 3360, 2942, 2859, 1728, 1644, 161
^{. 3, 1586 cm -1 1 H} -NMR (CDCl 3) δ: 1.28-2.20 (10H, m), 3.73 (3H,
s), 5.42 (2H, bs), 6.19 (1H, bs), 6.62-6.72 (2H,
m), 7.22 (1H, ddd, J = 8.8, 7.2, 1.6 Hz), 7.38 (1H,
. dd, J = 8.2, 1.4 Hz) Elemental analysis: Calculated _{C 15 H 20 N 2 O 3} (%):. C, 65.20; H, 7.30; N, 10.14 Found (%): C, 65.06 ; H, 7.19; N, 10.11.

Reference Example 138 Ethyl 5- (2-amino-5-fluorobenzamide) valerate In the same manner as in Reference Example 2, ethyl 5-aminovalerate hydrochloride (6.54) was used instead of 4-methoxybenzylamine.
g, 25.2 mmol) from 2-amino-5-fluorobenzoic acid (3.00 g, 19.3 mmol) using the title compound (4.91 g, 90 mmol).
%) As an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.56-1.
80 (4H, m), 2.37 (2H, t, J = 7.0 Hz), 3.12 (2H, q, J =
5.6 Hz), 4.28 (2H, q, J = 7.2 Hz), 5.29 (2H, bs), 6.2
6 (1H, bs), 6.64 (1H, dd, J = 9.2, 4.8 Hz), 6.81 (1
H, dt, J = 8.0, 2.6 Hz), 7.06 (1H, dd, J = 9.0, 3.0 H
z).

Reference Example 139 Ethyl 5- (2-amino-5-methoxybenzamide) valerate In the same manner as in Reference Example 2, except that 4-methoxybenzylamine was replaced with ethyl 5-aminovalerate hydrochloride. -Amino-5-methoxybenzoic acid (2.50 g, 15.0 mmo
The title compound (3.76 g, 85%) was obtained from l) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.58-1.
80 (4H, m), 2.37 (2H, t, J = 6.2 Hz), 3.42 (2H, dt, J
= 6.2 5.8 Hz), 3.77 (3H, s), 4.14 (2H, q, J = 7.4 H
z), 6.35 (2H, bs), 6.66 (1H, d, J = 8.4 Hz), 6.72-6.
84 (2H, m).

Reference Example 140 Ethyl 5- (2-amino-5-nitrobenzamide) valerate In the same manner as in Reference Example 2, except that 4-methoxybenzylamine was replaced with ethyl 5-aminovalerate hydrochloride, -Amino-5-nitrobenzoic acid (4.66 g, 25.6 mmol)
From there, the title compound (5.39 g, 68%) was synthesized. Recrystallized from ethyl acetate-isopropyl ether, melting point 86.0-88.0
C. Colorless crystals were obtained. IR (KBr): 3328, 2936, 1717, 1615, 1591, 1539, 1505
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.27 (3H, t, J = 7.0 Hz), 1.58-1.
84 (4H, m), 2.39 (2H, t, J = 6.2 Hz), 3.45 (2H, dt, J
= 6.2 5.8 Hz), 4.17 (2H, q, J = 7.4 Hz), 6.55 (2H, b
s), 6.58-6.70 (1H, m), 6.65 (1H, d, J = 9.2 Hz), 8.0
9 (1H, dd, J = 9.2, 1.8 Hz), 8.40 (1H, d, J = 2.6 Hz). Elemental analysis: C ₁₄ H ₁₉ N ₃ O ₅ Calculated (%): C, 54.36 H, 6.1;
9; N, 13.58. Found (%): C, 54.25; H, 6.32; N, 13.62.

Reference Example 141 Ethyl 5- (2-amino-5-hydroxybenzamido) valerate In the same manner as in Reference Example 2, except that 4-methoxybenzylamine was replaced with ethyl 5-aminovalerate hydrochloride, -Amino-5-hydroxybenzoic acid (7.38 g, 48.2 mm
ol) to give the title compound (12.9 g, 96%) as an oil. This product was used for the next reaction without further purification.

Reference Example 142 Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline
-3-Hexanoate Reference Example 13 by the same method as in Reference Example 26 (method 1).
The title compound (19.3) was obtained from ethyl 6- (2-aminobenzamide) hexanoate (18.9 g, 67.8 mmol) obtained in Step 4.
g, 93%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 103-104 ° C. IR (KBr): 3196, 3132, 2965, 2940, 1730, 1703, 163
^{. 0, 1601, 1493 cm -1} 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 6.8 Hz), 1.38-1.
54 (2H, m), 1.60-1.84 (4H, m), 2.32 (2H, t, J = 7.6 H
z), 4.04-4.20 (4H, m), 7.09 (1H, d, J = 8.4 Hz), 7.2
4 (1H, t, J = 7.2 Hz), 7.63 (1H, t, J = 8.8 Hz), 8.14
(1H, d, J = 8.0 Hz). Elemental analysis: C ₁₆ H ₂₀ N ₂ O ₄ Calculated (%): C, 63.14; H, 6.62; N, 9.20. Observed (%): C, 63.15; H, 6.54; N, 9.28.

Reference Example 143 Ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline
-3-octanoate Reference Example 13 by a method similar to Reference Example 26 (method 1).
The title compound (8.14 g) was obtained from ethyl 8- (2-aminobenzamide) octanoate (9.82 g, 32.0 mmol) obtained in Step 5.
g, 77%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 88-89 ° C. IR (KBr):. 3196, 2930, 1728, 1634, 1601, 1497 cm -1 1 H-NMR (CDCl 3) δ: 1.25 (3H, t, J = 6.8 Hz), 1.30-1.
50 (6H, m), 1.58-1.80 (4H, m), 2.28 (2H, t, J = 7.6 H
z), 4.06 (2H, t, J = 5.4 Hz), 4.12 (2H, q, J = 7.4 H
z), 7.09 (1H, d, J = 8.4 Hz), 7.23 (1H, t, J = 7.4 H
z), 7.62 (1H, t, J = 8.4 Hz), 8.14 (1H, d, J = 7.8 H
z). Elemental analysis: C ₁₈ H ₂₄ N ₂ O ₄ Calculated (%): C, 65.04; H, 7.28; N, 8.43. Found (%): C, 65.00; H, 7.14; N, 8.55.

Reference Example 144 Methyl 1- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) -1-cyclopentylcarboxylate In the same manner as in Reference Example 26 (method 2), Reference Example 13
The title compound (1.94 g, 58%) was synthesized from the methyl 1- (2-aminobenzamido) -1-cyclopentylcarboxylate (3.05 g, 11.6 mmol) obtained in 6. Ethyl acetate-
Recrystallization from isopropyl ether gave colorless crystals having a melting point of 164-165 ° C. IR (KBr):. 2949, 1719, 1671, 1618, 1609, 1493 cm -1 1 H-NMR (CDCl 3) δ: 1.68-2.06 (4H, m), 2.46-2.57 (4
H, m), 3.71 (3H, s), 7.03 (1H, d, J = 8.4 Hz), 7.21
(1H, d, J = 8.2 Hz), 7.60 (1H, t, J = 7.2 Hz), 8.06 (1
H, d, J = 7.0 Hz). Elemental analysis: C ₁₅ H ₁₆ N ₂ O ₄ Calculated (%): C, 62.49; H, 5.59; N, 9.72. Found (%): C, 63.09 ; H, 5.55; N, 10.13.

Reference Example 145 Methyl 1- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) -1-cyclohexylcarboxylate In the same manner as in Reference Example 26 (method 2), Reference Example 13
The title compound (5.72 g, 51%) was synthesized from the methyl 1- (2-aminobenzamido) -1-cyclohexylcarboxylate (10.3 g, 37.1 mmol) obtained in Step 7. Ethyl acetate-
Recrystallization from isopropyl ether gave colorless crystals having a melting point of 145-147 ° C. IR (KBr): 2938, 1746, 1717, 1667, 1620, 1609, 151
^{. 0, 1493 cm -1 1 H} -NMR (CDCl 3) δ: 1.50-1.88 (6H, m), 2.16-2.30 (2
H, m), 2.80-3.00 (2H, m), 3.72 (3H, s), 7.02 (1H,
d, J = 8.0 Hz), 7.21 (1H, t, J = 7.6 Hz), 7.60 (1H, dd
d, J = 8.4, 7.0, 1.4 Hz), 8.05 (1H, d, J = 7.6 Hz), 9.
55 (1H, bs). Elemental analysis: C ₁₆ H ₁₈ N ₂ O ₄ Calculated (%): C, 63.56; H, 6.00; N, 9.27. Found (%): C, 63.27; H, 6.04; N, 9.18.

Reference Example 146 Ethyl 2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazoline-3-valerate According to the same method as in Reference Example 26 (Method 1), Reference Example 13
The title compound (4.08 g, 76%) was synthesized from ethyl 5- (2-amino-5-fluorobenzamide) valerate (4.91 g, 17.4 mmol) obtained in 8. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 131-132 ° C. IR (KBr):. 3193, 1728, 1636, 1512, 1493 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.70-7.
82 (4H, m), 2.38 (2H, t, J = 7.0 Hz), 4.10 (2H, t, J =
7.4 Hz), 4.12 (2H, q, J = 6.8 Hz), 7.10 (1H, dd, J = 8.
8, 4.0 Hz), 7.36 (1H, dt, J = 7.6, 3.0 Hz), 7.80 (1
H, dd, J = 8.4, 3.0 Hz), 7.79 (1H, bs). Elemental analysis: C ₁₅ H ₁₇ N ₂ O ₄ F Calculated (%): C, 58.44; H, 5.56; N, 9.09 Found (%): C, 58.36; H, 5.46; N, 9.26.

Reference Example 147 Ethyl 2,4-dioxo-6-methoxy-1,2,3,4-tetrahydroquinazoline-3-valerate According to the same method as in Reference Example 26 (Method 2), Reference Example 13
From ethyl 5- (2-amino-5-methoxybenzamide) valerate (3.76 g, 12.8 mmol) obtained in 9, the title compound (4.91 g, almost 100%) was obtained as white crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.14 (3H, t, J = 7.0 Hz), 1.58-1.
74 (4H, m), 2.29 (2H, t, J = 6.6 Hz), 3.77 (3H, s),
3.96-4.08 (4H, m), 6.95 (1H, d, J = 8.8 Hz), 7.14 (1
H, dd, J = 8.8, 3.0 Hz), 7.45 (1H, d, J = 2.6 Hz), 9.7
7 (1H, bs).

Reference Example 148 Ethyl 2,4-dioxo-6-nitro-1,2,3,4-tetrahydroquinazoline-3-valerate According to the same method as in Reference Example 26 (Method 2), Reference Example 14
The title compound (3.63 g, 63%) was synthesized from ethyl 5- (2-amino-5-nitrobenzamide) valerate (5.33 g, 17.2 mmol) obtained in Step 0. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 173-174 ° C. IR (KBr): 3065, 2980, 2944, 1730, 1651, 1626, 160
^{. 1, 1545, 1485 cm -1} 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.0 Hz), 1.68-1.
80 (4H, m), 2.38 (2H, t, J = 6.8 Hz), 4.11 (2H, t, J =
6.6 Hz), 4.11 (2H, q, J = 7.2 Hz), 7.20-7.28 (1H, m),
8.47 (1H, dd, J = 8.8, 2.6 Hz), 9.02 (1H, d, J = 2.6
Hz), 9.96 (1H, bs). Elemental analysis: C ₁₅ H ₁₇ N ₃ O ₆ Calculated (%): C, 53.73; H, 5.11; N, 12.53. Found (%): C, 53.64 ; H, 5.05; N, 12.62.

Reference Example 149 Ethyl 2,4-dioxo-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate According to the same method as in Reference Example 26 (Method 2), Reference Example 14
The title compound (3.81 g, 28%) was synthesized from ethyl 5- (2-amino-5-hydroxybenzamide) valerate (12.9 g, 46.0 mmol) obtained in 1. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 105-107 ° C. IR (KBr): 3187, 2949, 1728, 1705, 1692, 1634, 160
^{. 5, 1518 cm -1 1 H} -NMR (CDCl 3 + DMSO-d 6) δ: 1.26 (3H, t, J = 7.0 Hz),
1.58-1.70 (4H, m), 2.18-2.28 (2H, m), 3.78-3.98
(2H, m), 3.99 (2H, q, J = 7.4 Hz), 6.90 (1H, d, J = 8.8
Hz), 6.95-7.03 (1H, m), 7.38 (1H, s), 10.45 (1H,
. bs) Elemental _{analysis: C 15 H 18 N 2 O} 5 Calculated (%):. C, 58.82 ; H, 5.92; N, 9.15 Found (%): C, 58.61; H, 5.81; N, 9.20.

Reference Example 150 Ethyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-hexanoate Obtained in Reference Example 142 in the same manner as in Reference Example 52. The title compound (6.90 g, 68%) was obtained as an oil from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-hexanoate (7.05 g, 23.2 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.34-1.
52 (2H, m), 1.62-1.81 (4H, m), 1.86-2.08 (4H, m),
2.31 (2H, t, J = 7.4 Hz), 3.50 (2H, t, J = 6.4 Hz), 4.
03-4.22 (6H, m), 7.18-7.31 (2H, m), 7.68 (1H, ddd,
J = 8.8, 7.2, 1.4Hz), 8.24 (1H, dd, J = 8.2, 1.6 Hz).

Reference Example 151 Ethyl 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-octanoate Obtained in Reference Example 143 in the same manner as in Reference Example 52. The title compound (8.72 g, almost 100%) was obtained as an oil from ethyl 2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-octanoate (6.00 g, 18.1 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 6.8 Hz), 1.30-1.
46 (6H, m), 1.54-1.76 (4H, m), 1.86-2.10 (4H, m),
2.28 (2H, t, J = 7.4 Hz), 3.38-3.54 (2H, m), 4.00-4.
24 (6H, m), 7.16-7.30 (2H, m), 7.68 (1H, t, J = 8.0
Hz), 8.23 (1H, dd, J = 7.6, 1.2 Hz).

Reference Example 152 Methyl 1- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl] -1-cyclopentylcarboxylate Ethyl methyl 1- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline obtained in Reference Example 144 in the same manner as in Reference Example 52. -3-yl) -1-cyclopentylcarboxylate (1.88 g, 6.52 mmol) from the title compound (1.53 g, 5
5%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 96-98 ° C. IR (KBr):. 2949, 1744, 1709, 1663, 1495, 1481 cm -1 1 H-NMR (CDCl 3) δ: 1.74-2.08 (8H, m), 2.33-2.58 (4
H, m), 3.48 (2H, t, J = 6.4 Hz), 3.70 (3H, s), 4.11
(2H, t, J = 7.0 Hz), 7.12-7.30 (2H, m), 7.67 (1H, t,
J = 8.0 Hz), 8.16 (1H, d, J = 8.2 Hz). Elemental analysis: Calculated as C ₁₉ H ₂₃ N ₂ O ₄ Br (%): C, 53.91; H, 5.48; N, 6.62. Found (%): C, 53.96; H, 5.34; N, 6.47.

Reference Example 153 Methyl 1- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl] -1-cyclohexylcarboxylate Ethyl methyl 1- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline obtained in Reference Example 145 in the same manner as in Reference Example 52. -3-yl) -1-cyclohexylcarboxylate (5.20 g, 17.2 mmol) from the title compound (8.52 g,
(Approximately 100%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.30-2.24 (12H, m), 2.78-2.94
(2H, m), 3.40-3.52 (2H, m), 3.72 (3H, s), 4.04-4.16
(2H, m), 7.12-7.30 (2H, m), 7.65 (1H, t, J = 7.4 H
z), 8.13 (1H, d, J = 8.2 Hz).

Reference Example 154 1- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] -1-cyclohexylcarboxylic acid Same as Reference Example 109 According to the method, methyl 1- [1- (4-bromobutyl) -2,4-dioxo-1,2,
The title compound (2.35 g, 69%) was obtained as an oil from 3,4-tetrahydroquinazolin-3-yl] -1-cyclohexylcarboxylate (3.52 g, 8.05 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.50-2.28 (12H, m), 2.82-3.00
(2H, m), 3.58 (2H, t, J = 6.0 Hz), 4.06-4.17 (2H,
m), 7.12-7.30 (2H, m), 7.65 (1H, d, J = 8.0 Hz), 8.14
(1H, dd, J = 8.0, 1.4 Hz).

Reference Example 155 Ethyl 1- (4-bromobutyl) -2,4-dioxo-6-fluoro-
1,2,3,4-tetrahydroquinazoline-3-valerate Ethyl 2,4-dioxo-6-fluoro-1,2,3,4-tetrahydrodiene obtained in Reference Example 146 in the same manner as in Reference Example 52. The title compound (2.46 g, 43%) was obtained as an oil from quinazoline-3-valerate (3.98 g, 12.9 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 6.8 Hz), 1.66-1.
78 (4H, m), 1.86-2.02 (4H, m), 2.36 (2H, t, J = 6.6 H
z), 3.49 (2H, t, J = 6.0 Hz), 4.04-4.20 (6H, m), 7.19
(1H, dd, J = 9.2, 4.2 Hz), 7.41 (1H, dt, J = 7.2, 3.0
Hz), 7.91 (1H, dd, J = 8.2, 3.0 Hz).

Reference Example 156 ethyl 1- (4-bromobutyl) -2,4-dioxo-6-methoxy-
1,2,3,4-tetrahydroquinazoline-3-valerate Ethyl 2,4-dioxo-6-methoxy-1,2,3,4-tetrahydrodiene obtained in Reference Example 147 in the same manner as in Reference Example 52. The title compound (3.14 g, 53%) was obtained as an oil from quinazoline-3-valerate (4.50 g, 14.0 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.68-2.
08 (8H, m), 2.32-2.42 (2H, m), 3.49 (2H, t, J = 5.8 H
z), 3.88 (3H, s), 4.05-4.20 (4H, m), 4.12 (2H, q,
J = 7.2 Hz), 7.14 (1H, d, J = 9.2 Hz), 7.29 (1H, dd, J
= 9.2, 2.8 Hz), 7.67 (1H, d, J = 3.0 Hz).

Reference Example 157 Ethyl 1- (4-bromobutyl) -2,4-dioxo-6-nitro-1,
2,3,4-tetrahydroquinazoline-3-valerate Ethyl 2,4-dioxo-6-nitro-1,2,3,4-tetrahydroquinazoline obtained in Reference Example 148 in the same manner as in Reference Example 52. The title compound (4.10 g, 59%) was obtained as an oil from 3-valerate (5.00 g, 14.9 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.66-1.
85 (4H, m), 1.90-2.08 (4H, m), 2.37 (2H, t, J = 6.2 H
z), 3.50 (2H, t, J = 5.8 Hz), 4.06-4.14 (2H, m), 4.12
(2H, q, J = 7.4 Hz), 4.22 (2H, t, J = 7.8 Hz), 7.34
(1H, d, J = 9.2 Hz), 8.52 (1H, dd, J = 9.2, 2.4 Hz),
9.09 (1H, d, J = 2.6 Hz).

Reference Example 158 Ethyl 2,4-dioxo-6- (2-methoxyethoxy) methoxy
-1,2,3,4-tetrahydroquinazoline-3-valerate The ethyl 2,4-dioxo-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate obtained in Reference Example 149 (3.50 g) , 11.8 mmol) in dichloromethane (35.0 ml) was suspended in N, N-diisopropylethylamine (2.05 ml, 17.
7 mmol) and 2-methoxyethoxymethyl chloride (2.02
ml, 17.7 mmol) was added dropwise under ice cooling, and the reaction mixture was allowed to stand at room temperature.
Stir for 18 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to remove the title compound (3.6
8 g, 79%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 105-107 ° C. IR (KBr): 3075, 2911, 1744, 1709, 1661, 1634, 1510
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.25 (3H, t, J = 7.0 Hz), 1.72-1.
80 (4H, m), 2.39 (2H, t, J = 7.0 Hz), 3.39 (3H, s),
3.55-3.61 (2H, m), 3.81-3.88 (2H, m), 4.10 (2H, t,
J = 6.8 Hz), 4.12 (2H, q, J = 7.0 Hz), 5.30 (2H, s),
7.06 (1H, d, J = 8.8 Hz), 7.35 (1H, dd, J = 8.8, 2.6 H
z), 7.76 (1H, d, J = 3.0 Hz), 9.81 (1H, bs). Elemental analysis: Calculated as C ₁₉ H ₂₆ N ₂ O ₇ (%): C, 57.86; H, 6.64; N , 7.10. Found (%): C, 57.70; H, 6.52; N, 7.35.

Reference Example 159 Ethyl 1- (4-bromobutyl) -2,4-dioxo-6- (2-methoxyethoxy) methoxy-1,2,3,4-tetrahydroquinazoline
3-Valerate Ethyl 2,4-dioxo-6- (2-methoxyethoxy) methoxy-1,2,3,4-tetrahydroquinazoline-3- obtained in Reference Example 158 in the same manner as in Reference Example 52. Balleret (6.
(00 g, 15.2 mmol) to give the title compound (4.74 g, 59%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 1.68-1.
80 (4H, m), 1.86-2.02 (4H, m), 2.36 (2H, t, J = 7.0 H
z), 3.38 (3H, s), 3.49 (2H, t, J = 6.6 Hz), 3.54-3.6
0 (2H, m), 3.80-3.87 (2H, m), 4.04-4.20 (4H, m),
4.12 (2H, q, J = 7.2 Hz), 7.04 (1H, d, J = 9.2 Hz), 7.
40 (1H, dd, J = 9.0, 3.0 Hz), 7.86 (1H, d, J = 3.0 Hz).

REFERENCE EXAMPLE 160 Ethyl 1- (4-bromobutyl) -2,4-dioxo-6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate Ethyl 1- ( 4-bromobutyl) -2,
4-dioxo-6- (2-methoxyethoxy) methoxy-1,2,3,4-
Tetrahydroquinazoline-3-valerate (4.74 g, 8.95 m
trifluoroacetic acid (1.38 ml, 17.9 mmol) was added dropwise to a dichloromethane (100 ml) solution of
Heated to reflux for an hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (5: 1, v / v) to give the title compound (3.31 g, 84%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.68-1.
80 (4H, m), 1.86-2.04 (4H, m), 2.32-2.62 (2H, m),
3.48 (2H, t, J = 5.6 Hz), 4.04-4.20 (4H, m), 4.12 (2
H, q, J = 7.2 Hz), 7.02 (1H, d, J = 9.2 Hz), 7.28 (1H,
dd, J = 8.8, 3.0Hz), 7.86 (1H, d, J = 2.6 Hz).

Reference Example 161 2- [2- (2-Aminobenzamide) ethoxy] ethanol In the same manner as in Reference Example 1, 2- (2-aminoethoxy) ethanol (1.44 m) was used instead of 4-methoxybenzylamine.
l, 73.6 mmol) to give the title compound (13.8 g, approximately 10
0%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 3.56-3.70 (6H, m), 3.70-3.80 (2
H, m), 5.49 (2H, bs), 6.56 (1H, bs), 6.60-6.72 (2H,
m), 7.21 (1H, ddd, J = 8.4, 7.0, 1.4 Hz), 7.34 (1H,
d, J = 8.0 Hz).

Reference Example 162 2- [2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-
3-yl) ethoxy] ethanol Reference Example 16 was obtained in the same manner as in Reference Example 26 (method 2).
The title compound (6.23) was obtained from 2- [2- (2-aminobenzamide) ethoxy] ethanol (13.8 g, 61.5 mmol) obtained in Step 1.
g, 41%). Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 149-151 ° C. IR (KBr): 3193, 2930, 2880, 1715, 1667, 1622, 1493
^{. cm -1 1 H-NMR (} CDCl 3) δ: 3.04 (1H, bs),
3.64-3.76 (4H, m), 3.85
(2H, t, J = 5.6 Hz), 4.34 (2
H, t, J = 5.6 Hz), 7.11 (1
H, d, J = 8.0 Hz), 7.20 (1
H, t, J = 7.4 Hz), 7.59 (1H,
ddd, J = 8.8, 7.4, 1.4H
z), 8.08 (1H, dd, J = 8.2,
1.2 Hz), 10.05 (1H, bs). Elemental analysis: C ₁₂ H ₁₄ N ₂ O ₄ .0.2H ₂ O Calculated (%): C, 56.78; H, 5.72; N, 11.04. Found (%): C, 56.81; H, 5.64; N, 11.07.

Reference Example 163 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Yl) ethoxyacetic acid 2- [2- (2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl) ethoxy] ethanol (6.23 g, 24.9 mmol) in acetone (300 ml)
Jones reagent was added dropwise and the reaction mixture was stirred at room temperature for 5 hours. Excess Jones reagent was decomposed with 2-propanol, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After washing the extract with water and drying (MgSO ₄ ),
The solvent was distilled off under reduced pressure to obtain the title compound (5.05 g, 77%) as white crystals. This product was used for the next reaction without further purification.

Reference Example 164 Ethyl 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) ethoxyacetate In the same manner as in Reference Example 107, the compound obtained in Reference Example 163 was obtained. -(2,4-dioxo-1,2,3,4-tetrahydroquinazoline
The title compound (2.91 g, 52%) was synthesized from (-3-yl) ethoxyacetic acid (5.05 g, 19.1 mmol). Recrystallization from ethyl ether gave colorless crystals having a melting point of 115-116 ° C. IR (KBr):. 3204, 2982, 1717, 1667, 1622, 1494 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 3.94 (2
H, t, J = 5.6 Hz), 4.16 (2H, s), 4.16 (2H, q, J = 7.0 H
z), 4.38 (2H, t, J = 5.6 Hz), 7.11 (1H, d, J = 8.0 H
z), 7.22 (1H, ddd, J = 8.0, 7.0, 1.0 Hz), 7.61 (1H,
ddd, J = 8.4, 7.0,1.4 Hz), 8.11 (1H, dd, J = 8.0, 1.6
Hz), 10.06 (1H, bs). Elemental analysis: C ₁₄ H ₁₆ N ₂ O ₅ Calculated (%): C, 57.53; H, 5.52; N, 9.58. Found (%): C, 57.43 ; H, 5.39; N, 9.70.

Reference Example 165 Ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-
[Tetrahydroquinazolin-3-yl] ethoxyacetate Ethyl 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) obtained in Reference Example 164 in the same manner as in Reference Example 52. Ethoxy acetate (2.81 g, 9.61 mmo
The title compound (1.71 g, 42%) was obtained from l) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.2 Hz), 1.75-2.
10 (4H, m), 3.49 (2H, t, J = 5.8 Hz), 3.88 (2H, t, J =
5.8 Hz), 4.10-4.28 (6H, m), 4.38 (2H, t, J = 5.4 H
z), 7.18-7.32 (2H, m), 7.69 (1H, t, J = 7.2 Hz), 8.2
4 (1H, d, J = 6.8 Hz), 10.06 (1H, bs).

Reference Example 166 Ethyl 2- (2-amino-6-fluorobenzamido) isobutyrate By the same method as in Reference Example 21, the title compound (4.75 g, 30.0 mmol) was obtained from 2-amino-6-fluorobenzoic acid (4.75 g, 30.0 mmol). 7.78 g, 9
7%) as an oil. IR (KBr): 3472, 3355, 2986, 1732, 1645, 1626, 158
^{. 8, 1518 cm -1 1 H} -NMR (CDCl 3) δ: 1.27 (3H, t, J = 7.2 Hz), 1.62 (6
H, s), 4.22 (2H, q, J = 7.2 Hz), 5.87 (2H, bs), 6.29
-6.45 (2H, m, ArH), 7.09 ( ¹ H, dt, J = 6.6 Hz, 8.2 H
z), 7.13 (1H, bs).

Reference Example 167 Ethyl 2- (2-amino-4,5-difluorobenzamido) isobutyrate In the same manner as in Reference Example 21, 2-amino-4,5-difluorobenzoic acid (5.35 g, 30.0 mmol) From the title compound (7.49
g, 87%) as an oil. IR (KBr): 3463, 3360, 2986, 1725, 1651, 1597, 157
^{. 4, 1532, 1510 cm -1} 1 H-NMR (CDCl 3) δ: 1.28 (3H, t,
J = 7.2 Hz), 1.64 (6H, s), 4.23 (2H, q, J = 7.2 Hz),
5.45 (1H, bs), 6.44 (1H, dd, J = 12.0 Hz, 6.6 Hz),
6.48 (1H, bs), 7.18 (1H, dd, J = 10.8 Hz, 8.6 Hz).

Reference Example 168 Ethyl 2- (2-amino-3-methoxybenzamido) isobutyrate In the same manner as in Reference Example 21, the title compound (5.12 g, 30.0 mmol) was obtained from 2-amino-3-methoxybenzoic acid (5.12 g, 30.0 mmol). 7.63 g, 9
1%) as an oil. IR (KBr): 3490, 3360, 2984, 2938, 1732, 1642, 1520
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.27 (3H, t, J = 7.2 Hz), 1.64 (6
H, s), 3.86 (3H, s), 4.23 (2H, q, J = 7.2 Hz), 5.74
(2H, bs), 6.60 (1H, bs), 6.60 (1H, t, J = 7.9Hz), 6.
81 (1H, d, J = 7.0 Hz), 6.99 (1H, d, J = 7.8 Hz).

Reference Example 169 Ethyl 2- (3-amino-2-naphthalenecarboxamide) isobutyrate In the same manner as in Reference Example 21, 3-amino-2-naphthalenecarboxylic acid (80%, 4.68 g, 20.0 mmol) was prepared. The title compound (4.11 g, 68%) was obtained as crystals. IR (KBr): 3466, 3364, 3052, 2984, 2938, 1728, 165
. 3, 1609, 1578, 1561 , 1522 cm -1 1 H-NMR (CDCl 3) δ: 1.30 (3H, t, J = 7.2 Hz), 1.71 (6
H, s), 4.26 (2H, q, J = 7.2 Hz), 5.16 (2H, bs), 6.83
(1H, bs), 6.98 (1H, s), 7.17-7.25 (1H, m), 7.35-7.
43 (1H, m), 7.55 (1H, d, J = 8.4 Hz), 7.69 (1H, d, J
= 8.4 Hz), 7.91 (1H, s).

Reference Example 170 Ethyl 2- (2,4-dioxo-5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (method 3). Reference Example 16
The title compound (4.34) was obtained from ethyl 2- (2-amino-6-fluorobenzamido) isobutyrate (7.77 g, 29.0 mmol) obtained in Step 6.
g, 51%). Melting point 168-170 ° C. IR (KBr): 3206-2826, 1736, 1719, 1665, 1636, 1603,
^{. 1526 cm -1 1 H-NMR} (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.87 (6
H, s), 4.20 (2H, q, J = 7.2 Hz), 6.81-6.93 (2H, m, A
rH), 7.53 (1H, dt, J = 8.2 Hz, 5.2 Hz), 10.21 (1H, br
s). Elemental analysis: C ₁₄ H ₁₅ N ₂ O ₄ F Calculated (%): C, 57.14; H, 5.14; N, 9.52 Found (%): C, 56.91; H, 5.17; N, 9.51

Reference Example 171 Ethyl 2- (2,4-dioxo-6,7-difluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate The same method as in Reference Example 42 (Method 3) Thus, Reference Example 16
Title compound from ethyl 2- (2-amino-4,5-difluorobenzamido) isobutyrate (7.48 g, 26.1 mmol) obtained in 7
(8.65 g, about 100%) was synthesized. 166-168 ° C (recrystallized from ethanol). IR (KBr): 3119, 3085, 3000, 2942, 2878, 1736, 171
. 7, 1659, 1640, 1626 , 1520, 1508 cm -1 1 H-NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.86 (6
H, s), 4.20 (2H, q, J = 7.2 Hz), 6.88 (1H, dd, J = 9.8
Hz, 6.2 Hz), 7.86 (1H, dd, J = 9.6 Hz, 8.2 Hz), 10.
13 (1H, brs). Elemental analysis: Calculated as C ₁₄ H ₁₄ N ₂ O ₄ F ₂ Calculated (%): C, 53.85; H, 4.52; N, 8.97 Found (%): C, 53.89; H , 4.49; N, 8.97

Reference Example 172 Ethyl 2- (2,4-dioxo-8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (method 3). Reference Example 16
The title compound (6.99 g) was obtained from ethyl 2- (2-amino-3-methoxybenzamide) isobutyrate (7.62 g, 27.2 mmol) obtained in Step 8.
g, 84%). Mp 144-145 ℃ (recrystallized from ethanol). IR (KBr): 3208, 2986, 2940, 1743, 1715, 1670, 166
. 1, 1624, 1609, 1516 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.85 (6
H, s), 3.96 (3H, s), 4.19 (2H, q, J = 7.2 Hz), 7.05-
7.17 (2H, m, ArH), 7.62 (1H, dt, J = 7.4 Hz, 1.6 H
z), 8.18 (1H, bs). Elemental analysis: Calculated as C ₁₅ H ₁₈ N ₂ O ₅ (%): C, 58.82; H, 5.92; N, 9.15 Found (%): C, 58.94; H, 5.64; N, 9.27

Reference Example 173 Ethyl 2- (2,4-dioxo-1,2,3,4-tetrahydrobenzo [g] quinazolin-3-yl) isobutyrate By the same method as in Reference Example 42 (method 3). Reference Example 16
The title compound was obtained from ethyl 2- (3-amino-2-naphthalenecarboxamide) isobutyrate (4.10 g, 13.7 mmol) obtained in Step 9.
(1.90 g, 42%) was synthesized. Melting point 194-197 ° C (recrystallized from ethanol). IR (KBr): 3235-2874, 1725, 1698, 1678, 1636, 1611,
^{. 1584, 1528 cm -1 1 H} -NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.93 (6
H, s), 4.23 (2H, q, J = 7.2 Hz), 7.38-7.61 (3H, m, A
rH), 7.81 (1H, d, J = 8.2 Hz), 7.93 (1H, d, J = 8.2 H
. z), 8.66 (1H, s), 9.56 (1H, bs) Elemental analysis: Calculated _{C 18 H 18 N 2 O 4} (%): C, 66.25; H, 5.56; N, 8.58 Found ( %): C, 65.98; H, 5.50; N, 8.42

Reference Example 174 Ethyl 2- (6-amino-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate 2- (2,4 -Dioxo-6-nitro-1,2,
Ethyl 3,4-tetrahydroquinazolin-3-yl) isobutyrate
(1.61 g, 5.0 mmol) was dissolved in a mixed solvent of ethanol (10 ml) and tetrahydrofuran (15 ml), and 10% palladium was dissolved.
-The catalyst was subjected to a catalytic reduction reaction in the presence of carbon (containing 50% water, 0.50 g) at normal temperature and normal pressure for 2 hours. After the catalyst was filtered off, the filtrate was concentrated to give the title compound (0.79 g, 54%) as crystals. IR (KBr): 3434, 3358, 3243, 3042, 2940, 1715, 165
^{. 6, 1636, 1520 cm -1} 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.85 (6
H, s), 4.19 (2H, q, J = 7.2 Hz), 6.82 (1H, d, J = 8.8
Hz), 6.97 (1H, dd, J = 8.5 Hz, 2.5 Hz), 7.32 (1H, d,
J = 2.4 Hz), 8.52 (1H, bs).

Reference Example 175 Ethyl 2- [2,4-dioxo-6- (1-pyrrolyl) -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (6-amino-2,4-dioxo-1,
Ethyl 2,3,4-tetrahydroquinazolin-3-yl) isobutyrate
(0.79 g, 2.71 mmol), a mixture of 2,5-dimethoxytetrahydrofuran (0.39 ml, 2.98 mmol) and acetic acid (5.0 ml) were stirred at 100 ° C. for 1 hour. After cooling, add water to the reaction solution,
Extracted with ethyl acetate. Wash the extract with water and dry (MgSO ₄ )
Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography, and n-hexane-ethyl acetate (2: 1, v
/ v) to give the title compound (0.62 g, 67%) as colorless crystals. IR (KBr): 3210-2876, 1732, 1713, 1663, 1634, 1522
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.90 (6
H, s), 4.21 (2H, q, J = 7.2 Hz), 6.38 (2H, t, J = 2.2
Hz), 7.10 (2H, t, J = 2.2 Hz), 7.11 (2H, d, J = 8.8 H
z), 7.66 (1H, dd, J = 8.8 Hz, 2.6 Hz), 8.06 (1H, d,
J = 2.6 Hz), 10.01 (1H, brs). Elemental analysis: Calculated as C ₁₈ H ₁₉ N ₃ O ₄ Calculated (%): C, 63.33; H, 5.61; N, 12.31 Observed (%): C , 63.19; H, 5.61; N, 12.11

Reference Example 176 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Yl) isobutyric acid ethyl 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (1.31
g, 5.0 mmol), 6N hydrochloric acid (10.0 ml) and acetic acid (5.0 ml)
Was heated to reflux for 30 minutes. After cooling, the mixture was diluted with water, and the precipitated crystals were collected by filtration and washed with water to give the title compound (1.00 g, 81%) as colorless crystals. 227-230 ° C. IR (KBr): 3275, 2992, 2940, 1748, 1725, 1707, 165
^{. 6, 1622, 1609 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.70 (6H, s), 7.13-7.23 (2H,
m, ArH), 7.61-7.69 (1H, m, ArH), 7.88 (1H, dd, J =
7.8 Hz, 1.2 Hz), 11.35 (1H, s). Elemental analysis: Calculated as C ₁₂ H ₁₂ N ₂ O ₄ (%): C, 58.06; H, 4.87; N, 11.28 Actual (%): C, 58.14; H, 4.80; N, 11.25

Reference Example 177 2- (2,4-Dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid The compound of Reference Example 44 was obtained in the same manner as in Reference Example 176. 2- (2,4-dioxo-6-methyl-
The title compound (2.19 g, 84%) was synthesized from ethyl 1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (2.90 g, 10.0 mmol). Melting point 268-271 ° C. IR (KBr): 3059, 2994, 2948, 1713, 1671, 1628, 161
^{. 3, 1518 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.70 (6H, s), 2.33 (3H, s),
7.06 (1H, d, J = 8.2 Hz), 7.47 (1H, dd, J = 8.4 Hz, 2.0
Hz), 7.67 (1H, s, ArH), 11.25 (1H, s). Elemental analysis: C ₁₃ H ₁₄ N ₂ O ₄ Calculated (%): C, 59.54; H, 5.38; N, 10.68 Value (%): C, 59.37; H, 5.34; N, 10.63

Reference Example 178 2- (2,4-Dioxo-5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid The compound of Reference Example 170 was obtained in the same manner as in Reference Example 176. Ethyl 2- (2,4-dioxo-5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (3.83 g, 13.0 mm
ol) to give the title compound (3.21 g, 93%). Melting point 258-260 ° C. IR (KBr): 3069, 3020, 2948, 2905, 2822, 1717, 167
. 1, 1634, 1603, 1528 cm -1 1 H-NMR (DMSO-d 6) δ: 1.68 (6H, s), 6.89-6.99 (2H,
m, ArH), 7.62 (1H, dt, J = 8.2 Hz, 5.4 Hz), 11.48 (1
H, bs). Elemental analysis: Calculated as C ₁₂ H ₁₁ N ₂ O ₄ F (%): C, 54.14; H, 4.16; N, 10.52 Observed (%): C, 54.27; H, 4.21; N, 10.44

Reference Example 179 2- (2,4-Dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid Obtained in Reference Example 46 in the same manner as in Reference Example 176. Ethyl 2- (2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (8.83 g, 30.0 mmo
The title compound (5.48 g, 69%) was synthesized from l). Melting point 249-253 ° C. IR (KBr): 3198, 3090, 2992, 2936, 1721, 1701, 167
^{. 1, 1630, 1510 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.71 (6H, s), 7.20 (1H, dd, J
= 8.5 Hz, 4.5 Hz), 7.53-7.63 (2H, m, ArH), 11.43 (1
H, bs). Elemental analysis: C ₁₂ H ₁₁ N ₂ O ₄ F Calculated (%): C, 54.14; H, 4.16; N, 10.52 Found (%): C, 54.23; H, 4.25; N, 10.51

Reference Example 180 2- (2,4-dioxo-6,7-difluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid Reference Example 171 was prepared in the same manner as in Reference Example 176. Ethyl 2- (2,4-dioxo-6,7-difluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (6.87 g, 2
The title compound (3.29 g, 53%) was synthesized from 2.0 mmol). Melting point: 242-244 ° C. IR (KBr): 3073, 3009, 2948, 1732, 1717, 1665, 163
^{. 8, 1624, 1518 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.69 (6H, s), 7.09 (1H, dd, J
= 10.9 Hz, 6.5 Hz), 7.85 (1H, dd, J = 10.3 Hz, 8.5 H
z), 11.51 (1H, bs). Elemental analysis: Calculated as C ₁₂ H ₁₀ N ₂ O ₄ F ₂ Calculated (%): C, 50.71; H, 3.55; N, 9.86 Actual (%): C, 50.84; H, 3.54; N, 9.68

Reference Example 181 2- (2,4-dioxo-8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid The compound of Reference Example 172 was obtained in the same manner as in Reference Example 176. Ethyl 2- (2,4-dioxo-8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (4.59 g, 15.0 mm
ol) to give the title compound (3.82 g, 92%). IR (KBr): 3200-2569, 1713, 1665, 1624, 1607, 1518
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.70 (6H, s), 3.89 (3H, s),
7.13 (1H, t, J = 8.1 Hz), 7.29 (1H, dd, J = 8.1 Hz, 1.1
. Hz), 7.45 (1H, d, J = 7.8 Hz), 10.73 (1H, bs) Elemental _{analysis: C 13 H 14 N 2 O} 5 Calculated (%): C, 56.11; H, 5.07; N , 10.07 Found (%): C, 56.47; H, 5.05; N, 10.00

Reference Example 182 2- (6-Chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid Obtained in Reference Example 48 in the same manner as in Reference Example 176. The title compound (6.43 g, 90%) was obtained from the obtained ethyl 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (7.90 g, 25.4 mmol). Was synthesized. Melting point 256-259 ℃. IR (KBr): 3193-2938, 1719, 1705, 1671, 1611, 1607,
^{. 1503 cm -1 1 H-NMR} (DMSO-d 6) δ: 1.69 (6H, s), 7.17 (1H, d, J =
8.8 Hz), 7.69 (1H, dd, J = 8.8 Hz, 2.6 Hz), 7.82 (1H,
d, J = 2.6 Hz), 11.49 (1H, s). Elemental analysis: Calculated as C ₁₂ H ₁₁ N ₂ O ₄ Cl Calculated (%): C, 50.99; H, 3.92; N, 9.91 Actual (% ): C, 51.08; H, 3.93; N, 9.85

Reference Example 183 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid Obtained in Reference Example 47 in the same manner as in Reference Example 176. The title compound (3.55 g, 84%) was obtained from ethyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (4.66 g, 15.0 mmol). Was synthesized. 260-263 ° C. IR (KBr): 3088, 2988, 2946, 2882, 1717, 1698, 166
^{. 3, 1617, 1605 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.69 (6H, s), 7.17-7.25 (2H,
m, ArH), 7.88 (1H, d, J = 8.2 Hz), 11.46 (1H, s). Elemental analysis: Calculated as C ₁₂ H ₁₁ N ₂ O ₄ Cl (%): C, 50.99; H, 3.92; N, 9.91 found (%): C, 51.03; H, 3.95; N, 9.94.

Reference Example 184 2- (2,4-Dioxo-1,2,3,4-tetrahydrobenzo [g] quinazolin-3-yl) isobutyric acid Obtained in Reference Example 173 in the same manner as in Reference Example 176. 2- (2,4-dioxo-1,2,3,4-
The title compound (1.37 g, 92%) was obtained from ethyl tetrahydrobenzo [g] quinazolin-3-yl) isobutyrate (1.63 g, 5.00 mmol).
%) Were synthesized. 273-276 ° C. IR (KBr): 3179-2826, 2668, 2571, 1717, 1710, 1665,
^{. 1638, 1588, 1532 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.74 (6H, s), 7.41-7.63 (3H,
m, ArH), 7.90 (1H, d, J = 8.2 Hz), 8.08 (1H, d, J = 7.8
Hz), 8.61 (1H, s, ArH), 11.40 (1H, bs). Elemental analysis: C ₁₆ H ₁₄ N ₂ O ₄ Calculated (%): C, 64.42; H, 4.73; N, 9.39 Value (%): C, 64.43; H, 4.56; N, 9.48

Reference Example 185 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-
Yl) phenacyl isobutyrate 2- (2,4-dioxo-1,2,3,4-
Tetrahydroquinazolin-3-yl) isobutyric acid (0.74 g, 3.0
mmol), 2-bromoacetophenone (0.61 g, 3.0 mmol), potassium fluoride (0.38 g, 6.6 mmol) and N, N-dimethylformamide (3.0 ml) were stirred at room temperature for 15 hours. The reaction mixture was diluted with water and extracted with ethyl ether. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (0.85 g, 77%) as colorless crystals. IR (KBr): 3266, 3212, 3069, 2994, 2940, 1750, 171
. 7, 1667, 1620, 1609 cm -1 1 H-NMR (CDCl 3) δ: 2.00 (6H, s), 5.36 (2H, s), 7.0
3 (1H, d, J = 8.0 Hz), 7.16-7.24 (1H, m, ArH), 7.27-
7.47 (2H, m, ArH), 7.53-7.63 (2H, m, ArH), 7.84-7.
88 (2H, m, ArH), 8.01-8.06 (1H, m, ArH), 9.87 (1H,
bs).

Reference Example 186 Phenacyl 2- (2,4-dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 177 was prepared. The title compound (1.91 g, 72%) was obtained from the obtained 2- (2,4-dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (1.84 g, 7.00 mmol). Was synthesized. Melting point 189-191 ° C. IR (KBr): 3280, 3208, 3065, 3031, 2992, 2940, 175
. 0, 1717, 1667, 1628 , 1599, 1518 cm -1 1 H-NMR (CDCl 3) δ: 1.99 (6H, s), 2.38 (3H, s), 5.3
5 (2H, s), 6.92 (1H, d, J = 8.2 Hz), 7.37-7.61 (4H,
m, ArH), 7.83-7.88 (3H, m, ArH), 9.54 (1H, bs). Elemental analysis: C ₂₁ H ₂₀ N ₂ O ₅ Calculated (%): C, 66.31; H, 5.30; N, 7.36 Found (%): C, 66.25; H, 5.24; N, 7.49

Reference Example 187 Phenacyl 2- (2,4-dioxo-8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 181 was prepared. The title compound (3.99 g, almost 100%) was obtained from the obtained 2- (2,4-dioxo-8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (2.78 g, 10.0 mmol). ) Was synthesized. 132-133 ° C. IR (KBr): 3210-2940, 1752, 1715, 1705, 1661, 1624,
^{. 1609, 1516 cm -1 1 H} -NMR (CDCl 3) δ: 1.97 (6H, s), 3.95 (3H, s), 5.3
4 (2H, s), 7.04-7.17 (2H, m, ArH), 7.41-7.64 (4H,
m, ArH), 7.87-7.92 (2H, m, ArH), 8.21 (1H, bs) .Elemental analysis: Calculated as C ₂₁ H ₂₀ N ₂ O ₆・ 0.5AcOEt. , 5.49; N, 6.36 Found (%): C, 62.76; H, 5.57; N, 6.43

Reference Example 188 Phenacyl 2- (2,4-dioxo-5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 178 was prepared. The title compound (3.15 g, 75%) was obtained from the obtained 2- (2,4-dioxo-5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (2.93 g, 11.0 mmol). Was synthesized. 179-180 ° C. IR (KBr): 3277, 3227, 3140, 3073, 3029, 2946, 172
. 1, 1701, 1671, 1632 , 1601, 1518 cm -1 1 H-NMR (CDCl 3) δ: 1.99 (6H, s), 5.37 (2H, s), 6.8
0-6.90 (2H, m, ArH), 7.40-7.61 (4H, m, ArH), 7.82-
7.87 (2H, m, ArH) , 10.04 (1H, bs) Elemental _{analysis: C 20 H 17 N 2 O} 5 F Calculated (%):. C, 62.50 ; H, 4.46; N, 7.29 Found ( %): C, 62.18; H, 4.42; N, 7.24

Reference Example 189 Phenacyl 2- (2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 179 was prepared. The title compound (3.10 g, 45%) was obtained from the obtained 2- (2,4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (4.79 g, 18.0 mmol). Was synthesized. Melting point 192-193 ℃ (recrystallized from ethanol). IR (KBr): 3202, 3085, 2998, 2940, 1721, 1705, 166
^{. 7, 1510 cm -1 1 H} -NMR (CDCl 3) δ: 2.00 (6H, s), 5.36 (2H, s), 7.0
1 (1H, dd, J = 8.9 Hz, 4.1 Hz), 7.27-7.62 (4H, m, Ar
H), 7.70 (1H, dd, J = 8.2 Hz, 2.8 Hz), 7.83-7.87 (2
. H, m, ArH) Elemental _{analysis: C 20 H 17 N 2 O} 5 F Calculated (%): C, 62.50; H, 4.46; N, 7.29 Found (%): C, 62.25; H, 4.47; N, 7.14

Reference Example 190 Phenacyl 2- (2,4-dioxo-6,7-difluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate By the same method as in Reference Example 185, Reference Example 2- (2,4-dioxo-6,7-difluoro-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (3.13 g, 11.0 mmol
The title compound (3.61 g, 82%) was synthesized from l). 174-176 ° C (recrystallized from ethanol). IR (KBr): 3121, 3088, 3004, 2949, 2876, 1748, 171
. 7, 1701, 1663, 1640 , 1628, 1518, 1505 cm -1 1 H-NMR (CDCl 3) δ: 1.99 (6H, s), 5.39 (2H, s), 6.8
5 (1H, dd, J = 6.2 Hz, 9.6 Hz), 7.41-7.63 (3H, m, Ar
. H), 7.77-7.89 (3H, m, ArH), 10.13 (1H, bs) Elemental _{analysis: C 20 H 16 N 2 O} 5 F 2 Calculated (%): C, 59.70; H, 4.01; N, 6.96 found (%): C. 59.55; H, 4.14; N, 6.96.

Reference Example 191 Phenacyl 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 182 The title compound (3.12 g, 78%) was obtained from the obtained 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (2.83 g, 10.0 mmol). Was synthesized. Melting point 197-199 ° C. IR (KBr): 3200, 3073, 3031, 2994, 2938, 1748, 171
. 7, 1667, 1618, 1599 cm -1 1 H-NMR (CDCl 3) δ: 1.99 (6H, s), 5.36 (2H, s), 6.9
7 (1H, d, J = 8.6 Hz), 7.40-7.63 (4H, m, ArH), 7.82-
7.86 (2H, m, ArH), 7.98 (1H, d, J = 2.4 Hz), 9.95 (1
. H, bs) Elemental _{analysis: C 20 H 17 N 2 O} 5 Calculated Cl (%): C, 59.93 ; H, 4.28; N, 6.99 Found (%): C, 59.84; H, 4.27; N, 6.94

Reference Example 192 Phenacyl 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 183 was prepared. The title compound (3.16 g, 79%) was obtained from the obtained 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) isobutyric acid (2.83 g, 10.0 mmol). Was synthesized. 203-204 ° C. IR (KBr): 3258, 3210-2936, 1732, 1719, 1701, 1672,
^{. 1618, 1601 cm -1 1 H} -NMR (CDCl 3) δ: 2.00 (6H, s), 5.40 (2H, s), 7.0
5 (1H, d, J = 1.8 Hz), 7.14 (1H, dd, J = 1.9 Hz, 8.5 H
z), 7.41-7.63 (3H, m, ArH), 7.85-7.89 (2H, m, Ar
. H), 7.95 (1H, d, J = 8.6 Hz) Elemental _{analysis: C 20 H 17 N 2 O} 5 Calculated Cl (%): C, 59.93 ; H, 4.28; N, 6.99 Found (% ): C, 59.96; H, 4.14; N, 7.02

Reference Example 193 Phenacyl 2- (2,4-dioxo-1,2,3,4-tetrahydrobenzo [g] quinazolin-3-yl) isobutyrate In the same manner as in Reference Example 185, Reference Example 184 was prepared. The obtained 2- (2,4-dioxo-1,2,3,4-tetrahydrobenzo [g]
The title compound (1.52 g, 91%) was synthesized from quinazolin-3-yl) isobutyric acid (1.19 g, 4.00 mmol). Melting point: 184-185 ° C (recrystallized from ethanol). IR (KBr): 3280, 3059, 2990, 2938, 1750, 1717, 166
^{. 9, 1638 cm -1 1 H} -NMR (CDCl 3) δ: 2.06 (6H, s), 5.38 (2H, s), 7.3
1-7.60 (6H, m, ArH), 7.75-7.93 (4H, m, ArH), 8.61
(1H, s, ArH), 9.65 (1H, bs). Elemental analysis: Calculated as C ₂₄ H ₂₀ N ₂ O ₅ , 0.5 EtOH (%): C, 68.33; H, 5.28; N, 6.37. (%): C, 68.37; H, 4.97; N, 6.55

Reference Example 194 2- [1- (4-bromobutyl) -2,4-dioxo-8-methoxy-1,2,
Ethyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate 2- (2,4-dioxo-8-methoxy-1,2,3,4) obtained in Reference Example 174 in the same manner as in Reference Example 52. Ethyl-tetrahydroquinazolin-3-yl) isobutyrate (0.61 g, 2.00 mmo
The title compound (0.55 g, 62%) was obtained from l) as an oil. IR (KBr):. 2982, 2942, 1744, 1707, 1663, 1603 cm -1 1 H-NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.2 Hz), 1.82 (6
H, s), 1.88-2.00 (4H, m), 3.42-3.48 (2H, m), 3.95
(3H, s), 4.11-4.25 (4H, m), 7.17-7.20 (2H, m, Ar
H), 7.71-7.76 (1H, m, ArH).

Reference Example 195 2- [1- (4-bromobutyl) -2,4-dioxo-6- (1-pyrrolyl)-
Ethyl 1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate 2- [2,4-dioxo-6- (1-pyrrolyl) obtained in Reference Example 175 in the same manner as in Reference Example 52. [1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.41 g, 1.20
mmol) to give the title compound (0.45 g, 79%) as an oil. IR (KBr):. 2984, 2940, 1740, 1707, 1663, 1516 cm -1 1 H-NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.86 (6
H, s), 1.85-2.05 (4H, m), 3.46-3.52 (2H, m), 4.07-
4.14 (2H, m), 4.20 (2H, q, J = 7.2 Hz), 6.38 (2H, t,
J = 2.0 Hz), 7.11 (2H, t, J = 2.0 Hz), 7.24 (1H, d, J
= 8.4 Hz), 7.70 (1H, dd, J = 8.9 Hz, 2.7 Hz), 8.16 (1
(H, d, J = 2.8 Hz).

Reference Example 196 Phenacyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate In the same manner as in Reference Example 52, 2- (2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3 obtained in Reference Example 185
The title compound (0.55 g, 48%) was obtained as an oil from phenacyl (-yl) isobutyrate (0.85 g, 2.30 mmol). IR (KBr):. 2992, 2940, 1752, 1705, 1661, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.85-2.03 (4H, m), 1.97 (6H,
s), 3.44-3.50 (2H, m), 4.08-4.15 (2H, m), 5.37 (2
H, s), 7.15-7.28 (2H, m, ArH), 7.43-7.71 (4H, m, A
rH), 7.89-7.93 (2H, m, ArH), 8.16 (1H, dd, J = 8.0 H
z, 1.4 Hz).

Reference Example 197 2- [1- (4-bromobutyl) -2,4-dioxo-6-methyl-1,2,3,
4-Tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, the 2- (2,4-dioxo-6-methyl-1,2,3,4-tetrahydrofuran obtained in Reference Example 186 was obtained. Phenacyl quinazolin-3-yl) isobutyrate (1.71 g, 4.50 mm
ol) to give the title compound (1.33 g, 57%) as an oil. IR (KBr): 2940, 1752, 1703, 1661, 1624, 1595, 1508
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.82-2.05 (4H, m), 1.96 (6H,
s), 2.40 (3H, s), 3.46 (2H, t, J = 6.3 Hz), 4.05-4.1
3 (2H, m), 5.36 (2H, s), 7.07 (1H, d, J = 8.6 Hz),
7.42-7.63 (4H, m, ArH), 7.89-7.96 (4H, m, ArH).

Reference Example 198 2- [1- (4-bromobutyl) -2,4-dioxo-8-methoxy-1,2,
3,4-tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, the 2- (2,4-dioxo-8-methoxy-1,2,3,4 -Tetrahydroquinazolin-3-yl) phenacyl isobutyrate (3.17 g, 8.00
mmol) to give the title compound (1.45 g, 34%) as an oil. IR (KBr):. 2992, 2942, 1752, 1703, 1659, 1601 cm -1 1 H-NMR (CDCl 3) δ: 1.88-2.00 (4H, m), 1.95 (6H,
s), 3.42-3.48 (2H, m), 3.95 (3H, s), 4.20-4.27 (2
H, m), 5.34 (2H, s), 7.18-7.20 (2H, m, ArH), 7.42-
7.92 (6H, m, ArH).

Reference Example 199 2- [1- (4-bromobutyl) -2,4-dioxo-5-fluoro-1,2,
3,4-Tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, the 2- (2,4-dioxo-5-fluoro-1,2,3,4 Phenacyl-tetrahydroquinazolin-3-yl) isobutyrate (2.69 g, 7.00
mmol) to give the title compound (1.81 g, 50%) as an oil. IR (KBr): 2992, 2942, 1752, 1709, 1671, 1618, 1597
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.83-2.04 (4H, m), 1.96 (6H,
s), 3.47 (2H, t, J = 6.2 Hz), 4.06-4.14 (2H, m), 5.3
7 (2H, s), 6.88-7.00 (2H, m, ArH), 7.43-7.66 (4H,
m, ArH), 7.89-7.93 (2H, m, ArH).

Reference Example 200 2- [1- (4-bromobutyl) -2,4-dioxo-6-fluoro-1,2,
3,4-Tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, 2- (2,4-dioxo-6-fluoro-1,2,3,4) obtained in Reference Example 189 was obtained. Phenacyl-tetrahydroquinazolin-3-yl) isobutyrate (2.88 g, 7.50
mmol) to give the title compound (1.72 g, 44%) as an oil. IR (KBr): 2992, 2940, 1752, 1705, 1663, 1624, 159
^{. 9, 1505 cm -1 1 H} -NMR (CDCl 3) δ: 1.84-2.03 (4H, m), 1.96 (6H,
s), 3.47 (2H, t, J = 6.2 Hz), 4.10 (2H, dt, J = 7.1 H
z, 1.4 Hz), 5.37 (2H, s), 7.16 (1H, dd, J = 9.2 Hz,
4.0 Hz), 7.35-7.64 (4H, m, ArH), 7.83 (1H, dd, J =
(8.3 Hz, 3.1 Hz), 7.89-7.93 (2H, m, ArH).

Reference Example 201 2- [1- (4-bromobutyl) -2,4-dioxo-6,7-difluoro-
1,2,3,4-tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, the 2- (2,4-dioxo-6,7-difluoro-1) obtained in Reference Example 190 was obtained. Phenacyl, 2,3,4-tetrahydroquinazolin-3-yl) isobutyrate (3.22 g,
8.00 mmol) to give the title compound (1.95 g, 45%) as an oil. IR (KBr): 2942, 1752, 1709, 1667, 1636, 1607, 1524
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.83-2.03 (4H, m), 1.95 (6H,
s), 3.44-3.50 (2H, m), 4.01-4.08 (2H, m), 5.37 (2
H, s), 7.00 (1H, dd, J = 11.2 Hz, 6.0 Hz), 7.44-7.64
(3H, m, ArH), 7.88-8.00 (3H, m, ArH).

Reference Example 202 2- [1- (4-bromobutyl) -6-chloro-2,4-dioxo-1,2,3,
4-Tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, 2- (6-chloro-2,4-dioxo-1,2,3,4-tetrahydrofuran obtained in Reference Example 191 was obtained. Phenacyl quinazolin-3-yl) isobutyrate (2.81 g, 7.00 mm
ol) to give the title compound (2.09 g, 56%) as an oil. IR (KBr):. 2942, 1752, 1707, 1665, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.84-2.05 (4H, m), 1.96 (6H,
s), 3.47 (2H, t, J = 6.2 Hz), 4.05-4.14 (2H, m), 5.3
6 (2H, s), 7.13 (1H, d, J = 8.8 Hz), 7.44-7.64 (4H,
m, ArH), 7.89-7.93 (2H, m, ArH), 8.12 (1H, d, J = 2.
6 Hz).

Reference Example 203 2- [1- (4-bromobutyl) -7-chloro-2,4-dioxo-1,2,3,
4-Tetrahydroquinazolin-3-yl] phenacyl isobutyrate In the same manner as in Reference Example 52, the 2- (7-chloro-2,4-dioxo-1,2,3,4-tetrahydrofuran obtained in Reference Example 192 was obtained. Phenacyl quinazolin-3-yl) isobutyrate (2.81 g, 7.00 mm
ol) to give the title compound (1.78 g, 48%) as an oil. IR (KBr):. 2940, 1752, 1709, 1667, 1605 cm -1 1 H-NMR (CDCl 3) δ: 1.84-2.05 (4H, m), 1.96 (6H,
s), 3.48 (2H, t, J = 6.4 Hz), 4.04-4.14 (2H, m), 5.3
7 (2H, s), 7.18-7.24 (2H, m, ArH), 7.43-7.62 (3H,
m, ArH), 7.89-7.93 (2H, m, ArH), 8.09 (1H, d, J = 8.
4 Hz).

Reference Example 204 Phenacyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydrobenzo [g] quinazolin-3-yl] isobutyrate Same as Reference Example 52 Phenacyl 2- (2,4-dioxo-1,2,3,4-tetrahydrobenzo [g] quinazolin-3-yl) isobutyrate obtained in Reference Example 193 (1.25 g, 3.00 mm)
ol) to give the title compound (0.93 g, 56%) as an oil. IR (KBr):. 2990, 2940, 1752, 1705, 1663, 1505 cm -1 1 H-NMR (CDCl 3) δ: 1.95-2.10 (10H, m), 3.51 (2H,
t, J = 6.0 Hz), 4.17-4.25 (2H, m), 5.38 (2H, s), 7.42
-7.66 (6H, m, ArH), 7.85-7.98 (4H, m, ArH), 8.76 (1
H, s, ArH).

Reference Example 205 Ethyl 5- (3-ethoxycarbonylamino-2-thiophenecarboxamide) valerate 3-ethoxycarbonylamino-2-thiophenecarboxylic acid
(4.30 g, 20.0 mmol) in tetrahydrofuran (20 ml) was stirred under ice-cooling while stirring oxalyl chloride (2.09 ml,
mmol) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours and concentrated. The residue was dissolved in tetrahydrofuran (20 ml), and ethyl 5-aminovalerate hydrochloride (4.36 g, 24.0 mmol) and then triethylamine (8.36 ml, 60.0 mmol) were added little by little while stirring under ice-cooling. The reaction mixture was stirred at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried (MgSO ₄ ) and concentrated. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (2: 1, v / v) to give the title compound (7.04 g, almost 100%).
%) As an oil. IR (KBr): 3360, 3280, 2980, 2938, 1732, 1624, 157
^{. 4, 1537 cm -1 1 H} -NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.30
(3H, t, J = 7.2 Hz), 1.58-1.80 (4H, m), 2.36 (2H, t,
J = 7.0 Hz), 3.36-3.46 (2H, m), 4.15 (2H, q, J = 7.2
Hz), 4.21 (2H, q, J = 7.2 Hz), 5.82 (1H, bs), 7.29
(1H, d, J = 5.4 Hz), 7.93 (1H, d, J = 5.4 Hz), 10.30 (1
H, bs).

Reference Example 206 Ethyl 2- (3-ethoxycarbonylamino-2-thiophenecarboxamide) isobutyrate According to a method similar to that of Reference Example 21, 3-ethoxycarbonylamino-2-thiophenecarboxylic acid (6.46 g, 30.0 mmol) To give the title compound (8.20 g, 83%) as an oil. IR (KBr): 3347, 3287, 2984, 2938, 1732, 1626, 157
^{. 4, 1522 cm -1 1 H} -NMR (CDCl 3) δ: 1.29 (3H, t, J = 7.2 Hz), 1.30 (3
H, t, J = 7.2 Hz), 1.66 (6H, s), 4.21 (2H, q, J = 7.2 H
z), 4.25 (2H, q, J = 7.2 Hz), 6.27 (1H, bs), 7.30 (1
H, d, J = 5.6 Hz), 7.93 (1H, d, J = 5.6 Hz), 10.18 (1
H, bs).

Reference Example 207 5- (2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-d]
Pyrimidin-3-yl) ethyl valerate Reference example 20 was obtained in the same manner as in Reference example 42 (method 3).
Ethyl 5- (3-ethoxycarbonylamino-2-thiophenecarboxamide) valerate obtained in 5 (6.85 g, 20.0 mmol)
From there, the title compound (4.36 g, 74%) was synthesized. IR (KBr): 3250, 3204, 3098, 3085, 2978, 2955, 287
. 4, 1717, 1636, 1578 , 1543 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.69-1.
77 (4H, m), 2.35-2.42 (2H, m), 4.04-4.17 (4H, m),
6.94 (1H, d, J = 5.4 Hz), 7.70 (1H, d, J = 5.2 Hz), 1
0.72 (1H, bs). Elemental analysis: Calculated as C ₁₃ H ₁₆ N ₂ O ₄ S Calculated (%): C, 52.69; H, 5.44; N, 9.45 Found (%): C, 52.69; H, 5.23; N, 9.46

Reference Example 208 2- (2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-d]
Pyrimidin-3-yl) ethyl isobutyrate Reference Example 20 was obtained in the same manner as in Reference Example 42 (Method 3).
Ethyl 2- (3-ethoxycarbonylamino-2-thiophenecarboxamide) isobutyrate (8.19 g, 24.9 mmol
The title compound (2.30 g, 33%) was synthesized from l). Melting point 156-157 ℃. IR (KBr): 3280, 3225, 3110, 2988, 2938, 1713, 165
^{. 1, 1582, 1537 cm -1} 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.86 (6
H, s), 4.19 (2H, q, J = 7.2 Hz), 6.84 (1H, d, J = 5.4
Hz), 7.68 (1H, d, J = 5.2 Hz), 10.31 (1H, bs). Elemental analysis: Calculated as C ₁₂ H ₁₄ N ₂ O ₄ S (%): C, 51.05; H, 5.00; N, 9.92 found (%): C, 51.20; H, 4.92; N, 10.03

Reference Example 209 Ethyl 5- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-d] pyrimidin-3-yl] valerate Reference In the same manner as in Example 52, the 5- (2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-
d] Pyrimidin-3-yl) ethyl valerate (2.07 g, 7.00 mmo
The title compound (2.34 g, 78%) was obtained from l) as an oil. IR (KBr): 3102, 2959, 2868, 1732, 1699, 1659, 165
^{. 1, 1568 cm -1 1 H} -NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.68-1.
73 (4H, m), 1.92-1.96 (4H, m), 2.32-2.39 (2H, m),
3.48 (2H, t, J = 6.2 Hz), 4.04-4.17 (6H, m), 6.96 (1
H, d, J = 5.4 Hz), 7.74 (1H, d, J = 5.2 Hz).

Reference Example 210 Ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-d] pyrimidin-3-yl] isobutyrate Reference In the same manner as in Example 52, 2- (2,4-dioxo-1,2,3,4-tetrahydrothieno [3,2-
d] Pyrimidin-3-yl) ethyl isobutyrate (0.85 g, 3.00 mm
ol) to give the title compound (1.09 g, 87%) as an oil. IR (KBr): 3106, 2986, 2938, 2903, 2870, 1740, 170
^{. 1, 1659, 1574 cm -1} 1 H-NMR (CDCl 3) δ: 1.25 (3H, t, J = 7.2 Hz), 1.84 (6
H, s), 1.89-1.97 (4H, m), 3.47 (2H, t, J = 6.1 Hz),
4.01 (2H, t, J = 7.0 Hz), 4.19 (2H, q, J = 7.2 Hz), 6.
93 (1H, d, J = 5.2 Hz), 7.71 (1H, d, J = 5.4 Hz).

Example 1 2,4-Dioxo-1- [3- (4-diphenylmethoxy-1-piperidinyl) propyl] -1,2,3,4-tetrahydroquinazoline 1- [ [3-Chloropropyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (1.00 g), 4-diphenylmethoxypiperidine (1.68 g), triethylamine (0.88 ml), sodium iodide (691 mg) And a mixture of acetonitrile (50 ml) were heated under reflux for 23 hours. The solvent was distilled off under reduced pressure, a saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate. Wash the extract with water and dry (Na ₂ SO ₄ )
Thereafter, the solvent was distilled off under reduced pressure to give the title compound (845 mg, 43%).
I got Recrystallized from ethyl acetate-methanol, mp 149
Colorless crystals at -151 ° C were obtained. IR (Nujor):. 1690, 1680, 1605 cm -1 1 H-NMR (CDCl 3) δ: 1.68-2.00 (6H, m), 2.04-2.20 (2
H, m), 2.41 (2H, t, J = 7.0 Hz), 2.68-2.82 (2H, m),
3.38-3.53 (1H, m), 4.16 (2H, t, J = 7.4 Hz), 5.52 (1
H, s), 7.18-7.42 (12H, m), 7.68 (1H, ddd, J = 8.6,
7.2, 1.4 Hz), 8.20 (1H, dd, J = 8.0, 1.6 Hz). Elemental analysis: C ₂₉ H ₃₁ N ₃ O ₃・ 0.5H ₂ O Calculated (%): C, 72.78; H, 6.74; N, 8.78 Found (%): C, 72.87; H, 6.69; N, 8.86

Example 2 2,4-Dioxo-1- [4- (4-diphenylmethoxy-1-piperidinyl) butyl] -1,2,3,4-tetrahydroquinazoline In the same manner as in Example 1, 1 -(4-chlorobutyl) -2,4
-Dioxo-1,2,3,4-tetrahydroquinazoline (compound 8
6) The title compound (891 mg, 47%) was synthesized from (1.00 g). 131-133 ° C (recrystallized from ethyl acetate-ethyl ether). (Method 4) 1- (4-bromobutyl)-obtained in Reference Example 86
2,4-dioxo-1,2,3,4-tetrahydroquinazoline (4.00
g), 4-diphenylmethoxypiperidine (5.40 g), triethylamine (2.81 ml) and N, N-dimethylformamide (80
ml) was stirred at room temperature for 28 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water and dried (Na ₂ SO ₄ ).
The solvent was distilled off under reduced pressure to obtain the title compound (5.98 g, 92%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 131-133 ° C. IR (KBr):. 2943, 1683, 1608, 1486 cm -1 1 H-NMR (CDCl 3) d: 1.50-1.82 (6H, m), 1.82-2.02 (2
H, m), 2.02-2.22 (2H, m), 2.39 (2H, t, J = 7.0 Hz),
2.70-2.84 (2H, m), 3.38-3.52 (1H, m), 4.12 (2H, t,
J = 8.2 Hz), 5.53 (1H, s), 7.20-7.42 (12H, m), 7.70
(1H, ddd, J = 8.4,6.8, 1.6 Hz), 8.20 (1H, dd, J = 8.
Elemental analysis: C ₃₀ H ₃₃ N ₃ O ₃・ 1.1H ₂ O Calculated (%): C, 71.58; H, 7.05; N, 8.35 Found (%): C, 71.20 ; H, 6.58; N, 8.58

Example 3 2,4-Dioxo-1- [5- (4-diphenylmethoxy-1-piperidinyl) pentyl] -1,2,3,4-tetrahydroquinazoline A reference was prepared in the same manner as in Example 1. 1- obtained in Example 85
The title compound (2.18 g, 66%) was synthesized from (5-chloropentyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (1.77 g). Recrystallization from ethyl acetate gives the melting point
Colorless crystals at 173-174 ° C were obtained. IR (KBr):. 1698, 1609, 1483 cm -1 1 H-NMR (CDCl 3) δ: 1.38-2.00 (10H, m), 2.06-2.24
(2H, m), 2.34 (2H, t, J = 8.4 Hz), 2.68-2.82 (2H,
m), 3.38-3.52 (1H, m), 4.08 (2H, t, J = 7.2 Hz), 5.51
(1H, s), 7.16-7.38 (12H, m), 7.70 (1H, ddd, J = 8.
4, 7.0, 1.4 Hz), 8.21 (1H, dd, J = 7.4, 1.4 Hz). Elemental analysis: C ₃₁ H ₃₅ N ₃ O ₃・ 0.3H ₂ O Calculated (%): C, 74.02; H, 7.13; N, 8.35 Found (%): C, 73.81; H, 7.07; N, 8.17

Example 4 2,4-Dioxo-1- [4- (4-diphenylmethyl-1-piperazinyl) butyl] -1,2,3,4-tetrahydroquinazoline hydrochloride In the same manner as in Example 1, Using 1- (4-diphenylmethyl) piperazine instead of 4-diphenylmethoxypiperidine, 1- (4-chlorobutyl) -2,4- obtained in Reference Example 84.
From dioxo-1,2,3,4-tetrahydroquinazoline (1.00 g), the free salt of the title compound (860 mg, 46%) was obtained as amorphous crystals. IR (KBr):. 1698, 1609, 1485, 1451 cm -1 1 H-NMR (CDCl 3) δ: 1.58-1.80 (6H, m), 2.36-2.58 (8
H, m), 4.11 (2H, t, J = 8.8 Hz), 4.25 (1H, s), 7.23-
7.46 (12H, m), 7.60 (1H, ddd, J = 8.8, 7.4, 1.4 Hz),
8.19 (1H, dd, J = 7.8, 1.6 Hz). Elemental analysis: Calculated as C ₂₉ H ₃₂ N ₄ O ₂・ 0.2H ₂ O (%): C, 73.76; H, 6.92; N, 11.87 Value (%): C, 73.61; H, 6.80; N, 11.75 The product (660 mg) was recrystallized from 4N hydrogen chloride in ethyl acetate to give the title compound (599 mg, 79%). Mp 161-163 ° C. (recrystallized from ethyl acetate) IR (KBr):.. 3600-2740, 1697, 1683, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.60-2.10 (8H, m ), 3.16-3.32 (2
H, m), 3.38-3.68 (4H, m), 4.18 (2H, t, J = 6.6 Hz),
5.05 (1H, s), 7.15-7.50 (12H, m), 7.72 (1H, t, J = 7.
6 Hz), 7.83 (2H, bs), 8.13 (1H, d, J = 6.6 Hz), 9.29
(1H, bs). Elemental analysis: C ₂₉ H ₃₂ N ₄ O ₂・ 2HCl ・ 1.7H ₂ O Calculated (%): C, 60.88; H, 6.59; N, 9.79 Found (%): C , 60.75; H, 6.40; N, 9.65

Example 5 2,4-Dioxo-1- [4- (4-diphenylhydroxymethylpiperidino) butyl] -1,2,3,4-tetrahydroquinazoline The same method as in Example 2 (Method 4) )), Using 4-diphenylhydroxymethylpiperidine instead of 4-diphenylmethoxypiperidine, and using 1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydro The title compound (1.07 g, 83%) was synthesized from soquinazoline (800 mg). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 187-189 ° C. IR (KBr):. 2940, 1685, 1608, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.46-1.86 (7H, m), 1.90-2.06 (3
H, m), 2.39 (2H, t, J = 6.6 Hz), 2.34-2.54 (1H, m),
2.92-3.05 (2H, m), 4.10 (2H, t, J = 8.0 Hz), 7.10-7.
50 (12H, m), 7.65 (1H, t, J = 7.4 Hz), 8.19 (1H, d,
J = 7.6 Hz). Elemental analysis: C ₃₀ H ₃₃ N ₃ O ₃・ 0.3H ₂ O Calculated (%): C, 73.15; H, 6.96; N, 8.53 Actual (%): C, 72.97 ; H, 6.79; N, 8.28

Example 6 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
[Propyl] -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine hydrochloride In the same manner as in Example 1, the compound 1- obtained in Reference Example 87 was obtained.
(3-Chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine (800 mg) to give the free base of the title compound (110 mg, 7.0%) Obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.75-1.88 (2H, m), 1.89-2.12 (4
H, m), 2.28-2.44 (2H, m), 2.58 (2H, t, J = 8.0 Hz),
2.76-2.90 (2H, m), 3.44-3.58 (1H, m), 4.36 (2H, t,
J = 7.2 Hz), 5.48 (1H, s), 7.14-7.38 (11H, m), 8.42
(1H, dd, J = 7.6,1.8 Hz), 8.64 (1H, dd, J = 4.8, 2.0
This product (130 mg) was recrystallized from 4N hydrogen chloride in ethyl acetate to give the title compound (86 mg, 57%) as colorless crystals. 131-133 ° C. IR (KBr):. 1705, 1601, 1489 cm -1 1 H-NMR (CDCl 3) δ: 1.94-2.10 (2H, m), 2.34-2.58 (4
H, m), 3.00-3.22 (4H, m), 3.33-3.48 (2H, m), 3.82-
3.90 (1H, m), 4.23 (2H, t, J = 6.2 Hz), 5.42 (1H, s),
7.20-7.40 (10H, m), 8.35-8.48 (2H, m), 8.67 (1H,
dd, J = 4.8, 1.8 Hz), 11.96 (1H, bs). Elemental analysis: C ₂₈ H ₃₀ N ₄ O ₃・ 2HCl ・ 1.0H ₂ O Calculated (%): C, 59.89; H, 6.10 ; N, 9.98 found (%): C, 59.68; H, 5.95; N, 10.05

Example 7 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine hydrochloride 1- (4-bromobutyl) obtained in Reference Example 88 by the same method (Method 4) as in Example 2. ) Free base (1.30 g, 53%) of the title compound was synthesized from -2,4-dioxo-1,2,3,4-tetrahydropyrido [2,3-d] pyrimidine (1.50 g). Ethyl acetate
Recrystallization from -ethyl ether gave colorless crystals having a melting point of 167-169. IR (KBr):. 1701, 1601, 1588, 1489, 1462 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.98 (8H, m), 2.08-2.24 (2
H, m), 2.38 (2H, t, J = 7.0 Hz), 2.70-2.84 (2H, m),
3.45-3.52 (1H, m), 4.31 (2H, t, J = 7.2 Hz), 5.51 (1
H, s), 7.18-7.40 (11H, m), 8.42 (1H, dd, J = 8.0, 2.
2 Hz), 8.66 (1H, dd, J = 4.8, 2.2 Hz). Elemental analysis: Calculated as C ₂₉ H ₃₂ N ₄ O ₃・ 0.3H ₂ O (%): C, 71.09; H, 6.71; N, 11.43 Found (%): C, 71.06; H, 6.64; N, 11.19 The product (500 mg) was recrystallized from 4N hydrogen chloride in ethyl acetate to give the title compound (413 mg, 72%). Obtained as colorless crystals having a melting point of 121-123 ° C. IR (KBr):. 1695, 1602, 1490 cm -1 1 H-NMR (CDCl 3) δ: 1.76-2.14 (6H, m), 2.36-2.58 (2
H, m), 2.96-3.20 (4H, m), 3.28-3.44 (2H, m), 3.84-
3.92 (1H, m), 4.33 (2H, t, J = 7.0 Hz), 5.43 (1H, s),
7.18-7.44 (10H, m), 8.39-8.43 (2H, m), 8.64-8.72
. (1H, m), 12.16 (1H, bs) Elemental _{analysis: C 29 H 32 N 4 O} 3 · 2HCl Calculated (%): C, 62.48; H, 6.15; N, 10.05 Found (%) : C, 62.29; H, 6.48; N, 10.48

Example 8 2,4-Dioxo-8- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydropteridine 1- (4-bromobutyl) -2,4-dioxo-1,2 obtained in Reference Example 89 by the same method as in Example 2 (Method 4). From the 3,3,4-tetrahydrobuteridine (1.36 g), the title compound (1.47 g, 6
7%). Recrystallized from ethyl acetate, melting point 157-15
9 ° C. colorless crystals were obtained. IR (KBr):. 2945, 1708, 1598, 1546, 1490 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.84 (4H, m), 1.84-2.02 (4
H, m), 2.14-2.34 (2H, m), 2.41 (2H, t, J = 7.8 Hz),
2.74-2.88 (4H, m), 3.38-3.52 (1H, m), 4.28 (2H, t,
J = 7.4 Hz), 5.50 (1H, s), 7.18-7.38 (10H, m), 8.56
(1H, d, J = 2.2 Hz), 8.62 (1H, d, J = 2.2 Hz). Elemental analysis: Calculated as C ₂₈ H ₃₁ N ₅ O ₃・ 0.4H ₂ O (%): C, 68.25 ; H, 6.50; N, 14.21 Found (%): C, 68.28; H, 6.41; N, 14.15

Example 9 7-Chloro-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline Method similar to that in Example 2. According to (Method 4), 1- (4-bromobutyl) -7-chloro-2,4-dioxo-1, obtained in Reference Example 90.
The title compound from 2,3,4-tetrahydroquinazoline (1.50 g)
(1.51 g, 64%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 169-171 ° C. IR (KBr):. 1699, 1607, 1580, 1495, 1456 cm -1 1 H-NMR (CDCl 3) δ: 1.54-2.02 (8H, m), 2.05-2.24 (2
H, m), 2.40 (2H, t, J = 6.2 Hz), 2.72-2.86 (2H, m),
3.38-3.54 (1H, m), 4.11 (2H, t, J = 8.0 Hz), 5.53 (1
. H, s), 7.18-7.42 ( 12H, m), 8.12 (1H, d, J = 8.4 Hz) Elemental _{analysis: C 30 H 32 N 3 O} 3 Calculated Cl (%): C, 69.55 ; H, 6.23; N, 8.11 Found (%): C, 69.15; H, 6.23; N, 8.01

Example 10 6-Chloro-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline Method similar to that in Example 2. According to (Method 4), 1- (4-bromobutyl) -6-chloro-2,4-dioxo-1, obtained in Reference Example 91.
The title compound from 2,3,4-tetrahydroquinazoline (1.50 g)
(2.02 g, 86%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 209-210 ° C. IR (KBr):. 1699, 1611, 1582, 1491, 1468 cm -1 1 H-NMR (CDCl 3) δ: 1.56-1.86 (6H, m), 1.86-2.04 (2
H, m), 2.04-2.25 (2H, m), 2.40 (2H, t, J = 6.6 Hz),
2.70-2.85 (2H, m), 3.40-3.54 (1H, m), 4.09 (2H, t,
J = 7.8 Hz), 5.53 (1H, s), 7.20-7.44 (11H, m), 7.63
(1H, dd, J = 8.8,2.6 Hz), 8.15 (1H, d, J = 2.6 Hz) Elemental analysis: C ₃₀ H ₃₂ N ₃ O ₃ Cl ・ 0.4H ₂ O Calculated (%): C , 68.60; H, 6.29; N, 8.00 Found (%): C, 68.60; H, 6.22; N, 7.93

Example 11 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-7-nitro-1,2,3,4-tetrahydroquinazoline 1- (4-bromobutyl) -2,4-obtained in Reference Example 92 by the same method as in Example 2 (Method 4). Dioxo-7-nitro-1,
The title compound (4.91 g, 79%) was synthesized from 2,3,4-tetrahydroquinazoline (4.00 g). Recrystallization from ethyl acetate gave yellow crystals with a melting point of 214-215 ° C. IR (KBr):. 2947, 1695, 1627, 1594, 1538, 1455 cm -1 1 H-NMR (CDCl 3) δ: 1.60-2.00 (8H, m), 2.09-2.23 (2
H, m), 2.41 (2H, t, J = 7.0 Hz), 2.74-2.88 (2H, m),
3.38-3.52 (1H, m), 4.22 (2H, t, J = 7.8 Hz), 5.52 (1
H, s), 7.18-7.38 (10H, m), 8.02-8.33 (2H, m), 8.36
(1H, d, J = 8.6 Hz). Elemental analysis: Calculated as C ₃₀ H ₃₂ N ₄ O ₅・ 1.0H ₂ O (%): C, 65.92; H, 6.27; N, 10.25 Actual (% ): C, 65.68; H, 5.98; N, 10.21

Example 12 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -6-nitro-1,2,3,4-tetrahydroquinazoline 1- (4-bromobutyl) -2,4-dioxo obtained in Reference Example 93 by the same method as in Example 2 (Method 4). -6-nitro-1,
The title compound from 2,3,4-tetrahydroquinazoline (5.00 g)
(6.96 g, 90%) was synthesized. Recrystallization from ethyl acetate gave yellow crystals having a melting point of 211-213 ° C. IR (KBr):. 2943, 1706, 1614, 1529, 1494 cm -1 1 H-NMR (CDCl 3) δ: 1.56-2.04 (8H, m), 2.08-2.25 (2
H, m), 2.41 (2H, t, J = 6.6 Hz), 2.73-2.86 (2H, m),
3.40-3.56 (1H, m), 4.17 (2H, t, J = 7.6 Hz), 5.53 (1
H, s), 7.20-7.38 (10H, m), 7.60 (1H, d, J = 9.2 Hz),
8.51 (1H, dd, J = 9.2, 2.6 Hz), 9.03 (1H, d, J = 2.4
Elemental analysis: C ₃₀ H ₃₂ N ₄ O ₅・ 0.3H ₂ O Calculated (%): C, 67.48; H, 6.15; N, 10.49 Found (%): C, 67.34; H, 6.04; N, 10.31

Example 13 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-6-methyl-1,2,3,4-tetrahydroquinazoline 1- (4-bromobutyl) -2,4-obtained in Reference Example 94 by the same method as in Example 2 (Method 4). Dioxo-6-methyl-1,
The title compound from 2,3,4-tetrahydroquinazoline (940 mg)
(627 mg, 42%) was synthesized. Recrystallization from ethyl acetate-ethyl ether gave yellow crystals having a melting point of 180-182 ° C. IR (KBr):. 2943, 1699, 1627, 1612, 1587 cm -1 1 H-NMR (CDCl 3) δ: 1.54-1.84 (6H, m), 1.86-2.02 (2
H, m), 2.08-2.25 (2H, m), 2.36-2.46 (2H, m), 2.40
(3H, s), 2.70-2.85 (2H, m), 3.40-3.54 (1H, m), 4.0
9 (2H, t, J = 8.0 Hz), 5.53 (1H, s), 7.20-7.40 (11H,
m), 7.50 (1H, dd, J = 8.4, 1.8 Hz), 7.99 (1H, s). Elemental analysis: C ₃₁ H ₃₅ N ₃ O ₃・ 0.8H ₂ O Calculated (%): C, 72.72; H, 7.20; N, 8.21 Found (%): C, 72.48; H, 6.83; N, 8.06

Example 14 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl)]-1,2,3,4-tetrahydroquinazoline-3-acetate methyl In the same manner as in Example 1, 2,2
4-Dioxo-1- (3-chloropropyl) -1,2,3,4-tetrahydroquinazoline-3-acetate (2.00 g)
93 g, 55%). Ethyl acetate-ethyl ether-n
Recrystallization from -hexane gave colorless crystals having a melting point of 109-110 ° C. IR (Nujor):. 1745, 1700, 1660, 1600, 1480 cm -1 1 H-NMR (CDCl 3) δ: 1.95-2.12 (2H, m), 2.30-2.58 (4
H, m), 3.02-3.30 (6H, m), 3.75 (3H, s), 3.80-3.88
(1H, m), 4.26 (2H, t, J = 6.4Hz), 4.84 (2H, s), 5.43
(1H, s), 7.16-7.48 (12H, m), 7.79 (1H, t, J = 7.8 H
z), 8.24 (1H, d, J = 8.0 Hz). Elemental analysis: Calculated as C ₃₂ H ₃₅ N ₃ O ₅ (%): C, 70.96; H, 6.51; N, 7.76 Actual (%) : C, 70.87; H, 6.31; N, 7.85

Example 15 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-acetate methyl In the same manner as in Example 1, 1-
(4-Chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-acetate methyl (2.00 g) from the title compound (3.06
g, 84%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 91-93 ° C. IR (KBr): 2949, 2810, 1756, 1710, 1668, 1610, 1486
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.56-2.02 (8H, m), 2.06-2.23 (2
H, m), 2.39 (2H, t, J = 9.0 Hz), 2.70-2.84 (2H, m),
3.40-3.52 (1H, m), 3.76 (3H, s), 4.15 (2H, t, J = 7.4
Hz), 4.85 (2H, s), 5.53 (1H, s), 7.20-7.40 (12H,
m), 7.70 (1H, ddd, J = 8.6, 7.2, 1.4 Hz), 8.24 (1H, d
. d, J = 7.8, 1.4 Hz) Elemental _{analysis: C 33 H 37 N 3 O} 5 Calculated (%): C, 71.33; H, 6.71; N, 7.50 Found (%): C, 70.98; H, 6.67; N, 7.56

Example 16 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl)]-1,2,3,4-Ethyl tetrahydroquinazoline-3-propionate In the same manner as in Example 1, the 1-ethylamine obtained in Reference Example 63 was obtained.
The title compound (2.11 g, 68%) was obtained as an oil from ethyl (3-chloropropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate (1.85 g). ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 1.65-2.
00 (6H, m), 2.03-2.20 (2H, m), 2.41 (2H, t, J = 6.6 H
z), 2.71 (2H, t, J = 8.0 Hz), 2.67-2.82 (2H, m), 3.40
-3.52 (1H, m), 4.08-4.22 (4H, m), 4.40 (2H, t, J =
7.0Hz), 5.53 (1H, s), 7.20-7.40 (12H, m), 7.65 (1
H, ddd, J = 8.4, 7.4, 1.0 Hz), 8.22 (1H, dd, J = 8.2,
1.4 Hz).

Example 17 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-propionic acid ethyl hydrochloride
Ethyl (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-propionate (2.50 g) gave the free salt of the title compound (2.86 g, 69%) as an oil. Was. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 1.54-2.
00 (8H, m), 2.02-2.20 (2H, m), 2.38 (2H, t, J = 6.2 H
z), 2.71 (2H, t, J = 7.4 Hz), 2.66-2.74 (2H, m), 3.38
-3.52 (1H, m), 4.06-4.20 (4H, m), 4.40 (2H, t, J =
7.6Hz), 5.53 (1H, s), 7.18-7.40 (12H, m), 7.66 (1
H, t, J = 7.0 Hz), 8.22 (1H, d, J = 8.2 Hz). To this product (1.03 g) was added 4N hydrogen chloride in ethyl acetate, and the mixture was concentrated. The title compound (734 mg, 67 %) Were obtained as amorphous crystals. IR (KBr):. 1732, 1703, 1658, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 6.8 Hz), 1.96-2.
20 (4H, m), 2.35-2.56 (2H, m), 2.70 (2H, t, J = 6.6 H
z), 2.94-3.22 (2H, m), 3.28-3.45 (2H, m), 3.82-3.9
0 (1H, m), 4.04-4.24 (4H, m), 4.38 (2H, t, J = 7.4 H
z), 5.43 (1H, s), 7.18-7.44 (12H, m), 7.71 (1H, t,
J = 6.6 Hz), 8.23 (1H, d, J = 8.0 Hz), 12.09 (1H, b
. s) Elemental _{analysis: C 35 H 41 N 3 O} 5 · HCl · 0.8H 2 O Calculated (%): C, 66.23; H, 6.92; N, 6.62 Found (%): C, 66.23; H, 7.06; N, 6.60

Example 18 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-butyrate ethyl 1- obtained in Reference Example 65 in the same manner as in Example 1.
The title compound (3.17 g) was obtained from ethyl (4-chlorobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3-butyrate (6.00 g).
g, 36%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.0 Hz), 1.56-2.
45 (12H, m), 2.34-2.45 (4H, m), 2.70-2.83 (2H, m),
3.38-3.52 (1H, m), 4.02-4.20 (6H, m), 5.53 (1H, s),
7.18-7.40 (12H, m), 7.66 (1H, ddd, J = 8.4, 7.6, 0.
8 Hz), 8.22 (1H, dd, J = 8.0, 1.2 Hz).

Example 19 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl)]-3-methyl-1,2,3,4-tetrahydroquinazoline hydrochloride
(3-chloropropyl) -2,4-dioxo-3-methyl-1,2,3,4-
The free salt of the title compound (920 mg, 48%) was obtained as an oil from tetrahydroquinazoline (1.00 g). ¹ H-NMR (CDCl ₃ ) δ: 1.68-2.00 (6H, m), 2.05-2.20 (2
H, m), 2.41 (2H, t, J = 6.8 Hz), 2.69-2.82 (2H, m),
3.38-3.52 (1H, m), 3.48 (3H, s), 4.19 (2H, t, J = 7.
4 Hz), 5.53 (1H, s), 7.19-7.40 (12H, m), 7.65 (1H,
ddd, J = 8.8, 7.0, 1.8 Hz), 8.24 (1H, dd, J = 7.8, 1.
This product (920 mg) was crystallized from 4N hydrogen chloride in ethyl acetate to give the title compound (568 mg, 58%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 127-128 ° C. IR (KBr):. 1701, 1659, 1609, 1487, 1454, 1427 cm -1 1 H-NMR (CDCl 3) δ: 1.94-2.10 (2H, m), 2.34-2.56 (4
H, m), 3.02-3.24 (4H, m), 3.32-3.46 (2H, m), 3.48
(3H, s), 3.82-3.90 (1H, m), 4.22-4.36 (2H, m), 5.4
2 (1H, s), 7.20-7.44 (12H, m), 7.74 (1H, t, J = 9.0
. Hz), 8.24 (1H, d, J = 7.8 Hz) Elemental _{analysis: C 30 H 33 N 3 O} 3 · HCl · 1.2H 2 O Calculated (%): C, 66.52; H, 6.77; N , 7.76 Found (%): C, 66.43; H, 6.76; N, 8.05

Example 20 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-3-methyl-1,2,3,4-tetrahydroquinazoline hydrochloride 1-amino acid obtained in Reference Example 67 in the same manner as in Example 1.
Free salt of the title compound from (4-chlorobutyl) -2,4-dioxo-3-methyl-1,2,3,4-tetrahydroquinazoline (1.00 g)
(1.13 g, 61%) was obtained. Recrystallization from ethyl acetate-isopropyl ether gave colorless crystals having a melting point of 141-142 ° C. IR (KBr):. 1702, 1660, 1610, 1486, 1453 cm -1 1 H-NMR (CDCl 3) δ: 1.60-1.86 (6H, m), 1.86-2.04 (2
H, m), 2.12-2.30 (2H, m), 2.42 (2H, t, J = 6.6 Hz),
2.72-2.86 (2H, m), 3.42-3.52 (1H, m), 3.48 (3H,
s), 4.15 (2H, t, J = 8.4 Hz), 5.52 (1H, m), 7.20-7.3
8 (12H, m), 7.66 (1H, ddd, J = 8.8, 7.4, 1.4 Hz), 8.
24 (1H, dd, J = 7.8, 1.8 Hz). Elemental analysis: C ₃₁ H ₃₅ N ₃ O ₃・ 0.5H ₂ O Calculated (%): C, 73.19; H, 7.16; N, 8.29 Value (%): C, 73.29; H, 6.96; N, 8.16 To this product (500 mg), add 4N hydrogen chloride in ethyl acetate,
After concentration, the title compound (443 mg, 83%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 233-235 ° C. IR (KBr):. 1701, 1655, 1609, 1487 cm -1 1 H-NMR (CDCl 3) δ: 1.79-1.93 (2H, m), 1.96-2.18 (4
H, m), 2.36-2.56 (2H, m), 2.95-3.22 (4H, m), 3.30-
3.46 (2H, m), 3.47 (3H, s), 3.84-3.92 (1H, m), 4.1
7 (2H, t, J = 7.4 Hz), 5.42 (1H, s), 7.20-7.42 (12H,
m), 7.70 (1H, ddd, J = 8.4, 7.0, 1.4 Hz), 8.25 (1H,
dd, J = 8.0, 1.4 Hz). Elemental analysis: Calculated as C ₃₁ H ₃₅ N ₃ O ₃ .HCl.0.5H ₂ O Calculated (%): C, 68.56; H, 6.87; N, 7.74 Found ( %): C, 68.47; H, 6.74; N, 7.84

Example 21 3- (1,1-Dimethylethyl) -2,4-dioxo-1- [3- (4-diphenylmethoxypiperidino) propyl] -1,2,3,4-tetrahydroquinazoline Hydrochloride 1-Acid obtained in Reference Example 68 in the same manner as in Example 1.
Free salt of the title compound from (3-chloropropyl) -3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (1.50 g) (857 mg, 32% ) Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.60-2.02 (15H, m), 2.08-2.24
(2H, m), 2.42 (2H, t, J = 6.8 Hz), 2.70-2.85 (2H,
m), 3.39-3.55 (1H, m), 4.07 (2H, t, J = 6.2 Hz), 5.52
(1H, m), 7.10-7.40 (12H, m), 7.56 (1H, t, J = 7.4 H
z), 8.06 (1H, d, J = 8.2 Hz). To this product (857 mg) was added 4N hydrogen chloride in ethyl acetate.
Concentration gave the title compound (647 mg, 71%) as amorphous crystals. IR (KBr):. 1705, 1663, 1607, 1480 cm -1 1 H-NMR (CDCl 3) δ: 1.72 (9H, s), 2.06-2.12 (2H,
m), 2.32-2.54 (4H, m), 2.88-3.20 (4H, m), 3.30-3.4
4 (2H, m), 3.82-3.90 (1H, m), 4.10-4.26 (2H, m),
5.42 (1H, s), 7.18-7.42 (12H, m), 7.58-7.70 (1H,
m), 8.07 (1H, d, J = 7.8 Hz). Elemental analysis: Calculated as C ₃₃ H ₃₉ N ₃ O ₃ .HCl.1.3H ₂ O Calculated (%): C, 67.69; H, 7.33; N , 7.18 Found (%): C, 67.43; H, 7.27; N, 7.56

Example 22 3- (1,1-Dimethylethyl) -2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydro Quinazoline hydrochloride In the same manner as in Example 1, 1-quinone was obtained in Reference Example 69.
Free salt of the title compound from (4-chlorobutyl) -3- (1,1-dimethylethyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (1.50 g) (953 mg, 36%) Was synthesized. Ethyl acetate
Recrystallization from -isopropyl ether gave colorless crystals having a melting point of 113-114 ° C. IR (KBr):. 1706, 1664, 1608, 1494, 1479, 1455 cm -1 1 H-NMR (CDCl 3) δ: 1.54-2.00 (17H, m), 2.08-2.22
(2H, m), 2.39 (2H, t, J = 6.4 Hz), 2.70-2.85 (2H,
m), 3.40-3.52 (1H, m), 4.04 (2H, t, J = 8.2 Hz), 5.52
(1H, m), 7.10-7.40 (12H, m), 7.58 (1H, ddd, J = 8.
6, 7.0, 1.6 Hz), 8.07 (1H, dd, J = 8.0, 1.6 Hz). Elemental analysis: C ₃₄ H ₄₁ N ₃ O ₃・ 0.3H ₂ O Calculated (%): C, 74.91; H, 7.69; N, 7.71 Found (%): C, 74.92; H, 7.40; N, 7.81 To this product (500 mg) was added 4N hydrogen chloride in ethyl acetate.
After concentration, the title compound (382 mg, 72%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 229-231 ° C. IR (KBr):. 1705, 1663, 1607, 1495, 1480 cm -1 1 H-NMR (CDCl 3) δ: 1.64-1.86 (11H, m), 1.94-2.14
(4H, m), 2.36-2.57 (2H, m), 2.95-3.22 (4H, m), 3.28
-3.44 (2H, m), 3.85-3.92 (1H, m), 4.07 (2H, t, J = 7.
6 Hz), 5.44 (1H, s), 7.11 (1H, d, J = 8.4 Hz), 7.19
(1H, t, J = 7.2 Hz), 7.22-7.40 (10H, m), 7.62 (1H, d
dd, J = 8.4, 6.8, 1.6 Hz), 8.08 (1H, dd, J = 7.8, 1.6
Elemental analysis: C ₃₄ H ₄₁ N ₃ O ₃ .HCl 1.1 H ₂ O Calculated (%): C, 68.50; H, 7.47; N, 7.05 Found (%): C, 68.50; H, 7.51; N, 7.03

Example 23 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-3- (3-pyridinylmethyl) -1,2,3,4-tetrahydroquinazoline hydrochloride 1- (4-bromobutyl) obtained in Reference Example 70 by the same method as in Example 2 (Method 4). ) -2,4-Dioxo-3- (3-pyridinylmethyl) -1,2,3,4-tetrahydroquinazoline (1.57 g)
To give the free salt of the title compound (1.35 g, 58%). ¹ H-NMR (CDCl ₃ ) δ: 1.58-2.02 (8H, m), 2.10-2.28 (2
H, m), 2.41 (2H, t, J = 7.0 Hz), 2.70-2.84 (2H, m),
3.40-3.55 (1H, m), 4.14 (2H, t, J = 7.0 Hz), 5.27 (2
H, s), 5.52 (1H, m), 7.20-7.40 (13H, m), 7.67 (1H,
t, J = 7.0 Hz), 7.85 (1H, dt, J = 8.0, 1.8 Hz), 8.24
(1H, dd, J = 8.2, 1.6 Hz), 8.50 (1H, dd, J = 4.8, 1.8 H
z), 8.79 (1H, d, J = 1.6 Hz). This product (1.35 g) was concentrated by adding 4N hydrogen chloride in ethyl acetate, and the title compound (1.06 g, 69%) was obtained as amorphous crystals. . IR (KBr): 3650-3150, 2933, 2850-2300, 1700, 1652,
^{. 1608, 1486 cm -1 1 H} -NMR (CDCl 3) δ: 1.72-2.60 (12H, m), 2.95-3.75
(5H, m), 4.10-4.26 (2H, m), 5.24 (1H, s), 7.20-7.44
(13H, m), 7.75 (1H, t, J = 7.0 Hz), 7.86-8.02 (1H,
m), 8.21 (1H, d, J = 7.8 Hz), 8.60-8.78 (1H, m), 8.9
1-9.02 (2H, m), 11.82 (1H, bs), 12.08 (1H, bs). Elemental analysis: C ₃₆ H ₃₈ N ₄ O ₃・ 2HCl ・ 2.8H ₂ O Calculated (%): C , 61.94; H, 6.58; N, 8.03 Found (%): C, 61.91; H, 6.73; N, 8.32.

Example 24 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -3-phenyl-1,2,3,4-tetrahydroquinazoline hydrochloride 1- (4-bromobutyl) -2,4 obtained in Reference Example 71 by the same method as in Example 2 (method 4). -Dioxo-3-phenyl-
The free salt of the title compound (500 mg, 22%) was obtained as an oil from 1,2,3,4-tetrahydroquinazoline (1.50 g). ¹ H-NMR (CDCl ₃ ) d: 1.50-2.00 (8H, m), 2.02-2.18 (2
H, m), 2.38 (2H, t, J = 7.0 Hz), 2.69-2.84 (2H, m),
3.18-3.52 (1H, m), 4.17 (2H, t, J = 6.6 Hz), 5.52 (1
H, m), 7.18-7.56 (17H, m), 7.72 (1H, t, J = 7.0 Hz),
8.26 (1H, dd, J = 8.0, 1.4 Hz). To this product (500 mg) was added 4N hydrogen chloride in ethyl acetate.
After concentration, the title compound (303 mg, 57%) was obtained as amorphous crystals. IR (KBr): 3397, 2938, 2656, 1707, 1663, 1609, 1481
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.80-3.92 (12H, m), 4.10-4.32
(4H, m), 5.24 (1H, m), 7.10-7.62 (17H, m), 7.79 (1
H, t, J = 7.4 Hz), 8.27 (1H, d, J = 6.6 Hz). Elemental analysis: C ₃₆ H ₃₇ N ₃ O ₃・ HCl ・ 1.5H ₂ O Calculated (%): C, 69.38; H, 6.63; N, 6.74 Found (%): C, 69.47; H, 6.77; N, 6.54

Example 25 3-Cyclohexyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline hydrochloride As in Example 2. (Method 4) to give the title compound from 1- (4-bromobutyl) -3-cyclohexyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline (1.50 g) obtained in Reference Example 72. (580 mg, 26%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.20-2.00 (16H, m), 2.00-2.20
(2H, m), 2.34-2.60 (4H, m), 2.70-2.82 (2H, m), 3.40
-3.52 (1H, m), 4.10 (2H, t, J = 6.4 Hz), 4.80-5.00
(1H, m), 5.52 (1H, m), 7.18-7.40 (12H, m), 7.62 (1
H, t, J = 7.0 Hz), 8.20 (1H, dd, J = 7.6, 1.0 Hz). To this product (580 mg) was added 4N hydrogen chloride in ethyl acetate.
The title compound (433 mg, 57%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 206-208 ° C. IR (KBr):. 3345, 2932, 1698, 1651, 1609, 1483 cm -1 1 H-NMR (CDCl 3) δ: 1.20-2.18 (19H, m), 2.33-2.59
(2H, m), 2.96-3.22 (2H, m), 3.30-3.42 (1H, m), 3.82
-3.92 (1H, m), 4.12 (2H, t, J = 7.0 Hz), 4.82-5.00
(1H, m), 5.44 (1H, m), 7.13-7.40 (12H, m), 7.67 (1
H, ddd, J = 8.6, 7.0, 1.6 Hz), 8.22 (1H, dd, J = 7.8,
1.4 Hz), 12.26 (1H, bs). Elemental analysis: Calculated as C ₃₆ H ₄₃ N ₃ O ₃ .HCl.0.4H ₂ O Calculated (%): C, 70.95; H, 7.41; N, 6.90 (%): C, 70.88; H, 7.67; N, 6.88

Example 26 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline 1- (4-bromobutyl)-obtained in Reference Example 52 by the same method as in Example 2 (Method 4). 2,4-dioxo-3- (4-methoxybenzyl) -1,2,3,4-tetrahydroquinazoline (600 m
g) to give the title compound (850 mg, 98%). Recrystallization from ethyl acetate-isopropyl ether-n-hexane gave colorless crystals having a melting point of 99-100 ° C. IR (KBr): 3650-3200, 2920, 1700, 1658, 1610, 1513,
^{. 1484 cm -1 1 H-NMR} (CDCl 3) δ: 1.54-2.00 (8H, m), 2.04-2.20 (2
H, m), 2.37 (2H, t, J = 5.8 Hz), 2.68-2.84 (2H, m),
3.38-3.52 (1H, m), 3.76 (3H, s), 4.13 (2H, t, J = 8.
4 Hz), 5.20 (2H, s), 5.52 (1H, s), 6.82 (2H, d, J =
8.4 Hz), 7.16-7.38 (12H, m), 7.49 (2H, d, J = 8.8 H
z), 7.65 (1H, t, J = 8.4 Hz), 8.23 (1H, d, J = 8.0 H
z). Elemental analysis: C ₃₈ H ₄₁ N ₃ O ₄ Calculated (%): C, 75.60; H, 6.84; N, 6.96 Found (%): C, 75.32; H, 6.81; N, 7.30

Example 27 Ethyl 2- [2,4-dioxo-1- [4- (4-diphenylmethoxy) piperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Hydrochloric acid Salt Ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate obtained in Reference Example 73 (0.90 g, 2.2 mmol) , 4-diphenylmethoxypiperidine (purity 90%, 0.79 g, 2.6 mmol), potassium carbonate
(0.36 g, 2.6 mmol) and N, N-dimethylformamide (5 m
The mixture of l) was stirred at room temperature for 15 hours. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl ether. Wash the extract with water,
After drying (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate to give the free salt of the title compound (1.24 g, 94%) as an oil. IR (KBr): 3028, 2943, 2869, 2810, 2779, 1743, 170
^{. 8, 1664, 1608 cm -1} 1 H-NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.1 Hz), 1.52-1.
98 (8H, m), 1.84 (6H, s), 2.05-2.16 (2H, m), 2.37
(2H, t, J = 6.9 Hz), 2.70-2.80 (2H, m), 3.39-3.51 (1
H, m), 4.03-4.11 (2H, m), 4.18 (2H, q, J = 7.1 Hz),
5.53 (1H, s), 7.17-7.37 (12H, m, ArH), 7.60 -7.68
(1H, m, ArH). 8.14 (1H, dd, J = 7.9 Hz, 1.5 Hz). This oil (1.16 g, 1.97 mmol) was added to ethyl acetate (10.0 ml)
And 4N hydrogen chloride in ethyl acetate (1.0 ml) was added and concentrated. The residue was dried at 50 ° C. in the presence of phosphorus pentoxide to give the title compound (1.11 g, 88%). IR (KBr): 2983, 2937, 2482, 2391, 1735, 1706, 166
^{. 2, 1608 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.12 (3H, dt, J = 7.2 Hz, 1.1 H
z), 1.60-2.23 (8H, m), 1.71 (6H, s), 2.80-3.75 (7H,
m), 4.00-4.12 (4H, m), 5.68 (1H, d, J = 10.6Hz), 7.
22-7.52 (12H, m, ArH), 7.74-7.81 (1H, m, ArH), 8.0
1 (1H, dt, J = 7.8 Hz, 1.4 Hz). Elemental analysis: C ₃₆ H ₄₃ N ₃ O ₅・ HCl ・ 0.5H ₂ O Calculated (%): C, 67.22; H, 7.05; N , 6.53 found (%): C, 67.22; H, 7.00; N, 6.54. The title compounds of Examples 28 to 38 below were synthesized in a similar manner.

Example 28 2- [1- [4- (4-Hydroxydiphenylmethylpiperidino) butyl] -1,2,3,4-tetrahydro-2,4-dioxoquinazoline-
3-yl] isobutyric acid ethyl ester hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] iso obtained in Reference Example 73 The title compound (0.50 g, 85%) was obtained as amorphous crystals from ethyl butyrate. IR (KBr): 3350, 2983, 2941, 2648, 2500, 1735, 171
^{. 0, 1664, 1608 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.1 Hz), 1.40-
1.90 (9H, m), 1.71 (6H, s), 2.75-3.52 (7H, m), 4.0
1-4.11 (4H, m), 7.13-7.34 (8H, m, ArH), 7.47-7.58
(4H, m, ArH), 7.73-7.81 (1H, m, ArH), 8.01 (1H, d
d, J = 1.6 Hz, 7.8 Hz). Elemental analysis: Calculated as C ₃₆ H ₄₃ N ₃ O ₅ .HCl.0.5 H ₂ O Calculated (%): C, 67.22; H, 7.05; N, 6.53 (%): C, 67.21; H, 7.13; N, 6.31.

Example 29 2- [2,4-Dioxo-1- [4- (4-diphenylmethylpiperazino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]
Ethyl isobutyrate dihydrochloride Titled from ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate obtained in Reference Example 73 The compound (0.42 g, 83%) was obtained as amorphous crystals. IR (KBr): 3420, 2987, 2941, 2400, 1735, 1708, 166
^{. 0, 1608 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.1 Hz), 1.60-
1.88 (4H, m), 1.71 (6H, s), 2.80-3.80 (10H, m), 4.
00-4.30 (3H, m), 4.06 (2H, q, J = 7.1 Hz), 7.26-8.00
(13H, m, ArH), 8.00 (1H, dd, J = 7.7 Hz, 1.5 Hz). Elemental analysis: C ₃₅ H ₄₂ N ₄ O ₄・ 2HCl ・ 0.5H ₂ O Calculated (%): C , 63.25; H, 6.82; N, 8.43 Found (%): C, 62.99; H, 7.06; N, 8.11.

Example 30 Methyl 2- [2,4-dioxo-1- [4- (4-diphenylmethoxy) piperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Hydrochloric acid Salt The free salt of the title compound from methyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate obtained in Reference Example 74 ( 1.76 g, 88%). A 4N solution of hydrogen chloride in ethyl acetate was added to this product (0.58 g), and the mixture was concentrated to give the title compound (0.52 g, 83%) as amorphous crystals. IR (KBr): 3390, 3030, 2989, 2947, 2491, 1741, 170
^{. 6, 1660, 1608 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.55-2.23 (8H, m), 1.71 (6H,
s), 2.85-3.75 (7H, m), 3.59 (3H, d, J = 1.0 Hz), 4.02
-4.11 (2H, m), 5.68 (1H, d, J = 10.6 Hz), 7.21-7.43
(11H, m, ArH), 7.50 (1H, d, J = 8.8 Hz), 7.73-7.82
(1H, m, ArH), 7.98-8.03 (1H, m, ArH). Elemental analysis: Calculated as C ₃₅ H ₄₁ N ₃ O ₅ .HCl.0.5H ₂ O Calculated (%): C, 66.81; H , 6.89; N, 6.68 Found (%): C, 66.63; H, 6.88; N, 6.56

Example 31 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-methyl-1,2,3,4-tetrahydroquinazoline
Ethyl 3--3-yl] isobutyrate 2- [1- (4-bromobutyl) -2,4-dioxo-6-methyl-1,2,3,4-tetrahydroquinazolin-3-yl obtained in Reference Example 75 ] Ethyl isobutyrate (0.56 g) from the free salt of the title compound (0.
74 g, 92%) as an oil. IR (KBr): 2980, 2942, 2867, 2809, 2772, 1744, 170
. 5, 1663, 1624, 1593 , 1510 cm -1 1 H-NMR (CDCl 3) δ:
1.22 (3H, t, = 7.2 Hz), 1.50-2.00 (8H, m), 1.83 (6
H, s), 2.05-2.15 (2H, m), 2.32-2.40 (2H, m), 2.38
(3H, s), 2.70-2.81 (2H, m), 3.39-3.51 (1H, m), 4.0
0-4.07 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 5.53 (1H,
s), 7.17-7.37 (11H, m, ArH), 7.44 (1H, dd, J = 8.4 H
z, 2.2 Hz) .7.93 (1H, d, J = 1.8 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.7 ml).
After concentration, the title compound (0.65 g, 82%) was obtained as amorphous crystals. IR (KBr): 3403, 2980, 2936, 2487, 2398, 1740, 170
. 1, 1661, 1624, 1595 , 1508 cm -1 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.0 Hz), 1.53
-2.22 (8H, m), 1.70 (6H, s), 2.37 (3H, s), 2.80-3.
76 (7H, m), 4.00-4.11 (4H, m), 5.68 (1H, d, J = 10.6
Hz), 7.21-7.42 (11H, m, ArH), 7.56-7.62 (1H, m, Ar
H), 7.80 (1H, s). Elemental analysis: Calculated as C ₃₇ H ₄₅ N ₃ O ₅ .HCl.0.5H ₂ O Calculated (%): C, 67.62; H, 7.21; N, 6.39 found ( %): C, 67.76; H, 7.37; N, 6.29

Example 32 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-nitro-1,2,3,4-tetrahydroquinazoline
Ethyl-3-yl] isobutyrate 2- [1- (4-bromobutyl) -2,4-dioxo-6-nitro-1,2,3,4-tetrahydroquinazolin-3-yl obtained in Reference Example 76 ] Ethyl isobutyrate (0.29 g) from the free salt of the title compound (0.
41 g, 99%) as an oil. IR (KBr): 2942, 2868, 2813, 1744, 1717, 1674, 161
^{. 5, 1530 cm -1 1 H} -NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.57-2.
00 (8H, m), 1.84 (6H, s), 2.05-2.20 (2H, m), 2.39
(2H, t, J = 6.7 Hz), 2.72-2.82 (2H, m), 3.41-3.53 (1
H, m), 4.09-4.25 (4H, m), 5.53 (1H, s), 7.24-7.38
(10H, m, ArH), 7.53 (1H, d, J = 9.2 Hz), 8.48 (1H, d
d, J = 2.8 Hz, 9.2 Hz), 9.01 (1H, d, J = 2.6 Hz) To this product, add 4N hydrogen chloride in ethyl acetate (0.3 ml), concentrate, and concentrate %) Were obtained as amorphous crystals. IR (KBr): 3400, 2938, 2488, 2398, 1740, 1717, 167
^{. 2, 1615, 1526 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.13 (3H, dt, J = 7.1 Hz, 1.0 H
z), 1.55-2.23 (8H, m), 1.72 (6H, s), 2.82-3.85 (7H,
m), 4.03-4.15 (4H, m), 5.68 (1H, d, J = 10.6Hz), 7.
21-7.43 (10H, m, ArH), 7.74 (1H, d, J = 9.2 Hz), 8.4
8-8.55 (1H, m, ArH), 8.68 (1H, dd, J = 2.6 Hz, 1.4 H
z). Elemental analysis: C ₃₆ H ₄₂ N ₄ O ₇・ HCl ・ 0.5H ₂ O Calculated (%): C, 62.83; H, 6.44; N, 8.14 Found (%): C, 62.64; H, 6.54; N, 7.98

Example 33 2- [1- [4- (4-Diphenylmethoxypiperidino) butyl] -2,
4-dioxo-6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyric acid ethyl hydrochloride 2- [1- (4-bromobutyl) -2,4-obtained in Reference Example 77 Dioxo-6-fluoro-1,2,3,4-tetrahydroquinazoline-3-
From ethyl [yl] isobutyrate (0.57 g), the free salt of the title compound (0.72 g, 88%) was obtained as an oil. IR (KBr): 2942, 2867, 2811, 1744, 1709, 1667, 1507
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.50-1.
95 (8H, m), 1.83 (6H, s), 2.05-2.17 (2H, m), 2.33-
2.40 (2H, m), 2.70-2.80 (2H, m), 3.40-3.51 (1H,
m), 4.01-4.09 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 5.5
3 (1H, s), 7.24-7.39 (12H, m, ArH), 7.81 (1H, dd,
J = 8.1 Hz, 2.5 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.6 ml).
After concentration, the title compound (0.64 g, 83%) was obtained as amorphous crystals. IR (KBr): 3420, 2984, 2938, 2500, 1740, 1707, 166
. 3, 1624, 1605, 1505 cm -1 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.1 Hz), 1.50-
2.23 (8H, m), 1.71 (6H, s), 2.82-3.75 (7H, m), 4.0
1-4.11 (4H, m), 5.68 (1H, d, J = 10.6 Hz), 7.21-7.42
(10H, m, ArH), 7.53-7.74 (3H, m, ArH). Elemental analysis: C ₃₆ H ₄₂ N ₃ O ₅ F.HCl.0.5H ₂ O Calculated (%): C, 65.39; H, 6.71; N, 6.36 Found (%): C, 65.31; H, 6.54; N, 6.20

Example 34 2- [7-Chloro-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate hydrochloride 2- [1- (4-bromobutyl) -7-chloro obtained in Reference Example 78
-2,4-Dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.49 g) to give the free salt of the title compound
(0.62 g, 89%) was obtained as an oil. IR (KBr): 2990, 2942, 2867, 2811, 1748, 1713, 166
^{. 9, 1605 cm -1 1 H} -NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.2 Hz), 1.50-2.
00 (8H, m), 1.82 (6H, s), 2.05-2.19 (2H, m), 2.38
(2H, t, J = 6.7 Hz), 2.71-2.81 (2H, m), 3.40-3.51 (1
H, m), 4.01-4.09 (2H, m), 4.18 (2H, q, J = 7.2 Hz),
5.53 (1H, s), 7.18 (1H, dd, J = 8.4 Hz, 1.8 Hz), 7.2
1-7.37 (11H, m, ArH), 8.06 (1H, d, J = 8.4 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.5 ml).
After concentration, the title compound (0.54 g, 81%) was obtained as amorphous crystals. IR (KBr): 3400, 2990, 2938, 2475, 2373, 1740, 170
^{. 9, 1665, 1605 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.1 Hz), 1.50-
2.24 (8H, m), 1.70 (6H, s), 2.82-3.74 (7H, m), 4.0
0-4.10 (4H, m), 5.68 (1H, d, J = 10.6 Hz), 7.21-7.42
(11H, m, ArH), 7.62 (1H, s, ArH), 7.99 (1H, dd, J
= 8.6 Hz, 1.4 Hz). Elemental analysis: C ₃₆ H ₄₂ N ₃ O ₅ Cl ・ HCl ・ 0.5H ₂ O Calculated (%): C, 63.81; H, 6.54; N, 6.20 Actual (% ): C, 64.05; H, 6.33; N, 6.15

Example 35 2- [6-Chloro-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] ethyl isobutyrate hydrochloride 2- [1- (4-bromobutyl) -6-chloro obtained in Reference Example 79
-2,4-Dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.61 g) to give the free salt of the title compound
(0.85 g, 98%) was obtained as an oil. IR (KBr): 3029, 2942, 2868, 2811, 2774, 1744, 170
. 9, 1667, 1609, 1591 cm -1 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.1 Hz), 1.50-1.
98 (8H, m), 1.82 (6H, s), 2.03-2.18 (2H, m), 2.33-
2.40 (2H, m), 2.70-2.80 (2H, m), 3.40-3.52 (1H,
m), 4.00-4.04 (2H, m), 4.18 (2H, q, J = 7.1 Hz), 5.5
3 (1H, s), 7.24-7.37 (11H, m, ArH), 7.58 (1H, dd,
J = 9.0 Hz, 2.4 Hz), 8.10 (1H, d, J = 2.2 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.5 ml).
After concentration, the title compound (0.73 g, 80%) was obtained as amorphous crystals. IR (KBr): 3400, 2982, 2938, 2485, 2400, 1740, 170
^{. 9, 1665, 1609 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, dt, J = 1.0 Hz, 7.1 H
z), 1.52-2.22 (8H, m), 1.70 (6H, s), 2.80-3.73 (7H,
m), 4.00-4.11 (4H, m), 5.68 (1H, d, J = 10.8Hz), 7.
20-7.43 (10H, m, ArH), 7.55 (1H, d, J = 8.8 Hz), 7.8
1 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.93 (1H, dd, J = 2.5
Elemental analysis: C ₃₆ H ₄₂ N ₃ O ₅ Cl ・ HCl ・ 0.5H ₂ O Calculated (%): C, 63.81; H, 6.54; N, 6.20 Actual (%): C, 63.65; H, 6.60; N, 6.15

Example 36 Ethyl 2- [2,4-dioxo-1- [3- (4-diphenylmethoxypiperidino) propyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Ethyl 2- [1- (3-bromopropyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.52 g, 1.31 mmol) obtained in Reference Example 80 To give the free salt of the title compound (0.59 g, 77%) as an oil. IR (KBr): 3029, 2980, 2942, 2814, 2780, 1744, 170
^{. 7, 1663, 1609 cm -1} 1 H-NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.2 Hz), 1.65-1.
98 (6H, m), 1.84 (6H, s), 2.05-2.16 (2H, m), 2.36-
2.42 (2H, m), 2.69-2.80 (2H, m), 3.39-3.51 (1H,
m), 4.07-4.14 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 5.5
3 (1H, s), 7.17-7.37 (12H, m, ArH), 7.58-7.67 (1H,
m, ArH), 8.13 (1H, dd, J = 7.8 Hz, 1.6 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.5 ml).
After concentration, the title compound (0.54 g, 85%) was obtained as amorphous crystals. IR (KBr): 3411, 2984, 2938, 2473, 2409, 1740, 170
^{. 5, 1663, 1609 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.2 Hz), 1.71
(6H, s), 1.75-2.20 (6H, m), 2.80-3.72 (7H, m), 4.0
1-4.15 (4H, m), 5.66 (1H, d, J = 8.6 Hz), 7.21-7.43
(11H, m, ArH), 7.52-7.57 (1H, m, ArH), 7.75-7.82
. (1H, m, ArH) , 8.01 (1H, d, J = 7.8 Hz) Elemental _{analysis: C 35 H 41 N 3 O} 5 · HCl · 0.5H 2 O Calculated (%): C, 66.81; H, 6.89; N, 6.68 Found (%): C, 66.94; H, 6.74; N, 6.91

Example 37 Ethyl 2- [2,4-dioxo-1- [5- (4-diphenylmethoxypiperidino) pentyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Ethyl 2- [1- (5-bromopentyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.62 g, 1.46 mmol) obtained in Reference Example 81 To give the free salt of the title compound (0.67 g, 75%) as an oil. IR (KBr): 2980, 2940, 2865, 2809, 2770, 1744, 170
^{. 7, 1665, 1609 cm -1} 1 H-NMR (CDCl 3) δ: 1.23 (3H, t, J = 7.2 Hz), 1.37-1.
96 (10H, m), 1.84 (6H, s), 2.05-2.17 (2H, m), 2.27-
2.34 (2H, m), 2.69-2.78 (2H, m), 3.39-3.50 (1H, m),
3.99-4.07 (2H, m), 4.18 (2H, q, J = 7.2 Hz), 5.52
(1H, s), 7.11-7.37 (12H, m, ArH), 7.60-7.69 (1H,
m, ArH), 8.15 (1H, dd, J = 8.0 Hz, 1.6 Hz). To this product, add 4N hydrogen chloride in ethyl acetate (0.5 ml),
After concentration, the title compound (0.62 g, 86%) was obtained as amorphous crystals. IR (KBr): 3400, 2938, 2508, 1740, 1705, 1661, 1609
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.12 (3H, t, J = 7.2 Hz), 1.71
(6H, s), 1.75-2.20 (6H, m), 2.80-3.72 (7H, m), 4.0
1-4.15 (4H, m), 5.66 (1H, d, J = 8.6 Hz), 7.21-7.43
(11H, m, ArH), 7.52-7.57 (1H, m, ArH), 7.75-7.82
. (1H, m, ArH) , 8.01 (1H, t, J = 7.8 Hz) Elemental _{analysis: C 37 H 45 N 3 O} 5 · HCl · 0.5H 2 O Calculated (%): C, 67.62; H, 7.21; N, 6.39 found (%): C, 67.50; H, 7.25; N, 6.20

Example 38 Ethyl 2- [2,4-dioxo-1- [6- (4-diphenylmethoxypiperidino) hexyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate Ethyl 2- [1- (6-bromohexyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.65 g, 1.48 mmol) obtained in Reference Example 82 To give the free salt of the title compound (0.83 g, 90%) as an oil. IR (KBr):. 2938, 2859, 1744, 1707, 1667, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.22 (3H, t, J = 7.1 Hz), 1.30-1.
96 (12H, m), 1.84 (6H, s), 2.05-2.17 (2H, m), 2.25-
2.31 (2H, m), 2.68-2.79 (2H, m), 3.38-3.48 (1H, m),
4.03 (2H, t, J = 8.0 Hz), 4.18 (2H, q, J = 7.1 Hz),
5.52 (1H, s), 7.11-7.35 (12H, m, ArH), 7.60-7.68
(1H, m, ArH), 8.14 (1H, dd, J = 7.9 Hz, 1.7 Hz). To this product was added 4N hydrogen chloride in ethyl acetate (0.7 ml).
After concentration, the title compound (0.79 g, 89%) was obtained as amorphous crystals. IR (KBr): 3410, 2938, 2868, 2487, 2410, 1740, 170
^{. 5, 1663, 1609 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.12 (3H, t, J = 7.1 Hz), 1.71
(6H, s), 1.28-2.21 (12H, m), 2.80-3.73 (7H, m), 4.
00-4.11 (4H, m), 5.67 (1H, d, J = 10.2 Hz), 7.20-7.4
9 (12H, m, ArH), 7.73-7.82 (1H, m, ArH), 8.00 (1H,
d, J = 7.2 Hz). Elemental analysis: Calculated as C ₃₈ H ₄₇ N ₃ O ₅・ HCl ・ 0.5H ₂ O Calculated (%): C, 67.99; H, 7.36; N, 6.26 Actual (%) : C, 68.17; H, 7.15; N, 6.34

Example 39 7-Amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline Obtained in Example 11. 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-7-nitro-1,2,3,4-tetrahydroquinazoline (3.00 g) in concentrated hydrochloric acid (10.0 ml), water
(50.0 ml), a mixture of ethanol (50.0 ml) and tetrahydrofuran (50.0 ml), and an excess amount of zinc dust was added little by little. After completion of the reaction, the reaction mixture is filtered, and the filtrate is filtered.
The mixture was made basic with 25% aqueous ammonia and extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure to obtain the title compound (1.95 g, 69%). Recrystallization from ethyl acetate gave yellow crystals with a melting point of 162-164 ° C. IR (KBr):. 3348, 3215, 2945, 1683, 1606, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.58-2.07 (8H, m), 2.07-2.24 (2
H, m), 2.41 (2H, t, J = 6.6 Hz), 2.74-2.88 (2H, m),
3.40-3.54 (1H, m), 4.02 (2H, t, J = 8.8 Hz), 4.37 (2
H, bs), 5.53 (1H, s), 6.40-6.48 (2H, m), 7.20-7.42
. (10H, m), 7.94 (1H, d, J = 8.4 Hz) Elemental _{analysis: C 30 H 34 N 4 O} 3 · 0.3H 2 O Calculated (%): C, 71.49; H, 6.92; N, 11.12 Found (%): C, 71.32; H, 6.77; N, 11.16

Example 40 6-Amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline Method similar to that in Example 39. As a result, the product was obtained in Example 12.
2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-6-nitro-1,2,3,4-tetrahydroquinazoline
(5.90 g) to give the title compound (4.62 g, 83%). Recrystallization from ethyl acetate gave yellow crystals with a melting point of 131-133 ° C. IR (KBr): 3353, 3181, 3029, 2946, 1682, 1588, 150
^{. 8, 1493 cm -1 1 H} -NMR (CDCl 3) δ: 1.50-2.02 (8H, m), 2.02-2.20 (2
H, m), 2.37 (2H, t, J = 6.2 Hz), 2.68-2.84 (2H, m),
3.38-3.52 (1H, m), 3.75 (2H, bs), 4.05 (2H, t, J = 7.
8 Hz), 5.53 (1H, s), 7.04 (1H, dd, J = 9.0, 3.0 Hz),
7.18-7.38 (11H, m), 7.44 (1H, d, J = 2.6 Hz). Elemental analysis: C ₃₀ H ₃₄ N ₄ O ₃・ 0.9H ₂ O Calculated (%): C, 69.99; H , 7.01; N, 10.88 Found (%): C, 69.98; H, 6.65; N, 11.10

Example 41 7-Dimethylamino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline Obtained in Example 39 7-amino-2,4-dioxo-1- [4- (4-
Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (500 mg) was suspended in methanol (5.00 ml), and acetic acid (0.5 ml) and 37% formaldehyde were added thereto.
(0.5 ml) and stirred for 1 hour. A solution of sodium cyanoborohydride (94.5 mg) in methanol (2.0 ml) was added dropwise, and the mixture was stirred at room temperature for 21 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and dried (Na ₂ SO ₄ ).
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (5:
The title compound (378 mg, 72%) was obtained from the eluted part of (1, v / v). Recrystallization from ethyl acetate-ethyl ether gave a melting point of 203.
Yellow crystals at -204 ° C were obtained. IR (KBr): 3174, 3027, 2943, 1679, 1608, 1571, 1542
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.52-1.98 (8H, m), 2.04-2.20 (2
H, m), 2.37 (2H, t, J = 7.0 Hz), 2.68-2.82 (2H, m),
3.10 (6H, s), 3.38-3.52 (1H, m), 4.08 (2H, t, J = 7.
8 Hz), 5.52 (1H, s), 6.18 (1H, d, J = 2.0 Hz), 6.57
(1H, dd, J = 9.0,2.0 Hz), 7.20-7.40 (10H, m), 7.99
(1H, d, J = 9.0 Hz), 8.15 (1H, bs). Elemental analysis: Calculated as C ₃₂ H ₃₈ N ₄ O ₃・ 0.5H ₂ O (%): C, 71.75; H, 7.34; N, 10.46 Found (%) Found: C, 71.53; H, 7.14; N, 10.31.

Example 42 6-Dimethylamino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline Obtained in Example 40 6-amino-2,4-dioxo-1- [4- (4-
Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (800 mg) was suspended in methanol (8.0 ml), and acetic acid (0.8 ml) and 37% formaldehyde were added thereto.
(0.8 ml) and stirred for 1.5 hours. A solution of sodium cyanoborohydride (141 mg) in methanol (4.0 ml) was added dropwise, and the mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water and dried (Na ₂ SO ₄ ).
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-ethyl acetate (5:
1, v / v) to give the title compound (420 mg, 50%).
Recrystallized from ethyl acetate-ethyl ether, melting point 165-167
C. Yellow crystals were obtained. IR (KBr): 3173, 2946, 1694, 1626, 1580, 1518, 1483
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.58-2.02 (8H, m), 2.10-2.28 (2
H, m), 2.42 (2H, t, J = 6.6 Hz), 2.73-2.85 (2H, m),
2.98 (6H, s), 3.40-3.55 (1H, m), 4.07 (2H, t, J = 7.
8 Hz), 5.52 (1H, s), 7.11 (1H, dd, J = 9.2, 2.6 Hz),
7.22-7.38 (11H, m), 7.43 (1H, d, J = 3.0 Hz) Elemental _{analysis: C 32 H 38 N 4 O} 3 · 1.0H 2 O Calculated (%):. C, 70.56 ; H , 7.40; N, 10.28 Found (%): C, 70.25; H, 7.04; N, 10.83

Example 43 N- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydro-7-quinazolinyl] ethylmalonamide 7-amino-2,4-dioxo-1- [4- (4- (4-
Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (700 mg) in tetrahydrofuran (10.
0ml), and triethylamine (0.24ml) and ethylmalonyl chloride (0.20ml) were added thereto while stirring under ice cooling. After stirring the reaction mixture at room temperature for 18.5 hours, water was added, and the mixture was extracted with ethyl acetate. Wash the extract with water and dry (Na ₂
After SO ₄ ), the solvent was distilled off under reduced pressure to give the title compound (690 mg, 8
0%) were obtained as amorphous crystals. IR (KBr):. 3029, 1682, 1597, 1549, 1495 cm -1 1 H-NMR (CDCl 3) δ: 1.34 (3H, t, J = 6.2 Hz), 1.55-2.
00 (8H, m), 2.04-2.24 (2H, m), 2.38 (2H, t, J = 6.8 H
z), 2.70-2.85 (2H, m), 3.37-3.55 (1H, m), 3.51 (2
H, s), 4.12 (2H, t, J = 6.6 Hz), 4.29 (2H, q, J = 7.2
Hz), 5.52 (1H, s), 7.10 (1H, d, J = 8.0 Hz), 7.18-7.
40 (10H, m), 8.04 (1H, s), 8.13 (1H, d, J = 8.6 Hz),
9.79 (1H, bs). Elemental analysis: Calculated as C ₃₅ H ₄₀ N ₄ O ₆・ 0.4H ₂ O Calculated (%): C, 67.81; H, 6.63; N, 9.04 Actual (%): C, 67.81; H, 6.67; N, 9.08

Example 44 N- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydro-6-quinazolinyl] ethylmalonamide By a method similar to that in Example 43, obtained in Example 40.
6-amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline
(1.78 g) to give the title compound (1.13 g, 52%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 152-153 ° C. IR (KBr): 3061,, 2946, 1696, 1628, 1601, 1557, 15
^{. 07 cm -1 1 H-NMR} (CDCl 3) δ: 1.34 (3H, t, J = 7.2 Hz), 1.50-2.
00 (8H, m), 2.08-2.26 (2H, m), 2.39 (2H, t, J = 4.6 H
z), 2.70-2.82 (2H, m), 3.40--3.54 (1H, m), 3.50 (2
H, s), 4.10 (2H, t, J = 8.4 Hz), 4.28 (2H, q, J = 7.0
Hz), 5.52 (1H, s), 7.18-7.38 (11H, m), 8.10 (1H, d,
J = 2.2 Hz), 8.15-8.24 (1H, m), 9.52 (1H, bs). Elemental analysis: Calculated as C ₃₅ H ₄₀ N ₄ O ₆ (%): C, 68.61; H, 6.58; N , 9.14 Found (%): C, 68.04; H, 6.60; N, 9.27

Example 45 7-acetoxyacetamide-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline As in Example 43 By using acetoxyacetyl chloride instead of ethylmalonyl chloride, 7-amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl obtained in Example 39) ] -1,2,3,4-tetrahydroquinazoline (710 mg) to give the title compound (563 mg, 66
%) Were synthesized. Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave colorless crystals having a melting point of 211-212 ° C. IR (KBr): 3030,, 2941, 1753, 1689, 1616, 1596, 15
^{. 44, 1459 cm -1 1 H} -NMR (CDCl 3) δ: 1.60-2.10 (8H, m), 2.18-2.40 (2
H, m), 2.25 (3H, s), 2.44-2.54 (2H, m), 2.76-2.94
(2H, m), 3.44-3.58 (1H, m), 4.03-4.36 (2H, m), 4.7
3 (2H, s), 5.50 (1H, s), 7.10-7.40 (12H, m), 8.00
(1H, bs), 8.03 (1H, d, J = 8.4 Hz). Elemental analysis: Calculated as C ₃₄ H ₃₈ N ₄ O ₆・ 0.5H ₂ O (%): C, 67.20; H, 6.47; N, 9.22 found (%): C, 67.04; H, 6.29; N, 9.35

Example 46 6-Acetoxyacetamide-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline Same as Example 45 Obtained in Example 40 by the method of
6-amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline (8
00 mg) to give the title compound (688 mg, 72%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 133-135 ° C. IR (KBr): 3061, 2946, 1750, 1694, 16130, 1601, 155
^{. 7, 1508 cm -1 1 H} -NMR (CDCl 3) δ: 1.58-2.00 (8H, m), 2.12-2.32 (2
H, m), 2.26 (3H, s), 2.35-2.50 (2H, m), 2.70-2.88
(2H, m), 3.40-3.54 (1H, m), 4.10 (2H, t, J = 7.0Hz),
4.74 (2H, s), 5.51 (1H, s), 7.20-7.40 (11H, m),
7.97 (1H, d, J = 2.6 Hz), 8.16 (1H, bs), 8.25-8.35
(1H, m). Elemental analysis: C ₃₄ H ₃₈ N ₄ O ₆・ 1.4H ₂ O Calculated (%): C, 65.29; H, 6.32; N, 9.33 Actual (%): C, 65.45 ; H, 6.59; N, 8.98

Example 47 [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydro-7-quinazolinyl] carbamoylacetic acid The obtained N- [2,4-dioxo-1- [4- (4-diphenylmethoxy-1-piperidinyl) butyl)]-1,2,3,4-tetrahydro-7-quinazolinyl] ethylmalonamide (690 mg)
To tetrahydrofuran (10.0 ml) and ethanol (10.0 m
l) and 1N aqueous sodium hydroxide solution (5.0 ml) was added. After stirring the reaction mixture at room temperature for 16 hours, the solvent was distilled off under reduced pressure, the residue was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. After washing the extract with water and drying (Na ₂ SO ₄ ),
The solvent was distilled off under reduced pressure to obtain the title compound (126 mg, 19%). Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave colorless crystals having a melting point of 230-232 ° C. IR (KBr): 3700-2400, 3340, 3028, 1685, 1617, 1594,
^{. 1535 cm -1 1 H-NMR} (CDCl 3) δ: 1.60-3.30 (15H, m), 3.38 (2H,
s), 3.68-4.10 (2H, m), 5.44 (1H, s), 7.20-7.40 (11
H, m), 7.42-7.58 (1H, m), 7.72-7.86 (1H, m), 9.96
(1H, bs). Elemental analysis: Calculated as C ₃₃ H ₃₆ N ₄ O ₆・ 1.5H ₂ O Calculated (%): C, 64.97; H, 6.43; N, 9.16 Found (%): C, 64.79 ; H, 6.27; N, 9.36

Example 48 [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydro-6-quinazolinyl] carbamoylacetic acid Was obtained in Example 44 by the same method as
Title from N- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydro-6-quinazolinyl] ethylmalonamide (800 mg) Compound (279 mg, 36
%) Were synthesized. Recrystallization from ethyl acetate-methanol gave colorless crystals having a melting point of 166-168 ° C. IR (KBr): 3700-2700, 3031, 1686, 1599, 1545, 1508
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.66-3.42 (15H, m), 3.68-3.78
(2H, m), 3.94-4.10 (2H, m), 5.48 (1H, s), 6.98-7.06
(1H, m), 7.20-7.52 (11H, m), 8.04 (1H, s), 8.08 (1
. H, bs), 10.90 ( 1H, bs) Elemental _{analysis: C 33 H 36 N 4 O} 6 · 1.3H 2 O Calculated (%): C, 65.18; H, 6.40; N, 9.21 Found ( %): C, 65.11; H, 6.25; N, 9.29

Example 49 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl)]-1,2,3,4-tetrahydroquinazoline-3-acetic acid Obtained in Example 14 by a method similar to that in Example 47.
2,4-dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl)]-1,2,3,4-tetrahydroquinazoline-3-acetate (1.00 g) to give the title compound (790 mg, 81%). Recrystallization from ethyl acetate-methanol-tetrahydrofuran gave colorless crystals having a melting point of 170-172 ° C. IR (Nujor): 3600-3300, 1690, 1650, 1610, 1590, 149
^{. 0 cm -1 1 H-NMR} (CDCl 3) δ: 1.80-2.22 (6H, m), 2.84-3.06 (4
H, m), 3.06-3.28 (2H, m), 3.62-3.74 (1H, m), 4.08-4.
20 (2H, m), 4.60 (2H, s), 5.42 (1H, s), 7.05-7.42
(12H, m), 7.59 (1H, t, J = 8.8 Hz), 8.11 (1H, d, J =
8.0 Hz). Elemental analysis: C ₃₁ H ₃₃ N ₃ O ₅・ 1.0H ₂ O Calculated (%): C, 68.23; H, 6.47; N, 7.70 Found (%): C, 67.87; H , 6.53; N, 7.78

Example 50 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-acetic acid Obtained in Example 15 by a method similar to that in Example 47.
2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-acetate (1.50 g) to give the title compound (1.22 g, 84%).
Recrystallization from ethyl acetate gave colorless crystals having a melting point of 184-186 ° C. IR (KBr): 3400-2800, 1702, 1656, 1606, 1571, 1484
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.74-2.08 (6H, m), 2.30-3.32 (8
H, m), 3.76-3.84 (1H, m), 4.25-4.38 (2H, m), 4.69
(2H, s), 5.43 (1H, s), 7.08-7.44 (12H, m), 7.61 (1
H, t, J = 8.4 Hz), 8.25 (1H, d, J = 7.6 Hz). Elemental analysis: C ₃₂ H ₃₅ N ₃ O ₅・ 1.7H ₂ O Calculated (%): C, 67.16; H, 6.76; N, 7.34 Found (%): C, 67.14; H, 6.70; N, 7.41.

Example 51 2,4-Dioxo-1- [3- (4-diphenylmethoxypiperidino)
Propyl] -1,2,3,4-tetrahydroquinazoline-3-propionic acid Obtained in Example 16 by a method similar to that in Example 47.
The title compound (882 mg) was obtained from ethyl 2,4-dioxo-1- [3- (4-diphenylmethoxypiperidino) propyl)]-1,2,3,4-tetrahydroquinazoline-3-propionate (945 mg). , 98
%) Were synthesized. Recrystallization from ethyl acetate-methanol-ethyl ether gave colorless crystals having a melting point of 150-151 ° C. IR (KBr):. 3400-2750, 1699, 1655, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.76-2.08 (6H, m), 2.54 (2H, t,
J = 7.4 Hz), 2.62-2.78 (4H, m), 2.82-3.06 (2H, m),
3.52-3.63 (1H, m), 4.13 (2H, t, J = 5.8 Hz), 4.34 (2
(H, t, J = 7.4Hz), 5.47 (1H, s), 7.10-7.38 (12H, m),
7.63 (1H, t, J = 7.4 Hz), 8.15 (1H, d, J = 8.0 Hz). Elemental analysis: C ₃₂ H ₃₅ N ₃ O ₅・ 1.5H ₂ O Calculated (%): C, 67.59; H, 6.74; N, 7.39 Found (%): C, 67.58; H, 6.39; N, 7.53

Example 52 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-propionic acid In the same manner as in Example 47, 2,4-dioxo-1- [4, a free salt of the compound obtained in Example 17 -(4-Diphenylmethoxypiperidino) butyl)]-1,2,3,4-tetrahydroquinazoline-3-propionate (1.83 g) to give the title compound (1.23 g, 71%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 107-108 ° C. IR (KBr):. 3640-3120, 1700, 1652, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.66-2.02 (8H, m), 2.14-2.32 (2
H, m), 2.54 (2H, t, J = 6.2 Hz), 2.80-3.10 (4H, m),
3.64-3.74 (1H, m), 4.26-4.38 (2H, m), 4.47 (2H, t,
J = 6.2 Hz), 5.47 (1H, s), 7.10-7.35 (12H, m), 7.63
(1H, t, J = 8.0 Hz), 8.24 (1H, d, J = 7.8 Hz) Elemental _{analysis:. C 33 H 37 N 3} O 5 · 1.1H 2 O Calculated (%): C, 68.87 ; H, 6.87; N, 7.30 Found (%): C, 68.68; H, 6.97; N, 7.17

Example 53 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-butyric acid Obtained in Example 18 by the same method as in Example 47.
2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl)]-1,2,3,4-tetrahydroquinazoline-3-butyrate (2.00 g) to give the title compound (857 mg, 45%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 132-133 ° C. IR (KBr):. 3200-2400, 1704, 1658, 1608, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.70-2.04 (8H, m), 2.04-2.18 (2
H, m), 2.36-2.55 (4H, m), 2.55-2.73 (2H, m), 2.75-
2.92 (2H, m), 3.48-3.60 (1H, m), 4.16-4.30 (4H, m
m), 5.47 (1H, s), 7.10-7.40 (12H, m), 7.61 (1H, t,
J = 8.2 Hz), 8.26 (1H, d, J = 8.0 Hz). Elemental analysis: Calculated as C ₃₄ H ₃₉ N ₃ O ₅ (%): C, 71.68; H, 6.90; N, 7.38 (%): C, 71.20; H, 6.80; N, 7.31

Example 54 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydro-3-quinazolinyl] ethylbenzoate 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-
Tetrahydro-3-quinazolinyl] ethylbenzoate (2.9
From 2 g), the title compound (3.25 g, 78%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.82 (6H, m), 1.82-2.00 (2
H, m), 2.00-2.20 (2H, m), 2.34 (2H, t, J = 6.6 Hz),
2.68-2.82 (2H, m), 3.37-3.52 (1H, m), 4.11 (2H, t,
J = 7.4 Hz), 4.50-4.64 (4H, m), 5.53 (1H, s), 7.18-
7.56 (15H, m), 7.67 (1H, t, J = 7.0 Hz), 7.99 (2H,
d, J = 8.4 Hz), 8.22 (1H, d, J = 7.8 Hz).

Example 55 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -3- (2-hydroxyethyl) -1,2,3,4-tetrahydroquinazoline Obtained in Example 54 by a method similar to Example 47.
The title compound (3.25 g) was obtained from 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydro-3-quinazolinyl] ethylbenzoate (3.25 g). 2.12 g, 78
%) Were synthesized. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 145-150 ° C. IR (KBr):. 3460, 2944, 1701, 1659, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.50-2.00 (8H, m), 2.00-2.22 (2
H, m), 2.39 (2H, t, J = 7.2 Hz), 2.68-2.84 (2H, m),
3.39-3.54 (1H, m), 3.93 (2H, t, J = 5.2 Hz), 4.15 (2
H, t, J = 7.6 Hz), 4.37) 2H, t, J = 5.4 Hz), 5.52 (1H,
s), 7.14-7.42 (12H, m), 7.68 (1H, ddd, J = 8.8, 7.
. 4, 1.4 Hz), 8.23 (1H, dd, J = 8.0, 1.4 Hz) Elemental analysis: Calculated _{C 32 H 37 N 3 O 4} (%): C, 72.84; H, 7.07; N, 7.96 Found (%): C, 72.44; H, 7.20; N, 7.82

Example 56 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -N-methyl-N- (2-phenethyl) -1,2,3,4-tetrahydroquinazoline-3-acetamide hydrochloride Obtained in Reference Example 100 by the same method as in Example 2 (Method 4). 1- (4-bromobutyl) -2,4-dioxo-N-methyl-N
-(2-phenethyl) -1,2,3,4-tetrahydroquinazoline-3-
The free salt of the title compound (1.77 g) from acetamide (1.55 g)
g, 82%) as amorphous crystals. IR (KBr):. 2941, 1706, 1662, 1610, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.54-2.00 (8H, m), 2.06-2.24 (2
H, m), 2.39 (2H, t, J = 7.0 Hz), 2.70-2.86 (2H, m),
2.85 (2H, t, J = 7.6 Hz, major), 2.94, (3H, s, mino
r), 2.99 (3H, s, major), 3.02 (2H, t, J = 7.6 Hz, mi
nor), 3.38-3.52 (1H, m), 3.52-3.64 (2H, m), 4.06-
4.20 (2H, m), 4.85 (2H, s, minor), 4.88 (2H, s, maj
or), 5.51 (1H, s), 7.10-7.42 (17H, m), 7.67 (1H,
t, J = 7.8 Hz), 8.18-8.27 (1H, m). Elemental analysis: Calculated as C ₄₁ H ₄₆ N ₄ O ₄・ 0.4H ₂ O (%): C, 73.94; H, 7.08; N , 8.41 Found (%): C, 73.83; H, 7.02; N, 8.36 To this product (1.00 g) was added 4N hydrogen chloride in ethyl acetate,
After concentration, the title compound (781 mg, 74%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 137-139 ° C. IR (KBr):. 2933, 1706, 1658, 1610, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.80-2.12 (8H, m), 2.30-2.35 (2
H, m), 2.70-3.18 (4H, m), 2.87, (3H, s, minor), 2.9
5 (3H, s, major), 3.28-3.62 (4H, m), 3.78-3.88 (1
H, m), 4.22 (2H, t, J = 6.6 Hz), 4.83 (2H, s, mino
r), 4.87 (2H, s, major), 5.37 (1H, s, major), 5.41
(1H, s, minor), 7.10-7.40 (17H, m), 7.70 (1H, t,
J = 7.4 Hz), 8.18-8.28 (1H, m), 12.02 (1H, bs). Elemental analysis: C ₄₁ H ₄₆ N ₄ O ₄・ HCl ・ 0.8H ₂ O Calculated (%): C, 69.39; H, 6.90; N, 7.89 Found (%): C, 69.43; H, 6.87; N, 7.99.

Example 57 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -3- (2-phenethyl) -1,2,3,4-tetrahydroquinazoline 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] obtained in Example 2 -1,2,3,4-tetrahydroquinazoline (420 mg) with N, N-dimethylformamide (20 ml)
, And potassium carbonate (180 mg) and 1-bromo-2-phenylethane (0.18 ml) were sequentially added, followed by stirring at 60 ° C for 16 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (5: 1, v / v) to give the title compound (247 mg, 48%). Recrystallized from ethyl acetate-ethyl ether-n-hexane, melting point 110-112 ℃
To obtain colorless crystals. IR (KBr):. 2745, 1702, 1658, 1610, 1484 cm -1 1 H-NMR (CDCl 3) δ: 1.54-2.04 (8H, m), 2.06-2.26 (2
H, m), 2.34-2.48 (2H, m), 2.70-2.86 (2H, m), 2.98
(2H, t, J = 7.8 Hz), 3.40-3.54 (1H, m), 4.14 (2H, t,
J = 8.8 Hz), 4.30 (2H, t, J = 8.0 Hz), 5.53 (1H, s),
7.14-7.44 (12H, m), 7.67 (1H, ddd, J = 8.4, 7.8, 0.6
Hz), 8.24 (1H, dd, J = 7.8, 1.2 Hz). Elemental analysis: Calculated as C ₃₈ H ₄₁ N ₃ O ₃ (%): C, 77.65; H, 7.03; N, 7.15 Found ( %): C, 77.31; H, 6.95; N, 7.27

Example 58 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -3- (3-phenylpropyl) -1,2,3,4-tetrahydroquinazoline hydrochloride 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) obtained in Example 2 ) Butyl] -1,2,3,4-tetrahydroquinazoline (1.0 g) was dissolved in N, N-dimethylformamide (30 ml), potassium carbonate (429 mg), sodium iodide (2
00 mg) and 1-bromo-3-phenylpropane (0.47 ml) were added successively, followed by stirring at 60 ° C. for 30 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. Wash the extract with water and dry (N
After a ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (5: 1, v / v) to give the free salt of the title compound (1.07
g, 86%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.58-2.22 (12H, m), 2.38 (2H,
t, J = 7.4 Hz), 2.73 (2H, t, J = 8.0 Hz), 2.67-2.83 (2
H, m), 3.38-3.52 (1H, m), 4.04-4.20 (4H, m), 5.52
(1H, s), 7.08-7.40 (12H, m), 7.65 (1H, ddd, J = 8.4,
7.0, 1.4 Hz), 8.21 (1H, dd, J = 7.8, 1.2 Hz). Add 4N hydrogen chloride in ethyl acetate to this product (1.07 g),
After concentration, the title compound (423 mg, 37%) was obtained as amorphous crystals. IR (KBr):. 2938, 1699, 1655, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.70-2.16 (8H, m), 2.30-2.52 (2
H, m), 2.72 (2H, t, J = 8.4 Hz), 2.94-3.16 (4H, m),
3.26-3.44 (2H, m), 3.82-3.90 (1H, m), 4.05-4.20 (4
H, m), 5.42 (1H, s), 7.08-7.40 (12H, m), 7.62-7.75
(1H, m), 8.23 ( 1H, d, J = 7.6 Hz) Elemental _{analysis: C 39 H 43 N 3 O} 3 · HCl · 1.2H 2 O Calculated (%): C, 70.99; H, 7.09 ; N, 6.37 found (%): C, 70.87; H, 7.10; N, 6.55

Example 59 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3- (2,2-dimethyl) butyric acid ethyl hydrochloride In the same manner as in Example 58, 2,2
4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (880 mg) to give the free salt of the title compound (640 mg, 56%) as an oil As obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.18-1.30 (9H, m), 1.54-1.98 (1
0H, m), 2.04-2.20 (2H, m), 2.38 (2H, t, J = 6.6 Hz),
2.68-2.84 (2H, m), 3.40-3.52 (1H, m), 4.04-4.20 (6
H, m), 5.53 (1H, s), 7.16-7.40 (12H, m), 7.65 (1H,
t, J = 8.8 Hz), 8.21 (1H, d, J = 7.6 Hz). To this product (640 mg) was added 4N hydrogen chloride in ethyl acetate.
After concentration, the title compound (376 mg, 56%) was obtained as amorphous crystals. IR (KBr):. 2938, 1701, 1655, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.20-1.34 (9H, m), 1.50-2.18 (8
H, m), 2.34-2.56 (2H, m), 2.94-3.22 (4H, m), 3.30-
3.42 (2H, m), 3.83-3.90 (1H, m), 4.00-4.20 (6H,
m), 5.44 (1H, s), 7.18-7.40 (12H, m), 7.70 (1H, t,
J = 7.6 Hz), 8.22 (1H, d, J = 8.0 Hz), 12.16 (1H, b
s). Elemental analysis: Calculated as C ₃₈ H ₄₇ N ₃ O ₃ .HCl.1.2H ₂ O Calculated (%): C, 66.74; H, 7.43; N, 6.14 Found (%): C, 66.78; H, 7.29; N, 6.26

Example 60 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-valeric acid According to a method similar to that in Example 58, 2,2
4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.80 g) to give the ethyl ester of the title compound (2.74 g, about 100%) Obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 6.8 Hz), 1.54-2.
00 (12H, m), 2.04-2.20 (2H, m), 2.30-2.44 (4H, m),
2.72-2.86 (2H, m), 3.38-3.52 (1H, m), 4.04-4.20 (6
H, m), 5.53 (1H, s), 7.18-7.40 (12H, m), 7.66 (1H,
ddd, J = 8.8, 7.2, 1.6 Hz), 8.21 (1H, dd, J = 8.2, 1.
This product (2.74 g) was treated in the same manner as in the synthesis of the title compound of Example 47 to give the title compound (732 mg, 34%) as amorphous crystals. IR (KBr): 3700-2300, 2949, 1699, 1655, 1609, 1485
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.57-2.10 (10H, m), 2.22-2.42
(2H, m), 2.31 (2H, t, J = 6.6 Hz), 2.96 (2H, t, J = 9.
0 Hz), 3.00-3.18 (2H, m), 3.20-3.36 (2H, m), 3.74-
3.84 (1H, m), 4.08-4.26 (4H, m), 5.44 (1H, s), 7.1
2-7.44 (12H, m), 7.67 (1H, t, J = 7.6 Hz), 8.24 (1H,
d, J = 7.6 Hz). Elemental analysis: C ₃₅ H ₄₁ N ₃ O ₅・ 2.6H ₂ O Calculated (%): C, 66.67; H, 7.38; N, 6.66 Actual (%): C , 66.40; H, 6.92; N, 6.45

Example 61 3-benzyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline hydrochloride Obtained in Example 2 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (0.48 g, 1.0 mmol) was added to N, N-dimethylformamide ( 4 ml) and sodium hydride (60% oily, 44
mg, 1.1 mmol). After stirring at room temperature for 15 minutes, benzyl bromide (0.18 g, 1.2 mmol) was added, and the mixture was further stirred for 1 hour. Ice water was added to the reaction mixture, and the mixture was extracted with ethyl ether. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and chloroform-methanol (20: 1, v / v
Elution with v) gave the free salt of the title compound (0.40 g, 70%) as an oil. To this product was added a 4N solution of hydrogen chloride in ethyl acetate, and the mixture was concentrated to give the title compound (0.35 g, 81%) as amorphous crystals. IR (KBr): 3400, 3085, 3060, 3031, 3002, 2952, 287
. 5, 2482, 1700, 1654 , 1608 cm -1 1 H-NMR (DMSO-d 6) δ: 1.60-2.21 (8H, m), 2.75-3.73
(7H, m), 4.10-4.20 (2H, m), 5.16 (2H, s), 5.67 (1
H, d, J = 11.4 Hz), 7.20-7.43 (16H, m, ArH), 7.55 (1
H, d, J = 8.4 Hz), 7.76-7.84 (1H, m), 8.11 (1H, d, J
= 7.8 Hz) Elemental _{analysis: C 37 H 40 N 3 O} 3 · HCl · 0.5H 2 O Calculated (%):. C, 71.65 ; H, 6.83; N, 6.78 Found (%): C, 71.31; H, 6.69; N, 6.63

Example 62 3-[(2-Methoxycarbonylphenyl) methyl] -2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl]-
1,2,3,4-Tetrahydroquinazoline hydrochloride In the same manner as in Example 61, 2,2,3,4-tetrahydroquinazoline hydrochloride obtained in Example 2 was obtained.
4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (0.97 g, 2.0 mm
ol) to give the free salt of the title compound (0.94 g, 74%) as an oil. To this product (0.54 g, 0.85 mmol) was added a 4N solution of hydrogen chloride in ethyl acetate, and after concentration, the title compound (0.47 g, 81
%) Were obtained as amorphous crystals. IR (KBr): 3404, 3060, 3030, 2950, 2491, 2376, 1700,
^{. 1654, 1608 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.60-2.20 (8H, m), 2.75-3.72
(7H, m), 3.89 (3H, d, J = 1.6 Hz), 4.10-4.21 (2H, m),
5.49 (1H, d, J = 3.6 Hz), 5.66 (1H, d, J = 13.6 Hz),
7.07-7.61 (15H, m, ArH), 7.79-7.96 (2H, m, ArH),
8.10 (1H, d, J = 7.8 Hz) Elemental _{analysis: C 39 H 41 N 3 O} 5 · HCl · H 2 O Calculated (%): C, 68.26; H, 6.46; N, 6.12 Found ( %): C, 68.25; H, 6.39; N, 6.14

Example 63 3-[(3-Methoxycarbonylphenyl) methyl] -2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl]-
1,2,3,4-Tetrahydroquinazoline hydrochloride In the same manner as in Example 61, 2,2,3,4-tetrahydroquinazoline hydrochloride obtained in Example 2 was obtained.
4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (0.48 g, 1.0 mm
ol) to give the free salt of the title compound (0.50 g, 79%) as an oil. To this product (0.40 g, 0.63 mmol) was added a 4N solution of hydrogen chloride in ethyl acetate, and after concentration, the title compound (0.37 g, 8
7%) were obtained as amorphous crystals. IR (KBr): 3400, 3058, 3030, 2950, 2499, 1718, 170
^{. 0, 1658, 1608 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.60-2.21 (8H, m), 2.78-3.73
(7H, m), 3.83 (3H, s), 4.11-4.20 (2H, m), 5.21 (1H,
s), 5.67 (1H, d, J = 11.6 Hz), 7.24-7.65 (14H, m, A
rH), 7.77-7.95 (3H, m, ArH), 8.09-8.13 (1H, m, Ar
H) Elemental _{analysis: C 39 H 41 N 3 O} 5 · HCl · 0.5H 2 O Calculated (%): C, 69.17; H, 6.40; N, 6.20 Found (%): C, 68.86; H , 6.39; N, 6.10

Example 64 3-[(4-Methoxycarbonylphenyl) methyl] -2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl]-
1,2,3,4-Tetrahydroquinazoline hydrochloride In the same manner as in Example 61, 2,2,3,4-tetrahydroquinazoline hydrochloride obtained in Example 2 was obtained.
4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.21 g, 2.5 mm
ol) to give the free salt of the title compound (0.56 g, 36%) as an oil. A 4N solution of hydrogen chloride in ethyl acetate was added to the product, and the mixture was concentrated to give the title compound (0.52 g, 85%) as amorphous crystals. IR (KBr): 3402, 3058, 3030, 2953, 2476, 2400, 171
. 8, 1700, 1654, 1610 cm -1 1 H-NMR (DMSO-d 6) δ: 1.60-2.20 (8H, m), 2.75-3.72
(7H, m), 3.83 (3H, s), 4.12-4.21 (2H, m), 5.22 (2H,
s), 5.66 (1H, d, J = 11.8 Hz), 7.21-7.58 (14H, m, A
rH), 7.77-7.93 (3H, m, ArH), 8.11 (1H, d, J = 7.8 H
z). Elemental analysis: Calculated as C ₃₉ H ₄₁ N ₃ O ₅ .HCl.H ₂ O Calculated (%): C, 68.26; H, 6.46; N, 6.12 Observed (%): C, 68.16; H , 6.16; N, 6.14

Example 65 3-[(2-carboxyphenyl) methyl] -2,4-dioxo-1- [4
-(4-Diphenylmethoxypiperidino) butyl] -1,2,3,4-
Tetrahydroquinazoline hydrochloride 3-[(2-methoxycarbonylphenyl) methyl] -2,4-dioxo-1- [4- is a free salt of the compound obtained in Example 62.
(4-Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (0.40 g, 0.63 mmol), 2N aqueous sodium hydroxide solution (1.0 ml), tetrahydrofuran (2.0 m
A mixture of l) and methanol (4.0 ml) was stirred at room temperature for 9 hours. The reaction mixture was made weakly acidic with 1N hydrochloric acid and extracted with chloroform. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was triturated with ethyl ether and collected by filtration to give the title compound (0.39 g, 91%)
Was obtained as a colorless powder. IR (KBr):. 2939, 2596, 1700, 1654, 1608 cm -1 1 H-NMR (DMSO-d 6) δ: 1.60-2.20 (8H, m), 2.70-3.70
(7H, m), 4.12-4.21 (2H, m), 5.52 (2H, s) 5.65 (1H,
s), 7.03 (1H, d, J = 7.4 Hz), 7.20-7.48 (13H, m, Ar
H), 7.59 (1H, d, J = 8.6 Hz), 7.79-7.97 (2H, m, Ar
. H), 8.11 (1H, dd, J = 1.5 Hz, 7.9 Hz) Elemental _{analysis: C 38 H 39 N 3 O} 5 · HCl · 1.5H 2 O Calculated (%): C, 67.00; H, 6.36; N, 6.17 found (%): C, 67.18; H, 6.16; N, 5.93

Example 66 3-[(3-Carboxyphenyl) methyl] -1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydro-
2,4-Dioxoquinazoline hydrochloride In the same manner as in Example 65, 3-[(3-methoxycarbonylphenyl) methyl] -2,4-dioxo- which is a free salt of the compound obtained in Example 63 1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline
(0.38 g, 0.60 mmol) gave the title compound (0.36 g, 88%). IR (KBr):. 2950, 2596, 1700, 1654, 1610 cm -1 1 H-NMR (DMSO-d 6) δ: 1.60-2.25 (8H, m), 2.70-3.75
(7H, m), 4.12-4.21 (2H, m), 5.20 (2H, s) 5.67 (1H,
s), 7.24-7.47 (12H, m, ArH), 7.53-7.62 (2H, m, Ar
H), 7.77-7.92 (3H, m, ArH), 8.12 (1H, dd, J = 7.8 H
. z, 1.6 Hz) Elemental _{analysis: C 38 H 39 N 3 O} 5 · HCl · 1.5H 2 O Calculated (%): C, 67.00; H, 6.36; N, 6.17 Found (%): C , 67.30; H, 6.23; N, 5.98

Example 67 3,3-Dimethyl-5- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3 -Yl] pentane-1- (N, N-dimethylaminomethylene) sulfonamide hydrochloride In the same manner as in Example 58, 5-iodo-3,3-dimethyl- was used instead of 1-bromo-3-phenylpropane. The 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1, obtained in Example 2 was obtained using 1-pentane- (N, N-dimethylaminomethylene) sulfonamide. The free salt of the title compound (3.26 g, 91%) was obtained as an oil from 2,3,4-tetrahydroquinazoline (2.42 g, 5.0 mmol). This product (0.72 g,
0.92 mmol) was added with 4N hydrogen chloride in ethyl acetate, and the mixture was concentrated to give the title compound (0.72 g, 92%) as amorphous crystals. IR (KBr): 3400, 2960, 2935, 2501, 1700, 1654, 162
^{. 9, 1610 cm -1 1 H} -NMR (DMSO-d 6) δ: 0.94 (6H, s), 1.37-2.73 (12H,
m), 2.80-3.75 (9H, m), 2.93 (3H, s), 3.13 (3H,
s), 3.88-3.98 (2H, m), 4.06-4.18 (2H, m), 5.67 (1H,
d, J = 10.0 Hz), 7.21-7.53 (12H, m, ArH), 7.73-7.81
(1H, m, ArH), 8.05 (1H, s), 8.05-8.09 (1H, m, Ar
H). Elemental analysis: C ₄₀ H ₅₃ N ₅ O ₅ S.HCl.1.5H ₂ O Calculated (%): C, 61.64; H, 7.37; N, 8.99 Found (%): C, 61.66 ; H, 7.06; N, 8.85

Example 68 3,3-Dimethyl-5- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3 -Yl] pentane-1-sulfonamide 3,3-dimethyl-5- [2,4-dioxo-1 obtained in Example 67
-[4- (4-Diphenylmethoxypiperidino) butyl] -1,2,3,
4-tetrahydroquinazolin-3-yl] pentane-1- (N, N-dimethylaminomethylene) sulfonamide (2.20 g, 3.07 m
mol), 2N sodium methoxide in methanol (15 m
A mixture of l) and methanol (30 ml) was heated at reflux for 8 days. The solvent was distilled off under reduced pressure, the residue was neutralized with 2N hydrochloric acid, and extracted with ethyl acetate. Wash the extract with water and dry (MgS
After O ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (20: 1 to 10: 1, v / v). Ethyl ether was added to the residue, and the mixture was pulverized, filtered and filtered to give the title compound (1.2
3 g, 59%) as a white powder. IR (KBr): 3251, 3085, 3062, 3028, 2941, 2871, 169
. 9, 1658, 1652, 1610 cm -1 1 H-NMR (CDCl 3) δ: 1.03 (6H, s), 1.54-2.10 (12H,
m), 2.15-2.55 (4H, m), 2.78-2.90 (2H, m), 3.21-3.29
(2H, m), 3.48-3.58 (1H, m), 4.04-4.18 (4H, m), 5.0
1 (2H, bs), 5.51 (1H, s), 7.21-7.37 (12H, m, ArH),
7.63-7.72 (1H, m, ArH), 8.20 (1H, dd, J = 1.6 Hz, 7.
Elemental analysis: C ₃₇ H ₄₈ N ₄ O ₅ S ・ 1.0H ₂ O Calculated (%): C, 65.46; H, 7.42; N, 8.25 Found (%): C, 65.03; H, 7.17; N, 8.07

Example 69 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -1,2,3,4-tetrahydroquinazoline-3-acetic acid methoxycarbonylmethyl hydrochloride 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidinobutyl] obtained in Example 50 A mixture of -1,2,3,4-tetrahydroquinazoline-3-acetic acid hydrochloride (0.58 g, 1.00 mmol), triethylamine (0.42 ml, 3.00 mmol) and N, N-dimethylformamide (2.0 ml) was heated to 60 ° C. After stirring for 15 minutes, methyl bromoacetate (0.11 ml, 1.20 mmol) was added dropwise, the reaction mixture was stirred at the same temperature for 6 hours, ice water was added, and the mixture was extracted with a mixed solvent of ethyl ether-ethyl acetate. After washing with water and drying (MgSO ₄ ), the solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography, eluted with chloroform-methanol (20: 1, v / v) to give the free title compound. (0.49 g, 80%) as an oil IR (KBr): 3060, 3028, 3008, 2949, 2889, 2868, 281
. 0, 2775, 1760, 1708 , 1668, 1610 cm -1 1 H-NMR (CDCl 3) δ: 1.55-1.98 (8H, m), 2.05-2.17 (2
H, m), 2.38 (2H, t, J = 6.9 Hz), 2.71-2.80 (2H, m),
3.39-3.51 (1H, m), 3.77 (3H, s), 4.11-4.19 (2H,
m), 4.72 (2H, s), 4.97 (2H, s), 5.53 (1H, s), 7.22
-7.40 (12H, m, ArH), 7.65-7.74 (1H, m, ArH), 8.24
(1H, dd, J = 7.8 Hz, 1.6 Hz). This oil was dissolved in ethyl acetate (5.0 ml), 4N hydrogen chloride in ethyl acetate (0.5 ml) was added, and the mixture was concentrated.
(0.41 g, 78%) was obtained as amorphous crystals. IR (KBr): 3400, 2954, 2507, 1756, 1706, 1664, 1610
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.60-2.21 (8H, m), 2.80-3.72
(7H, m), 3.67 (3H, s), 4.11-4.21 (2H, m), 4.79 (2H,
s), 4.84 (2H, s), 5.67 (1H, d, J = 9.8 Hz), 7.22-7.4
3 (11H, m, ArH), 7.59 (1H, d, J = 8.4 Hz), 7.80-7.89
(1H, m, ArH), 8.08-8.12 (1H, m, ArH). Elemental analysis: C ₃₅ H ₃₉ N ₃ O ₇・ HCl ・ 0.5H ₂ O Calculated (%): C, 63.77; H , 6.27; N, 6.37 Found (%): C, 63.39; H, 6.04; N, 6.42

Example 70 N- (1-ethoxycarbonyl-1-methyl) ethyl-2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2, 3,4-tetrahydroquinazolin-3-yl] acetamide 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-obtained in Example 50 Tetrahydroquinazoline-3-acetic acid hydrochloride (0.87 g, 1.50 mmol) was added to N, N
-Dimethylformamide (3 ml) was added and diethyl cyanophosphate (0.27 ml, 1.58 mmol) was added dropwise while stirring under ice-cooling. After stirring at the same temperature for 1 hour, ethyl 2-aminoisobutyrate hydrochloride (0.30 g, 1.80 mmol) and triethylamine (0.71 ml, 5.10 mmol) were added. Stir at room temperature overnight, dilute with ice water and extract with ethyl ether. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure.
The residue was subjected to silica gel column chromatography,
Elution with chloroform-methanol (20: 1, v / v) gave the title compound (0.59 g, 60%). IR (KBr): 3296, 2945, 2931, 2869, 2810, 2767, 173
. 9, 1706, 1658, 1610 , 1540 cm -1 1 H-NMR (CDCl 3) δ: 1.26 (3H, t, J = 7.2 Hz), 1.59 (6
H, s), 1.55-1.98 (8H, m), 2.05-2.18 (2H, m), 2.37
(2H, t, J = 7.2 Hz), 2.70-2.81 (2H, m), 3.40-3.51 (1
H, m), 4.10-4.18 (2H, m), 4.19 (2H, q, J = 7.2 Hz),
4.73 (2H, s), 5.53 (1H, s), 6.51 (1H, s), 7.20-7.3
4 (12H, m), 7.62-7.71 (1H, m), 8.22 (1H, dd, J = 1.6
Elemental analysis: C ₃₈ H ₄₆ N ₄ O ₆ Calculated (%): C, 69.70; H, 7.08; N, 8.56 Found (%): C, 69.37; N, 7.05; N, 8.30

Example 71 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-1-acetate Example 8 was prepared in the same manner as in Example 57, except that methyl bromoacetate was used instead of 1-bromo-2-phenylethane.
The title compound (760 mg, 44 mg) was obtained from 2,4-dioxo-3- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.52 g) obtained in Example 1. %) As an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.48-1.82 (6H, m), 1.82-1.98 (2
H, m), 2.04-2.21 (2H, m), 2.36 (2H, t, J = 7.2 Hz),
2.69-2.82 (2H, m), 3.36-3.50 (1H, m), 3.78 (3H,
s), 4.11 (2H, t, J = 7.0 Hz), 4.91 (2H, s), 5.52 (1
H, s), 6.95 (1H, d, J = 8.4 Hz), 7.18-7.40 (11H, m),
7.64 (1H, ddd, J = 8.8, 7.2, 1.6 Hz), 8.24 (1H, dd, J
= 8.0, 1.4 Hz).

Example 72 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-1-acetic acid Obtained in Example 71 by a method similar to that in Example 44.
2,4-dioxo-3- [4- (4-diphenylmethoxypiperidino)
The title compound (740 mg, 62%) was synthesized from methyl [butyl] -1,2,3,4-tetrahydroquinazoline-1-acetate (1.22 g).
Recrystallization from ethyl acetate-methanol gave colorless crystals having a melting point of 153-155 ° C. IR (KBr): 3100-2300, 2958, 1700, 1654, 1612, 1486
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.70-2.04 (6H, m), 2.10-2.34 (2
H, m), 2.90-3.12 (4H, m), 3.20-3.38 (2H, m), 3.68-
3.80 (1H, m), 4.10-4.20 (2H, m), 4.72 (2H, s), 5.4
1 (1H, s), 7.08-7.36 (12H, m), 7.58 (1H, ddd, J = 8.
. 4, 7.0, 1.4 Hz) , 8.15 (1H, dd, J = 7.6, 1.4 Hz) Elemental _{analysis: C 32 H 35 N 3 O} 5 · 1.5H 2 O Calculated (%): C, 67.59; H, 6.74; N, 7.39 Found (%): C, 67.34; H, 6.35; N, 7.64

Example 73 2,4-Dioxo-3- [3- (4-diphenylmethoxypiperidino)
Methyl propyl] -1,2,3,4-tetrahydroquinazoline-1-propionate 2,4-dioxo-3- [3- (4-diphenylmethoxypiperidino) propyl] -1 obtained in Example 79 , 2,3,4-tetrahydroquinazoline (3.50 g) and potassium carbonate (1.24 g) were added to N, N-
It was suspended in dimethylformamide (50.0 ml), and methyl acrylate (1.01 ml) was added. The reaction mixture was stirred at 120 ° C. for 20 hours, poured into ice water, and extracted with ethyl acetate.
After the extract was washed with water and dried (Na ₂ SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (3: 1, v / v) to give the title compound (1.73 g, 42%) as crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.54-1.96 (6H, m), 2.00-2.17 (2
H, m), 2.42 (2H, t, J = 7.2 Hz), 2.66-2.82 (2H, m),
3.32-3.46 (1H, m), 3.70 (3H, s), 4.04-4.20 (2H,
m), 5.48 (1H, s), 7.20-7.40 (12H, m), 7.67 (1H, t,
J = 7.4 Hz), 8.16-8.25 (1H, m).

Example 74 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-1-propionate methyl Obtained in Example 80 by a method similar to Example 73.
2,4-dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline (1.17 g) to give the title compound as crystals. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.50-1.96 (12H, m), 2.04-2.20
(2H, m), 2.35 (2H, t, J = 6.4 Hz), 2.68-2.84 (2H,
m), 3.36-3.50 (1H, m), 3.59 (3H, s), 4.10 (2H, t, J
= 7.2 Hz), 5.51 (1H, s), 7.14-7.40 (12H, m), 7.68
(1H, t, J = 9.2 Hz), 8.21 (1H, d, J = 7.6 Hz).

Example 75 2,4-Dioxo-3- [3- (4-diphenylmethoxypiperidino)
Propyl] -1,2,3,4-tetrahydroquinazoline-1-propionic acid Obtained in Example 73 by a method similar to that in Example 47.
2,4-dioxo-3- [3- (4-diphenylmethoxypiperidino)
The title compound (476 mg, 36%) was synthesized from methyl [propyl] -1,2,3,4-tetrahydroquinazoline-1-propionate (1.36 g). Recrystallized from ethyl acetate-methanol to give a melting point of 2
Colorless crystals at 37-238 ° C were obtained. IR (KBr):. 3200-2100, 1700, 1652, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.84-2.23 (6H, m), 2.52-2.65 (2
H, m), 2.74-2.89 (2H, m), 2.94-3.08 (4H, m), 3.62-
3.72 (1H, m), 4.12 (2H, t, J = 5.8 Hz), 4.49 (2H, t,
J = 7.8 Hz), 5.45 (1H, s), 7.06-7.22 (12H, m), 7.64
(1H, t, J = 7.6 Hz), 8.17 (1H, d, J = 8.0 Hz) Elemental _{analysis:. C 32 H 35 N 3} O 5 · 0.5H 2 O Calculated (%): C, 69.80 ; H, 6.59; N, 7.63 Found (%): C, 69.82; H, 6.59; N, 7.73

Example 76 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-1-propionic acid Obtained in Example 73 by a method similar to that in Example 47.
2,4-dioxo-3- [3- (4-diphenylmethoxypiperidino)
The title compound (179 mg, 13%) was synthesized from methyl propyl] -1,2,3,4-tetrahydroquinazoline-1-propionate. Recrystallization from ethyl acetate-ethyl ether gave a melting point of 110.
Colorless crystals at -112 ° C were obtained. IR (KBr):. 3400-2400, 1704, 1662, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.60-2.08 (4H, m), 2.16-2.40 (4
H, m), 2.48-2.60 (2H, m), 2.80-3.24 (2H, m), 3.65-
3.80 (2H, m), 3.98-4.30 (6H, m), 4.50-4.62 (1H,
m), 5.45 (1H, s), 7.05-7.22 (10H, m), 7.50-7.74 (2
H, m), 8.05 (1H, d, J = 8.2 Hz), 8.14-8.24 (1H, m). Elemental analysis: Calculated as C ₃₃ H ₃₇ N ₃ O ₅・ 0.5H ₂ O (%): C, 70.19; H, 6.79; N, 7.44 Found (%): C, 69.80; H, 6.60; N, 7.85

Example 77 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
Butyl] -1,2,3,4-tetrahydroquinazoline-1-butyrate Example 80 was prepared in the same manner as in Example 57, using ethyl 4-bromobutyrate instead of 1-bromo-2-phenylethane. The title compound was obtained as crystals from 2,4-dioxo-3- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.00 g) obtained in the above. This product was used for the next reaction without further purification. ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.0 Hz), 1.50-2.
24 (12H, m), 2.30-2.42 (2H, m), 2.48 (2H, t, J = 6.6
Hz), 2.70-2.84 (2H, m), 3.36-3.50 (1H, m), 4.06-4.2
4 (6H, m), 5.51 (1H, s), 7.20-7.46 (12H, m), 7.69
(1H, ddd, J = 8.4, 6.6, 1.8 Hz), 8.22 (1H, dd, J = 8.
0, 1.4 Hz).

Example 78 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-1-butyric acid Obtained in Example 77 by the same method as in Example 47.
2,4-dioxo-3- [4- (4-diphenylmethoxypiperidino)
The title compound (569 mg, 48% from the title compound of Example 80) was synthesized from ethyl [butyl] -1,2,3,4-tetrahydroquinazoline-1-butyrate. Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 227-229 ° C. IR (KBr): 3300-2200, 1731, 1697, 1652, 1608, 1484
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.42-2.40 (10H, m), 2.50-2.60
(2H, m), 2.80-3.25 (4H, m), 3.36-3.50 (2H, m), 3.78
-3.84 (1H, m), 4.14-4.22 (2H, m), 4.24-4.65 (2H, m
m), 5.42 (1H, s), 7.10-7.40 (12H, m), 7.67 (1H, t,
J = 7.8 Hz), 8.21 (1H, d, J = 8.2 Hz). Elemental analysis: Calculated as C ₃₄ H ₃₉ N ₃ O ₅・ 2.3H ₂ O (%): C, 66.82; H, 7.19; N, 6.88 Found (%): C, 66.75; H, 6.83; N, 6.87

Example 79 2,4-Dioxo-3- [3- (4-diphenylmethoxypiperidino)
Propyl] -1,2,3,4-tetrahydroquinazoline 2-amino-N- [3- (4-diphenylmethoxypiperidino) obtained in Reference Example 17 by the same method (Method 2) as in Reference Example 26. ) Propyl] benzamide (5.84 g) to give the title compound (4.12 g, 67%). Recrystallization from ethyl acetate-ethyl ether gave colorless crystals having a melting point of 173-175 ° C. IR (KBr):. 1717, 1653, 1624, 1605, 1493 cm -1 1 H-NMR (CDCl 3) δ: 1.56-1.76 (2H, m), 1.76-1.98 (4
H, m), 2.02-2.18 (2H, m), 2.45 (2H, t, J = 7.4 Hz), 2.
69-2.83 (2H, m), 3.34-3.46 (1H, m), 4.13 (2H, t, J
= 7.2 Hz), 5.50 (1H, s), 7.06 (1H, d, J = 8.6 Hz), 7.
16-7.36 (11H, m), 7.58 (1H, ddd, J = 8.6, 7.2, 1.4 H
z), 8.12 (1H, dd, J = 8.0, 1.4 Hz). Elemental analysis: Calculated as C ₂₉ H ₃₁ N ₃ O ₃ (%): C, 74.18; H, 6.65; N, 8.95 found ( %): C, 74.16; H, 6.70; N, 8.94

Example 80 2,4-Dioxo-3- [4- (4-diphenylmethoxypiperidino)
Butyl] -1,2,3,4-tetrahydroquinazoline The 2-amino-N- [4- (4-diphenylmethoxypiperidino) obtained in Reference Example 18 was obtained in the same manner as in Reference Example 26 (method 1). ) Butyl] benzamide (6.27 g) from the title compound
(5.00 g, 75%) was synthesized. Recrystallize from ethyl acetate
Colorless crystals at 140-142 ° C were obtained. IR (KBr): 2943, 1716, 1652, 1621, 1606, 1494 cm ^-1 .
¹ H-NMR (CDCl ₃ ) δ: 1.50-1.82 (6H, m), 1.82-1.96
(2H, m), 2.05-2.20 (2H, m), 2.36 (2H, t, J = 7.0 H
z), 2.70-2.84 (2H, m), 3.36-3.50 (1H, m), 4.09 (2
H, t, J = 7.6 Hz), 5.51 (1H, s), 7.04 (1H, d, J = 8.4
Hz), 7.16-7.18 (11H, m), 7.60 (1H, ddd, J = 8.4, 6.
. 8, 1.6 Hz), 8.11 (1H, dd, J = 7.6, 1.0 Hz) Elemental analysis: Calculated _{C 30 H 33 N 3 O 3} (%): C, 74.51; H, 6.88; N, 8.69 Found (%): C, 74.61; H, 6.72; N, 8.80

Example 81 N- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-6-yl]
Methanesulfonamide hydrochloride In the same manner as in Example 43, methanesulfonyl chloride (190 ml, 2.45) was used instead of ethylmalonyl chloride.
mmol) of 6-amino-2,4- obtained in Example 40.
Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.02 g, 2.05 m
mol), the free salt of the title compound (681 mg, 58%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 204-205 ° C. IR (KBr):. 3256, 2944, 1738, 1694, 1590, 1495 cm -1 1 H-NMR (CDCl 3) δ: 1.56-1.84 (6H, m), 1.84-2.04 (2
H, m), 2.04-2.23 (2H, m), 2.3-2.46 (2H, m), 2.72-2.
84 (2H, m), 3.01 (3H, s), 3.38-3.53 (1H, m), 4.11
(2H, t, J = 7.4 Hz), 5.53 (1H, s), 7.18-7.22 (11H,
m), 7.71 (1H, dd, J = 9.6, 3.0 Hz), 7.95 (1H, d, J =
3.0 Hz). Elemental analysis: C ₃₁ H ₃₆ N ₄ O ₅ S Calculated (%): C, 64.56; H, 6.2
9; N, 9.71. Found (%): C, 64.49; H, 6.44; N, 9.44. This product (350 mg, 0.607 mmol) in ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (0.50 ml) was added to synthesize the title compound (330 mg, 89%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 225-227 ° C. IR (KBr): 3700-2200, 3059, 1692, 1674, 1628, 1593,
^{. 1503 cm -1 1 H-NMR} (CDCl 3) δ: 1.56-3.04 (12H, m), 2.78 (3H,
s), 3.14-3.26 (2H, m), 3.66-3.74 (1H, m), 3.86-4.00
(2H, m), 5.26 (1H, s), 7.00-7.28 (11H, m), 7.46-7.
56 (1H, m), 7.87 (1H, d, J = 2.6 Hz), 9.35 (1H, bs),
11.80 (1H, bs). Elemental analysis: C ₃₁ H ₃₆ N ₄ O ₅ S Calculated (%): C, 57.67; H, 6.34; N, 8.68. Found (%): C, 57.41; H, 6.21; N, 9.08.

Example 82 Ethyl 3,5-dimethoxy-N- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline- 6-yl] -4-hydroxycinnamamide hydrochloride 6-amino-2,4-dioxo-1- [4- (4-
Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (800 mg, 1.60 mmol) and 3,5-dimethoxy-4-hydroxycinnamic acid (432 mg, 1.93 mmol)
After dissolving in N, N-dimethylformamide (20.0 ml), diethyl cyanophosphate (307 ml, 1.93 mmol) and then triethylamine (335 ml, 2.41 mmol) were added dropwise under ice cooling. After stirring the reaction mixture at room temperature for 17 hours, the solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure to obtain the free salt of the title compound (441 mg, 39%).
Recrystallization from ethyl acetate gave colorless crystals having a melting point of 184-186 ° C. IR (KBr): 3484, 3293, 3179, 3027, 2940, 2841, 169
. 0, 1630, 1597, 1552 , 1508 cm -1 1 H-NMR (CDCl 3) δ: 1.66-2.46 (12H, m), 2.70-2.86
(2H, m), 3.36-3.54 (1H, m), 3.92 (6H, s), 4.02-4.16
(2H, m), 5.52 (1H, s), 6.55 (1H, d, J = 15.4Hz), 6.
80 (2H, s), 7.16-7.40 (11H, m), 7.65 (1H, d, J = 15.
8 Hz), 8.09 (1H, d, J = 2.6 Hz), 8.45 (1H, d, J = 7.6
Hz), 9.02 (1H, bs). Elemental analysis: C ₄₁ H ₄₄ N ₄ O ₇ · 1.5H ₂ O Calculated (%): C, 67.29; H, 6.47; N, 7.66. ): C, 67.27; H, 6.36; N, 7.93. This product (200 mg, 0.284 mmol) in ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (0.15 ml) was added, followed by concentration to synthesize the title compound (173 mg, 82%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 180-182 ° C. IR (KBr): 3700-2300, 3061, 2942, 1690, 1630, 1601,
^{. 1552, 1507 cm -1 1 H} -NMR (CDCl 3) δ: 1.74-2.14 (6H, m), 2.32-2.52 (2
H, m), 3.00-3.22 (4H, m), 3.34-3.48 (2H, m), 3.82-
3.96 (1H, m), 3.92 (6H, m), 4.04-4.18 (2H, m), 5.45
(1H, s), 6.66 (1H, d, J = 15.4 Hz), 6.82 (2H, m),
7.10-7.40 (11H, m), 7.61 (1H, d, J = 15.4 Hz), 8.20-
8.38 (2H, m), 9.83 (1H, bs), 10.64 (1H, bs), 11.76
(1H, bs). Elemental analysis: C ₄₁ H ₄₄ N ₄ O ₇ · HCl Calculated (%): C, 63.35; H, 6.35; N, 7.21. Observed (%): C, 63.22; H , 6.53; N, 7.59.

Example 83 Methyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-5-carboxylate hydrochloride Example 2 By the same method (method 4) as described above, the methyl 1- (4-bromobutyl) -2,4-dioxo-1, obtained in Reference Example 124 was obtained.
From 2,3,4-tetrahydroquinazoline-5-carboxylate (1.83 g, 5.15 mmol), a free salt of the title compound (2.19 g) was obtained.
g, 79%) as amorphous crystals. IR (KBr):. 2948, 1736, 1701, 1595, 1499 cm -1 1 H-NMR (CDCl 3) δ: 1.55-1.82 (6H, m), 1.82-2.00 (2
H, m), 2.08-2.24 (2H, m), 2.39 (2H, t, J = 6.6 Hz),
2.70-2.84 (2H, m), 3.40-3.54 (1H, m), 3.97 (3H,
s), 4.07-4.20 (2H, m), 5.53 (1H, s), 7.18 (1H, d,
J = 7.4 Hz), 7.21-7.40 (10H, m), 7.48 (1H, d, J = 8.0
. Hz), 7.71 (1H, dd, J = 8.4, 7.4 Hz) Elemental _{analysis: C 32 H 35 N 3 O} 5 · 0.4H 2 O Calculated (%): C, 70.03; H, 6.57; N , 7.60. Found (%): C, 69.88; H, 6.48; N, 7.62. This product (500 mg, 0.923 mmol) in ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (1.00 ml) was added. After concentration, the title compound (393 mg, 74%) was obtained as amorphous crystals. IR (KBr):. 2949, 1732, 1698, 1595, 1501 cm -1 1 H-NMR (CDCl 3) δ: 1.60-2.20 (8H, m), 2.32-2.58 (2
H, m), 2.94-3.20 (4H, m), 3.30-3.42 (2H, m), 3.82-
3.90 (1H, m), 3.96 (3H, s), 4.15 (2H, t, J = 7.4 H
z), 5.44 (1H, s), 7.187.44 (12H, m), 7.76 (1H, d,
. J = 8.4 Hz), 8.52 (1H, bs), 12.14 (1H, bs) Elemental _{analysis: C 32 H 35 N 3 O} 5 · HCl · 1.7H 2 O Calculated (%): C, 63.14; H, 6.52; N, 6.90. Found (%): C, 63.10; H, 6.63; N, 6.68.

Example 84 Methyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylate As in Example 2. (Method 4), the methyl 1- (4-bromobutyl) -2,4-dioxo-1, obtained in Reference Example 125.
From 2,3,4-tetrahydroquinazoline-6-carboxylate (3.16 g, 8.56 mmol), the title compound (1.82 g, 38%)
Was synthesized. Recrystallized from ethyl acetate, mp 151-153 ℃
To obtain colorless crystals. IR (KBr): 3061, 3032, 2948, 2816, 1705, 1618, 158
. 3, 1508, 1493, 1472 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.85 (6H,
m), 1.85-2.02 (2H, m),
2.04-2.26 (2H, m), 2.40 (2
H, t, J = 7.4 Hz), 2.70-2.8
5 (2H, m), 3.38-3.54 (1H,
m), 3.95 (3H, s), 4.15
(2H, t.J = 6.8 Hz), 5.53
(1H, s), 7.20-7.40 (10H,
m), 7.44 (1H, d, J = 8.8H
z), 8.33 (1H, dd, J = 8.8,
2.2 Hz), 8.85 (1H, d, J =
2.0 Hz). Elemental _{analysis: C 32 H 35 N 3 O} 3 · 2.0H 2 O Calculated (%):. C, 70.44 ; H, 7.20; N, 7.70 Found (%): C, 70.34; H, 6.40; N, 7.84.

Example 85 Methyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-7-carboxylate As in Example 2. (Method 4), the methyl 1- (4-bromobutyl) -2,4-dioxo-1,2,
3,4-tetrahydroquinazoline-7-carboxylate (1.7
The title compound (1.78 g, 69%) was synthesized from 0 g (4.79 mmol). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 192-194 ° C. IR (KBr):. 2949, 1701, 1622, 1586, 1508, 1493 cm -1 1 H-NMR (CDCl 3) δ: 1.56-1.98 (8H, m), 2.04-2.20 (2
H, m), 2.38 (2H, t, J = 7.0 Hz), 2.70-2.85 (2H, m),
3.36-3.50 (1H, m), 3.98 (3H, s), 4.19 (2H, t.J = 7.
8 Hz), 5.52 (1H, s), 7.20-7.38 (10H, m), 7.83-7.90
. (2H, m), 8.23 (1H, d, J = 8.4 Hz) Elemental _{analysis: C 32 H 35 N 3 O} 5 Calculated (%):. C, 70.96 ; H, 6.51; N, 7.76 Found Values (%): C, 70.65; H, 6.56; N, 7.57.

Example 86: Methyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-6-acetate The same as in Example 2. By the method (Method 4), Reference Example 127
Methyl 1- (4-bromobutyl) -2,4-dioxo- obtained in
1,2,3,4-tetrahydroquinazoline-6-acetate (3.16
g, 8.56 mmol) to give the title compound (1.82 g, 38%) as amorphous crystals. IR (KBr): 3027, 2944, 1699, 1622, 1586, 1508, 1493
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.60-1.84 (6H, m), 1.84-2.01 (2
H, m), 2.06-2.22 (2H, m), 2.38 (2H, t, J = 6.6 Hz),
2.70-2.84 (2H, m), 3.38-3.52 (1H, m), 3.67 (3H,
s), 3.71 (2H, d, J = 21.2 Hz), 4.10 (2H, t.J = 8.2 H
z), 5.53 (1H, s), 7.18-7.38 (11H, m), 7.65 (1H, d
. d, J = 8.4, 2.2 Hz), 8.11 (1H, d, J = 2.2 Hz) Elemental _{analysis: C 33 H 37 N 3 O} 5 · 0.3H 2 O Calculated (%): C, 70.64; H, 6.75; N, 7.49. Found (%): C, 70.69; H, 6.75; N, 6.95.

Example 87 Methyl 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-6-
[Ill] -2-methylpropionate hydrochloride Reference Example 128 was obtained in the same manner as in Example 2 (method 4).
2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl] -2-methylpropionate (2.00 g, 5.03 mmol) )) To give the free salt of the title compound (1.82 g, 38%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 148-150 ° C. IR (KBr): 2948, 1730, 1698, 1622, 1586, 1507, 1474
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.62 (6H, s), 1.52-1.84 (6H,
m), 1.84-2.00 (2H, m), 2.02-2.22 (2H, m), 2.37 (2
H, t, J = 6.6 Hz), 2.70-2.84 (2H, m), 3.38-3.52 (1H,
m), 3.65 (3H, s), 4.10 (2H, t.J = 7.0 Hz), 5.52 (1
H, s), 7.16-7.38 (11H, m), 7.66 (1H, dd, J = 8.8, 2.
2 Hz), 8.18 (1H, d, J = 2.2 Hz), 8.22 (1H, bs). Elemental analysis: C ₃₅ H ₄₁ N ₃ O ₅ · 0.9H ₂ O Calculated (%): C, 70.07 H, 7.19; N, 7.00. Found (%): C, 70.06; H, 7.23; N, 7.00. Dissolve this product (870 mg, 1.49 mmol) in ethyl acetate (5.00 ml) and add 4N hydrogen chloride. Of ethyl acetate (1.00 ml) was added to synthesize the title compound (857 mg, 93%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 223-225 ° C. IR (KBr): 3500-2300, 2949, 1698, 1620, 1586, 1507,
^{. 1474 cm -1 1 H-NMR} (CDCl 3) δ: 1.53 (6H, s), 1.60-2.10 (6H,
m), 2.24-2.46 (2H, m), 2.84-3.12 (4H, m), 3.20-3.3
6 (2H, m), 3.58 (3H, s), 3.74-3.82 (1H, m), 3.96-
4.10 (2H, m), 5.34 (1H, s), 7.08-7.14 (11H, m), 7.
56-7.66 (1H, m), 8.09 (1H, d, J = 1.4 Hz), 12.12 (1
H, bs). Elemental analysis: C ₃₅ H ₄₁ N ₃ O ₅ · HCl · 0.4H ₂ O Calculated (%): C, 67.00; H, 6.88; N, 6.70. Observed (%): C , 66.86; H, 6.83; N, 6.71.

Example 88 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-5-carboxylic acid In the same manner as in Example 47, the methyl 2,4-dioxo-1- [4- (4-cy [Phenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-5-carboxylate (600 mg, 1.11 mmol) gave the title compound (584 mg, 100%) as amorphous crystals. IR (KBr): 3700-2300, 3179, 3029, 2949 1694, 1593,
^{. 1499 cm -1 1 H-NMR} (CDCl 3) δ: 1.68-2.10 (8H, m), 2.22-2.42 (2
H, m), 2.86-3.00 (2H, m), 3.00-3.30 (4H, m), 3.72-
3.86 (1H, m), 4.14 (2H, t, J = 6.8 Hz), 5.46 (1H,
s), 7.14-7.44 (12H, m ), 7.71 (1H, t, J = 7.8 Hz) Elemental _{analysis:. C 31 H 33 N 3} O 5 · 0.9H 2 O Calculated (%): C, 68.47; H, 6.45; N, 7.72. Found (%): C, 68.73; H, 6.67; N, 7.32.

Example 89 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylic acid In the same manner as in Example 47, the methyl 2,4-dioxo-1- [4- (4-cy [Phenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-6-carboxylate (1.63 g, 3.01 mmol) to give the title compound (920 mg, 58%). Recrystallization from methanol-chloroform gave colorless crystals having a melting point of 161-163 ° C. IR (KBr): 3700-2700, 3187, 3058, 3029, 2951 1698,
. 1615, 1563, 1493, 1472cm -1 1 H-NMR (CD 3 OD) δ: 1.86-2.00 (4H, m), 2.95-3.34 (1
0H, m), 3.60-3.72 (1H, m), 4.02-4.16 (2H, m), 5.51
(1H, s), 7.10-7.40 (11H, m), 8.14 (1H, d, J = 8.2 H
z), 8.60 (1H, s). Elemental analysis: C ₃₁ H ₃₃ N ₃ O ₅ · 1.5H ₂ O Calculated (%): C, 67.13; H, 6.54; N, 7.58. ): C, 67.12; H, 6.69; N, 7.46.

Example 90 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-7-carboxylic acid In the same manner as in Example 47, the methyl 2,4-dioxo-1- [4- (4-cy [Phenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-7-carboxylate (780 mg, 1.44 mmol) to synthesize the title compound (309 mg, 41%). Recrystallization from methanol-ethyl acetate gave colorless crystals having a melting point of 177-179 ° C. IR (KBr): 3300-2050, 3029, 1694, 1615, 1566, 1508
^{. cm -1 1 H-NMR (} CD 3 OD) δ: 1.50-2.30 (8H, m), 3.04-3.18 (4
H, m), 3.34-3.53 (2H, m), 3.76-3.88 (1H, m), 4.10-
4.24 (2H, m), 5.45 (1H, s), 7.20-7.38 (10H, m), 7.7
2 (1H, d, J = 8.4 Hz), 7.95 (1H, s), 8.09 (1H, d, J =
7.8 Hz), 8.21 (1H, bs), 8.60 (1H, s). Elemental analysis: C ₃₁ H ₃₃ N ₃ O ₅ · 1.3H ₂ O Calculated (%): C, 67.57; H, 6.51; N, 7.63. Found (%): C, 67.43; H, 6.22; N, 7.65.

Example 91 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-6-acetic acid In the same manner as in Example 47, the methyl 2,4-dioxo-1- [4- (4-phenyl) obtained in Example 86 was obtained. Methoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-6-acetate (1.00 g, 1.80 mmol) from the title compound (946 m
g, 97%) as amorphous crystals. IR (KBr): 3700-2300, 3167, 3029, 2935 1694, 1620,
^{. 1586, 1505, 1474 cm -1} 1 H-NMR (CDCl 3) δ: 1.42-1.82 (6H, m), 1.86-2.05 (2
H, m), 2.05-2.25 (2H, m), 2.74-2.92 (2H, m), 2.94-
3.24 (2H, m), 3.58-3.80 (5H, m), 5.44 (1H, s), 7.0
0 (1H, d, J = 8.8 Hz), 7.16-7.44 (10H, m), 7.68 (1H,
. d, J = 8.8 Hz) , 8.10 (1H, s), 8.60 (1H, s) Elemental _{analysis: C 32 H 35 N 3 O} 5 · 2.5H 2 O Calculated (%): C, 65.51; H, 6.87; N, 7.16. Found (%): C, 66.00; H, 6.73; N, 6.51.

Example 92 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-carbonitrile In the same manner as in Example 61, except that cyanogen bromide (657 mg, 6.20 mmol) was used instead of benzyl bromide. The title compound (1.69) was obtained from the obtained 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (2.50 g, 5.17 mmol).
g, 64%). Recrystallization from ethyl acetate to give a melting point of 10
Colorless crystals at 6-107 ° C were obtained. IR (KBr): 2946, 2265, 1744, 1709, 1607, 1493, 1478
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.50-1.86 (6H, m), 1.86-2.03 (2
H, m), 2.03-2.22 (2H, m), 2.39 (2H, t, J = 7.0 Hz),
2.70-2.84 (2H, m), 3.38-3.54 (1H, m), 4.18 (2H, t,
J = 8.2 Hz), 5.53 (1H, s), 7.18-7.46 (11H, m), 7.51
(1H, d, J = 8.8 Hz), 7.80 (1H, d, J = 8.4 Hz), 8.25
(1H, d, J = 8.0 Hz). Elemental analysis: C ₃₁ H ₃₂ N ₄ O ₃ Calculated (%): C, 73.21; H, 6.34; N, 11.02. Observed (%): C, 72.95; H, 6.14; N, 10.92.

Example 93 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-valeronitrile In the same manner as in Example 61, 5-bromovaleronitrile (1.09 ml, 9.31 mmol) was used instead of benzyl bromide.
Was used to obtain the 2,4-dioxo-1- [4- (4-
Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (3.00 g, 6.20 mmol) gave the free salt of the title compound (2.32 g, 66%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.64-2.00 (12H, m), 2.06-2.20
(2H, m), 2.34-2.49 (4H, m), 2.70-2.83 (2H, m), 3.38
-3.54 (1H, m), 4.08-4.20 (4H, m), 5.53 (1H, s), 7.2
0-7.40 (12H, m), 7.67 (1H, ddd, J = 8.8, 6.8, 2.0 H
z), 8.22 (1H, dd, J = 8.0, 1.8 Hz). This product (1.24 g, 2.20 mmol) was dissolved in ethyl acetate (5.00 ml), and 4N hydrogen chloride in ethyl acetate (1.00 ml) was added. The title compound (848 mg, 64%) was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 119-121 ° C. IR (KBr): 3700-3150, 2932, 2250, 1698, 1655, 1609,
^{. 1485 cm -1 1 H-NMR} (CDCl 3) δ: 1.64-2.00 (6H, m), 2.24-2.50 (4
H, m), 2.60-2.78 (2H, m), 2.96-3.18 (4H, m), 3.28-
3.46 (2H, m), 3.52-3.70 (2H, m), 3.84-3.92 (1H,
m), 4.06-4.24 (4H, m), 5.50 (1H, s), 7.20-7.44 (12
H, m), 7.62-7.80 (1H, m), 8.22 (1H, d, J = 8.0 Hz). Elemental analysis: Calculated as C ₃₅ H ₄₀ N ₄ O ₃ .HCl.1.0H ₂ O (% ): C, 67.89; H, 7.00; N, 9.05. Found (%): C, 67.79; H, 7.06; N, 9.06.

Example 94 Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-valerate hydrochloride Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1, obtained as intermediate
2,3,4-tetrahydroquinazoline-3-valerate (2.04
g, 3.33 mmol) in ethyl acetate (5.00 ml).
A solution of hydrogen chloride in ethyl acetate (1.00 ml) was added to give the title compound (1.89 g, 88%) as amorphous crystals. IR (KBr): 3700-3150, 2938, 2647, 2585, 2514, 1728,
. 1699, 1651, 1609, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.65-1.
78 (4H, m), 1.78-1.94 (2H, m), 1.94-2.20 (6H, m),
2.35 (2H, t, J = 6.6 Hz), 2.30-2.58 (2H, m), 3.00-3.
24 (4H, m), 3.35-3.48 (2H, m), 3.84-3.92 (1H, m),
4.02-4.20 (4H, m), 4.11 (2H, q, J = 7.0 Hz), 5.44 (1
H, s), 7.28-7.42 (12H, m), 7.69 (1H, t, J = 7.0 Hz),
8.21 (1H, d, J = 7.4 Hz), 11.58 (1H, bs). Elemental analysis: C ₃₇ H ₄₅ N ₃ O ₅ .HCl. 2.0 H ₂ O Calculated (%): C, 64.95; H , 7.37; N, 6.14. Found (%): C, 64.80; H, 7.08; N, 6.16.

Example 95 Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-hexanoate hydrochloride Reference Example 150 was obtained by the same method (Method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo- obtained in
From 1,2,3,4-tetrahydroquinazoline-3-hexanoate (6.90 g, 15.7 mmol), the free salt of the title compound (7.68 g)
g, 78%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.34-1.
84 (12H, m), 1.84-1.98 (2H, m), 2.04-2.20 (2H, m),
2.30 (2H, t, J = 7.2 Hz), 2.37 (2H, t, J = 8.0Hz), 2.6
8-2.84 (2H, m), 3.38-3.74 (1H, m), 4.00-4.20 (6H,
m), 5.53 (1H, s), 7.18-7.40 (12H, m), 7.65 (1H, t,
J = 8.4 Hz), 8.22 (1H, d, J = 7.8 Hz). Dissolve this product (6.90 g, 15.7 mmol) in ethyl acetate (10.0 ml) and add 4N hydrogen chloride in ethyl acetate (2.00 ml). In addition, the title compound (7.68 g, 78%) was synthesized. Recrystallization from n-hexane gave colorless crystals having a melting point of 149-151 ° C. IR (KBr): 3700-3150, 2938, 2649, 1728, 1701, 1655,
^{. 1609, 1485 cm -1 1 H} -NMR (CDCl 3) d: 1.24 (3H, t, J = 7.4 Hz), 1.32-1.5
0 (2H, m), 1.60-1.94 (8H, m), 1.94-2.20 (4H, m),
2.30 (2H, t, J = 7.4 Hz), 2.22-2.50 (2H, m), 2.95-3.
20 (4H, m), 3.52-3.68 (1H, m), 4.00-4.22 (4H, m),
4.10 (2H, q, J = 7.2 Hz), 5.50 (1H, s), 7.18-7.42 (1
2H, m), 7.60-7.76 (1H, m), 8.22 (1H, d, J = 7.4 Hz),
. 12.47 (1H, bs) Elemental _{analysis: C 38 H 47 N 3 O} 5 · HCl · 0.4H 2 O Calculated (%):. C, 68.18 ; H, 7.35; N, 6.28 Found (%) : C, 68.12; H, 7.48; N, 6.39.

Example 96 Methyl 1- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-
Yl] -1-cyclopentylcarboxylate hydrochloride Reference Example 152 was prepared in the same manner as in Example 2 (method 4).
Methyl 1- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] -1-cyclopentylcarboxylate obtained in (1.47 g, 3.47 mmol) Gave the title compound (2.01 g, 95%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.54-2.20 (14H, m), 2.36 (2H,
t, J = 7.0 Hz), 2.38-2.52 (4H, m), 2.68-2.82 (2H, m),
3.37-3.52 (1H, m), 3.69 (3H, s), 4.07 (2H, t, J = 6.
2 Hz), 5.52 (1H, s), 7.14-7.38 (12H, m), 7.63 (1H,
ddd, J = 8.4, 7.0, 1.4 Hz), 8.14 (1H, dd, J = 7.6, 1.
This product (2.01 g, 3.30 mmol) was dissolved in ethyl acetate (5.00 ml), and 4N hydrogen chloride in ethyl acetate (1.00 ml) was added to synthesize the title compound (1.49 g, 70%). . Recrystallization from ethyl acetate gave colorless crystals having a melting point of 178-180 ° C. IR (KBr): 3700-3100, 2949, 1740, 1707, 1661, 1607,
^{. 1481 cm -1 1 H-NMR} (CDCl 3) δ: 1.70-2.14 (10H, m), 2.30-2.60
(6H, m), 2.92-3.22 (4H, m), 3.28-3.46 (2H, m), 3.67
(3H, s), 3.84-3.92 (1H, m), 4.04-4.16 (2H, m), 5.5
2 (1H, s), 7.12-7.40 (12H, m), 7.67 (1H, t, J = 8.4
Hz), 8.15 (1H, d, J = 8.2 Hz), 12.14 (1H, bs). Elemental analysis: C ₃₇ H ₄₃ N ₃ O ₅ · HCl · 0.8H ₂ O Calculated (%): C, 67.17; H, 6.83; N, 6.54. Found (%): C, 67.27; H, 6.96; N, 6.36.

Example 97 Methyl 1- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-
Yl] -1-cyclohexylcarboxylate hydrochloride Reference Example 153 was prepared in the same manner as in Example 2 (method 4).
1- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] -1-cyclohexylcarboxylate (5.00 g, 11.4 mmol) obtained in To give the title compound (1.07 g, 15%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.46-2.00 (18H, m), 2.00-2.25
(2H, m), 2.26-2.42 (2H, m), 2.69-2.84 (2H, m), 3.38
-3.52 (1H, m), 3.70 (3H, s), 4.00-4.10 (2H, m), 5.5
2 (1H, s), 7.16-7.38 (12H, m), 7.63 (1H, t, J = 7.8
Hz), 8.12 (1H, d, J = 7.6 Hz). Dissolve the product (1.07 g, 1.72 mmol) in ethyl acetate (5.00 ml), add 4N hydrogen chloride in ethyl acetate (1.00 ml), and add the title. Amorphous crystals of the compound (863 mg, 76%) were obtained. IR (KBr): 3343, 2936, 2670, 1738, 1703, 1661, 160
^{. 7, 1481 cm -1 1 H} -NMR (CDCl 3) δ: 1.60-2.58 (18H, m), 2.80-3.26
(4H, m), 3.26-3.42 (2H, m), 3.64 (3H, s), 3.80-3.92
(1H, m), 4.08-4.30 (2H, m), 5.43 (1H, s), 7.16-7.
42 (12H, m), 7.67 (1H, t, J = 7.0 Hz), 8.13 (1H, d,
J = 8.0 Hz), 12.02 (1H, bs). Elemental analysis: C ₃₈ H ₄₅ N ₃ O ₅ .HCl.3.5 H ₂ O Calculated (%): C, 63.10; H, 7.39; N, 5.81 Found (%): C, 62.96; H, 7.36; N, 5.65.

Example 98 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-hexanoic acid In the same manner as in Example 47, the ethyl 2,4-dioxo-1- [4- (4-diphenyl) obtained in Example 95 was obtained. [Methoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-hexanoate (6.68 g, 10.7 mmol) to synthesize the title compound (5.83 g, 91%). Recrystallization from n-hexane-isopropyl ether gave colorless crystals having a melting point of 155-157 ° C. IR (KBr): 3700-3150, 2926, 2855, 1701, 1655, 1609,
^{. 1485 cm -1 1 H-NMR} (CDCl 3) δ: 1.22-1.40 (4H, m), 1.48-2.12 (6
H, m), 2.19 (2H, t, J = 6.0 Hz), 2.52-2.64 (2H, m),
2.80-3.00 (4H, m), 3.56-3.68 (1H, m), 4.18 (2H, t,
J = 6.0 Hz), 4.15-4.30 (2H, m), 5.45 (1H, s), 7.13
(1H, d, J = 8.8 Hz), 7.18-7.40 (11H, m), 7.64 (1H,
t, J = 7.0 Hz), 8.24 (1H, d, J = 8.0 Hz). Elemental analysis: C ₃₆ H ₄₃ N ₃ O ₅ · 1.1H ₂ O Calculated (%): C, 70.02; H, 7.38; N, 6.80. Found (%): C, 69.96; H, 7.09; N, 6.73.

Example 99 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -1,2,3,4-tetrahydroquinazoline-3-octanoic acid Reference Example 151 was prepared in the same manner as in Example 2 (method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo-1, obtained in
2,3,4-tetrahydroquinazoline-3-octanoate (5.0
0 g, 10.7 mmol) from the ethyl ester of the title compound (2.
(60 g, 37%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.4 Hz), 1.30-1.
43 (6H, m), 1.54-1.84 (10H, m), 1.84-1.98 (2H, m),
2.04-2.19 (2H, m), 2.28 (2H, t, J = 7.4 Hz), 2.38 (2
H, t, J = 7.0 Hz), 2.69-2.82 (2H, m), 3.38-3.53 (1H,
m), 4.00-4.18 (6H, m), 5.53 (1H, s), 7.18-7.36 (12
H, m), 7.65 (1H, ddd, J = 8.8, 7.0, 1.4 Hz), 8.22 (1
H, dd, J = 8.0, 1.4 Hz). The title compound (2.18 g, 88%) was obtained as amorphous crystals from this product (2.60 g, 3.98 mmol) in the same manner as in Example 47. IR (KBr): 3700-3150, 2932, 1701, 1655, 1609, 1485
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.46-2.15 (18H, m), 2.21 (2H,
t, J = 7.0 Hz), 2.64-3.00 (6H, m), 3.58-3.70 (1H, m),
4.04-4.20 (4H, m), 5.47 (1H, s), 7.12-7.42 (12H,
m), 7.65 (1H, t, J = 7.4 Hz), 8.22 (1H, d, J = 8.0 H
. z) Elemental _{analysis: C 38 H 47 N 3 O} 5 · HCl · 0.4H 2 O Calculated (%):. C, 68.18 ; H, 7.35; N, 6.28 Found (%): C, 68.12 ; H, 7.48; N, 6.39.

Example 100 1- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]-
1-Cyclohexylcarboxylic acid Reference Example 154 was obtained in the same manner as in Example 2 (Method 4).
1- [1- (4-bromobutyl) -2,4-dioxo-1,2, obtained in
From 3,4-tetrahydroquinazolin-3-yl] -1-cyclohexylcarboxylic acid (2.35 g, 5.55 mmol), the title compound (2
07 mg, 6.1%) as amorphous crystals. IR (KBr): 3200-2100, 2934, 2861, 1703, 1659, 1607,
^{. 1495, 1481 cm -1 1 H} -NMR (CDCl 3) δ: 1.32-2.10 (14H, m), 2.22-2.28
(2H, m), 2.30-2.52 (2H, m), 2.68-3.40 (6H, m), 3.72
-3.82 (1H, m), 4.18-4.40 (2H, m), 5.44 (1H, s), 7.0
6 (1H, d, J = 8.0 Hz), 7.12-7.42 (11H, m), 7.56 (1H,
t, J = 8.2 Hz), 8.12 (1H, d, J = 7.6 Hz). Elemental analysis: C ₃₇ H ₄₃ N ₃ O ₅・ 2.6H ₂ O Calculated (%): C, 67.68; H, 7.40; N, 6.40. Found (%): C, 67.59; H, 7.51; N, 6.32C.

Example 101 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -6-fluoro-1,2,3,4-tetrahydroquinazoline-
3- Valeric acid Reference Example 155 was prepared in the same manner as in Example 2 (method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo-6 obtained in
The ethyl ester of the title compound (2.41 g, 69%) was obtained as an oil from -fluoro-1,2,3,4-tetrahydroquinazoline-3-valerate (2.46 g, 5.55 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 1.55-1.
84 (10H, m), 1.84-2.00 (2H, m), 2.04-2.20 (2H, m),
2.30-2.42 (4H, m), 2.70-2.82 (2H, m), 3.38-3.54 (1
H, m), 4.05-4.18 (6H, m), 5.53 (1H, s), 7.20-7.40
(12H, m), 7.85-7.94 (1H, m). The title compound (2.12 g, 92%) was obtained as amorphous crystals from this product (2.41 g, 3.83 mmol) in the same manner as in Example 47. IR (KBr): 3700-3150, 2938, 1701, 1655, 1601, 1559,
^{. 1505, 1480 cm -1 1 H} -NMR (CDCl 3) δ: 1.45-2.15 (12H, m), 2.21 (2H,
t, J = 7.0 Hz), 2.64-3.00 (6H, m), 3.55-3.70 (1H, m),
4.17 (2H, t, J = 6.2 Hz), 4.20-4.30 (2H, m), 5.44 (1
H, s), 7.13 (1H, dd, J = 9.0, 4.4 Hz), 7.18-7.44 (11
H, m), 7.91 (1H, dd, J = 8.0, 3.0 Hz). Elemental analysis: C ₃₅ H ₄₀ N ₃ O ₅ F · 1.8H ₂ O Calculated (%): C, 66.29; H, 6.93; N, 6.63. Found (%): C, 66.57; H, 6.82; N, 6.24.

Example 102 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -6-methoxy-1,2,3,4-tetrahydroquinazoline-
3- Valerate hydrochloride Reference example 156 was prepared in the same manner as in Example 2 (method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo-6 obtained in
From -methoxy-1,2,3,4-tetrahydroquinazoline-3-octanoate (3.14 g, 7.42 mmol), the ethyl ester of the title compound (1.89 g, 40%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 1.55-1.
82 (12H, m), 1.82-2.00 (2H, m), 2.02-2.20 (2H, m),
2.32-2.44 (2H, m), 2.70-2.84 (2H, m), 3.40-3.52 (1
H, m), 3.86 (3H, s), 4.04-4.18 (6H, m), 5.52 (1H,
s), 7.20-7.40 (12H, m), 7.66 (1H, s). The free salt of the title compound was obtained as an oil from this product (1.89 g, 2.94 mmol) in the same manner as in Example 47. This was dissolved in ethyl acetate (5.00 ml), a 4N hydrogen chloride solution in ethyl acetate (1.00 ml) was added, and the title compound (1.54 g, 8
1%) as amorphous crystals. IR (KBr): 3500-2400, 2948, 1698, 1651, 1559, 1505,
^{. 1480 cm -1 1 H-NMR} (CDCl 3) δ: 1.50-2.30 (14H, m), 2.48-2.62
(2H, m), 2.84-2.96 (4H, m), 3.62-3.71 (1H, m), 3.88
(3H, s), 4.21 (2H, t, J = 5.2 Hz), 4.22-4.34 (2H,
m), 5.44 (1H, s), 7.08 (1H, d, J = 9.6 Hz), 7.18-7.3
4 (11H, m), 7.70 (1H, d, J = 3.0 Hz). Elemental analysis: C ₃₆ H ₄₃ N ₃ O ₆ · HCl · 1.0H ₂ O Calculated (%): C, 64.71; H , 6.94; N, 6.29. Found (%): C, 64.42; H, 6.58; N, 6.04.

Example 103 Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-methoxy-1,2,3,4-tetrahydroquinazoline-3-valerate Example Reference Example 157 was obtained in the same manner as in Example 2 (Method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo-6 obtained in
-Nitro-1,2,3,4-tetrahydroquinazoline-3-valerate (4.10 g, 8.72 mmol) from the title compound (3.77 g, 66
%) As an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.25 (3H, t, J = 7.0 Hz), 1.60-1.
88 (10H, m), 1.88-2.05 (2H, m), 2.10-2.30 (2H, m),
2.32-2.48 (4H, m), 2.72-2.86 (2H, m), 3.44-3.58 (1
H, m), 4.06-4.22 (4H, m), 4.13 (2H, q, J = 7.0 Hz),
5.53 (1H, s), 7.20-7.40 (10H, m), 7.56 (1H, d, J =
9.2 Hz), 8.49 (1H, dd, J = 9.0, 2.6 Hz), 9.08 (1H, d,
J = 1.6 Hz).

Example 104 6-Amino-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-
Valeric acid Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-methoxy-1,2,2 obtained in Example 103 in the same manner as in Example 39. The ethyl ester of the title compound (1.83 g, 75%) was obtained as an oil from 3,4-tetrahydroquinazoline-3-valerate (2.57 g, 3.91 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.56-1.
84 (10H, m), 1.84-2.02 (2H, m), 2.06-2.22 (2H, m),
2.30-2.44 (4H, m), 2.70-2.84 (2H, m), 3.40-3.54 (1
H, m), 3.72 (2H, bs), 4.02-4.18 (6H, m), 5.53 (1H,
s), 7.01 (1H, dd, J = 8.8, 2.4 Hz), 7.03-7.29 (11H,
m), 7.37 (1H, d, J = 2.4 Hz). The title compound (1.67 g, 96%) was obtained as amorphous crystals from this product (1.83 g, 2.92 mmol) in the same manner as in Example 47. IR (KBr): 3345, 3220, 2955, 1690, 1645, 1590, 150
^{. 8, 1487 cm -1 1 H} -NMR (CDCl 3) δ: 1.48-2.02 (12H, m), 2.16 (2H,
t, J = 6.2 Hz), 2.12-2.34 (2H, m), 2.68-2.84 (2H, m),
2.90-3.16 (2H, m), 3.04 (2H, bs), 3.66-3.78 (1H,
m), 4.06-4.22 (4H, m), 5.44 (1H, s), 6.96-7.02 (2
H, m), 7.20-7.36 (10H, m), 7.48 (1H, d, J = 2.2 Hz). Elemental analysis: Calculated as C ₃₅ H ₄₂ N ₄ O ₅・ 2.0H ₂ O Calculated (%): C, 66.23; H, 7.30; N, 8.83. Found (%): C, 66.08; H, 7.10; N, 8.42.

Example 105 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valeric acid Reference Example 160 was obtained in the same manner as in Example 2 (Method 4).
Ethyl 1- (4-bromobutyl) -2,4-dioxo-6 obtained in
The ethyl ester of the title compound (3.60 g, 77%) was obtained as an oil from -hydroxy-1,2,3,4-tetrahydroquinazoline-3-beralate (3.31 g, 7.50 mmol). ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.60-2.
42 (16H, m), 2.42-2.54 (2H, m), 2.66-2.92 (2H, m),
3.44-3.56 (1H, m), 4.00-4.16 (4H, m), 4.12 (2H, q,
J = 7.2 Hz), 5.51 (1H, s), 7.08-7.40 (12H, m), 7.47
(1H, s). The title compound (696 mg, 80%) was synthesized from this product (910 mg, 1.45 mmol) in the same manner as in Example 47. Recrystallization from ethyl ether gave colorless crystals having a melting point of 234-236 ° C. IR (KBr): 3600-2000, 2963 2944, 1694, 1647, 1584,
^{. 1491 cm -1 1 H-NMR} (CDCl 3 + DMSO-d 6) δ: 1.50-2.04 (12H, m), 2.1
0-2.32 (2H, m), 2.25 (2H, t, J = 7.4 Hz), 2.90-3.58
(4H, m), 3.62-3.74 (1H, m), 4.02-4.22 (4H, m), 5.4
7 (1H, s), 7.06 (1H, d, J = 8.8 Hz), 7.24-7.40 (11H,
m), 7.64 (1H, d, J = 2.4 Hz). Elemental analysis: C ₃₅ H ₄₁ N ₃ O ₆ · 1.5H ₂ O Calculated (%): C, 67.07; H, 7.08; N, 6.70 Found (%): C, 67.15; H, 6.93; N, 6.67.

Example 106 6-benzyloxy-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-valeric acid Ethyl 2,4-dioxo-1- [4- (4- (4-
Diphenylmethoxypiperidino) butyl] -6-hydroxy-
1,2,3,4-tetrahydroquinazoline-3-valerate (1.34
g, 2.13 mmol) and potassium carbonate (354 mg, 2.56 mmo
To a suspension of l) in N, N-dimethylformamide (50.0 ml) was added dropwise benzyl bromide (305 ml, 2.56 mmol), and the reaction mixture was stirred at room temperature for 18.5 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The extract is washed with water and dried (MgSO
₄ ) After that, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (5: 1, v / v) to obtain the ethyl ester of the title compound (450 mg, 29%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.0 Hz), 1.48-1.
80 (10H, m), 1.84-2.00 (2H, m), 2.06-2.28 (2H, m),
2.28-2.45 (4H, m), 2.68-2.84 (2H, m), 3.36-3.56 (1
H, m), 4.02-4.18 (4H, m), 4.11 (2H, q, J = 7.4 Hz),
5.12 (2H, s), 5.52 (1H, s), 7.22-7.45 (17H, m), 7.
74 (1H, d, J = 2.6 Hz). The title compound (445 mg, almost 100%) was obtained as amorphous crystals from this product (450 mg, 0.627 mmol) in the same manner as in Example 47. IR (KBr): 3700-2800, 3061, 3031, 2938 2870, 2523,
. 1698, 1651, 1593, 1476cm -1 1 H-NMR (CDCl 3) δ: 1.56-2.08 (10H, m), 2.31 (2H,
t, J = 6.2 Hz), 2.26-2.44 (2H, m), 2.85-2.98 (2H, m),
2.98-3.18 (2H, m), 3.18-3.34 (2H, m), 3.75-3.84
(1H, m), 4.14 (2H, t, J = 6.6 Hz), 4.19 (2H, t, J = 5.
4 Hz), 5.13 (2H, s), 5.44 (1H, s), 7.11 (1H, d, J =
9.2 Hz), 7.24-7.48 (11H, m), 7.77 (1H, d, J = 3.0 H
z). Elemental analysis: C ₄₂ H ₄₇ N ₃ O ₆・ 3.2H ₂ O Calculated (%): C, 67.49; H, 7.20; N, 5.62. Found (%): C, 67.38; H , 6.80; N, 5.40.

Example 107 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -6-methoxycarbonylmethyl-1,2,3,4-tetrahydroquinazoline-3-valeric acid Ethyl 2,4-dioxo-1- [obtained in Example 105 by the same method as in Example 106. From 4- (4-diphenylmethoxypiperidino) butyl] -6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.31 g, 2.09 mmol), methyl bromoacetate (instead of benzyl bromide) 237 ml (2.50 mmol) to give the ethyl ester of the title compound (990 mg, 68%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.24 (3H, t, J = 7.2 Hz), 1.55-1.
85 (10H, m), 1.85-2.02 (2H, m), 2.08-2.28 (2H, m),
2.32-2.46 (4H, m), 2.70-2.84 (2H, m), 3.42-3.54 (1
H, m), 3.82 (3H, s), 4.04-4.20 (4H, m), 4.12 (2H,
q, J = 7.0 Hz), 4.71 (2H, s), 5.52 (1H, s), 7.20-7.4
0 (12H, m), 7.60 (1H, d, J = 2.6 Hz). The title compound (885 mg, 96%) was obtained from this product (990 mg, 1.41 mmol) in the same manner as in Example 47, using amorphous crystals. As obtained. IR (KBr): 3700-3300, 2940, 2529, 1694, 1651, 1597,
^{. 1555, 1505, 1478 cm -1} 1 H-NMR (CDCl 3) δ: 1.56-2.08 (12
H, m), 2.08-2.32 (4H, m),
2.90-3.20 (4H, m), 3.74-
3.82 (1H, m), 4.02-4.20
(6H, m), 5.43 (1H, s), 7.
11 (1H, d, J = 8.0 Hz), 7.2
0-7.38 (11H, m), 7.57 (1
H, d, J = 2.2 Hz). Elemental _{analysis: C 37 H 43 N 3 O} 8 · 3.2H 2 O Calculated (%):. C, 62.12 ; H, 6.96; N, 5.87 Found (%): C, 62.01; H, 6.58; N, 5.54.

Example 108 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -6- (3-ethoxycarbonylpropoxy) -1,2,3,4
-Tetrahydroquinazoline-3-valerate hydrochloride Ethyl 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl]-obtained in Example 105 by a method similar to that in Example 106. From 6-hydroxy-1,2,3,4-tetrahydroquinazoline-3-valerate (1.53 g, 2.44 mmol), use ethyl bromobutyrate (523 ml, 3.66 mmol) in place of benzyl bromide to give the title compound ethyl. The ester (1.38 g, 76%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (6H, t, J = 7.4 Hz), 1.56-1.
83 (10H, m), 1.83-2.00 (2H, m), 2.06-2.22 (4H, m),
2.32-2.44 (4H, m), 2.51 (2H, t, J = 7.0 Hz), 2.68-2.8
2 (2H, m), 3.38-3.52 (1H, m), 4.02-4.22 (12H, m),
5.52 (1H, s), 7.20-7.40 (12H, m), 7.62 (1H, s). The free salt of the title compound was obtained as an oil from this product (1.38 g, 1.86 mmol) in the same manner as in Example 47. Obtained. This was dissolved in ethyl acetate (5.00 ml), a solution of 4N hydrogen chloride in ethyl acetate (1.00 ml) was added, and the title compound (1.38 g,
(Approximately 100%) as amorphous crystals. IR (KBr): 3400-2300, 2948, 1696, 1651, 1505, 1474
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.50-2.06 (14H, m), 2.18-2.40
(4H, m), 2.89-3.02 (2H, m), 3.02-3.20 (2H, m), 3.22
-3.44 (2H, m), 3.72-3.82 (1H, m), 3.96 (2H, t, J = 6.
6 Hz), 4.04-4.20 (4H, m), 5.43 (1H, s), 7.06 (1H,
d, J = 9.6 Hz), 7.16-7.42 (11H, m), 7.59 (1H, s). Elemental analysis: Calculated as C ₃₉ H ₄₇ N ₃ O ₈ · HCl · 2.2H ₂ O Calculated (%): C, 61.48; H, 6.93; N, 5.52. Found (%): C, 61.45; H, 6.37; N, 5.11.

Example 109 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -N-methoxycarbonylmethyl-1,2,3,4-tetrahydroquinazoline-3-acetamide hydrochloride 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidi) obtained in Example 50 No) butyl] -1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) and glycine methyl ester hydrochloride (278 mg, 2.66 mmol) in N, N-dimethylformamide (20.0 ml) To the solution, diethyl cyanophosphate (425 ml, 2.66 mmol) and triethylamine (926 ml, 6.65 mmol) were sequentially added, and the reaction mixture was stirred at room temperature for 17 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. After the extract was washed with water and dried (MgSO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and n-hexane-
Elution with ethyl acetate (5: 1, v / v) gave the methyl ester of the title compound (883 mg, 65%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.54-1.84 (6H, m), 1.84-1.98 (2
H, m), 2.00-2.16 (2H, m), 2.38 (2H, t, J = 8.8 Hz),
2.68-2.82 (2H, m), 3.48-3.52 (1H, m), 3.76 (3H,
s), 4.04-4.20 (4H, m), 4.82 (2H, s), 5.53 (1H, s),
6.30 (1H, bs), 7.18-7.38 (12H, m), 7.68 (1H, ddd,
J = 7.4, 5.4, 2.0 Hz), 8.23 (1H, dd, J = 8.2, 1.4 H
z). This product (399 mg, 0.650 mmol) was added to ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (1.00 ml) was added to give the title compound (275 mg, 65%) as amorphous crystals. IR (KBr):. 2938, 1748, 1661, 1609, 1547, 1485 cm -1 1 H-NMR (CDCl 3) δ: 1.70-2.82 (8H, m), 2.94-3.20 (4
H, m), 3.30-3.42 (2H, m), 3.84 (3H, s), 3.80-3.90
(1H, m), 3.92-4.28 (4H, m), 4.81 (2H, s), 5.43 (1H,
s), 6.60 (1H, bs), 7.16-7.40 (12H, m), 7.60-7.76
(1H, m), 8.21 ( 1H, d, J = 7.6 Hz), 11.79 (1H, bs) Elemental _{analysis:. C 35 H 40 N 4} O 6 · HCl · 1.0H 2 O Calculated (%) : C, 63.01; H, 6.50; N, 8.40. Found (%): C, 62.98; H, 6.38; N, 8.16.

Example 110 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -N-ethoxycarbonylmethyl-N-methyl-1,2,3,
4-Tetrahydroquinazoline-3-acetamide hydrochloride 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1 obtained in Example 50 in the same manner as in Example 109. , 2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol) was replaced with sarcosine ethyl ester hydrochloride (40%) instead of glycine methyl ester hydrochloride.
8 mg, 2.66 mmol) to give the ethyl ester of the title compound (1.19 g, 83%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.50-1.
84 (6H, m), 1.84-2.00 (2H, m), 2.00-2.18 (2H, m),
2.30-2.42 (2H, m), 2.68-2.82 (2H, m), 3.21 (3H,
m), 3.38-3.52 (1H, m), 4.04-4.20 (6H, m), 4.98 (2
H, s), 5.52 (1H, s), 6.30 (1H, bs), 7.12-7.38 (12
H, m), 7.66 (1H, t, J = 5.6 Hz), 8.22 (1H, d, J = 7.8
Hz). This product (561 mg, 0.875 mmol) was added to ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (1.00 ml) was added to synthesize the title compound (362 mg, 61%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 170-172 ° C. IR (KBr): 2936, 2800-2300, 1744, 1707, 1661, 1609,
^{. 1485 cm -1 1 H-NMR} (CDCl 3) δ: 1.26 (3H, t, J = 7.0 Hz), 1.80-2.
12 (8H, m), 2.32-2.58 (2H, m), 2.96-3.22 (4H, m),
3.17 (3H, s), 3.28-3.40 (2H, m), 3.80-3.90 (1H, m),
4.00-4.30 (6H, m), 4.96 (2H, s), 5.44 (1H, s), 7.
18-7.40 (12H, m), 7.70 (1H, t, J = 7.6 Hz), 8.23 (1
H, d, J = 8.0 Hz). Elemental analysis: C ₃₇ H ₄₄ N ₄ O ₆ .HCl.0.4H ₂ O Calculated (%): C, 64.93; H, 6.74; N, 8.19. (%): C, 64.74; H, 6.79; N, 8.27.

Example 111 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -N- (2-ethoxycarbonylethyl) -1,2,3,4-tetrahydroquinazoline-3-acetamide hydrochloride In the same manner as in Example 109, 2,4-dioxo obtained in Example 50 From -1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-acetic acid (1.20 g, 2.22 mmol), replace b with glycine methyl ester hydrochloride -Alanine ethyl ester hydrochloride (40
8 mg, 2.66 mmol) to give the ethyl compound of the title compound (1.06 g, 65%) as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.4 Hz), 1.54-1.
84 (6H, m), 1.84-2.00 (2H, m), 2.04-2.20 (2H, m),
2.37 (2H, t, J = 7.0 Hz), 2.54 (2H, t, J = 5.8 Hz), 2.
68-2.82 (2H, m), 3.38-3.62 (3H, m), 4.00-4.22 (4H,
m), 4.72 (2H, s), 5.53 (1H, s), 6.35 (1H, bs), 7.
18-7.38 (12H, m), 7.68 (1H, ddd, J = 8.8, 7.0, 1.8 H
z), 8.22 (1H, dd, J = 8.0, 1.4 Hz). This product (448 mg, 0.699 mmol) in ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (1.00 ml) was added to synthesize the title compound (313 mg, 66%). Recrystallization from ethyl acetate gave colorless crystals having a melting point of 123-124 ° C. IR (KBr): 2936, 2800-2300, 1728, 1705, 1659, 1611,
^{. 1551, 1485 cm -1 1 H} -NMR (CDCl 3) δ: 1.27 (3H, t, J = 7.2 Hz), 1.78-2.
16 (6H, m), 2.34-2.56 (2H, m), 2.51 (2H, t, J = 6.0 H
z), 2.92-3.20 (4H, m), 3.30-3.42 (2H, m), 3.44-3.5
8 (2H, m), 3.80-3.90 (1H, m), 4.16-4.28 (2H, m), 4.
15 (2H, q, J = 7.0 Hz), 4.71 (2H, s), 5.43 (1H, s),
6.42 (1H, bs), 7.18-7.40 (12H, m), 7.71 (1H, t, J =
7.2 Hz), 8.23 (1H, d, J = 7.6 Hz), 11.97 (1H, bs). Elemental analysis: C ₃₇ H ₄₄ N ₄ O ₆ · HCl · 1.6H ₂ O Calculated value (%): C , 62.94; H, 6.88; N, 7.94. Found (%): C, 62.92; H, 6.69; N, 7.90.

Example 112 2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino)
[Butyl] -N-methoxycarbonylmethyl-1,2,3,4-tetrahydroquinazoline-3-propionamide hydrochloride 2,4-dioxo-1-obtained in Example 52 by the same method as in Example 109 From [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-propionic acid (1.30 g, 2.34 mmol), methyl ester of the title compound (1.39 g, 95% ) Was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.56-1.84 (6H, m), 1.84-2.00 (2
H, m), 2.05-2.20 (2H, m), 2.35 (2H, t, J = 6.6 Hz),
2.72 (2H, t, J = 7.0 Hz), 2.68-2.82 (2H, m), 3.38-3.
52 (1H, m), 3.72 (3H, s), 4.00-4.18 (4H, m), 4.42
(2H, t, J = 7.0 Hz), 5.53 (1H, s), 6.60 (1H, bs), 7.
20-7.38 (12H, m), 7.67 (1H, ddd, J = 8.6, 7.0, 1.6 H
z), 8.22 (1H, dd, J = 8.2, 1.6 Hz). This product (616 mg, 0.983 mmol) in ethyl acetate (5.00 ml)
And 4N hydrogen chloride in ethyl acetate (1.00 ml) was added to obtain the title compound (380 mg, 58%) as amorphous crystals. IR (KBr): 2937, 1740, 1699, 1655, 1609, 1549, 1485
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.72-2.20 (6H, m), 2.20-2.46 (2
H, m), 2.65-2.80 (4H, m), 2.90-3.72 (4H, m), 3.80-
3.90 (1H, m), 4.03 (2H, d, J = 4.8 Hz), 4.18-4.30 (2
H, m), 4.34-4.48 (2H, m), 5.41 (1H, s), 7.10-7.42
(12H, m), 7.67 (1H, t, J = 8.4 Hz), 8.22 (1H, d, J =
. 7.4 Hz), 10.96 (1H , bs) Elemental _{analysis: C 36 H 42 N 4 O} 6 · HCl · 2.6H 2 O Calculated (%):. C, 60.90 ; H, 6.84; N, 7.89 Found Values (%): C, 60.89; H, 6.65; N, 8.11.

Example 113 N-Carboxymethyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-acetamide 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N-methoxycarbonylmethyl-1,2,3,4 obtained in Example 109 by the same method as in Example 47. -Tetrahydroquinazoline-3-acetamide (740 mg, 1.21 mm
ol) to give the title compound (690 mg, 95%) as amorphous crystals. IR (KBr): 3700-3150, 3031, 2934, 1701, 1655, 1609,
^{. 1485 cm -1 1 H-NMR} (CDCl 3) δ: 1.70-2.06 (2H, m), 2.38-2.58 (2
H, m), 2.69-2.80 (2H, m), 2.90-3.10 (2H, m), 3.10-
3.30 (2H, m), 3.74-3.86 (1H, m), 3.77 (2H, d, J = 4.0
Hz), 4.30-4.40 (2H, m), 4.79 (2H, s), 5.41 (1H,
s), 6.60 (1H, bs), 7.16-7.44 (12H, m), 7.69 (1H,
t, J = 8.4 Hz), 8.28 (1H, d, J = 7.8 Hz). Elemental analysis: C ₃₄ H ₃₈ N ₄ O ₆・ 0.9H ₂ O Calculated (%): C, 66.41; H, 6.52; N, 9.11. Found (%): C, 66.48; H, 6.88; N, 8.89.

Example 114 N-Carboxymethyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N-methyl-1,2,3,4-tetrahydroquinazoline-3 -Acetamide In a manner similar to that in Example 47, 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N-ethoxycarbonylmethyl-N-methyl obtained in Example 110 -1,
2,3,4-tetrahydroquinazoline-3-acetamide (626 m
g, 0.977 mmol) to give the title compound (362 mg, 61%) as amorphous crystals. IR (KBr): 3700-3100, 2957, 1705, 1661, 1609, 1485
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.56-2.38 (8H, m), 2.80-3.15 (6
H, m), 3.20 (3H, s), 3.70-3.82 (1H, m), 3.95 (2H,
s), 4.02-4.15 (2H, m), 4.92 (2H, s), 5.44 (1H, s),
7.06 (1H, t, J = 7.4 Hz), 7.13-7.42 (11H, m), 7.51
(1H, t, J = 7.4 Hz), 8.02 (1H, d, J = 7.2 Hz). Elemental analysis: C ₃₅ H ₄₀ N ₄ O ₆・ 2.7H ₂ O Calculated (%): C, 63.56 H, 6.92; N, 8.47. Found (%): C, 63.63; H, 6.69; N, 8.04.

Example 115 N- (2-Carboxyethyl) -carboxylmethyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N-methyl-1,2,3 , 4-tetrahydroquinazoline-3-acetamide 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N- obtained in Example 111 by a method similar to that in Example 47. (2-ethoxycarbonylethyl) -1,2,3,4-
Tetrahydroquinazoline-3-acetamide (950 mg, 1.5
5 mmol) to give the title compound (515 mg, 54%) as amorphous crystals. IR (KBr): 3700-3150, 2938, 1701, 1655, 1642, 1580,
^{. 1522, 1485 cm -1 1 H} -NMR (CDCl 3) δ: 1.58-2.14 (6H, m), 2.28-2.40 (4
H, m), 2.62-3.26 (6H, m), 3.38-3.52 (4H, m), 3.62-
3.72 (1H, m), 4.24-4.32 (2H, m), 4.73 (2H, s), 5.44
(1H, s), 6.79 (1H, bs), 7.10-7.38 (12H, m), 7.68
(1H, t, J = 9.0 Hz), 8.27 (1H, d, J = 9.6 Hz). Elemental analysis: C ₃₅ H ₄₀ N ₄ O ₆・ 0.5H ₂ O Calculated (%): C, 67.61 H, 6.65; N, 9.01. Found (%): C, 67.69; H, 7.19; N, 8.98.

Example 116 N-Carboxymethyl-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-propionamide hydrochloride Salt According to a method similar to that in Example 47, 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -N-methoxycarbonylmethyl-1,2,2 obtained in Example 112 3,4-tetrahydroquinazoline-3-propionamide (775 mg, 1.2
4 mmol) to give the free salt of the title compound as an oil.
This was dissolved in ethyl acetate (5.00 ml), a 4N hydrogen chloride solution in ethyl acetate (1.00 ml) was added, and the title compound (274 ml) was added.
g, 34%) as amorphous crystals. IR (KBr): 3700-3150, 2936, 1740, 1699, 1655, 1609,
^{. 1543, 1485 cm -1 1 H} -NMR (CDCl 3) δ: 1.70-3.24 (14H, m), 3.70 (2H,
t, J = 5.6 Hz), 3.86-3.92 (1H, m), 3.98-4.06 (2H, m),
4.10-4.32 (2H, m), 4.32-4.48 (2H, m), 5.44 (1H,
s), 7.10-7.42 (12H, m), 7.60-7.78 (1H, m), 8.22 (1
H, d, J = 6.6 Hz). Elemental analysis: C ₃₅ H ₄₀ N ₄ O ₆ · HCl · 2.2H ₂ O Calculated (%): C, 61.02; H, 6.64; N, 8.13. (%): C, 60.97; H, 6.92; N, 8.53.

Example 117 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]
Ethoxyacetic acid Reference Example 165 was prepared in the same manner as in Example 2 (Method 4).
Of the title compound from the ethyl 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl] ethoxyacetate (1.71 g, 4.00 mmol) obtained in The ethyl ester (1.51 g, 62%) was obtained as an oil. ¹ H-NMR (CDCl ₃ ) δ: 1.26 (3H, t, J = 7.0 Hz), 1.50-1.
85 (6H, m), 1.85-2.00 (2H, m), 2.06-2.22 (2H, m),
2.38 (2H, t, J = 7.6 Hz), 2.70-2.84 (2H, m), 3.36-3.5
2 (1H, m), 3.87 (2H, t, J = 5.8 Hz), 4.06-4.22 (6H,
m), 4.36 (2H, t, J = 5.6 Hz), 5.53 (1H, s), 7.18-7.40
(12H, m), 7.66 (1H, t, J = 7.4 Hz), 8.22 (1H, d, J =
The title compound (1.36 g, 95%) was obtained as amorphous crystals from this product (1.51 g, 2.46 mmol) in the same manner as in Example 47. IR (KBr): 3700-3150, 2948, 1699, 1659, 1609, 1485
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.60-2.10 (6H, m), 2.26-2.46 (2
H, m), 2.60-2.72 (2H, m), 2.88-3.06 (2H, m), 3.06-
3.24 (2H, m), 3.68-3.80 (1H, m), 3.85 (2H, t, J = 4.
4 Hz), 3.93 (2H, s), 4.22-4.36 (2H, m), 4.40 (2H,
t, J = 4.4 Hz), 5.42 (1H, s), 6.52 (1H, bs), 7.10 (1
H, d, J = 8.4 Hz), 7.18-7.40 (11H, m), 7.63 (1H, dd
d, J = 8.4, 7.2, 1.2 Hz), 8.26 (1H, d, J = 7.0 Hz). Elemental analysis: C ₃₄ H ₃₉ N ₃ O ₆・ 2.4H ₂ O Calculated (%): C, 64.93; H, 7.02; N, 6.68. Found (%): C, 64.89; H, 6.61; N, 6.45.

Example 118 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl Ethyl isobutyrate hydrochloride In the same manner as in Example 27, 2- [1- (4-bromobutyl) -2,4-dioxo-8-methoxy-1, obtained in Reference Example 194.
Ethyl 2,3,4-tetrahydroquinazolin-3-yl] isobutyrate
(0.54 g, 1.22 mmol) from the free salt of the title compound (0.69 g,
90%) as an oil. IR (KBr):. 2942, 1744, 1705, 1663, 1603 cm -1 1 H-NMR (CDCl 3) δ: 1.21 (3H, t, J = 7.2 Hz), 1.82 (6
H, s), 1.40-1.95 (8H, m), 2.04-2.17 (2H, m), 2.29-
2.36 (2H, m), 2.69-2.79 (2H, m), 3.38-3.48 (1H,
m), 3.90 (3H, s), 4.11-4.24 (4H, m), 5.51 (1H, s),
7.15-7.36 (12H, m, ArH), 7.73 (1H, dd, J = 5.6 Hz,
4.0 Hz). The product (0.69 g) was dissolved in ethyl acetate (3.0 ml), and concentrated by adding 4N hydrogen chloride in ethyl acetate (0.35 ml). The residue was dried at 50 ° C. in the presence of phosphorus pentoxide to give the title compound (0.6
(1 g, 82%) was obtained as amorphous crystals. IR (KBr): 3405, 2980, 2938, 2475, 2375, 1740, 170
^{. 5, 1659, 1603 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.10 (3H, t, J = 7.0 Hz), 1.50
-2.22 (8H, m), 1.69 (6H, s), 2.80-3.75 (7H, m), 3.
95 (3H, s), 3.99-4.09 (4H, m), 5.68 (1H, d, J = 10.6
Hz), 7.25-7.59 (13H, m, ArH). Elemental analysis: C ₃₇ H ₄₅ N ₃ O ₆・ HCl ・ 0.5H ₂ O Calculated (%): C, 66.01; H, 7.04; N, 6.24 Found (%): C, 66.25; H, 7.21; N, 6.29

Example 119 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6- (1-pyrrolyl) -1,2,3,4-tetrahydroquinazoline 3- [3-yl] ethyl isobutyrate hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-6- (1-pyrrolyl) obtained in Reference Example 195 in the same manner as in Example 27. The free salt of the title compound was obtained from ethyl -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.44 g, 0.92 mmol).
55 g, 90%) as an oil. IR (KBr): 2984, 2940, 2867, 2811, 2772, 1744, 170
^{. 7, 1665, 1516 cm -1} 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.1 Hz), 1.55-1.
98 (8H, m), 1.85 (6H, s), 2.05-2.20 (2H, m), 2.38
(2H, t, J = 6.9 Hz), 2.71-2.82 (2H, m), 3.41-3.51 (1
H, m), 4.05-4.12 (2H, m), 4.19 (2H, q, J = 7.1 Hz),
5.53 (1H, s), 6.37 (2H, t, J = 2.2 Hz), 7.10 (2H, t,
J = 2.2 Hz), 7.21-7.37 (10H, m, ArH), 7.41 (1H, d,
J = 9.0 Hz), 7.68 (1H, dd, J = 2.8 Hz, 8.8 Hz), 8.14
(1H, d, J = 2.6 Hz). This product (0.55 g) was dissolved in ethyl acetate (3.0 ml), and a 4N hydrogen chloride solution in ethyl acetate (0.35 ml) was added, followed by concentration. The residue was dried at 50 ° C in the presence of phosphorus pentoxide to give the title compound (0.4
8 g, 82%) were obtained as amorphous crystals. IR (KBr): 3400, 2980, 2938, 2485, 2400, 1736, 170
. 5, 1663, 1626, 1597 , 1514 cm -1 1 H-NMR (DMSO-d 6) δ: 1.14 (3H, t, J = 7.1 Hz), 1.55-
2.25 (8H, m), 1.73 (6H, s), 2.80-3.75 (7H, m), 4.0
2-4.12 (4H, m), 5.68 (1H, d, J = 10.4 Hz), 6.30 (2H,
t, J = 2.0 Hz), 7.20-7.45 (12H, m, ArH), 7.60 (1H,
d, J = 8.8 Hz), 7.96-8.04 (2H, m, ArH). Elemental analysis: Calculated as C ₄₀ H ₄₆ N ₄ O ₅・ HCl ・ 0.5H ₂ O Calculated (%): C, 67.83; H , 6.83; N, 7.91 Found (%): C, 68.08; H, 6.94; N, 7.61

Example 120 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]
Isobutyric acid hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline-3- obtained in Reference Example 196 in the same manner as in Example 27. Yl] phenacyl isobutyrate (0.54
g, 1.08 mmol) from the phenacyl ester of the title compound (0.
(70 g, 94%) as an oil. IR (KBr): 3061, 3029, 2942, 2867, 2811, 2774, 175
. 2, 1705, 1661, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.53-2.00 (8H, m), 2.05-2.18 (2
H, m), 2.33-2.40 (2H, m), 1.96 (6H, s), 2.70-2.78
(2H, m), 3.40-3.51 (1H, m), 4.04-4.11 (2H, m), 5.3
5 (2H, s), 5.52 (1H, s), 7.18-7.69 (16H, m, ArH),
7.88-7.93 (2H, m, ArH), 8.15 (1H, dd, J = 1.6 Hz, 8.
0 Hz). This product (0.62 g, 0.90 mmol), zinc dust (0.90 g), acetic acid (9.0 m
A mixture of l) and water (1.0 ml) was stirred vigorously at room temperature for 1 hour. After filtering off the zinc dust, the filtrate was extracted with chloroform. The extract was washed with water and dried (MgSO ₄ ), and concentrated by adding 4N hydrogen chloride in ethyl acetate (0.25 ml). The residue was treated with ethyl ether to give the title compound (0.4
8 g, 87%) as an amorphous powder. IR (KBr): 2940, 2700, 2600, 1740, 1705, 1663, 1607
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.70 (6H, s), 1.55-2.20 (8H,
m), 2.80-3.75 (7H, m), 4.02-4.11 (2H, m), 5.67 (1H,
s), 7.21-7.50 (12H, m, ArH), 7.72-7.80 (1H, m, Ar
H), 8.00 (1H, dd, J = 1.3 Hz, 7.7 Hz). Elemental analysis: C ₃₄ H ₃₉ N ₃ O ₅・ HCl ・ 0.5H ₂ O Calculated (%): C, 66.38; H, 6.72; N, 6.83 Found (%): C, 66.45; H, 6.77; N, 6.78

Example 121 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-methyl-1,2,3,4-tetrahydroquinazoline
-3-yl] isobutyric acid hydrochloride In the same manner as in Example 27, 2- [1- (4-bromobutyl) -6-methyl-2,4-dioxo-1,2, obtained in Reference Example 197.
Phenacyl ester of the title compound (0.97 g, 92%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.77 g, 1.50 mmol). IR (KBr): 2942, 1752, 1705, 1661, 1624, 1595, 1510
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.50-2.45 (12H, m), 1.95 (6H,
s), 2.38 (3H, s), 2.70-2.81 (2H, m), 3.40-3.51 (1
H, m), 4.01-4.10 (2H, m), 5.34 (2H, s), 5.51 (1H,
s), 7.16-7.61 (15H, m, ArH), 7.87-7.92 (3H, m, Ar
H). This product (0.70 g, 1.00 g) was obtained in the same manner as in Example 120.
mmol) to give the title compound (0.51 g, 82%) as an amorphous powder. IR (KBr): 2940, 2506, 1736, 1701, 1663, 1624, 159
^{. 5, 1510 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.69 (6H, s), 1.55-2.20 (8H,
m), 2.90-3.70 (7H, m), 2.36 (3H, s), 4.02-4.10 (2H,
m), 5.67 (1H, s), 7.21-7.41 (11H, m, ArH), 7.58 (1
. H, dd, J = 8.7 Hz, 1.9 Hz), 7.80 (1H, d, J = 1.8 Hz) Elemental _{analysis: C 35 H 41 N 3 O} 5 · HCl Calculated (%): C, 67.78; H, 6.83; N, 6.78 Found (%): C, 67.92; H, 6.70; N, 6.75

Example 122 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -8-methoxy-1,2,3,4-tetrahydroquinazolin-3-yl ] Isobutyric acid hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-8-methoxy-1, obtained in Reference Example 198, in the same manner as in Example 27.
The phenacyl ester of the title compound (1.74 g, 89%) was obtained as an oil from phenacyl 2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.44 g, 2.71 mmol). IR (KBr):. 2942, 1753, 1705, 1659, 1601 cm -1 1 H-NMR (CDCl 3) δ: 1.40-2.00 (8H, m), 1.94 (6H,
s), 2.03-2.40 (4H, m), 2.70-2.80 (2H, m), 3.39-3.5
0 (1H, m), 3.90 (3H, s), 4.19-4.27 (2H, m), 5.33
(2H, s), 5.51 (1H, s), 7.15-7.61 (15H, m, ArH), 7.
70-7.78 (1H, m, ArH), 7.87-7.92 (2H, m, ArH). In the same manner as in Example 120, this product (1.44 g, 2.00
mmol) to give the title compound (1.17 g, 92%) as an amorphous powder. IR (KBr): 2942, 2598, 2512, 1736, 1705, 1659, 1601
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.40-2.25 (8H, m), 1.68 (6H,
s), 2.75-3.75 (7H, m), 3.94 (3H, s), 4.00-4.10 (2H,
. m), 5.67 (1H, s), 7.22-7.62 (13H, m, ArH) Elemental _{analysis: C 35 H 41 N 3 O} 6 · HCl Calculated (%): C, 66.08; H, 6.65; N, 6.61 found (%): C, 66.05; H, 6.84; N, 6.45.

Example 123 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -5-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl ] Isobutyric acid hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-5-fluoro-1, obtained in Reference Example 199, in the same manner as in Example 27.
Phenacyl ester of the title compound (1.70 g, 69%) was obtained as an oil from phenacyl 2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.80 g, 3.47 mmol). IR (KBr): 2942, 2813, 1752, 1713, 1669, 1618, 1599
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.50-1.97 (8H, m), 1.95 (6H,
s), 2.03-2.17 (2H, m), 2.32-2.39 (2H, m), 2.70-2.8
0 (2H, m), 3.39-3.50 (1H, m), 4.02-4.10 (2H, m),
5.36 (2H, s), 5.52 (1H, s), 6.89 (1H, dd, J = 10.5 H
z, 8.3 Hz), 7.09-7.62 (15H, m, ArH), 7.88-7.93 (2
H, m, ArH). In the same manner as in Example 120, this product (1.41 g, 2.00
mmol) to give the title compound (1.13 g, 91%) as an amorphous powder. IR (KBr):. 2934, 2708, 1736, 1709, 1667, 1618 cm -1 1 H-NMR (DMSO-d 6) δ: 1.68 (6H, s), 1.50-2.20 (8H,
m), 2.80-3.73 (7H, m), 4.01-4.10 (2H, m), 5.67 (1H,
d, J = 7.6 Hz), 7.07 (1H, dd, J = 11.0 Hz, 8.2Hz), 7.
22-7.40 (11H, m, ArH), 7.68-7.79 (1H, m, ArH). Elemental analysis: Calculated as C ₃₄ H ₃₈ N ₃ O ₅ F.HCl (%): C, 65.43; H, 6.30; N, 6.73 Found (%): C, 65.07; H, 6.25; N, 6.58

Example 124 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl ] Isobutyric acid hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-6-fluoro-1, obtained in Reference Example 200, in the same manner as in Example 27.
The phenacyl ester of the title compound (2.06 g, 89%) was obtained as an oil from phenacyl 2,3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.71 g, 3.29 mmol). IR (KBr): 2942, 2867, 2811, 1752, 1707, 1665, 1505
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.55-1.98 (8H, m), 1.95 (6H,
s), 2.05-2.17 (2H, m), 2.33-2.39 (2H, m), 2.70-2.8
0 (2H, m), 3.40-3.49 (1H, m), 4.02-4.09 (2H, m),
5.35 (2H, s), 5.52 (1H, s), 7.22-7.61 (15H, m, Ar
H), 7.81 (1H, dd, J = 8.1 Hz, 2.7 Hz), 7.88-7.93 (2
H, m, ArH). This product (2.05 g, 2.90 g) was obtained in the same manner as in Example 120.
mmol) to give the title compound (1.60 g, 88%) as an amorphous powder. IR (KBr): 3027, 2938, 2600, 2515, 1734, 1705, 166
^{. 3, 1505 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.70 (6H, s), 1.55-2.20 (8H,
m), 2.80-3.75 (7H, m), 4.02-4.10 (2H, m), 5.67 (1H,
s), 7.20-7.40 (10H, m, ArH), 7.52-7.74 (3H, m, Ar
H). Elemental analysis: C ₃₄ H ₃₈ N ₃ O ₅ F ・ HCl Calculated (%): C, 65.43; H, 6.30; N, 6.73 Found (%): C, 65.21; H, 6.43; N, 6.52

Reference Example 125 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6,7-difluoro-1,2,3,4-tetrahydroquinazoline-3 -Yl] isobutyric acid hydrochloride In the same manner as in Example 27, 2- [1- (4-bromobutyl) -2,4-dioxo-6,7-difluoro-1,2, Phenacyl ester of the title compound (0.93 g, 36%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.94 g, 3.61 mmol). IR (KBr):. 2942, 1752, 1709, 1667, 1524 cm -1 1 H-NMR (CDCl 3) δ: 1.55-2.00 (8H, m), 1.94 (6H,
s), 2.05-2.21 (2H, m), 2.34-2.41 (2H, m), 2.70-2.8
0 (2H, m), 3.41-3.52 (1H, m), 3.98-4.05 (2H, m),
5.35 (2H, s), 5.52 (1H, s), 7.21-7.63 (15H, m, Ar
H), 7.88-7.97 (2H, m, ArH). In the same manner as in Example 120, this product (0.92 g, 1.27 g)
mmol) to give the title compound (0.70 g, 86%) as an amorphous powder. IR (KBr): 3063, 2934, 2614, 2514, 1740, 1709, 166
^{. 5, 1636, 1522 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.69 (6H, s), 1.50-2.20 (8H,
m), 2.80-3.75 (7H, m), 4.00-4.10 (2H, m), 5.68 (1H,
s), 7.24-7.40 (10H, m, ArH), 7.69-7.78 (1H, m, Ar
H), 7.91-8.00 (1H, m, ArH). Elemental analysis: C ₃₄ H ₃₇ N ₃ O ₅ F ₂ .HCl Actual (%): C, 63.60; H, 5.96; N, 6.54 Calculated (%): C, 63.45; H, 6.01; N, 6.31

Example 126 2- [6-Chloro-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl ] Isobutyric acid salt In the same manner as in Example 27, 2- [6-chloro-1- (4-bromobutyl) -2,4-dioxo-1,2,
The phenacyl ester of the title compound (1.26 g, 87%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.07 g, 2.00 mmol). IR (KBr):. 2942, 1752, 1707, 1667, 1609 cm -1 1 H-NMR (CDCl 3) δ: 1.55-2.25 (10H, m), 1.95 (6H,
s), 2.35-2.42 (2H, m), 2.71-2.82 (2H, m), 3.40-3.51
(1H, m), 4.01-4.09 (2H, m), 5.35 (2H, s), 5.52 (1
H, s), 7.24-7.62 (15H, m, ArH), 7.88-7.93 (2H, m,
ArH), 8.10 (1H, d, J = 2.6 Hz). In the same manner as in Example 120, this product (1.03 g, 1.43 g)
mmol) to give the title compound (0.82 g, 90%) as an amorphous powder. IR (KBr):. 2940, 2504, 1709, 1665, 1609 cm -1 1 H-NMR (DMSO-d 6) δ: 1.50-2.22 (8H, m), 1.68 (6H,
s), 2.75-3.67 (7H, m), 4.03-4.12 (2H, m), 5.67 (1H,
s), 7.21-7.50 (10H, m, ArH), 7.53 (1H, d, J = 8.8 H
z), 7.78 (1H, dd, J = 8.9 Hz, 2.5 Hz), 7.93 (1H, d,
J = 2.4 Hz). Elemental analysis: C ₃₄ H ₃₈ N ₃ O ₅ Cl ・ HCl Calculated (%): C, 63.75; H, 6.14; N, 6.56 Actual (%): C, 63.58; H , 6.38; N, 6.47

Example 127 2- [7-Chloro-2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl ] Isobutyric acid salt In the same manner as in Example 27, 2- [7-chloro-1- (4-fluoromethyl) -2,4-dioxo-1,2,3,4- Phenacyl tetrahydroquinazolin-3-yl] isobutyrate (1.0
7 g, 2.00 mmol) from the phenacyl ester of the title compound
(1.15 g, 80%) was obtained as an oil. IR (KBr):. 2992, 2942, 1750, 1709, 1667, 1605 cm -1 1 H-NMR (CDCl 3) δ: 1.60-2.25 (10H, m), 1.95 (6H,
s), 2.35-2.42 (2H, m), 2.71-2.81 (2H, m), 3.40-3.52
(1H, m), 4.02-4.10 (2H, m), 5.35 (2H, s), 5.51 (1
H, s), 7.15-7.61 (15H, m, ArH), 7.88-7.92 (2H, m,
ArH), 8.06 (1H, d, J = 8.4 Hz). In the same manner as in Example 120, this product (0.93 g, 1.29
mmol) to give the title compound (0.76 g, 92%) as an amorphous powder. IR (KBr): 2938, 2510, 1736, 1709, 1665, 1605, 1590
^{. cm -1 1 H-NMR (} DMSO-d 6) δ: 1.50-2.15 (8H, m), 1.68 (6H,
s), 2.80-3.70 (7H, m), 4.00-4.12 (2H, m), 5.67 (1H,
s), 7.20-7.42 (11H, m, ArH), 7.59 (1H, d, J = 1.4 H
z), 7.98 (1H, d, J = 8.4 Hz). Elemental analysis: Calculated as C ₃₄ H ₃₈ N ₃ O ₅ Cl.HCl (%): C, 63.75; H, 6.14; N, 6.56 (%): C, 64.14; H, 6.22; N, 6.16

Example 128 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydrobenzo [g] quinazoline
-3-yl] isobutyric acid hydrochloride 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4- obtained in Reference Example 204 in the same manner as in Example 27. Phenacyl ester of the title compound (1.01 g, 81%) was obtained as an oil from phenacyl tetrahydrobenzo [g] quinazolin-3-yl] isobutyrate (0.93 g, 1.69 mmol). IR (KBr):. 2942, 1752, 1705, 1663, 1632, 1603 cm -1 1 H-NMR (CDCl 3) δ: 1.50-2.00 (8H, m), 2.00 (6H,
s), 2.05-2.18 (2H, m), 2.39 (2H, t, J = 6.8 Hz), 2.7
2-2.81 (2H, m), 3.40-3.50 (1H, m), 4.14-4.22 (2H, m
m), 5.36 (2H, s), 5.52 (1H, s), 7.21-7.60 (16H, m,
ArH), 7.83-7.96 (4H, m, ArH), 8.74 (1H, s, ArH). In the same manner as in Example 120, this product (1.00 g, 1.36
mmol) to give the title compound (0.80 g, 90%) as an amorphous powder. IR (KBr): 2940, 2707, 1740, 1701, 1661, 1632, 160
^{. 3, 1518 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.74 (6H, s), 1.50-2.20 (8H,
m), 2.80-3.72 (7H, m), 4.13-4.22 (2H, m), 5.67 (1H,
s), 7.21-7.40 (10H, m, ArH), 7.47-7.55 (1H, m, Ar
H), 7.63-7.70 (1H, m, ArH), 7.90 (1H, s, ArH), 8.0
1-8.14 (2H, m, ArH) , 8.70 (1H, s, ArH) Elemental _{analysis: C 38 H 41 N 3 O} 5 · HCl Calculated (%):. C, 69.55 ; H, 6.45; N , 6.40 Found (%): C, 69.25; H, 6.41; N, 6.49

Example 129 2- [6-Chloro-2,4-dioxo-1- [4- [4- (4-fluorophenyl) -1-piperazinyl] butyl] -1,2,3,4-tetrahydro Quinazolin-3-yl] isobutyrate hydrochloride 2- [6-chloro-1- (4-bromobutyl) -2,4-dioxo-1,2 obtained in Reference Example 202 by a method similar to that in Example 27. ,
The phenacyl ester of the title compound (0.93 g, 76%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (1.02 g, 1.90 mmol). IR (KBr): 2944, 2818, 1752, 1707, 1665, 1609, 1508
^{. cm -1 1 H-NMR (} CDCl 3) δ: 1.55-1.85 (4H, m), 1.96 (6H,
s), 2.43-2.50 (2H, m), 2.59-2.64 (4H, m), 3.10-3.1
4 (4H, m), 4.05-4.13 (2H, m), 5.36 (2H, s), 6.83-
7.01 (15H, m, ArH), 7.23 (1H, d, J = 9.0 Hz), 7.43-
7.62 (4H, m, ArH), 7.88-7.93 (2H, m, ArH), 8.11 (1
H, d, J = 2.4 Hz). In the same manner as in Example 120, this product (0.65 g, 1.00
mmol) to give the title compound (0.46 g, 81%) as an amorphous powder. IR (KBr): 2944, 2710, 2620, 1744, 1707, 1665, 160
^{. 7, 1512 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.55-1.93 (4H, m), 1.71 (6H,
s), 3.00-3.22 (6H, m), 3.45-3.75 (4H, m), 4.06-4.12
(2H, m), 6.99-7.14 (4H, m, ArH), 7.57 (1H, d, J = 9.
0 Hz), 7.81 (1H, dd, J = 9.0 Hz, 2.6 Hz), 7.94 (1H,
d, J = 2.6 Hz). Elemental analysis: C ₂₆ H ₃₀ N ₄ O ₄ FCl ・ HCl ・ H ₂ O Calculated (%): C, 54.65; H, 5.82; N, 9.80 Actual (%) : C, 54.62; H, 5.85; N, 9.84

Example 130 2- [7-Chloro-2,4-dioxo-1- [4- [4- (4-fluorophenyl) -1-piperazinyl] butyl] -1,2,3,4-tetrahydro Quinazolin-3-yl] isobutyrate hydrochloride 2- [7-chloro-1- (4-bromobutyl) -2,4-dioxo-1,2 obtained in Reference Example 203 in the same manner as in Example 27. ,
Phenacyl ester of the title compound (0.54 g, 63%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.70 g, 1.31 mmol). IR (KBr): 2942, 2820, 1752, 1709, 1667, 1605, 158
^{. 0, 1510 cm -1 1 H} -NMR (CDCl 3) δ: 1.50-1.90 (4H, m), 1.96 (6H,
s), 2.48 (2H, t, J = 6.2 Hz), 2.60-2.65 (4H, m), 3.1
3-3.17 (4H, m), 4.05-4.13 (2H, m), 5.36 (2H, s),
6.85-7.01 (4H, m, ArH), 7.16-7.27 (2H, m), 7.42-7.
62 (3H, m, ArH), 7.88-7.93 (2H, m, ArH), 8.07 (1H,
d, J = 8.4 Hz). In the same manner as in Example 120, this product (0.53 g, 0.82
mmol) to give the title compound (0.46 g, 97%) as an amorphous powder. IR (KBr): 2990, 2942, 2510, 2450, 1734, 1709, 166
^{. 5, 1605, 1510 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.58-1.95 (4H, m), 1.71 (6H,
s), 3.03-3.26 (6H, m), 3.48-3.80 (4H, m), 4.07-4.14
(2H, m), 7.00-7.15 (4H, m, ArH), 7.34 (1H, dd, J =
1.6 Hz, 8.4 Hz), 7.63 (1H, d, J = 1.6 Hz), 8.00 (1H,
d, J = 8.4 Hz). Elemental analysis: C ₂₆ H ₃₀ N ₄ O ₄ FCl ・ HCl ・ 1.5H ₂ O Calculated (%): C, 53.80; H, 5.90; N, 9.65 Actual (% ): C, 54.22; H, 5.78; N, 9.82

Example 131 2- [2,4-Dioxo-1- [4- (4-diphenylmethyl-1-piperazinyl) butyl] -6-methyl-1,2,3,4-tetrahydroquinazoline-3- [Ill] isobutyric acid hydrochloride In the same manner as in Example 27, 2- [1- (4-bromobutyl) -6-methyl-2,4-dioxo-1,2,
The phenacyl ester of the title compound (0.63 g, 86%) was obtained as an oil from phenacyl 3,4-tetrahydroquinazolin-3-yl] isobutyrate (0.55 g, 1.07 mmol). IR (KBr): 3027, 2942, 2876, 2811, 2774, 1752, 170
. 5, 1661, 1624, 1597 , 1508 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.80 (4H, m), 1.95 (6H,
s), 2.25-2.60 (10H, m), 4.00-4.07 (2H, m), 4.21 (1
H, s), 5.34 (2H, s), 7.11-7.63 (15H, m, ArH), 7.88-
7.94 (3H, m, ArH). In the same manner as in Example 120, this product (0.57 g, 0.83 g
mmol) to give the title compound (0.49 g, 95%) as an amorphous powder. IR (KBr): 3400, 2940, 2580, 1730, 1701, 1655, 162
^{. 4, 1595, 1508 cm -1} 1 H-NMR (DMSO-d 6) δ: 1.69 (6H,
s), 1.50-1.85 (4H, m), 2.37 (3H, s), 2.70-3.90 (11
H, m, ArH), 4.00-4.12 (2H, m), 7.22-8.00 (13H, m,
ArH). Elemental analysis: C ₃₄ H ₄₀ N ₄ O ₄ .HCl.H ₂ O Calculated (%): C, 65.53; H, 6.95; N, 8.99 Found (%): C, 65.32; H , 7.13; N, 8.72

Example 132 2,4-Dioxo-1- [4- [4- (3-indolyl) piperidino] butyl] -1,2,3,4-tetrahydroquinazoline hydrochloride A method similar to that in Example 2 ( In method 4), 4- (3-indolyl) piperidine (445 mg, 2.22 mmol) was used in place of 4-diphenylmethoxypiperidine to obtain 1 obtained in Reference Example 86.
The free salt of the title compound (617 mg, 73%) was synthesized from-(4-bromobutyl) -2,4-dioxo-1,2,3,4-tetrahydroquinazoline (600 mg, 2.02 mmol). Recrystallization from ethyl acetate-methanol gave colorless crystals having a melting point of 146-147 ° C. IR (KBr):. 1695, 1684, 1608, 1486 cm -1 1 H-NMR (CDCl 3) δ: 1.50-1.98 (6H, m), 2.02-2.24 (4
H, m), 2.48 (2H, t, J = 6.8 Hz), 2.79-2.98 (2H, m),
3.02-3.16 (2H, m), 4.16 (2H, t, J = 7.8 Hz), 6.99 (1
H, s), 7.05-7.30 (3H, m), 7.34-7.44 (2H, m), 7.60-
7.75 (2H, m), 7.98 (1H, bs), 8.21 (1H, d, J = 7.2 H
z). Elemental analysis: C ₂₅ H ₂₈ N ₄ O ₂ .0.5H ₂ O Calculated (%): C, 70.56; H, 6.87; N, 13.17. Found (%): C, 70.48; H N, 12.87. This product (500 mg, 1.20 mmol) was dissolved in ethyl acetate (10.0 ml), 4N hydrogen chloride in ethyl acetate (1.00 ml) was added, and the title compound (609 mg, almost 100%) was added. ) Was synthesized. Recrystallization from ethyl acetate gave colorless crystals having a melting point of 250-252 ° C. IR (KBr): 3606, 3317, 3037, 2655, 2800-2200, 1697,
^{. 1675, 1608, 1486 cm -1} 1 H-NMR (CDCl 3) δ: 1.80-2.28 (6H, m), 2.40-2.70 (4
H, m), 2.80-3.24 (5H, m), 3.60-3.75 (2H, m), 4.08-
4.25 (2H, m), 7.02-7.46 (5H, m), 7.60-7.78 (2H, m
m), 8.19 (1H, d, J = 8.4 Hz), 9.65 (1H, bs), 10.60
(1H, bs), 12.06 (1H, bs). Elemental analysis: C ₂₅ H ₂₈ N ₄ O ₂ · HCl · 0.6H ₂ O Calculated (%): C, 64.74; H, 6.56; N, 12.08 Found (%): C, 64.68; H, 6.53; N, 11.83.

Example 133 3- [2- (2-Cyanomethoxy) ethyl] -2,4-dioxo-1- [4-
(4-Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino)
Butyl] -1,2,3,4-tetrahydroquinazoline (0.72 g, 1.5
mmol) in DMF (20 ml) and NaH (60% oily, 80 mg,
2.0 mmol) was added. After stirring for 10 minutes, (2-chloroethoxy) acetonitrile (0.27 g, 2.3 mmol) was added, and 90 ° C was added.
And stir overnight. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl ether. Wash the extract with water and dry (Na ₂ SO ₄ )
Thereafter, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (20: 1, v / v) to give the title compound (0.78 g, 92%) as an oil. IR (KBr):. 1702, 1660, 1610, 1484, 1401 cm -1 1 H-NMR (CDCl 3) δ: 1.54-2.25 (10H, m), 2.40 (2H, t,
J = 6.8 Hz), 2.69-2.86 (2H, m), 3.40-3.56 (1H, m),
3.93 (2H, t, J = 5.4 Hz), 4.14 (2H, t, J = 7.2 Hz), 4.
32 (2H, s), 4.37 (2H, t, J = 5.4 Hz), 5.53 (1H, s),
7.19-7.41 (12H, m), 7.68 (1H, dt, J = 1.8, 7.4 Hz),
8.22 (1H, dd, J = 1.8, 7.4 Hz).

Example 134 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl]
Ethoxyacetamide hydrochloride 3- [2- (2-cyanomethoxy) ethyl] -2,4-dioxo-1- [4-
(4-Diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline (1.13 g, 2.0 mmol), a mixture of potassium hydroxide (0.30 g) and ethanol (30 ml) was heated under reflux for 8 hours did. After cooling, the reaction mixture was acidified by adding concentrated hydrochloric acid, and extracted with chloroform. Wash the extract with water and dry (Na ₂
After SO ₄ ), the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with chloroform-methanol (20: 1, v / v) to give the free salt of the title compound (0.
53 g, 45%) as an oil. IR (KBr): 3332, 3278, 1700, 1652, 1608, 1484, 145
^{. 5, 1423, 1402 cm -1} 1 H-NMR (CDCl 3) δ: 1.56-2.04 (8H, m), 2.11-2.31 (2
H, m), 2.41 (2H, t, J = 6.6 Hz), 2.69-2.90 (2H, m),
3.42-3.61 (1H, m), 3.82 (2H, t, J = 5.2 Hz), 3.94 (2
H, s), 4.14 (2H, t, J = 6.4 Hz), 4.38 (2H, t, J = 5.2
Hz), 5.53 (1H, s), 5.91 (1H, br), 6.87 (1H, br), 7.
16-7.41 (12H, m), 7.68 (1H, dt, J = 7.9, 1.6 Hz), 8.
22 (1H, dd, J = 8.0, 1.6 Hz). This product was dissolved in methanol (8 ml), 4N hydrogen chloride in ethyl acetate (2.0 ml) was added, and the mixture was concentrated to give the title compound ( (0.35 g, 28%) as amorphous crystals. Elemental _{analysis: C 34 H 40 N 4 O} 5 · HCl · 0.5H 2 O Calculated (%): C, 64.80; H, 6.72; N, 8.89 Found (%): C, 64.63; H, 6.60 ; N, 8.84

Example 135 5- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydrothieno [3,2-d] pyrimidine 3- (3-yl) ethyl valerate hydrochloride 5- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4 obtained in Reference Example 209 in the same manner as in Example 27. The free salt of the title compound (3.10 g) was obtained from ethyl-tetrahydrothieno [3,2-d] pyrimidin-3-yl] valerate (2.33 g, 5.40 mmol).
g, 93%) as an oil. IR (KBr): 2944, 2867, 2811, 2774, 1732, 1698, 165
^{. 3, 1570 cm -1 1 H} -NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.52-1.
95 (12H, m), 2.04-2.16 (2H, m), 2.32-2.39 (4H, m),
2.68-2.79 (2H, m), 3.39-3.50 (1H, m), 4.00-4.18 (6
H, m), 5.52 (1H, s), 7.02 (1H, d, J = 5.2 Hz), 7.21-
7.38 (10H, m, ArH), 7.70 (1H, d, J = 5.4 Hz). Dissolve this product (0.56 g) in ethyl acetate (5.0 ml) and add 4N hydrogen chloride in ethyl acetate (0.30 ml). Added and concentrated. The residue was dried at 50 ° C in the presence of phosphorus pentoxide to give the title compound (0.
45 g, 75%) were obtained as amorphous crystals. IR (KBr): 3400, 3061, 3029, 2951, 2870, 2480, 173
. 0, 1698, 1653, 1568 cm -1 1 H-NMR (DMSO-d 6) δ: 1.16 (3H, t, J = 7.2 Hz), 1.40-
2.21 (12H, m), 2.31 (2H, t, J = 6.7 Hz), 2.70-3.74
(7H, m), 3.86-3.93 (2H, m), 3.98-4.09 (4H, m), 5.6
7 (1H, d, J = 9.8 Hz), 7.21-7.41 (11H, m), 8.18 (1H,
d, J = 5.4 Hz). Elemental analysis: C ₃₅ H ₄₃ N ₃ O ₅ S ・ HCl ・ 0.5H ₂ O Calculated (%): C, 63.38; H, 6.84; N, 6.34 Actual (% ): C, 63.75; H, 6.83; N, 6.51

Example 136 5- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydrothieno [3,2-d] pyrimidine -3-yl] valerate hydrochloride 5- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-obtained in Example 135 Ethyl tetrahydrothieno [3,2-d] pyrimidin-3-yl] valerate (2.
A mixture of 54 g, 4.11 mmol), 2N sodium hydroxide (4.0 ml), tetrahydrofuran (6.0 ml) and ethanol (6.0 ml) was stirred at room temperature for 6 hours, and neutralized with 2N hydrochloric acid.
Extracted with chloroform. Wash the extract with water and dry (MgSO ₄ )
Then, the mixture was concentrated. The residue was treated with ethyl ether to give the title compound (2.27 g, 86%) as an amorphous powder. IR (KBr): 2955, 2874, 2604, 2537, 1720, 1698, 164
^{. 9, 1568 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.45-2.35 (14H, m), 2.80-3.75
(7H, m), 3.87-3.94 (2H, m), 4.02-4.08 (2H, m), 5.
67 (1H, s), 7.21-7.41 (11H, m), 8.17 (1H, d, J = 5.2
Elemental analysis: C ₃₃ H ₃₉ N ₃ O ₅ S ・ HCl ・ H ₂ O Calculated (%): C, 61.52; H, 6.57; N, 6.52 Actual (%): C, 61.60; H, 6.39; N, 6.38

Example 137 2- [2,4-Dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydrothieno [3,2-d] pyrimidine 3- [3-yl] ethyl isobutyrate hydrochloride In the same manner as in Example 27, 2- [1- (4-bromobutyl) -2,4-dioxo-1,2,3,4 obtained in Reference Example 210 The free salt of the title compound (1.28 g, 2.59 mmol) was obtained from ethyl-tetrahydrothieno [3,2-d] pyrimidin-3-yl] isobutyrate (1.08 g, 2.59 mmol).
g, 82%) as an oil. IR (KBr):. 2942, 1740, 1701, 1659, 1574 cm -1 1 H-NMR (CDCl 3) δ: 1.24 (3H, t, J = 7.2 Hz), 1.50-1.
95 (8H, m), 1.83 (6H, s), 2.04-2.16 (2H, m), 2.34
(2H, t, J = 7.1 Hz), 2.68-2.78 (2H, m), 3.39-3.50 (1
H, m), 3.94-4.01 (2H, m), 4.18 (2H, q, J = 7.2 Hz),
5.52 (1H, s), 6.98 (1H, d, J = 5.4 Hz), 7.21-7.37 (1
0H, m, ArH), 7.67 (1H, d, J = 5.2 Hz). Dissolve this product (1.06 g) in ethyl acetate (5.0 ml), add 4N hydrogen chloride in ethyl acetate (0.50 ml) and concentrate. did. The residue was dried at 50 ° C in the presence of phosphorus pentoxide to give the title compound (1.0
3 g, 89%) were obtained as amorphous crystals. IR (KBr): 3400, 2984, 2938, 2500, 1738, 1698, 165
^{. 5, 1574 cm -1 1 H} -NMR (DMSO-d 6) δ: 1.13 (3H, t, J = 7.2 Hz), 1.70
(6H, s), 1.55-2.20 (8H, m), 2.80-3.75 (7H, m), 3.9
5-4.11 (4H, m), 5.67 (1H, d, J = 10.8 Hz), 7.20-7.41
(11H, m), 8.17 (1H, d, J = 5.2 Hz). Elemental analysis: Calculated as C ₃₄ H ₄₁ N ₃ O ₅ S ・ HCl ・ H ₂ O (%): C, 62.04; H, 6.74; N, 6.38 Found (%): C, 61.76; H, 6.53; N, 6.26

Experimental Example 1 Effect on Histamine-Induced Cutaneous Vascular Hyperpermeability in Guinea Pig Male (Hartley) Hartley-type guinea pig (body weight about 500)
g) was used. After shaving the back hair using an electric hair clipper under anesthesia with ethyl ether, 1 ml of 2.5% pontamine sky blue solution was intravenously administered, and 0.1 ml of a 3 μg / ml histamine solution was immediately injected into the skin on the right and left two places on the back. Was administered. Thirty minutes later the animals were stunned by beating on the head, then the neck was cut off and sacrificed by exsanguination. The back was peeled off, the major axis and minor axis (mm) of each blue spot were measured, the product was determined, and the average value of the products was defined as the vascular permeability index. Each drug was suspended in 5% gum arabic solution and orally administered in a volume of 0.2 ml / 100 g body weight one hour before histamine administration.
Animals in the control group received the same volume of 5% gum arabic solution. The inhibition rate of the subject for the main reaction is [Equation 1]
It calculated according to.

## EQU1 ## Inhibition rate of histamine-induced cutaneous vascular hyperpermeability (%) = 100 × (1−Drug administration index at the time of drug administration / Vessel permeability index of control group) The results are shown in Table 1.

[0422]

[Table 1]

Experimental Example 2 1) Preparation of guinea pig eosinophils Horse serum (Bio-Whittaker,
Inc.) 2 ml was intraperitoneally administered once a week for 8 consecutive weeks. 48 hours after the last administration, 75 ml of physiological saline was intraperitoneally injected,
The collected solution was centrifuged at 400 × g for 5 minutes. Perco the sediment
ll solution (specific gravity d = 1.07) suspended in 5 ml, Percoll specific gravity discontinuous layer (specific gravity d = 1.112,5 ml; d = 1.095,10 ml; 1.090,10 ml; d = 1.085,
5 ml) and centrifuged at 1000 × g for 25 minutes (20 ° C.). The cell layer formed at the interface with specific gravity d = 1.112 and d = 1.095 was collected. Erythrocytes mixed into the collected cell sediment were removed by hypotonic treatment (suspension in water for 30 minutes). Wash 3 times with Hanks solution (Hanks-Hepes) containing 10 mM Hepes (Dojin Chemical),
% Human serum albumin (Wako Pure Chemical Industries or Sigma)
Suspend in Hanks-Hepes solution (Hanks-Hepes-HSA), 5.56 × 10
^It was adjusted to ⁶ cells / ml. The eosinophils had a purity of 90% and a viability of 98% or more.

2) Assay for inhibition of chemotaxis reaction LTB ₄ suspended in Hanks-Hepes-HSA solution was placed in a 24-well culture dish in the lower chamber.
600 μl (final concentration 10 ⁻⁸ MCascade Biochemical Ltd.) was added, and the mixture was kept at 37 ° C. for 30 minutes in a carbon dioxide gas incubator. Also, the Chemotaxicell serving as the upper chamber was placed in the 24-well culture dish.
(Polycarbonate membrane, pore size 3μm, thickness 10μ
m), eosinophil suspension incubated at 37 ° C for 15 minutes in a thermostat, 200μl (5 × 10 ⁶ cells / ml)
Was added to the upper chamber. After reacting for 2 hours in a carbon dioxide gas incubator, the Chemotaxicell was removed, and 2% (W /
V) 60 μl of EDTA physiological saline solution was added. After ice-cooling, the number of cells that migrated into the lower chamber liquid was counted using a hemocytometer (Coulte
r Counter (product name)). In addition, the drug
Dissolve in N, N-dimethylformamide (DMF) to a final concentration of 10
^-5 M was added to both the lower and upper chambers.

(Equation 2) Was determined inhibition rate against chemotactic reaction by LTB ₄ of the subject (1 × 10 ^-5 M concentration). The results are shown in [Table 2].

[0425]

[Table 2]

Formulation Example 1 (1) Compound of Example 2 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Example 2 Using a mixture of 10.0 mg of the compound obtained in the above, 60.0 mg of lactose and 35.0 mg of corn starch in 0.03 ml of a 10% aqueous gelatin solution (3.0 mg as gelatin),
After granulating through a 1 mm mesh sieve, it was dried at 40 ° C. and sieved again. The granules thus obtained were mixed with 2.0 mg of magnesium stearate and compressed. The resulting core tablets were coated with a sugar coating in aqueous suspension of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Formulation Example 2 Using the compound obtained in Example 60, a coated tablet was obtained in the same manner as in Formulation Example 1. Formulation Example 3 A coated tablet was obtained in the same manner as in Formulation Example 1, except that the compound obtained in Example 120 was used. Formulation Example 4 Using the compound obtained in Example 124, a coated tablet was obtained in the same manner as in Formulation Example 1.

Formulation Example 5 (1) Compound of Example 2 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Example 10.0 mg of the compound obtained in Step 2 and 3.0 mg of magnesium stearate were added to an aqueous solution of soluble starch in 0.07 ml.
(7.0 mg as soluble starch), dried and mixed with 70.0 mg of lactose and 50.0 mg of corn starch. The mixture was compressed to give tablets.

Formulation Example 6 Using the compound obtained in Example 60, tablets were obtained in the same manner as in Formulation Example 5. Formulation Example 7 Using the compound obtained in Example 120, a tablet was obtained in the same manner as in Formulation Example 5. Formulation Example 8 A tablet was obtained in the same manner as in Formulation Example 5, using the compound obtained in Example 124.

Formulation Example 9 (1) 5.0 mg of the compound of Example 2 (2) 20.0 mg of sodium chloride (3) Make distilled water 2 ml in total volume 5.0 mg of the compound obtained in Example 2 and 20.0 mg of sodium chloride
Was dissolved in distilled water, and water was added to make a total volume of 2.0 ml.
The solution was filtered and filled under aseptic conditions into 2 ml ampules. The ampoule was sterilized and sealed to obtain a solution for injection.

Formulation Example 10 Using the compound obtained in Example 60, tablets were obtained in the same manner as in Formulation Example 9. Formulation Example 11 Using the compound obtained in Example 120, a tablet was obtained in the same manner as in Formulation Example 9. Formulation Example 12 Using the compound obtained in Example 124, tablets were obtained in the same manner as in Formulation Example 9.

[0432]

The compound (I) or a salt thereof has excellent antiallergic action, antihistamine action, antiinflammatory action,
It has an inhibitory effect on eosinophil chemotaxis and is useful as a prophylactic / therapeutic agent for asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, urticaria and the like.

────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. ⁶ identifications FI A61K 31/505 ADA A61K 31/505 ADA AED AED AEM AEM C07D 471/04 118 C07D 471/04 118Z 487/04 148 487/04 148 495/04 105 495/04 105Z

Claims (23)

[Claims] (1) Formula (1) Wherein ring A represents a cyclic hydrocarbon which may have a substituent or a nitrogen-containing heterocyclic ring which may have a substituent,
D and E are the same or different and each represent an oxygen atom or a sulfur atom, and ^one of R ¹ and R ² is a group represented by the formula: (Wherein, Ar ¹ and Ar ² be the have a substituent indicates an aromatic group, an Ar ¹ and Ar ² are adjacent optionally fused ring group which may have a substituent together with the carbon atoms Ring B may represent a nitrogen-containing heterocyclic ring which may have a substituent, and X and Y may be the same or different and each may be a bond, an oxygen atom, S (O) p (p is 0 Or an integer of 2 or less), NR ⁴ (R ⁴ represents a hydrogen atom or a lower alkyl group) or a divalent straight chain which may have a substituent and may have 1 to 3 heteroatoms. R ³ represents a hydrogen atom, a hydroxy group which may have a substituent or a carboxyl group which may be esterified.), And the other is a chain lower hydrocarbon group. It represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent. Or a salt thereof. (2) ring A is (i) a halogen atom, (ii) C _1-3 alkylenedioxy group, (iii) nitro group, (iv) cyano group, (v) halogen atom, hydroxy, carboxyl,
C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_1-6 alkyl group, (vi) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy - carbonyl, C _1-6 alkyl - carbonyl, amino, mono -
Or di-C _1-6 alkylamino, mono- or di-C _1-6
Alkyl-carbonylamino, sulfonamide, mono-
Or C optionally having di-C _1-6 alkylamino
Selected from _1-6 alkyl-sulfonamides and 5- to 10-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms or benzo-fused ring groups thereof A C _2-6 alkenyl group which may have a substituent, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and 5 to 10 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _2-6 alkynyl group optionally having a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof, (viii)
(A) a halogen atom, (b) C _1-3 alkylenedioxy,
(C) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) optionally halogenated C _2-6 alkenyl, (g) halogenated _C2-6 alkynyl, (h) _C3-6 cycloalkyl, (i)
Halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1- 6} alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen atom and a sulfur atom A C _1-6 alkoxy optionally having a substituent selected from a selected 5 to 10-membered heterocyclic group containing 1 to 3 heteroatoms or a benzo-fused ring group thereof, (j) halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino, (m) mono-C
_1-6 alkylamino, (n) di -C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl group, (v) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl,
(Y) C _6-10 aryl, (z) C _6-10 aryloxy,
(Aa) C _7-16 aralkyloxy, (bb) oxo, (cc)
Thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl,
(Gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-
C _3-6 cycloalkyl group optionally substituted by C _1-6 alkyl group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl - carbonyl, amino, mono- - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - have a or di -C _1-6 alkylamino A good C _1-6 alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms, or a benzo-fused ring group thereof. A selected C _1-6 alkoxy group optionally having a substituent, (x) an optionally halogenated C _1-6 alkylthio group, (xi) a hydroxy group, (xii)
An amino group, (xiii) a mono-C _1-6 alkylamino group, (x
iv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group,
(Xvii) carboxyl group, (xviii) C _1-6 alkoxy-
Carbonyl group, (xix) carbamoyl group, (xx) mono-
C _1-6 alkyl - carbamoyl group, (xxi) di -C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl - carbamoyl group, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group , (Xxv) (a) halogen atom, (b) C
_1-3 alkylenedioxy, (c) nitro, (d) cyano,
(E) an optionally halogenated C _1-6 alkyl,
(F) an optionally halogenated C _2-6 alkenyl,
(G) optionally halogenated C _2-6 alkynyl,
(H) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and In addition to the carbon atom, it may have a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, or a substituent selected from a benzo-fused ring group thereof. C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (1) amino, (m) mono-C _1-6 alkylamino,
(N) di-C _1-6 alkylamino, (o) 5- to 6-membered cyclic amino, (p) C _1-6 alkyl-carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl,
(S) carbamoyl, (t) mono-C _1-6 alkyl-carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C
_1-6 alkylsulfonyl, (y) C _6-10 aryl, (z)
C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C
_1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (h
h) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) C _6-10 aryl group optionally substituted with carboxyl-C _1-6 alkyl, (xxvi) (a) halogen atom, b) C _1-3 alkylenedioxy, (c) nitro,
(D) cyano, (e) optionally halogenated C _1-6
Alkyl, (f) optionally halogenated C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) a halogen atom, Hydroxy, carboxyl, C _1-6 alkoxy, C
_1-6 alkoxy - carbonyl, C _1-6 alkyl - carbonyl, amino, mono- - or di -C _1-6 alkylamino,
Mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamide,
And a 5- to 10-membered heterocyclic group containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom other than a carbon atom, or a substituent selected from a benzo-fused ring group thereof. Good C _1-6 alkoxy, (j)
Optionally halogenated C _1-6 alkylthio, (k)
Hydroxy, (1) amino, (m) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl- Carbonyl,
(Q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C _1-6 alkyl-
Carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl Good _C7-15 aralkyl groups, (xxvii) (a)
Halogen atom, (b) C _1-3 alkylenedioxy, (c)
Nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) optionally halogenated C
_2-6 alkenyl, (g) optionally halogenated C
_2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono _-Or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C _1-6 alkyl optionally having mono- or di-C _1-6 alkylamino Having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms or a benzo-fused ring thereof. Optionally, C _1-6 alkoxy, (j) optionally halogenated C _1-6 alkylthio, (k) hydroxy, (l) amino, (m) mono-C _1-6
Alkylamino, (n) di-C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl - carbamoyl, (u) di -C _1-6 alkylcarbamoyl, (v) C _6-10 aryl - carbamoyl,
(W) sulfo, (x) C _1-6 alkylsulfonyl, (y) C
_6-10 aryl, (z) C _6-10 aryloxy, (aa) C
_7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl,
(Ff) C _6-10 aryl-thiocarbamoyl, (gg) C
_7-16 aralkyl, (hh) a C _6-10 aryloxy group optionally substituted with (C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl,
(Xxviii) (a) a halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) halogen _Optionally substituted C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _{1 -6} alkoxy, C _1-6 alkoxy - carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_1-6 alkoxy, (j) optionally halogenated C
_1-6 alkylthio, (k) hydroxy, (l) amino,
(M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C
_1-6 alkyl-carbonyl, (q) carboxyl, (r)
C _1-6 alkoxy-carbonyl, (s) carbamoyl,
(T) mono-C _1-6 alkyl-carbamoyl, (u) di-
C _1-6 alkylcarbamoyl, (v) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl, (y) C _6-10 aryl, (z) C _6-10 aryl Oxy, (aa) C _7-16 aralkyloxy, (bb) oxo,
(Cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy - carbonyl -C _1-6 alkyl or (ii) carboxyl -C _1-6 alkyl optionally substituted C _7-16 aralkyloxy group, (xxix) Oxo group, (xxx) thiocarbamoyl group, (xxxi) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxii) di-C _1-6 alkyl-thiocarbamoyl group, (xxxiii) C _6-10 aryl-thio A carbamoyl group, (xxxiv) C _6-10 aryl-carbonyloxy,
(Xxxv) (a) halogen atom, (b) optionally halogenated C _1-6 alkyl group, (c) optionally halogenated C _2-6 alkenyl, (d) halogenated _C2-6 alkynyl, (e) _C3-6 cycloalkyl,
(F) halogen atom, hydroxy, carboxyl, C _1-6
Alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- Or di-C _1-6
C _1-6 alkyl-sulfonamide _{optionally having} alkylamino, and a 5- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms groups or may have a substituent group selected from benzo fused ring group C _1-6 alkoxy, (g) halogenated which may be C _1-6 alkylthio, (h) hydroxy, (i) amino (J) mono-C _1-6 alkylamino, (k) di-C _1-6 alkylamino, (l) 5- or 6-membered cyclic amino, (m) C _1-6 alkyl-carbonyl, (n) carboxyl , (O) C _1-6 alkoxy-carbonyl, (p) carbamoyl, (q) mono-
C _1-6 alkyl-carbamoyl, (r) di-C _1-6 alkylcarbamoyl, (s) C _6-10 aryl-carbamoyl, (t) sulfo, (u) C _1-6 alkylsulfonyl,
(V) C _6-10 aryl, (w) C _6-10 aryloxy,
(X) C _7-16 aralkyloxy, (y) thiocarbamoyl, (z) mono-C _1-6 alkyl-thiocarbamoyl,
(Aa) di-C _1-6 alkyl-thiocarbamoyl, (bb)
_{Having a} C _6-10 aryl-thiocarbamoyl, (cc) C _7-16 aralkyl, (dd) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ee) carboxyl-C _1-6 alkyl group. An aminocarbonyl, (xxxvi) a 5- or 6-membered heterocyclic group containing 1 to 4 one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, (xxxvii ) C _1-6 alkoxy-carbonyl-C _1-6 alkoxy-carbonyl group, (xxxviii)
C _1-6 Arukikokishi - carbonyl -C _1-6 alkyl - carbamoyl group, (xxxix) hydroxy -C _1-6 alkyl - carbamoyl group, (xxxx) C _1-6 alkoxy - carbonyl - carbamoyl group, (xxxxi) C _{6 -14} arylsulfonamide, (xxxxii) C _1-6 alkylsulfonamide, (x
xxxiii) carboxy-C _1-6 alkyl-carbonyl-amino group, (xxxxiv) C _1-6 alkoxy-carbonyl-C
_1-6 alkyl-carbonyl-amino group, (xxxxv) C _1-6
Substituted with an alkyl-carbonyloxy-C _1-6 alkyl-carbonyl-amino group, a (xxxxvi) hydroxy-C _1-6 alkyl-carbonyl-amino group, and (xxxxvii) hydroxy or (and) C _1-6 alkoxy. (1) a 3- to 10-membered cyclic hydrocarbon or (2) 1 which may have a substituent selected from the group consisting of a C _6-14 aryl-C _2-6 alkenyl-carbonylamide group, A 3- to 13-membered nitrogen-containing heterocyclic ring containing 1 to 3 nitrogen atoms and optionally 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Or differently representing an oxygen atom or a sulfur atom, and ^one of R ¹ and R ^{2 is} a group represented by the formula: [Wherein R ³ represents (1) a hydrogen atom, (2) (i) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, (iv) a cyano group, or (v) a halogen atom. Atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _1-6 alkyl group which may have, (vi) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _2-6 alkenyl group which may have a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _{1- 6} alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_2-6 alkynyl group, (viii) C _3-6 cycloalkyl group,
(Ix) halogen atom, hydroxy, carboxyl, C
_1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6
Alkyl-carbonyl, amino, mono- or di-C
_1-6 alkylamino, mono or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C
Which may have _1-6 alkylamino C _1-6 alkyl -
A sulfonamide, and a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a benzo-fused ring group thereof. C _1-6 which may be
An alkoxy group, (x) optionally halogenated C _1-6
Alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono-C _1-6 alkylamino group, (xiv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino Group, (xvi) a C _1-6 alkyl-carbonyl group, (xvi
i) carboxyl group, (xviii) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6
Alkyl - carbamoyl group, (xxi) di -C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl - carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (xxv) C _6-10 aryl group, (xxvi) C _6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 A substituent selected from the group consisting of an alkyl-thiocarbamoyl group, (xxxi) di-C _1-6 alkyl-thiocarbamoyl group, (xxxii) C _6-10 aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group (I) a hydroxy group optionally having a C _1-16 chain or cyclic hydrocarbon group, (3) a carboxyl group, or (4) a hydrogen atom of a carboxyl group, halogen atom, (ii) C _1-3 alkylenedioxy Alkoxy group, (iii) nitro group, (iv) cyano group, (v)
Halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1- 6} alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen atom and a sulfur atom A C _1-6 alkyl group optionally having a substituent selected from a selected 5 to 10-membered heterocyclic group containing 1 to 3 hetero atoms or a benzo-fused ring group thereof, (vi) a halogen atom, Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_2-6 alkenyl group, (vii) halogen atom, hydroxy,
Carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C
_1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and nitrogen atom besides carbon atom, an oxygen atom and a sulfur 1 selected from atoms
To three 5- to 10-membered heterocyclic group or a benzo-fused ring may have a substituent group selected from the group C _2-6 alkynyl group containing a hetero atom, (viii) C _3-6 cycloalkyl Group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen 1 selected from atoms and a sulfur atom to three 5- to 10-membered heterocyclic group or a C _1-6 alkoxy group which may have a substituent selected from the benzo-fused ring group containing a hetero atom, x) optionally halogenated and C _1-6 alkylthio group, (xi) hydroxy group, (xii)
An amino group, (xiii) a mono-C _1-6 alkylamino group, (x
iv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group,
(Xvii) carboxyl group, (xviii) C _1-6 alkoxy-
Carbonyl group, (xix) carbamoyl group, (xx) mono-
C _1-6 alkyl-carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl-carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (Xxv) a C _6-10 aryl group, (xxvi) C
_6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di -C _1-6 alkyl - thiocarbamoyl group and (xxxii) C _6-10 aryl - thiocarbamoyl and (xxxiii) C _7-16 may have a substituent group selected from the group consisting of aralkyl groups C _1- A carboxyl group having a _16- chain or cyclic hydrocarbon group, wherein Ar ¹ and Ar ² are (i) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, and (iv) a cyano group, respectively. Group, (v) halogen atom, hydroxy, carboxyl,
C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_1-6 alkyl group, (vi) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy - carbonyl, C _1-6 alkyl - carbonyl, amino, mono -
Or di-C _1-6 alkylamino, mono- or di-C _1-6
Alkyl-carbonylamino, sulfonamide, mono-
Or C optionally having di-C _1-6 alkylamino
Selected from _1-6 alkyl-sulfonamides and 5- to 10-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms or benzo-fused ring groups thereof A C _2-6 alkenyl group which may have a substituent, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and 5 to 10 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _2-6 alkynyl group optionally having a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof, (viii)
C _3-6 cycloalkyl group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _{1- 6} alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and carbon atoms, nitrogen atom in addition, 1 to 5 to 10-membered heterocyclic group or a benzo-fused ring may have a substituent group selected from the group C ₁ containing 3 hetero atoms selected from oxygen atom and a sulfur atom _-6 alkoxy group, (x) optionally halogenated C _1-6 alkylthio group, (xi) hydroxy group, (xii) amino group, (xiii) mono-C _1-6 alkylamino group, (xiv) di -C _1-6 A Kiruamino group,
(Xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xvii) carboxyl group, (xvii
i) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6 alkyl-carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxi)
i) C _6-10 aryl-carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (xxv) C
_6-10 aryl group, (xxvi) C _6-10 aryloxy group,
(Xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) a thiocarbamoyl group, (xxx) mono- -C
_1-6 alkyl-thiocarbamoyl group, (xxxi) di-C _1-6
Alkyl-thiocarbamoyl group and (xxxii) C _6-10
(1) C _6-14 aryl group, (2) nitrogen atom other than carbon atom, which may have a substituent selected from the group consisting of aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group; 5 to 8 containing 1 to 4 one or two hetero atoms selected from a sulfur atom and an oxygen atom
A 3-membered aromatic heterocyclic group or (3) a condensed heterocyclic group of the 5- to 8-membered aromatic heterocyclic group and a C _6-14 aromatic cyclic hydrocarbon, wherein Ar ¹ and Ar ² represent adjacent carbon atoms Along with the atom, the substituent may be the same as the substituent of the aromatic group represented by Ar ¹ and Ar ² above. [Wherein, R ³ has the same meaning as described above], and the ring B may be a (i) halogen atom, (i
i) C _1-3 alkylenedioxy group, (iii) nitro group, (i
v) cyano group, (v) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino , mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamide and nitrogen in addition to carbon atoms, C _1-6 alkyl optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms or a benzo-fused ring group thereof Group, (vi) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _2-6 alkenyl group which may be present, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or a C _1-6 aralkyl optionally having di -C _1-6 alkylamino A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atom, or a substituent selected from benzo-fused ring groups thereof. Optionally having a C _2-6 alkynyl group, (viii) a C _3-6 cycloalkyl group, (ix) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _1-6 alkoxy group optionally having a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (x) an optionally halogenated C _1-6 alkylthio group, (xi ) Hydroxy group, (xii) amino group, (xii
i) mono--C _1-6 alkylamino group, (xiv) di -C _{1 -6} alkylamino group, (xv) 5 or 6-membered cyclic amino group,
(Xvi) a C _1-6 alkyl-carbonyl group, (xvii) a carboxyl group, (xviii) a C _1-6 alkoxy-carbonyl group,
(Xix) carbamoyl group, (xx) mono-C _1-6 alkyl-
Carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl-carbamoyl, (xxii
i) a sulfo group, (xxiv) a C _1-6 alkylsulfonyl group,
(Xxv) a C _6-10 aryl group, (xxvi) a C _6-10 aryloxy group, (xxvii) a C _7-16 aralkyloxy group, (xxvii
i) an oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di-C _1-6 alkyl-thiocarbamoyl group and (xxxii)
C _6-10 aryl-thiocarbamoyl and (xxxiii) C
_7-16 optionally having a substituent selected from the group consisting of an aralkyl group, containing one nitrogen atom, and further containing one to three heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom And X and Y are the same or different and each represents (1) a bond, (2) an oxygen atom, (3) S (O) p (p
Represents an integer of 0 to 2), (4) NR ⁴ (R ⁴ represents a hydrogen atom or a C _1-6 alkyl group), or (5)
(I) a halogen atom, (ii) a C _1-3 alkylenedioxy group, (iii) a nitro group, (iv) a cyano group, (v) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _1-6 alkyl group which may have a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (vi) a halogen atom, hydroxy, carboxyl,
C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C
_1-6 alkyl-carbonyl, amino, mono- or di-
C _1-6 alkylamino, mono- or di-C _1-6 alkyl-
Carbonylamino, sulfonamide, mono- or di-
C _1-6 alkyl-sulfonamide optionally having C _1-6 alkylamino, and 5 to 10 containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms Which may have a substituent selected from a membered heterocyclic group or a benzo-fused ring group thereof
_2-6 alkenyl group, (vii) halogen atom, hydroxy,
Carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C
_1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides and nitrogen atom besides carbon atom, an oxygen atom and a sulfur 1 selected from atoms
A C _2-6 alkynyl group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing from 3 to 3 hetero atoms or a benzo-fused ring group thereof, (viii) a C _3-6 cycloalkyl Group, (ix) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 may have an alkyl amino C _1-6 alkyl - sulfonamide and nitrogen atom besides carbon atom, an oxygen A C _1-6 alkoxy group optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms and sulfur atoms or a benzo-fused ring group thereof, x) an optionally halogenated C _1-6 alkylthio group, (xi) a hydroxy group, (xii)
An amino group, (xiii) a mono-C _1-6 alkylamino group, (x
iv) di-C _1-6 alkylamino group, (xv) 5- or 6-membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group,
(Xvii) carboxyl group, (xviii) C _1-6 alkoxy-
Carbonyl group, (xix) carbamoyl group, (xx) mono-
C _1-6 alkyl-carbamoyl group, (xxi) di-C _1-6 alkylcarbamoyl group, (xxii) C _6-10 aryl-carbamoyl, (xxiii) sulfo group, (xxiv) C _1-6 alkylsulfonyl group, (Xxv) a C _6-10 aryl group, (xxvi) C
_6-10 aryloxy group, (xxvii) C _7-16 aralkyloxy group, (xxviii) oxo group, (xxix) thiocarbamoyl group, (xxx) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxi) di An oxygen atom optionally having a substituent selected from the group consisting of —C _1-6 alkyl-thiocarbamoyl group and (xxxii) C _6-10 aryl-thiocarbamoyl and (xxxiii) C _7-16 aralkyl group A C _1-6 alkylene group which may contain 1 to 3 heteroatoms selected from a sulfur atom and a nitrogen atom in the hydrocarbon chain,
A C _2-6 alkenylene group or a C _2-6 alkynylene group], the other being (1) a hydrogen atom,
(2) a cyano group, or (3) (i) a halogen atom, (i
i) C _1-3 alkylenedioxy group, (iii) nitro group, (i
v) cyano group, (v) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino , mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono- - or di -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamide and nitrogen in addition to carbon atoms, C _1-6 alkyl optionally having a substituent selected from a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from atoms, oxygen atoms and sulfur atoms or a benzo-fused ring group thereof Group, (vi) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino,
Mono - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6 Alkyl-sulfonamide, and a 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atoms, or a substituent selected from benzo-fused ring groups thereof. A C _2-6 alkenyl group which may be present, (vii) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or a C _1-6 aralkyl optionally having di -C _1-6 alkylamino A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms other than carbon atom, or a substituent selected from benzo-fused ring groups thereof. C _2-6 alkynyl group which may be present, (viii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) halogenated C _1-6 alkyl optionally, (f) C _2-6 alkenyl optionally halogenated, (g) C _2-6 alkynyl optionally halogenated, (h) C _3-6 cycloalkyl , (I) a halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_1-6 alkoxy, (j) optionally halogenated C
_1-6 alkylthio, (k) hydroxy, (l) amino,
(M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C
_1-6 alkyl-carbonyl, (q) carboxyl, (r)
C _1-6 alkoxy-carbonyl, (s) carbamoyl,
(T) mono-C _1-6 alkyl-carbamoyl, (u) di-
C _1-6 alkylcarbamoyl group, (v) C _6-10 aryl-
Carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo ,
(Cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) C _3-6 cycloalkyl optionally substituted by carboxyl-C _1-6 alkyl, (ix A) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _{1 -6} alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino C _1-6
Alkyl-sulfonamide, and 1 to 3 selected from nitrogen atom, oxygen atom and sulfur atom other than carbon atom
A C _1-6 alkoxy group which may have a substituent selected from a 5- to 10-membered heterocyclic group containing two hetero atoms or a benzo-fused ring group thereof, and (x) an optionally halogenated C _1-6 alkylthio group, (xi) hydroxy group, (xi
i) amino group, (xiii) mono-C _1-6 alkylamino group,
(Xiv) di-C _1-6 alkylamino group, (xv) 5-6
Membered cyclic amino group, (xvi) C _1-6 alkyl-carbonyl group, (xvii) carboxyl group, (xviii) C _1-6 alkoxy-carbonyl group, (xix) carbamoyl group, (xx) mono-C _1-6 Alkyl-carbamoyl group, (xxi) di-C
_1-6 alkyl carbamoyl group, (xxii) C _6-10 aryl-carbamoyl group, (xxiii) sulfo group, (xxiv) C _1-6
Alkylsulfonyl group, (xxv) (a) halogen atom,
(B) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) optionally halogenated C _{2- 6} alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) a halogen atom,
Hydroxy, carboxyl, C _1-6 alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl,
Amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, C ₁ optionally having mono- or di-C _1-6 alkylamino _-6 alkyl-sulfonamide, and 5 to 1 containing 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atom
A C _1-6 alkoxy optionally having a substituent selected from a 0-membered heterocyclic group or a benzo-fused ring group thereof, (j) an optionally halogenated C _1-6 alkylthio, and (k) hydroxy (1) amino, (m) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5-6
Membered cyclic amino, (p) C _1-6 alkyl-carbonyl,
(Q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C _1-6 alkyl-
Carbamoyl, (u) di-C _1-6 alkylcarbamoyl,
(V) _C6-10 aryl-carbamoyl, (w) sulfo,
(X) C _1-6 alkylsulfonyl, (y) C _6-10 aryloxy, (z) C _6-10 aryloxy, (aa) C _7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl,
(Dd) mono-C _1-6 alkyl-thiocarbamoyl, (e
e) di-C _1-6 alkyl-thiocarbamoyl, (ff) C
_6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl Good C _6-10 aryl groups, (xxvi) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C
_1-6 alkyl, (f) optionally halogenated C _2-6
Alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _1-6 alkoxy,
C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di- -C _1-6 C _1-6 alkyl optionally having alkylamino - sulfonamides, and nitrogen atom in addition to carbon atoms, 5 to containing three heteroatoms to 1 selected from oxygen atom and a sulfur atom A C _1-6 alkoxy optionally having a substituent selected from a 10-membered heterocyclic group or a benzo-fused ring group thereof, (j) an optionally halogenated C _1-6 alkylthio, and (k) hydroxy , (L) amino, (m) mono-C _1-6
Alkylamino, (n) di-C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl - carbamoyl, (u) di -C _1-6 alkylcarbamoyl, (v) C _6-10 aryl - carbamoyl,
(W) sulfo, (x) C _1-6 alkylsulfonyl, (y) C
_6-10 aryl, (z) C _6-10 aryloxy, (aa) C
_7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl,
(Ff) C _6-10 aryl-thiocarbamoyl, (gg) C
_7-16 aralkyl, (hh) a C _7-15 aralkyl group which may be substituted by (C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl, (xx
vii) (a) halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) halogenated _Optionally substituted C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _{1- 6} alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-
Carbonyl, amino, mono- - or di -C _1-6 alkylamino, mono- or di -C _1-6 alkyl - carbonyl amino, sulfonamido, mono - or may have a di -C _1-6 alkylamino Selected from C _1-6 alkyl-sulfonamides and 5- to 10-membered heterocyclic groups containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur other than carbon atoms or benzo-fused ring groups thereof C _1-6 alkoxy optionally having substituents, (j) C _1-6 alkylthio optionally halogenated, (k) hydroxy, (l) amino, (m) mono-C _{1- 6}
Alkylamino, (n) di-C _1-6 alkylamino,
(O) 5- or 6-membered cyclic amino, (p) C _1-6 alkyl-
Carbonyl, (q) carboxyl, (r) C _1-6 alkoxy-carbonyl, (s) carbamoyl, (t) mono-C
_1-6 alkyl - carbamoyl, (u) di -C _1-6 alkylcarbamoyl, (v) C _6-10 aryl - carbamoyl,
(W) sulfo, (x) C _1-6 alkylsulfonyl, (y) C
_6-10 aryl, (z) C _6-10 aryloxy, (aa) C
_7-16 aralkyloxy, (bb) oxo, (cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl,
(Ff) C _6-10 aryl-thiocarbamoyl, (gg) C
_7-16 aralkyl, (hh) a C _6-10 aryloxy group optionally substituted with (C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ii) carboxyl-C _1-6 alkyl,
(Xxviii) (a) a halogen atom, (b) C _1-3 alkylenedioxy, (c) nitro, (d) cyano, (e) optionally halogenated C _1-6 alkyl, (f) halogen _Optionally substituted C _2-6 alkenyl, (g) optionally halogenated C _2-6 alkynyl, (h) C _3-6 cycloalkyl, (i) halogen atom, hydroxy, carboxyl, C _{1 -6} alkoxy, C _1-6 alkoxy - carbonyl,
C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- or di-C _1-6 alkylamino A C _1-6 alkyl-sulfonamide which may have a nitrogen atom other than a carbon atom;
A 5- to 10-membered heterocyclic group containing 1 to 3 heteroatoms selected from an oxygen atom and a sulfur atom or an optionally substituted C-substituted group selected from benzo-fused ring groups thereof;
_1-6 alkoxy, (j) optionally halogenated C
_1-6 alkylthio, (k) hydroxy, (l) amino,
(M) mono-C _1-6 alkylamino, (n) di-C _1-6 alkylamino, (o) 5- or 6-membered cyclic amino, (p) C
_1-6 alkyl-carbonyl, (q) carboxyl, (r)
C _1-6 alkoxy-carbonyl, (s) carbamoyl,
(T) mono-C _1-6 alkyl-carbamoyl, (u) di-
C _1-6 alkylcarbamoyl, (v) C _6-10 aryl-carbamoyl, (w) sulfo, (x) C _1-6 alkylsulfonyl, (y) C _6-10 aryl, (z) C _6-10 aryl Oxy, (aa) C _7-16 aralkyloxy, (bb) oxo,
(Cc) thiocarbamoyl, (dd) mono-C _1-6 alkyl-thiocarbamoyl, (ee) di-C _1-6 alkyl-thiocarbamoyl, (ff) C _6-10 aryl-thiocarbamoyl, (gg) C _7-16 aralkyl, (hh) C _1-6 alkoxy - carbonyl -C _1-6 alkyl or (ii) carboxyl -C _1-6 alkyl optionally substituted C _7-16 aralkyloxy group, (xxix) Oxo group, (xxx) thiocarbamoyl group, (xxxi) mono-C _1-6 alkyl-thiocarbamoyl group, (xxxii) di-C _1-6 alkyl-thiocarbamoyl group, (xxxiii) C _6-10 aryl-thio A carbamoyl group, (xxxiv) C _6-10 aryl-carbonyloxy,
(Xxxv) (a) halogen atom, (b) optionally halogenated C _1-6 alkyl group, (c) optionally halogenated C _2-6 alkenyl, (d) halogenated _C2-6 alkynyl, (e) _C3-6 cycloalkyl,
(F) halogen atom, hydroxy, carboxyl, C _1-6
Alkoxy, C _1-6 alkoxy-carbonyl, C _1-6 alkyl-carbonyl, amino, mono- or di-C _1-6 alkylamino, mono- or di-C _1-6 alkyl-carbonylamino, sulfonamide, mono- Or di-C _1-6
C _1-6 alkyl-sulfonamide _{optionally having} alkylamino, and a 5- to 10-membered heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms C _1-6 alkoxy optionally having a substituent selected from the group or a benzo-fused ring group thereof, (g) C _1-6 alkylthio optionally halogenated, (h) hydroxy, (i) amino (J) mono-C _1-6 alkylamino, (k) di-C _1-6 alkylamino, (l) 5- or 6-membered cyclic amino, (m) C _1-6 alkyl-carbonyl, (n) carboxyl , (O) C _1-6 alkoxy-carbonyl, (p) carbamoyl, (q) mono-
C _1-6 alkyl-carbamoyl, (r) di-C _1-6 alkylcarbamoyl, (s) C _6-10 aryl-carbamoyl, (t) sulfo, (u) C _1-6 alkylsulfonyl,
(V) C _6-10 aryl, (w) C _6-10 aryloxy,
(X) C _7-16 aralkyloxy, (y) thiocarbamoyl, (z) mono-C _1-6 alkyl-thiocarbamoyl,
(Aa) di-C _1-6 alkyl-thiocarbamoyl, (bb)
_{Having a} C _6-10 aryl-thiocarbamoyl, (cc) C _7-16 aralkyl, (dd) C _1-6 alkoxy-carbonyl-C _1-6 alkyl or (ee) carboxyl-C _1-6 alkyl group. An aminocarbonyl, (xxxvi) a 5- or 6-membered heterocyclic group containing 1 to 4 one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom, (xxxvii ) C _1-6 alkoxy-carbonyl-C _1-6 alkoxy-carbonyl group, (xxxviii)
C _1-6 Arukikokishi - carbonyl -C _1-6 alkyl - carbamoyl group, (xxxix) hydroxy -C _1-6 alkyl - carbamoyl group, (xxxx) C _1-6 alkoxy - carbonyl - carbamoyl group, (xxxxi) C _{6 -14} arylsulfonamide, (xxxxii) C _1-6 alkylsulfonamide, (x
xxxiii) carboxy-C _1-6 alkyl-carbonyl-amino group, (xxxxiv) C _1-6 alkoxy-carbonyl-C
_1-6 alkyl-carbonyl-amino group, (xxxxv) C _1-6
Substituted with an alkyl-carbonyloxy-C _1-6 alkyl-carbonyl-amino group, a (xxxxvi) hydroxy-C _1-6 alkyl-carbonyl-amino group, and (xxxxvii) hydroxy or (and) C _1-6 alkoxy. A C _1-16 linear or cyclic hydrocarbon group which may have a substituent selected from the group consisting of an optionally substituted C _6-14 aryl-C _2-6 alkenyl-carbonylamide group]. Item 7. The compound according to Item 1. 3. The method according to claim 1, wherein the ring A is a benzene ring which may have a substituent, a pyridine ring which may have a substituent or a pyrazine ring which may have a substituent. Compound. 4. The compound according to claim 1, wherein Ar ¹ and Ar ² are each a phenyl group which may have a substituent. 5. The compound according to claim 1, wherein X is a bond or a C _1-6 alkylene group. 6. The compound according to claim 1, wherein Y is a C _1-6 alkylene group which may be substituted with a bond, an oxygen atom or a hydroxy group, and which may contain an oxygen atom in the alkylene chain. (7) ring B is a compound of the formula [In the formula, Z represents a nitrogen atom or a methine group, and Z ¹ and Z ² are the same or different, and each represents a straight-chain C _{1 which} may be substituted with a hydroxy group, an oxo group, or a C _1-6 alkyl group. _{-6 represents an} alkylene group. 2. The compound according to claim 1, which is a ring represented by the formula: (8) ring B is The compound according to claim 1, which is 9. The compound according to claim 1, wherein R ³ is a hydrogen atom or a hydroxy group. (10) ^one of R ¹ and R ² is a compound represented by the formula: (Wherein each symbol has the same meaning as described in claim 1), and the other group is a hydrogen atom, a cyano group, an optionally substituted C _1-6 alkyl group or a substituted 2. The compound according to claim 1, which represents a C _3-6 cycloalkyl group. 11. The method according to claim 11, wherein D and E are both oxygen atoms.
The compound according to 1. 12. A ring wherein (i) a halogen atom, (ii) a nitro group, (iii) a C _1-6 alkyl group optionally having carboxyl or C _1-6 alkoxy-carbonyl, (iv)
C _1-6 alkoxy group, (v) hydroxy group, (vi) amino group, (vii) mono- or di-C _1-6 alkylamino group,
(Viii) a carboxyl group, (ix) a C _1-6 alkoxy-carbonyl group, and (x) one to four heteroatoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. A 5- or 6-membered heterocyclic group, including (xi)
C _1-6 alkyl sulfonamide, (xii) carboxy-C
_1-6 alkyl-carbonyl-amino group, (xiii) C _1-6 alkoxy-carbonyl-C _1-6 alkyl-carbonyl-
An amino group, (xiv) a C _1-6 alkyl-carbonyl-oxy-C _1-6 alkyl-carbonyl-amino group and (xv)
C _6- which may have a substituent selected from the group consisting of C _6-14 aryl-C _2-6 alkenyl-carbonylamide group which may be substituted by hydroxy or (and) C _1-6 alkoxy; _{14 an} aryl ring, D and E each represent an oxygen atom, and ^one of R ¹ and R ² is a group represented by the formula: (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents X represents a C _1-6 alkylene group, Y represents a bond or an oxygen atom, and R ³ represents a hydrogen atom or a hydroxy group), the other being (1) a hydrogen atom, (2) Cyano group, (3) (i) halogen atom, (ii) carboxyl group, (iii) C _1-6 alkoxy-carbonyl group, (iv)
A 5- or 6-membered nitrogen-containing heterocyclic group, (v) having a substituent selected from C _7-15 aralkyl, carboxyl-C _1-6 alkyl and C _1-6 alkoxycarbonyl-C _1-6 alkyl. Carbamoyl group, (vi) C _6-14 aryl-carbonyloxy group, (vii) sulfamoyl group, (v
iii) Substitution selected from the group consisting of mono or di-C _1-6 alkyl-amino-methyleneaminosulfonyl group, (ix) C _1-6 alkoxy group optionally having carboxyl or carbamoyl and (x) cyano. A C _1-16 alkyl group optionally having a group, (4) a C _3-7 cycloalkyl group optionally having a carboxyl or C _1-6 alkoxycarbonyl, and (5) a C _6-14 aryl group The compound according to claim 1, which represents (6) an optionally substituted _C7-15 aralkyl group selected from _C1-6 alkoxy, carboxyl and _C1-6 alkoxy-carbonyl. (13) ring A is (i) a halogen atom or (ii)
A benzene ring which may have a C _1-6 alkyl which may be substituted with a C _1-6 alkoxy-carbonyl, D and E each represent an oxygen atom, and ^one of R ¹ and R ² has the formula Formula 10 (Wherein, Ar ¹ and Ar ^{2 each} represent a phenyl group, and ring B represents X represents a C _1-6 alkylene group, Y represents an oxygen atom, R ³ represents a hydrogen atom or a hydroxy group), and the other is (1) a hydrogen atom, (2) a cyano group, (3)
(I) a halogen atom, (ii) a C _1-6 alkoxy-carbonyl group, (iii) a carbamoyl group, (iv) a C _1-6 alkyl group which may have a substituent selected from the group consisting of cyano, (4) The compound according to claim 1, which represents a C _3-7 cycloalkyl group optionally having a C _1-6 alkoxycarbonyl. 14. A ring is a benzene ring which may have a halogen atom, D and E each represent an oxygen atom, R ¹ and R ²
Is one of the formulas (Wherein, Ar ¹ and Ar ² represent a phenyl group, and ring B represents X represents a C _1-6 alkylene group, Y represents an oxygen atom, and R ³ represents a hydrogen atom), and the other represents a C _1-6 alkyl group _optionally having carboxyl. 2. The compound of claim 1 wherein (15) 2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazoline-3-valeric acid or a salt thereof. (16) 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -1,2,3,4-tetrahydroquinazolin-3-yl] isobutyric acid or a salt thereof salt. 17. A method for producing 2- [2,4-dioxo-1- [4- (4-diphenylmethoxypiperidino) butyl] -6-fluoro-1,2,3,4-tetrahydroquinazolin-3-yl] Isobutyric acid or a salt thereof. 18. A compound of the formula [In the formula, Q ¹ represents a leaving group, and other symbols have the same meaning as in claim 1. And a salt thereof and a compound represented by the formula: [In the formula, Q ² represents a reactive group, R ² ′ represents a hydrogen atom, a cyano group or a hydrocarbon group which may have a substituent, and other symbols are as defined in claim 1. Is shown. ]
The method for producing a compound according to claim 1, wherein the compound is reacted with a compound represented by the formula: or a salt thereof. 19. A compound of the formula [Wherein the symbols have the same meanings as in claim 1]. Represented by] the compound or a salt thereof and Q ³ -CO-Q ⁴ compound according to claim 1, wherein the (Q ³ and Q ⁴ have each represents a leaving group) subjected to the allowed cyclization reaction Manufacturing method. [20] a pharmaceutical composition comprising the compound or a salt thereof according to the above [1]; 21. An antihistamine and / or eosinophil chemotactic inhibitor comprising the compound according to claim 1 or a salt thereof. 22. An antiallergic agent comprising the compound according to claim 1 or a salt thereof. (23) A prophylactic / therapeutic agent for asthma, allergic conjunctivitis, allergic rhinitis, urticaria or atopic dermatitis comprising the compound according to (1) or a salt thereof.