JP2000086659A - Octahydropyrido[1,2-alpha]pyrazine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having potent and sustainably excellent cell adhesion inhibitory activity and GPIIb/IIIa antagonism, and safely usable at low doses as a preventive/therapeutic agent for transient cerebral ischemia attack, unstable angina pectoris and the like. SOLUTION: This new compound (salt) is represented by formula I [R1 is a basic 5- to 7-membered N-contg. heterocyclic ring or an aryl carbonyl having a proton-accepting group or a group convertible thereto; R2 is H or a hydrocarbon; X is a lone pair or group of the formula X1-CH2CO (X1 is a lone pair, O or the like); Y is NH or O; Z is an alkylene; R5 is carboxyl], e.g. (2S)-3- 2-[(9 aR)-2-piperidin-4-ylmethyloctahydropyrido[1,2-a]pyrazin-8- yl]acetylamino}-2-(toluene-4-sulfonylamino)propionic acid. The compound of formula I is obtained using a compound of formula II as starting material and then through respective compounds of formula III and formula IV (R15 is a carboxyl-protecting group; denotes an asymmetric center), or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel octahydropyrido [1,2-a] pyrazine derivative or a salt thereof useful as a medicament, a GP IIb / IIIa antagonist containing the same as an active ingredient, a platelet aggregation inhibitor, The present invention relates to a pharmaceutical composition such as a cell adhesion inhibitor.

[0002]

2. Description of the Related Art Factors involved in the adhesion of animal cells to extracellular matrix include fibronectin, vitronectin, osteopontin, collagen, thrombospondin, fibrinogen and von Willebrand (von Vonbrand).
Willebrand) factors are known. These proteins contain the tripeptide -Arg-Gly-Asp- as a cell adhesion recognition site. This tripeptide is recognized by at least one protein belonging to the receptor integrin, a heterodimeric protein consisting of two membrane-bound subunits [Science, 238 , 491 (1987)]. ]. Integrin receptors that recognize the amino acid sequence -Arg-Gly-Asp- are known to be glycoproteins expressed on the extracellular surface of platelets, endothelial cells, leukocytes, lymphocytes, monocytes, and granulocytes. I have. Amino acid sequence-Arg
The compound having -Gly-Asp- competitively binds to the site to which the cell adhesion inhibitor binds,
Inhibits the binding of cell adhesion factors. As such a cell adhesion inhibitor, for example, H-Gly-Arg-Gl
y-Asp-Ser-Pro-OH is known. When a blood vessel is damaged, platelets are activated by collagen and the like under the blood vessel, binding of fibrinogen to platelets, that is, aggregation of platelets occurs, and a thrombus is formed. The interaction of platelets with fibrinogen occurs via GP IIb / IIIa, which is an important feature of platelet aggregation.

Cell adhesion inhibitory substances can inhibit platelet aggregation by platelet aggregation-inducing substances such as thrombin, epinephrine, ADP, collagen and the like, and are used for inhibiting metastasis of cancer cells (preventing adhesion and immobilization at the metastasis destination). It is also expected as a drug. As a conventionally known cell adhesion inhibitor, a linear peptide or a cyclic peptide containing an amino acid sequence of -Arg-Gly-Asp- (RGD) is known [Journal of Biological Chemistry (J. Biol. Chem.), 262 , 17294, (198
7), JP-A-2-174797, etc.]. JP-A-4-264
068 and EP-A-505868 disclose non-peptide compounds having an antithrombotic effect.
JP-A-5-97819 describes a pyridopyrazine derivative having a platelet aggregation inhibitory action.
07072 (WO94 / 18981) discloses a fused ring compound having a fibrinogen receptor antagonistic action. Today, drugs such as aspirin, heparin and ticlopidine used as antithrombotics are known to exhibit the undesirable side effect of prolonged bleeding time. JP-T-6-509551 discloses a cyclic peptide derivative as a platelet aggregation inhibitor having a small bleeding time prolonging effect.

[0004]

The above-mentioned known peptide derivatives are not sufficiently active in terms of activity, and their oral absorbability cannot be said to have obtained practically satisfactory results. In addition, these peptide derivatives are hydrolyzed by enzymes of aminopeptidase, carboxypeptidase, and various endopeptidases (for example, serine protease, etc.), and the stability of these enzymes in a solution or in vivo is insufficient. Thus, the solution has not been sufficiently solved for clinical application as a pharmaceutical. Further, among non-peptide compounds having an antithrombotic effect, compounds having stronger and more sustained activity than the above-mentioned known compounds having an antithrombotic effect have been demanded. Further, even in the conventionally known platelet aggregation inhibitor having a slight bleeding time prolonging effect, it cannot be said that the sustained action and oral absorbability are sufficient, and the compound exhibits a more sustained action and is orally administrable. Is required. An object of the present invention is to provide a compound having a stronger and more persistent cell adhesion inhibitory action at a lower dose than a conventionally known compound having an inhibitory action on cell adhesion.

[0005]

Means for Solving the Problems The present inventors have made intensive studies and as a result, have found that the octahydropyrido [1,2-a] pyrazine skeleton and its substituents have the formula (I) )

Embedded image (Wherein, R ¹ is (1) a 5- or 7-membered basic nitrogen-containing heterocyclic group which may be bonded via an optionally substituted alkylene group, may be substituted, or ( 2) an arylcarbonyl group which has a proton accepting group or a group which can be converted thereto and may further have a substituent, wherein R ² represents (1) a hydrogen atom or (2) a hydrocarbon which may be substituted; X represents (1) a bond or (2) a formula -X ¹ -CH ₂ CO- [X ¹ is a bond, -O-,
A group represented by -S- or an -NH-], Y is a -O- (1) -NH- or (2), Z is an alkylene group which may be substituted, R ⁵ is an ester A carboxyl group which may be amidated or amidated, respectively. ) Or a salt thereof (hereinafter referred to as compound (I)
For the first time), and found that these compounds have unexpectedly potent and long-lasting excellent cell adhesion inhibitory action and GP IIb / IIIa antagonistic action. The present invention has been completed.

That is, the present invention relates to (1) a compound (I); (2) R ¹ is a compound represented by the formula (1):-(CH ₂ ) _n -A A 5- to 7-membered nitrogen-containing heterocyclic group having the formula: n is an integer of 0 to 5), or (2) an alkyl group having an optionally substituted amino group, Selected from good amino groups, optionally substituted amidino groups, optionally substituted guanidino groups, optionally substituted amidoxime groups, optionally substituted oxadiazolyl groups and optionally substituted thiadiazolyl groups. (3) the compound according to (2), wherein A is a basic 6-membered nitrogen-containing heterocyclic group; and (4) R ² is hydrogen. Atom or optionally substituted Wherein an aralkyl group (1) The compound according; (5) X is a compound of -CH ₂ CO- in which said (1), wherein; (6) the Y is -NH- (1) compound described; (7) -ZR ⁵ is a group of the formula —CH ₂ —R ⁵ or —CHR ³
CHR ⁴ -R ⁵ (wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ represents a hydrogen atom or an optionally substituted amino group (8) the compound according to (7), wherein R ³ is a hydrogen atom; (9) the compound according to (7), wherein R ⁴ is substituted with a hydrogen atom or an acyl group. and an amino group (7) the compound according; (10) R ⁴ is formula -NH-SO ₂ -R ⁸ (wherein, even R ⁸ is is a hydrocarbon group or a substituted may be substituted A compound represented by the above (7), wherein R ⁵ is a group represented by the formula —CO—R ¹⁰ (wherein R ¹⁰ is a hydroxyl group,
(Indicating an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted aralkyloxy group or an optionally substituted amino group). (12) a compound described above;

Embedded image (Wherein A ^′ is an optionally substituted basic 5- to 7-membered nitrogen-containing heterocyclic group, n ′ is an integer of 0 to 3, R ^{2 ′} is a hydrogen atom or a substituted even aralkyl group, -Z'-R ^{5 'is} -CH ₂ -R ^5' or -CH
₂ CHR ^{4 ′} -R ^{5 ′} (wherein, R ^{4 ′} is a hydrogen atom or a formula —N
H-SO ₂ -R 8 are shown a group) represented by ^'(wherein, R ^8' represents a optionally substituted hydrocarbon group), R 5 ^'is an optionally esterified carboxyl (13) a compound of the above (12), wherein R ^{5 ′} is a carboxyl group or a C _1-6 alkoxy-carbonyl group; (14) a compound of the above (1). (15) a composition according to the above (14), which is a GP IIb / IIIa antagonist; and (16) a prophylactic / therapeutic agent for angina pectoris. (17) The composition according to (14); (17) the composition according to (1), which is an agent for preventing or treating unstable angina pectoris.
4) The composition according to the above; (18) Re-occlusion or restenosis of coronary artery after prophylactic or therapeutic agent for transient cerebral ischemic attack or percutaneous intracoronary angioplasty (PTCA) or after performing coronary thrombolytic therapy The composition according to (14), which is an agent for preventing or treating the onset;

[0007] The octahydropyrido [1,2-
a] The basic skeleton and numbering of the pyrazine derivative (I) are as follows.

Embedded image In the above formula (I), a “basic 5- to 7-membered nitrogen-containing heterocyclic group which may be bound via an optionally substituted alkylene group represented by R ¹ , Examples of the “basic 5- to 7-membered nitrogen-containing heterocyclic group” in the “cyclic group” include pyrrolyl (1-, 2- or 3
-Pyrrolyl), pyrazolyl (1-, 3- or 4-pyrazolyl), imidazolyl (1-, 2- or 4-imidazolyl), triazolyl (1,2,3-triazolyl, 1,2,
4-triazolyl), pyrrolidinyl (1-, 2- or 3
-Pyrrolidinyl), pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, thiazolyl (2-, 4- or 5-thiazolyl), isothiazolyl (3-, 4- or 5-isothiazolyl), thiadiazolyl (3- or 5- (1, 2,4-thiadiazolyl), 2
-Or 5- (1,3,4-thiadiazolyl), 4- or 5
-(1,2,3-thiadiazolyl), 3- or 4- (1,
2,5-thiadiazolyl)), oxazolyl (2-, 4
-Or 5-oxazolyl), isoxazolyl (3-,
4- or 5-isoxazolyl), oxadiazolyl (3- or 5- (1,2,4-oxadiazolyl), 1,
1 to 3 nitrogen atoms such as 3,4-oxadiazolyl)
5-membered heterocyclic group which may contain one or two heteroatoms selected from a sulfur atom and an oxygen atom in addition to a nitrogen atom and a carbon atom; for example, pyridyl (2-,
3- or 4-pyridyl), pyrimidinyl (2-, 4- or 5-pyrimidinyl), pyridazinyl (3- or 4-pyridazinyl), pyrazinyl, triazinyl (1,2,3)
-1,2,4- or 1,3,5-triazinyl), piperidyl (2-, 3- or 4-piperidyl), piperazinyl, pyridazinyl (3- or 4-pyridazinyl), pyrazinyl, thiazinyl (1,4 -Containing 1 to 3 nitrogen atoms, such as thiazinyl, 1,3-thiazinyl), thiomorpholinyl, morpholinyl, oxazinyl (1,2-, 1,3- or 1,4-oxazinyl), other than nitrogen and carbon atoms A 6-membered heterocyclic group optionally containing one or two heteroatoms selected from a sulfur atom, an oxygen atom and the like;
For example, azepinyl (1-, 2-, 3- or 4-azepinyl), diazepinyl (1-, 2-, 4- or 5- (1,
3-diazepinyl), 1-, 2- or 5- (1,4-diazepinyl)), oxazepinyl (1-, 2-, 4-,
5-, 6- or 7- (1,3-oxazepinyl), 1
-, 2-, 3-, 5-, 6- or 7- (1,4-oxazepinyl)), thiazepinyl (2-, 3-, 4-, 5)
-, 6- or 7- (1,3-thiazepinyl), 2-3
It contains 1 to 3 nitrogen atoms such as-, 4-, 5-, 6- or 7- (1,4-thiazepinyl)) and is selected from sulfur and oxygen atoms in addition to nitrogen and carbon atoms. A 7-membered heterocyclic group which may contain one or two hetero atoms is used.

Among them, a 6-membered heterocyclic group having basicity and containing 1 to 3 (preferably 1 or 2) nitrogen atoms (eg, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, piperidyl, piperazinyl,
Pyridazinyl, pyrazinyl, etc.), and more preferably pyridyl, pyrimidinyl, piperidyl, piperazinyl, etc., and piperidyl (preferably 4-piperidyl)
Is most preferred.

Such a heterocyclic group is substituted at a substitutable position,
For example, (1) C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), (2) C _2-6 alkenyl group (for example, vinyl, allyl, -Butenyl, 3-butenyl and the like),
(3) C _2-6 alkynyl group (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.), (4) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) C _3-8 cycloalkenyl group (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.), (6) C _7-12 aralkyl group (eg, phenyl-C _1-6 alkyl group such as benzyl, phenethyl, etc.), (7) C _6-10 aryl groups (eg, phenyl, naphthyl, etc.), (8) C _1-6 alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (9) a phenoxy group, (10) C _1-6 alkanoyl group (e.g. formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), (11) a benzoyl group, (12) C _1-6 alkanoyl Alkoxy group (e.g. formyloxy, acetyloxy, propionyloxy, butyryloxy, iso-butyryloxy, etc.), a benzoyloxy group, (13) carboxyl group,

(14) C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), (15) ) Carbamoyl, thiocarbamoyl, (16) N-mono-C
_1-6 alkylcarbamoyl group (e.g., N- methylcarbamoyl, N- ethylcarbamoyl, N- propylcarbamoyl, N- isopropylcarbamoyl, N- butylcarbamoyl, etc.), N- mono- -C _1-6 alkylthiocarbamoyl group, (17) N, N-di-C _1-6 alkylcarbamoyl groups (for example, N, N-dimethylcarbamoyl, N, N-diethylcarbamoyl, N, N-dipropylcarbamoyl,
N, N-dibutylcarbamoyl, etc.), N, N-di-C _1-6
Alkylthiocarbamoyl group, (18) cyclic aminocarbonyl group (for example, 1-aziridinylcarbonyl, 1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-
In addition to carbon atoms such as piperidinylcarbonyl, N-methylpiperazinylcarbonyl, thiomorpholinocarbonyl, morpholinocarbonyl and one nitrogen atom, 1 to 3 heteroatoms selected from oxygen, sulfur, nitrogen and the like. A 3- to 6-membered cyclic aminocarbonyl group optionally containing), (19) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (20) a halogeno-C _1-6 alkyl group (eg, chloromethyl, C _1-6 alkyl substituted with 1 to 3 halogens such as dichloromethyl, trifluoromethyl, trifluoroethyl and the like), (21) oxo group, (22) amidino group, (23) imino group, (24 ) Amino group, (25) mono-C
_1-6 alkylamino group (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (26) di -C _1-6 alkylamino group (e.g. dimethylamino, diethylamino, dipropylamino, diisopropylamino , Dibutylamino, etc.),

(27) 3- to 6-membered cyclic amino groups (eg aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, oxazolyl, imidazolyl, vilazolyl, imidazolidinyl, piperidino, thiomorpholino,
In addition to a carbon atom such as morpholino, dihydropyridyl, pyridyl, N-methylpiperazinyl, N-ethylpiperazinyl and one nitrogen atom, one or more heteroatoms selected from oxygen, sulfur, nitrogen, etc. (3 to 6-membered cyclic amino group optionally containing 3), (28) 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
A C _1-6 alkanoylamide group (eg, formamide, acetamide, trifluoroacetamide, propionylamide, butyrylamide, isobutyrylamide, etc.), (29) benzamide group, (30) carbamoylamino group Thiocarbamoylamino group, (31) NC
_1-6 alkylcarbamoylamino group (for example, N-methylcarbamoylamino, N-ethylcarbamoylamino,
N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), N—C _1-6 alkylthiocarbamoylamino group,
(32) N, N-di-C _1-6 alkylcarbamoylamino group (for example, N, N-dimethylcarbamoylamino, N, N-
Diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc., N, N-di-C _1-6 alkylthiocarbamoylamino group (33) C _1-3 alkylenedioxy group (for example, Methylenedioxy, ethylenedioxy, etc.), (34) sulfamoyl group,

(35) C _1-6 alkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N-propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl) Moir etc.), (36)
Di-C _1-6 alkylsulfamoyl group (eg, N, N-dimethylsulfamoyl, N, N-diethylsulfamoyl, N, N-dipropylsulfamoyl, N, N-dibutylsulfamoyl, etc.) , (37) C _1-6 alkylthio group (e.g., methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec- butylthio, tert- butylthio, etc.), (38) C _6-10 arylthio group (e.g., phenylthio), (39 ) C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), (40) C _6-10 arylsulfinyl group (eg, phenylsulfinyl, etc.), (41) C _1-6 alkylsulfonyl Groups such as methylsulfonyl, ethylsulfonyl, propylsulfonyl,
Butylsulfonyl and the like, and (42) a C _6-10 arylsulfonyl group (for example, phenylsulfonyl and the like) and may have 1 to 5 (preferably 1 to 2) substituents.

In the above-mentioned formula (I), the “optionally substituted, substituted or unsubstituted 5 to 7 basic alkylene group represented by R ¹ ,
Examples of the “alkylene group” in the “membered nitrogen-containing heterocyclic group” include linear C _1-6 alkylene (eg, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.) and the like. The alkylene group may be substituted (1) with a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (2) hydroxyl group, (3) oxo group, (4) C _1-6 alkoxy group (eg, methoxy , ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, etc.), (5) amino group, (6) C _1-6 alkylamino group (e.g. methylamino, ethylamino, propylamino, etc.) ,
(7) di-C _1-6 alkylamino group (for example, dimethylamino, diethylamino, dipropylamino, etc.), (8) C _1-6
Alkyl groups (eg, methyl, ethyl, propyl, etc.),
(9) a halogeno-C _1-6 alkyl group (for example, chloromethyl,
C _1-6 alkyl substituted with 1 to 3 halogens such as bromoethyl, trifluoroethyl, chloropropyl and the like; and (10) C _1-7 acyl group (for example, C _1-6 such as formyl, acetyl and propionyl). Alkanoyl, benzoyl and the like), (11) hydroxy-C _1-6 alkyl group (for example, hydroxymethyl, hydroxyethyl, hydroxypropyl and the like), (12) C _1-6 alkoxy-C _1-6 alkyl group (for example, methoxymethyl, 2-ethoxyethyl, etc.), and (13) C
_1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-
Butoxycarbonyl, etc.) and may have 1 to 5 (preferably 1 to 2) substituents.

As a "basic 5- to 7-membered nitrogen-containing heterocyclic group which may be bonded or may be substituted via an optionally substituted alkylene group" and is represented by R ^1. Is a group represented by the formula:-(CH ₂ ) _n -A, wherein n is an integer of 0 to 5 (preferably 0 to 3), and A is a 5- to 7-membered basic group which may be substituted And a nitrogen-containing heterocyclic group].

In the above formula (I), the "proton accepting group" in the "arylcarbonyl group having a proton accepting group or a group convertible thereto and optionally having a substituent" represented by R ¹ "" Means a group that receives a proton from a partner, that is, a Bronsted base, such as a group containing a positively chargeable nitrogen atom. Further, specific examples of the proton accepting group include an amino, amidino, or guanidino group which may be substituted, or an alkyl group having an amino group which may be substituted. Examples of the proton accepting group include (1) an unsubstituted amino, amidino or guanidino group,
(2) Secondary or tertiary substituted with C _1-4 alkyl, respectively
Grade amino, amidino or guanidino groups, (3) C _1-4
C having an amino group optionally substituted with alkyl
_1-4 alkyl and the like are preferred. Examples of the substituent of the amino, amidino or guanidino group which may be respectively substituted include: (1) a C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-
Butyl, pentyl, hexyl, etc.), C _2-6 alkenyl group (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, etc.), C _2-6 alkynyl group (eg, propargyl, ethynyl, butynyl, 1 -Hexyl, etc.), C _3-6 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl,
A C _6-14 aryl group (e.g., phenyl, tolyl, xylyl, 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl, etc.)
Particularly a phenyl group), a C _7-16 aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, triphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-naphthylmethyl,
Diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., especially a benzyl group)
(2) carbamoyloxy (eg, N, N-dimethylaminocarbonyloxy and the like) which may be substituted by 1 to 2 C _1-4 alkyls, and 1 to 2 the C _1-4 alkyl substituted optionally thio carbamoyloxy be, C _2-5 alkanoyloxy (e.g., pivaloyloxy, etc.) or a 5- to 6-membered Hajime Tamaki (e.g., 2- or 3-thienyl, 2
-Or 3-furyl, 1-, 2- or 3-pyrrolyl, 1
-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-
Oxazolyl, 2-, 4- or 5-thiazolyl, 3-,
Oxygen and sulfur atoms other than carbon atoms such as 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-tetrazolyl , A 5-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atoms and the like, for example, 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- -Or 5-pyrimidinyl, N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,
3-thiazinyl, piperazinyl, triazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3-
Or a 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon such as 4-pyridazinyl, preferably pyrrolidin-1-yl, morpholino and the like) It has been a C _1-4 alkyl group (e.g., methyl, etc.); (3) C _2-8 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, pentyloxycarbonyl,
(4) C _1-8 alkylaminocarbonyl (eg, n-hexylaminocarbonyl, n-octylaminocarbonyl, etc.); (5) C _2-8 alkoxycarbonyl Oxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy,
(6) a 5- or 6-membered heterocyclic group (for example, propoxycarbonyloxy, butoxycarbonyloxy, pentyloxycarbonyloxy, n-hexyloxycarbonyloxy, n-octyloxycarbonyloxy, etc., preferably methoxycarbonyloxy); 2- or 3-
Thienyl, 2- or 3-furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4-
Or 5-oxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5
-Imidazolyl, 1,2,3-triazolyl, 1,2,4-
5-membered ring groups containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon atoms such as triazolyl, 1H- or 2H-tetrazolyl, for example, 2
-, 3- or 4-pyridyl, N-oxide-2-, 3-
Or 4-pyridyl, 2-, 4- or 5-pyrimidinyl,
N-oxide-2-, 4- or 5-pyrimidinyl, thiomorpholinyl, morpholinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, 3- or 4 -Pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl and the like, in addition to carbon atoms, a 6-membered ring group containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen and the like, preferably Tetrahydrofuran-2-yl and the like). When two or more substituents on the amino, amidino or guanidino group are present, they may be bonded to each other to form a 5- or 6-membered heterocycle (pyrrolidine, piperidine, morpholine, imidazoline, etc.). Examples of the “optionally substituted amino group” in the “alkyl group having an optionally substituted amino group” include those similar to the “optionally substituted amino group” described above. The “alkyl group” in the above “alkyl group having an amino group which may be substituted” includes a C _1-6 alkyl group (for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl) -Butyl, pentyl,
Hexyl).

In the above formula (I), the “proton-accepting group” in the “arylcarbonyl group having a proton-accepting group or a group convertible thereto and optionally having a substituent” represented by R ¹ As the “convertible group”, a group capable of converting into a proton accepting group in a living body and accepting a physiologically active free proton is desirable. Examples of such a group include (1) an amidoxime group which may have a substituent on an oxygen atom [specific examples of the substituent include (a) lower (C
_1-4 ) alkyl (eg, methyl, ethyl, propyl, etc.), (b) acyl (eg, C _2-5 alkanoyl (eg, pivaloyl), benzoyl, etc.), (c) lower (C _1-4 ) alkoxy-carbonyl (Eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (d) lower (C _1-4 ) alkylthiocarbonyl (eg, methylthiocarbonyl, ethylthiocarbonyl, etc.), (e) acyloxycarbonyl (eg, C _2-5 alkanoyloxy Carbonyl (for example, pivaloyloxycarbonyl, etc.),
Benzoyloxycarbonyl, etc.), (f) optionally substituted C _6-12 aryloxycarbonyl (eg, phenoxycarbonyl) or C _7-14 aralkyloxycarbonyl (eg, benzyloxycarbonyl) (substituent Specific examples of cyano, nitro, amino, lower (C _1-4 ) alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.) and lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl Lower) (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.), mono- and di-lower (C _1-4 ) alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, etc.), hydroxy , amide or a lower (C _1-4) alkylthio (e.g. methylthio, ethyl Thio, etc.) and the like), (g) optionally C _6-12 aryl optionally having substituent -
Carbonyl group (for example, phenylcarbonyl) (specific examples of the substituent include lower (C _1-4 ) alkyl (for example, methyl, ethyl, propyl, etc.) and lower (C _1-4 ) alkenyl (for example, vinyl, allyl, etc.) Or lower (C _1-4 ) alkynyl (eg, ethynyl and the like) and the like, or
(h) an optionally substituted carbamoyl group or an optionally substituted thiocarbamoyl group (specific examples of the substituent include cyano, nitro, amino, lower (C _1-4 ) alkoxy-carbonyl (for example, methoxycarbonyl , Ethoxycarbonyl, propoxycarbonyl, etc.), lower (C
_1-4 ) alkyl (eg, methyl, ethyl, propyl, etc.), lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.), mono- and di-lower (C _1-4 ) alkylamino (eg, methylamino, Ethylamino, propylamino, dimethylamino and the like), hydroxy, amide and lower (C _1-4 ) alkylthio (for example, methylthio, ethylthio and the like) and the like), and (2) each having a substituent. An oxadiazolyl or thiadiazolyl group (here, as a substituent
(a) oxo, (b) thioxo, (c) hydroxy, (d) amino,
(e) mono- and di-lower (C _1-4 ) alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, etc.), (f) halogen (eg, fluorine, bromine, chlorine, etc.), (g) cyano, (h) azide, (i) lower (C _1-4 ) alkyl optionally substituted with halogen (eg, trifluoromethyl), (j) lower (C _1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.) ), (K) lower (C _1-4 ) alkylthio (eg methylthio, ethylthio, etc.), (l)
Lower (C _1-4 ) alkoxy-carbonyl (eg methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), (m) mono- or di-lower (C _1-4 ) alkylamino (eg methylamino, ethylamino, propylamino, dimethyl) Amino, etc.), (n) lower (C _1-4 ) alkylcarbamoyl or lower (C _1-4 ) alkylthiocarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), and (o) C ₆ optionally having a substituent. _-12 aryl group (for example, phenyl and the like) (specific examples of the substituent include cyano, nitro, amino, lower (C _1-4 ) alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and the like), lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, etc.), lower (C
_1-4 ) alkoxy (eg, methoxy, ethoxy, propoxy, etc.), mono- and di-lower (C _1-4 ) alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, etc.), hydroxy, amide or lower (C _1-4 ) alkylthio (eg, methylthio, ethylthio, etc.), or (p) C _7-14 aralkyl group (eg, benzyl, etc.) which may have a substituent (specific examples of the substituent) As cyano, nitro, amino, lower (C _1-4 ) alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), lower (C _1-4 ) alkyl (eg, methyl, ethyl, propyl, etc.), lower ( C _1-4) alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), mono- and di-lower (C _1-4) alkylamino (e.g. Chiruamino, ethylamino, propylamino, dimethylamino, etc.), hydroxy, amide or a lower (C _1-4) alkylthio (e.g. methylthio, ethylthio, etc.) and the like) and the like] and the like, the substituent Of the oxadiazolyl or thiadiazolyl groups which may be present, 1,2,4-oxadiazole-3 which may each have a substituent
-Yl or 1,2,4-thiadiazol-3-yl groups are preferred. When the substituent is oxo or thioxo, the substituent may be either keto or enol. C _6-12 aryloxycarbonyl or C _7-14 aralkyloxycarbonyl group which may have a substituent as a substituent of the amide oxime group or the oxadiazolyl or thiadiazolyl group, a carbamoyl group which may be substituted, Among the optionally substituted thiocarbamoyl groups, optionally substituted C _6-12 aryl groups and _optionally substituted C _7-14 aralkyl groups, cyano, nitro and lower Those substituted by (C _1-4 ) alkoxy-carbonyl or lower (C _1-4 ) alkoxy are preferred. Among the above-mentioned C _6-12 aryl-carbonyl groups which may have a substituent as a substituent of the amide oxime group, those substituted with a hydrogen atom or lower (C _1-4 ) alkyl are preferred.

More specifically, the groups which can be converted into proton-accepting groups are 5-oxo-1,2,4-oxadiazol-3-yl group and 5-oxo-1,2,4-thiadiazole-3. -Yl group, 5-thioxo-1,2,4-oxadiazol-3-yl group, 5-thioxo-1,2,4-thiadiazol-3-yl group, 4-methyl-5-oxo-1, Two,
4-oxadiazol-3-yl group, 4-ethyl-5-
Oxo-1,2,4-oxadiazol-3-yl group, 4
-Propyl-5-oxo-1,2,4-oxadiazol-3-yl group, 1,2,4-oxadiazol-3-yl group, 5-ethoxycarbonyl-1,2,4-oxadi Azol-3-yl group, 5-carbamoyl-1,2,4-oxadiazol-3-yl group, 5-thiocarbamoyl-
1,2,4-oxadiazol-3-yl group, 5-cyano-1,2,4-oxadiazol-3-yl group, 5-trifluoromethyl-1,2,4-oxadiazole- 3-yl group, 5-phenyl-1,2,4-oxadiazole-3
-Yl group, 5-amino-1,2,4-oxadiazole-
3-yl group, 5-propylamino-1,2,4-oxadiazol-3-yl group, 5-methylthio-1,2,4-oxadiazol-3-yl group, 5-azido-1, 2,4-
An oxadiazol-3-yl group, an amino (hydroxyimino) methyl group, an amino (methoxycarbonyloxyimino) methyl group, an amino (ethoxycarbonyloxyimino) methyl group, an amino (n-propyloxycarbonyloxyimino) methyl group, Amino (benzyloxycarbonyloxyimino) methyl group, amino (p-nitrobenzyloxycarbonyloxyimino) methyl group, amino (p-nitrophenyloxycarbonyloxyimino) methyl group, amino (p-nitrobenzoyloxycarbonyloxyimino) Methyl group, amino (methoxyimino) methyl group, amino (carbamoyloxyimino)
Methyl group, amino (thiocarbamoyloxyimino) methyl group, amino (methylcarbamoyloxyimino) methyl group, amino (methylthiocarbamoyloxyimino) methyl group, amino (ethylcarbamoyloxyimino) methyl group, amino (n-propylcarbamoyloxy) Examples thereof include an imino) methyl group and an amino (n-butylcarbamoyloxyimino) methyl group.

Above all, a 5-oxo-1,2,4-oxadiazol-3-yl group, a 5-oxo-1,2,4-thiadiazol-3-yl group, a 5-ethoxycarbonyl-1,2,
4-oxadiazol-3-yl group, 5-cyano-1,
2,4-oxadiazol-3-yl group, 5-trifluoromethyl-1,2,4-oxadiazol-3-yl group, amino (methoxycarbonyloxyimino) methyl group, amino (carbamoyloxyimino) A methyl group, an amino (methylcarbamoyloxyimino) methyl group, and an amino (ethylcarbamoyloxyimino) methyl group are preferred. In the formula (I), the “arylcarbonyl group having a proton-accepting group or a group that can be converted thereto and optionally having a substituent” represented by R ¹ can be converted into a proton-accepting group. Compound (I) or a salt thereof, which is an "arylcarbonyl group optionally having a substituent having a group" or a salt thereof, is advantageously used as an oral preparation.

In the above formula (I), the “proton accepting group or an arylcarbonyl group having a group convertible thereto and optionally having a substituent” represented by R ¹ is referred to as “proton accepting group or Examples of the substituent which may be further contained in addition to the “group convertible to” include, for example, (1) a C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, etc.), (2) C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (3) C _2-6 alkenyl group (eg, vinyl, allyl,
2-butenyl, 3-butenyl, etc.), (4) C _2-6 alkynyl group (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.), (5) C _3-8 cycloalkenyl group (eg, cyclopropenyl, cyclopentenyl) , Cyclohexenyl, etc.),
(6) C _6-10 aryl group (for example, phenyl, naphthyl and the like), (7) C _7-12 aralkyl group (for example, phenyl-C _1-6 alkyl such as benzyl and phenethyl), (8) nitro group, (8) 9) oxo group, (10) thioxo group, (11) cyano group, (1
2) carbamoyl group, thiocarbamoyl group, (13) carboxyl group, (14) _C1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- Butoxycarbonyl, tert-butoxycarbonyl, etc.), (15) sulfo group, (16) halogen atom (eg, fluorine, chlorine, bromine, iodine), (17) C _1-4 alkoxy group (eg, methoxy, ethoxy, propoxy, iso Propoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (19)
C _6-10 aryloxy group (for example, phenoxy and the like), (20)
C _1-6 alkylthio groups (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, se
c-butylthio, tert-butylthio, etc.), (21) C _6-10 arylthio group (eg, phenylthio), (22) C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.) (23) a C _6-10 arylsulfinyl group (eg, phenylsulfinyl), (24) a C _1-6 alkylsulfonyl group (eg, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), (25)
C _6-10 arylsulfonyl group (eg, phenylsulfonyl), (26) amino group, (27) acylamino group (eg, C _1-6 alkanoylamino, benzoylamino of acetylamino, propionylamino, etc.), (28) mono- Or di
A C _1-6 alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, etc.);
_3-8 cycloalkylamino group (for example, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, etc.), (30) C _6-10 arylamino group (for example, anilino), (31) C _1-6 acyl group (e.g. formyl, acetyl, C _1-6 alkanoyl propionyl, etc.), (32) C _6-10 aryl - carbonyl group (e.g., benzoyl, etc.), and (33) a nitrogen atom in addition to carbon atom, a sulfur atom and an oxygen atom 5- or 6-membered heterocyclic group containing 1 to 3 heteroatoms selected from, for example, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl,
Pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, furyl, oxazolyl, isoxazolyl, oxadiazolyl, pyridyl,
Pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, piperidyl, piperazinyl, pyridazinyl, pyrazinyl, thiazinyl, thiomorpholinyl, morpholinyl,
1 to 5 selected from pyranyl, oxazinyl, etc.)
(Preferably 1 or 2) substituents, for example, arylcarbonyl having a proton-accepting group represented by R ¹ or a group capable of being converted thereto and further optionally having a substituent. As the "group", an arylcarbonyl group having no further substituent other than the "proton accepting group or a group capable of being converted to the proton accepting group" is preferable.

In the above formula (I), the "arylcarbonyl group" in the "arylcarbonyl group having a proton-accepting group or a group convertible thereto and optionally having a substituent" represented by R ¹ Is a C _6-14 aryl-
Carbonyl groups (eg, phenyl, tolyl, xylyl,
A group in which 1-naphthyl, 2-naphthyl, biphenyl, 2-indenyl, 2-anthryl and the like are bonded to a carbonyl group)
Among them, a C _6-10 aryl-carbonyl group is preferable, and a benzoyl group is particularly preferable.
As R ¹ , (1) a formula — (CH ₂ ) _n —A ( _where A is an optionally substituted basic 5- to 7-membered nitrogen-containing heterocyclic group (preferably basic A 5- to 7-membered nitrogen-containing heterocyclic group, more preferably a basic 6-membered nitrogen-containing heterocyclic group), and n is an integer of 0 to 5 (preferably an integer of 0 to 3). Group or (2)
An alkyl group having an amino group which may be substituted, an amino group which may be substituted, an amidino group which may be substituted, a guanidino group which may be substituted, an amidoxime group which may be substituted, And a benzoyl group having a substituent selected from an optionally substituted oxadiazolyl group and an optionally substituted thiadiazolyl group.

In the above formula (I), the “hydrocarbon group” in the “optionally substituted hydrocarbon group” represented by R ² includes, for example, (1) a C _1-10 alkyl group (for example, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), preferably a C _1-6 alkyl group; (2) a C _2-10 alkenyl group (for example, vinyl, allyl,
- methallyl, 3-methallyl, 2-butenyl, 3-butenyl, 3-octenyl, etc.), preferably C _2-6 alkenyl groups; (3) C _2-10 alkynyl groups (e.g. ethynyl, 2-propynyl, 3-hexynyl , 1-octenyl, etc.), preferably a C _2-6 alkynyl group; (4) a C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .; (5) a C _3-8 cycloalkenyl group (eg, (6) a C _6-18 aryl group (eg, phenyl, tolyl, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.);
Xylyl, 1-naphthyl, 2-naphthyl, biphenyl,
2-indenyl, 2-anthryl, phenanthryl and the like), preferably a C _6-10 aryl group (for example, phenyl,
(7) a _C7-16 aralkyl group (for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,
Diphenylmethyl, o-, m- or p-methylbenzyl, o-, m- or p-ethylbenzyl, o-, m-
Or p-isopropylbenzyl, o-, m- or p
-Tert-butylbenzyl, 2,3-, 2,4-, 2,5
-, 2,6-, 3,4- or 3,5-dimethylbenzyl, 2,3,4-, 3,4,5- or 2,4,6-trimethylbenzyl, 5-isopropyl-2-methylbenzyl ,
2-isopropyl-5-methylbenzyl, 2-methyl-
5-tert-butylbenzyl, 2,4-, 2,5- or 3,5-diisopropylbenzyl, 3,5-di-tert-butylbenzyl, 1- (2-methylphenyl) ethyl, 1-
(3-methylphenyl) ethyl, 1- (4-methylphenyl) ethyl, 1- (2-isopropylphenyl) ethyl,
1- (3-isopropylphenyl) ethyl, 1- (4-isopropylphenyl) ethyl, 1- (2-tert-butylphenyl) ethyl, 1- (4-tert-butylphenyl) ethyl, 1- (2-isopropyl -4-methylphenyl) ethyl, 1- (4-isopropyl-2-methylphenyl) ethyl, 1- (2,4-dimethylphenyl) ethyl, 1- (2,
5-dimethylphenyl) ethyl, 1- (3,5-dimethylphenyl) ethyl, 1- (3,5-di-tert-butylphenyl) ethyl and the like), preferably a C _7-12 aralkyl group (eg, benzyl, phenethyl) Phenyl-C _1-6 alkyl).

The above-mentioned (1) C _1-10 alkyl group, (2)
A C _2-10 alkenyl group, (3) a C _2-10 alkynyl group,
(4) C _3-8 cycloalkyl group and (5) C _3-8 cycloalkenyl group may be, for example,
(1) (a) hydroxy, (b) amino, (c) mono- or di-
C _1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.), (d) C _1-6 alkoxy (e.g.,
Substituents 1 selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, etc.) and (e) halogen (eg, fluorine, chlorine, bromine, iodine, etc.) _{Or a} C _1-6 alkyl group _optionally substituted with 4 to 4 (eg, methyl, ethyl, propyl, etc.), (2) 1 to 2
Amino groups which may be substituted with one C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.); (3) C _1-7 acylamino groups (eg, formylamino, acetylamino, propionylamino, etc.) C _1-6 alkanoylamino, benziminoyl, etc.), (4) hydroxy group, (5) carboxyl group, (6) nitro group, (7) C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, iso propoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, etc.), (8) C _1-6 alkyl - carbonyl group (e.g., acetoxy, ethyl carbonyloxy, etc.), (9) C _1-7 acyl group (e.g. , Formyl, acetyl, propionyl, etc.
_1-6 alkanoyl, benzoyl, etc.), (10) C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxy) Carbonyl), and (11) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), and (12) an oxo group, etc., and 1 to 5 (preferably 1 to 2) substituents. You may have.

The above-mentioned (6) aryl group and (7) aralkyl group may be, for example, (1) (a) hydroxy, (b) amino, (c) mono- or di-C _{1-6 at} substitutable positions. Alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.), (d) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec) -Butoxy, tert-butoxy, hexyloxy, etc.) and (e) C _1-6 optionally substituted with 1 to 4 substituents selected from halogens (eg, fluorine, chlorine, bromine, iodine, etc.). Alkyl groups (eg, methyl,
(2) an amino group optionally substituted with one or two C _1-6 alkyl groups (eg, methyl, ethyl, propyl, etc.), (3) a C _1-7 acylamino group ( For example, C _1-6 alkanoylamino such as formylamino, acetylamino, propionylamino, benziminoyl, etc.), (4) hydroxy group, (5) carboxyl group, (6) nitro group, (7) C _1-6 Alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (8) C _1-6
Alkyl-carbonyloxy group (eg, acetoxy, ethylcarbonyloxy, etc.), (9) C _1-7 acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl, benzoyl, etc.), (10) C _{1 -6} alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, se
c-butoxycarbonyl, tert-butoxycarbonyl, etc.) and (11) 1 to 5 (preferably 1 to 2) substituents selected from halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) You may have.

[0024] As R ² is aralkyl group is preferably be a hydrogen atom or a substituent, inter alia, preferably a hydrogen atom or an optionally substituted C _7-12 aralkyl group, especially, a hydrogen atom or a C ₁ Preferred is phenyl-C _1-6 alkyl optionally substituted with a _-6 alkoxy group.

In the above formula (I), X represents a (1) bond or (2) a formula —X ¹ —CH ₂ CO— [X ¹ represents a bond, —O—,
-S- or -NH-], in which -X ¹ -CH ₂ CO- [X ¹ is a bond, -O
-, -S- or -NH- (preferably a bond)]. In the above formula (I), Y represents (1) -NH- or (2) -O-, and among them,
-NH- is preferred. Further, the compound in which Y is -O- is also useful as a synthetic intermediate for the compound in which Y is -NH-. In the above formula (I), the group represented by the formula -XYZR ⁵ is a group represented by the formula

Embedded image ^May be substituted at any of the 6- to 9-positions in the octahydropyrido [1,2-a] pyrazine skeleton represented by the formula: -XYZR5 When the group is substituted at the 8-position of the octahydropyrido [1,2-a] pyrazine skeleton, the compound (I) has the formula

Embedded image It is preferable to have a structure represented by X and Y
A preferable combination with is, for example, a compound represented by the formula -XY
A group represented by -Z- is the formula _{^{-X 1 -CH 2 CO-NH-}} Z
— (X ¹ represents a bond, —O—, —S— or —NH— (preferably a bond)) or a group represented by the formula —O—Z—.

In the above formula (I), Z represents an alkylene group which may be substituted. Examples of the “alkylene group” in the “optionally substituted alkylene group” represented by Z include linear C _1-6 alkylene (eg, methylene, dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, etc.) And the like, and among them, linear C _1-3 alkylene is preferable.
Methylene, dimethylene and the like are preferred. These alkylene groups may be substituted (1) halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (2) hydroxyl group, (3)
Oxo group, (4) C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (5) optionally substituted amino group, 6) an optionally substituted hydrocarbon group, (7) an optionally substituted heterocyclic group, (8)
A C _1-7 acyl group (for example, C _1-6 alkanoyl such as formyl, acetyl, propionyl, benzoyl, etc.), and (9)
C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert
-Butoxycarbonyl, etc.) and may have 1 to 5 (preferably 1 to 2) substituents.

The "optionally substituted heterocyclic group" as a substituent in the "optionally substituted alkylene group" for Z is, for example, 2- or 3-thienyl, 2- or 3 -Furyl, 1-, 2- or 3-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, 2-, 4- or 5-oxazolyl, 2-, 4- or 5-thiazolyl,
2-, 4- or 5-isoxazolyl, 2-, 4- or 5
-Isothiazolyl, 3- or 5- (1,2,4-oxadiazolyl), 1,3,4-oxadiazolyl, 3- or 5
-(1,2,4-thiadiazolyl), 1,3,4-thiadiazolyl, 4- or 5- (1,2,3-thiadiazolyl), 1,
2,5-thiadiazolyl, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H- or 2H-
In addition to carbon atoms such as tetrazolyl, oxygen atoms, sulfur atoms,
5-membered ring group containing 1 to 4 heteroatoms selected from nitrogen atoms and the like; for example, 2-, 3- or 4-pyridyl, N-oxide-2-, 3- or 4-pyridyl, 2-, 4- Or 5-pyrimidinyl, N-oxide-2-, 4- or 5-
Pyrimidinyl, thiomorpholinyl, morpholinyl, oxoimidazinyl, dioxotriazinyl, pyrrolidinyl, piperidinyl, pyranyl, thiopyranyl, 1,4-
Oxygen atoms other than carbon atoms such as oxazinyl, 1,4-thiazinyl, 1,3-thiazinyl, piperazinyl, triazinyl, oxotriazinyl, 3- or 4-pyridazinyl, pyrazinyl, N-oxide-3- or 4-pyridazinyl , A 6-membered ring group containing 1 to 4 heteroatoms selected from a sulfur atom, a nitrogen atom and the like; benzofuryl, benzothiazolyl, benzoxazolyl, tetrazolo [1,5-
b] pyridazinyl, triazolo [4,5-b] pyridazinyl, benzimidazolyl, quinolyl, isoquinolyl,
Cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, indolizinyl, quinolidinyl, 1,8-naphthyridinyl, prenyl, pteridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenanthridinyl, chromanyl, benzoxazinyl, phenazinyl,
A bicyclic or tricyclic fused ring group containing 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom, a nitrogen atom and the like in addition to carbon atoms such as phenothiazinyl and phenoxazinyl (preferably the 5-membered ring group Or a condensed ring group consisting of a 6-membered ring group and a benzene ring, or a condensed ring group composed of any two of the above-mentioned 5-membered or 6-membered ring groups).

Such a heterocyclic group may be, for example, a (1) C _1-6 alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, etc.), (2) _C2-6 alkenyl group (for example, vinyl, 1-methylvinyl, 1-propenyl,
(3) a _C2-6 alkynyl group (for example, ethynyl, 1-propynyl, 2-propynyl, propargyl, 3-hexynyl, etc.), (4) C
_3-8 cycloalkyl group (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) C
_3-8 cycloalkenyl group (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.), (6) C _6-10 aryl group (eg, phenyl, naphthyl, etc.), (7) C _7-12
Aralkyl groups (eg benzyl, α-methylbenzyl,
Phenyl-C _1-6 alkyl such as phenethyl), (8) C
_1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-
Butoxy, tert-butoxy, etc.), (9) phenoxy group, (1
0) C _1-6 alkanoyl group (eg, formyl, acetyl, propionyl, butyryl, isobutyryl, etc.), (11) benzoyl group, (12) C _1-6 alkanoyloxy group (eg, formyloxy, acetyloxy, propionyloxy) , Butyryloxy, isobutyryloxy, etc.), (13) benzoyloxy group, (14) carboxyl group, (15) _C1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxy Carbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), (16) carbamoyl group, thiocarbamoyl group,
(17) N-C _1-6 alkylcarbamoylamino group (for example, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), NC _1-6 alkylthiocarbamoyl amino group, (18) N, N- di -C _1-6 alkylcarbamoyl group (e.g. N, N-dimethylcarbamoylamino, N,
N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), N, N-di-C _1-6 alkylthiocarbamoylamino group, (19) cyclic aminocarbonyl group (for example, 1 -Acetylidinylcarbonyl, 1-aziridinylcarbonyl,
1-azetidinylcarbonyl, 1-pyrrolidinylcarbonyl, 1-piperidinylcarbonyl, N-methylpiperazinylcarbonyl, thiomorpholinocarbonyl, morpholinocarbonyl and other carbon atoms and an oxygen atom other than one nitrogen atom, A 3- to 6-membered cyclic aminocarbonyl group which may contain 1 to 3 hetero atoms selected from a sulfur atom, a nitrogen atom, etc.), (20) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), (21) halogeno-C _1-6 alkyl group (for example, C _1-6 alkyl substituted with 1 to 3 halogens such as chloromethyl, dichloromethyl, trifluoromethyl, trifluoroethyl and the like), (22) oxo Group, (23) amidino group, (24) imino group, (25) amino group,
(26) mono--C _1-6 alkylamino group (e.g. methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.), (27) di -C _1-6 alkylamino group (e.g. dimethylamino, diethylamino, Dipropylamino, diisopropylamino, dibutylamino, etc.), (28) a 3- to 6-membered cyclic amino group (for example, acetylidinyl, aziridinyl, azetidinyl, pyrrolidinyl,
Pyrrolinyl, pyrrolyl, oxazolyl, imidazolyl,
Pyrazolyl, imidazolidinyl, piperidino, thiomorpholino, morpholino, dihydropyridyl, pyridyl, N
May contain 1 to 3 heteroatoms selected from oxygen, sulfur, nitrogen and the like in addition to carbon and one nitrogen such as -methylpiperazinyl and N-ethylpiperazinyl3 (29) a C _1-6 alkanoylamide group (for example, formamide, acetamide, etc.) which may be substituted with 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) Trifluoroacetamide, propionylamide, butyrylamide,
Isobutyrylamide), (30) benzamide group, (31) carbamoylamino group, (32) thiocarbamoylamino group,
(33) N-C _1-6 alkylcarbamoylamino group (for example, N-methylcarbamoylamino, N-ethylcarbamoylamino, N-propylcarbamoylamino, N-isopropylcarbamoylamino, N-butylcarbamoylamino, etc.), NC _1-6 alkylthiocarbamoyl amino group, (34) N, N- di -C _1-6 alkylcarbamoyl group (e.g. N, N-dimethylcarbamoylamino, N,
N-diethylcarbamoylamino, N, N-dipropylcarbamoylamino, N, N-dibutylcarbamoylamino, etc.), N, N-di-C _1-6 alkylthiocarbamoylamino group, (35) C _1-3 alkylenedioxy Groups (eg, methylenedioxy, ethylenedioxy, etc.), (36) hydroxy group, (37) epoxy group, (38) nitro group, (39) cyano group,
(40) mercapto group, (41) sulfo group, (42) sulfino group,
(43) phosphono group, (44) dihydroxyboryl group, (45) sulfamoyl group, (46) C _1-6 alkylsulfamoyl group (for example, N-methylsulfamoyl, N-ethylsulfamoyl, N- Propylsulfamoyl, N-isopropylsulfamoyl, N-butylsulfamoyl, etc.),
(47) di-C _1-6 alkylsulfamoyl group (for example, N, N
- dimethylsulfamoyl, N, N-diethyl sulfamoyl, N, N-dipropyl sulfamoyl, N, N-dibutylsulfamoyl etc.), (48) C _1-6 alkylthio group (e.g., methylthio, ethylthio, Propylthio, isopropylthio, butylthio, sec-butylthio, tert-
Butylthio, etc.), (49) C _6-10 arylthio group (eg, phenylthio, etc.), (50) C _1-6 alkylsulfinyl group (eg, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, etc.), (51) C
_6-10 arylsulfinyl group (e.g. phenylsulfinyl etc.), (52) C _1-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, etc.), and (53) C _6-10 arylsulfonyl group (For example, phenylsulfonyl and the like) and may have 1 to 5 (preferably 1 to 2) substituents.

Examples of the “hydrocarbon group” in the “optionally substituted hydrocarbon group” as a substituent in the “optionally substituted alkylene group” represented by Z include (1) C _{1- A 10} alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), preferably a C _1-6 alkyl group; (2) a C _2-10 alkenyl group (eg, vinyl, allyl) , 2
- methallyl, 3-methallyl, 2-butenyl, 3-butenyl, 3-octenyl, etc.), preferably C _2-6 alkenyl groups; (3) C _2-10 alkynyl groups (e.g. ethynyl, 2-propynyl, 3-hexynyl , 1-octenyl, etc.), preferably a C _2-6 alkynyl group; (4) a C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc .; (5) a C _3-8 cycloalkenyl group (eg, (6) a C _6-18 aryl group (eg, phenyl, tolyl, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.);
Xylyl, 1-naphthyl, 2-naphthyl, biphenyl,
2-indenyl, 2-anthryl, phenanthryl and the like), preferably a C _6-10 aryl group (for example, phenyl,
(7) a _C7-16 aralkyl group (for example, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl,
Diphenylmethyl, o-, m- or p-methylbenzyl, o-, m- or p-ethylbenzyl, o-, m-
Or p-isopropylbenzyl, o-, m- or p
-Tert-butylbenzyl, 2,3-, 2,4-, 2,5
-, 2,6-, 3,4- or 3,5-dimethylbenzyl, 2,3,4-, 3,4,5- or 2,4,6-trimethylbenzyl, 5-isopropyl-2-methylbenzyl ,
2-isopropyl-5-methylbenzyl, 2-methyl-
5-tert-butylbenzyl, 2,4-, 2,5- or 3,5-diisopropylbenzyl, 3,5-di-tert-butylbenzyl, 1- (2-methylphenyl) ethyl, 1-
(3-methylphenyl) ethyl, 1- (4-methylphenyl) ethyl, 1- (2-isopropylphenyl) ethyl,
1- (3-isopropylphenyl) ethyl, 1- (4-isopropylphenyl) ethyl, 1- (2-tert-butylphenyl) ethyl, 1- (4-tert-butylphenyl) ethyl, 1- (2-isopropyl -4-methylphenyl) ethyl, 1- (4-isopropyl-2-methylphenyl) ethyl, 1- (2,4-dimethylphenyl) ethyl, 1- (2,
5-dimethylphenyl) ethyl, 1- (3,5-dimethylphenyl) ethyl, 1- (3,5-di-tert-butylphenyl) ethyl and the like), preferably a C _7-12 aralkyl group (eg, benzyl, phenethyl) Phenyl-C _1-6 alkyl).

The above-mentioned (1) C _1-10 alkyl group, (2)
A C _2-10 alkenyl group, (3) a C _2-10 alkynyl group,
(4) C _3-8 cycloalkyl group and (5) C _3-8 cycloalkenyl group may be, for example,
(1) (a) hydroxy, (b) amino, (c) mono- or di-
C _1-6 alkylamino (e.g., methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.), (d) C _1-6 alkoxy (e.g.,
Substituents 1 selected from methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, hexyloxy, etc.) and (e) halogen (eg, fluorine, chlorine, bromine, iodine, etc.) C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.) which may be substituted with 1 to 4 (2) 1 to 2 C _1-6 alkyl groups (eg, methyl, ethyl, propyl, etc.) )), (3) C _1-7 acylamino group (eg, C _1-6 alkanoylamino such as formylamino, acetylamino, propionylamino, benzoiminoyl, etc.), (4) hydroxy Group, (5) carboxyl group, (6) nitro group, (7) _C1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert -Butoxy, etc.), (8) C _1-6 alkyl-carbonyloxy group (eg, acetoxy, ethylcarbonyloxy, etc.), (9) C _1-7 acyl group (eg, formyl, acetyl, propionyl, etc.
_1-6 alkanoyl, benzoyl, etc.), (10) C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxy) Carbonyl, etc.), (11) halogen atom (for example, fluorine, chlorine,
Having 1 to 5 (preferably 1 to 2) substituents selected from bromine, iodine, etc.), (12) an oxo group, and (13) an optionally substituted heterocyclic group. Is also good.
As a specific example of the (13) optionally substituted heterocyclic group, the "optionally substituted heterocyclic group" as a substituent in the "optionally substituted alkylene group" represented by Z And the like.

The above-mentioned (6) aryl group and (7) aralkyl group may be, for example, (1) (a) hydroxy, (b) amino, (c) mono- or di-C _{1-6 at} substitutable positions. Alkylamino (eg, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, dipropylamino, etc.), (d) C _1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec) -Butoxy, tert-butoxy, hexyloxy, etc.) and (e) C _1-6 optionally substituted with 1 to 4 substituents selected from halogens (eg, fluorine, chlorine, bromine, iodine, etc.). An alkyl group (eg, methyl, ethyl, propyl, etc.), (2) an amino group optionally substituted by one or two C _1-6 alkyl groups (eg, methyl, ethyl, propyl, etc.), (3) C _1-7 acylami Groups (eg, C _1-6 alkanoylamino such as formylamino, acetylamino, propionylamino, benzoiminoyl, etc.), (4)
Hydroxy group, (5) carboxyl group, (6) nitro group, (7)
C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec
-Butoxy, tert-butoxy, etc.), (8) C _1-6 alkyl-
Carbonyloxy group (eg, acetoxy, ethylcarbonyloxy, etc.), (9) C _1-7 acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, propionyl, benzoyl, etc.), (10) C _1-6 Alkoxy-carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), and (11) halogen atoms (e.g., fluorine, chlorine, 1 to 5 (preferably 1 to 2) selected from bromine, iodine, etc.)
May have a substituent.

The “optionally substituted amino group” as a substituent in the “optionally substituted alkylene group” for Z is selected from an optionally substituted hydrocarbon group and an acyl group. And an amino group which may have one or two substituents. A "optionally substituted hydrocarbon group" which may be possessed by a "optionally substituted amino group" as a substituent in the "optionally substituted alkylene group" represented by Z As examples of the “hydrocarbon group” in “), (1) C _1-6
Alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.), (2) C _2-6 alkenyl group (eg, vinyl, allyl, 2-butenyl, 3-butenyl, etc.) (3) _C2-6 alkynyl group (eg, ethynyl, 2-propynyl, 3-hexynyl, etc.), (4) _C3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), (5) A C _3-8 cycloalkenyl group (eg, cyclopropenyl, cyclopentenyl, cyclohexenyl, etc.),
(6) C _6-10 aryl group (for example, phenyl, naphthyl, etc.), (7) C _7-12 aralkyl group (for example, phenyl-C _1-6 alkyl such as benzyl, phenethyl and the like) and the like are used.

Such a hydrocarbon group may be substituted at a substitutable position, for example, (1) a nitro group, (2) a hydroxyl group, (3) an oxo group, (4)
Thioxo group, (5) cyano group, (6) carbamoyl group, a thiocarbamoyl group, (7) carboxyl group, (8) C _1-6 alkoxy - carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , Butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), (9) halogen atom (for example, fluorine, chlorine,
Bromine, iodine, etc.), (10) C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc.), (11) phenoxy group, (12) halogeno Phenoxy groups (eg, o-, m- or p-chlorophenoxy, o-,
(13) a C _1-6 alkylthio group (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, tert-butylthio, etc.), a phenoxy substituted with 1 to 3 halogens such as m- or p-bromophenoxy, etc. , (14) phenylthio group, (15) C _1-6 alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl, propyl sulfinyl, butylsulfinyl etc.), (16) C _1-6 alkylsulfonyl group (e.g., methylsulfonyl, ethylsulfonyl Propylsulfonyl, butylsulfonyl),

(17) amino group, (18) C _1-6 acylamino group (for example, acetylamino, propionylamino, etc.
_1-6 alkanoylamino, etc.), (19) mono- or di-C _1-6
Alkylamino group (eg, methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, etc.), (20) C _1-6
Acyl group (eg, C _1-6 alkanoyl such as formyl, acetyl, etc.), (21) benzoyl group, (22) (a) halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), (b) C _1-6 An alkyl group (eg, methyl, ethyl, propyl, isopropyl, etc.) and (c) a halogenophenoxy group (eg, o-,
phenoxy substituted with 1 to 3 halogens such as m- or p-chlorophenoxy, o-, m- or p-bromophenoxy, etc.) and 1 to 4 substituents. A heteroatom selected from a nitrogen atom, a sulfur atom, an oxygen atom, etc., besides a carbon atom;
5 to 6-membered heterocyclic groups (e.g., pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, furyl, oxazolyl,
Isoxazolyl, oxadiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
Piperidyl, piperazinyl, pyridazinyl, pyrazinyl, thiazinyl, thiomorpholinyl, morpholinyl, pyranyl, oxazinyl, etc.), and (23) halogeno-C _1-6
One to five (preferably one to one) selected from alkyl groups (eg, C _1-6 alkyl substituted with one to three halogens such as difluoromethyl, trifluoromethyl, trifluoroethyl and trichloroethyl); 4)
And the hydrocarbon group may be a C _1-6
An alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, etc.) or a C _3-8 cycloalkyl group (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.) Or four.

The "acyl group" which may be possessed by the "amino group which may be substituted" as a substituent in the "alkylene group which may be substituted" represented by Z includes An acyl group derived from a carboxylic acid which may be substituted, an oxycarboxylic acid which may be substituted, a sulfonic acid which may be substituted, a sulfinic acid which may be substituted, and the like are mentioned. ⁶ CO—, R ⁷ OCO—, R ⁸ SO ₂ — or R ⁹ SO— wherein R ⁶ , R ⁷ , R ⁸ and R ⁹ are each an optionally substituted hydrocarbon group or heterocyclic group. Is shown. And the like. In the above formula, R ⁶ , R ⁷ , R ⁸
And R ⁹ each represent an optionally substituted hydrocarbon group or a heterocyclic group. Examples of the “optionally substituted hydrocarbon group” represented by R ⁶ , R ⁷ , R ⁸ and R ⁹ include the “optionally substituted alkylene group” represented by Z described above.
And the same as the “optionally substituted hydrocarbon group” as the substituent in the above. As the “optionally substituted heterocyclic group” represented by R ⁶ , R ⁷ , R ⁸ and R ⁹ , as the substituent in the aforementioned “optionally substituted alkylene group” represented by Z The same as the “optionally substituted heterocyclic group” are used. As the "optionally substituted amino group" as a substituent in the "optionally substituted alkylene group" represented by Z, an amino group optionally substituted with an acyl group is preferable. Formula R ⁸ SO ₂ — wherein R ⁸ is as defined above. And an amino group which may be substituted with a group represented by the formula:

The group represented by the formula -ZR ⁵ includes a group represented by the formula-
CH ₂ —R ⁵ or a formula —CHR ³ CHR ⁴ —R ⁵ (wherein R ³
Is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ is a hydrogen atom or an optionally substituted amino group). . In the above formula, the “optionally substituted hydrocarbon group” represented by R ³ is the “optionally substituted hydrocarbon group” as a substituent in the aforementioned “optionally substituted alkylene group” represented by Z. And the like. In the above formula, the “optionally substituted heterocyclic group” represented by R ^{3 includes} the “optionally substituted heterocyclic group” as a substituent in the aforementioned “optionally substituted alkylene group” represented by Z. And the same as those described in "Good heterocyclic group". In the above formula, the “optionally substituted amino group” represented by R ^{4 includes} “optionally substituted amino group” as the substituent in the aforementioned “optionally substituted alkylene group” represented by Z. The same as "good amino group" are used. In the above formula, R ³ is preferably a hydrogen atom, R ⁴ is preferably a hydrogen atom or an amino group substituted with an acyl group, and is represented by the formula —NH—SO ₂ —
A group represented by R ⁸ (wherein R ⁸ has the same meaning as described above) is more preferred.

In the above formula (I), R ⁵ represents a carboxyl group which may be esterified or amidated. R ⁵
The “carboxyl group which may be esterified or amidated” represented by is preferably a carboxyl group or a group to which compound (I) is administered as a prodrug and can be converted into a physiologically active compound in a living body, For example in the formula -CO-R ¹⁰ (wherein, R ¹⁰ is a hydroxyl group, an alkoxy group which may be substituted, an optionally substituted alkenyloxy group, also be also aralkyl group or a substituted substituted A good amino group) is used.

As the “alkoxy group” in the “optionally substituted alkoxy group” for R ¹⁰ ,
_1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, butoxy and the like) and the like. As the “alkenyloxy group” in the “optionally substituted alkenyloxy group”, a C _2-8 alkenyloxy group (for example, And the "aralkyloxy group" in the "optionally substituted aralkyloxy group" includes a _C7-12 aralkyloxy group (eg, benzyloxy, phenethyloxy, 3-phenylpropyloxy). phenyl -C _1-6 alkyl group, etc.), etc. and the like. These “alkoxy group”, “alkenyloxy group” and “aralkyloxy group” are each substituted at a substitutable position, for example, (1) a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.),
(2) hydroxyl group, (3) oxo group, (4) C _1-6 alkoxy group (for example, methoxy, ethoxy, propoxy, isopropoxy,
Butoxy, isobutoxy, sec- butoxy, tert- butoxy, etc.), (5) amino group, (6) C _1-6 alkylamino group (e.g. methylamino, ethylamino, propylamino, etc.), (7) di -C _{1 -6} alkylamino group (for example, dimethylamino, diethylamino, dipropylamino, etc.), (8)
C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.), (9) halogeno-C _1-6 alkyl group (eg, substituted with 1 to 3 halogens such as chloromethyl, bromoethyl, trifluoroethyl, chloropropyl, etc.) C _1-6 alkyl, etc.) that is, (10) C _1-7 acyl groups (e.g. formyl, acetyl, C _1-6 alkanoyl propionyl, benzoyl, etc.), (11) a hydroxy -C _1-6 alkyl group ( such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.), (12) C _1-6 alkoxy -C _1-6 alkyl group (e.g. methoxymethyl, 2-ethoxyethyl, etc.), and (1
3) C _1-6 alkoxy-carbonyl group (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
Isobutoxycarbonyl, sec-butoxycarbonyl, t
ert-butoxycarbonyl, etc.) and may have 1 to 5 (preferably 1 to 2) substituents.

As the "optionally substituted amino group" for R ¹⁰ , for example, -NR ¹¹ R ^{12 and the} like can be mentioned.
In NR ¹¹ R ¹² , R ¹¹ and R ¹² are the same or different and are each a hydrogen atom, a C _1-6 alkyl group (eg, methyl,
Ethyl, propyl, butyl, hexyl, etc.), a C _2-8 alkenyl group (eg, allyl, 2-butenyl, 3-pentenyl, etc.) or a C _7-12 aralkyl group (eg, phenyl-C ₁ such as benzyl, phenethyl, phenylpropyl, etc.) _-6 alkyl). Here, the aryl group (eg, phenyl group) in the aralkyl group may be a nitro group, a halogen atom (eg, chlorine, fluorine, bromine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.), and C _{1- It} may be substituted with one or two selected from ₆ alkoxy groups (for example, methoxy, ethoxy, propoxy, etc.).

When the compound (I) of the present invention is to be converted into a prodrug type oral preparation, R ¹⁰ may be, for example, a hydroxyl group or an optionally substituted amino group (for example, amino,
N—C _1-6 alkylamino, N, N-diC _1-6 alkylamino, etc.) or an optionally substituted alkoxy group [for example, (A) a hydroxyl group, an optionally substituted amino group (eg, amino, N, N-diC _1-6 alkylamino such as N-C _1-6 alkylamino, dimethylamino, diethylamino, etc., 3 to 3 such as piperidino, morpholino, thiomorpholino, etc.
A 6-membered cyclic amino, etc.), a halogen atom (eg, chlorine, fluorine, bromine, etc.), a C _1-6 alkoxy group (eg, methoxy,
Ethoxy, propoxy, etc.), C _1-6 alkylthio group (eg, methylthio, etc.), C _1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, etc.), propylidene group, 3-phthalidylidene group An optionally substituted aminocarbonyl group (for example, aminocarbonyl and the like) and an optionally substituted dioxoenyl group (for example, 5-methyl-2-oxy-1,3-dioxolan-4)
-Yl or the like, which may be substituted with 1 to 3 C _1-6 alkoxy groups selected from the group consisting of: (B) a formula —OCH (R ¹³ )
OCOR ¹⁴ wherein R ¹³ represents a hydrogen atom, a linear or branched C _1-6 alkyl group or a C _5-7 cycloalkyl group,
¹⁴ is (a) a linear or branched C _1-6 alkyl group, (b) C
_2-8 alkenyl group, (c) C _5-7 cycloalkyl group, (d) C
_5-7 cycloalkyl group or optionally substituted C _6-10
A C _1-3 alkyl group substituted with an aryl group, (e) a C _5-7 cycloalkyl group or a C _2-3 alkenyl group substituted with an _optionally substituted C _6-10 aryl group, (f) An optionally substituted C _6-10 aryl group, (g) a linear or branched C _1-6 alkoxy group, (h) a linear or branched C _2-8 alkenyloxy group, (i ) A C _5-7 cycloalkyloxy group,
(j) C _5-7 cycloalkyl group or optionally substituted C
_6-10 C _1-3 alkoxy group substituted with an aryl group, (k) C
A C _2-3 alkenyloxy group substituted with a _5-7 cycloalkyl group or an _optionally substituted aryl group, or
(l) represents an _optionally substituted C _6-10 aryloxy group. Here, the aryl moiety in R ¹⁴ is substituted with 1 to 3 substituents such as a halogen atom (eg, chlorine, fluorine, bromine, etc.), a C _1-6 alkyl group (eg, methyl, ethyl, propyl, etc.), and a nitro group. It may be. Etc.] are preferably introduced.

A “straight-chain or branched C” represented by R ¹³
Examples of " _1-6 alkyl group" include methyl, ethyl, n-
Propyl, isopropyl, n-butyl, isobutyl, t
-Butyl, n-pentyl, isopentyl, neopentyl and the like, and as the " _C5-7 cycloalkyl group", for example, cyclopentyl, cyclohexyl, cycloheptyl and the like are used. R ¹⁴ is specifically a straight-chain or branched C _1-6 alkyl group (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- -Butyl, n-pentyl, isopentyl, neopentyl and the like), (b) is a C _2-8 alkenyl group (for example, vinyl, propenyl, allyl, isopropenyl and the like), and (c) is a C _5-7 cycloalkyl Groups (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.), (d) includes a C _5-7 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted C _6-10 aryl group (eg, A C _1-3 alkyl group substituted with phenyl or the like (eg, benzyl, p-chlorobenzyl, phenethyl,
Cyclopentylmethyl, cyclohexylmethyl, etc.), (e) includes a C _5-7 cycloalkyl group (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted C _6-10 aryl group (eg, phenyl group, etc.) A substituted C _2-3 alkenyl group (for example, those having an alkenyl moiety such as vinyl such as cinnamyl, propenyl, allyl, and isopropenyl); and the above-mentioned (f), a C _6-10 aryl _optionally substituted Groups (eg, phenyl,
p-tolyl, naphthyl, etc.) and the above (g) include linear or branched C _1-6 alkoxy groups (for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n
-Pentyloxy, isopentyloxy, neopentyloxy, etc.);
_2-8 alkenyloxy group (for example, allyloxy, isobuterooxy, etc.); (i) as above, C _5-7 cycloalkyloxy group (for example, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.);
_5-7 cycloalkyl groups (eg, cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C _1-3 alkoxy groups (eg, benzyloxy, phenethyloxy) substituted with an optionally substituted C _6-10 aryl group (eg, phenyl group, etc.) Methoxy, ethoxy, n-propoxy, isopropoxy and the like having an alkoxy moiety such as cyclopentylmethyloxy and cyclohexylmethyloxy),
(k) The C _5-7 cycloalkyl group (e.g. cyclopentyl, cyclohexyl, cycloheptyl, etc.) or C _2-3 alkenyl substituted with optionally substituted C _6-10 aryl group (e.g. phenyl group) An oxy group (for example, one having an alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc. such as cinnamyloxy), or an optionally substituted aryloxy group (for example, phenoxy, p-nitrophenoxy) , Naphthoxy, etc.).

Particularly preferred examples of the “esterified carboxyl group” as R ⁵ when used as a prodrug include methoxycarbonyl, ethoxycarbonyl, tert-butoxycarboxymethyl, propoxycarbonyl, pivaloyloxymethoxy Carbonyl, 1- (cyclohexyloxycarbonyloxy)
Ethoxycarbonyl, 5-methyl-2-oxo-1,3
-Dioxolan-4-ylmethoxycarbonyl, acetoxymethyloxycarbonyl, propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, isobutyryloxymethoxycarbonyl, 1- (ethoxycarbonyloxy) ethoxycarbonyl, 1-
(Acetyloxy) ethoxycarbonyl, 1- (isobutyryloxy) ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamyloxycarbonyl, cyclopentylcarbonyloxymethoxycarbonyl,
N, N-dimethylaminocarbonylmethoxy, 2- (isobutyryloxycarbonyl) -2-propylideneethoxycarbonyl, (3-phthalidylidene) ethoxycarbonyl and the like can be mentioned.

[0043] Preferably the groups can be converted into a carboxyl group in the carboxyl group or in vivo as R ^5, among them a carboxyl group or a C _1-6 alkoxy - carbonyl group (e.g. methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert- butoxycarbonyl etc. Is preferred.

In the above formula (I), the formula (I ')

Embedded image (In the formula, A ′ is an optionally substituted, basic 5- to 7-membered nitrogen-containing heterocyclic group [A ′ is an optionally substituted R ¹ in the formula (I). The same as the basic 5- to 7-membered nitrogen-containing heterocyclic group "], n 'is an integer of 0 to 3, R ^2' is a hydrogen atom or an optionally substituted aralkyl group. [R
^{As the} “optionally substituted aralkyl group” for ^{2 ′} , the “optionally substituted aralkyl group” exemplified as the “optionally substituted hydrocarbon group” for R ² in formula (I) And the like)
The, -Z'-R ^{5 'is} -CH ₂ -R ^5' or -CH ₂ CHR
^4′- R ^{5 ′} (wherein R ^{4 ′} is a hydrogen atom or a formula —NH—SO
₂ -R 8 ^'(wherein, R ^8' as "optionally substituted hydrocarbon group" represented by the an optionally substituted hydrocarbon group [R ^{8 'is} represented by R ^8' R ^{5 ′} is a carboxyl group which may be esterified (R ^{5 ′} is an optionally substituted hydrocarbon group). as "carboxyl group which may be esterified" represented the formula carboxyl group which may be "esterified in the" esterified or amidated also optionally carboxyl group "as R ⁵ in (I) And the like), or a salt thereof.

Compound (I) can be produced, for example, by the following method or a method analogous thereto. In each of the following reactions, when the raw material compound has an amino group, a carboxyl group, or a hydroxyl group as a substituent, a protecting group generally used in peptide chemistry or the like is introduced into these groups. Alternatively, the target compound can be obtained by removing the protecting group as necessary after the reaction. Examples of the amino-protecting group (P) include an optionally substituted C _1-6 alkylcarbonyl (eg, formyl, methylcarbonyl, ethylcarbonyl, etc.), phenylcarbonyl, C _1-6 alkyloxycarbonyl (Eg, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, etc.), aryloxycarbonyl (eg, phenyloxycarbonyl, etc.), C _7-10 aralkyloxycarbonyl (eg, benzyloxycarbonyl, etc.), trityl, phthaloyl and the like are used. Can be These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), a C _1-6 alkylcarbonyl (eg, acetyl,
Propionyl, butyryl, etc.), nitro group and the like are used, and the number of substituents is about 1 to 3. Examples of the carboxyl-protecting group (R ¹⁵ ) include, for example, C _1-6 alkyl which may have a substituent (eg, methyl, ethyl,
Propyl, isopropyl, butyl, tert-butyl, etc.), phenyl, trityl, silyl and the like.
As these substituents, halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkylcarbonyl (eg, formyl, acetyl, propionyl, butyryl, etc.), nitro groups and the like are used. Is about one to three.

Examples of the hydroxyl-protecting group include C _1-6 alkyl which may have a substituent (for example, methyl, ethyl, propyl, isopropyl, butyl, tert.
- butyl, etc.), phenyl, C _7-10 aralkyl (e.g., benzyl etc.), C _1-6 alkylcarbonyl (e.g., formyl, acetyl, propionyl etc.), phenyloxycarbonyl, C _7-10 aralkyloxycarbonyl (e.g., Benzyloxycarbonyl), pyranyl, furanyl, silyl and the like. These substituents include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C _1-6 alkyl, phenyl, C _7-10
Aralkyl, nitro group, etc. are used, and the number of substituents is 1
Or about four. As a method for introducing and removing a protecting group, a method known per se or a method analogous thereto (for example, a method described in Protective Groups in Organic Chemistry (JFWMcOmie et al., Plenum Press)) is used, As a removing method, for example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

"Production of Compound (Ia) wherein X is -X ¹ -CH ₂ CO- (X ¹ = bond) and Y is -NH-" Method a)

Embedded image The symbols in the formula have the same meanings as described above. P represents a protecting group for an amino group, and R ¹⁵ represents a protecting group for a carboxyl group. * Indicates an asymmetric center, and Cbz-amino acid indicates an amino acid whose amino terminus is protected. "X is -X ¹ -CH ₂ C
O- (X ¹ = bond), wherein Y is —O—
a) Production Method a ′)

Embedded image The symbols in the formula have the same meanings as described above.

"X is -X ¹ -CH ₂ CO- (X ¹ = -O
-, -S- or -NH-) wherein Y is -NH- "Method b)

Embedded image The symbols in the formula have the same meanings as described above. D is -O-, -S-
Or -NH-. "X is -X ¹ -CH ₂ CO- (X
¹ = —O—, —S— or —NH—) and Y is —O— (Production Method b ′)

Embedded image The symbols in the formula have the same meanings as described above.

"Preparation of Compound (Ic) wherein X is a bond and Y is -NH-" Method c)

Embedded image The symbols in the formula have the same meanings as described above. "Production of Compound (Ic ') wherein X is a bond and Y is -O-" Method c')

Embedded image The symbols in the formula have the same meanings as described above.

The condensation reaction in the method a) or the method b) as a method for producing the compound (Ia) or (Ib) of the present invention is carried out by an amide bond formation reaction in a usual peptide, for example, an active ester or a mixed acid anhydride or acid chloride. It can be carried out using the method of the product. For example, compound (II) and Cbz-amino acid, compound (XII) and compound (XIII), or compound (XV
In the condensation reaction between I) and compound (XIII), 2,4,5-Cbz-amino acid, compound (XII) or compound (XVI)
Trichlorophenol, pentachlorophenol, 2-
Phenols such as nitrophenol and 4-nitrophenol or N-hydroxysuccinimide, N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), 1-hydroxybenztriazole (HOBT), N -Condensation with an N-hydroxy compound such as -hydroxypiperidine in the presence of a catalyst such as dicyclohexylcarbodiimide, conversion into an active ester form, and then condensation. Cbz
-A mixed acid anhydride can be obtained by reacting an amino acid, compound (XII) or compound (XVI) with isobutyl chloroformate, followed by condensation. Further, the condensation reaction between compound (II) and a Cbz-amino acid, compound (XII) and compound (XIII), or compound (XVI) and compound (XIII) is carried out by dicyclohexylcarbodiimide, N,
Condensation can also be carried out using a peptide-forming reagent such as N'-carbonyldiimidazole, diphenylphosphate azide and diethyl cyanophosphate alone.

In any of the above cases, the condensation reaction can be accelerated preferably by adding an organic base (eg, triethylamine, N-methylpiperidine, 4-N, N-dimethylaminopyridine). The reaction temperature is usually about -20 to about + 50 ° C, preferably about 0 ° C to around room temperature. Examples of commonly used solvents include, for example, dioxane, tetrahydrofuran, acetonitrile, pyridine, N, N-dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone, chloroform, methylene chloride and the like, and these may be used alone or as a mixed solvent. The carboxyl protecting groups contained in the product of the final process can be removed by methods known per se. For example, a compound having a benzyl ester group can be palladium, a carboxylic acid derivative can be obtained by hydrogenation in the presence of a noble metal catalyst such as platinum, and a compound having a tert-butyl ester group is trifluoroacetic acid. Carboxylic acid derivatives can be obtained by treatment with an acid such as hydrogen chloride.

In the catalytic reduction of the compound (III) and the compound (VIII), a catalyst is used, for example, a platinum-based catalyst such as platinum oxide, platinum black and platinum carbon; Rhodium-based catalysts such as rhodium carbon and rhodium alumina, Raney nickel and the like are used. The present reduction reaction may be carried out under pressure if necessary, and the pressure is about 1 to about 50 atm, preferably about 1 to about 20 atm. The reaction is generally performed in a solvent such as methanol, ethanol, propanol, isopropanol,
Alcohols such as butanol and tert-butanol, for example, dioxane, tetrahydrofuran, diethyl ether, tert-butyl methyl ether, diisopropyl ether, ethers such as ethylene glycol-dimethyl ether, for example, esters such as ethyl formate, ethyl acetate, and n-butyl acetate , For example, hydrocarbons such as n-hexane, benzene, and toluene, for example, formamide, N, N-
Amides such as dimethylformamide, N, N-dimethylacetamide, for example, acetone, methyl ethyl ketone,
In addition to ketones such as methyl isobutyl ketone, for example, nitriles such as acetonitrile and propionitrile, hexamethylphosphoramide, water and the like are used alone or as a mixed solvent. The reaction temperature is about -10 ° C to about 150
° C, preferably from about -5 ° C to about 120 ° C. The reaction time varies depending on the type of the compound, the type of the solvent and the type of the catalyst, but is usually about 15 minutes to about 72 hours, preferably about 30 minutes to about 24 hours.

The reduction reaction of the compound (IV) is carried out, for example, by catalytic reduction using a metal such as platinum, palladium, Raney nickel or a mixture thereof with an optional carrier; for example, lithium aluminum hydride, sodium borohydride, etc. By reduction with a metal hydride compound. Reaction conditions such as a reaction solvent, a reaction temperature, and a reaction time include the same conditions as in the above-described catalytic reduction. This reaction can be carried out under normal pressure or under pressure.

The reaction for protecting the nitrogen atom of compound (V) can be carried out by a method known per se or a method analogous thereto [for example, the method described in Protective Groups in Organic Chemistry (JFW McOmie et al., Plenum Press)]. Used. The deprotection reaction of compound (IX)
A method known per se or a method analogous thereto [for example, a method described in Protective Groups in Organic Chemistry (JFW McOmie et al., Plenum Press)] is used. Further, for example, a method of treating with an acid, a base, reduction, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate or the like is used.

In the oxidation reaction of compound (VI), the hydroxyl group of compound (VI) is oxidized by a known means, for example, using an oxidizing agent such as sulfur trioxide pyridine complex to produce ketone compound (VII). be able to. In the carbon increasing reaction of compound (VII), compound (VIII) can be produced by a means known per se, for example, using a base such as sodium hydride and an acetate derivative such as ethyl diethylphosphonoacetate.

The alkylation reaction of the compound (X) and the compound (V) is a usual alkylation reaction for an amino group, and is performed with an alkylating agent corresponding to the substituent R ¹ such as a 4-methanesulfonyloxyalkylpiperidine derivative. Compound (X) or compound (V) and a base (eg, sodium carbonate,
Inorganic bases such as potassium carbonate, potassium hydrogen carbonate and cesium fluoride, or triethylamine, pyridine, 4-N,
The reaction can be carried out in the presence of an organic base such as N-dimethylaminopyridine) at about 0 to 100 ° C., preferably at about room temperature, for about 15 minutes to 20 hours. Acetonitrile, N,
Organic solvents such as N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride and the like can be mentioned. The acylation reaction of the compound (X) and the compound (V) is performed, for example, under the same conditions as in the condensation reaction of the compound (II) with a Cbz-amino acid,
Reaction of an acylating agent such as a carboxylic acid or a derivative thereof corresponding to the substituent R ¹ with a compound (X) or a compound (V) to acylate the amino group of the compound (X) or the compound (V) It is.

The hydrolysis reaction of the compound (XI) and the compound (XV) is a reaction for converting the compound (XI) or the compound (XV) into a free acid.
^{When 15} is a lower alkyl group, the hydrolysis is carried out by acid or alkali. As the acid, for example, hydrochloric acid, sulfuric acid, hydrobromic acid and the like are preferably used. As the alkali, lithium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide and the like are used. When R ¹⁵ is a benzyl group which may be substituted, a free acid can be produced by catalytic reduction (hydrogenolysis) in addition to the acid or alkali hydrolysis. The esterification reaction of the compound (XII) and the compound (XVI) in the methods a ′) and b ′) is a reaction for converting a free acid into an ester by a means known per se, for example, a compound (XII) which is a free acid ) or a compound (XVI) or by reacting such alcohols corresponding to the substituent Z-R ⁵ and derivatives thereof ^{(HO-Z-R 5)} , or the compound is a free acid (XII) or the compound (XVI ) Or a salt thereof and an alkyl halide (WZR ⁵ (W = halogen atom)) corresponding to the substituent ZR ^5, and the like to give the compound (I
a ′) or compound (Ib ′) can be prepared.

The reaction for converting the compound (XIV) into the compound (XV) in the method b) is carried out by the Mitsunobu reaction (Synth
hesis), 1981, pp. 1-27) can also be used.
The reaction is carried out by reacting compound (XIV) with a compound of formula HD-CH ₂ COOR ¹⁵
Azodicarboxylates (eg,
The reaction is carried out in the presence of diethyl azodicarboxylate and the like and phosphines (eg, triphenylphosphine, tributylphosphine and the like). This reaction is advantageously performed using a solvent inert to the reaction. Such a solvent is not particularly limited as long as the reaction proceeds, for example, diethyl ether, tetrahydrofuran, dioxane,
Ethers such as 1,2-dimethoxyethane, hydrocarbons such as benzene, toluene, cyclohexane and hexane; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; dichloromethane, chloroform, carbon tetrachloride; Solvents such as halogenated hydrocarbons such as 1,2-dichloroethane, nitriles such as acetonitrile and propionitrile, sulfoxides such as dimethyl sulfoxide, and a mixed solvent thereof are preferable. The reaction time is generally 5 minutes to 48 hours, preferably 30 minutes to 24 hours. The reaction temperature is usually
The temperature is 20 to 200 ° C, preferably 0 to 100 ° C. Further, in the case of obtaining D compound is -O- and (XV) are known per se by means, for example, a substituent -CH ₂ C
Compound (XIV) is alkylated using an alkylating agent (such as an alkyl halide) corresponding to OOR ^15, and D is-
Compound (XV) which is O- can be produced.

In the method c), the compound (Ic) is prepared from the compound (XIV) by, for example, A) reacting the compound (XIV) with the compound (XIII) in the presence of a base and MsCl (methanesulfonyl chloride). B) Compound (XI)
V) and compound (XIII) by the Mitsunobu reaction (compound (XI
C) by subjecting compound (XIV) to the aforementioned oxidation reaction (a reaction similar to the oxidation reaction of compound (VI)). The reaction can be carried out by reacting compound (XVII) with compound (XIII) in the presence of NaBH ₃ CN. Further, the compound (XIV) is subjected to an alkylation reaction to give the compound (I
The production of c ′) can be carried out by using an alkylating agent (such as an alkyl halide) corresponding to the substituent —ZR ⁵ in the same manner as in the above-mentioned alkylation reaction of the compound (XIV). it can.

Compound (I) [Compound (Ia), Compound (I
a ′), compound (Ib), compound (Ib ′), compound (Ic) and compound (Ic ′)] can be obtained by the reaction itself for producing compound (I), According to the acid,
The salt of compound (I) as described above can also be produced by adding an alkali and a base. The target compound (I) of the present invention thus obtained can be simply separated from the reaction mixture by a conventional means of separation and purification, for example, extraction, concentration, neutralization, filtration, recrystallization, column chromatography, thin layer chromatography and the like. Can be released.

The compound (I) has one or more asymmetric carbon atoms (chiral atoms) on the basic skeleton, and has at least two stereoisomers (eg, 9aR-form, 9aS-form and the like).
May exist. Further, the carbon atom on the basic skeleton at the position where the substituent R ² (except when it is a hydrogen atom) and the group represented by the formula —XYZR ⁵ becomes a chiral atom, Occurs. All of these individual isomers and mixtures thereof are naturally included in the scope of the present invention, and these isomers can be individually produced if desired.
Compound (I) may be a hydrate, and both a hydrate and a non-hydrate are included in the scope of the present invention. By performing the above-mentioned reaction using a single isomer of the raw material compound represented by the above formula (II), a single optical isomer of the compound (I) can be obtained. When the product is a mixture of two or more isomers, it is separated by a conventional separation method, for example, an optically active acid (for example, camphorsulfonic acid, tartaric acid, dibenzoyltartaric acid, etc.), an optically active base (for example, cinchonine, cinchonidine, quinine,
Quinidine, α-methylbenzylamine, dehydroabiethylamine, etc.), and various isomers can be separated by separation means such as various kinds of chromatography and fractional recrystallization.

The starting compound (II) of the present invention can be prepared by a method known per se [for example, Jerry W. Skiles et al., Biological & M.
edicinal Chemistry Letters, Vol. 6, pp 963-966 (19
96), Patrick D. Bailey et al., Tetrahedron Letters,
Vol. 29, pp. 2231-2234 (1988), etc.].

In the above process for producing the compound (I) and intermediates thereof, the compound used in the reaction may be any one of inorganic compounds such as hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc. Acid salts such as acetate, tartrate,
Organic acid salts such as citrate, fumarate, maleate, toluenesulfonate, methanesulfonate, and trifluoroacetate, such as sodium salts, potassium salts, and metal salts such as aluminum salts, such as triethylamine salts; It may be used in the form of a pharmacologically acceptable salt such as a salt with a base such as a guanidine salt, an ammonium salt, a hydrazine salt or a quinine salt. When the compound (I) is obtained in a free form by the above-mentioned production method, it is converted to a salt thereof by a conventional method, and when the compound (I) is obtained as a salt of the compound (I), the salt is converted to a compound (I) by a conventional method. can do.

The compound (I) of the present invention (including salts and hydrates thereof) is a low-toxic and safe compound, and is a fibrinogen receptor (glycoprotein IIb / IIIa) for platelets
Binding of fibrinogen, fibronectin, and von willebrand factor to and their corresponding receptors on the surface of various types of cells, and of other adhesive proteins such as vitronectin, collagen and laminin Inhibits binding. Therefore, the compound (I) of the present invention affects cell-cell and cell-matrix interactions, and in particular, because the compound inhibits the formation of thrombus, mammals including humans (eg, mouse, rat, guinea pig, Dogs, rabbits,
Angina, unstable angina, acute myocardial infarction, Kawasaki disease, acute and chronic heart failure, transient ischemic attack (TI)
A), stroke, cerebral ischemic injury during acute cerebral thrombosis, dissociative aneurysm, cerebral vasospasm after subarachnoid hemorrhage, acute or chronic renal disease (for example, acute or chronic due to excessive aggregation such as snake venom and immune disease) Renal disease), chronic and acute glomerulonephritis, diabetic nephritis and neuropathy, nephrotic syndrome, liver disease, pulmonary embolism, bronchial asthma, pulmonary edema, adult respiratory distress syndrome (AR
DS), atherosclerosis obliterans, peripheral arterial occlusion, deep venous thrombosis, vibration disease, peripheral arterial occlusion associated with diabetes, thrombotic thrombocytopenic purpura (TTP), pancreatic intravascular coagulation (DI
C), sepsis, surgical or infectious shock, postoperative and postpartum trauma, early placental ablation, incompatible blood transfusion, systemic lupus erythematosus, Raynaud's disease, inflammation, arteriosclerosis, hemolytic uremic syndrome, targeted peripheral arterial necrosis It can be used for treatment or prevention of humiliation, hemorrhoidal disease. In addition, the compound (I) of the present invention is used for cardiopulmonary bypass surgery, cardiopulmonary bypass, atrial fibrillation, surgery associated with hip fracture, valve replacement, prevention of thrombosis by artificial blood vessels and organs, prevention of thrombocytopenia by artificial dialysis, Can be used for secondary prevention of myocardial infarction. Here, prevention of thrombocytopenia by artificial dialysis also means prevention of coagulation and residual blood in a hemodialysis extracorporeal circuit.

Further, the compound (I) of the present invention can be used for coronary artery thrombolysis therapy (for example, enhancement of the action of a thrombolytic agent such as tissue plasminogen activator (TPA) and prevention of reocclusion), P
Prevention of reocclusion and restenosis of coronary arteries after TCA (percutaneous intracoronary angioplasty), stent placement and atherectomy;
Prevention of reocclusion and restenosis after coronary artery bypass surgery, PTCA
Alternatively, it can be used for preventing ischemic complications (for example, myocardial infarction, death) during coronary thrombolytic therapy, and can be used as an antitumor agent by inhibiting cancer metastasis. When the compound (I) of the present invention is used in combination with a drug having the same or different pharmacological action, two or more drugs may be compounded in the same preparation, and the same preparation (eg, powder) at the time of administration , Injections, etc.). Further, separately formulated drugs may be administered to the same subject separately, simultaneously or at staggered times.

The pharmaceutical composition containing the compound (I) of the present invention can be orally administered, for example, in the form of tablets, lacquered tablets, sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions. Or in the form of suppositories, rectally or as a spray. However, the administration can also be effected parenterally, for example in the form of solutions for injection. Each of the above-mentioned formulations can be produced according to a conventional method, using an excipient as needed. In the composition of the present invention, the content of compound (I) varies depending on the dosage form, but is usually about 0.01 to about 100% by weight, preferably about 0.1 to about 50% by weight, based on the whole preparation. More preferably, it is about 0.5 to about 20% by weight. The active compounds can be mixed with pharmaceutically inert, inorganic or organic excipients to make tablets, lacquered tablets, sugar-coated tablets and gelatin capsules.
Representative examples of such excipients that can be used for tablets, sugar-coated tablets and gelatin capsules are lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof. Examples of suitable excipients for soft gelatin capsules are vegetable oils, waxes, fats, semi-solid and liquid polyols. However, if the physical properties of the active compound are appropriate, no excipients are required when using soft gelatin capsules. Examples of suitable excipients for the production of solutions and syrups are water, polyols, sucrose, invert sugar and glucose. Suitable examples for injectable solutions are water, alcohol,
Polyols, glycerol and vegetable oils.

Suitable examples for suppositories are natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. The pharmaceutical composition further contains preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts that alter osmotic pressure, buffers, coatings or antioxidants. can do. The dosage of the active compound for suppressing or preventing the aforementioned diseases can be varied within wide limits. And, of course, each must be adjusted to suit the individual situation in a particular case. The dosage varies depending on the target disease, symptom, administration subject, administration method, etc., for example, patients with unstable angina, patients with ischemic complications during PTCA or coronary thrombolytic therapy or patients with reocclusion or restenosis of the coronary artery When administered orally to a subject, the compound (I) of the present invention is usually administered in an amount of about 1 to about 500 mg, preferably about 10 to about 20 mg per day for an adult (about 60 kg).
It is appropriate to administer 0 mg in 1 to 3 divided doses. Parenteral administration to patients with transient ischemic attack (TIA), unstable angina pectoris, patients with ischemic complications during PTCA or coronary thrombolytic therapy, or patients with reocclusion or restenosis of coronary arteries For an adult (about 60 kg), about 0.05 to about 50 mg of the compound (I) of the present invention per day,
Preferably, about 1 to about 20 mg / kg is suitably administered in 1 to 3 divided doses.

[0068]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will now be described with reference to Formulation Examples, Examples,
The present invention will be described more specifically with reference to Experimental Examples and Reference Examples, but the present invention is not limited thereto. ^{The 1} H-NMR spectrum was measured with a Varian Gemini 200 (200 MHz) type spectrometer using tetramethylsilane as an internal standard, and all δ values were shown in ppm. In the mixed solvents, the numerical values shown in parentheses are the volume mixing ratios of the respective solvents. % Means percent by weight unless otherwise specified. s: singlet d: doublet t: triplet q: quartet dd: double doublet m: multiplet br: broad J: coupling constant WSC: water-soluble carbodiimide DMF: N, N-dimethylformamide THF: tetrahydrofuran Z ″: benzyloxy Carbonyl Boc: tert-butoxycarbonyl Bn: benzyl OTBDPS: tert-butyldiphenylsilanyloxy

[0069]

EXAMPLES Test Example 1 Guinea Pig Inhibition of Platelet Aggregation Test Method 3.15% as anticoagulant from male guinea pig
Blood was collected using a syringe containing citric acid (1 ratio to 9 blood). Then, at room temperature, 3-5 at 1000G
Platelet-rich plasma (PRP: pl
atelet rich plasma). 1000 more PRP
G for 10 minutes and platelet poor plasma (PPP: plat
elet poor plasma). The platelet count was measured with an automatic platelet counting device (Sysmex E2500, Toa Medical Electronics),
PRP was diluted with PPP so as to be 100,000 cells / μl.
Platelet aggregation was measured using an 8-channel aggregometer (NB
(SHEMA Tracer VI, manufactured by Nikko Bioscience)
It investigated as follows using. PRP (250μl)
Was incubated at 37 ° C. for 2 minutes, and physiological saline (control) or various concentrations of the test drug (25 μl) were added. After 2 minutes, 25 μl of adenosine diphosphate (hereinafter ADP) was added.
(Final concentration: 1 μM) to induce platelet aggregation. The inhibition rate was determined by comparing the maximum aggregation rate between the control and the test drug group.

The results are shown in [Table 1].

TABLE 1 Inhibition of guinea pig platelet aggregation by ADP of the compounds of the examples Example No. Inhibitory effect of ADP on platelet aggregation IC50 value (M) 1 3.3 × 10 ^-8 3 9.0 × 10 ^-8

Reference Example 1 (2R, 4S) -1-benzyloxycarbonylaminoacetyl-4
-Hydroxypiperidine-2-carboxylic acid methyl ester (2R, 4S) -4-hydroxypipecolic acid methyl ester (9.
20 g) and benzyloxycarbonyl-Gly-OH (15.7 g) were dissolved in acetonitrile (90 mL) and stirred at 0 ° C.
(16.0 g) was added. After stirring at room temperature for 3 hours, the reaction solution was poured into a 5% KHSO ₄ aqueous solution and extracted with ethyl acetate.
Subsequently, the ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (17.7 g, 87%).
Was obtained as a colorless amorphous powder. . IR (KBr) 2951, 1721 , 1651, 1437cm -1 1 H NMR (CD 3 OD) δ: 1.50-2.10 (3H, m), 2.30-2.55
(1H, m), 3.10-3.85 (2H, m), 3.69 (3H, s), 3.97 (1H,
d, J = 17.4Hz), 3.90-4.35 (1H, m), 4.20 (1H, d, J = 1
7.4Hz), 5.00-5.20 (1H, m), 5.10 (2H, s), 7.20-7.45
(5H, m).

Reference Example 2 (8S, 9aR) -8-Hydroxyhexahydropyrido [1,2-a] pyrazine-1,4-dione (2R, 4S) -1-benzyloxycarbonyl obtained in Reference Example 1 Aminoacetyl-4-hydroxypiperidine-2-carboxylic acid
Methyl ester (17.7 g) was dissolved in methanol (100 mL), 10% palladium-carbon (0.5 g) was added, and the mixture was stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to give the title compound (9.0
g, 97%) as a colorless crystalline powder. ¹ H NMR (DMSO + D ₂ O) δ: 1.00-1.40 (2H, m), 1.75-1.9
3 (1H, m), 2.20-2.38 (1H, m), 2.42-2.65 (1H, m),
3.50-3.95 (4H, m), 4.30-4.48 (1H, m). Melting point: 182-185 ° C Elemental analysis: C ₈ H ₁₂ N ₂ O ₃ Calculated: C: 52.17 H: 6.57 N: 15.21 Value: C: 52.20 H: 6.67 N: 15.19

Reference Example 3 (8S, 9aR) -octahydropyrido [1,2-a] pyrazin-8-ol (8S, 9aR) -8-hydroxyhexahydropyrido [1, 2-a] Pyrazine-1,4-dione (8.0 g) was added to anhydrous THF (400
mL), and lithium aluminum hydride (13.2 g) was slowly added with stirring at 0 ° C., and the mixture was refluxed for 18 hours. The reaction solution was cooled to 0 ° C., and water (20 mL), a 1N aqueous solution of sodium hydroxide (20 mL) and water (20 mL) were slowly added to terminate the reaction. After stirring at room temperature for 30 minutes, insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained oil was crystallized from methanol / ethyl acetate to give the title compound.
(6.7 g, 99%) as a pale yellow crystalline powder. ¹ H NMR (CD ₃ OD) δ: 1.14 (1H, q, J = 11.4Hz), 1.42-
1.66 (1H, m), 1.70-2.24 (5H, m), 2.36-2.52 (1H, m),
2.68-2.98 (5H, m), 3.48-3.68 (1H, m). Melting point: 158-162 ° C Elemental analysis: As C ₈ H ₁₆ N ₂ O Calculated: C: 61.50 H: 10.32. N: 17.93 Actual value : C: 61.28 H: 10.42 N: 17.66

Reference Example 4 (8S, 9aR) -8-hydroxyoctahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert-butyl ester (8S, 9aR) -octahydro obtained in Reference Example 3. Pyrid [1,2-a] pyrazin-8-ol (6.6 g) was dissolved in a mixed solution of water (66 mL) and 1,4-dioxane (66 mL), and sodium bicarbonate (3.9 g) and
`Di-tert-butyl dicarbonate (10.6 mL) was added with stirring at room temperature. After stirring at room temperature for 1.5 hours, the reaction mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate / diethyl ether to give the title compound (8.5 g, 78%) as a beige crystalline powder. ¹ H NMR (CD ₃ OD) δ: 1.16 (1H, q, J = 11.6Hz), 1.45
(9H, s), 1.40-1.68 (1H, m), 1.73-2.22 (5H, m), 2.45
-2.70 (1H, m), 2.70-3.05 (3H, m), 3.45-3.70 (1H, m
m), 3.77-4.07 (2H, m). Melting point: 159-161 ° C Elemental analysis: As C ₁₃ H ₂₄ N ₂ O ₃ Calculated: C: 60.91 H: 9.44 N: 10.93 Found: C: 60.76 H : 9.33 N: 10.88

Reference Example 5 (9aR) -8-methoxycarbonylmethyleneoctahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert-butyl ester (8S, 9aR) -8- obtained in Reference Example 4. Hydroxyoctahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert-butyl ester (5.5 g) and triethylamine (12 mL) were mixed with dimethyl sulfoxide (17 mL) and methylene chloride (17 mL). In sulfuric acid and stirred at 0 ° C. under stirring.
3.7 g) of a dimethyl sulfoxide solution (17 mL) was added.
After stirring at 0 ° C. for 1.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to obtain a brown oil. Separately prepared sodium hydride (60%, 1.2 g) was added to a THF solution (55 mL) of methyl diethylphosphonoacetate (4.4 mL), and the mixture was added at room temperature.
The mixture stirred for 15 minutes was added to a solution of the above oil in THF (55 mL).
Was added. After stirring at room temperature for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 10/1) to give the title compound (6.7 g, 100%) as a yellow oil. ¹ H NMR (CDCl ₃ ) δ: 1.46 (9H, s), 1.40-3.14 (10H,
m), 3.69 and 3.70 (total 3H, s for each), 3.64-4.2
0 (3H, m), 5.60-5.75 (1H, m).

Reference Example 6 (9aR) -8-methoxycarbonylmethyloctahydropyrido
[1,2-a] pyrazine-2-carboxylic acid tert-butyl ester (9aR) -8-methoxycarbonylmethyleneoctahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert obtained in Reference Example 5 -
Butyl ester (6.7 g), 10% palladium-carbon (0.67
g) and methanol (67 mL) were stirred at room temperature for 16 hours under a hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (6.4 g, 95%) as a pale-yellow oil. IR (KBr) 2924, 1740, 1698, 1422, 1273, 1250, 1169cm
_{^{. -1 1 H NMR (CDCl 3}} ) δ: 0.94 (1H, q, J = 11.6Hz), 1.20-
3.10 (13H, m), 1.46 (9H, s), 3.67 and 3.68 (total
3H, s for each), 3.60-4.10 (2H, m).

Reference Example 7 [(9aR) -octahydropyrido [1,2-a] pyrazin-8-yl] acetic acid methyl ester (9aR) -8-methoxycarbonylmethyloctahydropyride obtained in Reference Example 6 To a toluene solution (12 mL) of [1,2-a] pyrazine-2-carboxylic acid tert-butyl ester (6.40 g) was added trifluoroacetic acid (12 mL) with stirring at room temperature. 1 at room temperature
After stirring for an hour, the reaction solution was concentrated and dried under reduced pressure to obtain the title compound (9.0 g, 100%) as a pale yellow gel. ¹ H NMR (CD ₃ OD) δ: 0.95 (1H, q, J = 11.8Hz), 1.15-
3.35 (15H, m), 3.65 and3.66 (total 3H, s for eac
h).

REFERENCE EXAMPLE 8 4-[(9aR) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid tert-butyl ester Obtained in Reference Example 7. [(9aR) -octahydropyrido [1,2-a] pyrazin-8-yl] acetic acid methyl ester (0.60 g), triethylamine (1.28 mL), sodium iodide (0.55 g), 4-methanesulfonyloxy Methyl piperidine-1-carboxylic acid
A mixture of tert-butyl ester (1.08 g) and DMF (12 mL) was stirred at 50 ° C. for 18 hours. After cooling the reaction solution to room temperature, water was added, the pH was adjusted to pH 2-3 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The aqueous layer was adjusted to about pH 10 with saturated aqueous sodium hydrogen carbonate, and extracted again with ethyl acetate. The extract is dried over magnesium sulfate, concentrated under reduced pressure,
The title compound (0.68 g, 90%) was obtained as a yellow oil. . IR (KBr) 2928, 1738 , 1694, 1427, 1167cm -1 1 H NMR (CD 3 OD) δ: 0.85-2.15 (11H, m), 1.44 (9H,
s), 2.15-3.20 (14H, m), 3.66 and 3.67 (total 3H, s
for each), 3.97-4.13 (2H, m).

Reference Example 9 4-[(9aR) -8-carboxymethyloctahydropyrido [1,2-
a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid te
rt-butyl ester 4-[(9aR) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid tert-butyl ester obtained in Reference Example 8 ( 0.68g)
To a methanol solution of (13.6 mL) was added a 1N aqueous sodium hydroxide solution (5.0 mL), and the mixture was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH 5-6 with 1N hydrochloric acid and concentrated under reduced pressure.
The residue was subjected to CHP-20 column chromatography (eluent:
Purified by water / acetonitrile) and lyophilized to give the title compound (0.58 g, 87%) as a pale yellow amorphous powder. . IR (KBr) 1688, 1566 , 1426, 1171cm -1 1 H NMR (CD 3 OD) δ: 0.90-3.35 (25H, m), 1.45 (9H,
s), 3.95-4.15 (2H, m). Elemental analysis: C ₂₁ H ₃₇ N ₃ O ₄ · 0.4H ₂ O Calculated: C: 62.63 H: 9.46 N: 10.43 Actual: C: 62.77 H: 9.34 N: 10.40

Reference Example 10 4- _[ (9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene)
-4-sulfonylamino) ethylcarbamoyl] methyl] octahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid tert-butyl ester 4-[(9aR) obtained in Reference Example 9. -8-carboxymethyloctahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-
A mixture of 1-carboxylic acid tert-butyl ester (0.50 g), triethylamine (0.35 mL), HOBT.H ₂ O (0.29 g), WSC (0.48 g), and DMF (5.0 mL) was stirred at room temperature for 1 hour. . Β-alanine derivative (0.61 g), triethylamine
(0.35 mL) and a mixture of DMF (5.0 mL) were added, and the mixture was further stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by CHP-20 column chromatography (eluent: water / acetonitrile) and lyophilized to give the title compound (0.79 g, 91%) as a colorless amorphous powder. . . IR (KBr) 2928, 1740 , 1686, 1426, 1163cm -1 1 H NMR (CD 3 OD) δ: 0.85-4.20 (35H, m), 1.43 (9H,
s), 2.41 (3H, s), 7.35 (2H, d, J = 8.2Hz), 7.70 (2H,
d, J = 8.2Hz). Elemental analysis: C ₃₃ H ₅₃ N ₅ O ₇ S. 1.3H ₂ O Calculated: C: 57.67 H: 8.15 N: 10.19 Found: C: 57.61 H: 7.76 N: 10.22

Example 1 (2S) -3- [2-[(9aR) -2-piperidin-4-ylmethyloctahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] -2
-(Toluene-4-sulfonylamino) propionic acid 4- _[ (9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene-4-sulfonylamino) ethylcarbamoyl] obtained in Reference Example 10 Methyl] octahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid tert-butyl ester (0.3
7g), acetic acid (1.67 mL), concentrated sulfuric acid (0.24 mL) and water (1.48 m
The mixture of L) was stirred at 90 ° C. for 4 hours. After cooling, the reaction solution was adjusted to pH 5-6 with 25% aqueous ammonia, and concentrated under reduced pressure. The residue was purified by CHP-20 column chromatography (eluent: water / acetonitrile), and the target fraction was freeze-dried to obtain the title compound (0.24 g, 70%) as a colorless amorphous powder. IR (KBr) 1645, 1597, 1338, 1323, 1127. ¹ H NMR (CD ₃ OD) δ: 1.00-3.80 (30H, m), 2.40 (3H,
s), 7.34 (2H, d , J = 8.4Hz), 7.72 (2H, d, J = 8.4Hz) Elemental _{analysis:. C 26 H 41 N 5} O 5 S · 0.5H 2 SO 4 · 3.0H 2 As O Calculated: C: 48.89 H: 7.57 N: 10.96 Actual: C: 49.13 H: 7.38 N: 10.86

Example 2 (2S) -3- [2-[(9aS) -2-piperidin-4-ylmethyloctahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] -2
-(Toluene-4-sulfonylamino) propionic acid Example 1
In the same manner as in the above, the title compound (0.3 g) was obtained as a colorless amorphous powder. ¹ H NMR (CD ₃ OD) δ: 1.10-3.80 (30H, m), 2.39 (3H,
s), 7.33 (2H, d, J = 8.4Hz), 7.72 (2H, d, J = 8.4Hz). Elemental analysis: C ₂₆ H ₄₁ N ₅ O ₅ S ・ 0.5H ₂ SO ₄・ 3.0H ₂ As O: Calculated: C: 48.89 H: 7.57 N: 10.96 Actual: C: 48.62 H: 7.61 N: 11.17

Reference Example 11 4-[(9aR) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazin-2-yl] piperidine-1-carboxylic acid
tert-Butyl ester The title compound (0.26 g, 22%) was obtained as a yellow oil in the same manner as in Reference Example 8. ¹ H NMR (CD ₃ OD) δ: 0.80-3.00 (23H, m), 1.45 (9H,
s), 3.65 (3H, s), 4.02-4.18 (2H, m).

Example 3 (2S) -3- [2-[(9aR) -2-piperidin-4-yloctahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] -2- (Toluene-4-sulfonylamino) propionic acid The title compound (0.13 g, 30%) was obtained as a colorless amorphous powder in the same manner as in Example 1. . IR (KBr) 1649, 1387 , 1124cm -1 1 H NMR (CD 3 OD + DCl) δ: 1.20-3.80 (28H, m), 2.40
(3H, s), 7.34 (2H, d, J = 8.0Hz), 7.72 (2H, d, J = 8.0
Elemental analysis: C ₂₅ H ₃₉ N ₅ O ₅ S 1.0 H ₂ SO ₄ 0.5 H ₂ O Calculated: C: 47.76 H: 6.73 N: 11.14 Found: C: 47.54 H: 6.94 N : 10.87

Reference Example 12 4- [2-[(9aR) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazin-2-yl] ethyl] piperidine-1-
Carboxylic acid tert-butyl ester The title compound (2.0 g, 100%) was obtained as a yellow oil in the same manner as in Reference Example 8. . IR (KBr) 2926, 1738 , 1694, 1424, 1165cm -1 1 H NMR (CDCl 3) δ: 1.45 (9H, s), 0.85-3.00 (27H,
m), 3.67 (3H, s), 3.95-4.15 (2H, m).

Reference Example 13 4- [2-[(9aR) -8-carboxymethyloctahydropyrido]
[1,2-a] pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (1.86 g, 96%) was obtained as a yellow amorphous powder in the same manner as in Reference Example 9. . IR (KBr) 1692, 1566 , 1424, 1179cm -1 1 H NMR (CD 3 OD) δ: 1.44 (9H, s), 0.90-3.25 (27H,
m), 3.95-4.15 (2H, m).

Reference Example 14 4- [2-[(9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene-4-sulfonylamino) ethylcarbamoyl] methyl] methyl
Octahydropyrido [1,2-a] pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (0.72 g, 87%) was converted into a colorless amorphous powder in the same manner as in Reference Example 10. Obtained. . IR (KBr) 2926, 1740 , 1690, 1163cm -1 1 H NMR (CD 3 OD) δ: 0.80-4.20 (37H, m), 1.44 (9H,
s), 2.41 (3H, s), 7.34 (2H, d, J = 8.2Hz), 7.69 (2H,
d, J = 8.2Hz). Elemental analysis: C ₃₄ H ₅₅ N ₅ O ₇ S Calculated: C: 60.24 H: 8.18 N: 10.33 Actual: C: 60.14 H: 8.15 N: 10.24

Example 4 (2S) -3- [2-[(9aR) -2- (2- (piperidin-4-yl) ethyl) octahydropyrido [1,2-a] pyrazin-8-yl ] Acetylamino] -2- (toluene-4-sulfonylamino) propionic acid Synthesized in the same manner as in Example 1, added with hydrochloric acid and freeze-dried to obtain the title compound (0.15 g, 40%) as a colorless amorphous powder. Was. . IR (KBr) 1734, 1649 , 1456, 1431, 1159, 1128cm -1 1 H NMR (CD 3 OD) δ: 1.20-4.20 (32H, m), 2.41 (3H,
s), 7.35 (2H, d , J = 8.2Hz), 7.72 (2H, d, J = 8.2Hz) Elemental _{analysis:. C 27 H 43 N 5} O 5 S · 1.0H 2 SO 4 · 2.0HCl · 0.5 H ₂ O Calculated: C: 44.44 H: 6.63 N: 9.60 Actual: C: 44.36 H: 6.89 N: 9.60

Reference Example 15 (2R, 4S) -1-[(S) -2-benzyloxycarbonylamino-3-
(4-Methoxyphenyl) propionyl] -4-hydroxypiperidine-2-carboxylic acid methyl ester The title compound (10.2 g, 58%) was obtained as a colorless amorphous powder in the same manner as in Reference Example 1. . IR (KBr) 2951, 1713 , 1636, 1514, 1422, 1248cm -1 1 H NMR (CDCl 3 + D 2 O) δ: 0.72-0.96 (1H, m), 1.40-1.
80 (2H, m), 2.28-2.50 (1H, m), 2.84-3.08 (2H, m),
3.10-3.82 (2H, m), 3.69 (3H, s), 3.77 (3H, s), 3.9
0-4.20 (1H, m), 4.90-5.24 (4H, m), 6.80 (2H, d, J =
8.8Hz), 7.10 (2H, d, J = 8.8Hz), 7.20-7.50 (5H, m).

Reference Example 16 (3S, 8S, 9aR) -8-Hydroxy-3- (4-methoxybenzyl) hexahydropyrido [1,2-a] pyrazine-1,4-dione The title compound (6.9 g, 100%) was obtained as a colorless amorphous powder. ¹ H NMR (CDCl ₃ + D ₂ O) δ: 1.18-1.48 (2H, m), 1.90-2.
06 (1H, m), 2.18-2.39 (1H, m), 2.39-2.54 (1H, m),
2.95 (1H, dd, J = 2.8, 12.6Hz), 3.09 (2H, d, J = 5.0H
z), 3.55-3.85 (1H, m), 3.79 (3H, s), 4.25 (1H, t,
J = 5.0 Hz), 4.58-4.76 (1H, m), 6.84 (2H, d, J = 8.4H
z), 7.07 (2H, d, J = 8.4Hz).

Reference Example 17 (3S, 8S, 9aR) -3- (4-methoxybenzyl) octahydropyrido [1,2-a] pyrazin-8-ol The title compound (5.67 g) was obtained in the same manner as in Reference Example 3. , 90%) as a pale yellow crystalline powder (ethyl acetate / diethyl ether). . IR (KBr) 2936, 1613 , 1512, 1246cm -1 1 H NMR (CD 3 OD) δ: 1.12 (1H, q, J
= 11.4 Hz), 1.36-1.62 (1H,
m), 1.70-2.20 (5H, m), 2.3
8-3.04 (7H, m), 3.44-3.68
(1H, m), 3.76 (3H, s),
6.85 (2H, d, J = 8.6 Hz), 7.1
1 (2H, d, J = 8.6 Hz). Melting point: 114-117 ° C Elemental analysis: C ₁₆ H ₂₄ N ₂ O ₂ · 0.3 H ₂ O Calculated: C: 68.20 H: 8.80 N: 9.94 Actual: C: 68.38 H: 8.54 N: 9.97

Reference Example 18 (3S, 8S, 9aR) -8-Hydroxy-3- (4-methoxybenzyl) octahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert-
Butyl ester The title compound (5.51 g, 88%) was obtained as a pale yellow amorphous powder in the same manner as in Reference Example 4. . IR (KBr) 2934, 1690 , 1512, 1248cm -1 1 H NMR (CDCl 3 + D 2 O) δ: 1.38 (9H, s), 1.40-1.80 (3
H, m), 2.22 (1H, dd, J = 3.2, 11.6Hz), 2.60-3.04 (6
H, m), 3.45 (1H, dd, J = 4.4, 13.6Hz), 3.54-3.82 (3
H, m), 3.78 (3H, s), 4.08-4.24 (1H, m), 6.82 (2H,
d, J = 8.8Hz), 7.12 (2H, d, J = 8.8Hz).

Reference Example 19 (3S, 9aR) -3- (4-methoxybenzyl) -8-methoxycarbonylmethyleneoctahydropyrido [1,2-a] pyrazine-2-carboxylic acid tert-butyl ester Reference Example 5 The title compound (4.73 g, 75%) was obtained as a yellow oil. . IR (KBr) 2934, 1694 , 1514, 1248, 1165cm -1 1 H NMR (CDCl 3) δ: 1.38 and 1.40 (total 9H, s for
each), 1.20-3.20 (10H, m), 3.35-3.85 (3H, m), 3.68
and 3.69 (total 3H, s for each), 3.78 (3H, s), 4.19
-4.35 (1H, m), 5.68 (1H, s), 6.83 (2H, d, J = 8.8H
z), 7.05-7.20 (2H, m).

Reference Example 20 tert-butyl (3S, 9aR) -3- (4-methoxybenzyl) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazine-2-carboxylic acid Reference Example 6 In the same manner as in the above, the title compound (4.76 g, 100%) was obtained as a colorless oil. ¹ H NMR (CD ₃ OD) δ: 1.20-4.20 (17H, m), 1.40 (9H,
s), 3.66 and 3.68 (total 3H, s for each), 3.78 (3
H, s), 6.82 (2H, d, J = 8.6Hz), 7.12 (2H, d, J = 8.6H
z).

Reference Example 21 [(3S, 9aR) -3- (4-methoxybenzyl) octahydropyrido
[1,2-a] Pyrazin-8-yl] acetic acid methyl ester The title compound (5.85 g, 95%) was obtained as a colorless crystalline powder in the same manner as in Reference Example 7. Melting point: 154-158 ° C Elemental analysis: C ₁₉ H ₂₈ N ₂ O ₃ · 2.0 CF ₃ CO ₂ H Calculated: C: 49.29 H: 5.40 N: 5.00 Actual: C: 49.42 H: 5.19 N: 4.76

Reference Example 22 4-[(3S, 9aR) -3- (4-methoxybenzyl) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1- Carboxylic acid tert-butyl ester The title compound (0.24 g, 50%) was obtained as a yellow oil in the same manner as in Reference Example 8. . IR (KBr) 2932, 1738 , 1694, 1512, 1248, 1159cm -1 1 H NMR (CDCl 3) δ: 0.80-1.75 (7H, m), 1.46 (9H,
s), 1.75-2.08 (8H, m), 2.12-2.32 (3H, m), 2.42-2.90
(7H, m), 3.05 (1H, dd, J = 3.6, 13.6Hz), 3.66 (3H,
s), 3.78 (3H, s), 3.95-4.20 (2H, m), 6.79 (2H, d,
J = 8.4Hz), 7.05 (2H, d, J = 8.4Hz).

Reference Example 23 4-[(3S, 9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene-4-sulfonylamino) ethylcarbamoyl] methyl] methyl
-3- (4-Methoxybenzyl) octahydropyrido [1,2-a] pyrazin-2-ylmethyl] piperidine-1-carboxylic acid tert-
The title compound (0.3
8 g, 40%) as a colorless crystalline powder. Melting point: 101-107 ° C Elemental analysis: C ₄₁ H ₆₁ N ₅ O ₈ S · 0.2HCl Calculated: C: 62.23 H: 7.80 N: 8.85 Found: C: 62.29 H: 7.69 N: 9.01

Example 5 (2S) -3- [2-[(3S, 9aR) -3- (4-methoxybenzyl) -2- (piperidin-4-ylmethyl) octahydropyrido [1,2-a ] Pyrazin-8-yl] acetylamino] -2- (toluene-4-sulfonylamino) propionic acid In the same manner as in Example 1, the title compound (0.11 g, 51%) was obtained as a colorless amorphous powder. . IR (KBr) 1732, 1647 , 1514, 1456, 1252, 1159cm -1 1 H NMR (CD 3 OD) δ: 1.25-1.80 (4H, m), 1.90-2.50
(8H, m), 2.41 (3H, s), 2.70-3.05 (3H, m), 3.05-3.80
(12H, m), 3.78 (3H, s), 3.82-4.25 (4H, m), 6.93 (2
H, d, J = 8.6Hz), 7.27 (2H, d, J = 8.6Hz), 7.36 (2H,
d, J = 8.4Hz), 7.74 (2H, d, J = 8.4Hz). Elemental analysis: C ₃₄ H ₄₉ N ₅ O ₆ S ・ 3.0HCl ・ 4.0H ₂ O Calculated: C: 48.77 H: 7.22 N: 8.36 Observed value: C: 48.51 H: 6.99 N: 8.28

Reference Example 24 4- [2-[(3S, 9aR) -8-carboxymethyl-3- (4-methoxybenzyl) octahydropyrido [1,2-a] pyrazin-2-yl] ethyl] Piperidine-1-carboxylic acid tert-butyl ester The title compound (0.78 g, 100%) was obtained as a pale yellow oil in the same manner as in Reference Example 9. . IR (KBr) 1694, 1514 , 1429, 1250, 1179cm -1 1 H NMR (CD 3 OD) δ: 1.00-4.25 (30H, m), 1.45 (9H,
s), 3.78 (3H, s), 6.95 (2H, d, J = 8.8Hz), 7.26 (2H,
d, J = 8.8Hz).

Reference Example 25 4- [2-[(3S, 9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene-4-sulfonylamino) ethylcarbamoyl] methyl] -3- ( 4-methoxybenzyl) octahydropyrido [1,2-
a] pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid t
ert-butyl ester The title compound (0.60 g, 53%) was obtained as a colorless amorphous powder in the same manner as in Reference Example 10. . IR (KBr) 2928, 1740 , 1690, 1514, 1248, 1163cm -1 1 H NMR (CDCl 3) δ: 0.80-4.15 (35H, m), 1.12 and
1.13 (total 3H, t for each, J = 7.0Hz), 1.45 (9H,
s), 2.42 (3H, s), 3.78 (3H, s), 5.95-6.10 (1H, m),
6.25-6.40 (1H, m), 6.75-6.87 (2H, m), 7.00-7.13 (2
H, m), 7.22-7.36 (2H, m), 7.65-7.78 (2H, m).

Example 6 (2S) -3- [2-[(3S, 9aR) -3- (4-methoxybenzyl) -2- (2-
(Piperidin-4-yl) ethyl) octahydropyrido [1,2-
a] Pyrazin-8-yl] acetylamino] -2- (toluene-4-sulfonylamino) propionic acid In the same manner as in Example 1, the title compound (0.12 g, 47%) was obtained as a colorless amorphous powder. ^{_{[α] D 20 = + 29.7}} ° (c = 0.475, H 2 O) IR (KBr) 1682, 1514, 1204, 1161cm -1 1 H NMR (CD 3 OD) δ:.. 1.00-3.85 (33H, m ), 2.40 (3H,
s), 3.77 (3H, s), 6.89 (2H, d, J = 8.4Hz), 7.11-7.21
(2H, m), 7.28-7.39 (2H, m), 7.72 (2H, d, J = 8.0Hz). Elemental analysis: Calculated as C ₃₅ H ₅₁ N ₅ O ₆ S ・ 3.0HCl ・ 1.0H ₂ O Value: C: 52.73 H: 7.08 N: 8.78 Actual value: C: 52.92 H: 6.69 N: 8.41

Reference Example 26 4- [3-[(3S, 9aR) -3- (4-methoxybenzyl) -8-methoxycarbonylmethyloctahydropyrido [1,2-a] pyrazine-2-
[Ill] propyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (1.84 g, 66%) was obtained as a brown oil in the same manner as in Reference Example 8. . IR (KBr) 2930, 1738 , 1694, 1512, 1246cm -1 1 H NMR (CDCl 3) δ: 0.80-3.00 (29H, m), 1.46 (9H,
s), 3.10 (1H, dd, J = 3.6, 13.2Hz), 3.66 and 3.68 (t
otal 3H, s for each), 3.78 and 3.80 (total 3H, sf
or each), 3.95-4.20 (2H, m), 6.80 (2H, d, J = 8.8H
z), 7.06 (2H, d, J = 8.8Hz).

Reference Example 27 4- [3-[(3S, 9aR) -8-carboxymethyl-3- (4-methoxybenzyl) octahydropyrido [1,2-a] pyrazin-2-yl] propyl] Piperidine-1-carboxylic acid tert-butyl ester The title compound (2.0 g, 100%) was obtained as a brown amorphous powder in the same manner as in Reference Example 9. IR (KBr) 2932, 1686, 1514, 1426, 1366, 1248, 1177cm
_{^{. -1 1 H NMR (CD 3}} OD) δ: 0.90-2.15 (13H, m), 1.45 (9H,
s), 2.26 (2H, d, J = 6.6Hz), 2.40-3.50 (15H, m), 3.7
7 (3H, s), 3.95-4.15 (2H, m), 6.90 (2H, d, J = 8.4H
z), 7.18 (2H, d, J = 8.4Hz).

Reference Example 28 4- [3-[(3S, 9aR) -8-[(2S)-[2-ethoxycarbonyl-2- (toluene-4-sulfonylamino) ethylcarbamoyl] methyl] -3- ( 4-methoxybenzyl) octahydropyrido [1,2-
a] pyrazin-2-yl] propyl] piperidine-1-carboxylic acid
tert-Butyl ester The title compound (0.80 g, 86%) was obtained as a pale yellow amorphous powder in the same manner as in Reference Example 10. . IR (KBr) 2930, 1740 , 1686, 1512, 1246, 1163cm -1 1 H NMR (CD 3 OD) δ: 1.44 (9H, s), 1.03 (3H, t, J =
7.0Hz), 0.70-4.10 (37H, m), 2.41 (3H, s), 3.76 (3H,
s), 6.84 (2H, d, J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz),
7.35 (2H, d, J = 8.2Hz), 7.69 (2H, d, J = 8.2Hz) Elemental _{analysis:. C 43 H 65 N 5} O 8 S · 1.0H 2 O Calculated: C: 62.22 H : 8.14 N: 8.44 Observed value: C: 62.11 H: 7.79 N: 8.77

Example 7 (2S) -3- [2-[(3S, 9aR) -3- (4-methoxybenzyl) -2- (3-
(Piperidin-4-yl) propyl) octahydropyrido [1,2
-a] Pyrazin-8-yl] acetylamino] -2- (toluene-4-
Sulfonylamino) propionic acid The title compound (0.13 g, 32%) was obtained as a colorless amorphous powder in the same manner as in Example 1. IR (KBr) 2936, 1634, 1613, 1514, 1454, 1159, 1125cm
_{^{. -1 1 H NMR (CD 3}} OD) δ: 1.40-3.60 (34H, m), 2.39 (3H,
s), 3.65-3.80 (1H, m), 3.77 (3H, s), 6.88 (2H, d, J
= 8.8Hz), 7.18 (2H, d, J = 8.8Hz), 7.33 (2H, d, J = 8.2
Hz), 7.73 (2H, d, J = 8.2Hz). Elemental analysis: C ₃₆ H ₅₃ N ₅ O ₆ S · 1.0H ₂ SO ₄ · 1.5H ₂ O Calculated: C: 53.45 H: 7.23 N : 8.66 Observed value: C: 53.52 H: 7.22 N: 8.84

Reference Example 29 4- [2-[(3S, 9aR) -8-[(2S)-[2- (butane-1-sulfonylamino) -2-ethoxycarbonylethylcarbamoyl] methyl]
-3- (4-Methoxybenzyl) octahydropyrido [1,2-a] pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid tert-
Butyl ester The title compound (0.2 g, 41%) was obtained as a colorless amorphous powder in the same manner as in Reference Example 10. ¹ H NMR (CD ₃ OD) 0.96 (3H, t, J = 7.0 Hz), 1.30 (3H,
t, J = 7.0Hz), 1.45 (9H, s), 0.90-4.30 (39H, m), 3.79
(3H, s), 4.23 (2H, q, J = 7.0Hz), 6.95 (2H, d, J = 8.
4Hz), 7.27 (2H, d, J = 8.4Hz).

Example 8 (2S) -2- (butane-1-sulfonylamino) -3- [2-[(3S, 9aR)-
3- (4-methoxybenzyl) -2- (2- (piperidin-4-yl) ethyl) octahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] propionic acid Same as in Example 1. The title compound (0.10 g, 56%) was obtained as a colorless amorphous powder. . IR (KBr) 2932, 1610 , 1514, 1248, 1142cm -1 1 H NMR (CD 3 OD) δ: 0.94 (3H, t, J = 7.0Hz), 1.10-4.0
0 (39H, m), 3.76 (3H, s), 6.84 (2H, d, J = 8.4Hz), 7.
10 (2H, d, J = 8.4Hz). Elemental analysis: C ₃₂ H ₅₃ N ₅ O ₆ S.2.5H ₂ O Calculated: C: 56.45 H: 8.59 N: 10.29 Actual: C: 56.79 H : 8.28 N: 10.41

Reference Example 30 4- [2-[(3S, 9aR) -8-[[2- (tert-butoxycarbonyl) ethylcarbamoyl] methyl] -3- (4-methoxybenzyl) octahydropyrido [1 , 2-a] Pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (0.24 g, 39%) was obtained as a colorless oil in the same manner as in Reference Example 10. ¹ H NMR (CD ₃ OD) δ: 0.70-3.50 (32H, m), 1.44 (18H,
s), 3.75 (3H, s), 3.92-4.12 (2H, m), 6.84 (2H, d,
J = 8.6Hz), 7.09 (2H, d, J = 8.6Hz).

Example 9 3- [2-[(3S, 9aR) -3- (4-methoxybenzyl) -2- (2- (piperidin-4-yl) ethyl) octahydropyrido [1,2- a] Pyrazin-8-yl] acetylamino] propionic acid The title compound (0.16 g, 64%) was obtained as a colorless amorphous powder in the same manner as in Example 1. ¹ H NMR (CD ₃ OD) δ: 0.90-3.50 (34H, m), 3.77 (3H,
s), 6.87 (2H, d, J = 8.6Hz), 7.14 (2H, d, J = 8.6Hz). Elemental analysis: C ₂₈ H ₄₄ N ₄ O ₄・ 1.5CF ₃ CO ₂ H ・ 1.0H ₂ Calculated as O: C: 53.98 H: 6.94 N: 8.12 Actual value: C: 54.05 H: 7.01 N: 8.27

Reference Example 31 4- [2-[(3S, 9aR) -8-[(benzyloxycarbonylmethylcarbamoyl) methyl] -3- (4-methoxybenzyl) octahydropyrido [1,2-a] Pyrazin-2-yl] ethyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (0.30 g, 59%) was obtained as a yellow oil in the same manner as in Reference Example 10. . IR (KBr) 1748, 1694 , 1514, 1424, 1248, 1177cm -1 1 H NMR (CD 3 OD) δ: 0.70-3.25 (28H, m), 1.44 (9H,
s), 3.76 (3H, s), 3.90-4.15 (4H, m), 5.15 (2H, s),
6.84 (2H, d, J = 8.4Hz), 7.10 (2H, d, J = 8.4Hz), 7.2
2-7.40 (5H, m).

Example 10 [2-[(3S, 9aR) -3- (4-methoxybenzyl) -2- (2- (piperidin-4-yl) ethyl] octahydropyrido [1,2-a] Pyrazine
-8-yl] acetylamino] acetic acid In the same manner as in Example 1, the title compound (0.12 g, 46%) was obtained as a colorless amorphous powder. ¹ H NMR (CD ₃ OD) δ: 1.00-4.00 (32H, m), 3.77 (3H,
s), 6.89 (2H, d , J = 8.6Hz), 7.17 (2H, d, J = 8.6Hz) Elemental _{analysis:. C 27 H 42 N 4} O 4 · 2.0HCl · 2.0H 2 O Calculated : C: 54.45 H: 8.12 N: 9.41 Actual value: C: 54.42 H: 7.92 N: 9.14

Reference Example 32 4-[(9aR) -8-[(2-tert-butoxycarbonylethylcarbamoyl) methyl] octahydropyrido [1,2-a] pyrazine-2-
[Ilmethyl] piperidine-1-carboxylic acid tert-butyl ester The title compound (0.60 g, 90%) was obtained as a yellow amorphous powder in the same manner as in Reference Example 10. ¹ H NMR (CD ₃ OD) δ: 1.44 (9H, s), 1.45 (9H, s), 0.
80-2.95 (27H, m), 3.38 (2H, t, J = 6.6Hz), 3.95-4.13
(2H, m). Elemental analysis: C ₂₈ H ₅₀ N ₄ O ₅ · 0.5H ₂ O Calculated: C: 63.25 H: 9.67 N: 10.54 Actual: C: 63.53 H: 9.49 N: 10.52

Example 11 3- [2-[(9aR) -2- (piperidin-4-ylmethyl) octahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] propionic acid Example 1 In the same manner as in the above, the title compound (0.12 g, 55%) was obtained as a colorless amorphous powder. IR (KBr) 2942, 1645, 1572cm ^-1 . Elemental analysis: C ₁₉ H ₃₄ N ₄ O ₃ · 1.0H ₂ O Calculated: C: 59.35 H: 9.44 N: 14.57 Actual: C: 59.54 H: 9.49 N: 14.42

Reference Example 33 4- [2-[(9aR) -8-[(tert-butoxycarbonylmethylcarbamoyl) methyl] octahydropyrido [1,2-a] pyrazine-
2-yl] ethyl] piperidine-1-carboxylic acid tert-butyl ester In the same manner as in Reference Example 10, the title compound (0.60 g, 94%) was obtained as a colorless crystalline powder. . IR (KBr) 2930, 1746 , 1692, 1640, 1426, 1167cm -1 1 H NMR (CD 3 OD) δ: 0.80-2.00 (20H, m), 1.44 (9H,
s), 1.46 (9H, s), 2.00-2.48 (4H, m), 2.60-2.98 (3
H, m), 3.80 (2H, s), 3.95-4.13 (2H, m). Melting point: 134-135 ° C Elemental analysis: C ₂₈ H ₅₀ N ₄ O ₅ Calculated: C: 64.34 H: 9.64 N : 10.72 Observed value: C: 64.18 H: 9.75 N: 10.78

Example 12 [2-[(9aR) -2- (2- (piperidin-4-yl) ethyl) octahydropyrido [1,2-a] pyrazin-8-yl] acetylamino] acetic acid The title compound (0.23 g, 55%) was obtained as a colorless amorphous powder in the same manner as in Example 1. IR (KBr) 2932, 1572, 1391, 1132cm ^-1 . Elemental analysis: C ₁₉ H ₃₄ N ₄ O ₃ · 1.0 CH ₃ CO ₂ H · 1.8H ₂ O Calculated: C: 54.95 H: 9.14 N: 12.21 Observed value: C: 54.66 H: 9.00 N: 12.54

Reference Example 34 (3S, 8S, 9aR) -8-tert-butyldiphenylsilanyloxy-
3- (4-methoxybenzyl) hexahydropyrido [1,2-a] pyrazine-1,4-dione The compound (8.02 g) obtained in Reference Example 16, imidazole
(2.33 g) and DMF (80 mL) to a mixture of tert.
-Butyldiphenylsilyl chloride (8.24 mL) was added.
After stirring at room temperature for 13 hours, the reaction solution was poured into diluted hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was crystallized from hexane / ethyl acetate = 5/1 to give the title compound (11.
9g, 83%) as a colorless crystalline powder. . IR (KBr) 2932, 1663 , 1512, 1445, 1252, 1113cm -1 1 H NMR (CDCl 3) δ: 1.02 (9H, s), 1.27-1.80 (3H,
s), 1.98-2.20 (1H, m), 2.35-2.50 (1H, m), 2.90-3.20
(3H, m), 3.55-3.80 (1H, m), 3.77 (3H, s), 4.15-4.
26 (1H, m), 4.42-4.58 (1H, m), 5.91 (1H, br), 6.81
(2H, d, J = 8.6Hz), 7.05 (2H, d, J = 8.6Hz), 7.30-7.5
0 (6H, m), 7.55-7.70 (4H, m). Melting point: 140-142 ° C Elemental analysis: C ₃₂ H ₃₈ N ₂ O ₄ Si Calculated: C: 70.82 H: 7.06 N: 5.16 Actual value : C: 70.78 H: 7.00 N: 5.23

Reference Example 35 (3S, 8S, 9aR) -8-tert-butyldiphenylsilanyloxy-
3- (4-Methoxybenzyl) octahydropyrido [1,2-a] pyrazine The title compound (9.36 g, 83%) was obtained as a pale yellow oil in the same manner as in Reference Example 3. . IR (KBr) 2934, 1512 , 1248, 1111cm -1 1 H NMR (CDCl 3) δ: 1.03 (9H, s), 1.15-1.40 (1H,
m), 1.47-1.98 (7H, m), 2.37-2.78 (6H, m), 2.87-3.05
(1H, m), 3.50-3.72 (1H, m), 3.78 (3H, s), 6.82 (2
(H, d, J = 8.6Hz), 7.08 (2H, d, J = 8.6Hz), 7.30-7.48
(6H, m), 7.60-7.72 (4H, m).

Reference Example 36 (3S, 8S, 9aR) -8-tert-butyldiphenylsilanyloxy-
3- (4-methoxybenzyl) -2- (4-pyridin-4-ylbutyl)
Octahydropyrido [1,2-a] pyrazine The compound obtained in Reference Example 35 (2.0 g), 4- (4-chlorobutyl) pyridine hydrochloride (1.60 g), potassium carbonate (4.30 g),
A mixture of sodium iodide (1.24 g) and DMF (20 mL) was added to 50
Stirred at C for 2 days. After cooling, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (1.0 g, 40%) as a yellow oil. . . IR (KBr) 2938, 1601 , 1512, 1248, 1111cm -1 1 H NMR (CDCl 3) δ: 1.03 (9H, s), 1.18-1.86 (11H,
m), 1.98-2.72 (9H, m), 2.72-2.94 (1H, m), 3.02 (1H,
dd, J = 3.8, 13.8Hz), 3.48-3.68 (1H, m), 3.76 (3H,
s), 6.77 (2H, d, J = 8.6Hz), 7.00 (2H, d, J = 8.6H),
7.09 (2H, d, J = 6.2Hz), 7.28-7.48 (6H, m), 7.60-7.7
0 (4H, m), 8.48 (2H, d, J = 6.2Hz).

Reference Example 37 (3S, 8S, 9aR) -3- (4-methoxybenzyl) -2- (4-pyridine-4
-Ylbutyl) octahydropyrido [1,2-a] pyrazin-8-ol A solution of the compound (1.0 g) obtained in Reference Example 36 in THF (20 mL)
In THF solution of tetrabutylammonium fluoride (3.
1 mL) and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by CHP-20 column chromatography (water / acetonitrile) to give the title compound (0.69
g, 100%) as a yellow amorphous powder. . IR (KBr) 2938, 1605 , 1512, 1248, 1034cm -1 1 H NMR (CD 3 OD) δ: 0.96-1.22 (1H, m), 1.30-2.34
(12H, m), 2.38-3.02 (8H, m), 3.09 (1H, dd, J = 3.6,
13.4Hz), 3.46-3.68 (1H, m), 3.75 (3H, s), 6.83 (2
H, d, J = 8.6Hz), 7.04 (2H, d, J = 8.6Hz), 7.31 (2H,
d, J = 6.0Hz), 8.41 (2H, d, J = 6.0Hz).

Reference Example 38 4- [4-[(3S, 8S, 9aR) -8-hydroxy-3- (4-methoxybenzyl) octahydropyrido [1,2-a] pyrazin-2-yl] butyl ] Piperidine-1-carboxylic acid tert-butyl ester The compound (0.3 g) obtained in Reference Example 37, platinum oxide (0.03
g) and acetic acid (3.0 mL) were stirred under a hydrogen atmosphere for 1 hour. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in a mixed solvent of 1,4-dioxane (3.0 mL) and water (3.0 mL), and sodium bicarbonate (0.31 g) and di-tert-butyl dicarbonate (0.25 mL) were added with stirring at room temperature. . After completion of the reaction, the reaction solution was adjusted to pH 2-3 with 1N hydrochloric acid, and extracted with ethyl acetate. The aqueous layer was adjusted to about pH 10 with saturated aqueous sodium hydrogen carbonate, and extracted again with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (0.38 g, 100%) as a colorless oil. ¹ H NMR (CDCl ₃ + D ₂ O) δ: 0.90-4.20 (32H, m), 1.45
(9H, s), 3.78 (3H, s), 6.80 (2H, d, J = 8.6Hz), 7.06
(2H, d, J = 8.6Hz).

Reference Example 39 4- [4-[(3S, 8S, 9aR) -8-tert-butoxycarbonylmethoxy-3- (4-methoxybenzyl) octahydropyrido [1,2-a]
Pyrazin-2-yl] butyl] piperidine-1-carboxylic acid ter
t-butyl ester 0% was added to a toluene solution (5.0 mL) of the compound (0.38 g) obtained in Reference Example 38 and tert-butyl bromoacetate (0.32 mL).
Under stirring at ℃, tetrabutyl ammonium hydrogen sulfate (0.0
Aqueous solution (0.2 mL) and sodium hydroxide (0.073 g)
Aqueous solution (0.5 mL) was added. After stirring at room temperature for 4 days,
The reaction solution was separated into ethyl acetate and water. After drying the organic layer,
The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4 → ethyl acetate / methanol = 7/1) to give the title compound (0.18 g, 39
%) As a colorless oil. IR (KBr) 2930, 1750, 1694, 1514, 1366, 1246, 1171,
^{. 1123cm -1 1 H NMR (CDCl} 3) δ: 0.90-2.98 (28H, m), 1.45 (9H,
s), 1.47 (9H, s), 3.02-3.19 (1H, m), 3.23-3.45 (1
H, m), 3.78 (3H, s), 3.98 (2H, s), 3.90-4.20 (2H,
m), 6.80 (2H, d, J = 8.8Hz), 7.06 (2H, d, J = 8.8Hz).

Example 13 [(3S, 8S, 9aR) -3- (4-methoxybenzyl) -2- (4- (piperidin-4-yl) butyl) octahydropyrido [1,2-a] pyrazine
-8-yloxy] acetic acid Toluene solution of the compound (0.18 g) obtained in Reference Example 39
(3.6 mL) was added to trifluoroacetic acid (3.6 mL).
Stirred for hours. The reaction solution was concentrated under reduced pressure, and the residue
-20 column chromatography (water / acetonitrile)
The target compound fraction was lyophilized to give the title compound (0.0
9g, 48%) as a colorless amorphous powder. ^{_{[α] D 20 = + 15.1}} ° (c = 0.506, H 2 O) IR (KBr) 2938, 1682, 1613, 1514, 1202, 1128cm -1 1 H NMR (CD 3 OD) δ:.. 1.10-1.76 (11H, m), 1.82-2.02
(2H, m), 2.02-2.20 (2H, m), 2.20-3.04 (10H, m), 3.
10-3.60 (7H, m), 3.77 (3H, s), 3.96 (2H, s), 6.89
(2H, d, J = 8.8Hz ), 7.16 (2H, d, J = 8.8Hz) Elemental _{analysis:. C 27 H 43 N 3} O 4 · 1.3CF 3 CO 2 H · 1.5H 2 O Calculated : C: 54.79 H: 7.35 N: 6.48 Found: C: 55.03 H: 7.43 N: 6.69 The structures of the compounds obtained in Reference Examples and Examples are shown below.

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[0123]

According to the present invention, various diseases (eg, transient cerebral ischemic attack (TI)
A), octahydropyrido [1,2-a] that is effective for the prophylactic treatment of unstable angina, ischemic complications during PTCA or coronary thrombolysis, and reocclusion or restenosis of the coronary artery) A pyrazine derivative is provided. Further, the octahydropyrido [1,2-a] pyrazine derivative of the present invention exhibits a strong platelet aggregation inhibitory action without showing a prolonged bleeding time, and has a sufficient action persistence and oral absorbability. Therefore, it can be used as a prophylactic / therapeutic agent for the above-mentioned diseases safely and at a lower dose than a conventionally known compound having a cell adhesion inhibitory action.

Claims (18)

[Claims] (1) Formula (1) (Wherein, R ¹ is (1) a 5- or 7-membered basic nitrogen-containing heterocyclic group which may be bonded via an optionally substituted alkylene group, may be substituted, or ( 2) an arylcarbonyl group which has a proton accepting group or a group which can be converted thereto and may further have a substituent, wherein R ² represents (1) a hydrogen atom or (2) a hydrocarbon which may be substituted; X represents (1) a bond or (2) a formula -X ¹ -CH ₂ CO- [X ¹ is a bond, -O-,
A group represented by -S- or an -NH-], Y is a -O- (1) -NH- or (2), Z is an alkylene group which may be substituted, R ⁵ is an ester A carboxyl group which may be amidated or amidated, respectively. Or a salt thereof. 2. The method according to claim 1, wherein R ¹ is of the formula (1): — (CH ₂ ) _n —A
Is an optionally substituted 5- to 7-membered nitrogen-containing heterocyclic group, n is an integer of 0 to 5), or (2) an optionally substituted amino group Having an alkyl group, an optionally substituted amino group, an optionally substituted amidino group, an optionally substituted guanidino group, an optionally substituted amidoxime group,
The compound according to claim 1, which is a benzoyl group having a substituent selected from an optionally substituted oxadiazolyl group and an optionally substituted thiadiazolyl group. 3. The compound according to claim 2, wherein A is a basic 6-membered nitrogen-containing heterocyclic group. 4. The compound according to claim 1, wherein R ² is a hydrogen atom or an optionally substituted aralkyl group. 5. The compound according to claim 1, wherein X is --CH ₂ CO--. 6. The compound according to claim 1, wherein Y is -NH-. 7. A method according to claim 7, wherein -ZR ⁵ is a group of the formula —CH ₂ —R ⁵ or a group of the formula —
CHR ³ CHR ⁴ —R ⁵ (wherein, R ³ represents a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group, and R ⁴ represents a hydrogen atom or an optionally substituted The compound according to claim 1, which is a group represented by the following formula: 8. The compound according to claim 7, wherein R ³ is a hydrogen atom. 9. The compound according to claim 7, wherein R ⁴ is a hydrogen atom or an amino group substituted with an acyl group. 10. The method according to claim 10, wherein R ⁴ is of the formula —NH—SO ₂ —R ⁸ , wherein R ^{8 is}
Represents a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted).
A compound as described. 11. R ⁵ is a group represented by the formula —CO—R ¹⁰ (wherein R ¹⁰ is a hydroxyl group, an optionally substituted alkoxy group, an optionally substituted alkenyloxy group, an optionally substituted aralkyloxy group). A compound or an amino group which may be substituted). 12. A compound of the formula (Wherein A ^′ is an optionally substituted basic 5- to 7-membered nitrogen-containing heterocyclic group, n ′ is an integer of 0 to 3, R ^{2 ′} is a hydrogen atom or a substituted even aralkyl group, -Z'-R ^{5 'is} -CH ₂ -R ^5' or -CH
₂ CHR ^{4 ′} -R ^{5 ′} (wherein, R ^{4 ′} is a hydrogen atom or a formula —N
H-SO ₂ -R 8 are shown a group) represented by ^'(wherein, R ^8' represents a optionally substituted hydrocarbon group), R 5 ^'is an optionally esterified carboxyl Or a salt thereof. 13. The compound according to claim 12, wherein R ^{5 ′} is a carboxyl group or a C _1-6 alkoxy-carbonyl group. 14. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 15. The method according to claim 1, which is a GP IIb / IIIa antagonist.
A composition according to claim 4. 16. An agent for preventing or treating angina pectoris.
A composition as described. 17. The composition according to claim 14, which is an agent for preventing or treating unstable angina. 18. A method for preventing or treating transient cerebral ischemic attack or preventing onset or restenosis of a coronary artery after percutaneous intracoronary angioplasty or coronary thrombolysis.
15. The composition according to claim 14, which is a therapeutic agent.