JPH10237028A - Aromatic amine derivative having nos-inhibiting action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound exhibiting an excellent nNOS- inhibiting activity or an excellent iNOS-inhibiting activity and useful as a medicine for treating cerebrovascular diseases, head wounds, spinal injuries, headache, Parkinson's disease, Alzheimer's disease, etc. SOLUTION: A compound of formula I [R1 , R2 are each H, a (substituted) lower alkyl, an acryl, etc., R3 , R4 are each H, a (substituted) lower alkyl, etc.; R5 is H, a lower alkyl, an acyl, etc.; X1 -X4 are each H, a halogen, nitro, etc.; A is a (substituted) benzene ring or a (substituted) aromatic heterocyclic ring; (n), (m) are each 0, 1]. For example, 2-(3-(di-(t-butoxycarbonyl)aminomethyl) phenylamino)-3-nitropyridine. The compound of formula I is obtained by reacting a a substituted aniline of formula II [R5 is H, a (substituted) lower alkyl] with a compound of the formula: A-L (L is a releasing group) in the presence of a base and, if necessary, further a metal catalyst and a ligand in a proper solvent at a temperature of from room temperature to the boiling point of the reaction mixture.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an N-substituted aniline derivative, and more particularly to a nitric oxide synthase (nitri oxide synthase).
CO 2 has an inhibitory effect on nitric oxide (NO).
Cerebrovascular disorder (cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism]) in which excessive NO or NO metabolites are considered to be involved Transient ischemic attack, cerebral edema), head trauma, spinal injury, pain (headache [migraine, tension-type headache,
Cluster headache, chronic seizure headache]), useful for Parkinson's disease, Alzheimer's disease, convulsions, morphine tolerance and dependence, septic shock, rheumatoid arthritis, osteoarthritis, viral or non-viral infections, diabetes A compound represented by the general formula (1) or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof, and a prophylaxis characterized by containing these as an active ingredient: And therapeutic agents.

[0002]

2. Description of the Related Art In Japan, the number of deaths due to cerebrovascular disorders began to decrease around 1970 with the improvement of acute treatment, but it is still the second leading cause of adult illness after cancer. On the other hand, the incidence rate is considered to be unchanged from many statistical results, and it is presumed that the number of patients will increase in light of future aging unlike any other in the world. Declining mortality and aging have led to an increase in chronic cerebrovascular disease, which has become a national issue not only in terms of the individual and social aspects of patients, but also in terms of the health economics associated with long-term care. I have.
In cerebral infarction, which accounts for most of cerebrovascular disorders, cerebral artery occlusion causes ischemia on the peripheral side from the occluded site, resulting in an ischemic state. Most of the chronic symptoms of cerebral infarction are caused by the loss of nerve cells, and it is considered to be extremely difficult to establish a therapeutic agent or a treatment method for completely recovering these symptoms. Therefore, it is not an exaggeration to say that the improvement of therapeutic results for cerebral infarction depends on how to implement treatment in the acute phase for the purpose of protecting nerve cells and how much the symptoms can be improved in the acute phase. . However, the therapeutic agents currently used in the clinic are antiplatelet drugs, anticoagulants, thrombolytic drugs, etc., which do not have a direct neuroprotective effect (Kazuo Minematsu et al., "Medicina").
(Medical Shoin) 32, 1995; Hidehiro Mizusawa et al. “Internal Medicine” (Nan-Edo) 79, 1997). Therefore, it is desired to develop a drug having a completely new mechanism of action, which has a different mechanism of action from conventional therapeutic agents, as a therapy for cerebrovascular disorders, especially cerebral infarction.

The theory that NOS isoforms exist in at least three types is currently dominant from genetic analysis. That is, nNOS (type 1), which is constitutively present in nerve cells and is calcium-dependent, eNOS (type 3), which is constitutively present in vascular endothelial cells and is calcium-dependent, and macrophages and many other cells And cytokines in vivo and lipopolysa
iNOS (type 2), which is induced and synthesized by stimulus and apparently calcium-independent (Nathan et al., FAS).
EB J. 16, 3051-3064, 1992; Na
gafuji et al. , Mol. Chem. Ne
uropathol. 26, 107-157, 199
5).

[0004] Potential mechanisms of brain tissue damage associated with cerebral ischemia include elevated extracellular glutamate levels, abnormal activation of glutamate receptors present at the postsynapse, elevated intracellular calcium levels, and calcium-dependent enzymes. A series of pathways has been proposed for the activation of (Siesjoe, J .;
Cereb. Blood Flow Metab. 1,
155-185, 1981; Siesjoe, J .; Ne
urosurg. 60, 883-908, 1984; C
hoi, Trends Neurosci. 11,46
5-469, 1988; Siesjoe and B
engstsson, J. et al. Cereb. Blood F
low Metab. 9,127-140,198
9). As described above, since nNOS is calcium-dependent, it is thought that inhibiting abnormal activation of this type of NOS isoform exerts a protective effect on neurons by NOS inhibitors. (Daw
sonet al. , Annals Neurol. 3
2,297-311, 1992). In fact, nNOS m
RNA amount and the number of nNOS-containing neurons began to increase early after rat focal cerebral ischemia, and their time course was consistent with that of infarct lesions (Zhang et al., Brain).
Res. 654, 85-95, 1994). Further, in the mouse focal cerebral ischemia model, N ^G least infarct reduction effect is observed -nitro-L-arginin
In the e (L-NA) dose range, the inhibition rate of nNOS activity and the infarct size reduction rate are correlated (Carreau et a).
l. , Eur. J. Pharmacol. 256,24
1-249, 1994). Furthermore, it has been reported that the volume of infarct lesion observed after focal cerebral ischemia is significantly smaller in nNOS knockout mice than in controls (Huang et al., Science 26).
5,1883-1885, 1994).

On the other hand, NO is a vascular endothelium-derived relaxing factor (e
ndothelium-derived relaxi
ng factor (EDRF), it is thought to be involved in the regulation of vascular tension and blood flow (Moncada et al.,
Pharmacol. Rev .. 43, 109-142,
1991). In fact, when L-NA is administered to rats at a high dose, a decrease in cerebral blood flow and a decrease in cerebral blood flow are observed in a dose-dependent manner (Toru Matsui et al., Experimental Medicine, 11, 55-6).
0, 1993). The brain is equipped with a mechanism that maintains a constant cerebral blood flow regardless of a certain range of changes in body blood pressure (commonly called "self-regulatory mechanism"). PC, 24
7-249, 1990). Matsui et al.'S report suggests that this "self-regulatory mechanism" has ceased to operate. Therefore, when cerebral ischemia is observed, particularly when eNOS is inhibited to a certain degree or more, cerebral blood flow is decreased and body blood pressure is increased. In addition, in eNOS knockout mice, the infarct lesion observed after focal cerebral ischemia was larger than that of the control, which was significantly reduced by L-NA administration (Huang et al., J. Cere).
b. Blood Flow Metab. 16,981
-987, 1996). These reports indicate that NO derived from eNOS acts protectively on brain tissue, possibly through a vasodilatory action, a platelet aggregation inhibitory action, and the like.

Heretofore, the present inventors have reported that L-NA, which is a known substance known as an inhibitor of NOS, has been known to have cerebral edema and cerebral infarction (Nagafujie) occurring after experimental cerebral ischemia.
tal. , Neurosci. Lett. 147,15
9-162, 1992; JP-A-6-192080), nerve cell necrosis (Nagafuji et al.)
l. , Eur. J. Pharmacol. Env. To
x. 248, 325-328, 1993). On the other hand, it has been reported that relatively high doses of NOS inhibitors are ineffective or even exacerbate ischemic brain injury (Iadec).
ola et al. , J. et al. Cereb. Blood
Flow Metab. 14,175-192,199
4: Toshiaki Nagafuji, Toru Matsui, Experimental Medicine, 13, 127-13
5, 1995; Nagafuji et al. , Mo
l. Chem. Neuropathol. 26,107
-157, 1995). However, it is also true that the results of papers reporting changes in NO or NO-related metabolites in the brain and blood in the model of permanent or temporary cerebral ischemia are all consistently increasing (Nagato) Toshiaki, Toru Matsui, Experimental Medicine, 13,127-135,199
5; Nagafuji et al. , Mol. Che
m. Neuropathol. 26, 107-157,
1995).

[0007] Contradictory reports of the effects of NOS inhibitors on cerebral ischemia models may be due to the low selectivity of the NOS inhibitors used for nNOS. In fact, L-NA and N ^G -nitro-L
-Arginine methyl ester (L-
NAME) and other existing NOS inhibitors
None of the specific NOS isoforms have a high selective inhibitory action (Nagafuji et a
l. , Neuroreport 6,1541-154
5, 1995; Nagafuji et al. , Mo
l. Chem. Neuropathol. 26,107
-157, 1995). Therefore, it is considered that an agent having a selective inhibitory effect on nNOS is desirable as a therapeutic agent for ischemic cerebrovascular disorder. (Nowickie
t al. , Eur. J. Pharmacol. 20
4,339-340, 1991; Dawson et.
al. Proc. Natl. Acad. Sci. US
A 88, 6368-6371, 1991; Iadec
ola et al. , J. et al. Cereb. BloodF
low Metab. 15, 52-59, 1995; I
adecola et al. , J. et al. Cereb. Blo
od Flow Metab. 15,378-384,
1995; Toshiaki Nagafuji, Toru Matsui, Experimental Medicine, 13,127
-135, 1995; Nagafuji et a
l. , Mol. Chem. Neuropathol. 2
6, 107-157, 1995).

[0008] Note that nNOS inhibitors include head trauma (O
ury et al. , J. et al. Biol. Chem. 26
8, 15394-15398, 1993; MacKen
zie et al. , Neuroreport 6,
1789-1794, 1995; Mesheng et.
al. , J. et al. Neurotrauma. 13, 11-
16, 1996; Wallis et al. , Bra
in Res. , 710, 169-177, 199
6), headache and pain (Moore et al., Br.
J. Pharmacol. 102, 198-202, 1
991; Olesen. , Trends Pharma
col. 15, 149-153, 1994), Parkinson's disease (Youdim et al., Advance).
s Neurol. 60, 259-266, 1993;
SchulZ et al. , J. et al. Neuroche
m. 64, 936-939, 1995; Hantray
e et al. , Nature medicine
2, 1017-1021, 1996), Alzheimer's disease (Hu and EI-FaKahany, New)
oreport 4,760-762,1993; Me
da et al. , Nature 374, 647-
650, 1995), convulsions (Rigaud-Mone).
t et al. , J. et al. Cereb. Blood Fl
ow Metab. 14, 581-590; 199
4), morphine tolerance and dependence (Kolesnikove)
t al. , Eur. J. Pharmacol. 22
1, 399-400, 1992; Cappendijk
et al. , Neurosci Lett. 16
2,97-100, 1993) as a therapeutic agent.

On the other hand, iNOS is induced and synthesized in immunocompetent cells such as macrophages and glial cells and other cells by certain kinds of cytokines and LPS, and a large amount of NO generated expands blood vessels and causes fatal blood pressure decrease. To invite, i
NOS inhibitors are thought to be effective against septic shock (Kilbourn and Griffi)
th, J .; Natl. Cancer Inst. 84,
827-831, 1992; Cobb et al. ,
Crit. Care Med. 21, 1261-126
3, 1993; Lorente et al. , Cri
t. CareMed. 21,1287-1295,19
93). In addition, iNOS inhibitors have been used to treat rheumatoid arthritis and osteoarthritis (Farrel et al., An
n. Rheum. Dis. 51, 1219-1222
1992; Hauselmannet et al. , FEB
S Lett. 352, 361-364, 1994; I
slate et al. , Br. J. Pharma
col. 110, 701-706, 1993), viral or non-viral infections (Zembvitza).
nd Vane, Proc. Natl. Acad. Sc
i. USA 89, 2051-2055, 1992; K
oprowski et al. Proc. Nat
l. Acad. Sci. USA 90, 3024-30
27, 1993), diabetes (Kolb et al.,
Life Sci. PL213-PL217,199
It has been suggested to be useful as a therapeutic agent for 1).

As NOS inhibitors showing some selectivity for nNOS, ^NG- cyclopr
opyl-L-arginine (L-CPA) (La
mberte et al. , Eur. J. Pharm
acol. 216, 131-134, 1992), L-
NA (Furfine et al., Bioche)
m. 32, 8512-8517, 1993), S-me
thyl-L-thiocitrulline (LM
IN) (Narayanan and Griffith)
h. Med. Chem. 37,885-887,1
994; Furfine et al. , J. et al. Bio
l. Chem. 37, 885-887, 1994; Fu
rfine et al. , J. et al. Biol. Chem.
269, 26677-26683, 1994; WO95
/ 09419; Narayanan et a
l. , J. et al. Biol. Chem. 270, 11103-
11110, 1995; Nagafuji et a
l. , Neuroreport 6,1541-154
5, 1995), S-ethyl-L-thiocit
ruline (L-EIN) (Furfine et
al. , J. et al. Biol. Chem. 269, 2667
7-26683, 1994; WO 95/09619; Narayanan et al. , J. et al. Bio
l. Chem. 270, 11103-11110, 19
95), ARL17477 (Gentile et a
l. , WO 95/05363; Zhang et.
al. , J. et al. Cereb. Blood Flow
Metab. , 16, 599-604, 1996). Moreover, as inhibitors exhibit some selectivity for iNOS, N ^G -iminoethyl-L
-Ornithine (L-NIO) (McCall
et al. , Br. J. Pharmacol. 102,
234-238, 1991), aminoguanid
ine (AG) (Griffith et al., B
r. J. Pharmacol. 110,963-96
8, 1993; Hasan et al. , Eur.
J. Pharmacol. 249, 101-106, 1
993).

[0011]

SUMMARY OF THE INVENTION It is an object of the present invention to provide nNOS, which is constitutively present in nerve cells mainly in the brain and is calcium-dependent, or inducible and apparently calcium-independent. has an inhibitory effect on iNOS,
Cerebrovascular disorders (cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism], transient ischemic attack, cerebral edema), head injury, spinal injury, pain (headache)
[Migraine, tension headache, cluster headache, chronic seizure headache]),
To provide a novel compound useful as a therapeutic agent for Parkinson's disease, Alzheimer's disease, convulsions, morphine resistance or dependence, septic shock, rheumatoid arthritis, osteoarthritis, viral or non-viral infection, and diabetes .

[0012]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above problems, and as a result, the general formula (1)

[0013]

Embedded image

(Wherein R ₁ and R ₂ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, a lower alkoxycarbonyl group,
Together, they may form a 3- to 8-membered ring. R ₃ , R
₄ is the same or different and represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a monocyclic or condensed ring having 3 to 10 carbon atoms together. R
₅ represents a hydrogen atom, a lower alkyl group, an acyl group, or a lower alkoxycarbonyl group. X ₁ , X ₂ , X ₃ and X ₄ are the same or different and are each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkenyl group, a lower An alkynyl group, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, a phenyl group which may be substituted with a halogen atom and / or a lower alkyl group, NX ₅ X ₆ , C (＝ O) X ₇ , where:
X ₅ and X ₆ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, a lower alkoxycarbonyl group which may have a substituent, or X ₇ may be a hydrogen atom, a hydroxyl group, a lower alkyl group optionally having substituent (s), a lower alkoxy group optionally having substituent (s); , NX ₈ X ₉ wherein X ₈ and X ₉ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, or 3 to 3
An 8-membered ring may be formed. A is a benzene ring which may have a substituent, or may have a substituent,
And a 5- to 6-membered aromatic heterocyclic ring containing at least one nitrogen atom as a hetero atom. n and m are each 0 or 1
Indicates an integer. ) Or its possible tautomers, stereoisomers, optically active forms and pharmaceutically acceptable salts thereof are of the type 1 N
It has been found that it has an inhibitory effect on OS and the like, and exhibits a remarkable effect as a therapeutic agent for cerebrovascular disorders (particularly, a therapeutic agent for obstructive cerebrovascular disorders), thereby completing the present invention.

Further, the present invention provides a reaction route (A)

[0016]

Embedded image

A method for producing a compound of the general formula (1) represented by the general formula (2) (wherein R ₁ , R ₂ ,
R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , n and m are the same as those described above; R ₅ is a hydrogen atom or a lower alkyl group which may have a substituent. Is shown. ), And a compound represented by the general formula (3) (where A represents the same meaning as described above; L represents a leaving group), and reacted with a compound represented by the general formula (1) ) Is provided.

Further, the present invention provides a reaction route (B)

[0019]

Embedded image

The production method represented by the general formula (9), wherein R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ ,
X ₄ , L, n, and m are the same as those described above. ) And a substituted benzene represented by the general formula (10) (where A, R ₅
Indicates the same as above. The present invention also provides a method for producing a compound represented by the general formula (1) by reacting the compound represented by the general formula (1).

In the present invention, the 5- to 6-membered aromatic heterocyclic ring containing one or more nitrogen atoms as a hetero atom in A is a pyrrole ring, a pyrrole-1-oxide ring, a pyrazole ring, a pyrazole-1 ring. An oxide ring, a pyrazole-2-oxide ring, a pyrazole-1,2-dioxide ring, an imidazole ring, an imidazole-1-oxide ring,
Imidazole-3-oxide ring, imidazole-1,3
-Dioxide ring, isoxazole ring, isoxazole-2-oxide ring, oxazole ring, oxazole-
3-oxide ring, isothiazole ring, isothiazole-
1-oxide ring, isothiazole-1,1-dioxide ring, isothiazole-1,2-dioxide ring, isothiazole-2-oxide ring, thiazole ring, thiazole-
A 1-oxide ring, a thiazole-1,1-dioxide ring,
Thiazole-3-oxide ring, pyridine ring, pyridine-
N-oxide ring, pyridazine ring, pyridazine-1-oxide ring, pyridazine-1,2-dioxide ring, pyrimidine ring, pyrimidine-1-oxide ring, pyrimidine-1,
Examples include a 3-dioxide ring, a pyrazine ring, a pyrazine-1-oxide ring, and a pyrazine-1,4-dioxide ring.

The substituent in A is a hydroxyl group, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a lower alkoxy group, a lower alkyl group, a lower alkylthio group, NX ₁₀ X ₁₁ , C (＝ O) X ₁₂ Where; where
X ₁₀ and X ₁₁ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, a lower alkoxycarbonyl group which may have a substituent, or X ₁₂ may be a hydrogen atom, a hydroxyl group, a lower alkyl group optionally having substituent (s), a lower alkoxy group optionally having substituent (s); , NX ₁₃ X ₁₄ ; where X ₁₃ , X
₁₄ is the same or different and represents a hydrogen atom, a lower alkyl group which may have a substituent, or may form a 3- to 8-membered ring together.

A lower alkyl group is a straight-chain alkyl group having 1 to 6 carbon atoms.
Represents an alkyl group, a branched or cyclic alkyl group having 3 to 8 carbon atoms, for example, a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an i-propyl Group, i-butyl group, sec-butyl group, t-butyl group, i-pentyl group, neopentyl group,
t-pentyl group, i-hexyl group, cyclopropyl group,
Examples thereof include a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

A lower alkenyl group is a straight-chain C 2 -C 2 group.
6 represents an alkenyl group having 6 or 6 to 6 branched alkenyl groups, for example, a vinyl group, an allyl group, a 1-butenyl group, a 1-pentenyl group, a 1-hexenyl group, a 2-butenyl group, and a 2-pentenyl group. , 2-hexenyl group, isopropenyl group, 2-butenyl group, 1-methyl-1-propenyl group and the like.

The lower alkynyl group is a straight-chain C 2 -C 2 group.
6 represents an alkynyl group of 6 or a branched alkynyl group having 3 to 6 carbon atoms, for example, an ethynyl group, a 1-propynyl group,
Butynyl group, 1-pentynyl group, 1-hexynyl group, 2
-Propynyl group, 2-butynyl group, 2-pentynyl group,
2-hexynyl group, 1-methyl-2-propynyl group, 3
-Methyl-1-butynyl group, 1-ethyl-2-propynyl group and the like.

The lower alkoxy group is a straight-chain C 1 -C 1 group.
6 represents an alkoxy group, a branched or cyclic alkoxy group having 3 to 8 carbon atoms, for example, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy, i- Propoxy group, i-butoxy group, sec-butoxy group, t-butoxy group, i-pentoxy group, neopentoxy group, t-pentoxy group, i
-Hexoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy and the like.

A lower alkylthio group is a straight-chain alkyl group having 1 carbon atom.
-6 alkylthio groups, branched or cyclic C3-C3
8 represents an alkylthio group, for example, a methylthio group, an ethylthio group, an n-propylthio group, an n-butylthio group,
n-pentylthio group, n-hexylthio group, i-propylthio group, i-butylthio group, sec-butylthio group,
t-butylthio group, i-pentylthio group, neopentylthio group, t-pentylthio group, i-hexylthio group, cyclopropylthio group, cyclobutylthio group, cyclopentylthio group, cyclohexylthio group, cycloheptylthio group, cyclooctyl And a thio group.

An acyl group includes, in addition to a formyl group, an alkylcarbonyl group in which the alkyl moiety is a lower alkyl group,
Represents an arylcarbonyl group, such as acetyl, propionyl, butyryl, valeryl, isobutyryl, isovaleryl, pivaloyl, benzoyl, phthaloyl, and toluoyl;

The lower alkoxycarbonyl group means an alkoxycarbonyl group in which the alkyl moiety is a lower alkyl group, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, n-butoxycarbonyl, n-pentoxy. Carbonyl group, n-hexoxycarbonyl group, i-propoxycarbonyl group, i
-Butoxycarbonyl group, sec-butoxycarbonyl group, t-butoxycarbonyl group, i-pentoxycarbonyl group, neopentoxycarbonyl group, t-pentoxycarbonyl group, i-hexoxycarbonyl group, cyclopropoxycarbonyl group, cyclo Butoxycarbonyl group,
Examples thereof include a cyclopentoxycarbonyl group, a cyclohexoxycarbonyl group, a cycloheptoxycarbonyl group, and a cyclooctoxycarbonyl group.

The halogen atom is a fluorine atom, a chlorine atom,
Represents a bromine or iodine atom.

The leaving group means a halogen atom, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group or a methanesulfonyloxy group.

R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ ,
X ₄ , X ₅ , X ₆ , X ₇ , X ₈ , X ₉ , X ₁₀ , X ₁₁ , X ₁₂ , X
₁₃ and X ₁₄ , a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent,
Examples of the substituent in the lower alkylthio group which may have a substituent and the lower alkoxycarbonyl group which may have a substituent include a phenyl group which may be substituted with a halogen atom, a halogen atom or a lower alkyl group. ,
And a cyclic alkyl group having 3 to 8 carbon atoms.

A ring in which R ₁ and R ₂ may together form a 3- to 8-membered ring, a ring in which X ₅ and X ₆ may together form a 3- to 8-membered ring, _A ring in which ₈ and X ₉ may combine to form a 3- to 8-membered ring, a ring in which X ₁₀ and X ₁₁ may combine to form a 3- to 8-membered ring, X ₁₃ and X ₁₄ Together 3 ~
The ring which may form an 8-membered ring refers to a heterocyclic ring containing at least one nitrogen atom as a hetero atom, for example, a pyrrole ring,
Pyrazole ring, imidazole ring, triazole ring, aziridine ring, azetidine ring, pyrrolidine ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring,
An azepan ring, an azocan ring and the like can be mentioned.

Examples of the ring in which R ₃ and R ₄ may form a monocyclic or condensed ring having 3 to 10 carbon atoms include, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, Examples include a cycloheptane ring, a cyclooctane ring, an indane ring, and a tetralin ring.

NX ₅ X ₆ , NX ₈ X ₉ , NX ₁₀ X ₁₁ , NX ₁₃
X ₁₄ is, for example, an amino group, a methylamino group, a benzylamino group, an ethylamino group, a dimethylamino group,
Ethylmethylamino group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, acetamido group, benzamide group, N-methylacetamido group, benzamido group, tert-butoxycarbonylamino group, N- A methyl-t-butoxycarbonylamino group, a pyrrol-1-yl group, a pyrazol-1-yl group,
Imidazol-1-yl group, triazol-1-yl group, aziridin-1-yl group, azetidin-1-yl group, pyrrolidin-1-yl group, piperidin-1-yl group, piperazin-1-yl group, morpholine -4-yl group, thiomorpholin-4-yl group and the like.

As C (＝ O) X ₇ , for example, formyl group, carboxyl group, acetyl group, propionyl group,
Cyclobutyryl group, methoxycarbonyl group, ethoxycarbonyl group, t-butoxycarbonyl group, carbamoyl group, N-methylcarbamoyl group, N-ethylcarbamoyl group, N, N-dimethylcarbamoyl group, N-ethyl-
N-methylcarbamoyl group, pyrrolidinecarbonyl group,
Examples include a piperidine carbonyl group and a morpholine carbonyl group.

As R ₁ and R ₂ , a hydrogen atom is preferable.
As R ₃ and R ₄ , a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, and a monocyclic ring having 3 to 5 carbon atoms are preferable, and a hydrogen atom, a methyl group, an ethyl group, and a cyclobutyl group are particularly preferable.
R ₅ is preferably a hydrogen atom. X ₁ , X ₂ , X ₃ , X
Preferred as ₄ are a hydrogen atom, a halogen atom, a lower alkyl group having 1 to 3 carbon atoms and a lower alkoxy group having 1 to 3 carbon atoms, particularly, a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group, and a methoxy group. Groups, ethoxy groups and n-propoxy groups are preferred. As A, a benzene ring or a pyridine ring which may have a substituent is preferable. Among them, a nitro group, a lower alkyl group having 1 to 3 carbon atoms, a lower alkoxy group having 1 to 3 carbon atoms, and 1 carbon atom A benzene ring or a pyridine ring substituted with a lower alkylthio group of 1 to 3 is more preferable, and a 6-methoxy-3-nitrobenzene-2-yl group, a 6-methyl-3-nitropyridin-2-yl group, 6 -Methoxy-3-nitropyridine-
A 2-yl group and a 4-methylpyridin-2-yl group are preferred. When m and n are both 0, X ₁ ,
The benzene nucleus substituent of the substituents other than X ₂ , X ₃ and X ₄ is preferably meta-substituted, and when m + n = 1, X ₁ ,
The benzene nucleus of the substituents other than X ₂ , X ₃ and X ₄ is preferably ortho- or para-substituted.

The compound represented by the general formula (1) includes
2- (3-aminomethylphenylamino) -6-methoxy-3-nitropyridine, 2- (3-aminomethylphenylamino) -6-methyl-3-nitropyridine, 2-
(3-aminomethylphenylamino) -6-ethyl-3
-Nitropyridine, 2- (3-aminomethylphenylamino) -6-ethoxy-3-nitropyridine, 2- (3
-Aminomethylphenylamino) -6-methylthio-3
-Nitropyridine, 2- (3-aminomethylphenylamino) -6-methyl-3-nitrobenzene, 2- (3-
Aminomethylphenylamino) -6-methoxy-3-nitrobenzene, 2- (3-aminomethyl-2-methylphenylamino) -6-methoxy-3-nitropyridine,
2- (4-aminoethylphenylamino) -6-methoxy-3-nitropyridine, 2- (3- (1-amino-1
-Methylethyl) phenylamino) -6-methoxy-3
-Nitropyridine, 2- (3-aminomethyl-2-methoxyphenylamino) -6-methoxy-3-nitropyridine, 2- (3-aminomethyl-4-chlorophenylamino) -6-methoxy-3-nitropyridine , 2- (3
-Aminomethyl-4-fluorophenylamino) -6
Methoxy-3-nitropyridine, 2- (3-aminomethyl-2-ethoxyphenylamino) -6-methoxy-3
-Nitropyridine, 2- (3-aminomethyl-2-chlorophenylamino) -6-methoxy-3-nitropyridine, 2- (3-aminomethylphenylamino) -4-methylpyridine, 2- (3- (1 -Amino-1-methylethyl) phenylamino) -4-methylpyridine, 2-
(3-aminomethyl-2-methylphenylamino) -4
-Methylpyridine, 2- (3-aminomethyl-4-ethylphenylamino) -4-methylpyridine, 2- (3-
Aminomethyl-4-ethoxyphenylamino) -4-methylpyridine, 2- (2-aminoethylphenylamino) -4-methylpyridine, 2- (3-aminomethyl-
2-chlorophenylamino) -4-methylpyridine, 2
-(3- (1-amino-cyclobutyl) phenylamino) -4-methylpyridine, 2- (4-aminoethylphenylamino) -4-methylpyridine, 2- (3-aminomethyl-2-ethoxyphenylamino) -4-methylpyridine, 2- (3-aminomethyl-4-chlorophenylamino) -4-methylpyridine, 2- (3-aminomethyl-2- (n-propoxy) phenylamino) -4-
Methylpyridine, 2- (3-aminomethyl-4-chloro-2-ethoxyphenylamino) -4-methylpyridine, 2- (3-aminomethyl-2-ethoxy-4-methylphenylamino) -4-methylpyridine , 2- (3-
Preferred are aminomethyl-2-methoxyphenylamino) -4-methylpyridine and 2- (3-aminomethyl-2- (i-propoxy) phenylamino) -4-methylpyridine.

The present invention includes, besides the compound represented by the general formula (1), possible tautomers, stereoisomers, optically active isomers and mixtures thereof.

[0040]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention represented by the general formula (1) can be synthesized, for example, as follows.

[0041]

Embedded image

[0042]

Embedded image

The compound represented by the general formula (1) can be synthesized by reacting the compound represented by the general formula (2) with the general formula (3) as a starting material.
Here, in the general formulas (1), (2) and (3), R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X
₄ , X ₅ , X ₆ , X ₇ , X ₈ , X ₉ , A, L, n and m each have the same meaning as described above.

That is, the compound represented by the general formula (1) can be obtained by converting the compound represented by the general formula (2) and the compound represented by the general formula (3) into potassium carbonate, triethylamine, diisopropylethylamine, potassium t -Butoxide, sodium If necessary, in the presence of a base such as t-butoxide, a metal catalyst such as copper, palladium and nickel and diphenylphosphinoethane, diphenylphosphinopropane, diphenylphosphinoferrocene, and 2,2′-
A ligand such as bis (diphenylphosphino) -1,1′-binaphthyl is added, and in a solvent that does not affect the reaction,
For example, it can be synthesized by reacting in methanol, ethanol, alcohols such as i-propanol, or in dimethylformamide, tetrahydrofuran, acetonitrile, toluene, 1,4-dioxane at a temperature from room temperature to the boiling point of the reaction mixture. it can. Preferably, the reaction is carried out at 60 ° C. in dimethylformamide in the presence of triethylamine or diisopropylethylamine, or in the presence of potassium carbonate, potassium t-butoxide or sodium t-butoxide, a palladium catalyst and diphenylphosphinoferrocene or 2,2 ′.
It can be synthesized by adding a ligand of -bis (diphenylphosphino) -1,1′-binaphthyl and reacting in acetonitrile or toluene at a temperature from 80 ° C. to the boiling point of the reaction mixture.

The compound represented by the general formula (1) is
The compound can also be synthesized by reacting the compound represented by the general formula (9) with the general formula (10) as a starting material. However, the general formula (1), the general formula (9), and the general formula (1
0), R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ ,
X ₄ , R ₅ , A, L, m, and n each have the same meaning as described above.

That is, the compound represented by the general formula (1) can be obtained by combining the compound represented by the general formula (9) and the compound represented by the general formula (10) with potassium carbonate, triethylamine,
In the presence of a base such as potassium t-butoxide and sodium t-butoxide, preferably in the presence of potassium t-butoxide, if necessary, a metal catalyst such as copper, palladium and nickel and diphenylphosphinoethane, diphenylphosphinopropane, diphenyl Phosphinoferrocene, 2,2′-bis (diphenylphosphino) -1,
A ligand such as 1′-binaphthyl is added, preferably a palladium catalyst and a ligand of diphenylphosphinoferrocene are added, and an alcohol such as methanol, ethanol, i-propanol or the like is added in a solvent that does not affect the reaction. Or in dimethylformamide, tetrahydrofuran, acetonitrile, toluene, dioxane, preferably toluene, at a temperature from room temperature to the boiling point of the reaction mixture, preferably 80 ° C.

Among the compounds represented by the general formula (1), A
There is a pyridine ring optionally having a substituent, further one of the substituents, a lower alkoxy group, lower alkylthio group, a compound represented by NX ₁₀ X ₁₁ a is Formula (5) is removed It can also be synthesized using the general formula (4) to which a leaving group is bonded as a starting material. Here, general formulas (4), (5), (12), (13), (1)
In 4), R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ ,
X ₄ , L, m, and n each have the same meaning as described above; R ₆ represents an electron-withdrawing group such as a nitro group, a cyano group, a trifluoromethyl group, and C (＝ O) X ₇ ; R ₇ , R ₈
Represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a lower alkyl group, a lower alkylthio group, and NX, respectively.
₅ X ₆ , C (ＯO) X ₇ ; where X ₅ , X ₆ , X
₇ represents the same as above; R ₁₁ represents a lower alkoxy group, a lower alkylthio group, NX ₁₀ X ₁₁ ; R ₁₂ and X ₁₀ each represent a lower alkyl group;
X ₁₁ represents a hydrogen atom or a lower alkyl group. )

That is, the compound represented by the formula (5)
For example, the compound represented by the formula (4) is optionally combined with the corresponding compound represented by the general formula (12), (13) or (14) and a base such as triethylamine or sodium hydride. The reaction can also be synthesized in a solvent that does not affect the reaction, for example, dimethylformamide, tetrahydrofuran, or acetonitrile, at a temperature from room temperature to the boiling point of the reaction mixture.

Among the compounds represented by the general formula (1), A
Is a pyridine ring which may have a substituent, and one of the substituents is a lower alkyl group represented by the general formula (1)
The compound represented by 1) can also be synthesized by decarboxylating a compound obtained by subjecting a lower alkyl dicarbonate corresponding to the general formula (4) having a leaving group to a nucleophilic substitution reaction. Here, general formula (4) and general formula (11)
R ₁ , R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , X ₁ , X ₂ ,
X ₃ , X ₄ , L, m, and n each represent the same as described above; R ₁₄ represents a lower alkyl group.

That is, the compound represented by the general formula (11) is prepared by, for example, converting the compound represented by the general formula (4) with a corresponding lower alkyl dicarbonate, if desired, in the presence of a base such as sodium hydride. In a solvent that does not affect the reaction, for example, in dimethylformamide, tetrahydrofuran, acetonitrile, preferably in dimethylformamide, at a temperature from room temperature to the boiling point of the reaction mixture, preferably at room temperature, and then reacted in an aqueous sulfuric acid solution It can also be synthesized by reacting at the boiling point of the mixture.

Here, lower alkyl dicarbonate means dimethyl malonate, diethyl malonate, diethyl methyl malonate, diethyl ethyl malonate, diethyl n-propyl malonate, diethyl i-propyl malonate, n
Diethyl diethyl butylmalonate, diethyl i-butylmalonate, diethyl t-butylmalonate, diethyl n-pentylmalonate and the like.

In the general formula (1), A is a pyridine ring which may have a substituent, and
The compound represented by the general formula (7), one of which is an amino group,
For example, it can be synthesized by reducing the corresponding nitro group in the general formula (6). However, R ₁ , R ₂ , R ₃ , R ₄ , m, n in the general formulas (6) and (7)
Each represents the same meaning as described above; R ₆ , R ₇ , and R ₈
Represent each a hydrogen atom, a halogen atom, a trifluoromethyl group, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a lower alkylthio group, a NX ₅ X _6, COX _7;
Here, X ₅ , X ₆ , and X ₇ each have the same meaning as described above; X ₁ , X ₂ , X ₃ , and X ₄ each represent a hydrogen atom,
A halogen atom, a phenyl group which may be substituted with a halogen atom and / or a lower alkyl group, a hydroxyl group, a lower alkyl group which may have a substituent, a lower alkoxy group which may have a substituent, NX ₅ X ₆ and COX ₇ ; wherein X ₅ , X ₆ and X ₇ each have the same meaning as described above.

That is, the compound represented by the general formula (7) has an effect on the reaction of the compound represented by the general formula (6) with ethanol, methanol, ethyl acetate, acetic acid, 1,4-dioxane and the like. The catalyst is subjected to catalytic reduction using palladium-carbon, Raney nickel or platinum oxide as a catalyst at room temperature to the boiling point of the reaction mixture, preferably at room temperature, preferably in ethanol or methanol, under a hydrogen atmosphere in a hydrogen atmosphere. Alternatively, it can also be synthesized by performing a reduction reaction using nickel (II) chloride and sodium borohydride to reduce the nitro group.

In the general formula (1), A is a pyridine ring which may have a substituent, and
The compound represented by the general formula (8), one of which is NR ₉ R ₁₀ , can also be synthesized using the general formula (7) as a starting material. Here, general formula (7), general formula (8), general formula (1
5) In general formulas (16) and (17), R ₁ ,
R ₂ , R ₃ , R ₄ , R ₆ , R ₇ , R ₈ , R ₁₂ , X ₁ , X ₂ ,
_{X 3, X 4, L,} m, n are each the same meanings as defined above; R ₉ represents a hydrogen atom, a lower alkyl group; R ₁₀
Represents a lower alkyl group, an acyl group or a lower alkoxycarbonyl group; R ₁₃ represents a lower alkyl group which may be substituted by a phenyl group; and X represents a halogen atom.

That is, the compound represented by the general formula (8) can be obtained by converting the compound represented by the general formula (7) into the corresponding general formula (15), (16) or (17) if desired. Can be synthesized in a solvent that does not affect the reaction at a temperature from room temperature to the boiling point of the reaction mixture, preferably at room temperature, in the presence of a base such as triethylamine and potassium carbonate.

When synthesizing the compounds represented by the above formulas (1), (5), (7), (8), and (11), a primary or secondary amino group is added during the synthesis process. If a protecting group is required, after protecting with a suitable resin or
reen and Wuts. "PROTECTIVE
GROUPS IN ORGANIC SYNTHE
SIS "2nd Edition. John Wile
y & Sons Inc. , P. After protecting with a suitable protecting group described in US Pat. Moreover, the deprotection reaction is performed as needed. Examples of the amino-protecting group include a t-butoxycarbonyl group and a trifluoroacetyl group.

The protection reaction of the amino group, for example, t-butoxycarbonylation, in a solvent which does not affect the reaction, for example, alcohols such as methanol, ethanol, i-propanol, or methylene chloride, dimethylformamide, 1,4 Dicarbonate in dioxane in the presence of an organic base such as triethylamine or 4-dimethylaminopyridine;
The reaction can be carried out by reacting with t-butyl at 0 ° C. to room temperature. In addition, the protection reaction of the amino group using Wang Resin is performed in a solvent that does not affect the reaction.
For example, methylene chloride, dimethylformamide, 1,4-
In dioxane, in the presence of an organic base such as 4-methylmorpholine, triethylamine and 4-dimethylaminopyridine,
4-nitrophenyloxycarbonyl-Wang Re
sin (Tetrahedron Lett., 37,
937-940 (1996)) at 0 ° C. to room temperature.

In the deprotection reaction of the amino group, for example, when the protecting group is a t-butoxycarbonyl group, or when the protecting group is Wang resin as described above, a solvent which does not affect the reaction, such as methanol, ethanol, , 4-
It is preferable to use a deprotecting agent such as trifluoroacetic acid, hydrochloric acid, sulfuric acid, or methanesulfonic acid at 0 ° C. to room temperature in dioxane or methylene chloride or in the absence of a solvent, and particularly to use trifluoroacetic acid at room temperature under anhydrous conditions. Is preferred.

In the compound of the present invention represented by the general formula (1),
For those having an asymmetric carbon in the structure, those pure stereoisomers and optically active isomers can be obtained by a method known in the art, for example, a chromatographic method using an optical isomer separation column or fractional crystallization. Can be obtained.

The pharmaceutically acceptable salt of the compound of the present invention represented by the general formula (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, hydrochloric acid, sulfuric acid, nitric acid, hydrogen bromide Inorganic acid salts with acids, hydroiodic acid, etc., organic acid salts with formic acid, acetic acid, fumaric acid, tartaric acid, etc., alkali metal salts with sodium, potassium, etc., alkaline earth metal salts with calcium, magnesium, etc. Is mentioned. The compound of the present invention or a salt thereof, suitable excipients, auxiliaries, lubricants, preservatives,
Disintegrants, buffers, binders, stabilizers, wetting agents, emulsifiers, coloring agents, flavoring agents or fragrances, etc., tablets, granules,
It can be administered orally or parenterally in the form of fine granules, powders, capsules, syrups, elixirs, suspensions / emulsions, injections and the like. In the superacute stage (immediately after an attack), acute stage (up to 2 to 3 days after an attack), and subacute stage (2 to 3 days to 2 weeks after an attack) of cerebrovascular disorder, administration is mainly by intramuscular injection or intravenous injection . Furthermore, in the chronic phase (after the third week after the attack), oral intake is also possible as appropriate.

The dose of the compound of the present invention or a salt thereof can be appropriately selected depending on the patient's body type, age, physical condition, degree of disease, elapsed time after onset, and the like. ５5 mg / body, and parenterally 1-10 mg / body. In general, even if the same dose is administered, the blood concentration may vary greatly from patient to patient. Therefore, it is ideal to determine the optimal dose of the drug for each patient while monitoring the blood concentration of the drug. is there.
When formulated as an internal preparation, for example, as a carrier for the formulation, lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, or other starch or starch derivative, cellulose derivative, or gelatin can be used. It is possible to add a lubricant such as magnesium stearate, carbowax or polyethylene glycol at the same time, and to form a mixture thereof into granules, tablets, capsules, etc. by a conventional method. it can. When formulated as an aqueous preparation, for example, an effective amount of the main component is dissolved in distilled water for injection, and if necessary, an antioxidant, a stabilizer, a solubilizing agent,
After a buffer, a preservative and the like are added and completely dissolved, the solution is filtered, filled and sealed by a conventional method, and sterilized by a high-pressure steam sterilization method, a dry heat sterilization method or the like to prepare an injection. When formulated as a lyophilized agent, an aqueous solution in which the main component is dissolved in distilled water for injection may be freeze-dried by a conventional method, and if necessary, mannitol, Inositol, lactose, maltose,
It can be prepared by adding a sugar such as sucrose or a sugar alcohol or glycine and freeze-drying in the usual manner.

[0062]

EXAMPLES Tables 1 to 37 show a list of examples.

[0063]

[Table 1]

[0064]

[Table 2]

[0065]

[Table 3]

[0066]

[Table 4]

[0067]

[Table 5]

[0068]

[Table 6]

[0069]

[Table 7]

[0070]

[Table 8]

[0071]

[Table 9]

[0072]

[Table 10]

[0073]

[Table 11]

[0074]

[Table 12]

[0075]

[Table 13]

[0076]

[Table 14]

[0077]

[Table 15]

[0078]

[Table 16]

[0079]

[Table 17]

[0080]

[Table 18]

[0081]

[Table 19]

[0082]

[Table 20]

[0083]

[Table 21]

[0084]

[Table 22]

[0085]

[Table 23]

[0086]

[Table 24]

[0087]

[Table 25]

[0088]

[Table 26]

[0089]

[Table 27]

[0090]

[Table 28]

[0091]

[Table 29]

[0092]

[Table 30]

[0093]

[Table 31]

[0094]

[Table 32]

[0095]

[Table 33]

[0096]

[Table 34]

[0097]

[Table 35]

[0098]

[Table 36]

[0099]

[Table 37]

[0100]

Example 1 2- (3- (di- (t-butoxycarbonyl) aminome
Synthesis of tyl) phenylamino) -3-nitropyridine 3- (di- (t-butoxycarbonyl) aminomethyl)
Aniline (1.50 g), triethylamine (2.0 m
l), 2-chloro-3-nitropyridine (1.10 g)
After stirring a mixture of and anhydrous dimethylformamide (15 ml) at 60 ° C. for 20 hours, ethyl acetate and water were added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 3: 1) to give the title compound 1.
42 g were obtained (69% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.47 (18H, s), 4.81 (2H, s),
6.83 (1H, dd, J = 8.3, 4.3 Hz),
7.11 (1H, d, J = 7.9 Hz), 7.34 (1
H, dd, J = 7.9, 7.9 Hz), 7.55-7.
63 (2H, m), 8.47 (1H, dd, J = 4.
3,1.7 Hz), 8.53 (1H, dd, J = 8.
3, 1.7 Hz), 10.11 (1H, brs)

In the same manner as in Example 1, the compounds shown in Tables 38 to 43 were obtained using the corresponding anilines or the corresponding halogens. (Base under the reaction conditions in the table:
(1) represents triethylamine, and (2) represents diisopropylethylamine. )

[0102]

[Table 38]

[0103]

[Table 39]

[0104]

[Table 40]

[0105]

[Table 41]

[0106]

[Table 42]

[0107]

[Table 43]

[0108]

Example 2 2- (3-aminomethylphenylamino) -3-nitro
Synthesis of pyridine hydrochloride A mixture of the compound (95.2 mg) obtained in Example 1 and trifluoroacetic acid (2 ml) was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The obtained residue was dissolved in methanol (3 ml), a 1,4-dioxane solution of hydrogen chloride (4 N, 0.5 ml) was added at room temperature, and the mixture was concentrated under reduced pressure. Further, the obtained residue was recrystallized from ethanol-ethyl acetate to obtain 56.7 mg of the title compound (yield 9).
4%). ¹ H-NMR (DMSO-d ₆ ) δ: 4.03 (2H, q, J = 5.6 Hz), 7.03
(1H, dd, J = 8.2, 4.3 Hz), 7.28
(1H, d, J = 7.6 Hz), 7.42 (1H, d
d, J = 7.6, 7.6 Hz), 7.74 (1H,
s), 7.75 (1H, d, J = 7.6 Hz), 8.4
6 (3H, brs), 8.50-8.60 (2H,
m), 10.00 (1H, s)

In the same manner as in Example 2, the compounds shown in Tables 44 to 62 were obtained using the corresponding reactants.

[0110]

[Table 44]

[0111]

[Table 45]

[0112]

[Table 46]

[0113]

[Table 47]

[0114]

[Table 48]

[0115]

[Table 49]

[0116]

[Table 50]

[0117]

[Table 51]

[0118]

[Table 52]

[0119]

[Table 53]

[0120]

[Table 54]

[0121]

[Table 55]

[0122]

[Table 56]

[0123]

[Table 57]

[0124]

[Table 58]

[0125]

[Table 59]

[0126]

[Table 60]

[0127]

[Table 61]

[0128]

[Table 62]

[0129]

Example 3 3-Amino-2- (3- (di- (t-butoxycarbonyl)
L) Synthesis of aminomethyl) phenylamino) pyridine The compound obtained in Example 1 (1.41 g), 10% palladium-carbon (170 mg), methanol (60 ml)
And a mixture of ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature for 1 day. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to give the title compound 1.1
5 g was obtained (88% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 3.40 (2H, br)
s), 4.75 (2H, s), 6.20 (1H, br)
s), 6.77 (1H, dd, J = 7.6, 5.0H)
z), 6.84-6.90 (1H, m), 7.00 (1
H, dd, J = 7.6, 1.3 Hz), 7.13 (1
H, s), 7.19-7.23 (2H, m), 7.82.
1H, dd, J = 5.0, 1.3 Hz)

In the same manner as in Example 3, the compounds shown in Table 63 were obtained using the corresponding reactants.

[0131]

[Table 63]

[0132]

Example 5 3-Methylamino-2- (3- (di- (t-butoxyca)
Of rubonyl) aminomethyl) phenylamino) pyridine
Compound (88.5 mg) obtained in Synthesis Example 3, methyl iodide (15 μl) and dimethylformamide (2 m
l) in a mixture of sodium hydride (content 60%, 10
mg) and stirred at room temperature for 4 days. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 3) to give the title compound.
3 mg was obtained (yield 21%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (18H, s), 2.85 (3H, s),
3.48 (1H, brs), 4.74 (2H, s),
6.02 (1H, s), 6.82-6.95 (3H,
m), 7.03 (1H, s), 7.09 (1H, d, J
= 8.0 Hz), 7.20 (1H, dd, J = 8.0,
8.0 Hz), 7.75 (1H, dd, J = 4.3,
1.7Hz)

[0133]

Example 6 3-Methylamino-2- (3-aminomethylphenyla
Synthesis of mino) pyridine Using the compound obtained in Example 5 as a starting material and reacting in the same manner as in Example 2, the reaction mixture was concentrated under reduced pressure. The obtained residue is subjected to basic silica gel column chromatography (developing solution; chloroform: methanol = 10: 1).
And the title compound was obtained quantitatively. ¹ H-NMR (CDCl ₃ ) δ: 1.69 (2H, brs), 2.85 (3H,
s), 3.53 (1H, brs), 3.81 (2H,
s), 6.08 (1H, brs), 6.84-6.94.
(3H, m), 7.05 (1H, d, J = 7.6H
z), 7.12 (1H, s), 7.22 (1H, dd,
J = 7.6, 7.6 Hz), 7.76 (1H, dd, J
= 4.6, 2.0 Hz)

[0134]

Example 7 3-ethylamino-2- (3- (di- (t-butoxyca)
Of rubonyl) aminomethyl) phenylamino) pyridine
Using the compound obtained in Synthesis Example 3 as a starting material and ethyl iodide as a reactant, the title compound was obtained in the same manner as in Example 5 (yield 54%). ¹ H-NMR (CDCl ₃ ) δ: 1.28 (3H, t, J = 7.3 Hz), 1.45
(18H, s), 3.15 (2H, q, J = 7.3H
z), 3.30 (1H, brs), 4.74 (2H,
s), 6.05 (1H, s), 6.82-6.96 (3
H, m), 7.07 (1H, s), 7.12-7.18.
(1H, m), 7.18 (1H, dd, J = 7.3,
7.3 Hz), 7.75 (1H, dd, J = 4.6,
1.3Hz)

[0135]

Example 29 2- (3- (di- (t-butoxycarbonyl) aminome
Tyl) phenylamino) -6-methylamino-3-nitto
Synthesis of l-pyridine Compound (77.0 mg) obtained in Example 27, potassium carbonate (89 mg), methylamine / hydrochloride (22.0 mg)
mg) and acetonitrile (2 ml) in 60
After stirring at 6 ° C. for 6 hours, the reaction mixture was concentrated under reduced pressure. Ethyl acetate and water were added to the obtained residue. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; n-hexane: ethyl acetate = 2: 1) to obtain 71.0 mg of the title compound (yield: 93%). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (18H, s), 3.03 (3H, d, J
= 4.3 Hz), 4.81 (2H, s), 5.93 (1
H, d, J = 8.9 Hz), 6.98-7.80 (5
H, m), 8.20-8.42 (1H, m), 10.8
1 (1H, brs)

In the same manner as in Example 29, the compounds shown in Table 64 were obtained using the corresponding amines.

[0137]

[Table 64]

[0138]

Example 37 6-chloro-2- (3- (t-butoxycarbonylamido)
Synthesis of nomethyl) phenylamino) nicotinic acid 3- (di- (t-butoxycarbonyl) aminomethyl)
A mixture of aniline (81 mg), 2,6-dichloronicotinic acid (90%, 53 mg), di-i-propylethylamine (64 mg) and 1,4-dioxane (1 ml) was heated under reflux for 3 days, and then under reduced pressure. Concentrated. The obtained residue was purified by silica gel column chromatography (developing solution; methylene chloride: methanol = 20: 1),
24 mg of the title compound were obtained (yield 25%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.44 (9H, s), 4.14-4.26 (2
H, m), 6.72 (1H, d, J = 7.9 Hz),
6.89 (1H, d, J = 7.6 Hz), 7.09 (1
H, brt), 7.26 (1H, dd, J = 7.6,
7.6 Hz), 7.51 (1H, s), 7.71 (1
H, d, J = 7.6 Hz), 8.22 (1H, d, J =
7.9 Hz)

[0139]

Working Example 39 2- (3- (di- (t-butoxycarbonyl) aminome
Synthesis of tyl) phenylamino) -6-methoxypyridine 3- (di- (t-butoxycarbonyl) aminomethyl)
Aniline (50 mg), tetrakistriphenylphosphine palladium (18 mg), potassium carbonate (24 m
g), 2-chloro-6-methoxypyridine (25 mg)
And a mixture of toluene (3 ml) in a stream of nitrogen for 16 hours.
After heating under reflux for an hour, ethyl acetate and water were added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: hexane = 1: 4) to obtain 54.5 mg of the title compound (yield: 82%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 3.91 (3H, s),
4.77 (2H, s), 6.19 (1H, d, J = 7.
9Hz), 6.36 (1H, brs), 6.39 (1
H, d, J = 7.9 Hz), 6.93 (1H, d, J =
6.9 Hz), 7.23-7.30 (3H, m), 7.
39 (1H, dd, J = 7.9, 7.9 Hz)

In the same manner as in Example 39, Tables 65 to 73 were prepared using the corresponding aniline compound and the corresponding halogen compound.
Was obtained. (Palladium (Pd) under the reaction conditions in the table: (1) represents tetrakistriphenylphosphine palladium, (2) represents tris (dibenzylideneacetone) dipalladium, and base: (1) represents potassium t.
-Butoxide, (2) sodium t-butoxide,
(3) represents potassium carbonate, and a ligand (ligan)
d): (1) is diphenylphosphinoferrocene,
(2) is 2,2'-bis (diphenylphosphino)-
Represents 1,1′-binaphthyl. )

[0141]

[Table 65]

[0142]

[Table 66]

[0143]

[Table 67]

[0144]

[Table 68]

[0145]

[Table 69]

[0146]

[Table 70]

[0147]

[Table 71]

[0148]

[Table 72]

[0149]

[Table 73]

[0150]

Example 45 2- (3-aminomethylphenylamino) -6-methoxy
Synthesis of sinicotinic acid hydrochloride A mixture of the compound (37 mg) obtained in Example 43, potassium hydroxide (96 mg), water (2 ml) and 1,4-dioxane (2 ml) was heated and stirred at 60 ° C. for 2 hours. did. After cooling the reaction mixture, 2N hydrochloric acid was added to make it acidic,
Extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was quantitatively obtained in the same manner as in Example 2 to give the title compound. ¹ H-NMR (DMSO-d ₆ ) δ: 3.95 (3H, s), 4.01 (2H, br)
s), 6.27 (1H, d, J = 8.6 Hz), 7.1
4 (1H, d, J = 7.6 Hz), 7.39 (1H, d
d, J = 8.3, 7.6 Hz), 7.71 (1H,
s), 7.90 (1H, d, J = 8.3 Hz), 8.1
4 (1H, d, J = 8.6 Hz), 8.30 (3H, b
rs), 10.75 (1H, s), 13.06 (1H,
brs)

[0151]

Example 52 2- (3-aminomethylphenylamino) -6-methyl
Synthesis of -3-nitropyridine hydrochloride A mixture of the compound (118 mg) obtained in Example 446, concentrated sulfuric acid (1 ml) and water (2 ml) was heated and stirred at 120 ° C. for 4 hours. The reaction mixture was poured into ice water, adjusted to pH 8 with saturated sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in methanol (2 ml), a 1,4-dioxane solution of hydrogen chloride (4 N, 0.5 ml) was added at room temperature, and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from methanol-ethyl acetate to obtain 37.1 mg of the title compound (61).
%). ¹ H-NMR (DMSO-d ₆ ) δ: 2.49 (3H, s), 4.03 (2H, q, J =
5.6 Hz), 6.90 (1H, d, J = 8.6H)
z), 7.27 (1H, d, J = 7.9 Hz), 7.4
2 (1H, dd, J = 7.9, 7.9 Hz), 7.77
(1H, s), 7.86 (1H, d, J = 7.9H)
z), 8.31 (3H, brs), 8.45 (1H,
d, J = 8.6 Hz), 10.09 (1H, s)

[0152]

Example 53 2- (3-aminomethylphenylamino) -6-ethyl
Synthesis of -3-nitropyridine hydrochloride Using the compound obtained in Example 447 as a starting material, the title compound was obtained in the same manner as in Example 52 (yield: 85%). ¹ H-NMR (DMSO-d ₆ ) δ: 1.24 (3H, t, J = 7.3 Hz), 2.79
(2H, q, J = 7.3 Hz), 4.02 (2H, q,
J = 5.0 Hz), 6.92 (1H, d, J = 8.6H)
z), 7.26 (1H, d, J = 7.6 Hz), 7.4
3 (1H, dd, J = 7.6, 7.6 Hz), 7.75
(1H, s), 7.90 (1H, d, J = 7.6H)
z), 8.41 (3H, brs), 8.48 (1H,
d, J = 8.6 Hz), 10.10 (1H, s)

[0153]

Working Example 443 2- (3- (t-butoxycarbonylaminomethyl) fu
Synthesis of enylamino) -6-methoxyisonicotinic acid To a mixture of the compound (53.8 mg) obtained in Example 423 and methanol (3 ml) was added a 2N aqueous sodium hydroxide solution (1 ml). The reaction mixture was added at room temperature for 4 hours.
After stirring for an hour, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the obtained residue, and the mixture was extracted with water. The aqueous layer is p
After adjusting to H1, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 47.3 mg of the title compound (yield: 90).
%). ¹ H-NMR (CDCl ₃ ) δ: 7.49 (1H, d, J = 7.9 Hz), 7.45
(1H, s), 7.28 (1H, dd, J = 7.9,
7.3 Hz), 6.98 (1H, s), 6.93 (1
H, d, J = 7.3 Hz), 6.76 (1H, s),
4.92 (1H, brs), 4.31 (2H, d, J =
5.6 Hz), 3.95 (3H, s), 1.46 (9
H, s)

[0154]

Working Example 444 2- (3- (t-butoxycarbonylaminomethyl) fu
Enylamino) -4-hydroxymethyl-6-methoxy
Synthesis of pyridine Compound (155.3 mg) obtained in Example 423, tetrahydrofuran (4 ml) and methanol (2 m
Lithium borohydride (13 mg) was added to the mixture of 1). After stirring the reaction mixture at room temperature for one week, water was added and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 1) to give 86.1 mg of the title compound (yield 60%). ¹ H-NMR (CDCl ₃ ) δ: 7.37 (1H, s), 7.18-7.12 (2
H, m), 6.93-6.88 (1H, m), 6.42.
(1H, s), 6,42 (1H, s), 6.18 (1
H, s), 4.88 (1H, brs), 4.59 (2
H, s), 4.29 (2H, d, J = 5.6 Hz),
3.90 (3H, s), 1.45 (9H, s)

[0155]

Working Example 446 2- (2- (3- (di- (t-butoxycarbonyl) a)
Minomethyl) phenylamino) -3-nitropyridine-
Synthesis of 6-yl) malonic acid dimethyl ester The compound obtained in Example 27 (150 mg), dimethyl malonate (50 mg), and dimethylformamide (3
ml) of sodium hydride (content 60%, 15%).
mg) was added. After the reaction mixture was stirred at room temperature for 3 hours, ethyl acetate and water were added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; n-hexane: ethyl acetate = 2: 1) to obtain 123 mg of the title compound (yield: 68%). ¹ H-NMR (CDCl ₃ ) δ: 1.47 (18H, s), 3.76 (6H, s),
4.81 (2H, s), 4.91 (1H, s), 6.9
5 (1H, d, J = 8.6 Hz), 7.08 (1H,
d, J = 7.9 Hz), 7.32 (1H, dd, J =
7.9, 7.9 Hz), 7.44 (1H, s), 7.6
8 (1H, d, J = 7.9 Hz), 8.54 (1H, d, J = 7.9 Hz)
d, J = 8.6 Hz), 10.18 (1H, brs)

In the same manner as in Example 446, the compounds shown in Table 74 were obtained using the corresponding chloro compounds and the corresponding reactants.

[0157]

[Table 74]

[0158]

Working Example 449 2- (3- (t-butoxycarbonylaminomethyl) fu
Synthesis of phenylamino) -4-methylpyridine 3- (di- (t-butoxycarbonyl) aminomethyl)
Bromobenzene (260 mg), tris (dibenzylideneacetone) dipalladium (42 mg), diphenylphosphinoferrocene (50 mg), potassium t-butoxide (102 mg), 2-amino-4-methylpyridine (108 mg) and toluene (10 ml) Was heated and stirred at 80 ° C. for 22 hours under a nitrogen stream. Ethyl acetate and water were added to the reaction mixture. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 1) to obtain 29.2 mg of the title compound (yield: 10).
%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 2.26 (3H, s),
4.30 (2H, d, J = 5.9 Hz), 4.90 (1
H, brt), 6.59 (1H, d, J = 5.0H)
z), 6.60 (1H, s), 6.68 (1H, s),
6.94 (1H, d, J = 6.3 Hz), 7.21-
7.31 (3H, m), 8.06 (1H, d, J = 5.
0Hz)

In the same manner as in Example 449, the compounds shown in Table 75 were obtained using the corresponding amines.

[0160]

[Table 75]

[0161]

Working Example 452 2- (3- (t-butoxycarbonylaminomethyl) fu
Synthesis of (enylamino) -6-methoxynicotinic acid Using the compound obtained in Example 442 as a starting material, the title compound was obtained in the same manner as in Example 45 (yield 92%). ¹ H-NMR (CDCl ₃ -CD ₃ OD) δ: 1.46 (9H, s), 3.99 (3H, s),
4.30 (2H, s), 6.16 (1H, d, J = 8.
6 Hz), 6.94 (1H, d, J = 7.8 Hz),
7.28 (1H, dd, J = 7.8, 7.8 Hz),
7.58 (1H, d, J = 7.8 Hz), 7.73 (1
H, s), 8.16 (1H, d, J = 8.6 Hz)

[0162]

Embodiment 4532- (3- (t-butoxycarbonylaminomethyl) phenyl
Synthesis of (enylamino) -6-methoxynicotinamide  Compound (44 mg) obtained in Example 452, triethyl
Luamine (18 mg) and tetrahydrofuran (2 m
l) to the mixture at room temperature at room temperature.
g) was added and stirred at room temperature for 15 minutes. To the reaction mixture
Blow ammonia gas at room temperature and stir at room temperature for 5 minutes.
After stirring, the mixture was concentrated under reduced pressure. Saturated carbonic acid is added to the obtained residue.
Add aqueous sodium hydrogen solution and extract with methylene chloride.
Was. After washing the organic layer with saturated saline, anhydrous magnesium sulfate
And dried under reduced pressure. Prepare the residue
Latent thin layer chromatography (developing solution; methanol)
(Methylene chloride = 1: 20) to give the title compound 1
0 mg was obtained (11% yield).¹ H-NMR (DMSO-d₆) Δ: 1.39 (9H, s), 3.92 (3H, s),
4.12 (2H, d, J = 5.9 Hz), 6.20 (1
H, d, J = 8.6 Hz), 6.85 (1H, d, J =
7.6 Hz), 7.24 (1H, dd, J = 7.6,
7.6 Hz), 7.32-7.40 (2H, m), 7.
51 (1H, d, J = 7.6 Hz), 7.61 (1H,
s), 8.01 (1H, brs), 8.10 (1H,
d, J = 8.6 Hz)

[0163]

Working Example 454 2- (3- (t-butoxycarbonylaminomethyl) fu
Enylamino) -3-hydroxymethyl-6-methoxy
Synthesis of pyridine To a mixture of the compound (300 mg) obtained in Example 452, triethylamine (101 mg) and tetrahydrofuran (8 ml) was added ethyl chlorocarbonate (10 mg) under ice-cooling.
9 mg) in a tetrahydrofuran solution (1 ml).
Stirred at 150C for 15 minutes. After the reaction mixture was filtered, a solution of lithium borohydride in tetrahydrofuran (2 M, 0.8 ml) was added to the filtrate under ice cooling. Reaction mixture
After stirring at 30 ° C. for 30 minutes, a 1 N aqueous sodium hydroxide solution was added under ice cooling. Further, after the reaction mixture was stirred at 0 ° C. for 5 minutes, ether and water were added. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: methylene chloride = 1: 10) to obtain 199 mg of the title compound (yield: 69%). ¹ H-NMR (CDCl ₃ ) δ: 1.46 (9H, s), 3.93 (3H, s),
4.31 (2H, d, J = 5.6 Hz), 4.67 (2
H, d, J = 5.6 Hz), 4.79 (1H, br)
t), 6.15 (1H, d, J = 7.9 Hz), 6.8
9 (1H, d, J = 7.6 Hz), 7.21-7.31
(3H, m), 7.48 (1H, d, J = 7.6H)
z), 7.64 (1H, brs), 7.70 (1H, b
rs)

[0164]

Working Example 456 2- (3- (t-butoxycarbonylaminomethyl) fu
Enylamino) -6-methoxypyridine-3-carbo
A mixture of the compound (24 mg) obtained in Example 454, manganese tetroxide (40 mg) and benzene (8 ml) was stirred at room temperature for 2 days. After filtering the reaction mixture,
The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: methylene chloride = 1: 20) to give 14 mg of the title compound (yield 59%). ¹ H-NMR (CDCl ₃ ) δ: 1.47 (9H, s), 4.01 (3H, s),
4.33 (2H, d, J = 5.6 Hz), 4.82 (1
H, brt), 6.24 (1H, d, J = 8.3H)
z), 7.00 (1H, d, J = 7.6 Hz), 7.3
0 (1H, dd, J = 7.6, 7.6 Hz), 7.61
(1H, d, J = 7.6 Hz), 7.71 (1H, d,
J = 8.3 Hz), 7.72 (1H, s), 9.67
(1H, s), 10.95 (1H, s)

[0165]

Working Example 472 2- (3-Aminomethylphenylamino) -4-hydro
Synthesis of xymethyl-6-methoxypyridine dihydrochloride The compound obtained in Example 423 (109.5 mg), tetrahydrofuran (4 ml) and methanol (1 m
To the mixture of 1) was added lithium borohydride (19 mg). After the reaction mixture was stirred at room temperature for 44 hours, 2N hydrochloric acid was added, and the mixture was concentrated under reduced pressure. The obtained residue was subjected to basic silica gel column chromatography (developing solution; methanol: methylene chloride = 1: 19). To a mixture of the obtained purified product and methanol (3 ml) was added 1,4-dioxane solution of hydrogen chloride (4 N, 0.3 ml), and the mixture was concentrated under reduced pressure. The obtained residue was recrystallized from methanol-ethyl acetate to obtain 48 mg of the title compound (yield: 58%). ¹ H-NMR (DMSO-d ₆ ) δ: 9.18 (1H, brs), 8.39 (3H, br)
s), 7.78 (1H, s), 7.61 (1H, d, J
= 7.9 Hz), 7.29 (1H, dd, J = 7.9,
7.3 Hz), 7.08 (1H, brs), 7.02
(1H, d, J = 7.3 Hz), 6.47 (1H,
s), 6.11 (1H, s), 4.42 (2H, s),
3.94 (2H, q, J = 5.6 Hz), 3.87 (3
H, s)

[0166]

Working Example 507 2- (3- (t-butoxycarbonylaminomethyl) phenyl
Synthesis of phenylamino) -5-methylthiazole Propionaldehyde (72 μl), chloroform (1
ml) and 1,4-dioxane (1 ml) was added with bromine (52 μl). After the reaction mixture was stirred at room temperature for 30 minutes, N- (3- (t-butoxycarbonylaminomethyl) phenyl) thiourea (262 m
g), acetone (2 ml) and triethylamine (0.14 ml) were added. The reaction mixture was heated under reflux for 3.5 hours, and then concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to basic silica gel column chromatography (developing solution; methylene chloride: methanol = 9).
9: 1) to give 79.2 mg of the title compound (yield 27%). ¹ H-NMR (CDCl ₃ ) δ: 7.30-7.22 (4H, m), 7.17 (1
H, d, J = 7.6 Hz), 6.91 (1H, d, J =
1.0 Hz), 4.94 (1H, brs), 4.30
(2H, d, J = 5.6 Hz), 2.34 (3H, d,
J = 1.0 Hz), 1.47 (9H, s)

[0167]

Working Example 508 2- (3-Aminomethylphenylamino) -5-methyl
Synthesis of thiazole A mixture of the compound (73 mg) obtained in Example 507 and trifluoroacetic acid (5 ml) was stirred at room temperature for 1 hour, and then concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent: methylene chloride: methanol = 95: 5) to give 34.5 mg of the title compound (yield 67%). ¹ H-NMR (CDCl ₃ ) δ: 7.32-7.28 (3H, m), 7.19 (1
H, d, J = 7.3 Hz), 6.97 (1H, d, J =
7.3 Hz), 6.92 (1H, d, J = 1.0H)
z), 3.87 (2H, s), 2.35 (3H, d, J
= 1.0 Hz), 1.76 (2H, brs)

[0168]

Working Example 509 2- (3- (t-butoxycarbonylaminomethyl) fu
Synthesis of enylamino) -4-methylthiazole A mixture of N- (3- (t-butoxycarbonylaminomethyl) phenyl) thiourea (124 mg), chloroacetone (31 μl) and acetonitrile (2 ml) was heated under reflux for 9.5 hours. And concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 2) to give 43 mg of the title compound (yield 41%). ¹ H-NMR (CDCl ₃ ) δ: 7.33-7.22 (4H, m), 6.96 (1
H, d, J = 7.3 Hz), 6.20 (1H, s),
4.86 (1H, brs), 4.31 (2H, d, J =
5.3 Hz), 2.30 (3H, s), 1.47 (9
H, s)

[0169]

Example 510 2- (3-aminomethylphenylamino) -4-methyl
Synthesis of thiazole Using the compound obtained in Example 509 as a starting material, the title compound was obtained in the same manner as in Example 508 (yield: 91).
%). ¹ H-NMR (CDCl ₃ ) δ: 7.34-7.18 (4H, m), 7.00 (1
H, d, J = 7.3 Hz), 6.20 (1H, s),
3.87 (2H, s), 2.30 (3H, s), 1.6
0 (2H, brs)

[0170]

Working Example 511 2- (3- (di- (t-butoxycarbonyl) aminome
Tyl) phenylamino) -5-methyloxazole
Formed 3- (di - (t-butoxycarbonyl) aminomethyl)
Aniline (200 mg), dimethylaminopyridine (1
To a mixture of 66 mg) and methylene chloride (10 ml) was added thiophosgene (45 μl) under ice-cooling, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture under reduced pressure, the obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 3).
-(3- (Di- (t-butoxycarbonyl) aminomethyl) phenyl) isothiocyanate was obtained. The obtained compound (193 mg), 1-azido-propan-2-one (81 mg), triphenylphosphine (217 mg)
And a mixture of methylene chloride (5 ml) at room temperature for 15 minutes.
After stirring for an hour, oxalic acid (115 mg) was added at room temperature. After heating and stirring the reaction mixture at 60 ° C. for 30 minutes,
It was concentrated under reduced pressure. Ethyl acetate and 2N aqueous sodium hydroxide solution were added to the obtained residue. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 10).
And 78 mg of the title compound was obtained (33% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (18H, s), 2.25 (3H, d, J
= 1.0 Hz), 4.77 (2H, s), 6.51 (1
H, d, J = 1.0 Hz), 6.91 (1H, d, J =
7.6 Hz), 7.15 (1H, brs), 7.22-
7.26 (1H, m), 7.25 (1H, dd, J =
7.6, 7.6 Hz), 7.40 (1H, d, J = 7.
6Hz)

In the same manner as in Example 511, the compounds shown in Table 76 were obtained using the corresponding reactants.

[0172]

[Table 76]

[0173]

Example 515 2- (3-aminomethyl) phenylamino) -5-methyl
Synthesis of Luxazole Trifluoroacetate A mixture of the compound (292 mg) obtained in Example 511 and trifluoroacetic acid (2 ml) was stirred at room temperature for 2 hours, and then concentrated under reduced pressure. The obtained residue was recrystallized from ethanol-ethyl acetate-n-hexane to obtain 119 mg of the title compound (38%). ¹ H-NMR (DMSO-d ₆ ) δ: 2.24 (3H, s), 3.98 (2H, q, J =
5.6 Hz), 6.59 (1H, s), 7.00 (1
H, d, J = 7.3 Hz), 7.32 (1H, dd, J)
= 7.3, 7.3 Hz), 7.53 (1H, d, J =
7.3 Hz), 7.67 (1H, s), 8.16 (3
H, brs), 10.08 (1H, s)

In the same manner as in Example 515, the compounds shown in Table 77 were obtained using the corresponding reactants.

[0175]

[Table 77]

[0176]

Working Example 523 2- (3-Aminomethylphenylamino) -3,5-di
Synthesis of nitropyridine 3-aminobenzylamine (696 mg), dimethylaminopyridine (674 mg), 3-nitrophenyloxycarbonyl-Wang Resin (2.85 g, T
etrahedron Lett. , Vol. 37,9
37 (1996)) and tetrahydrofuran (60 m
The mixture of 1) was filtered after stirring at room temperature for 24 hours. The obtained resin is dimethylformamide, water, methanol,
After successive washing with methylene chloride and drying under reduced pressure, 3-aminobenzylaminocarbonyl-Wang Resin was obtained. The obtained resin (100 mg, 0.071 mol),
Potassium carbonate (100 mg), 2-chloro-3,5-dinitropyridine (72 mg), palladium (II) acetate
(16 mg), diphenylphosphinoferrocene (79
mg) and acetonitrile (9 ml) were stirred at 80 ° C under a nitrogen atmosphere, and then filtered. The obtained resin was sequentially washed with dimethylformamide, water, methanol and methylene chloride, dried under reduced pressure, trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. After filtering the reaction mixture, the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the obtained residue. The aqueous layer was washed with ethyl acetate and concentrated under reduced pressure. The resulting residue was Sep-PaK ^R Plus
Purification by C18 Cartridges (Waters) gave 1.7 mg of the title compound (8%). ¹ H-NMR (CD ₃ OD) δ: 4.16 (2H, s), 7.35 (1H, d, J =
7.9 Hz), 7.53 (1H, dd, J = 7.9,
7.9 Hz), 7.75 (1H, d, J = 7.9H)
z), 7.80 (1H, s), 9.25 (1H, d, J
= 2.4 Hz), 9.30 (1H, d, J = 2.4H)
z)

In the same manner as in Example 523, the compounds shown in Tables 78 to 80 were obtained using the corresponding chloro forms.

[0178]

[Table 78]

[0179]

[Table 79]

[0180]

[Table 80]

Further, among the compounds used in the reactions shown so far, novel compounds, Example 25e, Example 417e, Example 500b, Example 519e, Example 5
The synthesis method of 20d, Example 538e and Example 542a is shown below.

[0182]

Working Example 25e 2- (5-amino-2-ethylphenyl) -2- (t-
Synthesis of butoxycarbonylamino) indane

Example 25a Synthesis of 3- cyanomethyl-4-ethylnitrobenzene 3-chloromethyl-4-ethylnitrobenzene (4.0
To a mixture of g) and dimethyl sulfoxide (50 ml) was added sodium cyanide (982 mg). After stirring the reaction mixture at room temperature for 3 hours, ethyl acetate and n-
Hexane and water were added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to quantitatively obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7.6 Hz), 2.78
(2H, q, J = 7.6 Hz), 3.80 (2H,
s), 7.44 (1H, d, J = 8.6 Hz), 8.1.
8 (1H, dd, J = 8.6, 2.3 Hz), 8.35
(1H, d, J = 2.3Hz)

Example 25b 2-cyano-2- (2-ethyl-5-nitrophenyl)
Synthesis of Indane Compound (3.0 g) obtained in Example 25a, α, α ′
-Dichloro-o-xylene (4.15 g) and dimethylsulfoxide (200 ml) in a mixture of potassium
After adding t-butoxide (3.55 g) and stirring at room temperature for 3 hours, ethyl acetate and water were added. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (1.36 g) (yield 29).
%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (3H, t, J = 7.6 Hz), 3.11
(2H, q, J = 7.6 Hz), 3.61 (2H, d,
J = 15.5 Hz), 3.91 (2H, d, J = 15.
5 Hz), 7.25-7.33 (4H, m), 7.53
(1H, d, J = 9.2 Hz), 8.12-8.16
(2H, m)

Example 25c 2- (2-ethyl-5-nitrophenyl) -2-indane
To a mixture of the compound obtained in Example 25b (1.16 g) and acetic acid (10 ml) was added water (2 ml), concentrated sulfuric acid (20 ml).
ml) were added sequentially. The reaction mixture was heated under reflux for 13 hours, cooled, poured into ice water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the title compound (870 mg) (yield 71%). ¹ H-NMR (CDCl ₃ ) δ: 1.35 (3H, t, J = 7.6 Hz), 2.82
(2H, q, J = 7.6 Hz), 3.36 (2H, d,
J = 15.9 Hz), 3.95 (2H, d, J = 15.
9Hz), 5.13 (1H, brs), 5.43 (1
H, brs), 7.15-7.25 (4H, m), 7.
49 (1H, d, J = 8.3 Hz), 8.08 (1H,
dd, J = 8.3, 2.3 Hz), 8.17 (1H,
d, J = 2.3 Hz)

Example 25d 2- (t-butoxycarbonylamino) -2- (2-e
Synthesis of tyl -5-nitrophenyl) indane The compound (815 mg) obtained in Example 25c and t
-Lead tetraacetate (1.4 ml) was added to a mixture of butanol (12 ml).
0 g) was added. The reaction mixture was heated under reflux for 3 hours, cooled, added with water, and extracted with ethyl acetate-ethylene glycol. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform) to give the title compound (620 mg) (yield 62).
%). ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J = 7.6 Hz), 1.31
(9H, s), 2.93 (2H, q, J = 7.6H
z), 3.55 (2H, d, J = 15.9 Hz);
63 (2H, d, J = 15.9 Hz), 5.18 (1
H, s), 7.20-7.29 (4H, m), 7.40.
(1H, d, J = 8.6 Hz), 8.05 (1H, d
d, J = 8.6, 2.3 Hz), 8.32 (2H, d,
J = 2.3Hz)

Example 25e 2- (5-amino-2-ethylphenyl) -2- (t-
Synthesis of butoxycarbonylamino) indane Using the compound obtained in Example 25d as a starting material, the title compound was obtained in the same manner as in Example 3 (yield 97%). ¹ H-NMR (CDCl ₃ ) δ: 1.23 (3H, t, J = 7.6 Hz), 1.30
(9H, s), 2.74 (2H, q, J = 7.6H
z), 3.48-3.67 (6H, m), 5.02 (1
H, s), 6.56 (1H, dd, J = 8.3, 2.3)
Hz), 6.74 (1H, d, J = 2.3 Hz), 7.
03 (1H, d, J = 8.3 Hz), 7.15-7.2
4 (4H, m)

[0188]

Example 417e N- (3-amino-2-ethoxyphenylmethyl) imid
Synthesis of di-t-butyl nodicarboxylate

Example 417a Synthesis of ethyl 2-ethoxy-3-nitrobenzoate 3-nitrosalicylic acid (5.0 g), ethyl iodide (1
Potassium carbonate (9.4 g) was added to a mixture of 1 ml) and dimethylformamide (200 ml). After the reaction mixture was stirred at 60 ° C. for 4.5 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 1) to give 5.66 g of the title compound (87% yield). ¹ H-NMR (CDCl ₃ ) δ: 8.01 (1H, dd, J = 7.9, 1.7H)
z), 7.89 (1H, dd, J = 7.9, 1.7H
z), 7.26 (1H, dd, J = 7.9, 7.9H
z), 4.42 (2H, q, J = 7.3 Hz), 4.1
8 (2H, q, J = 6.9 Hz), 1.43 (3H,
t, J = 6.9 Hz), 1.42 (3H, t, J = 7.
3Hz)

Example 417b Synthesis of 2-ethoxy-3-nitrobenzyl alcohol The compound obtained in Example 417a (117 mg), tetrahydrofuran (5 ml) and methanol (2 ml)
To this mixture was added lithium borohydride (10.7 mg). After the reaction mixture was stirred at room temperature for 15 hours, water was added and the mixture was concentrated under reduced pressure. 2N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 2) to quantitatively obtain the title compound. ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, d, J = 7.9 Hz), 7.67
(1H, d, J = 7.3 Hz), 7.22 (1H, d
d, J = 7.9, 7.3 Hz), 4.80 (2H,
s), 4.08 (2H, q, J = 6.8 Hz), 2.1
0 (1H, brs), 1.44 (3H, t, J = 6.8)
Hz)

Example 417c Synthesis of 2-ethoxy-3-nitrobenzyl bromide The compound obtained in Example 417b (3.13 g), carbon tetrabromide (5.26 g) and methylene chloride (100 m
l) Triphenylphosphine (4.16 g)
Was added under ice cooling. The reaction mixture was stirred under ice cooling for 30 minutes, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 9) to give 3.59 g of the title compound.
Was obtained (87% yield). ¹ H-NMR (CDCl ₃ ) δ: 7.78 (1H, dd, J = 7.9, 1.7H)
z), 7.65 (1H, dd, J = 7.6, 1.7H
z), 7.20 (1H, dd, J = 7.9, 7.6H
z), 4.57 (2H, s), 4.17 (2H, q, J
= 6.9 Hz), 1.49 (3H, t, J = 6.9H)
z)

Example 417d N- (2-ethoxy-3-nitrophenylmethyl) imid
Synthesis of di-tert-butyl nodicarboxylate A mixture of di-tert-butyl iminodicarboxylate (3.23 g), dimethylformamide (50 ml) and sodium hydride (0.57 g) was stirred for 1 hour under ice cooling, and then stirred. A mixture of the compound (3.51 g) obtained in Example 417c and dimethylformamide (20 ml) was added under ice cooling. After the reaction mixture was stirred at room temperature for 14 hours, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 9) to give the title compound (5.09 g).
Was obtained (95% yield). ¹ H-NMR (CDCl ₃ ) δ: 7.72 (1H, dd, J = 7.9, 1.3H)
z), 7.38 (1H, dd, J = 7.3, 1.3H
z), 7.17 (1H, dd, J = 7.9, 7.3H
z), 4.91 (2H, s), 4.06 (2H, q, J
= 6.9 Hz), 1.45 (18H, s), 1.44.
(3H, t, J = 6.9Hz)

Example 417e N- (3-amino-2-ethoxyphenylmethyl) imid
Synthesis of di-t-butyl nodicarboxylate A mixture of the compound (5.09 g) obtained in Example 417d, nickel dichloride hexahydrate (61 mg) and methanol (130 ml) was added to sodium borohydride (1). .46 g) was added. The reaction mixture is kept at room temperature for 20 minutes.
After stirring for 2 minutes, 2N hydrochloric acid was added, and then the mixture was adjusted to pH 8 with a saturated aqueous solution of sodium hydrogen carbonate, and then concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 4) to obtain the title compound (yield: 85%). ¹ H-NMR (CDCl ₃ ) δ: 6.86 (1H, dd, J = 7.9, 7.6H)
z), 6.63 (1H, dd, J = 7.6, 1.0H
z), 6.53 (1H, dd, J = 7.9, 1.0H
z), 4.85 (2H, s), 3.90 (2H, q, J
= 6.9 Hz), 3.74 (2H, brs), 1.43
(18H, s), 1.41 (3H, t, J = 6.9H
z)

[0194]

Example 500b N- (5-amino-2- (pyrazol-1-yl) fe
Synthesis of t-butyl nylmethyl) carbamate

Example 500a N- (5-nitro-2- (pyrazol-1-yl) fe
Synthesis of di-t-butyl nylmethyl) iminodicarboxylate To a mixture of pyrazole (1.0 g) and dimethylsulfoxide (50 ml), sodium hydride (0.54 g) was added under ice-cooling. After the reaction mixture was stirred for 1 hour under ice cooling, di-t-butyl N- (2-fluoro-5-nitrophenylmethyl) iminodicarboxylate (5.0 g) was used.
Of dimethylsulfoxide (50 ml) was added. After stirring the reaction mixture at room temperature for 15 hours, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 1: 4) to give the title compound (yield 73%). ¹ H-NMR (CDCl ₃ ) δ: 8.22-8.19 (2H, m), 7.79-7.
78 (2H, m), 7.50 (1H, d, J = 9.6H)
z), 6.53 (1H, dd, J = 2.3, 2.0H
z), 4.95 (2H, s), 1.46 (18H, s)

Example 500b N- (5-amino-2- (pyrazol-1-yl) fe
Synthesis of t-butyl nylmethyl) carbamate Sodium borohydride was added to a mixture of the compound obtained in Example 500a (4.15 g), nickel dichloride hexahydrate (0.183 g) and methanol (300 ml). (2.43 g) was added. The reaction mixture is allowed to
After stirring for 2 minutes, 2N hydrochloric acid was added to make the reaction solution acidic, then a saturated aqueous sodium hydrogen carbonate solution was added to make the reaction solution basic, and the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-n-hexane to give the title compound (89% yield). ¹ H-NMR (CDCl ₃ ) δ: 7.69 (1H, d, J = 1.3 Hz), 7.57
(1H, d, J = 2.0 Hz), 7.06 (1H, d,
J = 8.3 Hz), 6.86-6.83 (1H, m),
6.60 (1H, dd, J = 8.3, 2.3 Hz),
6.41 (1H, dd, J = 2.0, 1.3 Hz),
5.62 (1H, brs), 4.01 (2H, d, J =
6.6 Hz), 3.82 (2H, brs), 1.43
(9H, s)

[0197]

Example 519e 3- (t-butoxycarbonylaminomethyl) -4-h
Synthesis of Rolo-2-ethoxyaniline

Example 519a5-bromo-4-chloro-2-fluoronitrobenzene
Synthesis of  4-chloro-2-fluoronitrobenzene (1.00
g), silver sulfate (1.95 g) and concentrated sulfuric acid (5 ml).
Bromine (0.32 ml) was added to the mixture under ice cooling, and the mixture was cooled to 0 ° C.
After stirring for 30 minutes, the mixture was stirred at room temperature for 1 hour. Reaction mixing
The material was put in ice water and extracted with ether. The organic layer is saturated with water
Wash sequentially with aqueous sodium bicarbonate and saturated saline
And dried over anhydrous sodium sulfate.
1.38 g of the title compound were obtained (yield 95%).¹ H-NMR (CDCl_Three) Δ: 7.47 (1H, d, J = 9.9 Hz), 8.37
(1H, d, J = 7.3Hz)

Example 519b 5-bromo-4-chloro-2-fluoro-3- ( trif
Fluoromethylcarbonylaminomethyl) nitrobenzene
Compound (204 mg) obtained in Synthesis Example 519a, N-
Hydroxymethyl-2,2,2-trifluoroacetamide (115 mg) and 10% fuming sulfuric acid (1.6 m
The mixture of 1) was stirred at 80 ° C. for 10 hours. After cooling, the reaction mixture was poured into ice water and extracted with ether. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solution; ethyl acetate: n-
Hexane = 1: 3) to give 85.1 mg of the title compound
Was obtained (yield 28%). ¹ H-NMR (CDCl ₃ ) δ: 4.86 (2H, d, J = 4.0 Hz), 6.73
(1H, brt), 8.39 (1H, d, J = 7.3H
z)

Example 519c 5-Bromo-3- (t-butoxycarbonylaminomethyl
L) Synthesis of 4-chloro-2-fluoronitrobenzene A mixture of the compound (601 mg) obtained in Example 519b, concentrated sulfuric acid (3 ml) and methanol (12 ml) was heated under reflux for 1 hour. After concentrating the reaction mixture under reduced pressure,
A 2N aqueous sodium hydroxide solution was added to make the mixture basic, and the mixture was extracted with methylene chloride (20 ml). Dicarbonate in organic layer
t-Butyl (414 mg) and a 2N aqueous sodium hydroxide solution (10 ml) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. The organic layer was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to obtain 402 mg of the title compound (yield 66%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 4.57-4.66 (2
H, m), 5.01 (1H, brt), 8.31 (1
H, d, J = 7.6 Hz)

Example 519d 5-bromo-3- (t-butoxycarbonylaminomethyl
L) Synthesis of 4-chloro-2- ethoxynitrobenzene The compound obtained in Example 519c (200 mg), ethanol (36 μl) and tetrahydrofuran (5 m
l) to a mixture of sodium hydride (content 60
%, 25 mg). After stirring the reaction mixture at 0 ° C. for 2 hours, water and ether were added. Water the organic layer,
After sequentially washing with saturated saline, the extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 1: 4) to obtain 197 mg of the title compound (yield: 92%). ¹ H-NMR (CDCl ₃ ) δ: 1.45 (9H, s), 1.47 (3H, t, J =
6.9 Hz), 4.08 (2H, q, J = 6.9H)
z), 4.62 (2H, d, J = 5.9 Hz), 4.9
3 (1H, brt), 8.10 (1H, s)

Example 519e 3- (t-butoxycarbonylaminomethyl) -4-h
Synthesis of Rolo-2-ethoxyaniline Using the compound obtained in Example 519d as a starting material, the title compound was obtained in the same manner as in Example 3 (86%). ¹ H-NMR (CDCl ₃ ) δ: 1.44 (3H, t, J = 7.3 Hz), 1.45
(9H, s), 3.78 (2H, brs), 3.92
(2H, q, J = 7.3 Hz), 4.47 (2H, d,
J = 5.3 Hz), 4.91 (1H, brt), 6.6
3 (1H, d, J = 8.3 Hz), 6.94 (1H,
d, J = 8.3 Hz)

[0203]

Example 520d: 3- (t-butoxycarbonylaminomethyl) -2-e
Synthesis of Toxi-6-methylaniline

Example 520a 3-Methyl-6-nitro-2- (trifluoromethylca
Synthesis of rubonylaminomethyl) phenol Using 5-methyl-2-nitrophenol as a starting material, the title compound was obtained in the same manner as in Example 545b (16).
%). ¹ H-NMR (CDCl ₃ ) δ: 2.57 (3H, s), 4.67 (2H, d, J =
6.3 Hz), 6.89 (1H, d, J = 8.6H)
z), 7.00 (1H, brs), 8.00 (1H,
d, J = 8.6 Hz), 11.23 (1H, s)

Example 520b 2- (t-butoxycarbonylaminomethyl) -4-me
Synthesis of tyl -6-nitrophenol A mixture of the compound (100 mg) obtained in Example 520a, potassium carbonate (99.4 mg), water (1.0 ml) and methanol (6.0 ml) was stirred at room temperature for 3 hours. After that, di-t-butyl dicarbonate (157 mg) was added. After stirring the reaction mixture at room temperature for 30 minutes, it was concentrated under reduced pressure. A saturated saline solution was added to the obtained residue, and the mixture was extracted with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solution; ethyl acetate: n-hexane = 3: 17) to obtain the title compound (yield 70%). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (9H, s), 2.55 (3H, s),
4.44 (2H, d, J = 6.3 Hz), 5.17 (1
H, brs), 6.82 (1H, d, J = 8.6H)
z), 7.94 (1H, d, J = 8.6 Hz), 11.
11 (1H, s)

Example 520c 3- (t-butoxycarbonylaminomethyl) -2-e
Synthesis of Toxy-4-methylnitrobenzene The compound (350 mg) obtained in Example 520b, cesium carbonate (404 mg), dimethylformamide (15
ml) and ethyl iodide (0.4 ml) in 6
Stirred at 0 ° C. for 2 hours. Ethyl acetate and water were added to the reaction mixture. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; ethyl acetate: n-hexane = 2: 8) to quantitatively give the title compound. ¹ H-NMR (CDCl ₃ ) δ: 1.44 (9H, s), 1.48 (3H, t, J =
6.9 Hz), 2.49 (3H, s), 4.03 (2
H, q, J = 6.9 Hz), 4.41 (2H, d, J =
5.6 Hz), 4.86 (1H, brs), 7.03
(1H, d, J = 8.6 Hz), 7.72 (1H, d,
J = 8.6Hz)

Example 520d 3- (t-butoxycarbonylaminomethyl) -2-e
Synthesis of Tox-4-methylaniline Using the compound obtained in Example 520c as a starting material, the title compound was obtained in the same manner as in Example 3 (92%). ¹ H-NMR (CDCl ₃ ) δ: 1.43 (3H, t, J = 6.9 Hz), 1.44
(9H, s), 2.26 (3H, s), 3.61 (2
H, brs), 3.89 (2H, q, J = 6.9H)
z), 4.34 (2H, d, J = 5.3 Hz), 4.7
0 (1H, brs), 6.61 (1H, d, J = 7.9)
Hz), 6.75 (1H, d, J = 7.9 Hz)

[0208]

Example 538e N- (3-Amino-2- (n-propoxy) phenyl methine
Synthesis of di-t-butyl tyl) iminodicarboxylate

Example 538a n- Propyl 3-nitro-2- (n-propoxy) benzoate
Synthesis of pill The title compound was obtained in the same manner as in Example 417a using 3-nitrosalicylic acid as a starting material and n-propyl iodide as a reactant (yield 29%). ¹ H-NMR (CDCl ₃ ) δ: 7.98 (1H, dd, J = 7.6, 1.7H)
z), 7.87 (1H, dd, J = 7.9, 1.7H)
z), 7.24 (1H, dd, J = 7.9, 7.6H
z), 4.31 (2H, t, J = 6.9 Hz), 4.0
5 (2H, t, J = 6.9 Hz), 1.90-1.71
(4H, m), 1.08-0.97 (6H, m)

Example 538b 3-Nitro-2- (n-propoxy) benzyl alcohol
Using the compound obtained in Example 538a as a starting material, the title compound was obtained in the same manner as in Example 417b (yield 7).
0%). ¹ H-NMR (CDCl ₃ ) δ: 7.76 (1H, dd, J = 8.3, 1.3H)
z), 7.68 (1H, dd, J = 7.3, 1.3H
z), 7.21 (1H, dd, J = 8.3, 7.3H
z), 4.80 (2H, s), 3.96 (2H, t, J
= 6.9 Hz), 2.13 (1H, brs), 1.91
−1.77 (2H, m), 1.04 (3H, t, J =
7.3 Hz)

Example 538c Synthesis of 3-nitro-2- (n-propoxy) benzyl bromide
Using the compound obtained in Synthesis Example 538b as a starting material, the title compound was obtained in the same manner as in Example 417c (yield 9).
5%). ¹ H-NMR (CDCl ₃ ) δ: 7.77 (1H, dd, J = 7.9, 1.3H)
z), 7.64 (1H, dd, J = 7.9, 1.3H
z), 7.19 (1H, dd, J = 7.9, 7.9H
z), 4.57 (2H, s), 4.05 (2H, t, J
= 6.6 Hz), 1.96-1.83 (2H, m),
1.07 (3H, t, J = 7.3 Hz)

Example 538d N- (3-Nitro-2- (n-propoxy) phenylmethine
Synthesis of di-tert-butyl tyl ) iminodicarboxylate Using the compound obtained in Example 538c as a starting material, the title compound was obtained in the same manner as in Example 417d (yield 6).
2%). ¹ H-NMR (CDCl ₃ ) δ: 7.70 (1H, dd, J = 7.9, 1.3H)
z), 7.37 (1H, dd, J = 7.9, 1.3H
z), 7.16 (1H, dd, J = 7.9, 7.9H
z), 4.91 (2H, s), 3.94 (2H, t, J
= 6.6 Hz), 1.91-1.80 (2H, m),
1.45 (18H, s), 1.05 (3H, t, J =
7.3 Hz)

Example 538e N- (3-Amino-2- (n-propoxy) phenylmethine
Synthesis of di-tert-butyl tyl ) iminodicarboxylate Using the compound obtained in Example 538d as a starting material, the title compound was quantitatively obtained in the same manner as in Example 417e. ¹ H-NMR (CDCl ₃ ) δ: 6.86 (1H, dd, J = 7.9, 7.6H)
z), 6.63 (1H, d, J = 7.9 Hz), 6.5
2 (1H, d, J = 7.6 Hz), 4.85 (2H,
s), 3.78 (2H, t, J = 6.6 Hz), 3.7
4 (2H, brs), 1.89-1.75 (2H,
m), 1.43 (18H, s), 1.07 (3H, t,
J = 7.3 Hz)

[0214]

Example 542a N- (3-amino-2- (i-propoxy) phenylmethine
Synthesis of 3-nitro salicylic acid chill) iminodicarboxylic acid di -t- butyl as a starting material, using the iodide i- propyl as a reactant, Example 417a~ Example 4
The title compound was obtained in the same manner as in 17e. ¹ H-NMR (CDCl ₃ ) δ: 6.85 (1H, dd, J = 7.9, 7.6H)
z), 6.62 (1H, d, J = 7.6 Hz), 6.5
3 (1H, d, J = 7.9 Hz), 4.83 (2H,
s), 4.26-4.15 (1H, m), 3.69 (2
H, brs), 1.42 (18H, s), 1.31 (6
H, d, J = 6.3 Hz)

[0215]

[Test example]

Test Example 1 The inhibitory effect of the compound of the present invention on three types of NOS isoforms known so far was examined.

Each crude enzyme preparation was prepared by the following procedure (N
agafuji et al. , Neuropore
t 6,1541-1545, 1995). A crude enzyme preparation of nNOS was prepared by the following procedure. Untreated male Sp
ratDawley (SD) rats (body weight 300
-400 g) was decapitated, the whole brain was quickly removed, and the cerebral cortex was fractionated on ice. Then, 5 times the amount of 50 mM Tr
An is-HCl, 1 mM DTT (pH 7.4) solution was added and homogenized for 3 minutes.
Centrifuged for 0 minutes. The obtained supernatant was subjected to 100,000 × g
And the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme preparation of nNOS.

A crude enzyme preparation of iNOS was prepared by the following procedure. LPS (10 mg / kg) was intraperitoneally administered to rats, and after 6 hours, the rats were percutaneously perfused with 10 U / ml of heparin-containing saline, and the lungs were removed. Then, 5 volumes of 50 mM Tris-HCl, 1 mM DTT
(PH 7.4) solution was added, homogenized for 3 minutes, and centrifuged at 1,000 × g for 10 minutes. The obtained supernatant was centrifuged at 100,000 × g for 60 minutes, and the soluble cytoplasmic fraction of the finally obtained supernatant was used as a crude enzyme preparation of iNOS.

A crude enzyme preparation of eNOS was prepared by the following procedure. Bovine pulmonary artery vascular endothelial cell line (CPAE) 20%
The cells were cultured in MEM medium containing FBS. A few days later, this was detached from the flask with a 0.25% trypsin, 1 mM EDTA solution, and an appropriate amount of FBS was added.
Centrifuged at 0 rpm for 10 minutes. Calcium and magnesium-free phosphate buffer solution (pH 7.
4) was added thereto and centrifuged at 1,000 rpm for 10 minutes. After washing the cells by repeating the same operation, 1% T
50 mM containing ritonX-100 and 1 mM DTT
Tris-HCl (pH 7.4) was added and left for 1 hour on ice. Subsequently, after homogenizing for 3 minutes, the mixture was left on ice for 30 minutes while repeating stirring. Finally 10
The supernatant obtained by centrifugation at 000 × g for 60 minutes was washed with eN
A crude enzyme preparation of OS was used.

The NOS activity was determined basically according to the method reported by the present inventors, by using one of the substrates, L- [ ³ H] arg.
L- [ ³ H] ci which is one of the reaction products from inine
It was measured by quantifying the amount of conversion to trulline (Nagafuji et al., in Br).
ain Edema IX (Ito et al. ed.
s. ) 60 pp. 285-288, 1994; Nag
afuji et al. , Neuroreport
6, 1541-1545, 1995). The reaction solution is 10
0 nM L- [ ³ H] arginine, crude enzyme preparation (10-30 μg / ml protein), 1.25 mM CaC
l ₂ , 1 mM EDTA, 10 μg / ml calmo
dulin, 1 mM NADPH, 100 μM tet
rahydrobiopterine, 10 μM FA
D, 10 μM FMN, 50 mM Tris-HCl
(PH 7.4) to which the compound of the present invention or a control compound was added.

The reaction was started by adding L- [ ³ H] Arginine, and the mixture was incubated at 37 ° C. for 10 minutes, and then 50 mM Tris-HCl (pH 5.5), 1 mM
2 ml of MEDTA was added and the reaction was stopped by placing on ice. The reaction solution is applied to a cation exchange resin column (Dowex).
AG50WX-8, Na ⁺ form, 3.2 ml) and the unreacted remaining substrate L- [ ³ H] argini.
ne and the reaction product L- [ ³ H] citrullin
e was separated. This eluate and an eluate obtained by further passing a certain amount of distilled water through a column are placed in a mini vial, and
[ ³ H] citrulline was recovered. Thereafter, a scintillator was added, the radioactivity was measured with a liquid scintillation counter, and L- [ ³ H] citrulline was measured.
Was quantified.

The activity of nNOS and eNOS is determined by CaCl ₂
The activity detected in the absence of CaCl ₂ and calmodulin was subtracted from the activity detected in the presence of calmodulin and calmodulin. The activity of iNOS is Ca
Detection was in the absence of Cl ₂ and calmodulin.
The protein concentration in the crude enzyme preparation was determined using a Bio-Rad microassay kit. All experiments were performed in duplicate.

In Table 81, the ratio of the IC50 value (concentration required for 50% activity inhibition) of the test compound to each NOS isoform and the ratio of each IC50 value as an index indicating the selectivity are shown.

[0223]

[Table 81]

[0224]

The compound of the present invention exhibits excellent nNOS inhibitory activity or iNOS inhibitory activity, and exhibits cerebrovascular disorders (cerebral hemorrhage, subarachnoid hemorrhage, cerebral infarction [atherothrombotic infarction, lacunar infarction, cardiogenic embolism]) , Transient cerebral ischemic attack, brain edema), head trauma, spinal injury, pain (headache [migraine, tension-type headache, cluster headache, chronic seizure headache]), Parkinson's disease, Alzheimer's disease, convulsions, Morphine tolerance and dependence,
It is useful as a therapeutic agent for septic shock, rheumatoid arthritis, osteoarthritis, viral or non-viral infection, and diabetes.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/275 ADY A61K 31/275 ADY 31/40 AAH 31/40 AAH 31/415 AAB 31/415 AAB AAM AAM AAY AAY ADP ADP ADX ADX AED AED 31/44 ABN 31/44 ABN 31/495 ADS 31/495 ADS 31/50 ACB 31/50 ACB 31/505 ABR 31/505 ABR C07C 209/10 C07C 209/10 209/22 209/22 211/56 211/56 217/90 217/90 233/43 233/43 255/35 255/35 255/47 255/47 271/20 271/20 271/28 271/28 271/66 271/66 323 / 36 323/36 323/39 323/39 C07D 207/34 C07D 207/34 207/36 207/36 213/74 213/74 213/75 213/75 213/76 213/76 213/80 213/80 213 / 81 213/81 213/82 213/82 213/85 213/85 231/38 231/38 B 239/26 239/26 401/12 231 401/12 231 (72) Inventor Nagafuji Toshiaki Gotemba, Shizuoka Prefecture Komakado 1-chome 135 address Chugai Pharmaceutical Co., Ltd. in

Claims (42)

[Claims] 1. A compound of the general formula (1) (Wherein, R ₁ and R ₂ are the same or different and each represents a hydrogen atom,
A lower alkyl group which may have a substituent, an acyl group,
Represents a lower alkoxycarbonyl group or is 3
It may form a to 8-membered ring. R ₃ and R ₄ are the same or different and each represent a hydrogen atom, a lower alkyl group which may have a substituent, or form a monocyclic or condensed ring having 3 to 10 carbon atoms together; Is also good. R ₅ represents a hydrogen atom, a lower alkyl group, an acyl group, or a lower alkoxycarbonyl group. X ₁ , X ₂ , X ₃ and X ₄ are the same or different,
Hydrogen atom, halogen atom, nitro group, cyano group, hydroxyl group, lower alkyl group which may have a substituent, lower alkenyl group, lower alkynyl group, lower alkoxy group which may have a substituent, substituent A phenyl group optionally substituted with a lower alkylthio group, a halogen atom and / or a lower alkyl group,
₅ X ₆ , C (＝ O) X ₇ , wherein X ₅ and X ₆ are the same or different and are a hydrogen atom, a lower alkyl group which may have a substituent, an acyl group, a substituent X ₇ may represent a lower alkoxycarbonyl group which may have, or together form a 3- to 8-membered ring; X ₇ may have a hydrogen atom, a hydroxyl group, a substituent Good lower alkyl group, lower alkoxy group which may have a substituent, NX
₈ shows an X _9; wherein, X _8, X _9, which may be the same or different, a hydrogen atom, or represents an lower alkyl group optionally having a substituent, or a 3-8 membered together A ring may be formed. A is a benzene ring which may have a substituent, or a 5- to 6-membered aromatic heterocyclic ring which may have a substituent and contains at least one nitrogen atom as a hetero atom. Is shown. n and m each represent an integer of 0 or 1. Or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof. 2. In the general formula (1), X ₁ , X ₂ , X ₃ ,
X ₄ is the same or different and is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group which may have a substituent, a lower alkenyl group, a lower alkynyl group,
A lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, a phenyl group which may be substituted with a halogen atom and / or a lower alkyl group, NX ₅ X ₆ , C (＝ O) X ₇ ; A is
2. The compound according to claim 1, which is a benzene ring or a pyridine ring which may have a substituent, or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof. 3. In the general formula (1), A may have a substituent and is a 5- to 6-membered aromatic heterocyclic ring having at least one nitrogen atom as a hetero atom (substituted Or the possible tautomers, stereoisomers, optically active forms thereof and pharmaceutically acceptable salts thereof, wherein the pyridine ring which may have a group is excluded.). 4. In the general formula (1), R ₁ is a hydrogen atom; R ₂ is a hydrogen atom, a lower alkyl group, an acyl group or a lower alkoxycarbonyl group; and A has a substituent. The compound according to claim 1, which is a benzene ring, or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof. 5. The compound according to claim 2, wherein in the general formula (1), A is a pyridine ring which may have a substituent, or a possible tautomer, stereoisomer or optical activity thereof. Body and their pharmaceutically acceptable salts. 6. In the general formula (1), R ₁ and R ₂ are hydrogen atoms; R ₅ is a hydrogen atom; X ₁ , X ₂ , X ₃ and X ₄
Are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group optionally having a substituent, a lower alkoxy group optionally having a substituent, NX ₅ X ₆ ;
Is a benzene ring which may have a substituent, a pyridine ring which may have a substituent, a pyrimidine ring which may have a substituent, an oxazole ring which may have a substituent, The compound according to claim 1, which is an optionally substituted thiazole ring, or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof. 7. The compound according to claim 6, wherein A is a benzene ring which may have a substituent or a pyridine ring which may have a substituent in the general formula (1). Tautomers, stereoisomers, optically active isomers and pharmaceutically acceptable salts thereof. 8. In the general formula (1), R ₃ and R ₄ are the same or different and each represent a hydrogen atom or a lower alkyl group;
May together form a monocyclic ring having 3 to 10 carbon atoms,
8. The compound according to claim 1 or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof. 9. In the general formula (1), X ₁ , X ₂ , X ₃ ,
X ₄ are the same or different, a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group optionally substituted with a phenyl group, an NX ₅ X _6; wherein, X _5,
X ₆ is the same or different and is a hydrogen atom, a lower alkyl group which may be substituted with a phenyl group, an acyl group, or may form a 3- to 8-membered ring together. Or the possible tautomers, stereoisomers, optically active forms thereof and pharmaceutically acceptable salts thereof. 10. In the general formula (1), A is a benzene ring which may have a substituent, a pyridine ring which may have a substituent, and the substituent is a nitro group,
10. The compound according to claim 6, 8 or 9, which is a lower alkoxy group, a lower alkyl group, or a lower alkylthio group, or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof. 11. In the general formula (1), X ₁ , X ₂ ,
X ₃ and X ₄ are the same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group and NX ₅ X ₆ ; wherein X ₅ and X ₆ are the same or different and are a hydrogen atom A compound according to claims 1 to 8 or 10 or a possible tautomer, stereoisomer thereof, which is a lower alkyl group, an acyl group or which together may form a 3- to 8-membered ring. Optically active substances and pharmaceutically acceptable salts thereof. 12. The method according to claim 1, wherein in formula (1), m and n are 0; and substituents on the benzene ring other than X ₁ , X ₂ , X ₃ and X ₄ are meta-substituted. Or a possible tautomer, stereoisomer, optically active form and pharmaceutically acceptable salt thereof. 13. The method according to claim 1, wherein in formula (1), m + n = 1; and the substituents on the benzene ring other than X ₁ , X ₂ , X ₃ and X ₄ are ortho or para-substituted. Or a possible tautomer, stereoisomer, optically active form and pharmaceutically acceptable salt thereof. 14. In the general formula (1), 2- (3-aminomethylphenylamino) -6-methoxy-3-nitropyridine, 2- (3-aminomethylphenylamino)-
6-methyl-3-nitropyridine, 2- (3-aminomethylphenylamino) -6-ethyl-3-nitropyridine, 2- (3-aminomethylphenylamino) -6-ethoxy-3-nitropyridine, 2 -(3-aminomethylphenylamino) -6-methylthio-3-nitropyridine, 2- (3-aminomethylphenylamino) -6-methyl-3-nitrobenzene, 2- (3-aminomethylphenylamino) -6 -Methoxy-3-nitrobenzene,
2- (3-aminomethyl-2-methylphenylamino)
-6-methoxy-3-nitropyridine, 2- (4-aminoethylphenylamino) -6-methoxy-3-nitropyridine, 2- (3- (1-amino-1-methylethyl) phenylamino) -6 -Methoxy-3-nitropyridine, 2- (3-aminomethyl-2-methoxyphenylamino) -6-methoxy-3-nitropyridine, 2-
(3-aminomethyl-4-chlorophenylamino) -6
-Methoxy-3-nitropyridine, 2- (3-aminomethyl-4-fluorophenylamino) -6-methoxy-
3-nitropyridine, 2- (3-aminomethyl-2-ethoxyphenylamino) -6-methoxy-3-nitropyridine, 2- (3-aminomethyl-2-chlorophenylamino) -6-methoxy-3-nitro Pyridine, 2-
(3-aminomethylphenylamino) -4-methylpyridine, 2- (3- (1-amino-1-methylethyl) phenylamino) -4-methylpyridine, 2- (3-aminomethyl-2-methylphenyl Amino) -4-methylpyridine, 2- (3-aminomethyl-4-ethylphenylamino) -4-methylpyridine, 2- (3-aminomethyl-4-ethoxyphenylamino) -4-methylpyridine, 2- (2-aminoethylphenylamino) -4-methylpyridine, 2- (3-aminomethyl-2-chlorophenylamino) -4-methylpyridine, 2- (3- (1
-Amino-cyclobutyl) phenylamino) -4-methylpyridine, 2- (4-aminoethylphenylamino)
-4-methylpyridine, 2- (3-aminomethyl-2-
Ethoxyphenylamino) -4-methylpyridine, 2-
(3-aminomethyl-4-chlorophenylamino) -4
-Methylpyridine, 2- (3-aminomethyl-2- (n
-Propoxy) phenylamino) -4-methylpyridine, 2- (3-aminomethyl-4-chloro-2-ethoxyphenylamino) -4-methylpyridine, 2- (3-
Aminomethyl-2-ethoxy-4-methylphenylamino) -4-methylpyridine, 2- (3-aminomethyl-
2-methoxyphenylamino) -4-methylpyridine,
The compound according to claim 1, which is selected from the group consisting of 2- (3-aminomethyl-2- (i-propoxy) phenylamino) -4-methylpyridine, and a pharmaceutically acceptable salt thereof. 15. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. Or a possible tautomer, stereoisomer, optically active form and a pharmaceutically acceptable salt thereof as an active ingredient. 16. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof as an active ingredient. 17. The therapeutic agent according to claim 16, wherein the cerebrovascular disorder is cerebral hemorrhage. 18. The therapeutic agent according to claim 16, wherein the type of cerebrovascular disorder is subarachnoid hemorrhage. (19) the therapeutic agent according to the above (16), wherein the type of cerebrovascular disease is cerebral infarction; 20. The therapeutic agent according to claim 19, wherein the subtype of cerebral infarction is atherothrombotic infarction. 21. The therapeutic agent according to claim 19, wherein the subtype of cerebral infarction is lacunar infarction. 22. The therapeutic agent according to claim 19, wherein the subtype of cerebral infarction is cardiogenic embolism. 23. The therapeutic agent according to claim 16, wherein the type of cerebrovascular disorder is transient cerebral ischemic attack (TIA). 24. The therapeutic agent according to claim 16, wherein the cerebrovascular disorder is cerebral edema. 25. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. Or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof as an active ingredient. 26. A compound of the general formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. Or a possible tautomer, stereoisomer, optically active form, and pharmaceutically acceptable salt thereof as an active ingredient. 27. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. Or an analgesic containing the possible tautomers, stereoisomers, optically active forms and pharmaceutically acceptable salts thereof as an active ingredient. 28. The therapeutic agent according to claim 27, wherein the type of pain is headache. 29. The subtype of headache is migraine.
The therapeutic agent as described above. 30. The therapeutic agent according to claim 28, wherein the subtype of headache is tension headache. 31. The therapeutic agent according to claim 28, wherein the subtypes of headache are cluster headache and chronic paroxysmal headache. 32. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. Or a possible tautomer, stereoisomer, optically active isomer or a pharmaceutically acceptable salt thereof as an active ingredient. 33. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or its possible tautomers, stereoisomers, optically active forms and pharmaceutically acceptable salts thereof as an active ingredient. 34. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or a possible tautomer, stereoisomer, optically active substance and pharmaceutically acceptable salt thereof as an active ingredient. 35. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or a possible tautomer, stereoisomer, optically active form and a pharmaceutically acceptable salt thereof as an active ingredient for the treatment of morphine resistance or dependence. 36. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof as a therapeutic agent for septic shock. 37. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or its possible tautomers, stereoisomers, optically active forms, and pharmaceutically acceptable salts thereof as a therapeutic agent for rheumatoid arthritis. 38. General formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or a possible tautomer, stereoisomer, optically active form and a pharmaceutically acceptable salt thereof as an active ingredient. 39. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ) Or an agent for treating viral or non-viral infectious diseases, which comprises, as an active ingredient, a compound represented by the following formula: or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof. 40. A compound of the formula (1) wherein R ₁ , R ₂ , R ₃ ,
R ₄ , R ₅ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, and A have the same meaning as defined in claim 1. ), Or a possible tautomer, stereoisomer, optically active isomer and a pharmaceutically acceptable salt thereof as an active ingredient. (41) a reaction route (A), 中 wherein R in the general formula (1), (2) or (3)
_{1, R 2, R 3,} R 4, X 1, X 2, X 3, X 4, n, m, A
Represents the same meaning as defined in claim 1; R ₅
Represents a hydrogen atom or a lower alkyl group which may have a substituent; L represents a leaving group. A method for producing the compound of claim 1, represented by｝. (42) a reaction route (B), 中 wherein R ₁ , R ₂ , R ₃ , R ₄ , X ₁ , X ₂ , X ₃ , X ₄ , n, m, A in the general formula (1), (9) or (10)
Represents the same meaning as defined in claim 1; R ₅
Represents a hydrogen atom or a lower alkyl group which may have a substituent; L represents a leaving group. A method for producing the compound of claim 1, represented by｝.