JPH115772A - Amide derivative, its production and use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amide compound or its salt having an osteoplastic factor action or neurotrophic factor action, especially reinforcing actions such as the differentiation actions of osteoblasts and neurocytes, the survival maintenance action of the neurocytes, etc., due to the osteoplastic factor or neurotrophic factor, and useful as a cell differentiation-inducing factor action agent, its action-reinforcing agent, etc. SOLUTION: A compound of formula I R<1> is (substituted) amino; R<2> is H, a (substituted) lower alkyl; X is (substituted) methine, N(O)m [(m) is 0, 1]; the ring A is a (substituted) homogeneous ring, a heterogeneous ring; the ring B is a (substituted) homogeneous ring, a heterogeneous ring} or its salt. For example, N-methyl-9-)1,3-benzodioxol-5-yl)-8-hydroxymethyl-naphtho[1,2-d]-1,3-d ioxol-7- carboxamide. The compound of formula I or its salt is obtained by amidating a compound of formula II or its ester or salt and, if necessary, further acylating the produced amide.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an excellent bone morphogenetic protein (BMP) action or its enhancing action or a neurotrophic factor (neurotrophic facto).
r) action [for example, nerve growth factor
r: NGF), brain-derived neurot
rophic factor: BDNF), neurotrophin-3 (neu
rotrophin-3: NT-3), glial cell line-derived neurotrophic factor: GDN
Amide derivative having a cell differentiation inducing action or a cell differentiation inducing factor action enhancing action such as F)
It relates to its production method and use.

[0002]

2. Description of the Related Art Bone morphogenetic proteins
in, BMP) is the only group of protein factors known to have ectopic osteoinductive ability isolated from demineralized bone.
Therefore, it is useful as an agent for promoting bone formation in fracture healing and bone reconstruction [AE Wang, Trends Biotechnol., Vol. 11, 379-383.
P. (1993)]. Substances having such BMP-enhancing activity include, to date, retinoic acid, vitamin D3, estrogens, and glucocorticoids (V. Rosen & RS Thies, Trends in Genetics) (Trends Genet.), Volume 8, 97-102
P. (1992); Y. Takuwa et al., Biochemical and.
Biophysical Research Communication (Bi
ochem. Biophys. Res.Commum.), 174, 96-101 (19
91)]. In addition, since BMP directly promotes osteoblast differentiation, its role as a coupling factor in bone remodeling is assumed, and it is considered that BMP is closely related to bone metabolism. It has also been reported that the BMP content in bone matrix in aged animals is considerably reduced [ML Urist, Bone and Mineral Research, vol. 6, (ed by WA Pe
ck), pp. 57-112, Elsevier, 1989], suggesting that BMP is deeply involved in maintaining bone mass. This suggests that BMP is promising as a therapeutic agent for various bone diseases such as osteoporosis. However, BMPs are usually present only in trace amounts in living organisms, and their sources are limited.
In addition, BMP has a problem when administered because it is a protein, and applicable target diseases are extremely limited.

Furthermore, it has been reported that BMP has a neurotrophic factor-like activity [VM Paralkar et al., J. Cell Biol., 1
19, 1721-1728 (1992)]. Also, strong expression of the BMP gene is known in brain tissue [E. Ozkaynak et al., Biochemical and Biophysical Research Communication (Biochem. Biophys. Res. Commu.
n.), 179, 116-123 (1991)]. It has also been suggested that BMPs play an important role in neural tube formation during embryonic development [K. Basler et al., Cell, 73, 687-7.
02 (1993)]. Neurotrophic factor
Is a group of proteinaceous factors that play an important role in the survival and functional development of neurons, and nerve growth factor (ne
rve growth factor (NGF), brain-derived neurotrophic factor (brai)
n-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), glial cell line-derived neurotrophy
c factor: GDNF). NGF promotes differentiation and maturation of sympathetic ganglion and dorsal root ganglion of the neural crest in the peripheral nervous system [AM Davies & RM Lindsay, Developmental Biology ( Dev. Biol.), 111
Vol. 62-72 (1985); R. Levi-Montalcini, Embo
Journal (EMBO J.), 6, 1145-1154 (1987)],
In the central nervous system, it acts on cholinergic neurons of septa in the septum (basal ganglia) [H. Gnahn et al., Developmental Brain Research (Dev. Brain. Res.), 9 Vol. 45-52 (1983); H. H.
atanaka & H. Tsukui, Dev. Brain Res., Volume 30, 47-56
F. Hefti, Journal of Neuroscience (J. Neurosci.), 6, 2155-2162 (1986)].
NGF is required to maintain neuronal function after neuronal cell differentiation is complete. BDNF acts on dorsal root ganglion cells and nodose ganglion cells in the peripheral nervous system, but does not act on sympathetic ganglion cells (RM Lindsay & H. Rohre
r, Dev. Biol., 112, 30-48 (1985); RM Lindsa
y et al., Dev. Biol., 112, 319-328 (1985); AMD.
avies et al., J. Neurosci., 6, 1897-1904 (1986)].
On the other hand, in the central nervous system, cholinergic neurons and gaba (γ-aminobutyric acid) neurons in the septal area, and dopaminergic neurons (dopamine) in the midbrain
rgic neurons of midbrain) [RF Alders
on et al., Neuron, 5, 297-306 (199
0); C. Hyman et al., Nature, 350, 230-2
32 (1991); B. Knusel et al., Proceedings of
The National Academy of Sciences
Of the United States of America (Proc. Natl. Acad. Sci. USA), 88, 961-965 (1
991)]. NT-3 overlaps with NGF and BDNF in the peripheral nervous system, but is characterized by showing a strong action on neural plate-derived sensory neurons (P. Ernfors et al., Proc. Natl. Acad. Sci. US
A, 87, 5454-5458 (1990); A. Rosenthal et al., Neuro.
n, 4, 767-773 (1990)]. However, neurons in the central nervous system that respond to NT-3 are not yet known.

[0004] As a substance having an NGF action, sabeluzole: 4- (2-Benzothiazolylmethylamino)-
α (p-fluorophenoxy) methyl] -1- (piperidine) ethano
l] has been reported [New Curren
t), Vol. 4, No. 26, p. 14 (1993)]
7746A [Neuroscience, 55
Volume, p. 629 (1993)], T-588 (Japanese Unexamined Patent Publication No. 4-9507).
0) and MS430 [Journal of University of Oppositional and Environmental Health (J.UOEN), Vol. 17, p. 131 (1995)
)] Have also been reported to enhance the action of NGF.
In addition, steroids, catechols and cytokines have been reported as compounds having an NGF secretion inducing action [Experimental Neurology (Experime
ntal Neurology), 124, 36-42 (1993)]. In Alzheimer's disease, extensive damage and loss of cerebral cortical neurons has been observed in addition to degeneration and loss of cholinergic neurons in the basal forebrain, including the septum, and NGF and new trophic factors Is also considered a candidate for its therapeutic agent (F.
Hefti & WJ Weiner, Annual Neurology, 20, 275-281 (1986)]. However, since these neurotrophic factors are proteins, their application is limited. Examples of low molecular compounds known to promote osteoblast proliferation and differentiation include ipriflavone (K. Notoya et al., Journal of Bone and Mineral Research (J.
Bone Miner. Res.), 9, 395-400 (1994)), vitamin K2 (Y. Akedo et al.), Biochemical and Biophysical Research (Biochem. Bi).
ophys. Res. Commun), vol. 187, pp. 814-820 (1992)), but does not have ectopic bone formation ability unlike BMP. Compounds having a neurotrophic factor-like effect such as a neurite outgrowth effect and a survival maintaining effect on nerve cells include lactacystin (O. et al.
l.), Journal of Antibiotics (J. Anti
Biot.), 40, 113-117 (1991)), retinoic acid (M. Minana et al.), Proceedings of National Academy of Science of the USA (Prod. Natl. Acad. .Sci.USA), 87
Vol., Pp. 4335-4339 (1990)), Staurosporine (TB Shea et al.), Journal of Neuroscience Research (J. Neurosci.R.)
es.), 33, 398-407 (1990)), K252a (G.
D. GDBorasio et al., Neuroscience Letters, 108, 2
07-212 (1990)), MS818 (A.Awaya et a
l.), Biological and Pharmaceutical Bulletin (Biol. Pharm. Bull.), 16, 248-253 (1993)).

(1)

Embedded image [Wherein, Ar ¹ is arylene- (R ⁸ ) ₂ (R ⁸ : hydrogen atom,
A halogen, lower alkyl, hydroxy, lower alkoxy, etc.), Ar ² represents aryl- (R ⁹ ) ₂ (R ⁹ : hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy, etc.), and R ¹ represents a hydrogen atom , Lower alkyl,
R ² represents a hydrogen atom, lower alkyl or a group forming と 共 に O together with R ¹ ,
R ³ represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy, etc .; R ⁴ represents a hydrogen atom or lower alkyl; R ⁷ represents a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy, etc .;
¹⁰ and R ¹¹ represent a hydrogen atom, halogen, lower alkyl, hydroxy, lower alkoxy, CON (R ¹⁶ ) ₂ (R ¹⁶ is a hydrogen atom, lower alkyl, OR ¹³ (R ¹³ is a hydrogen atom or lower alkyl)), etc. Naphthalenecarboxamide represented by the structural formula of US Pat. No. 5,308,852,

(2)

Embedded image [Wherein, R represents a hydrogen atom, acetyl or methyl]
The compound represented by JP-A-3-153625,

(3)

Embedded image The compound represented by the structural formula of Heterocycles (Hetero
cycles), Volume 38, Pages 103-111, (19
1994). However, publications that disclose the carboxamide-based compounds of the above (1) to (3) include cell differentiation inducing action or its enhancing action, bone morphogenetic protein (BMP) action or its enhancing action, and neurotrophic activity. Factor (neurotrophic fac
There is no description regarding the tor: NTF) action or its enhancing action.

[0008]

In view of the above, for example, a compound that enhances the action of BMP can enhance the action of BMP existing in the living body or BMP administered to the living body, It is useful as a therapeutic agent for bone diseases such as However, conventional substances are known to have side effects such as promoting bone resorption and hypercalcemia and occurrence of ovarian cancer when administered to the body, and are not always suitable as therapeutic agents for bone diseases. On the other hand, for example, a compound that enhances the action of NGF can enhance the action of NGF present in the living body or NGF administered to the living body, and is useful as a therapeutic drug for dementia and peripheral neuropathy. However, its mechanism of action has not yet been elucidated, and side effects such as headache, dizziness and fatigue have been observed in clinical trials, its effects in humans have not been clarified, or its activity is not sufficient. Some of them have no effect, have neurotoxicity, or have an unfavorable effect as a medicament such as a decrease in immunity, hypercalcemia, and promotion of bone resorption, which are not sufficiently satisfactory for practical use. Furthermore, since BMP or a cell differentiation inducing factor represented by a neurotrophic factor is a protein, there is a limit in administration to a living body. Therefore, a low molecular weight compound is preferable as a compound that enhances the action of a cell differentiation inducing factor present in a living body or a cell differentiation inducing factor administered in a living body. In addition, even when the compound itself has the action of a cell differentiation inducing factor represented by BMP or neurotrophic factor, if it is a low-molecular compound, it can be used as a bone formation promoting drug for bone fracture healing and bone reconstruction, dementia, and peripheral neuropathy. BMP as a therapeutic agent for
And neurotrophic factors. In other words, conventional compounds that have not only potentiation but also neurotrophic factor-like effects themselves have not been shown to have an effect on humans, and other compounds have high activity and toxicity. In this respect, it is not satisfactory enough for practical use. Therefore, the chemical structure is different from the above known substances, and has an excellent BMP action or neurotrophic factor action itself, or an action to enhance them,
There is a strong need for the development of compounds that are sufficiently satisfactory as pharmaceuticals.

[0009]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies based on such technical background, and as a result, the optionally substituted carbamoyl group -COR ¹ has specificity in chemical structure. formula

Embedded image [Wherein, R ¹ is an amino group which may have a substituent, R ²
Represents a hydrogen atom or a lower alkyl group which may have a substituent, X represents a methine group which may have a substituent or N (O) m (m represents 0 or 1); Ring A represents a homo or hetero ring substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group, and ring B represents a homo or hetero ring which may have a substituent. ] Or a salt thereof, and the compound represented by the formula (I) or a salt thereof unexpectedly has a BMP or neurotrophic factor action, and a compound represented by the formula (I) A low molecular weight compound that specifically enhances the effects of trophic factors such as osteoblast and neuronal cell differentiation and neuronal cell survival, and is useful as an agent for inducing cell differentiation and an agent for enhancing its action, etc. Can be satisfied enough It found that it was accomplished the present invention based on these findings.

That is, the present invention relates to [1] the above formula (I)
Or a salt thereof, [2] R ¹ is (1)
(I) a halogen atom, (ii) C _1-3 alkylenedioxy,
(Iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (Xi) hydroxy, (xii) amino, (xiii) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _{1- 6} alkoxycarbonylamino, mono--C _1-6 alkylaminocarbonyl amino, acylamino selected from C _1-6 alkylcarbonylamino and C _1-6 alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (x
viii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl,
(Xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl,
(Xxvi) C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 which may be substituted with a group selected from the group consisting of C _6-10 aryl and (xxvii) C _6-10 aryloxy Alkynyl group, C _3-6 cycloalkyl group, C _6-14 aryl group or C _7-16 aralkyl group, (2) (i) halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro,
(Iv) cyano, (v) optionally halogenated C _1-6
Alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) halogenated C _1-6 alkoxy optionally, (x) C _1-6 alkylthio optionally halogenated, (xi) hydroxy, (xii) amino, (xiii) mono-C _1-6 alkylamino, (xiv ) Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino, C _1-6 alkylcarbonylamino and Acylamino selected from C _1-6 alkylsulfonylamino, (xvi
i) C _1-6 alkyl-carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxi
ii) C _6-10 aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl groups, C _A hydroxy group optionally having a _2-6 alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group, a C _6-14 aryl group or a C _7-16 aralkyl group, or (3)
Formula ^{- (C = O) -R 7} , -SO 2 -R 7, -SO-R 7, -
(C = O) NR ⁸ R ⁷ ,-(C = O) OR ⁷ ,-(C =
S) O—R ⁷ or — (C ＝ S) NR ⁸ R ⁷ (R ⁷ is (1) a hydrogen atom or (2) (i) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) Nitro,
(Iv) cyano, (v) optionally halogenated C _1-6
Alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) halogenated C _1-6 alkoxy optionally, (x) C _1-6 alkylthio optionally halogenated, (xi) hydroxy, (xii) amino, (xiii) mono-C _1-6 alkylamino, (xiv ) Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino, C _1-6 alkylcarbonylamino and Acylamino selected from C _1-6 alkylsulfonylamino, (xvi
i) C _1-6 alkyl-carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxi
ii) C _6-10 aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl groups, C _{A 2-6} alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group, a C _6-14 aryl group or a C _7-16 aralkyl group, and R ⁸ represents a hydrogen atom or a C _1-6 alkyl group; An amino group which may be substituted with an acyl group represented by the following), (i) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, and (v) halogen C _1-6 alkyl which may be optionally halogenated, (vi) C _2-6 alkenyl which may be halogenated, (vii) C _2-6 alkynyl which may be halogenated, (viii) C _{3- 6}
Cycloalkyl, (ix) optionally halogenated C
_1-6 alkoxy, (x) optionally halogenated C
_1-6 alkylthio, (xi) hydroxy, (xii) amino,
(Xiii) mono-C _1-6 alkylamino, (xiv) di-C
_1-6 alkylamino, (xv) 5- or 6-membered cyclic amino,
(Xvi) C _1-6 alkoxycarbonylamino, mono-C
_1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl -
Carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi)
Mono-C _1-6 alkyl-carbamoyl, (xxii) di-C
_1-6 alkyl - carbamoyl, (xxiii) C _6-10 aryl - carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvi
i) in addition to a carbon atom and one nitrogen atom, which may be substituted with a group selected from the group consisting of C _6-10 aryloxy, 1 to 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom R ⁵ represents a group in which one hydrogen atom has been removed from a nitrogen atom in a 5- to 9-membered nitrogen-containing heterocyclic ring which may contain 3 hetero atoms, and R ² represents (1) a hydrogen atom or (2) ) (I) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _2-6 alkenyl, (vi
i) optionally halogenated C _2-6 alkynyl, (vi
ii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii)
Amino, (xiii) mono-C _1-6 alkylamino, (xiv)
Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (xviii) a carboxyl, (xix) C
_1-6 alkoxy-carbonyl, (xx) carbamoyl, (x
xi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl , (Xxvi) C _6-10 aryl and (xx
vii) a C _1-6 alkyl group which may be substituted with a group selected from the group consisting of C _6-10 aryloxy, wherein X is CR ⁶ ′ (R ⁶ ′ is (1) hydrogen atom, (2) Halogen atom,
(3) (i) halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) halogen Optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _{1 -6} alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii) amino, (xii
i) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi)
C _1-6 alkoxycarbonylamino, acylamino selected from mono -C _1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (Xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C
_1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C _6-10
A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkyl group which may be substituted with a group selected from the group consisting of aryloxy,
_2-6 alkynyl group, _C3-6 cycloalkyl group, _C6-14 aryl group or _C7-16 aralkyl group, or (4) -OR
⁶ ″ (R ⁶ ″ is a hydrogen atom or (i) a halogen atom, (i
i) C _1-3 alkylenedioxy, (iii) nitro, (iv)
Cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (Viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii) Amino, (xiii) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino,
C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C
_1-6 alkyl-carbonyl, (xviii) carboxyl,
(Xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl,
(Xxii) di-C _1-6 alkyl-carbamoyl, (xxiii)
C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xx
v) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl group,
C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group, C _6-14 aryl group or C _7-16 aralkyl group) or N ( O) m
(M represents 0 or 1), and ring A represents a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-3
(1) 3 to 10 substituted with an alkylenedioxy group
A 5- to 9-membered heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to (2) a carbon atom, and The substituted substituents may combine with each other to form a 3- to 10-membered cyclic hydrocarbon;
Halogen atom, (ii) C _1-3 alkylenedioxy, (ii
i) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated Good C _2-6 alkynyl, (viii) C _3-6 cycloalkyl,
(Ix) an optionally halogenated C _1-6 alkoxy,
(X) an optionally halogenated C _1-6 alkylthio,
(Xi) hydroxy, (xii) amino, (xiii) mono-C
_1-6 alkylamino, (xiv) di -C _1-6 alkylamino, (xv) 5 or 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono--C _1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (xvi
ii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (x
xiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxv
i) a group selected from the group consisting of C _6-10 aryl and (xxvii) C _6-10 aryloxy, which may be substituted with (1) a 3- to 10-membered cyclic hydrocarbon or (2) a carbon atom other than nitrogen atom, a sulfur atom and a (1) to 1 selected from oxygen atom indicates a 5- to 9-membered heterocyclic ring containing 4 heteroatoms compound according to claim, (3) R ¹ has the formula

Embedded image Wherein R ³ and R ⁴ are the same or different,
A hydrogen atom, a hydroxy group which may have a substituent, a lower alkyl group which may have a substituent, an acyl group, an aryl group which may have a substituent or a substituent And R ³ and R ⁴ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom]. The compound according to item (1), wherein [4] R ³ and R ⁴ each represent a hydrogen atom, an optionally substituted hydroxy group, an optionally substituted lower alkyl group or an acyl group. in addition, R ³ and the (3) R ⁴ forms a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom a compound according to claim, [5] R ³ and R ⁴ are each A lower alkyl which may be the same or different and may have a hydrogen atom or a substituent A compound according to item (3), which is a group;
[6] R ³ is a hydrogen atom or a C _1-6 alkyl group, and R ⁴ is (1) a hydrogen atom, (2) hydroxy, carboxyl,
C _1-6 alkoxy - carbonyl, amino and mono- - or di -C _1-6 optionally substituted by a group selected from the group consisting of alkylamino C _1-6 alkyl group, (3) C
_A C _6-14 aryl group optionally substituted with _1-6 alkoxy or (4) a C _7-16 aralkyl group optionally substituted with C _1-6 alkoxy or C _1-6 acylamino,
The compound according to item (3), wherein R ³ and R ⁴ together with the adjacent nitrogen atom form a 5- to 8-membered nitrogen-containing heterocyclic group which may be substituted by C _7-16 aralkyl, [ 7] R
The compound according to (1), wherein ² is a hydrogen atom or a lower alkyl group which may have a substituent, [8] wherein R ² is (1) a hydrogen atom or (2) hydroxy, C _1-6 alkyl the is optionally also carbamoyl and C _1-6 which may have a substituent selected from amino optionally having alkyl C _1-6 alkyl group has a (1) compound according to claim ,

[9] The compound according to (1), wherein X is a methine group which may have a substituent, and [10] a compound wherein X is a methine group which may be substituted with a C _1-6 alkyl group. (1) The compound according to (1), wherein [11] X is N (O) m (m represents 0 or 1),
[12] The compound of (1), wherein X is N, [1]
3] The compound according to item (1), wherein ring A is a benzene ring substituted with a halogen atom, lower alkyl group, lower alkoxy group or lower alkylenedioxy group, [14] ring A is halogen atom, C _1- The compound according to item (1), which is a C _6-12 aromatic hydrocarbon ring substituted with a group selected from the group consisting of ₆ alkyl, C _1-6 alkoxy and C _1-3 alkylenedioxy, [15] The compound according to (1), wherein the ring B is a benzene ring which may have a substituent, [16]
A group selected from the group consisting of halogen atom, C _1-6 alkyl optionally substituted with a halogen atom, C _1-6 alkoxy optionally substituted with a halogen atom, and C _1-3 alkylenedioxy _6-12 which may be substituted by
A 5- to 8-membered aromatic hydrocarbon ring or a C _1-6 alkyl group which may contain 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms A compound according to item (1), wherein [17] R ¹ is

Embedded image (R ³ ′ is a hydrogen atom or a C _1-6 alkyl group, R ⁴ ′ is (1) a hydrogen atom, (2) hydroxy, carboxyl,
C _1-6 alkoxy - carbonyl, amino and mono- - or di -C _1-6 optionally substituted by a group selected from the group consisting of alkylamino C _1-6 alkyl group, (3) C
_A C _6-14 aryl group optionally substituted with _1-6 alkoxy or (4) a C _7-16 aralkyl group optionally substituted with C _1-6 alkoxy or C _1-6 acylamino,
R ³ ′ and R ⁴ ′ may be substituted with a C _7-16 aralkyl together with an adjacent nitrogen atom to form a 5- to 8-membered nitrogen-containing heterocyclic group. Wherein R ² is a substituent selected from (1) a hydrogen atom or (2) carbamoyl optionally having hydroxy, C _1-6 alkyl and amino optionally having C _1-6 alkyl. in a C _1-6 alkyl group which may have, X is C _1-6 optionally substituted by an alkyl group methine group or N (O) m (m
Represents 0 or 1), wherein ring A is a halogen atom, C _1-6
A C _6-12 aromatic hydrocarbon ring substituted with a group selected from the group consisting of alkyl, C _1-6 alkoxy and C _1-3 alkylenedioxy, wherein ring B is substituted with a halogen atom or a halogen atom. And C _6-12 aromatic optionally substituted with a group selected from the group consisting of C _1-6 alkyl, C _1-6 alkoxy optionally substituted with a halogen atom and C _1-3 alkylenedioxy. A 5- to 8-membered heterocyclic group which may be substituted with a hydrocarbon ring or a C _1-6 alkyl group and which contains, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur A compound according to item (1), wherein [18] R ¹ is

Embedded image (R ³ ″ is a hydrogen atom, and R ⁴ ″ is a C _7-16 optionally substituted with (1) a hydrogen atom or (2) C _1-6 alkoxy.
Wherein R ² is a hydrogen atom or a C _1-6 alkyl group optionally having hydroxy, X is a methine group or N, and ring A is C _1-6 alkoxy or C _1-3 A C _6-12 aromatic hydrocarbon ring substituted with alkylenedioxy, wherein ring B is a halogen atom, C _1-6 alkoxy and C _1-3
(1) which is a C _6-12 aromatic hydrocarbon ring _optionally substituted with a group selected from the group consisting of alkylenedioxy;
Item [19] N-methyl-9- (1,3-
Benzodioxol-5-yl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxol-7
-Carboxamide or a salt thereof, [20] N-methyl-
8- (1,3-benzodioxol-5-yl) -7-
Hydroxymethyl-naphtho [2,3-d] -1,3-dioxole-6-carboxamide or a salt thereof, [2
1] 9- (1,3-benzodioxol-5-yl)-
8-hydroxymethyl-1,3-dioxolo [4,5-
f] quinoline-7-carboxamide or a salt thereof, [2
2] N-methyl-4- (1,3-benzodioxole-
5-yl) -6,7-diethoxy-3-hydroxymethyl-naphthalene-2-carboxamide or a salt thereof,
[23] 9- (4-methoxyphenyl) -N-[(4-
[Methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof, [24] 9- (1,3-benzodioxole-5)
-Yl) -N-[(4-methoxyphenyl) methyl]-
1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof, [25] 9- (4-fluorophenyl) -N-[(4-methoxyphenyl) methyl]
-1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof, [26]

Embedded image Wherein each symbol has the same meaning as described in the above item (1) or a salt thereof is subjected to a functional group conversion reaction or a (and) carbon-enrichment reaction.

Embedded image [Wherein, R ¹¹ represents a lower alkyl group which may have a substituent, and other symbols have the same meanings as described in the item (1)] or a method for producing a salt thereof, 27] Expression

Embedded image [Wherein each symbol has the same meaning as described in the item (1)], the compound or its ester or its salt is subjected to an amidation reaction and, if necessary, further subjected to an acylation reaction. [28] A method for producing the compound according to item (1) or a salt thereof, [28] a pharmaceutical composition comprising the compound according to item (1), [29]

Embedded image [Wherein the ring A ′ represents an optionally substituted homo- or heterocyclic ring, and other symbols have the same meanings as in the item (1)] or a salt thereof. A cell differentiation-inducing agent or a cell differentiation-inducing factor-enhancing agent comprising: (30) A ′ ring having (i) a halogen atom, (ii) C _1-3
Alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _2-6 alkenyl, (vi
i) optionally halogenated C _2-6 alkynyl, (vi
ii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii)
Amino, (xiii) mono-C _1-6 alkylamino, (xiv)
Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 acylamino, (xvii) C _1-6 alkyl-carbonyl, (xviii) carboxyl, (xix) C
_1-6 alkoxy-carbonyl, (xx) carbamoyl, (x
xi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl , (Xxvi) C _6-10 aryl and (xx
vii) (1) a 3- to 10-membered cyclic hydrocarbon which may be substituted with a group selected from the group consisting of C _6-10 aryloxy or (2) a nitrogen atom, a sulfur atom and an oxygen atom other than a carbon atom A 5- to 9-membered heterocyclic ring containing 1 to 4 heteroatoms selected, and adjacent substituents on the ring A ′ are bonded to each other to form (1) a 3- to 10-membered cyclic hydrocarbon, ( 2) 3- to 9-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen other than carbon, or (3) nitrogen, sulfur and oxygen other than carbon (31) The agent according to (29), which may form a 5- to 9-membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from atoms, [31] prevention of neurological diseases or bone and joint diseases. Item (28) which is a therapeutic agent And (32) the neurological disorder is cerebrovascular dementia, senile dementia or neurodegenerative disease in Alzheimer's disease, amyotrophic lateral sclerosis, diabetic peripheral neuropathy, or Parkinson's disease. 31) An agent according to item 31 is provided.

In the above formula, ring A represents "a homo- or heterocyclic ring substituted by a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group". The “homologous or heterocyclic” has an arbitrary number (preferably 1 to 5, more preferably 1 to 3) of the above substituents at substitutable positions, and when the number of the substituents is 2 or more, And each substituent may be the same or different, and two adjacent substituents may be bonded to each other to form a ring. Examples of the ring when two adjacent substituents on the ring A are bonded to each other to form a ring include, for example, 3 to 1
And a 0-membered cyclic hydrocarbon (preferably a 5- or 6-membered cyclic hydrocarbon). More specifically, for example, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, And C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.). Among them, for example, benzene, cyclopentane,
A 5- or 6-membered homocyclic ring such as a cyclohexane ring is preferred, and a benzene ring is particularly preferred. As a condensed ring formed together with the ring A when two adjacent substituents on the ring A are bonded to each other to form a ring, for example, naphthalene or the like is used.

In the above formula, the homocyclic ring represented by the ring A means a cyclic hydrocarbon composed of carbon atoms, for example, a 3- to 10-membered cyclic hydrocarbon, preferably a 5- or 6-membered cyclic hydrocarbon. And so on. Specifically, benzene, C
_3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.), C _3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) are used. Of these, a 5- or 6-membered homocyclic ring such as a benzene, cyclopentane, or cyclohexane ring is preferable, and a benzene ring is particularly preferable. In the above formula, as the heterocyclic ring represented by ring A, one or more heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to one or more carbon atoms (for example, 1 to 4 Pieces, preferably one to three
Aromatic heterocycles or non-aromatic heterocycles. Examples of the “aromatic heterocycle” include, for example, a 5- or 6-membered aromatic heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom in addition to a carbon atom (for example, Pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, imidazole, pyrazole, triazole, thiophene, furan, thiazole,
Isothiazole, oxazole, isoxazole ring and the like). Preferred aromatic heterocycles also include, for example, pyridine, pyrazine, thiophene, pyrrole, thiazole rings and the like. In particular, a 6-membered nitrogen-containing heterocyclic ring containing one or two nitrogen atoms other than a carbon atom (for example, a pyridine or pyrazine ring) is preferable.

The "non-aromatic heterocyclic ring" includes, for example, a 5- to 9-membered non-aromatic heterocyclic ring containing one to three hetero atoms selected from nitrogen, oxygen and sulfur atoms in addition to carbon atoms. Heterocycles, preferably 5- or 6-membered non-aromatic heterocycles and the like are included. For example, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene, dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, Piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran, morpholine,
Pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole ring and the like are used. Among them, a 6-membered non-aromatic heterocyclic ring containing one or two nitrogen atoms other than a carbon atom (eg, tetrahydropyridine, tetrahydropyrimidine, tetrahydropyridazine, piperidine, piperazine ring, etc.) is preferable, and particularly a piperazine ring is preferable. Used frequently.

In the above formula, (i) “halogen atom” of “homologous or heterocyclic ring substituted by halogen atom, lower alkyl group, lower alkoxy group or lower alkylenedioxy group” represented by ring A: And, for example, fluorine, chlorine, bromine and iodine. (Ii) Examples of the “lower alkyl group” include methyl, ethyl, propyl,
Isopropyl, butyl, isobutyl, sec-butyl, ter
Examples thereof include linear or branched C _1-6 alkyl groups (preferably methyl and the like) such as t-butyl, pentyl, and hexyl. (iii) Examples of the “lower alkoxy group” include:
For example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert
Linear or branched C _1-6 alkoxy groups such as -butoxy (preferably methoxy and the like);
v) As the “lower alkylenedioxy group”, for example,
C _1-3 alkylenedioxy groups such as methylenedioxy, ethylenedioxy and propylenedioxy (preferably methylenedioxy and the like) are used. As the ring A, a halogen atom, a lower alkyl group (eg, C _1-6 alkyl), a lower alkoxy group (eg, C _1-6 alkoxy) or a lower alkylenedioxy group (eg, C _1-3 alkylenedioxy) (Preferably a C _6-12 aromatic hydrocarbon ring such as a benzene ring), among which a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-6 alkoxy group is preferable.
A benzene ring substituted with a _1-3 alkylenedioxy group is more preferred.

In the above formula, the ring A ′ represents “an optionally substituted homocyclic or heterocyclic ring”. In the above formula, the "homocycle" and "heterocycle" represented by the ring A 'include, for example, the "halogen atom, lower alkyl group, lower alkoxy group or lower alkylenedioxy" represented by the above-mentioned ring A. “Homocycle” and “heterocycle” of “homocycle or heterocycle substituted with a group” are used. The "homologous or heterocyclic ring"
Is an arbitrary number (preferably 1 to 5) at a substitutable position.
, More preferably 1 to 3) substituents. When the number of substituents is 2 or more, each substituent may be the same or different. The substituents may combine with each other to form a ring. Examples of the ring when two adjacent substituents are bonded to each other to form a ring include (1) a 3- to 10-membered cyclic hydrocarbon (preferably a 5- or 6-membered cyclic hydrocarbon), (2) One or two heteroatoms selected from nitrogen, sulfur and oxygen other than carbon
(E.g., 1 to 4, preferably 1 to 3) 3 to 9-membered aromatic heterocycle (preferably 5 or 6-membered aromatic heterocycle), or (3) other than carbon atom A 5- to 9-membered non-aromatic compound containing one or more (for example, 1 to 4, preferably 1 to 3) one or more hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom An aromatic heterocycle (preferably a 5- or 6-membered non-aromatic heterocycle) or the like is used.

More specifically, the "cyclic hydrocarbon" of the above (1) includes, for example, benzene, C _3-10 cycloalkene (eg, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, etc.),
_3-10 cycloalkane (eg, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.) and the like are used. Of these, a 5- or 6-membered homocyclic ring such as a benzene, cyclopentane, or cyclohexane ring is preferable, and a benzene ring is particularly preferable.
Examples of the “aromatic heterocycle” in the above (2) include, for example, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole,
In addition to carbon atoms such as imidazole, pyrazole, triazole, thiophene, furan, thiazole, isothiazole, oxazole and isoxazole rings, other than carbon atoms such as nitrogen atom, oxygen atom and sulfur atom which contain 1 to 3 heteroatoms 5 to 5 A 9-membered (preferably 5- or 6-membered) aromatic heterocycle is used. Examples of the “non-aromatic heterocycle” in the above (3) include, for example, tetrahydropyridine, dihydropyridine, tetrahydropyrazine, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, dihydropyrrole, dihydroimidazole, dihydropyrazole, dihydrothiophene,
Dihydrofuran, dihydrothiazole, dihydroisothiazole, dihydrooxazole, dihydroisoxazole, piperidine, piperazine, hexahydropyrimidine, hexahydropyridazine, tetrahydropyran,
Morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrothiophene, tetrahydrofuran, tetrahydrothiazole, tetrahydroisothiazole,
A 5- to 9-membered (preferably 5- or 6-membered) non-carbon atom containing 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom such as a tetrahydrooxazole or tetrahydroisoxazole ring. An aromatic heterocycle or the like is used. As a fused ring formed together with the ring A when two adjacent substituents on the ring A 'are bonded to each other to form a ring, for example, naphthalene or the like is used.

In the above formula, examples of the substituent for the homo- or heterocyclic ring represented by the ring A ′ include (i) a halogen atom (for example, fluorine, chlorine, bromine, iodine, etc.), and (ii)
Lower alkylenedioxy group (for example, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.), (iii) nitro group, (iv) cyano group, (v) halogenated A lower alkyl group, (vi) an optionally halogenated lower alkenyl group, (vii) an optionally halogenated lower alkynyl group, (viii)
Lower cycloalkyl groups (for example, C 4 such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.)
_3-6 cycloalkyl group), (ix) an optionally halogenated lower alkoxy group, (x) an optionally halogenated lower alkylthio group, (xi) a hydroxy group,
(Xii) amino group, (xiii) mono-lower alkylamino group (for example, mono-lower alkylamino group such as methylamino, ethylamino, propylamino, isopropylamino, butylamino, etc.)
C _1-6, such as alkylamino group), (xiv) di - lower alkylamino group (e.g., dimethylamino, diethylamino, dipropylamino, di -C such dibutylamino
_1-6 alkylamino group, etc.), (xv) 5- or 6-membered cyclic amino group (for example, morpholino, piperazin-1-yl, piperidino, pyrrolidin-1-yl etc.), (xv
i) acylamino group, (xvii) lower alkyl-carbonyl group (for example, C _1-6 alkyl-carbonyl group such as acetyl, propionyl and the like), (xviii) carboxyl group, (xix) lower alkoxy-carbonyl group (for example,
C _1-6 alkoxy-carbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, etc.), (xx) carbamoyl group, (xx
i) mono-lower alkyl-carbamoyl group (for example, mono-C such as methylcarbamoyl, ethylcarbamoyl, etc.)
_1-6 alkyl - such as carbamoyl group), (xxii) di - lower alkyl - carbamoyl group (e.g., dimethylcarbamoyl, -C _1-6 alkyl, such as diethylcarbamoyl - such as carbamoyl group), (xxiii) aryl - carbamoyl ( For example, C _6-10 aryl-carbamoyl such as phenylcarbamoyl, naphthylcarbamoyl, etc.), (xxiv) sulfo group, (xxv) lower alkylsulfonyl group (eg, C _1-6 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, etc.) ), (Xxvi) aryl groups (for example, C _6-10 aryl groups such as phenyl and naphthyl) or (xxvii) aryloxy groups (for example, C _6-10 aryloxy groups such as phenyloxy and naphthyloxy) and the like. Is used.

The above-mentioned "optionally lower alkyl group" includes, for example, a lower alkyl group which may have 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.). (Eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
C such as c-butyl, tert-butyl, pentyl, hexyl, etc.
_1-6 such as an alkyl group), and the like. Specific examples include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, propyl,
3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl,
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, 6,6,6-trifluorohexyl and the like are used. Examples of the “optionally lower halogenated lower alkenyl group” include, for example, 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.)
A lower alkenyl group (e.g., C _2-6 such as vinyl, propenyl, isopropenyl, 2-buten-1-yl, 4-penten-1-yl, 5-hexen-1-yl and the like) Alkenyl group) and the like. As the “optionally lower halogenated alkynyl group”, for example, a lower alkynyl group optionally having 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine, etc.) (for example, And C _2-6 alkynyl groups such as 2-butyn-1-yl, 4-pentyn-1-yl and 5-hexyn-1-yl.

The "optionally lower halogenated lower alkoxy group" includes, for example, a lower alkoxy group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.). (E.g., methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,
And C _1-6 alkoxy groups such as isobutoxy, sec-butoxy and tert-butoxy). Specific examples thereof include, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoro Ethoxy, n-propoxy, isopropoxy, n-butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like are used. Examples of the “optionally lower halogenated lower alkylthio group” include, for example, a lower alkylthio group optionally having 1 to 3 halogen atoms (eg, fluorine, chlorine, bromine, iodine, etc.) (for example,
Methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tert-butylthio and other C _1-6 alkylthio groups) and the like. Specific examples include methylthio, difluoromethylthio, Trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio,
4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like are used.

The above "acylamino group" includes, for example, -NHCOOR ⁵ , -NHCONHR ⁵ , -NHCO
R ⁵ or —NHSO ₂ R ⁵ (R ⁵ represents a hydrocarbon group) or the like is used. The “hydrocarbon group” represented by R ⁵ is a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, and an aryl group. Group,
A chain or cyclic hydrocarbon group such as an aralkyl group is used. Among them, a chain (linear or branched) or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a) an alkyl group [preferably a lower alkyl group (eg, methyl, ethyl, propyl, Isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and other C _1-6 alkyl groups)], b) alkenyl groups [preferably lower alkenyl groups (eg, vinyl, allyl, isopropenyl, butenyl, isobutenyl, C _2-6 alkenyl group such as sec- butenyl)], c) alkynyl groups [preferably, lower alkynyl group (e.g., propargyl, ethynyl, butynyl, C _2-6 alkynyl groups such as 1-hexynyl D) cycloalkyl group [preferably lower cycloalkyl group (eg, cyclopropyl, cyclobutyl, Cyclopentyl, 1 to 3 lower alkoxy groups (eg,
A C _1-6 alkoxy group such as methoxy, etc.) and a C _3-6 cycloalkyl group such as cyclohexyl which may be condensed with a benzene ring which may have a), e) an aryl group (for example, phenyl, Tolyl, xylyl, biphenyl, 1-naphthyl, 2-naphthyl, 2-indenyl, 2-anthryl, 1-anthryl, 2-anthryl, 3-anthryl, 1-phenanthryl, 2-phenanthryl, 3-phenanthryl, 4-phenanthryl or A C _6-14 aryl group such as 9-phenanthryl, preferably a phenyl group), f) an aralkyl group [preferably a lower aralkyl group (eg, benzyl, phenethyl, diphenylmethyl, 1-
Naphthylmethyl, 2-naphthylmethyl, 2-phenylethyl, 2-diphenylethyl, 1-phenylpropyl,
And a C _7-16 aralkyl group such as 2-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl and 5-phenylpentyl, and more preferably a benzyl group)]. In the above formula, as the “substituent” of the “optionally substituted homo or heterocyclic ring” represented by the ring A ′, for example, preferably a halogen atom, a lower alkyl which may be halogenated, Group (especially methyl), lower alkoxy group (especially methoxy) which may be halogenated, lower alkylenedioxy group (especially methylenedioxy) or hydroxy group, and more preferably a halogen atom, A lower alkyl group (especially methyl), a lower alkoxy group (especially methoxy) or a lower alkylenedioxy group (especially methylenedioxy) is used. As the ring A ', a homocyclic ring which may have a substituent is preferably used, and a benzene ring which may have a substituent is more preferably used. In particular,
The same preferable examples as the above-mentioned ring A are used.

In the above formula, the ring B represents “an optionally substituted homo- or heterocyclic ring”. In the above formula, the “homocycle” and “heterocycle” represented by ring B include, for example, “halogen atom, lower alkyl group,
The "homocyclic ring" and "heterocyclic ring" of "a homo- or heterocyclic ring substituted with a lower alkoxy group or a lower alkylenedioxy group" are used. In the above formula, the “substituent” of the “homocycle” or the “heterocycle” represented by the ring B is, for example, the “optionally substituted substituent” represented by the above ring A ′. And the same as the “substituent” of the “element or heterocycle”. As the "substituent" of the "optionally substituted homo- or heterocyclic ring" represented by ring B,
For example, a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc., particularly fluorine, chlorine, etc.), a lower alkylenedioxy group (eg, C _1-3 alkylenedioxy group such as methylenedioxy, ethylenedioxy, etc.)
Especially a lower alkyl group which may be halogenated (eg, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl) , Propyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,
5,5-trifluoropentyl, hexyl, 6,6,6
An optionally halogenated C _1-6 alkyl group such as trifluorohexyl and the like, especially methyl, trifluoromethyl and the like, an optionally halogenated lower alkoxy group (for example, methoxy, difluoromethoxy,
Trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-
Butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy and the like, and optionally halogenated C _1-6 alkoxy groups, especially methoxy and the like are used. As the ring B, a benzene ring which may have a substituent is preferable. In particular, ring B is a group consisting of a halogen atom, C _1-6 alkyl optionally substituted with a halogen atom, C _1-6 alkoxy optionally substituted with a halogen atom, and C _1-3 alkylenedioxy. A C _6-12 aromatic hydrocarbon ring which may be substituted with a group selected from
Benzene ring) or a 5- to 8-membered heterocyclic group which may be substituted with a C _1-6 alkyl group and which contains, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Rings (eg, thienyl, etc.) are preferred.

In the above formula, X represents “a methine group which may have a substituent or N (O) m (m represents 0 or 1)”. In the above formulas (I) and (II), specific examples of the “methine group which may have a substituent” represented by X include CR ⁶ (R ⁶ is a hydrogen atom, a halogen atom (for example, fluorine) , Chlorine, bromine, iodine, etc.), or a hydrocarbon group which may have a substituent or a hydroxy group which may have a substituent). As the “hydrocarbon group” represented by R ⁶ , for example, the “hydrocarbon group” represented by R ⁵ and the like are used, and preferably a lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-
Butyl, pentyl, hexyl, etc.).
As the “substituent” of the “hydrocarbon group” represented by R ⁶ ,
For example, the "substituent" of the "optionally substituted homo- or heterocyclic ring" represented by the ring A 'is used. The “optionally substituted hydroxy group” for R ⁶ may be, for example, the aforementioned “optionally substituted substituent” in place of the hydrogen atom of (1) the hydroxy group or (2) the hydroxy group. A hydroxy group having one hydrocarbon group or the like, specifically, -OR ⁶ ″ described above, among which a hydroxy group or a lower alkyl group optionally having a substituent or the like; And a hydroxy group having one is preferred. As the “lower alkyl group”, for example, a linear or branched lower alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) As the substituent that the “lower alkyl group” may have, for example, a “substituent” of the “homocycle” or the “heterocycle” represented by the ring A ′ is used. Can be X is preferably, for example, a methine group optionally substituted with a C _1-6 alkyl group or N, and CH, C—CH ₃ or N is particularly preferable.

In the above formulas (I) and (II), R ¹ represents an “amino group which may have a substituent”. As the "substituent" of the "amino group", for example, a hydrocarbon group optionally having a substituent, a hydroxy group optionally having a substituent, an acyl group, and the like are used. Further, the “amino group optionally having a substituent” also includes a nitrogen-containing heterocyclic group optionally having a substituent having a bond at a ring-forming nitrogen atom. As the “hydrocarbon group” of the “hydrocarbon group optionally having substituent (s)”, for example, the “hydrocarbon group” represented by the above R ⁵ is used. As the "substituent" of the "hydrocarbon group", for example, "an optionally substituted homo- or heterocyclic ring" represented by the above-mentioned ring A '
And the like as the “substituent” of the above. As the “hydroxy group optionally having substituent (s)”, for example, the “hydroxy group optionally having substituent (s)” represented by R ⁶ above is used.

As the "acyl group", for example,-(C
_{^{= O) -R 7, -SO 2}} -R 7, -SO-R 7, - (C
= O) NR ⁸ R ⁷ ,-(C = O) O-R ⁷ ,-(C =
S) O—R ⁷ , — (C ＝ S) NR ⁸ R ⁷ (R ⁷ is a hydrogen atom or a hydrocarbon group which may have a substituent,
R ⁸ is a hydrogen atom or a lower alkyl group (eg, a C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc., especially methyl, ethyl,
C _1-3 alkyl groups such as propyl and isopropyl are preferred. ). ) Is used. Among preferably, - (C = O) -R 7, -SO 2 -R 7, -S
^{O-R 7, - (C} = O) NR 8 R 7, - (C = O) O-
R ⁷ , and more preferably — (C ＝ O) —R ⁷ . R ⁷
Represents a group obtained by removing one hydrogen atom from a hydrocarbon compound, and examples thereof include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, and an aralkyl group. Such a chain (straight-chain or branched) or cyclic hydrocarbon group is used. Specifically, the “hydrocarbon group” represented by R ⁵ above
Among them, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferred.
_1-6 ) An alkyl group is preferred. Examples of the substituent which the “hydrocarbon group” represented by R ⁷ may have include, for example, “substituted or homocyclic or heterocyclic ring which may have a substituent” represented by the above ring A ′. And the like.

The “nitrogen-containing heterocyclic group having a bond at the ring-forming nitrogen atom” as the “amino group optionally having substituent (s)” represented by R ¹ includes a carbon atom and one nitrogen atom. In addition to the atoms, for example, one to three hydrogen atoms such as a nitrogen atom, an oxygen atom and a sulfur atom, which may contain 1 to 3 heteroatoms such as a 5- to 9-membered nitrogen-containing heterocyclic ring. A group that has been removed is used. Specifically, for example,

Embedded image Are commonly used. As the “substituent” of the “nitrogen-containing heterocyclic group having a bond at the ring-constituting nitrogen atom” represented by R ¹ , for example, the “substituent which may have a substituent” represented by the above-mentioned ring A ′ And "substituent" of "primary or heterocyclic".

Preferred examples of the "amino group optionally having substituent (s)" for R ¹ include, for example,

Embedded image Wherein R ³ and R ⁴ are the same or different,
A hydrogen atom, a hydroxy group which may have a substituent, a lower alkyl group which may have a substituent, an acyl group, an aryl group which may have a substituent or a substituent And R ³ and R ⁴ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom]. Wherein R ³ and R ⁴ are each a hydrogen atom,
A hydroxy group which may have a substituent, a lower alkyl group or an acyl group which may have a substituent, and R ³ and R ⁴ have a substituent together with an adjacent nitrogen atom; It is preferable to form a nitrogen-containing heterocyclic group.

As the "hydroxy group optionally having substituent (s)", for example, the "hydroxy group optionally having substituent (s)" represented by R ⁶ above is used. Examples of the "lower alkyl group" of the "optionally substituted lower alkyl group" include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl and the like. And a straight-chain or branched C _1-6 alkyl group. The “substituent” of the “lower alkyl group optionally having substituent (s)” includes the “substituent” represented by the ring A ′ The "substituent" of the "homo- or heterocyclic ring which may have a substituent" is used. As the “acyl group”, for example, an “acyl group” as a “substituent” of the “amino group which may have a substituent” represented by the above R ¹ and the like are used.

The "nitrogen-containing heterocyclic group" formed by R ³ and R ⁴ together with an adjacent nitrogen atom includes, besides a carbon atom and one nitrogen atom (adjacent nitrogen atom), for example, nitrogen atom, oxygen A group obtained by removing one hydrogen atom from a nitrogen atom in a ring such as a 5- to 9-membered nitrogen-containing heterocyclic ring which may contain 1 to 3 heteroatoms such as an atom and a sulfur atom is used. Specifically, for example,

Embedded image Are commonly used. "Substituent" of the "nitrogen-containing heterocyclic group"
Examples of the substituent include the “substituent” of the “optionally substituted homo- or heterocyclic ring” represented by the ring A ′.

Preferably, R ³ and R ⁴ are the same or different and are each a hydrogen atom or a lower alkyl group which may have a substituent. In particular, R ³
Is a hydrogen atom or a C _1-6 alkyl group, and R ⁴ is (1) a hydrogen atom, (2) hydroxy, carboxyl, C _1-6 alkoxy-carbonyl, amino and mono- or di-C
_A C _1-6 alkyl group optionally substituted with a group selected from the group consisting of _1-6 alkylamino, (3) a C _6-14 aryl group optionally substituted with a C _1-6 alkoxy, or (4 A) C _7-16 aralkyl group optionally substituted by C _1-6 alkoxy or C _1-6 acylamino;
³ and R ⁴ together with adjacent nitrogen atoms may be substituted by C _7-16 aralkyl (eg benzyl).
It is preferable to form a membered nitrogen-containing heterocyclic group.

In the above formula, R ² represents a hydrogen atom or a lower alkyl group which may have a substituent. As the “lower alkyl group” for R ² , for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
A linear or branched C _1-6 alkyl group such as c-butyl, tert-butyl, pentyl and hexyl is used. As the “substituent” of the “optionally substituted lower alkyl group” for R ² , the “optionally substituted homo- or heterocyclic” for the ring A ′ And the like, and a hydroxy group is particularly preferable. R ² has a substituent selected from (1) a hydrogen atom or (2) carbamoyl optionally having hydroxy, C _1-6 alkyl and amino optionally having C _1-6 alkyl. And a C _1-6 alkyl group which may be substituted, and particularly a C _1-6 alkyl group which may be substituted with a hydrogen atom or a hydroxy group.

Compound (I) or compound (I) of the present invention
As I), for example, R ¹ is

Embedded image (R ³ ′ is a hydrogen atom or a C _1-6 alkyl group, R ⁴ ′ is (1) a hydrogen atom, (2) hydroxy, carboxyl,
C _1-6 alkoxy - carbonyl, amino and mono- - or di -C _1-6 optionally substituted by a group selected from the group consisting of alkylamino C _1-6 alkyl group, (3) C
_1-6 alkoxy optionally substituted C _6-14 aryl group (e.g., phenyl) or (4) C _1-6 alkoxy or C _1-6 optionally substituted by acylamino C _7-16
An aralkyl group (eg, a benzyl group), wherein R ³ and R ⁴ may be substituted with an adjacent nitrogen atom by a C _7-16 aralkyl (eg, benzyl);
R ² may form a (1) hydrogen atom or (2) hydroxy, C
Carbamoyl optionally having _1-6 alkyl and C
In _1-6 alkyl a has optionally also have a substituent group selected from an amino optionally C _1-6 alkyl group, X is C _1-6
A methine group optionally substituted with an alkyl group or N
(O) m (m represents 0 or 1), wherein ring A is substituted with a group selected from the group consisting of halogen atoms, C _1-6 alkyl, C _1-6 alkoxy and C _1-3 alkylenedioxy. and C _6-12 aromatic hydrocarbon ring (e.g., benzene ring) with, B ring is a halogen atom, optionally substituted by a halogen atom C _1-6 alkyl, optionally C ₁ optionally substituted by a halogen atom Substituted with a C _6-12 aromatic hydrocarbon ring (eg, benzene ring) or a C _1-6 alkyl group which may be substituted with a group selected from the group consisting of _-6 alkoxy and C _1-3 alkylenedioxy. The compound is preferably a 5- to 8-membered heterocycle containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in addition to a carbon atom.

In particular, when R ¹ is

Embedded image (R ³ ″ is a hydrogen atom, and R ⁴ ″ is a C _7-16 optionally substituted with (1) a hydrogen atom or (2) C _1-6 alkoxy.
An aralkyl group (eg, a benzyl group), R ² is a hydrogen atom or a C _1-6 alkyl group optionally having hydroxy, X is a methine group or N, and A ring is C _1-6 C substituted by alkoxy or C _1-3 alkylenedioxy
_{In a 6-12} aromatic hydrocarbon ring (eg, benzene ring), ring B may be substituted with a group selected from the group consisting of halogen atoms, C _1-6 alkoxy and C _1-3 alkylenedioxy. Compounds that are _6-12 aromatic hydrocarbon rings (eg, benzene rings) are preferred.

More specifically, compound (I) or compound (II) of the present invention includes N-methyl-9- (1,
3-benzodioxol-5-yl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxol-7-carboxamide, N-methyl-9- (4-methoxyphenyl) -8 -Hydroxymethyl-naphtho [1,2
-D] -1,3-dioxole-7-carboxamide,
N-methyl-9- (2-naphthyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-
7-carboxamide, N-methyl-9- (4-fluorophenyl) -8-hydroxymethyl-naphtho [1,2-
d] -1,3-Dioxole-7-carboxamide, N
-Methyl-9- (4-methylphenyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide, 9- (1,3-benzodioxole-5- Yl) -8-hydroxymethyl-1,3-
Dioxolo [4,5-f] quinolin-7-carboxamide, 9- (1,3-benzodioxol-5-yl)-
8-methyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide, N-methyl-8- (1,3-
Benzodioxol-5-yl) -7-hydroxymethyl-naphtho [2,3-d] -1,3-dioxol-6
-Carboxamide, N-methyl-4- (1,3-benzodioxol-5-yl) -6,7-diethoxy-3-
Hydroxymethyl-naphthalene-2-carboxamide,
9- (4-methoxyphenyl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-
f] Quinoline-7-carboxamide, 9- (1,3-benzodioxol-5-yl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-
f] quinoline-7-carboxamide, 9- (4-fluorophenyl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7
-Carboxamide and the like are used.

Compound (I) or Compound (I) of the present invention
Various methods for producing I) or salts thereof (hereinafter, simply referred to as compound (I) or compound (II)) can be considered in various ways, and typical examples thereof are shown in the following schemes 1 and 2. In addition,
In the following description of the production method, the compound as a raw material and the reaction product may form a salt that does not hinder the reaction. Examples of the “salt that does not interfere with the reaction” include the same as the salt of compound (I) or the salt of compound (II) described below. Among the compounds in which X is N (O) m (m represents 0 or 1) in compound (I) or compound (II), a compound in which m is 1 or a salt thereof is a compound in which m is 0 or At an appropriate stage of the salt or its production intermediate, a known chemical oxidation reaction [for example, Chemistry of the Heterocyclic Enooxide (Chemis
try of the Heterocyclic N-Oxide), 22-60 (1971), Academic Press
s), London & New Yor
k) or (G. Jones, Ed., “Quinolins Part 1”, John Wiley & Sons, 1st.
Chapters, pp. 61-62 (1977)] or a method analogous thereto.

Compound (XI) or compound (XI ') in which R ² is a hydrogen atom and X is a methine group which may be substituted in compound (I) or compound (II) can be obtained, for example, by the following scheme 1. It can be manufactured in the manner shown. (Scheme 1)

Embedded image

Embedded image [In the compounds (IV) to (XI) or (IV ′) to (XI ′) in the above scheme 1, E is a hydrogen atom or a halogen atom (eg, fluorine, chlorine, etc.), and R ⁹ is a lower alkyl group (eg, , Methyl, ethyl, etc.), and other symbols have the same meanings as described above. ]

In the compound (I), the benzene ring in which the ring A is substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group, the compound in which R ² is a hydrogen atom and X is N In Scheme 1, instead of compound (VI), a compound of the formula

Embedded image [In the formula, R ¹⁰ represents a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group which is present at 1 to 4 substitutable positions on the benzene ring, and other symbols are as defined above. Is shown. ] Using a compound represented by the formula (E.
C. Taylor, et.al.), Journal of Organic Chemistry, 32
Vol., Pp. 1899-1900 (1967)).

In the compound (I) or the compound (II), the compound (XIV) or the compound (XIV ′) wherein R ² is a lower alkyl group which may have a substituent may be prepared, for example, by the method shown in the following scheme 2. Can be manufactured. (Scheme 2)

Embedded image

Embedded image [In the compounds (XII) to (XIV) or (XII ′) to (XIV ′) in the above scheme 2, R ¹¹ represents a lower alkyl group which may have a substituent, and other symbols are those described above. Is equivalent to ]

Compound (I) or compound (II)
Is represented by the formula (XV) or (XV
'Can also be synthesized from the compound represented by formula (1). (Scheme 3)

Embedded image

Embedded image [Compound (XV) or (XV ′) in Scheme 3 above]
In the above, R ¹² represents a hydrogen atom or a lower alkyl group which may have a substituent, and other symbols have the same meanings as described above. As the “lower alkyl group” represented by R ^{9 to} R ¹² , for example, linear or branched such as methyl, ethyl, popyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc. C _1-6 alkyl group. As the “substituent” of the “lower alkyl group”, the “substituent” of the “optionally substituted homo- or heterocyclic ring” represented by the ring A ′ is used. Note that R ¹¹ is a hydroxymethyl group is not included.

The individual reactions of Schemes 1 to 3 in the above-mentioned production method will be described in more detail below. The reaction steps 1 and 2 are carried out by a method known per se (for example, JG Smith, et al., Journal of Organic Chemistry, 53).
2942-2953 (1988); Kuroda et al. (T. Kuroda,
et al.), Journal of Chemical Society
Chemical Communications (Journal of Chemical
Society, Chemical Communications), 1635-1636 (1
991); T. Kuroda, et al., Journal of Organic Chemistry
anic Chemistry), 59, 7353-7357 (1994), etc.)
It can be performed according to. That is, the reaction step 1
The production of compound [VI] or compound [VI '] by condensing dianion obtained by treating compound [IV] or compound [IV'] with a base is shown. As the base, for example, alkyl lithium is used, and preferable examples of the alkyl lithium include, for example, n-butyl lithium, sec-butyl lithium, tert-butyl lithium, methyl lithium, phenyl lithium, and the like. Lithium is particularly preferred.
The amount of the alkyl lithium to be used is generally 2 to 10 mol, preferably 2 to 3 mol, per 1 mol of compound [IV] or compound [IV ']. The amount of compound [V] to be used is generally 0.5 to 10 mol, preferably 1 to 3 mol, per 1 mol of compound [IV] or compound [IV ']. Further, the reaction can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely affect the reaction is used, and examples thereof include hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), amides ( For example, hexamethylphosphate triamide and the like, ureas (for example, 1,3-
Dimethyl-3,4,5,6-tetrahydro-2 (1H)
-Pyrimidine and the like). These solvents can be used alone or, if necessary,
Species or more kinds can be mixed at an appropriate ratio and used as a mixed solvent. The amount of the solvent to be used is generally 1 to 100 ml, preferably 5 to 20 ml, per 1 g of compound [IV] or compound [IV '].
Milliliters.

A base and compound [IV] or compound [IV ']
The reaction temperature for the reaction is usually from -72 ° C to 200 ° C, preferably from 0 ° C to 50 ° C. The reaction time is
Usually 30 minutes to 24 hours, preferably 30 minutes to 1 hour
2 hours. The reaction temperature for the subsequent condensation with compound [V] is usually from -72 ° C to 200 ° C, preferably from 0 ° C to 50 ° C. The reaction time is
Usually 30 minutes to 72 hours, preferably 30 minutes to 1 hour
8 hours. In the reaction step 2, the compound [VI] or the compound [VI '] is treated with an acid to generate a condensed furan derivative in the reaction system, and the compound [VII] or the compound [VIII] is condensed with the compound [VII]. ']. As the acid, an inorganic acid or an organic acid is used. Preferred examples of the inorganic acid include, for example, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, polyphosphoric acid and the like. Preferred examples of the organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid,
Oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,
Malic acid, methanesulfonic acid, benzenesulfonic acid, p-
And toluene sulfonic acid. The amount of acid used is
It is generally 0.01 to 10 mol, preferably 0.03 to 2 mol, per 1 mol of compound [VI] or compound [VI ']. The amount of the compound [VII] to be used depends on the amount of the compound [VI]
Or 1 to 10 usually per 1 mol of compound [VI '].
Mol, preferably 1 to 3 mol. Further, the reaction can be advantageously carried out in a solvent. As the solvent, a solvent that does not adversely affect the reaction is used, and examples thereof include hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, toluene, etc.), lower alcohols (eg, methanol, ethanol, propanol, etc.), ethers (Eg, diethyl ether, tetrahydrofuran, dioxane, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, etc.) and the like are used. Further, when the above-mentioned acids are liquid, those acids can be used as a solvent. These solvents can be used alone, or if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent used is the same as that of compound [VI]
Or 1 to 1 per gram of Compound [VI ']
It is 00 ml, preferably 5 to 20 ml. The reaction temperature is usually from −20 ° C. to 200 ° C.
To 25 ° C. to 150 ° C. are preferred. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes.
Minutes to 12 hours.

Reaction step 3 shows the production of compound (IX) or compound (IX ') by subjecting compound (VIII) or compound (VIII') to a hydrolysis reaction. As the hydrolysis reaction, for example, a method known per se (SR Sandler and W. Karo),
“Organic Functional Group Preparations I”
ions I ”) 2nd ed., Academic Press
Press) (1983), Chapter 9 (pages 271-273)). When the hydrolysis reaction is performed under acidic conditions, reaction step 4 occurs simultaneously with reaction step 3, and the compound (X) or compound (X ′) may be obtained.

In the reaction step 4, the compound (X) or the compound (X ') is subjected to an aromatization reaction in which the dehydration reaction and the decarboxylation reaction are simultaneously performed on the compound (IX) or the compound (IX').
′). The aromatization reaction is usually performed by treating the compound (IX) or the compound (IX ′) with an acid, and the compound (IX) or the compound (IX ′) is left or heated under a neutral condition. It can also be done by As the acid, an inorganic acid or an organic acid is used,
Preferred examples of the inorganic acid include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, polyphosphoric acid and the like. Preferred examples of the organic acid include, for example, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, fumaric acid,
Oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid,
Malic acid, methanesulfonic acid, benzenesulfonic acid, p
-Toluene sulfonic acid and the like. The amount of the acid to be used is generally 0.01 to 10 mol, preferably 0.03 mol, per 1 mol of compound (IX) or compound (IX ′).
Or 2 moles. The reaction can be advantageously performed in a solvent. As the solvent, a solvent that does not adversely influence the reaction is used, and examples thereof include hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, etc.), lower alcohols (eg, methanol, ethanol, propanol, etc.), ethers (eg, For example, diethyl ether, tetrahydrofuran, dioxane, and the like, and halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloroethane, and the like) are used. When the above-mentioned acids are liquid, they can be used as a solvent. These solvents can be used alone, or if necessary, two or more of them can be mixed in an appropriate ratio or used as a mixed solvent with water. The amount of the solvent to be used is generally 1-100 ml, preferably 5-20 ml, per 1 g of compound (IX) or compound (IX '). The reaction temperature is usually about -20 ° C to about 200 ° C, preferably about 25 ° C to about 150 ° C. The reaction time is generally 30 minutes to 24 hours, preferably 30 minutes to 12 hours.

In the reaction step 5, the compound (X) or the compound (X ') is subjected to an amidation reaction and, if necessary, further subjected to an acylation reaction to produce the compound (XI) or the compound (XI'). Is shown. As the amidation reaction, for example, a method known per se (SR Sandler and W. Karo, “Organic Functional Group Preparations I” (“Or
ganic Functional Group Preparations I ”) 2nd ed.,
Academic Press (1983),
Chapter 11 (pages 315 to 358) can be used. As the acylation reaction, for example, a method known per se (SR Sandler and W. Karo)
o), “Organic Functional Group Preparations I” (“Organic Functional Group Pr.
eparations I ”) 2nd ed., Academic Press (Aca
demic Press) (1983), Chapter 7 (pages 281-313)).

In the reaction step 6, the compound [XII] or the compound [XII '] is subjected to a ring opening reaction and, if necessary, further subjected to an acylation reaction to produce the compound [XIII] or the compound [XIII']. Is shown. Compound [XII] or compound [XII ′] as a raw material can be produced, for example, by a method known per se (R.
RS Burden et al., Journal of the Chemical Society, Section C (J. Chem. Soc.
(C)), 693-701, 1969; Achieves
Of Pharmacology (Arch.Paharmacol.), 328
(9), 640-644, 1995; Indian Journal of Chemistry (Indian J. Chem.), Sec.
t. B: Org.Chem.Include.Med.Chem., 33B (9), 8
39-846, 1994; Indian Journal of Chemistry (Indian J. Chem.), Sect. B, 3,
1B (7), pp. 401-406, 1992; Chemical and Pharmaceutical Britain (Chem. Phar
m.Bull.), 32 (1), pp. 31-7, 1984; Journal of the Chemical Society, Section C (J. Chem. Soc. (C)), (11), 2091-209.
4, 1971; Phytochemist
ry) 29 (9), 291-2993, 1990;
Journal of Natural Products
Natural Products), 43 (4), 482-486,
1980; M. Anzini et al., Heterocycles, 38, 103-111,
1994) or a lactone-based compound produced according to them.

The ring opening reaction is carried out by reacting compound [XII] or compound [XII '] with ammonia or an amine derivative represented by HR ¹ (R ¹ has the same meaning as described above). As the ammonia, ammonia water or gaseous or liquid ammonia is used. The amount of the ammonia or amine derivative is usually an equimolar amount to about 100-fold molar amount with respect to compound [XII] or compound [XII '], and preferably 2 to 10 times.
It is used in a double molar amount. The reaction can be advantageously performed in a solvent. As the solvent, a solvent that does not adversely influence the reaction is used. For example, hydrocarbons (for example,
Pentane, hexane, cyclohexane, benzene, etc.), lower alcohols (eg, methanol, ethanol, propanol, etc.), ethers (eg, diethyl ether, tetrahydrofuran, dioxane, etc.), amides (eg, N, N-dimethylformamide, hexamethylphosphine) Acid triamide, etc.), ureas (for example, 1,
3-dimethyl-3,4,5,6-tetrahydro-2 (1
H) -pyrimidine) and the like. Also, HR
^{When the} amine derivative represented by ¹ (R ¹ has the same meaning as described above) is a liquid, it can be used as a solvent. These solvents can be used alone,
If necessary, two or more kinds may be mixed at an appropriate ratio or used as a mixed solvent with water. The amount of the solvent to be used is generally 1 to 10 per gram of compound [XII] or compound [XII '].
It is 0 ml, preferably 5 to 20 ml. The reaction temperature is usually from −20 ° C. to 200 ° C., preferably from 25 ° C. to 150 ° C. In some cases, the reaction can be advantageously performed by performing the reaction in a sealed tube.
Further, R ¹ in HR ¹ (R ¹ is as defined above)
When is an acylated amino group, the reaction can advantageously proceed in the presence of a base. Examples of the base include alkyl lithium reagents (eg, methyllithium, n-butyllithium, s-butyllithium, t-butyllithium, etc., preferably n-butyllithium), inorganic bases (eg, sodium hydroxide, potassium hydroxide). , Sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, sodium hydride, sodium metal, etc.) and organic bases (eg, sodium methoxide, sodium ethoxide, triethylamine, pyridine, diethylisopropylamine, etc.). Used. The amount of the base to be used is generally an equimolar amount to about 10-fold molar amount, preferably an equimolar amount to 2-fold molar amount, relative to compound [XII] or compound [XII ']. The reaction time is generally 30 minutes to 1 week, preferably 30 minutes to 4 days. As the acylation reaction that is performed as necessary after the ring opening reaction, for example, the method described in the reaction step 5 is used.

In the reaction step 7, the compound (XIII) or the compound (XIII ′) is subjected to a functional group conversion reaction, a carbon-enrichment reaction, or an appropriate combination of these reactions to give the compound (XI
V) or the production of compound (XIV '). Examples of the functional group conversion reaction and carbon increase reaction include methods known per se (J.
Matthew and J. Vail-Rinal (J. Mathieu an
d J. Weil-Raynal), “The Formation of C-
C Bonds I-III ”(“ Formation of CC Bonds
I-III "), George Shime Publishers (Ge
orge Thieme Publishers, Stuttgart
t) (1973, 1975, 1979); R. Sandler
And W. Caro (SRSandler and W. Karo), “Organic Functional Group Preparations I-III” (“Organic Functional Group Prepa
rations I ”) 2nd ed., Academic Press (Academ
ic Press) (1983, 1986, 1989)).

In the reaction step 8, the compound (XV) or the compound (XV ') is subjected to an amidation reaction and, if necessary, further subjected to an acylation reaction to produce the compound (I) or the compound (II). Show. As the compound (XV) or compound (XV ′) as a raw material, a synthetic intermediate in Schemes 1 and 2, or a method known per se (for example,
G. FIG. G. Jones ed., “Kinolins Part 1
(Quinolines Part 1) ", John Wiley & Sons (1977), Chapter 2 (93-3)
18); S. LSEl-Assal et
al.), Journal of Chemical Society, pp. 1656-1662, (1
961); D. Delorme et al., Journal of Medicinal Chemistry (Journal
of Medicinal Chemistry), 39, 3951-3970, (199
6 years) or a carboxylic acid derivative produced according to them. As the amidation reaction, for example, a method known per se (SR Sandler and W. Karo, “Organic Functional Cloof Preparations I”)
(“Organic Functional Group Preparations I”) 2n
d ed., Academic Press (1983)
Year), Chapter 11 (pp. 315-358)).
For the acylation reaction, for example, the method described in the reaction step 5 is used. When the target compound is produced by the method shown in the above schemes 1 to 3, the compound (IV) to the compound (X
V) and the substituents on ring A and ring B in compound (IV ′) to compound (XV ′) are, for example, a hydroxyl group, an amino group, a mono-C _1-6 alkylamino group, a ketone, a carboxyl group or a tetrazolyl When a functional group such as a group is contained, these functional groups may be protected.
As a method of deprotection, a method known per se [TW Green and PGM Utz, "Protective Groups in Organic Chemistry", 2nd edition, John Willy and Sands, Inc. (1991) ( TWGreen and PGMWuts, “Pro
tective Groups in Organic Synthnthesis ”2nd.ed.,
John Wiley & Sons, Inc., (1991)]].

The compound (I) or compound (II) thus obtained or a salt thereof can be obtained by a method known per se (for example, phase transfer, concentration, solvent extraction, fractionation, crystallization, recrystallization, chromatography, etc.). Can be separated and purified. The compound (I) or compound (II) of the present invention or a salt thereof is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, or an organic compound. Salts with acids, salts with basic or acidic amino acids and the like are used. Preferred examples of the salt with an inorganic base include an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, etc.), an aluminum salt, an ammonium salt and the like. Preferred examples of the salt with an organic base include trimethylamine, triethylamine, pyridine,
Picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,
A salt with N'-dibenzylethylenediamine or the like is used. Preferred examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Preferred examples of the salt with an organic acid include, for example,
Salts with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like are used. Preferred examples of the salt with a basic amino acid include, for example, salts with arginine, lysine, ornithine and the like. Preferred examples of the salt with an acidic amino acid include, for example, a salt with aspartic acid and glutamic acid. When the target product is obtained in a free state, it may be converted to a salt according to a conventional method, and when the target product is obtained as a salt, it may be converted to a free form according to a conventional method. Good. The compound (I) or compound (II) or a salt thereof of the present invention may be a hydrate or an anhydrate. The compound (I) or compound (II) of the present invention or a salt thereof is isolated and purified by a means known per se, for example, solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography and the like. be able to. The starting compound of the compound (I) or compound (II) of the present invention or a salt thereof can be isolated and purified by the same known means as described above, but the reaction mixture can be used without isolation. As a raw material in the next step.

Compound (I) or compound (II) of the present invention
Or, when their salts contain optical isomers, stereoisomers, positional isomers or rotamers, these are also included in the compounds of the present invention, and can be synthesized by known synthesis techniques and separation techniques, respectively. It can be obtained as a single item. For example, when the compound of the present invention has an optical isomer, the optical isomer resolved from the compound is also included in the present invention. The optical isomer can be produced by a method known per se. Specifically, an optical isomer is obtained by using an optically active synthetic intermediate or by subjecting a final racemic mixture to optical resolution according to a conventional method. As the optical resolution method, a method known per se, for example, the following fractional recrystallization method, chiral column method, diastereomer method and the like are used.

(1) Fractional recrystallization method A method of forming a salt between a racemate and an optically active compound, separating the salt by a fractional recrystallization method and, if desired, subjecting to a neutralization step to obtain a free optical isomer. . (2) Chiral column method A method in which a racemate or a salt thereof is applied to a column for separation of optical isomers (chiral column) to separate the racemate or a salt thereof. For example, in the case of liquid chromatography, a mixture of optical isomers is added to a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation), and water,
Various buffers (eg, phosphate buffer, etc.), organic solvents (eg, ethanol, methanol, acetonitrile, etc.)
Is developed as a single or mixed solution to separate optical isomers. For example, in the case of gas chromatography, separation is performed using a chiral column such as CP-Chirasil-DeXCB (manufactured by GL Sciences). (3) Diastereomer method A racemic mixture is converted into a diastereomer mixture by a chemical reaction with an optically active reagent, and the mixture is subjected to a conventional separation means (for example, fractional recrystallization, chromatography, etc.) to form a single mixture. A method of obtaining an optical isomer by separating the optically active reagent site by a chemical treatment such as a hydrolysis reaction after converting the substance into a substance. For example, when the compound of the present invention has a hydroxyl group or a primary or secondary amino group in the molecule,
The compound and an optically active organic acid (for example, MPTA [α-
Methoxy-α- (trifluoromethyl) phenylacetic acid], (-)-menthoxyacetic acid, etc.) to give ester or amide diastereomers, respectively. On the other hand, when the compound of the present invention has a carboxylic acid, by subjecting the compound and an optically active amine or alcohol reagent to a condensation reaction,
An amide or ester diastereomer is obtained, respectively. The separated diastereomer is converted into an optical isomer of the original compound by subjecting it to acid hydrolysis or basic hydrolysis reaction.

The cell differentiation-inducing factors of interest in the present invention include osteogenic factors, neurotrophic factors, tumor growth factors (TG
F) Factors belonging to the TGF-β superfamily such as -β or activin, factors belonging to the FGF superfamily such as basic fibroblast growth factor (bFGF) or acidic fibroblast growth factor (aFGF), leukemia inhibitory factors ( leukemia
inhibitory factor; LIF or cholinergic differe
ntiation factor (sometimes called CDF) or serially neurotropic factor (cilialy ne)
urotrophic factor (CNTF) and other neuropoietic cytokine families
ine family), interleukin-1 (IL-
1, abbreviated hereinafter), IL-2, IL-3, IL-5, IL-6, IL-7, I
L-9, IL-11, tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), and other cells that maintain biological functions in specific tissues, such as osteoblasts and nerve cells, are undifferentiated Factors that induce traits characteristic of the process of differentiation from various precursors include bone formation factors and neurotrophic factors. As bone formation factors, BMP-2, -4, -5, -6-, -7, -8, -9,-, a protein that promotes bone formation and cartilage formation
BMP family such as 10, -11, -12, especially BMP-2, -4, -6
-,-7. The BMP may be a homodimer of each of the factors listed above or a heterodimer with all possible combinations. Neurotrophic factors include nerve growth factor (NGF) and brain-derived neurotrophic factor (BDN)
F), neurotrophin-3 (neurotrophin-3: NT-3)
And glial cell line-derived neurotrophic factor (glialcell line)
-derived neurotrophic factor (GDNF), and preferably the NGF family.

Compound (I) or Compound (I) of the present invention
I) or a salt thereof can be used as it is or according to a method known per se, in a pharmaceutical composition mixed with a pharmacologically acceptable carrier, for example, tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules , (Including soft capsules), syrups, emulsions, suspensions, injections (eg, subcutaneous injections, intradermal injections, intramuscular injections, etc.), suppositories, sustained release agents, etc., orally or parenterally It can be administered safely (eg, topically, rectally, intravenously, etc.). The content of compound (I) or compound (II) or a salt thereof in the preparation of the present invention is 0.1 to 100% by weight of the whole preparation. The dose varies depending on the administration subject, administration route, disease and the like. For example, when used as an agent for inducing cell differentiation or an agent for enhancing its effect, an adult (60 kg) is administered as an oral preparation per day to an oral agent. About 0.1 to 500 mg, preferably about 1 to 100 mg, more preferably about 5 to 100 mg
It can be administered once or several times a day. The injection is used in a manner known per se, that is, the compound (I) or the compound (II) or a salt thereof as it is or together with a substance having a cell differentiation-inducing factor action, for example, BMP or neurotrophic factor. Aqueous solutions for injection include physiological saline and isotonic solutions, and may be used in combination with the following suspending agents, if necessary. Examples of the oily liquid include sesame oil and soybean oil,
The following solubilizers may be used in combination. The prepared injection is usually filled in a suitable ampoule.

The pharmacologically acceptable carriers that may be used in the preparation of the preparation of the present invention include various organic or inorganic carrier substances commonly used as preparation materials. Agents, binders, disintegrants; solvents in liquid preparations, solubilizing agents, suspending agents, isotonic agents, buffers, soothing agents and the like. If necessary, additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can also be used. Excipients include, for example, lactose, sucrose, D-mannitol, starch,
Corn starch, crystalline cellulose, light anhydrous silicic acid, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.

Examples of the binder include crystalline cellulose,
Examples include sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, and sodium carboxymethylcellulose. Disintegrators include, for example, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, sodium carboxymethyl starch, L-hydroxypropyl cellulose and the like. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Examples of the dissolution aid include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As a suspending agent, for example, stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
Surfactants such as glyceryl monostearate; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium chloride, glycerin, D-mannitol and the like. Examples of the buffer include buffers such as phosphate, acetate, carbonate, and citrate. Examples of the soothing agent include benzyl alcohol and the like. As preservatives, for example, paraoxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Dehydroacetic acid, sorbic acid and the like. Examples of the antioxidant include sulfite and ascorbic acid.

Drugs containing compound (I) or compound (II) or a salt thereof have excellent cell differentiation inducing factor action and cell differentiation inducing factor action. Various neurological diseases [eg, cerebral vascular dementia, senile dementia or neurodegenerative diseases such as Alzheimer's disease, in combination with a substance having a factor action (eg, BMP, neurotrophic factor, etc.),
Amyotrophic lateral sclerosis (Low-Gerich disease), diabetic peripheral neuropathy (neuropathy) or Parkinson's disease, etc.) or bone / joint disease [eg, fracture, osteoporosis, osteoarthritis, rheumatoid arthritis, etc.] It is useful for the treatment and prevention of osteoarthritis, and specific examples of the treatment / prevention agent for bone / joint diseases include bone formation promoters, cartilage destruction inhibitors, fracture healing promoters, and bone reconstruction promoters. In addition, the role of BMPs and neurotrophic factors in vivo has not been fully elucidated, so enhancing BMPs and neurotrophic factors and other effects may lead to other diseases whose pathology is improved. There is also. The agent for acting on cell differentiation-inducing factor or the agent for enhancing action on cell differentiation-inducing factor of the present invention can also be used as a therapeutic or prophylactic agent for such diseases involving BMP, neurotrophic factor and the like. The agent for promoting cell differentiation-inducing factor or the agent for enhancing cell differentiation-inducing factor according to the present invention is applicable to the above diseases in humans and other mammals (eg, mice, rats, rabbits, dogs, cats, cattle, pigs, etc.). You can also. Moreover, the pharmaceutical composition comprising the compound (I) or the compound (II) of the present invention or a salt thereof has low toxicity and few side effects.

The agent for promoting cell differentiation or the agent for enhancing cell differentiation of the present invention has a strong activity of promoting osteogenesis. Therefore, it is mixed with a carrier for bone reconstruction as an agent for promoting osteogenesis during bone repair or bone transplantation. You can also. For example, the compound of the present invention can be used by being attached to or contained in an artificial bone made of metal, ceramic, or polymer.
The surface of the artificial bone is preferably made porous so that the cell differentiation inducing factor action enhancer of the present invention can be released from the living tissue when the artificial bone is implanted in a bone defect. The compound of the present invention is dispersed in a suitable dispersing agent, binder, diluent or the like (for example, collagen, physiological saline, citric acid solution, acetic acid solution, hydroxyapatite, fibrin or a mixture thereof). Can be attached or contained by applying or impregnating the artificial bone and drying. Such an artificial bone is implanted into a bone defect and firmly fixed to the defect. Immobilization agents for artificial bones
The active ingredient helioxanthin can be prepared by mixing with a physiologically acceptable dispersion medium, a binder, a diluent, and other ingredients (eg, calcium) effective for bone regeneration when used as a medicine. . The artificial bone fixative can also be used to fill the gap between the artificial bone implanted into the host bone defect and the bone defect without attaching or containing the artificial bone fixative to the artificial bone. The parenteral composition described here can also be used by attaching or containing a protein that promotes bone formation, such as the BMP family.

[0057]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention further includes the following reference examples,
The present invention will be described in detail with reference to Examples, Formulation Examples and Experimental Examples, but these Examples are merely examples, do not limit the present invention, and may be changed without departing from the scope of the present invention. . Elution in column chromatography (in parentheses indicates an elution solvent) in the following Reference Examples and Examples was performed under observation by TLC (Thin Layer Chromatography). In the TLC observation, Kieselgel 6 as a TLC plate was used.
0F ₂₅₄ (thickness 0.25mm, Merck (Merck) Co., Ltd.)
As a developing solvent, a solvent used as an elution solvent in column chromatography was used, and as a detection method, a UV detector, a coloring method using phosphomolybdic acid, and the like were employed. As the silica gel for the column, Kieselgel 60 (70 to 230 mesh, manufactured by Merck) was used. The NMR spectrum shows proton NMR ( ¹ H-NMR), and Gemini using tetramethylsilane as an internal or external standard.
200 (manufactured by VARIAN) and the δ value is p
Indicated in pm. The infrared absorption spectrum was measured by IR-810 (manufactured by JASCO Corporation). Melting point is Yanagimoto trace melting point analyzer
It was measured with MP-500D, and the uncorrected value was described. "Room temperature" in the following Reference Examples and Examples indicates 0 to 30 ° C, preferably about 15 to 25 ° C, and anhydrous magnesium sulfate or anhydrous sodium sulfate was used for drying the organic solvent. % Means percent by weight unless otherwise specified. In the chemical formulas of the following Examples and Reference Examples, Me represents a methyl group, and Ms represents a methanesulfonyl group. Abbreviations used in the text have the following meanings. s: singlet d: doublet dd: double doublet t: triplet m: multiplet br: broad J: coupling constant Hz: Hertz THF: tetrahydrofuran DMF: N, N-dimethylformamide DME: dimethoxyethane CDCl ₃ : heavy chloroform DMSO-d ₆ : heavy methyl sulfoxide NMR: proton nuclear magnetic resonance

[0058]

【Example】

Reference Example 1 10- (4-methoxyphenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9H) -one

Embedded image Helio alcohol (4.0 g) in benzene (200 m
l) Butyllithium (1.6 M hexane solution: 36 ml) was added dropwise to the solution at room temperature. After stirring at room temperature for 2 hours, a solution of 4-methoxybenzonitrile (3.9 g: 1.1 equivalents) in benzene (50 ml) was added dropwise. After stirring overnight at room temperature, water was added and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (250 m
l) and maleic anhydride (7.7 g) and p-toluenesulfonic acid (1.0 g) were added. After heating under reflux for 20 hours, the precipitated solid was removed by filtration, and the filtrate was concentrated under reduced pressure. Concentrated hydrochloric acid was added to the obtained residue, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the resulting tan precipitate was collected by filtration, washed with water, recrystallized from THF, and acid anhydride (about 3.
4 g) obtained. Sodium borohydride (0.8g)
The resultant was suspended in ME (80 ml), and the above-mentioned acid anhydride was gradually added at 0 ° C. After stirring at 0 ° C. for 30 minutes, the reaction solution was poured into ice-cooled diluted hydrochloric acid, and the product was extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate,
It was concentrated under reduced pressure. The obtained residue was purified by column chromatography (developing solvent: chloroform) to obtain the title compound (1.5 g). Some of them were recrystallized from THF and used for elemental analysis and instrumental measurement. _{Mp: 217-219 ℃ NMR (CDCl 3)} δ: 3.90 (3H, s), 5.20 (2H, s),
5.93 (2H, s), 6.99 (1H, d, J = 9Hz), 7.28 (1H, d,
J = 9Hz), 7.32 (1H, d, J = 9Hz), 7.72 (1H, d, J = 9H)
z), 8.43 (1H, s ) Elemental _{analysis:. C 20 H 14 O 5} · 0.5 H 2 O Calculated: C: 70.58%, H: 4.34% Found: C: 70.52%, H: 4.38%

Reference Example 2 10- (4-Chlorophenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxole-7 (9H)
-ON

Embedded image The title compound was obtained in the same manner as in Reference Example 1. Melting point: 225-227 ° C NMR (CDCl ₃ ) δ: 5.18 (2H, s), 5.93 (2H, s),
7.33 (3H, m), 7.44 (2H, d, J = 8Hz), 7.73 (1H, d,
J = 8Hz), 8.45 (1H , s) Elemental _{analysis:. C 19 H 11 O 4} Cl · 0.2H 2 O Calculated: C: 66.66%, H: 3.36% Found: C: 66.59%, H: 3.14%

Reference Example 3 10- (2-Naphthyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9H) -one

Embedded image The title compound was obtained in the same manner as in Reference Example 1. _{Mp: 224-226 ℃ NMR (CDCl 3)} δ: 5.13 (1H, d, J = 15.2Hz), 5.29
(1H, d, J = 15.2Hz), 5.85 (1H, d, J = 1.4Hz), 5.85
(1H, d, J = 1.4Hz), 7.334 (1H, d, J = 8.8Hz), 7.43
(1H, dd, J = 8.2Hz, J = 1.8Hz), 7.57 (2H, m), 7.75
(1H, d, J = 8.8Hz), 7.8-8.0 (4H, m), 8.48 (1H,
s). Elemental analysis: as C ₂₃ H ₁₄ O ₄ Calculated: C: 77.96%, H: 3.98% Actual: C: 77.57%, H: 4.10%

Reference Example 4 10- (4-fluorophenyl) -furo [3 ', 4': 6,7]
Naphtho [1,2-d] -1,3-dioxole-7 (9
H) -ON

Embedded image The title compound was obtained in the same manner as in Reference Example 1. Melting point: 215-218 ° C NMR (CDCl ₃ ) δ: 5.18 (2H, s), 5.92 (2H, s),
7.15 (2H, m), 7.33 (3H, m), 7.73 (1H, d, J = 8.8H
z), 8.45 (1H, s ) Elemental _{analysis:. C 19 H 11 O 4} F Calculated: C: 70.81%, H: 3.44% Found: C: 70.57%, H: 3.65%

Reference Example 5 10- (4-Methylphenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxole-7 (9H)
-ON

Embedded image The title compound was obtained in the same manner as in Reference Example 1. Melting point: 208-210 ° C NMR (CDCl ₃ ) δ: 1.45 (3H, s), 5.19 (2H, s),
7.25 (4H, s), 7.32 (1H, d, J = 8.4Hz), 7.72 (1H,
d, J = 8.4 Hz), 8.43 (1H, s). Elemental analysis: As C ₂₀ H ₁₄ O ₄ Calculated: C: 75.46%, H: 4.43% Observed: C: 75.17%, H: 4.52%

Reference Example 6 10- (1,3-benzodioxol-5-yl) -1,3-dioxolo [4,5-f] furo [3,4-b] quinoline-7 (9H)- on

Embedded image LAH (lithium aluminum hydride) (2.0 g)
9- (1,3-benzodioxol-5-yl) -1,3-dioxolo [4,5-f] quinoline-7,8-dicarboxylic acid in a THF (50 ml) suspension at 0 ° C. Diethyl (2.4 g) was gradually added, and after the addition was completed, the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution to stop the reaction, and the resulting precipitate was removed by filtration through Celite. The filtrate was extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in ethanol (100 ml).
% Pd-C (2.5 g) was added and the mixture was stirred at room temperature overnight. After filtering off the catalyst, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in chloroform (300 ml), manganese dioxide (20 g) was added, and the mixture was stirred at room temperature for 3 hours. Manganese dioxide was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were washed with diisopropyl ether to give the title compound (0.9 g). Some of them were recrystallized from THF and used for elemental analysis and instrumental measurement. Melting point: 272-274 ° C. NMR (CDCl ₃ ) δ: 5.30 (1H, d, J = 16 Hz), 5.41 (1
H, d, J = 16Hz), 6.05 (2H, d, J = 4Hz), 6.10 (2H, d,
J = 4Hz), 6.86 (2H, m), 6.95 (1H, d, J = 8Hz), 7.5
7 (1H, d, J = 9 Hz), 8.11 (1H, d, J = 9 Hz). Elemental analysis: C ₁₉ H ₁₁ NO ₆ Calculated: C: 65.33%, H: 3.17%, N: 4.01% Value: C: 64.91%, H: 3.07%, N: 4.18%

Reference Example 7 5-phenyl-7-methyl-furo [3,4-b] quinoline-2 (4H)-
on

Embedded image The title compound was obtained in the same manner as in Reference Example 6. _{Mp: 191-193 ℃ NMR (CDCl 3)} δ: 2.52 (3H, s), 5.38 (2H, s), 7.4
0-7.50 (2H, m), 7.57-7.75 (5H, m), 8.34 (1H, d, J = 9H
z). IR (KBr): 1780, 1500, 1455, 1372, 1131, 1054
cm ^-1 Elemental analysis: C ₁₈ H ₁₃ NO ₂ Calculated: C: 78.53%, H: 4.76%, N: 5.09% Found: C: 78.37%, H: 4.71%, N: 5.18%

Reference Example 8 5- (2,4-difluorophenyl) -7-methyl-furo [3,4-
b] Quinolin-2 (4H) -one

Embedded image The title compound was obtained in the same manner as in Reference Example 6. _{Mp: 218-220 ℃ NMR (CDCl 3)} δ: 2.54 (3H, s), 5.29 (1H, d, J = 15
Hz), 5.39 (1H, d, J = 15Hz), 7.06-7.21 (2H, m), 7.
34-7.50 (2H, m), 7.72 (1H, dd, J = 1.8Hz, 8Hz), 8.36
(1H, d, J = 8Hz). IR (KBr): 1768, 1500, 1455, 1423, 1374, 114
2, 1093, 1060 cm ^-1 Elemental analysis: as C ₁₈ H ₁₁ F ₂ NO ₂ Calculated: C: 69.45%, H: 3.56%, N: 4.50% Actual values: C: 69.33%, H: 3.56%, N ： 4.59%

Reference Example 9 9- (4-methoxyphenyl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid

Embedded image Helio alcohol (4.0 g) in benzene (100 m
l) Butyllithium (1.6 M hexane solution: 36 ml) was added dropwise to the solution at room temperature. After stirring at room temperature for 1 hour, a solution of 4-methoxybenzonitrile (3.85 g) in benzene (20 ml) was added dropwise. After stirring overnight at room temperature, water was added and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (75 ml), and dimethyl fumarate (7.58 g) and trichloroacetic acid (0.3 g) were added. After heating under reflux for 3 hours, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate,
The extract was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 50 g, developing solvent: ethyl acetate-hexane = 1: 2) to obtain tetrahydro-1,4-epoxy The naphthalene derivative (2.84 g) was obtained as a mixture of diastereomers. This was dissolved in THF (5 ml) and methanol (5 ml), and sodium hydroxide (1.1
g) (5 ml) was added and stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and washed with ethyl acetate. After adding concentrated hydrochloric acid to the aqueous layer until the pH became about 2, the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ether (50 ml), and concentrated hydrochloric acid (1 ml) was added to the residue.
Heated to reflux for minutes. After the reaction solution was concentrated under reduced pressure, water was added, and the resulting precipitate was collected by filtration. The obtained precipitate was washed with methanol and ether to give the title compound (2.64)
g) was obtained. Melting point: 264-266 ° C. NMR (CDCl ₃ + CD ₃ OD) δ: 3.89 (3H, s), 5.95 (2H,
s), 6.90-7.00 (2H, m), 7.27 (1H, d, J = 9Hz), 7.34-
7.43 (2H, m), 7.64 (1H, d, J = 9Hz), 7.86 (1H, d, J = 1.6
Hz), 8.55 (1H, d, J = 1.6Hz).

Reference Example 10 9- (4-trifluoromethylphenyl) -naphtho [1,2-d]
-1,3-dioxole-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 9. Melting point: 207-209 ° C NMR (DMSO) δ: 6.02 (2H, s), 7.52 (1H, d, J = 8H)
z), 7.69 (1H, d, J = 8Hz), 7.72 (1H, d, J = 1.4Hz), 7.7
8 (1H, d, J = 8Hz), 7.92 (1H, d, J = 8Hz), 8.66 (1H, d, J =
1.4Hz).

Reference Example 11 9- (1,3-benzodioxol-5-yl) -6-methyl-naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 9. Melting point: 233-235 ° C. NMR (CDCl ₃ + DMSO) δ: 2.96 (3H, s), 5.94 (2H,
s), 6.02 (2H, s), 6.79-6.93 (3H, m), 7.27 (1H, d, J
= 9Hz), 7.69 (1H, s), 7.86 (1H, d, J = 9Hz).

Reference Example 12 9- (1,3-benzodioxol-5-yl) -naphtho [1,2-
d] 1,3-dioxole-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 9. Melting point: 267-269 ° C NMR (DMSO) δ: 6.03 (2H, s), 6.09 (2H, s), 6.89
(1H, dd, J = 1.5Hz, 8Hz), 6.96 (1H, d, J = 8Hz), 7.00 (1
H, d, J = 1.5Hz), 7.47 (1H, d, J = 9Hz), 7.66 (1H, d, J = 1.
6Hz), 7.86 (1H, d, J = 9Hz), 8.57 (1H, d, J = 1.6Hz).

Reference Example 13 9- (1,3-benzodioxol-5-yl) -8-methyl-naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid (a) 9 Methyl-(1,3-benzodioxol-5-yl) -8-methanesulfonyloxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxylate

Embedded image To a solution of helioxanthin (1 g) in DMF (10 ml) was added 1N aqueous sodium hydroxide solution (2.9 ml), and
Heat at 0 ° C. for 30 minutes. The solvent is distilled off under reduced pressure,
The residue was dissolved in DMF (10 ml). Methyl iodide (5 ml) was added, and the mixture was heated at 60 ° C. for 1 hour. The solvent was distilled off under reduced pressure, water was added to the residue, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in THF (10 ml), and triethylamine (0.80 ml) was added. Under ice-cooling, methanesulfonyl chloride (0.22 ml) was added dropwise.
Stirred for minutes. Water was added to the reaction solution, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to obtain the title compound (1.25 g). The thus obtained crude product was used for the next reaction without further purification. NMR (CDCl ₃ ) δ: 3.00 (3H, s), 3.91 (3H, s), 5.2
4 (1H, d, J = 10Hz), 5.34 (1H, d, J = 10Hz), 5.91 (1H, d,
J = 1.2Hz), 5.94 (1H, d, J = 1.2Hz), 6.09 (1H, d, J = 0.8H
z), 6.13 (1H, d, J = 0.8Hz), 6.73 (1H, dd, J = 1.6Hz, 8H
z), 6.86 (1H, d, J = 1.6Hz), 6.98 (1H, d, J = 8Hz), 7.4
9 (1H, d, J = 9Hz), 7.81 (1H, d, J = 9Hz), 8.54 (1H, s).

(B) 9- (1,3-benzodioxole-5-
Il) -8-methyl-naphtho [1,2-d] -1,3-dioxole-7
-Methyl carboxylate

Embedded image 9- (1,3-benzodioxol-5-yl) -8-methanesulfonyloxymethyl-naphtho [1,2-d] -1,3-dioxole-
7-Methyl carboxylate (443 mg) in DMF (5 ml)
Sodium borohydride (36 mg) was added to the solution, and the mixture was stirred overnight. The reaction was stopped by adding water, and the product was extracted with ether. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel: 50 g, developing solvent: ethyl acetate: hexane = 1: 4) to give the title compound (1.5 g). NMR (CDCl ₃ ) δ: 2.34 (3H, s), 3.95 (3H, s), 5.8
1 (1H, d, J = 1.5Hz), 5.82 (1H, d, J = 1.5Hz), 6.03 (1H,
d, J = 1.4Hz), 6.06 (1H, d, J = 1.4Hz), 6.67 (1H, dd, J =
1.6Hz, 8Hz), 6.70 (1H, d, J = 1.6Hz), 6.86 (1H, d, J = 8H
z), 7.16 (1H, d, J = 9Hz), 7.49 (1H, d, J = 9Hz), 8.33
(1H, s).

(C) 9- (1,3-benzodioxol-5-yl) -8-methyl-naphtho [1,2-d] -1,3-dioxol-7-
carboxylic acid

Embedded image Methyl 9- (1,3-benzodioxol-5-yl) -8-methyl-naphtho [1,2-d] -1,3-dioxole-7-carboxylate (443 mg) was mixed with THF (6 ml). Methanol (3m
l), 1N sodium hydroxide (3 ml) was added, and the mixture was stirred for 4 days. 1N Hydrochloric acid was added to the reaction solution, water was added, and the resulting precipitate was collected by filtration to obtain the title compound (264 mg). Some of them were recrystallized from methanol-chloroform and used for elemental analysis and instrumental measurement. NMR (DMSO) δ: 2.24 (3H, s), 5.83 (1H, brs), 5.
86 (1H, brs), 6.05 (1H, brs), 6.11 (1H, brs), 6.65
(1H, dd, J = 1.6Hz, 8Hz), 6.78 (1H, d, J = 1.6Hz), 6.94
(1H, d, J = 8Hz), 7.32 (1H, d, J = 8Hz), 7.68 (1H, d, J = 8
Hz), 8.37 (1H, s).

Reference Example 14 9- (1,3-benzodioxol-5-yl) -8-methyl-1,3-
Dioxolo [4,5-f] quinoline-7-carboxylic acid (a) 9- (1,3-benzodioxol-5-yl) -8-methyl
Methyl 1,3-dioxolo [4,5-f] quinoline-7-carboxylate

Embedded image 5-Amino-1,3-benzodioxol-4-yl 1,3-benzodioxol-4-yl ketone (2.7 g) and methyl 2-ketobutyrate (1.9 g) were added to acetic acid (30 ml). Dissolve,
Sulfuric acid (0.3 ml) was added, and the mixture was heated under reflux for 1.5 hours.
After completion of the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with an aqueous solution of sodium hydrogen carbonate and water, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as yellow crystals (2.6 g). Melting point: 174-177 ° C. NMR (CDCl ₃ ) δ: 2.30 (3H, s), 4.04 (3H, s) , 5.8
9 (2H, m), 6.06 (2H, m), 6.68 (2H, m), 6.89 (1H, d,
J = 8Hz), 7.36 (1H, d, J = 9Hz), 7.81 (1H, d, J = 9Hz) Elemental analysis: As C ₁₉ H ₁₃ NO ₆ Calculated: C: 64.96%, H: 3.73%, N : 3.99% Actual value: C: 65.02%, H: 3.90%, N: 3.92%

(B) 9- (1,3-benzodioxol-5-yl) -8-methyl-1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid

Embedded image 9- (1,3-benzodioxol-5-yl) -8-methyl-1,3-
Methyl dioxolo [4,5-f] quinoline-7-carboxylate (3
00 mg) in methanol (20 ml)
An aqueous sodium hydroxide solution (20 ml) was added, and the mixture was heated under reflux for 1 hour. 1N hydrochloric acid is added to the reaction solution to make it weakly acidic (pH =
After 5), the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (252 mg) as yellow crystals. Some of them were recrystallized from THF and used for elemental analysis and instrumental measurement. Melting point: 219-222 ° C NMR (CDCl ₃ ) δ: 2.59 (3H, s), 5.93 (2H, m), 6.0
7 (2H, d, J = 5Hz), 6.67 (2H, m), 6.90 (1H, d, J = 8Hz),
7.43 (1H, d, J = 9Hz), 7.76 (1H, d, J = 9Hz) Elemental analysis: As C ₁₉ H ₁₃ NO ₆ Calculated: C: 64.96%, H: 3.73%, N: 3.99% : C: 65.02%, H: 3.90%, N: 3.92%

Reference Example 15 10- (4-trifluoromethoxyphenyl) -furo [3 ', 4
`: 6.7] Naphtho [1,2-d] -1,3-dioxole-7 (9H)-
on

Embedded image The title compound was obtained in the same manner as in Reference Example 1. Melting point: 222-225 ° C NMR (CDCl ₃ ) δ: 5.19 (2H, s), 5.92 (2H, s), 7.25-7.
45 (5H, m), 7.73 (1H, d, J = 8.8Hz), 8.46 (1H, s). Elemental analysis: as C ₂₀ H ₁₁ F ₃ O ₅ Calculated: C: 61.86%, H: 2.86% Measured value: C: 64.79%, H: 2.79%

Reference Example 16 9- (4-trifluoromethoxyphenyl) -naphtho [1,2-
d] 1,3-dioxole-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 9. Melting point: 296-300 ° C. NMR (CDCl ₃ ) δ: 5.94 (2H, s), 6.82 (2H, s), 7.20-7.
90 (4H, m), 8.58 (1H, m). IR (KBr): 2880, 1676, 1279 cm ^-1

Reference Example 17 4- (1,3-benzodioxol-5-yl) -6,7-diethoxy
-Naphtho [2,3-c] furan-1 (3H) -one

Embedded image The title compound was obtained in the same manner as in Reference Example 6. NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7 Hz), 1.57 (3H, t, J = 7
Hz), 4.04 (2H, q, J = 7Hz), 4.26 (2H, q, J = 7Hz), 5.22 (2H,
s), 6.08 (1H, d, J = 1.4Hz), 6.12 (1H, d, J = 1.4Hz), 6.80-6.
90 (2H, m), 6.99 (1H, d, J = 9Hz), 7.09 (1H, s), 7.30 (1H,
s), 8.28 (1H, s).

Reference Example 18 10- (4-trifluoromethoxyphenyl) -1,3-dioxolo [4,5-f] furo [3,4-b] quinolin-7 (9H) -one

Embedded image The title compound was obtained in the same manner as in Reference Example 6. NMR (CDCl ₃ ) δ: 5.33 (2H, s), 6.02 (2H, s), 7.30-7.
50 (3H, m), 7.58 (1H, d, J = 9Hz), 8.13 (1H, d, J = 9Hz).

Reference Example 19 5- (1,3-benzodioxol-5-yl) -7-methoxyfuro [3,4-b] quinolin-2 (4H) -one

Embedded image The title compound was obtained in the same manner as in Reference Example 6. NMR (CDCl ₃ ) δ: 3.85 (3H, s), 5.36 (2H, s), 6.13 (2
H, s), 6.85-7.10 (3H, m), 7.17 (1H, d, J = 3Hz), 7.51 (1H, d
d, J = 3,10Hz), 8.32 (1H, d, J = 10Hz).

Reference Example 20 8- (1,3-benzodioxol-5-yl) -naphtho [2,3-
d] -1,3-dioxole-6-carboxylic acid

Embedded image To a solution of 5-bromo-6-hydroxymethyl-1,3-benzodioxole (5.0 g) in ether (100 ml) was added -78.
Butyllithium (1.6M hexane solution: 30m
l) was added dropwise. After stirring at 0 ° C. for 1 hour, the mixture was stirred again at −78 ° C.
And cooled to 5-cyano-1,3-benzodioxole (3.52
A solution of g) in ether (50 ml) was added dropwise. 3 at room temperature
After stirring for an hour, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure.
The obtained residue was dissolved in toluene (100 ml), and dimethyl fumarate (3.13 g) and trichloroacetic acid (0.83 g) were added. After heating under reflux for 1 hour, the mixture was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate,
The extract was washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 50 g, developing solvent: ethyl acetate-hexane = 1: 2) to obtain tetrahydro-1,4-epoxy The naphthalene derivative (3.30 g) was obtained as a mixture of diastereomers. This was dissolved in THF (15 ml) and methanol (15 ml), an aqueous solution (5 ml) of sodium hydroxide (1.24 g) was added, and the mixture was stirred overnight. The reaction solution was concentrated under reduced pressure, diluted with water, and washed with ethyl acetate. After adding concentrated hydrochloric acid to the aqueous layer until the pH became about 2, the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in ether (10 ml), concentrated hydrochloric acid (0.5 ml) was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated under reduced pressure, water was added, and the resulting precipitate was collected by filtration. The obtained precipitate was washed with methanol and ether to give the title compound (0.38 g). NMR (DMSO) δ: 6.10 (2H, s), 6.12 (2H, s), 6.80-7.1
0 (4H, m), 7.42 (1H, s), 7.81 (1H, s), 8.35 (1H, s).

Reference Example 21 6-chloro-4- (4-chlorophenyl) naphtho [2,3-c] furan-1 (3H) -one

Embedded image To a suspension of sodium borohydride (0.5 g) in dimethoxyethane (20 ml) was added 6-chloro-4- (4-
A solution of (chlorophenyl) naphtho [2,3-c] furan-1,3-dione (1.0 g) in THF (20 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 1 N hydrochloric acid to stop the reaction, and the product was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: hexane-ethyl acetate = 3:
Purification in 1) and recrystallization from THF gave the title compound (300 mg). _{Mp: 205-207 ℃ NMR (CDCl 3)} δ: 5.25 (2H, s), 7.33 (2H, d, J = 8.4Hz),
7.58 (3H, m), 7.72 (1H, s), 8.05 (1H, d, J = 9.2Hz), 8.51
(1H, s). IR (KBr): 1771, 1632, 1491 cm ^-1 Elemental analysis: C ₁₈ H ₁₀ Cl ₂ O ₂ Calculated: C: 65.68%, H: 3.06% Observed: C: 65.11% , H: 2.92%

Reference Example 22 5- (4-fluorophenyl) -3,4-dihydro-7-methoxy-1
H-Pyrano [3,4-b] quinolin-1-one (a) Ethyl 3-ethoxycarbonylmethyl-4- (4-fluorophenyl) -6-methoxyquinoline-2-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.0 Hz), 1.46 (3H, t, J
= 7.0Hz), 3.71 (3H, s), 3.85 (2H, s), 4.11 (2H, q, J = 7.0H
z), 4.51 (2H, q, J = 7.0Hz), 6.54 (1H, d, J = 2.4Hz), 7.25 (4
H, m), 7.39 (1H, dd, J = 7.6,2.4Hz), 8.18 (1H, d, J = 9.6Hz).

(B) 2- [4- (4-fluorophenyl) -2-hydroxymethyl-6-methoxyquinolin-3-yl] -1-ethanol

Embedded image Lithium aluminum hydride (180mg) in THF
(15 ml) Ethyl 3-ethoxycarbonylmethyl-4- (4-fluorophenyl) -6-methoxyquinoline-2-carboxylate (1.0 g) was added to the suspension under ice cooling, and the mixture was added at 0 ° C. Stir for 30 minutes. The reaction was stopped by adding water to the reaction solution,
After filtering off the insoluble matter, the product was extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give crude crystals of the title compound (about 1 g).
I got The obtained crude crystals were used for the next reaction without purification. NMR (CDCl ₃ ) δ: 2.79 (2H, t, J = 7.4 Hz), 3.62 (2H, t, J
= 7.4Hz), 3.69 (3H, s), 4.97 (2H, s), 6.51 (1H, d, J = 3.0H
z), 7.27 (4H, m), 7.33 (1H, dd, J = 9.0,3.0Hz), 8.00 (1H,
d, J = 9.0Hz).

(C) 5- (4-fluorophenyl) -3,4-dihydro-7-methoxy-1H-pyrano [3,4-b] quinolin-1-one

Embedded image 2- [4- (4-fluorophenyl) -2-hydroxymethyl-6-
Manganese dioxide (10 g) was added to a solution of crude crystals (1.0 g) of methoxyquinolin-3-yl] -1-ethanol in chloroform (100 ml), and the mixture was stirred at room temperature for 2 hours. After removing manganese dioxide by filtration, the reaction solution was concentrated under reduced pressure, and the obtained residue was recrystallized from THF to obtain the title compound (335 mg). Melting point: 240-241 ° C. NMR (CDCl ₃ ) δ: 2.99 (2H, t, J = 5.8 Hz), 3.76 (3H, s),
4.54 (2H, t, J = 5.8Hz), 6.71 (1H, d, J = 3.0Hz), 7.30 (4H,
m), 7.43 (1H, dd, J = 9.6, 3.0 Hz), 8.31 (1H, d, J = 9.6 Hz). IR (KBr): 2959, 2926, 1740, 1620, 1497 cm ^-1 Elemental analysis: C ₁₉ H ₁₄ FNO ₃ Calculated: C: 70.58%, H: 4.36%, N: 4.33% Actual values: C: 70.49%, H: 4.57%, N: 4.26%

Reference Example 23 11- (1,3-benzodioxol-5-yl) -9,10-dihydro
-7H-1,3-dioxolo [4,5-f] pyrano [3,4-b] quinoline
-7-one (a) 9- (1,3-benzodioxol-5-yl) -8-ethoxycarbonylmethyl-1,3-dioxolo [4,5-f] quinoline-7
-Ethyl carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 1.21 (3H, t, J = 7.1)
Hz), 1.44 (3H, t, J = 7.2 Hz),
3.86 (2H, s), 4.12 (2H, q, J = 7.
1 Hz), 4.49 (2H, q, J = 7.2 Hz),
5.89 (2H, m), 6.06 (2H, m),
6.68 (1H, d, J = 7.6 Hz), 6.72
(1H, s), 6.86 (1H, d, J = 7.6H)
z), 7.41 (4H, d, J = 8.8 Hz),
7.89 (1H, d, J = 8.8 Hz).

(B) 2- [9- (1,3-benzodioxol-5-yl) -7-hydroxymethyl-1,3-dioxolo [4,5
-f] Quinolin-8-yl] -1-ethanol

Embedded image The title compound was obtained in the same manner as in Reference Example 22 (b). NMR (CDCl ₃ ) δ: 1.76 (1H, bs), 2.78 (2H, t, J = 7.4H
z), 3.63 (2H, t, J = 7.4Hz), 4.92 (2H, s), 5.24 (1H, br s),
5.83 (1H, d, J = 1.4Hz), 5.85 (1H, d, J = 1.4Hz), 6.04 (1H,
d, J = 1.4Hz), 6.07 (1H, d, J = 1.4Hz), 6.67 (1H, dd, J = 7.8,
0.8Hz), 6.70 (1H, d, J = 0.8Hz), 6.87 (1H, d, J = 7.8Hz), 7.
32 (1H, d, J = 8.8Hz), 7.67 (1H, d, J = 8.8Hz).

(C) 11- (1,3-benzodioxol-5-yl) -9,10-dihydro-7H-1,3-dioxolo [4,5-f] pyrano [3,4-b ] Quinoline-7-one

Embedded image The title compound was obtained in the same manner as in Reference Example 22 (c). NMR (CDCl ₃ ) δ: 3.00 (2H, dt, J = 1.8, 5.9 Hz), 4.51 (2
H, t, J = 5.9Hz), 5.95 (1H, d, J = 1.4Hz), 5.97 (1H, d, J = 1.4H
z), 6.06 (1H, d, J = 1.4Hz), 6.09 (1H, d, J = 1.4Hz), 6.65-
6.80 (2H, m), 6.91 (1H, d, J = 7.6Hz), 7.47 (1H, d, J = 8.8H
z), 8.05 (1H, d, J = 8.8Hz).

Reference Example 24 6-Chloro-4- (4-pyridyl) -2-quinolinecarboxylic acid (a) Ethyl 6-chloro-4- (4-pyridyl) -2-quinolinecarboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 1.50 (3H, t, J = 7.0 Hz), 4.58 (2H, q, J
= 7.0Hz), 7.46 (2H, dd, J = 4.4,1.8Hz), 7.73-7.85 (2H, m),
8.15 (1H, s), 8.35 (1H, d, J = 8.8Hz), 8.85 (2H, dd, J = 4.4,
. 1.4 Hz) Elemental _{analysis: C 17 H 13 N 2 O} 2 Cl Calculated: C: 65.29%, H: 4.19%, N: 8.96% Found: C: 65.01%, H: 4.12%, N: 8.98 %

(B) 6-chloro-4- (4-pyridyl) -2-quinolinecarboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (b). NMR (CDCl ₃ ) δ: 3.36 (1H, brs, COOH), 7.66 (2H, d, J
= 5.8Hz), 7.82 (1H, d, J = 2.2Hz), 7.95 (1H, dd, J = 8.8,2.2H
z), 8.06 (1H, s), 8.29 (1H, d, J = 8.8Hz), 8.82 (2H, d, J = 5.
Elemental analysis: C ₁₅ H ₉ N ₂ O ₂ Cl · 0.1H ₂ O Calculated: C: 62.88%, H: 3.24%, N: 9.78% Actual values: C: 62.72%, H: 3.34 %, N: 9.75%

Reference Example 25 9- (4-methoxyphenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid (a) 9- (4-methoxyphenyl) -1,3-dioxolo [4,5-
f] Quinoline-7-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.2 Hz), 3.90 (3H, s),
4.54 (2H, q, J = 7.2Hz), 6.02 (2H, s), 6.99 (2H, d, J = 8.8H
z), 7.43 (2H, d, J = 8.8Hz), 7.48 (1H, d, J = 8.8Hz), 7.96 (1
H, s), 8.03 (1H, d, J = 8.8Hz).

(B) 9- (4-methoxyphenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (b). NMR (CDCl ₃ ) δ: 3.83 (3H, s), 6.09 (2H, s), 7.02 (2
H, d, J = 8.6Hz), 7.48 (2H, d, J = 8.6Hz), 7.70 (1H, d, J = 8.8H
z), 7.77 (1H, s), 7.87 (1H, d, J = 8.8Hz).

Reference Example 26 9- (1,3-benzodioxol-5-yl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid (a) 9- (1,3 -Benzodioxol-5-yl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.2 Hz), 4.54 (2H, q, J
= 7.2Hz), 6.04 (2H, s), 6.06 (2H, s), 6.87-7.00 (3H, m),
7.48 (1H, d, J = 9.0Hz), 7.96 (1H, s), 8.03 (1H, d, J = 9.0H
z).

(B) 9- (1,3-benzodioxol-5-yl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (b). NMR (CDCl ₃ + DMSO-d ₆ ) δ: 6.06 (4H, s), 6.87-7.00
(3H, m), 7.50 (1H, d, J = 9.2Hz), 7.97 (1H, d, J = 9.2Hz), 8.
00 (1H, s).

Reference Example 27 9- (4-Fluorophenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid (a) 9- (4-fluorophenyl) -1,3-dioxolo [4,5-
f] Quinoline-7-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (DMSO-d ₆ ) δ: 1.38 (3H, t, J = 7.4 Hz), 4.43 (2H,
q, J = 7.4Hz), 6.11 (2H, s), 7.26-7.37 (2H, m), 7.57-7.62
(2H, m), 7.74 (1H, d, J = 8.8Hz), 7.81 (1H, s), 7.93 (1H, d,
J = 8.8Hz).

(B) 9- (4-fluorophenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (b). NMR (CDCl ₃ + DMSO-d ₆ ) δ: 6.03 (2H, s), 7.05-7.20
(2H, m), 7.35-7.55 (3H, m), 7.95-8.05 (2H, m).

Reference Example 28 3-bromomethyl-6-methoxy-4- (4-methoxyphenyl)
Methyl quinoline-2-carboxylate (a) Methyl 6-methoxy-4- (4-methoxyphenyl) -3-methylquinoline-2-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 14 (a). NMR (CDCl ₃ ) δ: 2.35 (3H, s), 3.71 (3H, s), 3.92 (3
H, s), 4.05 (3H, s), 6.66 (1H, d, J = 3Hz), 7.00-7.25 (4H,
m), 7.33 (1H, dd, J = 3,9Hz), 8.09 (1H, d, J = 9Hz).

(B) Methyl 3-bromomethyl-6-methoxy-4- (4-methoxyphenyl) quinoline-2-carboxylate

Embedded image Methyl 6-methoxy-4- (4-methoxyphenyl) -3-methylquinoline-2-carboxylate (8.27 g) was added to benzene (10
0 ml) and dissolved in N-bromosuccinimide (5.2
4g) and 2,2'-azobis (isobutyronitrile)
(0.40 g) and heated to reflux for 2 hours. After cooling to room temperature, the resulting precipitate was removed by filtration. The filtrate was washed with ethyl acetate (1
After washing with 1N sodium hydroxide and a saturated aqueous solution of sodium chloride, the mixture was dried over magnesium sulfate. The solvent is distilled off under reduced pressure,
The resulting residue was subjected to column chromatography (silica gel: 50 g, developing solvent: ethyl acetate-hexane = 1: 1).
Purified in 2). The obtained crude crystals were recrystallized from ethyl acetate-hexane to give the title compound (9.93 g) as colorless needles. NMR (CDCl ₃ ) δ: 3.72 (3H, s), 3.94 (3H, s), 4.10 (3
H, s), 4.84 (2H, s), 6.66 (1H, d, J = 3Hz), 7.05-7.35 (4H,
m), 7.40 (1H, dd, J = 3,9Hz), 8.14 (1H, d, J = 9Hz).

Reference Example 29 Ethyl 8-chloro-1,3-dioculo [4,5-g] quinoline-6-carboxylate

Embedded image A mixture of 3,4- (methylenedioxy) aniline (10 g), acetylenedicarboxylic acid diethyl ester (15 g) and ethyl alcohol (150 ml) was heated under reflux for 20 hours, and then the solvent was distilled off under reduced pressure. Diphenyl ether (50 ml) was added to the residue, and the mixture was heated at 200 ° C. for 1.5 hours. After cooling, the reaction mixture is diluted with isopropyl ether to give 8-hydroxy-1,3-dioxolo [4,5-g]
Equinoline-6-carboxylate brown crystals (10.6 g)
Was obtained as The obtained crystals (10.4 g), phosphoryl chloride (22.4 ml) and benzene (170 m
After stirring the mixture of 1) at room temperature for 3 days, the reaction mixture was poured into water and stirred at room temperature for 30 minutes. After the mixture was extracted with ethyl acetate, the extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound as brown crystals (8.59 g). NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.1 Hz), 4.53 (2H, q, J
= 7.1Hz), 6.20 (2H, s), 7.52 (1H, s), 7.58 (1H, s), 8.13 (1
H, s).

Reference Example 30 8- (1-piperidinyl) -1,3-diochiro [4,5-g] quinoline
Ethyl-6-carboxylate

Embedded image The 8-chloro-1,3-dioxolo [4,5-
g] ethyl quinoline-6-carboxylate (300 mg), piperidine (0.5 ml) and ethyl alcohol (5 m
The mixture of 1) was heated in a sealed tube at 140 ° C. for 17 hours.
After evaporating the solvent under reduced pressure, the residue was subjected to column chromatography using silica gel (hexane: ethyl acetate =
Purification by 3: 1) gave the title compound as colorless crystals (73.
6 mg). NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7.1)
Hz), 1.71 (2H, m), 1.84 (4H,
m), 3.15 (4H, m), 4.52 (2H,
q, J = 7.1 Hz), 6.12 (2H, s),
7.29 (1H, s), 7.51 (1H, s),
7.60 (1H, s).

Reference Example 31 Ethyl 8- (1-pyrrolidinyl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 30. NMR (CDCl ₃ ) δ: 1.46 (3H, t, J = 7.1 Hz), 2.05 (4H, m),
3.66 (4H, m), 4.50 (2H, q, J = 7.1Hz), 6.08 (2H, s), 7.29
(1H, s), 7.46 (1H, s), 7.51 (1H, s).

Reference Example 32 Ethyl 8- (4-morpholinyl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 30. NMR (CDCl ₃ ) δ: 1.48 (3H, t, J = 7.2 Hz), 3.20 (4H, m),
3.98 (4H, m), 4.53 (2H, q, J = 7.2Hz), 6.14 (2H, s), 7.31
(1H, s), 7.54 (1H, s), 7.63 (1H, s).

Reference Example 33 8- (4-methylpiperazin-1-yl) -1,3-dioxolo [4,
5-g] quinoline-6-carboxylate

Embedded image The title compound was obtained in the same manner as in Reference Example 30. NMR (CDCl ₃ ) δ: 1.47 (3H, t, J = 7.0Hz), 2.42 (3H, s),
2.71 (4H, m), 3.24 (4H, m), 4.53 (2H, q, J = 7.2Hz), 6.13
(2H, s), 7.30 (1H, s), 7.53 (1H, s), 7.62 (1H, s).

Example 1 N-methyl-9- (1,3-benzodioxol-5-yl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxol-7-
Carboxamide

Embedded image Helioxanthine (1.0 g) and benzene (10 ml)
Suspended in methylamine (40% methanol solution: 2 m
l) was added. The mixture was heated and stirred at 120 ° C. for 4 days in a sealed tube. The reaction solution is concentrated under reduced pressure, and the obtained residue is
To give the title compound (144 mg). Mp: 233-235 ℃ NMR (DMSO-d 6) δ: 2.83 (3H, d, J = 5Hz), 4.2
7 (2H, d, J = 6Hz), 4.95 (1H, t, J = 6Hz), 5.85 (1H, s),
5.86 (1H, s), 6.06 (1H, s), 6.12 (1H, s), 6.70 (1
H, dd, J = 1.6Hz, 8Hz), 6.81 (1H, d, J = 1.6Hz), 6.93 (1
H, d, J = 8Hz), 7.37 (1H, d, J = 9Hz), 7.63 (1H, d, J = 9H)
z), 8.01 (1H, s), 8.55-8.70 (1H, m). IR (KBr): 3340, 1615, 1485, 1445, 1435, 128
0, 1065 cm ^-1 elemental analysis: as C ₂₁ H ₁₇ NO ₆ · 0.2 H ₂ O Calculated: C: 63.47%, H: 4.82%, N: 3.52% Found: C: 63.50%, H: 4.61%, N: 3.81%

Example 2 N-methyl-9- (4-methoxyphenyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 10- (4-methoxyphenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9) obtained in Reference Example 1
The title compound was obtained in the same manner as in Example 1 using H) -one. Melting point: 187-190 ° C NMR (CDCl ₃ ) δ: 3.07 (3H, d, J = 5 Hz), 3.88 (3
H, s), 4.37 (2H, s), 5.79 (2H, s), 6.56 (1H, brs),
6.93 (2H, d, J = 8Hz), 7.19 (1H, d, J = 9Hz), 7.23 (2H, d, J = 9Hz)
d, J = 8 Hz), 7.44 (1 H, d, J = 9 Hz), 7.93 (1 H, s). Elemental analysis: As C ₂₁ H ₁₉ NO ₅ Calculated: C: 69.03%, H: 5.24%, N: 3.83% Found: C: 68.92%, H: 5.27%, N: 3.77%

Example 3 N-methyl-9- (4-chlorophenyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 10- (4-Chlorophenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxole-7 (9
The title compound was obtained in the same manner as in Example 1 using H) -one. _{Mp: 202-204 ℃ NMR (CDCl 3)} δ: 3.08 (3H, d, J = 5Hz), 4.35 (3
H, m), 5.80 (2H, s), 6.42 (1H, brs), 7.26 (3H, m),
7.38 (2, d, J = 8Hz), 7.46 (12H, d, J = 8Hz), 7.96 (1H,
s). Elemental analysis: as C ₂₀ H ₁₆ ClNO ₄ Calculated: C: 64.96%, H: 4.36%, N: 3.79% Found: C: 64.94%, H: 4.62%, N: 3.85%

Example 4 N-methyl-9- (2-naphthyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 10- (2-Naphthyl) -furo [3 ', 4' obtained in Reference Example 3:
The title compound was obtained in the same manner as in Example 1 using 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9H) -one. Melting point: 207-210 ° C. NMR (CDCl ₃ ) δ: 3.07 (3H, d, J = 5 Hz), 4.36 (3
H, m), 5.64 (2H, m), 6.56 (1H, brs), 7.22 (1H, m),
7.49 (4H, m), 7.84 (4H, m), 7.99 (1H, s). Elemental analysis: Calculated as C ₂₄ H ₁₉ NO ₄ Calculated: C: 74.79%, H: 4.97%, N: 3.63% : C: 74.28%, H: 5.21%, N: 3.60%

Example 5 N-methyl-9- (4-fluorophenyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 10- (4-Fluorophenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9
The title compound was obtained in the same manner as in Example 1 using H) -one. _{Mp: 210-213 ℃ NMR (CDCl 3)} δ: 3.08 (3H, d, J = 5Hz), 4.36 (3
H, m), 5.79 (2H, s), 6.48 (1H, brs), 7.09 (2H, t, J = 9
Hz), 7.27 (3H, m), 7.46 (1H, d, J = 8Hz), 7.95 (1H,
s). Elemental analysis: as C ₂₀ H ₁₆ FNO ₄ Calculated: C: 67.98%, H: 4.56%, N: 3.96% Found: C: 67.90%, H: 4.75%, N: 3.94%

Example 6 N-methyl-9- (4-methylphenyl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 10- (4-methylphenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxol-7 (9) obtained in Reference Example 5
The title compound was obtained in the same manner as in Example 1 using H) -one. Melting point: 210-212 ° C. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.07 (3H, d, J =
5Hz), 4.20-4.40 (3H, m), 5.78 (2H, s), 6.51 (1H, b
rs), 7.20 (5H, m), 7.45 (2H, d, J = 9Hz), 7.95 (1H,
s). Elemental analysis: as C ₂₁ H ₁₉ NO ₄ Calculated: C: 72.19%, H: 5.48%, N: 4.01% Found: C: 71.85%, H: 5.79%, N: 3.94%

Example 7 N-methyl-8- (1,3-benzodioxol-5-yl) -7-hydroxymethyl-naphtho [2,3-d] -1,3-dioxol-6-
Carboxamide

Embedded image 9- (1,3-benzodioxol-5-yl) -furo [3 ', 4': 6,
7] Naphtho [2,3-d] -1,3-dioxol-6 (8H) -one (Justicidin E: K. Ohta., Et al., Tetrahedronlett.,
1970 , 923) to obtain the title compound in the same manner as in Example 1. _{Mp: 222-224 ℃ NMR (CDCl 3)} δ: 3.07 (3H, d, J = 5Hz), 4.30-4.
50 (3H, m), 6.05 (4H, m), 6.51 (1H, brs), 6.77 (3
H, m), 9.94 (1H, d, J = 7Hz), 7.11 (1H, s), 7.83 (1H,
s). Elemental analysis: as C ₂₁ H ₁₇ NO ₆ Calculated: C: 66.49%, H: 4.52%, N: 3.69% Found: C: 66.35%, H: 4.73%, N: 3.61%

Example 8 9- (1,3-benzodioxol-5-yl) -8-hydroxymethyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 10- (1,3-benzodioxole-5- obtained in Reference Example 6
Yl) Using -8,9-dihydro-9H-1,3-dioxolo [4,5-f] pyrrolo [3,4-b] quinolin-7-one, the title compound was prepared in the same manner as in Example 1. Obtained. NMR (CDCl ₃ ) δ: 4.50-4.75 (2H, m), 5.02 (1
H, d, J = 8Hz), 5.72 (1H, m), 5.91 (1H, d, J = 1.4Hz),
5.93 (1H, d, J = 1.4Hz), 6.08 (1H, d, J = 1.2Hz), 6.08 (1
H, d, J = 1.2Hz), 6.75-6.83 (2H, m), 6.89 (1H, d, J = 8H
z), 7.43 (1H, d, J = 9Hz), 7.75 (1H, d, J = 9Hz), 8.15
(1H, m) Elemental _{analysis:. C 19 H 14 N 2} O 6 Calculated: C: 62.30%, H: 3.85%, N: 7.65% Found: C: 62.13%, H: 3.98%, N: 7.37%

Example 9 N-methyl- (3-hydroxymethyl-6-methyl-4-phenylquinoline) -2-carboxamide

Embedded image 5-phenyl-7-methyl-furo [3,4-
b] The title compound was obtained in the same manner as in Example 1 using quinolin-2 (4H) -one. Melting point: 136-137 ° C. NMR (CDCl ₃ ) δ: 2.43 (3H, s), 3.13 (3H, d, J =
5Hz), 4.64 (2H, d, J = 8Hz), 5.37 (1H, d, J = 8Hz), 7.2
3 (1H, brs), 7.30-7.40 (2H, m), 7.48-7.52 (4H, m),
7.98 (1H, d, J = 8 Hz), 8.44 (1 H, m). IR (KBr): 3460, 3398, 1652, 1533, 1488, 142
1, 1025 cm ^-1 elemental analysis: C ₁₉ H ₁₈ N ₂ O ₂ Calculated: C: 74.49%, H: 5.92%, N: 9.14% Actual values: C: 74.28%, H: 5.94%, N: 9.20 %

Example 10 N-methyl- [3-hydroxymethyl-6-methyl-4- (2,4-difluorophenyl) quinoline] -2-carboxamide

Embedded image 5- (2,4-difluorophenyl) -7- obtained in Reference Example 8
The title compound was obtained in the same manner as in Example 1 using methyl-furo [3,4-b] quinolin-2 (4H) -one. Melting point: 140-141 ° C. NMR (CDCl ₃ ) δ: 2.46 (3H, s), 3.13 (3H, d, J =
5Hz), 4.46 (2H, dd, J = 10Hz, 13Hz), 4.84 (1H, dd, J = 6H
z, 13Hz), 5.38 (1H, dd, J = 6Hz, 13Hz), 6.98-7.16 (3H,
m), 7.30-7.42 (1H, m), 7.59 (1H, dd, J = 1.8Hz, 8Hz),
8.02 (1H, d, J = 8Hz), 8.42 (1H, m). IR (KBr): 3464, 3402, 1652, 1509, 1139, 102
3,969 cm ^-1 elemental analysis: as C ₁₉ H ₁₆ F ₂ N ₂ O ₂ Calculated: C: 66.66%, H: 4.71%, N: 8.18% Found: C: 66.55%, H: 4.71%, N ： 8.23%

Example 11 9- (4-methoxyphenyl) -naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 9- (4-methoxyphenyl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid obtained in Reference Example 9 (200 m
g) was suspended in THF (6 ml) and DMF (1 drop) was added. Oxalyl chloride (0.1 ml) was added dropwise at room temperature, and the mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to give 9-
A crude product of (4-methoxyphenyl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid chloride was obtained. In a mixed solution of concentrated aqueous ammonia (2 ml) and THF (1 ml), a solution of the above-mentioned acid chloride in THF (3 ml) was added dropwise under ice-cooling. After stirring for 30 minutes, the product was extracted with ethyl acetate. The obtained extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethanol to give the title compound (134 mg). Melting point: 187-189 ° C NMR (CDCl ₃ ) δ: 3.89 (3H, s), 6.90-7.00 (2
H, m), 7.28 (1H, d, J = 8Hz), 7.33-7.41 (2H, m), 7.61
(1H, d, J = 1.6Hz), 7.62 (1H, d, J = 8Hz), 8.31 (1H, d, J
IR (KBr): 3365, 3168, 1681, 1666, 1459, 128
8, 1245, 1052 cm ^-1 Elemental analysis: C ₁₉ H ₁₅ NO ₄ Calculated: C: 71.02%, H: 4.71%, N: 4.36% Observed: C: 70.77%, H: 4.71%, N: 4.47 %

Example 12 9- (4-trifluoromethylphenyl) -naphtho [1,2-d]
-1,3-dioxole-7-carboxamide

Embedded image Using 9- (4-trifluoromethylphenyl) -naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid obtained in Reference Example 10 as in Example 11, the title compound I got Melting point: 207-209 ° C NMR (CDCl ₃ ) δ: 5.90 (2H, brs), 5.94 (2H,
s), 7.31 (1H, d, J = 8Hz), 7.57 (2H, brd, J = 8Hz), 7.6
4 (1H, d, J = 8Hz), 7.65 (1H, d, J = 1.8Hz), 7.67 (2H, d,
J = 8Hz), 8.34 (1H, d, J = 1.8Hz). IR (KBr): 3487, 3147, 1685, 1463, 1328, 129
3, 1108, 1072 cm ^-1 Elemental analysis: as C ₁₉ H ₁₂ F ₃ NO ₃ Calculated: C: 63.51%, H: 3.37%, N: 3.90% Observed: C: 63.21%, H: 3.36%, N ： 4.01%

Example 13 9- (1,3-benzodioxol-5-yl) -6-methyl-naphtho [1,2-d] -1,3-dioxol-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 11
Yl) -6-methyl-naphtho [1,2-d] -1,3-dioxole-7
-The title compound was obtained in the same manner as in Example 11 using carboxylic acid. Mp: 237-239 ℃ NMR (DMSO-d 6) δ: 2.67 (3H, brs), 5.98 (2
H, brs), 6.07 (2H, brs), 6.82-7.00 (3H, m), 7.15
(1H, brs), 7.44 (1H, d, J = 9Hz), 7.52 (1H, brs), 7.
80 (1H, brs), 7.85 (1H, brs). IR (KBr): 3398, 3178, 1648, 1615, 1492, 137
8, 1251, 1054cm ^-1 Elemental analysis: C ₂₀ H ₁₅ NO ₅ Calculated: C: 68.76%, H: 4.33%, N: 4.01% Found: C: 68.40%, H: 4.31%, N: 4.05 %

Example 14 9- (1,3-Benzodioxol-5-yl) -naphtho [1,2-
d] -1,3-dioxole-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 12
The title compound was obtained in the same manner as in Example 11 using yl) -naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid. Melting point: 267-269 ° C NMR (DMSO-d ₆ ) δ: 6.01 (2H, s), 6.08 (2H,
s), 6.90 (1H, dd, J = 1.4Hz, 8Hz), 6.97 (1H, d, J = 8H
z), 7.01 (1H, d, J = 1.4H), 7.43 (1H, brs), 7.44 (1
H, d, J = 9Hz), 7.72 (1H, d, J = 1.6Hz), 7.73 (1H, d, J = 9H)
z), 8.12 (1H, brs), 8.46 (1H, d, J = 1.6Hz). IR
(KBr): 3460, 1677, 1486, 1465, 1280,1233, 105
2 cm ^-1 elemental analysis: as C ₁₉ H ₁₃ NO ₅ Calculated: C: 68.06%, H: 3.91%, N: 4.18% Actual values: C: 67.81%, H: 3.91%, N: 4.17%

Example 15 N-methyl-9- (1,3-benzodioxol-5-yl) -naphtho [1,2-d] -1,3-dioxol-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 12
Yl) -naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid and methylamine (40
% Methanol solution) to give the title compound. Melting point: 206-208 ° C NMR (CDCl ₃ ) δ: 3.05 (5 Hz), 5.96 (2H, s),
6.03 (2H, s), 6.23 (1H, m), 6.80-6.93 (3H, m), 7.2
6 (1H, d, J = 8Hz), 7.56 (1H, d, J = 1.8Hz), 7.58 (1H, d,
J = 8Hz), 8.24 (1H, d, J = 1.8Hz). IR (KBr): 1639, 1536, 1488, 1286, 1226, 105
8, 1037 cm ^-1 Elemental analysis: As C ₂₀ H ₁₅ NO ₅ Calculated: C: 68.76%, H: 4.33%, N: 4.01% Observed: C: 68.37%, H: 4.31%, N: 3.98%

Example 16 N, N-dimethyl-9- (1,3-benzodioxol-5-yl)
-Naphtho [1,2-d] -1,3-dioxole-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 12
Yl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid and dimethylamine (5
(0% aqueous solution) to give the title compound. Melting point: 160-161 ° C NMR (CDCl ₃ ) δ: 3.11 (6H, brs), 5.95 (2H,
s), 6.02 (2H, s), 6.80-6.93 (3H, m), 7.24 (1H, d, J
= 8Hz), 7.31 (1H, d, J = 1.6Hz), 7.42 (1H, d, J = 8Hz),
7.85 (1H, d, J = 1.6 Hz). IR (KBr): 1629, 1496, 1486, 1280, 1232, 103
1, 1039 cm ^-1 Elemental analysis: C ₂₁ H ₁₇ NO ₅ Calculated: C: 69.41%, H: 4.72%, N: 3.85% Observed: C: 68.99%, H: 4.73%, N: 3.86%

Example 17 2- [9- (1,3-benzodioxol-5-yl) -naphtho [1,
2-d] -1,3-dioxole-7-carboxamide] ethyl acetate

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 12
Yl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid (200 mg) was suspended in THF (6 ml), and DMF was added.
(One drop) was added. Oxalyl chloride (0.
1 ml) was added dropwise and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a crude product of 9- (1,3-benzodioxol-5-yl) -naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid chloride. I got Sodium hydrogen carbonate (150 mg) was dissolved in water (1 ml), and glycine ethyl ester / hydrochloride (91 mg) and THF (2 ml) were added. Under ice-cooling, a solution of the above-mentioned acid chloride in THF (3 ml) was added dropwise. After stirring for 1 hour, the product was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and 1N hydrochloric acid, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (213 mg). Melting point: 171-173 ° C. NMR (CDCl ₃ ) δ: 1.33 (3H, t, J = 7 Hz), 4.28 (2
H, q, J = 7Hz), 4.29 (2H, d, J = 5Hz), 5.97 (2H, s), 6.0
3 (2H, s), 6.76 (1H, m), 6.82-6.93 (3H, m), 7.25
(1H, d, J = 9Hz), 7.60 (1H, d, J = 9Hz), 7.62 (1H, d, J =
1.8Hz), 8.28 (1H, d, J = 1.8Hz). IR (KBr): 1745, 1664, 1527, 1280, 1236, 121
4, 1203 cm ^-1 Elemental analysis: C ₂₃ H ₁₉ NO ₇ Calculated: C: 65.56%, H: 4.54%, N: 3.32% Observed: C: 65.19%, H: 4.59%, N: 3.31%

Example 18 2- [9- (1,3-benzodioxol-5-yl) -naphtho [1,
2-d] -1,3-dioxole-7-carboxamide] acetic acid

Embedded image 2- [9- (1,3-benzodioxole obtained in Example 17
-5-yl) -naphtho [1,2-d] -1,3-dioxole-7-carboxamide] ethyl acetate (200 mg) in THF (10 m
l) and methanol (5 ml), 1N aqueous sodium hydroxide solution (5 ml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in water, and the resulting aqueous solution was washed with ether. pH
Was adjusted to about 2, 1N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The obtained extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from methanol to give the title compound (163 mg). Melting point: 255-257 ° C. NMR (CDCl ₃ ) δ: 4.29 (2H, d, J = 5 Hz), 5.94 (2
H, s), 6.01 (2H, s), 6.78-7.00 (4H, m), 7.22 (1H, d,
J = 9Hz), 7.55 (1H, d, J = 9Hz), 7.59 (1H, brs), 8.25
(1H, brs). IR (KBr): 1720, 1625, 1529, 1492, 1282, 123
5, 1056 cm ^-1 elemental analysis: as C ₂₃ H ₁₅ NO ₇ · 1.5 H ₂ O Calculated: C: 62.16%, H: 4.08%, N: 3.15% Found: C: 62.22%, H: 4.24%, N: 3.37%

Example 19 N- (3-dimethylaminopropyl) -9- (1,3-benzodioxol-5-yl) -naphtho [1,2-d] -1,3-dioxole
-7-carboxamide hydrochloride

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 12
Yl) -naphtho [1,2-d] -1,3-dioxole-7-carboxylic acid (200 mg) was suspended in THF (6 ml), and DMF was added.
(One drop) was added. Oxalyl chloride (0.
1 ml) was added dropwise and stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product of naphthalene-7-carboxylic acid chloride. Under ice-cooling, the above-mentioned THF (6 ml) solution of the acid chloride was added dropwise to a THF (2 ml) solution of N, N-dimethylpropylenediamine (0.16 ml). After stirring for 1 hour, water was added, and the product was extracted with ethyl acetate. The obtained extract was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel 10 g, developing solvent: chloroform-methanol-aqueous ammonia = 20: 1: 0.1) to obtain a free amine (about 240 mg). This was dissolved in ethyl acetate (2 ml), and 4N hydrochloric acid-ethyl acetate (0.2 ml) was added. The resulting precipitate was collected by filtration and recrystallized from ethanol to give the title compound (166 mg). Mp: 235-240 ℃ NMR (DMSO-d 6) δ: 1.84-2.02 (2H, m), 2.75
(6H, s), 3.02-3.15 (2H, m), 3.30-3.45 (2H, m), 6.
02 (2H, s), 6.09 (2H, s), 6.90 (1H, dd, J = 1.6Hz, 8H
z), 6.97 (1H, d, J = 8Hz), 7.01 (1H, d, J = 1.6Hz), 7.4
5 (1H, d, J = 9Hz), 7.71 (1H, d, J = 1.8Hz), 7.75 (1H, d,
J = 9Hz), 8.45 (1H, d, J = 1.8Hz), 8.82 (1H, m). IR (KBr): 1646, 1535, 1488, 1291, 1232, 1038
cm ^-1 Elemental _{analysis: C 24 H 25 ClN 2 O} 5 Calculated: C: 63.09%, H: 5.51%, N: 6.13% Found: C: 62.85%, H: 5.44%, N: 6.10%

Example 20 N- (3-dimethylaminoethyl) -9- (1,3-benzodioxol-5-yl) -naphtho [1,2-d] -1,3-dioxol-7
-Carboxamide hydrochloride

Embedded image In the same manner as in Example 19, 9- (1,
3-benzodioxol-5-yl) -naphtho [1,2-d] -1,3-
The condensation reaction of dioxol-7-carboxylic acid with N, N-dimethylethylenediamine was performed to obtain the title compound. Melting point: 245-250 ° C NMR (DMSO-d ₆ ) δ: 2.83 (6H, s), 3.20-3.40
(2H, m), 3.55-3.75 (2H, m), 6.02 (2H, s), 6.09 (2
H, s), 6.90 (1H, dd, J = 1.4Hz, 8Hz), 6.98 (1H, d, J = 8H
z), 7.01 (1H, d, J = 1.4Hz), 7.47 (1H, d, J = 9Hz), 7.7
2 (1H, d, J = 1.6Hz), 7.77 (1H, d, J = 9Hz), 8.50 (1H, d,
J = 1.6Hz), 8.91 (1H, m). IR (KBr): 1648, 1544, 1500, 1488, 1288, 123
2,1039 cm ^-1 Elemental analysis: C ₂₃ H ₂₃ ClN ₂ O ₅ Calculated: C: 62.37%, H: 5.23%, N: 6.33% Actual values: C: 62.12%, H: 5.20%, N: 6.41 %

Example 21 9- (1,3-benzodioxol-5-yl) -8-methyl-naphtho [1,2-d] -1,3-dioxol-7-carboxamide

Embedded image Under ice cooling, 9- (1,3-benzodioxol-5-yl) -8-methyl-naphtho [1,2-d] -1,3-dioxol-7 obtained in Reference Example 13 -Carboxylic acid (50 mg) in DMF (1 m
l) To the solution were added WSC (1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride) (33 mg) and ammonia (3N ethanol solution: 0.14 ml). After stirring at room temperature for 2 hours, the reaction was stopped by adding water, and the resulting residue was subjected to column chromatography (silica gel 5 g, eluent: ethyl acetate-hexane = 1: 1).
Purification in 1) and recrystallization from methanol gave the title compound (23 mg). _{Mp: 244-246 ℃ NMR (CDCl 3)} δ: 2.41 (3H, s), 5.82 (1H, d, J =
1.6Hz), 5.83 (1H, d, J = 1.6Hz), 6.03 (1H, d, J = 1.4H)
z), 6.06 (1H, d, J = 1.4Hz), 6.68 (1H, dd, J = 1.6Hz, 8H
z), 6.73 (1H, d, J = 1.6Hz), 6.87 (1H, d, J = 8H), 7.18
(1H, d, J = 8Hz), 7.53 (1H, d, J = 8Hz), 8.55 (1H, s). IR (KBr): 1677, 1486, 1438, 1272, 1091, 1039
cm ^-1

Example 22 9- (1,3-benzodioxol-5-yl) -8-methyl-1,3-
Dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 14
Il) -8-Methyl-1,3-dioxolo [4,5-f] quinoline-7-
Carboxylic acid (150 mg) was added to THF (20 ml) and DM
F (2 drops) was dissolved in a mixed solvent, and oxalyl chloride (75 μl) was added dropwise. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was washed with THF (2
0 ml), slowly added to 28% aqueous ammonia (50 ml), and stirred at room temperature for 10 minutes. The product was extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as yellow crystals (135 mg). Some of the crude crystals were recrystallized from THF-ethyl acetate and used for elemental analysis and instrumental analysis. Melting point: 214-216 ° C NMR (CDCl ₃ ) δ: 2.50 (3H, s), 5.68 (1H, br)
s), 6.05 (2H, m), 6.67 (2H, m), 6.88 (1H, d, J = 8H
z), 7.34 (1H, d, J = 9Hz), 7.69 (1H, d, J = 9Hz), 7.84
(1H, brs). Elemental analysis: C ₁₉ H ₁₄ N ₂ O ₅ Calculated: C: 65.14%, H: 4.03%, N: 8.00% Observed: C: 64.84%, H: 3.92%, N: 7.76%

Example 23 N-methyl-9- (1,3-benzodioxol-5-yl) -8-methyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 14
Il) -8-Methyl-1,3-dioxolo [4,5-f] quinoline-7-
Carboxylic acid (150 mg) was added to THF (20 ml) and DM
F (2 drops) was dissolved in a mixed solvent, and oxalyl chloride (75 μl) was added dropwise. After stirring the reaction solution at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was washed with THF (2
0 ml), slowly added to methylamine (40% methanol solution: 20 ml), and stirred at room temperature for 10 minutes. The product was extracted with ethyl acetate, and the extract was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as yellow crystals (61 mg). Some of the crude crystals were recrystallized from THF-ethyl acetate and used for elemental analysis and instrumental analysis. _{Mp: 143-146 ℃ NMR (CDCl 3)} δ: 2.50 (3H, s), 3.05 (3H, d, J =
5Hz), 5.87 (1H, brs), 6.05 (2H, m), 6.67 (2H, m),
6.88 (1H, d, J = 8Hz), 7.34 (1H, d, J = 9Hz), 7.67 (1H,
d, J = 9 Hz), 7.90 (1H, brs). Elemental analysis: Calculated as C ₂₀ H ₁₆ N ₂ O ₅ Calculated: C: 65.93%, H: 4.43%, N: 7.69% Actual value: C: 65.67% , H: 4.24%, N: 7.53%

Example 24 N-methyl-9- (4-trifluoromethoxyphenyl) -8-
Hydroxymethyl-naphtho [1,2-d] -1,3-dioxole-
7-carboxamide

Embedded image 10- (4-Trifluoromethoxyphenyl) -furo [3 ', 4': 6,7] naphtho [1,2-d] -1,3-dioxole-7 (9H)-obtained in Reference Example 15 Using ON, the title compound was obtained in the same manner as in Example 1. Melting point: 195-197 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (CDCl ₃ ) δ: 1.76 (1H, brs), 3.09 (3H, d, J = 4.6H)
z), 4.35 (2H, s), 5.78 (2H, s), 6.37 (1H, br s), 7.20-7.
40 (5H, m), 7.47 (1H, d, J = 8.4Hz), 7.97 (1H, s). IR (KBr): 3297, 1634, 1254 cm ^-1 Elemental analysis: C ₂₁ H ₁₆ F ₃ NO ₅ Calculated value: C: 60.15%, H: 3.85%, N: 3.34% Observed value: C: 60.01%, H: 3.96%, N: 3.40%

Example 25 9- (4-Trifluoromethoxyphenyl) naphtho [1,2-
d] -1,3-dioxole-7-carboxamide

Embedded image Using 9- (4-trifluoromethoxyphenyl) -naphtho [1,2-d] -1,3-dioxol-7-carboxylic acid obtained in Reference Example 16 as in Example 11, the title compound I got Melting point: 188-190 ° C (recrystallized from ethyl acetate-isopropyl ether) NMR (CDCl ₃ ) δ: 5.60-6.20 (2H, brs), 5.94 (2H, s),
7.20-7.34 (3H, m), 7.46 (2H, d, J = 8.8Hz), 7.60-7.66 (2
H, m), 8.32 (1H, d, J = 1.4 Hz). IR (KBr): 1632, 1466, 1292 cm ^-1 Elemental analysis: Calculated as C ₁₉ H ₁₂ F ₃ NO ₄ Calculated: C: 60.81%, H: 3.22%, N: 3.73% Actual value: C: 60.74%, H: 3.34%, N: 3.69%

Example 26 N-methyl-4- (1,3-benzodioxol-5-yl) -6,7-
Diethoxy-3-hydroxymethyl-naphthalene-2-carboxamide

Embedded image 4- (1,3-benzodioxole-5- obtained in Reference Example 17
Ill) -6,7-diethoxynaphtho [2,3-c] furan-1 (3H)
The title compound was obtained in the same manner as in Example 1 using -one. NMR (CDCl ₃ ) δ: 1.41 (3H, t, J = 7 Hz), 1.54 (3H, t, J = 7
Hz), 3.08 (3H, d, J = 5Hz), 3.94 (2H, q, J = 7Hz), 4.30-4.50
(2H, m), 6.03 (1H, d, J = 1.4Hz), 6.09 (1H, d, J = 1.4Hz), 6.
42 (1H, m), 6.75-6.90 (3H, m), 6.95 (1H, d, J = 8Hz), 7.13
(1H, s), 7.85 (1H, s).

Example 27 N-methyl-9- (4-trifluoromethoxyphenyl) -8-
Hydroxymethyl-1,3-dioxolo [4,5-f] quinoline-7
-Carboxamide

Embedded image Using 10- (4-trifluoromethoxyphenyl) -1,3-dioxolo [4,5-f] furo [3,4-b] quinolin-7 (9H) -one obtained in Reference Example 18, The title compound was obtained in the same manner as in Example 1. NMR (CDCl ₃ ) δ: 3.12 (3H, d, J = 5 Hz), 4.57 (2H, d, J = 8
Hz), 5.30 (1H, t, J = 8Hz), 5.87 (1H, s), 7.25-7.40 (3H,
m), 7.43 (1H, d, J = 9Hz), 7.75 (1H, d, J = 9Hz), 8.28 (1H,
m).

Example 28 N-methyl-4- (1,3-benzodioxol-5-yl) -3-hydroxymethyl-6-methoxyquinoline-2-carboxamide

Embedded image 5- (1,3-benzodioxole-5- obtained in Reference Example 19
Yl) -7-Methoxyfuro [4,5-f] furo [3,4-b] quinolin-2 (4H) -one and the title compound was obtained in the same manner as in Example 1. NMR (CDCl ₃ ) δ: 3.12 (3H, d, J = 5H)
z), 3.77 (3H, s), 4.67 (2H,
d, J = 8 Hz), 5.39 (1H, t, J = 8H)
z), 6.06 (1H, d, J = 1.4 Hz),
6.11 (1H, d, J = 1.4 Hz), 6.75 −
7.00 (4H, m), 7.38 (1H, dd, J =
3.9 Hz), 7.99 (1H, d, J = 9 Hz),
8.48 (1H, m).

Example 29 8- (1,3-benzodioxol-5-yl) naphtho [2,3-
d] -1,3-dioxole-6-carboxamide

Embedded image 8- (1,3-benzodioxole-5- obtained in Reference Example 20
The title compound was obtained in the same manner as in Example 11 using yl) -naphtho [2,3-d] -1,3-dioxole-6-carboxylic acid. NMR (CDCl ₃ ) δ: 5.90-6.20 (2H, m), 6.06 (2H, s), 6.
07 (2H, s), 6.85-7.00 (3H, m), 7.22 (1H, s), 7.24 (1H, s),
7.60 (1H, d, J = 1.9Hz), 8.18 (1H, d, J = 1.9Hz).

Example 30 N-methyl-8- (1,3-benzodioxol-5-yl) naphtho [2,3-d] -1,3-dioxole-6-carboxamide

Embedded image NMR (CDCl ₃ ) δ: 3.05 (3H, d, J = 7H)
z), 6.05 (4H, s), 6.25 (1H,
m), 6.80-7.00 (3H, m), 7.20
(1H, s), 7.22 (1H, s), 7.55
(1H, d, J = 1.9 Hz), 8.12 (1H,
d, J = 1.9 Hz).

Example 31 6-Chloro-4- (4-chlorophenyl) -3-hydroxymethyl-N-methyl-naphthalene-2-carboxamide

Embedded image The title compound was obtained in the same manner as in Example 1 using 6-chloro-4- (4-chlorophenyl) naphtho [2,3-c] furan-1 (3H) -one obtained in Reference Example 21. . Melting point: 160 ° C. (decomp.) (Recrystallized from THF) NMR (CDCl ₃ ) δ: 3.09 (3H, d, J = 4.8 Hz), 4.39 (2H, s),
6.49 (1H, brs), 7.28 (2H, d, J = 8.4Hz), 7.39 (1H, m), 7.
34 (1H, m), 7.51 (2H, d, J = 8.4Hz), 7.81 (1H, d, J = 8.4Hz),
8.00 (1H, s). IR (KBr): 3285, 3083, 2942, 2876, 1634, 1555,
1483 cm ^-1

Example 32 4- (4-Fluorophenyl) -3- (2-hydroxyethyl)-
6-methoxy-N-methyl-2-carboxamide

Embedded image 5- (4-fluorophenyl) -3,4- obtained in Reference Example 22
Dihydro-7-methoxy-1H-pyrano [3,4-b] quinoline-1-
Using ON, the title compound was obtained in the same manner as in Example 1. Melting point: 139-140 ° C (recrystallized from ethyl acetate-THF) NMR (CDCl ₃ ) δ: 3.09 (3H, d, J = 5.0 Hz), 3.25 (2H, t, J)
= 6.0Hz), 3.69 (3H, s), 3.69 (2H, m), 4.52 (1H, m), 6.44 (1
H, d, J = 2.4Hz), 7.25 (4H, m), 7.35 (1H, dd, J = 9.2,2.4Hz),
7.98 (1H, d, J = 9.2Hz), 8.19 (1H, br s) IR (KBr):. 3316, 2942, 1651, 1618, 1493 cm -1 Elemental analysis: Calculated C ₁₉ H ₁₄ FNO _3: C: 70.58%, H: 4.36%, N: 4.33% Actual values: C: 70.49%, H: 4.57%, N: 4.26%

Example 33 9- (1,3-Benzodioxol-5-yl) -8- (2-hydroxyethyl) -N-methyl-1,3-dioxolo [4,5-f] quinoline- 7-carboxamide

Embedded image 11- (1,3-benzodioxole-5 obtained in Reference Example 23
-Yl) -9,10-dihydro-7H-1,3-dioxolo [4,5-f] pyrano [3,4-b] quinolin-7-one in the same manner as in Example 1 using the title compound I got NMR (CDCl ₃ ) δ: 3.07 (3H, d, J = 5.2)
Hz), 3.1-3.3 (2H, m), 3.71
(2H, t, J = 6.2 Hz), 5.87 (1H,
d, J = 1.4 Hz), 5.87 (1H, d, J =
1.4 Hz), 6.04 (1H, d, J = 1.4H)
z), 6.07 (1H, d, J = 1.4 Hz),
6.65-6.75 (2H, m), 6.86 (1H,
d, J = 7.8 Hz), 7.37 (1H, d, J =
8.8 Hz), 7.69 (1H, d, J = 8.8H)
z), 8.10 (1H, m).

Example 34 9- (1,3-benzodioxol-5-yl) -N-methyl-8-
Methylaminocarboxymethyl-1,3-dioxolo [4,5-
f] Quinoline-7-carboxamide

Embedded image 9- (1,3-Benzodioxol-5-yl) -8-ethoxycarbonylmethyl-1,3-dioxolo [4,5-f] quinoline-7-carboxyl obtained in Reference Example 23 (a) A mixture of acid ethyl ester (106 mg), 40% methylamine-methanol solution (5 ml) and THF (5 ml) was placed in a sealed tube,
Heated at 140 ° C. for 2 hours. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. After filtering off the insoluble matter and treating with isopropyl ether, the title compound was obtained as pale yellow crystals (4.6 m).
g). NMR (CDCl ₃ ) δ: 2.75 (3H, d, J = 4.8 Hz), 3.03 (3H, d, J
= 5.2Hz), 3.9-4.1 (2H, m), 5.02 (1H, m), 5.86 (1H, d, J = 1.
4Hz), 5.88 (1H, d, J = 1.4Hz), 6.01 (1H, d, J = 1.4Hz), 6.05
(1H, d, J = 1.4Hz), 6.73 (1H, dd, J = 7.8,1.6Hz), 6.78 (1H,
d, J = 1.6Hz), 6.86 (1H, d, J = 7.8Hz), 7.38 (1H, d, J = 8.8H
z), 7.70 (1H, d, J = 8.8Hz), 8.13 (1H, m).

Example 35 6-Chloro-4- (4-pyridyl) -2-quinolinecarboxamide

Embedded image 6-chloro-4- (4-pyridyl) -2- obtained in Reference Example 24
The title compound was obtained in the same manner as in Example 11 using quinolinecarboxylic acid. NMR (CDCl ₃ ) δ: 7.65 (2H, dd, J = 4.4, 1.4 Hz), 7.81 (1
H, d, J = 2.2Hz), 7.92 (1H, brs), 7.95 (1H, dd, J = 8.8,2.2H
z), 8.09 (1H, s), 8.24 (1H, d, J = 8.8Hz), 8.40 (1H, br s),
8.81 (2H, dd, J = 4.4,1.4Hz) Elemental analysis:. C ₁₅ H ₁₀ N ₃ Calculated OCl: C: 63.50%, H : 3.55%, N: 14.81% Found: C: 63.38%, H: 3.62%, N: 14.75%

Example 36 6-Chloro-N-methyl-4- (4-pyridyl) -2-quinolinecarboxamide

Embedded image 6-chloro-4- (4-pyridyl) -2- obtained in Reference Example 24
The title compound was obtained in the same manner as in Example 11 using quinolinecarboxylic acid. NMR (CDCl ₃ ) δ: 3.13 (3H, d, J = 5.2 Hz), 7.45 (2H, dd,
J = 4.4,1.4Hz), 7.75 (1H, dd, J = 8.8,2.2Hz), 7.83 (1H, d, J
= 2.2Hz), 8.13 (1H, d, J = 8.8Hz), 8.19 (1H, m), 8.29 (1H,
s), 8.84 (2H, dd , J = 4.4,1.6Hz) Elemental analysis:. C ₁₆ H ₁₂ N ₃ Calculated OCl: C: 64.54%, H : 4.06%, N: 14.11% Found: C: 64.55%, H: 4.09%, N: 14.06%

Example 37 6-Chloro-N- (4-methoxyphenyl) methyl-4- (4-pyridyl) -2-quinolinecarboxamide

Embedded image 6-chloro-4- (4-pyridyl) -2- obtained in Reference Example 24
The title compound was obtained in the same manner as in Example 11 using quinolinecarboxylic acid. NMR (CDCl ₃ ) δ: 3.82 (3H, s), 4.69 (2H, d, J = 5.8 Hz),
6.91 (2H, d, J = 8.8Hz), 7.36 (2H, d, J = 8.8Hz), 7.45 (2H, d
d, J = 4.4,1.8Hz), 7.73 (1H, dd, J = 8.8,2.2Hz), 7.83 (1H,
d, J = 2.2Hz), 8.11 (1H, d, J = 8.8Hz), 8.32 (1H, s), 8.47 (1
H, m), 8.84 (2H , dd, J = 4.4,1.8Hz) Elemental _{analysis:. C 23 H 18 N 3} O 2 Cl · 1 / 4H 2 O Calculated: C: 67.65%, H: 4.57% , N: 10.29% Found: C: 67.71%, H: 4.67%, N: 10.23%

Example 38 9- (4-Methoxyphenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-methoxyphenyl) -1,3- obtained in Reference Example 25
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.89 (3H, s), 5.70 (1H, brs), 6.02
(2H, s), 6.89 (2H, d, J = 8.8Hz), 7.43 (2H, d, J = 8.8Hz), 7.
46 (1H, d, J = 8.8Hz), 7.82 (1H, d, J = 8.8Hz), 8.00 (1H, br
s), 8.09 (1H, s).

Example 39 9- (4-methoxyphenyl) -N-methyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-methoxyphenyl) -1,3- obtained in Reference Example 25
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.10 (3H, d, J = 5.2)
Hz), 3.89 (3H, s), 6.00 (2H,
s), 6.98 (2H, d, J = 8.8 Hz),
7.43 (2H, d, J = 8.8 Hz), 7.45
(1H, d, J = 8.8 Hz), 7.79 (1H,
7. d, J = 8.8 Hz), 8.10 (1H, s),
17 (1H, m).

Example 40 9- (4-methoxyphenyl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-methoxyphenyl) -1,3- obtained in Reference Example 25
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.81 (3H, s), 3.89 (3H, s), 4.66 (2
H, d, J = 5.8Hz), 6.00 (2H, s), 6.90 (2H, d, J = 8.8Hz), 6.98
(2H, d, J = 8.4Hz), 7.3-7.5 (5H, m), 7.76 (1H, d, J = 8.8Hz),
8.13 (1H, s), 8.44 (1H, m).

Example 41 9- (1,3-benzodioxol-5-yl) -N, N-dimethyl
-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 26
Yl) Using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid, the title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.18 (3H, s), 3.21 (3H, s), 6.00 (2
H, s), 6.02 (2H, s), 6.83-6.98 (3H, m), 7.22 (1H, d, J = 9.0
Hz), 7.51 (1H, s), 7.78 (1H, d, J = 9.0 Hz). Elemental analysis: Calculated as C ₂₀ H ₁₆ N ₂ O ₅ Calculated: C: 65.93%, H: 4.43%, N: 7.69 % Measured value: C: 65.71%, H: 4.34%, N: 7.59%

Example 42 9- (1,3-benzodioxol-5-yl) -N-methyl-1,3-
Dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 26
Yl) Using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid, the title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.08 (3H, d, J = 5.2 Hz), 5.99 (2H, s),
6.01 (2H, s), 6.83-7.00 (3H, m), 7.39 (1H, d, J = 8.8Hz),
7.74 (1H, d, J = 8.8Hz), 8.07 (1H, s), 8.21 (1H, brd, J = 4.8H
z).

Example 43 9- (1,3-benzodioxol-5-yl) -N-propyl-1,
3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 26
Yl) Using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid, the title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 1.03 (3H, t, J = 7.6 Hz), 1.71 (2H, q, J
= 7.2Hz), 3.49 (2H, q, J = 7.0Hz), 6.02 (2H, s), 6.03 (2H,
s), 6.84-7.00 (3H, m), 7.43 (1H, d, J = 8.8Hz), 7.79 (1H,
d, J = 8.8 Hz), 8.08 (1H, s), 8.23 (1H, brs). Elemental analysis: Calculated as C ₂₁ H ₁₈ N ₂ O ₅ .3H ₂ O Calculated: C: 65.72%, H : 4.88%, N: 7.30% Found: C: 65.70%, H: 5.08%, N: 7.06%

Example 44 9- (1,3-Benzodioxol-5-yl) -N- (4-methoxyphenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 26
Yl) Using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid, the title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.84 (3H, s), 6.06 (4H, s), 6.87-7.
03 (5H, m), 7.30 (1H, s), 7.50 (1H, d, J = 8.8Hz), 7.76 (2H,
d, J = 9.2Hz), 7.91 (1H, d, J = 8.8Hz), 8.18 (1H, s) Elemental _{analysis:. C 25 H 18 N 2} O 6 · 0.2H 2 O Calculated: C: 67.32%, H: 4.15%, N: 6.28% Actual values: C: 67.21%, H: 4.11%, N: 6.25%

Example 45 9- (1,3-Benzodioxol-5-yl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7 -Carboxamide

Embedded image 9- (1,3-benzodioxole-5- obtained in Reference Example 26
Yl) Using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid, the title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 3.81 (3H, s), 4.67 (2H, d, J = 5.8 Hz),
6.03 (2H, s), 6.05 (2H, s), 6.80-7.08 (5H, m), 7.35 (2H,
d, J = 8.8Hz), 7.43 (1H, d, J = 9.2Hz), 7.76 (1H, d, J = 9.2H
z), 8.12 (1H, s ), 8.43 (1H, br s) Elemental _{Analysis:. C 26 H 20 N 2} O 6 · 0.1H 2 O Calculated: C: 68.15%, H: 4.44%, N : 6.11% Actual value: C: 68.04%, H: 4.70%, N: 6.20%

Example 46 9- (4-Fluorophenyl) -N-methyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-Fluorophenyl)-obtained in Reference Example 27
The title compound was obtained in the same manner as in Example 11 using 1,3-dioxolo [4,5-f] quinoline-7-carboxylic acid. Melting point: 233-235 ° C. NMR (CDCl ₃ ) δ: 3.10 (3H, d, J = 5.2 Hz), 6.00 (2H, s),
7.08-7.20 (2H, m), 7.40-7.50 (3H, m), 7.80 (1H, d, J = 9.0
Hz), 8.10 (1H, s ), 8.16 (1H, br s) Elemental _{Analysis:. C 18 H 13 N 2} O 3 F · 0.1H 2 O Calculated: C: 66.30%, H: 4.08%, N: 8.59% Actual value: C: 66.11%, H: 4.14%, N: 8.59%

Example 47 9- (4-Fluorophenyl) -N-[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-Fluorophenyl) -1,3- obtained in Reference Example 27
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. _{Mp: 171-173 ℃ NMR (CDCl 3)} δ: 3.81 (3H, s), 4.67 (2H, d, J = 6.2Hz),
5.99 (2H, s), 6.90 (2H, d, J = 8.4Hz), 7.06-7.22 (2H, m),
7.35 (2H, d, J = 8.4Hz), 7.40-7.55 (3H, m), 7.77 (1H, d, J =
8.8Hz), 8.12 (1H, s ), 8.44 (1H, s) Elemental _{analysis:. C 23 H 19 N 2} O 4 F · 0.1H 2 O Calculated: C: 69.47%, H: 4.47%, N: 6.48% Found: C: 69.31%, H: 4.51%, N: 6.45%

Example 48 N-benzyl-N- [9- (4-fluorophenyl) -1,3-dioxolo [4,5-f] quinoline-7-carbonyl] piperazine

Embedded image 9- (4-Fluorophenyl) -1,3- obtained in Reference Example 27
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. Melting point: 147-148 ° C. NMR (CDCl ₃ ) δ: 2.50 (2H, t, J = 4.8 Hz), 2.59 (2H, t, J
= 4.8Hz), 3.77 (2H, t, J = 4.8Hz), 3.88 (2H, t, J = 4.8Hz),
5.96 (2H, s), 7.02-7.20 (2H, m), 7.20-7.38 (5H, m), 7.38
-7.50 (3H, m), 7.52 (1H, s), 7.78 (1H, d, J = 9.2Hz) Elemental _{analysis:. C 28 H 24 N 3} O 3 F Calculated: C: 71.63%, H: 5.15%, N: 8.95% Found: C: 71.56%, H: 5.17%, N: 8.94%

Example 49 9- (4-Fluorophenyl) -N- [2- (4-methoxyphenyl) ethyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-Fluorophenyl) -1,3- obtained in Reference Example 27
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 2.94 (2H, t, J = 6.8 Hz), 3.66-3.82 (2
H, m), 3.81 (3H, s), 5.99 (2H, s), 6.89 (2H, d, J = 8.8Hz),
7.06-7.30 (4H, m), 7.43 (1H, d, J = 8.8Hz), 7.46 (2H, d, J =
8.8Hz), 7.77 (1H, d, J = 8.8Hz), 8.09 (1H, s), 8.26 (1H, br
s). Elemental analysis: as C ₂₆ H ₂₁ N ₂ O ₄ F Calculated: C: 70.26%, H: 4.76%, N: 6.30% Found: C: 70.19%, H: 4.83%, N: 6.29%

Example 50 N- [2- [4- (acetylamino) phenyl] ethyl] -9-
(4-Fluorophenyl) -1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-Fluorophenyl) -1,3- obtained in Reference Example 27
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 2.18 (3H, s), 2.96 (2H, t, J = 6.6Hz),
3.70-3.80 (2H, m), 6.00 (2H, s), 7.00-7.35 (5H, m), 7.3
5-7.60 (4H, m), 7.78 (1H, d, J = 8.8Hz), 8.08 (1H, s), 8.27
(1H, br s).

Example 51 9- (4-Fluorophenyl) -N- (2-hydroxyethyl)
-1,3-dioxolo [4,5-f] quinoline-7-carboxamide

Embedded image 9- (4-Fluorophenyl) -1,3- obtained in Reference Example 27
Using dioxolo [4,5-f] quinoline-7-carboxylic acid,
The title compound was obtained in the same manner as in Example 11. NMR (CDCl ₃ ) δ: 2.88 (1H, brs), 3.65-3.80 (2H, m),
3.90 (2H, br s), 6.00 (2H, s), 7.05-7.20 (2H, m), 7.38-
7.52 (3H, m), 7.81 (1H, d, J = 8.8Hz), 8.07 (1H, s), 8.55 (1
H, br s).

Example 52 3-dimethylaminomethyl-6-methoxy-4- (4-methoxyphenyl) -N-methyl-2-quinolinecarboxamide

Embedded image 3-bromomethyl-6-methoxy-4- obtained in Reference Example 28
After stirring a mixture of (4-methoxyphenyl) -2-quinolinecarboxylic acid methyl ester (152 mg), 50% aqueous dimethylamine solution (0.5 ml) and methanol (5 ml) at room temperature for 2 hours, water was added to the reaction mixture. , And extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. THF (5 ml) and 40% methylamine-methanol solution (5 ml) were added to the residue, and the mixture was heated under reflux for 16 hours, and then the solvent was distilled off under reduced pressure to obtain the title compound as a colorless powder (26 mg). NMR (CDCl ₃ ) δ: 2.06 (6H, s), 2.78 (3H, d, J = 5.2 Hz),
3.70 (3H, s), 3.72 (2H, m), 3.93 (3H, s), 6.66 (1H, d, J =
3.0Hz), 7.05 (2H, d, J = 8.8Hz), 7.16 (2H, d, J = 8.8Hz), 7.
34 (1H, dd, J = 9.0,3.0Hz), 8.01 (1H, d, J = 9.0Hz), 8.44 (1
H, m).

Example 53 N-methyl-8- (1-piperidinyl) -1,3-dioxolo [4,5
-g] quinoline-6-carboxamide

Embedded image Ethyl 8- (1-piperidinyl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate obtained in Reference Example 30 (60 m
g) and a 40% methylamine-methanol solution (5 m
After the mixture of 1) was stirred at room temperature for 3 hours, the solvent was distilled off under reduced pressure to obtain the title compound as a colorless powder (33.6 mg). NMR (CDCl ₃ ) δ: 1,5-2.0 (6H, m), 3.06 (3H,
d, J = 4.8Hz), 3.15 (4H, m), 6.11 (2H, s), 7.27 (1H,
s), 7.30 (1H, s), 7.71 (1H, s), 8.18 (1H, brs).

Example 54 N-methyl-8- (1-pyrrolidinyl) -1,3-dioxolo [4,5
-g] quinoline-6-carboxamide

Embedded image The title compound was obtained in the same manner as in Example 53 using ethyl 8- (1-pyrrolidinyl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate obtained in Reference Example 31. . NMR (CDCl ₃ ) δ: 2.03 (4H, m), 3.05 (3H, d, J =
5.2Hz), 3.68 (4H, m), 6.08 (2H, s), 7.23 (1H, s),
7.39 (1H, s), 7.53 (1H, s), 8.20 (1H, brs).

Example 55 N-methyl-8- (4-morpholinyl) -1,3-dioxolo [4,5
-g] quinoline-6-carboxamide

Embedded image The title compound was obtained in the same manner as in Example 53, using ethyl 8- (4-morpholinyl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate obtained in Reference Example 32. . NMR (CDCl ₃ ) δ: 3.07 (3H, d, J = 5.2 Hz), 3.21
(4H, m), 3.97 (4H, m), 6.13 (2H, s), 7.31 (2H,
s), 7.75 (1H, s), 8.17 (1H, m).

Example 56 N-methyl-8- (4-methylpiperazin-1-yl) -1,3-dioxolo [4,5-g] quinoline-6-carboxamide

Embedded image Using ethyl 8- (4-methylpiperazin-1-yl) -1,3-dioxolo [4,5-g] quinoline-6-carboxylate obtained in Reference Example 33, in the same manner as in Example 53 The title compound was obtained. NMR (CDCl ₃ ) δ: 2.41 (3H, s), 2.69 (4H, m),
3.07 (3H, d, J = 5.2Hz), 3.25 (4H, m), 6.12 (2H, s),
7.29 (2H, s), 7.74 (1H, s), 8.17 (1H, m).

Experimental Example 1 Induction of Alkaline Phosphatase (ALP) Production in Mouse Osteoblast Cell Line The mouse-derived osteoblast cell line MC3T3-E1 was isolated from 10% fetal bovine serum (FC
Α: Minimum essential medium containing S: fetal calf serum (MEM: min)
Seed a 96-well plate in imun essential medium) (8
000 / well) After 2 days, BMP-4 / 7 heterodimer (Japanese Patent Application No. 6-111)
A sample diluted to the concentration shown in Table 1 in a medium containing or not containing 3 ng / ml (described in No. 255) was added to the cells grown on one side (confluent), and the culture was continued for 72 hours. After washing the plate once with saline, the substrate solution was added and incubated at room temperature for 15 minutes. The reaction was stopped by adding 0.05N sodium hydroxide, and the absorbance at 405 nm was measured. As a result, as shown in [Table 1], the compound of the present invention
It was proved that BMP activity, that is, enhancement of ALP production induction by BMP, and excellent ALP production induction activity alone were exhibited irrespective of the presence or absence of BMP.

[Table 1]

Formulation Example 1 The following components (1) to (6) are mixed, and about 1,000 tablets of 6.5 mm in diameter containing 5 mg of the compound of Example 1 per tablet are prepared by a dosage form forming machine. it can. This is shown below (7)-
Coating with the component (9) gives a 6.6 mm diameter film-coated tablet. (1) 5 g of the compound of Example 1 (2) lactose 82.5 g (3) hydroxypropylcellulose 2.8 g (4) magnesium stearate 0.4 g (5) hydroxypropylmethylcellulose 2910 2.994 g (6) corn starch 19.3 g (7) Macrogol 6000 0.6g (8) Titanium oxide 0.4g (9) Iron trioxide 0.006g

Formulation Example 2 The following (1), (3), (4), (5), (6), (7)
The components of (8) and (8) are suspended or dissolved in purified water and coated on the core particles of (2) below to produce fine particles. The fine particles are coated with the following components (9) to (11) to form coated fine particles, and the following (12)
1% of the compound granules of Example 1, about 500 g. Divide this by 500mg. (1) 5 g of the compound of Example 1 (2) Lactose / crystalline cellulose (grain) 330 g (3) D-mannitol 29 g (4) Low substituted hydroxypropyl cellulose 20 g (5) Talc 25 g (6) Hydroxypropyl cellulose 50 g ( 7) Aspartame 3g (8) Dipotassium glycyrrhizinate 3g (9) Hydroxypropyl methylcellulose 2910 30g (10) Titanium oxide 3.5g (11) Yellow iron sesquioxide 0.5g (12) Light anhydrous silicic acid 1g

[0162]

EFFECTS OF THE INVENTION The cell differentiation-inducing factor or cell differentiation-inducing agent comprising the compound (I) or the compound (I) or a salt thereof of the present invention is, for example, a potent BMP-increasing agent and It has a formation promoting activity and acts on bone tissue to increase bone mass and strength. Therefore, the agent is useful for the treatment and prevention of various bone diseases such as osteoporosis, promotion of fracture healing or promotion of bone reconstruction. In addition, this drug,
Has neurotrophic factor action and neurotrophic factor action enhancing activity, and has Alzheimer's dementia and general senile dementia, Parkinson's disease, motor neuron disorders (such as amyotrophic lateral sclerosis), and diabetic peripheral nerves It is useful for treating and preventing various neurological diseases such as disorders.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/495 AAA A61K 31/495 AAA 31/535 31/535 C07D 215/48 C07D 215/48 317/60 317/60 317 / 70 317/70 401/04 213 401/04 213 405/04 215 405/04 215 491/056 491/056

Claims (32)

[Claims] (1) Formula (1) [Wherein, R ¹ is an amino group which may have a substituent, R ²
Represents a hydrogen atom or a lower alkyl group which may have a substituent, X represents a methine group which may have a substituent or N (O) m (m represents 0 or 1); Ring A represents a homo or hetero ring substituted with a halogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylenedioxy group, and ring B represents a homo or hetero ring which may have a substituent. . Or a salt thereof. (2) R ¹ is (1) (i) a halogen atom, (ii) C
_1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _2-6 alkenyl,
(Vii) an optionally halogenated C _2-6 alkynyl,
(Viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (x
ii) amino, (xiii) mono-C _1-6 alkylamino, (x
iv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxy-carbonylamino, mono-C _1-6 alkylaminocarbonylamino, C
_1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C
_1-6 alkylcarbonyl, (xviii) carboxyl, (xi
x) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xx
ii) di-C _1-6 alkyl-carbamoyl, (xxiii) C
_6-10 aryl-carbamoyl, (xxiv) sulfo, (xx
v) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl group,
C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group, C _6-14 aryl group or C _7-16 aralkyl group, (2) (i) halogen atom, (ii) C _{1 -3} alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii ) Optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _2-6
1-6 alkoxy, (x) optionally halogenated C
_1-6 alkylthio, (xi) hydroxy, (xii) amino,
(Xiii) mono-C _1-6 alkylamino, (xiv) di-C
_1-6 alkylamino, (xv) 5- or 6-membered cyclic amino,
(Xvi) C _1-6 alkoxycarbonylamino, mono-C
_1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl -
Carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi)
Mono-C _1-6 alkyl-carbamoyl, (xxii) di-C
_1-6 alkyl - carbamoyl, (xxiii) C _6-10 aryl - carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvi
i) C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group which may be substituted with a group selected from the group consisting of C _6-10 aryloxy , C
_A hydroxy group which may have a _6-14 aryl group or a C _7-16 aralkyl group, or (3) a formula of — (C −O) —R ⁷ , —SO ₂ —R ⁷ , —SO—R ⁷ , −
(C = O) NR ⁸ R ⁷ ,-(C = O) OR ⁷ ,-(C =
S) O—R ⁷ or — (C ＝ S) NR ⁸ R ⁷ (R ⁷ is (1) a hydrogen atom or (2) (i) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) Nitro,
(Iv) cyano, (v) optionally halogenated C _1-6
Alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) halogenated C _1-6 alkoxy optionally, (x) C _1-6 alkylthio optionally halogenated, (xi) hydroxy, (xii) amino, (xiii) mono-C _1-6 alkylamino, (xiv ) Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino, C _1-6 alkylcarbonylamino and Acylamino selected from C _1-6 alkylsulfonylamino, (xvi
i) C _1-6 alkyl-carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxi
ii) C _6-10 aryl-carbamoyl, (xxiv) sulfo,
(Xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl groups, C _{A 2-6} alkenyl group, a C _2-6 alkynyl group, a C _3-6 cycloalkyl group, a C _6-14 aryl group or a C _7-16 aralkyl group, and R ⁸ represents a hydrogen atom or a C _1-6 alkyl group; An amino group which may be substituted with an acyl group represented by the following), (i) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, and (v) halogen C _1-6 alkyl which may be optionally halogenated, (vi) C _2-6 alkenyl which may be halogenated, (vii) C _2-6 alkynyl which may be halogenated, (viii) C _{3- 6}
Cycloalkyl, (ix) optionally halogenated C
_1-6 alkoxy, (x) optionally halogenated C
_1-6 alkylthio, (xi) hydroxy, (xii) amino,
(Xiii) mono-C _1-6 alkylamino, (xiv) di-C
_1-6 alkylamino, (xv) 5- or 6-membered cyclic amino,
(Xvi) C _1-6 alkoxycarbonylamino, mono-C
_1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl -
Carbonyl, (xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi)
Mono-C _1-6 alkyl-carbamoyl, (xxii) di-C
_1-6 alkyl - carbamoyl, (xxiii) C _6-10 aryl - carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvi
i) in addition to a carbon atom and one nitrogen atom, which may be substituted with a group selected from the group consisting of C _6-10 aryloxy, 1 to 1 selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom R ⁵ represents a group in which one hydrogen atom has been removed from a nitrogen atom in a 5- to 9-membered nitrogen-containing heterocyclic ring which may contain 3 hetero atoms, and R ² represents (1) a hydrogen atom or (2) ) (I) a halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano,
(V) an optionally halogenated C _1-6 alkyl, (v
i) optionally halogenated C _2-6 alkenyl, (vi
i) optionally halogenated C _2-6 alkynyl, (vi
ii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii)
Amino, (xiii) mono-C _1-6 alkylamino, (xiv)
Di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (xviii) a carboxyl, (xix) C
_1-6 alkoxy-carbonyl, (xx) carbamoyl, (x
xi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl , (Xxvi) C _6-10 aryl and (xx
vii) a C _1-6 alkyl group which may be substituted with a group selected from the group consisting of C _6-10 aryloxy, wherein X is CR ⁶ ′ (R ⁶ ′ is (1) hydrogen atom, (2) Halogen atom,
(3) (i) halogen atom, (ii) C _1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) halogen Optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _{1 -6} alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii) amino, (xii
i) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi)
C _1-6 alkoxycarbonylamino, acylamino selected from mono -C _1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (Xviii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C
_1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C _6-10
A C _1-6 alkyl group, a C _2-6 alkenyl group, a C _1-6 alkyl group which may be substituted with a group selected from the group consisting of aryloxy,
_2-6 alkynyl group, _C3-6 cycloalkyl group, _C6-14 aryl group or _C7-16 aralkyl group, or (4) -OR
⁶ ″ (R ⁶ ″ is a hydrogen atom or (i) a halogen atom, (i
i) C _1-3 alkylenedioxy, (iii) nitro, (iv)
Cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated C _2-6 alkynyl, (Viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (xii) Amino, (xiii) mono-C _1-6 alkylamino, (xiv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono-C _1-6 alkylaminocarbonylamino,
C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C
_1-6 alkyl-carbonyl, (xviii) carboxyl,
(Xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl,
(Xxii) di-C _1-6 alkyl-carbamoyl, (xxiii)
C _6-10 aryl-carbamoyl, (xxiv) sulfo, (xx
v) C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C may be substituted with a group selected from the group consisting of _6-10 aryloxy C _1-6 alkyl group,
C _2-6 alkenyl group, C _2-6 alkynyl group, C _3-6 cycloalkyl group, C _6-14 aryl group or C _7-16 aralkyl group) or N ( O) m
(M represents 0 or 1), and ring A represents a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group or a C _1-3
(1) 3 to 10 substituted with an alkylenedioxy group
A 5- to 9-membered heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to (2) a carbon atom, and The substituted substituents may combine with each other to form a 3- to 10-membered cyclic hydrocarbon;
Halogen atom, (ii) C _1-3 alkylenedioxy, (ii
i) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl, (vi) optionally halogenated C _2-6 alkenyl, (vii) optionally halogenated Good C _2-6 alkynyl, (viii) C _3-6 cycloalkyl,
(Ix) an optionally halogenated C _1-6 alkoxy,
(X) an optionally halogenated C _1-6 alkylthio,
(Xi) hydroxy, (xii) amino, (xiii) mono-C
_1-6 alkylamino, (xiv) di -C _1-6 alkylamino, (xv) 5 or 6-membered cyclic amino, (xvi) C _1-6 alkoxycarbonylamino, mono--C _1-6 alkylaminocarbonyl amino, C _1-6 alkylcarbonylamino and C _1-6 acylamino selected from alkylsulfonylamino, (xvii) C _1-6 alkyl - carbonyl, (xvi
ii) carboxyl, (xix) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xxii) di-C _1-6 alkyl-carbamoyl, (xxiii) C _6-10 aryl-carbamoyl, (x
xiv) sulfo, (xxv) C _1-6 alkylsulfonyl, (xxv
i) a group selected from the group consisting of C _6-10 aryl and (xxvii) C _6-10 aryloxy, which may be substituted with (1) a 3- to 10-membered cyclic hydrocarbon or (2) a carbon atom other than The compound according to claim 1, which represents a 5- to 9-membered heterocyclic ring containing 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. (3) R ¹ is a compound represented by the formula: Wherein R ³ and R ⁴ are the same or different,
A hydrogen atom, a hydroxy group which may have a substituent, a lower alkyl group which may have a substituent, an acyl group, an aryl group which may have a substituent or a substituent And R ³ and R ⁴ may form a nitrogen-containing heterocyclic group which may have a substituent together with an adjacent nitrogen atom. The compound according to claim 1, which is a group represented by the formula: 4. R ³ and R ⁴ each represent a hydrogen atom, a hydroxy group which may have a substituent, a lower alkyl group or an acyl group which may have a substituent,
³ and 4. The compound of claim 3 wherein the R ⁴ to form a nitrogen-containing heterocyclic group which may have a substituent together with the adjacent nitrogen atom. 5. The compound according to claim 3, wherein R ³ and R ⁴ are the same or different and each is a hydrogen atom or a lower alkyl group which may have a substituent. 6. R ³ is a hydrogen atom or a C _1-6 alkyl group,
R ⁴ may be substituted by a group selected from the group consisting of (1) hydrogen atom, (2) hydroxy, carboxyl, C _1-6 alkoxy-carbonyl, amino and mono- or di-C _1-6 alkylamino. A good C _1-6 alkyl group,
(3) C _6-14 optionally substituted with C _1-6 alkoxy
An aryl group or a C _7-16 aralkyl group optionally substituted with (4) C _1-6 alkoxy or C _1-6 acylamino, wherein R ³ and R ⁴ are, together with an adjacent nitrogen atom,
The compound according to claim 3, which forms a 5- to 8-membered nitrogen-containing heterocyclic group which may be substituted with _7-16 aralkyl. 7. The compound according to claim 1, wherein R ² is a hydrogen atom or a lower alkyl group which may have a substituent. 8. A substituent wherein R ² is selected from (1) a hydrogen atom or (2) carbamoyl optionally having hydroxy, C _1-6 alkyl and amino optionally having C _1-6 alkyl. The compound according to claim 1, which is a C _1-6 alkyl group which may have a group. 9. The compound according to claim 1, wherein X is a methine group which may have a substituent. 10. The compound according to claim 1, wherein X is a methine group optionally substituted with a C _1-6 alkyl group. 11. The compound according to claim 1, wherein X is N (O) m (m represents 0 or 1). 12. The compound according to claim 1, wherein X is N. (13) A ring is a halogen atom, a lower alkyl group,
The compound according to claim 1, which is a benzene ring substituted with a lower alkoxy group or a lower alkylenedioxy group. 14. A ring is a halogen atom, C _1-6 alkyl,
The compound according to claim 1, which is a C _6-12 aromatic hydrocarbon ring substituted with a group selected from the group consisting of C _1-6 alkoxy and C _1-3 alkylenedioxy. 15. The compound according to claim 1, wherein ring B is a benzene ring which may have a substituent. 16. The ring B comprises a halogen atom, C _1-6 alkyl optionally substituted with a halogen atom, C _1-6 alkoxy optionally substituted with a halogen atom and C _1-3 alkylenedioxy. A C _6-12 aromatic hydrocarbon ring which may be substituted with a group selected from the group, or a C _1-6 alkyl group which may be substituted with a carbon atom other than a nitrogen atom, an oxygen atom and a sulfur atom The compound according to claim 1, which is a 5- to 8-membered heterocycle containing 1 to 3 selected heteroatoms. 17. The method according to claim 14, wherein R ¹ is (R ³ ′ is a hydrogen atom or a C _1-6 alkyl group, R ⁴ ′ is (1) a hydrogen atom, (2) hydroxy, carboxyl,
_1-6 alkoxy - carbonyl, amino and mono- - or di -C _1-6 optionally substituted by a group selected from the group consisting of alkylamino C _1-6 alkyl group, (3) C _1-6
Alkoxy optionally substituted C _6-14 aryl group or (4) C _1-6 an alkoxy or C _1-6 which may also be C _7-16 aralkyl group substituted with acylamino, also, R ³ ' and together with the nitrogen atom to which R ⁴ 'is adjacent, may be substituted with C _7-16 aralkyl, a group represented by a 5 to may form a 8-membered nitrogen-containing heterocyclic group), R ² Has a substituent selected from (1) a hydrogen atom or (2) carbamoyl optionally having hydroxy, C _1-6 alkyl and amino optionally having C _1-6 alkyl. A good C _1-6 alkyl group, wherein X may be substituted with a C _1-6 alkyl group, or a methine group or N (O) m (m
Represents 0 or 1), wherein ring A is a halogen atom, C _1-6
A C _6-12 aromatic hydrocarbon ring substituted with a group selected from the group consisting of alkyl, C _1-6 alkoxy and C _1-3 alkylenedioxy, wherein ring B is substituted with a halogen atom or a halogen atom. C _1-6 alkyl, C _6-12 aromatic optionally substituted by a group selected from the group consisting of C _1-6 alkoxy optionally substituted by halogen atoms and C _1-3 alkylenedioxy A 5- to 8-membered heterocyclic group which may be substituted with a hydrocarbon ring or a C _1-6 alkyl group and which contains, in addition to carbon atoms, 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur The compound according to claim 1, which is a ring. 18. The method according to claim 12, wherein R ¹ is (R ³ ″ is a hydrogen atom, and R ⁴ ″ is a C _7-16 optionally substituted with (1) a hydrogen atom or (2) C _1-6 alkoxy.
Wherein R ² is a hydrogen atom or a C _1-6 alkyl group optionally having hydroxy, X is a methine group or N, and ring A is C _1-6 alkoxy or C _1-3 A C _6-12 aromatic hydrocarbon ring substituted with alkylenedioxy, wherein ring B is a halogen atom, C _1-6 alkoxy and C _1-3
2. A C _6-12 aromatic hydrocarbon ring which may be substituted by a group selected from the group consisting of alkylenedioxy.
A compound as described. 19. N-methyl-9- (1,3-benzodioxol-5-yl) -8-hydroxymethyl-naphtho [1,2-d] -1,3-dioxol-7-carboxamide or Its salt. 20. N-methyl-8- (1,3-benzodioxol-5-yl) -7-hydroxymethyl-naphtho [2,3-d] -1,3-dioxol-6-carboxamide or Its salt. 21. 9- (1,3-benzodioxol-5)
-Yl) -8-hydroxymethyl-1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof. 22. N-methyl-4- (1,3-benzodioxol-5-yl) -6,7-diethoxy-3-hydroxymethyl-naphthalene-2-carboxamide or a salt thereof. 23. 9- (4-methoxyphenyl) -N-
[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof. 24. 9- (1,3-benzodioxol-5)
-Yl) -N-[(4-methoxyphenyl) methyl]-
1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof. 25. 9- (4-fluorophenyl) -N-
[(4-methoxyphenyl) methyl] -1,3-dioxolo [4,5-f] quinoline-7-carboxamide or a salt thereof. 26. A compound of the formula Wherein each symbol is as defined in claim 1 or a salt thereof is subjected to a functional group conversion reaction or (and) a carburization reaction. [Wherein, R ¹¹ represents a lower alkyl group which may have a substituent, and other symbols have the same meanings as those in claim 1] or a salt thereof. 27. The formula [Wherein each symbol has the same meaning as in claim 1], or a compound or an ester or a salt thereof, which is subjected to an amidation reaction and, if necessary, further subjected to an acylation reaction. A method for producing the compound according to claim 1 or a salt thereof. 28. A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof. 29. The formula [In the formula, the ring A 'represents a homocyclic ring or a heterocyclic ring which may have a substituent, and other symbols have the same meaning as in claim 1. ] Or a salt thereof, or a cell differentiation inducing factor action enhancing agent. 30. The ring A ′ is (i) a halogen atom, (ii) C
_1-3 alkylenedioxy, (iii) nitro, (iv) cyano, (v) optionally halogenated C _1-6 alkyl,
(Vi) optionally halogenated C _2-6 alkenyl,
(Vii) an optionally halogenated C _2-6 alkynyl,
(Viii) C _3-6 cycloalkyl, (ix) optionally halogenated C _1-6 alkoxy, (x) optionally halogenated C _1-6 alkylthio, (xi) hydroxy, (x
ii) amino, (xiii) mono-C _1-6 alkylamino, (x
iv) di-C _1-6 alkylamino, (xv) 5- to 6-membered cyclic amino, (xvi) C _1-6 acylamino, (xvii) C _1-6
Alkyl-carbonyl, (xviii) carboxyl, (xi
x) C _1-6 alkoxy-carbonyl, (xx) carbamoyl, (xxi) mono-C _1-6 alkyl-carbamoyl, (xx
ii) di-C _1-6 alkyl-carbamoyl, (xxiii) C
_6-10 aryl-carbamoyl, (xxiv) sulfo, (xx
v) (1) 3 to 10 which may be substituted with a group selected from the group consisting of C _1-6 alkylsulfonyl, (xxvi) C _6-10 aryl and (xxvii) C _6-10 aryloxy
A 5- to 9-membered heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to (2) a carbon atom, and The combined substituents are bonded to each other (1)
A 3- to 10-membered cyclic hydrocarbon, (2) a 3- to 9-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen in addition to carbon, or (3) carbon 30. The agent according to claim 29, which may form a 5- to 9-membered non-aromatic heterocyclic ring containing 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to the atom. (31) The agent according to the above (28), which is a preventive / therapeutic agent for a nerve disease or a bone / joint disease. 32. The neurological disorder wherein the neurological disorder is cerebrovascular dementia, senile dementia or Alzheimer's disease.
The agent according to claim 31, which is amyotrophic lateral sclerosis, diabetic peripheral neuropathy or Parkinson's disease.