JP2003155285A - Cyclic nitrogen-containing derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound usable for treating various kinds of diseases associated with CCR3. SOLUTION: This compound is represented by formula 1 [wherein, 1 denotes an integer of 0-2; R1 and R2 denote each, e.g. hydrogen; A denotes, e.g. a nitrogen-containing bivalent group such as C(O)NH; Ar1 denotes, e.g. an aryl group such as phenyl group or naphthyl group; and B denotes a group, e.g. 4-(4-hydroxybenzoyl)-1,4-diazepan-1-carbonyl group].

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a cyclic nitrogen-containing derivative or a pharmaceutically acceptable salt thereof, and a CCR3 inhibitor containing these as an active ingredient.

[0002]

Bronchial asthma, allergic rhinitis, atopic dermatitis, allergic bronchopulmonary aspergillosis,
One of the pathological features in inflammatory diseases such as Churg-Strauss syndrome, hypereosinophilic syndrome, parasitosis, or ulcerative colitis is the accumulation of eosinophils in inflamed areas (eg Samter's Immunologic Diseases Chapter 29, 501-5
27, 1995). For eosinophil cytoplasm, major basic pr
otein (MBP), eosinophil inhibitor protein (ECP), eo
sinophil-derived neurotoxin (EDN), eosinophil pero
There are granules mainly composed of basic proteins called xidase (EPO). In addition to their strong cytotoxic activity, these proteins stimulate basophils, mast cells, platelets, or eosinophils themselves, resulting in inflammatory effects such as histamine, serotonin, active oxygen, and interleukin-8. It is known to induce the release of mediators (eg Asthma Vol. 1, Chapter 45, 5
93-608, 1997). Eosinophils accumulated in the local area of inflammation play an important role in the development of the above-mentioned inflammatory diseases by releasing such granular proteins. Therefore, a drug that suppresses the tissue accumulation of eosinophils is considered to contribute to the treatment of such diseases.

Steroidal anti-inflammatory drugs are clinically used as effective therapeutic drugs for many chronic inflammatory diseases including eosinophilic inflammatory diseases, and can strongly suppress the accumulation of eosinophils in tissues. Are known. However, various side effects such as adrenal atrophy, growth inhibition, weakening of connective tissue due to inhibition of collagen synthesis, and gradual increase in the amount of use due to resistance acquisition have been pointed out for steroids. Development of a small amount of eosinophil accumulation inhibitor is desired.

In recent years, a group of proteinaceous mediators called chemokines have been found as cytokines that induce the migration reaction and activation of leukocytes. Due to their structural characteristics, chemokines are classified into C, CC, CXC and CX3C chemokines. Among them, chemokines such as eotaxin-1, eotaxin-2, MCP-3, MCP-4, and RANTES belonging to CC chemokines are reported to have strong chemotactic activity for eosinophils and mediator release promoting action ( For example,
N. Engl. J. Med. 338, 436-445, 1998). Leukocytes express chemokine receptors on their cell surfaces, and chemokine binding to the receptors induces leukocyte migration reaction and mediator release reaction. Chemokine receptors called CCR1 and CCR3 are expressed on the surface of eosinophils, and among them, CCR3 is known to be important for the chemokine response of eosinophils (J. B.
iol. Chem. 270, 16491-16494, 1995; J. Bio
l. Chem. 271, 7725-7730, 1996; J. Clin. In
vest. 99, 178-184, 1997). It has been reported that CCR3 is expressed not only on eosinophils but also on basophils and helper T cell type 2 (J. Clin. Invest. Vol. 100, 11
37-1143, 1997; J. Exp. Med. Volume 185, 2171-2176.
P., 1997; Science Vol. 277, 2005-2007 P., 1997
It is considered that a drug that specifically suppresses the CCR3-mediated leukocyte reaction can be a therapeutic drug for inflammatory diseases mainly involving eosinophils, especially allergic diseases.
As an example suggesting this, it has been reported that administration of anti-CCR3 antibody to mice depletes eosinophils in the bloodstream and tissues (J. Leukoc. Biol. Vol. 65, 846-85.
(Page 3, 1999), eotax, one of the ligands for CCR3
Neutralizing antibody against in has been shown to suppress eosinophil tissue accumulation in mice and guinea pig allergic inflammation models (J. Clin. Invest. Vol. 98, 2332-23).
45, 1996; J. Exp. Med. 185, 758-790, 199.
7 years; J. Clin. Invest. 100, 1657-1666, 1997
Year; J. Exp. Med. 188, pp. 157-167, 1998). To date, several examples of CCR3 inhibitors have been reported (for example, WO 98/04554). In addition, it has been clarified that CCR3 is one of the receptors for AIDS virus (HIV-1) entry into host cells, and CCR3 inhibitors are drugs that prevent the infection of some HIV-1 strains. (Cell Volume 85, 1135-1148, 1996; Nature 385)
Volume, 645-649, 1997). As an example to suggest this, e
It has been shown that otaxin protects cell lines from HIV-1 infection in vitro (Cell Volume 85, 1135-1148).
Page, 1996). Furthermore, infiltration of activated eosinophils was observed in the tissue extract of nasal polyps (chronic sinusitis), and the CCR3 ligands eotaxin, eotaxin-2 and MCP-4 were significantly increased (J Immunol. 163, 1545-1551, 1999).
That is, it has been revealed that CCR3-positive mononuclear cells in peripheral blood and bone fluid of RA patients are significantly increased as compared with those of healthy individuals (Arthritis Rheum. 44, 1022-1032, 2001).
Year).

[0005]

The problem to be solved by the present invention is to find lymphocytes by finding CCR3 inhibitors.
It is intended to enable prevention and treatment of allergic inflammatory diseases caused by leukocyte accumulation such as eosinophils and basophils.

[0006]

As a result of intensive studies, the present inventors have found that a specific cyclic nitrogen-containing derivative or a pharmaceutically acceptable salt thereof has a CCR3 inhibitory activity. Has been completed. That is, the present invention includes the following inventions.

Equation (1):

[Chemical 5] [In the formula, l is an integer of 0 to 2, R ₁ and R ₂ independently represent a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, or R ₁ and R ₂ are together. it may form a bridge of the chain members 1 to 4, a _{is, -NR 3 C (O) NR} 4 -, - NR 3 C (O) -, - C (O) NR 3 -, -
C (O) O-, -C (O)-, -OC (O)-, -OC (O) NR _3- , -NR ₃ C (O) O-,-
NR _3- , -O-, -SO ₂ NH-, -C (= NR ₅ ) NH- and -C (= CHNO ₂ ) NH-, R ₃ and R ₄ are independently a hydrogen atom or Carbon number
1 to 3 represents a straight-chain alkyl group, R ₅ is -CN, -SO ₂ NH ₂ , -C
Represents OOEt or —COOMe, Ar ₁ represents an optionally substituted aryl group or an optionally substituted heterocyclic group, and B represents 1) Formula 2:

[0008]

[Chemical 6] (In the formula 2, D represents a saturated 7-membered ring containing 1 to 2 nitrogen atoms, Ar ₂ is an optionally substituted aryl group, an optionally substituted heterocyclic group or a substituted Optionally represents a cycloalkyl group, V is (i) a bond (provided that l = 0
In, and, A is _{-NR 3 C (O) NR 4} -, - except in the case), (ii) -C (O ) - - C (O) NR 3 - or -NR ₃ (where, l = 0, and Ar ₂ is an unsubstituted phenyl group, or a halogen, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, C1-C6 haloalkoxy group, phenyl (C ₁ -C ₆ alkyl) group, S (O) ₂ (C _1-
C ₆ alkyl) group, C (O) NH ₂ , carboxyl group and carbon number 1
In the case of a phenyl group substituted only with a substituent selected from the alkoxycarbonyl group of ~ 6, and R ₁ and R ₂ are hydrogen atoms, l is 0 or 1, A is -C (O) NR ₃ , and D is (Except in the case of azepan which is bonded to A at a carbon atom which is a ring atom to be 1,2-diyl), (iii) -NR ₃ C (O)-, (iv) -C (O) NR _3- , (v) -SO ₂
-(However, R ₁ and R ₂ are hydrogen atoms, l is 0 or 1, A is -C (O) N
In R ₃ , except in the case of azepan in which D is bonded to A at a carbon atom which is a ring atom to form 1,2-diyl), (vi) -OC (O)-, (vi
i) -CR ₆ R ₇ C (O)-(R ₆ and R ₇ independently represent a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms (provided that both R ₆ and R ₇ are hydrogen atoms). Or R ₆ and R ₇ may form a 3- to 6-membered ring together with carbon atoms existing between them (provided that R ₁ and R ₂ are hydrogen atoms). , L is 0 or
1, except for Azepan in which A is -C (O) NR ₃ and D is bonded to A at a carbon atom that is a ring atom to form 1,2-diyl), (vii
i) -NR _3- (provided that l = 0 and Ar ₂ is a cycloalkyl group which may be substituted), (ix) carbon number 1 to
3 alkylene groups (where l = 0 and A is -NR ₃ C (O) NR ₄
-, -C (O) NR ₃ -or -NR _3- )), (x) -CH ₂ O-, (x
i) -CH ₂ NR _3- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group), (x
ii) -NR ₃ S (O) _2- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group)
Or (xiii) -S (O) ₂ NR _3- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group). A group represented by: 2) Formula 3:

[0009]

[Chemical 7] (In the formula 3, m is an integer of 0 to 2, R ₈ and R ₉ are independently a linear alkyl group having 1 to 3 carbon atoms, an aryl group which may be substituted or a substituted group. Represents a heterocyclic group, W is —NR ₃ — (except when R ₉ is a straight-chain alkyl group having 1 to 3 carbon atoms), a sulfur atom, —NHC (O) — (provided that R is ₉ is a straight-chain alkyl group having 1 to 3 carbon atoms), -C (O) NH
-, - CH ₂ O- (except when R ₉ is a straight chain alkyl group having 1 to 3 carbon _{atoms), - SO 2 NH -,} - C (O) O- or -OC (O) - and Represent)
Or a group represented by 3) Formula 4:

[0010]

[Chemical 8] (In the formula 4, R ₁₀ represents a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, R ₁₁ is a hydrogen atom, a linear alkyl group having 1 to 3 carbon atoms, an optionally substituted aryl Represents a group or a heterocyclic group which may be substituted) and a cyclic nitrogen-containing derivative represented by the above) or a pharmaceutically acceptable salt thereof.

(2) In the formula 1, B is the formula 2 (where Ar is₂Is ha
Rogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C₁-C₃Archi
(Le)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C (O) N (C₁-
C₃Alkyl)₂, -NHC (O) (C₁-C ₃Alkyl), -NHC (O) O (C₁-
C₃Alkyl), -CN, -NO₂, Straight-chain alkyl having 1 to 3 carbon atoms
Group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -CF₃, -OC
F₃, -SO₂NH₂, -SO₂NH (C₁-C ₃Alkyl), -SO₂N (C₁-C₃A
(Rukiru)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Archi
(Le)₂, -COOH, -C (O) O (C₁-C₃Alkyl), phenyl, fe
Nil (C₁-C₃Alkyl), cycloalkyl group, heterocyclic group
And substituted with 1 to 3 substituents selected from aryl groups.
Optionally mono- or bicyclic aryl having 6 to 10 carbon atoms
Group, or halogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C₁-
C₃Alkyl)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C
(O) N (C₁-C₃Alkyl)₂, -NHC (O) (C₁-C₃Alkyl), -NHC
(O) O (C ₁-C₃Alkyl), -CN, -NO₂, A straight chain C1-C3
Alkyl group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -C
F₃, -OCF₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C
₁-C ₃Alkyl)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃
Alkyl)₂, -COOH, -C (O) O (C₁-C₃Alkyl), pheny
Le, phenyl (C₁-C₃Alkyl), cycloalkyl group,
1-3 substituents selected from telocyclic group and aryl group
Optionally substituted with oxygen atom, sulfur atom and nitrogen atom.
5-6 members containing 1-3 heteroatoms selected from elementary atoms
Represents a monocyclic or bicyclic heterocyclic group), a formula
3 (However, R₈And R₉Are independently halogen, -NH₂, -NH (C
₁-C₃Alkyl), -N (C₁-C₃Alkyl)₂, -C (O) NH₂, -C (O)
NH (C₁-C₃Alkyl), -C (O) N (C₁-C₃Alkyl)₂, -NHC (O)
(C₁-C₃Alkyl), -NHC (O) O (C₁-C₃Alkyl), -CN, -NO
₂, A linear alkyl group having 1 to 3 carbon atoms, a linear alkyl group having 1 to 3 carbon atoms
Lucoxy group, -OH, -CF₃, -OCF₃, -SO₂NH ₂, -SO₂NH (C₁-C
₃Alkyl), -SO₂N (C₁-C₃Alkyl)₂, -NHSO₂(C₁-C₃A
Rukiru), -N (SO₂C₁-C₃Alkyl)₂, -COOH, -C (O) O (C₁-C
₃Alkyl), phenyl, phenyl (C₁-C₃Alkyl),
Selected from chloroalkyl group, heterocyclic group and aryl group
6 to 1 carbon atoms which may be substituted with 1 to 3 substituents
0 monocyclic or bicyclic aryl groups, or halogen, -NH₂,-
NH (C₁-C₃Alkyl), -N (C₁-C₃Alkyl)₂, -C (O) NH₂,-
C (O) NH (C₁-C₃Alkyl), -C (O) N (C₁-C₃Alkyl)₂, -NH
C (O) (C₁-C₃Alkyl), -NHC (O) O (C₁-C₃Alkyl), -C
N, -NO₂, A straight-chain alkyl group having 1 to 3 carbon atoms, 1 to 3 carbon atoms
Linear alkoxy group, -OH, -CF₃, -OCF₃, -SO₂NH₂, NHSO₂
(C₁-C₃Alkyl), -N (SO₂C₁-C₃Alkyl)₂, -COOH, -C
(O) O (C₁-C₃Alkyl), phenyl, phenyl (C₁-C₃Al
Kill), cycloalkyl group, heterocyclic group and aryl group
May be substituted with 1 to 3 substituents selected from
Selected from oxygen atom, sulfur atom and nitrogen atom.
5- to 6-membered mono- or bicyclic hetene containing 1-3 terror atoms
Or a group represented by Formula 4 (provided that R is₁₁Is
Hydrogen atom; halogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C
₁-C₃Alkyl)₂, -CN, -NO₂, A straight chain alk having 1 to 3 carbon atoms
Group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -CF₃, -OC
F₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C₁-C₃A
(Rukiru)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Archi
(Le)₂, -COOH, -C (O) O (C₁-C₃Alkyl), phenyl, fe
Nil (C₁-C₃Alkyl), cycloalkyl group, heterocyclic group
And substituted with 1 to 3 substituents selected from aryl groups.
Optionally mono- or bicyclic aryl having 6 to 10 carbon atoms
Group; or halogen, -NH₂, -NH (C₁-C₃Alkyl), N (C₁-C
₃Alkyl)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C
(O) N (C₁-C₃Alkyl)₂, -NHC (O) (C₁-C₃Alkyl), -NHC
(O) O (C₁-C₃Alkyl), -CN, -NO₂, A straight chain C1-C3
Alkyl group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -C
F₃, -OCF₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C
₁-C₃Alkyl)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃
Alkyl)₂, -COOH, -C (O) O (C₁-C₃Alkyl), pheny
Le, phenyl (C₁-C₃Alkyl), cycloalkyl group,
1-3 substituents selected from telocyclic group and aryl group
Optionally substituted with oxygen atom, sulfur atom and nitrogen atom.
5-6 members containing 1-3 heteroatoms selected from elementary atoms
Represents a monocyclic or bicyclic heterocyclic group) of
The cyclic nitrogen-containing derivative according to (1) above or a pharmaceutical thereof
Acceptable salt. (3) The cyclic nitrogen-containing derivative according to (1) or (2) above.
Or a pharmaceutically acceptable salt thereof as an active ingredient
CCR3 inhibitor.

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION As described above, the cyclic nitrogen-containing nitrogen of the present invention is used.
The elementary derivative is represented by the above formula 1. In the present specification, "1 carbon number
~ 3 straight-chain alkyl groups "and" C₁-C₃"Alkyl" means
Shows chill, ethyl, n-propyl, and isopropyl groups.
, "C1-6 alkyl group" and "C₁-C₆Archi
The term "ru" means a linear or branched alkyl group such as methyl.
Group, ethyl group, n-propyl group, isopropyl group, n-butane group
Cyl group, isobutyl group, sec-butyl group, t-butyl group, n-
Represents a pentyl group and n-hexyl group. "Cycloalkyl
The `` group '' is preferably a cycloalkyl group having 3 to 8 carbon atoms.
And more preferably cyclopropyl, cyclobutyl, or
Clopentyl and cyclohexyl. "C1-C6
A "haloalkyl group" is a linear or branched haloalkyl group.
Group such as trifluoromethyl group, difluoromethyl group
Group represents a pentafluoroethyl group. "A carbon number of 1-6
"Rukoxy group" means a linear or branched alkoxyl group.
Groups such as methoxy, ethoxy, n-propoxy,
Isopropoxy group, n-butoxy group, isobutoxy group, n-
Represents a pentyloxy group and n-hexyloxy group. "carbon
The `` haloalkoxy group of the number 1 to 6 '' means a linear or branched group.
A haloalkoxy group, for example a trifluoromethoxy group, di
Shows fluoromethoxy group and pentafluoroethoxy group
You "Phenyl (C₁-C₆An "alkyl) group" means an alkyl
A phenyl-substituted-alkyl group in which the carbon number of the moiety is 1-6,
For example, it represents a benzyl group or a phenethyl group. `` S (O)<sub>2</sub>(C<sub>1</sub>-C
<sub>6</sub>An `` alkyl) group '' has 1 to 6 carbon atoms in the alkyl portion.
Alkyl-substituted-sulfonyl group, for example methanesulphonyl
And a ethanesulfonyl group. "C1-6 al
"Coxycarbonyl group" means a carbon including a carbonyl carbon
An alkoxycarbonyl group whose number is 1 to 6, such as methoxy
A carbonyl group and an ethoxycarbonyl group are represented. "Halo
"Gen" represents -F, -Cl, -Br, -I. "Aryl group"
Is preferably a monocyclic to tricyclic aryl group having 6 to 14 carbon atoms.
And more preferably a phenyl group and a naphthyl group.
It "Heterocyclic group" means an oxygen atom, a sulfur atom and a nitrogen atom.
5-6 members containing 1 to 4 heteroatoms selected from elementary atoms
A monocyclic to tricyclic heterocyclic group, which is a saturated ring, an aromatic ring or
Including its partially hydrogenated ring groups, preferably
Lysyl, pyrazinyl, pyrimidyl, pyridazinyl, imimi
Dazolyl, pyrrolidyl, pyrrolyl, thienyl, furyl,
Thiazolyl, pyrazolyl, oxazolyl, isoxazol
Ril, quinolyl, isoquinolyl, tetrahydroquinoli
, Tetrahydroisoquinolyl, piperidyl, piperazi
Nil, tetrahydrofuranyl, morpholinyl, indoli
, Isoindolyl, indolinyl, tetrahydroben
Examples include zoimidazolyl and chromanyl groups. "Replaced
Optionally substituted aryl group ”,“ optionally substituted
Telocyclic group "," optionally substituted cycloalkyl ring "
The substituent in “group” is used as the substituent of these groups.
It is not particularly limited as long as it is a group capable of being
Kuha halogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C₁-C₃A
(Rukiru)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C (O) N
(C₁-C₃Alkyl)₂, -NHC (O) (C₁-C₃Alkyl), -NHC (O) O
(C₁-C₃Alkyl), -CN, -NO ₂, A straight chain alk having 1 to 3 carbon atoms
Group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -CF₃, -OC
F₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C₁-C₃A
(Rukiru)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Archi
(Le)₂, -COOH, -C (O) O (C₁-C₃Alkyl), phenyl, fe
Nil (C₁-C₃Alkyl), cycloalkyl group, heterocycle
A group selected from the group consisting of aryl groups and aryl groups.
It may have 1 to 3 substituents.

In the formula 1, l is an integer of 0 to 2 and R ₁ and R ₂
Independently represent a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, or R ₁ and R ₂ together form a chain member. 1-4 crosslinks,
For example, an alkylene group having 1 to 4 carbon atoms (specifically, methylene, ethylene, trimethylene, tetramethylene), or at least one methylene in the alkylene group having 1 to 4 carbon atoms is -O-, -S- or -NH- may be substituted to form a divalent group (in which case R ₁ and R ₂ together with the piperidine ring to which they are attached 8-azabicyclo [3.2.1] octane, 9 - azabicyclo [3.3.1] form a bridged ring such as nonane), a _{is, -NR 3 C (O) NR} 4 -, - NR 3 C (O) -, - C (O) NR
_3- , -C (O) O-, -C (O)-, -OC (O)-, -OC (O) NR _3- , -NR ₃ C (O)
O-, -NR _3- , -O-, -SO ₂ NH-, -C (= NR ₅ ) NH- and -C (= CHNO ₂ )
Selected from NH-, R ₃ and R ₄ are independently a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, specifically, a methyl group,
Represents an ethyl group and n-propyl group, R ₅ is —CN, —SO ₂ NH ₂ ,
Represents -COOEt (ethoxycarbonyl) or -COOMe (methoxycarbonyl), Ar ₁ is phenyl group, hydroxy-substituted phenyl group, cyano-substituted phenyl group, nitro-substituted phenyl group, halogen-substituted phenyl group, C ₁ -C ₆ alkyl-substituted Phenyl group, naphthyl group, hydroxy-substituted naphthyl group,
Cyano-substituted naphthyl group, nitro-substituted naphthyl group, halogen-substituted naphthyl group, optionally substituted aryl group such as C ₁ -C ₆ alkyl-substituted naphthyl group, or a thienyl group,
Furyl group, pyrrolyl group, indolyl group, quinolyl group, piperidyl group, C ₁ -C ₆ alkyl-substituted thienyl group, C ₁ -C ₆ alkyl-substituted furyl group, C ₁ -C ₆ alkyl-substituted pyrrolyl group, C _1-
C ₆ alkyl-substituted indolyl group, C ₁ -C ₆ alkyl-substituted quinolyl group, C ₁ -C ₆ alkyl-substituted piperidyl group, halogen-substituted thienyl group, halogen-substituted furyl group, halogen-substituted pyrrolyl group, halogen-substituted indolyl group, halogen-substituted quinolyl group Group, an optionally substituted heterocyclic group such as a halogen-substituted piperidyl group.

B is 1) Formula 2:

[Chemical 9] (In Formula 2, D is 1 to 2 such as azepane and 1,4-diazepane.
Represents a saturated 7-membered ring containing the nitrogen atom of₂Is phenyl
Group, hydroxy-substituted phenyl group, cyano-substituted phenyl
Group, nitro-substituted phenyl group, halogen-substituted phenyl group,
C₁-C₆Alkyl-substituted phenyl group, naphthyl group, hydroxy
Si-substituted naphthyl group, cyano-substituted naphthyl group, nitro-substituted
Naphthyl group, halogen-substituted naphthyl group, C₁-C₆Alkyl
An optionally substituted aryl such as a substituted naphthyl group
Group, thienyl group, furyl group, pyrrolyl group, indolyl
Group, quinolyl group, piperidyl group, C₁-C₆Alkyl-substituted
Enyl group, C ₁-C₆Alkyl-substituted furyl group, C₁-C₆Alkyl
Substituted pyrrolyl group, C₁-C₆Alkyl-substituted indolyl group, C₁-
C₆Alkyl-substituted quinolyl group, C₁-C₆Alkyl-substituted piperi
Zyl group, halogen-substituted thienyl group, halogen-substituted furyl
Group, halogen-substituted pyrrolyl group, halogen-substituted indolyl
Group, halogen-substituted quinolyl group, halogen-substituted piperidyl
Optionally substituted heterocyclic group such as group, or cyclo
Pentyl group, cyclohexyl group, C₁-C₆Alkyl-substituted
Clopentyl group, C₁-C₆Alkyl-substituted cyclohexyl
Group, halogen-substituted cyclopentyl group, halogen-substituted cyclo
Optionally substituted cycloalkyl such as lohexyl group
Represents a radical. V is an (i) bond (where l = 0 and A is-
NR₃C (O) NR_Four-, -C (O) NR₃-Or- NR₃-Except), (i
i) -C (O)-(where l = 0 and Ar₂Is an unsubstituted pheny
Group, halogen, nitro group, cyano group, 1 to 6 carbon atoms
Alkyl group, C1-6 haloalkyl group, C1
~ 6 alkoxy group, C1-6 haloalkoxy group,
Phenyl (C₁-C₆Alkyl) group, S (O)₂(C₁-C₆Alkyl)
Group, C (O) NH₂, Carboxyl groups and alcohols with 1 to 6 carbons
Substituted only with substituents selected from oxycarbonyl groups
In the case of a phenyl group, and R₁And R₂Is a hydrogen atom, l is 0 or
Is 1, A is -C (O) NR₃And D is a carbon atom that is a ring atom and A
Except in the case of azepan, which is combined to form 1,2-diyl), (i
ii) -NR₃C (O)-, (iv) -C (O) NR₃-, (V) -SO₂-(R₁And R₂
Is a hydrogen atom, l is 0 or 1, A is -C (O) NR₃And D is a ring atom
Azepan that combines with A at a carbon atom to form 1,2-diyl
, Except (), (vi) -OC (O)-, (vii) -CR₆R₇C (O)-(R
₆And R₇Are independently a hydrogen atom or a straight chain alkyl group having 1 to 3 carbon atoms.
Alkyl group, specifically, methyl group, ethyl group, n-propy
Represents a radical (provided that R₆And R₇When both are hydrogen atoms
, Or R₆And R₇Carbon that exists between these
Together with the atom, a 3- to 6-membered ring, specifically, cyclopro
Pan ring, cyclobutane ring, cyclopentane ring, cyclo
May form a xanthine ring (provided that R₁And R₂Is hydrogen
Child, l is 0 or 1, A is -C (O) NR₃And carbon where D is a ring atom
In the case of azepan, which is bonded to A at an atom and becomes 1,2-diyl
Except), (viii) -NR₃-(However, if l = 0 and Ar₂Is replaced
(Except in the case of an optionally substituted cycloalkyl group), (i
x) an alkylene group having 1 to 3 carbon atoms, specifically methyl
N, ethylene, trimethylene, methyl ethylene (however,
l = 0 and A is -NR₃C (O) NR_Four-, -C (O) NR₃-Or- NR₃-of
Except), (x) -CH₂O-, (xi) -CH₂NR₃-(However, l = 0
And, Ar ₂Is an unsubstituted phenyl group or an unsubstituted phenyl group
(Except for alkyl group), (xii) -NR₃S (O)₂-(However
, L = 0 and Ar₂Is an unsubstituted phenyl group or unsubstituted
Of cycloalkyl groups of) or (xiii) -S (O)₂NR
₃-(However, if l = 0 and Ar₂Is an unsubstituted phenyl group or
A group represented by (unless it is an unsubstituted cycloalkyl group)
Represents a group), 2) Formula 3:

[0015]

[Chemical 10] (In the formula 3, m is an integer of 0 to 2, and W is -NR.₃-(However,
R₉Is a linear alkyl group having 1 to 3 carbon atoms), io
C atom, -NHC (O)-(however, R₉Is a straight-chain alkyl having 1 to 3 carbon atoms
Group), -C (O) NH-, -CH₂O- (however, R₉Charcoal
(Except for straight-chain alkyl groups with a prime number of 1 to 3), -SO₂NH-,-
Represents C (O) O- or -OC (O)-, R₈And R₉Is an independent meth
Group, ethyl group, n-propyl group, which has 1 to 3 carbon atoms
Kill group, phenyl group, hydroxy-substituted phenyl group, sia
No-substituted phenyl group, nitro-substituted phenyl group, halogen unit
Substituted phenyl group, C₁-C₆Alkyl-substituted phenyl group, naphthy
Group, hydroxy-substituted naphthyl group, cyano-substituted naphthyl group
Group, nitro-substituted naphthyl group, halogen-substituted naphthyl group,
C₁-C₆Even if it is substituted with an alkyl-substituted naphthyl group, etc.
Good aryl group, or thienyl group, furyl group, pyrrolyl
Group, indolyl group, quinolyl group, piperidyl group, C₁-C₆
Alkyl-substituted thienyl group, C₁-C₆Alkyl-substituted furyl
Base, C₁-C₆Alkyl-substituted pyrrolyl group, C₁-C₆Alkyl substitution
Indolyl group, C₁-C ₆Alkyl-substituted quinolyl group, C₁-C₆A
Alkyl substituted piperidyl group, halogen substituted thienyl group, ha
Rogen-substituted furyl group, halogen-substituted pyrrolyl group, halogen
Group-substituted indolyl group, halogen-substituted quinolyl group, halogen
Optionally substituted hetero, such as a substituted piperidyl group
Represents a ring group) or 3) Formula 4:

[0016]

[Chemical 11] (In formula 4, R ₁₀ represents a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms (specifically, a methyl group, an ethyl group, an n-propyl group), and R ₁₁ represents a hydrogen atom or a carbon atom. Number 1 to 3 linear alkyl group (specifically, methyl group, ethyl group, n-propyl group), phenyl group, hydroxy-substituted phenyl group, cyano-substituted phenyl group, nitro-substituted phenyl group, halogen-substituted phenyl group, C ₁ -C ₆ alkyl-substituted phenyl group, naphthyl group, hydroxy-substituted naphthyl group, cyano-substituted naphthyl group, nitro-substituted naphthyl group, halogen-substituted naphthyl group,
Optionally substituted aryl group such as C ₁ -C ₆ alkyl-substituted naphthyl group, or thienyl group, furyl group, pyrrolyl group, indolyl group, quinolyl group, piperidyl group, C ₁ -C ₆
Alkyl-substituted thienyl group, C ₁ -C ₆ alkyl-substituted furyl group, C ₁ -C ₆ alkyl-substituted pyrrolyl group, C ₁ -C ₆ alkyl-substituted indolyl group, C ₁ -C ₆ alkyl-substituted quinolyl group, C ₁ -C ₆ Alkyl-substituted piperidyl group, halogen-substituted thienyl group, halogen-substituted furyl group, halogen-substituted pyrrolyl group, halogen-substituted indolyl group, halogen-substituted quinolyl group, halogen-substituted piperidyl group, etc. Represents a group represented by Examples of the compound of the present invention include the compounds shown in Tables 1 to 22.

[0017]

[Table 1]

[0018]

[Table 2]

[0019]

[Table 3]

[0020]

[Table 4]

[0021]

[Table 5]

[0022]

[Table 6]

[0023]

[Table 7]

[0024]

[Table 8]

[0025]

[Table 9]

[0026]

[Table 10]

[0027]

[Table 11]

[0028]

[Table 12]

[0029]

[Table 13]

[0030]

[Table 14]

[0031]

[Table 15]

[0032]

[Table 16]

[0033]

[Table 17]

[0034]

[Table 18]

[0035]

[Table 19]

[0036]

[Table 20]

[0037]

[Table 21]

[0038]

[Table 22] A method for producing a compound represented by Formula 1 (hereinafter, for example, "a compound represented by Formula 1 or the like" may be simply represented as "Formula 1" or the like) is shown below. It is not limited to them. Also, in various manufacturing methods,
The reaction conditions are appropriately selected from those described below.

When the cyclic nitrogen-containing derivative used in the present invention has one or more asymmetric carbon atoms, racemates, diastereomers and individual optical isomers may exist, but the present invention is All of them can be used. In the production method 1, A is -C (O) NR ₃ , R ₃ is a hydrogen atom, and B is
(I) At least one of the nitrogen atoms of D represented by the formula 2
Formula 6 in which five nitrogen atoms are bonded to A (N in the 7-membered ring indicates that another nitrogen may or may not be present), ( ii) Formula 7 represented by Formula 3 and (iii) Formula 8 represented by Formula 4 are represented by Formulas 5, 9, 10

[0040]

[Chemical 12]

[0041]

[Chemical 13] Respectively in a solvent such as dichloromethane or chloroform in the presence of a tertiary amine such as triethylamine or diisopropylethylamine, usually 0.5 to 2 equivalents of diphosgene, triphosgene, 1,1-carbonyldiimidazole, etc.

[0042]

[Chemical 14] It can be produced by reacting with. Equations 5, 9, 10 and Equation 11
The mixing ratio (molar ratio) with is not particularly limited, but is usually
It is about 1: 1 to 1: 2, and usually 1 at a temperature of about 0 to 50 ° C.
React for about 24 hours. The addition amount of the tertiary amine is not particularly limited, but usually diphosgene, triphosgene, 1,1-
It is about 1 to 4 equivalents to carbonyldiimidazole.

After reacting formula 11 with 4-nitrophenyl chloroformate or phenyl chloroformate in the presence of a base such as sodium hydrogen carbonate or a tertiary amine in a solvent such as acetonitrile or dichloromethane (first step) React with Formulas 5, 9 and 10 in the presence of tertiary amines such as triethylamine and diisopropylethylamine (second step)
Formulas 6, 7, and 8 can also be manufactured by. The base such as sodium hydrogen carbonate or tertiary amine used in the first step of the present production method is not particularly limited, but is usually about 1 to 4 equivalents relative to 4-nitrophenyl chloroformate or phenyl chloroformate. The addition amount of the tertiary amine used in the second step is not particularly limited, but is usually about 1 to 3 equivalents relative to Formula 11. First
The reaction temperature between the one-step formula 11 and 4-nitrophenyl chloroformate or phenyl chloroformate is not particularly limited, but is 0 ° C.
~ Room temperature, the reaction temperature of the second step is chloroformic acid 4
In the case of -nitrophenyl, it is usually about 0 to 50 ° C, and in the case of phenylchloroformate, it is about room temperature to heating under reflux temperature. In formula 5, V is a carbonyl group and formula 12:

[0044]

[Chemical 15] Formula 13 in which is represented by 1,4-diazepane:

[0045]

[Chemical 16] Can be manufactured by the following steps.

[0046]

[Chemical 17] (In the formula, P ₁ represents a protecting group for a nitrogen atom.) P _{1 in} Formula 14 represents a protecting group for a nitrogen atom, and the type of the protecting group and the introduction method thereof are, for example, Greene
And Wuts, Protective Groups in Organi
c Synthesis (3rd edition) ”. It may be appropriately used depending on these reaction conditions.

Step 1 is a step of condensing Formula 14 and Formula 15 or Formula 16. When Formula 15 is used, triethylamine, diisopropylamine or the like in a solvent such as tetrahydrofuran, dimethylformamide or dichloromethane is used.
It can be prepared by reacting Formula 14 and Formula 15 in the presence of a primary amine. The reactions of Formula 14 and Formula 15 are not particularly limited,
Usually, it can be carried out by reacting at a temperature of about 0 ° C. to room temperature for about 1 to 24 hours. The mixing ratio (molar ratio) of Formula 14 and Formula 15 is not particularly limited, but is usually about 1: 1 to 1: 2, and the addition amount of the tertiary amine is not particularly limited, but is usually relative to Formula 15. It is about 1 to 4 equivalents. Equation 14 and Equation
In the reaction of 16, dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris (dicyclopentylamino) phosphonium hexafluorophosphide salt (PyBop), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexanium Fluorophosphide salt (Bop), diphenylphosphoryl azide (DPP
A) and a condensing agent such as 1-ethyl-3- [3- (dimethylamino) propyl] carbodiimide (WSC) are used. The addition amount of these condensing agents is not particularly limited, but usually with respect to Formula 16
It is about 1 to 3 equivalents. Further, addition of an additive such as 1-hydroxybenzotriazole (HOBT) may be advantageous for the progress of the reaction.

Step 2 is a step of removing the nitrogen atom protecting group P ₁ . For its removal method, see "Protective Gro" above.
up in Organic Synthesis (3rd edition) ". It may be appropriately used depending on these reaction conditions. Equation 9
In the formula, R ₈ represents an optionally substituted aryl group or an optionally substituted heterocyclic group, W is —C (O) NH—, and R ₉ is a linear alkyl group having 1 to 3 carbon atoms, Formula 1 which is an optionally substituted aryl group or an optionally substituted heterocyclic group
8:

[0049]

[Chemical 18] Can be manufactured by the following steps.

[0050]

[Chemical 19] (In the formula, P ₂ represents a protecting group of a nitrogen atom.) P ₂ of the formula 19 represents a protecting group of a nitrogen atom, and the kind of the protecting group and the introduction method thereof are the same as those in the above-mentioned “Protective Groups”.
It may be appropriately used according to the reaction conditions described in “In Organic Synthesis (3rd edition)”.

Step 1 is usually accomplished by reacting Formula 19 with Formula 20 in the presence of an acid catalyst such as acetic acid, sulfuric acid or Lewis acid for 1 to 24 hours. The reaction temperature is not particularly limited, but is usually under ice cooling to about 100 ° C. The mixing ratio (molar ratio) of Formula 19 and Formula 20 is not particularly limited, but is usually 1: 1.
It is about 1:10. The amount of the acid used is not particularly limited, but is usually an excess amount (equivalent amount) with respect to Formula 19. Process
2 is the above-mentioned `` Protective Groups in Organic Synthesi
s (3rd edition) ”. Formula 11 can be manufactured by the following steps.

[0052]

[Chemical 20] (In the formula, L is halogen, methanesulfonyloxy, p-
A leaving group such as toluenesulfonyloxy, P ₃ represents a protecting group for a nitrogen atom. ) P _{3 in} Formula 22 represents a protecting group for a nitrogen atom, and the types of the protecting group and the method for introducing the protecting group are the same as those described in the above-mentioned “Protective Groups”.
It may be appropriately used according to the reaction conditions described in “In Organic Synthesis (3rd edition)”.

Step 1 is carried out by using formula 22 and formula 22 in the presence of a base such as potassium carbonate or sodium hydroxide in a solvent such as dimethylformamide, dimethylacetamide or acetonitrile.
By reacting 23 for about 1 to 24 hours, or
It can be produced by reacting with and then reducing the resulting Schiff base. The mixing ratio (molar ratio) of Formula 22 and Formula 23 is
Although not particularly limited, it is usually about 1: 1 to 1: 3, and the amount of the base used is not particularly limited, but is usually about 1 to 4 equivalents to the formula 23. The reaction temperature is not particularly limited, but is usually room temperature to heating under reflux. The formation of the Schiff base by the reaction of the formula 22 and the formula 24 is carried out by a titanium (IV) isopropoxide, titanium (IV) chloride, boron trifluoride-Lewis acid such as diethyl ether complex, p-toluenesulfonic acid, adipic acid, In the presence of an acid catalyst such as acetic acid or hydrochloric acid, or dehydration with molecular sieves or potassium hydroxide, or Dean-Stark
k) It is advantageous to use a trap to remove the water produced. The reaction temperature is appropriately set, but it is preferably room temperature to under reflux. Further, the reduction of the Schiff base is carried out by using a metal hydride complex (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, etc.),
Alternatively, it can be carried out by adding a reducing agent such as borane and heating from -20 ° C to reflux. Alternatively, in the presence or absence of an acid such as acetic acid or hydrochloric acid, a reducing catalyst (eg, palladium carbon, Raney nickel, etc.) is used, in a solvent such as methanol, ethanol, ethyl acetate, acetic acid or the like, from atmospheric pressure to 50 kg. /cm
It can also be carried out by reacting at a temperature of 0 to 100 ° C. under a hydrogen atmosphere of ² . Step 2 is the above-mentioned “Prote
It may be appropriately performed according to the reaction conditions described in “Ctive Groups in Organic Synthesis (3rd edition)”.

Formula 26 wherein B is Formula 2 and at least one of the nitrogen atoms of D is bonded to V:

[Chemical 21] (In the formula, X represents N or CH. The same applies hereinafter.) As the compound represented by the formula 27, amidation,
It can be synthesized by carrying out reactions such as alkylation, urea formation, sulfonamidation and the like.

[0055]

[Chemical formula 22] (In the formula, L is halogen, methanesulfonyloxy, p-
It represents a leaving group such as toluenesulfonyloxy. The same applies below. ) Amidation is performed by converting the starting compound 27 into a free carboxylic acid 28 or a reactive derivative thereof (for example, an acid halide, an acid azide, an active ester (for example, 1-hydroxybenzotriazole or N-
(Esters such as hydroxysuccinimide), symmetrical acid anhydrides, mixed acid anhydrides (eg, mixed acid anhydrides with isobutyl carbonic acid, ethyl carbonic acid, etc.) and the like. The reaction is carried out in an inert solvent such as dichloromethane, N, N-dimethylformamide or tetrahydrofuran under cooling to heating, preferably at -20 ° C to 60 ° C. It is advantageous for the reaction to proceed smoothly in the presence of a base (preferably triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine). is there. When using the free carboxylic acid 28, a condensing agent during the reaction,
For example, N, N'-dicyclohexylcarbodiimide, 1,1'-carbonyldiimidazole, N, N'-disuccinimidyl carbonate, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, or N, N ' It is preferable to use -bis (2-oxo-3-oxazolidinyl) phosphinic acid chloride or the like. Furthermore, it may be advantageous in the progress of the reaction to add an additive such as 1-hydroxybenzotriazole.

Alkylation is represented by the formula 29 in the starting compound 27 in the presence or absence of a base such as potassium carbonate or triethylamine in an inert solvent such as N, N-dimethylformamide or acetonitrile or without a solvent. It is carried out by reacting with a compound. In addition, raw material compound 27
Can be carried out by reacting with the corresponding aldehyde 30 to reduce the resulting Schiff base. in this case,
Schiff bases are produced in the presence of a Lewis acid such as titanium (IV) isopropoxide, titanium (IV) chloride, boron trifluoride-diethyl ether complex, etc., and an acid catalyst such as p-toluenesulfonic acid, adipic acid, acetic acid, hydrochloric acid, etc. Alternatively, it is advantageous to carry out dehydration with molecular sieves, potassium hydroxide or the like, or to remove water produced using a Dean-Stark trap. The reaction temperature is appropriately set, but it is preferably room temperature to under reflux.
In addition, the reduction of the Schiff base is carried out by adding a metal hydride complex (sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, etc.) or a reducing agent such as borane, and heating under reflux from -20 ° C. Can be done at. Alternatively, in the presence or absence of an acid such as acetic acid or hydrochloric acid, a reducing catalyst (eg, palladium carbon, Raney nickel, etc.) is used, in a solvent such as methanol, ethanol, ethyl acetate, acetic acid or the like, from atmospheric pressure to 50 kg. It can also be carried out by reacting at a temperature of 0 to 100 ° C. under a hydrogen atmosphere of / cm ² .

For the urea formation, the starting compounds 27 and 31 were used.
It can be carried out in the same manner as in the production method of the compounds of the above formulas 6, 7, and 8. Alternatively, it can be carried out by reacting the starting compound 27 with an isocyanate 32 prepared in-situ from carboxylic acid azide or the like. In the reaction, it is preferable to use the isocyanate 32 in an equal amount or an excess amount with respect to the compound 27.

Sulfonamidation can be carried out by reacting compound 27 with sulfonyl chloride 33. The reaction is carried out under almost the same conditions as in the amidation described above. In formula 1, A is -C (O)-, -C
(O) NR _3- , -NR ₃ C (O)-compounds represented by formula 34, 35, 36 are, for example, formula 37 and formula 38, formula 39 and formula 11, formula 41, respectively.
And a starting compound represented by Formula 38 can be synthesized by an amidation reaction similar to the production process of Formula 26.

[0059]

[Chemical formula 23] Formula 4 wherein A is -C (O) O-, -OC (O) NR _3- , -NR ₃ C (O) O-
The compounds represented by 1, 42 and 43 are, for example, the compounds of formula 37 and formula 4 respectively.
4, can be synthesized by carbamate reaction using the compounds represented by formula 45 and formula 11, and formula 40 and formula 44.

[0060]

[Chemical formula 24]

In this reaction, the amine derivative represented by the formula 37, formula 11, or formula 40 and the chlorocarbonic acid ester derivative represented by the formula 44, formula 45 are used in the same amount or in excess of one, and an organic compound inert to the reaction is used. Solvents such as pyridine, tetrahydrofuran,
It is carried out in a solvent such as dioxane, ether, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, N, N-dimethylformamide, ethyl acetate, acetonitrile and the like. The reaction temperature is appropriately selected depending on the type of reaction derivative. In some cases, addition of a base such as triethylamine, pyridine, picoline, dimethylaniline, potassium carbonate or sodium hydroxide may be advantageous in promoting the reaction. Pyridine can also serve as a solvent. Chlorocarbonic acid ester derivatives 44 and 45 are, for example, Comp.
rehensive Organic Functional Group Transformation,
According to the method described in 6 , 407, 1995, phosgene equivalents such as triphosgene and diphosgene can be used for synthesis.

In the formula 1, the compound represented by the formula 46 in which A is —C (═NR) NH— is a compound represented by Comprehensive Organic Functional Group
Transformation, 6 , 639, 1995 or J. Med. Chem,
41 , 271, 1998, the amine compounds 37 and 11 which are the starting compounds can be used for the production.

[0063]

[Chemical 25] (In the formula, R has the same meaning as the above R _5. ) In formula 1, A is —C (= CHNO ₂ ) NH— and B is formula 2, and at least one of the nitrogen atoms of D is The compound bound to A can be produced by using the amine compounds 37 and 11 as the starting compounds according to the method described in Pharmazie, 50 , 12, 1995 or US-5030738.

The reaction products obtained by the above-mentioned production methods are isolated and purified as various solvates such as free compounds, salts or hydrates thereof. The salt can be produced by subjecting it to ordinary salt-forming treatment. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization and various column chromatography.

Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. The optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography. The optical isomers are
A suitable optically active compound can also be manufactured as a raw material.

The pharmaceutically acceptable salt of the compound represented by the formula 1 includes inorganic acid salts such as hydrochloride, hydrobromide, sulfate, borate and phosphate, acetate, maleic acid. salt,
Organic acid salts such as fumarate, tartrate, succinate, malate, lactate, citrate, malonate, benzoate, paratoluenesulfonate and methanesulfonate,
Lysine, glycine, phenylalanine, asparagine,
Examples thereof include glutamate addition salts. Furthermore, the present invention also includes various hydrates and solvates of the compound of the present invention (Formula 1) and salts thereof, and polymorphic substances.

The cyclic nitrogen-containing derivative represented by the formula 1 or a pharmaceutically acceptable salt thereof inhibits the action of chemokine mediated by CCR3, as shown concretely in the Examples below. The cyclic nitrogen-containing derivative of the present invention or a pharmaceutically acceptable salt thereof is useful as a prophylactic and therapeutic drug for allergic diseases such as bronchial asthma, atopic dermatitis, allergic rhinitis and chronic sinusitis. In addition to this, it can be used as a prophylactic and therapeutic drug for various diseases associated with chemokines mediated by CCR3.

The compound represented by the formula 1 or a pharmaceutically acceptable salt thereof is orally or parenterally (eg transdermally) to a mammal as a powder or as a pharmaceutical composition in a suitable dosage form. Administration, intravenous administration, rectal administration, inhalation administration, etc.). Specific examples of the dosage form for administration include tablets, powders, pills, capsules, granules, syrups, solutions, injections, emulsions, suspensions and suppositories. Such a dosage form is produced by a method known per se, and contains various carriers usually used in the field of formulation. For example, excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations,
Examples include solubilizing agents, suspending agents, soothing agents, and the like. If necessary, antiseptics, antioxidants, coloring agents, sweeteners,
It is also possible to use additives such as adsorbents and wetting agents.

Examples of the excipient include lactose, D-mannitol, starch, sucrose, 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, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like. Examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, 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. As a solubilizing agent,
For example polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,
Examples thereof include cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. As the suspending agent, for example, stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride,
Examples thereof include surfactants such as glyceryl monostearate and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Examples of the tonicity agent include glucose, sodium chloride, D-sorbitol, D-mannitol and the like. Examples of the buffering agent include buffer solutions of phosphate, acetate, carbonate, citrate and the like. Examples of soothing agents include benzyl alcohol and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. As an antioxidant,
Examples thereof include sulfite and ascorbic acid.

The effective dose and frequency of administration of the compound represented by Formula 1 or a pharmaceutically acceptable salt thereof will vary depending on the administration form, age, weight of patient, nature or severity of symptoms to be treated, Usually, 1 to 1000 mg, preferably 1 to 300 mg per day for an adult can be administered once or in several divided doses.

Each dosage form may contain other therapeutically active ingredients, as long as it does not cause an unfavorable interaction with the compound of formula 1 or a salt thereof. For example, steroids, non-steroid anti-inflammatory agents, lipoxygenase inhibitors, leukotriene antagonists, bronchodilators, thromboxane synthesis inhibitors, thromboxane antagonists, histamine antagonists, histamine release inhibitors, platelet activating factor (PAF) Examples include antagonists, serotonin antagonists, adenosine receptor antagonists, adrenergic β stimulants, immunosuppressants, and immunomodulators.

[0072]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to the following examples. A method for synthesizing the raw material compounds is shown in Reference Example. Reference Example 1 4- [4- (4-chlorobenzyl) -1,4-diazepan-1-
Carbonyl] phenol (1)

[0073]

[Chemical formula 26]

1- (4-chlorobenzyl) -1,4-diazepane (1
70 mg), 4-hydroxybenzoic acid (104 mg) was dissolved in dichloromethane (4 ml), and Bop reagent (Aldrich, USA) (370 m
g) and diisopropylamine (0.5 ml) were added and the mixture was stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 5: 1) to give 274 mg of 4-.
[4- (4-chlorobenzyl) -1,4-diazepan-1-carbonyl]
Phenol was obtained (yield 100%). MS (m / z): 344 (M ⁺ ) IR (KBr): 3447, 1607, 1439, 1277, 1238, 1172, 1089,
847cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.00 (2H, m), 2.52-2.83
(4H, m), 3.43-3.81 (6H, m), 6.78 (2H, d, J = 6.0), 7.18
-7.32 (6H, m) Reference Example 2 4- (1,4-Diazepan-1-carbonyl) phenol
(2)

[0075]

[Chemical 27] To a solution of 4- [4- (4-chlorobenzyl) -1,4-diazepan-1-carbonyl] phenol (260 mg) in tetrahydrofuran (15 ml) was added acetic acid (1 ml), 10% palladium carbon (54 mg). In addition, the mixture was stirred under a hydrogen atmosphere overnight. After the palladium carbon was filtered off, the filtrate was concentrated. A 10% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate and then n-butanol. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is subjected to silica gel column chromatography (chloroform: methanol).
= 1: 1) to give 53 mg of 4- (1,4-diazepan-1-carbonyl) phenol (yield 32%). MS (m / z):
220 (M ⁺ ) IR (neat): 3421, 1617, 1420, 1278, 1171, 1051, 849,
768 cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.70-2.00 (2H, m), 2.80-3.12
(4H, m), 3.40-3.82 (4H, m), 6.75 (2H, d, J = 8.2), 7.22
(2H, d, J = 8.2) Reference Example 3 2- [4- (4-chlorobenzyl) -1,4-diazepan-1-
Carbonyl] phenol (3)

[0076]

[Chemical 28] A solution of 1- (4-chlorobenzyl) -1,4-diazepane (165 mg) and 2-hydroxybenzoic acid (105 mg) in dichloromethane (5 ml) was added with Bop reagent (360 mg) and diisopropylethylamine (0.5 mg).
ml) was added and the mixture was stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with chloroform. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane: ethanol = 5: 1) to obtain 191 mg of 2- [4- (4-chlorobenzyl) -1,4-diazepan-1-carbonyl] phenol ( Yield 75
%). MS (m / z): 344 (M ⁺ ) IR (KBr): 3162, 2941, 1737, 1613, 1455, 1372, 1244,
1088, 1046, 1016, 839, 755cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.94 (2H, quint, J = 6.4), 2.60-
2.80 (4H, m), 3.59 (2H, s), 3.69-3.80 (4H, m), 6.83
(1H, t, J = 7.4), 6.99 (1H, d, J = 8.2), 7.20-7.35 (6H, m) Reference Example 4 2- (1,4-diazepan-1-carbonyl) phenol
(Four)

[0077]

[Chemical 29] Acetic acid was added to a solution of 2- [4- (4-chlorobenzyl) -1,4-diazepan-1-carbonyl] phenol (174 mg) in ethanol (7 ml).
(1 ml) and 10% palladium carbon (38 mg) were added, and the mixture was stirred overnight under a hydrogen atmosphere. Palladium carbon was filtered off and the filtrate was concentrated. A 10% aqueous potassium carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate and n-butanol. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform: methanol = 3: 2) to obtain 85 mg of 2- (1,4-diazepan-1-carbonyl) phenol (yield 77%). MS (m / z): 220 (M ⁺ ) IR (KBr): 3437, 3257, 2927, 1619, 1472, 1449, 1370,
1292, 1268, 1244, 1223, 1121, 1034, 929, 768cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.91 (2H, quint, J = 5.6), 2.98
(2H, t, J = 5.5), 3.06 (2H, t, J = 6.3), 3.60 (2H, m), 3.73
(2H, t, J = 5.8), 6.87 (1H, t, J = 7.4), 6.92 (1H, d, J = 8.
0), 7.26-7.32 (2H, m) Reference Example 5 1- (2-phenylacetyl) -1,4-diazepane (5)

[0078]

[Chemical 30] 1,4-Diazepane (960 mg) in tetrahydrofuran (40 ml)
Phenylacetyl chloride (0.45 ml) and diisopropylethylamine (1.2 ml) were added to the solution, and the mixture was stirred at room temperature overnight. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amines (ethyl acetate: ethanol = 6: 1) to yield 445 m.
g of 1- (2-phenylacetyl) -1,4-diazepane was obtained
(Yield 60%). MS (m / z): 218 (M ⁺ ) IR (KBr): 3458, 2935, 1639, 1456, 1370, 1145, 1031,
728, 698cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.60-1.81 (2H, m), 2.72-2.79
(3H, m), 2.88 (1H, t, J = 5.3), 3.43-3.70 (4H, m), 3.70
(2H, s), 7.18-7.32 (5H, m) Reference Example 6 N- [1- (4-chlorobenzyl) -4-phenylpiperidin-4-yl] benzamide (6)

[0079]

[Chemical 31] 1- (4-chlorobenzyl) -4-phenylpiperidin-4-ol
(627 mg) was dissolved in benzonitrile (4 ml), acetic acid (0.6 ml) and sulfuric acid (0.6 ml) were added under ice cooling, and the mixture was stirred at room temperature overnight.
A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3: 1) to obtain 673 mg of N- [1- (4-chlorobenzyl) -4-phenylpiperidin-4-yl] benzamide ( Yield 80%). MS (m / z): 404 (M ⁺ ) IR (neat): 3333, 3060, 2937, 2815, 1644, 1526, 1489,
1306, 1128, 1107, 999, 800, 761, 694cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 2.19-2.27 (2H, m), 2.38 (2H,
t, J = 11.6), 2.50 (2H, d, J = 11.6), 2.82 (2H, d, J = 11.5),
3.52 (2H, s), 6.21 (1H, s), 7.22-7.35 (7H, m), 7.42-
7.52 (5H, m), 7.73-7.75 (2H, m) Reference Example 7 N- (4-phenylpiperidin-4-yl) benzamide (7)

[0080]

[Chemical 32] N- [1- (4-chlorobenzyl) -4-phenylpiperidine-4-i
Ru] benzamide (664 mg) in ethanol (30 ml) and tetra
Dissolve in hydrofuran (10 ml), add acetic acid (1 ml), 10% para.
Adddium carbon (51 mg) and stir overnight under hydrogen atmosphere.
I stirred. Palladium carbon was filtered off and the filtrate was concentrated.
It was To the residue was added 10% aqueous sodium carbonate solution,
Extracted with rum. Combine the organic layers and wash with saturated saline.
The extract was dried over anhydrous sodium sulfate and then concentrated. Residue
Chromatrex column chromatography for amines
280 m when purified with (ethyl acetate: ethanol = 6: 1)
g of N- (4-phenylpiperidin-4-yl) benzamide was obtained.
(Yield 61%). MS (m / z): 280 (M⁺) IR (KBr): 3320, 2945, 1645, 1533, 1491, 1443, 1298,
1140, 1026, 757, 698cm ^-1 NMR (300 MHz, CDCl₃) δ: 2.07-2.20 (2H, m), 2.51 (2H, m)
d, J = 11.8), 2.97-3.05 (4H, m), 6.29 (1H, s), 7.20-7.2
8 (2H, m), 7.34 (2H, t, J = 7.1), 7.41-7.56 (4H, m), 7.7
8-7.81 (2H, m)Reference example 8   tert-butyl 4- (2-acetoxybenzyl) -1,4-
Diazepan-1-carboxylate (8)

[0081]

[Chemical 33] tert-Butyl 1,4-diazepan-1-carboxylate (336m
g) in chloroform (5 ml) in diisopropylethylamine (0.5 ml), 2- (chloromethyl) phenylacetate (31
0 mg) was added and the mixture was stirred at room temperature overnight. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give 509 mg of tert-butyl 4- (2-acetoxybenzyl) -1,
4-Diazepane carboxylate was obtained (yield 67%).
MS (m / z): 348 (M ⁺ ) IR (neat): 2934, 1768, 1696, 1457, 1416, 1367, 121
0, 1176, 1012, 755cm ^-1 NMR (300MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.75-1.90 (2H, m),
2.29 (3H, s), 2.24-2.81 (4H, m), 3.37-3.59 (4H, m), 3.52
(2H, s), 7.01 (1H, d, J = 7.9), 7.20 (1H, d, J = 7.7), 7.26 (1
H, t, J = 7.6), 7.41 (1H, d, J = 7.2) Reference Example 9 1- (2-hydroxybenzyl) -1,4-diazepane
(9)

[0082]

[Chemical 34] tert-Butyl 4- (2-acetoxybenzyl) -1,4-diazepan-1-carboxylate (255 mg) in dichloromethane (6 ml)
Trifluoroacetic acid (1.1 ml) was added to the solution, and the mixture was stirred at room temperature overnight. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amine (ethyl acetate: hexane = 5: 1) to give 249 mg of
1- (2-hydroxybenzyl) -1,4-diazepane was obtained
(Yield 69%). MS (m / z): 206 (M ⁺ ) IR (neat): 3348, 2934, 2830, 1614, 1591, 1479, 145
8, 1412, 1259, 1153, 1089, 1036, 848, 757cm ^-1 NMR (300MHz, CDCl ₃ ) δ: 1.82 (2H, quint, J = 5.8), 2.74 (2
H, t, J = 5.0), 2.80 (2H, t, J = 6.0), 2.93-3.00 (4H, m), 3.8
2 (2H, s), 6.77 (1H, t, J = 7.4), 6.82 (1H, d, J = 7.2), 6.96 (1
H, d, J = 7.4), 7.17 (1H, t, J = 7.2) Reference Example 10 1-[(6-Fluoronaphthalen-2-yl) methyl]-
4-hydroxypiperidine (10)

[0083]

[Chemical 35] 2-Bromomethyl-6-fluoronaphthalene and potassium carbonate were added to a mixture of 4-hydroxypiperidine, acetonitrile and DMF, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction was post-treated and purified by silica gel column chromatography to obtain 1-[(6-fluoronaphthalen-2-yl) methyl] -4-hydroxypiperidine as pale brown plate crystals. FAB-MS: 260 (M + H) ⁺ . Reference Example 11 Chloroformic acid [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester hydrochloride (11)

[0084]

[Chemical 36] To a solution of 1-[(6-fluoronaphthalen-2-yl) methyl] -4-hydroxypiperidine in acetonitrile was added a suspension of triphosgene in acetonitrile under ice cooling, and the mixture was stirred at 0 ° C for 30
The mixture was stirred for 24 minutes at room temperature for 24 hours. The crystals precipitated in the reaction solution were collected by filtration and washed with diethyl ether to give chloroformic acid [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester hydrochloride colorless. Obtained as powdery crystals. EI-MS: 321 M ⁺ . Reference Example 12 1,4-diazepane-1,4-dicarboxylic acid 1-tert-
Butyl ester 4- [1-[(6-fluoronaphthalen-2-yl)
Methyl] piperidin-4-yl] ester (12)

[0085]

[Chemical 37] 1,4-diazepan-1-carboxylic acid tert-butyl ester,
A mixture of triethylamine and THF was cooled to -30 ° C, chloroformic acid [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester hydrochloride and THF were sequentially added, and the mixture was stirred at room temperature for 22 Stir for hours. After the reaction is post-treated and purified by silica gel column chromatography, 1,
4-Diazepane-1,4-dicarboxylic acid 1-tert-butyl ester 4- [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester was obtained as a light brown oil. FA
B-MS: 486 (M + H) ⁺ . Reference Example 13 1,4-diazepan-1-carboxylic acid [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester dihydrochloride (13)

[0086]

[Chemical 38] 1,4-Diazepane-1,4-dicarboxylic acid 1-tert-butyl ester 4- [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester in ethyl acetate 4M hydrogen chloride-ethyl acetate solution was added under cooling, and at room temperature for 2 hours 3
It was stirred for 0 minutes. By concentrating the reaction solution under reduced pressure, 1,4-
Diazepan-1-carboxylic acid [1-[(6-fluoronaphthalene-
2-yl) Methyl] piperidin-4-yl] ester dihydrochloride was obtained as a pale brown solid. EI-MS: 385 M ⁺ . Reference Example 14 4-aminomethyl-1-[(6-fluoronaphthalene-
2-yl) methyl] piperidine (14)

[0087]

[Chemical Formula 39] 2-Bromomethyl-6-fluoronaphthalene and potassium carbonate were added to an acetonitrile solution of 4-aminomethylpiperidine, and the mixture was stirred at room temperature for 4 hours and 30 minutes. The reaction was post-treated and purified by silica gel column chromatography to give 4-aminomethyl-1-[(6-fluoronaphthalen-2-yl) methyl] piperidine as a pale brown oil. EI-MS: 272 M ⁺ . Reference Example 15 [1-[(6-Fluoronaphthalen-2-yl) methyl]
Piperidin-4-yl] methylcarbamic acid phenyl ester (15)

[0088]

[Chemical 40] To a mixture of 4-aminomethyl-1-[(6-fluoronaphthalen-2-yl) methyl] piperidine, triethylamine and THF, a THF solution of phenyl chloroformate was added under ice cooling and stirred at room temperature for 3 days. . The reaction was post-treated and purified by silica gel column chromatography to give [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methylcarbamic acid phenyl ester as a pale brown powdery crystal. Obtained. FAB-MS: 393 (M + H) ⁺ . Reference Example 16 4-[([1-[(6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) carbamoyl] -1,4-diazepan-1-carboxylic acid tert-butyl ester (16 )

[0089]

[Chemical 41] [1-[(6-Fluoronaphthalen-2-yl) methyl] piperidine
-4-yl] methylcarbamic acid phenyl ester in acetonitrile solution, 1,4-diazepan-1-carboxylic acid tert-
Butyl ester, 1,8-diazabicyclo [5.4.0] undec-
Add a mixture of 7-ene and acetonitrile and add 1 at room temperature.
Stir for 9 hours. The reaction was post-treated and purified by silica gel column chromatography to give 4-[([1-[(6
-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) carbamoyl] -1,4-diazepan-1-carboxylic acid tert-butyl ester was obtained as a slightly brown foam. FAB
-MS: 499 (M + H) ⁺ . Reference Example 17 N-([1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) -1,4-diazepan-1-carboxamide dihydrochloride (17)

[0090]

[Chemical 42] 4-[([1-[(6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) carbamoyl] -1,4-diazepan-1-carboxylic acid in the same manner as in Reference Example 13 From tert-butyl ester, N-([1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) -1,4-diazepane
-1-Carboxamide dihydrochloride was obtained as a light brown solid. E
I-MS: 398 M ⁺ . Reference Example 18 Azepan-4-one hydrochloride (18)

[0091]

[Chemical 43] Azepan-4-one hydrochloride was prepared according to the method described by Synthetic Communications, 22: 1249, 1992. FAB-MS:
114 (M + H) ⁺ . Reference Example 19 2-[(4-hydroxyazepan-1-yl) methyl]
Benzonitrile (19)

[0092]

[Chemical 44] 2-Bromomethylbenzonitrile and potassium carbonate were added to a DMF solution of azepan-4-one hydrochloride, and the mixture was stirred at room temperature for 15 hours. The crude product obtained by post-treating the reaction was dissolved in methanol, sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction was post-treated and purified by silica gel column chromatography to give 2-[(4-hydroxyazepan-1-yl) methyl] benzonitrile as a pale brown oil. FAB-MS: 231 (M + H)
⁺ . Reference Example 20 (exo-8-azabicyclo [3.2.1] octane-3-yl) carbamic acid tert-butyl ester monohydrochloride (20)

[0093]

[Chemical formula 45] Tert-Butyl (exo-8-benzyl-8-azabicyclo [3.2.1] octane-3-yl) carbamate prepared according to the method described in Eur. J. Med. Chem. Chim. Ther., 19: 105, 1984. After dissolving the ester in a mixed solution of ethanol and methanol, palladium hydroxide was added, and catalytic hydrogen reduction was performed in a hydrogen atmosphere. By post-treating the reaction (exo-8
-Azabicyclo [3.2.1] octane-3-yl) carbamic acid te
rt-Butyl ester monohydrochloride was obtained as a colorless solid. FAB
-MS: 227 (M + H) ⁺ . Reference Example 21 2-Bromomethyl-6-fluoronaphthalene (21)

[0094]

[Chemical formula 46] 2-Bromomethyl-6-fluoronaphthalene was produced according to the method described in EP-0351194 using commercially available 2-fluoro-6-methylnaphthalene as a raw material. Reference Example 22 [exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] carbamic acid tert-butyl ester (22)

[0095]

[Chemical 47] (exo-8-Azabicyclo [3.2.1] octane-3-yl) carbamic acid tert-butyl ester monohydrochloride was added to acetonitrile and D
It was dissolved in a mixed solution of MF, 2-bromomethyl-6-fluoronaphthalene and potassium carbonate were added, and the mixture was stirred at room temperature for 20 hours. By post-treating the reaction, [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.
1] Octane-3-yl] carbamic acid tert-butyl ester was obtained as a pale yellow oil. FAB-MS: 385 (M + H) ⁺ . Reference Example 23 exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine dihydrochloride (23)

[0096]

[Chemical 48] [exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] carbamic acid tert-
Exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-by treatment of butyl ester with 4M hydrogen chloride-ethyl acetate solution in ethyl acetate Ilamine dihydrochloride was obtained as a colorless solid. FAB-M
S: 285 (M + H) ⁺ . Reference Example 24 4-([exo-8-[(6-fluoronaphthalen-2-yl)
Methyl] -8-azabicyclo [3.2.1] octane-3-yl] carbamoyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester (24)

[0097]

[Chemical 49] exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine (4.00g), sodium hydrogen carbonate (2.37g), chloroform-4-nitro Phenyl
(2.98 g) was added to dichloromethane (120 ml), and the mixture was stirred at room temperature for 2 hours. After cooling with ice, 1,4-diazepan-1-carboxylic acid tert-butyl ester (3.6 ml) and triethylamine were added to the reaction solution.
(3.9 ml) was added, and the mixture was stirred at room temperature for 3 hours. Aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatographic column chromatography for amines (hexane: ethyl acetate = 1: 1) to give 6.98 g of 4-([exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8- Azabicyclo [3.2.1] octane-3-yl] carbamoyl) -1,4-diazepan-1-carboxylic acid tert-butyl ester was obtained (yield 97%). MS (m / z): 510 (M ⁺ ) IR (KBr): 2930, 1688, 1626, 1533, 1480, 1416, 1365,
1246, 1169cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.45 (9H, s), 1.40-1.93 (8H, m),
2.05-2.15 (2H, m), 3.20-3.55 (10H, m), 3.66 (2H, s), 4.
00-4.16 (2H, m), 7.25-7.28 (1H, m), 7.43 (1H, dd, J = 10.2,
2.4), 7.57 (1H, d, J = 8.7), 7.72-7.82 (3H, m) Reference Example 25 N- [exo-8-[(6-fluoronaphthalen-2-yl)
Methyl] -8-azabicyclo [3.2.1] octane-3-yl] -1,4-
Diazepan-1-carboxamide (25)

[0098]

[Chemical 50] 4-([exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-
Azabicyclo [3.2.1] octane-3-yl] carbamoyl)-
1,4-Diazepan-1-carboxylic acid tert-butyl ester (6.9
7 g) was dissolved in dichloromethane (30 ml), trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 90 minutes. The reaction solution was concentrated under reduced pressure, 10% aqueous potassium carbonate solution was added, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 5.24 g of N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl. ] -1,4-Diazepan-1-carboxamide was obtained (94% yield). MS (m / z): 410 (M ⁺ ) IR (KBr): 2931, 1618, 1543, 1405, 1307, 1227, 1139c
m ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.43-2.15 (10H, m), 2.82-2.95
(4H, m), 3.22-3.27 (2H, m), 3.40-3.46 (4H, m), 3.66 (2H,
s), 4.00-4.15 (2H, m), 7.21-7.28 (1H, m), 7.43 (1H, dd, J
= 10.2, 2.7), 7.73 (1H, d, J = 8.1), 7.72-7.81 (3H, m) Example 1 N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8 -Azabicyclo [3.2.1] octane-3-yl] -4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] decan-8-ylcarboxamide (26)

[0099]

[Chemical 51] Exo-8-[(6-fluoronaphthalene-2-
(Iyl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine (163.0 mg) was dissolved in chloroform (8 ml), 4-nitrophenyl chloroformate (124 mg), sodium hydrogen carbonate (80 mg) Was added and stirred at room temperature for 1 hour. In the reaction solution
1-phenyl-1,3,8-triazaspiro [4,5] decan-4-one
(133 mg) and a solution of triethylamine (0.25 ml) in chloroform (10 ml) were added, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amines (ethyl acetate: ethanol = 25: 1) to give 305 mg of N- [exo.
-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4-oxo-1-phenyl-
1,3,8-Triazaspiro [4.5] decan-8-ylcarboxamide was obtained (yield 98%). MS (m / z): 541 (M ⁺ ) IR (KBr): 3325, 2926, 1709, 1620, 1540, 1507, 1377,
1244, 870, 746cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.54-2.12 (10H, m), 2.55 (2H,
dt, J = 12.6,3.5), 3.30 (2H, s), 3.61 (2H, dt, J = 12.6,2.
5), 3.69 (2H, s), 3.61 (1H, m), 4.40 (1H, d, J = 7.7),
4.71 (2H, s), 6.32 (1H, s), 6.70 (2H, d, J = 8.0), 6.84
(1H, t, J = 7.4), 7.21-7.27 (3H, m), 7.45 (1H, dd, J = 9.5,
2.2), 7.59 (1H, d, J = 9.5), 7.73-7.78 (3H, m) Example 2 N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [ 3.2.1] Octane-3-yl] -3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [4.5] decane-8-carboxamide (27)

[0100]

[Chemical 52] Exo-8-[(6-fluoronaphthalene-2-
Iyl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine (45 mg) was dissolved in dichloromethane (3.5 ml), and 4-nitrophenyl chloroformate (36 mg) and sodium hydrogen carbonate (33 mg) were dissolved. Was added and stirred at room temperature for 1 hour. 3-in the reaction solution
A solution of methyl-1-phenyl-1,3,8-triazaspiro [4,5] -decan-4-one (37 mg) and triethylamine (0.10 ml) in chloroform (5 ml) was added, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amine (ethyl acetate: hexane = 5: 2) to give 60 mg of N- [exo-8
-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro [ 4.5] Decan-8-carboxamide was obtained (68% yield). MS (m / z): 555 (M ⁺ ) IR (KBr): 3303, 2953, 1705, 1619, 1548, 1505, 1374,
1286, 1245, 1052, 874, 747cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.51-2.17 (8H, m), 2.56 (2H, d
t, J = 13.4,4.4), 3.01 (2H, s), 3.27 (2H, s), 3.62-3.85
(6H, m), 4.13 (1H, m), 4.32 (1H, d, J = 8.8), 4.68 (2H,
s), 6.7 (2H, d, J = 8.0), 6.82 (1H, t, J = 7.4), 7.20-7.26
(3H, m), 7.42 (1H, dd, J = 9.9,3.0), 7.57 (1H, d, J = 8.
2), 7.72-7.77 (3H, m) Example 3 N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl]- 4- (4-
Hydroxybenzoyl) -1,4-diazepan-1-carboxamide (28)

[0101]

[Chemical 53] Exo-8-[(6-fluoronaphthalene-2-
(Iyl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine (50 mg) dissolved in chloroform (3 ml), 4-nitrophenyl chloroformate (38 mg), sodium hydrogen carbonate
(30 mg) was added, and the mixture was stirred at room temperature for 1 hr. 4-in the reaction solution
A solution of (1,4-diazepan-1-carbonyl) phenol (46 mg) and triethylamine (0.1 ml) in chloroform (3 ml) was added, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: ethanol = 1
After purification with 0: 1), 69 mg of N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- ( 4-Hydroxybenzoyl) -1,4-diazepan-1-carboxamide was obtained (74% yield). MS (m /
z): 530 (M ⁺ ) IR (KBr): 3375, 2947, 1612, 1535, 1478, 1429, 1273,
1243, 1170, 847, 765cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.22-2.10 (10H, m), 3.24 (2H,
s), 3.35-4.38 (8H, m), 3.65 (2H, s), 6.73 (2H, d, J = 8.
5), 7.18 (2H, d, J = 8.5), 7.22-7.24 (1H, m), 7.42 (1H,
d, J = 9.9), 7.56 (1H, d, J = 8.5), 7.72-7.80 (3H, m) Example 4 N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl]- 8-Azabicyclo [3.2.1] octane-3-yl] -4- (2-
Hydroxybenzoyl) -1,4-diazepan-1-carboxamide (29)

[0102]

[Chemical 54] Exo-8-[(6-fluoronaphthalene-2-
(Iyl) methyl] -8-azabicyclo [3.2.1] octane-3-ylamine (38 mg) was dissolved in chloroform (3 ml), 4-nitrophenyl chloroformate (30 mg), sodium hydrogen carbonate
(20 mg) was added, and the mixture was stirred at room temperature for 1 hr. 2-in the reaction solution
A chloroform (4 ml) solution of (1,4-diazepan-1-carbonyl) phenol (30 mg) and triethylamine (0.1 ml) was added, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: ethanol = 1
After purification with 0: 1), 70 mg of N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- ( 2-Hydroxybenzoyl) -1,4-diazepan-1-carboxamide was obtained (yield 100%). MS (m /
z): 530 (M ⁺ ) IR (KBr): 3437, 2944, 1736, 1618, 1538, 1480, 1449,
1299, 758 cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.41-2.20 (8H, m), 3.24 (2H,
s), 2.48 (2H, m), 3.56 (2H, t, J = 5.8), 3.66 (2H, s),
3.68 (2H, t, J = 6.0), 3.81 (2H, t, J = 6.0), 4.04 (1H, m),
6.85 (1H, t, J = 7.7), 6.98 (1H, d, J = 8.5), 7.21-7.33
(3H, m), 7.42 (1H, dd, J = 10.1,2.4), 7.57 (1H, d, J = 9.
3), 7.72-7.81 (3H, m) Example 5 N- [1-[(6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] -4- (2-phenylacetyl) -1, Four-
Diazepan-1-carboxamide (30)

[0103]

[Chemical 55] 1-[(6-Fluoronaphthalen-2-yl) under argon atmosphere
Methyl] piperidin-4-ylamine (56 mg) was dissolved in chloroform (3 ml) and 4-nitrophenyl chloroformate (37
mg) and sodium hydrogen carbonate (30 mg) were added, and the mixture was stirred at room temperature for 1 hr. A solution of 1- (2-phenylacetyl) -1,4-diazepane (48 mg) and triethylamine (0.1 ml) in chloroform (3 ml) was added to the reaction solution, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amine (ethyl acetate: hexane = 3: 1) to give 67 mg of N- [1-[(6-
Fluoronaphthalene-2-yl) methyl] piperidin-4-yl] -4- (2-phenylacetyl) -1,4-diazepan-1-carboxamide was obtained (yield 62%). MS (m / z): 502 (M ⁺ ) IR (KBr): 3331, 2924, 1638, 1618, 1533, 1482, 1456,
1229, 1145, 1081, 873, 729cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.30-1.70 (4H, m), 1.86-1.96
(2H, m), 2.16 (2H, t, J = 10.7), 2.83 (2H, d, J = 11.0), 3.
22 (2H, q, J = 7.4), 3.41-3.54 (4H, m), 3.62 (2H, s), 3.
67-3.73 (4H, m), 4.18 (1H, m), 7.21-7.33 (6H, m), 7.4
2 (1H, dd, J = 9.9,2.5), 7.50 (1H, d, J = 8.0), 7.72-7.81
(3H, m) Example 6 4-Benzoylamino-N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4 -Phenylpiperidine-1-carboxamide (31)

[0104]

[Chemical 56] Exo-8-[(6-fluoronaphthalene-2-
(4) Nitromethyl chloroformate (47 mg) and sodium hydrogen carbonate (80 mg) in a solution of (3 ml) in dichloromethane (3 ml).
mg) was added and the mixture was stirred at room temperature for 1 hour. A solution of N- (4-phenylpiperidin-4-yl) benzamide (60 mg) and triethylamine (0.1 ml) in chloroform (4 ml) was added to the reaction solution, and the mixture was further stirred overnight. Water and 10% aqueous potassium carbonate solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: ethanol = 25:
Purified in 1), 94 mg of 4-benzoylamino-N- [exo-
8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4-phenylpiperidine-1
-Carboxamide was obtained (74% yield). MS (m / z): 59
0 (M ⁺ ) IR (KBr): 3338, 2929, 1647, 1614, 1538, 1245, 1216,
1139, 870, 699cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.45-2.20 (11H, m), 2.58 (2H,
d, J = 13.5), 3.15-3.24 (3H, m), 3.67 (2H, s), 3.83 (2
H, d, J = 13.6), 4.08 (1H, m), 4.31 (1H, d, J = 8.0), 6.27
(1H, s), 7.23-7.81 (16H, m) Example 7 N- [1-[(6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] -4- (2-hydroxybenzyl) -1,4
-Diazepan-1-carboxamide (32)

[0105]

[Chemical 57] 1-[(6-Fluoro-2-naphthyl) methyl] under argon flow
Piperidin-4-ylamine (68 mg) was added to chloroform (3 m
l), the solution was added with 4-nitrophenyl chloroformate (57 mg) and sodium hydrogen carbonate (44 mg), and the mixture was stirred at room temperature for 1 hour. A chloroform (3 ml) solution of 1- (2-hydroxybenzyl) -1,4-diazepane (65 mg) and triethylamine (0.1 ml) was added to the reaction solution, and the mixture was further stirred overnight. 10 in the reaction solution
% Aqueous potassium carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by Chromatolex column chromatography for amine (ethyl acetate: hexane = 3: 1) to give 79 mg of N- [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl]-. 4- (2-Hydroxybenzyl) -1,4-diazepan-1-carboxamide was obtained. (Yield 61%). MS (m / z): 490 (M ⁺ ) IR (neat): 3384, 1614, 1547, 1462, 1368, 1258, 984,
763 cm ^-1 NMR (300 MHz, CDCl ₃ ) δ: 1.30-2.00 (8H, m), 2.17 (2H, t, J =
12.4), 2.66-2.90 (4H, m), 3.45 (2H, t, J = 6.0), 3.57 (2H,
m), 3.63 (2H, s), 3.73 (1H, m), 3.78 (2H, s), 6.76-6.91
(2H, m), 6.82 (1H, d, J = 10.0), 7.18-7.24 (2H, m), 7.44 (1
H, m), 7.51 (1H, d, J = 8.6), 7.72-7.81 (3H, m) Example 8 4- (2-cyanobenzyl) -1,4-diazepan-1-carboxylic acid [1- [ (6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester (33)

[0106]

[Chemical 58] 1,4-Diazepan-1-carboxylic acid [1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] ester dihydrochloride 217 mg, 2-bromomethylbenzonitrile 82 mg, potassium carbonate 170 mg and A mixture of 2 ml of acetonitrile was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, 30 ml of ethyl acetate was added to the residue, and the mixture was washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (methanol / chloroform = 2/98) to give 4- (2-cyanobenzyl) -1,4-diazepan-1-carboxylic acid [1-[(6-fluoro 176 mg of naphthalen-2-yl) methyl] piperidin-4-yl] ester was obtained as a pale yellow oil. FAB-MS 501 (M + H) ⁺ NMR (CDCl ₃ ) δ: 3.64 (2H, s), 3.80 (2H, s), 4.74-4.
80 (1H, m) Example 9 4- (2-cyanobenzyl) -N-([1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl)
-1,4-diazepan-1-carboxamide (34)

[0107]

[Chemical 59] N-([1-[(6-Fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) -1,4-in the same manner as in Example 8.
From 221 mg of diazepan-1-carboxamide dihydrochloride, 4- (2
-Cyanobenzyl) -N-([1-[(6-fluoronaphthalen-2-yl) methyl] piperidin-4-yl] methyl) -1,4-diazepane
112 mg of 1-carboxamide was obtained as a colorless oil. FAB-
MS 514 (M + H) ⁺ NMR (CDCl ₃ ) δ: 3.63 (2H, s), 3.79 (2H, s), 7.64 (1
H, d, J = 8.0 Hz) Example 10 (±)-[exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] carbamine Acid [1- (2-cyanobenzyl) azepan-4-yl] ester (35)

[0108]

[Chemical 60] To a mixture of 2-231 (2-hydroxyazepan-1-yl) methyl] benzonitrile (231 mg) and acetonitrile (2 ml) was added a mixture of carbonic acid bis (trichloromethyl) ester (152 mg) and acetonitrile (2 ml) under ice-cooling. Stir for hours.
The residue obtained by concentration under reduced pressure was dissolved in 10 ml of THF, and under ice cooling, exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-
Azabicyclo [3.2.1] octan-3-ylamine dihydrochloride 37
6 mg and 0.49 ml of triethylamine were added, and the mixture was stirred at room temperature for 4 hours. The residue obtained by concentrating the reaction solution was dissolved in chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the resulting residue was subjected to silica gel column chromatography (methanol / chloroform = 1/99).
~ 2/98) to give (±)-[exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.
2.1] Octane-3-yl] carbamic acid [1- (2-cyanobenzyl) azepan-4-yl] ester 260 mg was obtained as a pale yellow oil. FAB-MS: 541 (M + H) ⁺ NMR (CDCl ₃ ) δ: 3.68 (2H, s), 3.80 (2H, s), 7.64 (1
H, d, J = 7.8 Hz) Example 11 N- [exo-8-[(6-fluoronaphthalen-2-yl)
Methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- (1
-Phenylcyclopropanecarbonyl) -1,4-diazepane-
1-carboxamide (36)

[0109]

[Chemical formula 61] Under an argon atmosphere, 1-phenyl-1-cyclopropanecarboxylic acid (49 mg) was dissolved in dichloromethane (4 ml), oxalyl chloride (0.03 ml) was added, and the mixture was stirred at room temperature for 4 hours.
The reaction solution was concentrated, and the residue was diluted with dichloromethane (4 ml) and N-
[exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -1,4-diazepan-1
-Carboxamide (80 mg), diisopropylethylamine
(0.3 ml) was added and stirred overnight. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: hexane = 3:
Purified in 1), 105 mg of N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- (1-phenyl Cyclopropanecarbonyl)-
1,4-diazepan-1-carboxamide was obtained. (Yield 63
%). MS (m / z): 555 ((M + 1) ⁺ ) IR (neat): 3463, 3364, 2947, 1622, 1532, 1481, 142
6, 1246, 700cm ^-1 NMR (300MHz, CDCl ₃ ) δ: 1.13 (2H, s), 1.19-2.10 (13H, m),
2.87 (1H, m), 3.14 (1H, t, J = 7.0), 3.19 (2H, s), 3.41 (1
H, m), 3.38-3.51 (4H, m), 3.58-3.70 (2H, m), 3.90-4.11
(2H, m), 7.18-7.26 (6H, m), 7.39 (1H, dd, J = 9.6,2.3), 7.
53 (1H, d, J = 9.1), 7.68-7.77 (3H, m) Example 12 N- [exo-8-[(6-fluoronaphthalen-2-yl)
Methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- (1
-Phenylcyclopentanecarbonyl) -1,4-diazepane-
1-carboxamide (37)

[0110]

[Chemical formula 62] Under an argon atmosphere, 1-phenyl-1-cyclopentanecarboxylic acid (56 mg) was dissolved in dichloromethane (4 ml), oxalyl chloride (0.03 ml) was added, and the mixture was stirred at room temperature for 4 hours.
The reaction solution was concentrated, and the residue was diluted with dichloromethane (4 ml) and N-
[exo-8-[(6-Fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -1,4-diazepan-1
-Carboxamide (80 mg), diisopropylethylamine
(0.4 ml) was added and stirred overnight. A 10% aqueous potassium carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue is chromatolex column chromatography for amine (ethyl acetate: hexane = 3:
Purified in 1), 118 mg of N- [exo-8-[(6-fluoronaphthalen-2-yl) methyl] -8-azabicyclo [3.2.1] octane-3-yl] -4- (1-phenyl Cyclopentanecarbonyl)-
1,4-diazepan-1-carboxamide was obtained. (Yield 69
%). MS (m / z): 583 ((M + 1) ⁺ ) IR (neat): 3363, 2951, 1621, 1531, 1617, 1478, 122
9, 869, 700cm ^-1 NMR (300MHz, CDCl ₃ ) δ: 0.91-2.13 (16H, m), 2.33 (2H, br
s), 2.53 (1H, brs), 3.02-3.21 (3H, m), 3.19 (2H, s), 3.2
8 (1H, s), 3.39 (2H, s), 3.62 (2H, s), 4.00 (2H, m), 7.12-
7.31 (6H, m), 7.38 (1H, dd, J = 9.6,2.5), 7.53 (1H, m), 7.6
8-7.80 (3H, m)

Example 13 Human CCR3 expressing cells (CCR3 / B300-
Intracellular Ca ²⁺ concentration evaluation using 19 cells) The final concentration of the fluorescent indicator, fura-2 AM (Dojindo Laboratories), in RPMI 1640 medium containing 1% fetal bovine serum was 5
Prepare a solution added so that it becomes μM, and add 1 × 10 ⁷ cells / m
Human CCR3-transformed B300-19 cells (Cell Vol. 27, pp. 381-390, 1981) were suspended so as to give l. 37 ° C
Incorporate fura-2 AM into the cells by allowing it to stand for 30 minutes, and then add 0.1% bovine serum albumin-containing basi
c salt solution (5.4mM KCl, 130mM NaCl, 2.5mM CaCl
₂ , 1 mM MgCl ₂ , 5.5 mM glucose, 20 mM HEPES, pH 7.4) and washed twice, and resuspended to 2 × 10 ⁶ cells / ml. The intracellular Ca ²⁺ concentration ([Ca ²⁺ ] _i ) was measured using CAF-110 (JASCO Corporation). Human eotaxin (Peprotech InP) was added to the cell suspension to a final concentration of 50 ng / ml.
c., USA), an increase in [Ca ²⁺ ] _i was observed. h
Add the test compound 1 minute before adding uman eotaxin, and
By measuring the effect of uman eotaxin on the increase of [Ca ²⁺ ] _i , the CCR3 inhibitory activity of the test compound was measured by the IC ₅₀ value (huma
increase in [Ca ²⁺ ] _i caused by the addition of n eotaxin
The concentration is shown as 50% inhibition). Table 23 shows the inhibitory activity of representative compounds.

[0112]

[Table 23]

[0113]

The compound of the present invention is useful as an active ingredient of a pharmaceutical preparation. Especially because it has a CCR3 antagonistic effect, CC
R3-related asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, chronic sinusitis, ulcerative colitis, allergic diseases such as Crohn's disease, or autoimmune diseases, and HIV infection and its associated encephalitis It is also useful as a preventive or therapeutic drug for dementia and the like.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 17/00 A61P 17/00 27/16 27/16 37/08 37/08 C07D 471/08 C07D 471 / 08 519/00 311 519/00 311 (72) Inventor Takayuki Imaoka 1111 Tehiro, Kamakura City, Kanagawa Prefecture Toray Equity Research Institute, Pharmaceutical Research Laboratories (72) Inventor Masatsune Kaneda 1111 Tehiro, Kamakura City, Kanagawa Prefecture Toray Co., Ltd. Company Basic Research Institute Pharmaceutical Research Institute (72) Inventor Masayuki Kaneko 1111 Tehiro, Kamakura City, Kanagawa Toray Co., Ltd.Basic Research Institute Pharmaceutical Research Institute (72) Inventor Miyuki Funabashi 1111 Tehiro, Kamakura City, Kanagawa Toray Co., Ltd. Basic Research Institute Pharmaceutical Research Laboratory (72) Inventor Hideki Kozono 1111 Tehiro, Kamakura City, Kanagawa Prefecture Toray Industries, Inc. Basic Research Laboratory Pharmaceutical Research Laboratory (72) Inventor Koichiro Taira 21 Miyukigaoka, Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Inami Miyukigaoka, Tsukuba City, Ibaraki Prefecture 21 Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Koichi Kubota Miyuki Tsukuba, Ibaraki Prefecture Oka 21 Yamanouchi Pharmaceutical Co., Ltd. Inside the company (72) Inventor Tatsuaki Hokata, Miyukigaoka 21 Tsukuba City, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. Inside the company (72) Makoto Takeuchi 21 Miyukigaoka Tsukuba City, Ibaraki Yamanouchi Pharmaceutical Co., Ltd. companies in the F-term (reference) 4C063 BB09 CC36 DD10 EE01 4C065 AA09 AA16 BB04 BB06 CC01 DD01 DD03 EE02 HH09 JJ01 JJ06 KK01 KK09 LL01 LL04 PP03 PP08 PP12 4C072 MM02 UU01 4C086 AA01 AA02 AA03 BC54 CB05 GA07 MA01 MA04 NA14 ZA34 ZA59 ZA89 ZB11 ZB13

Claims (3)

[Claims] 1. Formula 1: [In the formula, l is an integer of 0 to 2, R ₁ and R ₂ independently represent a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, or R ₁ and R ₂ are together. it may form a bridge of the chain members 1 to 4, a _{is, -NR 3 C (O) NR} 4 -, - NR 3 C (O) -, - C (O) NR 3 -, -
C (O) O-, -C (O)-, -OC (O)-, -OC (O) NR _3- , -NR ₃ C (O) O-,-
NR _3- , -O-, -SO ₂ NH-, -C (= NR ₅ ) NH- and -C (= CHNO ₂ ) NH-, R ₃ and R ₄ are independently a hydrogen atom or Carbon number
1 to 3 represents a straight-chain alkyl group, R ₅ is -CN, -SO ₂ NH ₂ , -C
Represents OOEt or —COOMe, Ar ₁ represents an optionally substituted aryl group or an optionally substituted heterocyclic group, and B is 1) Formula 2: embedded image (In the formula 2, D represents a saturated 7-membered ring containing 1 to 2 nitrogen atoms, Ar ₂ is an optionally substituted aryl group, an optionally substituted heterocyclic group or a substituted Optionally represents a cycloalkyl group, V is (i) a bond (provided that l = 0
In, and, A is _{-NR 3 C (O) NR 4} -, - except in the case), (ii) -C (O ) - - C (O) NR 3 - or -NR ₃ (where, l = 0, and Ar ₂ is an unsubstituted phenyl group, or a halogen, a nitro group, a cyano group, an alkyl group having 1 to 6 carbon atoms, a haloalkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, C1-C6 haloalkoxy group, phenyl (C ₁ -C ₆ alkyl) group, S (O) ₂ (C _1-
C ₆ alkyl) group, C (O) NH ₂ , carboxyl group and carbon number 1
In the case of a phenyl group substituted only with a substituent selected from the alkoxycarbonyl group of ~ 6, and R ₁ and R ₂ are hydrogen atoms, l is 0 or 1, A is -C (O) NR ₃ , and D is (Except in the case of azepan which is bonded to A at a carbon atom which is a ring atom to be 1,2-diyl), (iii) -NR ₃ C (O)-, (iv) -C (O) NR _3- , (v) -SO ₂
-(However, R ₁ and R ₂ are hydrogen atoms, l is 0 or 1, A is -C (O) N
In R ₃ , except in the case of azepan in which D is bonded to A at a carbon atom which is a ring atom to form 1,2-diyl), (vi) -OC (O)-, (vi
i) -CR ₆ R ₇ C (O)-(R ₆ and R ₇ independently represent a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms (provided that both R ₆ and R ₇ are hydrogen atoms). Or R ₆ and R ₇ may form a 3- to 6-membered ring together with carbon atoms existing between them (provided that R ₁ and R ₂ are hydrogen atoms). , L is 0 or
1, except for Azepan in which A is -C (O) NR ₃ and D is bonded to A at a carbon atom that is a ring atom to form 1,2-diyl), (vii
i) -NR _3- (provided that l = 0 and Ar ₂ is a cycloalkyl group which may be substituted), (ix) carbon number 1 to
3 alkylene groups (where l = 0 and A is -NR ₃ C (O) NR ₄
-, -C (O) NR ₃ -or -NR _3- )), (x) -CH ₂ O-, (x
i) -CH ₂ NR _3- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group), (x
ii) -NR ₃ S (O) _2- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group)
Or (xiii) -S (O) ₂ NR _3- (provided that l = 0 and Ar ₂ is an unsubstituted phenyl group or an unsubstituted cycloalkyl group). A group represented by: 2) Formula 3: embedded image (In the formula 3, m is an integer of 0 to 2, R ₈ and R ₉ are independently a linear alkyl group having 1 to 3 carbon atoms, an aryl group which may be substituted or a substituted group. Represents a heterocyclic group, W is —NR ₃ — (except when R ₉ is a straight-chain alkyl group having 1 to 3 carbon atoms), a sulfur atom, —NHC (O) — (provided that R is ₉ is a straight-chain alkyl group having 1 to 3 carbon atoms), -C (O) NH
-, - CH ₂ O- (except when R ₉ is a straight chain alkyl group having 1 to 3 carbon _{atoms), - SO 2 NH -,} - C (O) O- or -OC (O) - and Represent)
A group represented by: or 3) Formula 4: embedded image (In the formula 4, R ₁₀ represents a hydrogen atom or a linear alkyl group having 1 to 3 carbon atoms, R ₁₁ is a hydrogen atom, a linear alkyl group having 1 to 3 carbon atoms, an optionally substituted aryl Represents a group or a heterocyclic group which may be substituted) and a cyclic nitrogen-containing derivative represented by the above) or a pharmaceutically acceptable salt thereof. 2. In the formula 1, B is the formula 2 (provided that Ar is₂Is a halogen
-NH₂, -NH (C₁-C₃Alkyl), -N (C₁-C₃Alkyl)₂,
-C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C (O) N (C₁-C₃Al
kill)₂, -NHC (O) (C₁-C ₃Alkyl), -NHC (O) O (C₁-C₃Al
Kill), -CN, -NO₂, A straight-chain alkyl group having 1 to 3 carbon atoms, carbon
Number 1 to 3 straight-chain alkoxy group, -OH, -CF₃, -OCF₃, -SO₂NH
₂, -SO₂NH (C₁-C ₃Alkyl), -SO₂N (C₁-C₃Alkyl)₂,-
NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Alkyl)₂, -COO
H, -C (O) O (C₁-C₃Alkyl), phenyl, phenyl (C₁-C₃
Alkyl), cycloalkyl group, heterocyclic group and aryl
Even if it is substituted with 1 to 3 substituents selected from
A good monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, or ha
Rogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C₁-C₃Archi
(Le)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C (O) N (C₁-
C₃Alkyl)₂, -NHC (O) (C₁-C₃Alkyl), -NHC (O) O (C ₁-
C₃Alkyl), -CN, -NO₂, Straight-chain alkyl having 1 to 3 carbon atoms
Group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -CF₃, -OC
F₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C₁-C ₃A
(Rukiru)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Archi
(Le)₂, -COOH, -C (O) O (C₁-C₃Alkyl), phenyl, fe
Nil (C₁-C₃Alkyl), cycloalkyl group, heterocyclic group
And substituted with 1 to 3 substituents selected from aryl groups.
Optionally, oxygen atom, sulfur atom and nitrogen atom
5- to 6-membered monocyclic ring containing 1 to 3 heteroatoms selected from
Represents a bicyclic heterocyclic group), a group represented by formula 3 (wherein
Then R₈And R₉Are independently halogen, -NH₂, -NH (C₁-C₃
Alkyl), -N (C₁-C₃Alkyl)₂, -C (O) NH₂, -C (O) NH (C
₁-C₃Alkyl), -C (O) N (C₁-C₃Alkyl)₂, -NHC (O) (C₁-
C₃Alkyl), -NHC (O) O (C₁-C₃Alkyl), -CN, -NO₂,
C1-C3 straight chain alkyl group, C1-C3 straight chain alcohol
Xy group, -OH, -CF₃, -OCF₃, -SO₂NH ₂, -SO₂NH (C₁-C₃A
Rukiru), -SO₂N (C₁-C₃Alkyl)₂, -NHSO₂(C₁-C₃Archi
), -N (SO₂C₁-C₃Alkyl)₂, -COOH, -C (O) O (C₁-C₃A
Phenyl, phenyl, phenyl (C₁-C₃Alkyl), cyclo
1 selected from an alkyl group, a heterocyclic group and an aryl group
~ C6-10 optionally substituted with 3 substituents
Monocyclic or bicyclic aryl group, or halogen, -NH₂, -NH
(C₁-C₃Alkyl), -N (C₁-C₃Alkyl)₂, -C (O) NH₂, -C
(O) NH (C₁-C₃Alkyl), -C (O) N (C₁-C₃Alkyl)₂, -NHC
(O) (C₁-C₃Alkyl), -NHC (O) O (C₁-C₃Alkyl), -CN,
-NO₂, A straight chain alkyl group having 1 to 3 carbon atoms, a straight chain having 1 to 3 carbon atoms
Alkoxy group, -OH, -CF₃, -OCF₃, -SO₂NH₂, NHSO₂(C₁-
C₃Alkyl), -N (SO₂C₁-C₃Alkyl)₂, -COOH, -C (O) O
(C₁-C₃Alkyl), phenyl, phenyl (C₁-C₃Archi
Group), cycloalkyl group, heterocyclic group and aryl group?
It may be substituted with 1 to 3 substituents selected from
Hetero selected from oxygen atom, sulfur atom and nitrogen atom
5- to 6-membered mono- or bicyclic heterocycle containing 1 to 3 atoms
Represents a group) or a group represented by formula 4 (provided that R is₁₁Is hydrogen
Atom; halogen, -NH₂, -NH (C₁-C₃Alkyl), -N (C₁-C₃
Alkyl)₂, -CN, -NO₂, Straight-chain alkyl having 1 to 3 carbon atoms
Group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -CF₃, -OC
F₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C₁-C₃A
(Rukiru)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃Archi
(Le)₂, -COOH, -C (O) O (C₁-C₃Alkyl), phenyl, fe
Nil (C₁-C₃Alkyl), cycloalkyl group, heterocyclic group
And substituted with 1 to 3 substituents selected from aryl groups.
Optionally mono- or bicyclic aryl having 6 to 10 carbon atoms
Group; or halogen, -NH₂, -NH (C₁-C₃Alkyl), N (C₁-C
₃Alkyl)₂, -C (O) NH₂, -C (O) NH (C₁-C₃Alkyl), -C
(O) N (C₁-C₃Alkyl)₂, -NHC (O) (C₁-C₃Alkyl), -NHC
(O) O (C₁-C₃Alkyl), -CN, -NO₂, A straight chain C1-C3
Alkyl group, linear alkoxy group having 1 to 3 carbon atoms, -OH, -C
F₃, -OCF₃, -SO₂NH₂, -SO₂NH (C₁-C₃Alkyl), -SO₂N (C
₁-C₃Alkyl)₂, -NHSO₂(C₁-C₃Alkyl), -N (SO₂C₁-C₃
Alkyl)₂, -COOH, -C (O) O (C₁-C₃Alkyl), pheny
Le, phenyl (C₁-C₃Alkyl), cycloalkyl group,
1-3 substituents selected from telocyclic group and aryl group
Optionally substituted with oxygen atom, sulfur atom and nitrogen atom.
5-6 members containing 1-3 heteroatoms selected from elementary atoms
Represents a monocyclic or bicyclic heterocyclic group) of
The cyclic nitrogen-containing derivative according to claim 1 or its pharmaceutically acceptable
Salt to be contained. 3. A CCR3 inhibitor containing the cyclic nitrogen-containing derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.