JP2005255675A - Pharmaceutical composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition effectively suppressing or inhibiting α<SB>4</SB>-integrin-interposed cell adhesion and effective for preventing or treating chronic inflammatory diseases. <P>SOLUTION: This pharmaceutical composition contains as active ingredient a compound of formula(I) having α<SB>4</SB>-integrin-interposed cell adhesion inhibitory activity or a pharmaceutically acceptable derivative thereof. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

The present invention relates to a pharmaceutical composition for the prevention or treatment of chronic inflammatory diseases as an active ingredient a pyridone derivative which are inhibitors of alpha ₄ integrin mediated cell adhesion.

  Multiple adhesion interactions between leukocytes and endothelial cells or extracellular matrix proteins are important factors in the regulation of immunity and inflammation. The first event in leukocyte migration from the blood vessel at the site of inflammation is the rolling of leukocytes, followed by tight adhesion after changes in integrin affinity (Non-patent document 1, Non-patent document 2, Non-patent document). 3, Non-Patent Document 4, Non-Patent Document 5, Non-Patent Document 6, and Non-Patent Document 7). In response to chemotactic factors, leukocytes pass through two adjacent endothelial cells, some of which are extracellular matrix proteins fibronectin (FN) (see Non-Patent Document 8) and collagen (CN). ) (See Non-Patent Document 9 and Non-Patent Document 10). These important recognition molecules involved in the adhesion reaction belong to the integrin gene superfamily (see Non-Patent Document 3, Non-Patent Document 5, Non-Patent Document 6 and Non-Patent Document 12).

  Integrins are heterodimers composed of non-covalently assembled subunits called alpha (α) and beta (β) subunits. To date, 8 integrin β subunits have been identified, which can bind to 16 different α subunits to form 23 different integrins.

Α ₄ β ₁ integrin, also known as VLA-4 (very late antigen-4), is constitutively expressed on the surface of leukocytes such as lymphocytes, monocytes, eosinophils and basophils ( Non-patent document 12 and Non-patent document 13). It has been reported that VLA-4 is present in neutrophils of septic patients (Non-patent Document 14). VLA-4 binds to vascular cell adhesion molecule-1 (VCAM-1) on activated endothelial cells, and then leukocytes extravasate (see Non-Patent Document 15). When cells reach the extravascular space, VLA-4 binds to connecting segment 1 (CS-1), which is an alternative splicing region of the FNA chain (see Non-Patent Document 16). VLA-4 is also known to bind to osteopontin, a protein that is up-regulated in atherosclerotic plaques (see Non-Patent Document 17).

Batcher, Cell, 67: 1033-1036 (1991) Harlan, Blood, 3: 513-525 (1985) Hemler, Annu. Rev. Immunol., 8: 365-400 (1990) Osborne, Cell, 62: 3-6 (1990) Shimizu et al., Immunol. Rev., 114: 109-143 (1990) Springer, Nature, 346: 425-434 (1990) Springer, Cell, 76: 301-314 (1994) Weiner et al., J. Cell Biol., 105: 1873-1884 (1987) Bonestein et al., Ann. Rev. Biochem., 49: 957-1003 (1980) Miller, Extracellular Matrix Biochemistry, “Chemistry of Collagen and Its Distribution,” K.A. Piers and A.H. Regis, Euseviel Publishing, Amsterdam, 41-78 (1983) Highness, Cell, 48: 549-554 (1987) Hemler et al., J. Bio. Chem. 262: 11478-11485 (1987) Bokner et al., J. Exp. Med. 173: 1553-1556 (1991) Ibotson et al., Nature Med. 7: 465-470 (2001) Elises et al., Cell 60: 577-584 (1990) Wine et al., J. Cell Biol., 109: 1321-1330 (1989) Bayres et al., J. Cell Science 111: 1165-1174 (1998)

The present invention, suppression or inhibition of alpha ₄ integrin mediated cell adhesion is response, it is an object to provide a pharmaceutical composition effective in the prevention or treatment of chronic inflammatory diseases.

The present inventors have conducted extensive studies to solve the above problems, found a novel pharmaceutical composition comprising, as an active ingredient a pyridone derivative having an inhibitory effect on alpha ₄ integrin mediated cell adhesion, the present invention completed.
That is, the present invention relates to the formula (I):

{式中、
ＡおよびＢは独立してアリールまたはヘテロアリールを表す；
ＱはＣ、ＣＨ、またはＶもしくはＤと一緒になって５〜７員のヘテロ環を形成してもよい；
Ｄは水素、Ｃ_1-6アルキル、またはＱと一緒になって５〜７員のヘテロ環を形成してもよい；
Ｒ¹、Ｒ²およびＲ³は独立して、Ｃ_1-6アルキル、ハロゲン、Ｃ_1-6アルコキシ、ヒドロキシ、シアノ、ＣＦ₃、ニトロ、Ｃ_1-6アルキルチオ、アミノ、モノ−Ｃ_1-6アルキルアミノ、ジ−Ｃ_1-6アルキルアミノ、カルボキシ、Ｃ_1-6アルカノイル、アミド、モノ−Ｃ_1-6アルキルアミド、ジ−Ｃ_1-6アルキルアミド、−ＮＨＣＯＲ⁹もしくは−ＮＨＳＯ₂Ｒ⁹[ここで、Ｒ⁹はＣ_1-6アルキル、Ｃ_3-7シクロアルキルもしくはフェニル（フェニルはＣ_1-6アルキル、ハロゲン、Ｃ_1-6アルコキシ、シアノ、フェニルまたはＣＦ₃から選択される１〜３個の基で置換されていてもよい）]、または−Ｅ−(ＣＨ₂)_1-6ＮＲ^xＲ^y（Ｅは単結合または−ＯＣＨ₂−であり、Ｒ^xおよびＲ^yは独立して水素、Ｃ_1-6アルキル、もしくは一緒になって５〜７員のヘテロ環を形成してもよい）を表す； Ｒ⁴は水素、Ｃ_1-6アルキル、ハロゲンまたはＣ_1-6アルコキシを表す；
ＶはＯ、Ｓ、ＮＨ、Ｎ-Ｃ_1-6アルキル、ＮＮＯ₂またはＮＣＮであるか、Ｑと一緒になって５〜７員のヘテロ環を形成してもよい；
Ｗ、Ｘ、ＹおよびＺは独立してＣ、ＣＨまたはＣＨ₂を表す；
記号：

{Where
A and B independently represent aryl or heteroaryl;
Q may combine with C, CH, or V or D to form a 5-7 membered heterocycle;
D may be combined with hydrogen, C _1-6 alkyl, or Q to form a 5-7 membered heterocycle;
R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 Alkylamino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, —NHCOR ⁹ or —NHSO ₂ R ⁹ [ here, 1 to 3 R ⁹ is selected from C _1-6 alkyl, C _3-7 cycloalkyl or phenyl (phenyl C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl or CF ₃ Or -E- (CH ₂ ) _1-6 NR ^x R ^y (E is a single bond or —OCH ₂ —, and R ^x and R ^y are independently hydrogen, C _1-6 alkyl or form a heterocycle of 5-7 members together, Represent was may be); R ⁴ represents hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy;
V is O, S, NH, N—C _1-6 alkyl, NNO ₂ or NCN, or together with Q may form a 5-7 membered heterocycle;
W, X, Y and Z independently represent C, CH or CH ₂ ;
symbol:

は単結合または二重結合を表す；
Ｌは−(ＣＨ₂)_q−または−(ＣＨ₂)_q'Ｏ−（ｑは０、１、２または３、ｑ’は２または３である）を表す；
Ｊは以下の群：
(ｉ) −ＣＲ⁵＝ＣＲ⁶−（Ｒ⁵およびＲ⁶は独立して水素またはＣ_1-6アルキルである）；
(ｉｉ) −ＣＨＲ⁷−ＣＨＲ⁸−（Ｒ⁷およびＲ⁸は独立して水素、Ｃ_1-6アルキル、Ｃ_3-7シクロアルキル、アリール、ヘテロアリール、−ＮＨＣＯＲ⁹もしくは−ＮＨＳＯ₂Ｒ⁹（Ｒ⁹は前記と同意義である）または−(ＣＨ₂)_1-6ＮＲ^xＲ^y（Ｒ^xおよびＲ^yは前記と同意義である））；
(ｉｉｉ)単結合；
(ｉｖ) −ＣＨＲ⁶−（Ｒ⁶は前記と同意義である）；および
(ｖ) −Ｏ−ＣＨＲ¹⁰−、−ＮＲ¹¹−ＣＨＲ¹⁰−または−ＣＲ¹²Ｒ¹³−ＣＨＲ¹⁰−（Ｒ¹⁰およびＲ¹¹は独立して水素またはＣ_1-6アルキルであり、Ｒ¹²およびＲ¹³は独立してＣ_1-6アルキルであるか、Ｒ¹²およびＲ¹³は一緒になってＣ_3-7シクロアルキルまたは５〜７員のヘテロ環を形成していてもよい）
から選択される基を表す；
ｍ、ｎおよびｐは独立して０、１、２または３を表す；そして
ｔは０、１または２を表す}
で示される化合物またはその薬理学的に許容される誘導体を有効成分として含有することを特徴とする医薬組成物に関する。

Represents a single bond or a double bond;
L represents — (CH ₂ ) _q — or — (CH ₂ ) _{q ′} O— (q is 0, 1, 2 or 3, q ′ is 2 or 3);
J is the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl);
(ii) —CHR ⁷ —CHR ⁸ — (R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, heteroaryl, —NHCOR ⁹ or —NHSO ₂ R ⁹ ( R ⁹ is as defined above) or — (CH ₂ ) _1-6 NR ^x R ^y (R ^x and R ^y are as defined above));
(iii) a single bond;
(iv) —CHR ⁶ — (R ⁶ is as defined above); and
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ —CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ is independently C _1-6 alkyl, or R ¹² and R ¹³ may together form C _3-7 cycloalkyl or a 5- to 7-membered heterocycle)
Represents a group selected from
m, n and p independently represent 0, 1, 2 or 3; and t represents 0, 1 or 2}
Or a pharmacologically acceptable derivative thereof as an active ingredient.

  Of the compounds of formula (I), preferred compounds for the present invention are those of formula (Ia):

（式中、Ｒ¹、Ｒ²、Ｒ³、Ｒ⁴、Ｌ、Ｊ、ｍ、ｎ、ｐおよびｔは式(Ｉ)の定義と同意義である）
で示される化合物またはその薬理学的に許容される誘導体である。

(Wherein R ¹ , R ² , R ³ , R ⁴ , L, J, m, n, p and t are as defined in formula (I)).
Or a pharmacologically acceptable derivative thereof.

In the present specification, the terms described below have the following meanings unless otherwise specified.
“Halogen” means a group selected from fluorine, chlorine, bromine or iodine.
“C _1-6 alkyl” means a straight or branched alkyl group having 1 to 6 carbon atoms, or a part of a group containing them, such as methyl, ethyl, propyl, isopropyl, n- Examples include butyl, isobutyl, tert-butyl, pentyl and hexyl.

  “Aryl” means a phenyl group and naphthyl (naphth-1-yl and naphth-2-yl).

  “Heteroaryl” means an aromatic or benzo-fused aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur. Suitable examples of such aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of the benzo-fused aromatic ring include quinolyl, isoquinolyl, indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, and benzoxazolyl.

“5- to 7-membered heterocycle” means a non-aromatic heterocycle containing 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, such as piperidyl, piperazinyl, pyrrolidinyl and morpholinyl, etc. Is mentioned. The heterocycle may be substituted with C _1-6 alkyl.

“C _1-6 alkoxy” means a group formed by bonding an oxygen atom to the above alkyl group or a part of such a group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and sec-butoxy, tert-butoxy, pentoxy and hexoxy.

“C _1-6 alkanoyl” means a group formed by removing an “OH” group from a carboxyl group of a C _1-6 carboxylic acid, and examples thereof include formyl, acetyl, propionyl and butyryl.
“C _3-7 cycloalkyl” means a cyclic C _3-7 alkyl group, for example, cyclohexyl and cyclopentyl.

The compound (I) will be described in more detail.
Q can be C not only when it forms a 5-7 membered heterocycle, but also when it is substituted with an R ¹ group.
When A and / or B is aryl, it is preferably phenyl. When A and / or B is heteroaryl, it is preferably pyridyl.
More preferably, A is phenyl or pyridyl.
More preferably, B is phenyl.
R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 alkyl Amino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, —NHCOR ⁹ or —NHSO ₂ R ⁹ It is preferable. Wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or 1 to 3 groups selected from C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl or CF _3. Optionally substituted with phenyl, or -E- (CH ₂ ) _1-6 NR ^x R ^y (E is a single bond or —OCH ₂ —, R ^x and R ^y are independently hydrogen or C _1-6 Or a cyclic group such as a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group, which may be alkyl or may be substituted together with C _1-6 alkyl).

When Q and V together form a ring containing a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group, it may be substituted with C _1-6 alkyl.
Where Q and D together form a ring containing a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group, they may be substituted with C _1-6 alkyl.

J is preferably a group selected from the following group.
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl.)
(ii) —CHR ⁷ —CHR ⁸ — {wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, triazolyl, Imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, —NHCOR ⁹ or —NHSO ₂ R ⁹ [R ⁹ is as defined above], or — (CH ₂ ) _1-6 NR ^x R ^y (R ^x and R ^y are as defined above)},
(iii) Single bond
(iv) —CHR ⁶ — (R ⁶ is as defined above)
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ are Independently C _1-6 alkyl, or R ¹² and R ^{13 taken} together form C _3-7 cycloalkyl, tetrahydropyranyl, piperidyl, piperazinyl, pyrrolidinyl or morpholinyl.)

When m, n or p is other than 0, R ¹ , R ² and R ³ are each preferably C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano or CF ₃ . When m, n or p is 2 or 3, R ¹ , R ² and R ³ may be the same or different from each other.

  The ring containing W, X, Y and Z has the formula:

（式中、環窒素は基Ｌに結合している）
で示される基であることが好ましい。
Ｒ¹、Ｒ²およびＲ³は独立してＣ_1-6アルキル、ハロゲンまたはＣ_1-6アルコキシであることが好ましい。
ＱおよびＶが一緒になって５〜７員のヘテロ環を形成する場合、適当な例としてＱおよびＶがベンゾイミダゾールまたはベンゾオキサゾール環の一部を形成するものが挙げられる。
ＱおよびＤが一緒になって５〜７員のヘテロ環を形成する場合、適当な例としてＱおよびＤがインドリン環の一部を形成するものが挙げられる。
ＱがＣ、ＣＨ、またはＶもしくはＤと一緒になってベンゾイミダゾール、ベンゾオキサゾールまたはインドリン環の一部を形成し、
Ｄが水素、Ｃ_1-6アルキル、またはＱと一緒になってインドリン環の一部を形成し、；
ＶがＯ、またはＱと一緒になってベンゾイミダゾールまたはベンゾオキサゾール環の一部を形成し；
Ｒ^４は水素またはハロゲンであることが適当である。
ＱはＣＨまたはＲ¹基で置換されているＣであり、ＶはＯであり、Ｄは水素であることが好ましい。

(Wherein the ring nitrogen is bound to the group L)
It is preferable that it is group shown by these.
R ¹ , R ² and R ³ are preferably independently C _1-6 alkyl, halogen or C _1-6 alkoxy.
Where Q and V together form a 5-7 membered heterocycle, suitable examples include those where Q and V form part of a benzimidazole or benzoxazole ring.
Where Q and D together form a 5-7 membered heterocycle, suitable examples include those where Q and D form part of an indoline ring.
Q together with C, CH, or V or D forms part of a benzimidazole, benzoxazole or indoline ring;
D together with hydrogen, C _1-6 alkyl, or Q forms part of an indoline ring;
V together with O or Q forms part of a benzimidazole or benzoxazole ring;
Suitably R ⁴ is hydrogen or halogen.
Preferably Q is C substituted with CH or R ¹ groups, V is O and D is hydrogen.

L is suitably — (CH ₂ ) _q — (q is 0, 1, 2, or 3), and preferably —CH ₂ —.
J is preferably a group selected from the following group.
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl.)
(ii) —CHR ⁷ —CHR ⁸ — [wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl or —NHCOR ⁹ (R ⁹ is C _{1— 6} alkyl). ]
(iii) Single bond
(iv) —CHR ⁶ — (R ⁶ is as defined above)
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ are Independently C _1-6 alkyl or R ¹² and R ¹³ together form a C _3-7 cycloalkyl group.)

J is preferably a group; —CH═CH—, — (CH ₂ ) ₂ — or —CHR ⁷ —CH ₂ — (R ⁷ is C _1-6 alkyl).

The compound (Ia) will be described in more detail.
R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 alkyl Amino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, or —NHCOR ⁹ or —NHSO ₂ R ⁹ [ Wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or phenyl (wherein phenyl is selected from C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl or CF ₃ It may be substituted with 1 to 3 groups)].

When m is other than 0, preferred R ¹ includes halogen (particularly fluoro or chloro) or C _1-6 alkyl group (particularly methyl). When m is 2 or 3, R ¹ may be the same or different. More preferably, m is 1 and the R ¹ group is a methyl group that is ortho to the urea moiety.

When n is other than 0, preferred R ² includes halogen (particularly fluoro or chloro), C _1-6 alkyl group (particularly methyl), or C _1-6 alkoxy group (particularly methoxy). When n is 2 or 3, each R ¹ may be the same or different. More preferably, n is 0 or n is 1 and R ² is a methoxy group in the ortho position relative to the urea moiety.

When p is other than 0, preferred R ³ includes halogen (particularly fluoro or chloro) or C _1-6 alkyl group (particularly methyl). When p is 2 or 3, R ³ may be the same or different.
R ⁴ is preferably hydrogen.

L is preferably — (CH ₂ ) _q — (q is 0, 1, 2 or 3).

J is preferably a group selected from the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl), or
(ii) —CHR ⁷ —CHR ⁸ — [wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, or —NHCOR ⁹ or —NHSO ₂ R ⁹ (R ⁹ is as defined above) is there.)
More preferably, J is —CH═CH—, — (CH ₂ ) ₂ — or —CHR ⁷ —CH ₂ — (R ⁷ is C _1-6 alkyl).

  As a preferable drug for the pharmaceutical composition of the present invention, a compound selected from the following Production Examples 1 to 51 (P1 to P51) or a pharmacologically acceptable derivative thereof can be mentioned. Particularly preferred compounds are compounds selected from Production Examples 5, 9, 32, 41, 42 and 51 (P5, P9, P32, P41, P42 and P51) or pharmacologically acceptable derivatives thereof.

  Since the compounds of formula (I) have one or more asymmetric carbon atoms, they can exist as racemates, racemic mixtures and individual enantiomers or diastereomers. All such isomeric forms and mixtures can also be used in the pharmaceutical composition of the present invention.

  When the active compound of the invention contains an alkenyl or alkenylene group, cis (Z) and trans (E) isomerism can occur. The present invention includes the individual stereoisomers of the active compounds, optionally their individual tautomers, and mixtures thereof.

  Separation of diastereomers, or cis and trans isomers can be achieved in a conventional manner, such as by fractional crystallization, chromatography or HPLC. Alternatively, single stereoisomeric drugs may be prepared from the optically pure corresponding intermediates, if necessary, or the corresponding racemates resolved using appropriate chiral supports (e.g., HPLC Or a diastereomeric salt formed by the reaction of the corresponding racemate with a suitable optically active acid or base can be prepared by fractional crystallization. Alternatively, a mixture of enantiomers can be separated by chemical reaction with an appropriate chiral compound to form a new covalent species. For example, coupling of a racemic carboxylic acid with a chiral amine or chiral alcohol yields a diastereomeric mixture (amide or ester, respectively), which is separated by conventional techniques such as column chromatography, HPLC or fractional crystallization. The new covalent bond can then be cleaved with a suitable chemical reaction such as hydrolysis to convert one diastereomer to one enantiomer of the desired compound.

  In the present specification, the “pharmacologically acceptable derivative” means a pharmacologically acceptable salt, solvate, prodrug or the like (eg, ester) of the compound according to the present invention, When administered to a patient, a compound of the invention or an active metabolite or residue thereof can be given (directly or indirectly). Such derivatives can be obtained by one skilled in the art without undue experimentation. See, for example, Burger, Medicinal Chemistry and Drug Discovery, 5th edition, Volume 1, “Principles and Practice”. Preferred pharmacologically acceptable derivatives are salts, solvates, esters, carbamates and phosphates. Particularly preferred pharmacologically acceptable derivatives are salts, solvates and esters. The most preferred pharmacologically acceptable derivatives are salts and esters.

  Those skilled in the field of organic chemistry know that a large number of organic compounds can form or complex with the reaction solvent. These complexes are widely known as “solvates”. For example, a complex with water is known as a “hydrate”. Solvates of the compounds according to the invention are also within the scope of the invention.

  In the present specification, the “prodrug” means a compound that is converted into an active form having a pharmacological action by hydrolysis in the body, for example, in blood. Examples of pharmacologically acceptable prodrugs can be found in the literature [T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, “Bioreversible Carriers in Drug Design. Design) ”, Edward B. Roche, Ed., American Pharmaceutical Association and Pergamon Press, ACS Symposium Series, Volume 14, (1987); and D. Fleischer, S. Roman and H. Barbara , “Improved oral drug delivery: solubility limitations overcome by the use of prodrugs, Advanced Drug Delivery Reviews (1996) 19 (2): 115-130” ]It is described in.

  Prodrugs are carriers that release a compound of formula (I) that is covalently bound in vivo when administered to a patient. Prodrugs are usually prepared by modifying functional groups such that the modifying moiety is cleaved off by conventional means or in vivo to yield the parent compound. Examples of prodrugs include compounds in which the hydroxy, amine or sulfhydryl group of the active compounds of the present invention is attached to any group that is cleaved to give a hydroxy, amine or sulfhydryl group upon administration to a patient. Accordingly, representative examples of prodrugs include, but are not limited to, the following. Acetate, formate and benzoate derivatives at the alcohol, sulfhydryl and amine functions of the compounds of formula (I). Furthermore, in the case of carboxylic acid (—COOH), esters such as methyl ester, ethyl ester, and double ester can also be used. Esters are those that are active per se in humans and / or hydrolyzed under in vivo conditions, and suitable pharmacologically acceptable in vivo hydrolysable ester groups include those in the human body. Those which are easily decomposed to liberate the acid of the parent compound or a salt thereof.

  The compound according to the present invention may be in the form of a pharmacologically acceptable salt. Suitable salts are reviewed in the literature (Berge et al., J. Pharm. Sci., 66: 1-19 (1977)). .

  Usually, a pharmacologically acceptable salt can be easily produced by using a desired acid or base as required. The salt can be recovered by precipitating from solution and filtering or by distilling off the solvent.

  Suitable addition salts are formed with acids that form non-toxic salts. Such salts include hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate, Fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate, methanesulfonic acid Salts, ethane sulfonates, benzene sulfonates and p-toluene sulfonates are exemplified.

  As salts of pharmacologically acceptable bases, ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium, and primary, secondary and tertiary amines (eg isopropyl) Examples thereof include salts with organic bases including salts of amine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine and N-methyl-D-glucamine).

  The active compound (I) of the present invention has the formula (II):

（式中、Ｒ^１〜Ｒ^４、ｍ、ｎ、ｐ、ｔ、Ａ、Ｂ、Ｄ、Ｌ、Ｊ、Ｑ、Ｖ、Ｗ、Ｘ、ＹおよびＺは式(Ｉ)における定義と同意義であり、Ｒはカルボン酸エステルを形成しうる基である）
で示されるカルボン酸エステル誘導体を加水分解し、要すれば、次いで薬理学的に許容される誘導体を形成することにより製造することができる。

(Wherein R ^{1 to} R ⁴ , m, n, p, t, A, B, D, L, J, Q, V, W, X, Y and Z are as defined in the formula (I). And R is a group capable of forming a carboxylic acid ester)
Can be produced by hydrolyzing the carboxylic acid ester derivative represented by the formula (2) and then forming a pharmacologically acceptable derivative if necessary.

R is preferably C _1-6 alkyl such as methyl or t-butyl. Hydrolysis can be performed using an acid or base in a suitable solvent according to a conventional method. Those skilled in the art are familiar with such methods.

The compound of the above formula (II) can be produced by any of the following methods.
(a) Formula (III):

（式中、Ｒ²〜Ｒ⁴、n、p、t、A、B、L、J、R、W、X、YおよびZは式（Ｉ）または（ＩＩ）における定義と同意義である）
で示される化合物を式(ＩＶ)：

(Wherein R ^{2 to} R ⁴ , n, p, t, A, B, L, J, R, W, X, Y and Z are as defined in formula (I) or (II)).
A compound represented by formula (IV):

（式中、Ｒ¹、mおよびQは前記と同意義である）、（また、上記FG2とFG1は相互に反応してウレア部分を形成しうる適当な官能基を含む基である）
で示される化合物と反応させる。
(b)式(ＩＩＩ)の化合物（FG1は前記のうちNH₂である）を式（Ｖ）：

(Wherein R ¹ , m and Q are as defined above) (and FG2 and FG1 are groups containing an appropriate functional group capable of reacting with each other to form a urea moiety)
It is made to react with the compound shown by these.
(b) A compound of formula (III) (FG1 is NH ₂ of the above) is represented by formula (V):

（式中、Ｒ¹、Dおよびmは式(Ｉ)における定義と同意義であり、QおよびVは一緒になって５−７員のヘテロ環を形成し、ＬＧは脱離基である）
で示される化合物と反応させる。
(c)式(ＶＩ)：

(Wherein R ¹ , D and m are as defined in formula (I), Q and V together form a 5-7 membered heterocycle, and LG is a leaving group)
It reacts with the compound shown by these.
(c) Formula (VI):

（式中、Ｒ¹、Ｒ²、Ｒ⁴、m、n、t、A、B、D、Q、R、V、W、X、YおよびZは式(Ｉ)または(ＩＩ)における定義と同意義である）
で示される化合物を式(ＶIＩ)：

(Wherein R ¹ , R ² , R ⁴ , m, n, t, A, B, D, Q, R, V, W, X, Y and Z are as defined in formula (I) or (II)). (Same meaning)
A compound of formula (VII):

（式中、p、Ｒ、Ｒ³、J、BおよびLは式(I)または(II)における定義と同意義であり、LG1は脱離基である）
で示される化合物と反応させる。

(Wherein p, R, R ³ , J, B and L are as defined in formula (I) or (II), and LG1 is a leaving group)
It reacts with the compound shown by these.

Examples of suitable FG1 and FG2 groups in method (a) include the following.
or (i) FG1 is be -N = C = O FG2 is NH _2, or FG1 is NH _2, FG2 is N = C = O.
(ii) FG1 is NH ₂ and FG2 is NH ₂ with a suitable urea former.

In the case of (i) above, the reaction is usually carried out in an inert solvent such as dichloromethane or acetonitrile at ambient temperature.
In the case of (ii), the reaction is usually carried out at ambient temperature or elevated temperature in the presence of a suitable urea-forming agent such as carbonyldiimidazole or phosgene, and an appropriate organic solvent such as dimethylformamide, tetrahydrofuran or dichloromethane. Under, optionally in the presence of a base such as triethylamine or pyridine.

  In process (b), suitable leaving groups are halogen, in particular chloro. Examples of such reaction include those described in the literature (Young et al., J. Med. Chem., 34 (3), 1110 (1991); Passerini, J. Chem. Soc .: 2256 (1954)). It is done.

  In process (c), suitable leaving groups are halogen, in particular chloro. Usually the reaction is carried out at ambient temperature in an inert solvent such as tetrahydrofuran or acetonitrile.

  Formulas (III), (IV), (V), (VI) and (VII) are intermediate compounds that are commercially available or known to those skilled in the art using the methods described herein. It can be produced by methods or by methods analogous thereto.

  One skilled in the art needs to protect one or more reactive groups in the molecule to prevent undesirable side reactions in the preparation of the compounds of the invention or solvates thereof, and / or You will understand what is desirable. Suitable protecting groups for the present invention are well known to those skilled in the art and can be used according to conventional methods. See, for example, T.W. Green and P.G.M. Wout, “Protective groups in organic synthesis”, John Wiley & sons (1991) and P.J. Kohiensky, “Protecting groups” Georg Thieme Verlag (1994). Suitable amino protecting groups include, for example, acyl-type protecting groups (formyl, trifluoroacetyl, acetyl, etc.), aromatic urethane-type protecting groups (benzyloxycarbonyl (Cbz) and substituted Cbz, etc.), aliphatic urethane protecting groups ( 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl and the like) and alkyl-type protecting groups (benzyl, trityl, chlorotrityl and the like). Suitable oxygen protecting groups include, for example, alkylsilyl groups such as trimethylsilyl or tert-butyldimethylsilyl, alkyl ethers such as tetrahydropyranyl or tert-butyl, or esters such as acetate.

  The compound which is an active ingredient of the pharmaceutical composition of the present invention is integrin VLA-4 (very late antigen-4; α4β1; CD49d, CD29) expressed on Jurkat J6 cell membrane by Jurkat J6 scintillation proximity assay (SPA) assay. ) And the test compound can be used to test biological activity in vitro. The drug useful as an active ingredient of the pharmaceutical composition of the present invention has a pKi of preferably about 6.5 or more when tested by the method of Test Example 1. All of the compounds obtained in the production examples described below have a pKi of 6.5 or more, and were found to be useful as the pharmaceutical composition of the present invention.

Pharmaceutical compositions of the present invention containing the compound and a pharmacologically acceptable derivative of the formula (I) inhibits alpha ₄ integrin mediated cell adhesion, the treatment or prevention of disease states as shown below Can be used. For example, rheumatoid arthritis (RA); asthma; allergic diseases such as rhinitis; adult respiratory distress syndrome; AIDS dementia; Alzheimer's disease; cardiovascular disease; thrombosis or harmful platelet aggregation; reocclusion after thrombolysis; Injuries; skin inflammatory diseases such as psoriasis, eczema, contact dermatitis and atopic dermatitis; diabetes (eg, insulin-dependent diabetes, autoimmune diabetes); multiple sclerosis; systemic lupus erythematosus (SLE) Inflammatory bowel diseases such as ulcerative colitis, Crohn's disease (local) and cystitis (eg, bowel disease that occurs after colorectal resection and ileal anastomosis); pediatric steatosis, non-tropical sprue, seronegative joints Diseases involving leukocyte infiltration into the gastrointestinal tract, such as intestinal diseases related to infectious diseases, lymphoid or collagenous colitis, intestinal diseases related to eosinophilic gastroenteritis, etc .; skin, urinary tract, airways and joints Diseases related to leukocyte infiltration into other epithelial membrane tissues such as membranes; pancreatitis; mastitis (mammary gland); hepatitis; cholecystitis; cholangitis, perichonditis (bile duct and liver surrounding tissues); bronchitis; Inflammation; pulmonary inflammatory disease that causes interstitial fibrosis such as hypersensitivity pneumonia; collagen disease (SLE and RA); sarcoidosis; osteoporosis; osteoarthritis; atherosclerosis; metastasis of neoplasm or cancerous growth Neoplasmic diseases including: trauma (enhanced trauma healing); certain eye diseases such as retinal detachment, allergic conjunctivitis and autoimmune uveitis; Sjogren's syndrome; rejection after organ transplantation (chronic and acute); Graft or graft-versus-host disease; intimal thickening; arteriosclerosis (including graft arteriosclerosis after transplantation); percutaneous transluminal coronary angioplasty (PTCA) and percutaneous endoluminal revascularization Reinfarction or restenosis after surgery such as communication; nephritis Tumor angiogenesis; malignant tumor; multiple myeloma and myeloma-induced bone resorption; sepsis; and Meniere's disease; stroke, traumatic brain injury and spinal cord injury, such as central nervous system disorders.

  The pharmaceutical composition of the present invention has allergic pathologies such as asthma and rhinitis, inflammatory bowel diseases such as ulcerative colitis and Crohn's disease, rheumatoid arthritis, atopic dermatitis, multiple sclerosis and rejection after organ transplantation. It can be suitably used for treatment or prevention.

The pharmaceutical compositions of the present invention comprise the active compound (I) in a safe and effective amount, inhibition of alpha ₄ integrin mediated cell adhesion is useful in the treatment or prevention of beneficial conditions. In particular, the pharmaceutical composition of the present invention is useful in the treatment or prevention of the above pathological conditions.

  The pharmaceutical composition of the present invention contains the active compound represented by formula (I) in a pharmacologically effective amount together with a pharmaceutically acceptable carrier or diluent.

  The pharmaceutical composition of the present invention can be produced by mixing at least one compound (I) or a pharmaceutically acceptable derivative thereof together with a pharmaceutically acceptable carrier or diluent.

  The pharmaceutical compositions of the present invention are in the form of human and veterinary pharmaceutical formulations for use in humans or animals, and usually contain one or more pharmaceutically acceptable diluents, carriers or excipients. contains. Suitable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in the literature (Remington's Pharmaceutical Sciences, Mack Publishing Co, A. R. Genaro, Ed. (1985), etc.). The choice of pharmaceutically acceptable carrier, excipient or diluent should be selected in light of the intended route of administration and normal clinical practice. The carrier or diluent must be acceptable in the sense that it is not harmful to the patient. Pharmaceutically acceptable carriers or diluents include, for example, binders (syrup, gum arabic, gelatin, sorbit, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit) And glycine), lubricants (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrants (potato starch, etc.) and wetting agents (sodium lauryl sulfate, etc.).

  Examples of the administration (delivery) route of the pharmaceutical composition of the present invention include, but are not limited to, one or more exemplified below. Oral (tablets, capsules or solutions for oral ingestion, etc.), topical, transmucosal (nasal spray or aerosol for inhalation, etc.), nasal, parenteral (by injection, etc.), gastrointestinal tract, spinal cord, intraperitoneal, muscle Internal, intravenous, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intraventricular, intracerebral, subcutaneous, intraocular (including intravitreal or intraocular), transdermal, transrectal, Oral mucosa, epidural, sublingual.

  For example, after application, oral administration in the form of tablets, capsules, ovules, elixirs, solutions or suspensions suitable for immediate, delayed, modified, sustained, pulsed or controlled release of the compound can do. These preparations may contain fragrances or colorants. Tablets include excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and It may contain disintegrants such as certain silicic acid complexes and granulating binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. In addition, lubricants such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included. Similar types of solid ingredients can also be utilized as fillers in gelatin capsules. Preferred excipients in this regard include lactose, starch, cellulose, lactose or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the drug may be any of a variety of sweeteners or fragrances, coloring materials or pigments, emulsifiers and / or suspending agents, and diluents such as water, ethanol, propylene glycol and glycerin. Or can be prepared in combination with mixtures thereof.

  Upon formulation, the drug can be pulverized to a particle size suitable for tableting and other formulation types using known pulverization methods such as wet pulverization. Finely divided (nanoparticulate) drug preparations can be produced by methods known in the art (see WO 02/00196).

  When the pharmaceutical composition of the present invention is administered parenterally, for example, via an administration route such as intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurinary, intrasternal, intracranial, intramuscular or subcutaneous. And / or by infusion. For parenteral administration, the drug is best used in the form of a sterile aqueous solution, which contains sufficient salt or glucose to produce other substances, for example, isotonic solutions with blood. Also good. The aqueous solution is appropriately buffered if necessary (pH 3-9 is preferred). The production of parenteral preparations under sterile conditions can be easily performed by conventional pharmaceutical techniques well known to those skilled in the art.

  As noted above, the pharmaceutical compositions of the present invention can be administered intranasally or by inhalation, including from pressurized containers, pumps, sprays or nebulizers, dichlorodifluoromethane, tolchlorofluoromethane, dichlorotetrafluoroethane, Hydrofluoroalkanes such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane (eg Inneos Fluor), carbon dioxide or other suitable gas, etc. Delivery in the form of dry powder inhalation or sol spray using any suitable propellant is convenient. In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a measured amount. Pressurized containers, pumps, sprays or nebulizers contain, for example, drug solutions or suspensions with a mixture of ethanol and propellant as a solvent, which further includes lubricants such as sorbitan trioleate May be contained. Cartridges (eg, gelatinous) for use in capsules and inhalers can be formulated containing a powder mixture of drug and a suitable powder base (such as lactose or starch).

  Alternatively, the pharmaceutical composition of the present invention may be a suppository or vaginal suppository dosage form, or a dosage form for topical application of a gel, hydrogel, lotion, solution, cream, ointment or spray. . In addition, the pharmaceutical composition of the present invention can be made into a transdermal dosage form such as a skin patch. Furthermore, the dosage form may be administered via the pulmonary or rectal route. Moreover, it can be set as the dosage form for intraocular administration. For intraocular application, the drug may be formulated as a fine powder suspension in sterile saline, pH adjusted to isotonicity, or preferably with a preservative such as benzylalkonium chloride. It can be formulated as a solution in sterile physiological saline adjusted to be isotonic pH. Alternatively, it can be formulated in an ointment such as petrolatum.

  The pharmaceutical composition of the present invention for topical application to the skin is formulated as a suitable ointment containing, for example, a drug suspended or dissolved in a mixture of one or more of the following ingredients. Mineral oil, liquid petrolatum, white petrolatum, propylene glycol, emulsifying wax and water. Alternatively, it can be formulated as a suitable lotion or cream containing a drug suspended or dissolved in one or a mixture of two or more of the following ingredients. Mineral oil, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

The pharmaceutical composition of the present invention can be administered by direct injection.
The pharmaceutical composition of the present invention is preferably administered systemically (orally, buccal, sublingual, etc.), more preferably oral administration.
Therefore, the pharmaceutical composition of the present invention is preferably in a dosage form suitable for oral administration.

Usually, the optimal dose for an individual patient is determined by a physician. The specific dose level and dosing frequency for a particular individual will depend on the activity of the drug used, metabolic stability and duration of action, individual age, weight, overall health, sex and diet, mode of administration and time, elimination rate Can vary depending on a variety of factors, including concomitant medications, the severity of the particular condition, and even the treatment the individual is receiving.
For oral and parenteral administration to humans, the daily dose of the drug may be a single dose or a divided dose.

  The dosage of the drug (active ingredient) of the pharmaceutical composition of the present invention to a human (body weight of about 70 kg) is 0.1 mg to 1 g, preferably 1 mg to 500 mg (as the weight of the free base) per unit dose. The unit dose may be administered, for example, 1 to 4 times per day. The dose depends on the route of administration. Depending on the age and weight of the patient and the severity of the condition being treated, dosages will need to be routinely changed. The dose will also depend on the route of administration. The actual dose and route of administration will ultimately be at the discretion of the attending physician or veterinarian.

  In addition, the drug according to the present invention may be used in combination with other therapeutic agents. Accordingly, the present invention provides a combination preparation comprising a compound according to the present invention or a pharmaceutically acceptable derivative thereof together with other therapeutic drugs.

  When the compound according to the present invention or a pharmacologically acceptable derivative thereof is used in combination with a second drug that is active against the same disease pathology, the dosage of each drug is the same as when using them alone. It may be different from the dose. Appropriate doses can be readily appreciated by one skilled in the art. The amount of drug according to the present invention required for use in therapy varies depending on the nature of the condition to be treated and the age and symptoms of the patient, and is ultimately left to the judgment of the attending physician or veterinarian. It is done. Other active drugs that can be combined with the compound of formula (I) include, but are not limited to, those exemplified below. (a) other VLA-4 antagonists, (b) H1 histamine antagonists, (c) NSAIDs, (d) antidiabetic agents such as glitazones, (e) anticholinergic agents, (f) COX-2 inhibitors, (g) PDE-IV inhibitors, (h) steroids such as corticosteroids, (i) β agonists, (j) chemokine receptors such as CCR-2, CCR-3, CCR-5 and CCR-8 Antagonists, (k) appropriate multiple sclerosis drugs such as interferon and (l) LFA-1 antagonists.

  Pharmaceutical formulations for using the above combinations can be provided in a conventional manner, and therefore the present invention also includes pharmaceutical formulations containing the above combinations with a pharmaceutically acceptable carrier or excipient. To do. The individual components in such combinations can be administered sequentially or simultaneously from any convenient route of administration, as separate pharmaceutical formulations or combined pharmaceutical formulations. In the case of continuous administration, either the drug according to the present invention or the second therapeutic drug is administered first. In the case of simultaneous administration, the drugs used in combination can be administered in the same pharmaceutical preparation or in different pharmaceutical preparations.

  When used together in the same pharmaceutical formulation, the two drugs must be stable and compatible (coexisting) with each other and with other formulation components in the formulation. When formulated separately, each drug can be formulated in any convenient manner, but it is convenient to formulate each drug in a known manner.

The production method of the compound which is an active ingredient of the present invention will be described below by giving test examples, reference examples and production examples.
Test Example 1 Jarkat J6 Scintillation Proximity Assay (SPA)
The interaction between integrin VLA-4 (very late antigen-4; α4β1; CD49d, CD29) expressed on Jurkat J6 cell membrane and the test compound was examined by Jurkat J6 scintillation proximity assay.
Method
Wheat germ agglutinin coated SPA beads (Amersham, 1 mg / well) in J6 cells (1 million cells / well) in assay buffer containing 50 mM HEPES, 100 mM NaCl and 1 mM MnCl ₂ (pH adjusted to 7.5 with 4 M NaOH) ). Tritiated ³ H standard compound A (final concentration in assay 1 to ³ nM) and test compound are dissolved in a suitable solvent and diluted with assay buffer. Compounds are assayed once and fit to the four parameter curve fit of equation (I). The equilibrium dissociation constant of each compound was calculated according to the method of Cheng & Prusoff. Results (in vitro α ₄ β ₁ activity) were expressed in pKi.

（式中、ａは最小値、ｂは傾き、cはIC₅₀、ｄは最大値である。）
ここで、最大値および最小値は、化合物の非存在下、および2mM EDTA二カリウム塩(シグマケミカルズ,UK、製品番号ED2P)の存在下での接着と比較した場合の値である。データは平均pIC₅₀で示す。
後述の製造例で得た化合物を上記の方法で試験したところ、以下の表に示すように、全ての場合、pＫiは６.５以上であった。
表 １ ジャルカットJ6シンチレーション近接アッセイ Standard compound A is (2S) -3- [4-({[4- (aminocarbonyl) -1-piperidyl] carbonyl} oxy) phenyl] -2-[((2S) -4-methyl-2-{[ 2- (2-methylphenoxy) acetyl] amino} pentanoyl) amino] propanoic acid potassium salt (WO 00/37444). Production of the tritiated ³ H derivative was carried out according to a conventional method.
Equation (I):

(In the formula, a is the minimum value, b is the slope, c is IC ₅₀ , and d is the maximum value.)
Here, the maximum and minimum values are values compared to adhesion in the absence of compound and in the presence of 2 mM EDTA dipotassium salt (Sigma Chemicals, UK, product number ED2P). Data are shown as mean pIC ₅₀ .
When the compounds obtained in the production examples described later were tested by the above method, the pKi was 6.5 or more in all cases as shown in the following table.
Table 1. Jurkat J6 Scintillation Proximity Assay

Reference Example 1: 3- (4-Nitrophenyl) pyridine (S1)
1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) (0.2 g, 0.2 mmol) was stirred and degassed with 4-bromonitrobenzene (5 g, 24.8 mmol) and pyridine-3-boronic acid ( 3.4 g, 27.2 mmol) in dimethylformamide (50 mL) and 2N aqueous sodium carbonate (20 mL). The reaction mixture was stirred at 100 ° C. for 18 hours and then allowed to cool. The solution was filtered through celite (diatomaceous earth), ethyl acetate (200 mL) was added, and the organic phase was washed 3 times with saturated brine (200 mL). The organic phase was dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography (elution solvent: 30% (v / v) ethyl acetate in petroleum ether) to give the title compound as a solid.

Reference Example 2: 3- (4-Nitrophenyl) pyridine-1-oxide (S2)
m-Chloroperbenzoic acid (6.9 g, 40.0 mmol) was slowly added to a solution of 3- (4-nitrophenyl) pyridine (S1, 4 g, 20.0 mmol) in tetrahydrofuran (200 mL), and the reaction mixture was stirred at room temperature. Stir for 1 hour. This solution was poured into an aqueous sodium thiosulfate solution, and the resulting mixture was concentrated. Trituration with ethyl acetate gave the title compound as a solid.

Reference Example 3: 3- (4-Nitrophenyl) -1H-pyridin-2-one (S3)
3- (4-Nitrophenyl) pyridine-1-oxide (S2, 2.5 g, 11.6 mmol) was heated to reflux in acetic anhydride (25 mL) for 18 hours and then allowed to cool. The reaction mixture was concentrated and concentrated hydrochloric acid (25 mL) was added. The solution was heated to reflux for 4 hours and then allowed to cool. The reaction mixture was poured into ice water, filtered and then dried under high vacuum to give the title compound as a solid.

Reference Example 4: 3- (4-Hydroxymethylphenyl) acrylic acid ethyl ester (S4)
4-Bromobenzyl alcohol (10.5 g, 56.1 mmol), triphenylphosphine (0.5 g, 1.9 mmol) and palladium acetate (0.5 g, 2.2 mmol) were dissolved in ethyl acrylate (20 mL) and triethylamine (100 mL). After heating at reflux for an hour, the mixture was allowed to cool. The reaction mixture was filtered through celite (diatomaceous earth) and concentrated. The crude solid was purified by silica gel chromatography (elution solvent: 20% (v / v) ethyl acetate in petroleum ether) to give the title compound as an oil.

Reference Example 5: 3- (4-Hydroxymethylphenyl) propionic acid ethyl ester (S5)
3- (4-Hydroxymethylphenyl) acrylic acid ethyl ester (S4, 3 g, 14.5 mmol) and palladium on carbon (0.3 g) were stirred in ethanol (30 mL) under a normal pressure hydrogen atmosphere for 4 hours. The reaction mixture was filtered through celite (diatomaceous earth) and concentrated to give the title compound as an oil.

Reference Example 6: 3- (4-Chloromethylphenyl) propionic acid ethyl ester (S6)
To a stirred solution of 3- (4-hydroxymethylphenyl) propionic acid ethyl ester (S5, 2.9 g, 13.9 mmol) in triethylamine (4.0 mL, 27.8 mmol) and dichloromethane (30 mL) was added mesyl chloride (1.6 mL, 20.9 mmol). mmol) was added slowly at 0 ° C. The solution was stirred at room temperature for 18 hours and washed with 1N hydrochloric acid. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the title compound as an oil.

Reference Example 7: 3- {4- [3- (4-Nitrophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (S7)
3- (4-Nitrophenyl) -1H-pyridin-2-one (S3, 200 mg, 0.93 mmol), 3- (4-chloromethylphenyl) propionic acid ethyl ester (S6, 270 mg, 1.20 mmol) and carbonic acid Cesium (900 mg, 2.78 mmol) was stirred in dimethylformamide (5 mL) at room temperature for 18 hours. The reaction mixture was filtered through celite (diatomaceous earth), concentrated and the crude mixture was purified by silica gel chromatography (elution solvent: 50% (v / v) ethyl acetate in petroleum ether) to give the title compound as a solid.

Reference Example 8: 3- {4- [3- (4-aminophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (S8)
3- {4- [3- (4-Nitrophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (S7, 300 mg, 0.74 mmol) and palladium in ethanol (10 mL) Carbon (30 mg) was stirred at room temperature for 3 hours under atmospheric hydrogen atmosphere, and the reaction mixture was filtered through Celite and concentrated. The crude oil was purified by silica gel chromatography (elution solvent: 50% (v / v) ethyl acetate in petroleum ether) to give the title compound as an oil.

Reference Example 9: 3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl) -2H-pyridin-1-ylmethyl} phenyl) propionic acid ethyl ester (S9)
3- {4- [3- (4-aminophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (S8, 60 mg, 0.16 mmol) and o-tolyl isocyanate (40 μL, 0.32 mmol) was stirred in dichloromethane (5 mL) at room temperature for 3 hours and the reaction mixture was concentrated. Trituration with diethyl ether gave the title compound as a solid.

Reference Example 10: 3- {4- [3- (4-aminophenyl) -5-chloro-2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (S10)
Ethanol (10 mL) of 3- (4- [5-chloro-3- (4-nitrophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid ethyl ester (0.31 g, 0.72 mmol) Acetic acid (1 mL) and iron (160 mg, 2.9 mmol) were sequentially added to a solution of water (5 mL) with stirring, and the mixture was heated to reflux for 2 hours and then allowed to cool to room temperature. The mixture was filtered through a pad of celite (diatomaceous earth), the filtrate was evaporated to dryness, the residue was taken up in aqueous sodium bicarbonate / ethyl acetate, and the organic layer was washed with saturated brine. Washed, dried over anhydrous sodium sulfate, filtered, evaporated to dryness and purified by silica gel chromatography (elution solvent: gradient elution with 30-50% ethyl acetate in hexane) to give the title compound as an oil. .

Reference Example 11: (±) -3- {4- [3- (4-Aminophenyl-2-oxo-2H-pyridin-1-ylmethyl] phenyl} butyric acid methyl ester (S11)
Sodium borohydride (0.042 g, 1.1 mmol) was added to a solution of nickel dichloride hexahydrate (0.088 g, 0.37 mmol) in methanol (15 mL), and the mixture was stirred at room temperature for 30 minutes, then (E)- 3- {4- [3- (4-Nitrophenyl) -2H-oxo-2-pyridin-1-yl] phenyl} but-2-enoic acid methyl ester (0.3 g, 0.74 mmol) in methanol (10 mL) The solution was added. Additional sodium borohydride (0.098 g, 2.59 mmol) was added and stirring was continued overnight. Then sodium borohydride (0.15 g, 3.96 mmol) was added to complete the reaction. The mixture was filtered through celite, washed with methanol (50 mL), and the filtrate was concentrated under reduced pressure. The residue was extracted with chloroform (2 × 50 mL), the organic phase was washed with water (20 mL), the organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the title compound as an oil. Obtained.

  For the above synthesis, (E) -3- {4- [3- (4-nitrophenyl) -2H-oxo-2-pyridin-1-yl] phenyl} but-2-enoic acid methyl ester is Prepared from the compound (S3) obtained in Reference Example 3 and (E) -3- (4-methanesulfonyloxymethylphenyl) but-2-enoic acid methyl ester by the method of Reference Example 7, and (E) -3- (4-Methanesulfonyloxymethylphenyl) but-2-enoic acid methyl ester was obtained from (E) -3- (4-hydroxymethylphenyl) but-2-enoic acid methyl ester and methanesulfonyl chloride according to the method of Reference Example 6; Prepared by a similar method (in this case most were isolated as mesylate rather than chloride). (E) -3- (4-Hydroxymethylphenyl) but-2-enoic acid methyl ester was prepared from 4-bromobenzyl alcohol and methyl crotonic acid in the same manner as in Reference Example 4.

Reference Example 11a: (±) 3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) butyric acid methyl ester (S11a)
(±) -3- {4- [3- (4-Aminophenyl-2-oxo-2H-pyridin-1-ylmethyl] phenyl} butyric acid methyl ester (S11) and the title compound according to the method described in Reference Example 9 Prepared from o-tolyl isocyanate.

Reference Example 12: 1- [3-Fluoro-4- (2-methoxypyridin-3-yl) phenyl] -3-o-tolylurea (S12)
1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) (0.1 g) was replaced with 1- (4-bromo-3-fluorophenyl) -3-o-tolylurea (0.5 g, 1.5 mmol) and 2 -Methoxypyrid-3-ylboronic acid (258 mg, 1.7 mmol) in dimethylformamide (10 mL) and sodium carbonate aqueous solution (5 mL, 2N) in stirred degassed solution. The reaction mixture was stirred at 100 ° C. for 18 hours and then allowed to cool. The solution was concentrated then ethyl acetate (75 mL) was added and the organic phase was washed with water (3 × 75 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography (elution solvent: 20-40% (v / v) ethyl acetate in hexanes) to give the title compound as an oil.
MS (ES + ve) m / z: 352 [M + H] ⁺ (C ₂₀ H ₁₈ FN ₃ O ₂ ; m / z: 352 [M + H] ⁺ ).

Reference Example 13: 1- [3-Fluoro-4- (2-oxo-1,2-dihydropyridin-3-yl) phenyl] -3-o-tolylurea (S13)
1- [3-Fluoro-4- (2-methoxypyridin-3-yl) phenyl] -3-o-tolylurea (S12) (0.150 g, 0.43 mmol) in ethanolic hydrochloric acid (10 mL) was refluxed for 8 hours. While stirring. The reaction mixture was then allowed to cool and concentrated to give the title compound as a solid. MS (ES + ve) m / z: 338 [M + H] ⁺ (C ₁₉ H ₁₆ FN ₃ O ₂ ; m / z: 338 [M + H] ⁺ ).

Reference Example 14: Ethyl 4- [2-((S) -2-hydroxy-1-phenylethylcarbamoyl) -1- (R, S) -methylethyl] benzoate (S14)
Cooled in an ice bath, ethyl 4- (2-carboxy-1-methylethyl) benzoate (JI DeGraw et al. J. Med. Chem. 1986, 29, 1056) (3.54 g, 15 mmol) in dichloromethane (100 To the solution, oxalyl chloride (3.9 mL, 45 mmol) was added. Dimethylformamide (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residual acid chloride was dissolved in dichloromethane (60 mL) and dissolved in an ice-cold mixture of (S) -2-phenylglycinol (2.72 g, 20 mmol) and triethylamine (6.3 mL, 45 mmol) in dichloromethane (60 mL). Added over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid was added and the organic phase was separated then washed with water, dried over anhydrous magnesium sulfate and concentrated. The diastereomeric products were separated and obtained by flash chromatography (elution solvent: ethyl acetate followed by ethyl acetate / methanol (9: 1)).
Previously eluted (SS) diastereomer (S14a): TLC (silica gel; ethyl acetate) R _f 0.36; MS (ES + ve) m / z: 356 [M + H] ⁺ (C ₂₁ H ₂₅ NO ₄ , m / z: 356 [M + H] ⁺ )
Later eluting (RS) diastereomers (S14b): TLC (silica gel; ethyl acetate) R _f 0.19; MS (ES + ve): m / z: 356 [M + H] ⁺ , (C ₂₁ H ₂₅ NO ₄ ; m / z: 356 [M + H] ⁺ ).

Reference Example 15: 3- (R and S)-(4-hydroxymethylphenyl) -N-((S) -2-hydroxy-1-phenylethyl) butyramide (S15a and S15b)
A solution of lithium borohydride in tetrahydrofuran (2M, 15 mL, 30 mmol) was added to a solution of diastereomer (S14b) (2.42 g, 6.81 mmol) eluting later in tetrahydrofuran (100 mL). Methanol (1 mL) was added dropwise and the reaction mixture was stirred at room temperature for 2 hours. Additional lithium borohydride in tetrahydrofuran (2M, 10 mL, 20 mmol) and methanol (0.8 mL) were added and the mixture was stirred for an additional 3 hours and then cooled in an ice bath. 2M hydrochloric acid (100 mL) was carefully added and the mixture was concentrated in vacuo. Ethyl acetate was added, and the organic phase was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to obtain the (RS) diastereomer (S15b) of the title compound.
MS (ES-ve) m / z: 312 [MH] ⁻ (C ₁₉ H ₂₃ NO ₃ ; m / z: 312 [MH] ⁻ ).

  In a similar manner, the (SS) diastereomer (S15a) was prepared from the previously eluted diastereomer (S14a).

Reference Example 16: Methyl (R)-(-)-3- (4-hydroxymethylphenyl) butyrate (S16)
3N sulfuric acid (85 mL) was added to a diastereomer (S15b) (2.0 g, 6.38 mmol) in dioxane (85 mL). The mixture was heated at reflux for 6 hours, cooled and concentrated in vacuo. The concentrate was extracted three times with ethyl acetate, and the combined organic phases were washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residual solid was dissolved in methanol (90 mL) and concentrated sulfuric acid (2 mL) was added. The mixture was refluxed for 1 hour, cooled and concentrated in vacuo. Water and ethyl acetate were added, and the organic phase was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purification by flash chromatography (elution solvent: ethyl acetate / hexane (1: 1)) gave the title compound as a colorless oil. [α] _D ^{30 ° C.} −41.2 ° (c = 1.0, MeOH).

Reference Example 17: methyl (S)-(+)-3- (4-hydroxymethylphenyl) butyrate (S17)
The title compound was prepared from diastereomer (S15a) by a method similar to the method described in Reference Example 16. [α] _D ^{30 ° C.} + 42.4 ° (c = 1.0, MeOH).

Reference Example 18: (R)-(-)-3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) methyl butyrate (S18)
To a dichloromethane solution of the product of Reference Example 16 (S16) (0.4 g, 1.92 mmol) was added triethylamine (0.3 mL, 0.22 mmol) and then methanesulfonyl chloride (0.16 mL, 2.1 mmol) at 0 ° C. The mixture was stirred at 0 ° C. for 2 hours, then washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting mesylate was dissolved in dimethylformamide (20 mL) and 1- [4- (2-oxo-1,2-dihydropyridin-3-yl) phenyl] -3-o-tolylurea (0.612 g, 1.92 mmol) And cesium carbonate (1.25 g, 3.84 mmol) was added. The mixture was stirred at room temperature for 3 hours and concentrated in vacuo. The residue was partitioned between ethyl acetate and water, and the organic phase was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (elution solvent: ethyl acetate / toluene mixture) gave the title compound as a colorless gum. [α] _D ^{26 ° C.} −17.2 ° (c = 0.5, MeOH); MS (ES + ve) m / z: 510 [M + H] ⁺ (C ₃₁ H ₃₁ N ₃ O ₄ ; m / z: 510 [ M + H] ⁺ ).

Reference Example 19: (S)-(+)-3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) methyl butyrate (S19)
The title compound was produced from the compound (S17) obtained in Reference Example 17 by a method similar to that of Reference Example 18. [α] _D ^{30 ° C.} + 17.0 ° (c = 0.5, MeOH); MS (ES + ve) m / z: 510 [M + H] ⁺ (C ₃₁ H ₃₁ N ₃ O ₄ ; m / z: 510 [ M + H] ⁺ ).

Reference Example 20: 4- [2-Ethoxycarbonylethyl] phenylboronic acid (S20)
4- (2-Carboxyethyl) phenylboronic acid (4 g, 20.6 mmol) was stirred in ethanolic hydrochloric acid for 24 hours under reflux. The reaction mixture was cooled and then concentrated to give the title compound as an oil.

Reference Example 21: 3- (4-Pyridin-3-ylphenyl) propionic acid ethyl ester (S21)
1,1'-bis (diphenylphosphino) ferrocenedichloropalladium (II) (0.1 g, 0.1 mmol), 3-bromopyridine (1.5 ml, 15.6 mmol) and 4- [2-ethoxycarbonylethyl] phenylboronic acid (S20) (3.5 g, 15.8 mmol) was added to a stirred degassed solution of dimethylformamide (30 mL) and 2N aqueous sodium carbonate (15 mL). The reaction mixture was stirred at 100 ° C. for 18 hours and then allowed to cool. The solution was filtered through celite, ethyl acetate (100 mL) was added, and the organic phase was washed 3 times with saturated brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by silica gel chromatography (elution solvent: 30% (v / v) ethyl acetate in petroleum ether) to give the title compound as an oil.

Reference Example 22: 3- [4- (3- {4-[(1-2,3-dihydroindol-1-ylmethanoyl) amino] phenyl} -2-oxo-2H-pyridin-1-ylmethyl) phenyl] propion Acid methyl ester (S22)
3- {4- [3- (4-aminophenyl) -2-oxo-2H-pyridin-1-ylmethyl] phenyl} propionic acid methyl ester in triphosgene (0.135 g, 0.45 mmol) in tetrahydrofuran (5 mL) To a stirred solution in tetrahydrofuran (5 mL) was added at 0 ° C. Two hours later, a solution of indoline (0.054 g, 0.45 mmol) in tetrahydrofuran (2.5 mL) was added, and stirring was continued at room temperature for 18 hours. The mixture was poured into ethyl acetate (25 mL), washed successively with hydrochloric acid (10 mL, 1M), saturated aqueous sodium bicarbonate (10 mL) and saturated brine, and dried over anhydrous magnesium sulfate. After filtration and evaporation to dryness, the residue was treated with silica gel chromatography (elution solvent: ethyl acetate / hexane = 1: 1 to 3: 1 ascending gradient elution) to give the title compound as a solid.

Reference Example 23: (±) -3- (3- {2-oxo-3- [4- (3-o-tolylureido) phenyl] piperidin-1-ylmethyl} phenyl) propionic acid ethyl ester (S23)
(E) -3- {3- [3- (4-Nitrophenyl-2-oxo-2H-pyridin-1-ylmethyl] phenyl} acrylic acid ethyl ester (85 mg, 0.21 mmol) in ethanol (20 mL) 10 The reaction mixture was then filtered through Celite, evaporated to dryness and purified by silica gel chromatography (elution solvent: 70% ethyl acetate / petroleum ether) to give the title compound. Was obtained as an oil.
MS (AP + ve) m / z: 381 [M + H] ⁺ (C ₂₃ H ₂₈ N ₂ O ₃ , m / z: 381 [M + H] ⁺ ).

Reference Example 24: 3- {4- [3- (4-Nitrophenyl) -2-oxo-2H-pyridin-1-yl] phenyl} propionic acid ethyl ester (S24)
3- (4-nitrophenyl) -1H-pyridin-2-one (S3) (0.2 g, 0.92 mmol), copper (II) acetate (0.334 g, 2 eq), diisopropylethylamine (0.31 mL, 2 eq) and Pyridine (0.15 mL, 2 eq) was added to a stirred solution of 4- (2-ethoxycarbonylethyl) phenylboronic acid (0.308 g, 1.3 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature under argon for 4 hours. The solution was then filtered through celite, concentrated and purified by chromatography on silica gel (eluent: 50% (v / v) ethyl acetate in hexanes) to give the title compound as an oil.
MS (ES + ve) m / z: 393 [M + H] ⁺ (C ₂₂ H ₂₀ N ₂ O ₅ ; m / z 393: [M + H] ⁺ ).

Production Example 1: 3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) propionic acid (P1)

3-(4-{2-オキソ-3-[4-(3-o-トリルウレイド)フェニル)-2H-ピリジン-1-イルメチル}フェニル)プロピオン酸エチルエステル(S9, 55 mg, 0.11 mmol)および水酸化リチウム(50 mg, 2.5 mmol)を、テトラヒドロフラン(5 mL)および水(5 mL)中、60℃で30分間攪拌した。反応混合物を1N塩酸を用いてpH１まで酸性にし、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥し、蒸発乾固して表題の化合物を固体として得た。
¹H NMR δ (DMSO-d6): 2.21-2.27 (5H, m), 2.73-2.80 (2H, t), 5.12 (2H, s), 6.28-6.34 (1H, t), 6.89-6.95 (1H, m), 7.12-7.25 (6H, m), 7.51-7.63 (5H, m), 7.68-7.77 (2H, m), 9.28 (1H, s), 10.47 (1H, s)
MS (APCI-ve) m/z： 481[M]^-；m/z：480[M-H]^- (C₂₉H₂₇N₃O₄；m/z 480[M-H]^-)。

3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl) -2H-pyridin-1-ylmethyl} phenyl) propionic acid ethyl ester (S9, 55 mg, 0.11 mmol) and Lithium hydroxide (50 mg, 2.5 mmol) was stirred in tetrahydrofuran (5 mL) and water (5 mL) at 60 ° C. for 30 minutes. The reaction mixture was acidified with 1N hydrochloric acid to pH 1 and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness to give the title compound as a solid.
¹ H NMR δ (DMSO-d6): 2.21-2.27 (5H, m), 2.73-2.80 (2H, t), 5.12 (2H, s), 6.28-6.34 (1H, t), 6.89-6.95 (1H, m), 7.12-7.25 (6H, m), 7.51-7.63 (5H, m), 7.68-7.77 (2H, m), 9.28 (1H, s), 10.47 (1H, s)
MS (APCI-ve) m / z: 481 [M] ⁻ ; m / z: 480 [MH] ⁻ (C ₂₉ H ₂₇ N ₃ O ₄ ; m / z 480 [MH] ⁻ ).

Production Example 2: 3- (3- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) propionic acid (P2)
The title compound was prepared in a manner similar to that described in Preparation Example 1.
MS (ES + ve) m / z: 482 [M + H] ⁺ (C ₂₉ H ₂₇ N ₃ O ₄ , m / z: 482 [M + H] ⁺ ).

  The production example compounds described in Table 2 were produced by the same method as that described in Production Example 1 unless otherwise specified. Examples of production employing this method modification (represented as P7, P9, P11, P23, P30, P31, P32, P34, and P35, respectively) will be described later.

Table 2

Production Example 7: 3- (4- {5-Chloro-2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) propionic acid (P7)
The title compound was prepared in a manner similar to that described in Preparation 1 but with an additional step of chlorine introduction. 3- (4-Nitrophenyl) -1H-pyridin-2-one (S3) was prepared in a manner similar to that described in the literature (Imming et al., European J. Med. Chem. 36 (4), 375 (2001)). The method was treated with N-chlorosuccinimide to give 5-chloro-3- (4-nitrophenyl) -1H-pyrid-2-one. The change from the production method of Production Example 7 is that the nitro group is reduced by the method described in Reference Example 10.

Production Example 9: (±) -3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) butyric acid (P9)
(±) -3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) butyric acid methyl ester (0.21 g, 0.41 mmol) Was dissolved in tetrahydrofuran (3 mL), and an aqueous lithium hydroxide solution (0.5 M, 3 mL) was added with stirring. The mixture was heated at 65 ° C. for 2 hours, allowed to cool, and concentrated under reduced pressure. The mixture was acidified with hydrochloric acid (2M), extracted with ethyl acetate (2 × 25 mL), and the combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. Filtration and evaporation to dryness afforded the title compound as a white solid.
¹ H NMR δ (DMSO-d6): 11.92 (1H, br s), 9.08 (1H, s), 7.92 (1H, s), 7.85 (1H, d), 7.80 (1H, dd), 7.65 (2H, d), 7.59 (2H, d), 7.27 (2H, d), 7.22 (2H, d), 7.10-7.20 (2H, m), 6.94 (1H, t), 6.34 (1H, t), 5.14 (2H , s), 3.11 (1H, m), 2.25 (3H, s), 1.18 (3H, d).

Production Example 11: [Methyl- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) amino] acetic acid (P11)
Potassium trimethylsilanolate (0.035 g, 0.25 mmol) to [methyl- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) Amino] acetic acid ethyl ester (0.90 g, 0.17 mmol) in tetrahydrofuran (5 mL) was added and the mixture was stirred at room temperature for 2 hours. A solution of hydrochloric acid in diethyl ether (1M, 1 mL) was added and the solvent was concentrated. The residue was triturated with diethyl ether, filtered and dried to give the title compound as a solid.
¹ H NMR δ (DMSO-d6): 9.35 (1H, s), 8.10 (1H, s), 7.85 (1H, d), 7.75 (1H, dd), 7.65 (2H, d), 7.55 (1H, dd ), 7.47 (2H, d), 7.22 (2H, d), 7.10-7.20 (2H, m), 6.94 (1H, t), 6.61 (2H, d), 6.30 (1H, t), 5.03 (2H, s), 4.06 (2H, s), 2.94 (3H, s), 2.26 (3H, s).

According to the method described in Reaction Scheme 1, the compound [methyl- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) amino] acetic acid The ethyl ester was prepared.
Reaction formula 1

Production Example 23: 2-acetylamino-3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) propionic acid (P23)
The title compound was prepared by standard methods described herein. The alkylating agent was prepared from the alcohol obtained from the coupling of 4-bromobenzyl alcohol and methyl 2-methylacetamidoacrylate by the same method as described in Reference Example 4.

Production Example 30: 3- (4- {3- [2-Fluoro-4- (3-o-tolylureido) phenyl] -2-oxo-2H-pyridin-1-ylmethyl} phenyl) propionic acid (P30)
The title compound was prepared according to the methods described in Reference Examples 12 and 13, followed by alkylation by the method of Reference Example 7 and hydrolysis by the general method of Preparation Example 1.

Production Example 31: (S)-(+)-3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) butyric acid ( (P31)
The title compound was produced from the compound (S19) obtained in Reference Example 19 by a method similar to the method described in Production Example 32 later described. [α] _D ^{30 ° C.} + 14.0 ° (c = 0.5, MeOH); MS (ES + ve): m / z: 496 [M + H] ⁺ (C ₃₀ H ₂₉ N ₃ O ₄ ; m / z: 496 [M + H] ⁺ ).

Production Example 32: (R)-(-)-3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] -2H-pyridin-1-ylmethyl} phenyl) butyric acid ( (P32)
To a solution of the compound of Reference Example 18 (S18, 1.02 g, 2.0 mmol) in tetrahydrofuran (40 mL) was added an aqueous solution of lithium hydroxide (0.5M, 40 mL, 20 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated. Ethyl acetate was added and the mixture was acidified by adding 2N hydrochloric acid. The organic phase was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. Trituration with diethyl ether gave the title compound as a white solid; [α] _D ^{30 ° C.-} 14.2 ° (c = 0.5, MeOH); MS (ES + ve) m / z: 496 [M + H ] ⁺ (C ₃₀ H ₂₉ N ₃ O ₄ ; m / z: 496 [M + H] ⁺ ).

  Chiral ethyl substituted analogs (P34) and (P35) were similarly prepared from the corresponding methyl analogs (P31) and (P32). The required precursor 4- (1-carboxymethylpropyl) benzoic acid methyl ester was prepared from 4-hydroxypropiophenone by standard methods in four steps (corresponding triflate formation, to obtain the methyl ester Carbonylation with palladium acetate in the presence of methanol, Wittig reaction with anion of dimethyl (benzyloxycarbonyl) methylphosphonate to obtain a mixture of unsaturated benzyl esters, hydrogenation to obtain the required saturated acid) .

Production Example 38: 3- (4- {2-oxo-1- [4- (3-o-tolylureido) benzyl] -1,2-dihydropyridin-3-yl} phenyl) propionic acid (P38)

表題の化合物を製造するために用いる方法は製造例１および関連する参考例に記載の方法と同様の方法である。中間体ピリジンとして参考例20および21の方法で製造した3-(4-ピリジン-3-イルフェニル)プロピオン酸エチルエステルを用いた。次いで酸化および必要とするピリドンへの転位により、アルキル化のための適当な前駆体を得る。次いで、製造例１記載の方法で加水分解し、表題の化合物を固体として得た。
MS (APCI+ve) m/z： 482[M+H]⁺ (C₂₉H₂₇N₃O_4； m/z_： 482[M+H]⁺)。

The method used to produce the title compound is similar to the method described in Production Example 1 and related reference examples. As an intermediate pyridine, 3- (4-pyridin-3-ylphenyl) propionic acid ethyl ester prepared by the method of Reference Examples 20 and 21 was used. The appropriate precursor for alkylation is then obtained by oxidation and rearrangement to the required pyridone. Subsequently, hydrolysis was performed by the method described in Production Example 1 to obtain the title compound as a solid.
MS (APCI + ve) m / z: 482 [M + H] ⁺ (C ₂₉ H ₂₇ N ₃ O _4; m / z _: 482 [M + H] ⁺ ).

Production Example 39: 3- [4- (3- {4-[(2,3-Dihydroindol-1-ylmethanoyl) amino] phenyl} -2-oxo-2H-pyridin-1-ylmethyl) phenyl] propionic acid ( (P39)

製造例１に記載の方法により、対応するメチルエステル(S22)から表題の化合物を固体として製造した。
MS (ES+ve) m/z： 494[M+H]⁺ (C₃₀H₂₇N₃O₄； m/z： 494[M+H]⁺)。

The title compound was produced as a solid from the corresponding methyl ester (S22) by the method described in Production Example 1.
MS (ES + ve) m / z: 494 [M + H] ⁺ (C ₃₀ H ₂₇ N ₃ O ₄ ; m / z: 494 [M + H] ⁺ ).

Production Example 40: 3- {4- [2'-oxo-5- (3-o-tolylureido) -2'H- [2,3 '] bipyridinyl-1'-ylmethyl] phenyl} propionic acid (P40)
The title compound was prepared by the method shown in Reaction Scheme 2.
MS (ES + ve) m / z: 483 [M + H] ⁺ (C ₂₈ H ₂₆ N ₄ O ₄ ; m / z: 483 [M + H] ⁺ ).
Reaction formula 2

製造例41：(S)-(＋)-3-{4-[2'-オキソ-5-(3-o-トリルウレイド)-2'H-[2,3']ビピリジニル-1'-イルメチル]フェニル}酪酸ナトリウム塩(P41)

Production Example 41: (S)-(+)-3- {4- [2'-oxo-5- (3-o-tolylureido) -2'H- [2,3 '] bipyridinyl-1'-ylmethyl ] Phenyl} butyric acid sodium salt (P41)

製造例42と同様の方法で対応するメチルエステルから表題の化合物を固体として製造した。[α]_D ^30℃ ＋12.5°(c＝1.0, MeOH); MS (ES+ve) m/z： 497[M+H]⁺ (C₂₉H₂₈N₄O₄； m/z 497[M+H]⁺)。

The title compound was produced as a solid from the corresponding methyl ester in the same manner as in Production Example 42. [α] _D ^{30 ° C.} + 12.5 ° (c = 1.0, MeOH); MS (ES + ve) m / z: 497 [M + H] ⁺ (C ₂₉ H ₂₈ N ₄ O ₄ ; m / z 497 [ M + H] ⁺ ).

Production Example 42: (R)-(−)-3- {4- [2′-oxo-5- (3-o-tolylureido) -2′H- [2,3 ′] bipyridinyl-1′-ylmethyl ] Phenyl} butyric acid sodium salt (P42)
To a solution of the corresponding methyl ester (60 mg, 0.118 mmol) in tetrahydrofuran (5 mL) was added lithium hydroxide aqueous solution (0.5M, 5 mL, 2.5 mmol). The mixture was stirred at room temperature for 3 hours. Water (50 mL) and 2M hydrochloric acid (2 mL) were added. After adding saturated sodium bicarbonate (5 mL) to the resulting suspension, the solution was passed through a 10 g tC18 Sep-Pak® cartridge (Waters). The column was washed with dilute sodium bicarbonate, then eluted with a water / methanol mixture and concentrated to give the title compound as a solid [α] _D ^{30 ° C.} −12.3 ° (c = 1.0, MeOH). MS (ES + ve) m / z: 497 [M + H] ⁺ (C ₂₉ H ₂₈ N ₄ O ₄ , m / z: 497 [M + H] ⁺ ).
Production Example 43: (R)-(-)-3- {4- [2-oxo-6 '-(3-o-tolylureido) -2H- [3,3'] bipyridinyl-1-ylmethyl] phenyl} Butyric acid / hydrochloride (P43)

製造例11記載の方法により製造例43の化合物を固体として製造した。
MS (APCI+ve) m/z： 497[M+H]⁺ (C₂₉H₂₈N₄O₄・HCl，m/z： 497[M+H]⁺)。[α]_D ^29.4℃ −10.7°(c＝1.0, MeOH)。
製造例44：(R)-(-)-3-{4-[2'-オキソ-5-(3-フェニルウレイド)-2'H-[2,3']ビピリジニル-1'-イルメチル]フェニル}酪酸・塩酸塩(P44)

The compound of Production Example 43 was produced as a solid by the method described in Production Example 11.
MS (APCI + ve) m / z: 497 [M + H] ⁺ (C ₂₉ H ₂₈ N ₄ O ₄ · HCl, m / z: 497 [M + H] ⁺ ). [α] _D ^{29.4 ° C.} −10.7 ° (c = 1.0, MeOH).
Production Example 44: (R)-(-)-3- {4- [2'-oxo-5- (3-phenylureido) -2'H- [2,3 '] bipyridinyl-1'-ylmethyl] phenyl } Butyric acid / hydrochloride (P44)

製造例11記載の方法により製造例44の化合物を固体として製造した。
MS (APCI+ve) m/z： 483[M+H]⁺ (C₂₈H₂₆N₄O₄・HCl； m/z： 483[M+H]⁺)。[α]_D ^26.6℃ −13.2° (c＝0.5, MeOH)。
製造例45：(R)-(-)-3-(4-{5-[3-(2-フルオロフェニル)ウレイド]-2'-オキソ-2H-[2,3']ビピリジニル-1'-イルメチル}フェニル)酪酸・塩酸塩(P45)

The compound of Production Example 44 was produced as a solid by the method described in Production Example 11.
MS (APCI + ve) m / z: 483 [M + H] ⁺ (C ₂₈ H ₂₆ N ₄ O ₄ · HCl; m / z: 483 [M + H] ⁺ ). [α] _D ^{26.6 ° C} -13.2 ° (c = 0.5, MeOH).
Production Example 45: (R)-(-)-3- (4- {5- [3- (2-fluorophenyl) ureido] -2'-oxo-2H- [2,3 '] bipyridinyl-1'- (Ilmethyl} phenyl) butyric acid / hydrochloride (P45)

製造例11記載の方法により製造例45の化合物を固体として製造した。
MS (APCI+ve) m/z： 501[M+H]⁺ (C₂₈H₂₅FN₄O₄.HCl； m/z： 501 [M+H]⁺)。[α]_D ^29℃−10.3°(c＝0.5、MeOH)。

The compound of Production Example 45 was produced as a solid by the method described in Production Example 11.
MS (APCI + ve) m / z: 501 [M + H] ⁺ (C ₂₈ H ₂₅ FN ₄ O ₄ .HCl; m / z: 501 [M + H] ⁺ ). [[alpha]] _D ²⁹ [ ^deg. ] ^C -10.3 [ ^deg. ] (c = 0.5, MeOH).

Production Example 46: (±) -3- (3- {2-oxo-3- [4- (3-o-tolylureido) phenyl] piperidin-1-ylmethyl} phenyl) propionic acid (P46)
The title compound was produced in the same manner as in Production Example 1 except that the hydrogenation step was performed under the modified conditions detailed in Reference Example 23.

The production example compounds listed in Table 3 were produced in the same manner as described in Production Example 46 unless otherwise specified. A variation of this method is described in Preparation Example 50 below.
Table 3

Production Example 50: 3- (4- {2-oxo-3- [4- (3-o-tolylureido) phenyl] piperidin-1-yl} phenyl) propionic acid (P50)
The title compound was prepared from 3- {4- [3- (4-nitrophenyl) -2-oxo-2H-pyridin-1-yl] phenyl} propionic acid ethyl ester. After performing the method described in Reference Example 24, hydrogenation, urea formation and hydrolysis steps (respectively similar to the method described in Reference Example 23, the method described in Reference Example 9 and the method described in Production Example 1) are performed, The title compound was prepared.

Treatment or prevention of various diseases the pharmaceutical composition is effective inhibition of alpha ₄ integrin mediated cell adhesion of the present invention containing compounds of formula (I) and its pharmacologically acceptable derivatives as an active ingredient For example, rheumatoid arthritis, asthma, allergic disease, adult respiratory distress syndrome, AIDS dementia, Alzheimer's disease, cardiovascular disease, thrombosis or harmful platelet aggregation, reocclusion after thrombolysis, reperfusion Injury, skin inflammatory disease, diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, disease involving leukocyte infiltration into the gastrointestinal tract, disease involving leukocyte infiltration into epithelial tissue, pancreatitis, Mastitis, hepatitis, cholecystitis, cholangitis, perichonditis, bronchitis, sinusitis, pulmonary inflammatory disease, collagen disease, sarcoidosis, osteoporosis, osteoarthritis, atherosclerosis Sclerosis, neoplastic disease, trauma, eye disease, Sjogren's syndrome, rejection after organ transplantation, host versus graft or graft versus host disease, intimal thickening, arteriosclerosis, postoperative reinfarction or restenosis, nephritis It can be applied to the treatment or prevention of tumor angiogenesis, malignant tumors, multiple myeloma and myeloma-induced bone resorption, sepsis, central neuropathy and Meniere's disease.

Claims (13)

Formula (I):

{Where
A and B independently represent aryl or heteroaryl;
Q may combine with C, CH, or V or D to form a 5-7 membered heterocycle;
D may be combined with hydrogen, C _1-6 alkyl, or Q to form a 5-7 membered heterocycle;
R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 Alkylamino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, —NHCOR ⁹ or —NHSO ₂ R ⁹ [ here, 1 to 3 R ⁹ is selected from C _1-6 alkyl, C _3-7 cycloalkyl or phenyl (phenyl C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl or CF ₃ Or -E- (CH ₂ ) _1-6 NR ^x R ^y (E is a single bond or —OCH ₂ —, and R ^x and R ^y are independently hydrogen, C _1-6 alkyl or form a heterocycle of 5-7 members together, Represent was may be);
R ⁴ represents hydrogen, C _1-6 alkyl, halogen or C _1-6 alkoxy;
V is O, S, NH, N—C _1-6 alkyl, NNO ₂ or NCN, or together with Q may form a 5-7 membered heterocycle;
W, X, Y and Z independently represent C, CH or CH ₂ ;
symbol:

Represents a single bond or a double bond;
L represents — (CH ₂ ) _q — or — (CH ₂ ) _{q ′} O— (q is 0, 1, 2 or 3, q ′ is 2 or 3);
J is the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl);
(ii) —CHR ⁷ —CHR ⁸ — (R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, aryl, heteroaryl, —NHCOR ⁹ or —NHSO ₂ R ⁹ ( R ⁹ is as defined above) or — (CH ₂ ) _1-6 NR ^x R ^y (R ^x and R ^y are as defined above));
(iii) a single bond;
(iv) —CHR ⁶ — (R ⁶ is as defined above); and
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ —CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ is independently C _1-6 alkyl, or R ¹² and R ¹³ may together form C _3-7 cycloalkyl or a 5- to 7-membered heterocycle)
Represents a group selected from
m, n and p independently represent 0, 1, 2 or 3; and t represents 0, 1 or 2}
Or a pharmacologically acceptable derivative thereof as an active ingredient.   The pharmaceutical composition according to claim 1, wherein A is phenyl or pyridyl.   The pharmaceutical composition according to claim 1 or 2, wherein B is phenyl. R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 alkyl Amino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, —NHCOR ⁹ or —NHSO ₂ R ⁹ [here Wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl, or phenyl (the phenyl is selected from C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl, or CF _3; May be substituted with three groups)], or -E- (CH ₂ ) _1-6 NR ^x R ^y (where E is a single bond or —OCH ₂ —, R ^x and R ^y are independently Hydrogen or C _1-6 alkyl or together with C _1-6 alkyl Which may be substituted, may form a cyclic group selected from piperidyl, piperazinyl, pyrrolidinyl or morpholinyl groups);
When Q and V together form a ring containing a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group, it may be substituted with C _1-6 alkyl;
When Q and D together form a ring containing a piperidyl, piperazinyl, pyrrolidinyl or morpholinyl group, it may be substituted with C _1-6 alkyl;
J is the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl),
(ii) —CHR ⁷ —CHR ⁸ — {wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, triazolyl, Imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyridyl, quinolyl, isoquinolyl, indolyl, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, —NHCOR ⁹ or —NHSO ₂ R ⁹ [R ⁹ is as defined above], or — (CH ₂ ) _1-6 NR ^x R ^y (R ^x and R ^y are as defined above)},
(iii) single bond,
(iv) -CHR ^6- (R ⁶ is as defined above), and
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ are Independently C _1-6 alkyl, or R ¹² and R ^{13 taken} together form C _3-7 cycloalkyl, tetrahydropyranyl, piperidyl, piperazinyl, pyrrolidinyl or morpholinyl),
A group selected from:
A ring containing W, X, Y and Z has the formula:

The pharmaceutical composition in any one of Claims 1-3 represented by these. R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen or C _1-6 alkoxy:
Q together with C, CH, or V or D forms part of a benzimidazole, benzoxazole or indoline ring;
D together with hydrogen, C _1-6 alkyl, or Q forms part of the indoline ring;
V together with O or Q forms part of a benzimidazole or benzoxazole ring;
R ⁴ is hydrogen or halogen;
J is the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl),
(ii) —CHR ⁷ —CHR ⁸ — [wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, C _3-7 cycloalkyl, phenyl or —NHCOR ⁹ (R ⁹ is C _{1— 6} alkyl)),
(iii) single bond,
(iv) —CHR ⁶ — (R ⁶ is as defined above), or
(v) —O—CHR ¹⁰ —, —NR ¹¹ —CHR ¹⁰ — or —CR ¹² R ¹³ CHR ¹⁰ — (R ¹⁰ and R ¹¹ are independently hydrogen or C _1-6 alkyl, R ¹² and R ¹³ are Independently C _1-6 alkyl, or R ¹² and R ¹³ together form a C _3-7 cycloalkyl group)
The pharmaceutical composition according to any one of claims 1 to 4, which is selected from the group consisting of: As an active ingredient, the formula (Ia):

(Wherein R ¹ , R ² , R ³ , R ⁴ , L, J, m, n, p and t have the same meanings as defined in claim 1).
The pharmaceutical composition of Claim 1 containing the compound shown by these, or its pharmacologically acceptable derivative | guide_body. R ¹ , R ² and R ³ are independently C _1-6 alkyl, halogen, C _1-6 alkoxy, hydroxy, cyano, CF ₃ , nitro, C _1-6 alkylthio, amino, mono-C _1-6 alkyl Amino, di-C _1-6 alkylamino, carboxy, C _1-6 alkanoyl, amide, mono-C _1-6 alkylamide, di-C _1-6 alkylamide, or —NHCOR ⁹ or —NHSO ₂ R ⁹ [ Wherein R ⁹ is C _1-6 alkyl, C _3-7 cycloalkyl or phenyl, wherein phenyl is selected from C _1-6 alkyl, halogen, C _1-6 alkoxy, cyano, phenyl or CF ₃ 1 to 3 groups may be substituted)],
L is — (CH ₂ ) _q — (where q is 0, 1, 2 or 3);
J is the following group:
(i) —CR ⁵ ═CR ⁶ — (R ⁵ and R ⁶ are independently hydrogen or C _1-6 alkyl), or
(ii) —CHR ⁷ —CHR ⁸ — [wherein R ⁷ and R ⁸ are independently hydrogen, C _1-6 alkyl, or —NHCOR ⁹ or —NHSO ₂ R ⁹ (R ⁹ is defined in claim 1) Is equivalent to definition)],
The pharmaceutical composition according to any one of claims 1 to 6, wherein J is -CH = CH -, - (CH 2) 2 - or -CHR ⁷ -CH ₂ - (R ⁷ is C _1-6 alkyl) is a medicament according to any one of claims 1 to 7 Composition.   The pharmaceutical composition according to claim 1, comprising a compound selected from Production Examples 1 to 51 or a pharmacologically acceptable derivative thereof as an active ingredient.   The pharmaceutical composition according to claim 1, comprising a compound selected from Production Examples 5, 9, 32, 41, 42 and 51 or a pharmacologically acceptable derivative thereof as an active ingredient. The pharmaceutical composition according to any one of claims 1 to 10 Inhibition of alpha ₄ integrin mediated cell adhesion is a therapeutic or prophylactic agent for beneficial conditions.   Rheumatoid arthritis; asthma; allergic disease; adult respiratory distress syndrome; AIDS dementia; Alzheimer's disease; cardiovascular disease; thrombosis or harmful platelet aggregation; reocclusion after thrombolysis; reperfusion injury; Disease; diabetes; multiple sclerosis; systemic lupus erythematosus; inflammatory bowel disease; disease involving leukocyte infiltration into the gastrointestinal tract; disease involving leukocyte infiltration into epithelial tissue; pancreatitis; mastitis; hepatitis; Cholecystitis; cholangitis; perichonditis; bronchitis; sinusitis; pulmonary inflammatory disease; collagen disease; sarcoidosis; osteoporosis; osteoarthritis; atherosclerosis; neoplastic disease; Rejection after organ transplantation; host versus graft or graft versus host disease; intimal thickening; arteriosclerosis; post-surgical reinfarction or restenosis; nephritis; tumor angiogenesis; Sex myeloma and myeloma-induced bone resorption; sepsis; central nervous disorders; a condition selected from or Meniere's disease, a pharmaceutical composition according to any one of claims 1 to 11.   The pharmaceutical composition according to any one of claims 1 to 11, wherein the pathological condition is asthma, allergic disease, inflammatory bowel disease, rheumatoid arthritis, atopic dermatitis, multiple sclerosis or rejection after organ transplantation. .