JP2002543060A - Diphenyl urea derivative - Google Patents

Abstract

  (57) [Summary] Formula (I) Embedded image Wherein A ′ is NH or NR⁶ (Where R⁶ Is C₁ ~ C₆ -Alkyl, C ₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Alkanoyl or C₁ ~ C₆ -Alkoxycarbonyl), B is oxygen or sulfur, Y 'is a defined linker group, m is 0-5, n is 0-4, R is¹ And R ⁴ Is independently selected from organic groups defined independently, and R⁵ Is an acidic functional group], or a pharmaceutically acceptable salt or a biohydrolyzable derivative thereof. These compounds are associated with fibronectin and / or VCAM-1 (particularly VCAM-1) and integrin receptor α.₄ β₁ Useful for the treatment of diseases or medical conditions mediated by an interaction between

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to integrin α ₄ β ₁ , that is, Very Late Antigen-
4 (VLA-4) or CD49d / CD29 and compounds that are inhibitors of the interaction between their protein ligands, such as vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. The invention further relates to methods of making such compounds, pharmaceutical compositions containing them and their use in methods of therapeutic application.

[0002]₄β₁Are noncovalently linked glycoprotein subunits (α and β
) And involved in cell adhesion to other cells or extracellular matrix.
It is a member of the integrin family of terror dimer cell surface receptors. at least
14 different human integrin α subunits and at least 8 different
Β subunits, each β subunit may have one or more
A heterodimer having an α subunit can be formed. Integrins are
Reclassification can be based on β subunit composition. α₄β₁Integrins have several types of β ₁ A type of integrin, also known as very slow antigen (VLA).

[0003] The interaction between integrins and these protein ligands is fundamental for maintaining cell function, for example constraining cells at specific locations to facilitate cell migration, or their environment. To provide a survival signal to the cell. Ligands recognized by integrins include extracellular matrix proteins such as collagen and fibronectin, cytoplasmic proteins such as fibrinogen, and cell surface molecules such as the transmembrane proteins of the immunoglobulin superfamily and cell-associated complement. The specificity of the interaction between the integrin and the ligand is governed by the α and β subunit composition.

[0004] Integrin alpha ₄ beta ₁ is expressed on numerous hematopoietic cells, establish hematopoietic precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, monocytes, cell lines including thymocytes and eosinophils (Hemler, ME et al (1987), J. Biol. Chem., 262, 11478-114).
85; Bochner, BS et al (1991), J. Exp. Med., 173, 1553-1556]. Cells - unlike the other β1 integrins that bind only to the extracellular matrix proteins, alpha ₄ beta ₁ is, VCAM-1, i.e. the cell surface, such as an immunoglobulin superfamily member that are expressed on vascular endothelial cells, and Binds to fibronectin containing an alternatively spliced type III binding segment (CS-1 fibronectin) [Elices, MJ et al (1990), Cell, 60, 577-584; Wayner E. et al.
A. et al (1989), J. Cell Biol., 109, 1321-1330].

[0005] Activation and extravasation of blood leukocytes has an important role in the development and progression of inflammatory diseases. Cell adhesion to the vascular endothelium is required prior to cell migration from the blood into the inflamed tissue and is mediated by specific interactions between cell adhesion molecules on the surface of vascular endothelial cells and circulating leukocytes (Sharar, SR et al (1995), Springer Semin
Immunopathol., 16, 359-378]. alpha ₄ beta ₁ is lymphocyte during inflammation, is believed to have an important role in the recruitment of monocytes and eosinophils. alpha ₄ beta _{1 /} ligand binding even, T-cell proliferation, B- localization to germinal center cells, hematopoietic progenitor cells localization in the bone marrow,
It is also involved in placental development, muscle development and cancer cell metastasis.

[0006] Affinity for alpha ₄ beta ₁ of its ligands is normally low, but chemokines expressed by inflamed vascular endothelium act on leukocyte surface via receptor alpha 4 .beta.1
Up-regulate function (Weber, C. et al (1996), J. Cell Biol., 134, 1063-1073)
]. VCAM-1 expression is determined by inflammatory cytokines [Osborn L. et al (1989) Cell,
59, 1203-1211], and inflammatory diseases in humans such as rheumatoid arthritis [Morale
s-Ducret, J. et al (1992), J. Immunol., 149, 1424-1431), multiple sclerosis (
Canuella, B. et al (1995), Ann. Neurol., 37, 424-435), allergic asthma (Fukuda, T. et al (1996), Am. J. Respir. Cell Mol. Biol. 14, 84) -94] and atherosclerosis [O'Brien, KD et al (1993), J. Clin. Invest. 92
, 945-951].

[0007] Monoclonal antibodies against alpha ₄ integrin subunit, multiple sclerosis, rheumatoid arthritis, allergic asthma, contact dermatitis, transplant rejection, insulin-dependent diabetes mellitus, inflammatory abdominal diseases, and yarn It has been shown to be effective in a number of animal models of human inflammatory disease, including spherical nephritis.

[0008] Integrins recognize short peptide motifs in these ligands. C
Minimum alpha ₄ beta ₁ binding epitope in S-1 is leucine tripeptide - aspartic acid - valine (Leu-Asp-Val) [Komoriya, A. et al (1991) , J. B
iol. Chem., 266, 15075-15079], while VCAM-1 contains a similar sequence isoleucine-aspartate-serine [Clements, JM et al (1994), J. Cel.
l Sci., 107, 2127-2135]. Including the Leu Asp-Val motif 25-amino acid fibronectin fragment, CS-1 peptide, to _VCAM-1 α ₄ β 1
A competitive inhibitor of binding (Makarem, R., et al (1994), J. Biol. Chem., 269, 4
005-4011]. Small molecule alpha ₄ beta ₁ inhibitor based on Leu-Asp-Val sequence in CS-1, for example the linear molecule phenylacetic acid -Leu-Asp-Phe-D- Pr
o-amide [Molossi, S. et al (1995), J. Clin. Invest. 95, 2601-2610] and the disulfide cyclic peptide Cys-Trp-Leu-Asp-Val-Cy.
s [Vanderslice, P. et al (1997), J. Immunol. 158, 1710-1718].

More recently, non-peptidic and semi-peptidic compounds that inhibit α ₄ β ₁ / VCAM binding and can be administered orally are described, for example, in WO 96/22966 and WO 98/04247. It has been reported.

[0010] Another compound that inhibits the interaction between VCAM-1 and fibronectin with integrin alpha ₄ beta _1, and the Koto, a continuing need for compounds that can be administered by the oral route is still present.

Here we have discovered a group of compounds containing urethane or carbamosulfanyl linkages that inhibit this interaction.

Accordingly, the present invention provides a compound of formula (I)

[0013]

Embedded image

Wherein A ′ is NH or NR⁶ (Where R⁶ Is C₁~ C^6-Alkyl, C₂~ C₆ -Alkenyl, C₂ ~ C₆ -Alkanoyl or C1 -C6 -alkoxyka
B is oxygen or sulfur; and Y 'is one or more independently selected from oxygen, nitrogen and sulfur.
The above heteroatoms and / or monocyclic or bicyclic systems intervening,
A linker group consisting of a substituted hydrocarbyl chain, or a linker
The groups Y 'and A' together are optionally halogen, hydroxy, amino,
Nitro, trifluoromethyl, trifluoromethoxy, cyano, C₁ ~ C₆ −
Alkyl, C₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Alkynyl, C₁ ~ C
₆ -Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ ~ C₆ -Alkini
Luoxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C₆ -Alkyl)
Mino and C₂ ~ C₆ -Up to three independently selected from alkanoylamino
A 5- to 7-membered heterocyclic ring system substituted with a substituent, m is 0-5, n is 0-4, R₁ And R⁴ Is halogen, hydroxy, amino, nitro, trifluoromethyl
Chill, trifluoromethoxy, cyano, carboxy, carbamoyl, C₁ ~ C
₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₁ ~ C₆ -Alkanoyl, C
₂ ~ C₆ -Alkynyl, C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkene
Luoxy, C₂ ~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino,
Di-C₁ ~ C₆ -Alkyl] amino, C₂ ~ C₆ -Alkanoylamino,
N-C₁ ~ C₆ Alkylcarbamoyl, C₁ ~ C₆ -Alkoxycarboni
, N, N-di- [C₁ ~ C₆ -Alkyl] carbamoyl, C₁ ~ C₄ -A
Lucoxyl-C₁ ~ C₆ -Alkyl, (CH₂ )_t OH (where t is 1 or
Is 2), -CO₂ R^a And CONR^a R^b (Where R^a And R
^b Is independently hydrogen or C₁ ~ C₆ -Alkyl)
Selected or R⁴ One of which together with A is optionally halogen,
Droxy, amino, nitro, trifluoromethyl, trifluoromethoxy, shea
No, C₁ ~ C₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Al
Quinyl, C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ 
~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C ₆ -Alkyl] amino and C₂ ~ C₆ -Independently of alkanoylamino
Can form a 5- to 7-membered heterocycle substituted with up to three selected substituents;² And R³ Is hydrogen, C₁ ~ C₆ -Alkyl, C₁ ~ C₃ -Alkano
Il or C₁ ~ C₆ -Each independently selected from alkoxycarbonyl,
And R⁵ Is an acidic functional group] or a pharmaceutically acceptable salt thereof or an in vivo hydrolyzable derivative.
Provide conductors.

As used herein, the term “hydrocarbyl chain”
)) When used in connection with the linker Y ', for example, alkylene, alkenylene and alkenylene having 1 to 10 carbon atoms in the case of alkylene groups and 2 to 10 carbon atoms in the case of alkenylene and alkynylene groups. Reference is made to alkynylene groups, which may optionally be intervened by one or more of the groups listed above.

In particular, the linker group is a monocyclic ring system and an alkenylene chain optionally also intervening at least one heteroatom. The ring system is advantageously a monocyclic system as defined below.

Suitable substituents for the linker group Y ′ include any of the groups listed above for R ¹ and R ⁴ as well as aryl groups such as phenyl or naphthyl or aralkyl groups such as benzyl. In particular, the substituent _is C 1 -C ₆ - containing alkynyl, aryl, such as phenyl and aralkyl such benzyl - _alkyl, C 2 -C ₆ - _alkenyl, C 2 -C _6. If the linker group Y ′ contains a nitrogen heteroatom, a substituent may be present on said atom.

Suitably, the linker group is such that the spacing between group B and group R ⁵ does not exceed 10 atoms.

In an advantageous embodiment, a moiety containing a basic group, in particular at least one nitrogen, is present in the linker Y.

Advantageously, the group A ′ is located meta or para with respect to the ureido group of the formula (I), most advantageously the group A ′ is located para with respect to the ureido group of the formula (I) I do.

In a particular aspect, the present invention provides a compound of formula (1A)

[0022]

Embedded image

Wherein A is nitrogen or NR⁶ (Where R⁶ Is C₁ ~ C₆ -Alkyl, C₂ ~ C
₆ -Alkanoyl or C₁ ~ C₆ -Alkoxycarbonyl)
, B is oxygen or sulfur; Y is a group R⁵ And up to 10 atoms (where each atom
Is independently selected from carbon, oxygen, nitrogen and sulfur) is a linker group containing
And optionally a mono- or bicyclic ring system, or a linker group Y and
A together, optionally, halogen, hydroxy, amino, nitro, tri
Fluoromethyl, trifluoromethoxy, cyano, C₁ ~ C₆ -Alkyl, C ₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Alkynyl, C₁ ~ C₆ -Alkoki
Si, C₂ ~ C₆ -Alkenyloxy, C₂ ~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C₆ -Alkyl] amino and C₂ ~ C₆ -Substituted with up to three substituents independently selected from alkanoylamino
M is 0-5, n is 0-4, R is¹ And R⁴ Is halogen, hydroxy, amino, nitro, trifluoromethyl
Chill, trifluoromethoxy, cyano, carboxy, carbamoyl, C₁ ~ C
₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₁ ~ C₆ -Alkanoyl, C
₂ ~ C₆ -Alkynyl, C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkene
Luoxy, C₂ ~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino,
Di-C₁ ~ C₆ -Alkyl] amino, C₂ ~ C₆ -Alkanoylamino,
N-C₁ ~ C₆ Alkylcarbamoyl, C₁ ~ C₆ -Alkoxycarboni
, N, N-di- [C₁ ~ C₆ -Alkyl] carbamoyl, C₁ ~ C₄ -A
Lucoxyl-C₁ ~ C₆ -Alkyl, (CH₂ )_t OH (where t is 1 or
Is 2), -CO₂ R^a And CONR^a R^b (Where R^a And R
^b Is independently hydrogen or C₁ ~ C₆ -Alkyl)
Selected or R⁴ One of which together with A is optionally halogen,
Droxy, amino, nitro, trifluoromethyl, trifluoromethoxy, shea
No, C₁ ~ C₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Al
Quinyl, C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ 
~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C ₆ -Alkyl] amino and C₂ ~ C₆ -Independently of alkanoylamino
Can form a 5- to 7-membered heterocycle substituted with up to three selected substituents;² And R³ Is hydrogen, C₁ ~ C₆ -Alkyl, C₁ ~ C₃ -Alkano
Il or C₁ ~ C₆ -Each independently selected from alkoxycarbonyl,
And R⁵ Is an acidic functional group] and / or their pharmaceutically acceptable salts or hydrolyzable in vivo
Includes active derivatives.

Y or Y ′ is preferably a linker group that is unstable under acidic conditions found in the stomach of the human or animal body, such as, for example,

[0025]

Embedded image

It is understood that is excluded.

For the compounds of formula (I), the 5- to 7-membered heterocycle has up to three heteroatoms independently selected from nitrogen, oxygen and sulfur and is optionally substituted, saturated or unsaturated. Can be Examples of such rings are oxazolidinones, oxazolones and thiazolones.

[0028] The linker group Y or Y 'can include a monocyclic or bicyclic ring. With respect to the compounds of formula (I), "monocyclic ring" means a 5- to 7-membered ring. It can be an optionally substituted, preferably aromatic ring, having up to three heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of such rings include phenyl, pyrimidinyl, pyridyl, imidazolyl, thienyl, thiazolyl, pyridazinyl and pyrrolyl. Another example includes morpholino, tetrahydropyridyl or tetrahydropyrazolyl.

With respect to compounds of formula (I), “bicyclic ring” means an 8-10 membered fused ring system wherein one or both rings may contain ring heteroatoms. The ring system is fully or partially saturated, optionally substituted, and may contain up to 5 heteroatoms independently selected from oxygen, nitrogen or sulfur. Examples of suitable ring systems are naphthalene,
Includes quinazolines, benzothiophenes, benzoxazoles, benzothiazoles and benzofurans and the corresponding hydro derivatives, such as tetrahydronaphthalene and dihydroquinazoline.

The term “acidic functional group” means a group that incorporates an acidic hydrogen and includes carboxylic acids, tetrazoles, acylsulfonamides, sulfonic acids and sulfinic acids.

In one aspect of the invention, the groups Y ′ and Y are the groups —D— (E) _p — (F) _q —G— where D, E, F, G, p and q are , Defined below]. Accordingly, preferred compounds of the present invention have the formula (II)

[0032]

Embedded image

[Wherein A, B, R¹ ~ R⁵ , M and n are as defined above, and D and G are each independently C₁ ~ C₄ -Alkyl or C₂ ~ C₄ −
Alkenyl and each carbon is optionally halogen, hydroxy,
Amino, nitro, phenyl, trifluoromethyl, trifluoromethoxy, shea
No, carboxy, carbamoyl, C₁ ~ C₆ -Alkyl, C₂ ~ C₆ -Al
Kenil, C₁ ~ C₆ -Alkanoyl, C₂ ~ C₆ -Alkynyl, C₁ ~ C
₆ -Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ ~ C₆ -Alkini
Luoxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C₆ -Alkyl)
Mino, C₂ ~ C₆ -Alkanoylamino, NC₁ ~ C₆ -Alkyl carba
Moyle, C₁ ~ C₆ -Alkoxycarbonyl, N, N-di- [C₁ ~ C₆ −
Alkyl] carbamoyl, C₁ ~ C₄ -Alkoxyl-C₁ ~ C₆ -Archi
Le, (CH₂ )_r OH (where r is 1 or 2), -CO₂ R⁷ And
And CONR⁷ R⁸ (Where R⁷ And R⁸ Is independently hydrogen or C₁ ~ C
₆ Or D and A together when
More halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoro
Lomethoxy, cyano, C₁ ~ C₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C ₂ ~ C₆ -Alkynyl, C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkene
Luoxy, C₂ ~ C₆ Alkynyloxy, C₁ ~ C₆ -Alkylamino,
Di-C₁ ~ C₆ -Alkyl] amino and C₂ ~ C₆ -Alkanoylami
To form a 5- to 7-membered ring substituted with up to three substituents independently selected from
E is optionally both halogen, hydroxy, amino, nitro, trifluoro
Lomethyl, trifluoromethoxy, cyano, carboxy, carbamoyl, C₁ 
~ C₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₂ ~ C₆ Alkynyl,
C₁ ~ C₆ -Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ ~ C₆ −
Alkynyloxy, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C₆ -Al
Kill] amino, C₂ ~ C₆ -Alkanoylamino, C₃ ~ C₆ -Alkenoy
Ru-amino, C₃ ~ C₆ -Alkinoylamino, C₁ ~ C₆ -Alkoxyka
Rubonyl, NC₁ ~ C₆ -Alkylcarbamoyl, N, N-di- [C₁ ~
C₆ -Alkyl] carbamoyl, C₁ ~ C₆ -Alkanoyl, C₁ ~ C₄ 
-Alkoxyl-C₁ ~ C₆ -Alkyl, (CH₂ )_s OH (where s is 1
Or 2), -CO₂ R⁹ And CONR⁹ R¹⁰(Where R⁹ And
And R¹⁰Is independently hydrogen or C₁ ~ C₆ -Alkyl)
A phenyl or monocyclic heterocycle substituted with up to three substituents
Or E and D together are optionally halogen, hydroxy, amino, nitro
B, trifluoromethyl, trifluoromethoxy, cyano, C₁ ~ C₆ -Al
Kill, C₂ ~ C₆ -Alkenyl, C₂ ~ C₆ -Alkynyl, C₁ ~ C₆ −
Alkoxy, C₂ ~ C₆ -Alkenyloxy, C₂ ~ C₆ Alkynyloxy
Si, C₁ ~ C₆ -Alkylamino, di- [C₁ ~ C₆ -Alkyl] amino
And C₂ ~ C₆ -Substituted with up to three substituents selected from alkanoylamino
Where F is oxygen, sulfur, amino or CR¹¹R¹²Wherein p and q are each independently 0 or 1;¹¹And R¹²Is hydrogen, halogen, hydroxy, amino, nitro, phenyl
, Trifluoromethyl, trifluoromethoxy, cyano, carboxy, carba
Moyle, C₁ ~ C₆ -Alkyl, C₂ ~ C₆ -Alkenyl, C₁ ~ C₆ −
Alkanoyl, C₂ ~ C₆ -Alkynyl, C₁ ~ C₆ -Alkoxy, C₂ 
~ C₆ -Alkenyloxy, C₂ ~ C₆ Alkynyloxy, C₁ ~ C₆ 
-Alkylamino, di- [C₁ ~ C₆ -Alkyl] amino, C₂ ~ C₆ -A
Lucanoylamino, NC₁ ~ C₆ Alkylcarbamoyl, C₁ ~ C₆ −
Alkoxycarbonyl, N, N-di- [C₁ ~ C₆ -Alkyl] carbamoyl
, C₁ ~ C₄ -Alkoxyl-C₁ ~ C₆ -Alkyl, (CH₂ )_u OH
(Where u is 1 or 2), -CO₂ R^FifteenAnd CNNR^FifteenR¹⁶
(Where R^FifteenAnd R¹⁶Is independently hydrogen or C₁ ~ C₆ -Alkyl
) Is independently selected from⁴ From A, D and E
Or a group thereof cannot form more than one ring system) or a pharmaceutically acceptable salt or an in vivo hydrolyzable derivative thereof.
Conductor.

For the compounds of formula (II), the 5- to 7-membered ring which A and D can form together is a heterocycle. It has up to three heteroatoms independently selected from nitrogen, oxygen and sulfur and can be optionally substituted, saturated or unsaturated rings. Examples of such rings are oxazolidinones, oxazolones and thiazolones.

With respect to compounds of formula (II), “monocyclic ring” means a 5- to 7-membered ring. It has up to three heteroatoms independently selected from nitrogen, oxygen and sulfur;
It can be an optionally substituted, preferably aromatic ring. Examples of such rings include pyrimidinyl, pyridyl, imidazolyl, thienyl, thiazolyl, pyridazinyl and pyrrolyl.

In another advantageous embodiment, “monocyclic ring” is a non-aromatic heterocycle. Advantageously, the ring is linked to either of the groups D and / or F via a nitrogen atom. Such groups include morpholino, tetrahydropyridyl or tetrahydropyrazolyl.

With respect to compounds of formula (II), “bicyclic ring” means an 8-10 membered fused ring system wherein one or both rings may contain heteroatoms. The ring system is fully or partially saturated, optionally substituted, and may contain up to 5 heteroatoms independently selected from oxygen, nitrogen or sulfur. Examples of suitable ring systems are naphthalene,
Includes quinazolines, benzothiophenes, benzoxazoles, benzothiazoles and benzofurans and the corresponding hydro derivatives, such as tetrahydronaphthalene and dihydroquinazoline.

The term “acidic functional group” means a group incorporating an acidic hydrogen and includes carboxylic acids, tetrazoles, acylsulfonamides, sulfonic acids and sulfinic acids.

A particularly preferred value of E in formula (II) is phenyl. The radicals D and F are preferably arranged in the ortho- or meta-position on the phenyl ring E, most preferably located meta-to each other.

Alternatively, E is a monocyclic heterocycle as defined above, especially an N-linked 6-membered non-aromatic heterocycle.

Advantageously, A ′ in formula (I) is NH or NR⁶ (Where R⁶ Is C₁ ~ C
₆ -Alkyl, such as methyl or C₂ ~ C₆ Alkenyl, for example ethene
-2-yl). More advantageously, A '(or formulas (IA) and (
A) in II) is NH or NCH₃ And most advantageously A or A 'is
NH.

Advantageously, R ¹ is a C ¹ -C ⁶ -alkyl group, for example methyl, which is ortho to the ureido group on the phenyl ring. Preferably, m is 1.

Advantageously, R ² and R ³ are hydrogen or alkyl, and most preferably both are hydrogen.

A particularly preferred value for B is oxygen.

Particular values for R ⁴ include C ₁ -C ₆ -alkyl, such as methyl, or C ₁ -C ₆ -alkoxy, such as methoxy. In this case, n is preferably 0, 1 or 2. Particularly preferred groups of the compounds of the formula (I) are those of the formula (III)

[0046]

Embedded image

Wherein R ¹ , R ² , R ³ , A, B, Y, R ⁵ and m are as defined above, and R ^4a is hydrogen or C ₁ -C ₆ -alkoxy, for example Methoxy, and R ^4b is either hydrogen or C ₁ -C ₆ -alkyl, such as methyl].

An advantageous meaning of F in formula (II) is oxygen.

Alternatively, q is 0.

Most advantageously, R ⁵ is carboxy.

For R ^{1 to} R ⁴ , R ⁶ , R ^{11 to} R ¹⁶ and Y (or Y ′), D
, E, F, G or Y or Y 'and A or A', A or A 'and D, D and E
, Preferred meanings of for various substituents on any ring formed between the A or A 'and R ⁴ include the following.

For halogens: for fluoro, chloro, bromo and iodo, for C ₁ -C ₆ -alkyl: for methyl, ethyl, propyl, isopropyl and t-butyl, for C ₂ -C ₆ -alkenyl: vinyl, allyl And but-2-enyl, for C ₁ -C ₆ -alkanoyl: for formyl, acetyl, propionyl or butyryl, for C ₂ -C ₆ -alkynyl: ethynyl, 2-propynyl and but-2-ynyl C ₁ -C ₆ - to alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy, _C 2 -C ₆ - to alkenyloxy: vinyloxy and allyloxy, _C 2 -C ₆ - to alkynyloxy: ethynyloxy and 2-propynyloxy , C ₁ -C ₆ -alkyla Mino to: methylamino, ethylamino, propylamino, isopropylamino and butylamino, di _-C 1 -C ₆ - to alkylamino: dimethylamino, diethylamino, _C 2 -C ₆ - to alkanoylamino: acetamido, propionamide and butyramide, _N-C 1 ~C ₆ - to alkylcarbamoyl: N- methylcarbamoyl, N- ethylcarbamoyl and N- propylcarbamoyl, N, N- di _-C 1 -C ₄ - to alkylcarbamoyl: N, N- dimethylcarbamoyl, N- ethyl -N- methylcarbamoyl and N, N- diethylcarbamoyl, _C 1 -C ₆ - to alkoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and t- butoxy Carbonyl, _C 1 -C ₄ - alkoxy _-C 1 -C ₄ - to alkyl: methoxymethyl, ethoxymethyl, 1-methoxymethyl, 2-methoxyethyl.

Particularly preferred compounds of formula (II) or pharmaceutically acceptable salts thereof are, unless otherwise stated for each of R ¹ -R ¹⁶ , A, B, D-G, m, p-u: Sections a to h above or below include those having any of the meanings defined.

A) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen And R ⁵ is carboxy.

B) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen And is in the meta position with respect to E, and R ⁵ is carboxy.

C) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen Wherein R ⁵ is carboxy, and R ¹ and R ⁴ are each independently C ₁ -C ₆ -alkyl or C ₁ -C ₆ -alkoxy.

D) B is oxygen and D and G are each independently C₁ ~ C₄ -With alkyl
And optionally substituted as defined above, E is phenyl and F is an acid
Prime and R⁵ Is carboxy and R¹ And R⁴ Are each independently C
₁ ~ C₆ -Alkyl or C₁ ~ C₆ -Alkoxy and m and n
Are both 0 or 1.

E) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen Wherein R ⁵ is carboxy and R ² and R ³ are each independently C ₁ -C ₆ -alkyl, advantageously methyl.

F) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen R ⁵ is carboxy and R ⁶ is C ₁ -C ₆ -alkyl, advantageously methyl.

G) B is oxygen, D is C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, q is 0, and G is C _1-
C ₄ -alkyl or C ₁ -C ₄ -alkenyl, optionally substituted as defined above, and R ⁵ is carboxy.

H) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, E is phenyl, and F is oxygen And one of A and R ⁴ together forms a 5-membered ring, and R ⁵ is carboxy.

Another specific group is the following compounds:

I) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, q is 0, and E is a group N for G
- a bound and morpholino attached to D at two positions on the morpholine ring, and R ⁵ is carboxy.

J) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, q is 0, and E is a group N for G
- a bound and tetrahydropyridyl attached to D at 4 positions on the ring, and R ⁵ is carboxy.

K) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, q is 0, and E is a group N for D
- a bound and tetrahydropyridyl bound to G at 4 positions on the ring, and R ⁵ is carboxy.

L) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, q is 0, and E is a group N for G
- a bound and tetrahydropyridyl attached to D at two positions on the ring, and R ⁵ is carboxy.

M) B is oxygen, D and G are each independently C ₁ -C ₄ -alkyl, optionally substituted as defined above, q is 0, and E is a group a tetrahydropyridyl that N- coupled to the D and G, and R ⁵ is carboxy.

Pharmaceutically acceptable salts include acid addition salts, such as salts formed with inorganic acids, such as hydrohalic acids such as hydrochloric and hydrobromic, sulfonic and phosphonic, and organic acids, Especially citric acid, maleic acid, acetic acid, oxalic acid, tartaric acid,
And salts formed with mandelic acid, p-toluenesulfonic acid, and methanesulfonic acid. In other embodiments, suitable salts are base salts, such as alkali metal salts, such as sodium and potassium, alkaline earth metal salts, such as magnesium and calcium, aluminum and ammonium salts, and organic bases, such as ethanolamine, methylamine, And salts with diethylamine, isopropylamine and trimethylamine. Such salts can be prepared by any suitable method known in the art.

In vivo hydrolysable derivatives include, in particular, pharmaceutically acceptable esters that hydrolyze in the human body to form the parent compound. Such esters are, for example,
The test compound can be administered intravenously to the test compound and then examined to determine the body fluids of the test animal. Preferred in vivo hydrolysable esters are acetyl for hydroxy and for carboxy, for example, alkyl esters, dialkylaminoalkoxy esters and C ₁ -C ₆ -alkoxymethyl esters such as methoxymethyl, C ₁ -C ₆ - alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl _esters, C 3 -C ₈ - cycloalkyl alkoxycarbonyloxy _C 1 -C ₆ - alkyl esters for example 1-cyclohexylcarbonyloxyethyl, 1,3 dioxolan-2-yl methyl ester such as 5-methyl-1,3-dioxolan-2-ylmethyl, and _C 1 -C ₆ - including alkoxycarbonyloxy ethyl esters for example 1-methoxycarbonyloxy ethyl.

Insofar as some of the compounds of formula (I) as defined above may exist in optically active or racemic forms due to one or more asymmetric carbon atoms, the present invention provides Some are understood to include any such optically active or racemic form which has the property of inhibiting the interaction between VCAM-1 and fibronectin with integrin alpha ₄ beta _1. The synthesis of the optically active forms will be performed by standard techniques of organic chemistry well known in the art. These include, for example, methods from synthesis from optically active starting materials or resolution of racemic forms.

Specific examples of compounds of formula (I) are set forth in Tables 1, 2 and 3.

[0072]

[Table 1]

[0073]

[Table 2]

[0074]

[Table 3]

[0075]

[Table 4]

[0076]

[Table 5]

[0077]

[Table 6]

[0078]

[Table 7]

The activity of the compounds of the invention to inhibit the interaction between fibronectin and integrin α ₄ β ₁ may be determined using a number of in vitro and in vivo screens as defined above.

[0080] For example, compounds of formula (I) is advantageously lower ^{IC 50} than 10μM, the more advantageous with in MOLT-4 cells / fibronectin assay described below an ^{IC 50} less than 1 [mu] M.

For their use, the compounds of formula (I) or their pharmaceutically acceptable salts or in vivo hydrolysable derivatives are typically converted to pharmaceutical compositions according to standard pharmaceutical practice. Is blended as

Thus, according to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or derivative thereof in vivo and a pharmaceutically acceptable carrier. Provided.

The pharmaceutical compositions according to the invention may be in dosage forms suitable for oral use, such as tablets, capsules, aqueous or oily solutions, suspensions or emulsions, for nasal use eg olfactory, nasal spray or nasal Drops for vaginal or rectal use eg suppositories, for administration by inhalation eg finely divided powders or liquid aerosols, for sublingual or buccal use eg tablets or capsules, or parenteral use ( (Including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example, sterile aqueous or oil solutions or suspensions, or depot formulations with the drug in biodegradable polymers. The composition may be in a form suitable for topical application, such as creams, ointments and gels. Skin patches are also considered. For these purposes, the compositions of the present invention may be prepared by means known in the art, such as, for example, generally “Comprehensive Medicinal”.
Chemistry, Volume 5, Editor Hansch et al, Pergamon Press 1990)
. It may be blended as described in Chapter 2.

Further, the pharmaceutical compositions of the present invention may include one or more additional pharmacological agents suitable for treating one or more of the above-described disease states, wherein the compound is a compound of the present invention. In addition, it may be included. In another aspect, another pharmacological agent may be co-administered, simultaneously or sequentially, with a pharmaceutical composition of the present invention.

The composition of the present invention is generally administered to a human at a daily dose of 0.01 to 75 mg / kg.
(Body weight), advantageously 0.1 to 15 mg / kg (body weight).
Advantageous compositions of the present invention include compounds 1 to 5 according to the invention in each unit dose.
A unit dosage form containing, for example, tablets or capsules containing 1000 mg, advantageously 10-500 mg, which is suitable for oral administration.

Thus, according to yet another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt or hydrolyzed in vivo thereof for use in a method of therapeutic treatment of the human or animal body. Possible derivatives are provided.

[0087] In yet another aspect of the present invention, the present invention provides such a method of treatment of diseases mediated treated by the interaction between VCAM-1 and / or fibronectin and the integrin receptor alpha ₄ beta ₁ Provided when needed, including administering to the warm-blooded mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof.

The present invention relates to fibronectin and / or VCAM-1 (particularly VCAM-
Compounds of formula (I) or pharmaceutically acceptable salts thereof in the manufacture of a medicament for use in the treatment of a disease or medical condition mediated by the interaction between 1) and the integrin receptor α ₄ β ₁ Alternatively, the use of a derivative that can be hydrolyzed in vivo is provided.

In an advantageous embodiment, the mammal in need of treatment is multiple sclerosis, rheumatoid arthritis, asthma, coronary artery disease, psoriasis, atherosclerosis, transplant rejection, inflammatory abdominal disease, insulin-dependent diabetes And suffering from glomerulonephritis.

Preferred compounds of formula (I) for use in these various aspects of the invention are those described above and also include compounds of formula (IA) or (II).

In another aspect of the present invention, there is provided a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable derivative thereof, the process comprising: (IV)

[0092]

Embedded image

Wherein A ′, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in relation to formula (I), with a compound of formula (V)

[0094]

Embedded image

Wherein B and Y ′ are as defined in relation to formula (I), Z is a leaving group, for example halogen, and R ¹⁷ is as defined in relation to formula (I) R ⁵ or a protected form thereof], or (b) a compound of formula (VI)

[0096]

Embedded image

Wherein A ′, B, Y ′, R ³ , R ⁴ and n are defined in relation to formula (I) and R ¹⁷ is defined in relation to formula (V) With a compound of formula (VII)

[0098]

Embedded image

Wherein R ¹ and m are as defined in relation to formula (I), and then, if desired or necessary, i) any protecting group And ii) optionally forming pharmaceutically acceptable salts or in vivo hydrolysable derivatives, compounds of formula (I), pharmaceutically acceptable salts or in vivo hydrolysable derivatives thereof Production method.

A particular protecting group R ¹⁷ is an ester group, in particular a C ₁ -C ₆ -alkyl ester.

The starting materials for the present method may be obtained by standard organic chemistry. The preparation of such starting materials is described in the representative methods below in conjunction with the subsequent examples. Alternative starting materials can also be obtained by methods analogous to those described below and within the ordinary skill of an organic chemist.

One method (a) above involves coupling via combining the compounds of formulas (IV) and (V) above to form a urethane or carbamosulfanyl. The compounds are reacted together under basic conditions, preferably in the presence of an inert solvent.

[0103] A suitable solvent system for the above process is dichloromethane or tetrahydrofuran (THF) in the presence of pyridine.

Certain compounds of formula (V) have the formula (VIII)

[0105]

Embedded image

Wherein Y is a group —D— (E) _p — (F) _q —G— and B, D, E, F
, G, p and q are as defined above, and R ¹⁷ is COO-C ₁ -C ₆ -alkyl]. Particular examples of compounds of formula (IV) are of formula (IX)

[0107]

Embedded image

Wherein R ¹ , R ² , R ³ , R ⁴ , n and m are as defined in relation to formula (I).

Formula (VIII) [B is oxygen, D is CH ₂ , E is phenyl, p is 1, q is 1, F is oxygen, and G is C _3- Alkyl and R ¹⁷ is COOMe].

[0110]

Embedded image

Is as follows.

Compounds of formula (V) are of the formula (X)

[0113]

Embedded image

Can be prepared by reacting the compound with phosgene in the presence of toluene / dichloromethane. If B is oxygen, the compound corresponds to an alcohol.

These alcohols can be prepared by reacting 3-hydroxybenzyl alcohol with methyl 4-bromobutyrate under basic conditions. It is known that different alcohols can be prepared, for example, by replacing methyl 4-bromobutyrate with t-butyl bromoacetate.

Formula (IX) wherein m and n are both 1 and R¹ Is methyl and R
² And R³ Are both hydrogen and R⁴ Is methoxy.)
An example follows.

[0117]

Embedded image

Such compounds can be prepared from the corresponding 3-methoxy-4 (N ′-(2-methylphenyl) urea) nitrobenzene. The latter can be prepared from the reaction of the corresponding methoxy-nitroamine with methylphenyl isocyanate.

[0119] Experts in the art will recognize that in some reactions, it may be necessary to protect sensitive groups in the molecule. Protecting groups may be selected from any group typically described in the literature or known to the skilled artisan.

Suitable protecting groups for amino groups include, for example, formyl, and alkoxycarbonyl groups, for example, t-butoxycarbonyl.

Suitable protecting groups for hydroxyl groups include lower alkyl groups such as t-butyl, and acyl groups such as alkanoyl groups such as acetyl.

Suitable protecting groups for carboxy groups include esterified groups, for example methyl or ethyl groups.

These groups may be removed using any convenient method described in the literature or known to those skilled in the art for the removal of the particular group in question. The method of removal is chosen to minimize disruption to other groups in the molecule. For example, the protective group is an acyl group, or a C ₁ -C 2 _- when it is alkyl group, a suitable base, for example, may be removed by hydrolysis using sodium hydroxide. The t-butyl protecting group may be removed, for example, using an organic acid such as trifluoroacetic acid.

Another method of preparing compounds of formula (I) or pharmaceutically acceptable salts or in vivo hydrolysable derivatives thereof is to react compounds of formula (VI) and (VII) together To form a urea bond. The reaction is preferably performed in the presence of an inert solvent. Inert solvents suitable for the above process include dichloromethane, THF or ethyl acetate, as before, any functional groups being protected if necessary,
And i) removing all protecting groups; and ii) optionally preparing pharmaceutically acceptable salts or in vivo hydrolysable derivatives.

Particular examples of compounds of formula (VI) include compounds of formula (XI)

[0126]

Embedded image

[Wherein, Y is a group -D- (E) _p- (F) _q -G-, and R ⁴ , R ¹⁷ , B
, D, E, F, G, n, p and q are as defined above].
Particular examples of compounds of formula (VII) include compounds of formula (XII)

[0128]

Embedded image

Wherein R ¹ and m are as defined above.

Examples of compounds of formula (V) are

[0131]

Embedded image

Is as follows.

Such compounds can be prepared by reducing the corresponding nitroaniline derivative.
Thus, the compound of formula (VI) has the formula (XVI)

[0134]

Embedded image

Wherein A ′, Y ′, B, R ¹⁷ , R ⁴ and n are as defined above.

A preferred mode of reduction is iron powder in the presence of ammonium chloride / water / methanol.

A nitroaniline derivative of the formula (XVI) wherein A ′ is NH is represented by the formula (XVI)
IV)

[0138]

Embedded image

A suitable compound of the formula (XV) wherein B, Y ′ and R ¹⁷ are as defined above and B is especially oxygen is

[0140]

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Can be prepared by reacting with isocyanate of

The reaction is suitably carried out in an organic solvent such as dichloromethane or tetrahydrofuran (THF) in the presence of a base such as triethylamine.

Accordingly, an exemplary route is as follows.

[0144]

Embedded image

The present invention is further limited by the following biological test methods, data and non-limiting examples.

[0146]

【Example】

Example 1 Production of 4- (3-{[({4- [2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butyric acid (Compound 1 in Table 1)

[0147]

Embedded image

Methyl-4- (3-｛[((1) in dimethylsulfoxide (DMSO) (1 ml)
{4- [2-Toluidinocarbonyl) amino] anilino} carbonyl) oxy]
A 2N aqueous sodium hydroxide solution (0.2 ml) was added to (methyl @ phenoxy) butanoate (0.085 g). The mixture was stirred for 1 hour at room temperature and then water (5 m
l) was added. The pH was adjusted to pH 2 using concentrated hydrochloric acid. The precipitated solid cellulose was filtered, washed with water, and dried to give the acid (0.055 g) as a dark brown solid (68%).

Mass spectrum MH 476.8

[0150]

[Outside 1]

A) Preparation of methyl 4- (3-hydroxymethyl) phenoxybutyrate Potassium carbonate (5.6 g), 3-hydroxybenzyl alcohol (2.5 g) and methyl 4- (4-hydroxybenzyl) in N-methylpyrrolidinone (5 ml) Bromobutyrate (
2.2 ml) was added potassium iodide (2 g). Mix at room temperature for 48 hours.
Stir for an hour, add to water (30 ml), then extract with diethyl ether (100 ml). The organic phase was washed with dilute sodium hydroxide solution and brine. It was then dried over magnesium sulfate and evaporated to dryness. The residue was then treated with an increasing polar mixture of ethyl acetate / hexane (changed from 20% to 90%).
Purification by chromatography on silica using asingly polar mixture) gave methyl 4- (3-hydroxymethyl) phenoxybutyrate (3.1 g).
was gotten.

1H nmr (CDCl ₃ ) contained the following resonances:

[0153]

[Outside 2]

B) Preparation of methyl-4- (3-{[({4- [2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butanoate Methyl 4- (3-ml) in dichloromethane (3 ml) 20% phosgene in toluene (3 ml) in (3-hydroxymethyl) phenoxybutyrate (0.22 g) is added, the mixture is left for 18 hours, evaporated and then a portion of the residue in dichloromethane (2 ml) ( 0.15 g) in dichloromethane (0.1 g) containing pyridine (0.1 g).
4- (2-tolylureido) aniline (CAS Registry Number 20287) in 3 ml)
4-38-2, those described in WO 98/04247) (0.12 g)
Added to The mixture is stirred for 2 hours, then evaporated and the residue is purified by chromatography on silica using an increasing polarity mixture of methanol / chloroform (0% to 10%), which gives a mixture of evaporation and trituration in diethyl ether. Later the above material (0.15 g) was obtained.

Mass spectrum: M + H 492 1H nmr (DMSO-d6) contained the following resonances:

[0156]

[Outside 3]

Example 2 of 4- (3-{[({methyl-4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butyric acid (compound 5 in Table 1) Preparation This was performed using the method described in Example 1 to give methyl-4- (3-{[({methyl-4-
[(2-Toluidinocarbonyl) amino] anilino {carbonyl) oxy] methyl {phenoxy) butanoate was produced by hydrolysis.

Mass spectrum: MH 492 1H nmr (DMSO-d6) contained the following resonances:

[0159]

[Outside 4]

A) Preparation of methyl 4- [3-({[(4-nitroanilino) carbonyl] oxy} methyl) phenoxy] butanoate Methyl 4- (3-hydroxymethyl) phenoxybutyrate (2) in dichloromethane (10 ml) .24 g) to 4-nitrophenyl isocyanate (2 g)
And triethylamine (3 drops) were added. The mixture is stirred for 2 hours, evaporated to dryness and the residue is triturated with diethyl ether to give methyl 4- [3
-({[(4-Nitroanilino) carbonyl] oxy} methyl) phenoxy] butanoate was obtained as a yellow powder (3.5 g).

1H nmr (CDCl ₃ ) contained the following resonances:

[0162]

[Outside 5]

B) Preparation of methyl 4- [3-({[(methyl-4-nitroanilino) carbonyl] oxy} methyl) phenoxy] butanoate Methyl 4- [3-({[] in N-methylpyrrolidinone (5 ml) (4-nitroanilino) carbonyl] oxy {methyl) phenoxy] butanoate (1 g)
To this was added sodium hydride (1.1 eq) and methyl iodide (1.3 eq), then the mixture was stirred for 4 hours, added to water (20 ml), and extracted with diethyl ether (50 ml). This was washed with brine, dried and evaporated to dryness. Purification of the residue by chromatography on silica using an increasing polarity mixture of ethyl acetate / hexane (changed from 10% to 30%) gives the product as a gum (0.8 g) which, on standing, is crystalline. It has become.

1H nmr (CDCl ₃ ) contained the following resonances:

[0165]

[Outside 6]

C) Methyl 4- (3-{[({methyl-4-[(2-toluidinocarbonyl)
Preparation of amino] anilino {carbonyl) oxy] methyl} phenoxy) butanoate Methyl 4- [3-({[((methyl-4-nitroanilino) carbonyl] oxy} methyl) phenoxy] butanoate (0.7 g) in methanol (10 ml)
) To an iron powder (0.7 g) and ammonium chloride (0.13 g) in water (4 ml).
) Was added. The mixture was refluxed for 1 hour, ethyl acetate (30 ml) was added, then the mixture was filtered to remove metal salts and evaporated to dryness. The residue in dichloromethane was dried over magnesium sulfate, filtered and evaporated to dryness. The residue in dichloromethane (5 ml) was treated with o-tolyl isocyanate (1.
1 eq.), Left to stand for 18 hours, evaporated to dryness and triturated with diethyl ether to give methyl-4- (3-{[({methyl-4- [
(2-Toluidinocarbonyl) amino] anilino {carbonyl) oxy] methyl {phenoxy) butanoate (0.6 g) was obtained as an off-white solid.

1H nmr (DMSO-d ₆ ) contained the following resonances:

[0168]

[Outside 7]

Example 3 4- (3-{[({4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) acetic acid (Compound 6 in Table 1)
Preparation of t-butyl-4- (3-{[({4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) ethanolate (0.6
g) in a mixture of dichloromethane (4 ml) and trifluoroacetic acid (4 ml).
Stirred for hours then evaporated to dryness. Trituration of the residue in diethyl ether gives 4- (3-{[({4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) acetic acid as a white powder. (0.48 g, 87%) Mass spectrum: MH 448 1H nmr (DMSO-d6) contained the following resonances.

[0170]

[Outside 8]

A) Preparation of t-butyl 4- (3-hydroxymethyl) phenoxyacetate To 3-hydroxybenzyl alcohol (95 g) in acetone (10 ml)
Potassium carbonate (11 g) and one spoon of potassium iodide were added and the mixture was stirred while tert-butyl bromoacetate (6.5 ml) was added. The mixture was then stirred for a further 18 hours. The acetone is then evaporated and the residue is washed with water (60
ml) and ethyl acetate (60 ml). The organic phase was dried and evaporated and the residue was purified by chromatography on silica using an increasingly polar mixture of ethyl acetate in hexane. Evaporation of the appropriate fractions to dryness yielded 7 g of a white crystalline product.

1H nmr (CDCl ₃ ) contained the following resonances:

[0173]

[Outside 9]

B) Preparation of t-butyl-4- [3-({[(4-nitroanilino) carbonyl] oxy} methyl) phenoxy] ethanoate t-butyl 4- (3-hydroxymethyl) in dichloromethane (10 ml)
To phenoxyacetate (1.2 g) was added 4-nitrophenyl isocyanate (1.
1 equivalent) and triethylamine (3 drops). The mixture is stirred for 2 hours, evaporated to dryness and the residue is triturated with diethyl ether to give t-butyl-4- [3-({[(4-nitroanilino) carbonyl] oxy} methyl) phenoxy] Ethanoate was obtained as a yellow powder (1.7 g).

1H nmr (DMSO-d6) contained the following resonances:

[0176]

[Outside 10]

C) Preparation of t-butyl-4- (3-{[({4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] phenoxy) ethanoate t-butyl-4- [3 -({[(4-nitroanilino) carbonyl] oxy}
Methyl) phenoxy] ethanoate (0.7 g) was reduced by the method described in Example 2 and reacted with o-tolyl isocyanate to give t-butyl-4- (3-
{[{{4-[(2-toluidinocarbonyl) amino] anilino} carbonyl)
Oxy] methyl @ phenoxy) ethanoate (0.8 g) was obtained as an off-white solid.

1H nmr (DMSO-d6) contained the following resonances:

[0179]

[Outside 11]

Example 4 Production of 4- (3-{[({3-methoxy-4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butyric acid (Table 1) Compound 2) Methyl 4- (3-{[({3-methoxy-4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butanoate (0.15 g) was prepared in Example 1. When hydrolyzed according to the method described, the product 0.07
g was obtained as a dark powder.

Mass spectrum: M + H 508 1H nmr (DMSO-d6) contained the following resonances.

[0182]

[Outside 12]

A) Preparation of 3-methoxy-4 (N '-(2-methylphenyl) urea) nitrobenzene 2-methoxy-4-nitroaniline (16.8 g) in ethyl acetate (90 ml)
) Was treated with 2-methylphenyl isocyanate (16.1 ml) with stirring. The solution was heated at 60 ° C. for 12 hours. The solution was then cooled to 0 ° C., the precipitate was filtered and then washed with cold ethyl acetate. This gives 3-methoxy-4 (N'-
(2-Methylphenyl) urea) nitrobenzene (10 g) was obtained.

1H nmr (DMSO-d6) contained the following resonances:

[0185]

[Outside 13]

B) Preparation of N- (4-amino-2-methoxyphenyl) -N '-(2-methylphenyl) urea DMF containing 10% palladium on carbon (500 mg) at room temperature (50 ml)
3-methoxy-4 (N '-(2-methylphenyl) urea) nitrobenzene (
5 g) of the rapidly stirring solution was exposed to a hydrogen atmosphere. When hydrogen uptake was over, the solution was filtered and the filter cake was washed with dichloromethane. The combined filtrate was evaporated under reduced pressure to dryness, triturated with diethyl ether and filtered to give the product (4.14 g) as an off-white solid.

1H nmr (DMSO-d6) contained the following resonances:

[0188]

[Outside 14]

C) Preparation of methyl 4- (3-{[({3-methoxy-4-[(2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] methyl} phenoxy) butanoate N- (4- Amino-2-methoxyphenyl) -N '-(2-methylphenyl)
Treatment of urea (0.27 g) with the chloroformate of methyl 4- (3-hydroxymethyl) phenoxybutyrate as described in Example 1 gave the product (0.16 g).

1H nmr (DMSO-d6) contained the following resonances:

[0191]

[Outside 15]

Example 5 Preparation of 2- (3- {2 [({4 [2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] ethyl} phenoxy) acetic acid (Compound 7 in Table 1) t- Butyl-2- (3- {2 [({4 [2-toluidinocarbonyl) amino]]
Anilino {carbonyl) oxy] ethyl {phenoxy) ethanoate (0.5 g)
) Was hydrolyzed as described in Example 3 (0.41 g).

Mass spectrum: MH 462 1H nmr (DMSO-d6) contained the following resonances.

[0194]

[Outside 16]

A) Preparation of t-butyl 3- (2-hydroxyethyl) phenoxyacetate 3- (2-hydroxyethyl) phenol (2.8 g) in N-methylpyrrolidinone (8 ml) was mixed with potassium carbonate (5. 6 g) and t-butyl bromoacetate (4.4 g) were added. The mixture was stirred for 18 hours, added to water (40ml) and then extracted into diethyl ether. The organic layer was washed with brine, dried and evaporated to dryness to give t-butyl 3- (2-hydroxyethyl) phenoxyacetate (5.3 g), which was used without further purification .

1H nmr (CDCl ₃ ) contained the following resonances:

[0197]

[Outside 17]

B) Preparation of t-butyl 2- [3- (2-{[(4-nitroanilino) carbonyl] oxy} ethyl) phenoxy] ethanoate t-butyl 3- (2-hydroxyethyl) phenoxyacetate (2 .5g
) Was converted to 4-nitrophenyl isocyanate (1.6 g) by the method described in Example 3.
To give the product (2.9 g).

1H nmr (CDCl ₃ ) contained the following resonances:

[0200]

[Outside 18]

C) Preparation of t-butyl 2- (3- {2-[({4- [2-toluidinocarbonyl) amino] anilino} carbonyl) oxy] ethyl} phenoxy) ethanoate t-butyl 2- [ The reduction of 3- (2-{[(4-nitroanilino) carbonyl] oxy} ethyl) phenoxy] ethanoate (0.8 g) and the reaction of o-tolyl isocyanate according to the method described in Example 2 gives the product (0 0.7 g) was obtained as a white powder.

1H nmr (DMSO-d6) contained the following resonances:

[0203]

[Outside 19]

Example 6 Preparation of Compound 31 in Table 2 To a methyl ester of compound 31 (0.099 g) in MeOH (1 ml) was added 2N aqueous NaOH (0.08 ml) and the mixture was stirred at room temperature for 16 hours. did. It was then evaporated to dryness, the residue was dissolved in THF (5 ml) and acidified with concentrated hydrochloric acid. The solution is then adsorbed on silica and then purified by chromatography on silica using an increasing polarity mixture of CH2 Cl2 / MeOH (5% -20%) and the appropriate fractions are evaporated to dryness to give the compound 31 (0.054 g) was obtained as an off-white solid (56%).

The MS M + H 515 NMR spectrum (in DMSO-d6) contained the following resonances.

[0206]

[Outside 20]

A) Preparation of alcohol intermediate

[0208]

Embedded image

2- (Hydroxymethyl) morpholine (0.8 g) was added to acetonitrile (15 m
l), then add anhydrous potassium carbonate (2.85 g, 3 eq) to this solution,
Potassium iodide (0.025 g, catalytic amount) and methyl-4-bromobutyrate (0.95 ml, 1.05 eq) were added. The reaction mixture is then heated at 60 ° C for 1 hour.
Stir for 6 hours. The cooled suspension was then filtered, washed with copious amounts of acetonitrile, and the filtrate was concentrated under reduced pressure to give the desired alcohol as a yellow oil (1.48 g, 100% yield, Unrefined).

MS data: M + H 218 b) Preparation of nitrophenyl intermediate The alcohol intermediate of step 1 was reacted with 4-nitrophenyl isocyanate as described in example 2a to give the formula

[0211]

Embedded image

The corresponding nitro intermediate was obtained.

MS: M + H 426 NMR spectrum (in DMSO-d6) contained the following resonances.

[0214]

[Outside 21]

C) Preparation of the aniline intermediate

[0216]

Embedded image

The nitro compound from (b) (0.47 g) was dissolved in ethanol (10 ml) and ammonium formate (0.625 g, 10 eq) was added. The reaction flask was flushed with argon and then the catalyst (10% Pd / C, 0.047
mg, 0.1 mass equivalent). The reaction mixture was heated to reflux and stirred at this temperature for 1 hour. The reaction mixture was then cooled, filtered through a bed of celite and washed with copious amounts of ethanol. The solvent was removed under reduced pressure, then the residue was dissolved in ethyl acetate (50ml). The solution was then washed with water, brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the above aniline as a brown oil (0.43 g, 98% yield).

MS data: M + H 438 d) Preparation of methyl ester precursor to compound 31. The aniline intermediate of step c was reacted with o-tolyl isocyanate as described in Example 2c to give the required methyl ester. Obtained.

MS data: M + H 529 Example 7 Preparation of compound 29 in Table 2

[0220]

Embedded image

To the above methyl ester (0.075 g) in THF (2 ml) was added H 2 O (2 m
To a solution of LiOH.H2 O (0.04 g) in 1) was added and the mixture was stirred at room temperature for 16 hours. It was acidified with concentrated hydrochloric acid and then evaporated to dryness.
Purification by chromatography on silica using an increasingly polar mixture of CH2 Cl2 / MeOH (5% -20%) and evaporation of the appropriate fractions to dryness gave the above material (0.064 g) as an off-white solid Obtained (88%).

MS M + H 455 Example 8 Method A is described in Example 1, Method B is described in Example 2, Method C is described in Example 7 using the method of the above example and the structure is first. The following compounds described in Tables, Tables 2 and 3, were prepared.

[0223]

[Table 8]

[0224]

[Table 9]

[0225]

[Table 10]

[0226]

[Table 11]

[0227]

[Table 12]

A) The alkyl (usually methyl or ethyl) ester intermediate (
That is, the compound of formula (I) wherein R5 is methyl or ethyl carboxylate was generally obtained as described in Example 2c. The characteristic data of the available esters are given in Table 5.

[0229]

[Table 13]

[0230]

[Table 14]

[0231]

[Table 15]

[0232]

[Table 16]

[0233]

[Table 17]

In the table above, the compound number refers to the acid finally derived from the methyl ester. Examples with the note "alkylation" have the appropriate nitro intermediate alkylated as described in Example 2b.

Ai) The methyl ester of compound 3 in Table 1 was obtained from the urea carbamate ester intermediate-ureidoaniline + chloroformate using a method similar to that described in Example 1.

The NMR spectrum (in DMSO-d6) had the following resonance.

MS M + H 462

[0238]

[Outside 22]

B) Details of the intermediate aniline of the formula (VI) are described in Table 6. In this table,
The method is described below.

Y ¹ Fe / NH ₄ Cl / EtOH / H ₂ O Same as Example 2c Y ² HCO ₂ NH ₄ / Pd / C / EtOH Same as Example 6c Y ³ H ₂ / Pd / C / EtOH Example The same compound number as 4b refers to the compound of formula (I) that was ultimately derived from the intermediate.

[0241]

[Table 18]

C) The above anilines were obtained from the corresponding nitro compounds of formula (XIV) as described above using a method analogous to that of Example 2a. The data for the nitro compound is given in Table 7.

[0243]

[Table 19]

[0244]

[Table 20]

[0245]

[Table 21]

[0246]

[Table 22]

In this case as well, the column for the compound number refers to the compound of formula (I) finally obtained from this intermediate.

Ci) In the case of nitro compounds used in the preparation of compound 54 in Table 3 (ie the formula

[0249]

Embedded image

A modified route was used.

To methyl 4- (3-hydroxymethyl) phenoxybutyrate (1.12 g) in dichloromethane (6 ml) was added 20% phosgene in toluene (12 ml) and the mixture was left for 18 hours, evaporated 4-Nitroindoline (0.82 g) in pyridine (2 ml) was then added to the residue in dichloromethane (15 ml), then the mixture was stirred overnight, evaporated to dryness and partitioned between aqueous acid and diethyl ether. did. The crystalline material precipitated and was filtered, washed with ether and dried to give the above (0.8 g).

[0252] NMR

[0253]

[Outside 23]

The alcohol intermediate used in the preparation of the nitro compound (of the above general formula (XIV)) was prepared by various methods. These are outlined below or summarized in Table 8.

D1) Alcohol used for producing compound 28 in Table 1

[0256]

Embedded image

Dissolve piperidine methanol (0.5 g) in dichloromethane (10 ml), add triethylamine (0.64 ml, 1.05 eq), then add methyl-4
-Bromobutyrate (0.6 ml, 1.05 eq) was added. The resulting solution was stirred at room temperature for 16 hours, then diluted with a further 40 ml of dichloromethane and washed with water (25 ml). Organic solution into phase separation paper
It was dried using and concentrated under reduced pressure. Purification on a silica bond elution (Bond Elut) column using an increasingly polar dichloromethane / methanol mixture as eluent afforded the desired alcohol (Example 61d) as a yellow oil (0.3
09g, 33% yield).

MS data: M + H216

[0259]

[Outside 24]

D2) Alcohol used for the production of compound 30 in Table 1

[0261]

Embedded image

2- (Hydroxymethyl) morpholine (0.8 g) was added to acetonitrile (15 m
l), and anhydrous potassium carbonate (2.85 g, 3 equiv.), potassium iodide (0.025 g, catalytic amount) and methyl-4-bromobutyrate (0.
95 ml, 1.05 eq.). The reaction mixture was then stirred at 60 ° C. for 16 hours. The cooled suspension is then filtered and washed with a large amount of acetonitrile,
The filtrate was then concentrated under reduced pressure to give the desired alcohol (Example 63d) as a yellow oil (1.48 g, 100% yield, not purified).

MS data: M + H 218 d3) alcohol used for the preparation of compound 48 in Table 1

[0264]

Embedded image

Exactly as in method d2, except that alkyl chloride was used instead of alkyl bromide.

MS data: (EI +) M + 243 d4) Alcohol used for the preparation of compound 4 in Table 1 Potassium carbonate (13.8 g) and potassium iodide (7 g) in 3-hydroxyacetophenone (7 g) in NMP (70 ml) 2 g) and then methyl-4-bromobutyrate (6.2 ml) were added, the mixture was stirred for 18 hours and then water (200 ml) was added.
l) and extracted with ethyl acetate. Washing the organic extract with brine,
Evaporated to dryness, purified by chromatography on silica (hexane / ethyl acetate), then evaporated the appropriate fractions to dryness. 1 g of this material is dissolved in ethanol, sodium borohydride (0.16 g) is added and the mixture is diluted with 1
Stirred for 8 hours, evaporated, then partitioned between dilute acid and diethyl ether. The organic phase was separated, dried, evaporated and the residue was purified by chromatography on silica (10% to 90% ethyl acetate in hexane). Evaporation of the appropriate fractions to dryness gave an approximately 50:50 mixture of ethyl & methyl 4- (3- [1-hydroxy] ethyl) phenoxybutyrate.

[0267] NMR

[0268]

[Outside 25]

D5) Alcohol used for the preparation of compound 23 To 1,3-benzenedimethanol (1.4 g) in THF (10 ml) was added t-
Butyl acrylate (2 g) was added followed by two drops of benzyl methyl ammonium hydroxide solution. The mixture is stirred for 1 hour, evaporated and purified by chromatography on silica using an increasingly polar mixture of hexane / ethyl acetate, after evaporation of the appropriate fractions, tert-butyl (3-hydroxymethyl) benzyloxyprod. 0.55 g of pionate was obtained as an oil.

M + H 267 d6) Alcohol used for the preparation of compound 35 To 4-hydroxypiperidine (2 g) in DMF (35 ml) was added potassium carbonate (8.21) and methyl 4-bromobutyrate (2.9 ml). added. The mixture was stirred at 70 ° C. for 8 hours and then cooled, partitioned between ethyl acetate and water, the organic layer was washed with brine, dried and evaporated to dryness. The residue had a matching M + H and was used without further purification or testing.

D7) Alcohol used for the preparation of compound 41 4- (3-hydroxypropyl) pyridine (10 ml) in acetonitrile (10 ml)
To 1.4 g) was added t-butyl bromoacetate (2 g) and the mixture was allowed to evaporate for 24 hours. The residue was dissolved in methanol and hydrogenated at 55 ° C. for 16 hours at atmospheric pressure in the presence of a 10% palladium on carbon catalyst. The mixture was cooled, filtered and evaporated to give t-butyl 4- (3-hydroxypropyl) piperidinyl acetate. M + H 258.

D8) Alcohol used for the preparation of compound 43 4- (2-Hydroxyethyl) piperidine (1) in acetonitrile (5 ml)
. 29 g), t-butyl acrylate (1.28 g) was added, and the mixture was
Allowed to stand for 8 hours and evaporated to give t-butyl 4- (2-hydroxyethyl) piperidinyl propionate. M + H 258 d9) Alcohol used for the preparation of compound 25 3- (Hydroxyethoxy) phenol (CAS 49650-88-6) (1.54 g) in N-methylpyrrolidinone (3 ml) was added to potassium carbonate (2.8 g).
) And t-butyl bromoacetate (1.95 g) were added and the mixture was stirred for 18 hours, then added to a mixture of brine and diethyl ether. The organic layer was washed with brine, dried, evaporated to dryness and the residue was purified by chromatography using a rising polar mixture of hexane / ethyl acetate to give t-butyl 3- (
(Hydroxyethoxy) phenoxyacetate was obtained. M + H 269 d10) Methyl 4-iodophenyl acetate (300 ml) in alcohol acetonitrile (300 ml) used for the preparation of compound 26 in Table 1
27g), then palladium chloride (0.17g), copper (I) iodide (0
. 37 g), triphenylphosphine (0.51 g), 3-butyn-1-ol (8.85 g) and triethylamine (20 ml) were added and the mixture was stirred for 18 hours in an inert atmosphere, protected from light, and then the solvent was removed. Removed by evaporation, the residue was partitioned between water and ethyl acetate, the organic layer was removed, dried and evaporated to dryness. The residual monomer content was purified by chromatography on silica using an increasingly polar mixture of ethyl acetate / hexane. Evaporation of the appropriate fractions to dryness afforded methyl 4- (4-hydroxybut-3-ynyl) phenyl acetate (18
. 6 g) were obtained.

This was reduced in ethanol (250 ml) using a Pd / C catalyst (5%, 2 g) in hydrogen gas at a pressure of 3 atm for 1 hour, filtered and evaporated to dryness to give methyl 4- ( 4-Hydroxybutyl) phenyl acetate (18 g) was obtained as a yellow oil and was not further purified and tested.

[0274]

[Table 23]

[0275]

[Table 24]

Example 9 Compounds of the present invention or pharmaceutically acceptable salts thereof are described, for example, in lactose (
European Pharmacopoeia), sodium croscarmellose (Croscarmellose sodium)
Together with corn starch paste (5% w / v paste) and magnesium stearate may be incorporated into tablets for therapeutic or prophylactic use in humans. Tablets may be prepared by conventional methods well known in the pharmaceutical art and may be film coated with a typical coating material, for example, hydroxypropylmethylcellulose.

In Vitro and In Vivo Assays The following abbreviations have been used: Suitable sources of the materials are described below. MOLT-4 cells-human T-lymphoblastic leukemia cells (European Collection of Animal Cell C
ultures, Porton Down) Fibronectin-E. Nengwal, E. Luos Lati (E. Nengvall, E. R.
uoslahti, Int. J. Cancer, 1977, 20, pages 1-5) and Forsythe and others
(J. Forsyth et al, Methods in Enzymology, 1992, 215, 311-316) Purified from human plasma by gelatin-sepharose affinity chromatography according to the method described.

PRMI 1640-Cell Culture Medium (Life Technologies, Paisley, UK) PBS-Dulbecco's Phosphate Buffered Saline (Life Technologies) BSA-Bovine Serum Albumin, Fraction V (ICN Thame, UK) CFA-Complete Freund's Adjuvant (Life Technologies) References to compounds in the assays and models below refer to compounds of formula (I) according to the present invention.

[0279] 1.1 In order to study the interaction of the in vitro assay MOLT-4 cells / fibronectin adhesion assay MOLT-4 integrin alpha _{4-beta 1} and fibronectin expressed on the cell membrane, MOLT-4 cells / fibronectin adhesion The assay was used. Polystyrene 96-well plates were coated overnight at 4 ° C. with 100 μl of fibronectin, 10 μg / ml in PBS. Non-specific adhesion sites were blocked by adding 100 μl BSA, 20 mg / ml. After incubation for 1 hour at room temperature, the solution was aspirated. MOLT-4 cells were suspended in RPMI-1640 medium without serum at 2E6 cells / ml (50 μl), and then a solution of compound diluted in the same medium (50 μl) was added to each well. After incubation for 2 hours at 37 ° C. in a humidified atmosphere of 5 (v / v) CO ₂ , non-adherent cells were removed by gentle shaking and aspirated in vacuo. Adherent cells were quantified by a colorimetric acid phosphatase assay. 50 mM sodium acetate buffer containing 1% Triton X-100 in each well,
100 μl of p-nitrophenyl phosphate (6 mg / ml) in pH 5.0 was added. After incubation at 37 ° C. for 1 hour, sodium hydroxide (1M
) 50 μl was added to each well and the absorbance at 405 nm was measured using a microplate spectrometer. Compounds that showed adhesion showed low absorbance readings. Standards, controls and test conditions were assayed three times. Percentage inhibition was calculated for all (no inhibitor) and non-specific (no fibronectin) standards for each plate.

1.2 In Vivo Inflammation Model Compound activity can be tested in the following models.

1.2.1 Ovalbumin-Delayed Hypertension in Mice Balb / c female mice (20-25 g) were abdominated using a 1: 1 (v / v) emulsion of ovalbumin (2 mg / ml) and CFA. Immunized on the side. Seven days later, mice were challenged by intraplantar injection of 1% heat-aggregated ovalbumin in saline (30 μl) into the right hindpaw. Paw swelling occurred during 24 hours, after which the paw thickness was measured and compared to the thickness of the contralateral uninjected paw. The percentage increase in football thickness was calculated. The compound was administered by oral gavage to a group of 5 mice at 0.0
The dose ranged from 01 mg / kg to 100 mg / kg. Inhibition of the inflammatory response was calculated by comparing vehicle-treated and compound-treated animals.

1.2.2 Collagen-induced arthritis in mice DBA / 1 male mice were challenged with bovine collagen type II (2 m
g / ml) and 0.1 ml of an emulsion prepared from an equal volume of CFA. This mixture was injected at the base of the tail. After 20 days, 0.001 m of compound
Gavage was administered by gavage in the range of g / kg to 100 mg / kg. One day after the first dose, each animal received a 0.1 ml intraperitoneal booster injection of collagen type II in acetic acid. The mice were evaluated for the development and severity of arthritis in all four paws for 28 days. Arthritis inhibition was calculated by comparing vehicle-treated and compound-treated mice.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/5375 A61K 31/5375 4H006 A61P 19/02 A61P 19/02 29/00 29/00 43/00 101 43/00 101 C07C 275/40 C07C 275/40 C07D 209/08 C07D 209/08 211/22 211/22 211/34 211/34 265/30 265/30 295/14 295/14 A (81) EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ , LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZWF Term (reference) 4C054 AA02 BB01 CC03 DD01 EE04 EE12 EE19 EE25 FF01 4C056 AA02 AB01 AC03 AD01 AE01 EA07 EB01 EC14 ED06 4C086 AA01 AA02 AA03 BC13 BC21 BC50 BC73 MA01 NA14 ZA96 ZB01 ZB11 4C204 B B01 CB03 DB01 EB01 FB27 GB22 4C206 AA01 AA02 AA03 HA23 HA30 MA01 NA14 ZA96 ZB01 ZB11 4H006 AA01 AA03 AB20 AC56 AC57 BC10 RA48

Claims (10)

[Claims] 1. A compound of the formula (I) Wherein A ′ is NH or NR ⁶ (wherein R ⁶ is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₂ -C ₆ -alkanoyl or C ₁ -C ₆ -alkoxy. B is oxygen or sulfur; Y 'is one or more heteroatoms optionally selected independently from oxygen, nitrogen and sulfur and / or a mono- or bicyclic system Is a linker group consisting of an optionally substituted hydrocarbyl chain intervening, or the linker groups Y 'and A' are taken together, optionally with halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, _cyano, C 1 -C ₆ - _alkyl, C 2 -C ₆ - _alkenyl, C 2 -C ₆ - _alkynyl, C 1 -C ₆ - _alkoxy, C 2 -C - _alkenyloxy, C 2 -C ₆ - _{alkynyloxy, C} 1 ~
C ₆ - alkylamino, di - _[C 1 -C ₆ - alkyl] amino and _C 2 -C ₆ - 5 to 7 membered heterocyclic ring substituted with a substituent from alkanoylamino up to three independently selected M is 0-5, n is 0-4, R ¹ and R ⁴ are halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano, carboxy, carbamoyl, C _{1 to} C ₆ −
_Alkyl, C 2 _{~C 6} - _alkenyl, C 1 _{~C 6} - _alkanoyl, C 2 _{~C 6} -
_Alkynyl, C 1 _{~C 6} - _alkoxy, C 2 _{~C 6} - _{alkenyloxy, C} 2 ~
C ₆ - _alkynyloxy, C 1 -C ₆ - alkylamino, di - _[C 1 -C ₆ - alkyl] _amino, C 2 -C ₆ - alkanoylamino, _N-C 1 ~C ₆ - alkylcarbamoyl, _{C 1} -C ₆ - alkoxycarbonyl, N, N-di - _[C 1 -C ₆ - alkyl] _carbamoyl, C 1 -C ₄ - alkoxy _-C 1 -C ₆ - _{alkyl, (CH 2)} t OH _(in the formula, t is 1 or 2), —CO ₂ R ^a and CO
NR ^a R ^b , wherein R ^a and R ^b are independently hydrogen or C ₁ -C ₆ -alkyl, or each one of R ⁴ is taken together with A optionally substituted by halogen Te, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, _cyano, C 1 -C ₆ - _alkyl, C 2 -C ₆ - _alkenyl, C 2 -C ₆ - _alkynyl, C 1 -C ₆ - _alkoxy, C 2 -C ₆ - _alkenyloxy, C 2 -C ₆ - _alkynyloxy, C 1 -C ₆ - alkylamino, di - [
C ₁ -C ₆ - alkyl] amino and _C 2 -C ₆ - can form a 5- to 7-membered heterocyclic ring substituted with a substituent from alkanoylamino up to three independently selected, ^{R 2} and ^{R 3} Is independently selected from hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkanoyl or C ₁ -C ₆ -alkoxycarbonyl, and R ⁵ is an acidic functional group. Pharmaceutically acceptable salts or derivatives thereof that can be hydrolyzed in vivo. 2. The compound according to claim 1, wherein Y ′ is a monocyclic ring and / or an alkylene chain with an intervening heteroatom. 3. The group A ′ is located meta or para to the ureido group of the formula (I), and most preferably A ′ is located para to the ureido group of the formula (I). The compound of claim 1, wherein the compound is: 4. A compound of the formula (IA) Wherein A is nitrogen or NR ⁶ (wherein R ⁶ is C ₁ -C ₆ -alkyl, C _2-
C ₆ -alkanoyl or C ₁ -C ₆ -alkoxycarbonyl)
B is oxygen or sulfur; Y connects group B to group R ⁵ and has up to 10 atoms, each of which is independently selected from carbon, oxygen, nitrogen and sulfur. A linker group comprising
And optionally may comprise a mono- or bicyclic system, or the linker groups Y and A
Together, optionally halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, _cyano, C 1 -C ₆ - _{alkyl, C} 2 ~
C ₆ - _alkenyl, C 2 _{~C 6} - _alkynyl, C 1 _{~C 6} - _{alkoxy, C} 2 ~
C ₆ - _alkenyloxy, C 2 -C ₆ - _alkynyloxy, C 1 -C ₆ - alkylamino, di - _[C 1 -C ₆ - alkyl] amino and _C 2 -C ₆ - independently selected from alkanoylamino 5 to 7 membered heterocyclic ring substituted with up to three substituents, wherein m is 0-5, n is 0-4, and R ¹ and R ⁴ are halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, cyano, carboxy, _carbamoyl, C 1 -C ₆ -
_Alkyl, C 2 _{~C 6} - _alkenyl, C 1 _{~C 6} - _alkanoyl, C 2 _{~C 6} -
_Alkynyl, C 1 _{~C 6} - _alkoxy, C 2 _{~C 6} - _{alkenyloxy, C} 2 ~
C ₆ - _alkynyloxy, C 1 -C ₆ - alkylamino, di - _[C 1 -C ₆ - alkyl] _amino, C 2 -C ₆ - alkanoylamino, _N-C 1 ~C ₆ - alkylcarbamoyl, _{C 1} -C ₆ - alkoxycarbonyl, N, N-di - _[C 1 -C ₆ - alkyl] _carbamoyl, C 1 -C ₄ - alkoxy _-C 1 -C ₆ - _{alkyl, (CH 2)} t OH _(in the formula, t is 1 or 2), - _CO 2 in ^{R a} and CONR ^a R ^b (wherein ^{R a} and ^{R b} are independently hydrogen or _C 1 -C ₆ - independently from each is alkyl) selected whether or one of ^{R 4} is halogen optionally together with a, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, _cyano, C 1 -C ₆ - alkyl, C -C ₆ - _alkenyl, C 2 -C ₆ - _alkynyl, C 1 -C ₆ - _alkoxy, C 2 -C ₆ - _alkenyloxy, C 2 -C ₆ - _alkynyloxy, C 1 -C ₆ - alkylamino,
Di - _[C 1 -C ₆ - alkyl] amino and _C 2 -C ₆ - can form a 5- to 7-membered heterocyclic ring substituted with a substituent from alkanoylamino up to three independently selected, ^{R 2} And R ³ are each independently selected from hydrogen, C ₁ -C ₆ -alkyl, C ₁ -C ₃ -alkanoyl or C ₁ -C ₆ -alkoxycarbonyl, and R ⁵ is an acidic functional group. A compound according to claim 1 or a pharmaceutically acceptable salt or a biohydrolyzable derivative thereof. 5. A compound of the formula (II)[Wherein A, B, R¹~ R⁵, M and n are defined in claim 4, D and G are each independently C₁~ C₄-Alkyl or C₂~ C₄-Al
Enyl, and each carbon is optionally halogen, hydroxy,
, Nitro, phenyl, trifluoromethyl, trifluoromethoxy, cyano,
Carboxy, carbamoyl, C₁~ C₆-Alkyl, C₂~ C₆-Alkenyl,
C₁~ C₆-Alkanoyl, C₂~ C₆-Alkynyl, C₁~ C₆-Alkoxy
, C₂~ C₆-Alkenyloxy, C₂~ C₆Alkynyloxy, C₁~ C₆ -Alkylamino, di- [C₁~ C₆-Alkyl] amino, C₂~ C₆-Arca
Noylamino, NC₁~ C₆Alkylcarbamoyl, C₁~ C₆-Alkoki
Cicarbonyl, N, N-di- [C₁~ C₆-Alkyl] carbamoyl, C₁~ C ₄ -Alkoxyl-C₁~ C₆-Alkyl, (CH₂)_rOH (where r is 1 or
Or 2), -CO₂R⁷ And CONR⁷R⁸(Where R⁷And R⁸ Is independently hydrogen or C₁~ C₆-Alkyl) or D or
And A together are optionally halogen, hydroxy, amino, nitro, tri
Fluoromethyl, trifluoromethoxy, cyano, C₁~ C₆-Alkyl, C₂ ~ C₆-Alkenyl, C₂~ C₆-Alkynyl, C₁~ C₆-Alkoxy, C₂ ~ C₆-Alkenyloxy, C₂~ C₆Alkynyloxy, C₁~ C₆-Al
Killamino, di- [C₁~ C₆-Alkyl] amino and C₂~ C₆-Alkano
5- to 7-membered ring substituted with up to three substituents independently selected from ilamino
E can be both halogen, hydroxy, amino, nitro, trifluoro,
Lomethyl, trifluoromethoxy, cyano, carboxy, carbamoyl, C₁~
C₆-Alkyl, C₂~ C₆-Alkenyl, C₂~ C₆-Alkynyl, C₁~ C ₆ -Alkoxy, C₂~ C₆-Alkenyloxy, C₂~ C₆Alkynyloxy
Si, C₁ ~ C₆-Alkylamino, di- [C₁~ C₆-Alkyl] amino, C
₂~ C₆-Alkanoylamino, C₃~ C₆-Alkenoyl-amino, C₃~ C ₆ -Alkinoylamino, C₁~ C₆-Alkylcarbonyl, N-C₁~ C₆−
Alkylcarbamoyl, N, N-di- [C₁~ C₆-Alkyl] carbamoyl,
C₁~ C₆-Alkanoyl, C₁~ C₄-Alkoxyl-C₁~ C₆-Alkyl
, (CH₂)_s OH (where s is 1 or 2), -CO₂R⁹And C
ONR⁹R¹⁰(Where R⁹And R¹⁰Is independently hydrogen or C₁~ C₆-A
Phenyl substituted with up to three substituents selected from
Or E and D together form optionally
Logen, hydroxy, amino, nitro, trifluoromethyl, trifluorometh
Kiss, cyano, C₁~ C₆-Alkyl, C₂~ C₆-Alkenyl, C₂~ C₆−
Alkynyl, C₁~ C₆-Alkoxy, C₂~ C₆-Alkenyloxy, C₂~
C₆Alkynyloxy, C₁~ C₆-Alkylamino, di- [C₁~ C₆-A
Alkyl] amino and C₂~ C₆-Up to three selected from alkanoylamino
F can be an oxygen, sulfur, amino or CR¹¹R¹²Wherein p and q are each independently 0 or 1;¹¹And R¹²Is hydrogen, halogen, hydroxy, amino, nitro, phenyl
, Trifluoromethyl, trifluoromethoxy, cyano, carboxy, carba
Moyle, C₁~ C₆-Alkyl, C₂~ C₆-Alkenyl, C₁~ C₆-Arca
Noil, C₂~ C₆-Alkynyl, C₁~ C₆-Alkoxy, C₂~ C₆-Al
Kenyloxy, C₂~ C₆Alkynyloxy, C₁~ C₆-Alkylamino,
Di-C₁~ C₆-Alkyl] amino, C₂~ C₆-Alkanoylamino, N-
C₁~ C₆Alkylcarbamoyl, C₁~ C₆-Alkoxycarbonyl, N,
N-di- [C₁~ C₆-Alkyl] carbamoyl, C₁~ C₄-Alkoxyl-
C₁~ C₆-Alkyl, (CH₂)_uOH (where u is 1 or 2),-
CO₂R^FifteenAnd CNNR^FifteenR¹⁶(Where R^FifteenAnd R¹⁶Independently
Hydrogen or C₁~ C₆-Alkyl), each independently selected from
But R⁴, A, D and E take together two radicals to form more than one ring system
The compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof.
Or derivatives that can be hydrolyzed in vivo. 6. The compound according to claim 5, wherein E is phenyl or a monocyclic heterocycle. 7. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or derivative thereof in vivo and a pharmaceutically acceptable carrier. 8. A method for use in a method of therapeutic treatment of the human or animal body,
The compound according to any one of claims 1 to 6. 9. Fibronectin and / or VCAM-1 (particularly VC
Claims 1 in the manufacture of a medicament for use in the treatment of diseases or medical conditions mediated by the interaction between the AM-1) and the integrin receptor alpha ₄ beta ₁ 6
Or a pharmaceutically acceptable salt or a biohydrolyzable derivative thereof. 10. The method comprising the steps of: (a) preparing a compound of formula (IV) Wherein A ′, R ¹ , R ² , R ³ , R ⁴ , m and n are as defined in relation to formula (I), with a compound of formula (V) Wherein B and Y ′ are as defined in relation to formula (I), Z is a leaving group, for example halogen, and R ¹⁷ is R ⁵ or R ⁵ as defined in relation to formula (I) Or its protected form) or (b) a compound of formula (VI) Wherein A ′, B, Y ′, R ³ , R ⁴ and n are defined in relation to formula (I) and R ¹⁷ is defined in relation to formula (V). , Formula (VII) Wherein R ¹ and m are as defined in relation to formula (I), and then, if desired or necessary, i) except for any protecting groups, And ii) optionally forming pharmaceutically acceptable salts or in vivo hydrolysable derivatives, processes for the preparation of the compounds of formula (I), their pharmaceutically acceptable salts or in vivo hydrolysable derivatives .