JP2003516380A - VLA-4 integrin antagonist - Google Patents

Abstract

(57) Abstract: A compound of formula (I) useful as a VLA-4 integrin antagonist: Wherein Ar is carbocyclic or heterocyclic aryl or biaryl; Q is O, S or N—C≡N; X is arylene; V is NH, O, NHOH, CH ₂ or It is a bond; W is NH, O, NHOH, be CH ₂ or a direct bond; Alk is _{C 2 -C 7 - C 2 -C} 7 that alkylene or O, S, SO, is SO ₂ or NR ₃ inserted Y is amino, acylamino, mono- or di- (lower alkyl, aryl or aralkyl) -amino, pyrrolidino, perhydroazepino or a compound of the formula: Wherein M ₁ is N; M ₂ is CH ₂ , O, NR ₃ , S, SO or SO ₂ ]; R ₁ , R ₂ and R ₃ are independently hydrogen, lower Alkyl, lower alkenyl, cycloalkyl, aryl, cycloalkyl-lower alkyl, aryl-lower alkyl or aryl-lower alkenyl; Z is lower alkylene or one or more lower alkyl, lower alkenyl, cycloalkyl, aryl, Cycloalkyl-lower alkyl, aryl-lower alkyl or lower alkylene substituted with aryl-lower alkenyl; or Z is lower alkylene with O, S, SO, SO ₂ or NR ₃ inserted. Pharmaceutically acceptable esters and amides thereof; and pharmaceutically acceptable salts thereof.

Description

Detailed Description of the Invention

Cell adhesion (ie cells bind to each other, move towards a specific target,
Or the process of localization within the extracellular matrix) is the basis of many biological phenomena. Cell adhesion causes adhesion of hematopoietic cells to endothelial cells and subsequent migration of hematopoietic cells from blood vessels to the wound site and is thus involved in mammalian pathologies such as inflammation, immune reactions.

[0002] Various cell surface macromolecules (known as cell adhesion receptors) are associated with
It mediates cell-cell and cell-matrix interactions. For example, integrins are key mediators in the adhesive interactions between hematopoietic cells and other cells. Integrins are non-covalent heterodimeric complexes consisting of two subunits, α and β. Depending on the type of its α and β subunit components, each integrin is classified into its own subfamily. There are at least 12 different α subunits (α1-α6, α-L, α-M, α-
X, α-IIB, α-V and α-E), there are at least 9 different β subunits (β1-β9).

Integrin VLA-4 (late phase antigen-4), known as α4β1 integrin or as CD49d / CD29, is also a leukocyte cell surface receptor involved in various cell-cell and cell-matrix adhesions. Is. Integrin VLA-4 is a receptor for both the cytokine-induced endothelial cell surface protein vascular cell adhesion molecule-1 (VCAM-1) and the extracellular matrix protein fibronectin (FN). Anti-VLA-4 monoclonal antibody (mA
b's) inhibit VLA-4-dependent adhesive interactions both in vitro and in vivo . Inhibition of VLA-4-dependent cell adhesion prevents or inhibits several inflammatory and autoimmune diseases. VLA-4 antagonists are published, for example, in international application WO 96/22966.

SUMMARY OF THE INVENTION The present invention employs a compound as defined herein, which is a potent VLA-4 antagonist, a process for its preparation, a pharmaceutical composition comprising said compound and a pharmaceutical composition comprising said compound or said compound, Treating a mammalian condition responsive to VLA-4 inhibition,
It relates to a method of preventing or suppressing.

The compounds of the present invention are effective in inhibiting, preventing and inhibiting VLA-4-mediated cell adhesion. Thus, the compounds of the present invention are particularly effective in treating VLA-4-mediated conditions such as inflammation, autoimmune diseases such as immune reactions in organ transplantation. The condition in which VLA-4 is closely related is rheumatoid arthritis, respiratory diseases such as asthma, multiple sclerosis, and complication of organ transplantation such as transplantation of heart, lung, pancreas (Island of Langerhans). Including illness.

[0006] Detailed Description of the Invention The present invention relates to compounds of formula I:

[Chemical 9] [Wherein Ar is carbocyclic or heterocyclic aryl, or biaryl; Q is O, S or N—C≡N; X is arylene; V is NH, O, NHOH, CH ₂ or direct It is a bond; W is NH, O, NHOH, be CH ₂ or a direct bond; Alk is _{C 2 -C 7 - C 2 -C} 7 that alkylene or O, S, SO, is SO ₂ or NR ₃ inserted -Alkylene; Y is amino, acylamino, mono- or di- (lower alkyl, aryl, or aralkyl) -amino, pyrrolidino, perhydroazepino, or a formula:

[Chemical 10] [Where M is₁Is N; and M_TwoIs CH_Two, O, NR_Three, S, SO or SO
_TwoIs a group represented by; R₁, R_TwoAnd R_ThreeAre independently hydrogen, lower alkyl, lower alkenyl, cyclo
Alkyl, aryl, cycloalkyl-lower alkyl, aryl-lower alkyl  Or aryl-lower alkenyl; Z is lower alkylene, or one or more lower alkyl, lower alk
Nyl, cycloalkyl, aryl, cycloalkyl-lower alkyl, aryl-
Lower alkyl or lower alkylene substituted with aryl-lower alkenyl
Or Z is O, S, SO, SO_TwoOr NR_ThreeLower Alkyre with inserted
A compound thereof; pharmaceutically acceptable esters and amides thereof; and
It relates to novel compounds which are pharmaceutically acceptable salts.

The compounds of the invention may possess one or more asymmetric carbons and may exist as diastereomers, racemates and enantiomers, all of which are within the scope of the invention.

A particular embodiment of the invention is that V and W are NH or NHOH; or V is CH ₂ and W is NH; Is a direct bond and W is NH; or a compound wherein V is NH and W is CH ₂ ; and Q is O, S, or N—C≡N It also relates to certain of the above compounds.

Wherein V and W are NH; Q is O; X is phenylene; Ar
Is a carbocycle or heterocyclic aryl; Alk is _C 2 -C ₄ - is _{alkylene; R} 1, R ₂ and _{R 3} is hydrogen or lower alkyl; Y is formula:

[Chemical 11] [Wherein M ₁ is N and M ₂ is CH ₂ , O or S]; and Z is lower alkyl, lower alkenyl, carbocyclic aryl or heterocyclic aryl. substituted _C 2 -C ₅ - a straight-chain alkylene; or Z is O, S, SO
Or a compound of formula I wherein SO ₂ is an inserted C ₂ -C ₅ -straight chain alkylene;
The pharmaceutically acceptable esters and amides thereof; and the pharmaceutically acceptable salts are desirable.

[0010]   Furthermore, the formula II:

[Chemical 12] [Wherein Ar is a monocyclic carbocyclic aryl; Alk is C ₂ -C ₄ -alkylene;
R ₄ is lower alkyl, lower alkenyl, or monocyclic carbocyclic aryl;
m is 1 or 2]; pharmaceutically acceptable esters thereof; and pharmaceutically acceptable salts.

[0011]   Most preferred is Formula III:

[Chemical 13] [Where R_FourIs phenyl, or 1 to 3 C₁-C_FourAlkoxy, chlorine, fu
C or C₁-C_Four-Phenyl substituted with alkyl; and R₅Is C ₁ -C_FourAlkoxy, chlorine, fluorine or C₁-C_Four-Is an alkyl]
A pharmaceutically acceptable ester thereof, and a pharmaceutically acceptable salt thereof.
.

Unless otherwise stated, the general definitions used herein have the following meanings within the scope of the present invention.

Aryl represents carbocyclic or heterocyclic aryl, either monocyclic or bicyclic. Arylene is an aryl linking group in which the aryl is a heterocyclic or carbocyclic aryl, preferably a monocyclic carbocyclic aryl. Carbocyclic aryl bridging groups (X in Formula I) are optionally substituted, eg, in the ortho, meta, or para position, preferably in the para position, with two adjacent groups attached to each other. It is phenylene.

Monocyclic carbocyclic aryl is optionally substituted phenyl, preferably phenyl,
Or a phenyl substituted with 1 to 3 substituents, conveniently lower alkyl, hydroxy, lower alkoxy, acyloxy, halogen, cyano, trifluoromethyl, carbocyclic aryloxy or carbocyclic aryl-lower alkoxy. Represent Bicyclic carbocyclic aryl is 1- or 2-naphthyl, or lower alkyl,
1- or 2-naphthyl substituted with lower alkoxy or halogen.

Monocyclic heterocyclic aryl represents an optionally substituted thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl, pyrazinyl, pyridazinyl or pyrazolyl, preferably an optionally substituted thiazolyl, thienyl, furanyl or pyridyl. .

Optionally substituted furanyl represents 2- or 3-furanyl, preferably substituted with lower alkyl. Optionally substituted pyridyl represents 2-, 3- or 4-pyridyl, or preferably 2-, 3- or 4-pyridyl substituted with lower alkyl, halogen or cyano. Optionally substituted thienyl represents 2- or 3-thienyl, or preferably 2- or 3-thienyl substituted with lower alkyl. Optionally substituted thiazolyl represents, for example, 4-thiazolyl, or 4-thiazolyl substituted with lower alkyl.

Bicyclic heterocyclic aryl represents, for example, quinolinyl, isoquinolinyl, indolyl or benzothiazolyl, optionally substituted with hydroxy, lower alkyl, lower alkoxy or halogen.

Aryl, such as aryl-lower alkyl, is phenyl or phenyl substituted with 1 or 2 lower alkyl, lower alkoxy, hydroxy, acyloxy, halogen, trifluoromethyl or cyano; also optionally substituted. Naphthyl is preferred. Aryl-lower alkyl is conveniently benzyl or 1-optionally phenyl substituted by 1 or 2 lower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, halogen, cyano or trifluoromethyl.
Alternatively, it is 2-phenethyl.

Biaryl is substituted with a carbocyclic or heterocyclic aryl, such as 4-biphenyl, where the phenyl ring is attached at the ortho, meta or para position, conveniently the para position, as defined herein. Represents phenyl.

The term “lower” refers herein to an organic radical or organic compound as defined by up to and including 7, preferably up to and including 4, conveniently 1 or 2 carbon atoms. .

A lower alkyl group preferably contains 1-4 carbon atoms and represents, for example, ethyl, propyl, butyl or, conveniently, methyl. Lower alkylene groups preferably contain 1-4 carbon atoms and represent, for example, ethylene, propylene and the like.

Lower alkenyl groups preferably contain 2-4 carbon atoms and represent, for example, allyl. Cycloalkyl preferably represents cyclopentyl, cyclohexyl or cycloheptyl. A lower alkoxy group preferably contains 1-4 carbon atoms and represents for example methoxy, propoxy, isopropoxy, or conveniently ethoxy.

Halo preferably represents fluorine or chlorine, but may also be bromine or iodine. Acyl is derived from a carboxylic acid or carbonic acid, preferably optionally substituted lower alkanoyl, aroyl, lower alkoxycarbonyl, or aryl-
Represents lower alkoxycarbonyl, conveniently aroyl.

Lower alkanoyl is preferably acetyl, propionyl, butyryl or pivaloyl. Optionally substituted lower alkanoyl represents eg lower alkanoyl or lower alkanoyl substituted eg with lower alkoxycarbonyl, lower alkanoyloxy, lower alkanoylthio, lower alkoxy or lower alkylthio.

The aroyl is preferably a monocyclic carbocyclic aroyl or a monocyclic heterocyclic aroyl. The monocyclic carbocyclic aroyl is preferably benzoyl or benzoyl substituted with lower alkyl, lower alkoxy, halogen or trifluoromethyl. The monocyclic heterocyclic aroyl is preferably pyridylcarbonyl or thienylcarbonyl.

Acyloxy is preferably optionally substituted lower alkanoyloxy, lower alkoxycarbonyloxy, monocyclic carbocyclic aroyloxy or monocyclic heterocyclic aroyloxy. Aryl-lower alkoxycarbonyl is preferably monocyclic carbocycle-lower alkoxycarbonyl, conveniently benzyloxycarbonyl.

The pharmaceutically acceptable ester is preferably a prodrug ester derivative such that it is convertible by solvolysis or under physiological conditions into the free carboxylic acid of formula I.

Pharmaceutically acceptable esters are, for example, lower alkyl esters, cycloalkyl esters, lower alkenyl esters, benzyl esters, such as ω- (amino, mono- or di-lower alkylamino, carboxy, lower alkoxycarbonyl)- Convenient in the art, such as lower alkyl esters and mono- or di-substituted lower alkyl esters such as α- (lower alkanoyloxy, lower alkoxycarbonyl or di-lower alkylaminocarbonyl) -lower alkyl esters such as pivaloyloxy-methyl ester. Prodrug esters as commonly used are desirable.

The pharmaceutically acceptable amides are primary, secondary and tertiary amides, ie unsubstituted N-mono-lower alkyl, or N, N-di-lower alkyl amides, or, for example, And amides of cyclic amines such as piperidine, pyrrolidine, morpholine, or optionally substituted piperazine.

The pharmaceutically acceptable salts of the acids of the present invention include, for example, alkali metal salts (eg sodium, potassium salts), alkaline earth metal salts (eg magnesium, calcium salts), amine salts (eg ethanolamine, Salts derived from pharmaceutically acceptable bases conventionally used in the art, such as diethanolamine, lysine and tromethamine salts. When the compound of the present invention contains a basic group, salts are also such as inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or succinic acid, lactic acid, malic acid, citric acid, maleic acid, fumaric acid, It can be prepared from pharmaceutically acceptable non-toxic acids such as methane sulfonic acid, acetic acid and the like, for example organic acids such as fatty acids, aromatic carboxylic acids or aromatic attribute sulfonic acids.

The compounds of the present invention inhibit VLA-4, which aids in cell adhesion, and treat and ameliorate mammalian conditions in which VLA-4 is involved, eg, immune disorders, autoimmune disorders, inflammation, For prevention, it is particularly useful as a VLA-4 antagonist in mammals. The diseases include respiratory diseases (eg asthma), arthritis (eg rheumatoid arthritis), psoriasis, posttransplant rejection, multiple sclerosis, type I diabetes, inflammatory bowel disease, sickle cell anemia, Crohn's disease, grapes. Includes membranous, systemic lupus erythematosus, myasthenia gravis, gout, etc.

With respect to respiratory diseases, the compounds of the present invention are useful as agents for the treatment or prophylactic treatment of the symptoms of inflammatory tracheal diseases. The disease includes asthma of any type, or of any origin, including both intrinsic and extrinsic, especially extrinsic asthma. These include allergic asthma, both atopic (eg, IgE-mediated) and non-atopic, and bronchogenic asthma, exercise-induced asthma, occupational asthma, asthma induced by bacterial infection, and It is useful for treating other non-allergic asthma. The treatment of asthma is also understood to include the treatment of patients under the age of 4, 5 who exhibit Zeis symptoms, especially at night, and which are or can be diagnosed as "pediatric asthma".

The efficacy of prophylactic agents in the treatment of asthma is evidenced by a reduced incidence and reduced severity of symptomatic stroke. The efficacy of prophylactic agents may further be represented by symptomatic treatment, i.e. a reduction in the need for treatment for symptomatic seizures, or inhibition of symptomatic seizures, for example using corticosteroids for anti-inflammatory treatment. Or, it may be intended to arrest early in the event of a seizure.

Other inflammatory tracheal diseases that may be treated with the compounds of the invention are, for example, aluminosis,
Pneumoconiosis (inflammatory, generally occupational, lung disease caused by repeated inhalation of dust), including asbestosis, pneumoconiosis, ironosis, silicosis, tobacco disease and cotton disease Including.

Additional inflammatory tracheal disorders that may be treated with the compounds of the invention include adult respiratory distress syndrome (ARDS), exacerbated conditions of chronic obstructive pulmonary disease (COPD), and aspirin or β-agonist bronchial therapeutic therapies. Includes exacerbations of tracheal hyperactivity as a result of other drug treatments.

In view of their anti-inflammatory activity, especially with regard to the inhibition of eosinophil activity, the compounds according to the invention may also be for example eosinophilia, hypereosinophilic, eosinophilic pneumonia, parasites Invasion (localized eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa, eosinophilic granulomas, eosinophilia-related diseases affecting the trachea caused by drug reactions, etc. Is useful for the treatment of trachea-related diseases.

The compounds of the invention may also be used in allergic inflammatory diseases, such as allergic rhinitis.

The compounds of the invention are used in transplant patients (eg, heart, lung, heart-lung combinations, liver, heart, kidney, pancreas, skin, or corneal transplants), including allograft and xenograft rejection. , It is especially useful for inhibiting rejection after transplantation. The compounds of the invention are also required for the prevention of graft-versus-host disease such as that seen after bone marrow transplantation. The compounds of the invention may be used alone or in combination with known immunosuppressive agents. The immunosuppressants include cyclosporine, tacrolimus, mycophenolic acid (mycophenolate mofetil), brequener (brequner sodium), rapamycin and the like. The doses of these immunosuppressive agents required to achieve an immunosuppressive effect when used in combination can be reduced,
Thus, undesired side effects for certain known immunosuppressive agents may be reduced, eg, cyclosporine, nephrotoxicity in the case of tacrolimus.

The properties quoted above are manifested in in vitro and in vivo tests using convenient mammals such as rats, mice, dogs, monkeys and their isolated cells.
The compound may be used in vitro in the form of a solution, for example preferably in an aqueous solution, i
It may be used either enterally or parenterally in vivo, conveniently orally and intravenously. In vitro doses range between about ^10-5 and ^10-9 molar. In vivo doses range between about 0.1 and 100 mg / kg, depending on the method of administration.

The cell adhesion inhibitory activity of the present compounds is measured by determining the concentration of inhibitor required to block the binding of VLA-4-expressing cells to fibronectin- or CS1-coated plates. . In this assay, microtiter wells are coated with either fibronectin (containing CS-1 sequences) or CS-1. When using CS-1, to bind to the well, C
S-1 must be conjugated to a carrier protein such as bovine serum albumin. Once wells were coated, with appropriately labeled VLA-4 expressing cells,
Different concentrations of test compound are added. Alternatively, the test compound is added first and incubated with the coated wells before adding cells. The cells are incubated in the wells for at least 30 minutes. After incubation, the wells are emptied and washed. Inhibition of binding is measured by quantifying the fluorescence or radioactivity of various concentrations of test compound bound to the plate and controls without test compound.

VLA-4 expressing cells that can be utilized in this assay are Ramos cells, Jurkat
Cells, A375 melanoma cells, and human peripheral blood vessel lymophocytes (PBLs)
including. The cells used in this assay are fluorescently or radiolabeled.

Direct binding assays are also used to quantify the inhibitory activity of compounds of the invention. In this assay, VCAM (D1 bound on the hinge region of the IgG1 molecule
The VCAM-IgG fusion protein containing the first two immunoglobin domains of D2) binds to a marker enzyme such as alkaline phosphatase (AP). The synthesis of this VCAM-IgG fusion protein is described in PCT Publication WO 90/13300. The binding of this fusion protein to the marker enzyme is accomplished by the well-known cross-linking method. The VCAM-IgG enzyme conjugate was then labeled with Millipore Multiscan Assay Sy.
Place in the wells of a multi-well filtration plate, such as that included in the stem (Millipore Corp., Bedford, MA). Test inhibitor compounds with varying concentrations were VLA-4
Add after addition of expressing cells. The cells, compound and VCAM-IgG enzyme conjugate are mixed together and incubated at room temperature. After incubation, the wells are vacuum dried, leaving any VCAM associated with the cells. The quantification of bound VCAM is V
It is determined by adding an appropriate colorimetric substrate to the enzyme that binds to CAM-IgG and determining the reaction amount of the cell adhesion inhibiting activity.

To assess the VLA-4 inhibitory specificity of the compounds of the present invention, other major groups of integrins, β2 and β3 integrins, and VLA-5, V.
Assays for other β1 integrins such as LA-6 and α4β7. These assays are similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate integrin expressing cells and the corresponding ligand instead.
For example, polymorphonuclear cells (PMNs) express β2 integrin on their surface,
Connect to AM. β3 integrin is associated with platelet aggregation, and inhibition can be measured with a standard platelet aggregation assay. VLA-5 binds specifically to the Arg-Gly-Asp sequence, while VLA-6 binds laminin.

An in vivo assay for testing contact hypersensitivity inhibition in animals was performed by PL Chisho.
lm et al., Eur. J. Immunol., vol. 23, pp.682-688 (1993). An assay to measure inhibition of the Ascaris antigen-induced delayed phase tracheal response and tracheal hyperreactivity in asthmatic sheep is described by WM Abraham et al., J. Clin. Invest., Vol. 93, pp.
.776-87 (1994).

The compounds of the invention may also be tested in the antigen-induced lung eosinophilia assay in mice as described below. Male B6D2F1 / J mice received alum-precipitating antigen 0 containing 8 μg ovalbumin (OVA) absorbed in 2 mg aluminum hydroxide gel in saline vehicle
． Hypersensitivity by intraperitoneal injection of 5 ml. Five days later, the mice are boosted with OVA / alum. Control animals are hypersensitive only with alum. Ten mice were used for each group.

Mice are placed in a 12 × 14 × 10 inch Plexiglas chamber and exposed to nebulized OVA (0.5% in saline) for 1 hour at the beginning of the experiment (t = 0) and 5 hours later. The antagonist is soluble in 2% DMSO, 150 mM TRIS, pH 8.8. Solvent controls are included in each experiment. Drugs are administered orally 30 minutes prior to OVA exposure and 6 hours after the first OVA exposure.

[0047]   The% inhibition is the formula:

[Equation 1] [Where: Eos = average number of eosinophils OA group = challenged mice non-OA group = non-challenged mice] Animals are sacrificed by CO ₂ asphyxiation 24 hours after the first challenge. . The trachea is exposed and cannulated. Lung buffer (Hepes 10 mM, BSA0
． Wash with 0.6 ml of 5% heparin 10 U / ml Hank's buffered saline).
For each sample, the number of eosinophils in the wash is evaluated by calculating the total number of leukocytes and the percentage of eosinophils.

Immunosuppressive activity was also determined in experimental allergic encephalomyelitis, Freund's adjuvant, additional animal models of T cell-mediated immune responses such as collagen-induced arthritis, and models of graft-versus-host reactions. obtain.

Anti-arthritic activity can be determined in collagen II-induced arthritis in a mouse model. 6-8 week old DBA / 1 LacJ female mice are immunized by injecting 100 μg of avian type II collagen emulsified in Freund's complete adjuvant (FCA) at day 0 at the base of the tail. 17 days after collagen injection, P
Subcutaneous injection of 200 μg of LPS solubilized in BS enhances the immune response to type II collagen. The feet are 17, 21, 24, 28, 31, 35 and 42
Examine on day 1 to assess signs of arthritis based on features such as inflammation, swelling, and ankylosis. The compound was suspended in a vehicle of corn starch and orally administered to mice once a day.
Start on day 1 and continue on to day 42.

Protection against transplant rejection can be determined in the following mouse skin grafts on the tail.

In mice, Papaioannou and Fox method (Lab. Animal Science 1993; 43: 189-92)
By an intraperitoneal injection of tribromoethanol. A model for the rejection of skin grafts on the tail of mice has been described by Baily and Usama (Transpl. Bull. 19
60; 7: 424-5), which is a modification of the model described by Surgery (Day 0)
In, skin grafts at four positions per mouse, exchanged between species [C57BL / 10-SnJ (H -2K b) and ^{B10.BR / SgSnJ (H-2K k} )]. The fitted skin graft is removed with a scalpel and the tail graft site is protected by tubing for 2 days post surgery. The tails of the mice are evaluated for grafts on day 7. On day 7, a new graft (pate
The evaluation period is delayed only for the transplant site with nt graft). Grafts are evaluated numerically for signs of rejection, starting on day 14 to weekly recording intervals. Mean graft records of drug-treated groups are compared statistically. Day 20/21 and 2
Drug treatment is considered to be efficacious if at day 7/28 the implant record of compound-treated mice is lower than that of vehicle-treated mice.

The compound of the present invention can be prepared, for example, as shown in the following International Application WO 96/22966 (
It may be manufactured by the application of previously reported manufacturing methodologies, such as the United States, which is hereby incorporated by reference herein). An example is shown.

[0053]   The compound of formula I has formula IV:

[Chemical 14] [Wherein Ar, V, Q, W and X have the meanings as defined above], or a derivative of a reactive functional group thereof, and a compound of the formula V:

[Chemical 15] A carboxyl group is in a protected form and Alk, Y, R ₁ , R ₂ and Z have the meanings as defined above, and are prepared by reacting Convert, if any, to give other compounds of the invention.

The condensation is carried out by methodologies well known in the art in the formation of amides. For example, in an inert solvent (such as methylene chloride), preferably at room temperature, 1-
It is carried out in the presence of a condensation reagent such as [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and a base such as diisopropylethylamine.

Starting materials of formula IV, such as optionally substituted phenylureidophenylacetic acid, are prepared in an order known in the art or by methods known in the art. For example, it is prepared by condensing p-aminophenylacetic acid ester with a suitable arylisocyanate to obtain a corresponding phenylureidophenylacetic acid ester, and hydrolyzing the obtained ester.

[0056]   The starting material of formula V is then of the formula: in the presence of a base such as triethylamine.

[Chemical 16] A compound of the formula VII: wherein the carboxyl group is in protected form (eg as an alkyl ester) and Z has the meaning as defined above.

[Chemical 17] [Wherein R ₁ and R ₂ have the meanings as defined above, and L is a leaving group such as halo or (alkyl or aryl) -sulfonyloxy], preferably its reactivity By reacting with a derivative of the functional group, the compound of formula VIII:

[Chemical 18] Where the carboxylic acid is in protected form (eg as an alkyl ester) and L, R ₁ , R ₂ and Z have the meanings as defined above, and then: Formula IX:

[Chemical 19] [0000] where Y and Alk have the meanings as defined above, are reacted under conditions well known in the art to provide the protected form (eg, as an alkyl ester) of the starting material of Formula V. By obtaining, it is manufactured in order. Hydrolysis with a base such as aqueous lithium hydroxide provides the starting material of formula V.

As described in the steps cited above, the steps may be carried out during which, if necessary, temporarily protect any interfering reactive groups before the compounds of the present invention are protected. Can be released.

Among the starting materials and intermediates which are converted into the compounds of the invention by the methods described herein, functional groups such as carboxyl, amino, hydroxy groups are optionally conventional in synthetic organic chemistry. , Protected by conventional protecting groups.

Well-known protecting groups and their introduction are described, for example, in "Protective Groups" by JFW McOmie.
in Organic Chemistry ", Plenum Press, London, New York and TW Greene
It is described in his book "Protective Groups in Organic Synthesis", Wiley, New York. For example, a hydroxy group is conveniently protected in the form of a benzyl ether,
Cleavage by catalytic hydrogenation gives a hydroxy-substituted product.

The above reaction may be carried out according to standard methods in the presence or absence of a diluent, preferably a pharmaceutically inert diluent and its solvent, catalyst, ie condensing agent or other catalyst, and / or It is carried out at a low temperature, a room temperature or a elevated temperature (preferably at or near the boiling point of the solvent used) under an inert atmosphere, at atmospheric pressure or under pressure. Preferred solvents, catalysts, and reaction conditions are given in additional examples.

The present invention also relates to any novel starting material and process for its preparation. Any mixture of end products and mixtures of intermediates can be prepared by known methods, for example chromatography, distillation, fractional crystallization, on the basis of the physicochemical differences of the constituents.
Alternatively, it may be separated into the pure end product or intermediate, if appropriate under the circumstances, or possibly by salt formation.

The compounds or intermediates of the present invention may also be obtained in the form of hydrates or include other solvents used in crystallization.

Some of the compounds described herein contain one or more asymmetric centers and are therefore (R) in terms of enantiomers, diastereomers and absolute stereochemistry.
) Or (S), or with amino acids, other stereoisomeric forms may be defined which may be defined as (D) or (L). The present invention refers to all possible diastereomers, racemates and optically pure forms of interest. Optically active (R) and (S), or (D) and (L) isomers can be prepared using chiral synthetic elements or chiral reagents, or resolved using conventional methods. Compounds described herein are meant to include both E and Z geometric isomers, unless otherwise specified, if they contain olefinic double bonds or contain other geometric asymmetric centers. Similarly, it is intended to include tautomeric forms.

The present invention further provides VLA-4 antagonists, alone or as VLA-4 antagonists, comprising an effective amount of a pharmacologically active compound of the invention, alone or in combination with one or more pharmaceutically acceptable carriers. For enteral, transdermal, nasal, topical intraocular, and parenteral administration, such as oral or rectal, to mammals, including humans, useful in the treatment of diseases responsive to -4 Suitable pharmaceutical compositions.

The composition may be oral, rectal, topical (including transdermal devices, aerosols, creams, ointments, topical solutions, and powders), parenteral (subcutaneous, muscular, intravenous). Ingredients), ophthalmic (ophthalmic medications), pulmonary (nasal or oral inhalation), or nasal medications suitable compositions; in any case, the most suitable route is treatment It depends largely on the nature and severity of the condition to be treated and the nature of the active ingredient. The compounds of the present invention may conveniently be presented in unit dosage form, prepared by any of the methods well known in the art of pharmacy.

For example, in the treatment of tracheal diseases, the compounds of the invention may be administered orally, eg, in the form of tablets, or by inhalation, eg, using an appropriate inhalation device known in the art, an aerosol, or otherwise. May be administered by inhalation of an atomisable formulation or of a dry powder formulation. For use in the treatment of allergic rhinitis, the compounds of this invention may also be intranasally dosed. For the treatment of eye diseases, the compounds of the invention may also be administered topically, eg as eye drops, gels, ointments and the like.

The compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier by conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the nature of the desired mode of administration, oral, parenteral and the like. In the manufacture of oral dosage forms, in the case of oral liquid preparations (eg suspensions, elixirs and solutions) any conventional pharmaceutical solvent such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Or, in the case of oral solid preparations such as powders, capsules and tablets, carriers such as starch, sugars, microcrystalline cellulose, diluents, granulating reagents, lubricants, binders, disintegrants, etc. are used. obtain. Solid oral formulations are generally preferred over liquid oral formulations. Tablets and capsules are desirable oral unit dosage forms because of ease of dosing. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.

In addition to the dosage forms described above, the compounds of the invention may be administered by controlled release methods and devices, such as transdermal therapeutic systems. Pharmaceutical compositions of the invention suitable for oral administration may be in the form of powder or granules, as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active ingredient, or in aqueous or non-aqueous form. It may be prepared as a solution or suspension in an aqueous liquid, or as an oil-in-water or water-in-oil emulsion. The composition may be synthesized by any method known in the pharmaceutical art. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, well-divided solid carriers, or both, and then, if necessary, shaping the product into the desired shape. To manufacture. For example, a tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets are prepared by compressing on a suitable machine the active ingredients in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surfactant, dispersant. Can be manufactured by. Molded tablets are
Mixtures of powdered compounds moistened with an inert liquid diluent can be made by molding in a suitable machine.

Injectable compositions are preferably aqueous isotonic solutions, emulsions or suspensions, and suppositories may conveniently be prepared from fatty emulsions or suspensions. The composition may be sterilized and / or contain additives such as preservatives, stabilizers, humectants, emulsifiers, dissolution enhancers, salts and / or buffers to adjust the osmotic pressure. obtain. In addition, they may also contain other therapeutically valuable substances. The compositions may each be manufactured by conventional mixing, granulating or coating methods and contain about 0.1% of the active ingredient.
To 75%, preferably about 1 to 50%.

Suitable formulations for transdermal use include an effective amount of a compound of the invention with carrier.
Convenient carriers include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. Typically, transdermal devices are provided with a backing, a reservoir containing the compound, optionally with a carrier, to deliver the compound to the skin of the host over an extended period of time at an optionally controlled and predetermined rate. In the form of a bandage consisting of a path control barrier and an adhesive layer to secure the device to the skin.

Depending on the indication, the composition containing the compound of the present invention may also be, for example, a corticosteroid, a bronchodilator, an anti-asthma drug (mast cell stabilizer), an anti-inflammatory drug, an anti-rheumatic drug, an immunosuppressive drug. , Antimetabolites, immunomodulators, antipsoriatics, and antidiabetic agents. Specific compounds that can be used in combination are
Cyclosporine, FK-506, and rapamycin (immunosuppressive drug); cyclophosphamide and methotrexate (antimetabolite); and interferon (
Immunomodulator).

Furthermore, the present invention inhibits VLA-4 activity in mammals, and VLA-4 as described herein, such as, for example, autoimmune disease, posttransplant rejection, psoriasis, or respiratory disease. A method of treating or preventing a disease or condition responsive to a mammal in need thereof in combination with a compound of the invention, or one or more pharmaceutically acceptable carriers. A method comprising administering an effective amount of a pharmaceutical composition comprising a compound.

A particular embodiment thereof is that a mammal in need thereof is provided with a compound of the invention, or said compound in combination with one or more pharmaceutically acceptable carriers, for the corresponding inhibition. A method for inhibiting VLA-4-dependent cell adhesion in a mammal comprising administering an effective amount.

The prophylactic or therapeutic dose of a compound of the invention will vary with the nature and severity of the condition to be treated and the particular compound of the invention and its route of formulation. Generally, the daily dose will be in the range of 0.05 to 50 mg / kg of mammalian body weight, preferably in the range of 0.1 to 10 mg / kg, in single or divided doses. In some cases, it may be necessary to use doses outside these ranges. A mammalian unit dosage form of about 50 to 70 kg typically contains about 1 to 1 of the active ingredient.
Including amounts between 50 mg.

The following examples are intended to represent the present invention and should not be construed as limiting thereto. Temperatures are given in degrees Celsius. Unless otherwise stated, all distillations are performed under reduced pressure, preferably between about 15 and 100 mmHg. The structure of the final products, intermediates and starting materials can be determined, for example, by microanalysis and / or spectroscopic properties (MS
Confirm by standard analytical methods (IR, NMR, UV, etc.).

Depending on the chemical nature of the asymmetric carbon substituents, the enantiomers are designated (R) or (S) by conventional nomenclature rules. The following abbreviations have the following meanings: DIC = N, N'-diisopropylcarbodiimide DIEA = diisopropylethylamine DMAP = 4-dimethylaminopyridine DMSO = dimethylsulfoxide EDAC = 1- [3- (dimethylamino) propyl]. -3-Ethylcarbodiimide hydrochloride HOBT = N-hydroxybenzotriazole HOSu = N-hydroxysuccinimide HPLC = high pressure liquid chromatography MS = mass spectrometry NMR = nuclear magnetic resonance TEA = triethylamine TLC = thin layer chromatography TRIS = tris (hydroxymethyl) ) Aminomethane

Example 1 (S) -β-[[p- (o-tolylureido) -phenylacetyl-N- (2-morpholinoethyl) -glycyl] amino] -β- (3,4-dimethoxyphenyl) Propionic acid

[Chemical 20] Stage 1

[Chemical 21] To 300 ml of methanol, 30 g of 3,4-dimethoxycinnamic acid (144.2 mmol)
Add. 4 drops of H ₂ SO ₄ are added and the mixture is refluxed for 4 hours. The reaction is monitored by TLC with ethyl acetate / hexane 70/30. The mixture was evaporated to dryness in vacuo and grade 60, 70-230 using 20% ethyl acetate / 80% hexane.
Perform flash chromatography on 350 g of mesh silica gel,
Methyl 4-dimethoxyphenylcinnamate (Product A ) is obtained.

Stage 2

[Chemical formula 22] (R)-(+)-N-benzyl-α-methylbenzylamine 1 in 200 ml of THF
1.8 g (55.8 mmol) are added. The mixture is cooled to 0 ° C. and 34.9 ml (55.8 mmol) n-BuLi (1.6M in hexane) are added dropwise over 30 minutes. The mixture is stirred for another 30 minutes. The reaction is cooled to -78 ° C. Then TH
6.2 g of methyl 3,4-dimethoxycinnamate ( A ) dissolved in 150 ml of F.
9 mmol) is added dropwise over 1 hour. The mixture was slowly stirred for 30 minutes at -78 ° C., the temperature of saturated solution of NH 4 _Cl 25ml while maintaining the -78 ° C. was added and the mixture was allowed to warm to room temperature, washed with brine, and concentrated to dryness under reduced pressure. Ethyl acetate / hexane
Monitor the reaction using TLC with 50/50. The mixture is flash chromatographed on 180 g of Merck grade 9385 (230-400 mesh, 60A) silica gel to give product B as a dark yellow oil.

Stage 3

[Chemical formula 23]   B 5.0 g (11.5 mg) of CH_ThreeOH 250ml, H_TwoO 25ml, HOAc
Add to 7.5 ml. Pearlman catalyst (Pd (OH)_Two) Add 1 g. Baru
The mixture at room temperature with H 2_TwoReflux for 16 hours under atmosphere. 5% CH_Three OH / CH_TwoCl_TwoThe reaction is monitored using TLC with. The mixture is
Filter with light, CH_ThreeWash with OH and dry under reduced pressure. CH to dry product _Two Cl_TwoWas added, the solution was washed with brine, saturated NaHCO 3_ThreeTo make it basic. mixture
The product was evaporated to dryness under reduced pressure, and 150 g of silica gel (230-400 mesh) was added to give 1 to 4% C
H_ThreeOH / CH_TwoCl_TwoFlash chromatography as eluent,
Β-amino-β- (3,4-dimethoxy-phenyl) propene as a yellow oil
Methyl onate (productC) Get.

Step 4

[Chemical formula 24] 0.2 g (0.8 mmol) of C and 0.13 of triethylamine in 9 ml of CH ₂ Cl ₂
ml (0.9 mmol) is added. The mixture is stirred for 10 minutes and cooled to 0 ° C. Bromoacetyl bromide 0.08 ml (0.9 mmol) in 1 ml CH ₂ Cl _{2 is} added dropwise over 15 minutes. The mixture is stirred for 3 hours or more and the mixture is allowed to come to room temperature. Monitor the reaction using TLC with 50% ethyl acetate / 50% hexane. The mixture was evaporated to dryness in vacuo and Merck grade 9385 (230-400 mesh, 60A) silica gel 3 was used.
Flash chromatography using 0 g of 25% ethyl acetate / 75% hexane as eluent, β- (3,4-dimethoxyphenyl) -β- (bromoacetylamino) propionic acid as a dark yellow oil. Methyl (product D )
To get

Step 5

[Chemical 25] To 10 ml of DMF are added 0.36 g (1 mmol) of D and 0.35 g (2.5 mmol) of 4- (2-aminoethyl) morpholine. Add 0.23 ml TEA at room temperature. The mixture is stirred for 16 hours at room temperature. T with 10% CH ₃ OH in CH ₂ Cl ₂
Monitor the reaction using LC. The mixture was evaporated to dryness under reduced pressure and 12 g of silica gel,
Using CH ₃ OH in CH ₂ Cl ₂ starting from 2% and gradually increasing to 4%,
Flash chromatography gives methyl β-[(N-morpholinoethylglycyl) amino] -β- (3,4-dimethoxyphenyl) propionate (product E ) as a yellow oil.

Step 6

[Chemical formula 26] To 40 ml of CH ₂ Cl ₂ 1.2 g (3.0 mmol) of E are added. Then, N- (
o-Tolyl) -N '-(phenyl-4'-acetic acid) urea (partially soluble) 1.
0 g (3.5 mmol) and 0.57 ml of diisopropylethylamine (DIEA) (
4.1 mmol) is added and the mixture is stirred for 15 minutes to give a clear yellow solution. Then, 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (
0.70 g (3.5 mmol) of EDAC) are added and the mixture is stirred for 3 hours. CH ₂
Using TLC using of _CH 3 OH in Cl ₂ 10%, the reaction is monitored. The mixture was evaporated to dryness under reduced pressure, flash chromatographed, eluting with 2% CH ₃ OH in CH ₂ Cl _{2 and} (S) -β-[[p- (o-tolylureido) phenylacetyl- as a white foam. N- (2-morpholinoethyl) -glycyl] amino] -β- (3
Methyl 4-dimethoxyphenyl) propionate (product F ) is obtained.

Step 7

[Chemical 27] To 45 ml of THF and 13 ml of H ₂ O are added 1.4 g (2.1 mmol) of product F. 0.132 g (3.1 mmol) of LiOH dissolved in ₂ ml of H ₂ O are added dropwise over 5 minutes and the mixture is stirred at room temperature for 2 hours. Using TLC using of _CH 3 OH 10% CH ₂ Cl _2, to monitor the reaction. The mixture is dried under reduced pressure. Water was added to the solid, the mixture was adjusted to pH 2, neutralized to pH = 7, extracted with THF, dried and evaporated to give the title compound as a white solid; Boiling point: 120-125 ° C (decomposition) ^{); [α] -16.074 0,} DMSO in (10 mg / ml)

Example 2 The following compounds are prepared in the same manner as in Example 1 (the enantiomers described are optionally in active form).

[Chemical 28]

[Table 1]

[Table 2]

Example 3 The following compounds are produced in the same manner as in the production method of Example 1.

[Chemical 29]

[Table 3]

Example 4 Similar to the manufacturing method of Example 1, the formula:

[Chemical 30] Of which the melting point is 145-151 ° C (decomposition) is prepared.

Example 5 As in Example 1, the formula:

[Chemical 31] A compound having a melting point of 148-151 ° C.

The starting material is prepared as follows. Stage 1

[Chemical 32] To 30 ml of CH ₂ Cl ₂ 0.66 g (4.3 mmol) of A is added. At room temperature, B
1.0 g (4.2 mmol) and 1.5 ml DIEA (8.6 mmol) are added and the mixture is stirred for 15 minutes to give a clear yellow solution. EDAC 0.84 g (4.3 mmol)
Is added and the mixture is stirred for 3 hours. Monitor the reaction using MS. The mixture is evaporated to dryness under reduced pressure, in 2% by flash chromatography _{(CH 2} Cl 2 _CH 3 O
H) gives product C as a pale yellow oil.

Stage 2

[Chemical 33] To 50 ml of EtOH / 3 ml of H ₂ O are added 0.84 g (2.5 mmol) of C. P
0.07 g of d / C (as catalyst) is added to the mixture. The mixture is stirred under a hydrogen balloon for 2 hours. Monitor the reaction using MS. The mixture is filtered, EtO
Wash with H and dry to obtain product D as a pale yellow oil.

Stage 3

[Chemical 34] In 5 ml of DMSO, 0.1 g (0.5 mmol) of D, 0.046 g (0.25 mmol) of 4- (2-chloroethyl) morpholine hydrochloride, 0.10 g (0.75) of potassium carbonate.
mmol), and 0.04 g of sodium iodide (as a catalyst). The mixture is stirred for 24 hours. The reaction is monitored using MS. Dry the mixture under reduced pressure,
Subjected to flash chromatography _(CH 2 Cl ₂ in 2% _CH 3 OH), to give the product E as an oil of yellow-white. Conversion of product E to the title compound is carried out as in the final step of Example 1.

Example 6 (S) -β-[[p- (N'-o-tolylcyanoguanidino) phenylacetyl-
N- (2-morpholinoethyl) glycyl] amino] -β- (3,4-dimethoxyphenyl) propionic acid

[Chemical 35]

Stage 1

[Chemical 36] To 25 ml of EtOAc are added 1 g (6.7 mmol) of o-tolyl isothiocyanate and 1.32 g (6.7 mmol) of ethyl 4-aminophenylacetate. The mixture is
Stir for 12 hours at room temperature. T using 50% hexane in EtOAc as solvent
Monitor the reaction using LC. The mixture is evaporated to dryness under reduced pressure and flash chromatographed on 45 g of silica gel, eluting with CH ₂ Cl ₂ to give ethyl 4-N- (o-tolylaminothiocarbonyl) aminophenylacetate (product A ) as a yellow solid.

Stage 2

[Chemical 37] To 50 ml of EtOAc, 1.6 g (4.87 mmol) of A was added, and cyanamide of 0.1.
31 g (7.31 mmol) and N, N'-diisopropylcarbodiimide (DIC
) 0.92 g (7.31 mmol) are added. The mixture is heated to reflux and stirred for 60 hours. Monitor the reaction using MS. The mixture was evaporated to dryness under reduced pressure, flash chromatographed on 30 g of silica gel, eluting with CH ₂ Cl ₂ as a thick oil, ethyl 4- [p- (N′-o-tolylcyanoguanidino)] phenylacetate (product B ) Get.

Stage 3

[Chemical 38]   Into 15 ml of THF,B Add 356 mg (1.06 mg). H_TwoO 3.5 ml
92 mg (2.2 mmol) of LiOH dissolved in was added dropwise and the mixture was stirred at room temperature for 4 hours.
Stir. Monitor the reaction using MS. The mixture is dried under reduced pressure. Then the rest
H_TwoO was added and the solution was adjusted to pH 2 with 1N HCl and saturated Na 2_TwoCO_Threeso
Neutralize to pH = 7 and extract with THF. The extract is dried and the solvent is distilled off to give a white solid.
4- [p- (N'-o-tolylcyanoguanidino)] phenylacetic acid (product C ) Get.

The product C is condensed with the product D of example 1 and the resulting ester is hydrolyzed to the title product (similar to step 6 and step 7 of example 1) and flash chromatographed. subjected to chromatography, purified and eluted with 10% _CH 3 OH in _CH 2 Cl _2:
Melting point 102-106 ° C (decomposition).

Example 7 (S) -1- {β-[[p- (o-tolylureido) phenylacetyl-N- (2-
Morpholinoethyl) -glycyl] amino] -β- (3,4-dimethoxyphenyl)-
Propionyl} -4-hydroxyethylpiperazine

[Chemical Formula 39] In CH ₂ Cl ₂ 5ml, added compound 0.16mmol of Example 1; and 1- (2-hydroxyethyl) piperazine 0.022 mg (0.18 mmol), DM
22.5 mg (0.18 mmol) AP are added to the mixture. The mixture is stirred at room temperature for 5 minutes and 34 mg (0.18 mmol) EDAC are added. Monitor the reaction using TLC. After the reaction is completed, the mixture is dried under reduced pressure. The product is purified by HPLC to give the title compound.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 19/02 A61P 19/02 27/02 27/02 37/06 37/06 43/00 111 43/00 111 C07C 273/18 C07C 273/18 C07D 295/12 C07D 295/12 Z 295/18 295/18 A (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, 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, BZ, 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, MZ, 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 F-term (reference) 4C086 AA01 AA02 AA03 AA04 BC73 GA07 GA09 MA01 MA04 MA05 MA52 MA60 MA66 NA14 ZA59 ZA96 ZB08 ZC41 4C206 AA01 AA02 MA01 A03 MA03 A04 MA05 MA72 MA80 MA86 NA14 ZA59 ZA96 ZB08 ZC21 4H006 AA01 AA02 AA03 AB20 AB22 AC53

Claims (18)

[Claims] 1. Formula (I): [Chemical 1] [In the formula, Ar is carbocyclic or heterocyclic aryl, or biaryl; Q is O, S or N-C≡N; X is Arylene; V is NH, O, NHOH, CH_TwoOr a direct bond; W is NH, O, NHOH, CH_TwoOr a direct bond; Alk is C_Two-C₇-Alkylene, or S, O, SO, SO_TwoOr NR_ThreeBut
C inserted_Two-C₇-Is alkylene; Y is amino, acylamino, mono- or di- (lower alkyl, aryl, or
Or aralkyl) -amino, pyrrolidino, perhydroazepino, or the formula: [Chemical 2] [Where M is₁Is N; and M_TwoIs CH_Two, O, NR_Three, S, SO or SO
_TwoIs a group represented by; R₁, R_TwoAnd R_ThreeAre independently hydrogen, lower alkyl, lower alkenyl, cycloalkyl
Alkyl, aryl, cycloalkyl-lower alkyl, aryl-lower alkyl or
Or aryl-lower alkenyl; Z is lower alkylene, or one or more lower alkyl, lower alk
Nyl, cycloalkyl, aryl, cycloalkyl-lower alkyl, aryl-
Lower alkyl substituted by lower alkyl or aryl-lower alkenyl
Or Z is O, S, SO, SO_TwoOr NR_ThreeLower Al with inserted
Is a xylene]; a pharmaceutically acceptable ester or amide thereof;
Or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein V and W are NH or NHOH. 3. The compound according to claim 1, wherein V is CH ₂ and W is NH. 4. The compound according to claim 1, wherein V is a direct bond and W is NH. 5. The compound according to claim 1, wherein V is NH and W is CH ₂ . 6. The compound according to claim 1, wherein Q is O. 7. V and W are NH; Q is O; X is phenylene; Ar is carbocyclic or heterocyclic aryl; R ₁ , R ₂ and R ₃ are hydrogen or Is lower alkyl; Y is of the formula: Wherein M ₁ is N and M ₂ is CH ₂ , O or S; C is C ₂ optionally substituted by lower alkyl, lower alkenyl, carbocyclic aryl or heterocyclic aryl. -C ₅ - a straight-chain alkylene; or Z is O, S,
SO _C 2 -C ₅ or SO ₂ is inserted, - a straight-chain alkylene, claim 1
Or a pharmaceutically acceptable ester or amide thereof; or a pharmaceutically acceptable salt thereof. 8. Formula (II): embedded image Wherein, Ar is a monocyclic carbocyclic aryl; Alk is C ₂ -C 4 _- is alkylene; R ₄ is lower alkyl, lower alkenyl or monocyclic carbocyclic aryl; m is 1 or 2 The compound according to claim 1; a pharmaceutically acceptable ester thereof; or a pharmaceutically acceptable salt thereof. 9. Formula (III): embedded image [Wherein R ₄ is phenyl, or 1 to 3 C ₁ -C ₄ -alkoxy, chlorine,
Is phenyl substituted with fluorine or C ₁ -C ₄ -alkyl; and R ₅ is C ₁ -C ₄ alkoxy, chlorine, fluorine, or C ₁ -C ₄ -alkyl]. A compound; a pharmaceutically acceptable ester thereof;
Or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, wherein R ₅ is methyl, fluorine or methoxy. 11. A pharmaceutical composition comprising a compound according to claim 1 in an amount effective for inhibiting VLA-4 in combination with one or more pharmaceutically acceptable carriers. 12. Inhibiting VLA-4 activity in a mammal, which comprises administering to a mammal in need thereof a VLA-4 inhibiting amount of a compound of claim 1. Method. 13. Treatment of a VLA-4 dependent condition in a mammal comprising administering to the mammal in need thereof a VLA-4 inhibiting effective amount of a compound of claim 1. Method or preventive method. 14. A transplant rejection reaction in a mammal, which comprises administering to a mammal in need thereof a corresponding effective amount of the compound of claim 1.
Methods of treating arthritis or respiratory diseases. 15. Formula (IV): embedded image [Wherein Ar, V, Q, W and X have the meanings as defined above] or a derivative of a reactive functional group thereof, and a compound of formula (V): [Wherein the carboxyl group is in a protected form, and in the formula, Alk, Y, R ₁
, R ₂ and Z have the meanings as defined above], and, if necessary, converting the compound obtained to another compound of claim 1.
A method for producing the compound according to claim 1. 16. A method of treating a VLA-4 dependent condition in a mammal and / or
Alternatively, the use of the compound according to claim 1 in the manufacture of a pharmaceutical composition for a prophylactic method. 17. Formula (III): [Chemical 8] [Where R_FourIs phenyl, or 1 to 3 C₁-C_Four-Alkoxy, chlorine,
Fluorine or C₁-C_Four-Phenyl substituted with alkyl; and R₅Is C ₁ -C_Four-Alkoxy, chlorine, fluorine or C₁-C_Four-Alkyl]
A compound; a pharmaceutically acceptable ester thereof; or a pharmaceutically acceptable thereof
17. The method according to claim 16 in salt. 18. The use as claimed in claim 16, wherein the pharmaceutical composition is adapted for use in ophthalmic diseases.