JP2001089448A - Amide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a useful compound having an integrin VLA-4-inhibiting activity and useful for the prevention and treatment of a chronic inflammatory disease, an autoimmune disease, etc. SOLUTION: This amide derivative is a compound expressed by a general formula (1) (Ra is H or an ester residue forming a prodrug; Rb is morpholino or 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl group; Rc is an aryl allowed to have a substituting group or a heteroaryl group allowed to have a substituting group; and Rd, Re are each the same or different H or a lower alkyl group), i.e., an amide derivative or its salt having morpholinocarbonylamino group or 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-carnylamino broup at the β-position of a substituted phenylpropanoic acid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a drug, particularly a disease involving the integrin, which inhibits the binding of integrin VLA-4 expressed on leukocytes to a ligand of VLA-4 present on the cell surface or extracellular matrix. The present invention relates to a novel amide derivative useful as a prophylactic or therapeutic agent for amide.

[0002]

2. Description of the Related Art Integrins are membrane glycoproteins composed of α- and β-chain heterodimers, are widely present in many cells, and are involved in various physiological phenomena. In particular, it is involved in binding to extracellular matrix adhesion factors as a receptor on the cell membrane in cell adhesion, and transmits extracellular information into cells. Furthermore, in recent years, it has been shown that intracellular information is transmitted to outside the cell, and integrin is considered to be one of important molecules in physiological phenomena.

[0003] VLA-4 (CD49dCD29) is an integrin composed of an α4 chain and β1 chain heterodimer, which is expressed on most leukocytes such as lymphocytes and eosinophils, and has various functions such as cell adhesion, extravascular migration, differentiation and proliferation. Are involved in various cellular functions [Spr
inger Semin Immunopathol. 16: 379-389 (1995)]. VLA-4
Studies using monoclonal antibodies against VL
It has been suggested that suppression of A-4 mediated responses can control various inflammatory and immune responses [Ciba Foundation Sym
posium 189: 79-90 (1995)].

For example, contact hypersensitivity (CHS) and delayed hypersensitivity (DTH) [J. Immunol., 147: 4178-4184 (1991), E.
ur.J.Immunol., 23: 682-688 (1993)], Eosinophil infiltration into skin or nasal mucosa [J.Exp.Med.177: 561-566 (1993), Act
a. Otolaryngol Stockh., 116: 883-887 (1996)], Experimental Autoimmune Encephalomyelitis (EAE) [Nature, 356: 63-66 (1992), J. Ex.
p. Med., 177: 57-68 (1993), J. Neuroimmunol., 58: 1-10 (1
995), Hum. Antibodies, 8: 3-16 (1997)], arthritis [J. Clin. I
nvest., 89: 1445-1452 (1992)], transplant rejection [J. Immunol.,
153: 5810-5818 (1994)], graft-versus-host disease [J. Immunol., 15
5: 3856-3865 (1995)], asthma [J. Clin. Invest., 93: 776-787
(1994), J. Exp.Med., 180: 795-805 (1994), Am. J. Respir.Cr
it.Care Med., 149: 1186-1191 (1994)], vascular stenosis due to arterial endothelial detachment [J. Vasc. Surg., 26: 87-93 (1997)], nephritis [J.
Clin. Invest., 91: 577-587 (1993)], diabetes [Proc. Natl. A
cad.Sci.USA, 90: 10494-10498 (1993), Diabates, 43: 529-5
34 (1994)], tissue damage by immune complexes [J. Immunol., 15
0: 2401-2406 (1993)], colitis [J. Clin. Invest., 92: 372-3
80 (1993)], metastasis and invasion of cancer cells [J. Natl. Cancer In
t., 80: 108-116 (1988), Cancer Res., 54: 3233-3236 (199
4)], an anti-VLA-4 antibody has been reported to be effective in animal models.

[0005] VLA-4, as its ligand, is a surface antigen VCAM-1 (CD106) expressed on vascular endothelial cells and the like [Cell, 60: 577-58].
4 (1990)] and the extracellular matrix fibronectin
(FN) Type III connecting segment (IIICS) CS
-1 region [Cell, 60: 577-584 (1990), etc.] is different from other β1 integrins in that two regions exist.

It is known that the minimum amino acid sequence required for recognition of VLA-4 in the CS-1 region consisting of 25 amino acids is Leu-Asp-Val (LDV) [J. Cell. Biol., 116 : 489-497 (19
92) etc.], a similar sequence in VCAM-1, Ile-Asp-Ser-Pr
It has been reported that o-Leu (IDSPL) is involved in binding to VLA-4 [J. Cell. Biol., 124: 601-608 (1994) and the like]. This CS
It is known that mimetics of -1 peptide or the minimal sequence LDV inhibit various inflammatory reactions by inhibiting the binding between VLA-4 and its ligand [Ciba Foundation
Symposium 189: 79-90 (1995)].

For example, contact hypersensitivity [Proc. Natl. Acad.
i.USA, 88: 8072-8076 (1991)], rat arthritis due to bacterial cell wall components [J. Clin. Invest., 94: 655-662 (199).
4)], Rabbit asthma by mite antigen [Springer Semin.Immun
opathol., 16: 467-478 (1995)], lymphocyte infiltration and matrix production into grafts in rabbit heart transplantation [J. Clin. In
vest., 95: 2601-2610 (1995)]
Imetics have been reported to be useful.

In recent years, peptide mimetics such as CS-1 for inhibiting the binding of VLA-4 to a ligand and preventing or treating chronic inflammatory diseases have been reported (for example, WO96 / 22966, WO97 / 03094, W
O95 / 15973 publications). However, since these are peptides, they have a problem in in vivo stability. Therefore, non-peptide VLA-4 antagonists that are resistant to degradation by proteases and the like in the blood and can continuously inhibit the binding of VLA-4 to ligands are used for chronic inflammatory diseases, autoimmune diseases, It is expected as an agent for preventing or treating various diseases related to VLA-4 such as diseases.

[0009] WO 98/04247 discloses a known technique.
The backbone of other integrin (IIb / IIIa) antagonists
Has VLA-4 inhibitory activity combined with VLA-4 specific group
Are disclosed. Also, WO 99/2306
No. 3 discloses a wide range of compounds having VLA-4 inhibitory activity.
Disclosed therein are substituted amide derivatives represented by the following formula:
It has been disclosed. Where R¹Is H, lower alkyl, etc., X^Two
And X^ThreeIs N or CR^{1 0}, R2 is C_1-6Lower alkylene,
Ar¹Is Arylene etc., L^TwoIs -N (R¹²) -C (= O)
-R¹³Alkylene which may be substituted with
Boxy, R¹²Is H, R¹³Is heteroaryl, hetero
And cycloaryl and the like (for details, see the gazette).

Embedded image

[0010]

The present invention still has a clinically useful non-peptide type VLA-4 which can be orally administered.
Inhibitors are in great demand.

[0011]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on compounds that antagonize integrin VLA-4, and as a result, found that morpholino or 2,4-dioxo-1 was located at the β-position of a carboxylic acid via an amide. The amide derivative substituted with a 2,2,3,4-tetrahydropyrimidin-5-yl group has a good integrin VLA-4 inhibitory action, and is excellent in oral absorbability and in vivo persistence. The inventors have found that the present invention can be used as a clinically useful agent for preventing or treating a disease involving VLA-4, and completed the present invention.

That is, the present invention relates to an amide derivative represented by the following general formula (I) or a salt thereof.

[0013]

Embedded image (However, the symbols in the formula have the following meanings: Ra: H or a residue of an ester forming a prodrug, Rb: morpholino or 2,4-dioxo-1,2,3,
4-tetrahydropyrimidin-5-yl group, Rc: aryl which may have a substituent or heteroaryl group which may have a substituent, Rd, Re: same or different, H or lower alkyl group . The same applies hereinafter. )

Further, according to the present invention, there is provided a medicine, particularly an integrin VLA-4 inhibitor, comprising the amide derivative or a salt thereof.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the general formula (I) is further described as follows. "Aryl" means an aromatic hydrocarbon ring group, preferably aryl having 6 to 14 carbon atoms, more preferably phenyl, naphthyl and fluorenyl, and particularly preferably phenyl.

"Heteroaryl" is a 5- to 6-membered monocyclic heteroaryl containing 1 to 4 heteroatoms selected from N, S and O, and those having a benzene ring or an arbitrary heterocyclic ring. There are fused 2-3 cyclic heteroaryls, which may be partially saturated. here,
As the monocyclic heteroaryl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridyl, pyrimidinyl, pyridazinyl, and pyrazinyl are preferable. As the 2- or 3-cyclic heteroaryl, benzothiazolyl, benzimidazolyl, indolyl, isoindolyl , Indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,
Quinoxalinyl, benzodioxolyl, imidazopyridyl are preferred. Partially saturated heteroaryl includes 1,
2,3,4-tetrahydroquinolyl and the like. Particularly preferred are indolyl and 1H-indazolyl.

"Aryl optionally having substituent (s)",
The substituent in the “heteroaryl optionally having substituent (s)” is not particularly limited, but is preferably the following F:
1 to 4 substituents selected from the group.

Group F: lower alkyl optionally having a substituent of the group -E, lower alkenyl optionally having a substituent of the group -E, even having a substituent of the group -E optionally substituted lower alkynyl, - cycloalkyl, - halogen, - _{aryl, -NO 2, -CN, -OH,} -O-E group optionally substituted lower alkyl, -O-E group substituents which may have an aryl, -SH, -S- lower alkyl, -SO ₂ - lower alkyl, -SO- lower alkyl,
-O-lower alkylene-O-, -COOH, -COO-
Lower alkyl, -CO-E group optionally having a substituent, lower alkyl, -CO-E group optionally having a substituent, -lower alkyl-E group having a substituent Optionally substituted aryl, -NHCONH-E group optionally having substituent (s), -NHCO-lower alkyl-E group optionally having substituent (s), -NHS
Aryl optionally having a substituent of the O ₂ NH-E group,
-NHSO ₂ - lower alkyl -E group substituents aryl which may _{have, -CONH 2, -SO 2 NH 2} , - nitrogen-containing saturated hetero ring, -NH _2, -NH- lower alkyl and -N (Lower alkyl) ₂ .

Group E: -halogen, -NO ₂ , -CN,-
OH, -O- lower alkyl, -SH, -S- lower alkyl, -SO ₂ - lower alkyl, -SO- lower alkyl,
-COOH, -COO- lower alkyl, -CO- lower alkyl, -CONH _2, -NH _2, -NH- lower alkyl, -N (lower alkyl) _2, - nitrogen-containing saturated hetero ring,
-Cycloalkyl and -cycloalkenyl.

Here, the term "lower" refers to a group having 1 to 6 carbon atoms.
Means a straight or branched hydrocarbon chain. The “lower alkyl” is preferably an alkyl group having 1 to 3 carbon atoms, particularly preferably a methyl and ethyl group. The “lower alkenyl” is preferably a vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl group or the like. As the “lower alkynyl”, preferably, ethynyl, 1-
Examples thereof include a propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl group and the like. “Cycloalkyl” and “cycloalkenyl” are preferably cycloalkyl or cycloalkenyl having 3 to 8 carbon atoms. As the “nitrogen-containing saturated heterocycle”, one N atom is used as a ring atom.
5 to 7-membered nitrogen-containing saturated heterocycle which may further contain one or two O atoms and may further have a bridge, and is preferably 1-pyrrolidinyl, piperidino and morpholino It is. "Halogen" includes F, Cl, Br and I. As the “lower alkyl substituted with halogen”, —CF ₃ is preferable.

"Ester residue forming prodrug"
Is a residue of an ester that forms a reversible prodrug derivative that is reconstituted in vivo into the parent compound (original carboxylic acid compound). For example, Prog. Med. 5: 2157-2161 (1985)
It is a group described in. Preferably -lower alkyl,
- _{aryl, -CH 2 -COOH, -CH 2 -O} -CO-
O-R '(R' is a lower alkyl or cyclohexyl, hereinafter the _{same), - CH 2 -O-CO} -R ', - CH
_{(CH 3) -O-CO-} R ', - phthalidyl, 5-methyl-1,3-dioxolen-2-one-4-yl - methyl and the like.

Among the compounds of the present invention, compounds in which Rb is 2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl include keto-enol tautomers. Embraces isolated and mixtures of these isomers. Further, the compound of the present invention has an asymmetric carbon atom at the β-position of propanoic acid, and there are isomers based on this. The present invention relates to these optical isomers (R-form, S-form)
And isolated ones. In the compound of the present invention, the R isomer is more preferred. In addition, depending on the type of the substituent, a geometric variant, a tautomer, and an optical isomer may be present, and these are also included.

The compound of the present invention may form a salt. The acid addition salt is not particularly limited as long as it is a pharmaceutically acceptable salt. Specific examples of the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid. , Formic, acetic, propionic, oxalic, malonic, succinic, fumaric, maleic, lactic, malic, tartaric,
Acid addition salts with organic acids such as citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid, and the like.Examples of salts with bases include metals such as sodium, potassium, magnesium, calcium, and aluminum. Examples thereof include salts with inorganic bases, organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts. Furthermore, the present invention also includes various hydrates, solvates, and polymorphic substances of the compound (I) of the present invention and salts thereof.

(Production method) The compound of the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods by utilizing the characteristics based on the basic skeleton or the type of the substituent. Can be. At that time, depending on the type of the functional group, if it is effective from the viewpoint of production technology, it is effective to replace the functional group with an appropriate protecting group at the stage of the raw material or intermediate, that is, a group which can be easily converted to the functional group. There is. Thereafter, the desired compound can be obtained by removing the protecting group as necessary. Examples of such a functional group include an amino group, a hydroxyl group, a carboxyl group, and the like.
As such a protecting group, for example, Green (Green)
e) and Wuts, "Protective Groups"
in Organic Synthesis ", 2nd edition, and these may be appropriately used depending on the reaction conditions. Hereinafter, a typical production method of the compound of the present invention will be described.

(First production method)

Embedded image (In the formula, Ra ′ represents lower alkyl, Y ₁ represents a carboxylic acid or a reactive derivative thereof. The same applies hereinafter.) The compound (I) of the present invention is obtained by converting an amino compound (II) into a carboxylic acid or a reactive derivative thereof ( The compound can be produced by subjecting it to an amidation reaction with III) and, if desired, performing deesterification.

The amidation reaction can be carried out by a conventional method. When reacting with an acid halide or an acid anhydride as a reactive derivative, a base (an inorganic base such as sodium hydroxide or an organic base such as triethylamine (TEA), diisopropylethylamine, pyridine, N-methylmorpholine) is used. It is preferable to perform in the presence. When the reaction is carried out with the carboxylic acid, the condensing agent (1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide (WS
C), 1,1′-carbonylbis-1H-imidazole (CDI)).
In some cases, an additive such as 1-hydroxybenzotriazole (HOBt) may be added.

Here, as the reactive derivative of the carboxylic acid or the sulfonic acid, conventional ones can be mentioned, for example, acid halides (such as acid chloride), acid anhydrides, and active esters (N-hydroxysuccinimide ester). Etc.), lower alkyl esters, aralkyl esters, acid azides and the like. Such reactive derivatives can be easily obtained from the corresponding acid according to commonly used general methods.

Solvents include aromatic hydrocarbon solvents such as benzene and toluene, tetrahydrofuran (THF), 1,4
Ether solvents such as -dioxane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, amide solvents such as N, N-dimethylformamide (DMF) and N, N-dimethylacetamide, and basic solvents such as pyridine. No. When reacting with a lower alkyl ester derivative or the like, an alcohol solvent may be further used.

Deesterification can be carried out by an ordinary method using an acid or an alkali. Preferably, the reaction can be carried out by using 1 to several normal aqueous sodium hydroxide solution or lithium hydroxide aqueous solution and reacting at room temperature to heating. It can also be carried out by performing catalytic hydrogenation depending on the type of ester. Solvents include alcoholic solvents such as methanol and ethanol, THF, 1,
Ether solvents such as 4-dioxane, DMF, N, N-
Examples include amide solvents such as dimethylacetamide, and basic solvents such as pyridine.

(Second production method)

Embedded image The compound of the present invention can be produced from compound (IV) by the same amidation and, if desired, deesterification as in the first production method.

(Other manufacturing methods) The compound of the present invention may be further subjected to a known esterification reaction or N-
It is produced by performing an alkylation reaction, a substitution reaction and the like at a desired stage. For example, the esterification reaction can be performed by reacting the carboxylic acid compound of the present invention with a reactive derivative such as an alkyl halide. The reaction is preferably performed in a solvent that does not participate in the reaction, such as DMF, in the presence of a base, such as potassium hydroxide, at room temperature or under heating. Sodium iodide or the like may be added to promote the reaction.

The N-alkylation reaction can be carried out by reacting with an alkyl halide such as methyl iodide or ethyl iodide in a solvent not involved in the reaction such as DMF in the presence of a base such as potassium carbonate. . In the case of a primary amine, the reactivity can be improved with trifluoroacetic anhydride or the like, if necessary, and then the reaction can be subjected to an N-alkylation reaction. Further, it can be carried out by a so-called reductive alkylation reaction using an aldehyde or ketone derivative.

(Preparation of Starting Compound) The starting compound of the present invention can be prepared by a conventional method using a reaction known to those skilled in the art depending on the type of the substituent. Each reaction can be performed by applying ordinary reaction conditions used in the art. For example, it can be produced by the method shown in the following reaction scheme.

Embedded image

In the above formula, the protecting group is preferably a general-purpose protecting group for an amino group, for example, a tert-butoxycarbonyl group. Protection and deprotection can be performed by a conventional method. N-alkylation and amidation can be performed in the same manner as described above. Further, among the raw material compounds, the compound having an amino group can be produced from the corresponding nitro compound by a reduction reaction. The reduction reaction of the nitro compound can be performed by a conventional method, and preferably, a method of reducing the nitro compound using palladium-carbon or the like in an alcoholic solvent such as methanol under a hydrogen gas atmosphere is used.

Among the compounds of the present invention, optically active compounds can be synthesized from appropriate optically active starting compounds.
The optically active starting compounds are Cimarelli C, Palmieri
G, J. Org. Chem., 1996, 61, 5557-5563, and can be produced as described in Reference Example of the present application using a synthesis method using a benzoylacetic acid derivative as a raw material.

The reaction product obtained by each of the above production methods is
It is isolated and purified as various solvates such as a free compound, a salt or a hydrate thereof. The salt can be produced by subjecting the salt to a usual salt formation reaction. Isolation, purification, extraction, concentration,
It is performed by applying ordinary chemical operations such as distillation, crystallization, filtration, recrystallization, and various types of chromatography. Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, the optical isomers can be separated by a general optical resolution method, for example, fractional crystallization or chromatography.

[0037]

The compound of the present invention is useful as an active ingredient of a pharmaceutical preparation. In particular, it has an integrin VLA-4 inhibitory activity, and VLA-4 is involved in its pathology, allergic diseases such as bronchial asthma, allergic dermatitis, rhinitis, autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. , Graft-versus-host disease, graft rejection and associated arterial lesions during transplantation, inflammatory diseases such as colitis, nephritis, restenosis after PTCA, arteriosclerosis, cancer metastasis, diabetes, etc. It is useful as a prophylactic / therapeutic agent.

The action of the compound of the present invention was confirmed by the following pharmacological tests. (1) Cell adhesion test The in vitro binding inhibition effect of the compound was examined by a cell adhesion test using human leukemia cell line Jurkat cells labeled with calcein-AM (Dojindo, Cat. No. 349-07201).

(A) Preparation of labeled cells Jurkat cells were suspended at 2 × 10 ⁶ cells / ml in RPMI 1640 medium (10% FBS-RPMI) supplemented with 10% fetal bovine serum, and 20 μM of
Calcein-AM was added and the cells were labeled under 5% CO ₂ , 37 ° C., humidified conditions. Further, the labeled cells were subjected to 1200 rp at room temperature.
After centrifugation for 3 minutes, the supernatant was removed and the cells were resuspended in 10% FBS-RPMI supplemented with 2 mM manganese chloride. This operation was repeated twice to remove unreacted calcein-AM, and the cell suspension was finally adjusted to 1 × 10 ⁶ cells / ml.

(B) Acquisition of soluble VCAM-1 An expression plasmid having a His-tag sequence incorporated at the C-terminus of a gene containing three immunoglobulin-like domains at the N-terminus of the extracellular region of VCAM-1 extracellular region is constantly used in CHO cells. Was introduced. Soluble from TALON column (CLONTECH) from culture supernatant of this cell
VCAM-1 (sVCAM-1, a recombinant protein in the extracellular region of VCAM-1) was purified.

(C) Immobilization of VLA-4 ligand on a plate The above-described sVCAM-1 and biotinylated CS-1 peptide (biotinyl
-DELPQLVTLPHPNLHGPEILDVPST-COOH, Sawasdee Technology Co., Ltd.) was used as VLA-4 ligand. sVCAM-1
Is dissolved in 10 mM phosphate buffered saline (pH 7.4) (PBS (-)) containing no calcium and magnesium, and
μg / ml, 96-well plate (NUNC immunoplate
I, Cat.No.439454, Japan Intermed Co., Ltd.
1 / well, and allowed to stand at 4 ° C. for 24 hours to solidify.
On the other hand, CS-1 has previously been treated with streptavidin (Streptom
yces avidinii, Cat.No.S-4762, Sigma Chemical C
A solution of 1 μg / ml of biotinylated CS-1 was dispensed at 50 μl / well onto a plate coated with O), and allowed to stand at 37 ° C. for 1 hour to solidify. These plates are PB
After washing with S (-) three times to remove unbound ligand,
A Hanks balanced salt solution containing 30% bovine serum albumin (HBSS) was dispensed at 300 μl / well and left at 37 ° C. for 2 hours to block.

(D) Evaluation of Test Drug After preparing a 2 mM solution of the test drug with dimethylsulfoxide (DMSO), the test drug was diluted with PBS (-) to a concentration 100 times the working concentration. The final concentration of 100 was added to the cell suspension obtained in (a).
After adding a double concentration test drug solution or its solvent and gently infiltrating, incubating at room temperature for 15 minutes,
The ligand of (c) was dispensed at 1 / well onto a plate on which the ligand was immobilized. Then, it was left still for 1 hour under 5% CO ₂ , 37 ° C. and wet condition. After removing the non-adherent cells by washing the plate with PBS (-), the cells adhering to the plate are dissolved by dispensing a 0.5% Triton X-100 solution at 100 μl / well to increase the fluorescence intensity. 485 nm,
The emission wavelength was measured at 530 nm using a microplate fluorometer (Cytofluor-II, Perceptive Co., Ltd.).

The inhibition rate (%) of the cell adhesion by the test drug was calculated by the following equation.

## EQU00001 ## Inhibition rate (%) = ((SN)-(TN)) / (SN) .times.100 N: non-specific cell adhesion (solvent of test drug to well without added ligand) S: Cell adhesion at the time of adding a solvent (average count when cells containing only the solvent of the test drug were added to the well on which the ligand was immobilized) T) Cell adhesion at the time of addition of test drug (average value of count when cells with test drug added thereto were seeded on wells on which ligand was immobilized)

The IC ₅₀ value of the test drug was determined by linear regression analysis from the inhibition rates at three or more concentrations. The compounds of the present invention are VLA-4 ligands, sVCAM-1 and biotinylated CS
VLA-4 mediated adhesion of leukocyte cells to -1 peptide was well inhibited.

(2) Continuous test of plasma VLA-4 inhibitory activity <Preparation of test drug> The test drug is a mixed solution (dimethyl sulfoxide: Tween 80: 1N sodium hydroxide solution: sterile distilled water = 5: 1: 1: 93), 3 mg /
ml. This solution was further diluted with physiological saline according to the dose and used.

<Plasma sample collection> Male ICR mice (5
１２12 weeks old, body weight 25-45 g) and test drug (3 mg /
kg) was orally administered, and after 1, 2 to 4 hours, blood was collected from the abdominal vena cava under diethyl ether anesthesia to separate plasma.
Until this plasma sample is used for VLA-4 inhibitory activity measurement-
It was stored frozen at 40 ° C. (this is referred to as A).

<Measurement of VLA-4 Inhibitory Activity in Plasma> The cell suspension (1.2) prepared in the same manner as in the above in vitro test was used.
One volume of the plasma sample of A was mixed with 4 volumes of 5 × 10 ⁶ cells / ml), incubated at room temperature for 15 minutes, and the VLA-4 inhibitory activity was measured by a cell adhesion test. For the specific binding control and non-specific binding wells, the sera of mice to which vehicle was administered were used.

The compound of the present invention can be administered orally to sVCAM-
It successfully inhibited VLA-4-mediated adhesion of leukocyte cells to 1 and biotinylated CS-1 peptide, and the effect was long lasting.

(3) Contact hypersensitivity: Trini, a hapten
The response of contact hypersensitivity to trochlorobenzen (TNCB) was determined in Prop.J et al. (Cell.
l.99 73-84, 1986). In rat abdominal skin, dissolved in a mixture of acetone and olive oil
50 μl of 10% TNCB was applied. Six days later, 20 μl of a 1% TNCB solution was applied to the front and back of the pinna immediately after the measurement of the pinna thickness under ketamine / zylazine (50 / 2.5 mg / kg ip) anesthesia. The pinna thickness was measured again after 20 to 24 hours, indicating an increase in pinna thickness. Then, the pinna was cut off, and the ornithine decarboxylase activity in the tissue was measured using Immunol.
55 127-131, 1997. At the same time, either an increase in auricular pressure or an enzymatic activity over the response of naive rats subjected to the experiment was defined as a hypersensitivity reaction. Test compounds were administered orally, subcutaneously or nasally. The compound of the present invention successfully suppressed contact hypersensitivity.

A pharmaceutical composition containing one or more of the compound represented by the general formula (I) or a salt thereof as an active ingredient can be used as a pharmaceutical carrier commonly used in the art.
It can be prepared by a commonly used method using excipients and the like. Administration is oral, such as tablets, pills, capsules, granules, powders, solutions, inhalants, or injections such as intravenous and intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, Any form of parenteral administration such as an ointment, transdermal patch, transmucosal solution, transmucosal patch and the like may be used.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. It is mixed with magnesium acid and the like. The composition may contain, in a conventional manner, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrant such as calcium cellulose glycolate, a stabilizer such as lactose, glutamic acid or asparagine. A solubilizing agent such as an acid may be contained. If necessary, tablets or pills may be coated with a sugar coating such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, For example, it contains purified water and ethanol. The composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solutions and suspensions include, for example, distilled water for injection and physiological saline. Examples of water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name).
Etc. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, dispersing, stabilizing (eg, lactose) and solubilizing agents (eg, glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be used in the manufacture of a sterile solid composition which is dissolved in sterile water or a sterile solvent for injection before use.

Transmucosal agents such as nasal agents include solids, liquids,
It is semi-solid and can be produced according to a method known per se. For example, known pH adjusters, preservatives, thickeners and excipients are appropriately added, and the mixture is formed into a solid, liquid or semi-solid form. The nasal preparation is administered using a usual spray device, nasal drop container, tube, intranasal insert, or the like.

In the case of normal oral administration, the daily dose is about 0.0001 to 50 mg / kg, preferably 0.01 to 10 mg / kg per body weight. Administer in divided doses. When administered intravenously, the daily dosage should be about 0.0000 per body weight.
The dose is suitably 1 to 5 mg / kg, which is administered once or more than once a day. In the case of nasal administration, the daily dose is about 0.0001 to 50 mg / kg per body weight,
It is administered once or more than once a day. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.

[0056]

The present invention will be described below in more detail with reference to examples. The compounds of the present invention are not limited to the compounds described in the following examples. The method for producing the starting compounds used in the examples will be described as reference examples. The symbol used in the following description is F: FAB-MS (M +
H) ⁺ , FN: FAB-MS (M−H) ⁻ , N: Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ:
And a typical peak of N-2: nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: are shown, respectively.

Reference Example 1 After adding thionyl chloride to ethanol at -30 ° C. or lower, (RS) -3-amino-3 was added.
-(4-Nitrophenyl) propanoic acid was suspended in the solution and stirred at room temperature for 12 hours. After concentrating the reaction solution under reduced pressure, crystallized from ethanol-diethyl ether,
Ethyl (RS) -3-amino-3- (4-nitrophenyl) propanoate hydrochloride was obtained as colorless crystals (F: 2
39).

Reference Example 2 Ethyl (RS) -3-amino-3 (4-nitrophenyl) propanoate was dissolved in ethanol, a 4N hydrochloric acid-ethyl acetate solution, and the mixture was hydrogenated in the presence of 10% palladium-carbon. Stir for 12 hours. The reaction solution was filtered using celite, and the solvent of the obtained solution was distilled off under reduced pressure. The obtained residue was crystallized from ethanol-diethyl ether to give (RS) -3-amino-3- (4-
Ethyl aminophenyl) propanoate dihydrochloride was obtained as colorless crystals (F: 282).

Reference Example 3 (RS) -3-amino-3-
Ethyl (4-aminophenyl) propanoate dihydrochloride was suspended in dichloromethane, and triethylamine and 4-morpholinecarbonyl chloride were added thereto under ice-cooling and stirring, and reacted at room temperature for 12 hours. The product was extracted twice from the reaction solution with a 10% aqueous citric acid solution, the resulting aqueous layer was neutralized with sodium hydrogen carbonate, and the product was extracted twice with chloroform. The obtained organic layer was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution, and the organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. Ethyl acetate, 4N hydrochloric acid-ethyl acetate solution was added to the obtained residue, and the precipitated solid was collected by filtration, and (RS) -3- (4-aminophenyl) -3-[(morpholine-4-carbonyl) amino Ethyl propanoate hydrochloride was obtained as a pale yellow solid (F: 322).

Reference Example 4 (RS) -3-amino-3-
Ethyl (4-nitrophenyl) propanoate hydrochloride was suspended in dichloromethane, and triethylamine and
After sequentially adding morpholine carbonyl chloride, the mixture was reacted at room temperature for 12 hours. Ice and a 10% aqueous citric acid solution were added to the reaction solution, and the product was extracted twice with dichloromethane. The obtained organic layers were combined, washed sequentially with a 10% aqueous citric acid solution and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The obtained residue is crystallized from dichloromethane-diethyl ether,
Ethyl (RS) -3-[(morpholine-4-carbonyl) amino] -3- (4-nitrophenyl) propanoate was obtained as slightly yellow crystals (FN: 352).

Reference Example 5 Ethyl (RS) -3-[(morpholine-4-carbonyl) amino] -3- (4-nitrophenyl) propanoate was dissolved in ethanol and 10%
The mixture was stirred under a hydrogen atmosphere in the presence of palladium-carbon for 3 hours. The reaction solution was filtered using celite, and the solvent of the obtained solution was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, a 4N hydrochloric acid-ethyl acetate solution was added, and the precipitated solid was filtered, and the solution was filtered to give (RS) -3- (4-aminophenyl) -3-[(morpholine-4-carbonyl) )amino]
Ethyl propanoate hydrochloride was obtained as a pale yellow solid (F: 322).

Reference Example 6 Acetic acid was added to a benzene solution of 4-nitrobenzoylacetic acid ethyl ester and (R) -1-phenylethylamine at an ice temperature, and then heated under reflux for 4 hours under dehydrating conditions. Was. The solution is concentrated under reduced pressure,
The obtained residue was dissolved in a mixed solvent of acetonitrile and acetic acid. To this solution was added sodium triacetoxyborohydride at 10 ° C., and the reaction solution was stirred at room temperature for 4 days, and then the solution was concentrated under reduced pressure. After water was added to the residue and the mixture was extracted with ethyl acetate, the organic layer was washed with brine and dried over magnesium sulfate. A 4N hydrochloric acid-ethyl acetate solution was added to this solution, and the solution was concentrated under reduced pressure. The obtained residue was recrystallized twice from ethanol to give (3R, 1′R) -3- (4-nitro Phenyl) -3- (1-phenylethylamino) propionic acid ethyl ester hydrochloride was obtained as colorless crystals (F: 3
43; N-2: 1.93 (3H, d, J = 6.9H)
z), 7.87 (2H, d, J = 9.0 Hz), 8.3
0 (2H, d, J = 9.0 Hz)).

Reference Example 7 (3R, 1'R) -3- (4
-Nitrophenyl) -3- (1-phenylethylamino) propionic acid ethyl ester / hydrochloride is dissolved in ethanol, 4N hydrochloric acid in ethyl acetate is added, and the mixture is contacted with palladium hydroxide at room temperature for 3 days. Hydrogen reduction was performed. The reaction solution was filtered, the solution was concentrated under reduced pressure, and the obtained residue was solidified from ethanol and acetonitrile to give (R) -3-amino-3- (4-aminophenyl) propionic acid ethyl ester · 2 The hydrochloride was obtained as a white solid (F: 209; N: 3.01 (1H,
dd, J = 16.2 Hz, 9.3 Hz), 3.22 (1
H, dd, J = 16.2 Hz, 5.7 Hz), 7.64
(2H, d, J = 8.1 Hz)).

Reference Example 8 (R) -3-Amino-3-
(4-aminophenyl) propionic acid ethyl ester
To a solution of dihydrochloride in acetonitrile, pyridine and di-
Tert-butyl dicarbonate was added and the reaction was stirred at room temperature for 17 hours. The precipitated solid was collected by filtration and washed with ether to give (R) -3-amino-3-
[(4-tert-Butoxycarbonylamino) phenyl] propionic acid ethyl ester hydrochloride was obtained as a white solid (F: 309; N: 1.47 (9H, s),
7.40 (2H, d, J = 8.7 Hz), 7.46 (2
H, d, J = 8.7 Hz)).

Reference Example 9 (R) -3-amino-3-
In a methylene chloride solution of [(4-tert-butoxycarbonylamino) phenyl] propanoic acid ethyl ester,
Under ice cooling, pyridine and 4-nitrophenyl chloroformate were added, and the reaction solution was stirred for 30 minutes. A saturated aqueous sodium bicarbonate solution was added to the reaction solution, the product was extracted with chloroform, and the obtained organic layer was washed with saturated saline. Further, after the organic layer was dried over magnesium sulfate, the solution was concentrated under reduced pressure. The obtained residue was washed with diethyl ether to give (R) -3-([(4-ter
t-butoxycarbonylamino) phenyl] -3- (4
-Nitrophenoxycarbonylamino) propanoic acid ethyl ester was obtained as a pale yellow solid (F: 473).

Reference Example 10 (R) -3-[(4-te
rt-butoxycarbonylamino) phenyl] -3-
To a solution of ethyl (4-nitrophenoxycarbonylamino) propanoate in acetonitrile was added dropwise a solution of morpholine in acetonitrile under ice cooling, and the mixture was stirred for 3 hours. After adding a saturated aqueous solution of sodium hydrogen carbonate to the reaction solution, the target compound was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 9: 1), and recrystallized from ethyl acetate-hexane to obtain colorless crystals. The obtained crystals were dissolved in a mixed solvent of ethyl acetate-ethanol, a 4 N hydrochloric acid solution in ethyl acetate was added dropwise under ice cooling, and the mixture was stirred for 2 hours.
By distilling the reaction solution under reduced pressure, (R) -3- (4
Ethyl-aminophenyl)-[(3-morpholine-4-carbonyl) amino] propanoate was obtained as a colorless oil (F: 322).

(Reference Example 11) Methyl 5-methoxy-3-indoleacetate was dissolved in DMF, and sodium hydride was added at 0 ° C. After stirring for 5 minutes, methyl iodide was added,
Stirred at 0 ° C. for 10 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography, and methyl 5-methoxy-1-methyl-3-indoleacetate was obtained from a stream of ethyl acetate-hexane (1: 8). Methyl 5-methoxy-1-methyl-3-indoleacetate was dissolved in methanol, 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 3 hours. 1 in the reaction solution
After adding normal hydrochloric acid to make it acidic, water was added thereto, and the deposited precipitate was collected by filtration to obtain 5-methoxy-1-methyl-3-indoleacetic acid (F: 219).

Reference Example 12 (RS) -3- (4-aminophenyl) -3-[(morpholine-4-carbonyl)
Ethyl amino] propanoate dissolved in dichloromethane
Trifluoroacetic anhydride was added at −10 ° C. in the presence of pyridine, and reacted at the same temperature for 1 hour. Ethyl acetate was added to the reaction solution, and the organic layer was combined with a 10% aqueous citric acid solution, water and 5%
After washing with an aqueous sodium carbonate solution and a saturated saline solution in that order, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
The obtained residue was powdered with acetonitrile and collected by filtration,
Ethyl (RS) -3-[(morpholine-4-carbonyl) amino] -3- [4- (trifluoroacetyl) aminophenyl] propanoate was obtained as a colorless solid (F: 4
18). Next, potassium carbonate and methyl iodide were added to a DMF solution of this, and the mixture was stirred at room temperature for 12 hours.
Ice water was added to the reaction solution, and the product was extracted with ethyl acetate. The organic layer was washed successively with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from chloroform-ether to give (RS)
Ethyl-3- [N-methyl-4- (trifluoroacetyl) aminophenyl] -3-[(morpholine-4-carbonyl) amino] propanoate was obtained as colorless crystals (F: 432). Subsequently, potassium carbonate was added to a mixed solution of ethanol and water, and the mixture was reacted for 12 hours.
Water was added to the reaction solution, the product was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was crystallized from chloroform-ether to give ethyl (RS) -3- [N-methylaminophenyl] -3-[(morpholine-4-carbonyl) amino] propanoate as colorless crystals (F: 336).

Reference Example 13 3- (4-aminophenyl) -3-[(morpholine-4-carbonyl) amino]
Chloroacetyl chloride was added dropwise to a THF solution of ethyl propionate / hydrochloride and pyridine under ice cooling, and the solution was added at room temperature.
Stir for 1 hour. After concentrating the reaction solution, it is purified by a conventional method to give 3- [4- (2-chloroacetylamino) phenyl] -3-[(morpholine-4-carbonyl) amino].
Ethyl propionate was obtained as white crystals.

Example 1 5-methoxyindoleacetic acid and (RS) -3- (4-aminophenyl) -3-
Ethyl [(morpholine-4-carbonyl) amino] propanoate was dissolved in DMF and stirred at room temperature for 20 hours in the presence of HOBt and WSC hydrochloride. The reaction mixture was made basic by adding saturated sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate-methanol to give 3- {4- [2-
Ethyl (5-methoxy-1H-indol-3-yl) acetylamino] phenyl} -3-[(morpholine-4-carbonyl) amino] propanoate was obtained as white crystals.

Example 2 To a DMF solution of 4- [3- (2-methylphenyl) ureido] phenylacetic acid and triethylamine were added WSC hydrochloride and HOBt under ice-cooling.
Stir for 15 minutes. Subsequently, a DMF solution of ethyl (R) -3- (4-aminophenyl) -3-[(morpholine-4-carbonyl) amino] propanoate was added dropwise, and the mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water, and the precipitated colorless solid was collected by filtration to give (R) -3- [4- (2-
Ethyl {4- [3- (2-methylphenyl) ureido] phenyl} acetylamino) phenyl] -3-[(morpholine-4-carbonyl) amino] propanoate was obtained as a colorless solid.

Example 3 Oxalyl chloride was added to a dichloromethane solution of 5-methoxyindoleacetic acid under ice-cooling, and reacted at the same temperature for 1 hour and at room temperature for 1 hour. This solution was added dropwise to a solution of ethyl (RS) -3- [N-methylaminophenyl] -3-[(morpholine-4-carbonyl) amino] propanoate and pyridine in dichloromethane over 1 hour under ice cooling. The reaction was further performed at room temperature for 2 hours. Ice and a 10% aqueous citric acid solution were added to the reaction solution, and the product was extracted with dichloromethane. The organic layer was washed successively with water, a saturated aqueous solution of sodium carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give 3 as a colorless foam.
-{4- [2- (5-Methoxy-1H-indole-3)
-Yl) acetyl-N-methylamino] phenyl} -3
Ethyl-[(morpholine-4-carbonyl) amino] propanoate was obtained.

Example 4 To a solution of 1,2,3,4-tetrahydroquinoline obtained in acetone was added 3- [4- (2
-Chloroacetylamino) phenyl] -3-[(morpholine-4-carbonyl) amino] propionate ethyl;
Add sodium bicarbonate and sodium iodide, add 48
The mixture was refluxed under heating for an hour. After concentrating the reaction solution, it was purified by a conventional method to give 3- {4- [2- (3,4-dihydro-2H-quinolin-1-yl) acetylamino] phenyl} -3-.
Ethyl [(morpholine-4-carbonyl) amino] propionate was obtained as white crystals.

Example 5 3- {4- [2- (5-methoxy-1H-indol-3-yl) acetylamino]
Ethyl phenyl {-3-[(morpholine-4-carbonyl) amino] propanoate was suspended in methanol, a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 24 hours. After 1N hydrochloric acid was added to the reaction solution, it was concentrated under reduced pressure. The obtained residue was desalted by reversed-phase column chromatography, and then recrystallized from ethyl acetate-methanol to give 3-
{4- [2- (5-methoxy-1H-indole-3-
Il) acetylamino] phenyl} -3-[(morpholine-4-carbonyl) amino] propanoic acid was obtained as white crystals.

Example 6 3- {4- [2- (5-benzyloxy-1H-indol-3-yl) acetylamino] phenyl} -3-[(morpholine-4-carbonyl) amino] propanoic acid Was dissolved in methanol-THF, palladium carbon was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 17 hours. After filtering off the palladium carbon, the filtrate was concentrated under reduced pressure, and the obtained residue was recrystallized from acetonitrile-tetrahydrofuran to give 3- {4- [2- (5-hydroxy-1H-indol-3-yl) acetyl]. Amino] phenyl} -3-[(morpholine-4-carbonyl) amino] propanoic acid was obtained as white crystals.

Example 7 (R) -3- [4- (2-
{4- [3- (2-Methylphenyl) ureido] phenyl} acetylamino) phenyl] -3-[(morpholine-4-carbonyl) amino] propanoic acid is dissolved in ethanol and 0.1N hydroxylated A potassium / ethanol solution was added, and the mixture was stirred at room temperature. The solvent was concentrated under reduced pressure.
The obtained residue was dissolved in DMF, and under an argon atmosphere,
Under ice-cooling, 2,2-ethyl carbonate ethylchloromethyl ester and sodium iodide were added, and the mixture was stirred at room temperature. Ice and ethyl acetate were added to the reaction solution, a 5% aqueous potassium carbonate solution was added, and the organic layer was separated. The organic layer was washed with brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was recrystallized from DMF and methanol to give (R) -3- [4- (2- {4- [3- (2-
Methylphenyl) ureido] phenyl {acetylamino) phenyl] -3-[(morpholine-4-carbonyl) amino] propanoic acid ethoxycarbonyloxymethyl ester was obtained as a white solid.

Example 8 In a DMF solution of 2,4-dihydroxypyrimidine-5-carboxylic acid was added WSC hydrochloride and H
OBt was added and stirred at room temperature for 30 minutes. Further, ethyl (R) -3-amino-3- (4aminophenyl) propanoate dihydrochloride was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Subsequently, 4- [3- (2-methylphenyl) ureido] phenylacetic acid / triethylamine salt, W
SC hydrochloride and HOBt were added, and the mixture was stirred at room temperature for 12 hours. A saturated aqueous solution of sodium hydrogencarbonate and water were added to the reaction solution, and the precipitated solid was collected by filtration, and the obtained solid was washed with water and methanol in that order. TH of the obtained white solid
To a mixed solution of F and methanol was added a 1N aqueous solution of sodium hydroxide under ice-cooling and stirring, followed by stirring at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, a 10% aqueous citric acid solution was added to the obtained residue, and the precipitated solid was collected by filtration. The obtained solid was washed sequentially with water and methanol, and then washed with DMF-
Crystallized from methanol to give (R) -3- as colorless crystals
[(2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonyl) amino] -3- [4-
(2- {4- [3- (2-methylphenyl) ureido] phenyl} acetylamino) phenyl] propanoic acid was obtained.

The compounds of Examples 9 to 11 shown in Table 2 below were replaced with the compounds of Examples 12 to 36 shown in Tables 2 to 4 in the same manner as in Example 1 and Example 5. ,
In the same manner as in Example 8, Examples 37 to 4 shown in Table 5 below are shown.
Compound 0 was prepared.

Tables 1 to 5 show the structures and physicochemical properties of the compounds of the examples. Table 6 shows other compounds included in the present invention. These compounds can be readily prepared in analogy to the methods described in the above Examples or Preparations, or by applying to them some variations obvious to one skilled in the art.

The symbols in the table have the following meanings in addition to those defined above. Ex: Example number, Com: Compound number, R / S: Optical isomer {R: R-form, S: S-form, RS: RS-form}, DA
T: physicochemical properties, EA: elemental analysis value, Calcd: calculated value, Found: experimental value.

[0081]

[Table 1]

[0082]

[Table 2]

[0083]

[Table 3]

[0084]

[Table 4]

[0085]

[Table 5]

[0086]

[Table 6]

[0087]

[Table 7]

[0088]

[Sequence List] <110> Yamanouchi Pharmaceutical Co. Ltd. <120> amido derivatives <130> WP30382909 <160> 1 <210> 1 <211> 25 <212> PRT <213> human <400> 1 Asp Glu Leu Pro Gln Leu Val Thr Leu Pro His Pro Asn Leu His Gly 1 5 10 15 Pro Glu Ile Leu Asp Val Pro Ser Thr 20 25

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 3/10 A61P 3/10 4C063 9/10 101 9/10 101 4C065 11/06 11/06 4C072 29 / 00 29/00 4C086 101 101 4C204 35/04 35/04 37/06 37/06 37/08 37/08 43/00 105 43/00 105 C07D 209/18 C07D 209/18 213/56 213/56 215 / 06 215/06 231/56 231/56 A 235/08 235/08 239/557 277/40 277/40 295/20 Z 295/20 307/81 307/81 403/12 403/12 471/04 108A 471 / 04 108 487/04 144 487/04 144 498/06 498/06 239/54 A (72) Inventor Takashi Sugane 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture Yamanouchi Pharmaceutical Co., Ltd. (72) Inventor Susumu Igarashi Ibaraki (21) Inventor Koichiro Morihira, 21 Miyukigaoka, Tsukuba, Japan 21 Miyukigaoka, Tsukuba, Ibaraki Prefecture, Yamanouchi Pharmaceutical Co., Ltd. 21 Yamanouchi Pharmaceutical Company Limited (72) Inventor Makoto Takeuchi Miyukigaoka, Tsukuba City, Ibaraki Prefecture 21 Yamanouchi Pharmaceutical Company Limited F Term (Reference) 4C031 AA05 4C033 AD08 AD13 AD17 AD20 4C037 PA09 4C050 AA01 AA07 BB04 BB05 CC04 CC08 EE01 EE03 FF02 GG01 GG03 HH01 HH04 4C055 AA01 BA01 CA01 DA34 DB04 DB17 DB19 4C063 AA01 BB09 CC29 CC76 CC94 DD06 DD22 DD29 EE01 4C065 AA03 BB04 BB05 BB06 CC01 CC09 DD01 DD02 EE02 H0401 GG02 BB01 BB01 BB01 HH02 HH07 HH08 UU01 4C086 AA01 AA02 AA03 BC42 BC73 BC82 CB03 CB05 CB22 GA02 GA04 GA07 GA08 GA09 GA10 GA12 MA01 MA04 NA11 NA12 NA14 ZA02 ZA34 ZA45 ZA59 ZA66 ZA81 ZA89 ZB07 ZB11 ZB13 DBB ZB13 ZB13 DBB ZB13 ZB13 ZB13 ZB13 DBB01 FB24 GB01 GB11 GB23 GB25 GB26

Claims (3)

[Claims] 1. An amide derivative represented by the following general formula (I) or a salt thereof. Embedded image (However, the symbols in the formula have the following meanings: Ra: H or a residue of an ester forming a prodrug, Rb: morpholino or 2,4-dioxo-1,2,3,
4-tetrahydropyrimidin-5-yl group, Rc: aryl which may have a substituent or heteroaryl group which may have a substituent, Rd, Re: same or different, H or lower alkyl group . ) 2. A medicament comprising the amide derivative according to claim 1 or a salt thereof. 3. An integrin comprising the amide derivative according to claim 1 or a salt thereof as an active ingredient.
VLA-4 binding inhibitor.