KR20010034317A - VLA-4 Antagonists - Google Patents

Abstract

The compounds of formula (I) below and their pharmaceutically acceptable salts are VLA-4 antagonists.

<Formula I>

They are useful for the inhibition of cell adhesion and for the treatment or prophylactic treatment of inflammatory and autoimmune diseases, in particular inflammatory airway disease. They are particularly useful for reducing post-surgical inflammation, especially inflammation due to transplant surgery.

Description

ＶＬＡ-4 antagonist {VLA-4 Antagonists}

Cell adhesion (ie, the processes by which cells associate with each other, move toward a specific target, or locate in an extracellular matrix) is the basis of many biological phenomena. Cell adhesion results in adhesion of hematopoietic agents to endothelial cells, which then migrate out of blood vessels to the site of injury, playing a role in mammalian lesions such as inflammation and immune responses.

Several cell surface macromolecules (known as cell adhesion receptors) mediate cell-cell and cell-matrix interactions. For example, integrins are important mediators in adhesion interactions between hematopoietic agents and other cells. Integrins are non-covalent heterodimeric complexes consisting of two subunits α and β. Depending on the type of α and β subunit components, each integrin molecule is classified into a unique subclass. At least 12 different α subunits (α1-α6, α-L, α-M, α-X, α-IIB, α-V and α-E) and at least nine different β subunits (β1-β9) have.

Recent antigen-4 (VLA-1), also known as α4β1 integrin or CD49d / CD29, is a leukocyte cell surface receptor involved in various cell-cell and cell-matrix adhesions. It is a receptor for both cytokine-induced endothelial cell surface proteins vascular cell adhesion molecule-1 (VCAM-1) and extracellular matrix protein fibronectin (FN). Anti-VLA-4 monoclonal antibodies (mAb's) inhibit VLA-4 dependent adhesion interactions both in vitro and in vivo. Inhibition of such VLA-4 dependent cell adhesion can prevent or inhibit some inflammatory and autoimmune lesions.

International Patent Application Publication No. 96/22966 discloses compounds of the formula below which are useful for the inhibition, prevention and inhibition of VLA-4-mediated cell adhesion.

The present invention relates to an organic compound which is a VLA-4 antagonist, a method for preparing the compound and its use as a medicament.

It has now been found that certain novel compounds have very good VLA-4 antagonistic activity and useful pharmacological properties.

Accordingly, the present invention provides, in one aspect, a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Where

R ₁ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (aralkyl), aryl-substituted alkenyl or alkynyl, cycloalkyl- Substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy (arkoxy), aryl-substituted alkenoxy or alkynoxy, alkylamino , Alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylureido-substituted alkyl, N-arylureido- Substituted alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl-substituted aralkyl, oxo Carbocyclyl-fused aryl or heterocyclylalkyl .;

R ₂ is (CH ₂ ) _q -V- (CH ₂ ) _{q '} -V _r -R ₈ ;

R ₃ is H, alkyl, alkenyl, aryl or heteroaryl;

R ₄ is H, aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, heterocyclyl, heterocyclylcarbonyl, aminocarbonyl, amido, mono- or di- Alkylaminocarbonyl, mono- or di-arylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or di-acylaminocarbonyl, aromatic or aliphatic acyl; Or amino, halo, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy , Alkyl optionally substituted with a substituent selected from the group consisting of thioalkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl;

R ₅ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, aryl-substituted alkenyl or alkynyl; Or amino, halo, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy , Alkyl optionally substituted with a substituent selected from the group consisting of thioalkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl;

R ₆ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, alkoxy-substituted alkyl , Amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino) -substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio) -substituted alkyl , Thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholinocarbo Nyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, [N- (alkyl, alkenyl or alkynyl)-or N, N- (dialkyl, dialkyl or dialkyl) -amino] carbonyl -Substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl; Or arginine, asparagine, glutamine, S-methyl cysteine, methionine and the corresponding sulfoxide and sulfone derivatives, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine , An amino acid side chain selected from ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine and allothreonine;

R ₇ and R ₈ are independently H, alkyl, alkenyl, carbocyclic aryl, heteroaryl; Or amino, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thio Alkyl, alkenyl, carbocyclic aryl or heteroaryl substituted with 1 to 3 substituents selected from the group consisting of alkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl; or

R ₂ and R ₆ may form a heterocycle with the atoms to which they are attached;

V is O, NH, S, SO or SO ₂ ;

X is CO ₂ R ₅ , PO ₃ H, SO ₂ R ₅ , SO ₃ H, OPO ₃ H, CO ₂ H or CON (R ₄ ) ₂ ;

W is CH or N;

Y is CO, SO ₂ or PO ₂ ;

Z is (CH ₂ ) _{n '} , CHR ₆ or NR ₇ ;

n and n 'are independently 0-4;

m is 1 to 4;

p is 1 to 4;

q and q 'are independently 1 to 5;

r is 0 or 1;

Compounds of the invention, ie compounds of formula (I) and pharmaceutically acceptable salts thereof, are VLA-4 antagonists and are useful for preventing, inhibiting or inhibiting cell adhesion. Thus, they are useful for VLA-4-mediated cell adhesion disease states, particularly inflammatory and autoimmune diseases. They are particularly useful for surgical inflammations, especially transplant surgery. The compounds of the present invention can be used alone or in combination with other agents active in the prevention, inhibition or inhibition of cell adhesion.

Another embodiment of the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention, optionally together with a pharmaceutically acceptable carrier, in particular a composition for VLA-4 antagonism.

In another aspect, the invention also provides a compound of the invention, ie a compound of formula (I) or a pharmaceutically acceptable salt thereof, in particular for use as a medicament in VLA-4 antagonism.

In another aspect, the present invention provides a method of antagonizing VLA-4 in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of the compound of the invention, preferably a human. to provide.

In another aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for the treatment of a disease mediated by VLA-4.

Preferred compounds of the present invention are compounds of formula (Ia) or pharmaceutically acceptable salts thereof.

Where

R ₂ is C _1-4 alkyl-oxy-C _1-8 alkyl;

R ₄ is H, alkyl, alkenyl, carbocyclic aryl or heteroaryl;

X is CO ₂ H or CO ₂ alkyl;

The other symbols are as defined for formula (I).

More preferred compounds of the invention are those wherein R ₁ is aryl; R ₂ is methoxy-n-propyl; R ₃ is H; R ₄ is alkenyl or aryl; X is CO ₂ H; n is 0; Or a pharmaceutically acceptable salt thereof.

Certain embodiments of the present invention are compounds of formula (Ib): or pharmaceutically acceptable salts thereof.

Where

R ₁ is N-arylureidophenyl;

R ₂ is C ₁ -C ₄ -alkyl-oxy-C ₂ -C ₄ -alkyl;

R ₃ is H;

R ₄ is H, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl or carbocyclic aryl;

n is 1 or 2;

m is 1, 2 or 3;

X is COOH or CO ₂ R ₅ ;

R ₅ is optionally substituted lower alkyl.

R ₁ is N- (optionally substituted phenyl) -ureidophenyl; R ₂ is methoxypropyl; R ₃ is H; R ₄ is C ₂ -C ₄ -alkenyl or optionally substituted phenyl; n is 1; m is 1; Preference is given to compounds of the formula (lb) in which X is COOH.

Most preferred compounds of the present invention are compounds of formula (Ic) below or pharmaceutically acceptable salts thereof.

Where

R _a is H, CH ₃ , Cl or NH ₂ ;

R ₂ is (CH ₂ ) ₃ OCH ₃ or (CH ₂ ) ₄ OCH ₃ ;

R ₄ is-(CH) = (CH) -CH ₃ , phenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl;

T is NH or CH ₂ .

"Alkyl" means a straight or branched chain alkyl radical of 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, secondary-butyl, tert-butyl, pentyl, isoamyl, hexyl and decyl.

"Alkenyl" means a straight or branched chain alkenyl radical having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples of such radicals are ethenyl, E- and Z-propenyl, isopropenyl, E- and Z-butenyl, E- and Z-isobutenyl, E- and Z-pentenyl and dekenyl.

In the context of the terms "lower" means the radical having up to 6 carbon atoms.

The term "substituted" in connection with the above terms means that the radicals are for example amino, halo, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylalkylamino, mono- or di-aryl Substituted with amino, alkoxy, aryloxy, aryl, thioaryloxy, thioalkoxy or heterocyclyl.

"Alkynyl" means a straight or branched chain alkenyl radical having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms. Examples of such radicals are ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl and dekinyl.

"Cycloalkyl" means a cyclic alkyl radical having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Examples of such cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclopropyl methyl.

"Cycloalkenyl" means a cyclic carbocyclic ring having 4 to 8 carbon atoms, preferably 5 or 6 carbon atoms and containing at least one double bond. Examples of such cycloalkenyl radicals are cyclopentenyl, cyclohexenyl, cyclopentadienyl and 2-methyl-2-butenyl.

Aryl means carbocyclic or heterocyclic aryl (heteroaryl).

"Aryl" (carbocyclic aryl and heteroaryl) means a 5- or 6-membered carbocyclic aromatic or heteroaromatic ring containing 0 to 3 heteroatoms selected from O, N and S; 9 or 10 membered bicyclic aromatic or heteroaromatic ring systems containing 0 to 3 heteroatoms selected from O, N and S; Or a 13 or 14 membered tricyclic aromatic or heteroaromatic ring system containing 0 to 3 heteroatoms selected from O, N and S; Each ring is, for example, lower alkyl, alkenyl, alkynyl, substituted lower alkyl, substituted alkenyl, substituted alkynyl, = 0, NO ₂ , halogen, hydroxy, alkoxy, cyano, -NR'R Optionally substituted with one to three substituents selected from acylamino, phenyl, benzyl, phenoxy, benzyloxy, heteroaryl and heteroaryloxy, wherein said phenyl, benzyl, phenoxy, benzyloxy, heteroaryl and heteroaryloxy Are each lower alkyl, alkenyl, alkynyl, halogen, hydroxy, alkoxy, cyano, phenyl, phenoxy, benzyl, benzyloxy, carboxy, carboalkoxy, carboxamido, heteroaryl, heteroaryloxy , Optionally substituted with 1 to 3 substituents selected from NO ₂ and —NR′R ′, wherein R ′ is H or lower alkyl. Carbocyclic aromatic ring systems include phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl, anthracenyl. Heterocyclic aromatic ring systems include furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1, 2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3 , 5-tritianyl, indolinyl, indolyl, isoindoleyl, 3H-indolyl, indolinyl, benzo [b] furanyl, 2,3-dihydrobenzofuranyl, benzo [b] thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolinyl, quinolinyl, isoquinolinyl, cynolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, putridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl.

In the above formulas in particular "aryl" related to the R ₁ group is, for example, halo, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, alkenyl, alkynyl, cyano, carboxy, carboalkoxy , Ar'-substituted alkyl, Ar'-substituted alkenyl or alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy or alkynoxy, Ar'-substituted Alkoxy, Ar'-substituted alkenoxy or alkynoxy, alkylamino, alkenylamino or alkynylamino, Ar'-substituted alkylamino, Ar'-substituted alkenylamino or alkynylamino, Ar'- Substituted carbonyloxy, alkylcarbonyloxy, aliphatic or aromatic acyl (e.g. alkanoyl, Ar'-substituted alkanoyl or Ar'-substituted carbonyl, Ar'-substituted alkylcarbonyloxy, Ar'- Substituted carbonylamino, Ar'-substituted amino, Ar'-substituted oxy, alkylcarbonylamino, Ar'-substituted alkylcarbonyl Mino, Ar'-substituted aminocarbonylalkyl, alkoxy-carbonylamino, Ar'-substituted alkoxycarbonylamino, Ar'-oxycarbonylamino, alkylsulfonylamino, mono- or bis- (Ar'- Sulfonyl) amino, Ar'-substituted alkyl-sulfonylamino, morpholinocarbonylamino, thiomorpholinocarbonylamino, N-alkyl guanidino, N-Ar 'guanidino, N-Ar' Cyanoguanidino, NN- (Ar'-, alkyl) guanidino, N, N- (Ar ', Ar') guanidino, N, N-dialkyl guanidino, N, N, N-tree Alkyl guanidino, N-alkyl-ureido, N, N-dialkyl-ureido, N-Ar'-ureido, N, N- (Ar ', alkyl) ureido and N, N- (Ar' ) Carbocyclic or heterocyclic aryl optionally substituted with 1 to 3 substituents independently selected from ₂ ureido, in particular phenyl; acylcarbonylamino; Ar'-substituted aryl; aromatic acyl-substituted aromatic or aliphatic acyl; Ar '-Substituted heterocyclyl; A r'-substituted cycloalkyl or cycloalkenyl, heterocyclylalkoxy, N, N- (Ar ', hydroxyl) ureido; Ar'-substituted cycloalkyl and cycloalkenyl; Ar'-substituted biaryls; Ar'-substituted aminocarbonylamino; Ar'-mercapto-substituted alkyl; Ar'-amino-substituted aryl; Ar'-oxy-substituted alkyl; Ar'-substituted aminocycloalkyl and cycloalkenyl; Aralkylaminosulfonyl; Aralkoxyalkyl; N-Ar'-substituted thioureido; N-aralkoxyureido; N-hydroxyureido; N-alkenyl ureido; N, N- (alkyl, hydroxyl) ureido; Heterocyclyl; Thioaryloxy-substituted aryl; N, N- (aryl, alkyl) hydrazino; Ar'-substituted sulfonylheterocyclyl; Aralkyl-substituted heterocyclyl; Cycloalkyl and cycloalkenyl-substituted heterocyclyl; Cycloalkyl-fused aryl; Aryloxy-substituted alkyl; Heterocyclylamino; Ar'-substituted arylaminosulfonyl; Ar'-substituted alkenoyl; Aliphatic or aromatic acylaminocarbonyl; Aliphatic or aromatic acyl-substituted alkenyl; Ar'-substituted aminocarbonyloxy; Ar ', Ar'-disubstituted aryl; Aliphatic or aromatic acyl-substituted acyl; Benzofused heterocyclylcarbonylamino; Ar'-substituted hydrazino; Ar'-substituted aminosulfonyl; Ar'-substituted alkylamino; Ar'-substituted heterocyclyl; Ar ', Ar'-disubstituted alkanoylamino; Ar'-substituted cycloalkanoylamino; Heterocyclylalkoxy; N, N-Ar ', hydroxyureido; N, N'-Ar ', hydroxyureido; Heterocyclylcarbonylamino; Ar'-substituted aminocarbonylheterocyclyl; Ar'-substituted aminocarbonyl; Ar'-substituted carbonylamino; Ar'-substituted aminosulfonylamino; Ar'-substituted mercaptoalkyl; Ar'-amino substituted biaryls; Aralkylaminoalkoxy; Alkyl- and aryloxy-substituted alkoxy; Heterocyclylcarbonyl; Ar'-substituted sulfonylalkyl; Ar'-amino carbocyclyl; Aralkylsulfonyl; Aryl-substituted alkenyl; Heterocyclylalkylamino; Heterocyclylalkylaminocarbonyl; Ar'-substituted sulfonylaminoalkyl; Ar'-substituted cycloalkyl; Thioaryloxyalkyl; Thioaryloxy mercapto; Cycloalkylcarbonylalkyl; Cycloalkyl-substituted amino; Ar'-substituted arylamino; Aryloxycarbonylalkyl; Phosphorodiamidyl acid or ester; Aryloxydimethylsiloxy; 1,3-indandionylcarbonylalkyl; 1,3-indandionylcarbonyl; Oxamidyl; Heterocyclylalkylidedenyl; Formamidinyl; Benzalzinyl; Benzalhydrazino; Arylsulfonyl ureido; Benzylylamino; 4- (N-2-carboxyalkyl-1- (1,3-benzodioxol-5-yl) -amino-N-leucineylalkylamidylarylurea); Ar'-carbamoyloxy and alkyl- and aryloxy-substituted ureido, wherein "Ar" is hydrogen, halogen, hydroxyl, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, al Kenyl, alkynyl, 1,2-dioxymethylene, 1,2-dioxyethylene, alkoxy, alkenoxy, alkynoxy, alkylamino, alkenylamino or alkynylamino, alkylcarbonyloxy, aliphatic or aromatic A carbocyclic ring as defined above having 1 to 3 substituents selected from the group consisting of acyl, alkylcarbonylamino, alkoxycarbonylamino, alkylsulfonylamino, N-alkyl or N, N-dialkylureido Heterocyclic aryl.

"Alkoxy" means an alkyl ether radical. Examples of alkyl ether radicals are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, secondary-butoxy and tertiary butoxy. "Alkenoxy" means a radical of the general formula alkenyl-O-, provided that this radical is not an enol ether. Examples of alkenoxy radicals are allyloxy and E- and Z-3-methyl-2-propenoxy. "Alkynyloxy" means a radical of the general formula alkynyl-O- provided that this radical is not an inol ether. Examples of alkynyloxy radicals are propargyloxy and 2-butynyloxy. "Thioalkoxy" means a thioether radical of the general alkyl-S. "Alkylamino" means a mono- or di-alkyl-substituted amino radical (ie, a radical of the general alkyl-NH- or (alkyl) ₂ -N-). Examples of alkylamino radicals are methylamino, ethylamino, propylamino, isopropylamino, t-butylamino and N, N-diethylamino. "Alkenylamino" means a radical of the general formula alkenyl-NH- or (alkenyl) ₂ N-, provided that the radical is not enamine. An example of an alkenylamino radical is the allylamino radical. "Alkynylamino" means a radical of the general formula alkynyl-NH- or (alkynyl) ₂ N-, provided that the radical is not inamine. An example of an alkynylamino radical is the propargyl amino radical. "Aryloxy" means a radical of the general formula aryl-O-. Examples of aryloxy radicals are phenoxy, naphthoxy and pyridyloxy. "Arylamino" means a radical of the general formula aryl-NH-. Examples of arylamino radicals are phenylamino (anilide), naphthylamino, 2-, 3- or 4-pyridylamino. "Biaryl" means a radical of the general formula aryl-aryl-. "Thioaryl" means a radical of the general formula aryl-S-. An example of a thioaryl radical is the thiophenyl radical. The term "aryl-fused cycloalkyl" refers to a cycloalkyl radical which shares two adjacent atoms with an aryl radical. An example of an aryl-fused cycloalkyl radical is a benzofused cyclobutyl radical. By "aliphatic acyl" is meant a radical of the general alkyl-CO-, alkenyl-CO- or alkynyl-CO- derived from carboxylic acid. Examples of aliphatic acyl radicals are acetyl, propionyl, butyryl, valeryl, 4-methylvaleryl, acryloyl, crotyl, propionyl and methylpropionyl. "Aromatic acyl" means a radical of the general formula aryl-CO. Examples of aromatic acyl radicals are benzolyl, 4-halobenzolyl, 4-carboxybenzolyl, naphthoyl and pyridylcarbonyl. "Morpolynocarbonyl" and "thiomorpholinocarbonyl" refer to N-carbonylated morpholino and N-carbonylated tyromorpholino radicals, respectively. "Alkylcarbonylamino" means a radical of the general formula alkyl-CONH-. "Alkoxycarbonylamino" refers to a radical of the general formula alkyl-OCONH-. "Alkylsulfonylamino" refers to a radical of the general formula alkyl-SO ₂ NH-. "Arylsulfonylamino" refers to a radical of the general formula aryl-SO ₂ NH-. "N-alkylurea" or "N-alkylureido" means a radical of the general formula alkyl-NH-CO-NH-. "N-arylurea" or "N-arylureido" means a radical of the general formula aryl-NH-CO-NH-. "Halogen" or "halo" means fluoro, chloro, bromo and iodo. "Heterocycle" means a stable 3 to 7 membered monocyclic heterocyclic ring or 8 to 11 membered bicyclic heterocyclic ring which may be saturated or unsaturated, optionally benzo fused, unless otherwise defined . Each heterocycle consists of one or more carbon atoms and one to four heteroatoms selected from nitrogen, oxygen and sulfur, any oxidized form of nitrogen and sulfur, and a quaternized form of any basic nitrogen. Any ring nitrogen may be optionally substituted with substituent R ₄ as defined herein for the compound of formula (I). Heterocycles may be bonded at any inward ring carbon or heteroatom to produce a stable structure. Preferred hetero rings include 5 to 7 membered monocyclic hetero rings and 8 to 10 membered bicyclic hetero rings. The heterocycle may be optionally oxo-substituted at 1 to 3 ring positions, and may be optionally substituted independently with 1 to 4 aryl substituents. Heteroaryl groups as defined herein and saturated heterocycles such as piperidine, morpholine, pyrrolidine, thiazolidine, piperazine, and the like.

The definition of any substituent or symbol in a particular molecule is independent of the definition elsewhere in that molecule. Thus, for example, -N (R ₄ ) ₂ represents -NH ₂ , -NHCH ₃ , -N (CH ₃ ) _2, or the like.

Some of the compounds described herein contain one or more asymmetric centers and are therefore absolute stereochemically as (R) or (S), or (D) or (L) for enantiomers, diastereomers, and other amino acids. It can give rise to stereoisomers that can be defined. The present invention is intended to include all such possible diastereoisomers as well as their racemates and optically pure forms. Optically active (R) and (S), or (D) and (L) isomers can be prepared using chiral synthetic monomers or chiral agents or can be cleaved using conventional techniques. If the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they will include both E and Z geometric isomers unless otherwise specified. Likewise, all tautomeric forms will be included.

In a preferred group of compounds of the invention wherein W in formula (I) is CH, the stereochemistry at that carbon atom is (S). That is, the compounds of formula (Id) and pharmaceutically acceptable salts thereof.

Where

R ₁ , R ₂ , R ₃ , R ₄ , X, Y, Z, m, n and p are as defined for Formula (I).

The pharmaceutical compositions of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, and may contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases, including organic and inorganic acids or bases.

If the compound of the present invention is an acid, the salt may be prepared from a pharmaceutically acceptable non-toxic base. Salts derived from all stable forms of inorganic bases include aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, zinc and the like. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary and tertiary amines, substituted amines including naturally substituted amines, cyclic amines and basic ion exchange resins such as arginine, betaine, Caffeine, choline, N, N'-dibenzylethylenediamine, diethylamine, 2-diethyl-aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine , Glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc.) have.

If the compounds of the present invention are basic, the salts can be prepared from pharmaceutically acceptable non-toxic acids. Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, mandelic acid, methanesulfonic acid, muxic acid, Nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid and the like. Citric acid, hydrobromic acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid are particularly preferred. Base salts also include salts with ammonium, alkali metal and alkaline earth metal salts, salts with organic bases such as dicyclohexylamine salts and amino acids such as arginine and lysine. In addition, basic nitrogen-containing groups such as lower alkyl halides (e.g. methyl chloride), dialkyl sulfates (e.g. dimethyl sulphate), long chain halides (e.g. stearyl chloride) and aralkyl halides (e.g. benzyl chloride) May be quaternized with reagents.

The compounds of the invention are particularly useful as inhibitors of VLA-4 antagonists and VLA-4 related cell adhesion in mammals.

Because of the ability of compounds of formula (I) to inhibit VLA-4-associated cell adhesion, they are useful for the treatment, amelioration or prevention of various inflammatory, immune and autoimmune diseases. Preferably, the disease to be treated by the method of the invention is a respiratory disorder (e.g. asthma), arthritis, psoriasis, transplant rejection, multiple sclerosis, type I diabetes and inflammatory bowel disease, hepatocellular mobilization and implantation, And sickle cell disease. The compounds of formula (I) are also useful in transplant surgery, especially for the treatment of chronic and acute xenografts and allograft rejection.

For respiratory diseases, the compounds of the present invention are useful as agents for the symptomatic or prophylactic treatment of inflammatory airway disease. Such diseases include all types or developments of asthma, including endogenous (non-allergic) asthma and especially exogenous (allergic) asthma. They are useful for the treatment of bronchitis, asthma due to exercise, occupational asthma, asthma induced by bacterial infections and other non-allergic asthma. Treatment of asthma should also be understood to include the treatment of patients younger than 4 or 5 years of age who exhibit symptoms of whiskey, especially at night and can be diagnosed or diagnosed as "thousand infants".

The prophylactic efficacy of asthma treatment is manifested by reduced frequency or reduced severity of symptomatic attacks, improved lung function or improved airway hyperactivity. It is also manifested by a reduction in the need for symptomatic treatment, i.e. treatment to inhibit or arrest symptomatic attack when a symptom attack occurs, for example anti-inflammatory treatment with corticosteroids.

Other inflammatory airway diseases that can be treated with the compounds of the present invention include, for example, pneumoconiosis (arising from repeated inhalation of dust), including aluminumosis, asbestosis, asthma, ironosis, silicosis, tabacosis and asthma. Inflammatory, usually occupational lung disease).

Other inflammatory airway diseases that can be treated with the compounds of the invention include adult respiratory disease symptoms (ARDS), acute chronic obstructive pulmonary disease (COPD) and other drug treatments such as aspirin or b-agonist bronchodilators. There is a worsening of airway hyperactivity following treatment.

In view of anti-inflammatory activity, in particular anti-inflammatory activity associated with inhibition of eosinophilic activation, the compounds of the present invention are also useful for related disorders of the airways such as eosinophilia, hypereosinophilia, eosinophilic pneumonia, parasitic infections (including tropical eosinophilia). , Bronchopulmonary aspergillosis, multiple arteritis nodules, eosinophilic granuloma, and eosinophil-related disorders associated with the airways caused by drug reactions.

The compounds of the present invention can also be used for the treatment of allergic inflammatory diseases such as allergic rhinitis.

In accordance with the foregoing, the present invention relates to (A) a compound of the present invention for the preparation of a medicament for the treatment of inflammatory, immune or autoimmune diseases, in particular arthritis, transplant rejection or inflammatory airway disease, in particular asthma, as described above. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof; And (B) administering a compound of the invention as described above to a mammal, especially a human, in need thereof for the treatment of an inflammatory, immune or autoimmune disease, in particular arthritis, transplant rejection or inflammatory airway disease, in particular asthma. Methods of treating diseases.

The ex vivo dose may be about 10 ⁻⁶ to 10 ⁻¹⁰ molar concentrations, preferably about 10 ⁻⁷ to 10 ⁻⁹ molar concentrations.

The size of the prophylactic or therapeutic dose of a compound of the invention will depend on the nature and gastric severity of the condition to be treated, the particular mammal and the particular compound of the invention and its route of administration. In general, the daily dose is between 0.001 and 200 mg, preferably between 0.05 and 50 mg and most preferably between 0.1 and 1.0 mg per kg body weight of the mammal in single or divided doses. In some cases, it may be necessary to use doses outside this range. When a composition for intravenous administration is used, a suitable daily dosage range is about 0.0005 to 50 mg (preferably 0.01 to 20 mg) of the compound of the present invention per kg of body weight. When a composition for oral administration is used, a suitable daily dosage range is about 0.001-20 mg (preferably 0.01-10 mg) of the compound of the present invention per kg of body weight. When an ophthalmic composition is used, a suitable daily dosage range is typically from about 0.01 to 10% (preferably of the compound of the invention prepared as a 0.1 to 2.0% by weight compound solution or suspension in an acceptable eye formulation). 0.5 to 5.0%).

The compounds of the present invention can also be used in combination with other pharmaceutically active ingredients. For example, typical eye formulations may include compounds alone or in combination with b-adrenergic blockers (eg timolol maleate) or parasympathetic neurostimulants (eg pilocarpine). In combination, the two active ingredients are present in about the same amount.

Any suitable route of administration can be used to provide an effective dosage of a compound of the invention to a mammal, in particular a human. For example, oral, rectal, topical, parenteral, eye, lung, nasal, etc. routes can be used. Dosage forms include tablets, oral tablets, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.

The pharmaceutical compositions of the present invention comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof as the active ingredient, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutically active ingredients. The present invention includes compositions for use in the treatment of inflammatory, immune or autoimmune diseases, in particular arthritis, transplant rejection or inflammatory airway disease, in particular asthma.

The composition may be oral, rectal, topical (including percutaneous devices, aerosols, creams, ointments, lotions and sprays), parenteral (including subcutaneous, intramuscular and intravenous), eyes (eyes), lungs (nose or oral inhalation), or Although compositions suitable for nasal administration are included, the most suitable route in any given case will usually depend on the nature and severity of the condition to be treated and will depend on the nature of the active ingredient. They are conveniently present in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

For example, in the treatment of airway diseases, the compounds of the present invention can be administered orally, for example in the form of tablets, or by inhalation, for example, by aerosol or by using a suitable inhalation device as known in the art. It may be administered in other sprayable formulations or in a dry powder formulation. For use in the treatment of allergic rhinitis, the compounds of the present invention may be administered through the nose.

Compounds of the invention may be mixed as active ingredients in a homogeneous mixture with a pharmaceutical carrier according to conventional pharmaceutical formulation techniques. The carrier may take a wide variety of forms depending on the nature of the formulation desired for administration, ie oral, parenteral, and the like. When preparing oral dosage forms, in the case of oral liquid preparations (eg, suspensions, elixirs and solutions), conventional pharmaceutical media such as water, glycols, oils, alcohols, flavorings, preservatives, colorants 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 agents, lubricants, binders, disintegrating agents and the like can be used. Solid oral formulations are preferred over liquid oral formulations. Because of ease of administration, tablets and capsules are the preferred oral dosage unit form. If desired, capsules may be coated by standard aqueous or non-aqueous techniques.

In addition to the dosage forms described above, the compounds of the invention may be administered by sustained release means and devices.

Pharmaceutical compositions of the invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets containing a predetermined amount of active ingredient in powder or granule form, or in aqueous or non-aqueous liquids or in oil-in-water or water-in-oil emulsions. It can be prepared as a solution or a suspension. Such compositions may be prepared by any method known in the pharmaceutical art. Generally, this composition is prepared by mixing the active ingredient homogeneously and homogeneously with a liquid carrier, finely divided solid carrier or both, and then, if necessary, shaping the product into the desired form. For example, tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be compressed in a suitable machine into the free flowing form, such as powders or granules, optionally mixed with a binder, lubricant, inert diluent, or surfactant or dispersant. Molded tablets can be made by molding a mixture of moisturized powdered compound with an inert liquid diluent in a suitable machine. An eye insert is made from a compression molded film made on a Carver press by applying a compressive force of 12,000 lbs (gauge) at 149 ° C. for 1-4 minutes to a powdered mixture of the active ingredient and HPC. Cold water is circulated in the platen to cool the film under pressure. The inserts are then cut individually from the film with a rod punch. Each insert is placed in a vial and then placed in a wet box (88% relative humidity at 30 ° C.) for 2-4 days. After removal from the box, the vial is capped and then sterilized at 121 ° C. for 0.5 hour.

Compositions containing a compound of the present invention may also be used in a group consisting of corticosteroids, bronchodilators, anti-asthma agents (mast cell stabilizers), anti-inflammatory agents, antirheumatic agents, immunosuppressants, anti-metabolic agents, immunomodulators, anti-psoriasis agents and antidiabetics. It may include additional agents selected. Specific compounds include theophylline, sulfasalazine and aminosalicylates (anti-inflammatory); Cyclosporin, FK-506 and rapamycin (immunosuppressant); Cyclophosphamide and methotrexate (antimetabolites); And interferon (immunomodulators).

The present invention encompasses the aforementioned compounds of the present invention in inhalable form and inhalable medicaments comprising the compound in inhalable form, optionally together with a pharmaceutically acceptable carrier.

Inhalable forms include, for example, an aerosol comprising a compound of the invention in a solution or dispersion in a propellant or in a fuming composition comprising a dispersion of the compound of the invention in an aqueous, organic or aqueous / organic medium. Or sprayable compositions such as finely divided particulate form comprising a compound of the invention in finely divided form, optionally together with a pharmaceutically acceptable carrier in finely divided form.

Aerosol compositions suitable for use as inhalable forms can include the compounds of the present invention in a solution or dispersion in a propellant that can be selected from any propellant known in the art. Suitable such propellants are hydrocarbons such as n-propane, n-butane or isobutane or mixtures of two or more such hydrocarbons and halogen-substituted hydrocarbons such as fluorine-substituted methane, ethane, propane, butane, cyclopropane Or cyclobutanes, especially 1,1,1,2-tetrafluoroethane (HFA134a) and heptafluoropropane (HFA227), or mixtures of two or more halogen-substituted hydrocarbons. When the compounds of the invention are present as dispersions in the propellant, ie in the form of particulates dispersed in the propellant, the aerosol composition also contains lubricants and surfactants that can be selected from lubricants and surfactants known in the art. It may contain. The aerosol composition comprises up to about 5% by weight of the compound of the invention, for example 0.002 to 5%, 0,01 to 3%, 0.015 to 2%, 0.1 to 2% by weight based on the weight of the propellant , 0.5 to 2% by weight or 0.5 to 1% by weight. When present, the lubricant and surfactant may be up to 5% and up to 0.5% by weight of the aerosol composition, respectively. The aerosol composition may also contain up to 30% by weight of ethanol as cosolvent, especially for administration from a pressure metered dose inhalation device.

Finely divided particulate forms, ie dry powders, suitable for use as inhalable forms are those of the compounds of the invention in finely divided particulate form, optionally known as carriers of dry powder inhalation compositions, for example monosaccharides, disaka Finely divided particulate carriers that can be selected from saccharides, including lides and polysaccharides such as arabinose, glucose, fructose, ribose, mannose, sucrose, lactose, maltose, starch or dextran It can be included together. Particularly preferred carriers are lactose. The dry powder may be a capsule or blowing agent of gelatin or plastic for use in a dry powder inhalation device, preferably in dosage units of 5 μg to 40 mg of the active ingredient. Alternatively, the dry powder may be contained as a reservoir in a multiple dose dry powder inhalation device.

In finely divided particulate forms or aerosol compositions in which the compounds of the invention are in particulate form, the compounds of the invention may have an average particle diameter of about 10 μm or less, for example 1 to 5 μm. The particle size of the compounds of the present invention and the particle size of the solid carrier when present in the dry powder composition are determined by conventional methods, for example grinding, microprecipitation, spray-drying, in an air-jet mill, ball mill or vibrator mill, It may be reduced to the desired level by lyophilization or recrystallization from a supercritical medium.

Inhalable medicaments may be administered using inhalation devices suitable for inhalable forms, and such devices are well known in the art. Accordingly, the present invention also provides a pharmaceutical product comprising the compound of the present invention in inhalable form as described above with an inhalation device. In another aspect, the invention provides an inhalation device containing a compound of the invention in inhalable form as described above.

If the inhalable form is an aerosol composition, the inhalation device is known as an aerosol vial, ie a metered dose inhaler, with a valve adapted to deliver a metered dose, for example 10 to 100 μl, such as 25 to 50 μl of the composition. It may be a device. Suitable such aerosol vials and procedures for containing the aerosol composition under pressure therein are well known to those skilled in the art of inhalation therapy. If the inhalable form is a sprayable aqueous, organic or aqueous / organic dispersion, the inhalation device may contain, for example, a known nebulizer, for example, which may contain 1 to 50 ml, generally 1 to 10 ml of dispersion. Conventional pneumatic nebulizers, such as air jet nebulizers, or ultrasonic nebulizers; Or a hand-held sprayer such as AERx (former Aramid, USA) or BINEB (Boehringer Ingelheim) that allows much less spray volume than conventional sprayers. If the inhalable form is in the form of finely divided particulates, the inhalation device may be, for example, in a dry powder inhalation device or in a single operation adapted to deliver dry powder from a capsule or blowing agent containing a dosage unit of dry powder, for example. For example, a multiple dose dry powder inhalation device adapted to deliver 25 mg of dry powder. Suitable such dry powder inhalation devices are well known.

The activity and VLA-4 specificity of the compounds of the invention can be determined using in vitro and in vivo assays.

Cell adhesion inhibition activity of these compounds can be measured by determining the concentration of inhibitors necessary to block binding of fibronectin-, CS1- or VCAM-I-coated plates of VLA-4-expressing cells. In this assay microtiter wells are coated with fibronectin (containing the CS-1 sequence) or CS-1 or VCAM-I. If CS-1 is used, it must be conjugated to a carrier protein such as bovine serum albumin to bind to the wells. Once the wells are coated, various concentrations of test compound are added with appropriately labeled VLA-4-expressing cells. Alternatively, the test compound is added first and incubated with the coated wells before adding the cells. The cells are incubated in the wells for at least 30 minutes. After incubation, the wells are empty and washed. Inhibition of binding is determined by quantifying the fluorescence or radioactivity bound to the plate for various concentrations of the test compound and the control containing no test compound. VLA-4-expressing cells that can be used in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, and human peripheral blood lymphocytes (PBL). The cells used in this assay can be fluorescent or radiolabelled.

Direct binding assays can also be used to quantify the inhibitory activity of the compounds of the invention. In this assay, a VCAM-IgG fusion protein containing the first two immunoglobulin domains (VCAM 2D-IgG) of VCAM (D1D2) bound onto the hinge region of an IgG1 molecule was conjugated to a labeling enzyme such as alkaline phosphatase (AP). Gate. The synthesis of this VCAM-IgG fusion is described in PCT Publication No. 90/13300. Conjugation to the labeling enzyme of the fusion is by well known crosslinking methods. The VCAM-IgG enzyme conjugate is then placed in the wells of a multi-well filtration plate such as contained in the Millipore Multiscreen Assay System (Millipore Corporation, Bedford, Mass.). Various concentrations of test inhibitory compound are then added to the wells followed by the addition of VLA-4-expressing cells. Cells, compounds and VCAM-IgG enzyme conjugates are mixed together and incubated at room temperature. After incubation, the wells are drained in vacuo leaving the cells and bound VCAM. Quantification of bound VCAM is determined by adding the appropriate colorimetric substrate for the conjugated enzyme to VCAM-IgG and determining the response of cell adhesion inhibitory activity.

The compounds of the Examples exhibited IC 50 values for VLA-4 binding on the order of 1 nanomolar.

In order to assess the VLA-4 inhibition specificity of the compounds of the invention, assays for other major groups of integrins, i.e., β2 and β3, as well as other β1 integrins (e.g. VLA-5, VLA-6 and α4β7) do. These assays may be similar to the adhesion inhibition and direct binding assays described above, altering the appropriate integrin-expressing cells and corresponding ligands. For example, polymorphonuclear cells (PMN) express β2 integrins on their surface and bind to ICAM. β3 integrins are involved in platelet aggregation and can be measured by standard platelet aggregation assays. VLA-5 specifically binds to the Arg-Gly-Asp sequence, while VLA-6 binds to laminin. The compounds of the examples were found to be selective for VLA-4 over related integrins.

In vivo assays that test for inhibition of contact hypersensitivity in animals are described in P. L. Chisholm et al., Eur. J. Immunol., Vol. 23, pp. 682-688 (1993).

Assays for determining inhibition of the Ascaris antigen-induced terminal airway response and airway reactivity of asthma sheep are described by W. M. Abraham et al. Clin. Invest., Vol. 93, pp. 776-87 (1994).

Compounds of the invention can also be tested by the following assays.

Antigen-induced Pulmonary Eosinophilia in Rats

Rat sensitization: Male B6D2F1 / J mice are sensitized by intravenous injection of 0.5 ml of alum-deposited antigen containing 8 μg of ovalbumin (OVA) adsorbed on 2 mg of aluminum hydroxide gel in saline excipient. After 5 days, mice are injected with additional antigenic stimulation with OVA / Alum. Control animals are sensitized with Alum alone. Ten rats are used for each group.

Challenge and Drug Administration: Mice are placed in a 12 × 14 × 10 inch plexiglass chamber and exposed to nebulized OVA (0.5% in saline) for 1 hour and 5 hours after the beginning of the experiment (t = 0). Low molecular weight antagonists are dissolved in 2% DMSO and 150 mM TRIS, pH 8.8. Include solvent control for each experiment. Drugs are administered orally 30 minutes prior to OVA exposure and 6 hours after initial OVA exposure.

BAL fluid collection and analysis: Animals are sacrificed by CO ₂ asphyxiation 24 hours after initial challenge. The cannula is inserted by exposing the trachea. Lungs are washed with 0.6 ml of buffer (Hanks buffered saline with 10 mM Hepes, 0.5% BSA and 10 U / ml heparin). The total number of leukocytes in each sample and the percentage of eosinophils are counted to assess the number of eosinophils in the wash.

Inhibition rate (%) is calculated by the following equation.

Where

Eos is the average number of eosinophils,

OA is challenged rat,

Non-OAs are non-challenged mice.

In this assay, the compounds of the examples administered at a dose of 30 mg / kg provided up to 77% eosinophil inhibition.

The compounds of the present invention can be synthesized using known techniques. See, eg, International Patent Application Publication No. 96/22966, which is incorporated herein by reference, which teaches the synthesis of analogous compounds. The invention is also defined with reference to the following examples, which are intended to be illustrative and not limiting. For example, a representative compound of formula (I), wherein W is CH, reacts a compound of formula (II) or a reactive functional derivative thereof with a compound of formula (III), and optionally a compound so obtained Prepared by converting to another compound.

R _1- (CH ₂ ) _p -Y-OH

Where

R ₁ , p and Y have the meaning as defined above.

Where

Carboxyl groups are in protected form,

R ₂ to R ₄ , Z, n and m have the same meanings as defined above.

Condensation is inert in accordance with methods well known in the art of amide formation, for example in the presence of a condensing agent such as 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride and a base such as diisopropylethylamine. In a solvent such as methylene chloride, preferably at room temperature.

Starting materials of formula (II), such as optionally substituted phenylureidophenylacetic acid, are known in the art or according to methods known in the art, for example by condensing p-aminophenylacetic acid esters with a suitable aryl isocyanate The corresponding phenylureidophenylacetic acid esters are obtained and prepared by hydrolysis of the resulting esters.

The starting material of formula (III) is reacted with a compound of formula (IV) with a compound of formula (V) (preferably as a reactive action derivative thereof) in the presence of a base such as triethylamine Is obtained by reacting with an amine of formula (VII) under conditions well known in the art to obtain a starting material of formula (III) in protected form (eg, as alkyl ester).

Where

Carboxyl groups are in protected form (eg, as alkyl esters),

R ₃ , R ₄ and m have the same meaning as defined above.

LZ- (CH ₂ ) _n -COOH

Where

Z is (CH ₂ ) _{n '} or CHR ₆ ,

n, n 'and R ₆ have the meaning as defined above,

L is a leaving group such as halo or (alkyl or aryl) -sulfonyloxy.

Where

The carboxylic acid is in protected form (eg as alkyl ester),

L, R ₁ , R ₂ and Z have the same meanings as defined above.

R ₂ -NH ₂

Where

R ₂ has the same meaning as defined above.

For example, the starting material of formula (III) is obtained by hydrolysis with a base such as aqueous lithium hydroxide.

As indicated above in the cited processes, this process can be carried out by temporarily protecting the interfering reactive group (s), if necessary, and then releasing the product compounds of the present invention. In the starting materials and intermediates which are converted to the compounds of the invention in the manner described herein, existing functional groups such as carboxyl, amino and hydroxy groups are optionally protected by conventional protecting groups which are common in organic chemical preparation. Well known protecting groups and their introduction are described, for example, in JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London, New York, TW Greene, "Protective Groups in Orgainc Synthesis ", Wiley, New York. For example, hydroxy groups are advantageously protected in the form of benzyl ethers, which can be cleaved by catalytic hydrogenation to yield hydroxy substituted products.

The resulting compound of formula (I), wherein X is esterified carboxyl (COOR ₅ ), can be hydrolyzed and converted to the corresponding acid, for example according to methods well known in the art.

The abbreviations used in the examples below have the following meanings.

conc. = dark

DEIA = di-isopropylethylamine

DMSO = dimethyl sulfoxide

EDAC = 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride

HOBT = hydroxybenzotriazole

HOSu = hydroxysuccinamide

HPLC = High Pressure Liquid Chromatography

MS = mass spectroscopy

NMR = nuclear magnetic resonance

OR = Optical Rotation

TEA = triethylamine

TLC = Thin Layer Chromatography

TRIS = tris (hydroxymethyl) aminomethane

Example 1

(S) -β- [3-methoxypropyl) [[4-[(2-methylphenylaminocarbonylamino) phenyl] acetyl] amino] acetylamino-benzenepropanoic acid

To 45 mL of CH ₂ Cl ₂ is added 1 g (4.5 mmol) of 1,1-dimethyl ethyl (3S) -3-amino-3-phenylpropanoate. Then, 0.720 mL (5.17 mmol) of TEA is added. The mixture is stirred for 10 minutes and cooled to 0 ° C. To this mixture was added dropwise 0.450 mL (5.17 mmol) of brmoacetyl bromide in 5 mL of CH ₂ Cl ₂ over 15 minutes. The mixture is stirred over 3 hours and allowed to reach room temperature. Observe the reaction using TLC using 50% ethyl acetate / 50% hexanes. The mixture is dried and flash chromatographed with 30 g of silica gel (Merck, 9385 grade, 230-400 mesh, 60 cc), 25% ethyl acetate / 75% hexane to give 1.75 g of dark yellow oil, which is TLC Appears as a dot on the image. The product continues to be used for the next step.

To 50 mL of DMF is added 1.5 g of A and 1.0 g (11 mmol) of 3-methoxy-propylamine. 0.74 ml (5.3 mmol) of triethylamine are added at room temperature. The mixture is stirred at rt for 16 h. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture was dried and flash chromatographed using 45 g of silica gel, starting with 2% and gradually increasing to 4% of CH ₃ OH / CH ₂ Cl ₂ , yielding 1.6 g of yellow oil, which was one on TLC. Appear as dots. The product continues to be used for the next step.

To 50 ml of CH ₂ Cl ₂ add 1.5 g of B. Next, 1.4 g (4.8 mmol) of N- (2-methyl) -N '-(4'-acetic acid) diphenyl urea (partially soluble) and 0.74 mL (5.3 mmol) of DIEA are added. The mixture is stirred at room temperature for 15 minutes to give a clear yellow solution. 0.98 g (4.8 mmol) of EDAC is added and the mixture is stirred for 3 hours. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture is dried and flash chromatographed with 90 g of silica gel, starting with 1% and gradually increasing to 5% CH ₃ OH / CH ₂ Cl ₂ to obtain 1.93 g of white foam.

Add 1.7 g of C to 35 ml of CH ₂ Cl ₂ at room temperature. Then 8 ml of TFA acid is added dropwise together with 5 ml of CH ₂ Cl ₂ . The mixture is stirred for 2 hours. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . This mixture is dried. Fresh CH ₂ Cl ₂ is added several times to remove all TFA. Flash chromatography of the product with 50 g of silica gel and between 2% and 5% CH ₃ OH / CH ₂ Cl ₂ yields 1.5 g of the title compound as a white powder.

Melting point: 125-127 ℃

OR: -27.4 °, DMSO (10 mg / ml)

Example 2

(S)-[3-methoxypropyl) [[4- (2-methylphenylaminocarbonylamino) phenyl] acetyl] amino] acetylamino-4-hexanoic acid

0.146 g of dark yellow, following the procedure of Scheme 1-1 of Example 1 except starting with 0.834 g (4.5 mmol) of 1,1-dimethylethyl (3S) -3-amino-4-hexanoate Oil, which appears as a dot on the TLC. The product continues to be used for the next step.

Add 0.31 g (1 mmol) of A to 10 ml of DMF. Next, 0.18 g (2 mmol) of 3-methoxypropylamine is added. Add 0.23 mL (2 mmol) of TEA at room temperature. The mixture is stirred at rt for 16 h. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture was dried and flash chromatographed using 12 g of silica gel, starting with 2% and gradually increasing to 4% CH ₃ OH / CH ₂ Cl _2, to give 0.1 g of yellow oil, one on TLC. Appear as dots. The product continues to be used for the next step.

To 50 ml of CH ₂ Cl ₂ add 1.4 g (4.4 mmol) of B. Then 1.4 g (4.8 mmol) of N- (2-methyl) -N '-(4'-acetic acid) diphenyl urea (partially soluble) and 0.74 mL (5.3 mmol) DIEA were added and this mixture Stir for 15 minutes to get a clear yellow solution. 0.98 g (4.8 mmol) of EDAC is added and the mixture is stirred for 3 hours. Observe the reaction using TLC using 10% CH ₃ OH in CH ₂ Cl ₂ . The mixture is dried and flash chromatographed using 90 g of silica gel, starting with 1% and gradually increasing to 5% CH ₃ OH / CH ₂ Cl ₂ to obtain 1.8 g of white foam.

Add 1.7 g of C to 35 ml of CH ₂ Cl ₂ at room temperature. Then 8 ml of TFA is added dropwise with 5 ml of CH ₂ Cl ₂ . The mixture is stirred for 2 hours. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . This mixture is dried. Fresh CH ₂ Cl ₂ is added several times to remove all TFA. Flash chromatography of the product with 50 g of silica gel and between 2% and 5% CH ₃ OH / CH ₂ Cl ₂ yields 1.5 g of the title compound as a white powder.

Melting point: 88-90 ℃

Example 3

(S) -β- [3-methoxypropyl) [[4-[(2-methylphenylaminocarbonylamino) phenyl] acetyl] amino] acetylamino-3,4-dimethoxy-benzenepropanoic acid

30 g (144.2 mmol) of 3,4-dimethoxycinnamic acid are added to 300 mL of CH ₃ OH. 4 drops of H ₂ SO ₄ are added and the mixture is refluxed for 4 h. Observe the reaction using TLC using 70/30 ethyl acetate / hexanes. The mixture is dried and flash chromatographed using 20% ethyl acetate / 80% hexane on 350 g of silica gel (grade 60, 70-230 mesh) to afford 14.14 g of A.

To 200 mL THF add 11.8 g (55.8 mmol) of (R)-(+)-N-benzyl α-methylbenzylamine. The mixture is cooled to 0 ° C. and 34.9 mL (55.8 mmol) of n-buLi (1.6 M in hexane) is added dropwise over 30 minutes. The mixture is stirred for an additional 30 minutes. The reaction is cooled to -78 ° C. Then, 6.2 g (27.9 mmol) of methyl 3,4-dimethoxycinnamate dissolved in 150 mL of THF was added dropwise over 1 hour. The mixture is stirred slowly at -78 ° C for 30 minutes while maintaining -78 ° C, saturated NH ₄ Cl solution is added, the mixture is allowed to warm to room temperature, washed with brine and dried. Observe the reaction using TLC using 50/50 ethyl acetate / hexanes. The mixture is flash chromatographed on 180 g of silica gel (Merck, 9385 grade, 230-400 mesh, 60 cc) to give 10.5 g of a dark yellow oil.

To 250 mL CH ₃ OH, 25 mL H ₂ O and 7.5 mL HOAc is added 5.0 g (11.5 mmol) of B. 1 g of Pearlman catalyst (Pd (OH) ₂ ) is added. Using a balloon, the mixture is refluxed in H ₂ atmosphere for 16 hours at room temperature. Observe the reaction using TLC using 5% CH ₃ OH / CH ₂ Cl ₂ . The mixture is filtered through celite, washed with CH ₃ OH and dried. CH ₂ Cl ₂ is added to dry the product and washed with brine made basic with saturated NaHCO ₃ . The mixture is dried and flash chromatographed with 150 g of silica gel (230-400 mesh), 1-4% CH ₃ OH / CH ₂ Cl ₂ to give 1.54 g of yellow oil.

To 9 ml of CH ₂ Cl _{2 add} 0.2 g (0.8 mmol) of C and 0.13 ml (0.9 mmol) of TEA. The mixture is stirred for 10 minutes and the mixture is cooled to 0 ° C. 0.08 mL (0.9 mmol) of bromoacetyl bromide in 1 mL of CH ₂ Cl ₂ is added dropwise over 15 minutes. The mixture is stirred over 3 hours and the mixture is allowed to reach room temperature. Observe the reaction using TLC using 50% ethyl acetate / 50% hexanes. The mixture is dried and flash chromatographed with 30 g silica gel (Merck, 9385 grade, 230-400 mesh, 60 cc) and 2% ethyl acetate / 75% hexane to give 0.237 g of a dark yellow oil, which is TLC Appears as a dot on the image. The product continues to be used for the next step.

To 10 mL of DMF is added 0.36 g (1 mmol) of D and 0.18 g (2 mmol) of 3-methoxypropylamine. Add 0.23 ml of TEA at room temperature. The mixture is stirred at rt for 16 h. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture is dried and flash chromatographed with 12 g of silica gel starting at 2% and gradually increasing to 4% CH ₃ OH / CH ₂ Cl ₂ to give 0.1 g of yellow oil, which is one point on TLC. Appears. The product continues to be used for the next step.

To 5 ml of CHCl _{2 is} added 0.1 g (0.27 mmol) of E and 0.0853 g (0.30 mmol) of a partially soluble N- (2-methyl) -N '-(4'-acetic acid) diphenyl urea. 0.056 mL (0.34 mmol) of DIEA are added and the mixture is stirred at room temperature for 15 minutes to give a clear yellow solution. Add 0.058 g (0.30 mmol) of EDAC and stir the mixture for 3 hours. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture is dried and flash chromatographed with 90 g of silica gel starting at 1% and increasing to 5% CH ₃ OH / CH ₂ Cl ₂ to give 0.113 g of white foam.

Add 0.36 g (0.57 mmol) of F to 21 mL of THF and 8 mL of H ₂ O. 0.36 g (0.86 mmol) of LiOH dissolved in 1 mL of H ₂ O was added dropwise over 5 minutes, and the mixture was stirred at room temperature for 2 hours. Observe the reaction with 10% CH ₃ OH / CH ₂ Cl ₂ . The mixture is dried and flash chromatographed on 20 g of silica gel using 100% CH ₂ Cl ₂ to 5% CH ₃ OH / CH ₂ Cl ₂ to afford 0.36 g of the title compound as a white powder.

Melting Point: 118-120 ℃

OR: -33.6 ° C, DMSO (10 mg / ml)

Example 4

(S) -β- [3-methoxypropyl) [[4-[(2-methylphenylaminocarbonylamino) phenyl] acetyl] amino] acetylamino-4-methoxy-benzene propanoic acid, sodium hydrochloric acid

To 250 mL of CH ₃ OH 50 g (280.8 mmol) of 4-dimethoxycinnamic acid and ₂ mL of concentrated H ₂ SO ₄ are added. The mixture is refluxed for 6 hours. Observe the reaction using TLC using 70/30 ethyl acetate / hexanes. Remove about 30 ml of CH ₃ OH. The mixture is cooled to room temperature, then crystallized, filtered, washed with H ₂ O and dried to yield 49.23 g of the desired product.

THR 300ml (R)-(+)-N-benzyl- Add 10.99 g (52 mmol) of methylbenzylamine. The mixture is cooled to 0 ° C. and 32.5 ml (52 mmol) of n-buLi (1.6 M in hexane) are added dropwise over 30 minutes. The mixture is stirred for an additional 30 minutes. The reaction is cooled to -78 ° C. Then 5 g (26 mmol) of methyl 4-methoxycinnamate dissolved in 100 mL of THF are added dropwise over 1 hour. The mixture is stirred slowly at −78 ° C. for 30 minutes while maintaining −78 ° C., 25 ml of saturated NH ₄ Cl solution is added, the mixture is allowed to warm to room temperature, washed with brine and dried. Observe the reaction using TLC using 50/50 ethyl acetate / hexanes. The mixture is flash chromatographed on 180 g of silica gel (Merck, 9385 grade, 230-400 mesh, 60 cc) to give 9.738 g of dark pale yellow oil (recrystallized from EtOAc / hexanes to give white crystals).

To 250 ml CH ₃ OH, 25 ml H ₂ O and 7.5 ml HOAc are added 7.74 g (19.2 mmol) of B. 1 g of Perman catalyst is added. Using a hydrogen balloon, the mixture is refluxed in H ₂ atmosphere for 16 h at room temperature. Observe the reaction using TLC using 5% CH ₃ OH / CH ₂ Cl ₂ . The mixture is filtered through celite, washed with CH ₃ OH and dried. CH ₂ Cl ₂ is added to the dried product and washed with brine made basic with saturated NaHCO ₃ . The mixture was dried and flash chromatographed with 150 g of silica gel, 1-4% CH ₃ OH / CH ₂ Cl ₂ , used as 230-400 mesh to recrystallize from 3.4 g of a dark pale yellow oil (EtOH / hexanes). To obtain white crystals).

To 25 mL of CH ₂ Cl _{2 add} 0.8 g (3.82 mmol) of C and 0.62 mL (4.4 mmol) of TEA. The mixture is stirred for 10 minutes and the mixture is cooled to 0 ° C. 0.38 mL (4.4 mmol) of bromoacetyl bromide in 5 mL of CH ₂ Cl ₂ is added dropwise over 15 minutes. The mixture is stirred over 3 hours and the mixture is allowed to reach room temperature. Observe the reaction using TLC using 50% ethyl acetate / 50% hexanes. The mixture is dried and flash chromatographed with 30 g of silica gel (Merck, 9385 grade, 230-400 mesh, 60 cc) and 25% ethyl acetate / 75% hexane to give 0.13 g of dark yellow oil, which is TLC Appears as a point on the phase. The product continues to be used for the next step.

To 70 ml of DMF is added 1.3 g (3.94 mmol) of D and 0.667 g (7.49 mmol) of 3-methoxypropylamine. Add 0.105 mL (7.49 mmol) of TEA at room temperature. The mixture is stirred at rt for 16 h. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture was dried and flash chromatographed with 75 g of silica gel starting at 2% and gradually increasing to 4% CH ₃ OH / CH ₂ Cl ₂ to give 1.29 g of yellow oil, which was one point on TLC. Appears. The product continues to be used for the next step.

To 30 mL of CH ₂ Cl _{2 is} added 0.72 g (2.1 mmol) of E and 0.739 g (2.6 mmol) of a partially soluble N- (2-methyl) -N '-(4'-acetic acid) diphenyl urea. 0.46 mL (2.6 mmol) of DIEA is added and the mixture is stirred at room temperature for 15 minutes to give a clear yellow solution. 0.499 g (2.6 mmol) EDAC is added and the mixture is stirred for 3 hours. Observe the reaction using TLC using 10% CH ₃ OH / 90% CH ₂ Cl ₂ . The mixture is dried and flash chromatographed using 90 g of silica gel with starting at 1% and increasing to 5% CH ₃ OH / CH ₂ Cl ₂ to obtain 0.920 g of white foam.

Add 0.90 g (1.49 mmol) of F to 30 mL EtOH and 8 mL H ₂ O. To this mixture is added 0.057 g (1.42 mmol) of NaOH in 1 ml of H ₂ O. The mixture is stirred at room temperature for 3.5 hours. This mixture is filtered and dried to yield 0.720 g of the title compound as a white solid.

Melting Point: 118-216 ° C (Decomposition)

OR: -21.069 °, DMSO (5.3 mg / ml)

Example 5

The compounds of the formulas in Table 1 are prepared analogously to the preceding examples.

compound R _a T R ₂ R ₄ Melting Point (℃) (a) CH ₃ NH (CH ₂ ) ₄ OCH ₃ 3,4-dimethoxyphenyl 114-117 (Disassembly) (b) CH ₃ NH (CH ₂ ) ₄ OCH ₃ Phenyl 116-118 (decomposition) (c) CH ₃ CH ₂ (CH ₂ ) ₃ OCH ₃ 4-methoxyphenyl 127-130 (decomposition) (d) H NH (CH ₂ ) ₃ OCH ₃ Phenyl 107-111 (decomposition) (e) Cl NH (CH ₂ ) ₃ OCH ₃ Phenyl 118-122 (f) NH ₂ NH (CH ₂ ) ₃ OCH ₃ Phenyl 105-109 (Disassembly)

Claims (17)

A compound of formula (I) or a pharmaceutically acceptable salt thereof. <Formula I> Where R ₁ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl-fused cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl (aralkyl), aryl-substituted alkenyl or alkynyl, cycloalkyl- Substituted alkyl, cycloalkenyl-substituted cycloalkyl, biaryl, alkoxy, alkenoxy, alkynoxy, aryl-substituted alkoxy (arkoxy), aryl-substituted alkenoxy or alkynoxy, alkylamino , Alkenylamino or alkynylamino, aryl-substituted alkylamino, aryl-substituted alkenylamino or alkynylamino, aryloxy, arylamino, N-alkylurea-substituted alkyl, N-arylurea-substituted Alkyl, alkylcarbonylamino-substituted alkyl, aminocarbonyl-substituted alkyl, heterocyclyl, heterocyclyl-substituted alkyl, heterocyclyl-substituted amino, carboxyalkyl-substituted aralkyl, oxocarbosi Cyl-fused aryl or heterocyclylalkyl; R ₂ is (CH ₂ ) _q -V- (CH ₂ ) _{q '} -V _r -R ₈ ; R ₃ is H, alkyl, alkenyl, aryl or heteroaryl; R ₄ is H, aryl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl and aryl-substituted alkyl, heterocyclyl, heterocyclylcarbonyl, aminocarbonyl, amido, mono- or di- Alkylaminocarbonyl, mono- or di-arylaminocarbonyl, alkylarylaminocarbonyl, diarylaminocarbonyl, mono- or di-acylaminocarbonyl, aromatic or aliphatic acyl; Or amino, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thio Alkyl optionally substituted with a substituent selected from the group consisting of alkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl; R ₅ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, aryl-substituted alkyl, aryl-substituted alkenyl or alkynyl; Or amino, halo, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy , Alkyl optionally substituted with a substituent selected from the group consisting of thioalkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl; R ₆ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aralkyl, aryl-substituted alkenyl or alkynyl, hydroxy-substituted alkyl, alkoxy-substituted alkyl, alkoxy-substituted alkyl , Amino-substituted alkyl, (aryl-substituted alkyloxycarbonylamino) -substituted alkyl, thiol-substituted alkyl, alkylsulfonyl-substituted alkyl, (hydroxy-substituted alkylthio) -substituted alkyl , Thioalkoxy-substituted alkyl, acylamino-substituted alkyl, alkylsulfonylamino-substituted alkyl, arylsulfonylamino-substituted alkyl, morpholino-alkyl, thiomorpholino-alkyl, morpholinocarbo Nyl-substituted alkyl, thiomorpholinocarbonyl-substituted alkyl, [N- (alkyl, alkenyl or alkynyl)-or N, N- (dialkyl, dialkyl or dialkyl) -amino] carbonyl -Substituted alkyl, carboxyl-substituted alkyl, dialkylamino-substituted acylaminoalkyl; Or arginine, asparagine, glutamine, S-methyl cysteine, methionine and the corresponding sulfoxide and sulfone derivatives, glycine, leucine, isoleucine, allo-isoleucine, tert-leucine, norleucine, phenylalanine, tyrosine, tryptophan, proline, alanine , An amino acid side chain selected from ornithine, histidine, glutamine, valine, threonine, serine, aspartic acid, beta-cyanoalanine and allothreonine; R ₇ and R ₈ are independently H, alkyl, alkenyl, carbocyclic aryl, heteroaryl; Or amino, hydroxy, mercapto, mono- or di-alkylamino, mono- or di-arylamino, alkylarylamino, mono- or di-acylamino, alkoxy, alkenoxy, aryloxy, thioalkoxy, thio Alkyl, alkenyl, carbocyclic aryl or heteroaryl substituted with 1 to 3 substituents selected from the group consisting of alkenoxy, thioalkyoxy, thioaryloxy and heterocyclyl; or R ₂ and R ₆ may form a heterocycle with the atoms to which they are attached; V is O, NH, S, SO or SO ₂ ; X is CO ₂ R ₅ , PO ₃ H, SO ₂ R ₅ , SO ₃ H, OPO ₃ H, CO ₂ H or CON (R ₄ ) ₂ ; W is CH or N; Y is CO, SO ₂ or PO ₂ ; Z is (CH ₂ ) _{n '} , CHR ₆ or NR ₇ ; n and n 'are 0-4; m is 1 to 4; p is 1 to 4; q and q 'are 1 to 5; r is 0 or 1; The compound of claim 1, wherein R ₁ is aryl. The compound of claim 2, wherein R ₁ is N-arylureido-substituted phenyl. The compound of any one of claims 1-3, wherein R ₄ is H, alkyl, alkenyl, carbocyclic aryl, or heteroaryl. The compound of any one of claims 1-4 where X is CO ₂ H or CO ₂ alkyl. The compound of formula (Ia) according to claim 1 or a pharmaceutically acceptable salt thereof. <Formula Ia> Where R ₂ is C _1-4 alkyl-oxy-C _1-8 alkyl; R ₄ is H, alkyl, alkenyl, carbocyclic aryl or heteroaryl; X is CO ₂ H or CO ₂ alkyl; The other symbols are as defined for formula (I) in claim 1. The compound of claim 6, wherein R ₁ is aryl; R ₂ is methoxy-n-propyl; R ₃ is H; R ₄ is alkenyl or aryl; X is CO ₂ H; n is 0; W is CH. The compound of formula (Ib) according to claim 1 or a pharmaceutically acceptable salt thereof. <Formula Ib> Where R ₁ is N-arylureidophenyl; R ₂ is C ₁ -C ₄ -alkyl-oxy-C ₂ -C ₄ -alkyl; R ₃ is H; R ₄ is H, C ₁ -C ₄ -alkyl, C ₂ -C ₄ -alkenyl or carbocyclic aryl; n is 1 or 2; m is 1, 2 or 3; X is COOH or CO ₂ R ₅ ; R ₅ is optionally substituted lower alkyl. The compound of claim 8, wherein R ₁ is N- (optionally substituted phenyl) -ureidophenyl; R ₂ is methoxypropyl; R ₃ is H; R ₄ is C ₂ -C ₄ -alkenyl or optionally substituted phenyl; n is 1; m is 1; X is COOH. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof. <Formula Id> Where R ₁ , R ₂ , R ₃ , R ₄ , X, Y, Z, m, n and p are each as defined in claim 1. A compound of formula (Ic) or a pharmaceutically acceptable salt thereof. <Formula Ic> Where R _a is H, CH ₃ , Cl or NH ₂ ; R ₂ is (CH ₂ ) ₃ OCH ₃ or (CH ₂ ) ₄ OCH ₃ ; R ₄ is-(CH) = (CH) -CH ₃ , phenyl, 4-methoxyphenyl or 3,4-dimethoxyphenyl; T is NH or CH ₂ . A compound according to any one of claims 1 to 11 for use as a medicament. A pharmaceutical composition comprising as an active ingredient the compound according to claim 1, optionally together with a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 13 for use in a VLA-4 antagonist. The pharmaceutical composition of claim 13 for use in the treatment of an inflammatory, immune or autoimmune disease. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of a disease mediated by VLA-4. Use of a compound according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of an inflammatory, immune or autoimmune disease.