AU6660200A - Compounds that inhibit the binding of integrins to their receptors - Google Patents

Description

S&F Ref: 526796D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Texas Biotechnology Corporation 7000 Fannin Houston Texas 77030 United States of America Ian L Scott, Raju G Bore, Ronald J Biediger, Vanessa O Grabbe, Jamal M Kassir, Karin M Keller, Shuqun Lin, Robert V Market, Timothy P Kogan Spruson Ferguson St Martins Tower 31 Market Street Sydney NSW 2000 Compounds that Inhibit the Binding of Integrins to their Receptors The following statement is a full description of this invention, including the best method of performing it known to me/us:-

O

Fl Documents received on: B 0 I O 2000 Batch No: 5845c Compounds That Inhibit the Binding of Integrins to their Receptors Field of the Invention This invention is directed generally to the inhibition of the binding of o43p integrin to its receptors, for example VCAM-1 (vascular cell adhesion molecule-i) and fibronectin. The invention also relates to compounds that inhibit this binding; to pharmaceutically active compositions comprising such compounds; and the use of such compounds either as above, or in formulations for the control or prevention of disease states in which a4P1 is involved.

Background of the Invention When a tissue has been invaded by a microorganism or has been damaged, white blood cells, also called leucocytes, play a major role in the inflammatory response. One of the most important aspects of the inflammatory response involves the cell adhesion event. Generally, white blood cells are found circulating through the bloodstream. However, when a tissue is infected or becomes damaged, the white blood cells recognise the invaded or damaged tissue, bind to the wall of the capillary and migrate through the capillary into the affected tissue. These events are mediated by a family of proteins called cell adhesion molecules.

There are three main types of white blood cells: granulocytes, monocytes and lymphocytes.

The integrin a41 (also called VLA-4 for very late antigen-4) is a heterodimeric protein expressed on the surface of monocytes, lymphocytes and two subclasses of -granulocytes: eosinophils and basophils. This protein plays a key role in cell adhesion through its ability to recognise and bind VCAM-1 and fibronectin, proteins associated with the endothelial cells that line the interior wall of capillaries.

Following infection or damage of tissue surrounding a capillary, endothelial cells express a series of adhesion molecules, including VCAM-1, that are critical for binding the white blood cells that are necessary for fighting infection. Prior to binding to VCAM-1 or fibronectin, the white blood cells initially bind to certain adhesion molecules to slow their flow and allow the cells to "roll" along the activated endothelium. Monocytes, lymphocytes, basophils and eosinophils are then able to firmly bind to VCAM-1 or fibronectin on the blood vessel wall via the o4P1 integrin. There is evidence that such interactions are also involved in transmigration of these white blood cells into the damaged tissue, as well as the initial rolling event itself.

Although white blood cell migration to the site of injury helps fight infection and destroy foreign material, in many instances this migration can become uncontrolled, with white blood cells flooding to the scene, causing widespread tissue damage. Compounds capable of blocking this process, therefore, may be beneficial as therapeutic agents. Thus, it would be useful to develop inhibitors that would prevent the binding of white blood cells to VCAM-1 and fibronectin.

Some of the diseases that might be treated by the inhibition of a4pi binding include, but are not limited to, atherosclerosis, rheumatoid arthritis, asthma, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, sickle cell disease and type I diabetes. In addition to being found on some white blood cells and some reticulocytes, a41p is also found.on various cancer cells, including leukemia, melanoma, lymphoma and sarcoma cells. It has been suggested that cell adhesion involving a041 may be involved in the metastasis of certain cancers.

Inhibitors of a431 binding may, therefore, also be useful in the treatment of some forms of cancer.

LibC526796speci The isolation and purification of a peptide which inhibits the binding of a41p to a protein is disclosed in US 5 510 332. Peptides which inhibit binding are disclosed in WO 95/15973, EP 0 341 916, EP 0 422 938 A1, US 5 192 746 and WO 96/06108. Novel compounds which are useful for inhibition and prevention of cell adhesion and cell adhesion-mediated pathologies are disclosed in WO 96/22966, WO 98/04247 and WO 98/04913.

It is therefore an object of the invention to provide novel compounds which are inhibitors of a4P1 binding, and pharmaceutical compositions including such novel compounds.

The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

The present invention further relates to a process of inhibiting the binding of a413 integrin to VCAM-1 comprising exposure of a cell expressing a41 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The a41 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other cell that naturally expresses a43i.

The invention also provides a method for treating disease states mediated by a4P1 binding which comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.

Brief Summary of the Invention The invention is directed to novel compounds of Formula I as follows: x R2 J M R G Q A E T L R 4 Formula I wherein A is selected from the group consisting of and -NR 5 E is selected from the group consisting of -CH 2 and -NR 6 Q is selected from the group consisting of and -(CH2)kwherein k is an integer of 0 or 1; J is selected from the group consisting of and -NR 8 25 G is selected from the group consisting of and -(CH 2 ,wherein p is an integer of 0 or 1; T is selected from the group consisting of and -(CH2)b- wherein b is an integer of from to 3; L is selected from the group consisting of -NR 7 and -(CH 2 wherein n is an integer C. of 0 or 1; M is selected from the group consisting of-C(R9)(R 1 and -(CH 2 wherein u is an integer of from 0 to 3; X is selected from the group consisting of -C02B, -P0 3

H

2

-SO

3 H, -OP0 3

H

2 C(O)NHC(0)R 11 -C(O)NHS0 2

R

12 oxazolyl, tetrazolyl and hydrogen; B, R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8

R

9

R

1 0

R

11 and R 12 are independently selected from the group consisting of hydrogen, halogen, Shydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -CF 3 nitro, S. amino, cyano, -N(Cl-C 3 alkyl)-C(0)(Ci-C 3 alkyl), -C1-C3 alkylamino, alkenylamino, alkynylamino, di(Ci- 'C3 alkyl)amino,-C(0)O-(Cl-C3 alkyl), -C(0)NH-(C1-C3 alkyl), -CH=NOH, -P0 3

H

2 -OP0 3

H

2 -C(0)N(C 1 35 C3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, carboxyl and -C(O)NH(benzyl); wherein B, X, R 1

R

2

R

3

R

4

R

5

R

6

R

7

R

8

R

9

RI

0

R

11 and R 1 2 are unsubstituted or substituted with at least one electron donating or electron withdrawing LibC526796speci group; and wherein R 2 and R 3 taken together may form a first ring; R 4 and R 7 taken together may form a second ring; R 9 and RIO taken together may form a third ring; and pharmaceutically acceptable salts thereof.

For Formula 1, presently preferred compounds may have RI, R 2 and R 3 as hydrogen, alkoxy, alkoxyalkoxy, aryl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl or alkyl; R 4 as aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl or heterocyclylalkyl; X as -CO2B; and M as

C(R

9 wherein R 9 and RIO are hydrogen or lower alkyl.

More specifically, the compounds of the present invention may be described by Formula 11 below.

R

9 x R2 R3 0R10

H

R1 N N R 0o Formulal11 wherein X is selected from the group consisting Of -C0 2 B, -P0 3

H

2

-SO

3 H, -0P0 3

H

2 C(O)NHC(O)Rl', -C(O)NHSO 2 R1 2 oxazolyl, tetrazolyl and hydrogen; and B, R 1

R

2

R

3

R

4

R

5

R

6

R

9 RIO, R 1 1 and R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -OF 3 nitro, amino, cyano, -N(Cl-C 3 alkyl)-C(O)(CI-C 3 alkyl), -01-03 alkylamino, alkenylamino, alkynylamino, di(Cl-0 3 alkyl)amino,-C(O)O-(Cl-03 alkyl), -C(O)NH-(Cl-C 3 alkyl), -CH=NOH, -P0 3

H

2 -0P0 3

H

2 -C(O)N (01-03 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, :alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamnate, aryloxyalkyl, carboxyl and -C(O)NH(benzyl); wherein B, X, RI, R 2

R

3

R

4

R

5

R

6

R

9 RIO, R 1 1

R

1 2 and

R

1 3 are unsubstituted or substituted with at least one electron donating or electron withdrawing group.

For Formula 11, presently preferred compounds may have R 2 and R 3 as independently hydrogen, alkoxy, alkoxyalkoxy, aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl or alkyl; R 4 as aryl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl or alkyheterocyclyl; R 5 and R 6 as hydrogen; and R 9 and RIO are independently hydrogen or lower alkyl.

Presently preferred compounds are 1,3-benzodioxol-5-yl)-3-([((1 S)-1 thienylmethyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, 1,3-benzodioxol-5- S)-1 -[(2-acetylphenyl)aminojcarbonylpentyl)amino] carbonylamino)propanoic acid, (33)-3- (1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[(4-acetylphenyl)amino]carbonylpentyl)amino]carbonylamino) propanoic acid, 1,3-benzodioxol-5-yl)-3-([((l1S)-1 -[(4-(2-thienylmethyl)aminobenzyl)amino] carbon yl pentyl)amino]carbon ylam ino) propanoic acid, ,3-benzodioxol-5-yl)-3-([((1 S)-1 (2-meth yl ben zyloxy)-3-methoxybenzyl) am ino] carbonylpentyl) amino]carbonylamino)propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[(4-(2-methyl benzyl) am ino)benzyl) am ino]carbonylpentyl) aminolcarbonylamino) propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 8)-i 1,3-thiazol-2ylmethyl)aminobenzyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, 3(3S)-3-(1 ,3benzod ioxol-5-yl)-3-([((1 1 [(4-(5-meth yl-2-th ie nylmethyl) am inobenzyl) amino]ca rbon yl pen tyl) am ino] carbonylamino) propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[(4-(2-thienylsulfonamido) benzyl)aminoj carbonylpentyl)amino]carbonylamino)propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3- LibC526796speci S)-1-[(4-(2-(6-methylpyridyl)methyl)benzyl)amino]carbonylpentyl)amino]carbonyl amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1 S)-3-(methylsulfanyl)-l -((phenylsulfanyl)methyl)propyl) amino)carbonyl)amino)propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1 S)-2-((cyclopropylmethyl) thio)-1 -((phenylthio)methyl)ethyl)amino)carbonyl) amino)propanoic acid, (9S,13S)-13-(1,3-benzo dioxol-5-yl)-3,11-dioxo-1 -phenyl-9-{[(2-thienylmethyl)amino]carbonyl}-2-oxa-4,10,12-triazapenta decan-1 5-oic acid, (9S, 1 3S)-13-(1,3-benzodioxol-5-yl)-9-{[(3-hydroxy-4-methoxybenzyl)amino] carbonyl}-3,11 -dioxo-2-oxa-4, 10,12-triazapentadecan- 1 5-oic acid, 1 ,3-benzodioxol-5-yl)-3- S)-2-(benzylsulfanyl)-1 -[(phenylsulfanyl)methyl]ethyl}amino)carbonyl]amino}propanoic acid, (3S)- 3-(1,3-benzodioxol-5-yl)-3-{[({(1 S)-3-(methylsulfanyl)-1 -[({4-[(2-toluidinocarbonyl)amino]phenyl} sulfanyl)methyl]propyl}amino)carbonyl]amino}propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-[({( 1 S)- 2-(ethylsulfanyl)-1 -[(phenylsulfanyl)methyl]ethyl}amino) carbonyl]amino}propanoic acid, (9S,13S)-13- (1,3-benzodioxol-5-yl)-9-[({4-[(2-methylbenzyl)amino]benzyl} amino)carbonyl]-3,11-dioxo-1-phenyl-2oxa-4,10,12-triazapentadecan-15-oic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-[({(1 S)-3-(methylsulfanyl)- 1-[({3-[(2-toluidinocarbonyl)amino]phenyl}sulfanyl)methyl]propyl}amino)carbonyl]amino}propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-{[((1 S)-2-(ethylthio)-1-[(phenylthio)methyl]ethyl}oxy)carbonyl] aminoipropanoic acid, (9S,13S)-13-(1,3-benxodioxol-5-yl)-3,11-dioxo-1 -phenyl-9-(((4-((2-toluidino carbonyl)amino)benzyl)amino)carbonyl)-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, or pharmaceutically acceptable salts thereof.

Derivatives of Formulas I, and II include esters, carbamates, animals, amides, optical isomers and pro-drugs.

The present invention also relates to pharmaceutical compositions comprising a physiologically acceptable diluent and at least one compound of the present invention.

The present invention further relates to a process of inhibiting the binding of a411 integrin to VCAM-1 comprising exposure of a cell expressing a41 integrin to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention. The VCAM-1 may be on the surface of a vascular endothelial cell, an antigen presenting cell, or other cell type. The a4p1 may be on a white blood cell such as a monocyte, lymphocyte, granulocyte; a stem cell; or any other .*cell that naturally expresses a4P1.

The invention also provides a method for treating disease states mediated by 4 1 binding which 30 comprises administration of an effective amount of a compound of the present invention, either alone or in formulation, to an afflicted patient.

Detailed Description of the Invention Definitions of Terms The term "alkyl" as used herein alone or in combination refers to C1-C 1 2 straight or branched, substituted or unsubstituted saturated chain radicals derived from saturated hydrocarbons by the .removal of one hydrogen atom. Representative examples of alkyl groups include methyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl among others.

The term "alkenyl", alone or in combination, refers to a substituted or unsubstituted straightchain or substituted or unsubstituted branched-chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.

LibCS26796speci The term "alkynyl", alone or in combination, refers to a substituted or unsubstituted straight or substituted or unsubstituted branched chain alkynyl radical containing from 2 to 10 carbon atoms.

Examples of such radicals include, but are not limited to ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

The term "lower" modifying "alkyl", "alkenyl", "alkynyl" or "alkoxy" refers to a C1-Cs unit for a particular functionality. For example lower alkyl means C1-C6 alkyl.

The term "cycloalkyl" as used herein alone or in combination refers to a substituted or unsubstituted aliphatic ring system having 3 to 10 carbon atoms and 1 to 3 rings, including, but not limited to cyclopropyl, cyclopentyl, cyclohexyl, norbornyl, and adamantyl among others. Cycloalkyl groups can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide. This term is meant to encompass cycloalkenyl and cycloalkynyl groups. "Cycloalkyl" includes cis or trans forms.

Furthermore, the substituents may either be in endo or exo positions in the bridged bicyclic systems.

The term "cycloalkenyl" as used herein alone or in combination refers to a cyclic carbocycle containing from 4 to 8 carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclopentadienyl and the like.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl radical, including, but not limited to cyclohexyl methyl.

The term "halo" or "halogen" as used herein refers to I, Br, Cl or F.

The term "haloalkyl" as used herein refers to a lower alkyl radical, to which is appended at least one halogen substituent, for example chloromethyl, fluoroethyl, trifluoromethyl and pentafluoroethyl among others.

The term "alkoxy", alone or in combination, refers to an alkyl ether radical, wherein the term 25 "alkyl" is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

The term "alkenoxy", alone or in combination, refers to a radical of formula alkenyl-O-, provided that the radical is not an enol ether, wherein the term "alkenyl" is as defined above. Examples of suitable alkenoxy radicals include, but are not limited to, allyloxy, E- and Z- 3-methyl-2-propenoxy and 30 the like.

The term "alkynoxy", alone or in combination, refers to a radical of formula alkynyl-O-, provided that the radical is not an -ynol ether. Examples of suitable alkynoxy radicals include, but are not limited to, propargyloxy, 2-butynyloxy and the like.

The term "carboxyl" as used herein refers to -C0 2

H.

The term "thioalkoxy", refers to a thioether radical of formula alkyl-S-, wherein "alkyl" is as defined above.

The term "carboxaldehyde" as used herein refers to -C(O)R wherein R is hydrogen.

The term "carboxamide" as used herein refers to -C(O)NR2 wherein R is hydrogen, alkyl or any other suitable substituent.

The term "alkoxyalkoxy" as used herein refers to RbO-RcO- wherein Rb is lower alkyl as defined above and Rc is alkylene wherein alkylene is wherein n' is an integer from 1 to 6.

LibC526796speci Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, and tbutoxymethoxy among others.

The term "alkylamino" as used herein refers to RdNH- wherein Rd is a lower alkyl group, for example, ethylamino, butylamino, among others.

The term "alkenylamino" alone or in combination, refers to a radical of formula alkenyl-NH-or (alkenyl)2N-, wherein the term "alkenyl" is as defined above, provided that the radical is not an enamine. An example of such alkenylamino radical is the allylamino radical.

The term "alkynylamino", alone or in combination, refers to a radical of formula alkynyl-NH- or (alkynyl)2N- wherein the term "alkynyl" is as defined above, provided that the radical is not an amine.

An example of such alkynylamino radicals is the propargyl amino radical.

The term "dialkylamino" as used herein refers to ReRfN- wherein Re and Rf are independently selected from lower alkyl, for example diethylamino, and methyl propylamino, among others.

The term "amino" as used herein refers to H 2

N-.

The term "alkoxycarbonyl" as used herein refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl among others.

The term "aryl" or "aromatic" as used herein alone or in combination refers to a substituted or unsubstituted carbocyclic aromatic group having about 6 to 12 carbon atoms such as phenyl, naphthyl, indenyl, indanyl, azulenyl, fluorenyl and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1Hindazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, 25 quinazolinyl, quinoxalinyl, 1,8-naphthridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxyazinyl, pyrazolo[1,5-c]triazinyl and the like. "Arylalkyl" and "alkylaryl" employ the term "alkyl" as defined above. Rings may be multiply substituted.

The term "aralkyl", alone or in combination, refers to an aryl substituted alkyl radical, wherein the terms "alkyl" and "aryl" are as defined above. Examples of suitable aralkyl radicals include, but are 30 not limited to, phenylmethyl, phenethyl, phenylhexyl, diphenylmethyl, pyridylmethyl, tetrazolyl methyl, o furylmethyl, imidazolyl methyl, indolylmethyl, thienylpropyl and the like.

The term "aralkenyl", alone or in combination, refers to an aryl substituted alkenyl radical, wherein the terms "aryl" and "alkenyl" are as defined above.

The term "arylamino", alone or in combination, refers to a radical of formula aryl-NH-, wherein "aryl" is as defined above. Examples of arylamino radicals include, but are not limited to, phenylamino(anilido), naphthlamino, and 4- pyridylamino and the like.

The term "biaryl", alone or in combination, refers to a radical of formula aryl-aryl, wherein the term "aryl" is as defined above.

The term "thioaryl", alone or in combination, refers to a radical of formula aryl-S-, wherein the term "aryl" is as defined above. An example of a thioaryl radical is the thiophenyl radical.

LibC526796speci The term "aroyl", alone or in combination, refers to a radical of formula aryl-CO-, wherein the term "aryl" is as defined above. Examples of suitable aromatic acyl radicals include, but are not limited to, benzoyl, 4-halobenzoyl, 4-carboxybenzoyl, naphthoyl, pyridylcarbonyl and the like.

The term "heterocyclyl", alone or in combination, refers to a non-aromatic 3- to 10- membered ring containing at least one endocyclic N, O, or S atom. The heterocycle may be optionally aryl-fused.

The heterocycle may also optionally be substituted with at least one substituent which is independently selected from the group consisting of hydrogen, halogen, hydroxy, amino, nitro, trifluoromethyl, trifluoromethoxy, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl among others.

The term "alkylheterocyclyl" as used herein refers to an alkyl group as previously defined appended to the parent molecular moiety through a heterocyclyl group.

The term "heterocyclylalkyl" as used herein refers to a heterocyclyl group as previously defined appended to the parent molecular moiety through an alkyl group.

The term "aminal" as used herein refers to a hemi-acetal of the structure RCH(NH 2 The terms "electron-withdrawing" or "electron-donating" refer to the ability of a substituent to withdraw or donate electrons relative to that of hydrogen if hydrogen occupied the same position in the molecule. These terms are well-understood by one skilled in the art and are discussed in Advanced Organic Chemistry by J. March, 1985, pp. 16-18, incorporated herein by reference.

Electron withdrawing groups include halo, nitro, carboxyl, lower alkenyl, lower alkynyl, carboxaldehyde, carboxyamido, aryl, quaternary ammonium, trifluoromethyl, and aryl lower alkanoyl among others. Electron donating groups include such groups as hydroxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, aryloxy, mercapto, lower alkylthio, lower alkylmercapto, and disulfide among others. One skilled in the art will appreciate that the aforesaid substituents may have electron donating or electron withdrawing properties under different chemical conditions. Moreover, the present 25 invention contemplates any combination of substituents selected from the above-identified groups.

The most preferred electron donating or electron withdrawing substituents are halo, nitro, alkanoyl, carboxaldehyde, arylalkanoyl, aryloxy, carboxyl, carboxamide, cyano, sulfonyl, sulfoxide, heterocyclyl, guanidine, quaternary ammonium, lower alkenyl, lower alkynyl, sulfonium salts, hydroxy, lower alkoxy, lower alkyl, amino, lower alkylamino, di(lower alkyl)amino, amine lower alkyl mercapto, 30 mercaptoalkyl, alkylthio and alkyldithio.

Use of the above terms is meant to encompass substituted and unsubstituted moieties.

Substitution may be by one or more groups such as alcohols, ethers, esters, amides, sulfones, **sulfides, hydroxy, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, alkoxyalkoxy, acyloxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

The term "mammals" includes humans and other animals.

The term "heteroatom" as used herein encompasses nitrogen, sulfur and oxygen.

LibC526796speci The term "alpha" as used herein indicates the position immediately adjacent to the position described.

For example, R 1 in Formulas I and II above may independently be, but are not limited to, phenyl, isobutyl, n-butyl, 2-thienylmethyl, 1,3-thiazol-2-yl-methyl, benzyl, thienyl, 3-pyridinylmethyl, 3methyl-1-benzothiophen-2-yl, allyl, isobutyl, 3-methoxybenzyl, propyl, 2-ethoxyethyl, cyclopropylmethyl, 4-((2-toluidinocarbonyl)amino)benzyl, 2-pyridinylethyl, 2-(1 H-indol-3-yl)ethyl, 1Hbenzimidazol-2-yl, 4-piperidinylmethyl, 3-hydroxy-4-methoxybenzyl, 4-hydroxyphenethyl, 4aminobenzyl, phenylsulfonylmethyl, isopropyl or 2-oxo-1 -pyrrolidinyl.

Some of the substituents which may be linked to form a first, second or third ring as described above. Examples of such rings include 4-(2-thienylmethyl) piperazino, 4-(3-thienylmethyl)piperazino, 4-(2-methoxyphenyl)piperazino, 4-(2-thienylcarbonyl)piperazino, 4-(2-thienylsulfonyl)piperazino, 4- ((benzyloxy) carbonyl)piperazino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4-piperidinyl, and 4tetrahydropyranyl, pyrrolidino, 1-piperidino, 4-methyl-i -piperazino, 4-aceto-1 -piperazino, or 4morpholino among others. Rings so formed may be substituted by one or more groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxy, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyloxy, alkoxyalkoxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

The R 4 substituent for Formulas I and II above may be, but is not limited to, 1,3-benzodioxol-5yl, 1-naphthyl, thienyl, 4-isobutoxyphenyl, 2,6-dimethylphenyl, allyloxyphenyl, 3-bromo-4methoxyphenyl, 4-butoxyphenyl, 1-benzofuran-2-yl, 2-thienylmethyl, phenyl, methysulfanyl, S* phenylsulfanyl, phenethylsulfanyl, 4-bromo-2-thienyl, 3-methyl-2-thienyl, or 4,5-dihydro-1,3-oxazol-2yl. These substituents may be further substituted with groups such as alcohols, ethers, esters, amides, sulfones, sulfides, hydroxy, nitro, cyano, carboxy, amines, heteroatoms, lower alkyl, lower alkoxy, lower alkoxycarbonyl, acyloxy, alkoxyalkoxy, halogens, trifluoromethoxy, trifluoromethyl, alkyl, 30 aralkyl, alkenyl, alkynyl, aryl, cyano, carboxy, carboalkoxy, carboxyalkyl, cycloalkyl, cycloalkylalkyl, S heterocyclyl, alkylheterocyclyl, heterocyclylalkyl, oxo, arylsulfonyl and aralkylaminocarbonyl or any of the substituents of the preceding paragraphs or any of those substituents either attached directly or by suitable linkers. The linkers are typically short chains of 1-3 atoms containing any combination of or Rings may be substituted multiple times.

Abbreviations Abbreviations which have been used in the schemes and the examples which follow are: BOC for t-butyloxycarbonyl; EtOAc for ethyl acetate; DMF for dimethylformamide; THF for tetrahydrofuran; Tos for p-toluenesulfonyl; DCC for dicyclohexylcarbodiimide; HOBT for 1-hydroxybenzotriazole; TFAA for trifluoroacetic anhydride; NMM for N-methyl morpholine; DIPEA for diisopropylethylamine; DCM for methylene dichloride; LHMDS for lithium hexamethyl disilazide; NaHMDS for sodium hexamethyl disilazide; CDI for 1,1'-carbonyldiimidazole and TBS for TRIS-buffered saline.

LibC526796speci 9 The compound and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.

An example of a procedure that may be used to synthesise compounds of the formulae shown above is presented in Scheme 1.

1) EtOCOC1, 2 NMM, THF MsCI, Et 3 PhSH, NaBH4, i-PrOH-, THF HO0.<N-NHBOC 2) NaBH 4 $NHBOC DCM rNHBOC 0MeOH HO MsO 1) rNHBOC PhS 4 HCI, dioxane 1) C DI, i-Pr 2 EtN,

THF,

rNH 2 2) 0 PhS 5 Ot-Bu Hjq S 1 0 HCI, dioxane 0 OH PhSH O 8 Scheme I A second example is found in Scheme 2 below.

0@ 4 a TosO PrMgCI, Et 2

O,

cat. Cul, 0 -45 TC, 5 hrs OTos

OH

3-aminothiophenol,

K

2 C0 3 DMF, N 2 HN S S"A0H RT, overnight Br rJ 3K 2 C0 3 Acetone F 3 Cy Nq S-'O reflux, overnight o 12 TFAA, pyr.,

CH

2

CI

2 0 -C to RT FC N S kC 0 a) COCI 2

DIPEA,

THF, 0 0 C RT 30 min.; then OTC b) CO Et b) N 0 >1 -H,0 NaOH(aq) THF/Me6H, RT Scheme 2 LibC526796speci A third example is found in Scheme 3 below.

o U OH OH [.A.OTs BF3-OEt 2 G O ^A OTs 16 ,.-MgCl /S

OH

17 MsCI, NEt 3 O IOMs 1OMs 18 NaN3, DMF N 3 19 PPh3, H 2 0

THF

S

NH

2 a) CDI b) COCH

H

2

N

*HCI -O 21 OS 0 COOH 0 G N ON 0 H H O 22 0 Scheme 3 A fourth example is found in Scheme 4 below.

CbzHN S ,NH 2 CbzHN" NH2

H

HO NHBoc EDCI, HOBT N O NMM 0 0 0 O2N, 0 OEt CbzHN 0 0 H H O LiOH 6S t 0* 0@*e 0 *004 *e 0 0000 0 0 0*0@ *0 0 0*S@ 0 00SS 0@~0 V 0 0000 CbzHN^H OH -n N<N N 0 o H H H f I c 0 27 Scheme 4 5 A detailed description of the preparation of representative compounds of the present invention is set forth in the Examples.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase "pharmaceutically acceptable salt" means those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or is separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, 0 0 LibC526796speci glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate, methane sulfonate, nicotinate, 2naphthalene sulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, ptoluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternised with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminium salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium among others. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

Dosage forms for topical administration of a compound of this invention include powders, 25 sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which can be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention 30 can be varied so as to obtain an amount of the active compound(s) which is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present inventioncan be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat LibC526796speci

L

disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to a human or lower animal may range from about 0.0001 to about 1000mg/kg/day. For purposes of oral administration, more preferable doses can be in the range of from about 0.001 to about 5mg/kg/day. If desired, the effective daily dose can be divided into multiple doses for purposes of administration; consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

The present invention also provides pharmaceutical compositions that comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions can be specially formulated for oral administration in solid or liquid form, for parenteral injection or for rectal administration.

The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term "parenterally," as used 00000 25 herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

In another aspect, the present invention provides a pharmaceutical composition comprising a component of the present invention and a physiologically tolerable diluent. The present invention includes one or more compounds as described above formulated into compositions together with one e 30 or more non-toxic physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that are collectively referred to herein as diluents, for parenteral injection, for intranasal delivery, for oral administration in solid or liquid form, for rectal or topical administration, or the like.

The compositions can also be delivered through a catheter for local delivery at a target site, via an intracoronary stent (a tubular device composed of a fine wire mesh), or via a biodegragable polymer. The compounds may also be complexed to ligands, such as antibodies, for targeted delivery.

Compositions suitable for parenteral injection may comprise physiologically acceptable, sterile

S.

aqueous or nonaqueous solutions, dispersions, suspensions or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.

LibC526796speci These compositions can also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminium monostearate and gelatine.

Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled.

Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions 25 which are compatible with body tissues.

The injectable formulations can be sterilised, for example, by filtration through a bacterialretaining filter or by incorporating sterilising agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and 30 granules. In such solid dosage forms, the active compound may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

LibC526796speci Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatine capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well-known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilising agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring and perfuming agents.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature 25 but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances.

Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an 30 aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are natural and synthetic phospholipids and phosphatidyl cholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Bioloqy, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

The term "pharmaceutically acceptable prodrugs" as used herein represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. Prodrugs of the present invention may be rapidly transformed in vivo to the parent LibC526796speci compound of the above formula, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, V. 14 of the A.C.S.

Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Druq Desiqn, American Pharmaceutical Association and Pergamon Press (1987), hereby incorporated by reference.

The present invention contemplates both synthetic compounds of formulas I and II of the present invention, as well as compounds formed by in vivo conversion to compounds of the present invention.

Compounds of the present invention may exist as stereoisomers wherein asymmetric or chiral centres are present. These stereoisomers are or depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present invention may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centres or by preparation of racemic mixtures followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallisation or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.

In another aspect, the present invention contemplates a process of inhibiting the binding of a431 integrin to VCAM-1. A process of the present invention can be used either in vitro or in vivo. In 25 accordance with a process of the present invention, a cell expressing a401 integrin is exposed to a cell expressing VCAM-1 in the presence of an effective inhibiting amount of a compound of the present invention.

A cell expressing 0411 integrin can be a naturally occurring white blood cell, mast cell or other cell type that naturally expresses a411 on the cell surface, or a cell transfected with an expression 30 vector that contains a poly-nucleotide genomic DNA or cDNA) that encodes 0431 integrin. In an especially preferred embodiment, a411 integrin is present on the surface of a white blood cell such as a monocyte, a lymphocyte.or a granulocyte an eosinophil or a basophil).

A cell that expresses VCAM-1 can be a naturally occurring cell (eg. an endothelial cell) or a cell transfected with an expression vector containing a polynucleotide that encodes VCAM-1. Methods for producing transfected cells that express VCAM-1 are well known in the art.

Where VCAM-1 exists on the surface of cell, the expression of that VCAM-1 is preferably induced by inflammatory cytokines such as tumour necrosis factor-a, interleukin-4 and interleukin-1p.

Where the cells expressing a411 integrin and VCAM-1 are in a living organism, a compound of the present invention is administered in an effective amount to the living organism. Preferably, the compound is in a pharmaceutical composition of this invention. A process of the present invention is especially useful in treating diseases associated with uncontrolled migration of white blood cells to damaged tissue. Such diseases include, but are not limited to, asthma, atherosclerosis, rheumatoid LibC526796speci 16 arthritis, allergy, multiple sclerosis, lupus, inflammatory bowel disease, graft rejection, contact hypersensitivity, type I diabetes, leukemia, and brain cancer. Administration is preferably accomplished via intravascular, subcutaneous, intranasal, transdermal or oral delivery.

The present invention also provides a process of selectively inhibiting the binding of a431 integrin to a protein comprising exposing the integrin to the protein in the presence of an effective inhibiting amount of a compound of the present invention. In a preferred embodiment, the a41 integrin is expressed on the surface of a cell, either naturally occurring or a cell transformed to express a431 integrin.

The protein to which the a4p1 integrin binds can be expressed either on a cell surface or be part of the extracellular matrix. Especially preferred proteins are fibronectin or invasin.

The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples. These Examples are presented to describe preferred embodiments and utilities of the invention and are not meant to limit the invention unless otherwise stated in the claims appended hereto.

Example 1 Synthesis of (3S)-3-{[({(1S)-3-(methylsulfanyl)-1-[(phenylsulfanyl)methyl]propyl)amino)carbonyl]amino}-4- (phenylsulfanyl)butanoic acid (8) Step One: N-Boc-L-Methionine 1 (2g, 8mmol) was dissolved in THF (40mL) and the solution cooled to 0°C. N-Methylmorpholine (0.77mL, 8mmol) and ethyl chloroformate (0.88mL, 8mmol) were added and the mixture was stirred for 30 minutes while maintaining the low temperature. The mixture was quickly filtered and sodium borohydride (0.88g, 23mmol) was added. Methanol (100mL) was added slowly to the ice-cold solution. The ice-bath was removed and the solution stirred at room temperature for 1h. A standard aqueous work-up gave the primary alcohol 2 (1.8g, Step Two: To an ice-cold solution of the alcohol 2 (1.8g, 7.7mmol) in methylene chloride 25 was added triethylamine (1.6mL, 11.5mmol) and methanesulfonyl chloride (0.8mL, 10.4mmol). After minutes, the reaction was poured into water. A standard aqueous work-up gave the mesylate 3 (2.24g, 93%).

Step Three: To a solution of the mesylate 3 (1g, 3.2mmol) in a mixture of THF (10mL) and isopropanol (10mL) was added thiophenol (0.33mL, 3.2mmol) and sodium borohydride (0.15g, 3.9mmol). The mixture was stirred at room temperature overnight. A standard aqueous work-up gave the sulfide 4 (0.94g, Step Four To a solution of the sulfide 4 (0.94g, 2.9mmol) in 1,4-dioxane (3mL) was added hydrochloric acid (3mL, 4M: 1,4-dioxane) and the solution was stirred at room temperature for 4h.

Nitrogen was bubbled through the solution to drive off most of the excess HCI. Concentration under reduced pressure, followed by high vacuum, gave the amine hydrochloride 5 (0.86g). The excess weight was due to residual 1,4-dioxane.

Step Five: A solution of the amine hydrochloride 5 (0.21g, 0.8mmol), and carbonyldiimidazole (0.15g, 0.9mmol) in methylene chloride (2mL) was stirred at room temperature for 30 minutes. A solution of the amine 6 (prepared from Boc-L-Asp(OtBu)-OH following the above reaction sequence) (0.266g, 0.9mmol) in methylene chloride (1mL) was added and the mixture was stirred first at room temperature overnight and then at 40 0 C for 1h. A standard acid-base work-up, followed by purification LibC526796speci by flash chromatography (silica: eluent 3:1-2:1 hexanes:ethyl acetate) gave the urea 7 (0.427g, quant.).

Step Six: To a solution of the urea 7 (0.328g, 0.6mmol) in 1,4-dioxane (1mL) was added hydrochloric acid (1mL, 4M: 1,4-dioxane) and the solution was stirred at room temperature overnight.

A standard aqueous work-up, followed by flash chromatography (silica: chloroform-9:1 chloroform:methanol) gave the title compound 8 (0.065g, 1 H NMR: (400 MHz: DMSO-d 6 6 1.63 (1H, 1.88 (1H, 2.01 (3H, 2.35-2.60 (4H, 2.97 (1H, dd), 3.06 (1H, dd), 3.12 (1H, dd), 3.17 (1H, dd), 3.82 (1H, 4.06 (1H, br ddd), 6.01 (1H, d, NH), 6.14 (1H, d, NH), 7.17 (2H, 7.30 (4H, 7.38 (4H, m).

Example 2 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({(1 S)-1 -[({3-[(2-methylbenzyl)amino]phenyl}thio)methyl] pentyl}oxy)carbonyl]amino}propanoic acid Step One: Copper iodide (0.63g, 3.3mmol) was suspended in diethyl ether (100mL) and chilled to -45C under nitrogen, n-propylmagnesium chloride (16mL, 1.0M in diethyl ether, 16.0mmol) was added slowly to the solution. After 10 minutes, (2S)-(+)-glycidyl tosylate (5.00g, 21.9mmol) in diethyl ether (100mL) was added dropwise via cannula over 1h. After 5h, the mixture was warmed to 0°C and quenched with saturated, aqueous ammonium chloride (50mL). The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried over Na2SO 4 filtered, and concentrated under reduced pressure. Compound 9 (5.61g, 90%) was recovered as a clear oil and was used without further purification.

Step Two: Compound 9 (1.55g, 5.7mmol) was dissolved in DMF (20.5mL) at room temperature.

Potassium carbonate (1.07g, 7.7mmol) was added and the suspension was sparged with nitrogen gas for 15 minutes. 3-aminothiophenol (0.60mL, 5.7mmol) was introduced via syringe and the solution was stirred overnight. The mixture was diluted with water and ethyl acetate, and the pH of the aqueous layer was adjusted with dilute HCI to pH 5-6. The organic layer was washed with water and brine. The organic solution was dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 10 (1.25g, 98%) was recovered as a yellow oil and was used without further purification.

Step Three: Compound 10 (1.25g, 5.7mmol) and pyridine (1.3mL, 15.9mmol) were dissolved in 30 dichloromethane (23.5mL) and chilled to 0"C. The solution was treated with trifluoroacetic anhydride .(2.0mL, 14.1mmol) and allowed to warm to room temperature overnight. The mixture was washed with 2N HCI, water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 11 (2.05 g, 92%) was recovered as a yellow oil and was used without further purification.

Step Four: Compound 11 (0.52g, 1.25mmol) was dissolved in acetone (5.5mL). The resulting solution was treated with potassium carbonate and a-bromo-o-xylene (0.40mL, 3.0mmol) and refluxed overnight. The mixture was cooled and concentrated under reduced pressure. Purification by chromatography (silica gel, 4:1 hexanes:ethyl acetate) gave 12 (0.36g, 69%).

Step Five: Compound 12 (0.20g, 0.51mmol) was dissolved in THF (1.0mL) and N, Ndiisopropylethylamine (0.107mL, 0.61mmol) was added. The reaction mixture was chilled to 0°C under nitrogen, and phosgene (0.32mL, 20% in toluene) was added via syringe. The mixture was stirred 30 minutes at 0°C, then 2h at room temperature and then was recooled to 0°C. A solution of LibC526796speci ethyl 3-amino-3-(3,4-methylenedioxyphenyl)propionate (13) (0.13g, 0.56mmol) and N,Ndiisopropylethylamine (0.107mL, 0.61mmol) in THF (1.0mL) was added by dropwise via cannula. The mixture was warmed to room temperature and stirred an additional 1h. The mixture was diluted with ethyl acetate and washed with 2N HCI, water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by chromatography (silica gel, gradient elution 6:1 to 4:1 hexanes:ethyl acetate) gave 14 (0.19g, 58%).

Step Six: Compound 14 (0.19g, 0.29mmol) was dissolved in 3:1 THF/water (1.lmL) and treated with 2N NaOH(aq) (0.3mL, 0.6mmol) and methanol (0.3mL). After 1h at room temperature, the mixture was diluted with water and washed with dichloromethane. The ethyl acetate layer was acidified with excess 2N HCI and washed with ethyl acetate The organic layers were combined, washed with brine and dried over Na2SO 4 The organic solution was filtered and concentrated under reduced pressure to give compound 15 (0.15g, 1 H NMR (400 MHz, DMSO-ds): 6 7.62 J 7.7 Hz, 1H), 7.26 (dd, 1H), 7.14 4H), 6.99 (dd, J 7.9 Hz, 1H), 6.87 J 1.5 Hz, 1H), 6.79 J Hz 1H), 6.75 (dd, J 1.5, 8.0 Hz, 1H), 6.58 (br s, 1H), 6.53 (br d, J 7.3 Hz, 1H), 6.44 (br d, J is Hz, 1H), 5.96 2H), 4.83 (dd, J 8.0, 15.4 Hz, 1H), 4.67 1H), 4.21 2H), 3.0 2H), 2.63 (dd, J 8.3, 15.6 Hz, 1H), 2.56 (dd, J 6.6, 15.4 Hz 1H), 2.32 3H), 1.61 1H), 1.49 1H), 1.18 (m 4H), 0.78 (br, s, 3H). Example 3 Synthesis of (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({(1S)-1-[(2-thienylmethoxy)methyl]pentyl}amino)carbonyl] amino}propanoic acid (22).

Step One: To a solution of (S)-glycidyl tosylate (842mg, 3.69mmol) and 2-thiophenemethanol (842mg, 7.38mmol) in CH 2

CI

2 (7.4mL) cooled to 0°C under a dry nitrogen atmosphere, BF 3 OEt 2 (0.046mL, 0.37mmol) was added by syringe. The mixture was warmed to room temperature and stirred 4 days, then concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 3:2 hexanes:ethyl acetate increasing to 1:1 hexanes:ethyl acetate to yield a 2:1 mixture of 16:(S)-glycidyl tosylate (394mg) as a light yellow oil.

Step Two: To a solution of a 2:1 mixture of 16:(S)-glycidyl tosylate (320mg, assume 0.73mmol 16 and 0.37mmol (S)-glycidyl tosylate) in diethyl ether (22mL) cooled to -78*C under a dry nitrogen atmosphere, propylmagnesiumchloride (2.75mL of a 2.0M solution in diethyl ether, 5.5mmol) was added dropwise by syringe. The resulting mixture was stirred at -78"C for 15 minutes, then was allowed to warm to room temperature, stirred for 1h and quenched with saturated NH 4 CI. The mixture was diluted with ethyl acetate and washed with H 2 0 (2 times), and brine. The organic phase was dried over MgSO 4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 3:1 hexanes:ethyl acetate to yield 17 (95mg, for two steps).

Step Three: To a solution of 17 (116mg, 0.54mmol) in CH 2

CI

2 (3mL) at room temperature under a dry nitrogen atmosphere, triethylamine (0.11mL, 0.81mmol) and methanesulfonyl chloride (0.053mL, 0.68mmol) were added dropwise by syringe. The resulting mixture was stirred for 15 minutes, was diluted with 1:1 hexanes:ethyl acetate and was washed with saturated NaHCO 3 and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure to give 18 (153mg) as a light yellow oil. This material was used without purification.

LibC526796speci Step Four: To a solution of 18 (150mg, 0.51mmol) in DMF (2mL) cooled to 10°C under a dry nitrogen atmosphere, sodium azide (66mg, 1.0mmol) was added. The resulting mixture was heated to stirred for 2h, then was cooled to room temperature, diluted with 1:1 hexanes:ethyl acetate and washed with H 2 0 (3 times) and brine. The organic phase was dried over MgS04 and filtered and the filtrate was concentrated under reduced pressure to give 19 (119mg, 98%) as a light yellow oil. This material was used without purification.

Step Five: To a solution of 19 (119mg, 0.50mmol) in THF (2mL) at room temperature under a dry nitrogen atmosphere, H 2 0 (0.092mL, 5.1mmol) and triphenylphosphine (401mg, 1.53mmol) were added. The resulting mixture was stirred for 44h at which time TLC indicated only partial conversion.

Additional H 2 0 (0.092mL, 5.1mmol) and triphenylphosphine (401mg, 1.53mmol) were added and the mixture was stirred for 4 days. The mixture was diluted with CH 2 CI2 and was washed with approximately a 9:1 mixture of water/saturated NaHC03. The aqueous phase was extracted with

CH

2

CI

2 (2 times) and the combined organic phases were dried over MgS04 and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography, eluting with 19:1 hexanes:ethyl acetate then 19:1 chloroform:methanol to yield 70%) as a colourless oil.

Step Six: To a solution of 20 (75mg, 0.35mmol) in 1,2-dichloroethane (2mL) at room temperature under a dry nitrogen atmosphere, carbonyldiimidazole (62mg, 0.38mmol) was added.

The resulting mixture was stirred for 2h and N,N-diisopropylethylamine (0.078mL, 0.45mmol) and 21 (101mg, 0.41mmol) were added. The mixture was heated to reflux for 14h, cooled to room temperature, then was diluted with ethyl acetate and was washed with HCI (2N) and brine. The organic phase was dried over MgSO4 and filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with 9:1 chloroform:methanol then 4:1 chloroform:methanol to yield 22 (70mg, 45%) as a pale yellow powder. 1 H NMR (400 MHz, 25 CD 3

SOCD

3 6 0.81 J 6.6 Hz, 3H), 1.22 5H), 1.45 1H), 2.39 2H), 3.37 overlaps H20, 1H), 3.63 1H), 4.60 J 12.8 Hz, 1H), 4.64 J 12.8 Hz, 1H), 4.91 1H), 5.93 (s overlapping m, 3H), 6.61 1H), 6.75 3H), 6.84 (br. s, 1H), 7.02 2H), 7.49 J 5.12 Hz, 1H).

Example 4 30 Synthesis of (9S,13S)-13-(1,3-benzodioxol-5-yl)-3,11-dioxo-1-phenyl-9-{[(2-thienylmethyl)amino]carbonyl}- 2-oxa-4,10,12-triazapentadecan-15-oic acid (27).

Step One: N-a-t-BOC-N. -CBZ-L-Lysine (400.0mg, 1.05mmol) and thiophene 2-methylamine **(0.12mL, 1.16mmol) were dissolved in DMF (7mL). To this was added 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (222mg, 1.16mmol), 1-hydroxybenzotriazole (157.0mg, 1.16mmol), and 4-methylmorpholine (0.16mL, 1.16mmol). The reaction was then stirred at room temperature for 24h. The mixture was taken up in ethyl acetate (200mL), washed with water (2 x 100mL), a saturated solution of sodium bicarbonate (100mL), brine (100mL), dried over MgS04, and concentrated under reduced pressure to give compound 23 (451.7mg, which was used without further purification.

Step Two: Compound 23 (451mg, 0.95mmol) was dissolved in 2N HCI in dioxane (6mL) and stirred at room temperature for 2h. The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate (150mL) and a saturated solution of sodium bicarbonate LibC526796speci (150mL). The organic layer was separated, dried over MgSO4, and concentrated under reduced pressure to yield compound 24 (306.9mg, which was used without further purification.

Step Three: Compound 24 (128mg, 0.37mmol) and compound 25 (150mg, 0.37mmol) were dissolved in tetrahydrofuran (3mL). Triethylamine (0.05mL, 0.37mmol) was added and the reaction stirred at room temperature for 24h. The mixture was diluted with ethyl acetate (100mL) and washed several times with 0.5N aqueous NaOH (5 x 25mL), dried over MgSO4, and concentrated under reduced pressure to yield compound 26 (235.3mg, which was used without any further purification.

Step Four: Compound 26 (230mg, 0.36mmol) was dissolved in methanol (3mL), water (3mL), and tetrahydrofuran (3mL) and to this solution was added lithium hydroxide (45mg, 1.08mmol). The reaction was heated to 50 0 C and stirred for 24h. The mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate (100mL) and 0.5 N aqueous HCI (50mL). The organic layer was separated, dried over MgSO4,, and concentrated under reduced pressure to yield 171.1mg of compound 27. 1 H NMR(400 MHz, DMSO-ds): 6 8.5-8.6 1H), 7.3-7.4 6H), 7.1-7.2 1H), 6.9-7.0 2H), 6.85 1H), 6.7-6.8 2H), 6.5-6.6 2H), 5.9 2H), 5.0 2H), 4.8-4.9 1H), 4.3-4.5 2H), 4.0-4.1 1H), 2.9-3.0 2H), 2.4 2H), 1.5-1.6 2H), 1.3-1.5 2H), 1.1-1.3 2H).

Example Compound 34, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 S)-1-[(2-thienylmethyl)amino]carbonylpentyl) amino]carbonylamino)propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by substituting t-BOC-L-norleucine for N-a -t-BOC-N- E-CBZ-L-lysine in Step 1; mp 188-192°C.

9 Example 6 25 Compound 35, (3S)-3-(1,3-benzodioxol-5-yl)-3-([((1S)-1 -[(2-acetylphenyl)amino]carbonylpentyl) amino]carbonylamino)propanoic acid, of the structure shown below, was synthesised by the *00 procedure of Example 4 by starting with 2-aminoacetophenone and by substituting t-BOC-Lnorleucine for N-a -t-BOC-N-E -CBZ-L-lysine in Step 1.

0 44 H 0 OH H H O So 30 Example 7 Compound 36, 3-(3S)-3-(1,3-benzodioxol-5-yl)-3-([((1 R)-1-[(4-acetylphenyl)amino]carbonyl pentyl)amino]carbonylamino)propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by starting with 4-aminoacetophenone and by substituting t-BOC-Lnorleucine for N-a -t-BOC-N-E -CBZ-L-lysine in Step 1; mp 104-107 0

C.

LibC526796speci H 0 0OH N or

I

Ta 36 Example 8 Compound 37, ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[(4-(2-thienylmethyl)aminobenzyl) amino]carbonylpentyl)amino]carbonylamino) propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by starting with 4-(2-thienylmethylamino)benzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N-c -CBZ-L-lysine in Step 1; mp 183-187C.

H 0 sN 0 O O IrHH Example 9 Compound 38, ,3-benzodioxol-5-yl)-3-([((1 8)-i -[(4-(2-methylbenzyloxy)-3-methoxy benzyl)amino]carbonylpentyl)amino]carbonylamino) propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by starting with [(4-(2-methylbenzyloxy)-3- :methoxybenzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N- e -CBZ-L-lysine in Step 1; mp 150-1 55 0

C.

0 OH Compound 39, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)-l1-[(4-(2-methylbenzyl)amino)benzyl) amio~crboylpnty~ainocaronyamio)propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by starting with 4-(2-methylbenzylamino) and by substituting t-BOC-L-norleucine for N-a -t-BOC-N-E -CBZ-L-lysine in Step 1; mp 192-195 C.

H0 N N. OH q 0 39 Example 11 Compound 40, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 ,3-thiazol-2-ylmethyl)amino benzyl) am ino]carbon yl pentyl) am ino]carbon ylamni no) pro pano ic acid, of the structure shown below, was synthesised by the procedure of Example 4 starting with ,3-thiazol-2-ylmethyl)amino]benzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N- E -CBZ-L-lysine in Step 1; mp 190-1 LzbC526796speci O Example 12 Compound 41, 3(38)-3-(1 ,3-benzodioxol-5-yI)-3-([((1 S)-1 -[(4-(5-methyl-2-thienylmethyl)amino benzyl)amino]carbonylpentyl)amino]carbonylamino) propanoic acid, of the structure shown below, was synthesised by the procedure of Example 4 by substituting 4-[(5-methyl)-2thienylmethyl)amino]benzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N- E -CBZ-Llysine in Step 1; mp 195-198*C.

6H 0 -Y 0 H Z OH NI N Itz 0 0O41 Example 13 Compound 42, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 5)-i -[(4-(2-thienylsulfonamido)benzyl) amino]carbonylpentyl)amino]carbonylamino) propanoic acid of the structure shown below, may be synthesised by the procedure of Example 4 by starting with 4-(2-thienylsulfonamido)benzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N-E -CBZ-L-lysine in Step 1.

_S H 0 N N l)i 420 Example 14 *Compound 43, 3(3S)-3-(l ,3-benzod ioxo S)-1 [(4-(2-(6-methyl pyrid yl) methyl) ben zyl) amino]carbonylpentyl)amino]carbonyl amino)propanoic acid, of the structure shown below, may be synthesised by the procedure of Example 4 by starting with 4-[2-(6-methyl)pyridylmethyl)amino]benzylamine and by substituting t-BOC-L-norleucine for N-a -t-BOC-N- ,-CBZ-Llysine in Step 1; mp 186-191 00.

'j 0 N l 1 OH N k N 0 0 ~O 43 Synthetic procedures similar to those described above may be utilised to obtain the following compounds: 3-(i ,3-benzodioxol-5-yl)-3-{[({(i R)-1 -[(benzylsulfanyl)methyl]-2-methylpropyl~amino) carbonyl]aminolpropanoic acid, 3-(i ,3-benzodioxol-5-yl)-3-{[({(l S)-1 -[(ben zylsulIfanyl) methyl]-2methylpropyl} amino)carbonyl]amino~propanoic acid, 1,3-benzodioxol-5-yl)-3-[({(1 S)-2-methyl-l [(phenylsulfanyl)methyl]propyl~amino)carbonyl aminolpropanoic acid, 3-(1 ,3-benzodioxol-5-yl)-3- S)-i1 -[(ben zylsulIfonyl) methyl]-2-meth yl propyl} amino)carbonyl]amino~propanoic acid, 3-(1 ,3benzodioxol-5-yl)-3-{[((1 S)-1 -{[(4-methoxybenzyl)amino]carbonyl}-3-methylbutyl)amino]carbonyl} amino) propanoic acid, 3-(1 ,3-benzodioxol-5-yl)-3-({[((l R)-1 -{[(4-methoxybenzyl) amino]carbonyl}-3- LibC526796speci methylbutyl)amino]carbonyllamino)propanoic acid, ,3-benzodioxol-5-y)-3-[({( 1S)-2-methyl- 1 -[(phenylsulfanyl)methyl]propyl} amino) carbonyl]aminolpropanoic acid, 1,3-benzodioxol-5- S)-2-methyl-1 -((phenylsulfanyl)methyl)propyl)amino)carbonyl)amino)propanoic acid, (3S)-3- 1 -f{[bis-(phen ylsu lfanyl)] methyl}-2-methyl pro pyl] am inolcarbon yl) amino]-3-[(3,4-methylenedioxy) phenyllpropanoic acid, ,3-benzodioxol-5-y)-3-[({(l1S)-2-methyl.1 -[(phenethylsulfanyl)methyl] propyllamino)carbonyl]amino~propanoic ai, ,3-benzodioxol-5-y)-3-([((1 S)-2-methyl-1 phenylpropyl)sulfanyl]methyllpropyl)amino]carbonyl~amino) propanoic acid, (9S, 13S)-1 3-(1,3benzodioxol-5-yI)-3, 11 -dioxo-1 -phenyl-9-[({4-[(2-toluidinocarbonyl)aminolbenzyllamino)carbonyl]-2oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 3S)-1 1,3-benzodioxol-5-yI)-9-{[(4-hydroxy phenethyl)amino]carbonyl}-3, 1 -dioxo-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-3, 1 -dioxo-1 -phenyl-9-({[2-(2-pyridinyl)ethyl]amino~carbony)-2oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, 3-(1 ,3-benzodioxol-5-y)-3-[({(1 S)-3-methyl-1 toluidinocarbonyl)amino]benzyllamino)carbonyl]butyllamino) carbonyl] aminolpropanoic acid, (3S)-3- (1 ,3-benzodioxol-5-y)-3-(((((1 S)-3-(methylsulfanyl)-1 -((phenylsulfanyl)methyl)propyl)amino)carbonyl) amino)propanoic acid, ,3-benzodioxol-5-y)-3- S)-3-methyl-1 -[(phenylsulfanyl)methyl] butyllamino)carbonyl]aminolpropanoic acid, (8S, 1 2S)-1 1,3-benzodioxol-5-y)-3, 1 0-dioxo-8- ((phenylsulfanyl)methyl)-2-oxa-4,9, 11 -triazatetradecan-1 4-oic acid, (9S, 13S)-1 3-(1 yI)-3, 11 -dioxo-9-[(phenylsulfanyl)methyl]-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 13S)-1 3- (1 ,3-benzodioxol-5-yi)-3, 11 -dioxo-9-({[3-(2-oxo-1 -pyrrolidinyl)propyl]amino} carbon yl)- 1 -phenyl-2-oxa- 20 4,10,1 2-triazapentadecan-1 5-oic acid, (9S, 13S)-1 3-(1 ,3-benzodioxol-5-y)-9-({[2-(1 H-indol-3-yI)ethyI aminolcarbonyl)-3, 11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 1 H- :benzi mid azol-2-yl meth yl) am ino]ca rbon yl- 1 1,3-benzod ioxol-5-yI)-3, 1 Adioxo-2-oxa-4, 10,1 2-tri aza :pentadlecan-1 5-oic acid, (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-3, 1 -dioxo-9-{[(4-piperidinyimethyl) aminolcarbonyl}-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 3S)-1 3-(1 ,3-benzod 3,11 -dioxo-1 -phenyl-9-{[(2-thienylmethyl)aminolcarbonyl}-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 3S)- 1 1,3-ben~od ioxoI-5-yI)-9-{[(3-hyd roxy-4-methoxybenzy) amino] carbonyl}-3, 1 -dioxo-2- *oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-y)-9-{[(4-hydroxy phenethyl)amino]carbonyl}-3, 11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, (9S, aminobenzyl)amino] carbonyl}-1 3-(1 ,3-benzodioxol-5-yl)-3, 11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan- 30 1 5-oic acid, (9S, 13S)-1 3-(1 ,3-benzodioxol-5-yI)-3, 11 -dioxo-9-[(phenylsulfonyl) methyl]-2-oxa-4, 10,12triazapentadlecan-1 5-aic acid, (9S, 13S)-1 1,3-benzodioxol-5-yI)-9-[({4-[bis(2-methylbenzyl)amino] benzyl} amino)carbonyl]-3, 1 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, 1 S)-1 *(acetylamino)phenyljsulfanyllmethyl)-3-(methyisulfanyl)propyl]aminolcarbonyl) amino]-3-( 1,3-benzo acid, ,3-benzodioxol-5-y)-3-[({[(1 S)-1 -{[(4-methoxyphenyl)sulfanyl] methyl}-3-(methylsulfanyl)propyl] aminolcarbonyl) aminoipropanoic acid, S)-1 aminophenyl) sulfanyl]methyl}-3-(methylsulfanyl)propyl]aminolcarbonyl) aminol-3-(1 yI)propanoic acid, ,3-benzodioxol-5-y)-3-[([(1 S)-1 -{[(4-chloropheny) sulfanyl]methy}-3- (methylsulfanyl)propyl]amino} carbonyl) aminoipropanoic acid, ,3-benzodioxol-5-yI)-3- S)-2-(benzylsulfanyl)-1 -[(phenylsulfanyl)methyllethyllamino)carbonyllaminolpropanoic acid, (3S)- 3-(1 ,3-benzodioxol-5-y)-3-([(1 S)-1 -[({4-[(benzylsulfonyl)amino]phenyllsulfanyl)methyl]-3-(methy sulfanyl)propyl]aminolcarbonyl)aminolpropanoic acid, ,3-benzodioxol-5-y)-3-[((1 S)-3- (methylsulfanyl)-1 -[({4-[(methylsulIfonyl) amino] phenyllsuIfa nyl) meth yl] propyllamino)carbonyl]amino} LibC526796speci propanoic acid, ,3-benzodioxol-5-y)-3-[([(1 S)-1 [(4-methylphenyi)sulfonyl]amino} phenyI)sulfanyI]methyI}-3-(methylsulfanyI)propyIlaminolcarbonyI)aminojpropanoic acid, 1S)-3- (methylsulfanyl)-1 -[(phenylsulfanyl)methyl]propyllamino)carbonyl] amninolpropanoic acid, 1,3benzodioxol-5-y)-3-[({(1 S)-3-(methylsulfanyl)-1 -[({4-[(2-toluidinocarbonyl)amino]phenyl~sulfanyl) methyl]propyl~amino)carbonyl]amino~propanoic acid, S)-5-{[(benzyloxy)carbonyl]amino-1 {[(2-thienylmethyl)amino]carbonyl~pentyl) aminolcarbonyl~amino)butanedioic acid, ,3benzodioxol-5-y)-3-[({(1 S)-2-(ethylsulfanyl)-1 -[(phenylsulfanyl)methyl]ethyllamino)carbonyl] amino} propanoic acid, ,3-benzodioxol-5-y)-3-[({(1 S)-2-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl] ethyl~amino)carbonyl]amino} propanoic acid, N,N'-bis[(1 S)-1 ,3-benzodioxol-5-yI)-2-carboxyethyl] urea, (9S, 1 3S)- 1 3-(1 ,3-benzod ioxol-5-yI)-9-[({4- [(2-methyl ben zyl) am ino] ben zyl} amino)carbonyl]-3, 11dioxo-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, ,3-benzodioxol-5-y)-3-(((((1 R)- 2-(benzylsulfonyl)-1 -((phenylsulfanyl)methyl) ethyl)amino)carbonyl)amino)propanoic acid, ,3benzodioxol-5-y)-3-[({(1 S)-1 -[(phenyisulfanyl)methyl]pentyllamino) carbonyl]amino~propanoic acid, ,3-benzodioxol-5-y)-3-[([(1 S)-1 ,3-benzodioxol-5-yi)-3-(tert-butoxy)-3-oxopropyl]amino} carbonyl)amino]propanoic acid, S)-1 -{[(2-aminophenyl)sulfanyl]methyl}-3-(methylsulfanyl) propyllaminolcarbonyl) amino]-3-(1 ,3-benzodioxol-5-yI)propanoic acid, S)-1 -{[(2-methylphenyl)sulfanyl]methyl}-3-(methylsulfanyl)propyljamino~carbonyl)amino] propanoic acid, ,3-benzodioxol-5-y)-3-[([(1 S)-1 -{[(3-methylphenyl)sulfanyl]methyl}-3-(methy *:*:sulfanyl)propyllamino~carbonyl) amninoipropanoic acid, ,3-benzodioxol-5-yi)-3-(((2- (phenylsulfanyl) ethylamino)carbonyl)amino)propanoic acid, ,3-benzodioxol-5-y)-3-[({(1 S)-2- [(3-phenylpropyl)sulfanyl]-1 -[(phenylsulfanyl)methyl]ethyl~amino)carbonyllaminolpropanoic acid, (3S)- 3-(1 ,3-benzodioxol-5-y)-3-[({(1 S)-2-(phenylsulfanyl)-1 -[(propylsulfanyl)methyl]ethyllamino)carbonyl] :amino) propanoic acid, ,3-benzod ioxol-5-y)-3-[( 1 S)-3-(methylsulfanyl)- 1 [(phenylsulfanyl)methyl]propyllamino)carbothioyijaminolpropanoic acid, (3S)-4-(methylsulfanyl)-3- S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl]propyllamino)carbonyl]amino~butanoic acid, (3S)- S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl]propyllamino)carbonyl]amino}-4-(pheny sulfanyl) butanoic acid, ,3-benzodioxol-5-y)-3-[([(1 S)-1 -methyi-2-(phenylsulfanyl)ethyl] aminolcarbonyl)aminolpropanoic acid, ,3-benzodioxol-5-y)-3-{[({(1 S)-2-(octylsulfanyl)-l [(phenylsulfanyl)mneth~l] ethyllamino)carbonyll amino~propanoic acid, ,3-benzodioxol-5-yI)-3- 30 S)-3-(methylsulfanyl)-1 uid inocarbonyl) amino] phen ylls ulfanyl) methyljpropy~am ino) carbonyllamino} propanoic acid, ,3-benzodioxol-5-y)-3-[([( 1 S)-3-(methylsulfanyl)-1 (phenoxymethyl)propylJ aminolcarbonyl) aminoipropanoic acid, (3S)-3-(1,3-benzodioxol-5-y)-3- {[(methyl{(1 S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl]propyl~amino)carbonyi]amino~propanoic acid, ,3-benzodioxol-5-y)-3-{[({1 -[(phenylsulfanyl)methyl]pentyl~oxy)carbonyl]amino} propanoic acid, ,3-benzod hen ylsuIfanyl)- 1 -[(phen yls ulfa nyl) methyljethyl} amino)carbonyl]aminolpropanoic acid, ,3-benzodioxol-5-y)-3-[({( 1 S)-2-[(carboxymethyl) sulfanyl]-1 -[(phenyisulfanyl)methyllethyl~amino) carbonyl]amino~propanoic acid, aminophenyl)thiolmethy}-3-(methylthio)propyl]amino~carbonyl)amino-3-(1 propanoic acid, 1,3-benzodioxol-5-y)-3-[([(1 S)-1 -[({4-[(2-methylbenzyl)amino]phenylthio) methyl]-3-(methylthio)propyl] amino) carbonyl) amino] propanoic acid, ,3-benzodioxol-5-y)-3- S)-1 -[({3-[(methylsulfonyl)amino]phenyllthio)methyl]-3-(methylthio)propyl]amino~carbonyl)amino] propanoic acid, ,3-benzodioxol-5-yI)-3-[({(1 S)-3-(methylthio)-1 -[({3-[(propylsulfonyl)amino] LibC526796speci phenyl~thio)methyl]propyllamino)carbonyl]aminolpropanoic acid, 1 S)-2-(allyloxy)-1 [(phenylthio)methyl]ethyllamino)carbonyl]aminol-3-(1 ,3-benzodioxol-5-yl) propanoic acid, ,3benzodioxol-5-yl)-3-[({(1 S)-2-(benzyloxy)-1 -[(phenylthio)methyllethyllamino)carbonyl]amino} propanoic acid, ,3-benzodioxol-5-yl)-3-[([(1 R)-1 -phenyl-2-(propylthio)ethyl]amino~carbonyl) amino] propanoic acid, ,3-benzodioxol-5-yl)-3-(((((1 R)-1 -benzyl-2-(propylthio)ethyl)amino) carbonyl)amino)propanoic acid, ,3-benzodioxol-5-yl)-3-[({(1 S)-3-(phenylthio)-1 -[(phenyithia) methyl]propyllamino)carbonyl]amino~propanoic acid, 1,3-benzodioxol-5-yl)-3-[({( 1 S)-4hydroxy-1 -[(phenylthio)methyl]butyl} amino)carbonyl]aminolpropanoic acid, S)-2-ethoxy-1 -[(phenylthio)methyllethylloxy)carbonyl]aminolpropanoic acid, 1,3benzodioxol-5-yl)-3-[({(1 S)-2-(phenethyloxy)-1 -[(phenylthio)methyl]ethylloxy)carbonyl]amino} propanoic acid, ,3-benzodioxol-5-yl)-3-[({(1 S)-2-[(cyclopropylmethyl)thio]-1 -[(phenyithia) methyllethyllamino)carbonyl]aminolpropanoic acid, 1,3-benzod ioxol-5-yl)-3-[( (1 R)-2- (benzyloxy)-1 -[(benzylthio)methyl]ethyl~amino)carbonyllaminolpropanoic acid, 1,3-benzo dioxol-5-yl)-3-[({(1 R)-2-(benzyloxy)-1 -[(benzylthio)methyl] ethylloxy)carbonyl]aminolpropanoic acid, ,3-benzodioxol-5-yl)-3-[({(1 R)-2-(benzyloxy)-1 -[(ethylthio)methyl]ethyl~oxy)carbonyl]amino} propanoic acid, 1,3-benzodioxol-5-yl)-3-[({(l1S)-2-(ethylthio)-1 -[(phenylthio)methyl]ethyl~oxy) carbonyl]amino} propanoic acid, 1,3-benzodioxol-5-yl)-3-[({(1 S)-2-(benzylthio)-1 [(phenylthio)methyl]ethylloxy) carbonyl] aminolpropanoic acid, ,3-benzodioxol-5-yl)-3- S)-1 -[({4-[(2-toluidinocarbonyl)amino]phenyl~thio)methyl]pentyl~oxy)carbonyl]amino propanoic acid, ,3-benzod ioxol-5-yl)-3- 1 yl ben zyl) am ino]lphenyl~th io)meth yllpen tyl} oxy)carbonyl]amino} propanoic acid, ,3-benzodioxol-5-yl)-3-[({(1 S)-2-{[(4-methylphenyl) :sulfonyl] amino)- 1 -[(phenylthio)methyl]ethyl~amino) carbon yl]ami no~propan oic acid, 1,3benzodioxol-5-yl)-3-[({(1 S)-1 -[(2-thienylmethoxy)methyl] pentyllamino)carbonyl]aminolpropanoic acid, and pharmaceutically acceptable salts thereof.

Example The ability of compounds of the present invention to inhibit binding is described in detail hereinafter in the Examples by a procedure in which a 26-amino acid peptide containing the CS1 sequence of fibronectin with an N-terminal Cys was coupled to maleimide activated ovalbumnin.

Ovalbumin and OSi conjugated ovalbumnin were coated onto 96-well polystyrene plates at 5W.gmL in TBS (50mM Tris, pH7.5; 150mM NaCI) at 400 for 16h. The plates were washed three times with lBS and blocked with lBS containing 3% BSA at room temperature for 4h. Blocked plates were washed **three times in binding buffer (IBS; 1 MM MgCI2; 1 mM CaC2; 1 mM MnCI2) prior to assay. Ramos cells fluorescently labelled With calcein AMC-3099 were resuspended in binding buffer (107 cells/mL) and diluted 1:2 with same buffer with or without compound. The cells were added immediately to the wells (2.5 x 105 cells/well) and incubated for 30 minutes at 370. Following three washes with binding buffer, adherent cells were lysed and quantitated using a fluorometer.

The results are shown in Tables 1 and 2. IC50 is defined as the dose required to give inhibition. The lower the IC50 value and the greater the percentage of inhibition, the more efficient the compound is at prevention of cell adhesion. A stands for inhibition in Table 1, and the percent inhibition indicates the inhibition of cell adhesion when compound is included in the assay at a concentration of 100 LibC526796speci Table 1 Compound ICso A 3-(1 ,3-benzodioxo-5-y)-3-{[({( 1 R)-1 -[(benzylsuifanyl)methyl]-2-methylpropyl} 40 83 amino)carbonyllamino~propanoic acid 3-(1 ,3-benzodioxol-5-y)-3-{[({(1 S)-l -[(benzylsulfanyl)methyl]-2-methypropyl} 10 100 amino)carbonyllamino~propanoic acid 1,3-benzodioxol-5-y)-3-{[({(1 S)-2-methyl-1 -[(phenyisulfanyl)methyl]propyl} 5 99 amino carbonyllaminolpropanoic acid 3-(1 ,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[(benzylsulfonyl)methyl]-2-methylpropyl} 35 92 amino)carbonyllamino~propanoic acid 3-(1 ,3-benzodioxol-5-y)-3-({[((1 S)-1 -{[(4-methoxybenzyl)amino]carbony}-3-methylbutyl)amin 0.5 100 olcarbonyllamino)propanoic acid 3-(1 ,3-benzodioxol-5-y)-3-({[((1 R)-1 -{[(4-methoxybenzyl)amino]carbony}-3-methylbuty)amin 45 66 olcarbonyi~amino)propanoic acid 1,3-benzodioxol-5-y)-3-{[({(1 S)-2-methyl-1 -[(phenylsulfanyl)methyl]propyl~amino)carb 35 83 onyllamino~propanoic acid ,3-benzodioxol-5-y)-3-(((((1 S)-2-methyl-1 -((phenylsulfanyl)methyl)propyl) 2.5 100 amino)carbonyl)amino)propanoic acid -{[bis-(phenylsulfanyl)]methyl}-2-methylpropyljamino~carbony)amino]-3-[(3,4-meth 35 ylenedioxy henylI ropanoic acid 1,3-benzodioxol-5-y)-3-{[({( 1 S)-2-methyl-1 -[(phenethylsuifanyl)methy1] 20 98 1,3-benzodioxol-5-y)-3-({[((l1S)-2-methyl-1 -{[(3-phenylpropyl)sulfanyl] 20 99 (9S, 1 3S)-1 3-(1 ,3-benzodioxo-5-yI)-3, 1-dioxo-1 -phenyl-9-[({4-[(2-toluidino 0.000 100 carbonyi)aminolbenzyl~amino)carbonyl]-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid 3 (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yi)-9-{[(4-hydroxyphenethyl)amino]carbony-3, 11- 2 100 dioxo-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid (9S, 13S)-1 3-(1 ,3-benzodioxol-5-y)-3, 1-dioxo-1 -phenyl-9-({[2-(2-pyridinyl)ethyl] 2 100 amino)carbonyl)-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid 3-(1 ,3-benzodioxol-5-y)-3-{[({(1 S)-3-methyl-1 -[({4-[(2-toluidinocarbonyl)amino] 0.02 100 benzyllamino)carbonyllbutyllamino)carbonyllaminolpropanoic acid____ (9S, 13S)-1 1,3-benzodioxol-5-y)-9-({[2-(1 H-indoi-3-yI)ethyl]amino~carbonyl)-3, 45 78 1 1-dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-3-methyl-1 -[(phenylsulfanyl)methyl]butyl} 2 100 amino)carbonyl]amino~propanoic acid ,3-benzod 1 S)-3-(methylsulfanyl)-1 0.3 100 ((phenylsulfanyl)methyl)propyl)amino)carbonyl)amino)propanoic acid (9S, 13S)-1 3-(1 ,3-benzodioxol-5-y)-3, 1-dioxo-9-[(phenylsulfanyl)methyi]-2-oxa-4, 0.4 100 1 2-triazapentadecan-1 5-oic acid (8S, 1 2S)-1 2-(1 ,3-benzodioxol-5-y)-3, 10-dioxo-8-((phenylsulfanyl)methyl)-2-oxa-4,9, 11- 2 100 triazatetradecan-1 4-oic acid (9S, 13S)-1 3-(1 ,3-benzodioxol-5-y)-3, 1-dioxo-9-({[3-(2-oxo-1 -pyrrolidinyl)propyl] 3 100 amino)carbonyl)-1 -phenyl-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-y)-9-({[2-(1 H-indol-3-yI)ethyl]amino~carbonyl)-3, 3.5 100 11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid (9S, 1 [(l1 H-benzimidazo-2-ylmethy)amino]carbonyl-1 1,3-benzodioxo-5- 2 100 yI)-3, 1 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-y)-3, 1 -dioxo-9-{[(4-piperidinyimethyl)amino] 5 97 carbonyI 2-oxa-4, 10,1 2-triazapentadecan- 1 5-oic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-y)-3, 1 -dioxo-1 -phenyl-9-{[(2-thienylmethyl)aminocarbonyl- 0.2 100 2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, 27 (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-9-{[(3-hydroxy-4-methoxybenzyl)amino 0.2 100 carbonyi}-3, 11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-9-{[(4-hydroxyphenethyl)amino]carbony-3, 11- 6 100 dioxo-2-oxa-4, 10,1 2-tdazapentadecan-1 5-oic acid LibC526796speci Compound IC 5 0

A

(9S, 13S)-9-{[(4-aminobenzyl)amino]carbony-1 3-(1 ,3-benzodioxol-5-yI)-3, 1-dioxo-2-oxa-4, 1 0.3 100 0,1 2-triazapentadecan-1 5-oic acid (9S, 13S)- 1 3-(1 ,3-benzodioxol-5-y)-3, 1-dioxo-9-[(phenyisulfonyl)methyl]-2-oxa-4, 10,1 2-triaz >100 apentadecan-1 5-oic acid (9S, 1 3S)-1 3-(1 ,3-benzodioxol-5-yI)-9-[({4-[bis(2-methylbenzyl)aminolbenzyl~amino)carbonyll- 1 3,11 -dioxo-2-oxa-4, 10,1 2-triazapentadecan-1 5-oic acid S)-1 -({[4-(acetylamino)phenyl]sulfanyl~methyl)-3-(methylsulfany) 3 100 propyl]amino~carbonyl)amino]-3-(1 ,3-benzodioxol-5-yI)propanoic acid ,3-benzodioxol-5-y)-3-[({[(1 S)-1 -{[(4-methoxyphenyl)sulfanyl]methy}-3- 7 100 (methylsulfanyl)propyllamino~carbonyl)aminolpropanoic acid 1 S)-1 -{[(4-aminophenyl)sulfanyl]methyl}-3-(methylsulfanyl)propyl] 3 100 amino)carbonyl)amino]-3-(1 ,3-benzodioxol-5-yI)propanoic acid 1,3-benzodioxol-5-y)-3-[({[(1 S)-l1-{[(4-chlorophenyl)sulfanyl]methyl}-3- 3 100 (methylsulfanyl)propyl]amino~carbonyl)amino]propanoic 1,3-benzodioxo-5-yi)-3-{[({(1 S)-2-(benzylsulfanyl)-1 -[(phenylsulfanyl) 0.02 100 methyl]ethyllamino)carbonyl]aminolpropanoic acid ,3-benzodioxol-5-yl)-3-[({[(1 S)-1 -[({4-[(benzylsulfonyl)amino]phenyl} 0.3 100 sulfanyl)methyl]-3-(methylsulfanyl)propyl]amino~carbonyl)amino]propanoic acid ,3-benzodioxol-5-y)-3-{[({( 1 S)-3-(methylsulfanyl)-1 -[({4-[(methylsulfonyl) 0.5 100 amino]phenyllsulfanyl)methyl]propyl~amino)carbonyl]aminolpropanoic acid ,3-benzodioxo-5-y)-3-[({[(1 S)-1 -{[(4-[(4-methylphenyl)sulfonyl]amino} 0.4 100 phenyl)sulfanyl]methyl}-3-(methylsulfanyl)propyljamino~carbonyl)amino]propanoic acid S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl]propyllamino)carbonyl] 25 96 aminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-3-(methylsulfanyl)-1 -[({4-[(2-toluidino 0.000 100 *carbonyl)amino]phenyl~sulfanyl)methyl]propyllamino)carbonyllaminolpropanoic acid 9 **(2S)-2-({[((l1S)-5-{[(benzyloxy)carbonyl]amino}-1-{[(2-thienylmethyi)amino] 45 89 carbonyl~pentyl)aminolcarbonyllamino)butanedioic acidI 1,3-benzodioxol-5-y)-3-{[({(1 S)-2-(ethylsulfanyl)-1 -[(phenylsulfany)methyl]ethyllamin 0.05 100 o)carbonyl]amino~propanoic acid 1,3-benzodioxol-5-yi)-3-{[({(1 S)-2-(methylsulfanyl)-1 -[(phenylsulfanyl) 0.1 100 methyllethyI amino carbonyI amino propanoic acid *N,N'-bis[(l1S)-1 ,3-benzodioxol-5-yI)-2-carboxyethyl]urea 7 99 (9S, 13S)-1 3-(1 ,3-benzodioxol-5-yI)-9-[({4-[(2-methylbenzyl)amino]benzyllamino) 0.000 100 carbonyI -3,1 1-dioxo-1 phen Il-2-oxa-4,1 0,1 2-tri aza pentad ecan- 15-oic acid 4 ,3-benzodioxol-5-y)-3-(((((1 R)-2-(benzylsulfonyl)-1 1 100 ((phenylsulfanyl)methyl)ethyl)amino)carbonyl)amino)propanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[(phenylsulfanyl)methyl]pentyl~amino) 0.4 100 carbonyllamino~propanoic acid ,3-benzodioxol-5-y)-3-[({[(1 S)-1 ,3-benzodioxol-5-yI)-3-(tert-butoxy)-3- 4 100 *~*oxopropyl]amino)carbonyl)aminolpropanoic acid S)-1 -{[(2-aminophenyl)sulfanyl]methy}-3-(methylsulfanyl)propyl] 0.3 100 amino~carbonyl)amino]-3-(1 ,3-benzodioxol-5-yl)propanoic acid ,3-benzodioxol-5-y)-3-[({[(1 S)-1 -{[(2-methylphenyl)sulfanyl]methy}-3- 0.3 100 (methylsulfanyl)propyl]amino)carbonyl)amino]propanoic acid ,3-benzodioxol-5-y)-3-[({[(1 S)-1 -{[(3-methylphenyl)sulfanyllmethyl}-3- 0.3 100 (methylsulfanyl)propyl]amino~carbonyl)amino]propanoic acid ,3-benzodioxol-5-yI)-3-[({[2-(phenylsulfanyl)ethyl]amino~carbonyl)amino] propanoic 6 100 acid ,3-benzodioxol-5-y)-3-{[({(1 S)-2-[(3-phenylpropyl)sulfanyl]l--[(phenyl 2 100 sulfanyi)methyl]ethyllamino)carbonyllaminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-2-(phenylsulfanyl)-1 -[(propylsulfanyl) 0.5 100 methyllethyllamino)carbonyl]aminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl) 3 100 methyl]propyl~amino)carbothioyi]amino~propanoic acid LibC526796speci

S

*5 Compound

IC

5 0

%A

(3S)-4-(methylsulfanyl)-3-{[({(1 S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyl] 8 99 propyllamino)carbonyl]aminolbutanoic acid S)-3-(methylsulfanyl)-1 -[(phenylsulfanyl)methyi]propyl~amino) 4 100 carbonyI amino 4-(phenyIsulfanyI butanoic acid, 8 ,3-benzodioxol-5-y)-3-[({[( 1 S)-1 -methyl-2-(phenylsulfanyl)ethyl]amino} 3 100 carbonyi)amino]propanoic acid ,3-benzodioxo-5-y)-3-[({(1 S)-2-(octylsulfanyl)-1 -[(phenylsulfanyl)methyl]ethyl~amin 5 98 o)carbonyl]aminolpropanoic acid ,3-benzodioxol-5-y)-3-[({( 1 S)-3-(methylsulfanyl)-1 -[({3-[(2-toluidino 0.002 100 carbonyI amino phenyI sulfanyl methylI ropyI amino carbonyI amino propanoic acid ,3-benzodioxol-5-y)-3-[({[(1 S)-3-(methylsulfanyl)-1 -(phenoxymethyl) 20 100 propyllamino~carbonyl)amino]propanoic acid 1,3-benzodioxol-5-y)-3-{[(methyl{( 1 S)-3-(methylsufanyl)-1 -[(phenyl 35 78 sulfanyl)methyl]propyllamino)carbonyl]amino~propanoic acid ,3-benzodioxo-5-y)-3-{[({1 -[(phenylsulfanyl)methyl]pentyl)oxy)carbonyl 6 100 aminolpropanoic acid ,3-benzodioxol-5-yl)-3-{[({2-(phenylsulfanyl)-l1-[(phenylsuifanyl)methyl] 1.5 99 ethyllamino)carbonyljamino~propanoic acid ,3-benzodioxol-5-y)-3-{[({( 1 S)-2-[(carboxymethyl)sulfanyl]-1 -[(phenyl 2 100 sulfanyl)methyl]ethyl~amino)carbonyl]aminolpropanoic acid S)-1 -{[(3-aminophenyl)thiolmethy}-3-(methylthio)propyllamino 0.3 100 carbonyl)amino]-3-(1 ,3-benzodioxol-5-yl)propanoic acid ,3-benzodioxol-5-y)-3-[({[( 1S)-1 -[({4-[(2-methylbenzyl)amino]phenythio)methyl]-3-( 2 93 methylthio)propyl]amino~carbonyl)amino]propanoic acid ,3-benzodioxol-5-y)-3-[({[(l1S)-1 -[({3-[(methylsulfonyl)amino]phenyl~thio)methyl]-3-(m 0.4 100 ethylthio)propyl]amino~carbonyl)amino]propanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-3-(methylthio)-1 -[({3-[(propyl 0.5 100 sulfonyl )aminolphenyllthio)methyljpropyllamino)carbonyl]aminolpropanoic acid S)-2-(allyloxy)-1 -[(phenylthio)methyl]ethyllamino)carbonyl]amino-3- 0.3 100 (1 ,3-benzodioxol-5-yl)propanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-2-(benzyloxy)-1 -[(phenylthio)methyl]ethyllamino)carb 0.3 100 onyl]aminolpropanoic acid ,3-benzodioxol-5-y)-3-[({[( 1 R)-1 -pheny!-2-(propylthio)ethyl]amino} 25 100 carbonyl)amino]propanoic acid ,3-benzodioxol-5-y)-3-[({[( 1 R)-1 -benzyl-2-(propylthio)ethy]amino} 2 100 carbonyl)amino]propan6ic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-3-(phenylthio)-1 -[(phenylthio)methyl] 0.3 100 propyllamino)carbonyllaminolpropanoic acid 1,3-benzodioxol-5-y)-3-{[({(1 S)-4-hydroxy-1 -[(phenylthio)methyl]butyl} 2 100 amino)carbonyllaminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-2-ethoxy-1 -[(phenylthio)methyl]ethyl)oxy) 5 100 carbonyl]aminolpropanoic acid ,3-benzodioxol-5-yl)-3-[({( 1 S)-2-(phenethyloxy)-1 -[(phenylthio)methy] 4 100 ethyl)oxy)carbonyl]amino~propanoic acid 1,3-benzodioxol-5-y)-3-{[({( 1 S)-2-[(cyclopropylmethyl)thio]-1 -[(phenylthio)methyljethy 0.2 100 }amino)carbonyllaminolpropanoic acid ,3-benzodioxol-5-y)-3-[({(1 R)-2-(benzyloxy)-1 -[(benzylthio)methyl]ethyl~amino)carb 1 100 onyllaminolpropanoic acid ,3-benzodioxol-5-yI)-3-[({( 1 R)-2-(benzyoxy)-1 -[(benzylthio)methyl]ethyl~oxy)carbon 10 100 yI]aminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({( 1 R)-2-(benzyloxy)-1 -[(ethylthio)methyllethyl} 12 100 oxy)carbonyl]aminolpropanoic acid 1,3-benzodioxol-5-yl)3-{[({( 1 S)-2-(ethylthio)-1 -[(phenylthio)methyllethyl} 1 100 oxy)carbonyl]aminolpropanoic acid LibC526796speci Compound IC 50

%A

,3-benzodioxol-5-y)-3-{[({( 1 S)-2-(benzylthio)-1 -[(phenylthio)methyl]ethyl~oxy)carbon 3 100 yI]amino~propanoic acid 1,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[({4-[(2-toluidinocarbonyl)amino]phenyl~thio)methyl] 0.3 100 pentyl~oxy)carbonyllaminolpropanoic acid ,3-benzodioxol-5-y)-3-[({(1 S)-1 -[({3-[(2-methylbenzyl)amino]phenyllthio)methyl]pent 25 100 yI~oxy)carbonyI]amino~propanoic acid, 151 1,3-benzodioxol-5-yl)-3-{[({(1 S)-2-{[(4-methylphenyl)sulfonyljamino- 10 98 [(phenylthio)methyllethyl~amino)carbonyl]aminolpropanoic acid ,3-benzodioxol-5-y)-3-{[({(1 S)-1 -[(2-thienylmethoxy)methyllpentyllamino)carbonyl]a 1.5 100 _mino~propanoic acid, 22 Table 2 Comnpound Number 1050 (nM) 34 250 350 36 1000 37 38 39 120 41 100 42 43 120 All references cited are hereby incorporated by reference.

The present invention is illustrated by way of the foregoing description and examples. The foregoing description is intended as a non-limiting illustration, since many variations will become 5 apparent to those skilled in the art in view thereof. It is intended that all such variations within the scope and spirit of the appended claims be embraced thereby.

Changes can be made in the composition, operation and arrangement of the method of the present invention described herein without departing from the concept and scope of the invention as defined in the following claims: 000..

'00, 0 *0 0 00 0 0 0 0* 0 0 0 LibC526796speci

Claims (13)

1. A compound of the structure x\ R R J M R G R A E T L R 4 wherein A is selected from the group consisting of and -NR 5 E is selected from the group consisting of -CH 2 and -NR 6 Q is selected from the group consisting of and -(CH2)k- wherein k is an integer of 0 or 1; J is selected from the group consisting of and -NR 8 G is selected from the group consisting of and -(CH 2 ,wherein p is an integer of 0 or 1; T is selected from the group consisting of and -(CH2)b- wherein b is an integer of from 0 to 3; L is selected from the group consisting of -NR 7 and -(CH2)n- wherein n is an integer of 0 or 1; M is selected from the group consisting of -C(R 9 and wherein u is an integer of from 0 to 3; X is selected from the group consisting of -C02B, -P0 3 H 2 -SO 3 H, -OP0 3 H 2 -C(0)NHC(0)R 11 C(0)NHSO 2 R 1 2 oxazolyl, tetrazolyl and hydrogen; B, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 11 and R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -CF 3 nitro, amino, cyano, N(C1-C 3 alkyl)-C(0)(C1-C 3 alkyl), -C1-C3 alkylamino, alkenylamino, alkynylamino, di(C1-C 3 alkyl)amino,- C(0)0-(C1-C3 alkyl), -C(0)NH-(CI-C 3 alkyl), -CH=NOH, -P03H 2 -OP0 3 H 2 -C(0)N(C1-C 3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamate, aryloxyalkyl, 20 carboxyl and -C(0)NH(benzyl); wherein B, X, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 R 10 R 1 1 and R 12 are unsubstituted or substituted with at least one electron donating or electron withdrawing group; and wherein R 2 and R 3 taken together may form a first ring; R 4 and R 7 taken together may form a second ring; R 9 and R 1 0 taken together may form a third ring; and pharmaceutically acceptable salts thereof.

2. A compound of claim 1 further comprising derivatives of said compound selected from the group consisting of esters, carbamates, animals, amides and pro-drugs thereof.

3. A compound of claim 1 wherein R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, aryl, alkylaryl, arylalkyl, heterocyclyl, alkylheterocyclyl, oheterocyclylalkyl and alkyl; R 4 is selected from the group consisting of aryl, alkylaryl, arylalkyl, S 30 heterocyclyl, alkylheterocyclyl and heterocyclylalkyl; X is -C02B; and M is -C(R 9 wherein R 9 and R 1 0 are independently selected from the group consisting of hydrogen and lower alkyl.

4. A compound of claim 1 of the structure R 9 X R R 2 R3 0 Rio H N R1 N N R4 0 R R wherein X is selected from the group consisting of -CO2B, -P0 3 H 2 -S0 3 H, -OP0 3 H 2 C(O)NHC(0)R 11 -C(0)NHSO 2 R 1 2 oxazolyl, tetrazolyl and hydrogen; and B, R 1 R 2 R 3 R 4 R 5 R 6 R 9 LibC526796speci RIO, R 1 1 and R 12 are independently selected from the group consisting of hydrogen, halogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkenoxy, alkynoxy, thioalkoxy, aliphatic acyl, -OF 3 nitro, amino, cyano, -N(CI-0 3 alkyl)-C(O)(Cl-C3 alkyl), -01-03 alkylamino, alkenylamino, alkynylamino, di(Cl-03 alkyl)amino,-C(O)O-(Cl-C3 alkyl), -C(O)N H-(Ci-C 3 alkyl), -CH=NOH, -P0 3 H 2 -0P0 3 H 2 -C(O)N(Cl-0 3 alkyl)2, haloalkyl, alkoxylcarbonyl, alkoxyalkoxy, carboxaldehyde, carboxamide, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, aroyl, aryloxy, arylamino, biaryl, thioaryl, heterocyclyl, heterocycloyl, alkylaryl, aralkenyl, aralkyl, alkylheterocyclyl, heterocyclylalkyl, sulfonyl, sulfonamido, carbamnate, aryloxyalkyl, carboxyl and -C(O)NH(benzyl) wherein B, X, R 1 R 2 R 3 R 4 R 5 R 6 R 9 RIO, R' 1 R 12 and R 1 3 are unsubstituted or substituted with at least one electron donating or electron withdrawing group.

5. A compound of claim 4 further comprising derivatives of said compound selected from the group consisting of esters, carbamnates, animals, amides and pro-drugs thereof.

6. A compound of claim 4 wherein R 1 R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, aryl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl, alkylheterocyclyl and alkyl; R 4 is selected from the group consisting of aryl, alkylaryl, arylalkyl, heterocyclyl, heterocyclylalkyl and alkyheterocyclyl; R 5 and R 6 are hydrogen; and R 9 and RIO are independently selected from the group consisting of hydrogen and lower alkyl.

7. A compound of claim 1 selected from the group consisting of: ,3-benzodioxol-5-yl)-3-([((1 S)-1 -[(2-thienylmethyl)amino]carbonylpentyl)amino]carbony *:*:amino) propanoic acid, (3 ,3-benzod ioxol-5-yl)-3-([((1 1 -[(2-acetyl phen yl) am ino]carbon yl pentyl)amino]carbonylamino) propanoic acid, 1,3-benzodioxol-5-yl)-3-([((1 S)-1 acetylphenyl) amino] carbonyl pen tyl)ami no]carbonylam ino) propan oic acid, ,3-benzodioxol- S)-1 -[(4-(2-thienylmethyl)aminobenzyl)amino]carbonylpentyl)amino]carbonylamino) :propanoic acid, ,3-benzodioxol-5-yl)-3-([((1 S)-i -[(4-(2-methylbenzyloxy)-3- methoxybenzyl)amino]carbonylpentyl)amino]carbonylamino)propanoic acid, 3(3S)-3-(1 ,3-benzodioxo1- S)-1 -[(4-(2-methylbenzyl)amino)benzyl)aminolcarbonylpentyl)amino]carbonylamino) propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 8)-i ,3-thiazol-2-ylmethyl)aminobenzyl) amino]carbonylpentyl)amino]carbonylamino) propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)- -[(4-(5-methyl-2-thienylmethyl) aminobenzyl)aminolcarbonylpentyl)amino]carbonylamino) propanoic acid, 3(3S)-3-(1 ,3-benzodioxol-5-yl)-3-([((1 S)-1 ien ylsulIfonamid o) ben zyl) am ino]carbonyl pentyl)amino]carbonylamino)propanoic acid, 1,3-benzodioxol-5-yl)-3-([(( 1 S)-1 methylpyridyl)methyl)benzyl)amino] carbonylpentyl) aminolcarbonyl amino)propanoic acid, (3S)-3- (1 ,3-benzodioxol-5-yl)-3-(((((1 S)-3-(methylsulfanyl)-i -((phenylsulfanyl)methyl)propyl)amino)carbonyl) **amino) propanoic acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-(((((1 S)-2-((cyclopropylmethyl) thio)-1- ((phenylthio)methyl)ethyl)amino)carbonyl)amino)propanoic ai, (9S, 13S)-1 3-(i 3,11 -dioxo-1 -phenyl-9-{[(2-thienylmethyl)amino]carbonyl}-2-oxa-4, 10,1 2-triazapentadecan- 1 5-oic acid, (9S, 1 3S)-1 1, 3-benzodioxol-5-yl)-9-{[(3-hydroxy-4-methoxybenzyl)amino]carbonyl}-3, 1 -dioxo-2- oxa-4, 10,1 2-triazapentadecan-1 5-oic acid, ,3-benzodioxol-5-yl)-3-{[((1 S)-2-(benzylsulfanyl)- 1 -[(phenylsulfanyl)methyl]ethyl~amino)carbonyl]aminolpropanoic acid, ,3-benzodioxol-5-yl)-3- S)-3-(meth yls ufanyl)- 1 id inocarbonyl) ami no]phenyl~sulIfanyl) methyl] pro pyl~am ino) carbonyl]amino} propanoic acid, ,3-benzod ioxol-5-yl)-3-[({(i S)-2-(ethyls ufan yl)- 1 hen yl sulfanyl)methyllethyllamino) carbonyl]aminolpropanoic acid, (9S, 13S)-1 3-(1 ,3-benzodioxol-5-yl)-9- [({4-[(2-methyl benzyl) amino] benzyl~amino)carbonyl]-3, 1 Adioxo- 1 -phenyl-2-oxa-4, 10,1 2-triaza LibC526796speci acid, (3S)-3-(1,3-benzodioxol-5-yl)-3-{[({(1 S)-3-(methylsulfanyl)-1 toluidinocarbonyl)amino]phenyl}sulfanyl)methyl] propyl}amino)carbonyl]amino}propanoic acid, (3S)-3- (1,3-benzodioxol-5-yl)-3-{[({(1S)-2-(ethylthio)-1-[(phenylthio)methyl]ethyl}oxy)carbonyl]amino} propanoic acid, (9S, 13S)-13-(1,3-benxodioxol-5-yl)-3,11-dioxo-1 -phenyl-9-(((4-((2-toluidinocarbonyl) amino)benzyl)amino)carbonyl)-2-oxa-4, 10,12-triazapentadecan-15-oic acid, and pharmaceutically acceptable salts thereof.

8. A compound that inhibits of the binding of a41 integrin to its receptors, said compound being substantially as hereinbefore described with reference to any one of the examples.

9. A process for the preparation of a compound that inhibits of the binding of a4p1 integrin to its receptors, said process being substantially as hereinbefore described with reference to any one of the examples.

A pharmaceutical composition comprising: a compound of any one of claims 1 to 8 in a pharmaceutically acceptable carrier.

11. A method for selectively inhibiting a41 integrin binding in a mammal comprising administering to said mammal a therapeutic amount of a compound of any one of claims 1 to 8 or of a composition of claim

12. A compound according to any one of claims 1 to 8 or a composition according to claim when used in selectively inhibiting a41 integrin binding.

13. The use of a compound according to any one of claims to 8 for the manufacture of a medicament for selectively inhibiting a041 integrin binding. Dated 17 October 2000 TEXAS BIOTECHNOLOGY CORPORATION Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON so S. oo O LibC526796speci