[go: up one dir, main page]

WO2000002903A1 - Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation - Google Patents

Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation Download PDF

Info

Publication number
WO2000002903A1
WO2000002903A1 PCT/US1998/026605 US9826605W WO0002903A1 WO 2000002903 A1 WO2000002903 A1 WO 2000002903A1 US 9826605 W US9826605 W US 9826605W WO 0002903 A1 WO0002903 A1 WO 0002903A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
lower alkyl
ring structure
group
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1998/026605
Other languages
English (en)
Inventor
Thomas S. Arrhenius
Mariano J. Elices
Federico C. A. Gaeta
Ya-Bo He
Bernard G. Huyghe
Paul G. Chen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cytel Corp
Original Assignee
Cytel Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cytel Corp filed Critical Cytel Corp
Priority to AU19153/99A priority Critical patent/AU1915399A/en
Publication of WO2000002903A1 publication Critical patent/WO2000002903A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06104—Dipeptides with the first amino acid being acidic
    • C07K5/06113—Asp- or Asn-amino acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/081—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0819—Tripeptides with the first amino acid being acidic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/1013—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing O or S as heteroatoms, e.g. Cys, Ser
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic

Definitions

  • the present invention relates to binding of inflammatory cells to endothelial cells that express the CS-1 portion of fibronectin on their surfaces, and more particularly to the inhibition of that binding by peptidomimetic compounds of minimal length.
  • the immune response relies on leukocyte trafficking and immune surveillance as one of the underpinnings of host defense. Not only does this immune surveillance allow leukocytes to recirculate through lymphoid tissues normally, but also permits rapid leukocyte recruitment and extravasation to adjacent tissues at sites of inflammation.
  • the 4 ⁇ l (CD49d/CD29, VLA-4) cell adhesion receptor is an active participant in these leukocyte trafficking functions [Hemler, Ann . Rev . Immunol . , 8.:365-400 (1990); Hemler et al . , Immunol . Rev . , 114:45-65 (1990) ] .
  • VLA-4 integrin heterodimer was discovered independently by three research groups and identified as a surface antigen on lymphocytes [Sanchez-Madrid et al . , Eur. J. Immunol., 16: 1343-1349 (1986); Clayberger et al . , J. Immunol. ,
  • VLA-4 is unique on several counts: (I) in contrast to related members of the ⁇ l subfamily, VLA-4 is predominantly expressed on cells of the hematopoietic lineage [Hemler, Ann. Rev. Immunol.. 8.:365-400 (1990)], and is functionally involved in cell-cell, as well as cell-extracellular matrix (ECM) adhesive interactions [Hemler, Ann. Rev.
  • VLA-4 integrin appears to be one of the earliest adhesion receptors found on CD34 -expressing hematopoietic stem cells [Teixido et al . , J. Clin. Invest.. 90:358-367 (1992)] .
  • VLA-4 is expressed only on mature T and B lymphocytes, natural killer (NK) cells, monocytes, basophils and eosinophils, but not on erythrocytes, platelets and neutrophils [Hemler, Ann. Rev. Immunol., 8.: 365-400 (1990) Gismondi et al . , J. Immunol . , 146 : 384-392 (1991) Walsh et al .
  • VLA-4 vascular cell adhesion molecule-1
  • VCAM-1 cytokine-inducible vascular cell adhesion molecule-1
  • VCAM-1 is a member of the immunoglobulin (Ig) gene superfamily [Osborn et al . , Cell , 59: 1203-1211 (1989); Rice et al . , Science. 246:1303-1306 (1989)] that is expressed predominantly in vascular endothelium in response to pro-inflammatory cytokines such as IL-1, TNF ⁇ , and IL-4 [Osborn et al . , Cell, 59:1203-1211 (1989); Rice et al . , Science. 246: 1303-1306 (1989); Thornhill et al . , J. Immunol.,
  • VLA-4 binding sites on VCAM-1 have been mapped to the outermost N-terminal (first) Ig-like region of the 6-Ig-like domain VCAM-1 isoform [Taichman et al . , Cell Regul . , 2:347-355 (1991); Vonderheide et al . , . Exp . Med . , 175 : 1433-1442 (1992); Osborn et al . , J . Exp . Med .. 176:99-107 (1992)], and the first and fourth N-terminal Ig-like regions of the 7-Ig-like domain VCAM-1 isoform [Vonderheide et al . , J . Exp . Med .
  • VLA-4 binding amino acid motif Gln-Ile-Asp-Ser-Pro-Leu appears to be on an exposed loop, in the three dimensional structure of VCAM-1 [(Jones et al . , Nature , .373:539-544 (1995)] .
  • That sequence comprises a 25-amino acid residue stretch, termed CS-1 [Humphries et al., J. Cell Biol.. 103:2637-2647 (1986); Humphries et al . , J. Biol. Chem. , 2£2: 6886-6892 (1987) ] .
  • the FN gene contains three separate exons termed EIIIA, EIIIB and V or IIICS, which are subject to alternative splicing [Hynes, "Fibronectin", Springer-Verlag, New York (1990)] .
  • EIIIA EIIIA
  • EIIIB V or IIICS
  • additional acceptor and donor splice signals within the IIICS region permits generation of increased diversity in FN by virtue of multiple IIICS polypeptide variants, for instance, five in human FN [Vibe-Pedersen et al . , FEBS Lett.. 207:287-291 (1987); Hershberger et al . , Mol. Cell. Biol. , 10:
  • LDV Leu-Asp-Val
  • Cystine-linked cyclic peptides that mimic the RGD adhesion signal have also been described as inhibitors of VLA-4 mediated interactions [Nowlin et al . , J. Biol . Chem. , 2j68:20352-20359 (1993); Cardarelli et al . , J. Biol. Chem.. U269U:18668-18673 (1994)].
  • VLA-4 shares with other members of the ⁇ l integrin subfamily the ability to promote binding and penetration of microbial pathogens into mammalian cells.
  • ⁇ l integrins with the bacterial protein invasin [Isberg et al . , Cell. £0:861-871 (1990); Ennis et al . , J . Exp . Med .. 177.:207-212 (1993)], as well as the protozoan Trypanosoma cruzi [Fernandez et al . , Eur . J . Immunol . , 23:552-557 (1993)] have been described.
  • VLA-4 binding to VCAM-1 has been demonstrated in adhesion to cytokine-stimulated vascular endothelium by lymphocytes [Elices et al . , Cell, £0:577-584 (1990); Rice et al . , J . Ex . Med .. 171:1369-1374 (1990); Schwartz et al . , J. Clin. Invest.. 85:2019-2022 (1990); Carlos et al . , Blood, 7£:965-970 (1990);
  • VLA-4/VCAM-1 interactions are considered key in inflammation.
  • VLA-4/CS-1 interaction has been widely documented in hematopoiesis where adhesive interactions between hematopoietic progenitors expressing VLA-4 [Hemler et al . , Immunol . Rev. , 114:45-65 (1990); Williams et al . , Nature , 352:438-441 (1991); Roldan et al . , J . Exp . Med. , 175:1739-1747 (1992); Sawada et al . , J . Immunol . ,
  • CS-1 peptides have been shown to inhibit (I) attachment of murine hematopoietic stem cells to ECM derived from bone marrow stroma [Williams et al . , Nature , 352:438-441 (1991)], (ii) immunoglobulin secretion by bone marrow-derived B cell progenitors [Roldan et al . , J . Exp . Med .
  • VLA-4/CS-1 may also be involved in embryonic development, because CS-1 peptides have been shown to interfere with migration of avian neural crest cells [Dufour et al., EMBQ J.. 7:2661-2671 (1988)].
  • FN and CS-1 have also been implicated in the pathology of rheumatoid arthritis (RA) [Laffon et al . , J. Clin. Invest . , 81:546-552 (1992)].
  • RA rheumatoid arthritis
  • VLA-4 -expressing leukocytes [Kuijpers et al . , J . Exp .
  • VLA-4 plays a role in leukocyte trafficking and inflammation has been largely confirmed by in vivo studies using anti-VLA-4 antibodies in various animal models. Essentially, the skin, brain, kidney, lung and gut are targets of a wide variety of VLA-4 - dependent inflammatory reactions mostly resulting from recruitment of mononuclear leukocytes and eosinophils .
  • VLA-4 contributes to inflammatory responses that emulate chronic conditions in humans.
  • the CS-1 peptide partially inhibited recruitment of T lymphocytes to skin inflammatory sites [Ferguson et al . , Proc . Natl . Acad. Sci. USA, £8:8072-8076 (1991)].
  • VLA-4 and the CS-1 peptide in various chronic and acute immunoinflammatory disease states having been established, it would be of importance if compounds could be found that inhibit the VLA-4 -lymphocyte interaction and were other than anti-VLA-4 antibodies that can themselves induce an immune response on repeated administration or the CS-1 peptide that is large and costly to make, and also is subject to rapid degradation.
  • Novel CS-1 peptidomimetic inhibitor compounds of Formula IA and Formula IIA their compositions and methods of use for treating inflammation, asthma and cardiovascular disease Formula IA,
  • R x is a R x ring structure, lower alkyl, or lower amino alkyl; the R ring structure can form at R l7 between R and R 2 or between R and R 4 with the proviso that, if the R ring structure forms at R 1# the R ⁇ ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups; the spacer can be optionally substituted by an amino group; the R 1 ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6, 5-membered ring wherein, the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups; the R ⁇ ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms, and, if the R
  • R 2 is a H, lower alkyl, phenyl lower alkyl, or R 2 and R ⁇ form the R ⁇ ring structure group
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl, or di (lower alkyl) thioether
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched;
  • R 4 is a H or R 4 and R ⁇ form the R x ring structure
  • R 5 is H or R 5 and R 6 form a R 5 ring structure; the R 5 ring structure is a fused 6,6- ring structure and can be aromatic, partially saturated, or saturated;
  • R 6 is a benzyl, a 5, 6, or 7-membered heterocyclic saturated ring containing 1 or 2 nitrogen atoms optionally substituted by one or more lower alkyl, lower alkyl amide or acyl groups or 1,1 diphenylmethine group, the R 5 ring structure, a group of the formula
  • A is nitrogen or oxygen; when A is nitrogen,
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group; the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long; if the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6, 5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein, the heteroatom is a nitrogen atom; if the R 7 ring forms between R 7 and R 8 , the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein, the heteroatoms are 1 or 2 nitrogen atoms; the R 7 ring structure can optionally be substituted by an alcohol, nitro, or lower alkyl ether
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group; the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is an R 8 ring structure; the R 8 ring structure is a 5-, 6- 7- or fused 6, 5-membered heterocyclic ring wherein, the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms; the R 8 ring structure optionally can be substituted by one or more lower alkyl, lower dialkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, carboxamide, lower alkyl carboxylic acid, carbonyl, sulfox
  • Re is the R 8 ring structure, a lower alkyl, lower dialkyl, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group; and when A is oxygen:
  • R 8 is a lower alkyl that can be branched and R 9 is absent; or a pharmaceutically acceptable salt thereof.
  • R x is a R : ring structure, lower alkyl, or lower amino alkyl; the R ⁇ ring structure can form at R l t between R ⁇ and R 2 or between R x and R 4 with the proviso that, if the R ring structure forms at R x , the R x ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups; the spacer can be optionally substituted by an amino group; the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,
  • the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms, and, if the R ⁇ ring structure is formed between R ⁇ and R 4 , the heteroatoms are 2 nitrogen atoms
  • the R ⁇ ring structure can be conjugated, partially saturated, or saturated
  • the lower alkyl or lower amino alkyl group can be branched;
  • R 2 is a H, lower alkyl, phenyl lower alkyl, or R 2 and R form the R x ring structure group;
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl, or di (lower alkyl) thioether;
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long; the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched;
  • R 4 is a H or R 4 and R x form the R ⁇ ring structure
  • R 5 is H or R 5 and R 6 form a R 5 ring structure; the R 5 ring structure is a fused 6,6- ring structure and can be aromatic, partially saturated, or saturated;
  • R 6 is a benzyl, a 5 , 6 , or 7-membered heterocyclic saturated ring containing 1 or 2 nitrogen atoms optionally substituted by one or more lower alkyl, lower alkyl amide or acyl groups or 1,1 diphenylmethine group, the R 5 ring structure, a group of the formula
  • A is nitrogen or oxygen; when A is nitrogen;
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group; the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long; if the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6, 5 -membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein, the heteroatom is a nitrogen atom; if the R 7 ring forms between R 7 and R 8 , the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein, the heteroatoms are 1 or 2 nitrogen atoms; the R 7 ring structure can optionally be substituted by an alcohol, nitro, or lower alkyl
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group; the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is an R 8 ring structure; the R 8 ring structure is a 5-, 6- 7- or fused 6,5-membered heterocyclic ring wherein, the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms; the R 8 ring structure optionally can be substituted by one or more lower alkyl, lower dialkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carboxamide, carbonyl, sul
  • (N-morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups ;
  • R 9 is the R 8 ring structure, a lower alkyl, lower dialkyl, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group; when A is oxygen:
  • R 8 is a lower alkyl that can be branched and R 9 is absent;
  • J is oxygen or sulfur
  • R 17 is alkyl, alkyl optionally substituted by a hydroxyl, phenyl or phenyl sulfonyl, di (lower alkyl) sulfide, (lower alkoxy) lower alkyl, [(lower alkoxy) lower alkoxy] lower alkyl, (lower alkylcarbonyloxy) lower alkyl, [N- (lower alkyl) aminocarbonyl] lower alkyl, ⁇ [ (N- (lower alkyl) ] (N- (lower alkoxy) ⁇ amino-carbonyl) lower alkyl, (N,N-di (lower alkyl) aminocarbonyl) lower alkyl , (N' -morpholinocarbonyl) lower alkyl, (benzyloxycarbonyl) methyl ,
  • a contemplated method corresponds to a method of treating inflammation, asthma and cardiovascular disease by administering an above-described compound.
  • Fig. 1 is a graph illustrating the in vitro binding inhibition of VLA-4 -bearing Jurkat cells to the solid phase-bound CS-1 compound (SEQ ID NO:l) by that compound itself and shorter compounds having portions of the CS-1 compound sequence. Data are shown as percentages relative to the indicated “Standard” (SEQ ID NO: 3) . Data for compounds with deletions at the "N-terminus" of compound B12 (SEQ ID NO: 2) are shown to the left of the Standard, and data for compounds with deletions at the
  • C-terminus of compound B12 are shown to the right of the standard. Compound sequences are in single letter code.
  • Fig. 2 is a graph with data obtained and expressed similarly to those of Fig. 1. Here, binding inhibition by further, still shorter deletion compounds, is illustrated.
  • Fig. 3 is another graph of binding data obtained as discussed in Fig. 1. This graph utilizes an ordinate that is on a log scale. These data are arranged into five groups and are again shown relative to the indicated Standard compound (SEQ ID NO:3) , with D-proline being shown as "p" .
  • Fig. 4 shown in two panels as Fig. 4A and Fig. 4B illustrates the effects of a contemplated compound in treating asthma in the rabbit.
  • Fig. 4A shows the percent change in dynamic compliance (C dyn ) over a six-hour time period immediately following the onset of induced asthma attacks.
  • Fig. 4B shows results obtained for the percent change in lung resistance (L R ) from the same study, with data being presented as in Fig. 4A.
  • the ordinate is in units of percent change from the original lung resistance value, whereas the abscissa is in hours.
  • Fig. 5 is a graph showing the results of a study of the effect of the inhibitor compound N-phenyl acetyl-Leu-Asp-Phe-D-Pro-NH 2 on delayed type hypersensitivity measured in ears of 14 mice.
  • one group of seven mice was treated with only a saline solution provided by an implanted pump over a 24 -hour time period and challenged.
  • the other immunized group of seven mice was similarly challenged, but each was treated with an aqueous pharmaceutical composition containing the above inhibitor compound for the same 24 -hour time period, also supplied by implanted pumps.
  • the ordinate is in units of inches of swelling diameter at the challenge site .
  • FIG. 6 is a graph showing averaged clinical scores for six mice each in two evaluations of treatments of experimental autoimmune encephalomyelitis (EAE) . Darkened circles are for treatments using the inhibitor compound N-phenyl acetyl-Leu-Asp-Phe-D-Pro-NH 2 , whereas points shown as darkened squares are for treatments using the control sequence compound of Example 6. The ordinant shows the averaged score for the six mice in each study, whereas the abscissa is in days after initiation of EAE.
  • EAE experimental autoimmune encephalomyelitis
  • Fig. 7 is a graph showing the percentage of change in lung resistance, SR L , from base line for the asthmatic sheep model depicted as described in Fig. 4B.
  • the nebulized composition here contained N- phenyl acetyl-Leu-Asp-Phe-D-Pro-NH 2 in open circles and the control sequence of that compound (Example 6) in darkened circles, including error bars where appropriate.
  • the present invention contemplates a compound, a prodrug compound, a composition containing such a compound, and a method of using such a compound.
  • a contemplated compound inhibits binding between the CS-1 of fibronectin and the inflammatory cell VLA-4 surface receptor, and is therefore sometimes referred to herein as an inhibitor compound.
  • the present invention contemplates a compound and compositions that inhibits CS-1 binding to the VLA-4 receptor, e.g., a compound of Formula-IA.
  • R x is a R : ring structure, lower alkyl, or lower amino alkyl; the R ⁇ ring structure can form at R l between R x and R 2 or between R x and R 4 with the proviso that, if the R 2 ring structure forms at R 1; the R- L ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl , N-amido, N-sulfonimido, N-urea, N-carboxyl groups; the spacer can be optionally substituted by an amino group; the R ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein, the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups; the R ⁇ ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms,
  • R 2 is a H, lower alkyl, phenyl lower alkyl, or R 2 and R form the R ring structure group.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl, or di (lower alkyl) thioether; the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long; the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 4 is a H or R 4 and R x form the R 1 ring structure .
  • R 5 is H or R 5 and R 6 form a R 5 ring structure; the R 5 ring structure is a fused 6,6- ring structure and can be aromatic, partially saturated, or saturated.
  • R 6 is a benzyl, a 5 , 6 , or 7 -membered heterocyclic saturated ring containing 1 or 2 nitrogen atoms optionally substituted by one or more lower alkyl, lower alkyl amide or acyl groups or 1,1 diphenylmethine group, the R 5 ring structure, a group of the formula
  • A is nitrogen or oxygen
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group; the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long; if the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein, the heteroatom is a nitrogen atom; if the R 7 ring forms between R 7 and R 8 , the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein, the heteroatoms are 1 or 2 nitrogen atoms; the R 7 ring structure can optionally be substituted by an alcohol, nitro, or lower alkyl
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group; the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R g and is an R 8 ring structure; the R 8 ring structure is a 5-, 6- 7- or fused 6,5-membered heterocyclic ring wherein, the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms; the R 8 ring structure optionally can be substituted by one or more lower alkyl, lower dialkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, carboxamide, lower alkyl carboxylic acid, carbonyl, s
  • R 9 is the R 8 ring structure, a lower alkyl, lower dialkyl, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group;
  • R 8 is a lower alkyl that can be branched
  • R 9 is absent .
  • Preferred compounds of Formula IA are where R 2 is lower alkyl, or phenyl lower alkyl.
  • D is carbon optionally substituted by one or more lower alkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, or alkyl substituted phenyl sulfonamido groups, or
  • D is a nitrogen atom optionally substituted by a lower alkyl, amino carbonyl lower alkyl wherein the nitrogen atom of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, lower alkyl alcohol, lower hydroxy alkyl ether, or lower alkyl carboxylic acid groups, or
  • D is an oxygen atom
  • D is a sulfur atom optionally forming a sulfoxide or sulfone.
  • compounds of Formula IA are where R 6 is
  • R 13 is a lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, carboxamide, or H group.
  • the R e ring structure is: not a 5-membered heterocyclic ring; more preferably, not a 5-membered heterocyclic ring where the heteroatoms are 1 or 2 nitrogen atoms; more preferably, not a 5-membered heterocyclic ring where the heteroatoms is 1 nitrogen atom; more preferably, not a 5-membered heterocyclic nitrogen ring that is substituted as decribed above; and, more preferably, not a 5-membered heterocyclic nitrogen ring that is substituted with a caroxamide.
  • R keto is as described above, provided that R 6 is not the formula:
  • R :3 is as described above.
  • R 13 is as described above, provided that R 13 is not carboxamide or lower alkyl carboxamide and, more preferably, provided that R :3 is not carboxamide.
  • D is carbon optionally substituted by one or more lower alkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, or alkyl substituted phenyl sulfonamido groups, or
  • D is a nitrogen atom optionally substituted by a lower alkyl, amino carbonyl lower alkyl wherein the nitrogen atom of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, lower alkyl alcohol, lower hydroxy alkyl ether, or lower alkyl carboxylic acid groups, or
  • D is an oxygen atom
  • D is a sulfur atom optionally forming a sulfoxide or sulfone, or R ⁇ is
  • R 13 is a lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, carboxamide, or H group.
  • R 2 is lower alkyl and, more preferably, methyl, excluding compound numbers 1190.07 and 926.11 listed in Table 1 below.
  • R is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the ring structure formed between R 8 and R 9 selected from the group consisting of 4-morpholinyl, 4-methylpiperazinyl, and N-piperazinyl .
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-morpholinyl ring structure formed between R 8 and R 9.
  • R is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the N-piperazinyl ring structure formed between R 8 and R 9 _
  • a contemplated compound can be defined by the following structural formula:
  • R is a R x ring structure, lower alkyl, or lower amino alkyl.
  • the R ring structure can form at R 1# between R x and R 2 or between R x and R 4 with the proviso that, if the R x ring structure forms at Ri, the R x ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R 1 ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms, and, if the R; . ring structure is formed between R x and R 4 , the heteroatoms are 2 nitrogen atoms .
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 2 is a H or R 2 and R x form the R x ring structure group.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 4 is a H or R 4 and R x form the R ring structure.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long. If the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein the heteroatoms are 1 or 2 nitrogen atoms.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 8 is a ring structure, alkyl alcohol, or thioalkyl amide group.
  • the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is an R B ring structure.
  • the R 8 ring structure is a 5-, 6- or fused 6,5-membered heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms.
  • the R 8 ring structure optionally can be substituted by one or more lower alkyl, lower dialkyl, lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido groups.
  • the (N-morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups.
  • R 9 is the R 8 ring structure, a lower alkyl, amine, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group.
  • a contemplated compound can be defined by the following structural formula:
  • R x is a R x ring structure, lower alkyl, or lower amino alkyl.
  • the R x ring structure is connected by a spacer 0 to about 5 atoms long forming from one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms .
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long. If the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 8 is a ring structure, alkyl alcohol, or thioalkyl amide group .
  • the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is an R s ring structure.
  • the R 8 ring structure is a 5-, 6- or fused 6,5-membered heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms.
  • the R 8 ring structure optionally can be substituted by one or more lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido groups.
  • the (N-morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups .
  • R 9 is the R 8 ring structure, a lower alkyl, amine, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group.
  • a contemplated compound can be defined by the following structural formula:
  • D is a carbon, nitrogen, oxygen, or sulfur atom optionally substituted by or forming a lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido group.
  • Ri is a Ri ring structure, lower alkyl, or lower amino alkyl .
  • the R x ring structure can form at Ri, between R x and R 2 or between R x and R 4 with the proviso that, if the R ring structure forms at R 1# the Ri ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms, and, if the R x ring structure is formed between R x and R 4 , the heteroatoms are 2 nitrogen atoms .
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 2 is a H or R 2 and R x form the R ring structure group.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 4 is a H or R 4 and R x form the R x ring structure.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • a contemplated compound can be defined by the following structural formula:
  • D is a carbon, nitrogen, oxygen, or sulfur atom optionally substituted by or forming a lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido group.
  • Ri is a Ri ring structure, lower alkyl, or lower amino alkyl.
  • the R x ring structure is connected by a spacer 0 to about 5 atoms long forming from one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms.
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched .
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • D is a nitrogen atom optionally substituted by or forming a lower alkyl, amine lower alkyl, carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid or alkyl substituted phenyl sulfonamido group
  • R x is a lower alkyl or lower amino alkyl group, or 6 -membered aromatic ring structure connected by a lower alkyl group
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or cyclohexane connected by an alkyl group 0 to about 3 carbon atoms long
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or 6 -membered aromatic ring structure connected by an alkyl group 0 to about 3 carbon atoms long
  • D is a carbon atom optionally substituted by or forming a lower alkyl, amine lower alkyl, carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid or alkyl substituted phenyl sulfonamido group
  • R x is a lower alkyl or lower amino alkyl group, or 6-membered aromatic ring structure connected by a lower alkyl group
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or cyclohexane connected by an alkyl group 0 to about 3 carbon atoms long
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or 6 -membered aromatic ring structure connected by an alkyl group 0 to about 3 carbon atoms long
  • the lower alkyl, lower alkyl alcohol or lower thioalkyl group is a carbon
  • R x is a lower alkyl or lower amino alkyl group, or 6 -membered aromatic ring structure connected by a lower alkyl group
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or cyclohexane connected by an alkyl group 0 to about 3 carbon atoms long
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or 6 -membered aromatic ring structure connected by an alkyl group 0 to about 3 carbon atoms long
  • the lower alkyl, lower alkyl alcohol or lower thioalkyl group can be branched.
  • D is a sulfur atom optionally substituted by or forming a lower alkyl, amine lower alkyl, carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid or alkyl substituted phenyl sulfonamido group
  • R x is a lower alkyl or lower amino alkyl group, or 6 -membered aromatic ring structure connected by a lower alkyl group
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or cyclohexane connected by an alkyl group 0 to about 3 carbon acorns long
  • R 3 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or 6-membered aromatic ring structure connected by an alkyl group 0 to about 3 carbon atoms long
  • a contemplated compound can be defined by the following structural formula:
  • R is a R x ring structure, lower alkyl, or lower amino alkyl.
  • the R ring structure can form at R x , between R x and R 2 or between R x and R 4 with the proviso that, if the R x ring structure forms at Ri, the R x ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl , N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms, and, if the R x ring structure is formed between R x and R 4 , the heteroatoms are 2 nitrogen atoms .
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 2 is a H or R 2 and R x form the R x ring structure group .
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 4 is a H or R 4 and R form the R x ring structure .
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group .
  • R 13 is a formamide, lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, or H group.
  • a contemplated compound can be defined by the following structural formula:
  • R is a R x ring structure, lower alkyl, or lower amino alkyl.
  • the R x ring structure is connected by a spacer 0 to about 5 atoms long forming from one or more N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the Ri ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms .
  • the Ri ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl.
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 13 is a lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, or H group.
  • a contemplated compound is of the formula immediately above wherein R x is a lower alkyl or lower amino alkyl group or a 6 -membered aromatic ring structure connected by a lower alkyl group; R 3 is a lower alkyl, lower alkyl alcohol or lower thioalkyl group or a cyclohexane connected by an alkyl group 0 to about 3 carbon atoms long; R 7 is a lower alkyl, lower alkyl alcohol, or lower thioalkyl group or a 6-membered aromatic ring structure connected by a lower alkyl group; and R 13 is a lower alkyl carboxamide.
  • a contemplated compound can be defined by the following structural formula:
  • B is a carbon or nitrogen atom.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long. If the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group .
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group.
  • the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 3 and R 9 and is the R 8 ring structure.
  • the R 8 ring structure is a 5-, 6- or fused 6,5-membered heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms.
  • the R 8 ring structure optionally can be substituted by one or more lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido groups.
  • the (N-morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups .
  • R 9 is the R 8 ring structure, a lower alkyl, amine, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group.
  • Ri o is a H, lower alkyl phenyl group, or R 10 and R u form a R 10 ring structure group that is a fused 6- or fused 6, 6 -membered cyclic or heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • R 1X is a H, lower alkyl phenyl or the R 10 ring structure group .
  • a contemplated compound can be defined by the following structural formula:
  • B is a carbon or nitrogen atom and D is a carbon, nitrogen, oxygen, or sulfur atom optionally substituted by or forming a lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido group.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • Ri o is a H, lower alkyl phenyl group, or R 10 and R X1 form a R 10 ring structure group that is a fused 6- or fused 6, 6 -membered cyclic or heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • R u is a H, lower alkyl phenyl or the R 10 ring structure group .
  • a contemplated compound can be defined by the structural formula immediately above wherein B is a carbon atom and the R 10 ring structure group forms a phthalimido group.
  • a contemplated compound can be defined by the following structural formula:
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • Ri o is a H, lower alkyl phenyl group, or R 10 and R u form a R i0 ring structure group that is a fused 6- or fused 6,6-membered cyclic or heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • R u is a H, lower alkyl phenyl or the R 10 ring structure group .
  • Ri 3 is a formamide, lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, or H group.
  • a contemplated compound can be defined by the structural formula immediately above wherein B is a carbon atom and the R ⁇ 0 ring structure group forms a phthalimido group.
  • a contemplated compound can be defined by the following structural formula:
  • B is a carbon or nitrogen atom.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long. If the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group.
  • the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is the R 8 ring structure.
  • the R 8 ring structure is a 5-, 6- or fused 6,5-membered heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms.
  • the R 8 ring structure optionally can be substituted by one or more lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido groups.
  • the (N- morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups.
  • R 9 is the R 8 ring structure, a lower alkyl, amine, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group.
  • Ri o is a H, lower alkyl phenyl group, or R ⁇ 0 and R u form a R x0 ring structure group that is a fused 6- or fused 6, 6 -membered cyclic or heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • Ru is a H, lower alkyl phenyl or the R i0 ring structure group.
  • a contemplated compound can be defined by the following structural formula:
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long. If the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein the heteroatoms are 1 or 2 nitrogen atoms .
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group.
  • the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R 7 ring structure, or between R 8 and R 9 and is the R 8 ring structure.
  • the R 8 ring structure is a 5-, 6- or fused 6,5-membered heterocyclic ring wherein the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms.
  • the R 8 ring structure optionally can be substituted by one or more lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido groups.
  • the (N-morpholino) amino, alkyl, alkyl alcohol, or thioalkyl amide group can optionally contain one or more alcohol, amide, sulfhydryl, or alkyl ester groups .
  • R 9 is the R 8 ring structure, a lower alkyl, amine, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group.
  • R 12 is a R i2 ring structure or lower alkyl group.
  • the R i2 ring structure is a 6 -membered cyclic or heterocyclic ring wherein the heteroatoms are one or two nitrogen atoms and can be connected by an alkyl group 0 to 3 atoms long.
  • the lower alkyl group can be branched.
  • a contemplated compound corresponds to the following structural formula:
  • D is a carbon, nitrogen, oxygen, or sulfur atom optionally substituted by or forming a lower alkyl, amine lower alkyl carboxamide, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, sulfoxide, or alkyl substituted phenyl sulfonamido group.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R i2 is a R 12 ring structure or lower alkyl group.
  • the R 12 ring structure is a 6 -membered cyclic or heterocyclic ring wherein the heteroatoms are one or two nitrogen atoms and can be connected by an alkyl group 0 to 3 atoms long.
  • the lower alkyl group can be branched.
  • a contemplated compound corresponds to the following structural formula:
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group .
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group.
  • R 12 is a R 12 ring structure or lower alkyl group.
  • the R 12 ring structure is a 6-membered cyclic or heterocyclic ring wherein the heteroatoms are one or two nitrogen atoms and can be connected by an alkyl group 0 to 3 atoms long .
  • the lower alkyl group can be branched .
  • R 13 is a formamide, lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, or H group.
  • a contemplated compound corresponds to the following structural formula:
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl.
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 14 is a 6 -membered aromatic cyclic or heterocyclic ring wherein the heteroatom is a nitrogen atom.
  • R 15 is lower alkyl carboxamide or H group.
  • a contemplated compound corresponds to the following structural formula:
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl.
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 14 is a 6 -membered aromatic cyclic or heterocyclic ring wherein the heteroatom is a nitrogen atom.
  • R 16 is a lower alkyl, lower alkyl morpholine amide, or H group wherein the lower alkyl can be branched.
  • Table 1 provides the structural formula of exemplary compounds along with their binding inhibition potencies relative to the standard compound of SEQ ID NO: 3, assigned a relative potency of 1.
  • the compound ID number of Table 1 cross-references individual compounds herein.
  • the present invention further contemplates a compound that is a prodrug, where a prodrug is a compound that does not necessarily bind the VLA-4 receptor in vitro but is converted in vivo to a compound having such binding activity, e.g., a compound of Formula IIA.
  • R x is a R x ring structure, lower alkyl, or lower amino alkyl; the R x ring structure can form at R x , between R x and R 2 or between R and R 4 with the proviso that, if the R ring structure forms at R 1# the R x ring structure is connected by a spacer 0 to about 5 atoms long forming one or more alkyl, N-amido, N-sulfonimido, N-urea, N-carboxyl groups; the spacer can be optionally substituted by an amino group; the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein, the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups; the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms,
  • the lower alkyl or lower amino alkyl group can be branched
  • R 2 is a H, lower alkyl, phenyl lower alkyl, or R 2 and R x form the R x ring structure group;
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl, or di (lower alkyl) thioether;
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long; the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched;
  • R 4 is a H or R 4 and R x form the R x ring structure
  • R 5 is H or R 5 and R 6 form a R 5 ring structure ;
  • the R 5 ring structure is a fused 6,6- ring structure and can be aromatic, partially saturated, or saturated;
  • R 6 is a benzyl, a 5 , 6 , or 7-membered heterocyclic saturated ring containing 1 or 2 nitrogen atoms optionally substituted by one or more lower alkyl, lower alkyl amide or acyl groups or 1,1 diphenylmethine group, the R 5 ring structure, a group of the formula
  • A is nitrogen or oxygen; when A is nitrogen;
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group; the R 7 ring structure can form at R 7 or between R 7 and R 8 with the proviso that, if the R 7 ring structure forms at R 7 , the R 7 ring structure is connected by an alkyl group 0 to about 3 carbon atoms long; if the R 7 ring structure is formed at R 7 , the R 7 ring structure is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein, the heteroatom is a nitrogen atom; if the R 7 ring forms between R 7 and R g, the R 7 ring structure is a 5-, fused 6,6-, fused 6,5-, or 7- membered heterocyclic ring group wherein, the heteroatoms are 1 or 2 nitrogen atoms; the R 7 ring structure can optionally be substituted by an alcohol, nitro, or lower alkyl
  • R 8 is a ring structure, alkyl, alkyl alcohol, or thioalkyl amide group; the ring structure can form at R 8 and is (N-morpholino) amino, between R 7 and R 8 and is the R- ring structure, or between R 8 and R 9 and is an R 8 ring structure; the R 8 ring structure is a 5-, 6- 7- or fused 6,5-membered heterocyclic ring wherein, the heteroatoms are 1 or 2 nitrogen atoms and 0 or 1 oxygen or sulfur atoms; the R 8 ring structure 94
  • R 9 is the R 8 ring structure, a lower alkyl, lower dialkyl, lower alkyl carboxamide, lower alkyl morpholine amide, cyclohexane or H group;
  • R 8 is a lower alkyl that can be branched
  • R 9 is absent
  • J is oxygen or sulfur
  • R 17 is alkyl, alkyl optionally substituted by a hydroxyl, phenyl or phenyl sulfonyl, di (lower alkyl) sulfide, (lower alkoxy) lower alkyl, [(lower alkoxy) lower alkoxy] lower alkyl, (lower alkylcarbonyloxy) lower alkyl, [N- (lower alkyl) amino- carbonyl] lower alkyl, ⁇ [ (N- (lower alkyl) ] -
  • Preferred compounds of Formula IIA are where R 2 is lower alkyl, or phenyl lower alkyl.
  • D is carbon optionally substituted by one or more lower alkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, or alkyl substituted phenyl sulfonamido groups, or
  • D is a nitrogen atom optionally substituted by a lower alkyl, amino carbonyl lower alkyl wherein the nitrogen atom of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, lower 96 -
  • alkyl alcohol lower hydroxy alkyl ether, or lower alkyl carboxylic acid groups, or
  • D an oxygen atom
  • D is a sulfur atom optionally forming a sulfoxide or sulfone.
  • R 13 is a lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, carboxamide, or H group.
  • R 2 is lower alkyl, or phenyl lower alkyl and 97 -
  • D is carbon optionally substituted by one or more lower alkyl, lower alkyl carbonyloxy, aminocarbonyl lower alkyl wherein the nitrogen of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, alcohol, lower alkyl alcohol, lower hydroxy alkyl ether, carboxylic acid, lower alkyl carboxylic acid, carbonyl, or alkyl substituted phenyl sulfonamido groups, or
  • D is a nitrogen atom optionally substituted by a lower alkyl, amino carbonyl lower alkyl wherein the nitrogen atom of the amino group is bound to any combination of two groups selected from the group consisting of alkyl, aryl and H groups, lower alkyl alcohol, lower hydroxy alkyl ether, or lower alkyl carboxylic acid groups, or
  • D is an oxygen atom
  • D is a sulfur atom optionally forming a sulfoxide or sulfone, or - 9 !
  • R 13 is a lower alkyl carboxamide, lower alkyl alcohol, carboxylic acid, carboxamide, or H group.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 is H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is a ring structure formed between R 8 and R 9 selected from the group consisting of 4-methylpiperazinyl, and 4-morpholinyl
  • J is oxygen
  • R 17 is selected from the group consisting of ethyl, methyl, 2-propyl, cyclohexyl, and neopentyl.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9
  • J is oxygen
  • R 17 is ethyl.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9
  • J is oxygen
  • R 17 is methyl.
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-morpholinyl ring structure formed between R ⁇ and R 9j J is oxygen
  • R 17 is 2-propyl.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-morpholinyl ring structure formed between R 8 and R 9 J is oxygen
  • R 17 is ethyl.
  • R x is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9( J is oxygen
  • R 17 is 2-propyl .
  • R ⁇ is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9/ J is oxygen
  • R 17 is cyclohexyl .
  • R is benzyl
  • R 2 is methyl
  • R 3 is 2-methylpropyl
  • R 4 and R 5 are H
  • R 7 is benzyl
  • A is nitrogen
  • R 8 is the 4-methylpiperazinyl ring structure formed between R 8 and R 9
  • J is oxygen
  • R 17 is neopentyl.
  • a contemplated prodrug compound corresponds to the following structural formula:
  • J is a nitrogen, oxygen, or sulfur atom.
  • R 17 forms or is an alkyl ester, alkyl carboxylic ester, alkyl carboxamide carboxylic ester, phenyl alkyl, alkyl carboxamide, alkyl carboxylic acid, alkyl phosphonate, biotin, or H group.
  • R 18 is an alkyl ester, biotin or H group with the proviso that R 17 and R 18 cannot both be H groups .
  • R is a R x ring structure, lower alkyl, or lower amino alkyl.
  • the R x ring structure is connected by a spacer 0 to about 5 atoms long forming from one or more N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R x ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms.
  • the R x ring structure can be aromatic, partially 101
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or fused 6,5-membered aromatic or non-aromatic cyclic or heterocyclic ring group wherein the heteroatom is a nitrogen atom.
  • the R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group .
  • a contemplated prodrug compound corresponds to the following structural formula:
  • J is a nitrogen, oxygen, or sulfur atom.
  • R 17 forms or is an alkyl ester, alkyl carboxylic ester, alkyl carboxamide carboxylic ester, phenyl alkyl, alkyl carboxamide, alkyl carboxylic acid, alkyl phosphonate, biotin, or H group.
  • R 19 is a phenyl alkyl, alkyl carboxamide, alkyl carboxylic acid, alkyl carboxylic ester, alkyl phosphonate, alkyl carboxamide carboxylic ester, biotin or H group with the proviso that R 17 and R 19 cannot both be H groups.
  • R x is a R x ring structure, lower alkyl, or lower amino alkyl .
  • the R ring structure is connected by a spacer 0 to about 5 atoms long forming from one or more N-amido, N-sulfonimido, N-urea, N-carboxyl groups.
  • the spacer can be optionally substituted by an amino group.
  • the R x ring structure is a substituted or unsubstituted 5-, 6-, fused 6,6- or fused 6,5-membered ring wherein the substituent is one or more alkyl, carbonyl, alcohol, halogen, or alkyl phenyl groups.
  • the R ring structure is cyclic or heterocyclic with the proviso that the heteroatoms are 1 or 2 nitrogen atoms .
  • the R x ring structure can be aromatic, partially saturated, or saturated.
  • the lower alkyl or lower amino alkyl group can be branched.
  • R 3 is a R 3 ring structure, lower alkyl, lower alkyl alcohol or lower thioalkyl .
  • the R 3 ring structure group is a 6- membered ring that is connected by an alkyl group 0 to about 3 carbon atoms long.
  • the lower alkyl, lower alkyl alcohol, or lower thioalkyl group can be branched.
  • R 7 is a R 7 ring structure, lower alkyl, lower alkyl alcohol, lower thioalkyl or H group.
  • the R 7 ring structure forms at R 7 and can be connected by an alkyl group 0 to about 3 carbon atoms long and is a 6-, or - 103 -
  • R 7 ring structure can optionally be substituted by an alcohol, nitro or lower alkyl ether group .
  • Table 2 provides the structural formula of exemplary prodrug compounds along with their binding inhibition potencies relative to the standard compound of SEQ ID NO: 3, assigned a relative potency of 1.
  • the prodrug compound relative potency of Table 2 is the potency before the prodrug compound is enzymatically converted to an active form.
  • the compound ID number of Table 2 cross-references individual compounds herein.
  • a contemplated compound also includes a bioisoster of a disclosed compound.
  • bioisoster refers to a compound differing from a disclosed compound by an one or more atoms expected to produce an equivalent biological effect.
  • An example of a bioisosteric substitution is the interchange of nitrogen and carbon in an aromatic ring. See, for example, Medicinal Chemistry, ed. by Alfred Burger, Interscience Publishers, N.Y. (1960), which is incorporated herein by reference.
  • a contemplated compound includes a described compound coupled to a fluorescent group, a group that enhances solubility in an aqueous environment, or binding group, such as, for example, an europium epsilon amidocarproyl , N-acetyl glucosamine or biotin group, respectively.
  • a contemplated compound includes a compound containing two or more of the described compounds attached together to form a multi-valent compound by a linking group such as, for example, a tetraethylenepentatamine group .
  • lower alkyl refers to an alkyl group 1 to about 5 carbon atoms long.
  • alkyl refers to an alkyl group 1 to about 15 atoms long.
  • a contemplated inhibitor compound can also be defined using the single or triple letter abbreviation for an amino acid.
  • the abbreviations used herein for derivatives and residues of the twenty natural amino acids are reproduced in the following
  • the twenty naturally occurring amino acids can also be categorized according to the chemical structure their respective radicals.
  • amino acids are hydrophobic; acidic and basic amino acids are hydrophilic.
  • Other groupings of amino acids are not as readily assignable, for example in the case of the aromatic amino acids, phenylalanine is hydrophobic, while tyrosine is hydrophilic.
  • a contemplated inhibitor compound defined as an amino acid sequence corresponds to formula A:
  • B is an ⁇ -hydrophobic amino acid residue.
  • X is a group amide- linked to the nitrogen atom of the B ⁇ -amine.
  • the X group has a ring structure bonded to the carbonyl carbon of the amide-linkage by a spacer having a length of zero to about two methylene groups.
  • the length of X, including the spacer and carbonyl carbon is about that of a 3-quinoline carbonyl group or smaller.
  • the ring structure is a 5- and 6 -membered ring or a fused 6,6- or 6,5-membered ring.
  • the X substituent, including the spacer, cyclic ring structure, the carbonyl group and the ⁇ -amino nitrogen atom of B can also together form an aromatic ring-substituted cyclic imido group.
  • Z is selected from the group consisting of:
  • NCy 1 is a cyclic ring-containing group having a ring nitrogen atom that forms an amide bond with the ⁇ -carboxyl group of Xaa, and whose cyclic ring contains 5- or 6 -atoms including said ring nitrogen atom;
  • NCy 2 where the depicted nitrogen is an amine substituent of a cyclic group whose depicted nitrogen atom forms an amide bond with the ⁇ -carboxyl group of the Asp, and which amine substituent is bonded to a 6- or 7 -membered ring or to a fused 6,6- or 6, 7 -membered lactam ring system in which the ring bearing the amine substituent is saturated and contains the amine substituent ⁇ to the carbonyl group of the lactam.
  • a compound of formula A is water-soluble and inhibits the binding of Jurkat cells (ATCC TIB 152) to a solid phase -bound compound of SEQ ID NO:l in an in vitro assay in an aqueous buffer at a pH value of 7.2-7.4.
  • the binding inhibition exhibited by a compound is measured relative to that of SEQ ID NO: 3.
  • the binding inhibition of a compound is ten times or more that of SEQ ID NO: 3.
  • Exemplary B residues as amino acids are selected from the group consisting of leucine (Leu) , cyclohexylalanine, norleucine (Nle) , Methionine (Met) , homoserine, threonine (Thr) , phenylalanine (Phe) , valine (Val) , norvaline (Nva) , and isoleucine (He) .
  • B is most preferably Leu.
  • a contemplated inhibitor compound defined as an amino acid sequence corresponds to formula I :
  • X is a group amide-linked to the nitrogen atom of Leu, the group having a ring structure bonded to the carbonyl carbon of the amide-linkage by a spacer having a length of zero to about two methylene groups .
  • the length of X is about that of a 3-quinoline carbonyl group or smaller.
  • the ring structure is a 5- and 6 -membered ring or a fused 6,6- or 6,5-membered ring.
  • the X substituent including the spacer, cyclic ring structure, the carbonyl group and the ⁇ -amino nitrogen atom of Leu can also together form an aromatic ring-substituted cyclic imido group.
  • Z is selected from the group consisting of:
  • NCy 1 (a) Xaa-NCy 1 where Xaa is Val, He, Leu or an amino acid residue having a side chain that contains one or two fused aromatic rings and NCy 1 is a cyclic ring-containing group having a ring nitrogen atom that 116
  • the inhibition of a compound is ten times or more that of SEQ ID NO: 3.
  • That amide bond can be present as part of a carboxamide- [-C(0)NH-], urethane-
  • the cyclic ring structure broadly can be any 5- or 6 -membered ring that is saturated or contains ethylenic unsaturation.
  • the ring structure can contain one or more atoms other than carbon such as nitrogen, oxygen or sulfur.
  • the ring structure can also be a fused ring system where two 6 -membered rings are fused (6,6-) or where a 6 -membered ring is fused to a 5-membered ring (6,5-membered) .
  • the ring of the cyclic ring structure is preferably aromatic.
  • Exemplary ring structures include tetrahydrofuranyl, tetrahydropyranyl, cyclopentyl, cyclohexyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolidyl, furanyl, piperidinyl, naphthyl, quinolinyl, decalinyl, quinazolinyl, imidazyl, thiophenyl, and the like.
  • phenyl and pyridyl are particularly preferred.
  • a cyclic ring structure can be bonded directly to the carbonyl group [-C(O)-] of the amide bond to the B or Leu residue. That ring can also be spaced away from the carbonyl group by up to about the length of two methylene (-CH 2 -) groups or an ethylene group (-CH 2 -CH 2 -) .
  • Contemplated spacers include -HC (CH 3 ) -CH 2 - , -CH 2 -CH 2 -, -NH-0-, -HN-NH-, -CH 2 -0- and -CH 2 -NH-, and are preferably free of unsaturation.
  • the contemplated X groups include 3 -methyl - 3 -phenylpropionyl , 3 -phenylpropionyl , phenylhydroxaminocarbonyl [Ph-NH-O- C(O) -] , phenylhydrazidecarbonyl [Ph-NH-NH-C (0) -] , benzyloxycarbonyl [Ph-CH 2 -0-C (0) -] , phenoxyacetyl [Ph-0-CH 2 -C(0) -] , benzylaminocarbonyl [Ph-CH 2 -NH-C (O) -] , and anilinoacetyl [Ph-NH-CH 2 -C (0) -] , where "Ph" is a phenyl group .
  • a before- described ring structure be bonded to the carbonyl carbon of the B- or Leu-linked amide group by a spacer having a length of zero methylene groups (a direct bond), one or two methylene groups.
  • the spacer has the length of about an ethylene group or less .
  • a phenylacetyl , phenoxycarbonyl or anilinocarbonyl group bonded to the nitrogen of the B or Leu ⁇ -amino group contains a spacer having the length of about one methylene group .
  • Phenyl (benzoyl) 1- or 2 -naphthyl (1- or 2- naphthalenecarbonyl) , 2-, 3- or -pyridyl (2-, 3- or 4-pyridinecarbonyl) , 2- or 3-thiophenyl (2- or 3-thienyl; 2- or 3-thiophencarbonyl) and 2- or
  • an X group that utilizes a spacer having a length of zero methylene groups .
  • a spacer having a length of about two methylene groups is provided by an X group that is carbobenzyloxy [Ph-CH 2 -0-C(0) -] , carbobenzylamino [Ph-CH 2 -NH-C (0) -] , carbophenoxymethylene [Ph-0-CH 2 -C (0) -] ) and the like groups .
  • a contemplated 5- or 6 -membered ring structure can also be substituted with a C 1 -C 2 alkyl or hydroxyl group.
  • Exemplary substituted ring structures using a phenyl ring as illustrative thus include 2-, 3- or 4-ethylphenyl, 2,6-, 3,4- or 2, 3-dimethylphenyl, 2-, 3- or 4-hydroxyphenyl, 2, 6-, 2,4-, 3,4- and 3 , 5-dihydroxyphenyl, and the like.
  • the ring structure of the X substituent is thought to act in a contemplated inhibitor in some way to fit the inhibitor compound into the binding pocket of the VLA-4 receptor to position the B or Leu and Asp groups into a proper configuration. Because of that presumed role in fitting the compound into its receptor, there are some size constraints upon the ring structure-containing and spacer portions of X, in addition to those noted before as to the spacer group length. Thus, from the carbonyl-containing carbon of the amide bond to B or Leu, through the end of ring structure or its substituent furthest from the carbonyl group, the total length of the spacer plus ring structure-containing portion of X is about the size of a 3-quinolinecarbonyl group or smaller.
  • the length of a given X substituent can be readily determined, as discussed before. For example, one can use space-filling models to build exemplary cyclic ring structure-containing X groups and then compare the relative sizes of the prepared models. One can also use published bond lengths and bond angles to prepare a two-dimensional depiction of the sizes. Computer graphics programs are also well-known and available that can be used to prepare exemplary model X groups for length comparison to 3-quinolinoyl .
  • the X substituent including the spacer, cyclic ring structure, the carbonyl group and the ⁇ -amino nitrogen atom of B or Leu can also together form an aromatic ring-substituted cyclic imido group.
  • exemplary of such cyclic imido groups are phthalimido, which is preferred, each of 2,3- and 3, 4-pyridinedicarboximido, homophthalimido and 1,2,3, 4-tetrahydroquinazoline-2 , 4-dione-3-yl groups in which the aromatic ring and cyclic imido group are fused together.
  • the B or leucine nitrogen atom is an imido nitrogen atom within the ring of a 5-phenylhydantoin-3-yl group so that the aromatic phenyl ring is a substituent of a cyclic spacer and is spaced about one methylene away from the carbonyl group linked to the Leu residue.
  • a similarly structured imido nitrogen-containing X group is present in a 2-phenylsuccinimido group formed on the B or Leu nitrogen atom.
  • the cyclic imido- and hydantoin-containing portions of the above-discussed X groups can thus be viewed as specialized spacer groups that limit the conformational degrees of freedom of the ring structures.
  • the carbonyl, 121 whereas the carbonyl, 121
  • a phthalimido X group can only spin about the axis of the leucine nitrogen-methine bond.
  • X substituent must contain a cyclic ring structure that can be substituted as discussed before, that X substituent can also include a further substituent on other than the ring structure.
  • X preferably is an amino acid residue having a cyclic ring side chain that therefore includes a primary or secondary amine.
  • X is preferably a prolyl, phenylalanyl, tyrosinyl or phenylglycyl residue, the nitrogen atom of whose ⁇ -amino group is bonded to the further substituent.
  • That further substituent can be one amino acid residue through the remainder of the CS-1 compound sequence toward the N-terminus thereof, with the sequence of that compound beginning at the isoleucine of position 19 from the N-terminus of SEQ ID N0:1.
  • a single residue or 18 separate amino acid residue substituent sequences are thereby defined.
  • biotin Another exemplary further substituent linked via an amine group of X is biotin.
  • biotin amide-bonded to e-aminocaproic acid was amide-bonded to the ⁇ -amine of a phenylalanine (Phe) as an X group.
  • Phe phenylalanine
  • the resulting compound contained the biotin fused ring amide-linked to the Phe X group via a chain of twelve atoms .
  • an X group amino acid residue having a cyclic ring side chain can also be free of substituent groups.
  • the nitrogen atom of the ⁇ -amine of such a residue can also be acylated 122
  • acyl group such as formyl, acetyl, iso-butyryl, or hexanoyl group.
  • a C x -Cg acyl group bonded to the nitrogen of an ⁇ -amine group forms an amide bond at that nitrogen atom and provides no ionic charge to the compound at a pH value of 7.2-7.4 as compared to the positive charge provided by an unsubstituted free ⁇ -amine.
  • the Z group of a before-discussed formula can be one of two types of groups.
  • the Z group in one embodiment (A) is a hydrophobic amino acid residue Xaa compound-bonded to the Asp carboxyl and linked to a cyclic ring-containing group NCy 1 that has a ring nitrogen atom (the N of NCy 1 ) that forms an amide bond with the ⁇ -carboxyl group of Xaa.
  • the cyclic ring of NCy 1 contains 5- or 6-atoms, including the depicted nitrogen atom (N of NCy 1 ) .
  • Contemplated hydrophobic amino acid residues are those having aliphatic side chains such as valine, leucine and isoleucine.
  • Xaa more preferably contains a hydrophobic aromatic amino acid residue; i.e., Xaa is an amino acid residue having an aromatic side chain that contains one or two fused aromatic rings.
  • aromatic amino acids are phenylalanine, tyrosine and tryptophan that are naturally occurring (genetically encoded) as well as phenylglycine, homophenylalanine, P-nitrophenylalanine, thiophenylglycine (thienylglycine) , and the like.
  • NCy 1 groups include morpholinyl, t h i omo r ho 1 i ny 1 , t h i omo rpho 1 i ny 1 su 1 f one
  • NCy 1 cyclic ring can also be substituted with one or two substituent groups selected from the group consisting of carboxyl, carboxamide, C X - C alkylenecarboxyl C ⁇ -C 4 alkylenecarboxamide , hydroxyl, hydroxymethyl , 123
  • D-Pro (sometimes shown in bold face lower case single letter amino acid code as "P” or as D-Pro) is particularly preferred as its amido derivative (D-Pro-NH 2 ) as are morpholinyl, piperidyl, piperazinyl and 4 -hydroxypiperidyl .
  • Exemplary C ⁇ d alkyl groups include methyl, ethyl, iso-propyl, n-butyl and t-butyl.
  • a -d alkyl group can also form a quaternary ammonium group with a second nitrogen atom of NCy 1 such as piperazine.
  • NCy 1 such as piperazine.
  • d _ C 4 alkyl group is a methyl group
  • iodide is the anion
  • exemplary NCy 1 group is a 4,4-N, N-dimethylpiperaziniumyl iodide.
  • Exemplary d-C 4 alkylenecarboxyl and C - C x alkylenecarboxamide groups include methylenecarboxyl
  • NCy 1 includes a piperazinyl group
  • the second (4 -position) nitrogen atom cannot only be quaternized by alkylation, but also amidified.
  • acyl portions of the piperazinyl-4 -N-amides include -C ⁇ acyl groups such as formyl, acetyl, - 124 -
  • propanol isobutanoyl, hexanoyl and benzoyl, but also sulfonamides such as phenylsulfonamido , toluenesulfonamide (tosyl) , methanesulfonamide (mesyl) and trifluoromethylsulfonamido (trifyl) .
  • sulfonamides such as phenylsulfonamido , toluenesulfonamide (tosyl) , methanesulfonamide (mesyl) and trifluoromethylsulfonamido (trifyl) .
  • Xaa is a specified amino acid residue whose amine group forms an amide (compound) bond with the ⁇ - carboxyl of the depicted Asp residue, and whose carboxyl group forms an amide bond with a nitrogen atom present within the 5- or 6 -membered ring of NCy 1 .
  • Z is NCy 2 where the depicted nitrogen atom (N of NCy 2 ) is an amine substituent of a cyclic group (Cy 2 ) whose substituent nitrogen atom forms an amide bond with the ⁇ -carboxyl of the depicted Asp residue. That amine substituent is bonded to a cyclic group that is (I) a 6- or 7-membered ring or (ii) a fused 6,6- or 6, 7-membered lactam ring system in which the ring bearing the amine substituent is saturated (free of ethylenic unsaturation) and contains the amine substituent ⁇ to the carboxyl group of the lactam.
  • the nitrogen atom that links the ring system to the remainder of the compound is a substituent of a cyclic ring structure rather than being a ring atom as in NCy 1 .
  • the rings of which that nitrogen can be a substituent are of two types, 6- or 7-membered rings or 6,6- or 6,
  • 6- and 7-membered ring NCy 2 groups of this type include benzylamine, phenethylamine, 125
  • N- (valeroIactam-3-yl) amine groups that form the corresponding amides with the ⁇ -carboxyl of Asp.
  • Exemplary amino-substituted 6,6- and 6,7-fused ring lactam-containing NCy 2 groups include
  • the compound of SEQ ID NO: 4 having an N-terminal phenylacetyl group linked to the sequence Leu-Asp-Phe-Pro can further include a substituted tetraethylenediamine group amide-bonded to the Pro residue in which four phenylacetyl-Leu-Asp-Phe-Pro groups were amide-bonded to the tetraethylenediamine nitrogens and still exhibit VLA-4 binding inhibition that was better than the standard 10-mer compound of SEQ ID NO : 3.
  • the compound PheLeuAspPhe-D-Pro- NH 2 contained a europium-containing chelate at its N-terminus bonded to the nitrogen atom of the N-terminal Phe. That compound exhibited a binding inhibition better than that of the compound of SEQ ID NO: 3.
  • the compound of SEQ ID NO : 5 phenylacetyl-Leu-Asp-Phe-Pro-NH(CH 2 ) 5 C(0)NHC 18 H 37 , would be predicted to be a good inhibitor. However, that compound is not water-soluble and forms a turbid dispersion rather than a solution. That compound exhibits a binding inhibition similar to that exhibited by the standard 10-mer compound of SEQ ID NO: 3.
  • a preferred contemplated inhibitor compound inhibits the binding of inflammatory cells that contain the VLA-4 receptor [Jurkat cells
  • Binding inhibition is measured here as a concentration of compound that inhibits one-half the binding between a standard number of Jurkat cells and a standard amount of CS-1 compound bound to the 127
  • a compound of formulas A or I inhibits binding between the CS-1 compound region of fibronectin and the VLA-4 receptor. Those inhibitors that are at least ten-times better inhibitors than the compound of SEQ ID NO : 3 are preferred.
  • Ar is a pyrazolyl, phenyl, pyridyl
  • Y is a spacer that is absent, -CH 2 -, -CH(NH)-, -0- or -NH- ;
  • Ar-Y-C(O)- has a length of about 3-quinolinecarbonyl or less
  • Xaa is an aromatic amino acid residue; i . e . , an amino acid residue having an aromatic side chain, such as phenylalanine, tyrosine, tryptophan, - 128 -
  • NCy 1 is an amine-containing 5- or 6 -membered cyclic ring group whose depicted nitrogen atom, N of NCy 1 , is within the ring and forms an amide bond with the ⁇ -carboxyl of Xaa, as was discussed before.
  • Ar-Y-C(O), a more preferred X group of formula I is preferably benzoyl, phenylacetyl, 4-pyridinecarbonyl (isonicotinoyl) , 3-pyridinecarbonyl (nicotinoyl) , 3-pyridinacetyl, anilinocarbonyl , 3-quinolinoyl, pyrazolecarbonyl, tryptophyl and 3 , 4-dihydroxybenzoyl, with phenylacetyl
  • NCy 1 is preferably an amide of a morpholinyl, piperidinyl or substituted piperidinyl where the substituent is selected from the group consisting of hydroxyl, carboxyl, carboxamido groups, piperazinyl or 4 -substituted piperazinyl in which the 4 -substituent is selected from the group consisting of d-C 4 alkyl, d-C 4 alkylenecarboxyl, -d alkylenecarboxamide, ⁇ CK 2 CE 2 ) M where n is 1, 2 or 3 , thiomorpholinyl, L- or D-prolinyl amide, pyrrolidmyl, 3 , 4-dihydroxy-pyrrolidinyl, 2- (
  • a most preferred compound corresponds in sequence to a compound of formula III, below, 129
  • NCy 3 is a group of most preferred NCy 1 groups and is selected from the group consisting of morpholinamido, thiomorpholino, 4- (thiadioxo) piperidinamido, D-2- (carboxamido) pyrrolidinamido, piperazinamido, substituted piperazinamido where the substituent is selected from the group consisting of 4-N-carboxymethyl, 4-N-carboxamidomethyl, 4-N- (5-hydroxyethylenoxyethylene) and 4 -N-P-toluene-sulfonamido, pyrrolidinamido, piperidinamido and substituted piperidinamido where the substituent is selected from the group consisting of 4 -hydroxy, 4-carbamyl, 4 -carboxyl groups.
  • Table 4 lists exemplary compounds defined by the single letter amino acid sequence abbreviation format.
  • the compound ID number cross-references compounds herein.
  • a lower case letter in bold-faced type is used to designate a D-isomer of the L-amino acid resid designated in single letter code by the same capitol letter.
  • p D-proline
  • f D- phenylalanine
  • i D-isoleucine
  • the N-terminal ⁇ -amine is substituted as shown or indicated to b C ⁇ a "free amine".
  • Z is an amide formed between the C-terminal Pro carboxyl and a tetraethylenepentaamine containing four N-phenylacetyl-LDFF peptides amide-bonded thereto.
  • Relative activities of about one-tenth or less than that exhibited by the peptides of SEQ ID NO: 3 are assigned a potency activity of zero.
  • Figs. 1, 2 and 3 also illustrate the unexpected binding inhibitions exhibited by contemplated compounds relative to other compounds of the art .
  • the compound sequences are shown using single letter code.
  • FIG. 1 illustrates results of relative in vitro binding inhibition studies carried out using the CS-1 (SEQ ID NO:l) compound, the CS-1 compound B12 portion (CS-1 B12; SEQ ID NO:2), the 10-mer compound used as a standard above, elsewhere herein and in the art (SEQ ID NO: 3), and several deletion analogues of the B12 compound, each containing the Leu-Asp sequence. N-Terminal deletion analogues are shown to the left of the standard
  • the CS-1 compound is about three times more potent an inhibitor than is B12, the 10-mer or a 9-mer deletion analogue of the 10-mer. Those latter three compounds were all more potent than the other B12 -related compounds.
  • Fig. 2 illustrate binding inhibition results obtained using deletion analogues of the standard 10-mer compound.
  • deletions made at both N- and C-termini are shown to the left of the standard 10-mer to isolate the Leu-Asp-Val sequence at the C-terminus, whereas those shown to the right of the standard 10-mer isolate the Asp-Val-Pro sequence.
  • These compounds and those of Fig. 1 had free N-terminal amine groups and C-terminal carboxyl groups.
  • Fig. 3 The data of Fig. 3 were similarly obtained, but are shown on a log scale so that all of the data could be accommodated.
  • the data of Fig. 3 are shown in five groups, from left to right. - 141 -
  • the first group show data for CS-1 compound and the 10-mer standard.
  • the next three bars shown data for a pentamer C-amide having the sequence including Leu-Asp-Val of the native CS-1 compound, the enhanced effect of using D-proline instead of the native L-proline, and then the enhancement by use of phenylalanine and D-proline in place of valine and D-proline.
  • the next two bars illustrate the further enhancement obtained over the three previous compounds obtained when a cyclic ring-containing X group, here phenylalanine as the free amine, was used to replace the isoleucine of the native sequence.
  • the fourth group of bars illustrates the effects of three X groups of formula I as compared to the phenylalanine group, using the better compound sequence of the two adjacent sequence [XLDFp-NH 2 ] .
  • Phenylacetyl ( ⁇ Ac) was used as an X group in the last three compounds where the D-proline Z group of formula I was varied using three cyclic amines (NCy 1 ) .
  • NCy 1 three cyclic amines
  • the data of Fig. 3 show inhibitory potencies spanning about three orders of magnitude from the standard 10-mer and compounds of the art, through contemplated compounds that exhibit about a 10 -fold enhancement in potency over that standard to those contemplated compounds exhibiting about a 50-fold to about 100-fold enhancement in potency and those exhibiting an enhancement in potency of up to about 1000-fold.
  • a contemplated inhibitor compound in addition to being more potent than the CS-1 or standard 10-mer compounds, is relatively more stable in serum that is the CS-1 compound.
  • the inhibitor compounds N-phenylacetyl-Leu-Asp-Phe-morpholinamide and N-phenylacetyl-Leu-Asp-Phe-D-Pro-NH 2 exhibited no loss of potency after 24 hours in PBS at 7.2-7.4 that also contained 10 percent mouse or human serum. Contrariiy, the CS-1 compound lost its potency in less than one hour under the same conditions.
  • the contemplated inhibitors are compounds or compound derivatives, and as such, can be readily synthesized using well known synthetic methods. See for example, Stewart, J. M. and J.D. Young, Solid
  • Solid phase synthesis was used for those materials having a C-terminal amino acid amide or free acid residue.
  • the N-protected, C-terminal residue was linked to a solid support having a benzhydrylamine substituent.
  • Fmoc amine blocking groups were used in these syntheses, although t-Boc, CBZ or other blocking groups can also be used with other solid supports.
  • t-Boc, CBZ or other blocking groups can also be used with other solid supports.
  • Contemplated compounds can also be prepared using t-Boc N-protecting groups and another solid support, or a benzylamino-substituted solid support to which a P-hydroxymethylphenylcarboxyl (PAM) group is first reacted with the amine of the support to form a carboxamide. The hydroxyl group is then used to form an ester link to the first compound and standard t-Boc synthetic technology is thereafter followed.
  • PAM P-hydroxymethylphenylcarboxyl
  • Reaction of the completed, deprotected solid phase-linked compound with ammonia provides the C-terminal amide compound discussed before, whereas reaction with another amine such as morpholine or piperidine or other NCy 1 or NCy 2 amine provides a compound whose C-terminal residue is amide-bonded to an NCy 1 or NCy 2 group.
  • Reaction of a deprotected, PAM-linked compound with hydroxide provides the corresponding C-terminal carboxyl group.
  • liquid phase compound syntheses were utilized.
  • morpholine or other NCy or NCy 2 group was coupled in solution to a contemplated C-terminal, t-Boc-protected residue using a carbodiimide .
  • the t-Boc protecting group was removed with acid, a further t-Boc-protected residue 144
  • N-terminal X group such as phenylacetic acid was added after the last t-Boc removal step and the synthesis was completed, except for deprotecting the Asp residue. That step was carried out by catalytic hydrogenation where a benzyl ester protecting group was used.
  • an inhibitor compound is typically recovered and purified prior to use. Recovery and purification techniques are well known and will not be dealt with here .
  • Mass spectroscopy data confirmed the expected molecular weight of exemplary compounds. The data was obtained using fast atom bombardment mass spectrometry (FAB) , electrospray mass spectrometry (Electrospray) , or matrix assisted laser desorption mass spectroscopy (MALDI-TOF-MS) .
  • FAB fast atom bombardment mass spectrometry
  • Electrospray Electrospray
  • MALDI-TOF-MS matrix assisted laser desorption mass spectroscopy
  • FAB was done using a VG ZAB-VSE double focusing high resolution mass spectrometer equipped with a cesium ion gun.
  • the mass spectrometer was manually tuned to a resolution of 2000 (10% valley definition) with amplifier and multiplier gains of a million (300V) .
  • a 35 kev cesium ion beam was used as the fast ion beam and the accelerating voltage of the desorbed ions was 8 kV.
  • the mass spectra were acquired using CSI for calibration; typically ten spectra were accumulated and averaged. Spectra were recorded with a Digital VAX station 3100 and the peaks were automatically centroided.
  • a flat FAB sample holder was used. Standards having 98% or better purity were used. In 145
  • Electrospray mass spectroscopy was conducted on a API III PERKIN ELMER SCIEX triple-quadrupole mass spectrometer and API 100 PERKIN ELMER SCIEX Mass Spectrometer. Samples were introduced into the analyzer at a rate of 4.0 ⁇ l/minute. The positive ions generated by the ion evaporation process entered the analyzer through an interface plate and a 100 ⁇ m orifice, while the declustering potential was maintained between 50-250 V (typically 100V) to control the collision energy of the entering ions .
  • MALDI-TOF-MS spectroscopy was performed on a Vesdec Inc. Voyager Biospectrometry workstation.
  • Matrix Assisted ionization of a compound consists of mixing a dilute solution of a compound with a large excess of an appropriate matrix material .
  • the sample is placed in the mass spectrometer and irradiated with a laser.
  • the matrix gives off absorbed light energy which causes vaporization of the compound in the mass spectrometer.
  • the compound is prepared in a water and TFA solvent and appropriately diluted.
  • the matrix was the Alpha cyano-4-hydroxy-cinnamic acid, gentisic acid or sinapinic acid.
  • the laser was an N2 laser.
  • Prodrug compounds are transformed in vivo from compounds that do not necessarily bind the VLA-4 receptor in vitro to compounds having such binding activity in vivo.
  • Chemical modifications of drugs that make prodrugs are known in the art and include, for example, esters of carboxylic acids or carboxyamide phosphonate groups.
  • the synthesis of prodrugs is by well known methods and will not be detailed here. See, for example, Bundraard, Design of Prodrugs. Elsevier Science Pub. Co., N.Y. (1985), and Prodrugs as Novel Drug Delivery Systems Symposium. 168 th Annual Meeting, American Chemical Society, Atlantic City, N.J., Eds. T.
  • immune system leukocyte effector or inflammatory cells such as monocytes, T cells and eosinophils bear the VLA-4 receptor on their cell surfaces. Those cells bind to the CS-1 portion of fibronectin present on the surfaces of vascular endothelial cells at an early step in inflammatory cell emigration (trafficking) from the blood in the tissues. These inflammatory cells immunoreact with monoclonal antibody P4C2 discussed in Wayner et al . , J. Cell. Biol.. 109:1321-1330
  • the inflammatory cells enhance the inflammatory response through one or more - 151 -
  • cytokines and chemoattractants reactants such as interleukin-l ⁇ (IL-l ⁇ ) , IL-2, tumor necrosis factor ⁇ (TNF ) and lymphocyte-derived chemotactic factor are released by the inflammatory cells and cause further inflammatory cells to emigrate to the area.
  • the inflammatory cells mis-recognize cells of the mammal with the inflammatory disease state as being non-self and attack those cells, killing them.
  • a contemplated inhibitor compound blocks binding between CS-1 and VLA-4, and inhibits the resulting emigration of inflammatory cells bearing VLA-4 receptors into the tissues, and the exacerbation of the inflammatory condition that results. That inhibition of emigration of inflammatory cells results in a reduction of the fibronectin CS-1/VLA-4 -mediated inflammatory response caused by those inflammatory cells, and thereby reduces the observed inflammation.
  • inflammatory disease states that are mediated by CS-1 and VLA-4, and in which a contemplated inhibitor compound can diminish inflammation are quite broad.
  • inflammatory disease states that are mediated by CS-1 and VLA-4, and in which a contemplated inhibitor compound can diminish inflammation are quite broad.
  • arthritic conditions such as rheumatoid arthritis and osteoarthritis, allograft rejection, various types of skin inflammation, and demyelinating diseases of the central nervous system.
  • Specific pathological inflammatory conditions in which expression of CS-1 has been found to be implicated and where no such expression is observed in absence of a pathological condition include: rheumatoid arthritis (synovium) , osteoarthritis (synovium) , skin psoriasis, kidney transplant, asthmatic lung, and lymph node high endothelial venules (HEV) in humans, as well as in the gut of monkeys infected with SIV and those having inflammatory bowel disease, rabbits having asthmatic lungs and heart transplants, mouse brain in experimental autoimmune encephalomyelitis (EAE) and skin in delayed type hypersensitivity (DTH) , and the joints of rats with induced arthritis.
  • rheumatoid arthritis synovium
  • osteoarthritis osteoarthritis
  • HEV lymph node high endothelial venules
  • VLA-4 is expressed on mononuclear leukocytes, T cells, B cells and monocytes, as well as eosinophils. Since a contemplated inhibitor compound acts by binding to VLA-4, any inflammatory disease state which involves the aforementioned cells may be treated using the inhibitor compounds of the present invention. For example, inflammatory diseases states such as allergy, arthritis, asthma, atherosclerosis, colitis, diabetes, inflammatory bowel disease, kidney inflammation, skin inflammatory diseases multiple sclerosis, restenosis, and transplantation are VLA-4 dependent inflammatory diseases and can be treated by inhibitor compounds of the present invention.
  • inflammatory diseases states such as allergy, arthritis, asthma, atherosclerosis, colitis, diabetes, inflammatory bowel disease, kidney inflammation, skin inflammatory diseases multiple sclerosis, restenosis, and transplantation are VLA-4 dependent inflammatory diseases and can be treated by inhibitor compounds of the present invention.
  • potency is used to screen inhibitor compounds
  • the compound efficacy is the relevant parameter for clinical applications. Efficacy connotes the property of a drug to achieve a desired response.
  • a compound having relatively low potency but more selectivity can be the clinically - 153 -
  • a compound that binds to the VLA-4 receptor, but does not bind tighter than the CS-1 25-mer compound present in fibronectin, and has efficacy in vivo can be used in a pharmaceutical composition. See, for example, Remington ' s
  • a pharmaceutical composition or medicament containing a contemplated inhibitor compound dissolved or dispersed in a pharmaceutically acceptable carrier or diluent that is preferably aqueous is also contemplated for use in treating a CS-l/VLA-4 -mediated inflammatory disease state such as those discussed before.
  • a composition contains an effective amount of a contemplated compound.
  • such a composition contains the CS-l/VLA-4 binding-inhibiting (an inflammation-reducing) amount of a before-discussed, contemplated inhibitor compound.
  • the present invention also contemplates a pharmaceutical composition that can be used in treating one or more of the aforementioned conditions.
  • a contemplated pharmaceutical composition is comprised of a before-described inhibitor compound that inhibits the binding interaction between VLA-4 -containing leukocytes and the fibronectin compound CS-1 portion expressed on endothelial cell surfaces, which compound is dissolved or dispersed in a pharmaceutically acceptable diluent in a binding inhibitory (inflammation-reducing) amount.
  • a contemplated pharmaceutical composition is suitable for use in a variety of drug delivery systems .
  • the dose of the compound varies according to, e.g., the particular compound, the manner of administration, the particular disease being treated and its severity, the overall health and condition of the patient, and the judgment of the prescribing physician or veterinarian.
  • a pharmaceutical composition is intended for parenteral, topical, oral or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment.
  • a pharmaceutical composition can be administered in a variety of unit dosage forms depending upon the method of administration.
  • unit dosage forms suitable for oral administration include powder, tablets, pills, capsules and dragees .
  • a pharmaceutical composition also is administered intravenously.
  • a composition for intravenous administration is particularly contemplated that comprises a solution of a contemplated inhibitor compound dissolved or dispersed in a pharmaceutically acceptable diluent (carrier), preferably an aqueous carrier.
  • a pharmaceutically acceptable diluent carrier
  • aqueous carriers can be used, e.g., water, buffered water, 0.9 percent saline, buffered aqueous ethanol solutions and the like.
  • These compositions can be sterilized by conventional, well known sterilization techniques, or can be sterile filtered.
  • the resulting aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • a composition can contain pharmaceutically acceptable auxiliary 155
  • substances as required to approximate physiological conditions such as pH adjusting and buffering agents, conicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • the concentration of inhibitor compound utilized is usually at or at least about 0.0001 percent to as much as about 0.1 percent by weight and is selected primarily by fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion can be made up to contain 250 ml of sterile Ringer's solution normal saline or PBS, and about 0.25 mg to about 25 mg of the inhibitor compound.
  • Actual methods for preparing parenterally administrable compounds are known or apparent to those skilled in the art and are described in more detail in for example, Remington 1 s , supra .
  • nontoxic solid diluents for solid compositions, conventional nontoxic solid diluents (carriers) may be used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • a pharmaceutically acceptable nontoxic composition is formed by incorporating any of the normally employed excipients, such as those carriers previously listed, and generally 10-95 percent of active ingredient, that is, a before- described inhibitor compound preferably about 20 - 156 -
  • a contemplated inhibitor compound is preferably supplied in solution such as aqueous ethanol or DMSO solution along with a surfactant and propellant .
  • Typical percentages of an inhibitor compound are about 0.0001 percent to about 0.1 percent by weight, and preferably about 0.0001 percent to about 0.001 percent.
  • the surfactant must of course, be nontoxic, and preferably soluble in the propellant.
  • esters or partial esters of fatty acids containing from 6 to 22 carbon atoms such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, and the polyoxyethylene and polyoxypropylene derivatives of these esters.
  • an aliphatic polyhydric alcohol or its cyclic anhydride such as, for example, ethylene glycol, glycerol, erythritol, arabitol, mannitol, sorbitol, the hexitol anhydrides derived from sorbitol, and the polyoxyethylene
  • the surfactant can constitute about 0.1 to about 20 percent by weight of the composition, and preferably about 0.25 to about 5 percent.
  • the balance of the composition is ordinarily propellant.
  • Liquefied propellants are typically gases at ambient conditions, and are condensed under pressure.
  • suitable liquefied propellants are the lower alkanes containing up to 5 carbons, such as butane and propane; and preferably fluorinated or fluorochlorinated alkanes. Mixtures of the above can also be employed.
  • a container equipped with a suitable valve is filled with the appropriate propellant, containing the finely divided compounds and surfactant.
  • ingredients are thus maintained at an elevated pressure until released by action of the valve.
  • a pump-activated spray using air as propellant is also contemplated.
  • the dose of a contemplated compound is in the range of about 1 to 100 mg/day for a 2-3 kg animal.
  • that dose is in the range of about 1 to about 100 mg/day for a 70 kg patient.
  • Administration for asthma is typically by aerosol from a nebulizer. Ideally, therapeutic administration should begin as soon as possible after the attack begins .
  • a pharmaceutical composition embodiment is the inhibitor compound of the present invention and a liposome suitable for pharmaceutical use.
  • suitable liposomes include those disclosed in W09421281, W09421235, U.S. Patent 5,225,212, or WO8606959 wheich are herein incorporated by reference .
  • a pharmaceutical composition containing an inhibitor compound can be administered for prophylactic and/or therapeutic treatments.
  • a composition is administered to a patient already suffering from a disease, as described above, in an amount sufficient to inhibit binding between VLA-4 -expressing leukocytes and endothelial cells that express the CS-1 compound portion; i.e., reduce inflammation and thereby ac least partially arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as "therapeutically effective dose", or a "binding-inhibiting amount” or an "inflammation-reducing amount”.
  • a composition containing a contemplated compound is administered to a patient susceptible to or otherwise at risk of a particular disease.
  • Such an amount is defined to be a "prophylactically effective dose” and is also an amount sufficient to inhibit binding of VLA-4 - expressing leukocytes to CS-1 compound-expressing endothelial cells.
  • the precise amounts again depend on the patient ' s state of health and weight, but generally range from about 1 mg/kg/day to about 500 mg/kg/day, more commonly from about 1 mg/kg/day to about 20 mg/kg/day.
  • Another way to assess a binding- inhibiting amount of a contemplated inhibitor compound is to compare binding inhibition exhibited by the compound to that provided by CS-1 or the 10-mer standard in an in vitro study.
  • One convenient way to make that comparison is by use of IC 50 values of the two compared materials, and base the amount used on the amount of CS-1 or standard 10-mer compound and an amount of the inhibitor compound that is a multiple of the IC 50 value for that reference compound.
  • a compound whose IC 50 value is at least about one-tenth that of the standard 10-mer (ten-times more potent) , when used at one-tenth the molar amount of the 10-mer standard is a useful binding-inhibiting amount. More preferably, the amount is about one-fiftieth the amount of the - 159 -
  • the amount is equal to about one-hundredth that of the 10-mer. Inasmuch as those amounts inhibit binding by about 50 percent, greater concentrations that inhibit binding still further are preferred.
  • a minimal CS-l/VLA-4 -inhibiting amount is the IC 50 value.
  • the CS-l/VLA-4-inhibiting amount usually used begins with the IC 50 value concentration, and can decrease as required or one can increase to the solubility limit of the compound in the utilized aqueous medium; i.e., the aqueous medium at pH 7.2-7.4 used such as normal saline where parenteral administration is used or intestinal fluid where oral administration is used.
  • a composition can be carried out with dose levels and pattern being selected by the treating physician or veterinarian.
  • a pharmaceutical composition is formulated to provide a quantity of an inhibitor compound sufficient to effectively treat the patient.
  • a pharmaceutical composition embodiment is the inhibitor compound in a pharmaceutically acceptable salt .
  • a pharmaceutical composition embodiment is the inhibitor compound of the present invention and an antibody to P selectin. Such a composition can treat various conditions, including, for example, restinosis.
  • Another embodiment is the inhibitor compound and an inhibitor of the polylactosamino glycan, sialyl Le x .
  • composition can treat various conditions, including, for example, inflammation.
  • a process for treating fibronectin CS-l/VLA-4 -mediated inflammation is also contemplated wherein the inhibitor compound is administered to a mammal in need of such a treatment .
  • This administration is preferably via a before-discussed pharmaceutical composition.
  • the compound is administered in an inflammation-reducing (CS-l/VLA-4 binding inhibiting) amount.
  • the mammal such as mouse, rat, rabbit, monkey or human is maintained until the compound is eliminated by a natural bodily process.
  • Multiple administrations in a single day, over a period of days or weeks, or for the life of the host mammal, where the mammal is the recipient of an allograft, are contemplated, as are single administrations .
  • alkyl or phenyl lower alkyl more particularly, when R 2 is lower alkyl and, even more particularly, when R 2 is methyl.
  • Many such compounds are particularly resistant to metabolic degradation and, therefore, are useful for administration, including oral administration, having been shown to possess stability to intestinal proteases (see Example 11, below) .
  • many such compounds are useful for aerosol administration because they possess stability to lung proteases.
  • many such compounds are particularly useful for treating allergic conditions, including asthma (see Example 12, below) .
  • Boc-Phe-OH Boc-Asp (OBn) -OH and Boc-Leu-OH were purchased from

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention conccerne un composé de formule (I) et (II), qui inhibe la liaison entre VLA-4 et le composé de fibronectine CS-1. Elle porte aussi sur des compositions pharmaceutiques et sur des méthodes pour le traitement d'états immuno-inflammatoires, au moyen du composé de l'invention.
PCT/US1998/026605 1998-07-10 1998-12-15 Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation Ceased WO2000002903A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU19153/99A AU1915399A (en) 1998-07-10 1998-12-15 Cs-1 peptidomimetics, compositions and methods of using the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11368998A 1998-07-10 1998-07-10
US09/113,689 1998-07-10

Publications (1)

Publication Number Publication Date
WO2000002903A1 true WO2000002903A1 (fr) 2000-01-20

Family

ID=22350927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/026605 Ceased WO2000002903A1 (fr) 1998-07-10 1998-12-15 Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation

Country Status (2)

Country Link
AU (1) AU1915399A (fr)
WO (1) WO2000002903A1 (fr)

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001060826A3 (fr) * 2000-02-17 2002-01-17 Du Pont Pharm Co CARBOCYCLES ET HETEROCYCLES SUCCINOYLAMINO UTILISES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)
WO2001058852A3 (fr) * 2000-02-11 2002-03-14 Dompe Spa Amides servant a inhiber la chimiotaxie des neutrophiles associee a l'il-8
JP2003535865A (ja) * 2000-06-07 2003-12-02 バーテックス ファーマシューティカルズ インコーポレイテッド カスパーゼインヒビターおよびその使用
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6680333B2 (en) 2001-03-10 2004-01-20 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
US6962937B2 (en) 2001-08-01 2005-11-08 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation and their use
US6962913B2 (en) 1998-08-07 2005-11-08 Bristol-Myers Squibb Company Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7053081B2 (en) 2000-04-03 2006-05-30 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of A-β protein production
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US7858776B2 (en) 2002-10-03 2010-12-28 Astrazeneca Ab Lactams and uses thereof
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015973A1 (fr) * 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
WO1997003094A1 (fr) * 1995-07-11 1997-01-30 Biogen, Inc. Composes inhibiteurs d'adherence cellulaire
WO1998004913A1 (fr) * 1996-07-25 1998-02-05 Biogen, Inc. Modele moleculaire pour inhibiteurs vl4-4
US5770573A (en) * 1993-12-06 1998-06-23 Cytel Corporation CS-1 peptidomimetics, compositions and methods of using the same
WO1998042656A1 (fr) * 1997-03-21 1998-10-01 Cytel Corporation Nouveaux composes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995015973A1 (fr) * 1993-12-06 1995-06-15 Cytel Corporation Peptidomimetiques cs-1, compositions et procedes pour les utiliser
US5770573A (en) * 1993-12-06 1998-06-23 Cytel Corporation CS-1 peptidomimetics, compositions and methods of using the same
WO1997003094A1 (fr) * 1995-07-11 1997-01-30 Biogen, Inc. Composes inhibiteurs d'adherence cellulaire
WO1998004913A1 (fr) * 1996-07-25 1998-02-05 Biogen, Inc. Modele moleculaire pour inhibiteurs vl4-4
WO1998042656A1 (fr) * 1997-03-21 1998-10-01 Cytel Corporation Nouveaux composes

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6962913B2 (en) 1998-08-07 2005-11-08 Bristol-Myers Squibb Company Benzo-1,4-diazepin-2-ones as inhibitors of Aβ protein production
US7507815B2 (en) 1998-08-07 2009-03-24 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of a-β protein production
US7304055B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7304056B2 (en) 1998-08-07 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of Aβ protein production
US7101870B2 (en) 1998-08-07 2006-09-05 Bristol-Myers Squibb Pharma Company Succinoylamino lactams as inhibitors of A-β protein production
US7718795B2 (en) 1998-12-24 2010-05-18 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7304049B2 (en) 1998-12-24 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylaminobenzodiazepines as inhibitors of Aβ protein production
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7812038B2 (en) 1999-05-07 2010-10-12 Encysive Pharmaceuticals, Inc. Carboxylic acid derivatives that inhibit the binding of integrins to their receptors
US6668527B2 (en) 1999-12-28 2003-12-30 Pfizer Inc. Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6903128B2 (en) 1999-12-28 2005-06-07 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
US6667331B2 (en) 1999-12-28 2003-12-23 Pfizer Inc Non-peptidyl inhibitors of VLA-4 dependent cell binding useful in treating inflammatory, autoimmune, and respiratory diseases
RU2273630C2 (ru) * 2000-02-11 2006-04-10 Домпе С.П.А. (r)-2-арилпропионамиды, полезные при ингибировании ил-8-индуцированного хемотаксиса нейтрофилов, способ и промежуточные соединения для их получения, фармацевтическая композиция, ингибирующая хемотаксис нейтрофилов, индуцированный интерлейкином-8
AU2001244125B2 (en) * 2000-02-11 2006-11-09 Dompe' Farmaceutici S.P.A. Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
US7705050B2 (en) 2000-02-11 2010-04-27 Janete Peloia Barroso Gandolfi, legal representative Amides, useful in the inhibition of IL-8-induced chemotaxis of neutrophils
CZ302945B6 (cs) * 2000-02-11 2012-01-25 Dompé Pha.R.Ma S.P.A. (R)-enantiomery amidu kyseliny 2-arylpropionové a farmaceutické smesi s jejich obsahem
WO2001058852A3 (fr) * 2000-02-11 2002-03-14 Dompe Spa Amides servant a inhiber la chimiotaxie des neutrophiles associee a l'il-8
KR100884417B1 (ko) * 2000-02-11 2009-02-19 돔페 파르마 에스.피.에이. 호중구의 ｉｌ-8-유도된 화학주성의 저해에 유용한 아미드
WO2001060826A3 (fr) * 2000-02-17 2002-01-17 Du Pont Pharm Co CARBOCYCLES ET HETEROCYCLES SUCCINOYLAMINO UTILISES EN TANT QU'INHIBITEURS DE LA PRODUCTION DE LA PROTEINE A$g(b)
US6525044B2 (en) 2000-02-17 2003-02-25 Bristol-Myers Squibb Company Succinoylamino carbocycles and heterocycles as inhibitors of a-β protein production
US7053081B2 (en) 2000-04-03 2006-05-30 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of A-β protein production
US7390896B2 (en) 2000-04-03 2008-06-24 Bristol-Myers Squibb Pharma Corporation Cyclic malonamides as inhibitors of Aβ protein production
US7528249B2 (en) 2000-04-03 2009-05-05 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of aβ protein production
US7276496B2 (en) 2000-04-03 2007-10-02 Bristol-Myers Squibb Pharma Company Cyclic malonamides as inhibitors of Aβ protein protection
JP2003535865A (ja) * 2000-06-07 2003-12-02 バーテックス ファーマシューティカルズ インコーポレイテッド カスパーゼインヒビターおよびその使用
US6680333B2 (en) 2001-03-10 2004-01-20 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use and pharmaceutical preparations comprising them
US6962937B2 (en) 2001-08-01 2005-11-08 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation and their use
US7858776B2 (en) 2002-10-03 2010-12-28 Astrazeneca Ab Lactams and uses thereof
US7342007B2 (en) 2003-03-14 2008-03-11 Astrazeneca Ab Lactams and uses thereof
WO2004080983A1 (fr) * 2003-03-14 2004-09-23 Astrazeneca Ab Nouveaux lactames et leurs utilisations
US11116760B2 (en) 2018-10-30 2021-09-14 Gilead Sciences, Inc. Quinoline derivatives
US11174256B2 (en) 2018-10-30 2021-11-16 Gilead Sciences, Inc. Imidazopyridine derivatives
US11179383B2 (en) 2018-10-30 2021-11-23 Gilead Sciences, Inc. Compounds for inhibition of α4β7 integrin
US11224600B2 (en) 2018-10-30 2022-01-18 Gilead Sciences, Inc. Compounds for inhibition of alpha 4 beta 7 integrin
US12053462B2 (en) 2018-10-30 2024-08-06 Gilead Sciences, Inc. Quinoline derivatives
US11578069B2 (en) 2019-08-14 2023-02-14 Gilead Sciences, Inc. Compounds for inhibition of α4 β7 integrin

Also Published As

Publication number Publication date
AU1915399A (en) 2000-02-01

Similar Documents

Publication Publication Date Title
AU693143B2 (en) CS-1 peptidomimetics, compositions and methods of using the same
US5770573A (en) CS-1 peptidomimetics, compositions and methods of using the same
US5821231A (en) CS-1 peptidomimetics, compositions and methods of using same
US5869448A (en) Cyclic CS-1 peptidomimetics, compositions and methods of using same
US5936065A (en) CS-1 peptidomimetics, compositions and methods of using the same
WO2000002903A1 (fr) Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation
AU633872B2 (en) Glycine derivatives
US6255285B1 (en) Phenethylamine derivatives
US5114918A (en) Endothelin antagonistic cyclic pentapeptides
US5192746A (en) Cyclic cell adhesion modulation compounds
AU596783B2 (en) Peptide analogues for thrombogenesis inhibition
IE913120A1 (en) Enzyme inhibitors
EP0677060A1 (fr) Inhibiteurs peptidiques de l'adhesion cellulaire
JPH08502493A (ja) アルギニンケト‐アミド酵素阻害剤
CZ198497A3 (en) Cyclic peptides inhibiting fibronectin adhesion, process of their preparation and pharmaceutical compositions containing thereof
WO1993008823A1 (fr) Composes de guanidinyle et composes apparentes modulant l'adhesion cellulaire
JPH03118330A (ja) フイブリノーゲンレセプター拮抗剤
CS294791A3 (en) Fibrinogen receptor antagonists
JP2005272480A (ja) トロンボスポンジン−様活性を有するペプチド及びその治療のための使用
AU661659B2 (en) Anti-thrombotic peptide and pseudopeptide derivatives
Williams et al. Cyclic peptides as selective tachykinin antagonists
US6117840A (en) CS-1 peptidomimetics, compositions and methods of using the same
GREENSPOON et al. Novel ψ‐S‐CH2 peptide‐bond replacement and its utilization in the synthesis of nonpeptidic surrogates of the Leu‐Asp‐Val sequence that exhibit specific inhibitory activities on CD4+ T cell binding to fibronectin
JPH07316193A (ja) ペプチド誘導体およびその用途
HK1028409A (en) Phenethylamine derivatives

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase