WO1998042656A1 - Nouveaux composes - Google Patents

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Publication number
WO1998042656A1
WO1998042656A1 PCT/US1998/005709 US9805709W WO9842656A1 WO 1998042656 A1 WO1998042656 A1 WO 1998042656A1 US 9805709 W US9805709 W US 9805709W WO 9842656 A1 WO9842656 A1 WO 9842656A1
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group
lower alkyl
formula
ring
heterocyclic
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PCT/US1998/005709
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English (en)
Inventor
Ya-Bo He
Mariano J. Elices
Thomas S. Arrhenius
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Cytel Corporation
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Publication of WO1998042656A1 publication Critical patent/WO1998042656A1/fr

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    • 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
    • C07K5/02—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
    • C07K5/10—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

Definitions

  • the present invention relates to novel compounds that inhibit VLA-4 binding.
  • the VLA-4 receptor also known as the ⁇ 4 ⁇ l or CD49d/CD29 receptor, is expressed on the surface of some cells and is known to control the movement of those cells.
  • the VLA-4 receptor is expressed on and controls the movement of leukocytes including, for example, mature T and B lymphocytes, natural killer cells, monocytes, basophils and eosinophils. See, for example, Hemler, Ann. .Rev.
  • the VLA-4 receptor controls cell movement by binding to specific counter receptors.
  • Specific counter receptors include, for example, the cytokine-inducible vascular cell adhesion molecule-1 (VCAM-1) and the extracellular matrix protein fibronectin. See, for example, Elices et al . , Cell , 60:577-584 (1990) and ayner et al . , J " . Cell Biol . , 109:1321-1330 (1989) .
  • the VCAM-1 counter receptor is expressed on a variety of cells.
  • the VCAM-1 is expressed on the surface of endothelial cells, which line the vascular system.
  • the expression of VCAM-1 on those cells is induced by pro-inflammatory cytokines such as, IL-1, TNF ⁇ , and IL-4, and is an early event in the development of inflammation. See, for example, Osborn et al . , Cell , 59:1203-1211 (1989).
  • the amino acid sequence within VCAM-1 that binds to the VLA-4 receptor has the amino acid sequence Gln-Ile-Asp-Ser-Pro. See, for example, Clements et al . ,
  • the amino acid sequence within the fibronectin counter receptor that binds the VLA-4 receptor also has been identified. See, for example, Wayner et al . , J " . Cell . Biol . , 109:1321-1330 (1989).
  • That sequence comprises a 25-amino acid sequence, termed CS-1, and the minimal amino acid sequence within CS-1 that binds to the VLA-4 receptor has the amino acid sequence Leu-Asp-Val . See, for example,
  • the VLA-4 receptor is particularly important in the control of leukocyte movement into inflamed tissue.
  • the VLA-4 receptor guides the leukocytes to inflamed tissue by binding to counter receptors expressed as a result of inflammation, such as VCAM-1 on endothelial cells induced by pro- inflammatory cytokines . That binding causes the circulating leukocytes to stop circulating and attach to the vascular wall at the site of inflammation. The attached leukocytes can then migrate into adjacent inflamed tissues.
  • VLA-4 receptor's control of leukocyte movement during inflammation is provided by in vivo studies. Specifically, antibodies and small molecule antagonists to VLA-4 receptors that block the receptor's interaction with counter receptors have been shown to inhibit inflammatory reactions in vivo .
  • Inflammation in specific organs such as the skin, brain, kidney, lung and gut have been shown to be VLA-4 receptor dependent, mostly as a result of recruiting lymphocytes, monocytes and eosinophils. See, for example, Elices, M.J., "Cell Adhesion and Human Disease,” published by John Wiley & Sons, London, pp. 79-90, (1995); Lobb et al . , J. Clin . Invest . 94:1722- 1728 (1994) .
  • the present invention is directed to compounds that inhibit VLA-4 binding.
  • the invention is directed to the compounds of the following Formula (1) :
  • the invention is also directed to a pharmaceutically-acceptable derivative of a compound of Formula 1 as described below.
  • the invention is further directed to a pharmaceutical composition containing the compound of Formula 1 or a pharmaceutically-acceptable derivative thereof and a pharmaceutically-accepable carrier, also as described below.
  • the invention is directed to the compounds of the following Formula (1) :
  • R 1 is an alkyl group, an adamantyl group, or a 5-, 6-, 6,5-, or 6,6- membered non-heterocyclic, heterocyclic, aromatic, partially saturated or fully saturated ring that is optionally substituted by one or more nitro, fluoro, chloro, bromo, amino, lower alkylamino, di (lower alkyl) amino, hydroxy, lower alkyl, lower alkoxy, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonyl, or lower alkoxycarbonyl groups.
  • R 1 is such a ring, the ring is connected to R 2 either directly by a bond or indirectly through a lower alkyl group.
  • R 2 is a lower alkyl, a C 2 to C 4 alkenyl, or a C 2 to C 4 alkynyl group, in which each group optionally can contain a carbonyl , ether, thioether, aminocarbonyl , sulfonamido, sulfone, or sulfoxide group.
  • R 2 can be a group of the Formula (2) or (3) :
  • E is a CX 1 ⁇ 2 group, a NX 3 group or an oxygen atom and F is a CX 4 X 5 group, a NX 6 group or an oxygen atom, but E and F both are not simultaneously oxygen atoms.
  • X 1 , X 2 , X 3 , X 4, X 5 , and X 6 are independently selected from the group consisting of a hydrogen atom or a lower alkyl group. However, if R 1 is the alkyl group, R 2 must be a group of the Formula (2) or (3) .
  • R 3 is a 5-, 6-, 6,5-, or 6,6-membered aromatic ring optionally containing from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur atoms and is connected to the carbonyl carbon of the amide bond containing R 4 of Formula 1 either directly by a bond or indirectly through a lower alkyl group.
  • R 4 in the above Formula 1 is a hydrogen atom or a lower alkyl group .
  • R 5 in the above Formula 1 is hydrogen, a lower alkyl, or a lower alkyl amido group optionally substituted by lower hydroxyalkyl, di (lower alkyl) sulfide, or lower thioalkyl group, or a 5- or 6-membered non-heterocyclic saturated ring that is connected to the methinyl carbon of Formula 1 either directly by a bond or indirectly through a lower alkyl group .
  • R is a group of the
  • R 7 is a lower alkyl group.
  • R 8 is a lower alkyl, an amino, a loweralkylamino, or a di (loweralkyl) amino group.
  • R 6 is a group of the Formula
  • A is a nitrogen or oxygen atom.
  • R 9 is a hydrogen atom or a lower alkyl, lower hydroxyalkyl, lower thioalkyl, di (lower alkyl) sulfide group; a 6-membered non- heterocyclic aromatic, partially saturated or saturated ring or a 5-or 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen, oxygen, or sulfur atoms, or a 3-indolyl ring.
  • Each of these rings is connected to the methinyl carbon of Formula 6 either directly by a bond or indirectly through a lower alkyl group.
  • the non-heterocyclic or heterocyclic aromatic ring at R 9 can optionally be substituted by a hydroxy, nitro, primary carboxamide, lower alkyl primary carboxamide, or (lower alkoxy) lower alkyl group.
  • R 9 can be taken together with R 10 to form a 6, 6-membered ring of the Formula (7) :
  • R 10 when A is a nitrogen atom in Formula 6, R 10 can be a lower alkyl, a lower hydroxyalkyl, or a N-morpholino group. Alternatively, R 10 can be taken together with R 9 as described above, or taken together with R 11 to form a 5- or 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms and optionally containing an oxygen atom, a sulfur atom, a sulfone group or a sulfoxide group wherein the heterocyclic ring is aromatic, partially saturated or fully saturated.
  • the 5- or 6-membered heterocyclic ring optionally can be substituted by one or more hydroxy, lower alkyl, lower hydroxyalkyl, lower alkoxy, lower hydroxyalkoxy lower alkyl, (lower alkoxy) lower alkyl, carboxylic acid, lower alkyl carboxylic acid, primary carboxamide, lower alkyl primary carboxamide, lower alkylcarbonyloxy, phenyl, phenyl lower alkylsulfonyl, or phenylsulfonyl groups in which the phenyl group of the phenyl lower alkyl sulfonyl or phenyl sulfonyl group is optionally substituted by a lower alkyl moiety.
  • R 11 is a lower alkyl optionally substituted by one or more (lower alkyl) amino, or di (lower alkyl) amino, lower alkyl primary carboxamide, lower alkyl substituted by a morpholino group, a cyclohexyl group, a hydrogen atom or is taken together with R 10 as described above.
  • R 9 is as above except that the R 9 cannot be taken with R 10 .
  • R 10 is a lower alkyl or a 6-membered non-heterocyclic or heterocyclic ring that is aromatic, partially saturated, or saturated and is connected directly to the methinyl carbon of Formula 6 by a bond or indirectly through a lower alkyl group.
  • R 11 is absent.
  • a compound of Formula 1 includes a pharmaceutically acceptable salt of the compound of Formula 1. All chiral carbon centers of a Formula 1 compound can be in in a pure R form, pure S form, or a mixture of R and S forms in any proportion.
  • a compound of Formula 1 also includes a bioisostere of the compound of Formula 1.
  • a "lower alkyl” refers to a C to C 4 alkyl and denotes the methyl, ethyl, n-propyl, isopropyl, n- butyl, sec-butyl, t-butyl or isobutyl groups.
  • alkyl group is a saturated straight- or branched-carbon chain of from 1 to about 20 carbons and includes, for example, those groups exemplifying the terms "lower alkyl” and through to groups such as dodecanyl, pentadecanyl , heptadecanyl , 7- ethyloctadencanyl, 4-methyl-13-ethylheptadecanyl, eicosanyl, and the like.
  • C 2 to C 4 alkenyl group is meant a straight- or branched-carbon chain having at least one double bond and denotes radicals such as, vinyl
  • a "C 2 to C 4 alkynyl” group is a straight- or branched-carbon chain having at least one triple bond and denotes radicals such as, ethylynyl (-C ⁇ C-), propargyl, but-3-yn-l-yl , 2-but-2-yn-yl, as well as diynes of straight and branched chains, and the like.
  • a "(lower alkyl) amino” group is a lower alkyl radical bonded to an amino radical and denotes radicals such as methylamino (CH 3 NH-), t-butylamino, and the like.
  • a “di (lower alkyl) amino” group means two lower alkyl radicals bonded to an amino radical .
  • the lower alkyl groups can be the same or different.
  • the term denotes groups such as dimethylamino ((CH 3 ) 2 N-), (t-butyl) n-propylamine, and the like.
  • lower alkyl primary carboxamide a group is meant as being a primary amide bonded to a lower alkyl radical which lower alkyl radical is in turn bonded to Formula 1 and denotes radicals such as methylcarboxyamide (-CH 2 CONH 2 ) , n-butyl carboxyamide and the like.
  • a "lower hydroxyalkyl” group is a hydroxyl radical bonded to a lower alkyl radical and denotes radicals such as hydroxymethyl (-CH 2 OH) , 3 -hydroxy- n-butyl, and the like.
  • lower alkyl carboxylic acid is a carboxy radical bonded via its carbon atom to a lower alkyl radical as described above which lower alkyl radical in turn is bonded to Formula 1.
  • the term denotes radicals such as methylcarboxylic acid (-CH 2 COOH), n-butylcarboxylic acid and the. like.
  • a "lower alkoxy” group is a lower alkyl radical defined above bonded to an oxygen atom radical and denotes radicals such as methoxy (CH 3 0-), isopropyloxy, n-butyloxy, and the like.
  • a "(lower alkoxy) lower alkyl” group is an ether wherein the lower alkyl groups bound to both sides of the oxygen are the same or different and one of the lower alkyl groups is bound to the group so substituted.
  • the term denotes radicals such as isopropyloxymethyl ( (CH 3 ) 2 CHOCH 2 -) , 2- (n-butyloxy) ethyl, and the like.
  • a "lower alkoxycarbonyl” group is a lower alkyl radical bonded to an ester oxygen which is bonded to a carbonyl radical.
  • the term denotes radicals such as methoxycarbonyl (CH 3 OC(0)-), ethoxycarbonyl and the like.
  • lower hydroxyalkoxy lower alkyl denotes a hydroxy radical bonded to a lower alkyl radical which is bonded to an ethereal oxygen atom bound in turn to a lower alkyl radical and denotes radicals such as hydroxymethoxymethyl (CH 2 (OH) OCH 2 -) , 1 (hydroxy) n-propyloxyethyl, 4- (hydroxy ⁇ nethoxy) n-butyl, and the like.
  • alkylcarbonyl is an alkyl group bonded to a carbonyl radical and denotes radicals such as acetyi (CH 3 CO-), n-eicosanoyl , and the like.
  • a "lower alkylcarbonyloxy” group is a lower alkyl radical bonded to the carbonyl carbon of an ester group bound through an ethereal oxygen atom and denotes radicals such as methylcarbonyloxy (CH 3 COO-), n- butylcarbonyloxy, and the like.
  • a “lower alkyl amido” group is a lower alkyl radical bonded to the carbonyl carbon of the amide radical and denotes radicals such as methyl amido (CH 3 CONH-), n-hexylamido, and the like.
  • a "di (lower alkyl) sulfide” group is a thioether wherein the lower alkyl groups bound on both sides of the sulfide are the same or different and one of the lower alkyl groups is bound to the group so substituted.
  • the term denotes radicals such as methylthiomethyl (CH 3 SCH 2 -), methylthiobutyl, and the like.
  • a "lower thioalkyl” group is a lower alkyl radical bonded to a mercaptan group and denotes radicals such as methylthiol (-CH 2 SH) , n-butylthiol, and the like.
  • radicals such as methylthiol (-CH 2 SH) , n-butylthiol, and the like.
  • 5-, 6-, 6,5-, 6,6- membered non-heterocyclic ring aromatic, partially saturated or fully saturated is meant a monocyclic or fused bicyclic ring such as cyclopentyl, cyclohexyl, cyclohex-1, 4-dienyl, phenyl, indenyl, naphthalenyl, and the like.
  • 5- or 6-membered non-heterocyclic saturated ring denotes the radicals cyclopentanyl and cyclohexyl.
  • 6-membered non-heterocyclic aromatic, partially saturated or saturated ring is meant radicals such as cyclohexyl, cyclohex-1-enyl , phenyl, and the like.
  • a 5-, 6-, 6,5-, 6,6- membered heterocyclic ring aromatic, partially saturated or fully saturated denotes a monocyclic- or fused bicyclic ring optionally containing 1 to 3 nitrogen, oxygen, or sulfur atoms.
  • examples of such rings include pyrrolyl, 3-pyrrolinyl, pyrrolidinyl , furyl, thienyl, pyridinyl, piperidinyl, pyrazinyl, piperazinyl, morpholinyl, indolyl, benzofuranyl, benzisoxazolyl, quinazolinyl, quinazolinyl', and the like.
  • heterocyclic ring containing 1 or 2 nitrogen atoms and optionally containing an oxygen atom, a sulfur atom, a sulfone group or a sulfoxide group wherein the heterocyclic ring is aromatic, partially saturated, or fully saturated and denotes radicals such as pyrazolyl, pyrrolinyl, pyrrolidinyl , furyl, thiophenyl, thioxolyl, pyridinyl, pyridazinyl, piperidinyl , pyrimidinyl, dioxanyl, morpholinyl 1,3 thiaoxaolidinyl S-oxide or S- dioxide, 1,3 thiaoxaoinyl S-oxide or S-dioxide, 1,3 thiaoxaoperhydryl S-oxide or S-dioxide, and the like.
  • a 5-, 6-, 6,5-, or 6, 6-membered aromatic ring optionally containing from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur denotes a ring such as pyrazolyl, phenyl, pyridazinyl, indolyl , isoquinolinyl, and the like.
  • pharmaceutically-acceptable salt encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations such as those chosen from the alkali and alkaline earth metals, (for example, lithium, sodium, potassium, magnesium, barium and calcium) ; ammonium; and the organic cations (for example, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis (2 -hydroxyethyl) ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations) .
  • the organic and inorganic cations such as those chosen from the alkali and alkaline earth metals, (for example, lithium, sodium, potassium, magnesium, barium and calcium) ; ammonium; and the organic cations (for example, dibenzylammonium, benzylammonium, 2- hydroxyethylammonium, bis (2 -hydroxye
  • cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, and the protonated forms of basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine, and arginine, and acetic acid-like counter-ions such as acetate and trifluoroacetate .
  • any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term.
  • a preferred cation for the carboxylate anion is the sodium cation.
  • the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and organic or inorganic acids.
  • Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and the like acids.
  • the compounds of Formula 1 above and Formula 29 below may also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent.
  • the solvates and hydrates of such compounds are included within the scope of this invention.
  • bioisostere refers to a compound differing from a compound of the invention by one or more atoms expected to produce an equivalent biological effect.
  • An example of a bioisostereic substitution is the interchange of nitrogen and carbon in an aromatic ring. See, for example, "Medicinal Chemistry,” Alfred Burger, Ed., Interscience Publishers, N.Y., 1960, pp 78-80, which is incorporated herein by reference.
  • D is an oxygen or sulfur atom or a sulfone, sulfoxide, CH 2 , or NH group and the CH 2 or NH group can be optionally substituted by a lower alkyl, primary carboxamide, lower alkyl primary carboxamide, hydroxy, lower hydroxyalkyl, lower alkoxy, (lower alkoxy) lower alkyl, lower hydroxyalkoxy lower alkyl, alkylcarbonyl, carboxylic acid, lower alkyl carboxylic acid, phenyl, phenyl lower alkyl sulfonyl, phenylsulfonyl in which the phenyl of the phenyl lower alkyl sulfonyl or phenylsulfonyl is optionally substituted by a lower alkyl, or a lower alkylcarbonyloxy group.
  • R 9 is a hydrogen atom or a lower alkyl, lower hydroxyalkyl, lower thioalkyl, di (lower alkyl) sulfide; a 5-or 6-membered non-heterocyclic aromatic, partially saturated or saturated ring or a 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen, oxygen or sulfur atoms, or a 3-indolyl ring.
  • Each of these rings is connected to the methinyl carbon of Formula 9 either directly by a bond or indirectly through a lower alkyl group.
  • the non-heterocyclic or heterocyclic aromatic ring at R 9 can optionally be substituted by a hydroxy, nitro, primary carboxamide, lower alkyl primary carboxamide, or (lower alkoxy) lower alkyl group.
  • R 1 , R 2 , R 3 , R 4 , and R 5 in Formula 9 are as in Formula 1 above .
  • R 9 is a hydrogen atom or a lower alkyl, lower hydroxyalkyl, lower thioalkyl, di (lower alkyl) sulfide; a 6-membered non-heterocyclic aromatic, partially saturated or saturated ring or a 5- or 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen, oxygen or sulfur atoms, or a 3-indolyl ring.
  • Each of these rings is connected to the methinyl carbon of Formula 10 either directly by a bond or indirectly through a lower alkyl group.
  • the non-heterocyclic or heterocyclic aromatic ring at R 9 can optionally be substituted by a hydroxy, nitro, primary carboxamide, lower alkyl primary carboxamide, or (lower alkoxy) lower alkyl group.
  • R 12 is a hydrogen atom, carboxylic acid, a lower alkyl carboxylic acid, a primary carboxamide, a lower alkyl primary carboxamide, a lower alkyl group or a lower hydroxyalkyl .
  • R 1 , R 2 , R 3 , R 4 , and R 5 in Formula 10 are as in Formula 1 above.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 11 are as in Formula 1 above .
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 11 are as in Formula 1 above.
  • a group of optimum compounds within that of Formula 1 has the following Formula (13) :
  • Optimum compounds of Formula 1 also occur when:
  • R 1 is a 5-, 6-, 6,5-, or 6, 6-membered non- heterocyclic or heterocyclic, aromatic, partially saturated or fully saturated ring that is optionally substituted by one or more nitro, fluoro, chloro, bromo, amino, lower alkylamino, di (lower alkyl) amino, hydroxy, lower alkyl, lower alkoxy, alkylcarbonyloxy, alkylcarbonylamino, alkylcarbonyl, or lower alkoxycarbonyl groups and the ring is connected to R 2 either directly by a bond or indirectly through a lower alkyl group; and R is a group of the Formula (2)
  • E is a CX X X 2 group, a NX 3 group or an oxygen atom and F is a CX 4 X 5 group, a NX 6 group or an oxygen atom, but E and F both are not simultaneously oxygen atoms and X 1 , X 2 , X 3 , X 4, X 5 , and X 6 are independently selected from the group consisting of a hydrogen atom or a lower alkyl group.
  • R 3 is a 6-membered aromatic ring optionally containing from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen or sulfur atoms and is connected to the carbonyl carbon of the amide bond containing R 4 of Formula 1 either directly by a bond or indirectly through a lower alkyl group .
  • optimum compounds contain a R 5 that is a lower alkyl group or a 6-membered non-heterocyclic saturated ring that is connected to the methinyl carbon of Formula 1 either directly by a bond or indirectly through a lower alkyl group.
  • R 5 that is a lower alkyl group or a 6-membered non-heterocyclic saturated ring that is connected to the methinyl carbon of Formula 1 either directly by a bond or indirectly through a lower alkyl group.
  • R 6 is a group of the Formula (4!
  • R 6 is a group of the Formula (6)
  • R 9 is taken together with R 10 to form a group of the Formula (8) :
  • R 2 is a group of the Formula (2) :
  • E is a CX X X 2 group, a NX 3 group or an oxygen atom and F is a CXX 5 group, a NX 6 group or an oxygen atom; and X 1 , X 2 , X 3 , X 4 ' X 5 , and X 6 are independently selected from the group consisting of a hydrogen atom or a lower alkyl group with the provisios that E and F both are not simultaneously oxygen atoms; and if R 1 is the alkyl group, R 2 must be a group of the Formula (2) or (3) .
  • 6-membered non-heterocyclic aromatic partially saturated or saturated ring or the 6-membered heterocyclic aromatic ring containing from 1 to 3 nitrogen atoms, or the 3-indolyl ring as described above.
  • the invention further encompasses a group of compounds using any combination of the substituents at R 1 , R 2 , R 3 , R 4 , and R 6 set forth above in compounds of the Formulas (14) through (79) .
  • the invention also encompasses a compound selected from the group of compounds consisting of the Formulas (35), (43), (71), (76), (77), (78), and (79).
  • the invention is also directed to a pharmaceutically acceptable derivative of the compound of Formula 1.
  • a pharmaceutically acceptable derivative is a compound of Formula 1 to which a chemical group is attached that facilitates the use of the compound in vi tro or in vivo .
  • Such prophylactic or pharmaceutical derivatives include compounds that inhibit VLA-4 binding after in vivo processing.
  • Such derivatives can be enzymatically or hydrolytically cleaved in vivo to liberate a compound that inhibits VLA-4 binding.
  • a pharmaceutically acceptable derivative also includes a derivative of a compound of Formula 1 that improves the water-solubility, bioavailability or oral availability of the compound.
  • a derivative of a compound of Formula 1 that improves the water-solubility, bioavailability or oral availability of the compound.
  • Such a derivative can, but does not have to be, in vivo processed for improved water-solubility, bioavailability or oral availability.
  • the invention is directed to a pharmaceutically acceptable derivative having the following Formula (80) :
  • J is an oxygen or a sulfur atom. Furthermore, R is
  • a lower cyclohexyl alkyl that is optionally substituted by a hydroxyl, phenyl, phenyl sulfonyl, pyridinyl, pyridinyl N-oxide, a (lower alkyl] amino, a di (lower alkyl) amino, a (lower alkyl) amide, a di (lower alkyl) amide, a di (lower alkyl) sulfide, a (lower alkoxy) lower alkyl, a ((lower alkoxy) lower alkoxy) lower alkyl, a (((lower alkoxy) lower alkoxy) lower alkyl, a (((lower alkoxy) lower alkoxy) lower alkoxy) lower alkyl, a (lower alkylcarbonyloxy) lower alkyl, (N- (lower alkyl) aminocarbonyl) lower alkyl, a
  • a cyclohexyl a phenyl, a pyridinyl, a pridinyl N-oxide, a 1,3- dioxan-2-yl, a 3-tetrahydropyranyl, a (4-hydroxybutyric) lacton-3-yl , or a phthalidyl ring, wherein said ring is connected to J either directly by a bond or indirectly by a lower alkyl group.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 in Formula 80 are as in Formula 1 above.
  • a “lower alkyl,” a “(lower alkyl) amino”, a “di (lower alkyl) amino,” a “di (lower alkyl) sulfide, " and "(lower alkoxy) lower alkyl” group in Formula 80 are as defined above.
  • a " (lower alkyl) amide” group in Formula 80 is a lower alkyl radical bonded to the nitrogen atom of an amide radical and denotes radicals such as methyl amide (CH 3 NCO-) t-butyl amicle and the like.
  • a "di (lower alkyl) amide” group means two lower alkyl radicals bonded to the nitrogen atom of an amide radical .
  • the lower alkyl groups can be the same or different.
  • the term denots groups such as dimethyl amide ((CH 3 ) 2 NCO-), (t-butyl) n-propyl amide and the like.
  • a "((lower alkoxy) lower alkoxy) lower alkyl” group is a lower alkoxy radical bonded to a lower alkoxy radical which is bonded to a lower alkyl radical .
  • the term denotes groups such as methoxymethoxymethyl (CH 3 OCH 2 OCH 2 -) , 3 (2 ' (ethoxy) ethoxy) propyl, and the like.
  • a " ( ( lower alkoxy) lower alkoxy) lower alkoxy) lower alkyl” group is a lower alkoxy radical bonded to a lower alkoxy radical which is bonded to another lower alkoxy radical which is bonded to a lower alkyl radical .
  • the term denotes groups such as methoxy ⁇ nethoxymethoxymethyl (CH 3 OCH 2 OCH 2 OCH 2 -) , 3 ( (2 ' (ethoxy) 2 ' ethoxy) ethoxy) propyl and the like.
  • a "(lower alkylcarbonyloxy) lower alkyl” group is a lower alkyl group bonded to a carbonyl group of an ester radical bound to a lower alkyl radical and exemplified by such groups as methylcarbonyloxymethyl (CH 3 COOCH 2 -) , pivaloyloxyethyl, and the like.
  • (N- (lower alkyl) aminocarbonyl) lower alkyl contains a lower alkyl radical bonded to an amino radical which is bonded to the carbon of a carbonyl radical which is bonded to a lower alkyl radical .
  • the term denotes groups such as methylaminocarbonylmethyl (CH 3 NHCOCH 2 -) , 3- (4 ' (n-butylaminocarbonyl) ) n-propyl and the like.
  • (N- (lower alkyl) ) (N- (lower alkoxy) ) aminocarbonyl) - lower alkyl is meant a lower alkyl radical and a lower alkoxy radical bonded to an amino radical which is bonded to a carbonyl radical and denotes groups such as N-methyl-N-methoxyaminocarbonylmethyl (CH 3 (CH 3 0) NCOCH 2 - ), N- (n-but-4-yl) -N- (ethoxy) aminocarbonylethyl and the like.
  • (N,N' -di (lower alkyl) aminocarbonyl) lower alkyl is defined as two lower alkyl radicals bonded to an amino radical which is bond to a carbonyl radical which is bonded to a lower alkyl radical .
  • the term denotes such groups as N-methyl-N-ethylaminocarbonylmethyl (CH 3 (CH 3 CH 2 ) NCOCH 2 - ) , N(n-but-4-yl) -N- (n-prop-3-yl) ) aminocarbonylmethyl , and the like.
  • a " (N-morpholinocarbonyl) lower alkyl” group is a morpholinyl radical bonded by the nitrogen atom of the morpholino group to the carbon atom of the carbonyl which is bonded to a lower alkyl radical .
  • the term denotes groups such as (N' -morpholinocarbonyl) methyl , 3 (N' -morpholinocarbonyl) n-butyl, and the like.
  • a 1- ( (O- ( (lower alkylcarbonato) ) eth-l-yl is a lower alkyl radical bonded to one of the two ether oxygens of a carbonate group, the ethereal oxygen of which is bound to Formula 80.
  • a "2-oxo-l, 3-dioxolen-4-ylmethyl” group includes, for example,
  • a "phthalidyl” ring includes 3 -phthalidyl, or 5, 6-dimethylphthalidyl rings.
  • a pharmaceutically-acceptable derivative of Formula 80 includes a pharmaceutically-acceptable salt of such derivatives. All chiral carbon centers of a Formula 89 compound can be in in a pure R form, pure S form, or a mixture of R and S forms in any proportion. A compound of Formula 80 also includes a bioisostere of the compound of Formula 80.
  • a group of pharmaceutically-acceptable derivatives of note within Formula 80 has the following Formula (81) :
  • a group of optimum compounds with the compounds of Formula 80 has the following Formula (82) : ( 82 ;
  • a group of optimum compounds of Formula 80 has an R 2 which is a group of the Formula (2) :
  • E is a CX ⁇ 2 group, a NX 3 group or an oxygen atom and F is a CX 4 X 5 group, a NX 6 group or an oxygen atom; and X 1 , X 2 , X 3 , X 4 ' X 5 , and X 6 are independently selected from the group consisting of a hydrogen atom or a lower alkyl group with the provisios that E and F both are not simultaneously oxygen atoms; and if R 1 is the alkyl group, R 2 must be a group of the Formula (2) or (3) .
  • the folLowing are exemplary compounds of
  • the invention further encompasses a group of pharmaceutical compositions using any combination of the substituents at R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , J, and R 13 set forth above in the compounds of Formulas (83) through (99) .
  • the invention also encompasses a pharmaceutically-acceptable derivative selected from the group of compounds consisting of the Formulas (95) , (96) , (97) , (98) , and (99) .
  • left terminus and the right terminus of the compound may be synthesized prior to coupling them to the remainder of the compound, or after one or both the nascent termini are already in place.
  • left terminus and “right terminus” is meant the R 1 -R 2 -R 3 - group and the -N-R 6 group of Formula 1, respectively.
  • R z can be of the formula:
  • Y is a reactive functionality that will eventually become a portion of R 2 .
  • Y is of the formula Y-R 3 -, it can be reacted at any point in the following Schemes 7 through 10 with a reagent of the formula R 1 -X, wherein the reaction between X and Y results in the formation of R 2 .
  • R 1 -X a reagent of the formula R 1 -X
  • Y is a reactive functionality that can be incorporated into R 2 . This reactive functionality is, of course, protected at the appropriate stages of the following Schemes 7 through 10.
  • the amino function of the aminophenyl group on the left terminus of the substrate molecule is the "Y” function of an "Y-R 3 " group, while portions of the CDI (carbonyldiimidazole) and the R 1 -NH 2 reagents represent the "X" portion of an R 1 -X reagent.
  • the modified aspartic acid that composes the right terminus of Formula 1 can be synthesized before adding such a modified residue to the remainder of the precursor molecule.
  • a molecule of Formula L a molecule of Formula L:
  • R w in the above Scheme 6 can be R 6 , as defined above for Formula 1, or a group of the Formula F:
  • any reactive subsituent on R 5 or R 9 can be selectively made temporarily unreactive, (i.e., "protected") and subsequent to said reactions, protected groups can be made reactive again (i.e., "deprotected” ) , by conditions and protecting groups known in the art for the purposes of the reactions in instant Schemes.
  • the coupling reaction in Scheme 6 above is carried out under standard amino acid coupling conditions.
  • Such conditions include the presence of a standard peptide coupling agent such as the combinations of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) , N,N' - di (isopropyl) carbodiimide (DIC) and HOBt, and ethyl-3-
  • a standard peptide coupling agent such as the combinations of dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) , N,N' - di (isopropyl) carbodiimide (DIC) and HOBt, and ethyl-3-
  • R w is a group of Formula F
  • the synthesis of the right terminus of the molecule can be finished at any time before or during the reactions outlined below in Schemes 7 through 9, by removing the carboxy protecting group or removing it from the solid support and reacting it with groups of the Formulas G or H;
  • R 10 and R 11 are as defined for Formula 1. These reactions would be carried out under standard coupling conditions for amide and ester forming reactions as described above and below. Turning to the synthesis of the precursor molecule to Formula 1, Scheme 7 below sets forth a general synthetic strategy.
  • the precursor molecule of K in the above Scheme 7 can be made by solid phase synthesis.
  • J can be coupled to a solid support through the ⁇ -carboxy residue of the modified aspartic acid.
  • A is coupled to I using the coupling conditions discussed above for Scheme 6.
  • the bound precursor molecule is cleaved from the solid support to give that of K.
  • Scheme 8 sets forth the strategy for completing the right terminus of a precursor molecule once the precursor backbone has been assembled using Scheme 7 above.
  • the precursor molecular K is reacted with H 2 N-R W , wherein R w is as described above for the synthesis of Formula L.
  • R w is as described above for the synthesis of Formula L.
  • Scheme 8 are standard peptide coupling conditions as discussed for the above Schemes.
  • a and I are those as discussed above for Scheme 7. Again, reactive groups are protected and deprotected as necessary.
  • L is as discussed above for the synthesis of the right terminus.
  • the reaction set forth in Scheme 9 can be performed in solution phase. Thus, either A and I or I and L are first coupled, then either L or A are coupled to the joined subunits, respectively, to give the precursor molecule M.
  • the reactions in Scheme 9 can be carried out under solid phase conditions, as was the case for Scheme 7.
  • the carboxy protecting group is removed from L and the molecule is attached through the side chain carboxy group to a solid support.
  • I is coupled to L followed by coupling of A to I .
  • the bound molecule is then cleaved from solid support under standard conditions such as hydrogen fluoride, trifluoroacetic acid or other such conditions to again give a precursor molecule of Formula M, wherein P is hydrogen.
  • Scheme 10 sets forth a method for synthesizing the compounds of Formula 1 when the right terminus is a proline residue, that is, when R 10 and R 11 form a five-membered ring substituted by a carboxylic acid or a primary carboxamide.
  • R is usally a Rink Amide MBHA resin or Wang resin.
  • N- Fluorenymethoxcarbonyl (N-Fmoc) group is used for the protecting amino group of amino acid.
  • N-Fmoc N- Fluorenymethoxcarbonyl
  • the next N-Fmoc protected amino acid is coupled. That coupling is followed by further deprotecting, coupling, deprotecting, steps until a solid phase-linked compound of a desired sequence is prepared.
  • R from Scheme 10, can be subsituted for J in Scheme 7 and Scheme 7 can be carried out in a similar fashion with R.
  • a compound is typically recovered and purified prior to use .
  • Recovery and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, thin layer chromatography, preparative high pressure liquid chromatography, or a combination of these procedures.
  • suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, thin layer chromatography, preparative high pressure liquid chromatography, or a combination of these procedures.
  • other equivalent separation or isolation procedures can also be used.
  • Various known methods can be used to characterize the structure of a compound of Formula 1 or pharmaceutically-acceptable derivative. Such methods include proton and 13 carbon nuclear magnetic resonance spectroscopy (NMR) and mass spectroscopy (MS) .
  • NMR proton and 13 carbon nuclear magnetic resonance spectroscopy
  • MS mass spectroscopy
  • H-NMR spectra can be recorded, for example, on a GE QE-300, 300 MHz NMR spectrometer.
  • MS can be analyzed on a PE-SCIEX API100 Electrospray mass spectrometer .
  • VLA-4 inhibitory activity of a compound or a pharmaceutically-acceptable derivative can be analyzed by known methods and those described below.
  • Known methods include, for example, assaying in vi tro adhesion of radioactive cells that express. VLA-4 to a substrate containing known VLA-4 receptors in the presence of the compound. See, for example, Elices et al . Cell , 60:577-584 (1990), which is incorporated herein by reference.
  • the anti-inflammatory activity of a compound of Formula (1) or a pharmaceutically- acceptable derivative of Formula (80) can be determined using a known animal model or assay for inflammation.
  • Known animal models include, for example, the measurement of dynamic compliance or lung resistance in asmatic animals, edema formation in delayed type hypersensitivity animal models, or allograft rejection in animals receiving organ transplants. See, for example, Molossi et al . J. Clin . Invest . , 95:2601-2610
  • the anti-inflammatory activity of a compound of Formula (1) or a pharmaceutically- acceptable derivative of Formula (80) can be measured in patients using known methods. For example, the number of painful joints or the amount of mobility in an arthritic patient can be measured.
  • This invention is further directed to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the compounds of Formula (1) and (80) , and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle (hereinafter collectively referred to as “pharmaceutically-acceptable carriers”).
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin; buffer substances such as the various phosphates, ⁇ glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxy ⁇ nethylcellulose, polyarylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and the like.
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. Oral and parenteral administration are preferred.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra- articular, intrasynovial , intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques .
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol .
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides .
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant .
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions.
  • carrier which are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible to topical application.
  • the pharmaceutical composition For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions of' this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-applied transdermal patches are also included in this invention.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such pharmaceutical compositionss are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in ' the art.
  • VLA-4 binding which prevents leukocyte movement into inflammed tissue and, thereby, treats or prevents inflammation.
  • the compound, pharmaceutically- acceptable derivative or pharmaceutical composition can treat or prevent inflammation in a wide range of conditions.
  • the invention can be used in the treatment or prevention of 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 a compound or pharmaceutically-acceptable derivative of the present invention.
  • Specific pathological inflammatory conditions 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
  • the term "effective amount” refers to dosage levels of the order of from about 0.05 milligrams to about 140 milligrams per kilogram of body weight per day for use in the treatment of the above-indicated conditions (typically about 2.5 milligrams to about 7 grams per patient per day) .
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 milligrams of the compound per kilogram of body weight per day (about 0.5 milligrams to about 3.5 grams per patient per day) .
  • the amount of the compounds of Formula 1 or 80 that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 milligrams to 5 grams of a compound of Formula 1 or 80 combined with an appropriate and convenient amount of a pharmaceutically-acceptable carrier which may vary from about 5 to about 95 percent of the total pharmaceutical composition.
  • Dosage unit forms will generally contain between from about 1 milligram to about 500 milligrams of an active compound of Formula 1 or 80.
  • a compound's potency at inhibiting VLA-4 binding is used to screen compounds, but a. compound's 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 preferred compound for a pharmaceutical composition.
  • Boc-Phe-OH Boc-Asp (OBzl) -OH
  • Boc-Leu-OH Boc-N-Me-Leu
  • Boc-Ile BocLys (Cbz) -OH
  • Pro methyl ester Pro methyl ester
  • Fmoc-Pro Fmoc-Phe, Fmoc-Asp(OBu ), Fmoc-Leu, Fmoc-N-Me-Leucine, Fmoc-cyclohexylalanine, Fmoc-Gly, Fmoc-Ser (Bu fc ) , Fmoc- Met, Fomc-Nle, Fmoc-Tyr (Bu ) , Fmoc-Trp (Boc) , Rink amide MBHA resin, MBHA resin, benzotriazole-1-yl-oxy-tris- (dimethylamino) -phosphoniumhexafluorophosphate (BOP) , and di-t-butyl-carbonate (Boc 2 0) , N-
  • Ethyl-3- (3 -dimethylamino) -propylcarbodimide - HCI (EDC) was obtained from Bachem Co., Torrance, CA.
  • 1-hydroxy- 7-azabenzotriazole (HOAt) was purchased from Perseptive Biosystems.
  • Fmoc- ⁇ - (2-thienyl) alanine, and (3S) -Fmoc- 3 -amino- 1-carboxymethyl-caprolactame were purchased from Neosystem.
  • Tetrakis (triphenylphosphine) palladium (0) was purchased from Lancaster.
  • Preparative TLC plates (silica gel 0.25mm or 0.5mm x 20cm x 20cm) were purchased from Aldrich or VWR.
  • Analytical HPLC was conducted on either a Beckman System Gold Gilson System.
  • the Beckman System Gold contains a model 507e autosampler, model no. 125 solvent module and model PDA 168 detector.
  • the Gilson system contains a model 234 sampling injector, a model 119 UV/VIS detector, two model 306 pumps, a model 806 manometric module and 811C dynamic mixer.
  • a Vydac Protein and Peptide C18 column (0.46 x 25 cm) was used. Flow rate: 1 ml/min, detected at 214 nm.
  • Preparative HPLC was conducted on Waters HPLC system comprising a with Water's 600E controller, and UV detector 441, and a Gilson' s auto sampler 231 and fraction collector FC203B.
  • a Vydac protein and peptide C18 semi-prep column (2.2 x 25 cm) was used at a flow rate of 15 ml/min, detected at 215 nm.
  • HPLC solvents were as follows: solvent A: water with 0.1% trifluoroacetic acid (TFA); solvent B: acetonitrile with 0.1% trifluoroacetic acid (TFA) .
  • Linear gradient conditions were usually used, as indicated in Table 1. For example, the gradient condition 5-70%B/35 min means that the concentration of HPLC solvent B increases from 5% to 70% over 35 min.
  • the water used in the HPLC solvents is Milli Q water; acetonitrile was purchased from VWR, HPLC grade EM Science; and TFA (HPLC grade) was purchased from Pierce.
  • the 1 H-NMR spectra were recorded at 300 MHz on a GE QE-300 NMR spectrometer.
  • the Mass spectrometry experimens were performed on an API 100 Perkin Elmer Sciex mass spectrometer.
  • the electrospray technic was used in both positive mode, and negtive mode, usually yielding both MH + and MH " .
  • Boc-Phe-Morpholinamide (12.8 g, 38 mmol) was placed in a 250 ml flask, 4N HCI in dioxane (30 ml) was added. The mixture was stirred for 6 hours at which time thin layer chromatography (silica gel; CHC1 3 : MeOH: acetic acid, 90 : 8 : 2) indicated that the reaction was completed. Dioxane and excess HCI were removed. A white solid, 10.3 g, identified by 1 H-NMR as Phe-Morpholinamide hydrochloride salt, was obtained.
  • Boc-Asp (OBzl) -OH and Boc-Leu-OH were sequentially added to Phe-Morpholinamide hydrochloride salt using the coulpling and deprotection procedures, described above.
  • the white solid, thus obtained, was characterized by " " " " H-NMR as the title product in total 95% yield.
  • the DMF was removed by evaporation, ethyl acetate and water were added and the layers were separated.
  • the aqueous layer was extracted with ethyl acetate (50 mL x 2) , combined extracts were washed with IN HCI, saturated NaHC0 3 , water and brine. After drying with MgS0 4 , the solution was filtered and concentrated to give 2.62 g (95%) of the coupled product as a pale yellow solid which was taken to the next step with no further purification.
  • This compound could also be made by an alternative way as described below for the compound of Formula (17) .
  • This methyl ester (500 mg, 1.75 mmol) underwent hydrolysis by reflux with sodium hydroxide (280 mg, 7 mmol) in water (20 ml) and methanol (10 ml) until a clear solution was formed. The methanol was evaporated and the remaining solution was acidified with acetic acid. The white precipitant was filtered and washed with ethanol (5 ml x 2) to give the title product 4- (N' - (2 -pyridyl) urea) phenyl acetic acid (290 mg) .
  • Boc-Phe (8.3 g, 31.29 mmol) and 1-methylpiperazine (3.1 g, 31.29 mmol) were dissolved in 100 ml DMF, cooled to - 30°C with a bath (acetonitrile + dry ice) .
  • HOAt or HOBt
  • EDC 5.9 g, 31.29 mmol
  • EtOAc was added to the residue, and the resultant solution was washed with saturated sodium bicarbonate aqueous solution and brine.
  • the solutoin was dried over magnesium sulfate.
  • the product (10.8 g, 31.1 mmol) was obtained after filtration and evaporation.
  • Boc-Phe- (N-methyl) piperazine (10.8 g, 31.1 mmol) was stirred with 4N Hcl (150ml) in dioxane for 2 hours. The starting material was completely consumed. The excess HCI and the solvent were then evaporated. Hcl-Phe- (N-methyl) piperazine (8.8 g, 31.0 mmol) was thus obtained.
  • This product was coupled with Boc-Asp (OBzl) (10.1 g, 31.2 mmol) as procedure A (0°C instead of -30°C) to give- 16.5 g Boc- Asp (OBzl) -Phe- (N-methyl) piperazine.
  • Boc-Asp (OBzl) -Phe- (N-methyl) piperizine was treated with 4N HCI in dioxane then further coupled with Boc-N-Me-Leu to give Boc-N-Me-Leu-Asp (OBzl) -Phe- (N-methyl) piperazine .
  • 4-aminophenylacetic acid (15.0 g, 99.3 mmol) was placed in a 1000 ml round bottom flask. 500 ml ethyl acetate was added. To the stirring mixture was added 12.3 ml o-tolyl isocynate (12.3 ml, 99.3 mmol), the reaction mixture was stirred for 1 hour at room temperature and then heated to reflux for another hour. The reaction mixture was then cooled to room temperature and filtered to give the solid product. The solid was recrystallized in methanol twice to provide 18.0 g of the title product.
  • Boc-N-Me-Leu-Asp(OBzl) -Phe- (N- methyl) piperizine (5.8 g, 8.9 mmol) was treated with 4N HCI in dioxane, further coupled with 4-(N'-(o- tolyl) urea) -phenyl acetic acid (2.53 g, 8.9 mmol).
  • the 4- (N 1 - (o-toluyl) urea) -phenylacetyl-N-Me-Leu-Asp (OBzl) - Phe- (N-methyl) piperazine was obtained.
  • the reaction protocol was the same as described above.
  • This benzyl ester of Formula (54) was purified by silica gel flash column chromatography, using EtOAc and methanol (from 90:1 to 90:10) as the eluent to give 6.8 g of the title product was obtained.
  • the above benzyl ester (1.66 g, 1.96 mmol) was dissolved in 200 ml methanol. The solution was flashed with argon. A catalytic amount of 10% palladium on activated carbon was added. The mixture was flashed with hydrogen. The reaction was carried out under a H 2 atmosphere by using a hydrogen balloon for seven hours. TLC showed the starting material was completely consumed. The solid residue was filtered off by a celite-packed funnel. The pure compound Formula (54) (1.28 g) was obtained after concentration.
  • Boc-Phe (3.0 g, 11.3 mmol) and Na 2 C0 3 (1.8 g, 16.95 mmol) in 100 ml DMF was added allyl bromide (3.9 ml, 45.23 mmol). The reaction mixture was stirred overnight at room temperature. The solid was filtered off and DMF was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with IN HCI, saturated aqueous sodium bicarbonate and brine, then dried over magnesium sulfate. The solution was concentrated to give 3.2 g Boc-Phe-OAllyl .
  • Boc-Leu-Asp (OBzl) - Phe-OAllyl was obtained by treating Boc-Phe-OAllyl with 4N HCI followed by coupling with Boc-Asp (OBzl) to form Boc-Asp (OBzl) -Phe-OAllyl .
  • the Boc group was removed with 4N HCI in dioxane followed by coupling with Boc- Leu to form Boc-Leu-Asp (OBzl) -Phe-O-Allyl .
  • the reaction protocol was the same as described above.
  • reaction mixture was diluted with ethyl acetate (50 ml) and washed with IN hydrochloric acid, saturated sodium bicarbonate, and brine. After drying with magnesium sulfate and filtering, the solvent was removed under reduced pressure. The products obtained in this way were used for the following steps without further purification.
  • the benzyl ester was dissolved in DMF and the solution was saturated with argon. After addition of palladium on carbon (10% w/w) the mixture was stirred under an atmosphere of hydrogen for 4 to 15 h. The catalyst is removed by filtration over a bed of celite and the solvent is removed under reduced pressure. The final product was purified by preparative HPLC.
  • N-Me-leucine was incorporated instead of leucine in the molecules, the synthetic methods were the same except Boc-N-Me-Leu was employed.
  • 1- (benzyl acetate) -piperazine was used to couple to the left side of molecule followed by hydrogenolysis to remove two benzyl esters.
  • 1-Boc- piperazine was used to couple to the left side of molecule followed by treatment of 4N HCI and hydrogenolysis to produce Formula (53) .
  • Boc-Asp (OBzl) -OH (3.23 g, 10 mmol) was dissolved in DMF.
  • Sodium bicarbonate (1.68 g, 20 mmol) was added followed by allylbromide and the mixture was stirred overnight at room temperature. After dilution with ethyl acetate (100 ml) the mixture was washed with water, saturated sodium bicarbonate, and 1 N hydrochloric acid and dried with magnesium sulfate. After filtering and removal of the solvent under reduced pressure the title product was obtained as a colorless oil (3.59 g, 9.88 mmol, 99%).
  • Boc-Asp (OBzl) -OAllyl (3.59 mg, 9.88 mmol) was reacted with 4 N HCI in dioxane for 1 h at room temperature . After removal of the solvent under reduced pressure, the product was dried in vacuo. This material was dissolved in DMF (20 ml) and the pH was adjusted to pH 9 by addition of DIEA (1.74 ml, 10 mmol) . HOBt (1.89 g, 14 mmol) was added followed by Boc-Leu-OH'H 2 0 (3.24 g, 14 mmol), and the mixture was cooled to 0°C. EDC (2.68 g, 14 mmol) was added and the reaction was allowed to warm to room temperature and stirred overnight.
  • Boc-Lys (Cbz) -NMe (OMe) (985 mg, 2.33 mmol) was dissolved in anhydrous THF (20 ml) under an argon atmosphere and the solution was cooled on an ice-bath.
  • a solution of L1AIH 4 in diethyl ether (3ml, IN) was added dropwise with a syringe and the mixture was stirred for 30 min at 0°C. After quenching- with a solution of KHSO 4 (0.57g) in water (10 ml) the mixture was extracted three times with ethyl ether. The combined extracts were washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine and dried with magnesium sulfate.
  • Boc-Lys (Cbz) -CHO (796 mg, 2.18 mmol) was dissolved in methanol (450 ml) and the solution was saturated with argon. After addition of palladium on carbon (10%, 80 mg) the mixture was stirred under an atmosphere of hydrogen for 3 days . The catalyst was removed by filtration over a bed of celite and the solvent was removed under reduced pressure. The title product (472 mg, 2.20 mmol, 100%) was obtained as a pale yellow oil which was used for the next step without further purification.
  • N-Benzyloxycarbonylmethyl- (S) -3- t-butyloxycarbonylamino-homopiperidine (2.71 g, 7.5 mmol) was dissolved in methanol and the solution was saturated with argon. After addition of palladium on carbon (10%, 300 mg) the mixture was stirred under an atmosphere of hydrogen for 4 h. The catalyst was removed by filtration over a bed of celite and the solvent was removed under reduced pressure. The title product (2.07 g, 7.60 mmol) was obtained as an amorphous foam which was used for the following step without further purification.
  • N-Carboxymethyl- (S) -3- t-butyloxycarbonylamino-homopiperidine 72 mg, 0.26 mmol
  • HOBt 27 mg, 0.20 mmol
  • dimethylamine hydrochloride 18 mg, 0.22 mmol
  • DIEA 0.038 ml, 0.22 mmol
  • EDC 38 mg, 0.22 mmol
  • N-aminocarbonylmethyl- (S) -3-amino- homopiperidine can also been prepared by the following method: Preparation M
  • N-aminocarbonylmethyl- (S) -3-amino- homopiperidine.HCl salt (59 mg, 0.24 mmol) was dissolved in DMF (1 ml) , and the pH of the solution was adjusted to pH 9 by addition of DIEA (0.084 ml, 0.48 mmol) .
  • DIEA 0.084 ml, 0.48 mmol
  • the Fmoc-Rink Amide MBHA resin was washed three times with DMF, then treated with 20% piperidine in DMF for 5 min. The solution was drained by filtration and the resin was again treated with 20% piperidine in DMF for 20 min. The solution was drained by filtration, and the resin was washed five times with DMF, once with isopropanol and four times with DMF.
  • the 3 equivalent of HOBt ester of Fmoc-D-proline in DMF (formed by reacting a solution of equimolar amount of F-moc-D-proline, HOBt and DIC in DMF) was added to the resin and allowed to react for 2 hours. The resin was washed five times with DMF, once with isopropanol, two times with DMF and two times with DCM. The coupling of amino acid to the resin was then checked by standard Kaiser's test.
  • the compound was cleaved from the resin by treatment of the resin with 95% TFA/2.5% TIS/2.5% water at room temperature for 90 min. After filtration and evaporation, ice cold ether was added to the residue. The resultant precipitate was isolated by centrifugation and washed three times with ether. The precipitate was subjected to preparative HPLC to yield the compounds of Formulas (26), (27), (28), (29), (33), (44), (46), (50), (51), (52), (55), (62), (63), (64), (65) , (69) and (74) were prepared by this method.
  • MBHA-resin was washed five times with DCM and three times with DMF.
  • a solution of 2 equivalents of N-carboxymethyl- (S) -3- t-butyloxycarbonylamino-homopiperidine, 2 equivalent of HOBt (1.0 mmol), and 2 equivalent of DIC (1.0 mmol) in 5 mL of DMF was added to the resin and allowed to react for 4 h.
  • the solution was drained by filtration and the resin was washed three times with DMF, three times with DCM, once with 2-propanol, and three times with DCM.
  • the coupling of amino acid to the resin was then checked by standard Kaiser's test.
  • the resin was treated with TFA/anisole/DCM: 25/5/70 for 2 min.
  • the solution was drained by filtration and the resin was treated again with TFA/anisole/DCM: 25/5/70 for 30 min.
  • the resin was washed three times with DCM, once with 2- propanol, once with DCM, once with 2-propanol, once with DCM, once with 2-propanol, and three times with DCM.
  • the resin was treated three times with 10% DIEA in DCM for 2 min.
  • the solution was drained by filtration and the resin was washed three times with DCM and three times with DMF.
  • the resin (0.1 meq) was placed in a teflon reaction vessel and anisole (0.2 mL) was added as a scavenger.
  • anisole 0.2 mL
  • methyl sulfide (0.2 mL) was included in the reaction mixture.
  • the reaction vessel was flushed with nitrogen and cooled to -78°C.
  • HF approximately 5mL
  • HF was evaporated by flushing with nitrogen, and the vessel containing the resin was dried in vacuo over KOH.
  • the resin was washed three times with TFA (2 mL) and filtered.
  • ester prodrugs were synthesized by esterification of the side chain carboxyl group of aspartic acid in the molecules.
  • VLA-4 antagonists were reacted with different alcohols to form ester prodrugs after purification on preparative HPLC or preparative TLC.
  • the typical procedure was as follows :
  • the compound of Formulas (84) and (99) are all benzyl esters which can be synthesized in a manner to the compounds above .
  • Jurkat cells (ATCC TIB 152) , a human T lymphoblastic line, labeled with Europium were used to assay in vi tro binding inhibition by compounds discussed herein.
  • Jurkat cells were washed twice with phosphate buffered saline at 37°C and resuspended in 1 ml of labeling buffer (labeling buffer was made up in 50 mM HEPES pH 7.4 , 93 mM NaCl, 5 mM KCl , 2 mM MgCl 2 containing 2.5 mM DTPA, 0.5 mM EuCl 3 , 0.1 mg/ml dextran sulfate) . Cells were incubated in labeling buffer for 30 min at 4°C.

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Abstract

L'invention porte sur des composés de formule (1) et sur leurs dérivés pharmacocompatibles.
PCT/US1998/005709 1997-03-21 1998-03-20 Nouveaux composes WO1998042656A1 (fr)

Applications Claiming Priority (4)

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US82182597A 1997-03-21 1997-03-21
US8624197P 1997-03-21 1997-03-21
US60/086,241 1997-03-21
US08/821,825 1997-03-21

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US6034238A (en) * 1997-09-23 2000-03-07 Hoechst Marion Roussel Deutschland Gmbh Heterocyclic compounds, their preparation and their use as leucocyte adhesion inhibitors and VLA-4-antagonists
US6291453B1 (en) 1997-07-31 2001-09-18 Athena Neurosciences, Inc. 4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6331552B1 (en) 1997-11-19 2001-12-18 Aventis Pharma Deutschland Gmbh Substituted imidazolidine derivatives, their preparation, their use and pharmaceutical preparations including them
US6362341B1 (en) 1997-07-31 2002-03-26 Athena Neurosciences, Inc. Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6399643B1 (en) 1999-05-17 2002-06-04 Aventis Pharma Deutschland Gmbh Spiroimidazolidine derivatives, their preparation, their use and pharmaceutical preparations formed therefrom
US6407066B1 (en) 1999-01-26 2002-06-18 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6423688B1 (en) 1997-07-31 2002-07-23 Athena Neurosciences, Inc. Dipeptide and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6489300B1 (en) 1997-07-31 2002-12-03 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492421B1 (en) 1997-07-31 2002-12-10 Athena Neurosciences, Inc. Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
JP2002544209A (ja) * 1999-05-05 2002-12-24 アベンティス・フアーマ・リミテッド 細胞接着調節剤としての尿素
WO2003031410A1 (fr) * 2001-10-09 2003-04-17 Neurocrine Biosciences, Inc. Ligands de recepteurs de la melanocortine et compositions et methodes associees
US6559127B1 (en) 1997-07-31 2003-05-06 Athena Neurosciences, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6583139B1 (en) 1997-07-31 2003-06-24 Eugene D. Thorsett Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6667334B1 (en) 1998-05-14 2003-12-23 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, the production thereof, their use and pharmaceutical preparations containing the same
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
WO2004041279A1 (fr) 2002-10-30 2004-05-21 Merck & Co., Inc. Modulateurs gamma-aminoamides de l'activite de recepteur de chimiokine
US6759424B2 (en) 1997-09-18 2004-07-06 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use, and pharmaceutical preparations comprising them
US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
US6962937B2 (en) 2001-08-01 2005-11-08 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation and their use
WO2005122379A2 (fr) * 2004-05-27 2005-12-22 The Regents Of The University Of California Ligands d'integrine alpha-4 beta-1 destines a l'imagerie et utilises en therapie
US7030114B1 (en) 1997-07-31 2006-04-18 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
WO2010061329A1 (fr) 2008-11-26 2010-06-03 Pfizer Inc. 3-aminocyclopentanecarboxamides en tant que modulateurs des récepteurs de chimiokines
WO2010090764A1 (fr) 2009-02-09 2010-08-12 Supergen, Inc. Inhibiteurs pyrrolopyrimidinyle de l'axi kinase
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
CN103880746A (zh) * 2014-02-26 2014-06-25 南通大学 一种(s)-3-(Boc-氨基)氮杂环庚烷的化学合成方法
US8808698B2 (en) 2006-02-03 2014-08-19 The Regents Of The University Of California Methods for inhibition of lymphangiogenesis and tumor metastasis
US9119884B2 (en) 2010-09-02 2015-09-01 The Regents Of The University Of California LLP2A-bisphosphonate conjugates for osteoporosis treatment
US9403908B2 (en) 2003-09-29 2016-08-02 The Regents Of The University Of California Method for altering hematopoietic progenitor cell adhesion, differentiation, and migration
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 (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5492896A (en) * 1993-02-15 1996-02-20 Bayer Aktiengesellschaft Pseudopeptides having an antiviral action
US5516784A (en) * 1991-08-13 1996-05-14 Schering Corporation Anti-HIV (AIDS) agents
US5654451A (en) * 1993-01-14 1997-08-05 Magainin Pharmaceuticals Inc. Amino acids and peptides having modified C-terminals and modified N-terminals
US5654301A (en) * 1985-02-15 1997-08-05 Research Corporation Technologies, Inc. Amino acid derivative anticonvulsant

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5654301A (en) * 1985-02-15 1997-08-05 Research Corporation Technologies, Inc. Amino acid derivative anticonvulsant
US5516784A (en) * 1991-08-13 1996-05-14 Schering Corporation Anti-HIV (AIDS) agents
US5654451A (en) * 1993-01-14 1997-08-05 Magainin Pharmaceuticals Inc. Amino acids and peptides having modified C-terminals and modified N-terminals
US5654451B1 (en) * 1993-01-14 2000-02-22 Magainin Pharma Amino acids and peptides having modified c-terminals and modified n-terminals
US5492896A (en) * 1993-02-15 1996-02-20 Bayer Aktiengesellschaft Pseudopeptides having an antiviral action

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE STN REGISTRY 1 January 1900 (1900-01-01), XP002910699, Database accession no. 193218-32-5 *

Cited By (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6559127B1 (en) 1997-07-31 2003-05-06 Athena Neurosciences, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6291453B1 (en) 1997-07-31 2001-09-18 Athena Neurosciences, Inc. 4-amino-phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6583139B1 (en) 1997-07-31 2003-06-24 Eugene D. Thorsett Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7166580B2 (en) 1997-07-31 2007-01-23 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US6362341B1 (en) 1997-07-31 2002-03-26 Athena Neurosciences, Inc. Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US7030114B1 (en) 1997-07-31 2006-04-18 Elan Pharmaceuticals, Inc. Compounds which inhibit leukocyte adhesion mediated by VLA-4
US7229970B2 (en) 1997-07-31 2007-06-12 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6423688B1 (en) 1997-07-31 2002-07-23 Athena Neurosciences, Inc. Dipeptide and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6489300B1 (en) 1997-07-31 2002-12-03 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6492421B1 (en) 1997-07-31 2002-12-10 Athena Neurosciences, Inc. Substituted phenylalanine type compounds which inhibit leukocyte adhesion mediated by VLA-4
US6939855B2 (en) 1997-07-31 2005-09-06 Elan Pharmaceuticals, Inc. Anti-inflammatory compositions and method
US6900179B2 (en) 1997-07-31 2005-05-31 Eugene D. Thorsett Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6525026B2 (en) 1997-07-31 2003-02-25 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US7320960B2 (en) 1997-07-31 2008-01-22 Elan Pharmaceuticals, Inc. Carbamyloxy compounds which inhibit leukocyte adhesion mediated by VLA-4
US6586602B2 (en) 1997-07-31 2003-07-01 Eugene D. Thorsett Benzyl compounds which inhibit leukocyte adhesion mediated by VLA-4
US6759424B2 (en) 1997-09-18 2004-07-06 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, their preparation, their use, and pharmaceutical preparations comprising them
US6034238A (en) * 1997-09-23 2000-03-07 Hoechst Marion Roussel Deutschland Gmbh Heterocyclic compounds, their preparation and their use as leucocyte adhesion inhibitors and VLA-4-antagonists
US6331552B1 (en) 1997-11-19 2001-12-18 Aventis Pharma Deutschland Gmbh Substituted imidazolidine derivatives, their preparation, their use and pharmaceutical preparations including them
US6521654B2 (en) 1997-11-19 2003-02-18 Aventis Pharma Deutschland Gmbh Substituted imidazolidine derivatives, their preparation, their use and pharmaceutical preparations including them
US6667334B1 (en) 1998-05-14 2003-12-23 Aventis Pharma Deutschland Gmbh Imidazolidine derivatives, the production thereof, their use and pharmaceutical preparations containing the same
WO2000002903A1 (fr) * 1998-07-10 2000-01-20 Cytel Corporation Peptidomimetique de cs-1, compositions et leurs procedes d'utilisation
US7101855B2 (en) 1999-01-26 2006-09-05 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
US6407066B1 (en) 1999-01-26 2002-06-18 Elan Pharmaceuticals, Inc. Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
JP4707240B2 (ja) * 1999-05-05 2011-06-22 アベンティス・フアーマ・リミテッド 細胞接着調節剤としての尿素
JP2002544209A (ja) * 1999-05-05 2002-12-24 アベンティス・フアーマ・リミテッド 細胞接着調節剤としての尿素
US6399643B1 (en) 1999-05-17 2002-06-04 Aventis Pharma Deutschland Gmbh Spiroimidazolidine derivatives, their preparation, their use and pharmaceutical preparations formed therefrom
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
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
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
WO2003031410A1 (fr) * 2001-10-09 2003-04-17 Neurocrine Biosciences, Inc. Ligands de recepteurs de la melanocortine et compositions et methodes associees
WO2004041279A1 (fr) 2002-10-30 2004-05-21 Merck & Co., Inc. Modulateurs gamma-aminoamides de l'activite de recepteur de chimiokine
US9403908B2 (en) 2003-09-29 2016-08-02 The Regents Of The University Of California Method for altering hematopoietic progenitor cell adhesion, differentiation, and migration
WO2005122379A2 (fr) * 2004-05-27 2005-12-22 The Regents Of The University Of California Ligands d'integrine alpha-4 beta-1 destines a l'imagerie et utilises en therapie
US7576175B2 (en) * 2004-05-27 2009-08-18 The Regents Of The University Of California Alpha-4 beta-1 integrin ligands for imaging and therapy
WO2005122379A3 (fr) * 2004-05-27 2007-02-08 Univ California Ligands d'integrine alpha-4 beta-1 destines a l'imagerie et utilises en therapie
US8808698B2 (en) 2006-02-03 2014-08-19 The Regents Of The University Of California Methods for inhibition of lymphangiogenesis and tumor metastasis
EP2510941A2 (fr) 2007-02-20 2012-10-17 Merrimack Pharmaceuticals, Inc. Procédés de traitement de la sclérose en plaques par administration d'une alpha-foetoprotéine combinée à un antagoniste de l'intégrine
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
EP2860260A1 (fr) 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain et de leurs conjugués
WO2010061329A1 (fr) 2008-11-26 2010-06-03 Pfizer Inc. 3-aminocyclopentanecarboxamides en tant que modulateurs des récepteurs de chimiokines
WO2010090764A1 (fr) 2009-02-09 2010-08-12 Supergen, Inc. Inhibiteurs pyrrolopyrimidinyle de l'axi kinase
US9119884B2 (en) 2010-09-02 2015-09-01 The Regents Of The University Of California LLP2A-bisphosphonate conjugates for osteoporosis treatment
US9561256B2 (en) 2010-09-02 2017-02-07 The Regents Of The University Of California LLP2A-bisphosphonate conjugates for osteoporosis treatment
US10494401B2 (en) 2010-09-02 2019-12-03 The Regents Of The University Of California LLP2A-bisphosphonate conjugates for osteoporosis treatment
CN103880746A (zh) * 2014-02-26 2014-06-25 南通大学 一种(s)-3-(Boc-氨基)氮杂环庚烷的化学合成方法
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

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