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WO1999026922A1 - Derives de pyrrole a substitution tenant lieu d'inhibiteurs d'adhesion cellulaire - Google Patents

Derives de pyrrole a substitution tenant lieu d'inhibiteurs d'adhesion cellulaire Download PDF

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Publication number
WO1999026922A1
WO1999026922A1 PCT/US1998/024635 US9824635W WO9926922A1 WO 1999026922 A1 WO1999026922 A1 WO 1999026922A1 US 9824635 W US9824635 W US 9824635W WO 9926922 A1 WO9926922 A1 WO 9926922A1
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Prior art keywords
compound
independently selected
optionally substituted
mammal
ioalkyl
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PCT/US1998/024635
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English (en)
Inventor
Linda Chang
William K. Hagmann
Malcolm Maccoss
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Merck & Co., Inc.
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Publication date
Priority claimed from GBGB9804400.1A external-priority patent/GB9804400D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU14634/99A priority Critical patent/AU1463499A/en
Publication of WO1999026922A1 publication Critical patent/WO1999026922A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/48—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings
    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • 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
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to novel substituted pyrrole derivatives which are useful for the inhibition and prevention of leukocyte adhesion and leukocyte adhesion-mediated pathologies.
  • This invention also relates to compositions containing such compounds and methods of treatment using such compounds.
  • CAMs cell adhesion molecules
  • selectins include the selectins, integrins, cadherins and immunoglobulins.
  • CAMs play an essential role in both normal and pathophysiological processes. Therefore, the targetting of specific and relevant CAMs in certain disease conditions without interfering with normal cellular functions is essential for an effective and safe therapeutic agent that inhibits cell-cell and cell-matrix interactions.
  • the integrin superfamily is made up of structurally and functionally related glycoproteins consisting of ⁇ and ⁇ heterodimeric, transmembrane receptor molecules found in various combinations on nearly every mammalian cell type, (for reviews see: E. C. Butcher, Cell, 67, 1033 (1991); T. A. Springer, Cell, 76, 301 (1994); D. Cox et al., "The Pharmacology of the Integrins.” Medicinal Research Rev. 14. 195 (1994) and V. W. Engleman et al., "Cell Adhesion Integrins as Pharmaceutical Targets.” in Ann. Repts. in Medicinal Chemistry. Vol. 31, J. A. Bristol, Ed.; Acad. Press, NY, 1996, p. 191).
  • VLA-4 (“very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ l) is an integrin expressed on all leukocytes, except platelets and mature neutrophils, including dendritic cells and macrophage-like cells and is a key mediator of the cell-cell and cell-matrix interactions of of these cell types (see M. E. Hemler, "VLA Proteins in the Integrin Family: Structures,
  • VCAM-1 vascular cell adhesion molecule- 1
  • FN fibronectin
  • VCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells at sites of inflammation.
  • VCAM-1 is produced by vascular endothelial cells in response to pro-inflammatory cytokines (See A. J. H. Gearing and W. Newman, "Circulating adhesion molecules in disease.”, Immunol. Today. 14, 506 (1993).
  • the CS-1 domain is a 25 amino acid sequence that arises by alternative splicing within a region of fibronectin. (For a review, see R. O.
  • VLA-4/CS-1 interactions A role for VLA-4/CS-1 interactions in inflammatory conditions has been proposed (see M. J. Elices, "The integrin o ⁇ i (VLA- 4) as a therapeutic target" in Cell Adhesion and Human Disease. Ciba Found. Symp., John Wiley & Sons, NY, 1995, p. 79).
  • ⁇ 4 ⁇ 7 also referred to as LPAM-1 and ⁇ 4 ⁇ p
  • LPAM-1 and ⁇ 4 ⁇ p is an integrin expressed on leukocytes and is a key mediator of leukocyte trafficking and homing in the gastrointestinal tract (see C. M. Parker et al., Proc. Natl. Acad. Sci.
  • the ligands for ⁇ 4 ⁇ 7 include mucosal addressing cell adhesion molecule-1 (MadCAM-1) and, upon activation of ⁇ 4 ⁇ 7, VCAM-1 and fibronectin (Fn).
  • MadCAM-1 is a member of the Ig superfamily and is expressed in vivo on endothelial cells of gut-associated mucosal tissues of the small and large intestine ("Peyer's Patches") and lactating mammary glands. (See M. J. Briskin et al., Nature. 363. 461 (1993); A. Hamann et al., J. Immunol.. 152. 3282 (1994)).
  • MadCAM-1 can be induced in vitro by proinflammatory stimuli (See E. E. Sikorski et al. J. Immunol.. 151. 5239 (1993)). MadCAM-1 is selectively expressed at sites of lymphocyte extravasation and specifically binds to the integrin, ⁇ 4 ⁇ 7.
  • Neutralizing anti-0.4 antibodies or blocking peptides that inhibit the interaction between VLA-4 and/or 4 ⁇ 7 and their ligands have proven efficacious both prophylactically and therapeutically in several animal models of disease, including i) experimental allergic encephalomyelitis, a model of neuronal demyelination resembling multiple sclerosis (for example, see T. Yednock et al., "Prevention of experimental autoimmune encephalomyelitis by antibodies against 0C4 ⁇ integrin.” Nature. 356, 6J3 (1993) and E. Keszthelyi et al., "Evidence for a prolonged role of 0-4 integrin throughout active experimental allergic encephalomyelitis.” Neurology.
  • VLA-4 interactions in other diseases, including rheumatoid arthritis; various melanomas, carcinomas, and sarcomas; inflammatory lung disorders; acute respiratory distress syndrome (ARDS); atherosclerotic plaque formation; restenosis; uveitis and circulatory shock (for examples, see A. A. Postigo et al., "The ⁇ 4 ⁇ * ⁇ /VCAM-l adhesion pathway in physiology and disease.”, Res. Immunol.. 144. 723 (1994) and J.-X. Gao and A. C.
  • VLA-4- and ⁇ 4 ⁇ 7-dependent cell adhesion that have improved pharmacokinetic and pharmacodynamic properties such as oral bioavailability and significant duration of action.
  • Such compounds would prove to be useful for the treatment, prevention or suppression of various pathologies mediated by VLA-4 and ⁇ 4 ⁇ 7 binding and cell adhesion and activation.
  • the compounds of the present invention are antagonists of the VLA-4 integrin ("very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and 4 ⁇ p), thereby blocking the binding of VLA-4 integrin ("very late antigen-4"; CD49d/CD29; or ⁇ 4 ⁇ l) and/or the ⁇ 4 ⁇ 7 integrin (LPAM-1 and 4 ⁇ p), thereby blocking the binding of
  • VLA-4 to its various ligands, such as VCAM-1 and regions of fibronectin and/or ⁇ 4 ⁇ 7 to its various ligands, such as MadCAM-1, VCAM-1 and fibronectin.
  • these antagonists are useful in inhibiting cell adhesion processes including cell activation, migration, proliferation and differentiation.
  • VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation are useful in the treatment, prevention and suppression of diseases mediated by VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation, such as multiple sclerosis, asthma, allergic rhinitis, allergic conjunctivitis, inflammatory lung diseases, rheumatoid arthritis, septic arthritis, type I diabetes, organ transplantation, restenosis, autologous bone marrow transplantation, inflammatory sequelae of viral infections, myocarditis, inflammatory bowel disease including ulcerative colitis and Crohn's disease, certain types of toxic and immune-based nephritis, contact dermal hypersensitivity, psoriasis, tumor metastasis, and atherosclerosis.
  • diseases mediated by VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation such as multiple sclerosis, asthma, allergic rhinitis, allergic conjunctivitis, inflammatory lung diseases, rheum
  • the present invention provides novel compounds of Formula I
  • X is 1) -C(O)ORd
  • Z is 1) a bond
  • Rl is 1) Ci-ioalkyl
  • Cy-(Cy) p -C 2 -10alkenyl 8) Cy-(Cy) p -C 2 -10alkynyl, alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and Cy is optionally substituted with one to four substituents independently selected from R* 3 ;
  • R4 is 1) hydrogen, 2) Ci-ioalkyl,
  • R5, R6, and R' 7 are each independently 1) hydrogen, or 2) a group selected from Rb; or R5 and R" or R" and R' and the two adjacent carbon atoms to which they are attached, together form a 5-7 membered saturated or unsaturated monocyclic ring containing zero to two heteroatoms selected from N, O or S; R8 is 1) hydrogen,
  • R9 is 1) hydrogen
  • Cy-C ⁇ _ 10 alkyl wherein alkyl, alkenyl and alkynyl are optionally substituted with one to four substituents selected from Ra, and Cy is optionally substituted with one to four substituents independently selected from R D .
  • R a is 1) -CF 3 ;
  • R D is 1) a group selected from R a , 2) Ci-io alkyl,
  • Rd and R e are independently selected from the group consisting of
  • Cy Ci-ioalkyl wherein alkyl, alkenyl, alkynyl and Cy is optionally substituted with one to four substituents independently selected from R c ; or d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; Rf and RS are independently selected from hydrogen, Ci-ioalkyl, Cy and
  • Rf and RS together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen; R n is 1) hydrogen,
  • heteroaryl Cl-ioalkyl or 10) -SO2R 1 ; wherein alkyl, alkenyl, and alkynyl are optionally substituted with one to four substituents independently selected from R a ; and aryl and heteroaryl are each optionally substituted with one to four substituents independently selected from R D ; Ri 1) Ci-ioalkyl,
  • alkyl, alkenyl, alkynyl and aryl are each optionally substituted with one to four substituents independently selected from R c ;
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10; and p is 0 or 1.
  • Rl is Cy or Cy-Ci- l ⁇ alkyl where Cy and alkyl are optionally substituted as provided above.
  • Cy is preferably aryl optionally substituted with one or two groups selected from Rb.
  • Rl is aryl optionally substituted with one or two groups independnetly selected from R";
  • R3 is 1) Ci-ioalkyl,
  • alkyl as well as other groups having the prefix "alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl. pentyl, hexyl, heptyl, octyl, nonyl, and the like.
  • alkenyl means carbon chains which contain at least one carbon-carbon double bond, and which may be linear or branched or combinations thereof. Examples of alkenyl include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl, 2- methyl-2-butenyl, and the like.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-l-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms. The term also inccludes monocyclic ring fused to an aryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms.
  • the term also includes aryl group fused to a monocyclic cycloalkyl or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • aryl include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3- dihydrobenzofuranyl, benzopyranyl, 1,4-benzodioxanyl, and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • Heterocyclyl means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms.
  • the term also includes monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • heterocyclyl include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3- dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • Halogen includes fluorine, chlorine, bromine and iodine.
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of the general Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2- dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, trometh
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • VLA-4 and/or ⁇ 4 ⁇ 7 integrin makes them useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of VLA-4 and or ⁇ 4 ⁇ 7to their various respective ligands.
  • these antagonists will inhibit cell adhesion processes including cell activation, migration, proliferation and differentiation.
  • another aspect of the present invention provides a method for the treatment (including prevention, alleviation, amelioration or suppression) of diseases or disorders or symptoms mediated by VLA-4 and/or ⁇ 4 ⁇ 7 binding and cell adhesion and activation, which comprises administering to a mammal an effective amount of a compound of Formula I.
  • Such diseases, disorders, conditions or symptoms are for example (1) multiple sclerosis, (2) asthma, (3) allergic rhinitis, (4) allergic conjunctivitis, (5) inflammatory lung diseases, (6) rheumatoid arthritis, (7) septic arthritis, (8) type I diabetes, (9) organ transplantation rejection, (10) restenosis, (11) autologous bone marrow transplantation, (12) inflammatory sequelae of viral infections, (13) myocarditis, (14) inflammatory bowel disease including ulcerative colitis and Crohn's disease, (15) certain types of toxic and immune-based nephritis, (16) contact dermal hypersensitivity, (17) psoriasis, (18) tumor metastasis, (19) hepatitis, and (20) atherosclerosis.
  • prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0J to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a suitable dosage range is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about OJ mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
  • a suitable dosage range is, e.g.
  • ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
  • the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.
  • the compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device.
  • the preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons.
  • MDI metered dose inhalation
  • Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, macrocrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
  • Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to: (a) other VLA-4 antagonists such as those described in US 5,510,332, WO97/03094, WO97/02289, WO96/40781, WO96/22966, WO96/20216,
  • steroids such as beclomethasone, methylprednisolone, betamethasone, prednisone, dexamethasone, and hydrocortisone;
  • immunosuppressants such as cyclosporin, tacrolimus, rapamycin and other FK-506 type immunosuppressants;
  • antihistamines Hl- histamine antagonists
  • steroids such as be
  • the weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the
  • Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
  • the compounds of Formula I may be prepared by several general synthetic methods as described in for example, Principles of Pepetide Synthesis, 2nd Ed., M. Bodanszky, Springer Verlag, Berlin Heidelberg, 1993.
  • the compound of the present invention can be prepared by procedures illustrated in the accompanying schemes. In general, these compounds are constructed in such a way that the pyrrole nitrogen is elaborated before modifications are made to the pyrrole 2- carbonyl position.
  • reaction schemes described below are reasonably general, it will be understood by those skilled in the art of organic synthesis that one or more functional groups present in a given compound of Formula I may render the molecule incompatible with a particular synthetic sequence. In such a case an alternative route, an altered order of steps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions (including reagents, solvent, temperature, and time) should be chosen so that they are consistent with the nature of the functionalities present in the molecule.
  • the ester moiety is then hydrolyzed under appropriate non-basic conditions to provide 3.
  • Compound 3 is then coupled with an appropriately elaborated amino acid ester 4 under suitable conditions to provide 5 which upon hydrolysis yields the target compound 6.
  • Scheme 2 addresses further elaborations at R and or R of compound 6.
  • the example shown is that for derivatizations on H-L- (OtBu)Tyr-(OR") as 4. Starting with 5a, the free phenol is restored under standard conditions to provide the key intermediate ⁇ . This compound can be further elaborated for example via alkylation or acylation to grant entry into a variety of functional groups. When the desired R has been obtained, the ester is hydrolyzed to the acid to provide the desired targets 6a
  • Scheme 3 shows a route to elaborate R3 and/or R4 of Compound 6 via the 4-iodophenylalanine derivative 3a.
  • this compound can be used directly in a Pd(0) catalyzed coupling reaction with an appropriately substituted boronic acid to form the biaryl compound.
  • the ester is hydrolyzed to give the target compounds 8.
  • Some biaryl compounds are more accessible by the trimethylstannyl derivative 5c which can be prepared from 5b as indicated.
  • Step A tert-Butyl pyrrole-2-carboxylate.
  • Step C N-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carboxylic acid
  • tert-butyl (N-3,5- dichlorobenzenesulfonyD-pyrrole 2-carboxylate obtained from Step B) (88 mg, 0.234 mmol) dissolved in anhydrous dichloromethane (0.2 mL) was added dropwise a 1:1 solution of trifluoroacetic acid and dichloromethane solution (0.4 mL). After 3 minutes, the ice bath was removed and the pinkish reaction mixture was allowed to stirred at room temperature for 40 min. The excess trifluoroacetic acid was removed by a stream of nitrogen gas.
  • Step D NJN-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyri-(L)- phenylalanine. tert-butyl ester.
  • N-3,5- dichlorobenzenesulfonyl)pyrrole-2-carboxylic acid obtained from Step C
  • 1- hydroxybenzotriazole hydrate (19 mg, 0.137 mmol
  • N-methylmorpholine 35 ⁇ L, 32 mg, 0.313 mmol
  • (L)-phenylalanine, tert-butyl ester hydrochloride 39 mg, 0.15 mmol.
  • Step E N-fN-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyll-(L)- phenylalanine
  • N-[(N-3,5- dichlorobenznesulfonyl)pyrrole-2-carbonyl]-(L)-phenylalanine, tert-butyl ester 8.5 mg, 0.016 mmol
  • anhydrous dichloromethane 50 ⁇ L
  • Step A N-Carbobenzyloxy-(L)-homophenylalanine. tert-butyl ester At room temperature, to a solution of (N-carbobenzyloxy)-
  • Step B (L)-Homophenylalanine.
  • tert-butyl ester A solution of (N-carbobenzyloxy)-(D-homophenylalanine, tert-butyl ester (100 mg, 0.281 mmol) in anhydrous ethanol (2 mL) and anhydrous ethyl acetate (2 mL) was degassed and the reaction flask filled with hydrogen. 10% Palladium on carbon catalyst (25 mg) was added and the mixture was hydrogenated under a balloon of hydrogen at room temperature for 2.3 hr. The catalyst was removed by filtration through a pad of celite, and solvent was removed from the filtrate by rotoevaporation.
  • Step C N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)- homophenylalanine
  • the title compound was prepared in two steps from N-(3,5- dichlorobenzenesulfonyl)pyrrole-2-carboxylic acid (obtained from Example 1, Step C) and (L)-homophenylalanine, tert-butyl ester
  • Step A N-rN-(3.5-Dichlorobenznesulfonylpyrrole-2-carbonvH-(L)-
  • Step A N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyn-(L)- tyrosine. methyl ester
  • N-KN-3,5- dichlorobenznesulfonyl-2-carbonyl)pyrrole]-(L)-O-tert-butyl-tyrosine methyl ester (obtained from Example 4, Step A) (0.344 g, 0.622 mmol) in dichloromethane (1 mL) was added dropwise a 1:1 (v/v) solution of trifluoroacetic acid/dichloromethane (0.958 mL).
  • reaction mixture was allowed to warm up to room temperature slowly and stirred for a total of 4 hr.
  • the excess trifluoroacetic acid was removed by a stream of nitrogen gas and the residue was coevaporated with dichloromethane and then pumped under reduced pressure overnight to give the title compound (316 mg, 95%) as a foam, homogeneous by TLC (1/1 hexane / ethyl acetate). This material was used in the subsequent reaction without further purification.
  • Step B N-rN-(3,5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyri-(L)-
  • the mixture was filtered and the solvents were removed rotoevaporation.
  • the crude product was purified via Chromatotron (gradient elution using hexane/ethyl acetate) to afford the title compound (12.4 mg), homogeneous by TLC in 1/1 hexane/ethyl acetate), and recovered starting material (46 mg).
  • Step C N-rN-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)-
  • reaction mixture was diluted with ethyl acetate and water in the cold, and acidified with l.ON acetic acid to pH 4-5. After separation of the layers, the aqueous phase was re-extracted with ethyl acetate (3X).
  • Step A N-Butoxycarbonyl-L-4-iodophenyIalanine tert-butyl ester
  • Step B (L)-4-iodophenylalanine. tert-butyl ester hydrochloride
  • N-butoxycarbonyl-(L)-4-iodophenylalanine (723 mg, 1.62 mmol) was dissolved in anhydrous ethyl acetate (0.5 mL) at room temperature and then cooled to 0°C.
  • IN Hydrochloric acid in ethyl acetate (4.0 mL) was added dropwise and the ice bath removed 30 minutes after completion of the addition. The reaction mixture was allowed to stir at room temperature overnight. Additional IN Hydrochloric acid in ethyl acetate (4.0 mL) was added and the mixture allowed to stir for another 24 hr.
  • Step C N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonvn-(L)-
  • Step D N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)-
  • Tetrakis(triphenylphosphine)palladium(0) (8.2 mg, 0.0071 mmol) was added and the flask degassed/filled with dry nitrogen twice.
  • the reaction ,mixture was heated in an oil bath to 60°C for 6 hr. After cooling to room temperature, the solvents were removed by rotoevaporation and the residue was dissolved in 5% aqueous sodium carbonate, then extracted with ethyl acetate (3X). The combined organic layers were washed with water and saturated salt solution and dried over anhydrous sodium sulfate. The mixture was filtered and the solvents removed from the filtrate by rotoevaporation.
  • Step E N-[N-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyll-(L)-
  • hexamethylditin (166 ⁇ L, 0.862 mmol) was added and the mixture was again degassed and filled with dry nitrogen (3X) before tetrakis(triphenylphonphine)palladium(0) (50 mg, 0.043 mmol) was added.
  • the resulting yellow reaction mixture was stirred in an oil bath at 95°C and for 2.5 hr. After cooling to room temperature, the reaction mixture was dissolved in ethyl acetate (30 L) and washed wtih 5% sodium bicarbonate solution (2 x 5 mL) and saturated salt solutin (2 x 5 mL), and dried over anhydrous magnesium sulfate.
  • Step B N-[N-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyll-
  • the resulting mixture was again degassed and filled with dry nitrogen (2X) before being placed in a preheated oil bath at 100°C for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with 5% sodium bicarbonate solution (2X). The combined organic layers were washed with saturated salt solution (2X), and dried over anhydrous sodium sulfate. The mixture was filtered and the solvents removed by rotoevaporation.
  • Step C N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)-
  • Step A N-fN-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonvn-(L)- (4-(2-tetrazolylphenyl)phenylalanine t-butyl ester N-[N-(3,5-Dichlorobenznesulfonyl)pyrrole-2-carbonyl]-(L)- (4-(2-cyanophenyl)phenylalanine t-butyl ester (44 mg, 0.070 mmoL, obtained from Example 8, Step B) was dissolved in toluene and 66 mg (0.32 mmoL) of trimethyl tin azide was added. The mixture was stirred and refluxed for 36 h.
  • Step B N- [N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll -(D-
  • Example 1 Step E to afford the title compound in 50% yield as a white foam, homogeneous by TLC (10% methanol/dichloromethane).
  • Step A N- TN-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyn -(h)-
  • Step B N-rN-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)-
  • Step C N-[N-(3.5-Dichlorobenznesulfonyl)pyrrole-2-carbonyll-(L)-
  • Example 1 Step E to afford the title compound in 65% yield as a white foam, homogeneous by TLC (10% methanol/dichloromethane).
  • Step B N-rN-(3.5-Dichlorobenzenesulfonyl)pyrrole-2-carbonyn-
  • Step A Preparation of CS-1 Coated Plates.
  • Untreated 96 well polystyrene flat bottom plates were coated with bovine serum albumin (BSA; 20 ⁇ g/ml) for 2 hours at room temperature and washed twice with phosphate buffered saline (PBS).
  • BSA bovine serum albumin
  • PBS phosphate buffered saline
  • the albumin coating was next derivatized with 10 ⁇ g/ml 3-(2- pyridyldithio) propionic acid N-hydroxysuccinimide ester (SPDP), a heterobifunctional crosslinker, for 30 minutes at room temperature and washed twice with PBS.
  • SPDP 3-(2- pyridyldithio) propionic acid N-hydroxysuccinimide ester
  • the CS-1 peptide (Cys-Leu-His-Gly-Pro-Glu-Ile- Leu-Asp-Val-Pro-Ser-Thr), which was synthesized by conventional solid phase chemistry and purified by reverse phase HPLC, was next added to the derivatized BSA at a concentration of 2.5 ⁇ g/ml and allowed to react for 2 hours at room temperature. The plates were washed twice with PBS and stored at 4°C.
  • Step B Preparation of Fluorescently Labeled Jurkat Cells.
  • Jurkat cells obtained from the American Type Culture Collection (Rockville, MD; cat # ATCC TIB-152) were grown and maintained in RPMI- 1640 culture medium containing 10% fetal calf serum (FCS), 50 units/ml penicillin, 50 ⁇ g/ml streptomycin and 2 mM glutamine. Fluorescence activated cell sorter analysis with specific monoclonal antibodies confirmed that the cells expressed both the oc4 and ⁇ l chains of VLA-4. The cells were centrifuged at 400xg for five minutes and washed twice with PBS.
  • FCS fetal calf serum
  • the cells were incubated at a concentration of 2 x 10 cells/ml in PBS containing a 1 ⁇ M concentration of a fluorogenic esterase substrate (2', 7'-bis-(2-carboxyethyl)-5-(and -6)- carboxyfluorescein, acetoxymethyl ester; BCECF-AM; Molecular Probes Inc., Eugene, Oregon; catalog #B-1150) for 30-60 minutes at 37°C in a 5% CO2/air incubator.
  • the fluorescently labeled Jurkat cells were washed two times in PBS and resuspended in RPMI containing 0.25% BSA at a final concentration of 2.0 x 10 cells/ml.
  • Compounds of this invention were prepared in DMSO at lOOx the desired final assay concentration. Final concentrations were selected from a range between 0.001 nM-100 ⁇ M. Three ⁇ L of diluted compound, or vehicle alone, were premixed with 300 ⁇ L of cell suspension in 96-well polystyrene plates with round bottom wells. 100 ⁇ L aliquots of the cell /compound mixture were then transferred in duplicate to CS-1 coated wells. The cells were next incubated for 30 minutes at room temperature. The non-adherent cells were removed by two gentle washings with PBS.
  • the signal peptide as well as domains 1 and 2 of human VCAM were amplified by PCR using the human VCAM cDNA (R & D Systems) as template and the following primer sequences: 3'-PCR primer:5'-AATTATAATTTGATCAACTTAC CTGTCAATTCTTTTACAGCCTGCC-3'; 5'-PCR primer: 5'-ATAGGAATTCCAGCTGCCACCATGCCTGGGAAGATGGTCG-3'.
  • the 5'-PCR primer contained EcoRI and PvuII restriction sites followed by a Kozak consensus sequence (CCACC) proximal to the initiator methionine ATG.
  • the 3'-PCR primer contained a Bell site and a splice donor sequence. PCR was performed for 30 cycles using the following parameters: 1 min. at 94 C, 2 min. at 55 C, and 2 min. at 72 C.
  • the resulting PCR product of 650 bp was digested with EcoRI and Bell and ligated to expression vector pig-Tail (R & D Systems, Minneapolis, MN) digested with EcoRI and BamHI.
  • the pig-Tail vector contains the genomic fragment which encodes the hinge region, CH2 and CH3 of human IgGl (GenBank Accession no. Z17370).
  • the DNA sequence of the resulting VCAM fragment was verified using Sequenase (US Biochemical, Cleveland, OH).
  • the fragment encoding the entire VCAM-Ig fusion was subsequently excised from pig-Tail with EcoRI and NotI and ligated to pCI-neo (Promega, Madison, WI) digested with EcoRI and NotI.
  • the resulting vector designated pCI-neo/VCAM-Ig was transfected into CHO-K1 (ATCC CCL 61) cells using calcium-phosphate DNA precipitation (Specialty Media, Lavalette, NJ).
  • Stable VCAM-Ig producing clones were selected according to standard protocols using 0.2-0.8 mg/ml active G418 (Gibco, Grand Island, NY), expanded, and cell supernatants were screened for their ability to mediate Jurkat adhesion to wells previously coated with 1.5 ⁇ g/ml (total protein) goat anti-human IgG (Sigma, St. Louis, MO).
  • VCAM- Ig was purified from crude culture supernatants by affinity chromatography on Protein A/G Sepharose (Pierce, Rockford, IL) according to the manufacturer's instructions and desalted into 50 mM sodium phosphate buffer, pH 7.6, by ultrafiltration on a YM-30 membranes (Amicon, Beverly, MA).
  • Step B Preparation of 125 I-VCAM-Ig VCAM-Ig was labeled to a specific radioactivity greater that
  • Compounds of this invention were prepared in DMSO at lOOx the desired final assay concentration. Final concentrations were selected from a range between 0.001 nM-100 ⁇ M.
  • Jurkat cells were centrifuged at 400xg for five minutes and resuspended in binding buffer (25 mM HEPES, 150 mM NaCl, 3 mM KC1, 2 mM glucose, 1 mM MnCl 2 , 0.1% bovine serum albumin, pH 7.4) without MnCl2. The cells were centrifuged again and resuspended in complete binding buffer.
  • VCAM-Ig in the presence of 10 nM unlabeled VCAM-Ig was usually less than 5% of that observed in the presence of vehicle alone. Percent inhibition was then calculated for each test well and the IC50 was determined from a ten point titration using a validated four parameter fit algorithm.
  • Compounds of Examples 1-8 showed IC50 values of less than 10 nM in the inhibition of VCAM-Ig binding to VLA-4.
  • IC50 values for the inhibition of VGAM-Ig binding to VLA-4 are provided below for representative compounds:
  • EXAMPLE 17 Antagonism of aft- Dependent Binding to VCAM-Ig Fusion Protein.
  • Step A ⁇ Cell line.
  • RPMI-8866 cells (a human B cell line ⁇ ⁇ . ⁇ ; a gift from Prof. John Wilkins, University of Manitoba, Canada) were grown in
  • the cells (1.25 x 10 6 cells/well) were pelleted at 1000 rpm for 5 minutes and then washed twice in binding buffer (25 mM Hepes, 150 mM NaCl , 0.1 % BSA, 3 mM KC1, 2 mM Glucose, pH 7.4). Cells were then resuspended at 3.3 x 10 7 cells/ml.

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Abstract

L'invention concerne des dérivés de pyrrole à substitution représentés par la formule (I), qui sont des antagonistes pour VLA-4 et/ou α4β7, agissant donc utilement dans l'inhibition ou la prévention de l'adhésion cellulaire et des pathologies dont la médiation est assurée par cette adhésion. Les composés considérés peuvent être formulés en compositions pharmaceutiques appropriées au traitement de l'asthme, de l'allergie, de l'inflammation, de la sclérose en plaques et autres maladies inflammatoires et auto-immunes.
PCT/US1998/024635 1997-11-21 1998-11-18 Derives de pyrrole a substitution tenant lieu d'inhibiteurs d'adhesion cellulaire WO1999026922A1 (fr)

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Cited By (29)

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GB2354440A (en) * 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US6482849B1 (en) 1997-06-23 2002-11-19 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6630503B1 (en) 1999-08-13 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
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
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6685617B1 (en) 1998-06-23 2004-02-03 Pharmacia & Upjohn Company Inhibitors of α4β1 mediated cell adhesion
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
JP2005535710A (ja) * 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド アリールおよびヘテロアリール化合物ならびに凝固を調節する方法
US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
WO2009126920A2 (fr) 2008-04-11 2009-10-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain, et ses conjugués
US8222286B2 (en) 2009-11-20 2012-07-17 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
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
US8394853B2 (en) 2009-05-28 2013-03-12 Novartis Ag Substituted aminopropionic derivatives as neprilysin inhibitors
US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ARTICO et al., "Synthesis of Pyrryl Aryl Sulfones", ARCH. PHARM., December 1995, Vol. 328, No. 3, pages 223-229. *

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US6482849B1 (en) 1997-06-23 2002-11-19 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
US6596752B1 (en) 1997-06-23 2003-07-22 Tanabe Seiyaku Co., Ltd. Inhibitors of α4β1 mediated cell adhesion
US6521666B1 (en) 1998-01-20 2003-02-18 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6855843B2 (en) 1998-01-20 2005-02-15 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US6329362B1 (en) 1998-03-16 2001-12-11 Celltech Therapeutics Limited Cinnamic acid derivatives
US6521626B1 (en) 1998-03-24 2003-02-18 Celltech R&D Limited Thiocarboxamide derivatives
US6685617B1 (en) 1998-06-23 2004-02-03 Pharmacia & Upjohn Company Inhibitors of α4β1 mediated cell adhesion
US6465471B1 (en) 1998-07-03 2002-10-15 Celltech Therapeutics Limited Cinnamic acid derivatives
US6677339B2 (en) 1998-09-28 2004-01-13 Celltech R & D Limited Phenylalanine derivatives
US6953798B1 (en) 1998-11-30 2005-10-11 Celltech R&D Limited β-alanine derivates
US6518283B1 (en) 1999-05-28 2003-02-11 Celltech R&D Limited Squaric acid derivatives
GB2354440A (en) * 1999-07-20 2001-03-28 Merck & Co Inc Aryl amides as cell adhesion inhibitors
US7034043B2 (en) 1999-08-13 2006-04-25 Biogen Idec Ma Inc. Cell adhesion inhibitors
US6630503B1 (en) 1999-08-13 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
US6534513B1 (en) 1999-09-29 2003-03-18 Celltech R&D Limited Phenylalkanoic acid derivatives
US6455539B2 (en) 1999-12-23 2002-09-24 Celltech R&D Limited Squaric acid derivates
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
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
US6610700B2 (en) 2000-04-17 2003-08-26 Celltech R & D Limited Enamine derivatives
US6780874B2 (en) 2000-04-17 2004-08-24 Celltech R & D Limited Enamine derivatives
US6545013B2 (en) 2000-05-30 2003-04-08 Celltech R&D Limited 2,7-naphthyridine derivatives
US6403608B1 (en) 2000-05-30 2002-06-11 Celltech R&D, Ltd. 3-Substituted isoquinolin-1-yl derivatives
US6740654B2 (en) 2000-07-07 2004-05-25 Celltech R & D Limited Squaric acid derivatives
US6469025B1 (en) 2000-08-02 2002-10-22 Celltech R&D Ltd. 3-substituted isoquinolin-1-yl derivatives
US7026501B2 (en) 2000-08-31 2006-04-11 Tanabe Seiyaku Co., Ltd. Inhibitors of α4 mediated cell adhesion
US7456217B2 (en) 2000-08-31 2008-11-25 Mitsubishi Tanabe Pharma Corporation Inhibitors of alpha4 mediated cell adhesion
US8501809B2 (en) 2000-08-31 2013-08-06 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7671090B2 (en) 2000-08-31 2010-03-02 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
US7872151B2 (en) 2000-08-31 2011-01-18 Mitsubishi Tanabe Pharma Corporation Inhibitors of α4 mediated cell adhesion
JP2005535710A (ja) * 2002-08-09 2005-11-24 トランス　テック　ファーマ，インコーポレイテッド アリールおよびヘテロアリール化合物ならびに凝固を調節する方法
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
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
EP2860260A1 (fr) 2008-04-11 2015-04-15 Merrimack Pharmaceuticals, Inc. Lieurs d'albumine de sérum humain et de leurs conjugués
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US8263629B2 (en) 2009-05-28 2012-09-11 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
US9603819B2 (en) 2009-05-28 2017-03-28 Novartis Ag Substituted aminobutyric derivatives as neprilysin inhibitors
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US8642635B2 (en) 2009-11-20 2014-02-04 Novartis Ag Substituted carbamoylmethylamino acetic acid derivatives as novel NEP inhibitors
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US9102635B2 (en) 2013-02-14 2015-08-11 Novartis Ag Substituted bisphenyl butanoic acid derivatives as NEP inhibitors with improved in vivo efficacy
US9163040B2 (en) 2013-02-14 2015-10-20 Novartis Ag Substituted bisphenyl butanoic phosphonic acid derivatives as NEP inhibitors
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