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WO1992008464A1 - Composes d'uree substitues et composes associes utilises dans la modulation de l'adhesion cellulaire - Google Patents

Composes d'uree substitues et composes associes utilises dans la modulation de l'adhesion cellulaire Download PDF

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WO1992008464A1
WO1992008464A1 PCT/US1991/008528 US9108528W WO9208464A1 WO 1992008464 A1 WO1992008464 A1 WO 1992008464A1 US 9108528 W US9108528 W US 9108528W WO 9208464 A1 WO9208464 A1 WO 9208464A1
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hydrogen
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Thomas C. Mckenzie
Gilbert M. Rishton
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Mitsubishi Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/08—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/10—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to novel substituted urea and related compounds, as well as to the use of such compounds for the modulaton of cell adhesion.
  • the compounds have application to the study and treatment of disease conditions mediated by cell adhesion. Specifically, the compounds have application to the study, diagnosis, treatment or prevention of diseases and conditions such as, for example, cardiovascular disease, harmful platelet aggregation, neoplastic disease including metastasis of neoplastic growth, wound healing, inflammation and autoimmune disease or other diseases or conditions involving cell adhesion.
  • diseases and conditions such as, for example, cardiovascular disease, harmful platelet aggregation, neoplastic disease including metastasis of neoplastic growth, wound healing, inflammation and autoimmune disease or other diseases or conditions involving cell adhesion.
  • the extracellular matrix is that material which surrounds the muscle and is the major component of connective tissue of all mammals.
  • the extracellular matrix provides for structural integrity, and promotes cell migration and cellular differentiation. As part of these functions, the extracellular matrix has been shown to support adhesion for various types of cells in vitro. Molecules such as the collagens, fibronectin, vitronectin, laminin, von Willebrand factor, thrombospondin, bone sialoprotein, fibrinogen, and tenascin have been found to possess this property of mediating cell adhesion.
  • the above cell-adhesive molecules have been found to exhibit a structural similarity in their respective binding sites, each of which contains the amino acid sequence arginine-glycine-aspartic acid, or RGD using conventional single letter nomenclature.
  • the cell-binding site in fibronectin has been reproduced synthetically.
  • the cellular receptor site for fibronectin has been identified for various cells, in addition, cellular receptors that recognize RGD-containing sequences in other extracellular matrix proteins (e.g., the vitronectin receptor) have been identified.
  • cytoskeleton Horwitz et al., Nature, 1986, 320, 531.
  • the larger of the two polypeptides, the ⁇ subunit contains a number of regions that are structurally similar to caimodulin and that apparently mediate the binding of calcium to the receptor. The presence of such divalent cations is required for the receptor to bind ligand.
  • the ⁇ subunit is somewhat smaller and conformationally compact due to numerous intrachain disulfide bonds.
  • the cytoplasmic domain of the ⁇ subunit contains a potentially phosphorylated tyrosine. Hirst et al., PNAS-USA, 1986, 83, 6470; Tamkun et al., Cell, 1986, 46, 271-282.
  • RGD-directed receptors as well as other "orphan" receptors the ligand for which is unknown, have also been characterized. This putative RGD
  • the integrins can be grouped on the basis of the identity of their ⁇ subunit.
  • the ⁇ subunit as disclosed above for the fibronectin receptor, is corhpact due to a high degree of cross-linking.
  • the first group of integrins includes the very late activation antigen (VLA) proteins, which themselves include the fibronectin receptor
  • a limited number of compounds containing sequences of natural amino acids or derivatives other than RGD may also possess the capability for affecting cell adhesion. These non-RGD-containing peptides are not well characterized. See,
  • the present invention relates to compounds having activity as cell adhesion modulators.
  • the compounds are characterized by the structure
  • Z is preferably an aromatic or electron-withdrawing group such as a sulfonyl, substituted sulfonyl, nitro, or haloalkyl group, or a substituted carbonyl, oxy, carboxyl, oxycarbonyl, amino or thio-containing group;
  • Y is a suitable double-bonded atom or substituent group, preferably including sulfur, nitrogen or oxygen; and each R-group is hydrogen or a suitable hydrocarbon-containing or heteroatomic substituent, including amidinyl.
  • Y is a double-bonded oxygen atom
  • the resulting compound is a substituted urea compound.
  • Y is a double-bonded sulfur atom
  • a substituted thiourea compound results; and where Y includes a double-bonded nitrogen atom, a substituted guanidino (i.e., an iminoanalog of a urea
  • the compounds in one aspect, sufficiently mimic extracellular matrix ligands or other cell adhesion ligands so as to bind to cell surface receptors.
  • receptors include integrin receptors in general, including the fibronectin, collagen, laminin, LFA-1 , MAC-1 , p150,95, vitronectin and gpllb/llla receptors.
  • the present compounds have been found to modulate cell adhesion by competing, for example, with RGD-containing ligands and by binding to
  • One object of the present invention is to provide novel compounds which act to modulate cell adhesion.
  • Another object of the present invention is to provide substituted urea and related thiourea, guanidino and biguanidino compounds which are capable of binding with a cellular receptor.
  • Another object of the present invention is to provide a novel method for modulating cell adhesion using the present compounds.
  • the compounds of the present invention are those having the property of modulating cell adhesion.
  • ARDS adult respiratory distress syndrome
  • the attachment of inappropriate cells to the lung lining induces an inflammatory response.
  • Preliminary in vitro results show that such detrimental attachment, in which the leukocyte adheres to endothelial cells or the lung extracellular matrix, is mediated by RGD-containing protein and
  • RGD-recognizing receptors on the leukocytes In this situation, compounds with a binding affinity to RGD receptors are desirable as competitive antagonists and should be useful in treating ARDS and asthma. Such compounds are disclosed herein.
  • HIV Human immunodeficiency virus
  • tat a gene for transactivating protein, termed tat, which contains an RGD sequence. It is reported that this tat protein functions in the ceil adhesion of the virus to target cells, and that, by inhibiting such cell adhesion function, transcriptional activation by the tat protein can be inhibited. It has further been found that such inhibition of tat mediated transcriptional activation inhibits, i.e., prevents or slows, progression, including initiation, of disease states resulting from abnormal gene expression. Such disease states include immune dysfunction resulting in immunodeficiency as well as other disease states associated with Immunodeficiency Virus infestion such as Kaposi's Sarcoma. See, e.g., Vogel et al., Nature, 1988, 335, 606.
  • Z is a pharmaceutically suitable substituent group or salt thereof, preferably including an aromatic or electron-withdrawing group, and most preferably one selected from R 4 -
  • each X- is individually a halogen atom
  • R 3 is a pharmaceutically suitable substituent group, preferably one selected from hydrogen, amino from linear and branched, unsubstituted and substituted C 1 -C 8 lower alkyl, C 2 -C 8 alkenyls, C 2 -C 8 alkynyls, C 3 -C 14 cycloalkyls, from groups of the form Ar— , from a group of the form and from a group of the form wherein n is an integer of from 1 to 4 and Ar is an unsubstituted or substituted aryl, aralkyl group, preferably one having from 5 to about 14 ring atoms, and optionally containing one or more of 0, N or 5 as a ring heteroatom;
  • each of R 1 , R 2 , R 4 and R 5 is individually a
  • the compounds of the invention further include pharmaceutically acceptable base- or acid-addition salts of the compositions of Formula I.
  • compositions of the invention include such compounds
  • Substituents R 2 and R 3 are most preferably hydrogen or unsubstituted or substituted lower alkyl or cycloalkyl groups. Methyl, ethyl, isopropyl,
  • the preferred substituents are aromatic groups of the form Ar as well as aromatic sulfonyl groups of the form Ar(SO 2 )-where Ar is an aromatic group as defined above such as a C 6 -C 14 aryl, a C 7 -C 14 alkaryl or a C 7 -C 14 aralkyl.
  • Ar is an aromatic group as defined above such as a C 6 -C 14 aryl, a C 7 -C 14 alkaryl or a C 7 -C 14 aralkyl.
  • the most highly preferred substituents are unsubstituted or substituted single-ring aryl, alkaryl, arylsulfonyl and alkarylsulfonyl groups, especially p-toluenesulfonyl and 3'- and/or 4'-substituted (o- and/or p-substituted) phenyl substituents.
  • substituents occur on the aromatic portion of such a Z-group, these are most preferably lower alkyl (e.g., methyl), lower alkoxy (e.g., methoxy) or electron-withdrawing groups (e.g., nitro, chloro, fiuoro or trifluoromethyl).
  • lower alkyl e.g., methyl
  • lower alkoxy e.g., methoxy
  • electron-withdrawing groups e.g., nitro, chloro, fiuoro or trifluoromethyl
  • each X may be a halogen atom, most preferably fiuoro. Trifluoromethyl is especially preferred for such a Z-group.
  • the most highly preferred R 5 substituent is hydrogen, and relatively non-bulky substituents such as lower alkyl groups are also preferred.
  • the cyclic structure may contain one or more heteroatoms selected from N, O and S, and may be mono- or polycyclic. Single-ring structures are preferred.
  • the cyclic structure can be saturated, as in morphoiinyl, thiamorpholinyl, piperidyl, piperazinyl, pyrrolidinyl, pyrazoiidinyl, quinuclidinyl, imidazolidinyl, and other structures, or unsaturated or aromatic, as in imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyrrolyl, pyrrolinyl, pyridazinyl, pyrrodiazolyl, isothiazolyl, thiophenyl, thiazinyl, isoxazolyl, furazanyl and other structures.
  • Polycyclic structures such as indolyl, quinoiyl, quinazolinyl, phenoxazinyl, phenazinyl, phenothiazinyl, benzo[b]thienyl, phenanthrolinyl or others may be employed. Attachment of such cyclic substituents with the remainder of the compound may occur through a carbon or (provided that a point of bonding is present on a heteroatom) through a heteroatom within the heterocyclic group, or attachment may be achieved through, for example, an intermediate alkylene moiety which links the cyclic group with the remainder of the compound. A preferred aralkyl group having such a structure is the benzyl group. Such cyclic substituents may also be substituted with pharmaceutically suitable substituents as is now discussed.
  • R 6 , R 7 and R 8 are each a pharmaceutically suitable substituent group, preferably one selected from hydrogen, amino, from linear and branched, unsubstituted and substituted C 1 -C 8 lower alkyls, C 2 -C 8 alkenyls; C 2 -C 8 alkynyls, C 3 -C 14 cycloalkyls, from gropus of the form Ar— , and, in the case of -NR 7 R 8 , from cyciized groups forming (in attachment with the nitrogen atom) a 5-8 membered heterocyclic ring optionally containing one or more of O, N or S as a further ring heteroatom, wherein Ar— is an unsubstituted or substituted aryl or aralkyl ("aromatic") group, preferably one having from 5 to about 14 ring atoms, and optionally containing one or more of O, N or S as a ring heteroatom.
  • aromatic is an unsubstituted or
  • substituents include hydroxyl, amino, lower ( C 1 -C 8 ) alkoxy I, and, in the case particularly of aromatic groups, the foregoing substituents as well as nitro and halogen (especially chloro and bromo) moieties.
  • substituents to one or more of R 1 through R 5 may be used, for example, to alter bioactivity, solubility and/or biodistribution characteristics of the subject compounds.
  • a hydroxyl substituent on a lower alkyl R-group is particularly preferred.
  • R-group includes an aromatic portion (as in certain preferred Z groups)
  • substituents occurring on the meta and/or para positions i.e., 3'- and/or 4'-positions
  • Preferred forms of such aromatic substituents thus include 3'- and/or 4'[di/mono]methylphenyl
  • the compounds of this invention may be prepared using synthetic methods such as those described hereinafter, or, In view of the present disclosure, by other synthetic methods known in the art.
  • the following examples are intended to be illustrative only, and should not be construed as limiting the scope of the present invention.
  • Sulfonyl thioureas such as p-toluenesulfonyl thioureas, that are substituted with hydrogen at each of positions R 2 and R 3 may be prepared by reacting an appropriate sulfonyl compound (such as p-toluenesulfonyl chloride, 1) with a reactive cyano-containing compound (such as calcium cyanamide) to yield a reactive sulfonylcyano intermediate (such as a p-toluenesulfonyl-cyanamide salt, 2), and thereafter reacting with an appropriate reducing agent (such as sodium thiosulfate) to yleld the sulfonyl thiourea product (3).
  • an appropriate sulfonyl compound such as p-toluenesulfonyl chloride, 1
  • a reactive cyano-containing compound such as calcium cyanamide
  • a reactive sulfonylcyano intermediate such
  • Sulfonylthioureas that are singly or multiply substituted with non-hydrogen moieties at one or more of positions R 2 and R 3 may be prepared by reacting an appropriate sulfonamide (such as p-toluenesulfonamide, 4) with carbon disulfide to form a sulfoniminodithiocarbonate (such as p-toluenesulfoniminodithiocarbonate salt, 5), then reacting to form a sulfonylisothiocyanate compound (e.g., 6), followed by reaction with one or more amine compounds to form the amino-substituted sulfonylthlourea product (e.g., 7).
  • an appropriate sulfonamide such as p-toluenesulfonamide, 4
  • carbon disulfide such as p-toluenesulfoniminodithiocarbonate salt, 5
  • the dipotassium salt of p-toluenesulfoniminodithio-carbonate (5) was first prepared by mixing 15.27 g (0.2 mole) of carbon disulfide and 34.28 g (0.2 mole) of p-toluenesulfonamide (4) in 200 mL of dimethylformamide and stirring mechanically as 11.35 g (86.4%, 0.0.175 mole) of potassium hydroxide was added under N 2 over 1-hour. After an additional hour, an additional 14.66 g (0.225 mole) of KOH was added. In one additional hour 200 mL of ethyl acetate was added and the resulting golden slurry cooled in an ice bath.
  • the p-toluenesulfonyiisothiocyanate intermediate (6) was prepared by mixing the first crop from the previous reaction with 3 g of potassium chloride and grinding to a fine powder with a mortar and pestle. The powder was suspended in 200 mL of methylene chloride and the slurry cooled to 0°F. A 90 mL portion of 1.93 M solution of phosgene in toluene was added dropwise over 45 minutes.
  • the 1-(p-toluenesulfonyl)-3-cyclohexylthiourea salt (Z) was prepared by dissolving a 0.49 g (2.3) mmole) portion of the isothiocyanate from above in a mixture of 10 mL of isopropyl ether and 5 mL of ethyl acetate. To this solution
  • Purification of the compounds of the invention may be achieved using methods known in the art.
  • any of the synthetic procedures involve the use of fluorine or fluoride ion
  • a potentially important aspect in final purification is the removal of fluoride, which if present in even small amounts may alter the biological profile of the compound.
  • Salts of acidic groups of the product compounds may be prepared in the usual manner by contacting the compound with one or more equivalents of a desired base such as, for example, a metallic hydroxide base such as, for example, sodium hydroxide; a metal carbonate base such as, for example, sodium carbonate; or an amine base such as, for example, triethylamine,
  • a desired base such as, for example, a metallic hydroxide base such as, for example, sodium hydroxide
  • a metal carbonate base such as, for example, sodium carbonate
  • an amine base such as, for example, triethylamine
  • Acid salts of the compounds may be prepared by contacting a basic group in the compound with one or more equivalents of the desired inorganic or organic acid, such as, for example, hydrochloric, acetic, citric, oxalic, maionic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, sulfuric, phosphoric, methanesuifonic or other acid.
  • a basic group in the compound such as, for example, hydrochloric, acetic, citric, oxalic, maionic, salicyclic, malic, gluconic, fumaric, succinic, ascorbic, maleic, sulfuric, phosphoric, methanesuifonic or other acid.
  • compositions can thus be administered orally, sublingually, topically (e.g., on the skin or in the eyes), parenterally (e.g., intramuscularly, intravenously, subcutaneously or intradermally), or by inhalation, and in the form of either solid, liquid or gaseous dosage including tablets, suspensions, soluates, hydrates and aerosols, as is discussed in more detail below.
  • administration can be conducted in single unit dosage form with continuous therapy or in single dose therapy ad libitum. It is expected in particular that the present compounds may have suitably high cell adhesion modulation activity when administered via the oral route in view of the relative nonlability of the chemical bonds in the compounds.
  • Useful pharmaceutical carriers for the preparation of the pharmaceutical compositions hereof can be solids, liquids or gases; thus, the compositions can take the form of tablets, pills, capsules, powders, enterically coated or other protected formulations (such as by binding on ion exchange resins or other carriers, or packaging in lipid protein vesicles or adding additional terminal amino acids), sustained release formulations, solutions (e.g., ophthalmic drops), suspensions, elixirs, aerosols, and the like.
  • Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly (when isotonic) for injectable solutions.
  • compositions may be subjected to conventional pharmaceutical expedients such as sterilization and may contain conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • conventional pharmaceutical additives such as preservatives, stabilizing agents, wetting or emulsifying agents, salts for adjusting osmotic pressure, buffers, and the like.
  • Suitable pharmaceutical carriers and their formulations are described in Martin, Remington's Pharmaceutical Sciences, 15th Ed. (Mack Publishing Co.,
  • the particular dosage of pharmaceutical composition to be administered to the subject will depend on a variety of considerations including the nature of the disease, the severity thereof, the schedule of administration, the age and physical
  • Topical dosages may utilize formulations containing generally as low as 0.1 mg of compound per ml of liquid carrier or excipient, with multiple daily applications being
  • the compounds and therapeutic or pharmaceutical compositions of the invention are useful in the study or treatment of diseases or other conditions which are mediated by the binding of integrin receptors to ligands, including conditions involving inappropriate (i.e., excessive or insufficient) binding of cells to natural or other ligands.
  • diseases and conditions include inflammatory diseases such as rheumatoid arthritis, asthma, allergy conditions, adult respiratory distress syndrome, inflammatory bowel diseases (e.g., ulcerative colitis and regional enteritis) and ophthalmic inflammatory diseases;
  • autoimmune diseases thrombosis or inappropriate platelet aggregation
  • neoplastic disease including metastasis conditions, and acquired
  • derivatives of the present compounds may be useful in the generation of antigens which, in turn, may be useful to generate antibodies.
  • These antibodies will, in some cases, themselves be effective in inhibiting cell adhesion or modulating immune activity by acting as receptors for matrix proteins or other cell adhesion ligands, or, if anti-idiotypic, by acting to block cellular receptors.
  • the following assay established the activity of the present compounds in inhibiting cell adhesion in a representative in vitro system.
  • the assay was a competition assay in which both fibronectin and a test compound were present.
  • the cell line U937 was purchased from American Type Tissue Culture
  • the cells were cultured in RPMI media (J.R. Scientific Company,
  • Microtiter plates (96-well, Falcon) were coated overnight at 4°C with 5 ⁇ g/ml fibronectin (FN) (for a total volume of 0.1 ml) or, as a control, 5 ⁇ g/ml bovine serum albumin (BSA) diluted in phosphate buffered saline (PBS, 0.01 M NaPO 4 in 0.9% NaCl at pH 7.2 to 7.4). Unbound proteins were removed from plates by washing with PBS. The plates were then coated with 100 ⁇ l of PBS containing 2.5 mg/ml BSA for one hour at 37°C. This procedure is a modification of a previously published method, Cardareili, P.M. and M.D. Pierschbacher,
  • DMEM Dulbecco's Modified Eagles Medium
  • BSA BSA
  • Subject compounds were then dissolved in DMEM and BSA, and the pH was adjusted to 7.4 with 7.5% sodium bicarbonate.

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Abstract

L'invention se rapporte à des composés d'urée, de thio-urée et de guanidino substitués, ainsi qu'à des composés et des sels associés, qui sont utiles comme antagonistes de récepteurs cellulaires, afin de moduler l'adhésion cellulaire par l'intermédiaire de récepteurs d'intégrine et/ou de récepteurs de fibronectine. Des procédés servant à synthétiser, à tester, à formuler et à utiliser ces composés comme agents thérapeutiques sont également décrits.
PCT/US1991/008528 1990-11-15 1991-11-14 Composes d'uree substitues et composes associes utilises dans la modulation de l'adhesion cellulaire Ceased WO1992008464A1 (fr)

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WO1994017041A1 (fr) * 1993-01-27 1994-08-04 G.D. Searle & Co. Derives d'uree a substitution amidinophenyle, de thiouree ou de guanidino utiles comme inhibiteurs de l'agregation plaquettaire
WO1994028897A3 (fr) * 1993-06-07 1995-03-23 Us Health Utilisation d'un medicament suppresseur des molecules de la classe i du complexe majeur d'histocompatibilite (cmh) dans le traitement des maladies autoimmunes et du rejet de greffe
WO1996030329A1 (fr) * 1995-03-30 1996-10-03 Biocryst Pharmaceuticals, Incorporated Derives de benzene substitues, utiles comme inhibiteurs de la neuraminidase
WO1996040641A1 (fr) * 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. Derives de sulfonamides servant a moduler l'adherence cellulaire
AU676492B2 (en) * 1992-09-21 1997-03-13 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
WO1997036858A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives de l'acide alcanoique de cyclopropyle
WO1997036861A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives meta-substitues du sulphonamide de phenylene
WO1997036859A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives d'acide phenylpropanoique para-substitues, utilises comme antagonistes de l'integrine
WO1998004247A1 (fr) * 1996-07-25 1998-02-05 Biogen, Inc. Inhibiteurs d'adhesion cellulaire
WO1999020617A1 (fr) * 1997-10-21 1999-04-29 Active Biotech Ab Urees thiadiazoles anti-inflammatoires agissant comme inhibiteurs lfa-1 et mac-1
US6239108B1 (en) 1996-07-11 2001-05-29 Biogen, Inc. Cell adhesion inhibitors
US6248713B1 (en) 1995-07-11 2001-06-19 Biogen, Inc. Cell adhesion inhibitors
US6306840B1 (en) 1995-01-23 2001-10-23 Biogen, Inc. Cell adhesion inhibitors
EP1157985A1 (fr) * 1996-03-29 2001-11-28 G.D. Searle & Co. Dérivés de phénylène para-substitués et leur utilisation comme antagonistes d'intégrin
US6495525B1 (en) 1998-05-28 2002-12-17 Biogen, Inc. VLA-4 inhibitor: oMePUPA-V
AU759063B2 (en) * 1996-07-25 2003-04-03 Biogen Idec Ma Inc. Cell adhesion inhibitors
US6552216B1 (en) 1996-07-25 2003-04-22 Biogen, Inc. Molecular model for VLA-4 inhibitors
US6630503B1 (en) 1999-08-13 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
US6686350B1 (en) 1996-07-25 2004-02-03 Biogen, Inc. Cell adhesion inhibitors
ES2200617A1 (es) * 2001-01-19 2004-03-01 Almirall Prodesfarma Sa Derivados de urea como antagonistas de integrinas alfa 4.
US6875743B1 (en) 2000-11-28 2005-04-05 Biogen, Inc. Cell adhesion inhibitors
US7001921B1 (en) 1995-01-23 2006-02-21 Biogen Idec Ma Inc. Cell adhesion inhibitors
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
EP1539248A4 (fr) * 2002-03-29 2007-12-26 Univ Maryland Inhibiteurs de l'interaction proteine-proteine s100-p53 et methode d'inhibition du cancer utilisant lesdits inhibiteurs
EP2065050A1 (fr) 1998-09-14 2009-06-03 Board of Regents, The University of Texas System Procédés de traitement de myélome multiple et de résorption osseuse liée au myélome utilisant des antagonistes d'intégrine
EP2140881A1 (fr) 1999-12-16 2010-01-06 Biogen Idec MA Inc. Procédés de traitement de maladie hémorragique ou ischémique du système nerveux central, utilisant des antagonistes d'intégrine anti alpha 4
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
WO2018140510A1 (fr) 2017-01-25 2018-08-02 Biogen Ma Inc. Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc
US11666888B2 (en) 2018-02-05 2023-06-06 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand

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AU676492B2 (en) * 1992-09-21 1997-03-13 Allergan, Inc. Non-acidic cyclopentane heptanoic acid, 2-cycloalkyl or arylalkyl derivatives as therapeutic agents
WO1994017041A1 (fr) * 1993-01-27 1994-08-04 G.D. Searle & Co. Derives d'uree a substitution amidinophenyle, de thiouree ou de guanidino utiles comme inhibiteurs de l'agregation plaquettaire
WO1994028897A3 (fr) * 1993-06-07 1995-03-23 Us Health Utilisation d'un medicament suppresseur des molecules de la classe i du complexe majeur d'histocompatibilite (cmh) dans le traitement des maladies autoimmunes et du rejet de greffe
US5556754A (en) * 1993-06-07 1996-09-17 The United States Of America As Represented By The Department Of Health And Human Services Methods for assessing the ability of a candidate drug to suppress MHC class I expression
US5871950A (en) * 1993-06-07 1999-02-16 Singer; Dinah S. Methods of treating autoimmune diseases and transplantation rejection
US6630512B2 (en) 1995-01-23 2003-10-07 Biogen, Inc. Cell adhesion inhibitors
US7001921B1 (en) 1995-01-23 2006-02-21 Biogen Idec Ma Inc. Cell adhesion inhibitors
US6624152B2 (en) 1995-01-23 2003-09-23 Biogen, Inc. Cell adhesion inhibitors
US6376538B1 (en) 1995-01-23 2002-04-23 Biogen, Inc. Cell adhesion inhibitors
US6306840B1 (en) 1995-01-23 2001-10-23 Biogen, Inc. Cell adhesion inhibitors
US5602277A (en) * 1995-03-30 1997-02-11 Biocryst Pharmaceuticals, Inc. Substituted benzene derivatives useful as neuraminidase inhibitors
WO1996030329A1 (fr) * 1995-03-30 1996-10-03 Biocryst Pharmaceuticals, Incorporated Derives de benzene substitues, utiles comme inhibiteurs de la neuraminidase
US5707985A (en) * 1995-06-07 1998-01-13 Tanabe Seiyaku Co. Ltd. Naphthyl-, quinolyl- and isoquinolyl- sulfonamide derivatives as cell adhesion modulators
WO1996040641A1 (fr) * 1995-06-07 1996-12-19 Tanabe Seiyaku Co., Ltd. Derives de sulfonamides servant a moduler l'adherence cellulaire
US6248713B1 (en) 1995-07-11 2001-06-19 Biogen, Inc. Cell adhesion inhibitors
US6596687B1 (en) 1995-07-11 2003-07-22 Biogen, Inc. Cell adhesion inhibitors
US5843906A (en) * 1996-03-29 1998-12-01 G. D. Searle & Co. Meta-substituted phenylene sulphonamide derivatives
WO1997036858A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives de l'acide alcanoique de cyclopropyle
US6677308B1 (en) 1996-03-29 2004-01-13 G. D. Searle & Co. Meta-substituted phenylene sulphonamide derivatives
EP1157985A1 (fr) * 1996-03-29 2001-11-28 G.D. Searle & Co. Dérivés de phénylène para-substitués et leur utilisation comme antagonistes d'intégrin
WO1997036861A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives meta-substitues du sulphonamide de phenylene
WO1997036859A1 (fr) * 1996-03-29 1997-10-09 G.D. Searle & Co. Derives d'acide phenylpropanoique para-substitues, utilises comme antagonistes de l'integrine
US6239108B1 (en) 1996-07-11 2001-05-29 Biogen, Inc. Cell adhesion inhibitors
CZ298080B6 (cs) * 1996-07-25 2007-06-13 Biogen Idec Ma Inc. Inhibitory bunecné adheze, zpusob jejich prípravya farmaceutické prostredky s jejich obsahem
US6949534B2 (en) 1996-07-25 2005-09-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
WO1998004247A1 (fr) * 1996-07-25 1998-02-05 Biogen, Inc. Inhibiteurs d'adhesion cellulaire
AU759063B2 (en) * 1996-07-25 2003-04-03 Biogen Idec Ma Inc. Cell adhesion inhibitors
CZ298089B6 (cs) * 1996-07-25 2007-06-20 Biogen Idec Ma Inc. Inhibitory bunecné adheze, zpusob jejich prípravya farmaceutické prostredky s jejich obsahem
US6552216B1 (en) 1996-07-25 2003-04-22 Biogen, Inc. Molecular model for VLA-4 inhibitors
US6686350B1 (en) 1996-07-25 2004-02-03 Biogen, Inc. Cell adhesion inhibitors
AU737372B2 (en) * 1996-07-25 2001-08-16 Biogen Idec Ma Inc. Cell adhesion inhibitors
WO1999020617A1 (fr) * 1997-10-21 1999-04-29 Active Biotech Ab Urees thiadiazoles anti-inflammatoires agissant comme inhibiteurs lfa-1 et mac-1
US6495525B1 (en) 1998-05-28 2002-12-17 Biogen, Inc. VLA-4 inhibitor: oMePUPA-V
EP2065050A1 (fr) 1998-09-14 2009-06-03 Board of Regents, The University of Texas System Procédés de traitement de myélome multiple et de résorption osseuse liée au myélome utilisant des antagonistes d'intégrine
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
EP2140881A1 (fr) 1999-12-16 2010-01-06 Biogen Idec MA Inc. Procédés de traitement de maladie hémorragique ou ischémique du système nerveux central, utilisant des antagonistes d'intégrine anti alpha 4
EP2332578A1 (fr) 1999-12-16 2011-06-15 Biogen Idec MA Inc. Procédés de traitement de maladie hémorragique ou ischémique du système nerveux central, utilisant des antagonistes de l'intégrine alpha 4
US6875743B1 (en) 2000-11-28 2005-04-05 Biogen, Inc. Cell adhesion inhibitors
ES2200617A1 (es) * 2001-01-19 2004-03-01 Almirall Prodesfarma Sa Derivados de urea como antagonistas de integrinas alfa 4.
US7253171B2 (en) 2001-01-19 2007-08-07 Laboratorios Almirall, S.A. Urea derivatives as integrin α4 antagonists
EP1539248A4 (fr) * 2002-03-29 2007-12-26 Univ Maryland Inhibiteurs de l'interaction proteine-proteine s100-p53 et methode d'inhibition du cancer utilisant lesdits inhibiteurs
US8053477B2 (en) 2002-03-29 2011-11-08 University Of Maryland, Baltimore Inhibitors of the S100-p53 protein-protein interaction and method of inhibiting cancer employing the same
US7196112B2 (en) 2004-07-16 2007-03-27 Biogen Idec Ma Inc. Cell adhesion inhibitors
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9422282B2 (en) 2010-04-01 2016-08-23 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
WO2018140510A1 (fr) 2017-01-25 2018-08-02 Biogen Ma Inc. Composition et méthodes de traitement d'un accident vasculaire cérébral et d'autres troubles du snc
US11666888B2 (en) 2018-02-05 2023-06-06 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand
US12194432B2 (en) 2018-02-05 2025-01-14 Bio-Rad Laboratories, Inc. Chromatography resin having an anionic exchange-hydrophobic mixed mode ligand

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