EP1189612A1 - Vla-4 hemmende verbindungen - Google Patents
Vla-4 hemmende verbindungenInfo
- Publication number
- EP1189612A1 EP1189612A1 EP00945035A EP00945035A EP1189612A1 EP 1189612 A1 EP1189612 A1 EP 1189612A1 EP 00945035 A EP00945035 A EP 00945035A EP 00945035 A EP00945035 A EP 00945035A EP 1189612 A1 EP1189612 A1 EP 1189612A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- group
- chosen
- mmol
- mixture
- substituted
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
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- 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
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P37/02—Immunomodulators
- A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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- A—HUMAN NECESSITIES
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
- C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
-
- 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
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
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Definitions
- the present invention relates to compounds that selectively inhibit the binding of ligands to the adhesion receptor, 4 ⁇ j integrin, also known as VLA-4.
- Compounds of the present invention are useful in the treatment and prevention of pathologies associated with VLA-4 mediated cell adhesion, such as inflammatory and autoimmune diseases, and tumor metastasis.
- a primary feature of such pathologies as inflammation and autoimmune diseases is the accumulation of activated leukocytes in affected tissues.
- the process by which leukocytes transmigrate from the circulation at a site of inflammation involves a cascade of interactions that can be divided into four major steps: tethering and rolling, activation, firm adhesion, and transmigration (Springer, T., Ann. Rev. Physiol.. 57:827 (1995)).
- leukocytes are lightly tethered to the endothelium and roll along its surface. This is followed by cell activation, mediated by soluble chemotactic stimuli, which initiates the development of a firmer bond between individual leukocytes and endothelial cells.
- the firm bond then results in the successful adhesion and transmigration of the leukocytes through endothelial cell junctions.
- the steps occur in series and each is essential for transmigration to occur. This also means that transmigration can be modulated at each step, thus providing a number of potential targets for pharmacological inhibition.
- the receptors involved in leukocyte migration have, to a large extent, been characterized as belonging to particular cell adhesion molecule families (Carlos and Harlan, Blood, 84:2068 (1994)).
- the initial attachment and rolling step is mediated by a family of adhesion receptors referred to as selectins.
- Firm adhesion is mediated by interaction of leukocyte surface integrins with molecules of the immunoglobulin superfamily expressed on the surface of the endothelium. Both integrins and the immunoglobulin-type adhesion molecules are also primarily involved in leukocyte transmigration. After transmigration, the leukocytes rely on integrins to traverse through the extracellular matrix and remain at the site of inflammation.
- Integrins are a large family of heterodimeric glycoproteins composed of two noncovalently associated subunits, ⁇ and ⁇ (Hynes, R., Cell, 69: 11 (1992)). There are at least 16 different ⁇ subunits ( ⁇ - ⁇ 9 , ⁇ L , ⁇ M , ⁇ D , ⁇ x ⁇ E , ⁇ , ⁇ ,,) and at least 9 different ⁇ ( ⁇ - ⁇ 9 ) subunits. Integrins are divided into sub-families, based upon the ⁇ subunit.
- Leukocytes express a number of different integrins, including ⁇ 4 ⁇ b ⁇ 5 ⁇ ⁇ 6 ⁇ ,, ⁇ 4 ⁇ 7 , ⁇ L ⁇ 2 , ⁇ x ⁇ 2> and ⁇ v ⁇ 3 .
- ⁇ 4 ⁇ , integrin also known as very late antigen-4 (VLA-4) or CD49d/CD29, is expressed on monocytes, lymphocytes, eosinophils, and basophils, all of which are key effector cells in various inflammatory disorders (Helmer, M., Ann. Rev. Immunol.. 8:365 (1990)).
- ⁇ 4 ⁇ , integrin serves as a receptor for vascular cell adhesion molecule-1 (VCAM-1), as well as to the extracellular protein fibronectin (FN) (Elices et al. , Cell. 60:577 (1990)).
- Anti-inflammatory effects and delayed disease progression have been demonstrated after in vivo monoclonal antibody blockade of the ⁇ 4 ⁇ ,/VCAM-l pathway (Lobb et ⁇ /.. J. Clin. Invest. 94:1722-28 (1994)).
- anti- ⁇ 4 inhibited both antigen-induced bronchial hyperreactivity and leukocyte recruitment in bronchoalveolar lavage fluid (Pretolani et al, J. Exp. Med., 180:795 (1994)).
- Antibodies to ⁇ 4 or VCAM-1 prevented antigen-induced eosinophil infiltration of the mouse trachea (Nakajima et al, J. Exp.
- ⁇ 4 or VCAM- 1 monoclonal antibody treatment also delayed or prevented cutaneous delayed hypersensitivity response in mice and monkeys (Chisholm et al. , Eur. J. Immunol. 23:682 (1993); Silber et al. , I Clin. Invest.. 93:1554 (1993); cardiac allograft rejection in mice, accompanied by specific immunosuppression (Isobe et al, J. Immunol.. 153:5810 (1994); graft-versus-host disease in mice after bone marrow transfer (Yang et al. , Proc. Natl. Acad. Sci. USA.
- Rational drug design studies have produced soluble VCAM-Ig fusion protein containing the two N-terminal domains of human VCAM-1 fused to a human IgGl constant region.
- In vivo administration of the fusion protein significantly delays the onset of adoptively transferred autoimmune diabetes in nonobese diabetic mice (Jakubowski et al, J. Immunol., 155:938 (1995)).
- Another approach has used three-dimensional crystallographic structures of VCAM-1 fragments to synthesize cyclic peptide antagonists that closely mimicked the 4 integrin binding loop in domain 1 of VCAM-1.
- VCAM-1 peptide CQIDSPC was able to inhibit the adhesion of VLA-4- expressing cells to purified VCAM-1 (Wang et al, Proc. Natl. Acad. Sci. USA, 92:5714 (1995)).
- the compounds of the present invention selectively inhibit the binding of ligands to ⁇ 4 ⁇ , and therefore, are useful for inhibition, prevention and suppression of VLA-4-mediated cell adhesion and the pathologies associated with that adhesion, such as, for example, inflammation, asthma, arthritis, diabetes, autoimmune responses, multiple sclerosis, psoriasis, transplantation rejection, and tumor metastasis.
- the present invention provides a compound represented by Formula I, or a salt thereof,
- W is chosen from aryl group, substituted aryl group, heteroaryl group and substituted heteroaryl group
- W 1 is chosen from arylene group, substituted arylene group, heteroarylene group and substituted heteroarylene group
- R is chosen from a direct bond, alkyenylene group and -(CH 2 ) n -, wherein n is chosen from 1 and 2,
- X is chosen from -C(O)-, -CH 2 - and S(0) 2 ,
- R 1 , R 2 and R 3 are independently chosen from -H, -OH,-NH 2 , halogen atom, alkyl group, substituted alkyl group, aryl group, substituted aryl group, alkoxy group, substituted alkoxy group, monoalkylammo group, substituted monoalkyla ⁇ uno group, dialkylamino group, substituted dialkyla ⁇ uno group, cycloalkylammo group, substituted cycloalkylamino group, alkylsulfbnylamino group, substituted alkylsulfonylamino group, arylsulfonylamino group, substituted arylsulfonylamino group, aryloxy group, substituted aryloxy group, heteroaryloxy group, substituted heteroaryloxy group, benzyloxy group
- Y is a direct bond or a divalent radical chosen from -C(O)-, -C(0)NH-, alkenylene group, alkynylene group and -(CH 2 ) k Y 2 , wherein k is chosen from 1, 2 and 3, and Y 2 is a direct bond or a divalent radical chosen from -0-, -S-,
- Z is chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group and substituted cycloalkylene group
- a 1 is a direct bond or a divalent radical chosen from alkenylene group, alkynylene group, -(CH 2 ) t - and -O CH ⁇ wherein t is chosen from 1, 2 and 3, and v is chosen from 0, 1, 2, and 3, and
- R is chosen from -OH, lower alkoxy group, -N(H)OH, N N and
- R 6 and R 7 are independently chosen from -H, -OH, halogen atom, alkyl group and alkoxy group
- Y 1 is a divalent radical chosen from -0-, -S-, -S(O)-, -S(0) 2 - and -NY 4 -, wherein Y 4 is chosen from -H and lower alkyl group
- Z 1 is a divalent radical chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group and substituted cycloalkylene group,
- a 2 is a direct bond or a divalent radical chosen from alkenylene group, alkynylene group and -(CH 2 ) e wherein e is chosen from 1, 2 and 3, and
- H H R is chosen from -OH, lower alkoxy group, -N(H)OH, N ⁇ N and
- N f is a divalent 4-, 5-, 6- or 7-membered heterocychc moiety, optionally substituted with from 1 to 3 substitutents chosen independently from alkyl group, alkoxy group, hydroxyalkyl group, -OH, benzyloxy group, -NH 2 , halogen atom, aryl group and heteroaryl group, said moiety may be fused to 1 or 2 additional carbocyclic or heterocychc residues optionally substituted with from 1 to 3 substitutents chosen independently from alkyl group, aryloxy group, alkoxy group, hydroxyalkyl group, -OH, benzyloxy group, -NH 2 , , halogen atom, aryl group and heteroaryl group, m and q are independently chosen from 0, 1, 2 and 3,
- R 9 is chosen from -H and lower alkyl group
- R is chosen from -COOH, lower alkoxycarbonyl group
- Z 2 is chosen from -H, COOH and lower alkoxycarbonyl group
- R is chosen from --o0--, a m nd ⁇ -N ra R ⁇
- R 12 is chosen from -H, alkyl group, substituted alkyl group, cycloalkyl group, substituted cycloalkyl group, aryl group, substituted aryl group, benzyl group, substituted benzyl group, lower alkenyl group, substituted lower alkenyl group and lower alkynyl group the left hand bond is the point of attachment to -X- and the right hand bond is the point of attachment to -Z 3 ;
- Z 3 is chosen from a direct bond, a divalent aliphatic hydrocarbon moiety having 1 to 12 carbon atoms, wherein one or more carbon atoms may be replaced with -O- or -NR 13 -
- R 13 is chosen from -H and lower alkyl group, and one or more hydrogen atoms attached to an aliphatic carbon atom may be replaced with lower alkyl group;
- R 14 is chosen from -H, -OH and halogen atom
- R u is -NR 12 , wherein l-z 4 wherein
- R 14a is chosen from -H, -OH, lower alkyl group and halogen atom
- Q -.2 is a divalent radical chosen from arylene group, substituted arylene group, heterocyclylene group, substituted heterocyclylene group, cycloalkylene group, substituted cycloalkylene group,
- R 15 and R 16 are independently chosen
- R 1 and R 18 are independently chosen
- L 1 is chosen from -COOH and -COOR 19 wherein R 19 is a lower alkyl group.
- R 19 is a lower alkyl group.
- M is In this
- Preferred compounds of this embodiment are those wherein W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof
- W 1 is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-
- M is In another preferred embodiment of Formula I, M is In
- Preferred compounds of this embodiment are those wherein W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof
- W 1 is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-
- M is In this
- L is preferably chosen from
- L is chosen from
- L is chosen from
- W 1 is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-.
- Still another preferred embodiment of Formula I includes compounds wherein M is _ R 11_ Z 3_ Q 2_ L 1
- W is unsubstituted phenyl group or phenyl group having one or two substituents chosen from lower alkyl group and halogen atom at the ortho positions thereof.
- W 1 is preferably unsubstituted phenylene group or phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-.
- preferred compounds are those wherein R 11 i os A. or -NR 12 , more preferably NR 12 , wherein
- R 12 is chosen from -H, lower alkyl group and substituted lower alkyl group, most preferably dihydroxy lower alkyl group.
- Preferred choices for Z is a divalent aliphatic hydrocarbon moiety having 4, 5 or 6 carbon atoms.
- a preferred choice for W 1 is phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-.
- R examples include -H. -OH and -F
- W 1 is phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-.
- Q 2 is ⁇ R 17R 8 and Z 3 is Y ° CH
- R 11 is preferably
- W 1 is phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-
- R 11 is preferably
- R 12 is preferably lower alkyl group
- Preferred compounds of this embodiment also include those wherein at least one of R 17 and R 18 is lower alkyl group or substituted lower alkyl group
- R 11 is preferably
- -NH- and R 1 and R 1 are each preferably -H
- a preferred choice for W 1 is phenylene group having a substituent chosen from methoxy group, lower alkyl group and halogen atom at the ortho position to -NH-
- Z 3 ,Z 3 is preferably a divalent aliphatic hydrocarbon moiety
- Yet another embodiment of the invention is a compound represented by Formula ⁇ ,
- R ,20 is preferably chosen from -H and lower alkyl, CH,
- Still another embodiment of the invention is a compound represented by Formula HI,
- the principles of the present invention also provide a method for inhibiting cell adhesion, and in particular, VLA-4 mediated cell adhesion at ⁇ 4 ⁇ l receptor sites in a mammal, wherein the method comprises administering an effective amount of a compound represented by Formula I.
- inhibiting cell adhesion is intended to include inhibiting, suppressing and preventing VLA-4 mediated cell adhesion-associated conditions, including but not limited to, inflammation and cell adhesion-associated immune or autoimmune responses.
- the principles of the present invention therefore also provide a method of treating a condition associated with VLA-4 mediated cell adhesion, wherein the method comprises administering to a mammal in need of such treatment, an effective amount of a compound represented by Formula I.
- Such conditions include for example, but are not limited to, inflammatory and autoimmune responses, diabetes, asthma, arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, transplantation rejection, and tumor metastasis.
- treatment of a mammal is intended to include prophylaxis as well.
- the compounds of the present invention may be administered as a monotherapy, or in combination with antiinflammatory or immunosuppressive agents.
- combination therapies can involve the administration of the various pharmaceuticals as a single dosage form or as multiple dosage forms administered at the same time or at different times.
- Suitable routes of administration may be employed for providing a patient with an effective amount of a compound of the present invention.
- Suitable routes of administration may include, for example, oral, rectal, nasal, buccal, parenteral (such as, intravenous, intrathecal, subcutaneous, intramuscular, intrasternal, intrahepatic, intralesional, intracranial, intra-articular, and intra-synovial), transdermal (such as, for example, patches), and the like.
- parenteral such as, intravenous, intrathecal, subcutaneous, intramuscular, intrasternal, intrahepatic, intralesional, intracranial, intra-articular, and intra-synovial
- transdermal such as, for example, patches
- oral dosage forms such as, for example, tablets, troches, dispersions, suspensions, solutions, capsules, soft gelatin capsules, and the like, may be preferred.
- Administration may also be by controlled or sustained release means and delivery devices. Methods for the preparation of such dosage forms are well known in
- compositions incorporating compounds of the present invention may include excipients, a pharmaceutically acceptable carrier, in addition to other therapeutic ingredients.
- Excipients such as starches, sugars, microcrystalline cellulose, diluents, lubricants, binders, coloring agents, flavoring agents, granulating agents, disintegrating agents, and the like may be appropriate depending upon the route of administration. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
- the compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorgamc or organic bases.
- suitable pharmaceutically acceptable base addition salts include, but are not limited to, ammonium salts, alkali metal salts, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, organic salts made from chloroprocaine, choline, N.N'-dibenzylethylenediamine, dicyclohexylamine, diethanolamine, ethylenediamine, lysine, meglumine (N-methylglucamine) and procaine, as well as salts with amino acids, such as arginine, lysine, and so forth.
- the compounds of the invention may be used in the form of pharmaceutically acceptable non-toxic organic or inorganic acids.
- Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfomc, methanesulfomc, fuma ⁇ c, glucomc, glutamic, hydrobromic, hydrochlonc, lactic, maleic, malic, mandehc, nitnc, pamoic, pantothemc, phosphonc, succinic, sulfunc, tartanc, p- toluenesulfomc acids, and the like Particularly prefened are citnc, hydrochlonc, maleic, fumanc, phosphonc, sulfunc, tartanc and -toluenesulfonic acids
- Compounds of the invention may also be in the form of hydrates
- H HEEKK cceellllss 293E human embryonic kidney cells
- Ac acetyl ant ⁇ - ⁇ 4-PE conjugated monoclonal antibody against integnn ⁇ 4 subumt
- phycoerythnn conjugated anti- ⁇ l-FITC conjugated monoclonal antibody against integrin ⁇ l subumt
- HOBt 1 -hydroxybenzotriazole human IgGl human immunoglobulin Gl ICAM intracellular adhesion molecule
- LiHMDS lithium 1,1,1,3,3,3 -hexamethyldisilazane
- VCAM-1 (D1D7) vascular cell adhesion molecule containing one to seven immuloglobulin domains
- VCAM-IgG fusion protein a VCAM IgG fusion protein containing the one to seven immunoglobulin domains of human VCAM-1 (D1D7) attached above the hinge region of an IgGl molecule
- Alkyl group is intended to include linear or branched hydrocarbon radicals and combinations thereof of 1 to 20 carbons.
- “Lower alkyl group” means alkyl groups of from 1 to about 10, preferably from 1 to about 8, and more preferably, from 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, «-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, wo-amyl, hexyl, octyl groups and the like.
- Alkylene group means a divalent radical formed by removing a hydrogen atom from an
- Aryl group means a radical formed from an aromatic hydrocarbon ring of 4 to about 16 carbon atoms, preferably of 6 to about 12 carbon atoms, and more preferably of 6 to about 10 carbon atoms.
- the rings may optionally be substituted with 1-3 substituents selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, phenyl and heteroaryl.
- substituents selected from alkyl, halogen, hydroxy, alkoxy, aryloxy, haloalkyl, phenyl and heteroaryl. Examples of aryl groups are phenyl, biphenyl, 3,4-dichlorophenyl and naphthyl.
- Allene group means a divalent radical formed by removing a hydrogen atom from an “aryl group.”
- Arylalkyl group denotes a structure comprising an alkyl attached to an aryl ring. Examples include benzyl, phenethyl, 4-chlorobenzyl, and the like.
- Cycloalkyl group refers to a saturated hydrocarbon ring radical of from 3 to 12 carbon atoms, and preferably from 3 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl, myrtanyl groups and the like. “Lower cycloalkyl group” refers to cycloalkyl of 3 to 6 carbons.
- Cycloalkylene group means a divalent radical formed by removing a hydrogen atom from a “cycloalkyl group.”
- “Divalent C t to C 20 aliphatic hydrocarbon moiety” includes alkylene, cycloalkylene, alkenylene, alkynylene groups and combinations thereof. Examples include ethylene, propylene, propynylene, 2,4-heptadienylene groups and the like.
- Heterocyclyl group refers to a cyclic radical having from 1 to 6 carbon atoms, preferably 3 to 6 carbon atoms, and from 1 to 4 heteroatoms chosen from O, N and S. Examples include: pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thienyl, furyl, azetidiyl, tetrazolyl, 2-pyrrolinyl, 3-pynolinyl, pynolindinyl, 1,3-dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3 -triazolyl, 1,3,4
- Heterocyclylene group means a radical formed by removing a hydrogen atom from a “heterocyclyl group.”
- Heteroaryl group refers to an aromatic cyclic radical having from 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms, and from 1 to 4 heteroatoms chosen from O, N and S; or a bicyclic 9- or 10-membered heteroaromatic ring system containing 1-4 heteroatoms selected from O, N and S.
- the methine H atoms of a heterocyclyl or heteroaryl structure may be optionally substituted with alkyl, alkoxy or halogen.
- Examples include: imidazolyl, pyridyl, indolyl, thienyl, benzopyranyl, thiazolyl, furyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrimidinyl, pyrazinyl, tetrazolyl, pyrazolyl groups and the like.
- Heteroarylene group means a divalent radical formed by removing a hydrogen atom from a “heteroaryl group.”
- Alkoxy group means a straight, branched or cyclic hydrocarbon configuration and combinations thereof, including from 1 to 20 carbon atoms, preferably from 1 to 8 carbon atoms, more preferably from 1 to 4 carbon atoms, and an oxygen atom at the point of attachment.
- Suitable alkoxy groups include methoxy, ethoxy, w-propoxy, isopropoxy, n-butoxy, / ' so-butoxy, sec- butoxy, te -butoxy, cyclopropoxy, cyclohexyloxy groups and the like.
- “Lower alkoxy group” refers to alkoxy groups having from 1 to 4 carbon atoms.
- Alkenyl group refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond.
- “Lower alkenyl group” refers to such radicals containing from 2 to 10 carbon atoms, preferably from 2 to 8 carbon atoms and more preferably from 2 to 6 carbon atoms.
- alkenyl radicals examples include propenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl groups and the like.
- Alkenylene group means a divalent radical formed by removing a hydrogen atom from an “alkenyl group.”
- Alkynyl group refers to an unsaturated acyclic hydrocarbon radical containing at least one triple bond. Examples include ethynyl, propynyl groups, and the like.
- Alkynylene group means a divalent radical formed by removing a hydrogen atom from an alkynyl group.”
- Substituted alkyl group means a linear or branched alkyl group wherein at least one hydrogen atom attached to an aliphatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- substituent groups include methyl, isopropyl, methoxy, ethoxy, propoxy, amino, methylamino, phenyl, naphthyl groups, chlorine, fluorine and the like.
- Substituted alkylene group means a linear or branched alkylene group wherein at least one hydrogen atom attached to an aliphatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkyl
- Substituted cycloalkyl group means a cycloalkyl group wherein at least one hydrogen atom attached to a ring carbon atom is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, al
- Substituted cycloalkyene group means a cycloalkylene group wherein at least one hydrogen atom attached to a ring carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alky
- Substituted aryl group means an aryl group wherein at least one methine hydrogen atom attached to an aromatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkyl
- Substituted arylene group means an arylene group wherein at least one hydrogen atom attached to an aromatic carbon is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulf
- Substituted heteroaryl group or “substituted heterocyclyl group” means a heteroaryl or heterocyclyl group wherein at least one hydrogen atom attached to a ring thereof is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalky
- Substituted heteroarylene group or “substituted heterocyclylene group” means a heteroarylene or heterocyclylene group wherein at least one hydrogen atom attached to a ring thereof is replaced with a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, alkoxycarbonylalkyl, haloalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- a substituent such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalky
- Substituted arylalkyl group means an arylalkyl having one or more substituents such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, arylthio, carboxyalkyl, haloalkyl, alkoxycarbonylalkyl, acylamino, dialkylamino, cyclicamino groups, halogen atom and nitro.
- substituents such as alkyl, amino, alkoxy, hydroxy, aryl, cyano, carboxy, alkoxycarbonyl, monoalkylamino, alkyloxy, cyanoalkyl, cycloalkyl, alkylthio, alkylsulfinyl, alkylsul
- Halogen is intended to include for example, F, Cl, Br and I.
- prodrug refers to a chemical compound that is converted to an active agent by metabolic processes in vivo. [See, e.g., N. Boder and J.J. Kaminski, Ann. Rep. Med. Chem. 22:303 (1987) and H. Bundgand, Adv. Drug Delivery Rev., 3:39 (1989)].
- prodrug precursors of compounds of the present invention in any of the methods described herein is contemplated and is intended to be within the scope of the invention.
- a protecting group refers to a group which is used to mask a functionality during a process step in which it would otherwise react, but in which reaction is undesirable.
- the protecting group prevents reaction at that step, but may be subsequently removed to expose the original functionality. The removal or “deprotection” occurs after the completion of the reaction or reactions in which the functionality would interfere.
- the functionalities that must be protected are amines. Suitable groups for that purpose are discussed in standard textbooks in the field of chemistry, such as Protective Groups in Organic Synthesis by T.W.Greene [John Wiley & Sons, New York, 1991], which is incorporated herein by reference. Particular attention is drawn to the chapter entitled "Protection for the Amino Group” (pages 309-405). Prefened protecting groups include BOC and Fmoc. Exemplary methods for protecting and deprotecting with these groups are found in Greene and Wuts on pages 318 and 327.
- the materials upon which the syntheses described herein are performed are refened to as solid supports, beads, and resins. These terms are intended to include: (a) beads, pellets, disks, fibers, gels, or particles such as cellulose beads, pore-glass beads, silica gels, polystyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol, poly- acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with N.N'-bis- acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; and (b) soluble supports such as polyethylene glycol or low molecular weight, non-cross-linked polystyrene.
- the solid supports may, and usually do, have functional groups such as amino, hydroxy, carboxy, or halo groups; where amino groups are the most common.
- TentagelTM NH 2 (Rapp Polymere, Tubingen, Germany) is a prefened amine functionalized polyethylene glycol- grafted polystyrene resin.
- Tentagel IM -S-PHB resin has a para- hydroxy benzyl linker which can be cleaved by the use of 90% trifluoroacetic acid in dichloromethane. Techniques for fiinctionalizing the surface of solid phases are well known in the art.
- Optical Isomers - Diastereomers - Geometric Isomers Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisometric forms which may be defined in terms of absolute stereochemistry as (R)- or (S)- , or as (D)- or (L)- for amino acids. The present invention is meant to include all such possible diastereomers as well as their racemic and optically pure forms.
- Optically active (R)- and (S)-, or (D)- and (Z,)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
- the compounds of the present invention have demonstrated utility as selective inhibitors at VLA-4 receptors.
- the inhibitory concentration (IC 50 ) and the VLA-4 selectivity of test compounds for an ⁇ 4 ⁇ 1 receptor using in vitro assays are determined in direct binding assays and competitive assays with other integrin receptors such as ⁇ 2 (LFA-1 and Mac-1), ⁇ 3 (GPIIb/IIIa and ⁇ v ⁇ 3) and ⁇ l ( ⁇ 4 ⁇ 7).
- Compounds of the present invention have K, values ⁇ 1 ⁇ M.
- Prefened compounds of the invention are those having K, values ⁇ 300 nM, more preferably ⁇ lOOnM, even more preferably ⁇ 50 nM, and most preferably, ⁇ 12nM.
- prefened compounds having a K, value ⁇ 50 nM are shown below. These examples are provided by way of illustration only, and are not intended to limit the invention thereto.
- VLA-4-expressing cells were seeded in a 96-well microtiter plate. The cells were allowed to grow for 2 days until confluent. Various concentrations of the test compound were added together with 2 nM of the europium-labeled, VCAM-IgG fusion protein. The cells were allowed to incubate at room temperature in the microwells for at least 30 minutes. Following incubation, the microwells were emptied and washed. The amount of europium-labeled VCAM- IgG fusion protein bound was determined by time-resolved fluorescence measurement. Inhibition of binding was determined by quantifying the fluorescence bound to the plate for each of the various concentrations of test compound, as well as for controls containing no test compound.
- the VLA-4-expressing cells used in this assay was a CHO cell line stably transfected with the cDNA of the human ⁇ 4 and ⁇ l subunits. Construction and maintenance of the cell line are described in the assay procedures.
- a VCAM IgG fusion protein containing the one to seven immunoglobulin domains of human VCAM-1 (D1D7) attached above the hinge region of an IgGl molecule was labeled with europium chelates. The preparation and labeling of the fusion protein are described in the assay procedures.
- the cell adhesion inhibitory activity of the test compound was determined by blocking the Jurkat cell attachment to the D1D7-VCAM IgG fusion protein.
- Jurkat cell is a human lymphocytic cell line expressing VLA-4 on cell surface.
- each of the 96-well microtiter wells was coated with 75 ng of the VCAM IgG fusion protein. The wells were then blocked by the addition of 1% bovine serum albumin to remove nonspecific adhesive sites. Varying concentrations of the test compound were added together with the calcein-labeled Jurkat cells. The cells were allowed to adhere to the VCAM coated wells at room temperature for 1 hour in the dark.
- the plate was washed by immersing face down into a container filled with phosphate buffered saline. The wells were blotted dry on paper towel. Quantitation of the adhered cell was determined by fluorescence measurement. Decreased fluorescence indicated inhibition of cell adhesion by the test compound.
- LFA-1 binds to ICAM-1 and mediates the emigration of leukocytes into inflammatory sites.
- Mac-1 binds to a number of ligands, including ICAM-1 and fibrinogen, and plays an important role in neutrophil phagocytosis and oxygen free radical generation.
- GPIIb/IIIa on platelet surface binds to fibrinogen in plasma and induces platelet aggregation.
- ⁇ v ⁇ 3 binds to a number of extracellular matrix proteins, including vitronectin and mediates cell migration and prevents cell apoptosis.
- ⁇ 4 ⁇ 7 shares the same ligands as VLA-4 (VCAM-1, MAdCAM-l.and fibronectin), but with different preference. This receptor is expressed on lymphoid cells and is involved in lymphocyte migration to mucosal tissues.
- Assays of LFA-1, Mac-1, GPIIb/IIIa and ⁇ v ⁇ 3 involved coating the purified receptor on a 96-well microtiter plate. The specific ligands for these receptors were labeled with europium chelates.
- an ICAM-1 IgG fusion protein containing the one to five immunoglobulin domains of human ICAM-1 (D1D5) attached above the hinge region of an IgGl molecule was used.
- In the assays of GPIIb/IIIa and ⁇ v ⁇ 3 europium-labeled fibrinogen and vitronectin, respectively, was used.
- the purified receptors were allowed to incubate in the wells with various concentrations of test compound, in the presence of europium-labeled ligands. Following incubation, the wells are emptied and washed. The amount of europium-labeled ligand bound was determined by time-resolved fluorescence measurement.
- Assay of ⁇ 4 ⁇ 7 is similar to the adhesion inhibition assay of VLA-4 described above, and uses the ⁇ 4 ⁇ 7-expressing cell, RPMI-8886.
- a MAdCAM-1 IgG fusion protein containing the one and two immunoglobulin domains of human MAdCAM-1 and mucin-like repeat domain, is used as the corresponding ligand for ⁇ 4 ⁇ 7.
- Eu + - VCAM-1 IgG binding to CHO/VLA-4 cells may be determined as follows. 4B4 cells
- CHO VLA-4 cells are distributed into each well of a 96-well microtiter plate at 3 x 10 /well. The plate is incubated at 37 °C, 5% C0 2 for 48 hours and then washed twice with washing buffer, then blot dried. 50 ⁇ l of the inhibitor solution diluted with assay buffer (2% DMSO final) is added to each well, followed by 50 ⁇ l of Eu 3+ -VCAM-1 IgG diluted with assay buffer at 2 nM. The plate is incubated at room temperature for at least 30 min. Each well is then washed four times with washing buffer and blot dried. 100 ⁇ l of DELFIA Enhancement solution is added to each well, followed by agitation of the plate at room temperature for 5 min.
- the washing buffer comprises 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM CaCl 2 , 1 mM MgCl 2 ,and 4 mM MnCl 2 ;
- the assay buffer comprises 25 mM HEPES (pH 7.5), 150 mM NaCl, 1 mM CaCl 2 , 1 mM MgCl 2 , 4 mM MnCl 2 , 1% BSA, and 20 ⁇ M DTPA.
- the VLA-4 inhibitors may be further characterized in in vivo assays.
- One such assay examines the inhibition of eosinophil infiltration into the bronchoalveolar lavage fluid in the mouse (murine) model.
- the animals are treated with cyclophosphamide on day 0.
- the animals are immunized intraperitoneally with Ascaris suum extract.
- the animals are treated with various doses of the VLA-4 inhibitor.
- the animals are challenged t Ascaris suum extract by instillation into the trachea. Bronchoalveolar lavage of the animal is performed by instilling saline into the lung, 48 hours later. Total cell and eosinophil counts in the lavage are determined.
- the compounds of the present invention may also be further characterized in other in vivo assays, such as the eosioophil accumulation model tested in the rat.
- Fifty ⁇ g of Compound 48/80 was injected into the pleural cavities of male Sprague Dawley rats. After 24 hrs, each cavity was washed twice with Hank's Balanced Salt Solution containing 0.2% EDTA. Total cell and eosinophil counts were determined.
- Test compounds were given intraveneously, orally or subcutaneously, b.i.d. at 0 and 8 hours. The dosage, route of administration and inhibitory effect for the test compounds are shown in Table 6.
- mice Female Balb/c mice (7-9 weeks old) were given the compound orally. Blood samples were collected from the postcaval vein of the anesthetized mice after fifteen minutes. Serum was prepared and stored at -20 °C. Serum concentration of the compound was determined from inhibitory activities of the diluted serum by a direct binding assay using VLA-4-expressing cells and VCAM-IgG fusion protein. Serum concentration determined by this method correlated well with the concentration determined by LC/MS/MS methodologies. The dosage, route of administration and resulting inhibitory effect for the test compounds are shown in Table 7.
- VCAM-1 Binding assay of VCAM-1 to VLA-4 expressing cells
- VCAM IgG fusion protein A VCAM IgG fusion protein containing the one to seven immunoglobulin domains of
- VCAM-1 (D1D7) ligated to the hinge (H), CH2 and CH3 regions of human IgGl was used in the binding assay.
- D1D7 VCAM IgG fusion protein Purification of D1D7 VCAM IgG fusion protein The cells were cultured in DMEM with 10% fetal calf serum for 2 days, then changed to
- the D1D7-VCAM IgG fusion protein was dialyzed against 50 mM NaHC0 3 , 0.9% NaCl, pH 8.5.
- the fusion protein was added to one vial of europium-labeling reagent (DELFIA labeling kit from Wallac, Gaithersberg, MD; catalog no. 1244-302) and incubated at room temperature in the dark overnight.
- the labeled protein was purified using a Sepharose G10 column and assayed for the europium content and protein concentration. The protein was stored at minus 80°C until used.
- a CHO cell line stably transfected with the cDNA of ⁇ 4 and ⁇ l was used in the binding assay.
- the gene for human 4 was obtained from the American Type Culture Collection and recloned between the Xhol and Xba sites of the mammalian expression vector pCI-neo (Promega, Madison, WI).
- the ⁇ 1 gene was amplified by PCR from human peripheral leukocyte cDNA and engineered such that the start codon was placed in the context of a consensus Kozak sequence. The gene was recloned into pCI-neo downstream of the CMV promoter and chimeric intron.
- CHO-K1 cells were stably co-transfected with plasmids encoding the ⁇ 4 and ⁇ l genes, and single cells expressing high levels of VLA-4 were selected by fluorescence cell sorting (FACS).
- the antibodies used in FACS analysis were: anti- ⁇ 4-PE conjugated (PharMingen, San Diego, CA) and anti- ⁇ l-FITC conjugated (Biosource, Camarillo, CA).
- a cell line 4B4 which expresses 400,000 and 300,000 sites/cell of the ⁇ x4 and ⁇ l subunit, respectively, was used in the binding assay.
- the subunit numbers were determined by FACS analysis, using Quantum Simply Cellular microbeads (Flow Cytometiy Standards Corporation, Puerto Rico) as standards.
- the cells were maintained in F12 medium, containing 10% fetal bovine serum, 10 mM HEPES, pH 7.5, 0.5 mg/mL G418, using a 1:48 passage/week.
- Binding Assay The CHO/VLA-4 cells were seeded in a 96-well microtiter plate at 30,000 cells/well and incubated at 37°C, 5% C0 2 for 48 hours until confluent. On the day of assay, the wells were emptied and washed twice with 350 ⁇ l of a washing buffer containing 25 mM HEPES, pH 7.5, 150 mM NaCl, 1 mM MgCl 2, 1 mM CaCl 2 2 mM MnCl 2 . The plate was then drained and blotted dry on paper towels to remove buffer.
- test compound was serially diluted in assay buffer (washing buffer together with 0.1% bovine serum albumin, 20 ⁇ M DTPA and 1% dimethysulfoxide), in the presence of 2 nM of europium-labeled D1D7-VCAM IgG fusion protein. Final concentrations used ranged from 0.1 nM-10 ⁇ M. 50 ⁇ l aliquot of the test compound mixture was added to duplicate wells in the plate. Control wells for total binding received no test compound. Non-specific binding wells contained an anti- ⁇ 4 monoclonal antibody (L25.3, Becton Dickinson, Bedford, MA).
- the cells were allowed to incubate with the test compound mixture, in the presence of europium-labeled D1D7-VCAM IgG fusion protein at room temperature for at least 30 minutes. The cells were then washed three times with 350 ⁇ l of washing buffer, using a Skatron plate washer and blot dry. An 100 ⁇ l aliquot of DELFIA Enhancement solution was added to each well, followed by gentle agitation at room temperature for 10 minutes. The amount of europium-labeled VCAM-IgG fusion protein bound was determined by time-resolved fluorescence measurement (Model: VictorTM, Wallac Inc., Gaithersberg, MD).
- Percent binding was calculated as: [(F T -F NS ) - (F,-F NS )] / (F T -F NS ) x 100 wherein F ⁇ and F NS is the fluorescence signal of the europium labeled D1D7-VCAM IgG fusion protein bound to cells, in the absence of test compound and containing an anti- ⁇ 4 monoclonal antibody, respectively. F, is the fluorescence in wells containing a test compound.
- the IC 50 concentration of the inhibitor to inhibit 50% binding of VACM to CHO/VLA-4 cell was determined by a curve fitting routine, PRIZM (GraphPad Software, Inc., San Diego, CA).
- Adhesion of VLA-4 expressing cell to VCAM-1 This secondary functional assay was used to determine the potency of a test compound in inhibiting VLA-4 mediated cell adhesion.
- a 50 ⁇ l aliquot of the D1D7-VCAM IgG fusion protein (1.5 ⁇ g/mL in phosphate buffered saline, PBS) was added to each well of a 96-well Costar flat bottom plate (Costar, Franklin Lakes, NJ, catalog no. 2580). The plate was then incubated overnight at 4°C. On the day of assay, the wells were emptied and washed twice with 350 ⁇ l of PBS. The plate was then blocked with 100 ⁇ l of 1% bovine serum albumin (BSA, Sigma, cat# A9418) in PBS at room temperature for at least a hour.
- BSA bovine serum albumin
- Jurkat cell (clone E6-1) was obtained from American Type Cultured Collection and was maintained in RPMI medium, 10 mM HEPES, pH 7.5, 1 mM sodium pyruvate, 10% FCS, using a 1 :64 passage/week. Just prior to running the assay, Jurkat cells were labeled with 5 ⁇ M of calcein- AM (Molecular Probe, Eugene, OR, catalog no. C1430) in RPMI medium, at room temperature for 30 min in the dark. Following labeling, cells were washed twice with RPMI medium and resupended at 1 x 10 6 cells/mL.
- calcein- AM Molecular Probe, Eugene, OR, catalog no. C1430
- the BSA solution was emptied from the VCAM-coated plate. The plate was then washed twice with RPMI medium. A 100 ⁇ l aliquot of the labeled Jurkat cells was added to each well, followed by the addition of 50 ⁇ l of the inhibitor solutions. Final inhibitor concentrations range from 1 nM to 10 ⁇ M and each concentration was tested in triplicates. The inhibitor and cells were allowed to incubate at room temp for 1 hr in the dark. Following the incubation, the plate was immersed gently into a container filled with PBS, then inverted face down under PBS. The wells were drained and blotted dry on a layer of paper towel.
- the solution was cooled to room temp, made basic with 150 mL of an aqueous solution of 40% sodium hydroxide, extracted with 3 x 125 mL CH 2 C1 2 , and the combined organic layers were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and the solvent was removed under educed pressure to give 15.0 g (63.0 mmol, 86%) of 2-(2- bromobenzyl)-l-pyrolline.
- the alkene ester (1.32 g, 4.1 mmol) was then subjected to hydrogenation.
- the alkene was placed in a Parr hydrogenation bottle, EtOAc (10 mL) and 10% Pd C (100 mg) was added under inert atmosphere.
- the bottle was then pressurized with hydrogen at 45 psi and shaken for 4 hr at room temp.
- the solution was then filtered through celite and concentrated in vacuo to afford 1.29 g of the alkane ester.
- the alkane ester (1.29 g, 4.0 mmol) was dissolved in THF (30 mL), MeOH (20mL), and water (10 mL) and saponified with LiOH (200 mg, 8.0 mmol). The reaction was stirred at room temp for 3 hr and then poured into 1 N HCl (50 mL). This solution was then extracted 3x with EtOAc, dried over MgS0 4 , and then concentrated in vacuo to afford 1.02 g of the alkane acid as a yellow solid.
- the alkane acid (1.02 g, 3.3 mmol) was then deprotected by the addition of a 25% TFA CH 2 C1 2 solution and stirred for 2 hr at room temp.
- the resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 C0 3 (1.2 g), and Fmoc-Cl (1.08 g, 4.0 mmol). This mixture was stirred at room temp for 14 hr and then poured in 1 N HCl (100 mL). The solution was then extracted 3x with EtOAc, dried over MgS0 4 , and then concentrated in vacuo to afford 495 mg 1 as a white crystalline solid.
- the dried resin (500 mg, 0.14 mmol) was placed into a small shaker vessel. The vessel was then charged with 9 mL of DMF (2 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol), and DMAP (17 mg, 0.14 mmol). The vessel was subsequently shaken for 16 hr at room temp. The contents were drained and the resin was washed 3x with DMF, MeOH, and CH 2 C1 2 . The Fmoc group was then removed by the addition of 10 mL of 50% piperidine/DMF to the shaker vessel and shaking for 2 hr at room temp. The resulting amine resin was washed 3x with DMF, MeOH, and CH 2 C1 2 .
- a solution of dicyclohexylborane was generated by the addition of borane-THF (12.0 mL, 12 mmol), at 0°C to a solution of cyclohexene (2.3 mL) in 6 mL of anhydrous THF. This solution was stirred for an additional 1 hr at 0°C The acetylene (2) (2.0 g, 5.84 mmol) was then added dropwise over 15 min at 0°C and then allowed to warm to room temp over 1 hr. The reaction mixture was then diluted with MeOH (20 mL) and then recooled to 0°C A solution of 2 N NaOH (6 mL) and 30% H 2 0 2 (3.5 mL) was then added dropwise.
- the reaction mixture was then stirred at 0°C for 1 hr and then warmed to 40°C for 2.5 hr. The mixture was then cooled to room temp and an additional 6 mL of 2 N NaOH was added. The organics were removed in vacuo and the remaining aqueous solution was extracted 3x Et 2 0 and the organics were discarded. The aqueous extracts were then acidified with 1 N HCl and extracted with EtOAc dried over MgS0 4 , and then concentrated in vacuo to afford 1.7 g of the phenylacetic acid as a tan crystalline solid.
- the acid (1.7 g, 5.6 mmol) was then deprotected by the addition of a 25% TFA/CH 2 C1 2 solution and stirred for 2 hr at room temp.
- the resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 C0 3 (15g), and Fmoc-Cl (1.4 g, 5.5 mmol).
- This mixture was stirred at room temp for 14 hr and then poured in 1 N HCl (100 mL).
- the solution was then extracted 3x with EtOAc, dried over MgS0 4 , and then concentrated in vacuo to afford 1.7 g 3 as a white crystalline solid.
- the dried resin (500 mg, 0.14 mmol) was placed into a small shaker vessel. The vessel was then charged with 9 mL of DMF, 3 (180 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol), and DMAP (17 mg, 0.14 mmol). The vessel was subsequently shaken for 16 hr at room temp. The contents were drained and the resin was washed 3x with DMF, MeOH, and CH 2 C1 2 . The Fmoc group was then removed by the addition of 10 mL of 50% piperidine/DMF to the shaker vessel and shaking for 2 hr at room temp. The resulting amine resin was washed 3x with DMF, MeOH, and CH 2 C1 2 .
- the alkane acid (0.71 g ) was then deprotected by the addition of a 25% TFA/CH 2 C1 2 solution and stirred for 2 hr at room temp.
- the resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 C0 3 (15 g), and Fmoc-Cl (1.29 g, 4.9 mmol). This mixture was stirred at room temp for 14 hr and then poured in 1 N HCl (100 mlL).
- the solution was then extracted 3x with EtOAc, dried over MgS0 4 , and then concentrated in vacuo to afford 4 as a brown oil.
- the oil was then chromatographed with 5% MeOH/ dichloromethane to afford 110 mg of the desired compound.
- the dried resin (500 mg, 0.14 mmol) was placed into a small shaker vessel. The vessel was then charged with 9 mL of DMF, 4 (184 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol), and DMAP (17 mg, 0.14 mmol). The vessel was subsequently shaken for 16 hr at room temp. The contents were drained and the resin was washed 3x with DMF, MeOH, and CH 2 C1 2 . The Fmoc group was then removed by the addition of 10 mL of 50% piperidine/DMF to the shaker vessel and shaking for 2 hr at room temp. The resulting amine resin was washed 3x with DMF, MeOH, and CH 2 C1 2 .
- the iodide (A) (0.5 g, 1.3 mmol) was placed into THF (20 mL) and cooled to minus
- the benzoic acid (0.32 g, 1.68 mmol) was then deprotected by the addition of a 25% TFA/CH 2 C1 2 solution and stirred for 2 hr at room temp. The resulting mixture was then concentrated in vacuo and immediately protected by dissolving the deprotected acid in 50% dioxane/water, adding K 2 C0 3 (15 g), and Fmoc-Cl (0.44 g, 1.67 mmol). This mixture was stirred at room temp for 14 hr and then poured in 1 N HCl (100 mL). The solution was then extracted 3x with EtOAc, dried over MgS0 4 , and then concentrated in vacuo to afford 0.38 g 5 as a white crystalline solid. The dried resin (500 mg, 0.14 mmol) was placed into a small shaker vessel. The vessel was then charged with 9 mL of DMF, 5 (173 mg, 0.42 mmol), DIC (102 mg, 0.84 mmol), and
- the resin was washed with DMF (x3), MeOH (x3), CH 2 C1 2 (x3).
- 2-chlorophenyl isocyanate (0.050 mL, 0.41 mmol) was added to a suspension of resin in THF (1 mL) and CH 2 C1 2 (1 mL). The mixture was shaken for 20 hr and drained.
- the resin was washed with DMF (x3), MeOH (x3), CH 2 C1 2 (x3).
- To the resin was added a solution of TFA in CH 2 C1 2 (25 % v/v, 2 mL) and the mixture was shaken for 1.5 hr. The mixture was filtered and the filtrate was concentrated in vacuo.
- Pr 2 NH (10 mL). The mixture was stirred for 1 hr under N 2 and a solution of l-(tert- butoxycarbonyl)-2-ethynylpyrrolidine (488 mg, 2.5 mmol) in /-Pr 2 NH (10 mL) was added to the mixture. After stirring for 2 hr, the mixture was poured into H 2 0 and extracted with EtOAc. The extract was washed with brine, dried over MgS0 4 , and evaporated.
- N-tert-butoxycarbonyl-2-methylproline methyl ester (3.20g, 0.013 lmol) in THF (20mL) was added IN NaOH (15.7mL) at room temp. After the resulting mixture was stirred for 24 hr, the mixture was diluted with water and washed with EtOAc. The separated aqueous layer was acidified by the addition of IN HCl, and extracted with EtOAc. The extract was dried over Na 2 S0 4 and evaporated in vacuo to afford 1.71g(57%) N-tert- butoxycarbonyl-2-methylproline as a yellow syrup.
- 'H-NMR (CDC1 3 ) ⁇ 1.42 (s, 9H), 1.48 (s, 3H), 1.88-2.31 (m, 4H), 3.34-3.57 (m, 2H), 9.35 (br s, IH)
- Methyl 4-[l-(4-benzyloxycarbonylaminophenylacetyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy] benzoate (300 mg, 0.576 mmol) was tsdded EtOH-THF (5: 1, 30 ml) and the solution was hydrogenated over 5% Pd/C (300 ml) for 12 h while stirring. The mixture was filtered to remove the catalyst. The filtrate was concentrated under a reduced pressure.
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Applications Claiming Priority (7)
Application Number | Priority Date | Filing Date | Title |
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US14169299P | 1999-06-30 | 1999-06-30 | |
US14160199P | 1999-06-30 | 1999-06-30 | |
US14160299P | 1999-06-30 | 1999-06-30 | |
US141601P | 1999-06-30 | ||
US141602P | 1999-06-30 | ||
US141692P | 1999-06-30 | ||
PCT/US2000/018079 WO2001000206A1 (en) | 1999-06-30 | 2000-06-30 | Vla-4 inhibitor compounds |
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EP1189612A1 true EP1189612A1 (de) | 2002-03-27 |
EP1189612A4 EP1189612A4 (de) | 2005-02-16 |
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EP00945035A Withdrawn EP1189612A4 (de) | 1999-06-30 | 2000-06-30 | Vla-4 hemmende verbindungen |
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EP (1) | EP1189612A4 (de) |
JP (1) | JP2003503350A (de) |
CN (1) | CN1391473A (de) |
AR (1) | AR035011A1 (de) |
AU (1) | AU781438B2 (de) |
BR (1) | BR0012068A (de) |
CA (1) | CA2369308A1 (de) |
HK (1) | HK1043318A1 (de) |
IL (1) | IL146288A0 (de) |
MX (1) | MXPA01013406A (de) |
NO (1) | NO324892B1 (de) |
TW (1) | TWI283240B (de) |
WO (1) | WO2001000206A1 (de) |
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AU784813B2 (en) | 2000-01-17 | 2006-06-29 | Bayer Aktiengesellschaft | Substituted aryl ketones |
DE10006453A1 (de) * | 2000-02-14 | 2001-08-16 | Bayer Ag | Piperidylcarbonsäuren als Integrinantagonisten |
JP2004516237A (ja) | 2000-06-21 | 2004-06-03 | ブリストル−マイヤーズ・スクイブ・ファーマ・カンパニー | ケモカイン受容体活性調節剤としてのピペリジンアミド類 |
CA2430978C (en) | 2000-12-28 | 2012-05-15 | Daiichi Pharmaceutical Co., Ltd. | Vla-4 inhibitors |
WO2003002531A2 (en) | 2001-06-27 | 2003-01-09 | Smithkline Beecham Corporation | Fluoropyrrolidines as dipeptidyl peptidase inhibitors |
GB0123765D0 (en) * | 2001-10-03 | 2001-11-21 | Bayer Ag | Para-amino benzoic acids |
US7956219B2 (en) * | 2002-05-09 | 2011-06-07 | Baker IDI Heart and Diabetes | Amino acid analogues |
RU2340605C2 (ru) | 2002-06-27 | 2008-12-10 | Ново Нордиск А/С | Арилкарбонильные производные в качестве терапевтических средств |
CA2744893A1 (en) | 2002-06-27 | 2004-01-08 | Novo Nordisk A/S | Aryl carbonyl derivatives as glucokinase activators |
AU2003241836A1 (en) | 2002-10-03 | 2004-04-23 | Ono Pharmaceutical Co., Ltd. | Lpa receptor antagonists |
GB0225944D0 (en) * | 2002-11-06 | 2002-12-11 | Glaxo Group Ltd | Novel compounds |
JPWO2004099136A1 (ja) | 2003-05-09 | 2006-07-13 | 第一製薬株式会社 | ピロリジン誘導体の製造方法 |
TWI340134B (en) | 2003-07-24 | 2011-04-11 | Daiichi Seiyaku Co | Cyclohexanecarboxylic acids |
EP1680109A4 (de) * | 2003-10-07 | 2009-05-06 | Renovis Inc | Amid-derivate als ionenkanal-liganden und pharmazeutische zusammensetzungen und anwendungsverfahren |
MXPA06007667A (es) | 2004-01-06 | 2006-09-01 | Novo Nordisk As | Heteroaril-ureas y su uso como activadores de glucocinasa. |
JP2005350417A (ja) * | 2004-06-11 | 2005-12-22 | Dai Ichi Seiyaku Co Ltd | 還元的エーテル化法を用いたピロリジン誘導体の製造法 |
EP1781686B1 (de) * | 2004-08-16 | 2009-05-06 | Merck & Co., Inc. | Vla-4-antagonisten |
EP1961750B1 (de) | 2005-12-13 | 2013-09-18 | Daiichi Sankyo Company, Limited | Vla-4-hemmendes arzneimittel |
CN101827826A (zh) | 2007-10-16 | 2010-09-08 | 诺瓦提斯公司 | 4-苯基-5-氧代-咪唑衍生物、其药物组合物及其应用 |
EA019033B1 (ru) * | 2008-03-26 | 2013-12-30 | Новартис Аг | Ингибиторы дезацетилазы в, основанные на гидроксамате |
PT2513085T (pt) * | 2009-11-18 | 2016-11-14 | Suven Life Sciences Ltd | Compostos bicíclicos como ligantes do recetor da acetilcolina nicotínico alfa4beta2 |
EP2694472B1 (de) | 2011-04-05 | 2020-03-11 | Takeda Pharmaceutical Company Limited | Sulfonamidderivat und seine verwendung |
CN112040945A (zh) | 2018-06-12 | 2020-12-04 | Vtv治疗有限责任公司 | 葡萄糖激酶激活剂与胰岛素或胰岛素类似物组合的治疗用途 |
CA3115820A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Compounds for inhibition of .alpha.4.beta.7 integrin |
CA3114240C (en) | 2018-10-30 | 2023-09-05 | Gilead Sciences, Inc. | Imidazopyridine derivatives as alpha4beta7 integrin inhibitors |
WO2020092375A1 (en) | 2018-10-30 | 2020-05-07 | Gilead Sciences, Inc. | Quinoline derivatives as alpha4beta7 integrin inhibitors |
CN112969504B (zh) | 2018-10-30 | 2024-04-09 | 吉利德科学公司 | 用于抑制α4β7整合素的化合物 |
BR112021010400A2 (pt) | 2019-02-26 | 2021-08-24 | Bayer Aktiengesellschaft | Derivados heterocíclicos bicíclicos condensados como agentes de controle de praga |
CA3148613A1 (en) | 2019-08-14 | 2021-02-18 | Gilead Sciences, Inc. | Phenylalanine derived compounds and their use as inhinitors of alpha 4 beta 7 integrin |
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US6306840B1 (en) * | 1995-01-23 | 2001-10-23 | Biogen, Inc. | Cell adhesion inhibitors |
US6248713B1 (en) * | 1995-07-11 | 2001-06-19 | Biogen, Inc. | Cell adhesion inhibitors |
CA2291778A1 (en) * | 1997-05-29 | 1998-12-03 | Merck & Co., Inc. | Heterocyclic amide compounds as cell adhesion inhibitors |
WO1999054321A1 (en) * | 1998-04-21 | 1999-10-28 | Aventis Pharma Limited | Substituted diamines and their use as cell adhesion inhibitors |
EA004792B1 (ru) * | 1998-06-30 | 2004-08-26 | Пфайзер Продактс Инк. | Непептидные ингибиторы vla-4-зависимого клеточного связывания, полезные в лечении воспалительных, аутоиммунных и респираторных заболеваний |
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- 2000-06-30 EP EP00945035A patent/EP1189612A4/de not_active Withdrawn
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WO1999020272A1 (en) * | 1997-10-21 | 1999-04-29 | Merck & Co., Inc. | Azapeptide acids as cell adhesion inhibitors |
WO1999023063A1 (en) * | 1997-10-31 | 1999-05-14 | Aventis Pharma Limited | Substituted anilides |
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JP2003503350A (ja) | 2003-01-28 |
AU5903100A (en) | 2001-01-31 |
NO20016319L (no) | 2002-02-28 |
IL146288A0 (en) | 2002-07-25 |
NO20016319D0 (no) | 2001-12-21 |
BR0012068A (pt) | 2002-05-14 |
AR035011A1 (es) | 2004-04-14 |
HK1043318A1 (zh) | 2002-09-13 |
CA2369308A1 (en) | 2001-01-04 |
CN1391473A (zh) | 2003-01-15 |
EP1189612A4 (de) | 2005-02-16 |
TWI283240B (en) | 2007-07-01 |
MXPA01013406A (es) | 2003-09-04 |
AU781438B2 (en) | 2005-05-26 |
NO324892B1 (no) | 2007-12-27 |
WO2001000206A1 (en) | 2001-01-04 |
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