WO2000043372A1 - Derives d'acyle utiles pour traiter des affections associees a vla-4 - Google Patents

Derives d'acyle utiles pour traiter des affections associees a vla-4 Download PDF

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Publication number
WO2000043372A1
WO2000043372A1 PCT/US2000/001686 US0001686W WO0043372A1 WO 2000043372 A1 WO2000043372 A1 WO 2000043372A1 US 0001686 W US0001686 W US 0001686W WO 0043372 A1 WO0043372 A1 WO 0043372A1
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WO
WIPO (PCT)
Prior art keywords
substimted
alkyl
heteroaryl
aryl
heterocyclic
Prior art date
Application number
PCT/US2000/001686
Other languages
English (en)
Inventor
Andrei Konradi
Michael A. Pleiss
Eugene D. Thorsett
Susan Ashwell
Gregory S. Welmaker
Anthony Kreft
Dimitrios Sarantakis
Darren B. Dressen
Francine S. Grant
Christopher Semko
Ying-Zi Xu
Original Assignee
Elan Pharmaceuticals, Inc.
American Home Products
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR0007663-5A priority Critical patent/BR0007663A/pt
Priority to EA200100797A priority patent/EA006301B1/ru
Application filed by Elan Pharmaceuticals, Inc., American Home Products filed Critical Elan Pharmaceuticals, Inc.
Priority to IL14392900A priority patent/IL143929A0/xx
Priority to JP2000594788A priority patent/JP4754693B2/ja
Priority to AU34724/00A priority patent/AU773538B2/en
Priority to AT00913245T priority patent/ATE455106T1/de
Priority to DE60043692T priority patent/DE60043692D1/de
Priority to DK00913245.7T priority patent/DK1144388T3/da
Priority to MXPA01007335A priority patent/MXPA01007335A/es
Priority to HU0201213A priority patent/HUP0201213A3/hu
Priority to EP00913245A priority patent/EP1144388B1/fr
Priority to CA2359115A priority patent/CA2359115C/fr
Publication of WO2000043372A1 publication Critical patent/WO2000043372A1/fr
Priority to IL143929A priority patent/IL143929A/en
Priority to NO20013600A priority patent/NO323373B1/no
Priority to HK02107038.7A priority patent/HK1046132B/zh

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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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • 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
    • C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D233/66—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
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    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
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    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
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    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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    • C07D251/48—Two nitrogen atoms
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    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
    • C07D251/48—Two nitrogen atoms
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    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40—Nitrogen atoms
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    • C07D251/26—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
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    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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Definitions

  • This invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
  • VLA-4 (also referred to as 4 ⁇ , integrin and CD49d/CD29), first identified by Hemler and Takada 1 is a member of the ⁇ l integrin family of cell surface receptors, each of which comprises two subunits, an ⁇ chain and a ⁇ chain.
  • VLA-4 contains an ⁇ 4 chain and a ⁇ l chain.
  • VLA-4 for example, binds to fibronectin.
  • VLA-4 also binds non-matrix molecules that are expressed by endothelial and other cells. These non-matrix molecules include VCAM-1, which is expressed on cytokine -activated human umbilical vein endothelial cells in culture. Distinct epitopes of VLA- 4 are responsible for the fibronectin and VCAM-1 binding activities and each activity has been shown to be inhibited independently. 2
  • Intercellular adhesion mediated by VLA-4 and other cell surface receptors is associated with a number of inflammatory responses.
  • activated vascular endothelial cells express molecules that are adhesive for leukocytes.
  • the mechanics of leukocyte adhesion to endothelial cells involves, in part, the recognition and binding of cell surface receptors on leukocytes to the corresponding cell surface molecules on endothelial cells. Once bound, the leukocytes migrate across the blood vessel wall to enter the injured site and release chemical mediators to combat infection.
  • adhesion receptors of the immune system see, for example, Springer 3 and Osborn 4 .
  • Inflammatory brain disorders such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis (MS) and meningitis, are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • EAE experimental autoimmune encephalomyelitis
  • MS multiple sclerosis
  • M multiple sclerosis
  • meningitis are examples of central nervous system disorders in which the endothelium/leukocyte adhesion mechanism results in destruction to otherwise healthy brain tissue.
  • Large numbers of leukocytes migrate across the blood brain barrier (BBB) in subjects with these inflammatory diseases.
  • BBB blood brain barrier
  • the leukocytes release toxic mediators that cause extensive tissue damage resulting in impaired nerve conduction and paralysis.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • tissue damage also occurs via an adhesion mechanism resulting in migration or activation of leukocytes.
  • the initial insult following myocardial ischemia to heart tissue can be further complicated by leukocyte entry to the injured tissue causing still further insult (Vedder et al. 5 ).
  • inflammatory or medical conditions mediated by an adhesion mechanism include, by way of example, asthma 6"8 , Alzheimer's disease, atherosclerosis 9 10 , AIDS dementia", diabetes 12 14 (including acute juvenile onset diabetes), inflammatory bowel disease 15 (including ulcerative colitis and Crohn's disease), multiple sclerosis 16"17 , rheumatoid arthritis 18"21 , tissue transplantation 22 , tumor metastasis 23'28 , meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • This invention provides compounds which bind to VLA-4.
  • Such compounds can be used, for example, to assay for the presence of VLA-4 in a sample and in pharmaceutical compositions to inhibit cellular adhesion mediated by VLA-4, for example, binding of VCAM-1 to VLA-4.
  • the compounds of this invention have a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less (as measured using the procedures described in Example A below).
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula la and/or lb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula lb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen,
  • R 3 and R 3' are independently selected from the group consisting of hydrogen, isopropyl, -CH 2 Z where Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substituted alkyl, carboxyl-cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-substimted heteroaryl, carboxylheterocyclic, carboxyl-substimted heterocyclic, cycloalkyl, substimted alkyl, substimted alkoxy, substimted aryl, substimted aryloxy, substimted aryloxyaryl, substimted cycloalkyl, heteroaryl, substimted heteroary
  • Q is selected from the group consisting of -O-, -S-, -S(O)-, -S(O) > , and -NR 4 -;
  • R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic or, optionally, R 4 and R 1 or R 4 and R 2 , together with the atoms to which they are bound, are joined to form a heteroaryl, a substimted heteroaryl, a heterocyclic or a substimted heterocyclic group;
  • W is selected from the group consisting of nitrogen and carbon; and W is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O) 2 ;
  • X is selected from the group consisting of hydroxyl, alkoxy, substimted alkoxy, alkenoxy, substimted alkenoxy, cycloalkoxy, substimted cycloalkoxy, cycloalkenoxy, substimted cycloalkenoxy, aryloxy, substimted aryloxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula la and/or lb
  • R 3 is -(CH 2 ) X -Ar-R°, where Ar is aryl, substimted aryl, heteroaryl and substimted heteroaryl;
  • R 9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxy thiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; and x is an integer from 0 to 4.
  • R 3 is preferably alkyl or hydrogen; more preferably, R 3 is hydrogen. More preferably, R 3 is a group of the formula:
  • R 9 and x are as defined herein.
  • R 9 is in the para position of the phenyl ring; and x is an integer of from 1 to 4, more preferably, x is 1.
  • R° is selected from -O-Z-NR u R u' and -O-Z-R 12 wherein R 11 and R 11 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, and where R" and R u are joined to form a heterocycle or a substimted heterocycle, R 12 is selected from the group consisting of heterocycle and substimted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO 2 -. More preferably, R° is -OC(O)NR 11 R 11' , wherein R 11 and R 11 are as defined herein.
  • Z is preferably -C(O)-.
  • Q is -NR 4 -
  • the above method employs a compound of formula Ila or lib:
  • R 3 , R 3' and X are as defined herein; ring A and ring B independently form a heteroaryl or substimted heteroaryl group having two nitrogen atoms in the heteroaryl ring;
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R° is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycl
  • ring A forms a pyridazine, pyrimidine or pyrazine ring; more preferably, a pyrimidine or pyrazine ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen.
  • ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or a l,l-dioxo-l,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or a l,l-dioxo-l,2,5- thiadiazole ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted hetero
  • the method employs a compound of formula Ilia, IIIc, Hid, Hie or Illf:
  • R 3 , R 3' and X are as defined herein;
  • R 4' is selected from the group consisting of hydrogen and alkyl or, optionally, one of, R 4' and R 5 , R 4 ' and R 6 , R 5 and R 6 , R 5 and R 8 , or R 6 and R 8 , together with the atoms to which they are bound, are joined to form a heterocyclic, a substimted heterocyclic, a heteroaryl or substimted heteroaryl group optionally containing from 1 to 3 additional hetero ring atoms selected from the group consisting of oxygen, nitrogen and sulfur;
  • R 4" is selected from the group consisting of hydrogen and alkyl
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl; R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, subs
  • R 16 and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic;
  • R 20 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
  • the method employs a compound of formula Hid, Hie or
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula IVa and/or IVb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula IVb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen
  • R 13 is selected from the group consisting of hydrogen, C 0 alkyl, Cy, and Cy-C,. ⁇ alkyl, wherein alkyl is optionally substimted with one to four substiments independently selected from R a ; and Cy is optionally substimted with one to four substiments independently selected from R ;
  • R 14 is selected from the group consisting of hydrogen, C,. 10 alkyl,
  • alkyl, alkenyl, and alkynyl are optionally substimted with one to four substiments selected from phenyl and R x , and Cy is optionally substimted with one to four substiments independently selected from R y ; or R 13 , R 14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
  • R 15 is selected from the group consisting of C 0 alkyl, C 2 . 10 alkenyl, C 2 . ⁇ 0 alkynyl, aryl, aryl- .jo alkyl, heteroaryl, heteroaryl-C 0 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments selected from R , and aryl and heteroaryl are optionally substimted with one to four substiments independently selected from R y ; or R 14 , R 15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S; R is selected from the group consisting of Cy and a group selected from R ⁇ wherein Cy is optionally substimted with one to four substiments independently selected from R c;
  • R D is selected from the group consisting of R a , C l 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl C,. 10 alkyl, heteroaryl .,,, alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substimted with a group independently selected from R c ;
  • R c is selected from the group consisting of halogen, NQ, C(O)OR f , C M alkyl, C M alkoxy, aryl, aryl C M alkyl, aryloxy, heteroaryl, NR f R g , R f C(O)R g , NR f C(O)NR f R g , and CN;
  • R d and R e are independently selected from hydrogen, C M0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, Cy and Cy . ⁇ alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substiments independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g are independently selected from hydrogen, C,. 10 alkyl, Cy and Cy-C 0 alkyl wherein Cy is optionally substimted with C 0 alkyl; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h is selected from the group consisting of hydrogen, C 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, cyano, aryl, aryl C 0 alkyl, heteroaryl, heteroaryl C 10 alkyl, and -SO 2 R'; wherein alkyl, alkenyl, and alkynl are optionally substimted with one to four substimtents independently selected from R a ; and aryl and heteroaryl are each optionally substimted with one to four substiments independently selected from R b ;
  • R is selected from the group consisting of C 0 alkyl, C 2 . ⁇ 0 alkenyl, C 2 . 10 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substiments independently selected from R c ;
  • R x is selected from the group consisting of -OR d , -NO 2 , halogen, -S(O) m R d , -SR d , -S(O) 2 OR d , -S(O) m NR R e , -NR d R e , -O(CR f R g ) n NR d R e ,
  • R y is selected from the group consisting of R ⁇ C 0 alkyl, C 2 .
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10;
  • W is selected from the group consisting of carbon and nitrogen
  • W is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O) 2 ;
  • X' is selected from the group consisting of -C(O)OR d ,
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substimted heteroaryl group having two nitrogen atoms in the heteroaryl ring.
  • the heteroaryl ring may contain other heteroatoms such as oxygen or sulfur.
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or 1,1- dioxo-l,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1- oxo-l,2,5-thiadiazole or l ,l-dioxo-l,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or 1,1-dioxo- 1,2,5-thiadiazole ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino
  • X' is -C(O)OR d .
  • the above method employs a compound of formula Va, Vc, Vd, Ve or Vf:
  • R 13 , R 14 , R 15 and X' are as defined herein;
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl; and
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R'° and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cyclo
  • R 20 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enatiomers, diastereomers and pharmaceutically acceptable salts thereof. More preferably, the above method employs a compound of formula Vd, Ve or Vf.
  • this invention is directed to a method for treating a disease mediated by VLA-4 in a patient, which method comprises administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula Via and/or VIb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula VIb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen,
  • R 23 is selected from the group consisting of hydrogen, . 10 alkyl optionally substimted with one to four substiments independently selected from R a and Cy optionally substimted with one to four substiments independently selected from R b ;
  • R 24 is selected from the group consisting of Ar'-Ar 2 -C 1 . 10 alkyl, Ar'-Ar -C 2 . 10 alkenyl, Ar'-Ar 2 -C 2 . 10 alkynyl, wherein Ar 1 and Ar 2 are independently aryl or heteroaryl each of which is optionally substimted with one to four substiments independently selected from R b ; alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments independently selected from R a ;
  • R 25 is selected from the group consisting of hydrogen, C,., 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl, aryl . ⁇ alkyl, heteroaryl, and heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments selected from R a , and aryl and heteroaryl are optionally substimted with one to four substiments independently selected from R b' ;
  • R a is selected from the group consisting of Cy, -OR d , -NO 2 , halogen -S(O) m R d' , -SR d , -S(O) 2 OR° , -S(O) m NR d' R e , -NR d R e , -O(CR' R g ) n NR d R e ,
  • R b is selected from the group consisting of R a' , C 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl C,. 10 alkyl, heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substimted with a group independently selected from R c ;
  • R c' is selected from the group consisting of halogen, amino, carboxy, C ⁇ - 4 alkyl, C M alkoxy, aryl, aryl C M alkyl, hydroxy, CF 3 , and aryloxy;
  • R d' and R e are independently selected from hydrogen, C,. 10 alkyl, C 2 . , 0 alkenyl, C 2 . 10 alkynyl, Cy and Cy C,. 10 alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substiments independently selected from R c ; or R d' and R e' together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g are independently selected from hydrogen, C,. 10 alkyl, Cy and Cy-C,. 10 alkyl; or R f and R g together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h' is selected from the group consisting of hydrogen, C,. 10 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, cyano, aryl, aryl C 0 alkyl, heteroaryl, heteroaryl C,. 10 alkyl, or -SO 2 R' ; wherein alkyl, alkenyl, and alkynyl are optionally substimted with one to four substimtents independently selected from R a ; and aryl and heteroaryl are each optionally substimted with one to four substiments independently selected from R b ; R 1' is selected from the group consisting of C 0 alkyl, C 2 . 10 alkenyl,
  • alkynyl, and aryl wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substiments independently selected from R° ;
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • X" is selected from the group consisting of -C(O)OR d' ,
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl or substimted heteroaryl group having two nitrogen atoms in the heteroaryl ring.
  • the heteroaryl ring may contain other heteroatoms such as oxygen or sulfur.
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or 1,1- dioxo-l,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, 1- oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or 1,1-dioxo-
  • 1,2,5-thiadiazole ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen.
  • X" is -C(O)OR d' .
  • R 24 is and R 25 is hydrogen.
  • the above method employs a compound of formula Vila, VIIc, Vlld, Vile or Vllf:
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl; and
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 16 and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloal
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
  • the compound employed in the above method is selected from formula Vlld, Vile or Vllf.
  • the compounds and pharmaceutical compositions of this invention are useful for treating disease conditions mediated by VLA-4 or leucocyte adhesion.
  • disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, Ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg- Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary
  • the disease condition mediated by VLA-4 is an inflammatory disease.
  • the present invention is also directed to novel compounds useful for treating a disease condition mediated by VLA-4 or leucocyte adhesion. Accordingly, in one of its composition aspects, this invention is directed to a compound of formula la and/or lb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula lb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen,
  • R 3 is -(CH 2 ) X -Ar-R°, where Ar is aryl, substimted aryl, heteroaryl and substimted heteroaryl; R° is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxythiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4; R 3 is selected from the group consisting of hydrogen, isopropyl,
  • Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl- substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-substimted heteroaryl, carboxylheterocyclic, carboxyl-substimted heterocyclic, cycloalkyl, substimted alkyl, substimted alkoxy, substimted aryl, substimted aryloxy, substimted aryloxyaryl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic;
  • Q is selected from the group consisting of -
  • R 4 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic or, optionally, R 4 and R 1 or R 4 and R 2 , together with the atoms to which they are bound, are joined to form a heteroaryl, a substimted heteroaryl, a heterocyclic or a substimted heterocyclic group; W is selected from the group consisting of nitrogen and carbon; and
  • W is selected from the group consisting of nitrogen, carbon, oxygen, sulfur, S(O), and S(O) 2 ;
  • X is selected from the group consisting of hydroxyl, alkoxy, substimted alkoxy, alkenoxy, substimted alkenoxy, cycloalkoxy, substimted cycloalkoxy, cycloalkenoxy, substimted cycloalkenoxy, aryloxy, substimted aryloxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy and -NR"R" where each R" is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic; and enantiomers, diasteromers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula la and/or lb has
  • R 3 is a group of the formula:
  • R 9 and x are as defined herein.
  • R 9 is in the para position of the phenyl ring; and x is an integer of from 1 to 4, more preferably, x is 1.
  • R 3' is hydrogen
  • R 9 is selected from the group consisting of -O-Z-NR 11 R 11 and -O-Z-R 12 wherein R 11 and R 11 ' are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, and where R" and R" are joined to form a heterocycle or a substimted heterocycle, R 12 is selected from the group consisting of heterocycle and substimted heterocycle, and Z is selected from the group consisting of -C(O)- and -SO,-. More preferably, R 9 is
  • Z is -C(O)- and Q is preferably -NR 4 -.
  • this invention is directed to compounds of formula Ila or lib:
  • R 3 is -(CH 2 ) X -Ar-R 9 , where Ar is aryl, substimted aryl, heteroaryl and substimted heteroaryl;
  • R 9 is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxy thiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl;
  • x is an integer from 0 to 4;
  • R 3' is selected from the group consisting of hydrogen, isopropyl, -
  • Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl- substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-substimted heteroaryl, carboxylheterocyclic, carboxyl-substimted heterocyclic, cycloalkyl, substimted alkyl, substimted alkoxy, substimted aryl, substimted aryloxy, substimted aryloxyaryl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic; ring A and ring B independently form a heteroary
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R° is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycl
  • R 3' is preferably hydrogen.
  • x is an integer from 1 to 4; more preferably, x is 1.
  • ring A forms a pyridazine, pyrimidine or pyrazine ring; more preferably, a pyrimidine or pyrazine ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen.
  • ring B forms a pyridazine, pyrimidine, pyrazine, 1-oxo- 1,2,5-thiadiazole or a l,l-dioxo-l,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or a l,l-dioxo-l,2,5- thiadiazole ring; wherein the pyridazine, pyrimidine or pyrazine ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted hetero
  • this invention is directed to compounds of formula Ilia, IIIc, Hid, Hie or Illf:
  • R 3 is -(CH 2 ) X -Ar-R°, where Ar is aryl, substimted aryl, heteroaryl and substimted heteroaryl; R° is selected from the group consisting of acyl, acylamino, acyloxy, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, oxycarbonylamino, oxy thiocarbonylamino, thioamidino, thiocarbonylamino, aminosulfonylamino, aminosulfonyloxy, aminosulfonyl, oxysulfonylamino and oxysulfonyl; x is an integer from 0 to 4;
  • R 3' is selected from the group consisting of hydrogen, isopropyl, -
  • Z is selected from the group consisting of hydrogen, hydroxyl, acylamino, alkyl, alkoxy, aryloxy, aryl, aryloxyaryl, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl- substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-substimted heteroaryl, carboxylheterocyclic, carboxyl-substimted heterocyclic, cycloalkyl, substimted alkyl, substimted alkoxy, substimted aryl, substimted aryloxy, substimted aryloxyaryl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic; R 4' is selected from the group consisting of hydrogen and
  • R 4" is selected from the group consisting of hydrogen and alkyl
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl;
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 16 and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic;
  • R 20 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
  • R 3' is preferably hydrogen.
  • x is an integer from 1 to 4; more preferably, x is 1.
  • the compound is selected from formula Hid, Hie or Illf.
  • this invention is directed to a compound of formula IVa:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form a heteroaryl group having two nitrogen atoms in the heteroaryl ring; and further wherein said heteroaryl group is optionally substimted, on any ring atom capable of substimtion, with 1-3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, substimted amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substimted aryloxyaryl, substimted aryloxyaryl, cyano, halogen, hydroxyl,
  • R 14 is selected from the group consisting of hydrogen, C,. 10 alkyl, C 2 . 10 alkenyl, C 2 _ 10 alkynyl, Cy, Cy-C 0 alkyl, Cy-C 2 . 10 alkenyl and Cy-C 2 . 10 alkynyl, wherein alkyl, alkenyl, and alkynyl are optionally substimted with one to four substiments selected from phenyl and R x , and Cy is optionally substimted with one to four substiments independently selected from R y ; or R 13 , R 14 and the atoms to which they are attached together form a mono- or bicyclic ring containing 0-2 additional heteratoms selected from N, O and S;
  • R 15 is selected from the group consisting of C[. 10 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl, aryl-C 0 alkyl, heteroaryl, heteroaryl- ., 0 alkyl, wherein alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments selected from R ⁇ and aryl and heteroaryl are optionally substimted with one to four substiments independently selected from R y ; or R 14 , R 15 and the carbon to which they are attached form a 3-7 membered mono- or bicyclic ring containing 0-2 heteroatoms selected from N, O and S;
  • R a is selected from the group consisting of Cy and a group selected from R ⁇ wherein Cy is optionally substimted with one to four substiments independently selected from R c:
  • R b is selected from the group consisting of R a , C,., 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, aryl C O alkyl, heteroaryl ., 0 alkyl, wherein alkyl, alkenyl, alkynyl, aryl, heteroaryl are optionally substimted with a group independently selected from R c ;
  • R c is selected from the group consisting of halogen, NO,, C(O)OR f , C M alkyl, C w alkoxy, aryl, aryl C M alkyl, aryloxy, heteroaryl, NR f R g , R f C(O)R g , NR f C(O)NR f R g , and CN;
  • R d and R e are independently selected from hydrogen, C 0 alkyl, C 2 . 10 alkenyl, C 2 ., 0 alkynyl, Cy and Cy . ⁇ alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substiments independently selected from R c ; or R d and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R f and R g are independently selected from hydrogen, C 0 alkyl, Cy and Cy-C 0 alkyl wherein Cy is optionally substimted with C,. 10 alkyl; or R f and R together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h is selected from the group consisting of hydrogen, . 10 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, cyano, aryl, aryl ., 0 alkyl, heteroaryl, heteroaryl C,_ I0 alkyl, and -SO 2 R'; wherein alkyl, alkenyl, and alkynl are optionally substimted with one to four substimtents independently selected from R a ; and aryl and heteroaryl are each optionally substimted with one to four substiments independently selected from R b ;
  • R 1 is selected from the group consisting of C,. 10 alkyl, C 2 . 10 alkenyl, 2 - ⁇ o alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substiments independently selected from R c ;
  • R x is selected from the group consisting of -OR d , -NO 2 , halogen, -S(O) m R d , -SR d , -S(O) 2 OR d , -S(O) m NR d R e , -NR d R e , -O(CR f R g ) n NR d R e , -C(O)R d , -CO 2 R d , -CO 2 (CR f R g ) n CONR d R e , -OC(O)R d , -CN, -C(O)NR d R e , -NR C(O)R e , -OC(O)NR d R e , -NR d C(O)OR e , -NR d C(O)NR d R e , -CR d (N-OR e ),
  • R y is selected from the group consisting of R ⁇ C,., 0 alkyl, C 2 ., 0 alkenyl, C 2 . 10 alkynyl, aryl C O alkyl, heteroaryl C,. 10 alkyl, cycloalkyl, heterocyclyl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substimtents independently selected from R x ;
  • Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl; m is an integer from 1 to 2; n is an integer from 1 to 10;
  • W is selected from the group consisting of carbon and nitrogen; W is selected from the group consisting of carbon, nitrogen, oxygen, sulfur, S(O) and S(O) 2 ;
  • X' is selected from the group consisting of -C(O)OR d , -P(O)(OR d )(OR e ), -P(O)(R d )(OR e ), -S(O) m OR d , -C(O)NR d R h , and -5- tetrazolyl; and enatiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compound of formula IV has a binding affinity to VLA-4 as expressed by an IC 50 of about 15 ⁇ M or less; and provided that when R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a 2- arylpyrimidin-4-yl group and R 14 is hydrogen, then R 15 is not alkyl of from 1 to 6 carbon atoms optionally substimted with hydroxyl; and when R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined
  • R 1 and R 2 are preferably joined to form an pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or 1,1-dioxo- 1,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, l-oxo-1,2,5- thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring is optionally substimted with 1 to 3 substiments selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted
  • X' is -C(O)OR d .
  • this invention is directed to compounds of of formula Va, Vc, Vd, Ve or Vf:
  • R 13 , R 14 , R 15 and X' are as defined herein;
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl; and
  • R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 16 and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substituted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl
  • R 20 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof. More preferably, the compound is selected from formula Vd, Ve or Vf.
  • this invention is directed to a compound of formula Via and/or VIb:
  • R 1 and R 2 together with the carbon atom and W to which they are bound respectively, are joined to form an aryl, cycloalkenyl, heteroaryl or heterocyclic group having at least five atoms in the aryl, cycloalkenyl, heteroaryl or heterocyclic group and optionally containing or additionally containing in the case of heteroaryl and heterocyclic groups 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein the heteroaryl or heterocyclic group is mono-cyclic; in formula VIb, R 1 and R 2 , together with the carbon atom and W to which they are bound respectively, are joined to form a cycloalkyl, cycloalkenyl or heterocyclic group having at least five atoms in the cycloalkyl, cycloalkenyl or heterocyclic group and optionally containing or additionally containing in the case of the heterocyclic group 1 to 3 heteroatoms selected from the group consisting of oxygen,
  • each R is independently hydrogen or alkyl, -NRS(O) 2 -alkyl, -NRS(O) 2 -substituted alkyl, -NRS(O) 2 -aryl, -NRS(O) 2 - substituted aryl, -NRS(O) 2 -heteroaryl, -NRS(O) 2 -substituted heteroaryl, -NRS(O) 2 -heterocyclic, -NRS(0) 2 -substituted heterocyclic, -NRS(O) 2 -NR- alkyl, -NRS(O) 2 -NR-substituted alkyl, -NRS(O) 2 -NR-aryl, -NR
  • R 23 is selected from the group consisting of hydrogen, C,. 10 alkyl optionally substimted with one to four substiments independently selected from R ' and Cy optionally substimted with one to four substiments independently selected from R b' ;
  • R 24 is selected from the group consisting of alkyl, Ar'-Ar 2 -C 2 . 10 alkenyl, Ar ⁇ Ar ⁇ C ⁇ o alkynyl, wherein Ar 1 and Ar 2 are independently aryl or heteroaryl each of which is optionally substimted with one to four substiments independently selected from R b ; alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments independently selected from R a ;
  • R 25 is selected from the group consisting of hydrogen, C,. 10 alkyl, C 2 - ⁇ o alkenyl, C 2 _ 10 alkynyl, aryl, aryl C O alkyl, heteroaryl, and heteroaryl
  • alkyl wherein alkyl, alkenyl and alkynyl are optionally substimted with one to four substiments selected from R a , and aryl and heteroaryl are optionally substimted with one to four substiments independently selected from R b' ;
  • R a' is selected from the group consisting of Cy, -OR 1' , -NO 2 , halogen
  • R b is selected from the group consisting of R a , C 0 alkyl, C 2 _ ⁇ 0 alkenyl, C 2 . 10 alkynyl, aryl C,. 10 alkyl, heteroaryl C,. 10 alkyl, wherein alkyl, alkenyl, aryl, heteroaryl are optionally substimted with a group independently selected from R c ;
  • R c' is selected from the group consisting of halogen, amino, carboxy, C alkyl, C M alkoxy, aryl, aryl C .alkyl, hydroxy, CF 3 , and aryloxy;
  • R d' and R e' are independently selected from hydrogen, C 0 alkyl, C 2 . 10 alkenyl, C 2 . 10 alkynyl, Cy and Cy C O alkyl, wherein alkyl, alkenyl, alkynyl and Cy are optionally substimted with one to four substiments independently selected from R c ; or R d' and R e together with the atoms to which they are attached form a heterocyclic ring of 5 to 7 members containing 0-2 additional heteroatoms independently selected from oxygen, sulfur and nitrogen; R r and R g' are independently selected from hydrogen, C 10 alkyl, Cy and alkyl; or R f' and R g' together with the carbon to which they are attached form a ring of 5 to 7 members containing 0-2 heteroatoms independently selected from oxygen, sulfur and nitrogen;
  • R h' is selected from the group consisting of hydrogen, C ⁇ ., 0 alkyl, C 2 ., 0 alkenyl, C 2 . 10 alkynyl, cyano, aryl, aryl C ⁇ _ 10 alkyl, heteroaryl, heteroaryl C 0 alkyl, or -SO 2 R ; wherein alkyl, alkenyl, and alkynyl are optionally substimted with one to four substimtents independently selected from R a ; and aryl and heteroaryl are each optionally substimted with one to four substiments independently selected from R b ;
  • R' is selected from the group consisting of C 0 alkyl, C 2 . 10 alkenyl, C 2 ., 0 alkynyl, and aryl; wherein alkyl, alkenyl, alkynyl and aryl are each optionally substimted with one to four substiments independently selected from R ; Cy is cycloalkyl, heterocyclyl, aryl, or heteroaryl;
  • X" is selected from the group consisting of -C(O)OR d , -P(O)(OR d' )(OR e ), -P(O)(R d' )(OR e ), -S(O) m OR d' , -C(O)NR d' R h , and -5- tetrazolyl; m is an integer from 1 to 2; n is an integer from 1 to 10; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof; and further wherein the compounds of formula Via and/or VIb have a binding affinity to VLA-4 as expressed by an I o of about 15 ⁇ M or less.
  • R 1 and R 2 are preferably joined to form a heteroaryl or substimted heteroaryl group having two nitrogen atoms in the heteroaryl ring. More preferably, R 1 and R 2 are joined to form a pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; more preferably, a pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring; wherein the pyridazine, pyrimidine, pyrazine, l-oxo-l,2,5-thiadiazole or l,l-dioxo-l,2,5-thiadiazole ring is optionally substimted with 1 to 3 substiments selected from the group consist
  • X" is -C(O)OR
  • R 24 is preferably -CH 2 -Ar 2 -Ar' and R 25 is preferably hydrogen.
  • this invention is directed to compounds of formula Vila, VIIc, Vlld, Vile or Vllf:
  • R 5 is selected from the group consisting of alkyl, substimted alkyl, alkenyl, substimted alkenyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl;
  • R 6 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substimted aryl, heteroaryl, substimted heteroaryl, and -SO 2 R 10 where R 10 is selected from the group consisting of alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, cycloalkenyl, substimted cycloalkenyl, heterocyclic, substimted heterocyclic, aryl, substituted aryl, heteroaryl, substimted heteroaryl; and R 7 and R 8 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, cycloalkyl, substimted cycloalkyl, aryl, substimted
  • R 16 and R 17 are independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen; and
  • R 18 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic;
  • R 20 is selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkoxy, substimted alkoxy, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and halogen;
  • R 21 is selected from the group consisting of alkyl, substimted alkyl, alkoxy, substimted alkoxy, amino, substimted amino, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heterocyclic and substimted heterocyclic; b is 1 or 2; and enantiomers, diastereomers and pharmaceutically acceptable salts thereof.
  • the compound is selected from formula Vlld, Vile or Vllf.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of the compounds defined herein.
  • X when X is other than -OH or pharmaceutical salts thereof, X is preferably a substiment which will convert (e.g., hydrolyze, metabolize, etc.) in vivo to a compound where X is -OH or a salt thereof.
  • suitable X groups are any art recognized pharmaceutically acceptable groups which will hydrolyze or otherwise convert in vivo to a hydroxyl group or a salt thereof including, by way of example, esters (X is alkoxy, substimted alkoxy, cycloalkoxy, substimted cycloalkoxy, alkenoxy, substimted alkenoxy, cycloalkenoxy, substimted cycloalkenoxy, aryloxy, substimted aryloxy, heteroaryloxy, substimted heteroaryloxy, heterocyclooxy, substimted heterocyclooxy, and the like).
  • R 3 and R 15 in the above compounds are preferably selected from all possible isomers arising by substimtion with the following groups: 4-methylbenzyl,
  • 3,4-dioxyethylenebenzyl i.e., 3,4-ethylenedioxybenzyl
  • 3,4-dioxymethylenebenzyl i.e., 3,4-methylenedioxybenzyl
  • R 5 in the above compounds is selected from the group consisting of alkyl, substimted alkyl, aryl, substimted aryl, heterocyclic, substimted heterocylic, heteroaryl and substimted heteroaryl.
  • R 5 is selected from the group consisting of 4-methylphenyl, methyl, benzyl, n-butyl, n-hexyl, 4-chlorophenyl, 1 -naphthyl, 2-naphthyl, 4- methoxyphenyl, phenyl, 2,4,6-trimethylphenyl, 2-(methoxycarbonyl)phenyl, 2-carboxyphenyl, 3,5-dichlorophenyl, 4-trifluoromethylphenyl, 3,4- dichlorophenyl, 3,4-dimethoxyphenyl, 4-(CH 3 C(O)NH-)phenyl, 4- trifluoromethoxyphenyl, 4-cyanophenyl, isopropyl, 3,5-di- (trifluoromethyl)phenyl, 4-t-butylphenyl, 4-t-butoxy phenyl, 4-nitrophenyl, 2- thienyl, l-N-methyl-3-methyl-5-
  • R 13 in the above compounds is selected from hydrogen or C ⁇ _ 6 alkyl; more preferably, hydrogen or _ 3 alkyl; and still more preferably, hydrogen or methyl.
  • R 14 in the above compounds is preferably hydrogen and R 15 is preferably C 0 alkyl or Cy-C 0 alkyl, wherein alkyl is optionally substimted with one to four substiments selected from phenyl and R x , and Cy is optionally substimted with one to four substiments independently selected from R y , or R 14 and R 15 and the carbon to which they are attached together from a 3-7 membered mono- or bicyclic carbon only ring.
  • Cy is preferably aryl, more preferably phenyl.
  • R 15 is phenyl-C,.
  • R 16 is substimted amino; R 17 and/or R 20 are hydrogen; and R 18 and/or R 21 are alkyl, substimted alkyl, aryl or substimted aryl.
  • R 23 in the above compounds is hydrogen.
  • R 24 in the above compounds is Ar'-Ar 2 -C,_ I0 alkyl wherein Ar 1 and Ar 2 are optionally substimted with from 1 to 4 groups independently selected from R b and R 25 is hydrogen. More preferably, R 24 is Ar ⁇ A ⁇ -C ⁇ alkyl wherein Ar 1 and Ar 2 are optionally substimted with from 1 to 4 groups independently selected from R b ; still more preferably, R 24 is -CH 2 -Ar 2 -Ar' and R 25 is hydrogen. Additional preferred embodiments are disclosed in International Patent Application Publication No. WO 98/53817, which application is inco ⁇ orated herein by reference in its entirety.
  • R 3 and R 3 , or R 14 and R 15 , or R 24 and R 25 are derived from L-amino acids or other similarly configured starting materials.
  • racemic mixmres can be used.
  • x in the above compounds is an integer from 1 to 4.
  • This invention also provides methods for binding VLA-4 in a biological sample which method comprises contacting the biological sample with a compound of this invention under conditions wherein said compound binds to VLA-4.
  • the pharmaceutical compositions may be used to treat disease conditions mediated by VLA-4 or leucocyte adhesion.
  • disease conditions include, by way of example, asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, mmor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • disease conditions include, but are not limited to, inflammatory conditions such as erythema nodosum, allergic conjunctivitis, optic neuritis, uveitis, allergic rhinitis, ankylosing spondylitis, psoriatic arthritis, vasculitis, Reiter's syndrome, systemic lupus erythematosus, progressive systemic sclerosis, polymyositis, dermatomyositis, Wegner's granulomatosis, aortitis, sarcoidosis, lymphocytopenia, temporal arteritis, pericarditis, myocarditis, congestive heart failure, polyarteritis nodosa, hypersensitivity syndromes, allergy, hypereosinophilic syndromes, Churg-Strauss syndrome, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic active hepatitis, interstitial cystitis, autoimmune endocrine failure, primary biliary
  • Preferred compounds of this invention include those set forth in the Tables below: WO 00/43372 PCTVUSOO/01686
  • Ph phenyl
  • Ph phenyl
  • Ph phenyl
  • this invention relates to compounds which inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4.
  • VLA-4 leukocyte adhesion mediated by VLA-4.
  • alkyl refers to alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl and the like.
  • “Substimted alkyl” refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkyl amidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substimted aryloxyaryl, cyano, halogen, hydroxyl, nitro, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxyl
  • Alkoxy refers to the group “alkyl-O-" which includes, by way of example, methoxy, ethoxy, n-p ⁇ opoxy, iso-p ⁇ opoxy, «-butoxy, tert-butoxy, -yec-butoxy, /z-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
  • Substimted alkoxy refers to the group “substimted alkyl-O-”.
  • Alkenoxy refers to the group “alkenyl-O-”.
  • Substimted alkenoxy refers to the group “substimted alkenyl-O-”.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substimted alkyl- C(O)-, alkenyl-C(O)-, substimted alkenyl-C(O)-, alkynyl-C(O)-, substimted alkynyl-C(O)- cycloalkyl-C(O)-, substimted cycloalkyl-C(O)-, aryl-C(O)-, substimted aryl-C(O)-, heteroaryl-C(O)-, substimted heteroaryl-C(O), heterocyclic-C(O)-, and substimted heterocyclic-C(O)- wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl
  • Acylamino refers to the group -C(O)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and where each R is joined to form together with the nitrogen atom a heterocyclic or substimted heterocyclic ring wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocycl
  • Thiocarbonylamino refers to the group -C(S)NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, aryl, substimted aryl, cycloalkyl, substimted cycloalkyl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic and where each R is joined to form, together with the nitrogen atom a heterocyclic or substimted heterocyclic ring wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substim
  • Acyloxy refers to the groups alkyl-C(O)O-, substimted alkyl- C(O)O-, alkenyl-C(O)O-, substimted alkenyl-C(O)O-, alkynyl-C(O)O-, substimted alkynyl-C(O)O-, aryl-C(O)O-, substimted aryl-C(O)O-, cycloalkyl-C(O)O-, substimted cycloalkyl-C(O)O-, heteroaryl-C(O)O-, substimted heteroaryl-C(O)O-, heterocyclic-C(O)O-, and substimted heterocyclic-C(O)O- wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl,
  • Oxysulfonyl refers to the groups alkyl-SO 2 O-, substimted alkyl- SO 2 O-, alkenyl-SO 2 O-, substimted alkenyl-SO 2 O-, alkynyl-SO 2 O-, substimted alkynyl-SO 2 O-, aryl-SO 2 O-, substimted aryl-SO 2 O-, cycloalkyl-SO 2 O-, substimted cycloalkyl-SO 2 O-, heteroaryl-SO 2 O-, substimted heteroaryl-SO 2 O- , heterocyclic-SO 2 O-, and substimted heterocyclic-SO 2 O- wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted ary
  • Alkenyl refers to alkenyl group preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation.
  • Substimted alkenyl refers to alkenyl groups having from 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substimted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-substim
  • Alkynyl refers to alkynyl group preferably having from 2 to 10 carbon atoms and more preferably 3 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation.
  • Substimted alkynyl refers to alkynyl groups having from 1 to 5 substiments selected from the group consisting of alkoxy, substimted alkoxy, acyl, acylamino, thiocarbonylamino, acyloxy, amino, amidino, alkylamidino, thioamidino, aminoacyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aryl, substimted aryl, aryloxy, substimted aryloxy, aryloxyaryl, substimted aryloxyaryl, halogen, hydroxyl, cyano, nitro, carboxyl, carboxylalkyl, carboxyl-substimted alkyl, carboxyl-cycloalkyl, carboxyl-substimted cycloalkyl, carboxylaryl, carboxyl-substimted aryl, carboxylheteroaryl, carboxyl-sub
  • Amino refers to the group -NH 2 .
  • Substimted amino refers to the group -NRR, where each R group is independently selected from the group consisting of hydrogen, alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic, substimted heterocyclic, -SO 2 -alkyl, -SO 2 -substituted alkyl, -SO 2 -alkenyl, -SO 2 -substituted alkenyl, -SO 2 - cycloalkyl, -SO 2 -substituted cycloalkyl, -SO 2 -aryl, -SO 2 -substituted aryl, -SO 2 -heteroaryl, -SO 2 -substi
  • Aminoacyl refers to the groups -NRC(O)alkyl, -NRC(O)substituted alkyl, -NRC(O)cycloalkyl, -NRC(O)substimted cycloalkyl, -NRC(O)alkenyl, -NRC(O)substimted alkenyl, -NRC(O)alkynyl, - NRC(O)substimted alkynyl, -NRC(O)aryl, -NRC(O)substimted aryl, -NRC(O)heteroaryl, -NRC(O)substimted heteroaryl, -NRC(O)heterocyclic, and -NRC(O)substimted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted
  • Aminosulfonyl refers to the groups -NRSO 2 alkyl, -NRSO 2 substituted alkyl, -NRSO 2 cycloalkyl, -NRSO 2 substituted cycloalkyl, -NRSO 2 alkenyl, -NRSO 2 substituted alkenyl, -NRSO 2 alkynyl, -NRSO 2 substituted alkynyl, -NRSO 2 aryl, -NRSO 2 substituted aryl,
  • R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Aminocarbonyloxy refers to the groups -NRC(O)O-alkyl, -NRC(O)O-substituted alkyl, -NRC(O)O-alkenyl, -NRC(O)O-substituted alkenyl, -NRC(O)O-alkynyl, -NRC(O)O-substituted alkynyl, -NRC(O)O- cycloalkyl, -NRC(O)O-substituted cycloalkyl, -NRC(O)O-aryl, -NRC(O)O- substimted aryl, -NRC(O)O-heteroaryl, -NRC(O)O-substituted heteroaryl, -NRC(O)O-heterocyclic, and -NRC(O)O-substimted heterocyclic where R is hydrogen or alkyl and wherein
  • Aminosulfonyloxy refers to the groups -NRSO 2 O-alkyl, -NRSO 2 O-substituted alkyl, -NRSO 2 O-alkenyl, -NRSO 2 O-substituted alkenyl, -NRSO 2 O-alkynyl, -NRSO 2 O-substituted alkynyl, -NRSO 2 O-cycloalkyl, -NRSO 2 O-substituted cycloalkyl, -NRSO 2 O-aryl, -NRSO 2 O-substimted aryl, -NRSO 2 O-heteroaryl, -NRSO 2 O-substimted heteroaryl, -NRSO 2 O-heterocyclic, and -NRSO 2 O-substituted heterocyclic where R is hydrogen or alkyl and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, and
  • Oxycarbonylamino refers to the groups -OC(O)NH 2 , -OC(O)NRR,
  • -OC(O)NR-alkyl -OC(O)NR-substituted alkyl, -OC(O)NR-alkenyl, -OC(O)NR-substituted alkenyl, -OC(O)NR-alkynyl, -OC(O)NR-substituted alkynyl, -OC(O)NR-cycloalkyl, -OC(O)NR-substituted cycloalkyl, -OC(O)NR-aryl, -OC(O)NR-substimted aryl, -OC(O)NR-heteroaryl, -OC(O)NR-substimted heteroaryl,- OC(O)NR-heterocyclic, and
  • R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substimted heterocyclic ring and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Oxythiocarbonylamino refers to the groups -OC(S)NH 2 , -OC(S)NRR, -OC(S)NR-alkyl, -OC(S)NR-substituted alkyl, -OC(S)NR- alkenyl, -OC(S)NR-substituted alkenyl, -OC(S)NR-alkynyl, -OC(S)NR- substimted alkynyl, -OC(S)NR-cycloalkyl, -OC(S)NR-substituted cycloalkyl, -OC(S)NR-aryl, -OC(S)NR-substimted aryl, -OC(S)NR-heteroaryl, -OC(S)NR-substituted heteroaryl, -OC(S)NR-heterocyclic, and -OC(S)NR-substimted heterocyclic where R is hydrogen,
  • Oxysulfonylamino refers to the groups -OSO 2 NH 2 , -OSO 2 NRR, -OSO 2 NR-alkyl, -OSO 2 NR-substituted alkyl, -OSO 2 NR-alkenyl, -OSO 2 NR-substituted alkenyl, -OSO 2 NR-alkynyl, -OSO 2 NR-substituted alkynyl, -OSO 2 NR-cycloalkyl, -OSO 2 NR-substituted cycloalkyl, -OSO 2 NR-aryl, -OSO 2 NR-substituted aryl, -OSO 2 NR-heteroaryl,
  • -OSO 2 NR-substituted heteroaryl -OSO 2 NR-heterocyclic, and -OSO 2 NR-substituted heterocyclic
  • R is hydrogen, alkyl or where each R is joined to form, together with the nitrogen atom a heterocyclic or substimted heterocyclic ring and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Aminocarbonylamino refers to the groups -NRC(O)NRR,
  • aminothiocarbonylamino refers to the groups -NRC(S)NRR,
  • Aminosulfonylamino refers to the groups -NRSO 2 NRR, -NRSO 2 NR-alkyl, -NRSO 2 NR-substituted alkyl, -NRSO 2 NR-alkenyl, -NRSO 2 NR-substituted alkenyl, -NRSO 2 NR-alkynyl, -NRSO 2 NR-substituted alkynyl, -NRSO 2 NR-aryl, -NRSO 2 NR-substituted aryl, -NRSO 2 NR-cycloalkyl, -NRSO 2 NR-substituted cycloalkyl, -NRSO 2 NR-heteroaryl, and -NRSO 2 NR-substituted heteroaryl, -NRSO 2 NR-heterocyclic, and -NRSO 2 NR-substituted heterocyclic, where each R is independently hydrogen, alkyl,
  • Aryl or “Ar” refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g., 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)- one-7yl, and the like).
  • Preferred aryls include phenyl and naphthyl.
  • Substimted aryl refers to aryl groups which are substimted with from 1 to 3 substiments selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl-substim
  • R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- substimted arylamino, mono- and di-heteroarylamino, mono- and di- substimted heteroarylamino, mono- and di-heterocyclic amino, mono- and di
  • Substimted aryloxy refers to substimted aryl-O- groups.
  • Aryloxyaryl refers to the group -aryl-O-aryl.
  • “Substimted aryloxyaryl” refers to aryloxyaryl groups substimted with from 1 to 3 substiments on either or both aryl rings selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, aminocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy, carboxyl,
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 8 carbon atoms having a single cyclic ring including, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like. Excluded from this definition are multi-ring alkyl groups such as adamantanyl, etc.
  • Cycloalkenyl refers to cyclic alkenyl groups of from 3 to 8 carbon atoms having single or multiple unsaturation but which are not aromatic.
  • Cycloalkoxy refers to -O-cycloalkyl groups.
  • Substimted cycloalkoxy refers to -O-substituted cycloalkyl groups.
  • Cycloalkenoxy refers to -O-cycloalkenyl groups.
  • Substimted cycloalkenoxy refers to -O-substituted cycloalkenyl groups.
  • each R is independently hydrogen and alkyl as well as where one of the amino groups is blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like and wherein alkyl, substimted alkyl, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, cycloalkyl, substimted cycloalkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic are as defined herein.
  • Halo or halogen refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
  • Heteroaryl refers to an aromatic carbocyclic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring or oxides thereof.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • the heteroatoms of the heteroaryl group may be oxidized, i.e., to form pyridine N-oxides or l,l-dioxo-l,2,5- thiadiazoles and the like.
  • heteroaryls include pyridyl, pyrrolyl, indolyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, l-oxo-l,2,5-thiadiazolyl and l,l-dioxo-l,2,5-thiadiazolyl.
  • heteroaryl having two nitrogen atoms in the heteroaryl ring refers to a heteroaryl group having two, and only two, nitrogen atoms in the heteroaryl ring and optionally containing 1 or 2 other heteroatoms in the heteroaryl ring, such as oxygen or sulfur
  • Substimted heteroaryl refers to heteroaryl groups which are substimted with from 1 to 3 substiments selected from the group consisting of hydroxy, acyl, acylamino, thiocarbonylamino, acyloxy, alkyl, substimted alkyl, alkoxy, substimted alkoxy, alkenyl, substimted alkenyl, alkynyl, substimted alkynyl, amidino, alkylamidino, thioamidino, amino, aminoacyl, a inocarbonyloxy, aminocarbonylamino, aminothiocarbonylamino, aryl, substimted aryl, aryloxy, substimted aryloxy, cycloalkoxy, substimted cycloalkoxy, heteroaryloxy, substimted heteroaryloxy, heterocyclyloxy, substimted heterocyclyloxy, carboxyl, carboxylalkyl, carboxyl,
  • R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-substimted arylamino, mono- and di-heteroarylamino, mono- and di-substimted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-substimted heterocyclic amino, unsymmetric di-substimted amines having different substiments selected from alkyl, substimted alkyl, aryl, substimted aryl, heteroaryl, substimted heteroaryl, heterocyclic and substimted heterocyclic and amino groups on the substimted aryl blocked by conventional blocking groups such as Boc, Cbz, formyl, and the like or subs
  • Heteroaryloxy refers to the group -O-heteroaryl and "substimted heteroaryloxy” refers to the group -O-substituted heteroaryl.
  • Heterocycle or “heterocyclic” refers to a samrated or unsaturated group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring wherein, in fused ring systems, one or more of the rings can be aryl or heteroaryl.
  • R is hydrogen or alkyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di- substimted arylamino, mono- and di-heteroarylamino, mono- and di- substimted heteroarylamino, mono- and di-heterocyclic amino, mono- and di-heterocyclic amino, mono-
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,
  • Heterocyclyloxy refers to the group -O-heterocyclic and “substimted heterocyclyloxy” refers to the group -O-substituted heterocyclic.
  • Thiol refers to the group -SH.
  • Thioalkyl refers to the groups -S-alkyl
  • Substimted thioalkyl refers to the group -S-substimted alkyl.
  • Thiocycloalkyl refers to the groups -S-cycloalkyl. - Ill -
  • Substimted thiocycloalkyl refers to the group -S-substimted cycloalkyl.
  • Thioaryl refers to the group -S-aryl and "substimted thioaryl” refers to the group -S-substimted aryl.
  • Thioheteroaryl refers to the group -S-heteroaryl and "substimted thioheteroaryl” refers to the group -S-substimted heteroaryl.
  • Thioheterocyclic refers to the group -S-heterocyclic and "substimted thioheterocyclic” refers to the group -S-substimted heterocyclic.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • the compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
  • the compounds of this invention will typically contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixmres. All such stereoisomers (and enriched mixmres) are included within the scope of this invention, unless otherwise indicated. Pure stereoisomers (or enriched mixmres) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixmres of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents and the like.
  • the compounds of this invention are prepared by coupling an amino acid derivative of the formula:
  • R 3 and R 3 are as defined herein and P 1 is a carboxylic acid protecting group (such as an alkyl group, i.e. methyl, ethyl and the like), with a suitably functionalized heteroaryl or heterocyclic intermediate.
  • a carboxylic acid protecting group such as an alkyl group, i.e. methyl, ethyl and the like
  • such coupling reactions may be performed by displacing a leaving group, such as chloro, bromo, iodo, tosyl and the like, from the heteroaryl or heterocyclic intermediate with the amino group of the amino acid derivative; or by reductive alkylation of the amino group of amino acid derivative with a carbonyl-functionalized intermediate.
  • Such coupling reactions are well- known to those skilled in the art.
  • 5-nitrouracil, 1, (commercially available from Aldrich Chemical Company, Milwaukee, Wisconsin USA) is treated with phosphorus oxychloride and NN-dimethylaniline according to the procedure described in Whittaker, J. Chem. Soc. 1951, 1565 to give l,3-dichloro-4- nitropyrimidine, 2.
  • the nitro group of intermediate 3 is then reduced using a conventional reducing agent, such as hydrogen and a palladium on carbon catalyst.
  • a conventional reducing agent such as hydrogen and a palladium on carbon catalyst.
  • hydrogen and palladium on carbon are employed as the reducing agent, the chloro group of intermediate 3 is also removed.
  • This reaction is typically conducted by contacting 3 with a Degussa-type palladium on carbon catalyst (typically 20%) and excess sodium bicarbonate in an inert diluent, such as methanol, under hydrogen (typically about 55 psi) for about 12 to 36 hours at ambient temperamre to afford amino intermediate 4.
  • Amino intermediate 4 is then reacted with a sulfonyl chloride of the formula: R 5 -S(O) 2 -Cl, where R 5 is as defined herein, to provide sulfonamide intermediate 5.
  • This reaction is typically conducted by reacting the amino intermediate 4 with at least one equivalent, preferably about 1.1 to about 2 equivalents, of the sulfonyl chloride in an inert diluent such as dichloromethane and the like.
  • the reaction is conducted at a temperamre ranging from about -70°C to about 40°C for about 1 to about 24 hours.
  • this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • Suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmo ⁇ holine and the like.
  • the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like, as the base.
  • aqueous alkali such as sodium hydroxide and the like
  • heteroaryl intermediates may also be employed in the above described reactions including, but not limited to, 2-chloro-3-nitropy razine (J. Med. Chem. 1984, 27, 1634); 4-chloro-5-nitroimidazole (J. Chem. Soc. 1930, 268); and the like.
  • amino acid derivatives employed in the above reactions are either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures.
  • amino acid derivatives can be prepared by C-alkylating commercially available diethyl 2- acetamidomalonate (Aldrich, Milwaukee, Wisconsin, USA) with an alkyl or substimted alkyl halide. This reaction is typically conducted by treating the diethyl 2-acetamidomalonate with at least one equivalent of sodium ethoxide and at least one equivalent of an alkyl or substimted alkyl halide in refluxing ethanol for about 6 to about 12 hours.
  • the resulting C-alkylated malonate is then deacetylated, hydrolyzed and decarboxylated by heating in aqueous hydrochloric acid at reflux for about 6 to about 12 hours to provide the amino acid, typically as the hydrochloride salt.
  • amino acid derivatives suitable for use in the above reactions include, but are not limited to, L-alanine methyl ester, L-isoleucine methyl ester, L-leucine methyl ester, L-valine methyl ester, ⁇ -tert-butyl-L- aspaitic acid methyl ester, L-asparagine tert-butyl ester, e-Boc-L-lysine methyl ester, e-Cbz-L-lysine methyl ester, ⁇ -tert-butyl-L-glutamic acid methyl ester, L-glutamine tert-butyl ester, L-(N-methyl)histidine methyl ester, L-(N-benzyl)histidine methyl ester, L-methionine methyl ester, L-(0- benzyl)serine methyl ester, L-tryptophan methyl ester, L-phenylalanine methyl ester, L-pheny
  • D,L-homophenylalanine methyl ester L-(O-methyl)tyrosine methyl ester, L- (O-tert-butyl)tyrosine methyl ester, L-(O-benzyl)tyrosine methyl ester, L-3,5- diiodotyrosine methyl ester, L-3-iodotyrosine methyl ester, ⁇ -(l-naphthyl)-L- alanine methyl ester, ⁇ -(2-naphthyl)-L-alanine methyl ester, ⁇ -(2-thienyl)-L- alanine methyl ester, ⁇ -cyclohexyl-L-alanine methyl ester, ⁇ -(2-pyridyl)-L- alanine methyl ester, ⁇ -(3-pyridyl)-L-alanine methyl ester, ⁇ -(4-pyridyl
  • ⁇ -hydroxy and ⁇ -thio carboxylic acids may also be employed in the above-described reactions.
  • Such compounds are well-known in the art and are either commercially available or may be prepared from commercially available starting materials using conventional reagents and reaction conditions.
  • the sulfonyl chlorides employed in the above reaction are also either known compounds or compounds that can be prepared from known compounds by conventional synthetic procedures. Such compounds are typically prepared from the corresponding sulfonic acid, i.e., from compounds of the formula R 5 -SO 3 H where R 5 is as defined above, using phosphorous trichloride and phosphorous pentachloride.
  • This reaction is generally conducted by contacting the sulfonic acid with about 2 to 5 molar equivalents of phosphorous trichloride and phosphorous pentachloride, either neat or in an inert solvent, such as dichloromethane, at temperamre in the range of about 0°C to about 80 °C for about 1 to about 48 hours to afford the sulfonyl chloride.
  • the sulfonyl chloride can be prepared from the corresponding thiol compound, i.e., from compounds of the formula R 5 -
  • sulfonyl chlorides suitable for use in this invention include, but are not limited to, methanesulfonyl chloride, 2-propanesulfonyl chloride, 1-butanesulfonyl chloride, benzenesulfonyl chloride, 1- naphthalenesulfonyl chloride, 2-naphthalenesulfonyl chloride, p- toluenesulfonyl chloride, ⁇ -toluenesulfonyl chloride, 4- acetamidobenzenesulfonyl chloride, 4-amidinobenzenesulfonyl chloride, 4- rt-butylbenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2- carboxybenzenesulfonyl chloride, 4-cyanobenzenesuIfonyl chloride, 3,4- dichlorobenzenesulfonyl chlor
  • a sulfonyl fluoride, sulfonyl bromide or sulfonic acid anhydride may be used in place of the sulfonyl chloride in the above reaction to form the sulfonamide intermediate 5.
  • sulfonamide intermediate 5 can be alkylated at the sulfonamide nitrogen atom to provide compound 6.
  • 5 can be contacted with excess diazomethane (generated, for example, using 1-methyl- 3-nitro-l-nitrosoguanidine and sodium hydroxide) to afford 6 where R 6 is methyl.
  • diazomethane generated, for example, using 1-methyl- 3-nitro-l-nitrosoguanidine and sodium hydroxide
  • Other conventional alkylation procedures and reagents may also be employed to prepare various compounds of this invention.
  • R 3 , Q and X are as defined herein;
  • A' is heteroaryl, substituted heteroaryl, heterocyclic or substimted heterocyclic containing two nitrogen atoms in the heteroaryl or heterocyclic ring; and
  • L 1 is a leaving group, such as chloro, bromo, iodo, sulfonate ester and the like.
  • this reaction is conducted by combining approximately stoichiometric equivalents of 7 and 8 in a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like, with an excess of a suitable base such as sodium bicarbonate, sodium hydroxide, etc. to scavenge the acid generated by the reaction.
  • a suitable inert diluent such as water, dimethylsulfoxide (DMSO) and the like
  • a suitable base such as sodium bicarbonate, sodium hydroxide, etc.
  • compounds of this invention in which Q is NR 4 can be prepared by reductive amination of a suitable 2- oxocarboxylic acid ester, 10, such as a pyruvate ester, as shown in Scheme 3:
  • A', R 3 and X are as defined herein.
  • this reaction is conducted by combining equamolar amounts of 10 and 11 in an inert diluent such as methanol, ethanol and the like under conditions which provide for imine formation (not shown).
  • the imine formed is then reduced under conventional conditions by a suitable reducing agent such as sodium cyanoborohydride, H 2 /palladium on carbon and the like to form the product 12.
  • the reducing agent is H 2 /palladium on carbon which is inco ⁇ orated into the initial reaction medium thereby permitting imine reduction in situ in a one pot procedure to provide 12.
  • the reaction is preferably conducted at from about 20 °C to about 80 °C at a pressure of from 1 to 10 atmospheres until reaction completion which typically occurs within 1 to about 24 hours.
  • reaction completion the product 12 is recovered by conventional methods including chromatography, filtration and the like.
  • A" is heteroaryl or substimted heteroaryl containing two nitrogen atoms in the heteroaryl ring, and R 3 and X (preferably alkoxy) are as defined herein.
  • this reaction is conducted using rhodium acetate dimer, Rh 2 (OAc) 4 , in an inert diluent such as toluene at a temperamre ranging from about 25°C to about 80°C for about 1 to 12 hours to afford 15.
  • Rh 2 (OAc) 4 Rh 2 (OAc) 4
  • X 3 is halogen, such as chloro, bromo or iodo (preferably iodo), and R 3 and X (preferably alkoxy) are as defined herein.
  • this reaction is conducted using copper iodide (Cul) and potassium carbonate in an inert diluent such as N,N-dimethyl acetamide (DMA) at a temperamre ranging from about 60 °C to about 120°C for about 12 to 36 hours to afford 15.
  • DMA N,N-dimethyl acetamide
  • the compounds of this invention are typically prepared as an ester, i.e., where X is an alkoxy or substimted alkoxy group and the like.
  • the ester group can be hydrolysed using conventional conditions and reagents to provide the corresponding carboxylic acid.
  • this reaction is conducted by treating the ester with at least one equivalent of an alkali metal hydroxide, such as lithium, sodium or potassium hydroxide, in an inert diluent, such as methanol or mixmres of methanol and water, at a temperamre ranging about 0°C to about 24 °C for about 1 to about 12 hours.
  • an alkali metal hydroxide such as lithium, sodium or potassium hydroxide
  • an inert diluent such as methanol or mixmres of methanol and water
  • benzyl esters may be removed by hydrogenolysis using a palladium catalyst, such as palladium on carbon, and tert-butyl esters can be removed using for
  • a nitro group present on a substiment of a compound of formula I- VII or an intermediate thereof may be readily reduced by hydrogenation in the presence of a palladium catalyst, such as palladium on carbon, to provide the corresponding amino group.
  • This reaction is typically conducted at a temperamre of from about 20 °C to about 50 °C for about 6 to about 24 hours in an inert diluent, such as methanol.
  • Compounds having a nitro group on the R 3 and/or R 3' substiment can be prepared, for example, by using a 4- nitrophenylalanine derivative and the like in the above-described coupling reactions.
  • a pyridyl group can be hydrogenated in the presence of a platinum catalyst, such as platinum oxide, in an acidic diluent to provide the corresponding piperidinyl analogue.
  • a platinum catalyst such as platinum oxide
  • this reaction is conducted by treating the pyridine compound with hydrogen at a pressure ranging from about 20 psi to about 60 psi, preferably about 40 psi, in the presence of the catalyst at a temperamre of about 20 °C to about 50 °C for about 2 to about 24 hours in an acidic diluent, such as a mixmre of methanol and aqueous hydrochloric acid.
  • R 3 and/or R 3' substiment of a compound of formula I- VII or an intermediate thereof contains a primary or secondary amino group
  • such amino groups can be further derivatized either before or after the above coupling reactions to provide, by way of example, amides, sulfonamides, ureas, thioureas, carbamates, secondary or tertiary amines and the like.
  • Compounds having a primary amino group on the R 3 and/or R 3' substiment may be prepared, for example, by reduction of the corresponding nitro compound as described above.
  • a compound of formula I- VII or an intermediate thereof having a substiment containing a primary or secondary amino group, such as where R 3 is a (4-aminophenyl)methyl group can be readily N-acylated using conventional acylating reagents and conditions to provide the corresponding amide.
  • This acylation reaction is typically conducted by treating the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of a carboxylic acid in the presence of a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like, in an inert diluent, such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, N,N- dimethylformamide and the like, at a temperamre ranging from about 0°C to about 37°C for about 4 to about 24 hours.
  • a coupling reagent such as a carbodiimide, BOP reagent (benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphonate) and the like
  • a promoter such as N-hydroxysuccinimide, 1-hydroxy-benzotriazole and the like, is used to facilitate the acylation reaction.
  • carboxylic acids suitable for use in this reaction include, but are not limited to, N-tert- butyloxycarbonylglycine, N-tert-butyloxycarbonyl-L-phenylalanine, N-tert- butyloxycarbonyl-L-aspartic acid benzyl ester, benzoic acid, N-tert- butyloxycarbonylisonipecotic acid, N-methylisonipecotic acid, N-tert- butyloxycarbonylnipecotic acid, N-tert-buty loxycarbony 1-L- tetrahydroisoquinoline-3-carboxylic acid, N-(toluene-4-sulfonyl)-L-proline and the like.
  • a compound of formula I- VII or an intermediate thereof containing a primary or secondary amino group can be N-acylated using an acyl halide or a carboxylic acid anhydride to form the corresponding amide.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the acyl halide or carboxylic acid anhydride in an inert diluent, such as dichloromethane, at a temperamre ranging from about -70°C to about 40°C for about 1 to about 24 hours.
  • an acylation catalyst such as 4- (N,N-dimethylamino)pyridine may be used to promote the acylation reaction.
  • the acylation reaction is preferably conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmo ⁇ holine and the like.
  • the reaction can be conducted under Schotten-Baumann-type conditions using aqueous alkali, such as sodium hydroxide and the like.
  • acyl halides and carboxylic acid anhydrides suitable for use in this reaction include, but are not limited to, 2-methylpropionyl chloride, trimethylacetyl chloride, phenylacetyl chloride, benzoyl chloride, 2- bromobenzoyl chloride, 2-methylbenzoyl chloride, 2-trifluoro-methylbenzoyl chloride, isonicotinoyl chloride, nicotinoyl chloride, picolinoyl chloride, acetic anhydride, succinic anhydride, and the like.
  • Carbamyl chlorides such as N,N-dimethylcarbamyl chloride, N,N-diethylcarbamyl chloride and the like, can also be used in this reaction to provide ureas.
  • dicarbonates such as di-tert-butyl dicarbonate, may be employed to provide carbamates.
  • a compound of formula I- VII or an intermediate thereof containing a primary or secondary amino group may be N-sulfonated to form a sulfonamide using a sulfonyl halide or a sulfonic acid anhydride.
  • Sulfonyl halides and sulfonic acid anhydrides suitable for use in this reaction include, but are not limited to, methanesulfonyl chloride, chloromethanesulfonyl chloride, / toluenesulfonyl chloride, trifluoromethanesulfonic anhydride, and the like.
  • sulfamoyl chlorides such as dimethylsulfamoyl chloride, can be used to provide sulfamides (e.g., > N-SO 2 -N ⁇ ).
  • a primary and secondary amino group present on a substiment of a compound of formula I- VII or an intermediate thereof can be reacted with an isocyanate or a thioisocyanate to give a urea or thiourea, respectively.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.2 equivalents, of the isocyanate or thioisocyanate in an inert diluent, such as toluene and the like, at a temperamre ranging from about 24°C to about 37°C for about 12 to about 24 hours.
  • isocyanates and thioisocyanates used in this reaction are commercially available or can be prepared from commercially available compounds using well-known synthetic procedures.
  • isocyanates and thioisocyanates are readily prepared by reacting the appropriate amine with phosgene or thiophosgene.
  • isocyanates and thioisocyanates suitable for use in this reaction include, but are not limited to, ethyl isocyanate, rt-propyl isocyanate, 4-cyanophenyl isocyanate, 3-methoxyphenyl isocyanate, 2-phenylethyl isocyanate, methyl thioisocyanate, ethyl thioisocyanate, 2-phenylethyl thioisocyanate, 3- phenylpropyl thioisocyanate, 3-(N,N-diethylamino)propyl thioisocyanate, phenyl thioisocyanate, benzyl thioisocyanate, 3-pyridyl thioisocyanate, fluorescein isothiocyanate (isomer I) and the like.
  • a compound of formula I- VII or an intermediate thereof contains a primary or secondary amino group
  • the amino group can be reductively alkylated using aldehydes or ketones to form a secondary or tertiary amino group.
  • This reaction is typically conducted by contacting the amino compound with at least one equivalent, preferably about 1.1 to about 1.5 equivalents, of an aldehyde or ketone and at least one equivalent based on the amino compound of a metal hydride reducing agent, such as sodium cyanoborohydride, in an inert diluent, such as methanol, tetrahydrofuran, mixmres thereof and the like, at a temperamre ranging from about 0°C to about 50 °C for about 1 to about 72 hours.
  • Aldehydes and ketones suitable for use in this reaction include, by way of example, benzaldehyde, 4- chlorobenzaldehyde, valeraldehyde and the like.
  • a compound of formula I- VII or an intermediate thereof has a substiment containing a hydroxyl group
  • the hydroxyl group can be further modified or derivatized either before or after the above coupling reactions to provide, by way of example, ethers, carbamates and the like.
  • Compounds having a hydroxyl group on the R 3 substiment can be prepared using an amino acid derivative derived from tyrosine and the like in the above-described reactions.
  • a compound of formula I- VII or an intermediate thereof having a substiment containing a hydroxyl group, such as where R 3 is a (4-hydroxyphenyl)methyl group can be readily O-alkylated to form ethers.
  • This O-alkylation reaction is typically conducted by contacting the hydroxy compound with a suitable alkali or alkaline earth metal base, such as potassium carbonate, in an inert diluent, such as acetone, 2-butanone and the like, to form the alkali or alkaline earth metal salt of the hydroxyl group.
  • This salt is generally not isolated, but is reacted in situ with at least one equivalent of an alkyl or substimted alkyl halide or sulfonate, such as an alkyl chloride, bromide, iodide, mesylate or tosylate, to afford the ether.
  • an alkyl or substimted alkyl halide or sulfonate such as an alkyl chloride, bromide, iodide, mesylate or tosylate
  • this reaction is conducted at a temperamre ranging from about 60°C to about 150°C for about 24 to about 72 hours.
  • a catalytic amount of sodium or potassium iodide is added to the reaction mixmre when an alkyl chloride or bromide is employed in the reaction.
  • alkyl or substimted alkyl halides and sulfonates suitable for use in this reaction include, but are not limited to, tert-butyl bromoacetate, N-tert-buty 1 chloroacetamide, 1-bromoethylbenzene, ethyl ⁇ - bromophenylacetate, 2-(N-ethyl-N-phenylamino)ethyl chloride, 2-(N,N- ethylamino)ethyl chloride, 2-(N,N-diisopropylamino)ethyl chloride, 2-(N,N- dibenzylamino)ethyl chloride, 3-(N,N-ethylamino)propyl chloride, 3-(N- benzyl-N-methylamino)propyl chloride, N-(2-chloroethyl)mo ⁇ holine, 2-
  • a hydroxyl group present on a substiment of a compound of formula I- VII or an intermediate thereof can be O-alkylating using the Mitsunobu reaction.
  • an alcohol such as 3-(N,N- dimethylamino)-l -propanol and the like, is reacted with about 1.0 to about 1.3 equivalents of triphenylphosphine and about 1.0 to about 1.3 equivalents of diethyl azodicarboxylate in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about -10°C to about 5°C for about 0.25 to about 1 hour.
  • a compound of formula I- VII or an intermediate thereof containing an aryl hydroxy group can be reacted with an aryl iodide to provide a diary 1 ether.
  • this reaction is conducted by forming the alkali metal salt of the hydroxyl group using a suitable base, such as sodium hydride, in an inert diluent such as xylenes at a temperamre of about - 25 °C to about 10°C.
  • the salt is then treated with about 1.1 to about 1.5 equivalents of cuprous bromide dimethyl sulfide complex at a temperamre ranging from about 10°C to about 30°C for about 0.5 to about 2.0 hours, followed by about 1.1 to about 1.5 equivalents of an aryl iodide, such as sodium 2-iodobenzoate and the like.
  • the reaction is then heated to about 70°C to about 150°C for about 2 to about 24 hours to provide the diaryl ether.
  • a hydroxy-containing compound can also be readily derivatized to form a carbamate.
  • a hydroxy compound of formula I- VII or an intermediate thereof is contacted with about 1.0 to about 1.2 equivalents of 4-nitrophenyl chloroformate in an inert diluent, such as dichloromethane, at a temperamre ranging from about -25 °C to about 0°C for about 0.5 to about 2.0 hours.
  • Treatment of the resulting carbonate with an excess, preferably about 2 to about 5 equivalents, of a trialkylamine, such as triethylamine, for about 0.5 to 2 hours, followed by about 1.0 to about 1.5 equivalents of a primary or secondary amine provides the carbamate.
  • amines suitable for using in this reaction include, but are not limited to, piperazine, 1- methylpiperazine, 1-acetylpiperazine, mo ⁇ holine, thiomo ⁇ holine, pyrrolidine, piperidine and the like.
  • a hydroxy- containing compound is contacted with about 1.0 to about 1.5 equivalents of a carbamyl chloride in an inert diluent, such as dichloromethane, at a temperamre ranging from about 25 °C to about 70 °C for about 2 to about 72 hours.
  • this reaction is conducted in the presence of a suitable base to scavenge the acid generated during the reaction.
  • suitable bases include, by way of example, tertiary amines, such as triethylamine, diisopropylethylamine, N-methylmo ⁇ holine and the like.
  • At least one equivalent (based on the hydroxy compound) of 4-(N,N- dimethylamino)pyridine is preferably added to the reaction mixmre to facilitate the reaction.
  • carbamyl chlorides suitable for use in this reaction include, by way of example, dimethylcarbamyl chloride, diethylcarbamyl chloride and the like.
  • hydroxyl groups can be readily converted into a leaving group and displaced to form, for example, amines, sulfides and fluorides.
  • a chiral compound is employed in these reactions, the stereochemistry at the carbon atom attached to the derivatized hydroxyl group is typically inverted.
  • These reactions are typically conducted by first converting the hydroxyl group into a leaving group, such as a tosylate, by treatment of the hydroxy compound with at least one equivalent of a sulfonyl halide, such as •-toluenesulfonyl chloride and the like, in pyridine. This reaction is generally conducted at a temperamre of from about 0°C to about 70°C for about 1 to about 48 hours.
  • the resulting tosylate can then be readily displaced with sodium azide, for example, by contacting the tosylate with at least one equivalent of sodium azide in an inert diluent, such as a mixmre of N,N-dimethylformamide and water, at a temperamre ranging from about 0°C to about 37°C for about 1 to about 12 hours to provide the corresponding azido compound.
  • the azido group can then be reduced by, for example, hydrogenation using a palladium on carbon catalyst to provide the amino (- ⁇ H 2 ) compound.
  • a tosylate group can be readily displaced by a thiol to form a sulfide.
  • This reaction is typically conducted by contacting the tosylate with at least one equivalent of a thiol, such as thiophenol, in the presence of a suitable base, such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in an inert diluent, such as N,N-dimethylformamide, at a temperamre of from about 0°C to about 37 °C for about 1 to about 12 hours to provide the sulfide.
  • a thiol such as thiophenol
  • a suitable base such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU)
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • a compound of formula I- VII or an intermediate thereof having a substiment containing an iodoaryl group for example, when R 3 is a (4-iodophenyl)methyl group, can be readily converted either before or after the above coupling reactions into a biaryl compound.
  • this reaction is conducted by treating the iodoaryl compound with about 1.1 to about 2 equivalents of an arylzinc iodide, such as 2-(methoxycarbonyl)phenylzinc iodide, in the presence of a palladium catalyst, such as palladium tetra(triphenylphosphine), in an inert diluent, such as tetrahydrofuran, at a temperamre ranging from about 24 °C to about 30 °C until reaction completion.
  • a palladium catalyst such as palladium tetra(triphenylphosphine
  • an inert diluent such as tetrahydrofuran
  • the compounds of formula I- VII or intermediates thereof may contain substiments having one or more sulfur atoms.
  • sulfur atoms can be oxidized either before or after the above coupling reactions to provide a sulfoxide or sulfone compound using conventional reagents and reaction conditions.
  • Suitable reagents for oxidizing a sulfide compound to a sulfoxide include, by way of example, hydrogen peroxide, 3-chloroperoxybenzoic acid (MCPBA), sodium periodate and the like.
  • the oxidation reaction is typically conducted by contacting the sulfide compound with about 0.95 to about 1.1 equivalents of the oxidizing reagent in an inert diluent, such as dichloromethane, at a temperamre ranging from about -50 °C to about 75 °C for about 1 to about 24 hours.
  • an oxidizing reagent such as hydrogen peroxide, MCPBA, potassium permanganate and the like.
  • the sulfone can be prepared directly by contacting the sulfide with at least two equivalents, and preferably an excess, of the oxidizing reagent. Such reactions are described further in March, "Advanced Organic Chemistry", 4th Ed., pp. 1201-1202, Wiley Publisher, 1992.
  • compositions When employed as pharmaceuticals, the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • compositions which contain, as the active ingredient, one or more of the compounds of formula I- VII above associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient employed is typically an excipient suitable for administration to human subjects or other mammals.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy- benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound acmally administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixmre of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixmres of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be inco ⁇ orated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixmres thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • Stearic acid 5.0 The components are blended and compressed to form tablets, each weighing 240 mg.
  • Formulation Example 3 A dry powder inhaler formulation is prepared containing the following components:
  • the active mixmre is mixed with the lactose and the mixmre is added to a dry powder inhaling appliance.
  • Formulation Example 4 Tablets, each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No.
  • Quantity Ingredient (mg/capsule)
  • the active ingredient, cellulose, starch, an magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are inco ⁇ orated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixmre is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent
  • Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Direct or indirect placement techniques may be used when it is desirable or necessary to introduce the pharmaceutical composition to the brain. Direct techniques usually involve placement of a drug delivery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Patent 5,011,472 which is herein inco ⁇ orated by reference.
  • Indirect techniques usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier.
  • the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
  • the compounds of this invention can be employed to bind VLA-4 (o ⁇ , ⁇ , integrin) in biological samples, i.e., the compounds bind VLA-4 with an IC 50 of 15 ⁇ M or less in a competitive binding assay as described herein. Accordingly, these compounds have utility in, for example, assaying such samples for VLA-4. In such assays, the compounds can be bound to a solid support and the VLA-4 sample added thereto. The amount of VLA-4 in the sample can be determined by conventional methods such as use of a sandwich ELISA assay. Alternatively, labeled VLA-4 can be used in a competitive assay to measure for the presence of VLA-4 in the sample. Other suitable assays are well known in the art.
  • certain of the compounds of this invention inhibit, in vivo, adhesion of leukocytes to endothelial cells mediated by VLA-4 by competitive binding to VLA-4. Accordingly, the compounds of this invention can be used in the treatment of diseases mediated by VLA-4 or leucocyte adhesion.
  • Such diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, mmor metastasis, meningitis, encephalitis, stroke, and other cerebral traumas, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury such as that which occurs in adult respiratory distress syndrome.
  • diseases include inflammatory diseases in mammalian patients such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), inflammatory bowel disease (including ulcerative colitis and Crohn's disease), multiple sclerosis, rheumatoid arthritis, tissue transplantation, mmor metastasis, meningitis, encephalitis,
  • the biological activity of the compounds identified above may be assayed in a variety of systems.
  • a compound can be immobilized on a solid surface and adhesion of cells expressing VLA-4 can be measured. Using such formats, large numbers of compounds can be screened.
  • Cells suitable for this assay include any leukocytes known to express VLA-4 such as T cells, B cells, monocytes, eosinophils, and basophils.
  • a number of leukocyte cell lines can also be used, examples include Jurkat and U937.
  • test compounds can also be tested for the ability to competitively inhibit binding between VLA-4 and VCAM-1, or between VLA-4 and a labeled compound known to bind VLA-4 such as a compound of this invention or antibodies to VLA-4.
  • the VCAM-1 can be immobilized on a solid surface.
  • VCAM-1 may also be expressed as a recombinant fusion protein having an Ig tail (e.g., IgG) so that binding to VLA-4 may be detected in an immunoassay.
  • VCAM-1 expressing cells such as activated endothelial cells or VCAM-1 transfected fibroblasts can be used.
  • the assays described in International Patent Application Publication No. WO 91/05038 are particularly preferred. This application is inco ⁇ orated herein by reference in its entirety.
  • the labelling systems can be in a variety of forms.
  • the label may be coupled directly or indirectly to the desired component of the assay according to methods well known in the art.
  • a wide variety of labels may be used.
  • the component may be labelled by any one of several methods. The most common method of detection is the use of autoradiography with 3 H, 125 I, 35 S, 14 C, or 32 P labelled compounds or the like.
  • Non-radioactive labels include ligands which bind to labelled antibodies, fluorophores, chemiluminescent agents, enzymes and antibodies which can serve as specific binding pair members for a labelled ligand.
  • the choice of label depends on sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation.
  • EAE experimental autoimmune encephalomyelitis
  • Compounds having the desired biological activity may be modified as necessary to provide desired properties such as improved pharmacological properties (e.g., in vivo stability, bio-availability), or the ability to be detected in diagnostic applications. Stability can be assayed in a variety of ways such as by measuring the half-life of the proteins during incubation with peptidases or human plasma or serum. A number of such protein stability assays have been described (see, e.g., Verhoef et al., Eur. J. Drug Metab. Pharmacokinet., 1990, 150):83-93).
  • a wide variety of labels may be linked to the compounds, which may provide, directly or indirectly, a detectable signal.
  • the compounds of the subject invention may be modified in a variety of ways for a variety of end pu ⁇ oses while still retaining biological activity.
  • various reactive sites may be introduced at the terminus for linking to particles, solid substrates, macromolecules, or the like.
  • Labeled compounds can be used in a variety of in vivo or in vitro applications.
  • a wide variety of labels may be employed, such as radionuclides (e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Il l), fluorescers (e.g., fluorescein), enzymes, enzyme substrates, enzyme cofactors, enzyme inhibitors, chemiluminescent compounds, bioluminescent compounds, and the like.
  • radionuclides e.g., gamma-emitting radioisotopes such as technetium-99 or indium-Il l
  • fluorescers e.g., fluorescein
  • enzymes enzyme substrates
  • enzyme cofactors enzyme inhibitors
  • chemiluminescent compounds chemiluminescent compounds
  • bioluminescent compounds bioluminescent compounds
  • In vitro uses include diagnostic applications such as monitoring inflammatory responses by detecting the presence of leukocytes expressing VLA-4.
  • the compounds of this invention can also be used for isolating or labeling such cells.
  • the compounds of the invention can be used to assay for potential inhibitors of VLA-4/VCAM-1 interactions.
  • radioisotopes are typically used in accordance with well known techniques.
  • the radioisotopes may be bound to the peptide either directly or indirectly using intermediate functional groups.
  • chelating agents such as diethylenetriaminepentacetic acid (DTPA) and ethylenediaminetetraacetic acid (EDTA) and similar molecules have been used to bind proteins to metallic ion radioisotopes.
  • the complexes can also be labeled with a paramagnetic isotope for pu ⁇ oses of in vivo diagnosis, as in magnetic resonance imaging (MRI) or electron spin resonance (ESR), both of which are well known.
  • MRI magnetic resonance imaging
  • ESR electron spin resonance
  • any conventional method for visualizing diagnostic imaging can be used.
  • gamma- and positron-emitting radioisotopes are used for camera imaging and paramagnetic isotopes are used for MRI.
  • the compounds can be used to monitor the course of amelioration of an inflammatory response in an individual. By measuring the increase or decrease in lymphocytes expressing VLA-4 it is possible to determine whether a particular therapeutic regimen aimed at ameliorating the disease is effective.
  • compositions of the present invention can be used to block or inhibit cellular adhesion associated with a number of diseases and disorders.
  • a number of inflammatory disorders are associated with integrins or leukocytes.
  • Treatable disorders include, e.g., transplantation rejection (e.g., allograft rejection), Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes (including acute juvenile onset diabetes), retinitis, cancer metastases, rheumatoid arthritis, acute leukocyte-mediated lung injury (e.g., adult respiratory distress syndrome), asthma, nephritis, and acute and chronic inflammation, including atopic dermatitis, psoriasis, myocardial ischemia, and inflammatory bowel disease (including Crohn 's disease and ulcerative colitis).
  • the pharmaceutical compositions are used to treat inflammatory brain disorders, such as multiple sclerosis (MS), viral meningitis and encephalitis.
  • Inflammatory bowel disease is a collective term for two similar diseases referred to as Crohn 's disease and ulcerative colitis.
  • Crohn 's disease is an idiopathic, chronic ulceroconstrictive inflammatory disease characterized by sha ⁇ ly delimited and typically transmural involvement of all layers of the bowel wall by a granulomatous inflammatory reaction. Any segment of the gastrointestinal tract, from the mouth to the anus, may be involved, although the disease most commonly affects the terminal ileum and/or colon.
  • Ulcerative colitis is an inflammatory response limited largely to the colonic mucosa and submucosa. Lymphocytes and macrophages are numerous in lesions of inflammatory bowel disease and may contribute to inflammatory injury.
  • Asthma is a disease characterized by increased responsiveness of the tracheobronchial tree to various stimuli potentiating paroxysmal constriction of the bronchial airways.
  • the stimuli cause release of various mediators of inflammation from IgE-coated mast cells including histamine, eosinophilic and neutrophilic chemotactic factors, leukotrines, prostaglandin and platelet activating factor. Release of these factors recruits basophils, eosinophils and neutrophils, which cause inflammatory injury.
  • Atherosclerosis is a disease of arteries (e.g., coronary, carotid, aorta and iliac).
  • the basic lesion, the atheroma consists of a raised focal plaque within the intima, having a core of lipid and a covering fibrous cap.
  • Atheromas compromise arterial blood flow and weaken affected arteries.
  • Myocardial and cerebral infarcts are a major consequence of this disease. Macrophages and leukocytes are recruited to atheromas and contribute to inflammatory injury.
  • Rheumatoid arthritis is a chronic, relapsing inflammatory disease that primarily causes impairment and destruction of joints. Rheumatoid arthritis usually first affects the small joints of the hands and feet but then may involve the wrists, elbows, ankles and knees. The arthritis results from interaction of synovial cells with leukocytes that infiltrate from the circulation into the synovial lining of the joints. See e.g., Paul, Immunology (3d ed., Raven Press, 1993).
  • Another indication for the compounds of this invention is in treatment of organ or graft rejection mediated by VLA-4.
  • organs such as skin, kidney, liver, heart, lung, pancreas and bone marrow.
  • the principal outstanding problem is the lack of satisfactory agents for inducing immunotolerance in the recipient to the transplanted allograft or organ.
  • the host immune system is likely to mount an immune response to foreign antigens in the transplant (host-versus-graft disease) leading to destruction of the transplanted tissue.
  • CD8 + cells, CD4 cells and monocytes are all involved in the rejection of transplant tissues.
  • Compounds of this invention which bind to alpha-4 integrin are useful, wter alia, to block alloantigen-induced immune responses in the donee thereby preventing such cells from participating in the destruction of the transplanted tissue or organ. See, e.g., Paul et al., Transplant International 9, 420-425 (1996); Georczynski et al., Immunology 81, 573-580 (1996); Georcyznski et al., Transplant. Immunol. 3, 55-61 (1995); Yang et al., Transplantation 60, 71-76 (1995); Anderson et al., APMIS 102, 23-27 (1994).
  • GVHD graft versus host disease
  • GVHD is a potentially fatal disease that occurs when immunologically competent cells are transferred to an allogeneic recipient. In this situation, the donor's immunocompetent cells may attack tissues in the recipient. Tissues of the skin, gut epithelia and liver are frequent targets and may be destroyed during the course of GVHD.
  • the disease presents an especially severe problem when immune tissue is being transplanted, such as in bone marrow transplantation; but less severe GVHD has also been reported in other cases as well, including heart and liver transplants.
  • the therapeutic agents of the present invention are used, inter alia, to block activation of the donor T-cells thereby interfering with their ability to lyse target cells in the host.
  • a further use of the compounds of this invention is inhibiting mmor metastasis.
  • mmor metastasis Several mmor cells have been reported to express VLA-4 and compounds which bind VLA-4 block adhesion of such cells to endothelial cells. Steinback et al., Urol. Res. 23, 175-83 (1995); Orosz et al., Int. J.
  • a further use of the compounds of this invention is in treating multiple sclerosis.
  • Multiple sclerosis is a progressive neurological autoimmune disease that affects an estimated 250,000 to 350,000 people in the United States. Multiple sclerosis is thought to be the result of a specific autoimmune reaction in which certain leukocytes attack and initiate the destruction of myelin, the insulating sheath covering nerve fibers.
  • murine monoclonal antibodies directed against VLA-4 have been shown to block the adhesion of leukocytes to the endothelium, and thus prevent inflammation of the central nervous system and subsequent paralysis in the animals 16 .
  • Pharmaceutical compositions of the invention are suitable for use in a variety of drug delivery systems. Suitable formulations for use in the present invention are found in Remington 's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, PA, 17th ed. (1985).
  • the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds.
  • a variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Patent Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is inco ⁇ orated herein by reference.
  • the amount administered to the patient will vary depending upon what is being administered, the pu ⁇ ose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like.
  • compositions are administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications.
  • An amount adequate to accomplish this is defined as “therapeutically effective dose. " Amounts effective for this use will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the inflammation, the age, weight and general condition of the patient, and the like.
  • compositions administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11 , more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of the compounds of the present invention will vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the dose will typically be in the range of about 20 ⁇ g to about 500 ⁇ g per kilogram body weight, preferably about 100 ⁇ g to about 300 ⁇ g per kilogram body weight.
  • Suitable dosage ranges for intranasal administration are generally about 0.1 pg to 1 mg per kilogram body weight.
  • Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • Compounds of this invention are also capable of binding or antagonizing the actions of ⁇ 6 ⁇ ,, ⁇ 9 ⁇ ,, ⁇ 4 ⁇ 7 , d ⁇ 2 , e ⁇ 7 integrins (although ⁇ and ⁇ 9 ⁇ , are preferred in this invention). Accordingly, compounds of this invention are also useful for preventing or reversing the symptoms, disorders or diseases induced by the binding of these integrins to their respective ligands.
  • compounds that bind ⁇ d ⁇ 2 and ⁇ e ⁇ 7 integrins are particularly useful for the treatment of asthma and related lung diseases. See, for example, M. H. Grayson et al., J. Exp. Med. 1998, 188(11) 2187-2191.
  • Compounds that bind ⁇ e ⁇ 7 integrin are also useful for the treatment of systemic lupus erythematosus (see, for example, M. Pang et al., Arthritis Rheum. 1998, 41(8), 1456-1463); Crohn's disease, ulcerative colitis and infammatory bowel disease (IBD) (see, for example, D. Elewaut et al., Scand J.
  • Gastroenterol 1998, 33(1) 743-748 Sjogren's syndrome (see, for example, U. Kroneld et al., Scand J. Gastroenterol 1998, 27(3), 215-218); and rheumatoid arthritis (see, for example, Scand J. Gastroenterol 1996, 44(3), 293-298).
  • compounds that bind c i may be useful in preventing fertilization (see, for example, H. Chen et al., Chem. Biol. 1999, 6, 1-10).
  • Boc 2 O di-tert-butyl dicarbonate
  • EDC l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride
  • NaHCO 3 sodium bicarbonate
  • NMM N-methylmo ⁇ holine
  • Method A Methyl Ester Preparation Procedure Amino acid methyl esters can be prepared using the method of Brenner and Huber He/v. Chim. Acta 1953, 36, 1109.
  • Method B BOP Coupling Procedure The desired dipeptide ester was prepared by the reaction of a carboxylic acid (1 equivalent) with the appropriate amino acid ester or amino acid ester hydrochloride (1 equivalent), benzotriazol-1-yloxy- tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (2.0 equivalent), triethylamine (1.1 equivalent), and DMF. The reaction mixmre was stirred at room temperamre overnight. The crude product is purified flash chromatography to afford the dipeptide ester.
  • the work-up of the reaction solution was as follows: 50 mL EtOAc and 50 mL hexanes was added to the reaction mixmre, and the resulting mixmre was washed with 0.5 M citric acid (3 x 50 mL), water (2 x 50 mL),10% K 2 CO 3 (2 x 50 mL), and sat. NaCl (1 x 50 mL); dried with MgSO 4 , filtered and evaporated to afford the desired compound.
  • Triethylamine (29.38 mL, 21.33 g, 210.81 mmol, 2.5 eq) was added over five minutes with stirring and the stirring was continued at - 10 to -15 °C for 1 h.
  • N-Methyl piperazine (9.35 mL, 8.45 g, 84.34 mmol, 1.0 eq) was added over three minutes with stirring and stirring was continued overnight while warming to room temperamre.
  • the reaction mixmre was diluted with 700 mL hexanes and the resulting mixmre was washed repeatedly with 10% K 2 CO 3 , until no yellow color (from 4-nitrophenol) is observed in the aqueous layer. The mixmre was then washed with sat.
  • reaction mixmre was then cooled, diluted with water and ethyl acetate, and the organic phase was washed with 0.2 N citric acid, water, samrated NaHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated.
  • the cooled reaction mixmre was diluted with ethyl acetate and washed with water, samrated NaHCO 3 , dried (MgSO 4 ), filtered and concentrated. Either column chromatography or preparative thin layer chromatography on silica gel using ethyl acetate/hexanes afforded the desired product.
  • the cooled reaction mixmre was diluted with ethyl acetate and water and washed with water, brine, dried (MgSO 4 ), filtered and concentrated. The residue was purified by preparative thin layer chromatography on silica gel using ethyl acetate/hexanes to afford the desired product.
  • reaction mixmre was then diluted with ethyl acetate and water and washed with 0.2 ⁇ citric acid, water, samrated ⁇ aHCO,, brine, dried (MgS0 4 ), filtered and concentrated.
  • the residue was chromatographed on a silica gel column using ethyl acetate/hexanes. 'H ⁇ MR analysis showed that the desired product to be contaminated with the iodopyrimidine starting material. However, the product was used without further purification.
  • N-(6-Chloropyrimidin-4-yl')-L-4-(N.N-dimethylcarbamyloxy ' )phenylalanine tert-Butyl Ester A solution 4,6-dichloropyrimidine (1.2 eq), L-4-(N,N- dimethylcarbamyloxy)-phenylalanine tert-butyl ester (1.0 eq), and triethylamine (1.05 eq) in ethanol was heated at reflux for 16 hours. The reaction mixmre was cooled and concentrated, and the residue was taken-up in water and ethyl acetate.
  • reaction mixmre was then cooled and diluted with water and ethyl acetate, and the organic phase was washed with 0.2 N citric acid, water, samrated NaHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated.
  • the residue was purified by either silica gel column or preparative thin layer chromatography using ethyl acetate/hexanes to afford the desired product.
  • reaction mixmre was then cooled, diluted with water and ethyl acetate, and the organic phase was washed with 0.2 ⁇ citric acid, water, samrated ⁇ aHCO 3 , brine, dried (MgSO 4 ), filtered and concentrated.
  • Column chromatography on silica gel using ethyl acetate/hexanes afforded the desired product.
  • 5-Alkyl-4-N-alkylamino-6-chloropyrimidine or 5-Alkoxy-4-N-alkylaminopyrimidine To a solution of a 5-alkyl-4,6-dichloropyrimidine or a 5-alkoxy-4- chloropyrimidine (1.0 eq) in ethanol were added an alkyl amine (1.2 eq, typically L-4-(NN-dimethylcarbamyloxy)-phenylalanine tert-butyl ester) and diisopropylethylamine (2.0 eq).
  • the mixmre was sealed in a pressure tube and heated to 120°C for 48 h, at which point TLC indicated consumption of the 5-alkyl-4,6-dichloropyrimidine or the 5-alkoxy-4-chloropyrimidine.
  • the organic extracts were washed with samrated sodium chloride, treated with anhydrous magnesium sulfate, filtered, and evaporated.
  • N-Benzyloxycarbonyl-L-4-CN.N-Dimethylcarbamyloxy)phenylalanine tert-Butyl Ester A mixmre of N-benzyloxycarbonyl-L-tyrosine tert-butyl ester (1.0 eq), 4-dimethylaminopyridine (1.0 eq), triethylamine (1.5 eq), dimethylcarbamylchloride (1.2 eq), and dichloromethane was heated to 37 °C for 16 h. The mixmre was diluted with additional dichloromethane and washed sequentially with 1.0 M potassium bisulfate, water, samrated sodium bicarbonate, and samrated sodium chloride.
  • Method AAA Preparation of 2.4-Dichloro-5-nitropyrimidine 5- ⁇ itrouracil was treated with phosphorus oxychloride and N,N- dimethylaniline, according to the procedure of Whittaker (J. Chem. Soc. 1951, 1565), to give 2,4-dichloro-5-nitropyrimidine as an orange oil, which was used without distillation immediately in the next step.
  • Method BBB

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Abstract

L'invention concerne des composés représentés par les formules Ia et Ib, qui se lient à VLA-4. Certains de ces composés inhibent également l'adhérence leucocytaire et, en particulier, l'adhérence leucocytaire dépendant de VLA-4. Ces composés sont utiles pour traiter des maladies inflammatoires chez un patient mammifère, p. ex. l'être humain, telles que l'asthme, la maladie d'Alzheimer, l'athérosclérose, le syndrome démentiel lié au SIDA, le diabète, l'affection intestinale inflammatoire, la polyarthrite rhumatoïde, la greffe de tissus, les métastases de tumeur et l'ischémie myocardique. Les composés peuvent également être administrés pour traiter des affections cérébrales inflammatoires telles que la sclérose en plaques.
PCT/US2000/001686 1999-01-22 2000-01-21 Derives d'acyle utiles pour traiter des affections associees a vla-4 WO2000043372A1 (fr)

Priority Applications (15)

Application Number Priority Date Filing Date Title
MXPA01007335A MXPA01007335A (es) 1999-01-22 2000-01-21 Derivados de acilo los cuales tratan trastornos relacionados con alfa4 beta1 integrina y cd49d/cd29 (vla-4).
DK00913245.7T DK1144388T3 (da) 1999-01-22 2000-01-21 Acyl-derivater, som behandler VLA-4-relaterede lidelser
IL14392900A IL143929A0 (en) 1999-01-22 2000-01-21 Acyl derivatives which treat vla-4 related disorders
EA200100797A EA006301B1 (ru) 1999-01-22 2000-01-21 Ацильные производные, используемые для лечения опосредованных vla-4 расстройств
AU34724/00A AU773538B2 (en) 1999-01-22 2000-01-21 Acyl derivatives which treat VLA-4 related disorders
AT00913245T ATE455106T1 (de) 1999-01-22 2000-01-21 Acyl derivate zur behandlung von krankheiten die in zusammenhang mit vla-4 stehen
HU0201213A HUP0201213A3 (en) 1999-01-22 2000-01-21 Pirimidinyl, pirazinyl and thiadiazolyl phenylalanin derivatives which treat vla-4 related disorders and pharaceutical compositions containing them
BR0007663-5A BR0007663A (pt) 1999-01-22 2000-01-21 Derivados de acila para uso no tratamento de doenças relacionadas com o vla-4
JP2000594788A JP4754693B2 (ja) 1999-01-22 2000-01-21 Ｖｌａ−４関連障害を処置するアシル誘導体
DE60043692T DE60043692D1 (de) 1999-01-22 2000-01-21 Acyl derivate zur behandlung von krankheiten die in zusammenhang mit vla-4 stehen
EP00913245A EP1144388B1 (fr) 1999-01-22 2000-01-21 Derives d'acyle utiles pour traiter des affections associees a vla-4
CA2359115A CA2359115C (fr) 1999-01-22 2000-01-21 Derives d'acyle utiles pour traiter des affections associees a vla-4
IL143929A IL143929A (en) 1999-01-22 2001-06-21 Noble history of VLA-4-related diseases
NO20013600A NO323373B1 (no) 1999-01-22 2001-07-20 Acylderivater, farmasoytisk sammensetning omfattende samme, anvendelse av samme for fremstilling av medikament og fremgangsmate for a binde VLA-4 i en biologisk prove.
HK02107038.7A HK1046132B (zh) 1999-01-22 2002-09-26 用於治療與vla-4有關的疾病的酰基衍生物

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US11692399P 1999-01-22 1999-01-22
US60/116,923 1999-01-22
US60/160,999 1999-10-21

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PCT/US2000/001540 WO2000043369A1 (fr) 1999-01-22 2000-01-21 Composes inhibant l'adhesion aux leucocytes a mediation assuree par vla-4

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EP2275107A2 (fr) 2004-08-14 2011-01-19 Boehringer Ingelheim International GmbH Combinaison pour le traitment de maladies liées à la proliferation cellulaire
WO2011101369A1 (fr) 2010-02-17 2011-08-25 Boehringer Ingelheim International Gmbh Dihydroptéridinones, procédé pour la production et l'utilisation de celles-ci
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