Methods of treating inflammatory and autoimmune diseases with alpha-4 inhibitory compounds

Abstract

Alpha 4 inhibitors are used in treatment of inflammatory and autoimmune diseases, such as multiple sclerosis, Crohn's Disease, rheumatoid arthritis and asthma. Rare occurrences of progressive multifocal leucoencephalopathy during treatment with an alpha-4 agent suggest the possibility that it may be related to such treatment. Monitoring for the JC virus and educating caregivers and patients about the manifestations of progressive multifocal leucoencephalopathy can improve the safety of alpha 4 inhibitor therapy.

1 - 109 . (canceled) 
     
     
         110 . A method of using an alpha-4 inhibitor compound to treat a patient with an inflammatory or autoimmune disease comprising:
 (A) administering a pharmaceutically effective amount of the alpha-4 inhibitor compound;   (B) monitoring the patient for JC virus in the patient's urine, blood, and/or cerebrospinal fluid; and   (C) discontinuing administration of the alpha-4 inhibitor compound when at least one indicator of progressive multifocal leukoencephalopathy is present;   wherein the monitoring improves safety of treatment; and   wherein the alpha-4 inhibitor compound is chosen from:
 i) a compound, a pharmaceutically acceptable salt or ester of Formula I: 
   
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is selected from the group consisting of C 1  to C 4  alkyl, C 1  to C 4  haloalkyl, heteroaryl and —N(R 5 )(R 6 ), 
 where R 5  and R 6  are independently selected from the group consisting of hydrogen, C 1  to C 4  alkyl or R 5  and R 6  together with the nitrogen pendent thereto join to form a heterocyclic ring; 
 R 2  is selected from the group consisting of C 1  to C 4  alkyl, C 2  to C 4  alkenyl, and C 2  to C 4  alkynyl; and 
 R 3  and R 4  are independently C 1  to C 3  alkyl or R 3 , R 4  together with the nitrogen atom pendent thereto join to form a heterocyclic ring;
 ii) a compound, a pharmaceutically acceptable salt or ester of Formula III: 
 
 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1  comprises a halogen atom; X 2  comprises a halogen atom; Q comprises a —CH 2 — group or a —(CH 2 )2— group; Y comprises a C 1-6  alkyl group; and CO 2 R comprises a carboxyl group which may be esterified;
 iii) a compound, a pharmaceutically acceptable salt or ester of Formula IV; 
 
 
       
         
           
           
               
               
           
         
         
           iv) a compound, a pharmaceutically acceptable salt or ester of Formula VI; 
         
       
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is a group of the formula Y-1 
 
       
         
           
           
               
               
           
         
         wherein R 22  and R 23  are independently hydrogen, lower alkyl, lower alkoxy, cycloalkyl, aryl, arylalkyl, nitro, cyano, lower alkylthio, lower alkylsulfinyl, lower alkyl sulfonyl, lower alkanoyl, halogen, or perfluoro lower alkyl and at least one of R 22  and R 23  is other than hydrogen, and R 24  is hydrogen, lower alkyl, lower alkoxy, aryl, nitro, cyano, lower alkyl sulfonyl, or halogen; 
         or R 1  is a group of the formula Y-2, which is a five or six membered heteroaromatic ring bonded via a carbon atom to the amide carbonyl wherein said ring contains one, two or three heteroatoms selected from the group consisting of N, O and S and one or two atoms of said ring are independently substituted by lower alkyl, cycloalkyl, halogen, cyano, perfluoro lower alkyl, or aryl and at least one of said substituted atoms is adjacent to the carbon atom bonded to the amide carbonyl; 
         or R 1  is a group of the formula Y-3 which is a 3-7 membered ring of the formula: 
       
       
         
           
           
               
               
           
         
         wherein R 25  is lower alkyl, unsubstituted or fluorine substituted lower alkenyl, or a group of formula R 26 —(CH 2 ) e —, R 26  is aryl, heteroaryl, azido, cyano, hydroxy, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkanoyl, nitro, or R 26  is a group of formula —NR 28 R 29 , wherein R 28  is hydrogen or lower alkyl, R 29  is hydrogen, lower alkyl, lower alkoxycarbonyl, lower alkanoyl, aroyl, perfluoro lower alkanoylamino, lower alkyl sulfonyl, lower alkylaminocarbonyl, arylaminocarbonyl; or R 28  and R 29 , taken together with the attached nitrogen atom, form a 4, 5 or 6-membered saturated heterocyclic ring optionally containing one additional heteroatom selected from O, S, and N—R 40 , Q is —(CH 2 ) f O—, —(CH 2 ) f S—, —(CH 2 ) f N(R 27 )—, —(CH 2 ) f —, R 27  is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, R 40  is H, lower alkyl, aryl, lower alkanoyl, aroyl or lower alkoxycarbonyl, the carbon atoms in the ring are unsubstituted or substituted by lower alkyl or halogen, e is an integer from 0 to 4, and f is an integer from 0 to 3; R 2  is hydrogen, lower alkyl, substituted lower alkyl, aryl, or aryl lower alkyl; 
         R 3  is hydrogen, halogen, lower alkyl, trifluoromethyl, or aryl; R 4  is hydrogen, halogen, lower alkyl, or aryl; 
         R 5  is hydrogen, lower alkyl, lower alkoxy, or trifluoromethyl, or OH; 
         R 6  is hydrogen, lower alkyl, lower alkylcarbonyloxy lower alkyl, 
         or R 6  is a group of formula P-3: 
       
       
         
           
           
               
               
           
         
         wherein: R 32  is hydrogen or lower alkyl; R 33  is hydrogen, lower alkyl, aryl; R 34  is hydrogen or lower alkyl; 
         h is an integer from 0 to 2; 
         g is an integer from 0 to 2; the sum of h and g is 1 to 3; 
         or R 6  is a group of formula P-3: 
       
       
         
           
           
               
               
           
         
         wherein: R 32 , g, and h are as previously defined; Q′ is O, S, —(CH 2 )j-, or a group of the formula N—R 35 ; wherein R 35  is hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl; j is 0, 1 or 2; and 
         R 7  is hydrogen, chloro, lower alkoxy, or lower alkyl; and
 v) a compound, a pharmaceutically acceptable salt or ester of Formula VII; 
 
       
       
         
           
           
               
               
           
         
         wherein B is a bio-compatible polymer moiety optionally covalently attached to a branched-arm hub molecule; 
         q is from about 2 to about 100; 
         A at each occurrence is independently a compound of formula IIa 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 J is selected from:
 1) a group of formula (a): 
 
 
       
         
           
           
               
               
           
         
          wherein R 31  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 31  is —H, R 31′ , —NH 2 , —NHR 31′  or —N(R 31′ ) 2 , —NC 3 -C 6 cyclic, —OR 31′ , —SR 31′ , wherein each R 31′  is independently an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, 
          and R 32  is a covalent bond to the polymer moiety which optionally comprises a linker, or R 32  is —H, —NO 2 , haloalkyl or the group —N(MR 41 )R 42  wherein M is a covalent bond, —C(O)— or —SO 2 —, R 41  is R 41′ , N(R 41′ ) 2 , or —OR 41′ , 
          wherein each R 41′  is independently hydrogen, an optionally substituted straight or branched C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclic or an optionally substituted heteroaryl, wherein optional substitutions are halide, C 1 -C 6  alkyl, or —OC 1 -C 6 alkyl, 
          and R 42  is hydrogen or R 41′ ; and
 2) a group of formula (b): 
 
       
       
         
           
           
               
               
           
         
          wherein R is selected from the group consisting of a covalent bond to the polymer moiety, amino, hydroxyl, substituted amino, alkyl, alkyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, thiol, arylthio, heteroarylthio, heterocyclylthio and substituted alkyl wherein each amino, substituted amino, alkyl and substituted alkyl is optionally covalently bound to the polymer moiety wherein, in each case, the polymer moiety optionally comprises a linker which covalently links the polymer moiety; 
          Ar 1  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 1 ; 
          X is selected from the group consisting of —NR 1 —, —O—, —S—, —SO—, —SO 2  and optionally substituted —CH 2 — where R 1  is selected from the group consisting of hydrogen and alkyl; 
          m is an integer equal to 0, 1 or 2; and 
          n is an integer equal to 0, 1 or 2; 
         Ar 2  is selected from the group consisting of aryl, substituted aryl, heteroaryl and substituted heteroaryl wherein each of aryl, substituted aryl, heteroaryl and substituted heteroaryl is optionally covalently bound to the polymer moiety wherein the polymer moiety optionally comprises a linker which covalently links the polymer moiety to Ar 2 ; 
         T is selected from:
 1) a group of formula (c) 
 
       
       
         
           
           
               
               
           
         
         
           wherein Y is selected from the group consisting of —O— and —NR 1 — wherein R 1  is selected from the group consisting of hydrogen and alkyl; 
           W is selected from the group consisting of a covalent bond to a polymer moiety which optionally comprises a linker and —NR 2 R 3  wherein R 2  and R 3  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, and where R 2  and R 3 , together with the nitrogen atom bound thereto, form a heterocyclic ring or a substituted heterocyclic ring wherein each of alkyl, substituted alkyl, heterocyclic and substituted heterocyclic is optionally covalently bound to a polymer moiety which further optionally comprises a linker; and 
           2) a group of formula (d) 
         
       
       
         
           
           
               
               
           
         
         
           wherein G is an optionally substituted aryl or optionally substituted heteroaryl 5 or 6 membered ring containing 0 to 3 nitrogens, wherein said aryl or heteroary optionally further comprises a covalent bond to a polymer moiety which optionally comprises a linker; 
           R 6  is a covalent bond to a polymer moiety which optionally comprises a linker, or R 6  is —H, alkyl, substituted alkyl, or —CH 2 C(O)R 17 , wherein R 17  is —OH, —OR 18 , or —NHR 18 , wherein R 18  is alkyl, substituted alkyl, aryl or substituted aryl; 
         
         R 55  is selected from the group consisting of amino, substituted amino, alkoxy, substituted alkoxy, cycloalkoxy, substituted cycloalkoxy, aryloxy and substituted aryloxy, and —OH; and provided that: 
         a) at least one of R, Ar 1 , Ar 2 , and T contains a covalent bond to the polymer moiety; 
         b) when R is covalently bound to the polymer moiety, n is one and X is not —O—, —S—, —SO—, or —SO 2 —; 
         c) when X is —O— or —NR 1 —, then m is two; and 
         d) the conjugate of formula VII has a molecular weight of no more than 100,000. 
       
     
     
         111 . The method of  claim 110 , wherein the disease is chosen from multiple sclerosis, relapsing-remitting multiple sclerosis, secondary progressive multiple sclerosis, primary progressive multiple sclerosis, chronic progressive multiple sclerosis, inflammatory bowel disease, Crohn's Disease, and rheumatoid arthritis. 
     
     
         112 . The method of  claim 110 , wherein the monitoring comprises:
 a) serially removing samples of the patient's blood, measuring an amount of IgG antibodies to JC virus in the samples, and comparing the amount of the antibodies in the samples to each other; and/or   b) serially removing samples of the patient's blood, measuring an amount of IgM antibodies to JC virus in the samples, and comparing the amount of the IgM and IgG antibodies in the samples to each other.   
     
     
         113 . The method of  claim 112 , wherein the monitoring detects seroconversion and/or an increasing titer of JC virus in the patient's blood, and further comprises
 (a) removing a sample of the patient's cerebrospinal fluid when comparison of the blood samples detects seroconversion and/or an increasing titer of JC virus; and   (b) testing the cerebrospinal fluid for JC virus.   
     
     
         114 . The method of  claim 110 , wherein the monitoring further comprises testing for at least one symptom chosen from clinical and radiologic symptoms of progressive multifocal leukoencephalopathy. 
     
     
         115 . The method of  claim 114 , wherein the testing for clinical symptoms comprises testing for new or progressing neurological symptoms. 
     
     
         116 . The method of  claim 115 , wherein the neurological symptoms comprise one or more of central blindness, mental confusion, personality change, and dyskinesia. 
     
     
         117 . The method of  claim 114 , wherein the testing for radiologic symptoms comprises performing a Gd-enhanced magnetic resonance imaging scan. 
     
     
         118 . The method of  claim 110 , further comprising when at least one indicator of progressive multifocal leukoencephalopathy is present, providing antiviral therapy comprising administering at least one therapeutically effective dose of an antiviral agent selected from cytosine arabinoside (cytarabine), cidofovir, and a serotonin antagonist. 
     
     
         119 . The method of  claim 118 , wherein the serotonin antagonist is comprises 5HT2a antagonist. 
     
     
         120 . The method of  claim 110 , wherein the alpha-4 inhibitor compound is a monotherapy without an immunosuppressive or antineoplastic agent. 
     
     
         121 . The method of  claim 120 , wherein the immunosuppressive or antineoplastic agent is selected from one or more of chlorambucil, melphalan, 6-mercaptopurine, thiotepa, ifodfamide, dacarbazine, procarbazine, temozolomide, hexamethylmelamine, doxorubicine, daunarubicine, idarubicin, epirubicin, irinotecan, methotrexate, etoposide, vincristine, vinblastine, vinorelbine, cytarabine, busulfan, amonifide, 5-fluorouracil, topotecan, mustargen, bleomycin, lomustine, semustine, mitomycin C, mutamycin, cisplatin, carboplatin, oxaliplatin, methotrexate, trimetrexate, raltitrexid, fluororodeoxyuridine, capecitabine, ftorafur, 5-ethynyluracil, 6-thioguanine, cladribine, pentostatin, teniposide, mitoxantrone, losoxantrone, actinomycin D, vindesine, docetaxel, amifostine, interferon alpha, tamoxefen, medroxyprogesterone, megestrol, raloxifene, letrozole, anastrzole, flutamide, bicalutamide, retinoic acids, arsenic trioxide, rituximab, CAMPATH-1, mylotarg, mycophenolic acid, tacrolimus, glucocorticoids, sulfasalazine, glatiramer, fumarate, laquinimod, FTY-720, interferon tau, daclizumab, infliximab, IL10, anti-IL2 receptor antibody, anti-IL-12 antibody, anti-IL6 receptor antibody, CDP-571, adalimumab, entaneracept, leflunomide, anti-interferon gamma antibody, abatacept, fludarabine, cyclophosphamide, azathioprine, cyclosporine, intravenous immunoglobulin, 5-ASA (mesalamine), and a β-interferon. 
     
     
         122 . The method of  claim 119 , wherein the immunosuppressive agent comprises a β-interferon. 
     
     
         123 . The method of  claim 110 , wherein prior to the administering of step (A), removing a sample of blood from the patient; testing the serum or plasma of the sample for IgG antibodies to JC virus; and initiating the administering of step (A) if the sample is negative for IgG antibodies to JC virus. 
     
     
         124 . The method of  claim 110 , wherein prior to the administering of step (A), removing a sample of blood from the patient; testing the serum or plasma of the sample for IgG antibodies to JC virus; and initiating the administering of step (A) if the sample is positive for IgG antibodies to JC virus. 
     
     
         125 . The method of  claim 119 , further comprising educating a prescribing physician and the patient about mental and physical symptoms of progressive multifocal leukoencephalopathy and instructing the patient to report to the physician when at least one symptom is present.