Integrin expression inhibitors

Abstract

The present invention provides an integrin expression inhibitor, and an agent for treating arterial sclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, an anticoagulant, or a cancer metastasis suppressor on the basis of an integrin inhibitory action. Namely, it provides an integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the following formula (I), a pharmacologically acceptable salt thereof or a hydrate of them. In the formula, B means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated; K means a single bond, —CH═CH— or —(CR 4b R 5b ) m b — (wherein R 4b and R 5b are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m b means an integer of 1 or 2); R 1 means hydrogen atom or a C1-C6 alkyl group; Z means a single bond or —CO—NH—; and R means a C6-C10 aryl ring or 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated, respectively.

1 . 1) An agent for treating arterial sclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant, 3) a cancer metastasis suppressor or 4) an antiangiogenic agent on the basis of an integrin expression inhibitory action.  
     
     
         2 . 1) The agent for treating arterial sclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant, 3) a cancer metastasis suppressor or 4) an antiangiogenic agent on the basis of integrin expression inhibitory action as claimed in  claim 1 , wherein the integrin is integrin α2, α3, α5, α6, αv, β1, β3, β4, β5, α2β1, α3β1, α5β1, α6β1, αvβ1, αvβ3 or αvβ5.  
     
     
         3 . An integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the formula (I), a pharmacologically acceptable salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, B represents a C6-C10 aryl ring or a 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated; K represents a single bond, —CH═CH— or —(CR 4b R 5b ) m   b — (where R 4b  and R 5b  are the same as or different from each other and each represents hydrogen atom or a C1-C4 alkyl group; and m b  means an integer of 1 or 2); R 1  represents hydrogen atom or a C1-C6 alkyl group; Z represents a single bond or —CO—NH—; and R represents a C6-C10 aryl ring or a 6- to 10-membered heteroaryl ring which may have a substituent and in which a part of the ring may be saturated, respectively.  
       
     
     
         4 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in  claim 3 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein R is indole, quinoline or isoquinoline.  
     
     
         5 . An integrin expression inhibitor comprising, as an active ingredient, a sulfonamide compound represented by the formula (I a ), a pharmacologically acceptable salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, the A a  ring a monocyclic or bicyclic aromatic ring which may have a substituent; the B a  ring represents an optionally substituted 6-membered cyclic unsaturated hydrocarbon or unsaturated 6-membered heterocycle containing one nitrogen atom as a heteroatom; the C a  ring represents an optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atoms; R 1a  represents hydrogen atom or a C1-C6 alkyl group; W a  represents a single bond or —CH═CH—; Y a  represents carbon atom or nitrogen atom; and Z a  represents —N(R 2a )—(wherein R 2a  means hydrogen atom or a lower alkyl group) or nitrogen atom, respectively.  
       
     
     
         6 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in  claim 5 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein W a  is a single bond.  
     
     
         7 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in  claim 5 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein W a  is a single bond; Z a  is —NH—; and Y a  is carbon atom.  
     
     
         8 . The integrin expression inhibitor comprising, as an active ingredient, a the sulfonamide compound as claimed in any of claims  5 ,  6  and  7 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein the B a  ring is an optionally substituted benzene or pyridine.  
     
     
         9 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in any of  claims 5  to  8 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein the C a  ring is an optionally substituted pyrrole.  
     
     
         10 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in  claim 5 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein the A a  ring is a benzene or pyridine which may have a substituent; the B a  ring is benzene which may have a substituent; the C a  ring is pyrrole which may have a substituent; W a  is a single bond; and Z a  is —NH—.  
     
     
         11 . An integrin expression inhibitor comprising, as an active ingredient, a sulfonamide-containing heterocyclic compound represented by the formula (I b ), a pharmacologically acceptable salt thereof or a hydrate of them.  
       
         
           
           
               
               
           
         
         In the formula, A b  represents hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl or alkoxy group which may be substituted with a halogen atom, cyano group, —(CO) k   b NR 2b R 3b  (wherein R 2b  and R 3b  are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and k b  means 0 or 1), a C2-C4 alkenyl or alkynyl group which may have a substituent, or a phenyl or phenoxy group which may have a substituent selected from the following group A; B b  means an aryl group or monocyclic heteroaryl group which may have a substituent selected from the following group A, or the following formula:  
         
           
             
             
                 
                 
             
           
         
         (wherein the ring Q b  means an aromatic ring which may have one or two nitrogen atoms; and the ring M b  means a C5-C12 unsaturated monocycle or heterocycle having a double bond in common with the ring Q b . The ring may have 1 to 4 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom, the ring Q b  and the ring M b  may jointly have nitrogen atom, and the ring Q b  and the ring M b  may have a substituent selected from the following group A); K b  means a single bond or —(CR 4b R 5b )m b —(wherein R 4b  and R 5b  are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group; and m b  means an integer of 1 or 2); T b , W b , X b  and Y b  are the same as or different from each other and each means ═C(D b )—(wherein D b  represents hydrogen atom, a halogen atom, hydroxyl group, a C1-C4 alkyl or alkoxy group which may be substituted with a halogen atom, cyano group, —(CO) n   b NR 6b R 7b  (wherein R 6b  and R 7b  are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and n b  means 0 or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent, respectively) or nitrogen atom; U b  and V b  are the same as or different from each other and each means ═C(D b )—(wherein D b  has the same meaning as above), nitrogen atom, —CH 2 —, oxygen atom or —CO—; Z b  means a single bond or —CO—NH—; R 1b  means hydrogen atom or a C1-C4 alkyl group; and   means a single bond or a double bond.  
         Group A: a halogen atom, hydroxyl group, a C1-C4 alkyl or alkoxy group which may be substituted with a halogen atom, cyano group, —R 8b R 9b N(NH) p   b —(wherein R 8b  and R 9b  are the same as or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and p b  means 0 or 1. Further, R 8b  and R 9b  may form a 5- or 6-membered ring together with the nitrogen atom to which they are bound, and the ring may further contain nitrogen atom, oxygen atom or sulfur atom, and also may have a substituent.), an aminosulfonyl group which may be substituted with a mono- or di-C1-C4 alkyl group, a C1-C8 acyl group which may have a substituent, a C1-C4 alkyl-S(O) s   b —C1-C4 alkylene group (wherein s b  means an integer of 0, 1 or 2), a phenylsulfonylamino group which may have a C1-C4 alkyl or a substituent, —(CO) q   b NR 10b R 11b  (wherein R 10b  and R 11b  are the same as or different from each other and each means hydrogen atom, or a C1-C4 alkyl group which may substituted with an amino group which may be substituted with a halogen atom or a C1-C4 alkyl group; and q b  means 0 or 1), or an aryl group or heteroaryl group which may have a substituent.  
       
     
     
         12 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide-containing heterocyclic compound as claimed in  claim 11 , a pharmacologically acceptable salt thereof or a hydrogen of them, wherein U b  and V b  are ═C(D b )—(wherein D b  has the same meaning as above) or nitrogen atom.  
     
     
         13 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide-containing heterocyclic compound as claimed in  claim 11  or  12 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein Z b  is a single bond.  
     
     
         14 . An integrin expression inhibitor comprising, as an active ingredient, a sulfonamide-containing heterocyclic compound as claimed in any of  claims 11  to  13 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein at least one of T b , U b , V b , W b , X b  and Y b  is nitrogen atom.  
     
     
         15 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide-contain ng heterocyclic compound as claimed in any of  claims 11  to  14 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein A b  represents a halogen atom, a C1-C4 alkyl group or alkoxy group which may be substituted with a halogen atom, cyano group, —(CO) r   b NR 12b R 13b  (wherein R 12b  and R 13b  are the same as or different from each other and each represents hydrogen atom or a C1-C4 alkyl group which may be substituted with a halogen atom; and r b  means 0 or 1) or a C2-C4 alkenyl or alkynyl group which may have a substituent.  
     
     
         16 . An integrin expression inhibitor comprising, as an active ingredient the sulfonamide-containing heterocyclic compound as claimed in any of  claims 11  to  15 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein only one of T b , U b , V b , W b , X b  and Y b  is nitrogen atom.  
     
     
         17 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide-containing heterocyclic compound as claimed in any of  claims 11  to  16 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein only one of T b , W b  and Y b  is nitrogen atom.  
     
     
         18 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in any of  claims 5  to  17 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein the integrin is integrin α2, α3, Ε5, α6, αv, β1, β3, β4 or β5.  
     
     
         19 . An integrin expression inhibitor comprising, as an active ingredient, the sulfonamide compound as claimed in any of  claims 5  to  17 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein the integrin is integrin α2β1, α3β1, α5β1, α6β1, αvβ1, αvβ3 or αvβ5.  
     
     
         20 . 1) An agent for treating arterial sclerosis, psoriasis, cancer, retinal angiogensis, diabetic retinopathy or inflammatory diseases, 2) an anticoagulant, 3) a cancer metastasis suppressor or 4) an antiangiogenic agent on the basis of an integrin expression inhibitory action, which comprises, as an active ingredient, the sulfonamide compound as claimed in any of  claims 5  to  17 , a pharmacologically acceptable salt thereof or a hydrate of them.  
     
     
         21 . 1) An agent for treating arterial sclerosis, psoriasis or osteoporosis or 2) an anticoagulant on the basis of an integrin expression inhibitory action, which comprises, as an active ingredient, the sulfonamide compound as claimed in any of  claims 5  to  17 , a pharmacologically acceptable salt thereof or a hydrate of them.  
     
     
         22 . A method for preventing, treating or improving a disease against which an integrin expression inhibition is effective, by administering a pharmacologically effective dose of the compound as claimed in any of claims  3 ,  5  and  11 , a pharmacologically acceptable salt thereof or a hydrate of them to a patient.  
     
     
         23 . Use of the compound as claimed in any of claims  3 ,  5  and  11 , a pharmacologically acceptable salt of the compound or hydrate of them, for producing an agent for preventing, treating or improving a disease against which integrin expression inhibition is effective.