Substituted flavonoid compounds, their salts, their manufacture and their use in combination with interleukin-2

Abstract

The use of substituted flavonoid compounds which have the immunomodulatory activity of (1) boosting natural killer activity in vivo and (2) inducing interferon, and (3) belong to the family of flavonoids of the formula (I): <IMAGE> in conjunction with interleukin-2 in cancer therapy is disclosed.

What is claimed as new and desired to be secured by Letters Patent of the United States is: 
     
       1. A method for treating cancer in a patient in need thereof, comprising coadministering to said patient an effective amount of (i) interleukin-2 or a protein having the in vivo activity of interleukin-2, and (ii) at least one flavonoid compound which has the immunomodulatory activity of (iia) boosting natural activity and (iib) inducing interferon, and (iic) belongs to the family of flavonoids of the formula (I): ##STR147## wherein X is N, O, Se, or S(O) n , wherein n is 0, 1 or 2; R 1  is H; C 1-7  alkyl; naphthyl; phenyl; phenyl substituted by at least one member selected from the group consisting of halogens, C 1-12  alkyl, trifluoromethyl, hydroxyl, C 1-6  alkoxy, --C 1-6  -alkylene)COOR 10 , nitro, C 1-6  --alkyl)carboylamino, benzoyl, C 1-6  --alkyl)carboyl, CONR 10  R 11 , , where R 10  and R 11  are each independently H or C 1-6  alkyl, NR 10  R 11 , --N═N--NR 10  R 11 , phenyl substituted by at least one halogen atom, phenol, --O--C 1-6  alkylene--NR 10  R 11 , thiazolyl, and thiazolyl substituted by C 1-6  alkyl or amino; or R 1  is pyridyl; pyridyl substituted by at least one member selected from the group consisting of C 1-6  alkyls and halogens; trifluoromethyl; benzoyl or benzyl;   R 2  is H; phenyl; OH; C 1-3  alkyl; or C 1-3  alkoxy;   R 3  and R 4  are each, independently of each other, H; C 1-6  alkyl; OH; C 1-6  alkoxy; or halogen;   R 5  is H; C 1-3  alkyl; CN; or COOR 10     R 6  is H; C 1-6  alkyl; OH; --C 1-3  alkylene--CN; COOR 10  ; --O--CO--C 1-6  alkyl);   or R 5  and R 6  together are a group ═CR 10  R 11 , or a group ═NOH, or a group ═O or a group ═CHR 12 , where R 12  is phenyl, pyridyl, phenyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C 1-3  alkyls or pyridyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C 1-3  alkyls;   R 7  is H; CHO; COOR 10  ; CH 2  HC 2  COOR 10  ; --CH═CH--COOR 10  ; --P(O)(OR 10  R 11 ) 2  ; NR 13  R 14  (where R 13  and R 14  are independently H; phenyl; phenyl substituted by a halogen atom or a C 1-3  alkyl group or a group --COOR 10 , --CO--O--CH(CH 3 )--COOR 10 , morpholinyl, --C(CH 2  OH) 2  (CH 3 ), imidazolinyl, --C 1-6  alkylene--OH, --C 1-6  alkylene--COOR 10 , or C 1-3  alkoxy, or wherein R 13  and R 14  together with the nitrogen atom to which they are both bound form an imidazole or a N--C 1-3  alkyl)piperazinyl, or   R 7  is --CO(C 1-6  alkyl); --S--(C 1-6  alkyl); --SH; --S--CO--C 1-3  alkyl); --S--CH 2 ) m  COOR 10  (with 0<m≦6); --CO--O--C 1-6  alkylene)--NR 10  R 11  ; --O--C 1-6  alkylene--NR 10  R 11  ; --NR 10  NR 10  R 11  ; C 1-6  alkyl; --CONR 10  R 11  ; --CSNR 10  R 11  ; thiazolyl; thiazolyl substituted by at least one member selected from the group consistin of --NH 2 , C 1-3  alkyl, phenyl, and COOR 10  ; --NH--CO--C 1-3  -alkyl); or --C 1-3  -alkylene--CH(NH 2  (COOH); or   --CR 5  R 6  R 7  is a group of one of the formulae ##STR148## wherein Q is at least one member selected from the group consisting of H; COOR 10  ; phenyl; --O--C 1-3  -alkylene--COOR 10  ; C 1-3  alkyl; --O--CS--NR 10  R 11  ; --O--C 1-3  -alkylene--NR 10  R 11  ; OH; C 1-3  alkoxy; and NR 10  R 11  ; or wherein any two of R 3 , R 4 , R 5 , R 6  and R 7  together --C 1-3  --alkylene--COOR 10  ; --C 1-3  -alkyl--OH, COOR 10 , or --C 1-3  -form a benzene ring; or a benzene ring substituted by alkylene--O--CO--C 1-3  -alkyl); or a naphthalene system; or a naphthalene system substituted by --C 1-3  -alkylene--COOR 10 , --C 1-3  -alky--OH, COOR 10 , or --C 1-3  -alkylene--O--CO--C 1-3  -alkyl); and   physiologically acceptable salts thereof,   with the proviso that when --CR 5  R 6  R 7  is situated at the 8-position of formula (I) and X is O, (i) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is CN, R 1  is other than phenyl, 2-thenyl, 3,4-dimethoxy phenyl, 3-methoxy phenyl, para-tolyl, 2-furyl, 2-naphthyl, 4-methoxy phenyl, benzyl, methyl, or cyclohexyl;   (ii) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is COOH, R 1  is other than phenyl, 2-thenyl, 3-methoxy phenyl, 3,4-dimethoxy phenyl, 2-furyl, para-tolyl, 2-naphthyl, 4-methoxy phenyl, cyclohexyl, benzyl, or methyl;   (iii) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--CH 2  CH 2  --N(C 2  H 5 ) 2 , R 1  is other than phenyl, 2-thenyl, para-tolyl, or 4-methoxy phenyl;   (iv) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is ##STR149##  R 1  is other than phenyl; (v) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--CH 2  -- 3  N(CH 3 ) 2 , R 7  is other than phenyl;   (vi) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--C 2  H 5 , R 1  is other than phenyl;   (vii) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--CH 3 , R 1  is other than phenyl or 2-thenyl;   (viii) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--Na, R 1  is other than phenyl;   (ix) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--O--CH 2  CH 2  OH, R 1  is other than phenyl;   (x) when R 2 , R 3 , R 4 , R 5  and R 6  are all H and R 7  is --CO--NH--CH 2  CH 2  N(C 2  H 5 ) 2 , R 1  is other than phenyl;   (xi) when R 2 , R 4 , R 5  and R 6  are all H, R 3  is methyl at the 6-position of formula (I) (6-CH 3 ) and R 7  is COOH, R 1  is other than phenyl;   (xii) when R 2 , R 4 , R 5  and R 6  are all H, R 3  is 6-CH 3  and R 7  is COOH 3 , R 1  is other than phenyl;   (xiii) when R 2 , R 4 , R 5  and R 6  are all H, R 3  is 6-CH 3  or 6-OCH 3  and R 7  is --CO--O--CH 2  CH 2  --N(CH 2  H 5 ) 2 , R 1  is other than phenyl;   (xiv) when R 2  and R 3  are H, R 4  is H or 6-CH 3 , R 5  is methyl, R 6  is --COOC 2  H 5 , and R 7  is --COOC 2  H 5 , R 1  is other than phenyl;   (xv) when R 2  and R 3  are H, R 4  is H or 6--CH 3 , R 5  is H, R 6  is CH 3  and R 7  is COOH, R 1  is other than phenyl;   (xvi) when R 2 , R 3 , R 4  and R 5  are all H, R 6  is CH 3  and R 7  is --CO--O--CH 2  CH 2  N(C 2  H 5 ) 2 , R 1  is other than phenyl;   (xvii) when R 2 , R 3 , R 4  and R 7  are all H, R 5  and R 6  are ═O, R 1  is other than phenyl;   (xviii) when R 2 , R 3 , R 4 , and R 5  are all H and --CR 5  R 6  R 7  is --CH═CH--COOH, --CH═CH--COOCH 2  CH 2  N(C 2  H 5 ) 2 , ##STR150##  --CH 2  CH(COOC 2  H 5 ) 2 , or --CH 2  CH 2  COOH, R 1  is other than phenyl;   (xix) when R 2  and R 3  are both H, R 4  is 6-CH 3  or 6-OCH 3 , R 6  and R 7  are H and R 5  is CN, R 1  is other than phenyl; (xx) when R 2  and R 3  are H, R 4  is 6-OCH 3  or 6-OH, and R 5  and R 6  are H and R 7  is COOH, R 1  is other than phenyl;   (xxi) when R 2  is phenyl, R 3  and R 4  are H, R 5  and R 6  are ═O, or R 6  is CN or COOH, R 1  is other than phenyl.       
     
     
       2. The method of claim 1, wherein R 7  is --CHO, --COOR 10 , P(O)(OR 10  R 11 ) 2 , --CH 2  CH 2  COOR 10  or --CONR 10  R 11 . 
     
     
       3. A method for treating cancer in a patient in need thereof, comprising coadministering to said patient an effective amount of (i) interleukin-2 or a protein having the in vivo activity of interleukin-2, and (ii) a flavonoid compound which is at least one member selected from the group consisting of ##STR151## 
     
     
       4. A method for treating cancer in a patient in need thereof, comprising coadministering to said patient an effective amount of (i) interleukin-2 or a protein having the in vivo activity of interleukin-2, and (ii) at least one flavonoid compound which has the immunolodulatory activity of (iia) boosting natural activity and (iib) inducing interferon, wherein said flavonoid compound belongs to the family of flavonoids of the formula (II): ##STR152## wherein: X is N, O, Se, or S(O) n , wherein n is 0, 1 or 2; R 1  is methyl, phenyl, or substituted phenyl, biphenyl, or trifluoromethyl;   R 2  is hydrogen, OH; or   R 1  and R 2  together form a naphthalene system fused to the flavonoid nucleus;   R 3  and R 4  are hydrogen, C 1-6  -alkyl, C 1-6  alkoxyhydroxyl, halogen; or   R 3  and R 4  together form a benzene system fused to the flavonoid nucleus;   R 15  is hydrogen when R 16  is a carboxylic radical, a carboamyl radical, a mercapto radical, a carboxymethythio radical, an aminoether radical, a phosphonic group, a substituted hydrazine group, an amino group, a substituted amino group, a lower alkyl group, a group --CONHR 17  or --CSNHR 18 , where R 17  and R 18  are C 1-6  alkyl, an oximino group, a substituted thiazolyl group, or a group --NR 19  R 20 ,   where R 19  and R 20  are independently hydrogen, an aromatic group, a substituted aromatic group, a C 1-6  hydroxyalkyl group, a carboxymethylene group, or R 19  and R 20  together form imidazolyl or N-methyl-piperazinyl; or   when R 15  is R--CH═, R 1  is hydrogen, phenyl, 3-pyridyl or 4-pyridyl and R 16  is COOH; or   R 15  and R 16  together are a tetronic moiety substituted tetronic moiety of the formula: ##STR153## when R 16  is ═O, R 15  is COOH, --CHCOOH, --CH 3 , --CH 3 , --CH 2  Br or --CH═CHAr, with Ar being H, phenyl, 3-pyridyl or 4-pyridyl; or   R 15  and R 16  together are indolizinyl, imidazo[2,1-b] thiazolyl, imidazo[1,2-a]pyridino, tetrahydropyrane which is substituted or a cyclic lactonic moiety; or   when R 4  and R 15  together form a benzene system, R 16  is --COOH or --CH 2  COOH; or   when R 1  and R 2  together form a naphthalene system, R 15  is H and R 16  is --COOH; or   when R 3  and R 4  form a benzene system, R 15  is H and R 16  COOH; or   when R 15  hydroxyl, R 16  is --COOH or --CH 2  CH 2  COOH; or   when R 15  is ═O, R 16  is --COOh, --CH 2  CH 2  COOH or --CH═CHCOOH.   
     
     
       5. A method for treating cancer in a patient in need thereof, comprising coadministering to said patient an effective amount of (i) interleukin-2 or a protein having the in vivo acitivity of interleukin-2, and (ii) at least one flavonoid compound which as the immunomodulatory activity of (iia) boosting natural activity and (iib) inducing interferon, wherein said flavonoid compound belongs to the family of flavonoinds of the formula (IV): ##STR154## wherein: AR 26  is phenyl, substituted phenyl, biphenyl, pyridyl, or trifluoromethyl R 2  is hydrogen, hydroxyl, or C 1-3  alkoxy;   R 22  is hydrogen, hydroxyl, or C 1-6  alkoxy;   R 23  is hydrogen or fluoro;   R 24  is hydrogen or hydroxy;   R 25  is hydrogen, 2-methylpyridyl, benzylidene, 4-methylenepyridyl or methylene; or   R 22  and R 23  together form a benzene ring fused to the flavonoid nucleus; or   R 23  and R 24  together form a benzene ring fused to the flavonoid nucleus; or   R 25  and R 24  together form a benzene ring fused to the flavonoid nucleus.