Claims
- 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).sub.n, wherein n is 0, 1 or 2;
- R.sub.1 is H; C.sub.1-7 alkyl; naphthyl; phenyl; phenyl substituted by at least one member selected from the group consisting of halogens, C.sub.1-12 alkyl, trifluoromethyl, hydroxyl, C.sub.1-6 alkoxy, --C.sub.1-6 -alkylene)COOR.sub.10, nitro, C.sub.1-6 --alkyl)carboylamino, benzoyl, C.sub.1-6 --alkyl)carboyl, CONR.sub.10 R.sub.11, , where R.sub.10 and R.sub.11 are each independently H or C.sub.1-6 alkyl, NR.sub.10 R.sub.11, --N.dbd.N--NR.sub.10 R.sub.11, phenyl substituted by at least one halogen atom, phenol, --O--C.sub.1-6 alkylene--NR.sub.10 R.sub.11, thiazolyl, and thiazolyl substituted by C.sub.1-6 alkyl or amino; or R.sub.1 is pyridyl; pyridyl substituted by at least one member selected from the group consisting of C.sub.1-6 alkyls and halogens; trifluoromethyl; benzoyl or benzyl;
- R.sub.2 is H; phenyl; OH; C.sub.1-3 alkyl; or C.sub.1-3 alkoxy;
- R.sub.3 and R.sub.4 are each, independently of each other, H; C.sub.1-6 alkyl; OH; C.sub.1-6 alkoxy; or halogen;
- R.sub.5 is H; C.sub.1-3 alkyl; CN; or COOR.sub.10
- R.sub.6 is H; C.sub.1-6 alkyl; OH; --C.sub.1-3 alkylene--CN; COOR.sub.10 ; --O--CO--C.sub.1-6 alkyl);
- or R.sub.5 and R.sub.6 together are a group .dbd.CR.sub.10 R.sub.11, or a group .dbd.NOH, or a group .dbd.O or a group .dbd.CHR.sub.12, where R.sub.12 is phenyl, pyridyl, phenyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C.sub.1-3 alkyls or pyridyl substituted by at least one member selected from the group consisting of halogen atoms, trifluoromethyl and C.sub.1-3 alkyls;
- R.sub.7 is H; CHO; COOR.sub.10 ; CH.sub.2 HC.sub.2 COOR.sub.10 ; --CH.dbd.CH--COOR.sub.10 ; --P(O)(OR.sub.10 R.sub.11).sub.2 ; NR.sub.13 R.sub.14 (where R.sub.13 and R.sub.14 are independently H; phenyl; phenyl substituted by a halogen atom or a C.sub.1-3 alkyl group or a group --COOR.sub.10, --CO--O--CH(CH.sub.3)--COOR.sub.10, morpholinyl, --C(CH.sub.2 OH).sub.2 (CH.sub.3), imidazolinyl, --C.sub.1-6 alkylene--OH, --C.sub.1-6 alkylene--COOR.sub.10, or C.sub.1-3 alkoxy, or wherein R.sub.13 and R.sub.14 together with the nitrogen atom to which they are both bound form an imidazole or a N--C.sub.1-3 alkyl)piperazinyl, or
- R.sub.7 is --CO(C.sub.1-6 alkyl); --S--(C.sub.1-6 alkyl); --SH; --S--CO--C.sub.1-3 alkyl); --S--CH.sub.2).sub.m COOR.sub.10 (with 0<m.ltoreq.6); --CO--O--C.sub.1-6 alkylene)--NR.sub.10 R.sub.11 ; --O--C.sub.1-6 alkylene--NR.sub.10 R.sub.11 ; --NR.sub.10 NR.sub.10 R.sub.11 ; C.sub.1-6 alkyl; --CONR.sub.10 R.sub.11 ; --CSNR.sub.10 R.sub.11 ; thiazolyl; thiazolyl substituted by at least one member selected from the group consistin of --NH.sub.2, C.sub.1-3 alkyl, phenyl, and COOR.sub.10 ; --NH--CO--C.sub.1-3 -alkyl); or --C.sub.1-3 -alkylene--CH(NH.sub.2 (COOH); or
- --CR.sub.5 R.sub.6 R.sub.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.sub.10 ; phenyl; --O--C.sub.1-3 -alkylene--COOR.sub.10 ; C.sub.1-3 alkyl; --O--CS--NR.sub.10 R.sub.11 ; --O--C.sub.1-3 -alkylene--NR.sub.10 R.sub.11 ; OH; C.sub.1-3 alkoxy; and NR.sub.10 R.sub.11 ; or
- wherein any two of R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 together --C.sub.1-3 --alkylene--COOR.sub.10 ; --C.sub.1-3 -alkyl--OH, COOR.sub.10, or --C.sub.1-3 -form a benzene ring; or a benzene ring substituted by alkylene--O--CO--C.sub.1-3 -alkyl); or a naphthalene system; or a naphthalene system substituted by --C.sub.1-3 -alkylene--COOR.sub.10, --C.sub.1-3 -alky--OH, COOR.sub.10, or --C.sub.1-3 -alkylene--O--CO--C.sub.1-3 -alkyl); and
- physiologically acceptable salts thereof,
- with the proviso that when --CR.sub.5 R.sub.6 R.sub.7 is situated at the 8-position of formula (I) and X is O,
- (i) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is CN, R.sub.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.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is COOH, R.sub.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.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--CH.sub.2 CH.sub.2 --N(C.sub.2 H.sub.5).sub.2, R.sub.1 is other than phenyl, 2-thenyl, para-tolyl, or 4-methoxy phenyl;
- (iv) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is ##STR149## R.sub.1 is other than phenyl; (v) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--CH.sub.2 --.sub.3 N(CH.sub.3).sub.2, R.sub.7 is other than phenyl;
- (vi) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--C.sub.2 H.sub.5, R.sub.1 is other than phenyl;
- (vii) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--CH.sub.3, R.sub.1 is other than phenyl or 2-thenyl;
- (viii) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--Na, R.sub.1 is other than phenyl;
- (ix) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--O--CH.sub.2 CH.sub.2 OH, R.sub.1 is other than phenyl;
- (x) when R.sub.2, R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are all H and R.sub.7 is --CO--NH--CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2, R.sub.1 is other than phenyl;
- (xi) when R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are all H, R.sub.3 is methyl at the 6-position of formula (I) (6-CH.sub.3) and R.sub.7 is COOH, R.sub.1 is other than phenyl;
- (xii) when R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are all H, R.sub.3 is 6-CH.sub.3 and R.sub.7 is COOH.sub.3, R.sub.1 is other than phenyl;
- (xiii) when R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are all H, R.sub.3 is 6-CH.sub.3 or 6-OCH.sub.3 and R.sub.7 is --CO--O--CH.sub.2 CH.sub.2 --N(CH.sub.2 H.sub.5).sub.2, R.sub.1 is other than phenyl;
- (xiv) when R.sub.2 and R.sub.3 are H, R.sub.4 is H or 6-CH.sub.3, R.sub.5 is methyl, R.sub.6 is --COOC.sub.2 H.sub.5, and R.sub.7 is --COOC.sub.2 H.sub.5, R.sub.1 is other than phenyl;
- (xv) when R.sub.2 and R.sub.3 are H, R.sub.4 is H or 6--CH.sub.3, R.sub.5 is H, R.sub.6 is CH.sub.3 and R.sub.7 is COOH, R.sub.1 is other than phenyl;
- (xvi) when R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are all H, R.sub.6 is CH.sub.3 and R.sub.7 is --CO--O--CH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2, R.sub.1 is other than phenyl;
- (xvii) when R.sub.2, R.sub.3, R.sub.4 and R.sub.7 are all H, R.sub.5 and R.sub.6 are .dbd.O, R.sub.1 is other than phenyl;
- (xviii) when R.sub.2, R.sub.3, R.sub.4, and R.sub.5 are all H and --CR.sub.5 R.sub.6 R.sub.7 is --CH.dbd.CH--COOH, --CH.dbd.CH--COOCH.sub.2 CH.sub.2 N(C.sub.2 H.sub.5).sub.2, ##STR150## --CH.sub.2 CH(COOC.sub.2 H.sub.5).sub.2, or --CH.sub.2 CH.sub.2 COOH, R.sub.1 is other than phenyl;
- (xix) when R.sub.2 and R.sub.3 are both H, R.sub.4 is 6-CH.sub.3 or 6-OCH.sub.3, R.sub.6 and R.sub.7 are H and R.sub.5 is CN, R.sub.1 is other than phenyl; (xx) when R.sub.2 and R.sub.3 are H, R.sub.4 is 6-OCH.sub.3 or 6-OH, and R.sub.5 and R.sub.6 are H and R.sub.7 is COOH, R.sub.1 is other than phenyl;
- (xxi) when R.sub.2 is phenyl, R.sub.3 and R.sub.4 are H, R.sub.5 and R.sub.6 are .dbd.O, or R.sub.6 is CN or COOH, R.sub.1 is other than phenyl.
- 2. The method of claim 1, wherein R.sub.7 is --CHO, --COOR.sub.10, P(O)(OR.sub.10 R.sub.11).sub.2, --CH.sub.2 CH.sub.2 COOR.sub.10 or --CONR.sub.10 R.sub.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).sub.n, wherein n is 0, 1 or 2;
- R.sub.1 is methyl, phenyl, or substituted phenyl, biphenyl, or trifluoromethyl;
- R.sub.2 is hydrogen, OH; or
- R.sub.1 and R.sub.2 together form a naphthalene system fused to the flavonoid nucleus;
- R.sub.3 and R.sub.4 are hydrogen, C.sub.1-6 -alkyl, C.sub.1-6 alkoxyhydroxyl, halogen; or
- R.sub.3 and R.sub.4 together form a benzene system fused to the flavonoid nucleus;
- R.sub.15 is hydrogen when R.sub.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.sub.17 or --CSNHR.sub.18, where R.sub.17 and R.sub.18 are C.sub.1-6 alkyl, an oximino group, a substituted thiazolyl group, or a group --NR.sub.19 R.sub.20,
- where R.sub.19 and R.sub.20 are independently hydrogen, an aromatic group, a substituted aromatic group, a C.sub.1-6 hydroxyalkyl group, a carboxymethylene group, or R.sub.19 and R.sub.20 together form imidazolyl or N-methyl-piperazinyl; or
- when R.sub.15 is R--CH.dbd., R.sub.1 is hydrogen, phenyl, 3-pyridyl or 4-pyridyl and R.sub.16 is COOH; or
- R.sub.15 and R.sub.16 together are a tetronic moiety substituted tetronic moiety of the formula: ##STR153## when R.sub.16 is .dbd.O, R.sub.15 is COOH, --CHCOOH, --CH.sub.3, --CH.sub.3, --CH.sub.2 Br or --CH.dbd.CHAr, with Ar being H, phenyl, 3-pyridyl or 4-pyridyl; or
- R.sub.15 and R.sub.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.sub.4 and R.sub.15 together form a benzene system, R.sub.16 is --COOH or --CH.sub.2 COOH; or
- when R.sub.1 and R.sub.2 together form a naphthalene system, R.sub.15 is H and R.sub.16 is --COOH; or
- when R.sub.3 and R.sub.4 form a benzene system, R.sub.15 is H and R.sub.16 COOH; or
- when R.sub.15 hydroxyl, R.sub.16 is --COOH or --CH.sub.2 CH.sub.2 COOH; or
- when R.sub.15 is .dbd.O, R.sub.16 is --COOh, --CH.sub.2 CH.sub.2 COOH or --CH.dbd.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.sub.26 is phenyl, substituted phenyl, biphenyl, pyridyl, or trifluoromethyl
- R.sub.2 is hydrogen, hydroxyl, or C.sub.1-3 alkoxy;
- R.sub.22 is hydrogen, hydroxyl, or C.sub.1-6 alkoxy;
- R.sub.23 is hydrogen or fluoro;
- R.sub.24 is hydrogen or hydroxy;
- R.sub.25 is hydrogen, 2-methylpyridyl, benzylidene, 4-methylenepyridyl or methylene; or
- R.sub.22 and R.sub.23 together form a benzene ring fused to the flavonoid nucleus; or
- R.sub.23 and R.sub.24 together form a benzene ring fused to the flavonoid nucleus; or
- R.sub.25 and R.sub.24 together form a benzene ring fused to the flavonoid nucleus.
Parent Case Info
This application is a continuation of application Ser. No. 07/233,423, filed on Aug. 18, 1988, now abandoned, which is a continuation-in-part of Ser. No. 07/178,315, filed on Apr. 6, 1988, now abandoned.
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Continuations (1)
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Continuation in Parts (1)
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