Claims
- 1. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula: ##STR9## or a pharmaceutically acceptable salt, ester, amide or prodrug thereof wherein the ester is selected from C.sub.1 -to-C.sub.6 alkyl esters, C.sub.5 -to-C.sub.7 cycloalkyl esters and arylalkyl esters and wherein the amide results from reaction of a carboxylic acid moiety in the compound of formula I with NH.sub.3, NH.sub.2 (C.sub.1 -to-C.sub.6 alkyl), NH(C.sub.1 -to-C.sub.6 alkyl).sub.2 or a 5- or 6-membered heterocycle containing one nitrogen atom and wherein the prodrug is selected from the group consisting of (a) acyloxymethyl esters of carboxylic acids, (b) (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters of carboxylic acids, (c) esters derived from alcohol groups in the parent drug by reaction with succinic acid, phosphoric acid, dialkylaminoacetic acid or an amino acid (d) N-Mannich bases of amides or amines, (e) N-hydroxymethyl derivatives of amides, (f) N-acyloxyalkyl derivatives of amides or heterocyclic amines, (g) oxazolidinones derived from ketone groups in the parent drug by reaction with 2-aminoethanol, N-methyl-2-aminoethanol, N-(2-hydroxyethyl)-2-aminoethanol, 2-aminopropanol, 2-amino-2-methylpropanol, 2-amino-2-hydroxymethylpropanol, 3-amino-2-hydroxypropane, 2-amino-1-phenylethanol, 3-aminopropanol or N-methyl-2-amino-1-phenylpropanol and (h) enol esters derived from ketone groups in the parent drug, wherein
- R.sup.100 is selected from the group consisting of hydrogen, hydroxy, halogen and --OR.sup.8 wherein R.sup.8 is defined as herein;
- R.sup.101 is selected from the group consisting of methyl, ethyl, allyl and propyl;
- R.sup.102 is hydrogen and R.sup.103 is selected from the group consisting of (a) hydrogen, (b) hydroxy, and (c) hydroxy protected by a hydroxy-protecting group selected from dimethylthexylsilyl, tri(C.sub.1 -to-C.sub.8 -alkyl)silyl, C.sub.1 -to-C.sub.12 -alkyldiarylsilyl, triarylsilyl, tri(aryl-C.sub.1 -to-C.sub.12 -alkyl)silyl trimethylsilylethoxycarbonyl, methylthiomethoxyethoxycarbonyl, benzenesulfonylethoxycarbonyl and trimethylsilylethoxymethyl or, taken together, R.sup.102 and R.sup.103 form a bond; and
- one of R.sup.104 and R.sup.105 is hydrogen, and the other of R.sup.104 and R.sup.105 is a radical having the formula ##STR10## where Z is a divalent radical selected from the group consisting of ##STR11## --(C.sub.2 -to-C.sub.8 alkylidene)-- and --(C.sub.2 -to-C.sub.4 alkylidene)--Q--(C.sub.2 -to-C.sub.4 alkylidene)-- where each such radical is optionally substituted with between one and three radicals independently selected from the group consisting of --OR.sup.8, --S(O).sub.s R.sup.8, --S(O).sub.2 NR.sup.8 R.sup.8', --NR.sup.8 R.sup.8', --SO.sup.3 H, .dbd.NOR.sup.8, --R.sup.399 and --R.sup.400 wherein --Q--, R.sup.8, s, R.sup.8', R.sup.399 and R.sup.400 are defined as herein;
- R.sup.1, R.sup.6 and R.sup.7 in the above are independently selected from the group consisting of (i) hydrogen; (ii) --C(.dbd.NH)NH.sub.2 ; (iii) aryl substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are as defined herein; (iv) heterocyclic substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are defined as herein; and (v) alkyl having j carbon atoms where j is an integer between 1 and 10, inclusive, substituted with between zero and 5 but no more than j radicals independently selected from the group consisting of --OR.sup.8, --S(O).sub.s R.sup.8 where s is an integer between zero and two, inclusive, --S(O).sub.2 NR.sup.8 R.sup.8', --NR.sup.8 R.sup.8', --SO.sub.3 H, .dbd.NOR.sup.8, --R.sup.399 and --R.sup.400 wherein R.sup.8, R.sup.8', R.sup.399 and R.sup.400 are defined as herein;
- R.sup.2 and R.sup.3 are independently selected from the group consisting of (i) hydrogen, (ii) C.sub.1 -to-C.sub.8 -loweralkyl, (iii) hydroxy-C.sub.1 -to-C.sub.12 -alkyl, (iv) --COOH, (v) --COO--(C.sub.1 -to-C.sub.8 -loweralkyl), (vi) aminoalkyl of the formula (NR.sup.403 R.sup.404)-C.sub.1 -to-C.sub.8 -loweralkyl wherein R.sup.403 and R.sup.404 are independently selected from hydrogen, C.sub.1 -to-C.sub.8 -loweralkyl, aryl and aryl-C.sub.1 -to-C.sub.12 -alkyl or, taken together, R.sup.403 and R.sup.404 are --(CH.sub.2).sub.bb -- where bb is 2 to 6, (vii) aryl-C.sub.1 -to-C.sub.12 -alkyl and (viii) carboxy-C.sub.1 -to-C.sub.12 -alkyl, or, taken together, R.sup.2 and R.sup.3 form an oxo group, subject to the proviso that at least one of R.sup.2 and R.sup.3 must be other than --COOH or --COO--(C.sub.1 -to-C.sub.8 -loweralkyl);
- R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen, hydroxy, amino, mono-(C.sub.1 -to-C.sub.12 -alkyl)amino, C.sub.1 -to-C.sub.8 -loweralkyl, hydroxy-C.sub.1 -to-C.sub.12 -alkyl, --COOH, --COO--(C.sub.1 -to-C.sub.8 -loweralkyl), aminoalkyl independently as defined above, dialkylamino of the formula --N(C.sub.1 -to-C.sub.8 -loweralkyl)(C.sub.1 -to-C.sub.8 -loweralkyl), aryl-C.sub.1 -to-C.sub.12 -alkyl, and carboxy-C.sub.1 -to-C.sub.12 -alkyl, or, taken together, R.sup.4 and R.sup.5 form an oxo group, subject to the provisos that (i) at least one of R.sup.4 and R.sup.5 must be other than --COOH or --COO--(C.sub.1 -C.sub.8 -loweralkyl) and (ii) at least one of R.sup.4 and R.sup.5 must be other than hydroxy, amino, mono-(C.sub.1 -C.sub.12 -alkyl)amino or dialkylamino independently as defined above;
- n is an integer between zero and five, inclusive;
- R.sup.399 is selected from the group consisting of
- (i) hydroxy;
- (ii) --C(O)OH;
- (iii) --C(O)OR.sup.8 wherein R.sup.8 is defined as herein;
- (iv) --(C.sub.3 -to-C.sub.7 cycloalkyl);
- (v) oxo;
- (vi) thiooxo;
- (vii) epoxy;
- (viii) halogen;
- (ix) --CN;
- (x) --N.sub.3 ;
- (xi) --NO.sub.2 ;
- (xii) --OR.sup.11' wherein R.sup.11' is defined as herein;
- (xiii) --OR.sup.12' wherein R.sup.12' is defined as herein;
- (xiv) --OR.sup.12 -- wherein R.sup.12" is defined as herein; and
- (xv) guanidino substituted by a radical selected from the group consisting of hydrogen, C.sub.1 -C.sub.8 -loweralkyl, aryl, C.sub.1 -C.sub.12 -alkyl-C(O)-- or aryl--C(O)--, arylsulfonyl, C.sub.1 -C.sub.8 -alkoxycarbonyl, aryl-C.sub.1 -C.sub.8 -alkoxycarbonyl, aryloxycarbonyl and C.sub.1 -C.sub.12 -alkylsulfonyl;
- R.sup.400 is selected from the group consisting of
- (i) aryl substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (ii) --Q--aryl where aryl is substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (iii) heterocyclic substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (iv) --Q--heterocyclic where heterocyclic is substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (v) biaryl substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (vi) --Q--biaryl where biaryl is substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (vii) --aryl--Q--aryl where each aryl group is independently substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (viii) --aryl--Q--heterocyclic where heterocyclic and aryl are independently substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (ix) --heterocyclic--Q--aryl where heterocyclic and aryl are independently substituted by R.sup.301, R.sup.302 and R.sup.303 ;
- (x) --heterocyclic--aryl where heterocyclic and aryl are independently substituted by R.sup.301, R.sup.302 and R.sup.303 ; and
- (xi) --aryl--heterocyclic where heterocyclic and aryl are independently substituted by R.sup.301, R.sup.302 and R.sup.303
- wherein at each occurrence, R.sup.301, R.sup.302 and R.sup.303 are defined as herein,
- where --Q-- is a divalent radical selected from the group consisting of
- (i) --(C.sub.1 -to-C.sub.6 alkyl)--,
- (ii) --(C.sub.2 -to-C.sub.6 alkenyl)--,
- (iii) --(C.sub.2 -to-C.sub.6 alkynyl)--,
- (iv) --(CH.sub.2).sub.m" O-- where m" is between zero and six, inclusive,
- (v) --O(CH.sub.2).sub.m" -- where m" is defined as above,
- (vi) --N(R.sup.8)C(O)-- wherein R.sup.8 is defined as herein,
- (vii) --C(O)N(R.sup.8)-- wherein R.sup.8 is defined as herein,
- (viii) --S(O).sub.s -- wherein s is defined as above,
- (ix) --N(R.sup.8)-- wherein R.sup.8 is defined as herein,
- (x) --N(R.sup.8)S(O).sub.2 -- wherein R.sup.8 is defined as herein,
- (xi) --S(O).sub.2 N(R.sup.8)-- wherein R.sup.8 is defined as herein,
- (xii) --C(O)--,
- (xiii) --NN--,
- (xiv) --CHN,
- (xv) --NCH--,
- (xvi) --ONCH--, and
- (xvii) --CHNO--;
- R.sup.8 and R.sup.8' are independently selected from the group consisting of
- (i) hydrogen;
- (ii) aryl substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are defined as herein;
- (iii) heterocyclic substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are defined as herein,
- (iv) --(C.sub.1 -to-C.sub.6 alkyl) substituted by R.sup.331, R.sup.332 and R.sup.333 wherein R.sup.331, R.sup.332 and R.sup.333 are defined as herein;
- (v) --(C.sub.3 -to-C.sub.6 alkenyl) substituted by R.sup.331, R.sup.332 and R.sup.333 wherein R.sup.331, R.sup.332 and R.sup.333 are defined as herein; and
- (vi) --(C.sub.3 -to-C.sub.6 alkynyl) substituted by R.sup.331, R.sup.332 and R.sup.333 wherein R.sup.331, R.sup.332 and R.sup.333 are defined as herein;
- R.sup.331, R.sup.332 and R.sup.333 are independently selected from the group consisting of
- (A) hydrogen,
- (A') halogen,
- (B) hydroxy,
- (C) mono-(C.sub.1 -to-C.sub.12 -alkyl)amino or dialkylamino independently as defined above,
- (D) carboxyl,
- (E) carboxamido of the formula --C(O)NH.sub.2,
- (F) thiol,
- (G) C.sub.1 -to-C.sub.8 -alkylthioether,
- (H) C.sub.1 -to-C.sub.8 -alkylether,
- (I) guanidino,
- (J) C.sub.1 -to-C.sub.8 -alkoxycarbonyl,
- (K) aryl-C.sub.1 -to-C.sub.12 -alkoxycarbonyl,
- (L) C.sub.1 -to-C.sub.8 -alkoxycarbonylamino,
- (M) acyl independently as defined above,
- (N) aryl-C.sub.1 -to-C.sub.12 -alkoxycarbonylamino,
- (O) aryloxycarbonylamino,
- (P) acylguanidino wherein acyl is independently as defined above,
- (Q) arylsulfonylguanidino,
- (R) C.sub.1 -to-C.sub.8 -alkoxycarbonylguanidino,
- (S) amino,
- (T) aryl-C.sub.1 -to-C.sub.12 -alkoxycarbonylguanidino,
- (U) aryloxycarbonylguanidino,
- (V) N-alkylcarboxamido of the formula --C(O)NH(C.sub.1 -to-C.sub.12 -alkyl),
- (X) N,N-dialkylcarboxamido of the formula --C(O)N(C.sub.1 -to-C.sub.12 -alkyl)(C.sub.1 -to-C.sub.12 -alkyl),
- (Y) N-arylcarboxamido,
- (Z) N,N-diarylcarboxamido,
- (AA) --OSO.sub.2 R.sup.11 where R.sup.11 is defined as herein,
- (BB) oxo,
- (CC) epoxy,
- (DD) arylether,
- (EE) arylthioether,
- (FF) aryl-C.sub.1 -to-C.sub.12 -alkylether,
- (GG) aryl-C.sub.1 -to-C.sub.12 -alkylthioether,
- (HH) (heterocyclic)ether,
- (II) (heterocyclic)thioether,
- (JJ) (heterocylic)-C.sub.1 -to-C.sub.12 -alkylether,
- (KK) (heterocyclic)-C.sub.1 -to-C.sub.12 -alkylthioether,
- (LL) aryl,
- (MM) heterocyclic,
- (NN) --SO.sub.3 H,
- (OO) --S(O).sub.2 NR.sup.16' R.sup.16" wherein R.sup.16', and R.sup.16" are defined as herein, and
- (PP) --S(O).sub.s R.sup.14' wherein s is defined as above and R.sup.14' is defined as herein,
- where each aryl and heterocyclic moiety is independently substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are defined as herein,
- R.sup.11 is independently selected from the group consisting of C.sub.1 -to-C.sub.8 -loweralkyl, aryl-C.sub.1 -to-C.sub.12 -alkyl substituted by R.sup.301, R.sup.302 and R.sup.303, and aryl substituted by R.sup.301, R.sup.302 and R.sup.303 wherein R.sup.301, R.sup.302 and R.sup.303 are defined as herein,
- R.sup.14' is selected from the group consisting of hydrogen, (C.sub.1 -to-C.sub.8 -loweralkyl, aryl-C.sub.1 -to-C.sub.12 -alkyl, C.sub.3 -to-C.sub.8 -cycloalkyl and C.sub.3 -to-C.sub.8 -cycloalkyl-C.sub.1 -to-C.sub.8 -alkyl, and
- R.sup.16' and R.sup.16" are independently selected from the group consisting of hydrogen, C.sub.1 -to-C.sub.8 -loweralkyl, hydroxy-C.sub.1 -to-C.sub.8 -loweralkyl, carboxy-C.sub.1 -to-C.sub.12 -alkyl, thio-C.sub.1 -to-C.sub.8 -loweralkyl, thioalkoxy-C.sub.1 -to-C.sub.8 -alkyl, guanidino-C.sub.1 -to-C.sub.12 -alkyl, aminoalkyl independently as defined above and aryl-C.sub.1 -to-C.sub.12 -alkyl;
- or, when appended to a nitrogen atom, R.sup.8 and R.sup.8', taken together with the nitrogen atom to which they are connected, form a 5- to 7-membered heterocyclic ring; and
- R.sup.301, R.sup.302 and R.sup.303 are independently selected from the group consisting of
- (i) hydrogen;
- (ii) --(C.sub.1 -to-C.sub.7 alkyl);
- (iii) --(C.sub.2 -to-C.sub.6 alkenyl);
- (iv) halogen;
- (v) --(CH.sub.2).sub.m NR.sup.8 R.sup.8', where m is an integer between zero and four, inclusive wherein R.sup.8 and R.sup.8' are defined as above;
- (vi) --CN;
- (vii) --CHO;
- (viii) mono-, di-, tri-, or perhalogenated C.sub.1 -C.sub.12 -alkyl;
- (ix) --S(O).sub.s R.sup.8 wherein s and R.sup.8 are defined as above;
- (x) --C(O)NR.sup.8 R.sup.8' wherein R.sup.8 and R.sup.8' are defined as above;
- (xi) --(CH.sub.2).sub.m OR.sup.8 wherein R.sup.8 is defined as above;
- (xii) --CH(OR.sup.12')(OR.sup.12"), where R.sup.12' and R.sup.12" are independently --(C.sub.1 -to-C.sub.3 alkyl) or, taken together, form an ethylene or propylene bridge;
- (xiii) --(CH.sub.2).sub.m OC(O)R.sup.8 wherein R.sup.8 is defined as above;
- (xiv) --(CH.sub.2).sub.m C(O)OR.sup.8 wherein R.sup.8 is defined as above;
- (xv) --OR.sup.11', where R.sup.11' is selected from the group consisting of
- (A) --PO(OH)OH,
- (B) --SO.sub.3 H, and
- (C) --C(O)(CH.sub.2).sub.m C(O)OH;
- (xvi) --S(O).sub.2 NR.sup.8 R.sup.8' wherein R.sup.8 and R.sup.8' are defined as above;
- (xvii) --NO.sub.2 ;
- (xviii) --N.sub.3 ; and
- (xviv) guanidino optionally substituted by a radical selected from the group consisting of C.sub.1 -C.sub.8 -loweralkyl, aryl, C.sub.1 -C.sub.12 -alkyl--C(O)-- or aryl--C(O)--, arylsulfonyl, C.sub.1 -C.sub.8 -alkoxycarbonyl, aryl-C.sub.1 -C.sub.8 -alkoxycarbonyl, aryloxycarbonyl and C.sub.1 -C.sub.12 -alkylsulfonyl,
- wherein at each occurrence the term aryl is independently selected from phenyl, 1-naphthyl, 2-naphthal, fluorenyl, (1,2)-dihydronaphthyl, indenyl, and indanyl;
- wherein at each occurrence the term heterocyclic is independently selected from the group consisting of pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, triazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, isoquinolinyl, thyminyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl,
- subject to the proviso that each of substituents R.sup.301, R.sup.302 and R.sup.303 may comprise no more than twenty non-hydrogen atoms;
- or, taken together, any two adjacent groups R.sup.301, R.sup.302 and R.sup.303 and the atoms to which they are attached form a carbocyclic or heterocyclic ring having between five and seven ring atoms.
- 2. A method according to claim 1 wherein Z is a radical having the formula ##STR12## wherein n, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined therein.
- 3. A method according to claim 1 wherein n is an integer between zero and five, inclusive.
- 4. A method according to claim 1 wherein R.sup.1, R.sup.6 and R.sup.7 are independently selected from the group consisting of (i) hydrogen; (ii) --C(.dbd.NH)NH.sub.2 ; (iii) aryl substituted by R.sup.301, R.sup.302 and R.sup.303 ; and (iv) alkyl having j carbon atoms where j is an integer between 1 and 10, inclusive, substituted with between zero and 5 but no more than j radicals selected from the group consisting of --OR.sup.8, --S(O).sub.s R.sup.8 where s is zero through two, --S(O).sub.2 NR.sup.8 R.sup.8', --NR.sup.8 R.sup.8', --SO.sub.3 H, .dbd.NOR.sup.8, --R.sup.399 and --R.sup.400 wherein s, R.sup.8, R.sup.8', R.sup.301, R.sup.302, R.sup.303, R.sup.399 and R.sup.400 are as defined therein.
- 5. A method according to claim 1 wherein Z is --(C.sub.2 -to-C.sub.8 alkylidene)--, optionally substituted with between one and three radicals independently selected from the group consisting of --OR.sup.8, --S(O).sub.s R.sup.8, --S(O).sub.2 NR.sup.8 R.sup.8', --NR.sup.8 R.sup.8', --SO.sub.3 H, .dbd.NOR.sup.8, --R.sup.399 and --R.sup.400 wherein S, R.sup.8, R.sup.8', R.sup.399 and R.sup.400 are as defined therein.
- 6. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula: ##STR13## wherein R.sup.105 is a radical having the formula ##STR14## where Z is a divalent radical of the formula ##STR15## wherein R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =--(CH.sub.2).sub.3 --NH.sub.2 ;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=2; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Bu; and R.sup.7 =Bu;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =OH; n=1; R.sup.6 =Et; and R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =--(CH2)2--OH; and R.sup.7 =--(CH.sub.2).sub.2 --OH;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =Me; R.sup.5 =Me; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; and R.sup.6, R.sup.7 and the nitrogen to which they are attached=NMe.sub.3 Cl;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =--(CH2)2--OH; and R.sup.7 =--(CH.sub.2).sub.2 --OH;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =Me; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =Me; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =iPr; and R.sup.7 =iPr;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =--(CH.sub.2).sub.2 --NH.sub.2 ; and R.sup.7 =--C.sub.12 H.sub.25 ;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =--(CH.sub.2).sub.2 --NEt.sub.2 ;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =--(CH.sub.2).sub.2 --OH;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Bu;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =CO2H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =CO2H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Me; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =--(CH2)3NMe2; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Me; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =--(CH.sub.2).sub.3 NHMe;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Et; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Et; and R.sup.7 =--(CH.sub.2).sub.3 NHEt;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Et; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =--(CH2)2--OH; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Me; R.sup.2 =H; R.sup.3 =H; R.sup.4 and R.sup.5 taken together are O; n=0; R.sup.6 =Me; and R.sup.7 =--CH.sub.2 --CO.sub.2 H;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Me; Z=--CH.sub.2 --C(R.sup.399)--; R.sup.399 =oxo; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Me; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =--(CH.sub.2).sub.2 NHMe;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =--(CH2)2--NEt2; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =--(CH2)2--NMe2; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Et; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; and R.sup.7 =--(CH.sub.2).sub.2 NEt(CH.sub.2).sub.2 NHEt;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =H; and R.sup.7 =--(CH.sub.2).sub.2 NMe.sub.2 ;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =--(CH2)2--NH2; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =--CO2tBu; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=3; R.sup.6 =Boc; and R.sup.7 =H;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =--CO2H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=3; R.sup.6 =H; and R.sup.7 =H;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =--CO2H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=3; R.sup.6 =H; and R.sup.7 =--C(.dbd.NH)NH.sub.2 ;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =--CO2H; R.sup.4 =H; R.sup.5 =H; n=3; R.sup.6 =H; and R.sup.7 =H;
- R.sub.100 =H; R.sub.101 =allyl; R102=H; R103=OH; R104=H; R1=H; R2=H; R3=H; R4=H; R5H; n=1; R6=Me; and R7=Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.105 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 and R.sub.103 taken together form a bond; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =H; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =propyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =methyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =OH; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =H; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =F; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =H; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- R.sub.100 =OC(O)CH.sub.3 ; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =H; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me; or
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; and R.sup.7 =Me;
- or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein the ester is selected from C.sub.1 -to-C.sub.6 alkyl esters, C.sub.5 -to-C.sub.7 cycloalkyl esters and arylalkyl esters and wherein the amide results from reaction of a carboxylic acid moiety in the compound of formula I with NH.sub.3, NH.sub.2 (C.sub.1 -to-C.sub.6 alkyl), NH(C.sub.1 -to-C.sub.6 alkyl).sub.2 or a 5- or 6-membered heterocycle containing one nitrogen atom and wherein the prodrug is selected from the group consisting of (a) acyloxymethyl esters of carboxylic acids, (b) (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters of carboxylic acids, (c) esters derived from alcohol groups in the parent drug by reaction with succinic acid, phosphoric acid, dialkylaminoacetic acid or an amino acid (d) N-Mannich bases of amides or amines, (e) N-hydroxymethyl derivatives of amides, (f) N-acyloxyalkyl derivatives of amides or heterocyclic amines, (g) oxazolidinones derived from ketone groups in the parent drug by reaction with 2-aminoethanol, N-methyl-2-aminoethanol, N-(2-hydroxyethyl)-2-aminoethanol, 2-aminopropanol, 2-amino-2-methylpropanol, 2-amino-2-hydroxymethylpropanol, 3-amino-2-hydroxypropane, 2-amino-1-phenylethanol, 3-aminopropanol or N-methyl-2-amino-1-phenylpropanol and (h) enol esters derived from ketone groups in the parent drug.
- 7. A method for providing immunomodulation comprising administering to a human in need of such treatment a therapeutically effective amount of a compound having the formula: ##STR16## wherein R.sup.105 is a radical having the formula ##STR17## where Z is a divalent radical of the formula ##STR18## wherein R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; R.sup.7 =Me;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; R.sup.7 =Et;
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.104 =H; R.sup.1 =Et; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=0; R.sup.6 =Et; R.sup.7 =Et; or
- R.sub.100 =H; R.sub.101 =ethyl; R.sub.102 =H; R.sub.103 =OH; R.sub.105 =H; R.sup.1 =H; R.sup.2 =H; R.sup.3 =H; R.sup.4 =H; R.sup.5 =H; n=1; R.sup.6 =Me; R.sup.7 =Me;
- or a pharmaceutically acceptable salt, ester, amide or prodrug thereof, wherein the ester is selected from C.sub.1 -to-C.sub.6 alkyl esters, C.sub.5 -to-C.sub.7 cycloalkyl esters and arylalkyl esters and wherein the amide results from reaction of a carboxylic acid moiety in the compound of formula I with NH.sub.3, NH.sub.2 (C.sub.1 -to-C.sub.6 alkyl), NH(C.sub.1 -to-C.sub.6 alkyl).sub.2 or a 5- or 6-membered heterocycle containing one nitrogen atom and wherein the prodrug is selected from the group consisting of (a) acyloxymethyl esters of carboxylic acids, (b) (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl esters of carboxylic acids, (c) esters derived from alcohol groups in the parent drug by reaction with succinic acid, phosphoric acid, dialkylaminoacetic acid or an amino acid (d) N-Mannich bases of amides or amines, (e) N-hydroxymethyl derivatives of amides, (f) N-acyloxyalkyl derivatives of amides or heterocyclic amines, (g) oxazolidinones derived from ketone groups in the parent drug by reaction with 2-aminoethanol, N-methyl-2-aminoethanol, N-(2-hydroxyethyl)-2-aminoethanol, 2-aminopropanol, 2-amino-2-methylpropanol, 2-amino-2-hydroxymethylpropanol, 3-amino-2-hydroxypropane, 2-amino-1-phenylethanol, 3-aminopropanol or N-methyl-2-amino-1-phenylpropanol and (h) enol esters derived from ketone groups in the parent drug.
Parent Case Info
This application is a division of U.S. patent application Ser. No. 08/099,976, filed Jul. 30, 1993, now U.S. Pat. No. 5,457,194 which is a continuation-in-part of the United States patent application Ser. No. 08/032,958, filed on Mar. 17, 1993, now abandoned.
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5189042 |
Goulet et al. |
Feb 1993 |
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Divisions (1)
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Number |
Date |
Country |
Parent |
99976 |
Jul 1993 |
|
Continuation in Parts (1)
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Number |
Date |
Country |
Parent |
32958 |
Mar 1993 |
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