Compounds to inhibit or augment an inflammatory response
Isolated and purified chemokine peptides, variants, and derivatives thereof, as well as chemokine peptide analogs, are provided.
1. A compound of formula (XIV):
wherein:
R 1 is:
O(Ra) wherein Ra is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C i -C 6 )alkanoyloxy, (C 6 -C 10 )aryl or (C 6 -C 10 )heteroaryl; or
N(Rb)(Rc) wherein each Rb and Rc is independently H or (C 1 -C 6 )alkyl;
R 2 is:
O(Ra) wherein Ra is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 6 -C 10 )aryl or (C 6 -C 10 )heteroaryl; or
N(Rb)(Rc) wherein each Rb and Rc is independently H or (C 1 -C 6 )alkyl;
R 3 is H, C(═O) or C(═S);
R 4 is:
H, C(═O), C(═S), O(Ra), or
N(Rb)(Rc) wherein each Ra is H, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkanoyl, (C 6 -C 10 )aryl or (C 6 -C 10 )heteroaryl, and each Rb and Rc is independently H or (C 1 -C 6 )alkyl; and
n is an integer between 1 and 6, inclusive;
wherein any (C 6 -C 10 )aryl, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyloxy, (C 6 -C 10 )heteroaryl or (C 1 -C 6 )alkanoyl or the benzo ring in formula (XIV) is optionally substituted with at least one substituent selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, methoxydioxy, hydroxy, C(═O), sulfino (SO 2 H), sulfo (SO 3 H), and N(Rb)(Rc);
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein:
R 1 is N(Rb)(Rc) wherein each Rb and Rc is independently H or (C 1 -C 6 )alkyl;
R 2 is OH;
R 3 is H;
R 4 is H; and
n is 1;
wherein any (C 1 -C 6 )alkyl or the benzo ring in formula (XIV) is optionally substituted with at least one substituent selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, methoxydioxy, hydroxy, C(═O), SO 2 H, SO 3 H, and N(Rb)(Rc).
3. The compound according to claim 1 , wherein:
R 1 is N(Rb)(Rc) wherein Rb is H and Rc is H;
R 2 is O(Ra) wherein Ra is H, —CH 2 C(OH)C(OH)C(OH)C(OH)CHO or —CH 2 C(OH)C(OH)C(OH)C(NH 2 )CHO;
R 3 is H;
R 4 is H; and
n is 1.
4. The compound according to claim 1 , wherein the compound possesses a ring stereochemistry of yohimbine, alloyohimbine or rauwolscine.
5. A compound of formula (XIV):
wherein:
R 1 is O(R a ), an amino acid, or N(R b )(R c );
R 2 is O(R a ) or N(R b )(R c );
R 3 is H, oxo or thioxo;
R 4 is H, oxo, thioxo, O(R a ) or N(R b )(R c );
n is 1, 2, 3, 4, 5 or 6;
each R a is independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, aryl, heteroaryl, or a saccharide;
R b and R c are each independently H or (C 1 -C 6 )alkyl;
wherein any (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 )alkyl, (C 1 C 6 )alkoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkanoyloxy, (C 1 -C 6 )alkoxycarbonyl, hydroxy, oxo, sulfino (SO 2 H), sulfo (SO 3 H), and N(R b )(R c );
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 , wherein:
R 1 is N(Rb)(Rc) wherein Rb is H and Rc is H;
R 2 is O(Ra) wherein Ra is H, —CH 2 C(OH)C(OH)C(OH)C(OH)CHO or —CH 2 C(OH)C(OH)C(OH)C(NH 2 )CHO;
R 3 is H;
R 4 is H; and
n is 1.
7. The compound according to claim 5 , wherein the benzo ring of formula (XIV) is substituted.
8. The compound according to claim 5 , wherein the compound possesses a ring stereochemistry of yohimbine, alloyohimbine or rauwolscine.