Claims
- 1. A method for enhancing interferon-gamma (IFN-.gamma.) induction of the major histocompatibility (MHC) proteins in a mammalian cell responsive to IFN-.gamma., said method comprising contacting said cell with an effective amount of a fused pyrrolo�2,3-c!carbazole-6-one represented by a formula selected from the group consisting of: ##STR4## wherein: a) R.sup.1 is selected from the group consisting of H, alkyl of 1-4 carbons, aryl arylalkyl heteroaryl, heteroarylalkyl; C(.dbd.O)R.sup.9 where R.sup.9 is alkyl of 1-4 carbons or aryl; (CH.sub.2).sub.n OR.sup.9, where n is an integer of 1-4; OR.sup.10, where R.sup.10 is H or alkyl of 1-4 carbons; (CH.sub.2).sub.n OR.sup.14 where R.sup.14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; OR.sup.14, NR.sup.7 R.sup.8 ; (CH.sub.2).sub.n NR.sup.7 R.sup.8, and O(CH.sub.2).sub.n NR.sup.7 R.sup.8 ; and either
- (1) R.sup.7 and R.sup.8 independently are H or alkyl of 1-4 carbons; or
- (2) R.sup.7 and R.sup.8 are combined together to form a linking group of the general formula --(CH.sub.2).sub.2 --X.sup.1 --(CH.sub.2).sub.2 --, where X.sup.1 is O, S or CH.sub.2 ;
- b) R.sup.2 is selected from the group consisting of H, SO.sub.2 R.sup.9, CO.sub.2 R.sup.9, C(.dbd.O)R.sup.9, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, alkynyl of 2-8 carbons, and a monosaccharide of 5-7 carbons, wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted hydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons; wherein either
- 1) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons is unsubstituted; or
- 2) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons independently is substituted with 1-3 groups selected from the group consisting of aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, O-tetrahydropyranyl, NH.sub.2, NR.sup.7 R.sup.8, NR.sup.10 COR.sup.9 ; NR.sup.10 CO.sub.2 R.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, NHC(.dbd.NH)NH.sub.2, NR.sup.10 SO.sub.2 R.sup.9 ; S(O).sub.y R.sup.11, wherein R.sup.11 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl, and y is 1 or 2; SR.sup.11, CO.sub.2 R.sup.9, CONR.sup.7 R.sup.8, CHO, COR.sup.9, CH.sub.2 OR.sup.7, CH.sub.2 OR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNHCH(N.dbd.NH)NH.sub.2 ; SO.sub.2 NR.sup.12 R.sup.13 ; wherein either
- (1a) R.sup.12 and R.sup.13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl; or
- (2a) R.sup.12 and R.sup.13 are combined together to form a --(CH.sub.2).sub.2 -X.sup.1 -(CH.sub.2).sub.2 linking group;
- PO(OR.sup.11).sub.2, NHR.sup.14, NR.sup.10 R.sup.14, OR.sup.14, and a monosaccharide of 5-7 carbons wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted hydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons;
- c) each R.sup.3 and R.sup.4, independently, is selected from the group consisting of H, aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, CF.sub.3, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, NH.sub.2, (CH.sub.2).sub.n OR.sup.9, (CH.sub.2).sub.n OR.sup.10, (CH.sub.2).sub.n OR.sup.14, OR.sup.14, NHR.sup.14, NR.sup.7 R.sup.8, NR.sup.7 (CH.sub.2).sub.n NR.sup.7 R.sup.8,NR.sup.10 COR.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, SR.sup.11, S(O).sub.y R.sup.11, CO.sub.2 R.sup.9, COR.sup.9, CONR.sup.7 R.sup.8, CHO, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, (CH.sub.2).sub.n SR.sup.9, (CH.sub.2).sub.n S(O).sub.y R.sup.9 ; CH.sub.2 SR.sup.15, where R.sup.15 is alkyl of 1-4 carbons; CH.sub.2 S(O).sub.y R.sup.14, (CH.sub.2).sub.n NR.sup.7 R.sup.8, (CH.sub.2).sub.n NBR.sup.14, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
- 1) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons or alkynyl of 2-8 carbons is unsubstituted; or
- 2) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons is independently substituted as described in b)2) above;
- d) R.sup.5 is selected from the group consisting of alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
- 1) each alkyl, alkenyl, or alkenyl group is unsubstituted ; or
- 2) each alkyl, alkenyl, or alkynyl group is substituted with 1-3 groups selected from the group consisting of F, Cl, Br, I, CN, CF.sub.3, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, NH.sup.2, (CH.sub.2).sub.n OR.sup.9, (CH.sub.2).sub.n OR.sup.14, NR.sup.7 R.sup.8, NR.sup.7 (CH.sub.2).sub.n NR.sup.7 R.sup.8, NR.sup.10 COR.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, SR.sup.11, S(O).sub.y R.sup.11, CO.sub.2 R.sup.9, COR.sup.9, CONR.sup.7 R.sup.8, CHO, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, (CH.sub.2).sub.n SR.sup.9, (CH.sub.2).sub.n S(O).sub.y R.sup.9, CH.sub.2 SR.sup.15, CH.sub.2 S(O).sub.y R.sup.14, (CH.sub.2).sub.n NR.sup.7 R.sup.8, and (CH.sub.2).sub.n NHR.sup.14.
- e) X is selected from the group consisting of --N--, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2 --, alkylene of 1-3 carbons, --C(.dbd.O)--, --C(R.sup.2).dbd.C(R.sup.2)--, --C(R.sup.2).sub.2 --, --CH.dbd.CH--, --CH(OH)--CH(OH)--, --C(.dbd.NOR.sup.11 I)--, --C(OR.sup.11)(R.sup.11)--, --C(.dbd.O)CH(R.sup.15)--, --CH(R.sup.15)C(.dbd.O)--; --CH.sub.2 --Z--, --Z--CH.sub.2 --, --CH.sub.2 ZCH.sub.2 --, where Z is selected from the group consisting of --C(OR.sup.11)(R.sup.11)--, O, S, C(.dbd.O), and NR.sup.11 ; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R.sup.5 substituent group, SR.sup.10, OR.sup.10, OR.sup.14, R.sup.15, phenyl, naphthyl, and arylalkyl of 7-14 carbons.
- thereby causing increased expression of MHC proteins on the surface of said cell.
- 2. The method of claim 1, wherein said cell is in vitro.
- 3. The method of claim 2, wherein said cell is a human cell.
- 4. The method of claim 3, wherein said cell is selected from the group consisting of a monocyte, a B-lymphocyte, and a dendritic cell.
- 5. The method of claim 4, wherein said cell is a monocyte.
- 6. The method of claim 2, wherein said MHC proteins include an MHC class I protein or an MHC class II protein.
- 7. The method of claim 6, wherein said MHC class II protein is selected from the group consisting of HLA-DP, HLA-DQ, and HLA-DR.
- 8. The method of claim 2, wherein said increased expression of MHC proteins on the surface of said cell enhances an immune system function.
- 9. The method of claim 2, further comprising the step of contacting said cell with an effective amount of exogenous IFN.gamma..
- 10. The method of claim 1, wherein said cell is in vivo.
- 11. The method of claim 10 wherein said cell is in a human patient.
- 12. The method of claim 10, wherein said cell is selected from the group consisting of a monocyte, a B-lymphocyte, and a dendritic cell.
- 13. The method of claim 12, wherein said cell is a monocyte.
- 14. The method of claim 10, wherein said MHC proteins include an MHC class I protein or an MHC class II protein.
- 15. The method of claim 14, wherein said MHC class II protein is selected from the group consisting of HLA-DP, HLA-DQ, and HLA-DR.
- 16. The method of claim 10, wherein said increased expression of MHC proteins on the surface of said cell enhances an immune system function.
- 17. The method of claim 10, further comprising the step of contacting said cell with an effective amount of exogenous IFN-.gamma..
- 18. A method for potentiating the effect of a neurotrophic factor on a mammalian neurotrophic factor-responsive cell, said method comprising contacting said cell with an effective amount of a fused pyrrolo�2,3-c! carbazole-6-one represented by a formula selected from the group consisting of: ##STR5## wherein: a) R.sup.1 is selected from the group consisting of H, alkyl of 1-4 carbons, aryl arylalkyl heteroaryl, heteroarylalkyl; C(.dbd.O)R.sup.9 where R.sup.9 is alkyl of 1-4 carbons or aryl; (CH.sub.2).sub.n OR.sup.9, where n is an integer of 1-4; OR.sup.10, where R.sup.10 is H or alkyl of 1-4 carbons; (CH.sub.2).sub.n OR.sup.14 where R.sup.14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; OR.sup.14, NR.sup.7 R.sup.8 ; (CH.sub.2).sub.n NR.sup.7 R.sup.8, and O(CH.sub.2).sub.n NR.sup.7 R.sup.8 ; and either
- (1) R.sup.7 and R.sup.8 independently are H or alkyl of 1-4 carbons; or
- (2) R.sup.7 and R.sup.8 are combined together to form a linking group of the general formula --(CH.sub.2).sub.2 --X.sup.1 --(CH.sub.2).sub.2 --, where X.sup.1 is O, S or CH.sub.2 ;
- b) R.sup.2 is selected from the group consisting of H, SO.sub.2 R.sup.9, CO.sub.2 R.sup.9, C(.dbd.O)R.sup.9, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, alkynyl of 2-8 carbons, and a monosaccharide of 5-7 carbons, wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted hydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons; wherein either
- 1) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons is unsubstituted; or
- 2) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons independently is substituted with 1-3 groups selected from the group consisting of aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, O-tetrahydropyranyl, NH.sub.2, NR.sup.7 R.sup.8, NR.sup.10 COR.sup.9 ; NR.sup.10 CO.sub.2 R.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, NHC(.dbd.NH)NH.sub.2, NR.sup.10 SO.sub.2 R.sup.9 ; S(O).sub.y R.sup.11, wherein R.sup.11 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl, and y is 1 or 2; SR.sup.11, CO.sub.2 R.sup.9, CONR.sup.7 R.sup.8, CHO, COR.sup.9, CH.sub.2 OR.sup.7, CH.sub.2 OR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNHCH(N.dbd.NH)NH.sub.2 ; SO.sub.2 NR.sup.12 R.sup.13 ; wherein either
- (1a) R.sup.12 and R.sup.13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl; or
- (2a) R.sup.12 and R.sup.13 are combined together to form a --(CH.sub.2).sub.2 -X.sup.1 -(CH.sub.2).sub.2 linking group;
- PO(OR.sup.11).sub.2, NHR.sup.14, NR.sup.10 R.sup.14, OR.sup.14, and a monosaccharide of 5-7 carbons wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted hydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons;
- c) each R.sup.3 and R.sup.4, independently, is selected from the group consisting of H, aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, CF.sub.3, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, NH.sub.2, (CH.sub.2).sub.n OR.sup.9, (CH.sub.2).sub.n OR.sup.10, (CH.sub.2).sub.n OR.sup.14, OR.sup.14, NHR.sup.14, NR.sup.7 R.sup.8, NR.sup.7 (CH.sub.2).sub.n NR.sup.7 R.sup.8,NR.sup.10 COR.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, SR.sup.11, S(O).sub.y R.sup.11, CO.sub.2 R.sup.9, COR.sup.9, CONR.sup.7 R.sup.8, CHO, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, (CH.sub.2).sub.n SR.sup.9, (CH.sub.2).sub.n S(O).sub.y R.sup.9 ; CH.sub.2 SR.sup.15, where R.sup.15 is alkyl of 1-4 carbons; CH.sub.2 S(O).sub.y R.sup.14, (CH.sub.2).sub.n NR.sup.7 R.sup.8, (CH.sub.2).sub.n NBR.sup.14, alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
- 1) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons or alkynyl of 2-8 carbons is unsubstituted; or
- 2) each alkyl of 1-8 carbons, alkenyl of 2-8 carbons, or alkynyl of 2-8 carbons is independently substituted as described in b)2) above;
- d) R.sup.5 is selected from the group consisting of alkyl of 1-8 carbons, alkenyl of 2-8 carbons, and alkynyl of 2-8 carbons; and either
- 1) each alkyl, alkenyl, or alkenyl group is unsubstituted ; or
- 2) each alkyl, alkenyl, or alkynyl group is substituted with 1-3 groups selected from the group consisting of F, Cl, Br, I, CN, CF.sub.3, NO.sub.2, OH, OR.sup.9, O(CH.sub.2).sub.n NR.sup.7 R.sup.8, OCOR.sup.9, OCONHR.sup.9, NH.sup.2, (CH.sub.2).sub.n OR.sup.9, (CH.sub.2).sub.n OR.sup.14, NR.sup.7 R.sup.8, NR.sup.7 (CH.sub.2).sub.n NR.sup.7 R.sup.8, NR.sup.10 COR.sup.9, NR.sup.10 CONR.sup.7 R.sup.8, SR.sup.11, S(O).sub.y R.sup.11, CO.sub.2 R.sup.9, COR.sup.9, CONR.sup.7 R.sup.8, CHO, CH.dbd.NOR.sup.11, CH.dbd.NR.sup.9, CH.dbd.NNR.sup.11 R.sup.12, (CH.sub.2).sub.n SR.sup.9, (CH.sub.2).sub.n S(O).sub.y R.sup.9, CH.sub.2 SR.sup.15, CH.sub.2 S(O).sub.y R.sup.14, (CH.sub.2).sub.n NR.sup.7 R.sup.8, and (CH.sub.2).sub.n NHR.sup.14.
- e) X is selected from the group consisting of --N--, --O--, --S--, --S(.dbd.O)--, --S(.dbd.O).sub.2 --, alkylene of 1-3 carbons, --C(.dbd.O)--, --C(R.sup.2).dbd.C(R.sup.2)--, --C(R.sup.2).sub.2 --, --CH.dbd.CH--, --CH(OH)--CH(OH)--, --C(.dbd.NOR.sup.11 I)--, --C(OR.sup.11)(R.sup.11)--, --C(.dbd.O)CH(R.sup.15)--, --CH(R.sup.15)C(.dbd.O)--; --CH.sub.2 --Z--, --Z--CH.sub.2 --, --CH.sub.2 ZCH.sub.2 --, where Z is selected from the group consisting of --C(OR.sup.11)(R.sup.11)--, O, S, C(.dbd.O), and NR.sup.11 ; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R.sup.5 substituent group, SR.sup.10, OR.sup.10, OR.sup.14, R.sup.15, phenyl, naphthyl, and arylalkyl of 7-14 carbons.
- thereby causing an effect selected from the group consisting of: enhancing the function of said cell, and enhancing the survival of said cell.
- 19. The method of claim 18, wherein said cell is in vitro.
- 20. The method of claim 19, wherein said cell is a human cell.
- 21. The method of claim 20, wherein said cell selected from the group consisting of: a neuron, a monocyte, a B-lymphocyte, and a neoplastic cell.
- 22. The method of claim 18, wherein said cell is in vivo .
- 23. The method of claim 22, wherein said cell is a human cell.
- 24. The method of claim 23, wherein said cell selected from the group consisting of: a neuron, a monocyte, a B-lymphocyte, and a neoplastic cell.
- 25. The method of claim 24, wherein said neuron is a cholinergic neuron.
- 26. The method of claim 18, wherein said trophic factor is selected from the group consisting of: a ciliary neurotrophic factor (CTNF), a basic fibroblast growth factor (bFGF), insulin, an insulin-like growth factor, an interferon, an interleukin, and a neurotrophin.
- 27. The method of claim 26, wherein said neurotrophin is selected from the group consisting of: neurotrophin 3, neurotrophin-4/5, and brain derived neurotrophic factor (BDNF).
Parent Case Info
This is a continuation of application Ser. No. 08/604,474, filed Feb. 21, 1996 now U.S. Pat. No. 5,616,724.
US Referenced Citations (6)
Number |
Name |
Date |
Kind |
4552842 |
Nettleton, Jr. et al. |
Nov 1985 |
|
4912107 |
Kleinschroth et al. |
Mar 1990 |
|
4923986 |
Murakata et al. |
May 1990 |
|
5057614 |
Davis et al. |
Oct 1991 |
|
5185260 |
Crissman et al. |
Feb 1993 |
|
5405864 |
Broka |
Apr 1995 |
|
Foreign Referenced Citations (3)
Number |
Date |
Country |
0 370 236 |
May 1990 |
EPX |
0 384 349 |
Aug 1990 |
EPX |
0 434 057 |
Jun 1992 |
EPX |
Continuations (1)
|
Number |
Date |
Country |
Parent |
604474 |
Feb 1996 |
|