CA2241852C - Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon - Google Patents
Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon Download PDFInfo
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- CA2241852C CA2241852C CA002241852A CA2241852A CA2241852C CA 2241852 C CA2241852 C CA 2241852C CA 002241852 A CA002241852 A CA 002241852A CA 2241852 A CA2241852 A CA 2241852A CA 2241852 C CA2241852 C CA 2241852C
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Disclosed in this patent document are synthetic, biologically active molecules referred to as fused pyrrolo(2,3-c)carbazole-6-ones. These molecules are represented by general formulae (I) and (II). Methods for making and using the fused pyrrolo(2,3-c)carbazole-6-ones are also disclosed.
Description
FUSED PYRROLO(2.3-C)CARBAZOLE-6-ONES WHdCH POTENTIATE AC3.'IVTrY OF GAMMA
TNTERFERON
FIELD OF INVENTION
This invention is related to pharmaceutical compounds which are referred to in this patent document as "fused pyrrolo(2,3-c]carbazole-6-ones." Also disclosed are methods for making these compounds. and methods for using the compounds.
BACKGROUND OF THE INVENTION
Human interferon-gamma ( IFN-y) is a natural human immunoregulatory protein.
It has been established as an agent effective in the treatment of tumors and virus infections in humans. The precise mechanisms by which IFN-y inhibits virus and tumor growth in vivo remain unknown. There is evidence that 1FN-y works by at least one of two mechanisms: ( 1) by acting directly on the virus infected cell and the tumor cell and/or (2) by first activating cells of the immune system which then destroy the virus-infected cell or tumor cell [Interferons and other Regulatory Cytokines, E. De Maeyer and J. De Maeyer-Guignard, John Whey & Sons, New York ( 1988)].
One manifestation of a stimulated immune system is the enhanced expression on the surface of immune cells of the proteins of the Major Histocompability Complex (MHC). The MHC is made of class I, II, and III genes that code for the respective class I, II, and III proteins. Class I and II proteins reside on the cell surface and are involved in controlling the immune response, whereas the class III proteins appear in the serum and are not involved in controlling the immune response. Class I and II proteins on antigen presenting cells e.g. monocytes, B Lymphocytes, dendritic cells, present foreign antigens to T Lymphocytes with subsequent destruction of the cell containing the foreign antigen. The enhanced expression of the class I and II proteins is essential for the immune system to rid an animal of virus-infected cells and enhance specific antibody production.
1FN-y is one ofthe major regulators of the immune response due to its ability to enhance the expression of MHC class I and II proteins. An example of the benefit of MHC I enhancement by 1FN-y is the enhancement of class I proteins on virus-infected cells. The virus infected cell presents synthesized viral antigens on its cell surface to the T cell receptor on cytotoxic T
cells {CD4 cells) with the subsequent destruction of the virus infected cell by the cytotoxic T cell. An example of the benefit of MHC II enhancement by IFN-y is the enhancement of class II proteins on monocytes. Monocytes can ingest invading microorganisms and the class II proteins on the monocyte surface present peptides derived from the invading microorganism. These peptides held by the class II proteins are presented to the T cell receptor on helper T cells (CD8) with subsequent secretion of Iymphokines by the CD8 cell. The secreted lymphokines cause proliferation of the antibody synthesizing B
lymphocytes which syntliesize large amounts of antibody against the invading microorganism It can be seem from the above examples that a compound that enhances the IF2T-y induction of MHC molecules would be useful in combination with IFN-y for the treatment of infections by microorgaiusms. Such a compound might permit a reduction in the dose of IFN-y, thereby advantageously giving the same therapeutic effect as with IFN-y alone but with fewer of the IF'N-y related side effects.
There are at Ieast three reports of compounds tliat potentiate the IFN-y-induced MHC expression [Coutinho. G.C., Dudrieu-Trautmann, O., Strosberg, A.D., and Couraud, P.O., Catecholamines Stimulate the IFN-y-induced Class II MHC
Expression on Bovine Brain Capillary Endothelial Cells, J. Immunol., I47, 2525-2529 (199/);
Zhu, J., Mix, E., Olsson, T., and Link, H.' "Influence of Ion Channel Modulation of in Vitro Interferon-y Induced MHC Class I and II Expression on Macrophages", Immunopharmacology and Immunotoxicology, 17, 109-136 (1995); Mothes, T., Bendix, U." Pfannschmidt, C." and Lehmann, L, ''Effect of Gliadin and Other Food Peptides on Expression ofMHC Class II Molecules by HT-29 Cells", Gut, 36, 548-552 (1995)].
SUMMARY OF THE INVENTION
Disclosed herein are a novel class of molecules represented by Formulae I and II, which we refer to as fused pynrolo[2,3-c]carbazole-6-ones.
FORMULA I
R5 N~R1 N X
~2 R
TNTERFERON
FIELD OF INVENTION
This invention is related to pharmaceutical compounds which are referred to in this patent document as "fused pyrrolo(2,3-c]carbazole-6-ones." Also disclosed are methods for making these compounds. and methods for using the compounds.
BACKGROUND OF THE INVENTION
Human interferon-gamma ( IFN-y) is a natural human immunoregulatory protein.
It has been established as an agent effective in the treatment of tumors and virus infections in humans. The precise mechanisms by which IFN-y inhibits virus and tumor growth in vivo remain unknown. There is evidence that 1FN-y works by at least one of two mechanisms: ( 1) by acting directly on the virus infected cell and the tumor cell and/or (2) by first activating cells of the immune system which then destroy the virus-infected cell or tumor cell [Interferons and other Regulatory Cytokines, E. De Maeyer and J. De Maeyer-Guignard, John Whey & Sons, New York ( 1988)].
One manifestation of a stimulated immune system is the enhanced expression on the surface of immune cells of the proteins of the Major Histocompability Complex (MHC). The MHC is made of class I, II, and III genes that code for the respective class I, II, and III proteins. Class I and II proteins reside on the cell surface and are involved in controlling the immune response, whereas the class III proteins appear in the serum and are not involved in controlling the immune response. Class I and II proteins on antigen presenting cells e.g. monocytes, B Lymphocytes, dendritic cells, present foreign antigens to T Lymphocytes with subsequent destruction of the cell containing the foreign antigen. The enhanced expression of the class I and II proteins is essential for the immune system to rid an animal of virus-infected cells and enhance specific antibody production.
1FN-y is one ofthe major regulators of the immune response due to its ability to enhance the expression of MHC class I and II proteins. An example of the benefit of MHC I enhancement by 1FN-y is the enhancement of class I proteins on virus-infected cells. The virus infected cell presents synthesized viral antigens on its cell surface to the T cell receptor on cytotoxic T
cells {CD4 cells) with the subsequent destruction of the virus infected cell by the cytotoxic T cell. An example of the benefit of MHC II enhancement by IFN-y is the enhancement of class II proteins on monocytes. Monocytes can ingest invading microorganisms and the class II proteins on the monocyte surface present peptides derived from the invading microorganism. These peptides held by the class II proteins are presented to the T cell receptor on helper T cells (CD8) with subsequent secretion of Iymphokines by the CD8 cell. The secreted lymphokines cause proliferation of the antibody synthesizing B
lymphocytes which syntliesize large amounts of antibody against the invading microorganism It can be seem from the above examples that a compound that enhances the IF2T-y induction of MHC molecules would be useful in combination with IFN-y for the treatment of infections by microorgaiusms. Such a compound might permit a reduction in the dose of IFN-y, thereby advantageously giving the same therapeutic effect as with IFN-y alone but with fewer of the IF'N-y related side effects.
There are at Ieast three reports of compounds tliat potentiate the IFN-y-induced MHC expression [Coutinho. G.C., Dudrieu-Trautmann, O., Strosberg, A.D., and Couraud, P.O., Catecholamines Stimulate the IFN-y-induced Class II MHC
Expression on Bovine Brain Capillary Endothelial Cells, J. Immunol., I47, 2525-2529 (199/);
Zhu, J., Mix, E., Olsson, T., and Link, H.' "Influence of Ion Channel Modulation of in Vitro Interferon-y Induced MHC Class I and II Expression on Macrophages", Immunopharmacology and Immunotoxicology, 17, 109-136 (1995); Mothes, T., Bendix, U." Pfannschmidt, C." and Lehmann, L, ''Effect of Gliadin and Other Food Peptides on Expression ofMHC Class II Molecules by HT-29 Cells", Gut, 36, 548-552 (1995)].
SUMMARY OF THE INVENTION
Disclosed herein are a novel class of molecules represented by Formulae I and II, which we refer to as fused pynrolo[2,3-c]carbazole-6-ones.
FORMULA I
R5 N~R1 N X
~2 R
FORMULA II
Rj-N RS
N X
Constituent numbers are defined, infra. Preferred methods for preparing these compounds are disclosed infra.
We have discovered that our fused py~olo[2,3-c]carbazole-6-one compounds (numbering as designated for K-252a and K-252c set forth in Moody et. al, J.
Org.
Chem., 1992, 57, 2105) potentiate the activity ofhuman IFN-y in inducing the expression of MHC on the surface of receptive cells. The compounds of the invention show ability for enhancing the effectiveness of the immune system, and this in turn provides, beneficially, an enhancement in inhibiting virus andlor tumor growth. We have also discovered that the fused pyrrolo[2,3-c]carbazole-6-one compounds ofthe invention are useful for potentiating, preferably, neurotrophin-3 (NT-3) activity.
DETAIi,ED DESCRIPTION
We first describe the drawings.
i. Drawings Figure 1 is a graph sliowing the enliancement of IFN-y-induced expression of HLA-DR MHC II molecule by pyrrolo[2,3-c]-carbazole-6-ones of the invention.
Figure 2 is a schematic drawing outlining the chemical synthesis ofthe pyrrolo[2,3-- c]carbazole-6-ones of Formula I, Section V (A)-(D).
Figure 3 is a schematic drawing showing the synthesis of intermediates to pyrrolo[2,3-c]carbazole-6-ones.
y Figure 4 is a scliematic drawing showing an alternate synthesis of intermediates to pytrolo[2,3-c]carbazole-6-ones.
Figure S is a schematic drawing showing the synthesis ofpyrrolo[2,3-c]carbazole-6-ones of Formula LI.
Figure 6 is a schematic drawing showing the synthesis ofpyrrolo[2,3-c]carbazoie-6-ones in which X is C=O from the corresponding compounds in which X is CHa.
Figure 7 is a schematic drawing showing the synthesis of intermediate I I to pyrroio[2,3-c]carbazole-6-ones.
II. Fused pyrrolo[2,3-cJcarbazole-6-ones The novel compounds of this invention, which are referred to as fused pytroio[2,3-c]carbazole-6-one derivatives are represented by the following Formulae:
O O
R6 N-R~ R'~_.N RS
N X )( I and II
wherein:
a) R I is selected from the group consisting of H, alkyl of 1-4 carbons, aryl, arylalkyI, heteroaryl, lieteroarylalkyl; C(=O)R9. where R9 is alkyl of I-4 carbons or aryl; (CH2)"OR9, where n is an integer of 1-4; OR1°, where Rl°
is H or allcyl of I-4 carbons; (CH~)"OR''' _ where R 1'l is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed ; OR''', NR~RB; (CH2}aNR~Rg, and O(CH2~NR7R8: and either WO 97/31002 PCTlLTS97/02905 " (I) R~ and R8 independently are H or alkyl of 1-4 carbons; or (2) R~ and R8 are combined together to form a linking group of the general formula -(CH2)2-X1-{CH2)2-, where X1 is O, S or CH2;
b) R2 is selected form tire group consisting ofH, S02R9, C02R9, C(=O)R9, alkyl of I-8 carbons, alkenyl of 1-8 carbons, alkynyl of 1-8 carbons, and a monosaccharide of ~-7 carbons. wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted liydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-S carbons, and allcoxy of 1-4 carbons; wherein either 1) each alkyl of 1-8 carbons, allcenyl of 1-8 carbons, or alkynyl of 1-8 carbons is unsubstituted; or 2} each alkyl of 1-8 carbons, allcenyl of 1-8 carbons, or alkynyl of I-8 carbons independently is substituted with I-3 groups selected from the group consisting of aryl of f>- I O carbons, heteroaryI, F, Cl, Br, I, CN, N02, OH, OR9, O(CH2)aNR~RB, OCOR9, OCONHR9, O-tetraliydropyranyl, NH2, NR~RB, NR10COR9~ NR10C02R9, NR10CONR7R8, NHC(=NH)NH2, NR10S02R9; S(Oh,Rll, wherein R11 is H, alkyl of 1-~ carbons, aryl of 6-10 carbons, or heteroaryI, and y is I or 2; SR11, C02R~, CONR7R8, CHO, COR9, CH20R7, CHaOR9, CH=NNR11R12, CH=NOR11, CH=NR9>
CH=NNHCH(N=NH)NH2. SO2NR12R13; wherein either (la) R12 and R13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons,or heteroaryl; or (2a) R 12 and R 13 are combined together to form a .-(CH2)2-X 1-(CH2)2 ~g ~'ouP~
POOR 1 1 )2. NHR", NR'°R~'', OR 14, and a monosaccharide of S-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, alkyicarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons;
c) each R3 and R4, independently, is selected from the group consisting of H, aryl of6-10 carbons, heteroaryl, F, CI, Br, I, CN, CFA, N02, OH, OR9, O(CH2}nNR~RB. OCOR9, OCONHR9, NH2, (CH2~OR9, (CHa)~ORIO, (CH2)nORI4, ORS''. NHR''', NR7R8, NR'(CH2~NR~RB,NRIOCOR9, ~lOC0~7R8, SRI I, S(O)yRI I, C02Rg, COR9, CONR~RB, CHO, CH=NORl I, CH=NR9, CH=NNRI 1RI2, (CH2~SR9, (CH2~S(Oh,R9;
CH2SRI5, where RIS is alkyl of I-~I carbons; CH2S(Oh,RI4, (CH2~NR~RB, (CH2~NHR14, all.-yi of I-8 carbons, alkenyl of I-8 carbons, and alhynyl of I-8 carbons; and either I) each alkyl of I-8 carbons, allcenyl of 1-8 carbons or alkynyl of I-8 carbons is unsubstituted; or 2) each alkyl of I-8 carbons, alkenyI of I-8 carbons, or alkynyl of I-8 carbons is independently substituted as described in b)2) above;
d) RS is selected from the group consisting of alkyl of I-8 carbons, alkenyl of I-8 carbons, and aikynyl of 1-8 carbons; and either 1) each alkyl, alkenyl, or allcenyl group is unsubstituted ; or 2) each alkyl, allcenyl, or alkynyl group is substituted with I-3 groups selected from the group consisting of F, CI, Br, I, CN, CF3, N02, OIL
OR9, O(CH2~NR~RB, OCOR9, OCONHR9, NH2, (CH2~OR9, (CH2)nORI4. NR7R8, NR'(CH2}nNR~RB.NRI0COR9, NRIOCONR~RB, SRI I. S(O}yRI I, C02Rg, COR9, CONR~RB, CHO, CH=NORI i, CH=NR9, CH=NNRI IR12, (CH2~SR9, (CH2~S(O~,R9, CH2SR15, CH2S(O}yRl4 (CH2}nNR~RB, and (CH2}nNHR''':
e) X is selected from the group consisting of -N-, -O-, -S-, -S(=O)-, -S(=O}Z-, alkylene of I-3 carbons, -C(=O)-, -C(R2)=C(RZ}-, -C(RZ}Z-, -CH=CH-, -CH(OH)-CH(OH)-, -C(=NOR11)-, -C(OR11)(R11)_, _C(=O)CH(R15)-, -CH(R15)C(=O)-;
-CH2-Z-, -Z-CH2-, -CH2ZCHz- where Z is selected from the group consisting of -C(OR11)(R")-, O, S, C(=O), and NR11; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one RS substituent group, SR'o, OR'°, OR''', R''S, phenyl, naphthyl, and arylallcyl of 7-I4 carbons.
As used lierein, the term "aryl" means monocyclic and polycyclic aromatic groups including, for example, phenyl, naplitliyl, biphenyl, and xylyl groups. Aryl groups may be unsubstituted or substituted with, for example, alkyl and halogen groups.
Halogens include fluorine, chlorine, bromine, and iodine. Preferred are aryl groups which contain 6-carbons. Phenyl and naphthyl groups are particularly preferred.
As used herein, the term '9ieteroaryl" means an aryl moiety which contains at least one basic nitrogen atom and 0-4 heteroatoms selected from O, S, and N.
Examples of heteroaryl groups include pyrrolyl, pyranyl, thiopyranyl, furyl, imidazolyl, pyridyi, thiazolyl, triazinyl, phthalimido, indolyl. purinyl, and benzothiazolyl.
As used herein witli reference to the definition of R 14, the term "amino acid"
means a molecule containing both an amino group and a carboxyl group. Tt includes an "a.-amino acid" which lias its usual meaning as a carboxylic acid which bears an amino functionality on the carbon adjacent to the carboxyl group. oc-Amino acids can be naturally occurring or non-naturally occurring. Amino acids also include "dipeptides"
which are defined herein as two amino acids which are joined in a peptide amide linkage.
Thus, constituents of dipeptides are not limited to a-amino acids, and can be any molecule containing both an amino group and a carboxyl group. Preferred are a.-amino acids, dipeptides such as Iysyl-~i-aianine, and aminoalkanoic acids of 2-8 carbons, e.g., 3-dimethylaminobutyric acid.
- Preferred "alkyl", "alkenyl", and "alkynyl" groups contain 1-4 carbon atoms.
Preferred R' groups include H, alkyl of 1-4 carbons, substituted or unsubstituted phenyl, OR'°, and O(CH2)"NR'R°. Preferred phenyl substituents include alkyl of 1-4 r carbons, and halogen. Most preferred is H.
Preferred RZ groups include H, C(=O)R9, allcyl of 1-8 carbons, and alkyl of 1-carbons substituted with one OR'', OH. OCOR9, NR'R8, NH2, NR'°COR9, or NR'°R''' group. Most preferred is H.
Preferred R; and R'' groups include H, lialogen, CN, OH, OR9, ORl'', NHa, NR'R8, (CHa)~OR'°, (CFiz)~OR'''. COR''. NR'°COR', NHR''', and O(CHZ)~NR'R8. Most preferred is H.
Preferred RS groups include H, and alkyl of 1-4 carbons. Most preferred is H.
Preferred X groups include -N-, -O-, -S-, allcylene of 1-3 carbons, -C=O-, -CH2-Z- and -Z-CHZ-. Most preferred are -N-, -O-, -S-, and -CH2- groups.
IQ. Fused Pvrrolo[2,3-c] carbazole-6-one Utilities Our fused pyrrolo[2,3-c]carbazole-6-ones have evidenced a panoply ofimportant functional activities which find utility in a variety of settings, including both research and therapeutic arenas. For ease of presentation, and in order not to Limit the range of utilities for which these compounds can be characterized, the preferred activities of the fused pyrroio [2,3-c] carbazole-6-ones can be generally described as follows:
A. Enhancement of IFN-y induction of MHC molecules;
B. Potentiation of function and/or survival of trophic factor responsive cells.
Enhancement of IFN-y induction of MHC molecules can preferably be established using a human monocyte cell line that responds to IFN-y; a particularly preferred cell line is WO 97/31002 PCTlUS97/02905 q available from the American Type Culture Collection (ATCC), referred to as THP-1, under accession number ATCC TIB-202. 1FN-y is laiown to induce expression ofthe three MHC II heterodimers. HLA-DP, HLA-DQ and HLA-DR; in THP-!cells.
Potentiation of function and/or survival of trophic factor responsive cells, e.g., cells of neuronal lineage, can be preferably establislied using a cultured spinal cord choIine acetyltransferase ("ChAT") assay.
As used herein, the term 'poteutiation" when used to modify the terms "function"
and "survival" means a positive alteration or change. Potentiation which is positive can also be referred to herein as an "enliancement" or "enhancing."
As used herein. the teens ''enhance" or "enhancing" or enhancement when used to modify the terms "fllnCt10I1" or wsmvival" or ''induction" means that the presence of a fused pyrrolo[2,3-c]carbazole-6-one has a comparatively greater effect on the function and/or survival of a tropliic factor responsive cell or, in the case of IFN-y, induction of MHC molecules, than a comparative cell not presented with the fused pyrrolo[2,3-c]carbazole-6-one.
As used herein the term 'neuron," "cell of neuronal lineage" and 'heuronal cell"
includes, but is not limited to. a heterogeneous population of neuronal types having singular or multiple transmitters and/or singular or multiple functions;
preferably, these are cholinergic neurons. As used herein, the phrase "choIinergic neuron" means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; exemplary are basal forebrain and spinal cord neurons.
As used herein a "trophic factor" is a molecule that directly or indirectly affests the survival or function of a trophic factor responsive cell. Exemplary trophic factors include CiIiary Neurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF), insulin and insulin-like growth factors (e.g., IGF-L, IGF-II, IGF-III), interferons, interleukins, cytokines, and the neurotrophiits. sncludtng Netve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophiii-=1/5 (NT--I/~) and Brain Derived Neurotrophic Factor (BDNF).
A "trophic factor-responsive cell," as defined herein, is a cell which includes a receptor to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells).
lo As used herein, "tropliic factor- activity" and "trophic factor induced activity" are defined as any response which directly or indirectly results from the binding of a trophic factor (e:g., NT-3) to a cell comprising a trophic factor receptor.
As used in the pln~ases "trophic factor activity" and "trophic factor-induced activity," the term "trophic factor" includes both endogenous and exogenous trophic factors, where "endogenous" refers to a tropluc factor already present and "exogenous"
refers to a trophic factor added to a system. As defined, "trophic factor induced activity"
includes activity induced by ( 1 ) endogenous trophic factors; (2) exogenous trophic factors;
and (3) a combination of endogenous and exogenous trophic factors.
A. Enhancement of 1FN-y Induction of MHC Molecules The compounds of the invention can be used to enhance IFN-y induction of MHC molecules. IFN-y has shown e$'ectiveness in the treatment ofvirus infections and certain tumors. Due to its dose limiting side e$'ects, however, the utility of IF'N-y has been limited. In an immunocompromised situation, e.g., in a patient evidencing viral infection, enhancement of au 1FN-y mediated immune response would he beneficial, given that IFN-y induces expression of MHC molecules. Thus, the compounds ofthis invention which enhance the ability of endogenous IFN-y or exogenously administered IFN-y to induce MHC expression are of benefit.
As detailed in Section V below, the ability of a fused pyrrolo[2,3-c]carbazole-one to enhance 1FN-y induction of MHC molecules is preferably assessed using the THP- I
cell line. This cell line evidences expression of the MHC II heterodimer HLA-DR.
Computing the expression of HLA-DR in the presence of IFN-y and IFN-y plus one or more fused pyrrolo[2,3-c]carbazole-6-ones oftlie present invention provides a rapid and e$icient method for deterLniziation of enhancement of IFN-y induction of MHC
molecules can be assessed.
The compounds of this invention can be used in the development of in vitro models of enhancement of expression of MHC molecules, function, identification, or for the screening of other synthetic compounds which have activities similar to that of the fizsed pyrrolo[2,3-c]carbazole-6-ones. The compounds can be utilized in a research environment to investigate, refine and determine molecular targets associated with fimctional responses.
For example, by radiolabelling a fused pyrolo[2,3-c]carbazole-6-one associated with a specific cellular fimction (e.g., HLA-DR induction), the target entity to which the fused pyrrolo[2,3-c]carbazole-6-one binds can be identified, isolated, and purified for characterization. In yet anotlier example, a fused pyrrolo[2,3-c]carbazole-6-one can be used as a screening tool to discover agents which have marginal activity, but when combined with at least one disclosed fused pyrrolo[2,3-c]carbazole-6-one are capable of enhancing IFN-y induction of MHC molecules. Because the disclosed fused pyrrolo[2,3-c]carbazole-6-ones are useful in enhancing 1FN-y induction of MHC molecules, the disclosed compounds beneficially lend tliemselves to utility as therapeutic agents. Such enhancement is ofvalue in an immunocompromised patient.
B. Potentiation of function and/or survival of trophic factor responsive cells The fused pyrrolo[2,3-c]carbazole-6-ones of this invention can be used to enhance the fimction and/or survival of cells ofneuronal lineage. The fused pyrrolo[2,3-c]carbazole-6-ones can be utilized individually or with other fused pyrrolo[2,3-c]carbazole-6-ones, or in combination witli other beneficial molecules such as indolocarbazoles whicli also liave the ability to potentiate the fimction and/or survival of a designated cell: In. situations wliere the fused pyrroio[2,3-c]carbazole-6-one is intended to enhance a biological activity, e.g., neurotrophin activity, exogenous neurotrophins such as NT-3 may be utilized in conjunction with the fused pyrrolo[2,3-c]carbazole-6-one.
A variety of neurological disorders are characterized by neuronal cells which are dying, injured, fimctionally comprised, undergoing axonal degeneration, at risk of dying, etc. These disorders include, but are not limited to: Alzheimer's; motor neuron disorders (e.g., amyotrophic lateral sclerosis); Parkinson's; cerebrovascular disorders {e.g., multiple sclerosis; peripheral neuropathies (e.g., those affecting DRG neurons in chemotherapy-associated peripheral neuropathy); disorders induced by excitatory amino acids; disorders associated with concussive or penetrating injuries of the brain or spinal cord.
WO 97!31002 PCT/LTS97/02905 /~
As described in Section V below, the ability of a fused pyrrolo[2,3-c]carbazole-6-one to enhance the function and/or survival of cells of a neuronal lineage can be determined by employing a basal forebrain ChAT activity assay. ChAT catalyzes the synthesis of the neurotransmitter acetylcholine and is considered an enzymatic marker for a functional cholinergic neuron. A functional neuron is also capable of survival.
Enhancement of a neurotrophiu such as NT-3 can be determined by comparing the functional activity of the neurotropliin with or without the fused pyrolo[2,3-c]carbazole-6-one present.
Pharmaceutically acceptabie salts of the fused pyrrolo[2,3-c]carbazole-6-ones also fall within the scope of the present uivention. The term "pharmaceutically acceptable salts" as used herein means au inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fizmarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and pipetidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine.
Compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers. Such compositions can be prepared for use in parenteral administration, particularly in the foam ofliquid solutions or suspensions; or oral administration, particularly in the form oftablets or capsules; or iutranasally, particularly in the form ofpowders, nasal drops, or aerosols;
or deimaIly, via, for example. trans-dermal patches.
The composition can be conveniently administered in unit dosage foam and may be prepared by any ofthe methods well known in the pliarmaceutical art, for example, as described in Renzirrgtorz's Plrarnrcrcezrtical Sciences (Mack Pub. Co., Easton, PA, 19$0).
Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, Wb 97/31002 PCTIUS97/02905 hydrogenated naphthaleues and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipieuts to control the release of the active compounds.
Other potentially useful pareuteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions coutaiving, for example, polyoxyethylene-9-lauryl ether, glycocholate and deo~cycholate. or oily solutions for administration in the form ofnasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccai administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for trans-dermal patches are preferably lipophilic emulsions.
The compounds of this invention can be employed as the sole active agent in a pharmaceutical composition. Alternatively, tliey can be used in combination with other active ingredients, e.g., synthetic iFN-y and/or other growth factors which facilitate potentiation ofNT-3 sucli as tliose disclosed in U.S. Patent No. 5,468,872 and International Publication No. WO 95/0791 1 (publication date: March 23, 1995).
The concentrations of the compounds of this invention in a therapeutic composition can vary. Tlie concentration will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) ofthe compounds employed. and the route ofadministration. The compounds ofthis invention typically are provided in au aqueous pliysiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about 1 p.g/kg to about I g/kg ofbody weight per day; a preferred dose range is from about 0.01 mg/kg to I 00 mg/kg of body weight per day. A preferred dosage of drug to be administered is likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological afficacv of the compound selected, and formulation of the compound excipient, and its route of adnmustration.
ey IV. General Description of the Synthetic Processes Two synthetic routes were employed to prepare the fused pyrrolo[2,3-c]carbazole-6-one derivatives of the inventiou. In Metliod A (FIG 2) a 2-{aryl) or 2-(heteroaryl)indole derivative (1-4.) which is either uusubstituted or substituted at carbons 4-7 (inclusive) of the indole ring (R') or substituted or unsubstituted in the (hetero)aryl portion (R4) is reacted with maleimide in the presence of a catalyst such as, trifluoroacetic acid (TFA) to give the fused pyrrolocarbazoie-6-one derivatives ofFormula I (Examples I-IV).
Additional Lewis acid cataIysts_ such as SnCl.~, A1C13, EtAICI2, or EtzAICI
may also be used to effect the reaction. The reaction may also be run in a solvent such as TFA, toluene, CH2CIz or 1,2-dichloroethane.
The bi-aryl indole intennediates. 2,2'-biindoie 1 (X = N, R2, R3, R4 = H), 2-{2-furyl)indole 2 (X = O, R2, R3, R4 = H) and 2-(benzothienyl)indole 3 (X = S, R2, R3, R4 = H) may be prepared using standard literature procedures (Hudkins, RL.; et.
al J.
Org.Chem., 1995, 60, 6218) {FIG 2). 2-(2-Tndenyl)indole 4 (FIG 3) (X = CH2, R2, R-', R4 = H), or 2-(2-indenyl)uidote derivatives substituted with an R' or R4 group, may be prepared by reacting 1-carboxy-2-(tributylstannyl)indole 5, or 1-carboxy-2-(tributylstannyl)indote substituted with au R3 group (Hudlcins, RL. et. a1 .I.
Org.Chem., 1995, b0, 6218) with 2-bromoindeue 6 (J. Org. Chem., 1982, 47, 705) or a 2-bromoindene substituted with an R'~ group. Alternatively, 2-(2-indenyl)indole 4 (X = CH2, R2, R3, R4 = H), or 2-{2-iudeuyl)indole derivatives substituted with an R3 or R4 group, may be prepared by reaction of 1H-indole or a derivative thereof containing an R3 group, protected as a lzthium iudole-1-carbo~cylate intermediate (Tetrahedron Lett.
26:5935 (1985)), then treated with a strong base, such as t-Bui..i, then alkylated with an appropriate 2-indanone, or 2-indanoue derivative substituted with an R4 group to give the corresponding tertiary alcohol 7 (FIG 4). The resulting tertiary alcohol 7 is treated with a dilute acid {e.g., 2N HCl in acetone) to give the corresponding 2-(2-indenyl)indole 4 (US
Patent 5,475,110). Using other Benzocycloallcan-2-ones such as 2-tetralone in the reaction sequence shown in Figure 4 will give 2-{2-(3,4-dihydronaphthyl)indole 8 (X =
CH2CH2, R2, R3, R4 = H) ( US Patent 5.475,110). Tlie palladium-catalyzed cross-coupling methodology (Stille reaction) may be used to prepare other dernratives, for example, where X in Figure 3 has 1-3 carbons (inclusive), by coupling the - 2-(trifluoromethanesuIfouate)- or the 2-iodo- or 2-bromovinyl derivative ofthe corresponding cyclic ketone with I-carboxy-2-tributylstannylindole to give 2-(2-benzocycloalkenyl)indoles.
The starting 1 H-iudole derivative described previously is converted to a 1-substituted indole derivative (R2 not H) by standard methodology, for example, by treatment of the 1H-indole with base and an alkylating agent to give a I-substituted indole. In these examples, the iudole derivative can be directly treated with a strong base (e.g., t-BuLi, sec-BuLi, n-BuLi, lithium diisopropylamide) followed by alkylation with a 2-indanone derivative to give the corresponding tertiary alcohol 7, which includes R2 substituents in position one of the indole ring. The 2-{aryl)- or 2-(heteroaryl)indole derivative (1-3), 2-(2-indenyl)indole 4, or 2-(2-( 1,2-diliydronaphthyl)indole 8 may be converted to intermediates which contain R' substituents in position one ofthe indole ring by the method described above for iudole derivatives.
Compounds of general formulae I and )Q which contain R' groups, not = H, may be prepared by starting with the appropriate R' substituted maleimide (FIG 2, Method A).
Compounds of general formulae I and LI. in which RI is hydrogen, can be allcylated in the presence ofbase (e.g., liydrides. alkoxides. hydroxides of alkali or alkaline earth metals, or oforgano-lithium compowids) by treatment with RIL in which L is a leaving group such as a halogen, mesylate or tosyiate to give a fused pyrrolocarbazole-6-one derivative which has an Rl group bound to the lactam nitrogen. Compounds of general formulae I
and II, in which RS is hydrogen, may be converted to derivatives where one or two RS
groups may be added by treatment of a fused pyrrolocarbazole-6-one derivative with one equivalent or an excess of a strong base ( e.g., liydrides. allcoxides, hydroxides of alkali or alkaline earth metals. or of oraano-lithium compounds) with R5L in which L is a leaving group such as a halogen. or by condensation with an RS containing ketone or aldehyde carbonyl derivative to give a fused pyrrolocarbazole-6-one derivative which has one or two an RS groups. The derivatives from the ketone or aldehyde condensation reactions would give vinyl derivatives at R5.
The indole derivatives are prepared using standard methodology (U.S. Patent 3,976,639; U.S. Patent 3,732.245; The Chemistry of Heterocyclic Compounds, Indoles Parts One and Two; HouIihan Ed.. Wiley-Interscience ( 1972)}. The 2-indanone derivatives can be prepared usiua previously described procedures (see U. S.
Patent 4,192,888; U.S. Patent 4,128.666; J. ~Inz. Chenz. Soc. 89:4524 ( 1967);
Tetrahedron Lett.
43:3789 ( 1974); Chenz. Ber. 122: 1791 ( I 989); Can. J. Chem. 60:2678 ( 1982); Helvetiea Chimica Acta 70:179 I ( I 987); Chenz. Plzarnz. Bull. 33:3336 ( 1985 ); J.
Org. Chem.
55:4835 ( 1990}; Tetrahedron ~15: t 44 I ( 1989); Synthesis 818 ( 1981 )}.
l~
In Method B (FiG 2), a 2-{heteroaryI)indoie derivative (1-3), or 2-(aryl}indole derivative such as 2-{2-indenyi)indole 4 is reacted with ethyl cis-(3-cyanoacrylate in the presence of a catalyst such as SnCL:;, AlCl3, EtAlCl2, Et2A1C1 or TFA in CH2C12, C2H4C12 or toluene as solvent to give the 6-oxo carbazole compounds offormula I ofthe invention.
Compounds of Foi~nula II are prepared as outlined in FIG 5. Addition of 2-(aryl)-or 2-(heteroaryl)indolyIzinc reagents (Tetrahedron Lett., 1994, 35, 793;
Tetrahedron Lett., 1994. 35, 7123: Tetr-al~edroiz Lett.. 1993, 3=F, 5955: Tetrahedron Lett., I993, 34, 6245) to succanimide. or an R' substituted succinimide derivative, via a Reformatzsky type reaction (Synthesis. 1975. 685) followed by dehydration would give compounds ofthe general structure 9. PalladiuFn catalyzed ring closure (US Patent 5,475,1 I0;
Tetrahedron Lett., 1993, 34, 8361) would yield pyrrolo[2.3-c]carbazole compounds ofFormula II.
Compounds in which X = (C=O) (general structure 10) are prepared by oxidation of derivatives of general Formula I (or II) where X = CH2, using standard oxidizing reagents (e.g., Se02,. Cr03. Na2Cr07, or Mn02) (FIG 6). Alternatively, 2-(2-indenyl}indole 4 may be oxidized to 2-(2-( t-oxoindenyl)indole and used to prepare compounds of Formula I or II where X = {C=O) by the methods shown in FIGS 2 and 5.
Alternatively, 2-(2-( 1-oxoindenyl))indole I 1 may prepared using the palladium-catalyzed cross-coupling methodology (F1G 3) by coupling I-carboxy-2-tributylstannylindole 5 or its derivatives with 2-(trifluorotnethanesulfonyl)oxyinden-I-one or 2-bromoinden-I-one 12 (FIG 7) (J. Org. Chenz.. I994, 59, 3453) or one ofits derivatives.
Compounds ofthe general structure 10 (X = (C=O)) may undergo a variety of olefination, addition and condensation reactions known to those skilled in the art of organic synthesis to give derivatives, for example, but not limited to, X = (C=C(R2)2), C{R2)2, C{ORI
I)(RI I}.
Fused pyrrolocarbazole-6-one derivatives where X is S(=O) or S(=O)2 may be prepared by oxidation of X = S derivatives in a mamier similar to X = (C=O).
a ~7 EXAMPLES
V. Specific Description of the Synthetic Processes The following examples are presented for purposes of illustration and are not to be construed as limiting the scope of the invention in any way.
A. Exanapte I: SH, 7H, 13H-Benzofurano[2,3-a]pyrrolo[2,3-cJcarbazole-6(6H}one (X = O; R!, R2, R3, R4, RS = H) A miocture of 2-(2-benzofuryl)indole 2 (250 mg; I.0 mmol) and maleimide {110 mg; I.2 mmol) in triffuoroacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C
for 18 h. The solid precipitated was collected. washed with TFA and dried to give 150 mg (48 %) of product. Recrystallization (THF} gave a tan solid; mp >300 °C., MS (ES+) 312 (M+}, 1H NMR {DMSO- d~) cS =1.00 (s, 2H). 4. I3 (s, 2H), 7.12 (t, 1H), 7.37 (t, 2H), 7.45 (t, 2H), 7.71 (d, 1H). 7.95 (d. 1H), 8.54 (d, 1H'), 10.12 (s, IH), 11.79 (s, 1H). Anal. calcd for CzoFilzNzOz'0.4 HzO; C. 75. 18; H, 4.04; N, 8.77. Found: C, 75.29, H, 3.86, N, 8.60.
B. Example IZ: 5H, 7H, 13H-Benzothieno[2,3-a]pyrrolo[2,3-c]carbazole-6(6H)one (X = S: R1, R2, R3, R4, RS = H) A miacture of 2-(2-benzothienyl)indole 3 ( 100 mg, 0.4 mmol} and maleimide (40 mg; 0.4 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C
for 16 h. The solid precipitated was collected, washed with cold methanol and dried to give 80 mg (58 %) of product. Recrystallization (THF) gave a tan solid; mp >300 °C., MS
(ES+) 328 (M+), IH NlViR (DMSO- d~) 8 4.10 (s, 2H), 7.20 (t, 1H), 7.40-7.60 (m, 4H), 8.10 (d, 1H), 8.80 (m. 1H). l0.86 (s, 1H), 11.80 (s, 1H). Anal. calcd for CzaHlzNzSO.
0.5 HzO; C, 71.20; H, 3.88: N, 8.30. Found: C, 70.86, H, 3.61, N, 8.39.
C. Example III: SH. 7H. 12H, 13H-lndolo[2,3-a]pyrrolo[2,3-cJcarbazole-6(6H)one (X = N: R!. R2, R-'. R4, R~ = H) (1} Method A
To a mi,~cture of 2-2'-biindole 1 (250 mg; 1.0 mmol) and maleimide (110 mg; 1.2 mmol) suspended in toluene (50 mL) was added trifluoroacetic WO 97/31002 PCTlUS97/02905 1g acid (0.5 mL). The solution was heated at refIux for 18 h., cooled to rt, and concentrated to approximately 20 mL. The solution was cooled in an ice bath, the solid precipitate was collected, washed with cold etlier and dried to give I50 mg (55 %} of product.
Purification by column chromatography (EtOAc: liexanes; 2:1} gave a brown-tan solid, mp >320 °C., MS (ES+) 3 I I (M+), ~H NMR (DMSO- ds) 8 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.67 (d. 2H}, 8.03 (d, IH), 8.58 {d, IH), 10.87 (s, IH), 10.92 (s,lH), 11.18 (s, 1H). Anal. calcd for C~oH,~N~02' 0.5 HaO; C, 74.99; H, 4.41;
N, 13.12.
Found: C, 75.24, H,4.02, N. 13.05.
(2) Method I3 A mixture of 2-2'-biindole 1 ( I00 mg; 0.43 mmol) and ethyl cis-[3-cyanoacrylate (50 mg; 0..4 imnol) ui metliyiene chloride ( 10 mL) was added 25 mL
of SnCl.,. The mixture was stirred at rt for 30 min. The suspension was cooled on an ice bath, the solid collected, washed with cold ether and dried to give 36 mg (27 %) of product. Purification by column chromatography (EtOAc: hexanes; 2:I) gave a brown-tan solid; mp >320 °C., MS (ES~} 3 I 1 (M+), ~H NMR (DMSO- d6) 8 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.67 (d, 2H), 8.03 {d, IH}, 8.58 (d, 1H}, 10.87 (s, 1H), 10.92 (s,lH}, 11.18 (s, 1H).
This compound showed identical spectral and analytical characteristics as that prepared by Method A.
I~. Example (V: 5H, 7H. 12H, I3H-Indeno[2,3-a]pyrrolo[2,3-c)carbazole-6(6H)one (X = CHI; RI, R2, R3, R4, R5 = H) (1) Method A
A mixture of 2-(2-indenyl)indole 4 (300 mg, I.3 mmol) and maleimide ( 160 mg; 1.6 nunol} in trifluoroacetic acid {2 mL) was heated in a sealed reaction vial at 160 °C for 18 h. Tlie solution was evaporated and the solid dissolved in ethyl acetate, then waslied with water and dried {MgS04) to give brown solid product.
The crude product was ctwomatographed (silica gel, EtOac: hexanes; 1:1) to give a product which was treated with THF and filtered. The concentrated residue was trittutrated with MeOH to Give tl~e product: mp 275-280 °C., MS {ES+) 310 (M+), 'H ' - NMR (DMSO- d6) 8 4.00 (s, 2H), -I. 13 (s. 2H), 7. 17 (t, 1H), 7.25-7.42 (m, 3H), 7.50 (d, 1H), 7.7I (d, 1H), 8.00 (d, 1H), 8.37 (d, 1H), 10.75 (s, 1H), 11.33 (s, 1H).
IR (KBr) 1650-1700 cm l. Anal. calcd for C~,Hi.~N~O 0.7 H20; C, 78.1b; H, 4.81; N, 8.65. Found:
C,78.13,H,4.41,N,8.L0.
(2) Method B
A mi,~-ture of 2-(2-indenyl)indole 4 {75 mg; 0.32 mmol) and ethyl cis-(3-cyanoacrylate {81 mg: 0.64 mmol) in trifluoroacetic acid (1 mL) was heated in a sealed reaction vial at 120 "C for I li., followed by 4 h at 160 °C.
The mvmue was evaporated at reduced pressure and the residue was triturated with ether. The resulting solid was chromatographed (silica gel; EtOAc: hexanes; 1:i) to give I2 mg {12%) of tan solid product; mp 275-280 "C._ MS (ES+) 310 (M+). This compound showed identical spectral data as tliat prepared in Method A.
E. Example V: Enhancement by Fused Pyrroio[2,3-c]carbazole-6-ones of the Induction by LFN-y of the MHC II Antigen EILA-DR
A human cell rule derived from liuman monocytes, THP- I {ATCC TIB 202) that responds to IFN-y, was used to demonstrate enhancement of HLA-DR by the fused pyrolo[2,3-c]carbazole-6-ones.
THP-1 cells were grown in RPMI 1640 medium containing 20 uM
mercaptoethanol and 10% fetal bovine serum at 37°C in an atmosphere of5%C02:95%
air at 100% humidity. For determination of enhancement of HLA-DR by the compounds of the invention, cells were either left untreated as controls, treated with IFN-y only at 100 units/ml, or treated with compounds of the uivention at 1 uM final concentration for 30 min. prior to the addition of IFN-y at 100 units/mi. Duplicate cultures were used in all experiments. The treated THP-1 cells were incubated at 37°C for 48 hours and then prepared for analysis of HLA-DR by Flow Cytometry. Induction of HL.A-DR was performed by standard procedures as described in Lnterferons and Other Re atory Cytokines, Edward De Maeyer and Jacqueline De Maeyer Guignard, Chapter 9, John Wiley & Sons, New York. 1988. Cells were prepared for flow cytometry and analyzed for HLA-DR by flow cytometry as instructed in Current Protocols in Immcmoloay.
Vol. I, pages 5Ø1-5.8.8, Jolu~ Wiley & Sous. 1994. One million cells from each treatment were collected by centrifugation and washed twice with phosphate-buffered saline (PBS). The cells were resuspended in 100 u1 of PBS containing 10 ug ofpurified rabbit IgG
to block non-specific sites on the cell surface. After 20 min. on ice, 20 u1 of anti-HLA-DR
monoclonal antibody tagged with the fluorescent label FITC was added and the cells left on ice an additional 30 min to allow the antibody to bind to the HLA-DR The cells were WO 97/31002 g'CT/US97/02905 ~D
then washed 2 times with PBS each wash and fixed in 0.5 mt of0.5%
paraformaldehyde.
The fixed cells were stored at .4°C until analyzed by flow cytometry.
The enlxancement of E-1LA-DR by representative fused pyrrolo[2,3-c)carbazale-5-ones is shown in FIG 1. Tlie enhancement of HLA-DR by IFN-y alone is designated 100% on the Y axis. There is no sigiu$cant uiduction of HL.A-DR by the representative compounds alone at I uM (F1G t ). All of the representative compounds enhance the induction of HLA-DR by IFN-y above the induction by IFN-y alone, i.e. above 100%.
The percent enliancement above IFN-y alone by the four compounds is shown in Table I.
For example. at: 2l.tM. the compound of Section V(D) (Example IV) enhanced IFN-y induction of HLA-DR by 60% over 1FN-y alone.
Compound of Conc. of Fused Conc. of Ig'N-y,Percent Euample # Pyrrolo[2,3- Units/ml Enhancement cjcarbazole-b-one, of a VI HLA.-DR
1 - 100* 100 1 ? I00 I08 U - _ 0 B - I00* I00 B t 100 133 B ? 100 153 ITI _ _ 0-- 100* 100 N - 100* 100 ~ ? t00 160 arm-y alone is aennea as ~ uu ro.
F. Eiample vI. NT-3 Potentiadoa of ChAT Activity in Basal Forebrain Cultures by Pyrrolo[2,3-c]carbazole-6-ones The ability of pyrrolo[2,3-c]carbazole-6-ones to potentiate NT-3 activity in basal forebrain cultures was determined using chotine acetyltransferase (ChAT) activity as a measure of cholinergic neuron function or survival. The compounds alone had no effect on ChAT activity. However, in the presence ofNf-3, the representative compounds gave a dose dependent potentiation of ChAT activity to levels greater than those elicited by NT-3 alone. The results shown in Table 2 are the result of a single application ofNT-3 and the compound to be tested on the day of culture initiation, indicating a prolonged effect on the stuvival or function of basal forebrain cholintrgic neurons. The methods employed are descn'bed in U.S. Patent 5,468,872, Columns 18 and 19.
Table 2 Compound of '/. Basui % NT 3 Eiample # (mean (mean SD) SD) laDnM 300nM 100nM
300aM
NT-3+I I84+3 221+2 113+2 136+1*
NT3 + II 2I2 + 4 228 + 13 0+ 140 +
13 2* 1 NT3+IZZ 180+3 203+2 114+2 129+1*
NT 3 (100 ng/ml) iaon~sed ChAT Activityr 163 ~ 5 % (rncaa ~ SD) over control calt~s. Test c~ands ahe had basal (100°!0) level of aetMty.
*p < 0.05, statistically swim ooaaparod to NT-3 activhy alone by Duandt t st~istics.
Those skdIed in the art will appreaate that numerous chaages and modifications may be made to the prtfetred embodiments of the imrention and that such changes and modifications may be made without departing from the spirit of the invention.
It is therefore intended that the appended claims coves all e~quNalent variations as fall within the true spirit and scope of the invention.
Rj-N RS
N X
Constituent numbers are defined, infra. Preferred methods for preparing these compounds are disclosed infra.
We have discovered that our fused py~olo[2,3-c]carbazole-6-one compounds (numbering as designated for K-252a and K-252c set forth in Moody et. al, J.
Org.
Chem., 1992, 57, 2105) potentiate the activity ofhuman IFN-y in inducing the expression of MHC on the surface of receptive cells. The compounds of the invention show ability for enhancing the effectiveness of the immune system, and this in turn provides, beneficially, an enhancement in inhibiting virus andlor tumor growth. We have also discovered that the fused pyrrolo[2,3-c]carbazole-6-one compounds ofthe invention are useful for potentiating, preferably, neurotrophin-3 (NT-3) activity.
DETAIi,ED DESCRIPTION
We first describe the drawings.
i. Drawings Figure 1 is a graph sliowing the enliancement of IFN-y-induced expression of HLA-DR MHC II molecule by pyrrolo[2,3-c]-carbazole-6-ones of the invention.
Figure 2 is a schematic drawing outlining the chemical synthesis ofthe pyrrolo[2,3-- c]carbazole-6-ones of Formula I, Section V (A)-(D).
Figure 3 is a schematic drawing showing the synthesis of intermediates to pyrrolo[2,3-c]carbazole-6-ones.
y Figure 4 is a scliematic drawing showing an alternate synthesis of intermediates to pytrolo[2,3-c]carbazole-6-ones.
Figure S is a schematic drawing showing the synthesis ofpyrrolo[2,3-c]carbazole-6-ones of Formula LI.
Figure 6 is a schematic drawing showing the synthesis ofpyrrolo[2,3-c]carbazoie-6-ones in which X is C=O from the corresponding compounds in which X is CHa.
Figure 7 is a schematic drawing showing the synthesis of intermediate I I to pyrroio[2,3-c]carbazole-6-ones.
II. Fused pyrrolo[2,3-cJcarbazole-6-ones The novel compounds of this invention, which are referred to as fused pytroio[2,3-c]carbazole-6-one derivatives are represented by the following Formulae:
O O
R6 N-R~ R'~_.N RS
N X )( I and II
wherein:
a) R I is selected from the group consisting of H, alkyl of 1-4 carbons, aryl, arylalkyI, heteroaryl, lieteroarylalkyl; C(=O)R9. where R9 is alkyl of I-4 carbons or aryl; (CH2)"OR9, where n is an integer of 1-4; OR1°, where Rl°
is H or allcyl of I-4 carbons; (CH~)"OR''' _ where R 1'l is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed ; OR''', NR~RB; (CH2}aNR~Rg, and O(CH2~NR7R8: and either WO 97/31002 PCTlLTS97/02905 " (I) R~ and R8 independently are H or alkyl of 1-4 carbons; or (2) R~ and R8 are combined together to form a linking group of the general formula -(CH2)2-X1-{CH2)2-, where X1 is O, S or CH2;
b) R2 is selected form tire group consisting ofH, S02R9, C02R9, C(=O)R9, alkyl of I-8 carbons, alkenyl of 1-8 carbons, alkynyl of 1-8 carbons, and a monosaccharide of ~-7 carbons. wherein each hydroxyl group of said monosaccharide is independently selected from the group consisting of unsubstituted liydroxyl and a replacement moiety replacing said hydroxyl group selected from the group consisting of H, alkyl of 1-4 carbons, alkylcarbonyloxy of 2-S carbons, and allcoxy of 1-4 carbons; wherein either 1) each alkyl of 1-8 carbons, allcenyl of 1-8 carbons, or alkynyl of 1-8 carbons is unsubstituted; or 2} each alkyl of 1-8 carbons, allcenyl of 1-8 carbons, or alkynyl of I-8 carbons independently is substituted with I-3 groups selected from the group consisting of aryl of f>- I O carbons, heteroaryI, F, Cl, Br, I, CN, N02, OH, OR9, O(CH2)aNR~RB, OCOR9, OCONHR9, O-tetraliydropyranyl, NH2, NR~RB, NR10COR9~ NR10C02R9, NR10CONR7R8, NHC(=NH)NH2, NR10S02R9; S(Oh,Rll, wherein R11 is H, alkyl of 1-~ carbons, aryl of 6-10 carbons, or heteroaryI, and y is I or 2; SR11, C02R~, CONR7R8, CHO, COR9, CH20R7, CHaOR9, CH=NNR11R12, CH=NOR11, CH=NR9>
CH=NNHCH(N=NH)NH2. SO2NR12R13; wherein either (la) R12 and R13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons,or heteroaryl; or (2a) R 12 and R 13 are combined together to form a .-(CH2)2-X 1-(CH2)2 ~g ~'ouP~
POOR 1 1 )2. NHR", NR'°R~'', OR 14, and a monosaccharide of S-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, alkyicarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons;
c) each R3 and R4, independently, is selected from the group consisting of H, aryl of6-10 carbons, heteroaryl, F, CI, Br, I, CN, CFA, N02, OH, OR9, O(CH2}nNR~RB. OCOR9, OCONHR9, NH2, (CH2~OR9, (CHa)~ORIO, (CH2)nORI4, ORS''. NHR''', NR7R8, NR'(CH2~NR~RB,NRIOCOR9, ~lOC0~7R8, SRI I, S(O)yRI I, C02Rg, COR9, CONR~RB, CHO, CH=NORl I, CH=NR9, CH=NNRI 1RI2, (CH2~SR9, (CH2~S(Oh,R9;
CH2SRI5, where RIS is alkyl of I-~I carbons; CH2S(Oh,RI4, (CH2~NR~RB, (CH2~NHR14, all.-yi of I-8 carbons, alkenyl of I-8 carbons, and alhynyl of I-8 carbons; and either I) each alkyl of I-8 carbons, allcenyl of 1-8 carbons or alkynyl of I-8 carbons is unsubstituted; or 2) each alkyl of I-8 carbons, alkenyI of I-8 carbons, or alkynyl of I-8 carbons is independently substituted as described in b)2) above;
d) RS is selected from the group consisting of alkyl of I-8 carbons, alkenyl of I-8 carbons, and aikynyl of 1-8 carbons; and either 1) each alkyl, alkenyl, or allcenyl group is unsubstituted ; or 2) each alkyl, allcenyl, or alkynyl group is substituted with I-3 groups selected from the group consisting of F, CI, Br, I, CN, CF3, N02, OIL
OR9, O(CH2~NR~RB, OCOR9, OCONHR9, NH2, (CH2~OR9, (CH2)nORI4. NR7R8, NR'(CH2}nNR~RB.NRI0COR9, NRIOCONR~RB, SRI I. S(O}yRI I, C02Rg, COR9, CONR~RB, CHO, CH=NORI i, CH=NR9, CH=NNRI IR12, (CH2~SR9, (CH2~S(O~,R9, CH2SR15, CH2S(O}yRl4 (CH2}nNR~RB, and (CH2}nNHR''':
e) X is selected from the group consisting of -N-, -O-, -S-, -S(=O)-, -S(=O}Z-, alkylene of I-3 carbons, -C(=O)-, -C(R2)=C(RZ}-, -C(RZ}Z-, -CH=CH-, -CH(OH)-CH(OH)-, -C(=NOR11)-, -C(OR11)(R11)_, _C(=O)CH(R15)-, -CH(R15)C(=O)-;
-CH2-Z-, -Z-CH2-, -CH2ZCHz- where Z is selected from the group consisting of -C(OR11)(R")-, O, S, C(=O), and NR11; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one RS substituent group, SR'o, OR'°, OR''', R''S, phenyl, naphthyl, and arylallcyl of 7-I4 carbons.
As used lierein, the term "aryl" means monocyclic and polycyclic aromatic groups including, for example, phenyl, naplitliyl, biphenyl, and xylyl groups. Aryl groups may be unsubstituted or substituted with, for example, alkyl and halogen groups.
Halogens include fluorine, chlorine, bromine, and iodine. Preferred are aryl groups which contain 6-carbons. Phenyl and naphthyl groups are particularly preferred.
As used herein, the term '9ieteroaryl" means an aryl moiety which contains at least one basic nitrogen atom and 0-4 heteroatoms selected from O, S, and N.
Examples of heteroaryl groups include pyrrolyl, pyranyl, thiopyranyl, furyl, imidazolyl, pyridyi, thiazolyl, triazinyl, phthalimido, indolyl. purinyl, and benzothiazolyl.
As used herein witli reference to the definition of R 14, the term "amino acid"
means a molecule containing both an amino group and a carboxyl group. Tt includes an "a.-amino acid" which lias its usual meaning as a carboxylic acid which bears an amino functionality on the carbon adjacent to the carboxyl group. oc-Amino acids can be naturally occurring or non-naturally occurring. Amino acids also include "dipeptides"
which are defined herein as two amino acids which are joined in a peptide amide linkage.
Thus, constituents of dipeptides are not limited to a-amino acids, and can be any molecule containing both an amino group and a carboxyl group. Preferred are a.-amino acids, dipeptides such as Iysyl-~i-aianine, and aminoalkanoic acids of 2-8 carbons, e.g., 3-dimethylaminobutyric acid.
- Preferred "alkyl", "alkenyl", and "alkynyl" groups contain 1-4 carbon atoms.
Preferred R' groups include H, alkyl of 1-4 carbons, substituted or unsubstituted phenyl, OR'°, and O(CH2)"NR'R°. Preferred phenyl substituents include alkyl of 1-4 r carbons, and halogen. Most preferred is H.
Preferred RZ groups include H, C(=O)R9, allcyl of 1-8 carbons, and alkyl of 1-carbons substituted with one OR'', OH. OCOR9, NR'R8, NH2, NR'°COR9, or NR'°R''' group. Most preferred is H.
Preferred R; and R'' groups include H, lialogen, CN, OH, OR9, ORl'', NHa, NR'R8, (CHa)~OR'°, (CFiz)~OR'''. COR''. NR'°COR', NHR''', and O(CHZ)~NR'R8. Most preferred is H.
Preferred RS groups include H, and alkyl of 1-4 carbons. Most preferred is H.
Preferred X groups include -N-, -O-, -S-, allcylene of 1-3 carbons, -C=O-, -CH2-Z- and -Z-CHZ-. Most preferred are -N-, -O-, -S-, and -CH2- groups.
IQ. Fused Pvrrolo[2,3-c] carbazole-6-one Utilities Our fused pyrrolo[2,3-c]carbazole-6-ones have evidenced a panoply ofimportant functional activities which find utility in a variety of settings, including both research and therapeutic arenas. For ease of presentation, and in order not to Limit the range of utilities for which these compounds can be characterized, the preferred activities of the fused pyrroio [2,3-c] carbazole-6-ones can be generally described as follows:
A. Enhancement of IFN-y induction of MHC molecules;
B. Potentiation of function and/or survival of trophic factor responsive cells.
Enhancement of IFN-y induction of MHC molecules can preferably be established using a human monocyte cell line that responds to IFN-y; a particularly preferred cell line is WO 97/31002 PCTlUS97/02905 q available from the American Type Culture Collection (ATCC), referred to as THP-1, under accession number ATCC TIB-202. 1FN-y is laiown to induce expression ofthe three MHC II heterodimers. HLA-DP, HLA-DQ and HLA-DR; in THP-!cells.
Potentiation of function and/or survival of trophic factor responsive cells, e.g., cells of neuronal lineage, can be preferably establislied using a cultured spinal cord choIine acetyltransferase ("ChAT") assay.
As used herein, the term 'poteutiation" when used to modify the terms "function"
and "survival" means a positive alteration or change. Potentiation which is positive can also be referred to herein as an "enliancement" or "enhancing."
As used herein. the teens ''enhance" or "enhancing" or enhancement when used to modify the terms "fllnCt10I1" or wsmvival" or ''induction" means that the presence of a fused pyrrolo[2,3-c]carbazole-6-one has a comparatively greater effect on the function and/or survival of a tropliic factor responsive cell or, in the case of IFN-y, induction of MHC molecules, than a comparative cell not presented with the fused pyrrolo[2,3-c]carbazole-6-one.
As used herein the term 'neuron," "cell of neuronal lineage" and 'heuronal cell"
includes, but is not limited to. a heterogeneous population of neuronal types having singular or multiple transmitters and/or singular or multiple functions;
preferably, these are cholinergic neurons. As used herein, the phrase "choIinergic neuron" means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; exemplary are basal forebrain and spinal cord neurons.
As used herein a "trophic factor" is a molecule that directly or indirectly affests the survival or function of a trophic factor responsive cell. Exemplary trophic factors include CiIiary Neurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF), insulin and insulin-like growth factors (e.g., IGF-L, IGF-II, IGF-III), interferons, interleukins, cytokines, and the neurotrophiits. sncludtng Netve Growth Factor (NGF), Neurotrophin-3 (NT-3), Neurotrophiii-=1/5 (NT--I/~) and Brain Derived Neurotrophic Factor (BDNF).
A "trophic factor-responsive cell," as defined herein, is a cell which includes a receptor to which a trophic factor can specifically bind; examples include neurons (e.g., cholinergic neurons) and non-neuronal cells (e.g., monocytes and neoplastic cells).
lo As used herein, "tropliic factor- activity" and "trophic factor induced activity" are defined as any response which directly or indirectly results from the binding of a trophic factor (e:g., NT-3) to a cell comprising a trophic factor receptor.
As used in the pln~ases "trophic factor activity" and "trophic factor-induced activity," the term "trophic factor" includes both endogenous and exogenous trophic factors, where "endogenous" refers to a tropluc factor already present and "exogenous"
refers to a trophic factor added to a system. As defined, "trophic factor induced activity"
includes activity induced by ( 1 ) endogenous trophic factors; (2) exogenous trophic factors;
and (3) a combination of endogenous and exogenous trophic factors.
A. Enhancement of 1FN-y Induction of MHC Molecules The compounds of the invention can be used to enhance IFN-y induction of MHC molecules. IFN-y has shown e$'ectiveness in the treatment ofvirus infections and certain tumors. Due to its dose limiting side e$'ects, however, the utility of IF'N-y has been limited. In an immunocompromised situation, e.g., in a patient evidencing viral infection, enhancement of au 1FN-y mediated immune response would he beneficial, given that IFN-y induces expression of MHC molecules. Thus, the compounds ofthis invention which enhance the ability of endogenous IFN-y or exogenously administered IFN-y to induce MHC expression are of benefit.
As detailed in Section V below, the ability of a fused pyrrolo[2,3-c]carbazole-one to enhance 1FN-y induction of MHC molecules is preferably assessed using the THP- I
cell line. This cell line evidences expression of the MHC II heterodimer HLA-DR.
Computing the expression of HLA-DR in the presence of IFN-y and IFN-y plus one or more fused pyrrolo[2,3-c]carbazole-6-ones oftlie present invention provides a rapid and e$icient method for deterLniziation of enhancement of IFN-y induction of MHC
molecules can be assessed.
The compounds of this invention can be used in the development of in vitro models of enhancement of expression of MHC molecules, function, identification, or for the screening of other synthetic compounds which have activities similar to that of the fizsed pyrrolo[2,3-c]carbazole-6-ones. The compounds can be utilized in a research environment to investigate, refine and determine molecular targets associated with fimctional responses.
For example, by radiolabelling a fused pyrolo[2,3-c]carbazole-6-one associated with a specific cellular fimction (e.g., HLA-DR induction), the target entity to which the fused pyrrolo[2,3-c]carbazole-6-one binds can be identified, isolated, and purified for characterization. In yet anotlier example, a fused pyrrolo[2,3-c]carbazole-6-one can be used as a screening tool to discover agents which have marginal activity, but when combined with at least one disclosed fused pyrrolo[2,3-c]carbazole-6-one are capable of enhancing IFN-y induction of MHC molecules. Because the disclosed fused pyrrolo[2,3-c]carbazole-6-ones are useful in enhancing 1FN-y induction of MHC molecules, the disclosed compounds beneficially lend tliemselves to utility as therapeutic agents. Such enhancement is ofvalue in an immunocompromised patient.
B. Potentiation of function and/or survival of trophic factor responsive cells The fused pyrrolo[2,3-c]carbazole-6-ones of this invention can be used to enhance the fimction and/or survival of cells ofneuronal lineage. The fused pyrrolo[2,3-c]carbazole-6-ones can be utilized individually or with other fused pyrrolo[2,3-c]carbazole-6-ones, or in combination witli other beneficial molecules such as indolocarbazoles whicli also liave the ability to potentiate the fimction and/or survival of a designated cell: In. situations wliere the fused pyrroio[2,3-c]carbazole-6-one is intended to enhance a biological activity, e.g., neurotrophin activity, exogenous neurotrophins such as NT-3 may be utilized in conjunction with the fused pyrrolo[2,3-c]carbazole-6-one.
A variety of neurological disorders are characterized by neuronal cells which are dying, injured, fimctionally comprised, undergoing axonal degeneration, at risk of dying, etc. These disorders include, but are not limited to: Alzheimer's; motor neuron disorders (e.g., amyotrophic lateral sclerosis); Parkinson's; cerebrovascular disorders {e.g., multiple sclerosis; peripheral neuropathies (e.g., those affecting DRG neurons in chemotherapy-associated peripheral neuropathy); disorders induced by excitatory amino acids; disorders associated with concussive or penetrating injuries of the brain or spinal cord.
WO 97!31002 PCT/LTS97/02905 /~
As described in Section V below, the ability of a fused pyrrolo[2,3-c]carbazole-6-one to enhance the function and/or survival of cells of a neuronal lineage can be determined by employing a basal forebrain ChAT activity assay. ChAT catalyzes the synthesis of the neurotransmitter acetylcholine and is considered an enzymatic marker for a functional cholinergic neuron. A functional neuron is also capable of survival.
Enhancement of a neurotrophiu such as NT-3 can be determined by comparing the functional activity of the neurotropliin with or without the fused pyrolo[2,3-c]carbazole-6-one present.
Pharmaceutically acceptabie salts of the fused pyrrolo[2,3-c]carbazole-6-ones also fall within the scope of the present uivention. The term "pharmaceutically acceptable salts" as used herein means au inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fizmarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt. Examples of pharmaceutically acceptable ammonium salts are ammonium salt and tetramethylammonium salt. Examples of pharmaceutically acceptable organic amine addition salts are salts with morpholine and pipetidine. Examples of pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine.
Compounds provided herein can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers. Such compositions can be prepared for use in parenteral administration, particularly in the foam ofliquid solutions or suspensions; or oral administration, particularly in the form oftablets or capsules; or iutranasally, particularly in the form ofpowders, nasal drops, or aerosols;
or deimaIly, via, for example. trans-dermal patches.
The composition can be conveniently administered in unit dosage foam and may be prepared by any ofthe methods well known in the pliarmaceutical art, for example, as described in Renzirrgtorz's Plrarnrcrcezrtical Sciences (Mack Pub. Co., Easton, PA, 19$0).
Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, Wb 97/31002 PCTIUS97/02905 hydrogenated naphthaleues and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipieuts to control the release of the active compounds.
Other potentially useful pareuteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions coutaiving, for example, polyoxyethylene-9-lauryl ether, glycocholate and deo~cycholate. or oily solutions for administration in the form ofnasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccai administration, a salicylate for rectal administration, or citric acid for vaginal administration. Formulations for trans-dermal patches are preferably lipophilic emulsions.
The compounds of this invention can be employed as the sole active agent in a pharmaceutical composition. Alternatively, tliey can be used in combination with other active ingredients, e.g., synthetic iFN-y and/or other growth factors which facilitate potentiation ofNT-3 sucli as tliose disclosed in U.S. Patent No. 5,468,872 and International Publication No. WO 95/0791 1 (publication date: March 23, 1995).
The concentrations of the compounds of this invention in a therapeutic composition can vary. Tlie concentration will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) ofthe compounds employed. and the route ofadministration. The compounds ofthis invention typically are provided in au aqueous pliysiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about 1 p.g/kg to about I g/kg ofbody weight per day; a preferred dose range is from about 0.01 mg/kg to I 00 mg/kg of body weight per day. A preferred dosage of drug to be administered is likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological afficacv of the compound selected, and formulation of the compound excipient, and its route of adnmustration.
ey IV. General Description of the Synthetic Processes Two synthetic routes were employed to prepare the fused pyrrolo[2,3-c]carbazole-6-one derivatives of the inventiou. In Metliod A (FIG 2) a 2-{aryl) or 2-(heteroaryl)indole derivative (1-4.) which is either uusubstituted or substituted at carbons 4-7 (inclusive) of the indole ring (R') or substituted or unsubstituted in the (hetero)aryl portion (R4) is reacted with maleimide in the presence of a catalyst such as, trifluoroacetic acid (TFA) to give the fused pyrrolocarbazoie-6-one derivatives ofFormula I (Examples I-IV).
Additional Lewis acid cataIysts_ such as SnCl.~, A1C13, EtAICI2, or EtzAICI
may also be used to effect the reaction. The reaction may also be run in a solvent such as TFA, toluene, CH2CIz or 1,2-dichloroethane.
The bi-aryl indole intennediates. 2,2'-biindoie 1 (X = N, R2, R3, R4 = H), 2-{2-furyl)indole 2 (X = O, R2, R3, R4 = H) and 2-(benzothienyl)indole 3 (X = S, R2, R3, R4 = H) may be prepared using standard literature procedures (Hudkins, RL.; et.
al J.
Org.Chem., 1995, 60, 6218) {FIG 2). 2-(2-Tndenyl)indole 4 (FIG 3) (X = CH2, R2, R-', R4 = H), or 2-(2-indenyl)uidote derivatives substituted with an R' or R4 group, may be prepared by reacting 1-carboxy-2-(tributylstannyl)indole 5, or 1-carboxy-2-(tributylstannyl)indote substituted with au R3 group (Hudlcins, RL. et. a1 .I.
Org.Chem., 1995, b0, 6218) with 2-bromoindeue 6 (J. Org. Chem., 1982, 47, 705) or a 2-bromoindene substituted with an R'~ group. Alternatively, 2-(2-indenyl)indole 4 (X = CH2, R2, R3, R4 = H), or 2-{2-iudeuyl)indole derivatives substituted with an R3 or R4 group, may be prepared by reaction of 1H-indole or a derivative thereof containing an R3 group, protected as a lzthium iudole-1-carbo~cylate intermediate (Tetrahedron Lett.
26:5935 (1985)), then treated with a strong base, such as t-Bui..i, then alkylated with an appropriate 2-indanone, or 2-indanoue derivative substituted with an R4 group to give the corresponding tertiary alcohol 7 (FIG 4). The resulting tertiary alcohol 7 is treated with a dilute acid {e.g., 2N HCl in acetone) to give the corresponding 2-(2-indenyl)indole 4 (US
Patent 5,475,110). Using other Benzocycloallcan-2-ones such as 2-tetralone in the reaction sequence shown in Figure 4 will give 2-{2-(3,4-dihydronaphthyl)indole 8 (X =
CH2CH2, R2, R3, R4 = H) ( US Patent 5.475,110). Tlie palladium-catalyzed cross-coupling methodology (Stille reaction) may be used to prepare other dernratives, for example, where X in Figure 3 has 1-3 carbons (inclusive), by coupling the - 2-(trifluoromethanesuIfouate)- or the 2-iodo- or 2-bromovinyl derivative ofthe corresponding cyclic ketone with I-carboxy-2-tributylstannylindole to give 2-(2-benzocycloalkenyl)indoles.
The starting 1 H-iudole derivative described previously is converted to a 1-substituted indole derivative (R2 not H) by standard methodology, for example, by treatment of the 1H-indole with base and an alkylating agent to give a I-substituted indole. In these examples, the iudole derivative can be directly treated with a strong base (e.g., t-BuLi, sec-BuLi, n-BuLi, lithium diisopropylamide) followed by alkylation with a 2-indanone derivative to give the corresponding tertiary alcohol 7, which includes R2 substituents in position one of the indole ring. The 2-{aryl)- or 2-(heteroaryl)indole derivative (1-3), 2-(2-indenyl)indole 4, or 2-(2-( 1,2-diliydronaphthyl)indole 8 may be converted to intermediates which contain R' substituents in position one ofthe indole ring by the method described above for iudole derivatives.
Compounds of general formulae I and )Q which contain R' groups, not = H, may be prepared by starting with the appropriate R' substituted maleimide (FIG 2, Method A).
Compounds of general formulae I and LI. in which RI is hydrogen, can be allcylated in the presence ofbase (e.g., liydrides. alkoxides. hydroxides of alkali or alkaline earth metals, or oforgano-lithium compowids) by treatment with RIL in which L is a leaving group such as a halogen, mesylate or tosyiate to give a fused pyrrolocarbazole-6-one derivative which has an Rl group bound to the lactam nitrogen. Compounds of general formulae I
and II, in which RS is hydrogen, may be converted to derivatives where one or two RS
groups may be added by treatment of a fused pyrrolocarbazole-6-one derivative with one equivalent or an excess of a strong base ( e.g., liydrides. allcoxides, hydroxides of alkali or alkaline earth metals. or of oraano-lithium compounds) with R5L in which L is a leaving group such as a halogen. or by condensation with an RS containing ketone or aldehyde carbonyl derivative to give a fused pyrrolocarbazole-6-one derivative which has one or two an RS groups. The derivatives from the ketone or aldehyde condensation reactions would give vinyl derivatives at R5.
The indole derivatives are prepared using standard methodology (U.S. Patent 3,976,639; U.S. Patent 3,732.245; The Chemistry of Heterocyclic Compounds, Indoles Parts One and Two; HouIihan Ed.. Wiley-Interscience ( 1972)}. The 2-indanone derivatives can be prepared usiua previously described procedures (see U. S.
Patent 4,192,888; U.S. Patent 4,128.666; J. ~Inz. Chenz. Soc. 89:4524 ( 1967);
Tetrahedron Lett.
43:3789 ( 1974); Chenz. Ber. 122: 1791 ( I 989); Can. J. Chem. 60:2678 ( 1982); Helvetiea Chimica Acta 70:179 I ( I 987); Chenz. Plzarnz. Bull. 33:3336 ( 1985 ); J.
Org. Chem.
55:4835 ( 1990}; Tetrahedron ~15: t 44 I ( 1989); Synthesis 818 ( 1981 )}.
l~
In Method B (FiG 2), a 2-{heteroaryI)indoie derivative (1-3), or 2-(aryl}indole derivative such as 2-{2-indenyi)indole 4 is reacted with ethyl cis-(3-cyanoacrylate in the presence of a catalyst such as SnCL:;, AlCl3, EtAlCl2, Et2A1C1 or TFA in CH2C12, C2H4C12 or toluene as solvent to give the 6-oxo carbazole compounds offormula I ofthe invention.
Compounds of Foi~nula II are prepared as outlined in FIG 5. Addition of 2-(aryl)-or 2-(heteroaryl)indolyIzinc reagents (Tetrahedron Lett., 1994, 35, 793;
Tetrahedron Lett., 1994. 35, 7123: Tetr-al~edroiz Lett.. 1993, 3=F, 5955: Tetrahedron Lett., I993, 34, 6245) to succanimide. or an R' substituted succinimide derivative, via a Reformatzsky type reaction (Synthesis. 1975. 685) followed by dehydration would give compounds ofthe general structure 9. PalladiuFn catalyzed ring closure (US Patent 5,475,1 I0;
Tetrahedron Lett., 1993, 34, 8361) would yield pyrrolo[2.3-c]carbazole compounds ofFormula II.
Compounds in which X = (C=O) (general structure 10) are prepared by oxidation of derivatives of general Formula I (or II) where X = CH2, using standard oxidizing reagents (e.g., Se02,. Cr03. Na2Cr07, or Mn02) (FIG 6). Alternatively, 2-(2-indenyl}indole 4 may be oxidized to 2-(2-( t-oxoindenyl)indole and used to prepare compounds of Formula I or II where X = {C=O) by the methods shown in FIGS 2 and 5.
Alternatively, 2-(2-( 1-oxoindenyl))indole I 1 may prepared using the palladium-catalyzed cross-coupling methodology (F1G 3) by coupling I-carboxy-2-tributylstannylindole 5 or its derivatives with 2-(trifluorotnethanesulfonyl)oxyinden-I-one or 2-bromoinden-I-one 12 (FIG 7) (J. Org. Chenz.. I994, 59, 3453) or one ofits derivatives.
Compounds ofthe general structure 10 (X = (C=O)) may undergo a variety of olefination, addition and condensation reactions known to those skilled in the art of organic synthesis to give derivatives, for example, but not limited to, X = (C=C(R2)2), C{R2)2, C{ORI
I)(RI I}.
Fused pyrrolocarbazole-6-one derivatives where X is S(=O) or S(=O)2 may be prepared by oxidation of X = S derivatives in a mamier similar to X = (C=O).
a ~7 EXAMPLES
V. Specific Description of the Synthetic Processes The following examples are presented for purposes of illustration and are not to be construed as limiting the scope of the invention in any way.
A. Exanapte I: SH, 7H, 13H-Benzofurano[2,3-a]pyrrolo[2,3-cJcarbazole-6(6H}one (X = O; R!, R2, R3, R4, RS = H) A miocture of 2-(2-benzofuryl)indole 2 (250 mg; I.0 mmol) and maleimide {110 mg; I.2 mmol) in triffuoroacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C
for 18 h. The solid precipitated was collected. washed with TFA and dried to give 150 mg (48 %) of product. Recrystallization (THF} gave a tan solid; mp >300 °C., MS (ES+) 312 (M+}, 1H NMR {DMSO- d~) cS =1.00 (s, 2H). 4. I3 (s, 2H), 7.12 (t, 1H), 7.37 (t, 2H), 7.45 (t, 2H), 7.71 (d, 1H). 7.95 (d. 1H), 8.54 (d, 1H'), 10.12 (s, IH), 11.79 (s, 1H). Anal. calcd for CzoFilzNzOz'0.4 HzO; C. 75. 18; H, 4.04; N, 8.77. Found: C, 75.29, H, 3.86, N, 8.60.
B. Example IZ: 5H, 7H, 13H-Benzothieno[2,3-a]pyrrolo[2,3-c]carbazole-6(6H)one (X = S: R1, R2, R3, R4, RS = H) A miacture of 2-(2-benzothienyl)indole 3 ( 100 mg, 0.4 mmol} and maleimide (40 mg; 0.4 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C
for 16 h. The solid precipitated was collected, washed with cold methanol and dried to give 80 mg (58 %) of product. Recrystallization (THF) gave a tan solid; mp >300 °C., MS
(ES+) 328 (M+), IH NlViR (DMSO- d~) 8 4.10 (s, 2H), 7.20 (t, 1H), 7.40-7.60 (m, 4H), 8.10 (d, 1H), 8.80 (m. 1H). l0.86 (s, 1H), 11.80 (s, 1H). Anal. calcd for CzaHlzNzSO.
0.5 HzO; C, 71.20; H, 3.88: N, 8.30. Found: C, 70.86, H, 3.61, N, 8.39.
C. Example III: SH. 7H. 12H, 13H-lndolo[2,3-a]pyrrolo[2,3-cJcarbazole-6(6H)one (X = N: R!. R2, R-'. R4, R~ = H) (1} Method A
To a mi,~cture of 2-2'-biindole 1 (250 mg; 1.0 mmol) and maleimide (110 mg; 1.2 mmol) suspended in toluene (50 mL) was added trifluoroacetic WO 97/31002 PCTlUS97/02905 1g acid (0.5 mL). The solution was heated at refIux for 18 h., cooled to rt, and concentrated to approximately 20 mL. The solution was cooled in an ice bath, the solid precipitate was collected, washed with cold etlier and dried to give I50 mg (55 %} of product.
Purification by column chromatography (EtOAc: liexanes; 2:1} gave a brown-tan solid, mp >320 °C., MS (ES+) 3 I I (M+), ~H NMR (DMSO- ds) 8 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.67 (d. 2H}, 8.03 (d, IH), 8.58 {d, IH), 10.87 (s, IH), 10.92 (s,lH), 11.18 (s, 1H). Anal. calcd for C~oH,~N~02' 0.5 HaO; C, 74.99; H, 4.41;
N, 13.12.
Found: C, 75.24, H,4.02, N. 13.05.
(2) Method I3 A mixture of 2-2'-biindole 1 ( I00 mg; 0.43 mmol) and ethyl cis-[3-cyanoacrylate (50 mg; 0..4 imnol) ui metliyiene chloride ( 10 mL) was added 25 mL
of SnCl.,. The mixture was stirred at rt for 30 min. The suspension was cooled on an ice bath, the solid collected, washed with cold ether and dried to give 36 mg (27 %) of product. Purification by column chromatography (EtOAc: hexanes; 2:I) gave a brown-tan solid; mp >320 °C., MS (ES~} 3 I 1 (M+), ~H NMR (DMSO- d6) 8 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.67 (d, 2H), 8.03 {d, IH}, 8.58 (d, 1H}, 10.87 (s, 1H), 10.92 (s,lH}, 11.18 (s, 1H).
This compound showed identical spectral and analytical characteristics as that prepared by Method A.
I~. Example (V: 5H, 7H. 12H, I3H-Indeno[2,3-a]pyrrolo[2,3-c)carbazole-6(6H)one (X = CHI; RI, R2, R3, R4, R5 = H) (1) Method A
A mixture of 2-(2-indenyl)indole 4 (300 mg, I.3 mmol) and maleimide ( 160 mg; 1.6 nunol} in trifluoroacetic acid {2 mL) was heated in a sealed reaction vial at 160 °C for 18 h. Tlie solution was evaporated and the solid dissolved in ethyl acetate, then waslied with water and dried {MgS04) to give brown solid product.
The crude product was ctwomatographed (silica gel, EtOac: hexanes; 1:1) to give a product which was treated with THF and filtered. The concentrated residue was trittutrated with MeOH to Give tl~e product: mp 275-280 °C., MS {ES+) 310 (M+), 'H ' - NMR (DMSO- d6) 8 4.00 (s, 2H), -I. 13 (s. 2H), 7. 17 (t, 1H), 7.25-7.42 (m, 3H), 7.50 (d, 1H), 7.7I (d, 1H), 8.00 (d, 1H), 8.37 (d, 1H), 10.75 (s, 1H), 11.33 (s, 1H).
IR (KBr) 1650-1700 cm l. Anal. calcd for C~,Hi.~N~O 0.7 H20; C, 78.1b; H, 4.81; N, 8.65. Found:
C,78.13,H,4.41,N,8.L0.
(2) Method B
A mi,~-ture of 2-(2-indenyl)indole 4 {75 mg; 0.32 mmol) and ethyl cis-(3-cyanoacrylate {81 mg: 0.64 mmol) in trifluoroacetic acid (1 mL) was heated in a sealed reaction vial at 120 "C for I li., followed by 4 h at 160 °C.
The mvmue was evaporated at reduced pressure and the residue was triturated with ether. The resulting solid was chromatographed (silica gel; EtOAc: hexanes; 1:i) to give I2 mg {12%) of tan solid product; mp 275-280 "C._ MS (ES+) 310 (M+). This compound showed identical spectral data as tliat prepared in Method A.
E. Example V: Enhancement by Fused Pyrroio[2,3-c]carbazole-6-ones of the Induction by LFN-y of the MHC II Antigen EILA-DR
A human cell rule derived from liuman monocytes, THP- I {ATCC TIB 202) that responds to IFN-y, was used to demonstrate enhancement of HLA-DR by the fused pyrolo[2,3-c]carbazole-6-ones.
THP-1 cells were grown in RPMI 1640 medium containing 20 uM
mercaptoethanol and 10% fetal bovine serum at 37°C in an atmosphere of5%C02:95%
air at 100% humidity. For determination of enhancement of HLA-DR by the compounds of the invention, cells were either left untreated as controls, treated with IFN-y only at 100 units/ml, or treated with compounds of the uivention at 1 uM final concentration for 30 min. prior to the addition of IFN-y at 100 units/mi. Duplicate cultures were used in all experiments. The treated THP-1 cells were incubated at 37°C for 48 hours and then prepared for analysis of HLA-DR by Flow Cytometry. Induction of HL.A-DR was performed by standard procedures as described in Lnterferons and Other Re atory Cytokines, Edward De Maeyer and Jacqueline De Maeyer Guignard, Chapter 9, John Wiley & Sons, New York. 1988. Cells were prepared for flow cytometry and analyzed for HLA-DR by flow cytometry as instructed in Current Protocols in Immcmoloay.
Vol. I, pages 5Ø1-5.8.8, Jolu~ Wiley & Sous. 1994. One million cells from each treatment were collected by centrifugation and washed twice with phosphate-buffered saline (PBS). The cells were resuspended in 100 u1 of PBS containing 10 ug ofpurified rabbit IgG
to block non-specific sites on the cell surface. After 20 min. on ice, 20 u1 of anti-HLA-DR
monoclonal antibody tagged with the fluorescent label FITC was added and the cells left on ice an additional 30 min to allow the antibody to bind to the HLA-DR The cells were WO 97/31002 g'CT/US97/02905 ~D
then washed 2 times with PBS each wash and fixed in 0.5 mt of0.5%
paraformaldehyde.
The fixed cells were stored at .4°C until analyzed by flow cytometry.
The enlxancement of E-1LA-DR by representative fused pyrrolo[2,3-c)carbazale-5-ones is shown in FIG 1. Tlie enhancement of HLA-DR by IFN-y alone is designated 100% on the Y axis. There is no sigiu$cant uiduction of HL.A-DR by the representative compounds alone at I uM (F1G t ). All of the representative compounds enhance the induction of HLA-DR by IFN-y above the induction by IFN-y alone, i.e. above 100%.
The percent enliancement above IFN-y alone by the four compounds is shown in Table I.
For example. at: 2l.tM. the compound of Section V(D) (Example IV) enhanced IFN-y induction of HLA-DR by 60% over 1FN-y alone.
Compound of Conc. of Fused Conc. of Ig'N-y,Percent Euample # Pyrrolo[2,3- Units/ml Enhancement cjcarbazole-b-one, of a VI HLA.-DR
1 - 100* 100 1 ? I00 I08 U - _ 0 B - I00* I00 B t 100 133 B ? 100 153 ITI _ _ 0-- 100* 100 N - 100* 100 ~ ? t00 160 arm-y alone is aennea as ~ uu ro.
F. Eiample vI. NT-3 Potentiadoa of ChAT Activity in Basal Forebrain Cultures by Pyrrolo[2,3-c]carbazole-6-ones The ability of pyrrolo[2,3-c]carbazole-6-ones to potentiate NT-3 activity in basal forebrain cultures was determined using chotine acetyltransferase (ChAT) activity as a measure of cholinergic neuron function or survival. The compounds alone had no effect on ChAT activity. However, in the presence ofNf-3, the representative compounds gave a dose dependent potentiation of ChAT activity to levels greater than those elicited by NT-3 alone. The results shown in Table 2 are the result of a single application ofNT-3 and the compound to be tested on the day of culture initiation, indicating a prolonged effect on the stuvival or function of basal forebrain cholintrgic neurons. The methods employed are descn'bed in U.S. Patent 5,468,872, Columns 18 and 19.
Table 2 Compound of '/. Basui % NT 3 Eiample # (mean (mean SD) SD) laDnM 300nM 100nM
300aM
NT-3+I I84+3 221+2 113+2 136+1*
NT3 + II 2I2 + 4 228 + 13 0+ 140 +
13 2* 1 NT3+IZZ 180+3 203+2 114+2 129+1*
NT 3 (100 ng/ml) iaon~sed ChAT Activityr 163 ~ 5 % (rncaa ~ SD) over control calt~s. Test c~ands ahe had basal (100°!0) level of aetMty.
*p < 0.05, statistically swim ooaaparod to NT-3 activhy alone by Duandt t st~istics.
Those skdIed in the art will appreaate that numerous chaages and modifications may be made to the prtfetred embodiments of the imrention and that such changes and modifications may be made without departing from the spirit of the invention.
It is therefore intended that the appended claims coves all e~quNalent variations as fall within the true spirit and scope of the invention.
Claims (16)
1. A fused pyrrolo[2,3-c]carbazole-6-one represented by a formula selected from the group consisting of:
wherein:
a) R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted or unsubstituted aryl, arylalkyl, heteroaryl, heteroarylalkyl; C(=O)R9, where R9 is alkyl of 1-4 carbons or aryl; (CH2)n OR9, where n is an integer of 1-4; OR10, where R10 is H or alkyl of 1-4 carbons; (CH2)n OR14, where R14 is the residue of as amino acid after the hydroxyl group of the carboxyl group is removed ; OR14, NR7R8;
(CH2)n NR7R8, and O(CH2)n NR7R8; and either (1) R7 and R8 independently are H or alkyl of 1-4 carbons; or (2) R7 and R8 are combined together to form a linking group of the general formula (CH2)2-X1-(CH2)2-, where X1 is O, S or CH2;
b) R2 is selected form the group consisting of H, SO2R9, CO2R9, C(=O)R9, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, alkenyl of 1-8 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 1-8 carbons, or alkynyl of 1-8 carbons is unsubstituted; or 2) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons, or alkynyl of 1-8 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, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, O-tetrahydropyranyl, NH2, NR7R8, NR10COR9; NR10CO2R9, NR10CONR7R8, NHC(=NH)NH2, NR10SO2R9; S(O)y R11, wherein R11 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl, and y is 1 or 2; SR11, CO2R9, CONR7R8, CHO, COR9, CH2OR7, CH2OR9, CH=NNR11R12, CH=NOR11, CH=NR9, CH=NNHCH(N=NH)NH2;
SO2NR12R13, wherein either (1a) R12 and R13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons,or heteroaryl; or (2a) R12 and R13 are combined together to form a -(CH2)2-X1-(CH2)2 linking group;
PO(OR11)2, NHR14, NR10R14 OR14, 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 R3 and R4, independently, is selected from the group consisting of H, aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, CF3, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, NH2, (CH2)n OR9, (CH2)~OR10, (CH2)n OR14, OR14, NHR14, NR7R8, NR7(CH2)n NR7R8.NR10COR9, NR10CONR7R8, SR11, S(O)y R11, CO2R9, COR9, CONR7R8, CHO, CH=NOR11, CH=NR9, CH=NNR11R12, (CH2)n SR9, (CH2)n S(O)y R9;
CH2SR15, where R15 is alkyl of 1-4 carbons; CH2S(O)y R14, (CH2)n NR7R8, (CH2)n NHR14, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 carbons; and either 1) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons or alkynyl of 1-8 carbons is unsubstituted; or 2) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons, or alkynyl of 1-8 carbons is independently substituted as described in b)2) above;
d) R5 is selected from the group consisting of hydrogen, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 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, CF3, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, NH2, (CH2)n OR9, (CH2)n OR14, NR7R8, NR7(CH2)n NR7R8, NR10COR9, NR10CONR7R8, SR11, S(O)y R11, CO2R9, COR9, CONR7R8, CHO, CH=NOR11, CH=NR9, CH=NNR11R12, (CH2)n SR9, (CH2)n S(O)y R9, CH2SR15, CH2S(O)y R14, (CH2)n NR7R8, and (CH2)n NHR14;
e) X is selected from the group consisting of -N-, -O-, -S-, -S(-O)-, -S(=O)2-, alkylene of 1-3 carbons, -C(=O)-, -C(R2)=C(R2)-, -(CR2)2, -CH=CH-, -CH(OH)-CH(OH)-, -C(=NOR11)-, -C(OR11)(R11)-, -C(=O)CH(R15)-, -CH(R15)C(=O)-;
-CH2-Z-, -Z-CH2-, -CH2ZCH2-, where Z is selected from the group consisting of -C(OR11)(R11)-, O, S, C(=O), and NR11; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R5 substituent group, SR10, OR10, OR14, R15, phenyl, naphthyl, and arylalkyl of 7-14 carbons.
wherein:
a) R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted or unsubstituted aryl, arylalkyl, heteroaryl, heteroarylalkyl; C(=O)R9, where R9 is alkyl of 1-4 carbons or aryl; (CH2)n OR9, where n is an integer of 1-4; OR10, where R10 is H or alkyl of 1-4 carbons; (CH2)n OR14, where R14 is the residue of as amino acid after the hydroxyl group of the carboxyl group is removed ; OR14, NR7R8;
(CH2)n NR7R8, and O(CH2)n NR7R8; and either (1) R7 and R8 independently are H or alkyl of 1-4 carbons; or (2) R7 and R8 are combined together to form a linking group of the general formula (CH2)2-X1-(CH2)2-, where X1 is O, S or CH2;
b) R2 is selected form the group consisting of H, SO2R9, CO2R9, C(=O)R9, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, alkenyl of 1-8 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 1-8 carbons, or alkynyl of 1-8 carbons is unsubstituted; or 2) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons, or alkynyl of 1-8 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, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, O-tetrahydropyranyl, NH2, NR7R8, NR10COR9; NR10CO2R9, NR10CONR7R8, NHC(=NH)NH2, NR10SO2R9; S(O)y R11, wherein R11 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaryl, and y is 1 or 2; SR11, CO2R9, CONR7R8, CHO, COR9, CH2OR7, CH2OR9, CH=NNR11R12, CH=NOR11, CH=NR9, CH=NNHCH(N=NH)NH2;
SO2NR12R13, wherein either (1a) R12 and R13, independently, are H, alkyl of 1-4 carbons, aryl of 6-10 carbons,or heteroaryl; or (2a) R12 and R13 are combined together to form a -(CH2)2-X1-(CH2)2 linking group;
PO(OR11)2, NHR14, NR10R14 OR14, 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 R3 and R4, independently, is selected from the group consisting of H, aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, CF3, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, NH2, (CH2)n OR9, (CH2)~OR10, (CH2)n OR14, OR14, NHR14, NR7R8, NR7(CH2)n NR7R8.NR10COR9, NR10CONR7R8, SR11, S(O)y R11, CO2R9, COR9, CONR7R8, CHO, CH=NOR11, CH=NR9, CH=NNR11R12, (CH2)n SR9, (CH2)n S(O)y R9;
CH2SR15, where R15 is alkyl of 1-4 carbons; CH2S(O)y R14, (CH2)n NR7R8, (CH2)n NHR14, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 carbons; and either 1) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons or alkynyl of 1-8 carbons is unsubstituted; or 2) each alkyl of 1-8 carbons, alkenyl of 1-8 carbons, or alkynyl of 1-8 carbons is independently substituted as described in b)2) above;
d) R5 is selected from the group consisting of hydrogen, alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 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, CF3, NO2, OH, OR9, O(CH2)n NR7R8, OCOR9, OCONHR9, NH2, (CH2)n OR9, (CH2)n OR14, NR7R8, NR7(CH2)n NR7R8, NR10COR9, NR10CONR7R8, SR11, S(O)y R11, CO2R9, COR9, CONR7R8, CHO, CH=NOR11, CH=NR9, CH=NNR11R12, (CH2)n SR9, (CH2)n S(O)y R9, CH2SR15, CH2S(O)y R14, (CH2)n NR7R8, and (CH2)n NHR14;
e) X is selected from the group consisting of -N-, -O-, -S-, -S(-O)-, -S(=O)2-, alkylene of 1-3 carbons, -C(=O)-, -C(R2)=C(R2)-, -(CR2)2, -CH=CH-, -CH(OH)-CH(OH)-, -C(=NOR11)-, -C(OR11)(R11)-, -C(=O)CH(R15)-, -CH(R15)C(=O)-;
-CH2-Z-, -Z-CH2-, -CH2ZCH2-, where Z is selected from the group consisting of -C(OR11)(R11)-, O, S, C(=O), and NR11; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R5 substituent group, SR10, OR10, OR14, R15, phenyl, naphthyl, and arylalkyl of 7-14 carbons.
2. The compound of Claim 1 wherein R9 is selected from the group consisting of alkyl of 1-4 carbons, phenyl, and naphthyl.
3. The compound of Claim 1 or 2, wherein R11, R12, and R13 are each independently selected from the group consisting of H, alkyl of 1-4 carbons, phenyl, naphthyl, and heteroaryl.
4. The compound of Claim 1, 2, or 3, wherein R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted phenyl, unsubstituted phenyl, OR10, and O(CH2)n NR7R8.
5. The compound of any one of Claims 1 to 4, wherein R2 is selected from the group consisting of H, C(=O)R9, alkyl of 1-8 carbons, and alkyl of 1-8 carbons substituted with one group selected from the group consisting of OR9, OH, OCOR9, NR7R8, NH2, NR10COR9, and NR10R14.
6. The compound of any one of Claims 1 to 5, wherein R3 and R4 are each independently selected from the group consisting of H, halogen, CN, OH, OR9, OR14, NH2, NR7R8, (CH2)n OR10, (CH2)n OR14, COR9, NR10COR9, NHR14, and O(CH2)n NR7R8.
7. The compound of any one of Claims 1 to 6, wherein R5 is selected from the group consisting of H and alkyl of 1-4 carbons.
8. The compound of any one of Claims 1 to 7, wherein X is selected from the group consisting of -N-, -O-, -S-, alkylene of 1-3 carbons, -C=O-, -CH2-Z-, and -Z-CH2-.
9. The compound of Claim 8 wherein X is selected from the group consisting of -N-, -O-, -S-, and -CH2-.
10. The compound of Claim 9 wherein R1, R2, R3, R4, and R5 are each H.
11. The compound of Claim 1 represented by Formula I.
12. The compound of Claim 11 wherein R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted phenyl, unsubstituted phenyl, OR10, and O(CH2)n NR7R8.
13. The compound of Claim 11 or 12, wherein R2 is selected from the group consisting of H, C(=O)R9, alkyl of 1-8 carbons, and alkyl of 1-8 carbons substituted with one group selected from the group consisting of OR9, OH, OCOR9, NR7R8, NH2, NR10COR9, and NR10R14.
14. The compound of Claim 11, 12, or 13, wherein R3 and R4 are each independently selected from the group consisting of H, halogen, CN, OH, OR9, OR14, NH2, NR7R8, (CH2)n OR10, (CH2)n OR14, COR9, NR10COR9, NHR14, and O(CH2)n NR7R8.
15. The compound of any one of Claims 11 to 14, wherein R5 is selected from the group consisting of H and alkyl of 1-4 carbons.
16. The compound of any one of Claims 11 to 15, wherein X is selected from the group consisting of -N-, -O-, -S-, alkylene of 1-3 carbons, -C=O-, -CH2-Z-, and -Z-CH2-.
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PCT/US1997/002905 WO1997031002A1 (en) | 1996-02-21 | 1997-02-20 | Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon |
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