WO1997031002A1 - 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 PDF

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Publication number
WO1997031002A1
WO1997031002A1 PCT/US1997/002905 US9702905W WO9731002A1 WO 1997031002 A1 WO1997031002 A1 WO 1997031002A1 US 9702905 W US9702905 W US 9702905W WO 9731002 A1 WO9731002 A1 WO 9731002A1
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carbons
group
alkyl
compound
cor
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PCT/US1997/002905
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French (fr)
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WO1997031002A9 (en
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Robert L. Hudkins
James L. Diebold
Ernest Knight, Jr.
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Cephalon, Inc.
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Priority to AU21914/97A priority Critical patent/AU716265B2/en
Application filed by Cephalon, Inc. filed Critical Cephalon, Inc.
Priority to AT97914792T priority patent/ATE195124T1/en
Priority to CA002241852A priority patent/CA2241852C/en
Priority to NZ330837A priority patent/NZ330837A/en
Priority to DE69702705T priority patent/DE69702705T2/en
Priority to BR9707659A priority patent/BR9707659A/en
Priority to EP97914792A priority patent/EP0885229B1/en
Priority to JP9530385A priority patent/JP2000505458A/en
Priority to DK97914792T priority patent/DK0885229T3/en
Publication of WO1997031002A1 publication Critical patent/WO1997031002A1/en
Publication of WO1997031002A9 publication Critical patent/WO1997031002A9/en
Priority to HK99101243A priority patent/HK1017673A1/en
Priority to GR20000402223T priority patent/GR3034533T3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
    • C07D493/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • 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.
  • EFN- ⁇ Human interferon-gamma
  • IFN- ⁇ Human interferon-gamma
  • MHC Major Histocompability Complex
  • the MHC is made of class I, II, and III genes that code for the respective class I, EL, 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.
  • IFN- ⁇ is one of the 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 IFN- ⁇ 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- ⁇ 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.
  • helper T cells CD8
  • the secreted lymphokines cause proliferation of the antibody synthesizing B lymphocytes which synthesize large amounts of antibody against the invading
  • Chem., 1992, 57, 2105) potentiate the activity of human IFN- ⁇ 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 and/or tumor growth.
  • the fused pyrrolo[2,3-c]carbazole-6-one compounds of the invention are useful for potentiating, preferably, neurotrophin-3 (NT-3) activity.
  • Figure 1 is a graph showing the enhancement of IFN- ⁇ -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 of the py ⁇ olo[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.
  • Figure 4 is a schematic drawing showing an alternate synthesis of intermediates to pyrrolo[2,3-c]carbazole-6-ones.
  • Figure 5 is a schematic drawing showing the synthesis of pyrrolo[2,3-c]carbazole- 6-ones of Formula II.
  • Figure 7 is a schematic drawing showing the synthesis of intermediate 11 to pyrrolo[2,3-c]carbazole-6-ones. II. Fused pyrrolo[2,3-cjcarbazole-6-ones
  • novel compounds of this invention which are referred to as fused pyrrolo[2,3- c]carbazole-6-one derivatives are represented by the following Formulae:
  • R 14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed ; OR 14 , NR 7 R 8 ; (CH2) n NR 7 R 8 , and O(CH2) n NR 7 R 8 ; and either ( 1) R 7 and R 8 independently are H or alkyl of 1-4 carbons; or
  • R 7 and R 8 are combined together to form a linking group of the general formula -(CH 2 ) 2 -X 1 -(CH 2 ) 2 -, where X 1 is O, S or CH 2 ;
  • 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
  • each alkyl of 1-8 carbons, alkenyl of 1-8 carbons, or alkynyl of 1-8 carbons is unsubstituted; or
  • 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, NO 2 , OH, OR 9 , O(CH 2 ) n NR 7 R 8 , OCOR 9 , OCONHR 9 ,
  • R 12 and R 13 independently, are H, alkyl of 1-4 carbons, aryl of 6- 10 carbons.or heteroaryl; or
  • 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;
  • each R 3 and R 4 independently, is selected from the group consisting of H, aryl of 6-10 carbons, heteroaryl, F, Cl, Br, I, CN, CF 3 , NO 2 , OH, OR 9 ,
  • CH 2 SR 15 where R 15 is alkyl of 1-4 carbons; CH 2 S(O) y R 14 , (CH 2 ) n NR 7 R 8 , (CH 2 ) n NHR 14 , alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 carbons; and either
  • each alkyl of 1-8 carbons, alkenyl of 1-8 carbons or alkynyl of 1-8 carbons is unsubstituted;
  • R 5 is selected from the g ⁇ oup consisting of alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 carbons; and either
  • each alkyl, alkenyl, or alkenyl group is unsubstituted ;
  • each alkyl, alkenyl, or alkynyl group is substituted with 1-3 groups selected from the group consisting of F, Cl, Br, I, CN, CF 3 , NO 2 , OH, OR 9 , O(CH 2 ) n NR 7 R 8 , OCOR 9 , OCONHR 9 , NH 2 , (CH 2 ) n OR 9 , (CH 2 ) n OR 14 .
  • aryl means monocyclic and polycyclic aromatic groups including, for example, phenyi, naphthyl, 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- 10 carbons. Phenyi and naphthyl groups are particularly preferred.
  • heteroaryl means an aryl moiety which contains at least one basic nitrogen atom and 0-4 heteroatoms selected from O, S, and N.
  • heteroaryl groups include pyrroiyl, pyranyl, thiopyranyl, furyl, imidazolyl, pyridyl, thiazolyL, triazinyl, phthalimido. indolyl. purinyl, and benzothiazolyl.
  • amino acid means a molecule containing both an amino group and a carboxyl group. It includes an " ⁇ -amino acid” which has its usual meaning as a carboxylic acid which bears an amino functionality on the carbon adjacent to the carboxyl group. ⁇ -Amino acids can be naturally occurring or non-naturally occurring. Arnino 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 ⁇ -amino acids, and can be any molecule containing both an amino group and a carboxyl group. Preferred are ⁇ - amino acids, dipeptides such as lysyl- ⁇ -alanine, and aminoalkanoic acids of 2-8 carbons, e.g., 3- ⁇ methylaininobutyric acid.
  • Preferred "alkyl”, “alkenyl”, and “alkynyl” groups contain 1-4 carbon atoms.
  • Preferred R 1 groups include H, alkyl of 1-4 carbons, substituted or unsubstituted phenyi, OR 10 , and O(CH2) n NR 7 R 8 .
  • Preferred phenyi substituents include alkyl of 1-4 carbons, and halogen. Most preferred is H.
  • R 3 and R 4 groups include H, halogen, CN, OH, OR 9 , OR 14 , NH 2 , NR 7 R 8 , (CH 2 ) n OR 10 , (CH 2 ) n OR 14 . COR 9 . NR 10 COR 9 . NHR 14 , and O(CH 2 ) n NR 7 R 8 . Most preferred is H.
  • R 5 groups include H, and alkyl of 1-4 carbons. Most preferred is H.
  • Enhancement of EFN- ⁇ induction of MHC molecules can preferably be estabhshed using a human monocyte cell line that responds to IFN- ⁇ ; a particularly preferred cell line is available from the American Type Culture Collection (ATCC), referred to as THP-1, under accession number ATCC TDB-202.
  • IFN- ⁇ is known to induce expression of the three MHC II heterodimers. HLA-DP, HLA-DQ and HLA-DR; in THP-1 cells.
  • Potentiation of function and/or survival of trophic factor responsive cells can be preferably estabhshed using a cultured spinal cord choline acetyltransferase ("ChAT") assay.
  • ChAT spinal cord choline acetyltransferase
  • Potentiation 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 “'enhancement” or "enhancing.”
  • the terms “enhauce” or “enhancing” or enhancement when used to modify the terms “function” or “”survival” or “induction” means that the presence of a fused pyrrolo[2,3-c]carbazole-6-oue has a comparatively greater effect on the function and/or survival of a trophic factor responsive cell or, in the case of IFN- ⁇ , induction of MHC molecules, than a comparative cell not presented with the fused pyrrolo[2,3- c]carbazole-6-one.
  • neuronal neuron As used herein the term “neuron,” “cell of neuronal lineage” and “neuronal 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.
  • cholinergic neuron means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholiue; exemplary are basal forebrain and spinal cord neurons.
  • 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 Ciliary Neurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF), insulin and insulin-like growth factors (e.g., IGF- I, IGF- II, IGF- III), interferons, interleukins, cytokines, and the neurotrophins. including Nerve Growth Factor (NGF), Ne ⁇ rotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Brain Derived Neurotrophic Factor (BDNF).
  • Ciliary Neurotrophic Factor Ciliary Neurotrophic Factor
  • bFGF basic Fibroblast Growth Factor
  • insulin and insulin-like growth factors e.g., IGF- I, IGF- II, IGF- III
  • interferons interleukins
  • cytokines interleukins
  • cytokines interferons
  • a “trophic factor-respousive 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-ueuronal cells (e.g., monocytes and neoplastic cells).
  • trophic 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.
  • trophic factor activity As used in the phrases "trophic factor activity" and “trophic factor-induced activity,” the term “trophic factor” includes both endogenous and exogenous trophic factors, where “endogenous” refers to a trophic factor already present and “exogenous” refers to a trophic factor added to a system.
  • 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.
  • the compounds of the invention can be used to enhance IFN- ⁇ induction of
  • IFN- ⁇ has shown effectiveness in the treatment of virus infections and certain tumors. Due to its dose limiting side effects, however, the utility of BFN- ⁇ has been limited. In an immunocompromised situation, e.g., in a patient evidencing viral infection, enhancement of an LFN- ⁇ mediated immune response would be beneficial, given that IFN- ⁇ induces expression of MHC molecules.
  • the compounds of this invention which enhance the ability of endogenous IFN- ⁇ or exogenously administered EFN- ⁇ to induce MHC expression are of benefit.
  • the ability of a fused pyrrolo[2,3-c]carbazole-6- one to enhance IFN- ⁇ induction of MHC molecules is preferably assessed using the THP- 1 cell line. This cell line evidences expression of the MHC II heterodimer HLA-DR.
  • Comparing the expression of HLA-DR in the presence of IFN- ⁇ and IFN- ⁇ plus one or more fused pyrrolo[2,3-c]carbazole-6-ones of the present invention provides a rapid and efficient method for determination of enhancement of IFN- ⁇ 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 fused 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 functional responses. For example, by radiolabelhug a fused pyrrolo[2,3-c]carbazole-6-one associated with a specific cellular function (e.g., HLA-DR induction), the target entity to which the fused pyrrolo[2,3-c]carbazole-6-oue binds can be identified, isolated, and purified for characterization.
  • 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- ⁇ induction of MHC molecules. Because the disclosed fused pyrrolo[2,3- c]carbazole-6-ones are useful in enhancing IFN- ⁇ induction of MHC molecules, the disclosed compounds beneficially lend themselves to utility as therapeutic agents. Such enhancement is of value in an irnmunocompromised patient.
  • the fused pyrrolo[2,3-c]carbazole-6-ones of this invention can be used to enhance the function and/or survival of cells of neuronal 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 with other beneficial molecules such as
  • indolocarbazoles which also have the ability to potentiate the function and/or survival of a designated cell.'
  • 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, functionally 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.
  • 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.
  • 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 neurotrophin such as NT-3 can be determined by comparing the functional activity of the neurotrophin with or without the fused pyrrolo[2,3-c]carbazole- 6-one present.
  • Pharmaceutically acceptable salts of the fused pyrrolo[2,3-c]carbazole-6-ones also fall within the scope of the present invention.
  • pharmaceutically acceptable salts as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate.
  • pharmaceutically acceptable metal salts are alkah 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.
  • pharmaceutically acceptable organic arnine addition salts are salts with morpholine and piperidine.
  • pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine. and phenylalanine.
  • compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers.
  • Such compositions can be prepared for use in parenteral adrninistration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermaily, via, for example, trans-dermal patches.
  • compositions can be conveniently administered in unit dosage form and may be prepared by any of the methods well knowu in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA- 1980).
  • Formulations for parenteral administration may contain as common excipients sterile water or saline, poryalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible. biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
  • parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposom.es.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene- 9-lauryl ether, glycocholate and deoxycholate. or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration may also include glycocholate for buccal 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, they can be used in combination with other active ingredients, e.g., synthetic EFN- ⁇ and/or other growth factors which facilitate potentiation of NT- 3 such as those disclosed in U.S. Patent No. 5,468,872 and
  • the concentrations of the compounds of this invention in a therapeutic composition can vary. The concentration will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration.
  • the compounds of this invention typically are provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about 1 ⁇ g/kg to about I g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day.
  • a preferred dosage of drug to be acbninistered 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 efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
  • Method A a 2-(aryI) or 2-(heteroaryl)indole derivative (1-4) which is either unsubstituted or substituted at carbons 4-7 (inclusive) of the indole ring (R 3 ) or substituted or unsubstituted in the (hetero)aryl portion (R 4 ) is reacted with maleimide in the presence of a catalyst such as, trifluoroacetic acid (TFA) to give the fused pyrrolocarbazole-6-one derivatives of Formula I (Examples I-IV).
  • a catalyst such as, trifluoroacetic acid (TFA)
  • Additional Lewis acid catalysts such as SuCL, AlCl 3 , EtAlCl 2 , or Et 2 AlCl may also be used to effect the reaction.
  • the reaction may also be run in a solvent such as TFA, toluene, CH 2 Cl 2 or 1,2-dichloroetl ⁇ ane.
  • the palladium-catalyzed cross- coupling methodology ( Stilie reaction) may be used to prepare other derivatives, for example, where X in Figure 3 has 1-3 carbons (inclusive), by coupling the
  • the indole 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 R 2 substituents in position one of the indole ring.
  • a strong base e.g., t-BuLi, sec-BuLi, n-BuLi, lithium diisopropylamide
  • the 2-(aryI)- or 2-(heteroaryl)indole derivative (1-3), 2-(2-indenyl)i ⁇ dole 4, or 2-(2-( 1,2-dihydronaphthyl)indole 8 may be converted to intermediates which contain R 2 substituents in position one of the indole ring by the method described above for indole derivatives.
  • R 1 substituted maleimide (FIG 2, Method A).
  • R 1 substituted maleimide (FIG 2, Method A).
  • Compounds of general formulae I and II. in which R 1 is hydrogen can be alkylated in the presence ofbase (e.g., hydrides, alkoxides. hydroxides of alkah or alkaline earth metals, or of organ o-Uthium compounds) by treatment with R 1 L in which L is a leaving group such as a halogen, mesylate or tosylate to give a fused pyrrolocarbazole-6-one derivative which has an R 1 group bound to the lactam nitrogen.
  • base e.g., hydrides, alkoxides. hydroxides of alkah or alkaline earth metals, or of organ o-Uthium compounds
  • R 5 is hydrogen
  • a fused pyrrolocarbazole-6-one derivative with one equivalent or an excess of a strong base (e.g., hydrides, alkoxides, hydroxides of alkah or alkaline earth metals, or of organo-Uthium compounds) with R 5 L in which L is a leaving group such as a halogen, or by condensation with an R 5 containing ketone or aldehyde carbonyl derivative to give a fused pyrrolocarbazole-6-one derivative which has one or two an R 5 groups.
  • a strong base e.g., hydrides, alkoxides, hydroxides of alkah or alkaline earth metals, or of organo-Uthium compounds
  • R 5 L in which L is a leaving group such as a halogen
  • condensation with an R 5 containing ketone or aldehyde carbonyl derivative to give a fused pyrrolocarbazole-6-one derivative which has one or
  • 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; Houlihan Ed.. Wiley- Interscience (1972)).
  • the 2-indanone derivatives can be prepared using previously described procedures (see U.S. Patent 4,192,888; U.S. Patent 4.128.666; J. Am. Chem. Soc. 89:4524 (1967); Tetrahedron Lett. 43:3789 ( 1974); Chem. Ber. 122: 1791 ( 1989); Can. J. Chem. 60:2678 (1982); Helvetica Chimica Acta 70: 1791 ( 1987); Chem. Pharm. Bull. 33:3336 (1985); J. Org. Chem.
  • Method B a 2-(heteroaryl)indole derivative (1-3), or 2-(aryl)indole derivative such as 2-(2-indenyl)indole 4 is reacted with ethyl cis- ⁇ -cyanoacrylate in the presence of a catalyst such as S n CI 4 , AlCI 3 , EtAlCl 2 , Et 2 AlCl or TFA in CH 2 CI 2 , C 2 H 4 CI 2 or toluene as solvent to give the 6-oxo carbazole compounds of formula I of the invention.
  • a catalyst such as S n CI 4 , AlCI 3 , EtAlCl 2 , Et 2 AlCl or TFA in CH 2 CI 2 , C 2 H 4 CI 2 or toluene as solvent to give the 6-oxo carbazole compounds of formula I of the invention.
  • 2-(2-( 1-oxoindenyl))indole 11 may prepared using the palladium-catalyzed cross-coupling methodology (FIG 3) by coupling l-carboxy-2-tributylstannylindole 5 or its derivatives with 2-(trifluoromethanesulfonyl)oxyinden-1-one or 2-bromoinden- 1-one 12 (FIG 7) (J. Org. Chem.. 1994. 59. 3453) or one of its derivatives.
  • This compound showed identical spectral and analytical characteristics as that prepared by Method A.
  • THP-1 A human cell line derived from human monocytes, THP-1 (ATCC TIB 202) that responds to JFN- ⁇ , was used to demonstrate enhancement of HLA-DR by the fused pyrrolo[2,3-c]carbazole-6-oues
  • THP- 1 cells were grown in RPMI 1640 medium containing 20 uM
  • HLA-DR mercaptoethanol and 10% fetal bovine serum at 37°C in an atmosphere of 5%CO2:95% air at 100% humidity.
  • cells were either left untreated as controls, treated with IFN- ⁇ only at 100 units/ml or treated with compounds of the invention at 1 uM final concentration for 30 min. prior to the addition of EFN- ⁇ at 100 units/ml. 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 HLA-DR was performed by standard procedures as described in Interferons and Other Regulatory Cytokines.
  • the enhancement of HLA-DR by representative fused pyr ⁇ olo[2,3-c]carbazole-6- ones is shown in FIG 1.
  • the enhancement of HLA-DR by EFN- ⁇ alone is designated 100% on the Y axis. There is no significant bduction of HLA-DR by the representative compounds alone at 1 uM (FIG 1 ). All of the representative compounds enhance the induction of HLA-DR by IFN- ⁇ above the induction by IFN- ⁇ alone, i.e. above 100%.
  • the percent enhancement above IFN- ⁇ alone by the four compounds is shown in Table 1. For example, at 2 ⁇ M, the compound of Section V(D) (Example IV) enhanced IFN- ⁇ induction of HLA-DR by 60% over IFN- ⁇ alone.

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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 WHICH POTENTIATE ACTIVITY OF GAMMA INTERFERON
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-γ) 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 EFN-y inhibits virus and tumor growth in vivo remain unknown. There is evidence that EFN-γ 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 Wiley & 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, EL, 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. IFN-γ is one of the 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 IFN-γ 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-γ 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 lymphokines by the CD8 cell. The secreted lymphokines cause proliferation of the antibody synthesizing B lymphocytes which synthesize large amounts of antibody against the invading
microorganism.
It can be seem from the above examples that a compound that enhances the IFN-γ induction of MHC molecules would be useful in combination with IFN-γ for the treatment of infections by microorganisms. Such a compound might permit a reduction in the dose of IFN-γ, thereby advantageously giving the same therapeutic effect as with IFN-γ alone but with fewer of the IFN-γ related side effects.
There are at least three reports of compounds that potentiate the IFN-γ-induced MHC expression [Coutinho. G.C., Dudrieu-Trautmann, O., Strosberg, A.D., and
Couraud, P.O., Catecholamines Stimulate the IFN-γ-induced Class II MHC Expression on Bovine Brain Capillary Endothelial Cells, J. Immunol. 147, 2525-2529 (1991); Zhu, J., Mix, E., Olsson, T., and Link, H.. "Influence of Ion Channel Modulation of in Vitro Interferon-γ Induced MHC Class I and II Expression on Macrophages",
Immunopharmacology and Iinmunotoxicology, 17, 109-136 (1995); Mothes, T., Bendix, U.„ Pfannschmidt, C.„ and Lelimann, I., "Effect of Gliadin and Other Food Peptides on Expression of MHC 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 pyrrolo[2,3-c]carbazole-6-ones.
FORMULA I
Figure imgf000004_0001
FORMULA II
Figure imgf000005_0001
Constituent numbers are defined, infra. Preferred methods for preparing these compounds are disclosed infra.
We have discovered that our fused pyrτolo[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 of human IFN-γ 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 and/or tumor growth. We have also discovered that the fused pyrrolo[2,3-c]carbazole-6-one compounds of the invention are useful for potentiating, preferably, neurotrophin-3 (NT-3) activity.
DETAILED DESCRIPTION
We first describe the drawings. I. Drawings
Figure 1 is a graph showing the enhancement of IFN-γ-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 of the pyιτolo[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. Figure 4 is a schematic drawing showing an alternate synthesis of intermediates to pyrrolo[2,3-c]carbazole-6-ones.
Figure 5 is a schematic drawing showing the synthesis of pyrrolo[2,3-c]carbazole- 6-ones of Formula II.
Figure 6 is a schematic drawing showing the synthesis of pyrrolo[2,3-c]carbazole- 6-ones in which X is C=O from the corresponding compounds in which X is CH2.
Figure 7 is a schematic drawing showing the synthesis of intermediate 11 to pyrrolo[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 pyrrolo[2,3- c]carbazole-6-one derivatives are represented by the following Formulae:
Figure imgf000006_0001
wherein:
a) R1 is selected from the group consisting of H, alkyl of 1-4 carbons, aryl, arylalkyl, heteroaryl, heteroarylalkyl; C(=O)R9 where R9 is alkyl of 1-4 carbons or aryl; (CH2)nOR9, where n is an integer of 1-4; OR10, where R10 is H or alkyl of 1-4 carbons; (CH2)nOR14. where R 14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed ; OR14, NR7R8; (CH2)nNR7R8, and O(CH2)nNR7R8; 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, alkynyl 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)nNR7R8, OCOR9, OCONHR9,
O-tetrahydropyranyl. NH2, NR7R8, NR10COR9; NR10CO2R9,
NR10CONR7R8, NHC(=NH)NH2, NR10SO2R9; S(O)yR1 1, wherein R11 is H, alkyl of 1 -4 carbons, aryl of 6- 10 carbons, or heteroaryl, and y is 1 or 2; SR1 1, CO2R9, CONR7R8, CHO, COR9, CH2OR7, CH2OR9, CH=NNR1 1R12, CH=NOR1 1, 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) R12 and R13 are combined together to form a
-(CH2)2-X L(CH2)2 linking group;
PO(OR1 1)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)nNR7R8, OCOR9 OCONHR9 NH2, (CH2)nOR9, (CH2)nOR10,
(CH2)nOR14, OR14. NHR14, NR7R8, NR7(CH2)nNR7R8.NR10COR9,
NR10CONR7R8, SR1 1 , S(O)yR1 l, CO2R9, COR9, CONR7R8, CHO,
CH=NOR 11, CH=NR9, CH=NNR1 1R12, (CH2)nSR9, (CH2)nS(O)yR9;
CH2SR15, where R15 is alkyl of 1-4 carbons; CH2S(O)yR14, (CH2)nNR7R8, (CH2)nNHR14, 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 gτoup consisting of 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)nNR7R8, OCOR9, OCONHR9, NH2, (CH2)nOR9, (CH2)nOR14. NR7R8, NR7(CH2)nNR7R8.NR10COR9,
NR10CONR7R8, SR1 1. S(O)yR1 1, CO2R9, COR9, CONR7R8, CHO, CH=NOR1 1 , CH=NR9, CH=NNR1 1R12 (CH2)nSR9, (CH2)nS(O)yR9, CH2SR15, CH2S(O)yR14, (CH2)nNR7R8, and (CH2)nNHR14. 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)-. C(R2)2 , CH=CH-, -CH(OH)- CH(OH)-, -C(=NOR1 1)-, -C(OR1 1)(R1 1)-, -C(=O)CH(R15) -CH(R15)C(=O)-; -CH.-Z-, -Z-CH2-, -CH2ZCH2- where Z is selected from the group consisting of -C(OR1 1)(R11)-, O, S, C(=O), and NR1 1 ; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R5 substituent group, SR10, OR10, OR14, R 5, phenyi, naphthyl, and arylalkyl of 7-14 carbons.
As used herein, the term "aryl" means monocyclic and polycyclic aromatic groups including, for example, phenyi, naphthyl, 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- 10 carbons. Phenyi and naphthyl groups are particularly preferred.
As used herein, the term "heteroaryl" 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 pyrroiyl, pyranyl, thiopyranyl, furyl, imidazolyl, pyridyl, thiazolyL, triazinyl, phthalimido. indolyl. purinyl, and benzothiazolyl.
As used herein with reference to the definition of R14, the term "amino acid" means a molecule containing both an amino group and a carboxyl group. It includes an "α-amino acid" which has its usual meaning as a carboxylic acid which bears an amino functionality on the carbon adjacent to the carboxyl group. α-Amino acids can be naturally occurring or non-naturally occurring. Arnino 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 α-amino acids, and can be any molecule containing both an amino group and a carboxyl group. Preferred are α- amino acids, dipeptides such as lysyl-β-alanine, and aminoalkanoic acids of 2-8 carbons, e.g., 3- άmethylaininobutyric acid.
Preferred "alkyl", "alkenyl", and "alkynyl" groups contain 1-4 carbon atoms. Preferred R1 groups include H, alkyl of 1-4 carbons, substituted or unsubstituted phenyi, OR10, and O(CH2)nNR7R8. Preferred phenyi substituents include alkyl of 1-4 carbons, and halogen. Most preferred is H.
Preferred R2 groups include H, C(=O)R9, alkyl of 1-8 carbons, and alkyl of 1-8 carbons substituted with one OR9, OH. OCOR9, NR7R8, NH2, NR10COR9, or NR10R14 group. Most preferred is H.
Preferred R3 and R4 groups include H, halogen, CN, OH, OR9, OR14, NH2, NR7R8, (CH2)nOR10, (CH2)nOR14. COR9. NR10COR9. NHR14, and O(CH2)nNR7R8. Most preferred is H.
Preferred R5 groups include H, and alkyl of 1-4 carbons. Most preferred is H.
Preferred X groups include -N-, -O-, -S-, alkylene of 1-3 carbons, -C=O-, -CH 2-Z- and -Z-CH2-. Most preferred are -N-, -O-, -S-, and -CH2- groups. III . Fused Pyrrolo{2,3-c] carbazole-6-one Utilities Our fused pyrrolo[2,3-c]carbazole-6-ones have evidenced a panoply of important 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 pyrrolo [2,3-c] carbazole-6-ones can be generally described as follows:
A. Enhancement of EFN-γ induction of MHC molecules;
B. Potentiation of function and/or survival of trophic factor responsive cells.
Enhancement of EFN-γ induction of MHC molecules can preferably be estabhshed using a human monocyte cell line that responds to IFN-γ; a particularly preferred cell line is available from the American Type Culture Collection (ATCC), referred to as THP-1, under accession number ATCC TDB-202. IFN-γ is known to induce expression of the three MHC II heterodimers. HLA-DP, HLA-DQ and HLA-DR; in THP-1 cells.
Potentiation of function and/or survival of trophic factor responsive cells, e.g., cells of neuronal lineage, can be preferably estabhshed using a cultured spinal cord choline acetyltransferase ("ChAT") assay.
As used herein, the term ""potentiation" 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 "'enhancement" or "enhancing."
As used herein, the terms "enhauce" or "enhancing" or enhancement when used to modify the terms "function" or ""survival" or "induction" means that the presence of a fused pyrrolo[2,3-c]carbazole-6-oue has a comparatively greater effect on the function and/or survival of a trophic factor responsive cell or, in the case of IFN-γ, 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 "neuronal 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 "cholinergic neuron" means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholiue; 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 Ciliary Neurotrophic Factor (CNTF), basic Fibroblast Growth Factor (bFGF), insulin and insulin-like growth factors (e.g., IGF- I, IGF- II, IGF- III), interferons, interleukins, cytokines, and the neurotrophins. including Nerve Growth Factor (NGF), Neιιrotrophin-3 (NT-3), Neurotrophin-4/5 (NT-4/5) and Brain Derived Neurotrophic Factor (BDNF).
A "trophic factor-respousive 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-ueuronal cells (e.g., monocytes and neoplastic cells). As used herein, "trophic 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 phrases "trophic factor activity" and "trophic factor-induced activity," the term "trophic factor" includes both endogenous and exogenous trophic factors, where "endogenous" refers to a trophic 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 EFN-γ Induction of MHC Molecules
The compounds of the invention can be used to enhance IFN-γ induction of
MHC molecules. IFN-γ has shown effectiveness in the treatment of virus infections and certain tumors. Due to its dose limiting side effects, however, the utility of BFN-γ has been limited. In an immunocompromised situation, e.g., in a patient evidencing viral infection, enhancement of an LFN-γ mediated immune response would be beneficial, given that IFN-γ induces expression of MHC molecules. Thus, the compounds of this invention which enhance the ability of endogenous IFN-γ or exogenously administered EFN-γ to induce MHC expression are of benefit.
As detailed in Section V below, the ability of a fused pyrrolo[2,3-c]carbazole-6- one to enhance IFN-γ induction of MHC molecules is preferably assessed using the THP- 1 cell line. This cell line evidences expression of the MHC II heterodimer HLA-DR.
Comparing the expression of HLA-DR in the presence of IFN-γ and IFN-γ plus one or more fused pyrrolo[2,3-c]carbazole-6-ones of the present invention provides a rapid and efficient method for determination of enhancement of IFN-γ 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 fused 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 functional responses. For example, by radiolabelhug a fused pyrrolo[2,3-c]carbazole-6-one associated with a specific cellular function (e.g., HLA-DR induction), the target entity to which the fused pyrrolo[2,3-c]carbazole-6-oue binds can be identified, isolated, and purified for characterization. In yet another 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-γ induction of MHC molecules. Because the disclosed fused pyrrolo[2,3- c]carbazole-6-ones are useful in enhancing IFN-γ induction of MHC molecules, the disclosed compounds beneficially lend themselves to utility as therapeutic agents. Such enhancement is of value in an irnmunocompromised 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 function and/or survival of cells of neuronal 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 with other beneficial molecules such as
indolocarbazoles which also have the ability to potentiate the function and/or survival of a designated cell.' In situations where the fused pyrrolo[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, functionally 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. 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 neurotrophin such as NT-3 can be determined by comparing the functional activity of the neurotrophin with or without the fused pyrrolo[2,3-c]carbazole- 6-one present.
Pharmaceutically acceptable salts of the fused pyrrolo[2,3-c]carbazole-6-ones also fall within the scope of the present invention. The term "pharmaceutically acceptable salts" as used herein means an inorganic acid addition salt such as hydrochloride, sulfate, and phosphate, or an organic acid addition salt such as acetate, maleate, fumarate, tartrate, and citrate. Examples of pharmaceutically acceptable metal salts are alkah 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 arnine addition salts are salts with morpholine and piperidine. 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 adrninistration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermaily, via, for example, trans-dermal patches.
The composition can be conveniently administered in unit dosage form and may be prepared by any of the methods well knowu in the pharmaceutical art, for example, as described in Remington's Pharmaceutical Sciences (Mack Pub. Co., Easton, PA- 1980). Formulations for parenteral administration may contain as common excipients sterile water or saline, poryalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible. biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds. Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposom.es. Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene- 9-lauryl ether, glycocholate and deoxycholate. or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration may also include glycocholate for buccal 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, they can be used in combination with other active ingredients, e.g., synthetic EFN-γ and/or other growth factors which facilitate potentiation of NT- 3 such as those 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. The concentration will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration. The compounds of this invention typically are provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration. Typical dose ranges are from about 1 μg/kg to about I g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day. A preferred dosage of drug to be acbninistered 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 efficacy of the compound selected, and formulation of the compound excipient, and its route of administration. 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 invention. In Method A (FIG 2) a 2-(aryI) or 2-(heteroaryl)indole derivative (1-4) which is either unsubstituted or substituted at carbons 4-7 (inclusive) of the indole ring (R3) 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 pyrrolocarbazole-6-one derivatives of Formula I (Examples I-IV).
Additional Lewis acid catalysts, such as SuCL, AlCl3, EtAlCl2, or Et2AlCl may also be used to effect the reaction. The reaction may also be run in a solvent such as TFA, toluene, CH2Cl2 or 1,2-dichloroetlιane.
The bi-aryl indole intermediates. 2,2'-biindole 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, R.L.; et. alJ.
Org.Chem., 1995, 60, 6218) (FIG 2). 2-(2-Indenyl)indole 4 (FIG 3) (X = CH2, R2, R3, R4 = H), or 2-(2-indenyl)mdoIe derivatives substituted with an R3 or R4 group, may be prepared by reacting l-carboxy-2-(tributylstannyl)indole 5, or l-carboxy-2- (tributylstannyl)indole substituted with an R3 group (Hudkins, R.L. et. al J. Org.Chem., 1995, 60, 6218) with 2-bromoindene 6 (J. Org. Chem., 1982, 47, 705) or a 2- bromoindene substituted with an R4 group. Alternatively, 2-(2-indenyl)indole 4 (X = CH2, R2, R3, R4 = H), or 2-(2-indenyl)indole derivatives substituted with an R3 or R4 group, may be prepared by reaction of l H-indole or a derivative thereof containing an R3 group, protected as a lithium indole- 1-carboxylate intermediate (Tetrahedron Lett. 26:5935 (1985)), then treated with a strong base, such as t-BuLi, then alkylated with an appropriate 2-indanone, or 2-indanone 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 Benzocycloalkan-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, 1 10). The palladium-catalyzed cross- coupling methodology ( Stilie reaction) may be used to prepare other derivatives, for example, where X in Figure 3 has 1-3 carbons (inclusive), by coupling the
2-(trifluoromethanesulfonate)- or the 2-iodo- or 2-bromovinyl derivative of the corresponding cyclic ketone with 1-carboxy-2-tributylstannylindole to give 2-(2- benzocycloalkenyl)indoles. The starting 1H-indole 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 alkyiating agent to give a 1-substituted indole. In these examples, the indole 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-(aryI)- or 2-(heteroaryl)indole derivative (1-3), 2-(2-indenyl)iιιdole 4, or 2-(2-( 1,2-dihydronaphthyl)indole 8 may be converted to intermediates which contain R2 substituents in position one of the indole ring by the method described above for indole derivatives.
Compounds of general formulae I and II which contain R1 groups, not = H, may be prepared by starting with the appropriate R1 substituted maleimide (FIG 2, Method A). Compounds of general formulae I and II. in which R1 is hydrogen, can be alkylated in the presence ofbase (e.g., hydrides, alkoxides. hydroxides of alkah or alkaline earth metals, or of organ o-Uthium compounds) by treatment with R1L in which L is a leaving group such as a halogen, mesylate or tosylate to give a fused pyrrolocarbazole-6-one derivative which has an R1 group bound to the lactam nitrogen. Compounds of general formulae I and II, in which R 5 is hydrogen, may be converted to derivatives where one or two R 5 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., hydrides, alkoxides, hydroxides of alkah or alkaline earth metals, or of organo-Uthium compounds) with R 5L in which L is a leaving group such as a halogen, or by condensation with an R 5 containing ketone or aldehyde carbonyl derivative to give a fused pyrrolocarbazole-6-one derivative which has one or two an R5 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; Houlihan Ed.. Wiley- Interscience (1972)). The 2-indanone derivatives can be prepared using previously described procedures (see U.S. Patent 4,192,888; U.S. Patent 4.128.666; J. Am. Chem. Soc. 89:4524 (1967); Tetrahedron Lett. 43:3789 ( 1974); Chem. Ber. 122: 1791 ( 1989); Can. J. Chem. 60:2678 (1982); Helvetica Chimica Acta 70: 1791 ( 1987); Chem. Pharm. Bull. 33:3336 (1985); J. Org. Chem.
55:4835 (1990); Tetrahedron 45: 1441 ( 1989); Synthesis 818 (1981)). In Method B (FIG 2), a 2-(heteroaryl)indole derivative (1-3), or 2-(aryl)indole derivative such as 2-(2-indenyl)indole 4 is reacted with ethyl cis-β-cyanoacrylate in the presence of a catalyst such as S nCI4, AlCI3, EtAlCl2, Et2AlCl or TFA in CH2CI2, C2H4CI2 or toluene as solvent to give the 6-oxo carbazole compounds of formula I of the invention.
Compounds of Formula II are prepared as outlined in FIG 5. Addition of 2-(aryl)- or 2-(heteroaryl)indolylzinc reagents (Tetrahedron Lett., 1994, 35, 793; Tetrahedron Lett., 1994. 35. 7123; Tetrahedron Lett.. 1993, 34, 5955: Tetrahedron Lett. , 1993, 34, 6245) to succinimide. or an R1 substituted succinimide derivative, via a Reformatzsky type reaction (Synthesis. 1975. 685) followed by dehydration would give compounds of the general structure 9. Palladium catalyzed ring closure (US Patent 5,475, 110; Tetrahedron Lett., 1993, 34, 8361) would yield pyrrolo[2,3-c]carbazole compounds of Formula 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., SeO2- CrO3 Na2CrO7, or MnO2) (FIG 6). Alternatively, 2-(2- indenyl)indole 4 may be oxidized to 2-(2-( l-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 11 may prepared using the palladium-catalyzed cross-coupling methodology (FIG 3) by coupling l-carboxy-2-tributylstannylindole 5 or its derivatives with 2-(trifluoromethanesulfonyl)oxyinden-1-one or 2-bromoinden- 1-one 12 (FIG 7) (J. Org. Chem.. 1994. 59. 3453) or one of its derivatives. Compounds of the 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 gfve derivatives, for example, but not limited to, X = (C=C(R2)2), C(R2)2, C(OR1 )(R1 1). 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 manner similar to X = (C=O). 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. Example I: 5H, 7H. 13H-Benzofurano[2,3-a]pyrrolo[2,3- c]carbazole-6(6H)one (X = O; R1, R2, R3, R4, R5 = H)
A mixture of 2-(2-beuzofuryI)indole 2 (250 mg; 1.0 mmol) and maleimide (110 mg; 1.2 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C for 18 h. The sohd precipitated was collected, washed with TFA and dried to give 150 mg (48 %) of product. Recrystalhzation (THF) gave a tan sohd; mp >300 °C, MS (ES+) 312 (M+), 1H NMR (DMSO- d6) δ 4.00 (s, 2H). 4.13 (s, 2H), 7.12 (t, 1H), 7.37 (t, 2H), 7.45 (t, 2H), 7.71 (d, 1H). 7.95 (d. IH). 8.54 (d, 1H), 10.12 (s, 1H), 11.79 (s, 1H). Anal, calcd for C20H12N2O20.4 H2O; C. 75.18; H, 4.04; N, 8.77. Found: C, 75.29, H, 3.86, N, 8.60.
B. Example D: 5H, 7H, 13H-Benzothieno[2,3-a]pyrrolo[2,3- c]carbazole-6(6H)one (X = S; R1, R2, R3, R4, R5 = H)
A mixture of 2-(2-benzothienyl)indole 3 ( 100 mg, 0.4 mmol) and maleimide (40 mg; 0.4 mmol) in trifluoiOacetic acid (2 mL) was heated in a sealed reaction vial at 125 °C for 16 h. The sohd precipitated was collected, washed with cold methanol and dried to give 80 mg (58 %) of product. Recrystalhzation (THF) gave a tan sohd; mp >300°C, MS (ES+) 328 (M+), Η NMR (DMSO- d6) δ 4.10 (s, 2H), 7.20 (t, 1H), 7.40-7.60 (m, 4H), 8.10 (d, 1H), 8.80 (m. 1H). 10.86 (s, 1H), 1 1.80 (s, 1H). Anal, calcd for C20H12N2SO. 0.5 H2O; C, 71.20; H, 3.88: N, 8.30. Found: C, 70.86, H, 3.61, N, 8.39.
C. Example HI: 5H, 7H. I2H, 13H-Indolo[2,3-a]pyrrolo[2,3- c]carbazole-6(6H)one (X = N; R 1. R2, R3. R4, R5 = H)
(1) Method A
To a mixture 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 acid (0.5 mL). The solution was heated at reflux for 18 h., cooled to rt, and concentrated to approximately 20 mL. The solution was cooled in an ice bath, the sohd precipitate was collected, washed with cold ether and dried to give 150 mg (55 %) of product. Purification by column chromatography (EtOAc: hexanes; 2: 1) gave a brown-tan sohd, mp >320 °C, MS (ES+) 3 1 1 (M+), Η NMR (DMSO- cLJ δ 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m, 2H), 7.67 (d. 2H), 8.03 (d, 1H), 8.58 (d, 1H), 10.87 (s, 1H), 10.92 (S,1H), 11.18 (s, 1H). Anal, calcd for C20H12N2O2 0.5 H2O; C, 74.99; H, 4.41; N, 13.12. Found: C, 75.24, H.4.02. N. 13.05.
(2) Method B
A mixture of 2-2'-biindole 1 ( 100 mg; 0.43 mmol) and ethyl CΛS-β-cyanoacrylate (50 mg; 0.4 mmol) in methylene chloride ( 10 mL) was added 25 mL of SnCLi- 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: 1) gave a brown-tan sohd; mp >320 °C. MS (ES+) 31 1 (M+), Η NMR (DMSO- ds) δ 4.00 (s, 2H), 7.17-7.22 (m, 2H), 7.37-7.42 (m. 2H), 7.67 (d, 2H), 8.03 (d, 1H), 8.58 (d, 1H), 10.87 (s, 1H), 10.92 (s,1H), 11.18 (s, 1H).
This compound showed identical spectral and analytical characteristics as that prepared by Method A.
D. Example IV: 5H. 7H. 12H, 13H-Indeno[2,3-a]pyrrolo[2,3- c]carbazole-6(6H)one (X = CH2; R1. R2, R3. R4. R5 = H)
(1) Method A
A mixture of 2-(2-indenyl)indole 4 (300 mg, 1.3 mmol) and maleimide (160 mg; 1.6 mmol) in trifluoroacetic acid (2 mL) was heated in a sealed reaction vial at 160 °C for 18 h. The solution was evaporated and the sohd dissolved in ethyl acetate, then washed with water and dried (MgSO4) to give brown sohd product. The crude product was chromatographed (silica gel, EtOac: hexanes; 1: 1) to give a product which was treated with THF and filtered. The concentrated residue was tritutrated with MeOH to give the product; mp 275-280 °C, MS (ES+) 310 (M+), 1H NMR (DMSO- de) δ 4.00 (s. 2H), 4. 13 (s. 2H), 7. 17 (t, 1H), 7.25-7.42 (m, 3H), 7.50 (d, 1H), 7.71 (d, 1H), 8.00 (d. 1H), 8.37 (d. 1H), 10.75 (s, 1H), 11.33 (s, 1H). IR (KBr) 1650-1700 cm-1. Anal, calcd for C21H14N2O 0.7 H2O; C, 78.10; H, 4.81; N, 8.65. Found: C, 78.13, H, 4.41, N, 8.1.0. (2) Method B
A mixture of 2-(2-indenyl)indole 4 (75 mg; 0.32 mmol) and ethyl cis-β-cyanoacrylate (81 mg; 0.64 mmol) in trifluoroacetic acid ( 1 mL) was heated in a sealed reaction vial at 120 ºC for 1 h. followed by 4 h at 160 °C. The mixture was evaporated at reduced pressure and the residue was triturated with ether. The resulting sohd was chromatographed (silica gel; EtOAc: hexanes; 1:1) to give 12 mg (12%) of tan sohd product; mp 275-280 °C. MS (ES+) 310 (M+). This compound showed identical spectral data as that prepared in Method A.
E. Example V: Enhancement by Fused Pyrrolo[2,3-c]carbazole- 6-ones of the Induction by IFN-γ of the MHC H Antigen HLA-DR
A human cell line derived from human monocytes, THP-1 (ATCC TIB 202) that responds to JFN-γ, was used to demonstrate enhancement of HLA-DR by the fused pyrrolo[2,3-c]carbazole-6-oues
THP- 1 cells were grown in RPMI 1640 medium containing 20 uM
mercaptoethanol and 10% fetal bovine serum at 37°C in an atmosphere of 5%CO2:95% 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-γ only at 100 units/ml or treated with compounds of the invention at 1 uM final concentration for 30 min. prior to the addition of EFN-γ at 100 units/ml. 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 HLA-DR was performed by standard procedures as described in Interferons and Other Regulatory 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 Tmmunology Vol. 1, pages 5.0.1-5.8.8, John Wiley & Sous. 1994. One milhon cells from each treatment were collected by centrifugation and washed twice with phosphate-buffered saline (PBS). The cells were resuspended in 100 ul of PBS containing 10 ug of purified rabbit IgG to block non-specific sites on the cell surface. After 20 min. on ice, 20 ul 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 then washed 2 times with PBS each wash and fixed in 0.5 ml of 0.5% paraformaldehyde. The fixed cells were stored at 4°C until analyzed by flow cytometry.
The enhancement of HLA-DR by representative fused pyrτolo[2,3-c]carbazole-6- ones is shown in FIG 1. The enhancement of HLA-DR by EFN-γ alone is designated 100% on the Y axis. There is no significant bduction of HLA-DR by the representative compounds alone at 1 uM (FIG 1 ). All of the representative compounds enhance the induction of HLA-DR by IFN-γ above the induction by IFN-γ alone, i.e. above 100%. The percent enhancement above IFN-γ alone by the four compounds is shown in Table 1. For example, at 2μM, the compound of Section V(D) (Example IV) enhanced IFN-γ induction of HLA-DR by 60% over IFN-γ alone.
Figure imgf000022_0001
F. Example VI. NT-3 Potentiation of ChAT Activity in Basal Forebrain Cultures by PyrroIo[2,3-cjcarbazole-6-oπes
The ability of pyrroIo[2.3-c]carbazole-6-ones to potentiate NT-3 activity in basal forebrain cultures was determined using choline 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 of NT-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 of NT- 3 and the compound to be tested on the day of culture initiation, indicating a prolonged effect on the survival or function of basal forebrain cholinergic neurons. The methods employed are described in U.S. Patent 5,468,872, Columns 18 and 19.
Figure imgf000023_0001
Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention 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 cover all equivalent variations as fall within the true spirit and scope of the invention. Documents cited throughout this patent disclosure are hereby incorporated hereiu by reference.

Claims

WHAT IS CLAIMED IS:
1. A fused pyrτolo[2.3-c]carbazole-6-one represented by a formula selected
from the group consisting of:
Figure imgf000024_0001
wherein:
C
Figure imgf000024_0002
hU d a) R1 is selected from the group consisting of H, alkyl of 1-4 carbonsjaryl,
axylalkyl, heteroaryl. beteroarylalkyl; C(=O)R9. where R9 is alkyl of 1-4 caibons or aiyi; (CH2)nOR9, where n is an integer of 1-4; OR10, where R10 is H or alkyl of 1-4 carbons; (CH2)nOR14. where R14 is the residue of an amino acid after the
hydroxyl group of the carboxyl group is removed ; OR14, NR7R8; (CH2)n NR7R8, and CKCH2)uNR7R8; 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, alkynyl 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, Q, Br, I, CN, NO2, OR OR9, O(CH2)nNR7R8, OCOR9, OCONHR9,
O-tetrahydropyranyl, NH2, NR7R8, NR10COR9; NR1 0CO2R9,
NR10C0NR7R8, NHC(=NH)NΗ2, NR10SO2R9; S(O)yR1 1, wherein R1 1 is H, alkyl of 1-4 carbons, aryl of 6-10 carbons, or heteroaiyl, and y is 1 or 2; SR1 1, CO2R9, CONR7R8, CHO, COR9, CH2OR7, CH2OR9,
CH=NNR1 1 R I2, CH=NOR1 1,C H=NR9, CH= NNHCH(N=NH)NH2; SO2NR12R13. wherein either
(la) R12 and R13, independently, are H, alkyl of 1-4 caibons, 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(OR1 1 )2, NHR14, NR10R14 O R14, 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 caibons, alkylcarbonyloxy of 2-5 carbons, and alkoxy of 1-4 carbons;
c) each R 5 and R4. ύidependently, 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)nNR7R8, OCOR9, OCONHR9, NH2, (CH2)χ_OR9, (CH2)BOR10,
(CH2)nOR14, OR,a. NHR14 NR7R8, NR7(CH2)nNR7R8.NR10COR9,
NR10CONR7R8, SR1 1. S(O)yR1 1, CO2R9, COR9, CONR7R8, CHO,
CH=NOR1 1, CH=NR9, CH=NNR 1 1 R12, (CH2)nSR9, (CH2)nS(O)yR9; CH2SR15, where R15 is alkyl of 1-4 caitons; CH2S(O)yR14, (CH2)nNR7R8, (CH2)nNHR14, 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;
Figure imgf000026_0001
^ ,
d) R5 is selected from the group consisting of alkyl of 1-8 carbons, alkenyl of 1-8 carbons, and alkynyl of 1-8 carbons; and eithe
Figure imgf000026_0002
r
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)nNR7R8, OCOR9;' OCONHR9, NH2, (CH2)nOR9, (CH2)nOR14, NR7R8, NR7(CH2)nNR7R8.NR10COR9,
NR10CONR7R8, SR1 1, S(O)yR1 1, CO2R9, COR9, CONR7R8, CHO, CH-NOR1 1, CH=NR9, CH=NNR1 0R12, (CH2)nSR9, (CH2)nS(O)yR9, CH2SR15, CH2S(O)yR14 (CH2)nNR7R8, and (CH2)nNHR,4: e) X is selected from the group consisting of -N-, -O-, -S-, -S(=O>, -S=O)2-, alkylene of 1-3 carbons, -C(=OK -C(R=C(R2)-. -(CR2)2 , -CH=CH-, -CH(OH) CH(OH)-, -C(=NOR1 1 K -C(O R11 tyR1 1K -C(0)CH(R1 5)-, -CH(R15)C(=O); -CHrZ-, -Z-CH2-, -CH2ZCH2-, where Z is selected from the group consisting of -C(OR11XR1 1)-, O, S, C(=O), and NR1 1 ; and alkylene of 1-3 carbons substituted with a group selected from the group consisting of one R5 subsύtuent group, SR10, OR10, OR14, R15, phenyL, naphthyl, and arylalkyl of 7-14 carbons.
2. The compound of Claim I wherein R9 is selected from the group consisting ofalkyl of 1-4 carbons, phenyi, and naphthyl.
3. The compound of Claim 1 wherein R1 1, R13, and R13 are each
independently selected from the group consisting of H, alkyl of 1-4 caibons, phenyi, naphthyl, and heteroaryl.
4. The compound of Claim 1 wherein R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted phenyi, unsubstituted phenyi, OR10, and O(CH2)nNR7R8.
5. The compound of Claim 1 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 whh one group selected from the group consisting of OR9, OH, OCOR9, NR7R8, NH2, NR10COR9, and NR10R14.
6. The compound of Claim 1 wherein R3 and R4 are each independently selected from the group consisting of H, halogen, CN, OH, OR9, OR14, NH3, NR7R8 , (CH2)nOR10, (CHa)nOR14, COR9, NR10COR9, NHR14, and C(CH2)n NR7R8.
7. The compound of Claim 1 wherein R5 is selected from the group consisting of H and alkyl of 1-4 carbons.
8. The compound of Claim 1 wherein X is selected from the group consisting of -N-, -O-, -S-, alkylene of 1-3 carbons, -C=O-, -CH.-Z-, and -Z-CHn
9. The compound of Claim 8 wherein X is selected from the group consisting of -N-, -O-, -S-, and -CHn
10. The compound of Claim 9 wherein R1, R2, R3, R4, and R3 are each H.
11. The compound of Claim 1 represented by Formula L
12. The compound of Claim 1 1 wherein R1 is selected from the group consisting of H, alkyl of 1-4 carbons, substituted phenyi, unsubstituted phenyi, OR10, and
O(CH2)nNR7R8.
13. The compound of Claim 11 wherein R2 is selected from the group consisting of H, C(=O)R9, alkyl of 1-8 carbons, and alkyl of 1-8 caibons substituted with one group selected from the group consisting of OR9, OH, OCOR9, NR7R8, NH2, NR10COR9, and NR10R14
14. The compound of Claim 1 1 wherein R3 and R4 are each independently selected from the group consisting of H, halogen, CN, OH, OR9, OR14, NH2, NR7R8 , ((CH2)nOR10, (CH2)nOR14, COR9, NR10COR9, NHR14, and O(CH2)nNR7R8.
15. The compound of Claim 11 wherein R5 is selected from the group consisting of H and alkyl of 1-4 carbons.
16. The compound of Claim 1 1 wherein X is selected from the group consisting of -N-, -O-, -S-, alkylene of 1-3 carbons, -C=O-, -CH2-Z-, and -Z-CH2-.
PCT/US1997/002905 1996-02-21 1997-02-20 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon WO1997031002A1 (en)

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BR9707659A BR9707659A (en) 1996-02-21 1997-02-20 Pyrrole (2,3-C) carbarzol-6-ones that potentiate gamma interferon activity
AT97914792T ATE195124T1 (en) 1996-02-21 1997-02-20 CONDENSED PYRROLO(2,3-C) CARBAZOLE-6-ONE WHICH POTENTIATE THE ACTIVITY OF GAMMA INTERFERON
CA002241852A CA2241852C (en) 1996-02-21 1997-02-20 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon
NZ330837A NZ330837A (en) 1996-02-21 1997-02-20 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon
DE69702705T DE69702705T2 (en) 1996-02-21 1997-02-20 CONDENSED PYRROLO (2,3-C) CARBAZOLE-6-ONE THAT POTENTIFY THE ACTIVITY OF GAMMA INTERFERON
AU21914/97A AU716265B2 (en) 1996-02-21 1997-02-20 Fused pyrrolo(2,3-C)carbazole-6-ones which potentiate activity of gamma interferon
EP97914792A EP0885229B1 (en) 1996-02-21 1997-02-20 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon
JP9530385A JP2000505458A (en) 1996-02-21 1997-02-20 Condensed pyrrolo (2,3-C) carbazol-6-ones that increase the activity of gamma interferon
DK97914792T DK0885229T3 (en) 1996-02-21 1997-02-20 Condensed pyrrolo [2,3-c] carbazol-6-ones which potentiate gamma interferon activity
HK99101243A HK1017673A1 (en) 1996-02-21 1999-03-24 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon
GR20000402223T GR3034533T3 (en) 1996-02-21 2000-10-02 Fused pyrrolo(2,3-c)carbazole-6-ones which potentiate activity of gamma interferon

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US08/604,474 US5616724A (en) 1996-02-21 1996-02-21 Fused pyrrolo[2,3-c]carbazole-6-ones
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507480A (en) * 1999-08-20 2003-02-25 セフアロン・インコーポレーテツド Isomeric fused pyrrolocarbazoles and isoindolones

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2686899B1 (en) * 1992-01-31 1995-09-01 Rhone Poulenc Rorer Sa NOVEL BIOLOGICALLY ACTIVE POLYPEPTIDES, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
US6127401A (en) * 1998-06-05 2000-10-03 Cephalon, Inc. Bridged indenopyrrolocarbazoles
US6200968B1 (en) 1998-08-06 2001-03-13 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
US7795246B2 (en) * 1998-08-06 2010-09-14 Cephalon, Inc. Particle-forming compositions containing fused pyrrolocarbazoles
KR100628847B1 (en) 1998-09-25 2006-09-29 세파론, 인코포레이티드 Methods for Preventing/Treating Damage to Sensory Hair Cells and Cochlear Neurons
US6656474B1 (en) * 1999-01-15 2003-12-02 Regeneron Pharmaceuticals, Inc. Methods of using a neurotrophin and its analogues for the treatment of gastrointestinal hypomotility disorders
US6841567B1 (en) 1999-02-12 2005-01-11 Cephalon, Inc. Cyclic substituted fused pyrrolocarbazoles and isoindolones
FR2798931B1 (en) * 1999-09-22 2001-11-16 Oreal NOVEL INDOLIC COMPOUNDS, THEIR USE FOR DYEING AND MAKE-UP OF KERATINIC MATERIALS, COMPOSITIONS CONTAINING THEM AND DYEING METHODS
US6630500B2 (en) 2000-08-25 2003-10-07 Cephalon, Inc. Selected fused pyrrolocarbazoles
US7018999B2 (en) * 2001-05-16 2006-03-28 Cephalon, Inc. Methods for the treatment and prevention of pain
EP1463751B1 (en) 2001-12-21 2013-05-22 Human Genome Sciences, Inc. Albumin fusion proteins
US7169802B2 (en) * 2003-12-23 2007-01-30 Cephalon, Inc. Fused pyrrolocarbazoles
US7241779B2 (en) * 2003-12-23 2007-07-10 Cephalon, Inc. Fused pyrrolocarbazoles
US20060134174A1 (en) * 2004-12-22 2006-06-22 Bausch & Lomb Incorporated Pharmaceutical delivery system and method of use
US20060134176A1 (en) * 2004-12-22 2006-06-22 Bausch & Lomb Incorporated Pharmaceutical delivery system and method of use
US20060134175A1 (en) * 2004-12-22 2006-06-22 Stephen Bartels Drug eluting pharmaceutical delivery system for treatment of ocular disease and method of use
US20060293378A1 (en) * 2005-06-28 2006-12-28 Mcintire Gregory Method of lowering intraocular pressure
US20090155352A1 (en) * 2007-11-20 2009-06-18 Cephalon, Inc. Microemulsion containing indolocarbazole compound and dosage forms containing the same
CN103965204B (en) * 2008-11-19 2016-09-07 赛福伦公司 The new model of indazole also [5,4-A] pyrrolo-[3,4-C] carbazole compound
EP2192121A1 (en) 2008-11-27 2010-06-02 Cephalon France Regioselective reduction of fused pyrrolocarbazoles-5,7-diones

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0434057A2 (en) * 1989-12-21 1991-06-26 Gödecke Aktiengesellschaft Indolocarbazole derivatives, processes for their preparation and their use
WO1991009127A1 (en) * 1989-12-20 1991-06-27 Schering Corporation BCRF1 PROTEINS AS INHIBITORS OF INTERFERON-$g(g)

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4552842A (en) * 1983-01-28 1985-11-12 Bristol-Myers Company Process for producing rebeccamycin
EP0303697B1 (en) * 1987-03-09 1997-10-01 Kyowa Hakko Kogyo Co., Ltd. Derivatives of physiologically active substance k-252
DE3835842A1 (en) * 1988-10-21 1990-04-26 Goedecke Ag INDOLOCARBAZOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS
CZ280738B6 (en) * 1988-02-10 1996-04-17 F. Hoffmann - La Roche And Co., Aktiengesellschaft Substituted pyrroles, their use for preparing medicaments and medicaments based thereon
DE3833008A1 (en) * 1988-09-29 1990-04-05 Goedecke Ag PYRROLOCARBOZOL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT
MC2096A1 (en) * 1989-02-23 1991-02-15 Hoffmann La Roche SUBSTITUTED PYRROLES
US5185260A (en) * 1991-08-29 1993-02-09 The United States Of America As Represented By The United States Department Of Energy Method for distinguishing normal and transformed cells using G1 kinase inhibitors
NZ245203A (en) * 1991-11-29 1997-07-27 Banyu Pharma Co Ltd 5h-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6h)-dione derivatives substituted in position-13 by a pentose or hexose group; corresponding indolo-furano(anhydride)intermediates
US6271242B1 (en) * 1992-02-10 2001-08-07 Bristol-Myers Squibb Co. Method for treating cancer using a tyrosine protein kinase inhibitor
US5405864A (en) * 1993-10-15 1995-04-11 Syntex (U.S.A.) Inc. Chemotherapeutic maleimides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991009127A1 (en) * 1989-12-20 1991-06-27 Schering Corporation BCRF1 PROTEINS AS INHIBITORS OF INTERFERON-$g(g)
EP0434057A2 (en) * 1989-12-21 1991-06-26 Gödecke Aktiengesellschaft Indolocarbazole derivatives, processes for their preparation and their use

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507480A (en) * 1999-08-20 2003-02-25 セフアロン・インコーポレーテツド Isomeric fused pyrrolocarbazoles and isoindolones
JP4776842B2 (en) * 1999-08-20 2011-09-21 セフアロン・インコーポレーテツド Isomeric condensed pyrrolocarbazoles and isoindolones

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