MXPA98004706A - Isoindolone fused as protein quinasac inhibitors - Google Patents

Abstract

Inorganic non-indole containing compounds are disclosed, referred to as fused isoindolones, which are represented by the general formula (I). The fused isoindolones can be obtained by complete chemical synthesis. Methods for manufacturing and using fused isoindolones are disclosed

Description

ISOINDOLONE FUSED AS PROTEIN OUINASE C INHIBITORS Field of the Invention The invention relates to fused isoindol-2 and -2,4-dions fused with aryl and heteroaryl, which are referred to herein as "fused isoindolones". The invention also relates to methods for making these compounds, and methods for using the compounds. Background of the Invention The publications cited herein are incorporated by reference. The material derived from microbes referred to as "K-252a" has gained significant attention over the past few years, due to the variety of functional activities it possesses. K-252a is an indolocarbazole alkaloid that was originally isolated from a Nocordiosis sp culture.

(Kase, H. and collaborators, 39 J. Antibiotics 1059, 1986). K-252a is an inhibitor of several enzymes, including protein kinase C ("PKC"), and tyrosine kinase trk. The reported functional activities of K-252a are numerous and diverse, eg, tumor inhibition (U.S. Patent Nos. 4,877,776 and 5,063,330; European Publication Number 238,011 in the name of Nomato); anti-insecticidal activity (U.S. Patent No. 4,735,939); inhibition of inflammation (U.S. Patent Number 4,816,450); treatment of diseases associated with neuronal cells (Publication of O PI Number WO 94/02488, published on February 3, 1994, in the name of Cephalon, Inc. and Kyowa Ha ko Kogyo Co., Ltd). The reported indolocarbazoles share several common attributes. In particular, each comprises a heterocyclic fraction of bis-indole. Staurosporine (derived from Streptoinyces sp.) And K-252a (derived from Nocordiosis sp.) Each also comprise a sugar fraction linked by means of two N-glycosidic bonds (linked with the indole nitrogens) . Both K-252a and staurosporine have been extensively studied with respect to their utility as therapeutic agents. The indolocarbazoles are in general lipophilic, which allows their comparative ease in the crossing of biological membranes, and unlike the proteinaceous materials, they manifest a longer life in vivo. Although K-252a possesses these varied and useful activities, one drawback of the compound is that, due to its microbial origin, it must be derived from a culture medium by means of a fermentation process. Recently, the total synthesis of K-252a has been reported in the literature, but the synthesis is not practical for commercial use (Wood, J. et al., J. Am. Chem. Soc. 1995, 117, 10413). Accordingly, compounds which possess the desired functional activities of K-252a, but which can be easily obtained using chemical synthesis techniques, would offer distinct advantages over the indolocarbazole compounds currently available. SUMMARY OF THE INVENTION The invention provides compounds referred to herein as "fused isoindolones". These compounds are biologically active. Fused isoindolones are molecules that do not contain indole, which can be synthesized chemically de novo. The fused isoindolones of this invention are different from the indolocarbazoles, because they do not include a nitrogen at positions 12 or 13 (the ring alphabetic designations stipulated in Porter et al., 57 J. Org. Chem. 2105, 1992, are used for of reference). Additionally, the fused isoindolones do not include a sugar fraction linked by means of two N-glycoside linkages. Because these compounds do not include this sugar fraction, synthetic production can be easily achieved. In a beneficial and surprising way, these compounds that do not contain indole, which are not of microbial origin, can be easily synthesized, and possess biological activities that allow a wide range of applications observed so far only with certain indolocarbazoles. The fused isoindolones of the invention are represented by the following general formula (Formula I): The preferred fused isoindolones are represented by Formula II: The constituent members are described in detail later. Both in the formula I and in the formula II, in the rings C and E, the constituent "X" is not nitrogen. Preferred synthetic routes are also described herein, including methodologies for the preparation of lactam isomers.

The fused isoindolones can be used in a variety of ways, for example, to improve the function and / or survival of cells of the neuronal lineage, either individually or in combination with neurotrophic and / or indolocarbazole factors; the inhibition of protein kinase C (PKC); and the inhibition of tyrosine kinase activity trk. This latter activity indicates the activity for the inhibition of the proliferation of cancer cells, including the cancerous conditions of the prostate. Due to these varied activities, the compounds of this invention find utility in a variety of establishments, including research and therapeutic environments. Detailed Description I. Brief Description of the Drawings Figure 1 is a graph that gives evidence of the effect of the fused isoindolone derivatives 1-1 and 1-2 on the ChAT activity of the spinal cord. Figure 2 is a graph that gives evidence that fused isoindolones promote ChAT activity in the basal forebrain. Figure 3 shows a scheme for the synthesis of bis-indene derivatives. Figure 4 shows a scheme for the synthesis of fused isoindolones.

Figure 5 shows a scheme for the synthesis of fused isoindolones, where X is -C (= 0) -. Figure 6 shows a scheme for the synthesis of fused isoindolones (X = carbonyl) from 1-indanones. Figure 7 shows a scheme for the synthesis of fused isoindolones containing two carbonyl groups. Figure 8 shows a scheme for the synthesis of fused isoindolones using a Michael reaction. Figure 9 shows a scheme for the synthesis of selected fused isoindolones, using a Wittig reaction. Figure 10 shows a scheme for the synthesis of X-bis-alkylated fused isoindolones. Figure 11 shows a scheme for the synthesis of ring-B heterocyclic fused isoindolones. Figure 12 shows a scheme for the synthesis of b-ring and F ring b-heterocyclic isoindolones. Figure 13 shows a scheme for the synthesis of bis-benzothiafen derivatives. Figure 14 shows a scheme for the synthesis of indenyl-benzothiaphene derivatives. Figure 15 shows a scheme for the synthesis of fused isoindolones, using a Diels-Alder reaction with acetylene dicarboxylate.

II. Fused Isoindolones The invention provides fused isoindolones represented by formula I: wherein: ring B and ring F are independently selected from the group consisting of: (a) a 6-membered carbocyclic aromatic ring, wherein up to 3 carbon atoms are replaced by nitrogen atoms; (b) a 5-membered carbocyclic aromatic ring; and (c) a 5-membered carbocyclic aromatic ring, wherein: (1) a carbon atom is replaced by an oxygen, nitrogen, or sulfur atom; or (2) two carbon atoms are replaced by a nitrogen atom and a sulfur atom, or by a nitrogen atom and an oxygen atom; R1 is selected from the group consisting of H; alkyl of 1 to 4 carbon atoms; aril; Arylalkyl; heteroaryl; heteroarylalkyl; COR9, wherein R9 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, aryl, and heteroaryl; -OR10, wherein R10 is selected from the group consisting of H and alkyl of 1 to 4 carbon atoms; -CONH2, -NR7R8, - (CH2) nNR7R8, and -0 (CH2) = nNR7R7, wherein n is from 1 to 4, and (a) R7 and R8 are independently selected from the group consisting of H and alkyl from 1 to 4 carbon atoms; or (b) R7 and R8 together form a linking group of the formula - (CH2) 2-X1- (CH2) 2-, wherein X1 is selected from the group consisting of -0-, -S-, and -CH2-; A1 and A2, in pairs, are selected from the group consisting of: H, H; H, -OR 11, wherein R 11 is H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, or heteroaryl; H, -SR11; H, -N (R1: L) 2; = 0; = S; y = NR11, wherein A1 and A2 can together represent a double-linked atom; B1 and B2, in pairs, are selected from the group consisting of: H, H; H, -OR11; H, -SR11; H, -N (R1: L) 2; = 0; = S; y = NR1: L, wherein B1 and B2 can together represent a double-bonded atom; with the proviso that at least one of the pairs A1 and A2, and B1 and B2, is = 0; X, in each position, is independently selected from the group consisting of: (a) an unsubstituted alkylene of 1 to 3 carbon atoms; (b) an alkylene of 1 to 3 carbon atoms substituted with R2, wherein R2 is selected from the group consisting of: (1) OR10; -SR10; R15, wherein R15 is alkyl of 1 to 4 carbon atoms; phenyl; naphthyl; Arylalkyl of 7 to 15 carbon atoms; H; -S02R9; -C02R9; -COR9; alkyl, alkenyl, and alkynyl of 1 to 8 carbon atoms, wherein: (i) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is unsubstituted; or (ii) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is substituted with a substituent selected from the group consisting of 1 to 3 aryls of 6 to 10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; -N02; OH; -OR9; -O (CH2) nNR7R8, where n is 1 to 4; -OCOR9; -OCONHR9; O-tetrahydropyranyl; NR2; -NR7R8; NR10COR9; -NR10CO2R9; -NR10CONR7R8; -NHC (= NH) NH2; -NR10SO2R9; - S (0) vR1: L, where y is 1 or 2; -SR11; -C02R9; -CONR7R8; -CHO; COR9; -CH2OR7; -CH = NNR11R12, wherein R12 is selected from the group consisting of H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, and heteroaryl; -CH = NOR?: L; -CH = NR9; -CH = NNHCH (N = NH) NH2; -S02NR12R13, wherein R13 is selected from the group consisting of H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, and heteroaryl, or R12 and R13 together form a linking group; -PO (OR?: L) 2, -OR14, wherein R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; or (2) a monosaccharide of 5 to 7 carbon atoms, wherein each hydroxyl group of the monosaccharide is independently unsubstituted, or is replaced by H, alkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 2 to 5 carbon atoms, or alkoxy of 1 to 4 carbon atoms; and (c) a functional group selected from the group consisting of -CH = CH-; -CHOH-CHOH-; -0-; -S-; -S (= 0) -; -S (S = 0) 2-; -C (R10) 2-; -C = C (R2) 2; -C (= 0) -; -C (= NOR1: L) -; -CÍOR11) (R11) -; -C (= 0) CH (R15) -; -CH (R15) C (= 0) -; -C (= N0R1: L) CH (R15) -; -CH (R15) C (= N0R11) -; CONR15; NR15C0; -CH2Z-; -ZCH2-; and -CH2ZCH2-, wherein Z is -CR11; -0-; -S-; -C (= 0) 0R?: L; -C (= NOR1: L); and -NR11; R3, R4, R5, and R6 are each independently selected from the group consisting of: H aryl; heteroaryl; F; Cl; Br; I; -CN; CF3; -N02; OH; -OR9 -0 (CH2) nNR7R8; -OCOR9; -0C0NHR9; NH2; -CH20H; -CH2OR14; -NR7R8 -NR10COR9; -NR10CONR7R8; -SR11; -SÍOjyR11, where y is 1 or 2 -C02R9; -COR9; -C0NR7R8; -CHO; -CH = N0R1: L; -CH = NR9; -CH = NNR11R12 - (CH2) nSR9, wherein n is from 1 to 4; - (CH2) nS (0) and R9; -CH2SR15, wherein R15 is alkyl of 1 to 4 carbon atoms; -CH2S (0) and R14; - (CH2) nNR7R9; - (CH2) nNHR14; alkyl, alkenyl, alkynyl of 1 to 8 carbon atoms, wherein: (a) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is unsubstituted; or (b) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is substituted with 1 to 3 aryls of 6 to 10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; -N02; OH; -OR9; -0 (CH2) nNR7R8; -OCOR9; -OCONHR9; O-tetrahydropyranyl; NH2; -NR7R8; -NR10COR9; -NR10CO2R9; -NR10CONR7R8; -NHC (= NH) NH2; -NR10SO2R9; -S (0) and R13-, where y is 1 or 2; -SR11; -C02R9; -C0NR7R8; -CHO; COR9; -CH2OR7; -CH = NNR1: LR12; -CH = NOR1: L; -CH = NR9; -CH = NNHCH (N = NH) NH2; -S02NR12R13; -PO (OR1: L) 2; OR14; or a monosaccharide of 5 to 7 carbon atoms, wherein each hydroxyl group of the monosaccharide is independently unsubstituted, or is replaced by H, alkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 2 to 5 carbon atoms, or alkoxy of 1 to 4 carbon atoms. Preferred embodiments of the invention are fused isoindolones represented by formula II: Preferably, A1 and A2 are selected in pairs from the group consisting of H, H; H, OH; y = 0; and B1 and B2 are selected in pairs from the group consisting of H; H; H, OH; y = 0; with the understanding that A1 and A2, or B1 and B2, are = 0. Preferably, R1 is H. When R1 is COR9, and R9 is aryl, preferably R9 is phenyl or naphthyl. Preferably, X, in any position, or both, is an unsubstituted alkylene of 1 to 3 carbon atoms, -0-, or -S-. When X has a substituent R2, a preferred R2 group is OR10. When the group R2 is arylalkyl of 7 to 14 carbon atoms, it is preferably benzyl. When R2 is an alkyl, alkenyl, or alkynyl, it is preferably an alkyl, alkenyl, or alkynyl of 1 to 4 carbon atoms. When R2 is a substituted alkyl, alkenyl, or alkynyl, and the substituent is aryl, preferably the aryl is phenyl or naphthyl. When a substituent on R2 is -S (0) and R1-L, and R11 is aryl, preferably R11 is phenyl or naphthyl. When a substituent on R2 is -CH = NNR11R12 or -S02NR12R13, and R12 or R13 is aryl, it is preferably phenyl or naphthyl. When R12 and R13 together represent a linking group, preferably the linking group is - (CH2) 2-X1- (CH2) 2-, wherein X1 is selected from the group consisting of -0-; -S-; and -CH2-. Preferably, R3, R4, R5, and R6 are H. When at least one of R3, R4, R5, and R6 is aryl, it is preferably aryl of 6 to 10 carbon atoms, and more preferably is phenyl or naphthyl, provided that either R3 or R4 is H, and any of R5 or R6 is H. When at least one of R3, R4, R5, and R6 is alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms, preferably it is alkyl, alkenyl, or alkynyl of 1 to 4 carbon atoms, with the understanding that either R3 or R4 is H, and any of R5 or R6 is H. Whenever numerical ranges are specified herein, the range It is inclusive. For example, "1 to 4 carbon atoms" includes the values 1, 2, 3, and 4. Unless otherwise specified, provided the terms "aryl" or "heteroaryl" are used herein, it should be understood that the aryl or heteroaryl group may be substituted or unsubstituted. As used in the definition of R14, the term "amino acid" denotes a molecule that contains both an amino group and a carboxyl group. It includes an "α-amino acid", which has its usual meaning as a carboxylic acid that carries an amino functionality on the carbon atom adjacent to the carboxyl group. The a-amino acids may occur naturally, or may not occur naturally. Amino acids also include "dipeptides" which are defined herein as two amino acids that are linked in a peptide bond. Accordingly, the constituents of the dipeptides are not limited to α-amino acids, and can be any molecule that contains both an amino group and a carboxyl group. Preferred are α-amino acids, dipeptides such as lysyl- / 3-alanine, and aminoalkanoic acids of 2 to 8 carbon atoms, for example, 3-dimethylaminobutyric acid. The pharmaceutically acceptable salts of the fused isoindolone derivatives also fall within the scope of the compounds disclosed herein. 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 the 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 tetramethyl ammonium salt. Examples of the pharmaceutically acceptable organic amine addition salts are salts with morpholine and piperidine. Examples of the pharmaceutically acceptable amino acid addition salts are salts with lysine, glycine, and phenylalanine. The compounds provided herein may be formulated into pharmaceutical compositions by mixing them with pharmaceutically acceptable non-toxic excipients and vehicles. As noted above, these compositions can be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or in oral administration, particularly in the form of tablets or capsules; or intranasally, in particular in the form of powders, nasal drops, or aerosols; or dermally, by means, for example, of transdermal patches. The composition can be conveniently administered in a unit dosage form, and can be prepared by any of the methods well known 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 whey, polyalkylene glycols, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes, and the like. In particular, the lactide polymer, the lactic / glycolide copolymer, or the biocompatible and biodegradable polyoxyethylene-polyoxypropylene copolymers can be useful excipients for controlling the release of the active compounds. Other potentially useful parenteral application systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for administration by inhalation contain as excipients, for example, lactose, or they may be aqueous solutions containing, for example, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or oily solutions to be administered 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, or salicylate for rectal administration, or citric acid for vaginal administration. Formulations for transdermal patches are preferably lipophilic emulsions. The materials of this invention can be used as the sole active agent in a pharmaceutical product, or they can be used in combination with other active ingredients, for example, other growth factors that facilitate neuronal survival or axonal regeneration in diseases or disorders, therapy for cancer, or therapy for HIV infection. The concentrations of the compounds described herein in a therapeutic composition will vary depending on a number of factors, including the dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, and the route of administration. In general terms, the compounds of this invention can be provided in an aqueous physiological buffer solution containing from about 0.1 to 10 weight percent / volume of the compound for parenteral administration. Typical dosing scales are from about 1 microgram / kilogram to about 1 gram / kilogram of body weight per day; A preferred dosage scale is from about 0.01 milligrams / kilogram to 100 milligrams / kilogram of body weight per day. The preferred dosage of the drug to be administered possibly depends on variables such as the type and degree of progress of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the selected compound, and the formulation of the excipient of the compound, and its route of administration.

III. Utilities of Fused Isoindolone Fused isoindolones have demonstrated important functional pharmacological activities that find utility in a variety of facilities, including both research and therapeutic areas. In general, the activities of the fused isoindolones show positive effects on the function and / or survival of the cells that respond to the trophic factor, and demonstrate inhibition of the enzymatic activity, ie, of trk and PKC.

The effect on the function and / or survival of the cells that respond to the trophic factor, for example, the cells of a neuronal lineage, can be established using any of the following assays: (1) choline acetyltransferase assay ("ChAT ") of cultured spinal cord; or (2) assay of ChAT activity of cultured basal brain neuron ("BFN"). Inhibition of enzyme activity can be determined using PKC inhibition assays and tyrosine trk kinase inhibition assays. As used herein, the term "effect," when used to modify the terms "function" and "survival," means a positive or negative alteration or change. An effect that is positive can be referred to herein as an "improvement" or an "improvement", and an effect that is negative can be referred to herein as "inhibition" or "inhibitor". As used herein, the terms "improve" or "improvement" when used to modify the terms "function" or "survival" mean that the presence of a fused isoindolone has a positive effect on function and / or the survival of a cell that responds to the trophic factor, comparing with a cell in the absence of the fused isoindolone. For example, and not by way of limitation, with respect to the survival of, for example, a cholinergic neuron, the fused isoindolone would show improvement in the survival of a cholinergic neuronal population at risk of dying (due, for example, to injury , to a disease condition, to a degenerative condition, or to a natural progress), when compared with a cholinergic neuronal population that does not present this fused isoindolone, if the treated population has a comparatively greater period of functionality than the untreated population. As used herein, "inhibit" and "inhibition" means that a specified response of a designated material (e.g., enzyme activity) decreases comparatively in the presence of a fused isoindolone. As used herein, the term "neuron", "neuronal cell line", and "neuronal cell" includes, but is not limited to, a heterogeneous population of neuronal types that have single or multiple transmitters, and / or individual or multiple functions; preferably these are cholinergic and sensory neurons. As used herein, the phrase "cholinergic neuron" means neurons of the System Nervous Central (CNS), and Peripheral Nervous System (PNS), whose neurotransmitter is acetylcholine; the examples are the neurons of the basal forebrain and the spinal cord. As used herein, the phrase "sensory neuron" includes neurons that respond to environmental cues (e.g., temperature, movement) of, e.g., skin, muscle, and joints; An example is a DRG neuron. A "cell responsive to the trophic factor," as defined herein, is a cell that includes a receptor with which a trophic factor can be specifically linked. Examples include neurons (e.g., cholinergic and sensory neurons), and non-neuronal cells (e.g., monocytes and neoplastic cells). As used herein, the term "trk" refers to the family of high affinity neurotrophin receptors currently comprising trk A, trk B, and trk C, and other membrane associated proteins with which a neurotrophin.

A. Effect on the Function and / or Survival of the Cells Responding to the Trophic Factor The fused isoindolones disclosed can be used to improve the function and / or survival of cells of the neuronal lineage. In this context, the fused isoindolones can be used individually or with other fused isoindolones, or in combination with other beneficial molecules, such as indolocarbazoles, which also give evidence of the ability to affect the function and / or survival of a designated cell. A variety of neurological disorders are characterized by neuronal cells that are dying, injured, functionally compromised, suffering axonal degeneration, at risk of dying, and so on. These disorders include, but are not limited to: Alzheimer's disease; disorders of motor neurons (eg, amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (eg, embolism, ischemia); Huntington's disease; dementia due to AIDS; epilepsy; multiple sclerosis; peripheral neuropathies (for example, those that affect DRG neurons in peripheral neuropathy associated with chemotherapy), including diabetic neuropathy; disorders induced by excitation amino acids; disorders associated with concussive or penetrating injuries of the brain or spinal cord. As stipulated in the examples of this section of the disclosure, the ability of a fused isoindolone to enhance the fusion and / or survival of the cells of a neuronal lineage can be determined by employing: (1) the activity assay of ChAT of the spinal cord; or (2) the assay of ChAT activity of the basal forebrain. ChAT catalyzes the synthesis of the acetylcholine neurotransmitter, and is considered an enzymatic marker for a functional cholinergic neuron. A functional neuron is also able to survive. The neuronal survival is tested by quantifying the specific recovery and the enzymatic conversion of a dye (for example, calcein AM) by living neurons. Due to their varied utilities, the fused isoindolones disclosed herein find utility in a variety of establishments. The compounds can be used in the development of models for survival, function, identification of neuronal cells, or for the selection of other synthetic compounds that have activities similar to that of fused isoindolones. The compounds can be used in a research environment, to investigate, define, and determine the molecular targets associated with functional responses. For example, by radiolabelling of fused isoindolones associated with a specific cellular function (eg, mitogenesis), the target entity with which the fused isoindolones bind can be identified, isolated, and purified for characterization. The degeneration, death, or non-functioning of neurons, is a feature of many human neurological disorders, including, but not limited to, Alzheimer's disease; disorders of motor neurons (for example, ALS); Parkinson's disease; cerebrovascular disorders (eg, embolism, ischemia); Huntington's disease; dementia due to AIDS; epilepsy, multiple sclerosis; concussive or penetrating injuries of the brain or spinal cord; peripheral neuropathies; and disorders induced by excitation amino acids. Because the disclosed compounds have shown utility, for example, in the improvement of ChAT activity, the utility of the compounds in the treatment of disorders associated with, for example, a decrease in ChAT activity or DRG neuron death is within the scope of this invention.

Example III (A) (1): Spinal Cord ChAT Activity Assay As noted, ChAT is a specific biochemical label for functional cholinergic neurons. The cholinergic represent the main cholinergic input to the formation of the hippocampus, the olfactory nucleus, the interpeduncular nucleus, the cortex, the tonsils, and the parts of the thalamus. In the spinal cord, motor neurons are cholinergic neurons containing ChAT (Phelps et al., J \ Comp.Neurol., 273: 459-472 (1988)). The activity of ChAT has been used to study the effects of neurotrophins (for example, NGF or NT-3) on the survival and / or function of cholinergic neurons. The ChAT assay also serves as an indication of the regulation of ChAT levels in cholinergic neurons.

The fused isoindolone derivatives increased ChAT activity in the dissociated rat embryonic spinal cord culture assay (Figure 1). Compound 1-2 increased the 150% ChAT activity on the control cultures (not treated with the fused isoindolone) after allowing a coating period of 2 to 3 hours for the cells to bind to the cavities of the cells. control tissue culture. In these assays, a fused isoindolone was directly added to a dissociated spinal cord culture. The compounds of the invention increased the ChAT activity of the spinal cord. Compounds that increased ChAT activity at least 120 percent of the control activity are considered active. The increased ChAT activity was observed after a single application of the fused isoindolone. The compound was added on the same day that the culture of dissociated spinal cord cells was started. The increased ChAT activity could be detected 48 hours later. Methods: Fetal rat spinal cord cells were dissociated, and experiments were performed as described (Smith et al., "Cell Biology 101: 1608-1621 (1985); Glicksman et al., J. Neurochem. 61: 210- 221 (1993).) Dissociated cells were prepared from spinal cords dissected from rats (embryonic day 14-15) by standard trypsin dissociation techniques (Smith et al., J. Cell Biology 10: 1608-1621 (1985)). The cells were coated in 6 x 10 5 cells / square centimeter, over culture pockets of plastic tissue coated with poly-1-ornithine in an N2 medium free of serum supplemented with 0.05 percent bovine serum albumin (BSA). (Bottenstein et al., PNAS USA 76: 514-517 (1979)) The cultures were incubated at 37 ° C in a humidified atmosphere of 5 percent P02 / 95 percent air for 48 hours. measured after 2 days in vitro, using a modi Fonnum procedure (Fonnum, J. Neuroc em. 24: 407-409 (1975)) in accordance with McManaman et al., And Glicksman et al.

(McManaman et al., Developmental Biology 125: 311-320 (1988); Glicksman et al., J "Neurochem 61: 210-221 (1993)).

Example III (A) (2): Basal Anterior Brain ChAT Activity Assay Fused isoindolone derivatives were tested for the ability to increase the ChAT activity of the basal forebrain cultures. It was found that fused isoindolones increase ChAT activity in basal forebrain cultures (Figure 2). The control cultures did not receive fused isoindolone. In preliminary trials of ChAT activity of the basal forebrain, compounds 1-3 and 1-4 did not increase ChAT activity. Methods: The basal forebrain was dissected from rat embryos (day 17 or 18 embryos), and the cells were dissociated with a neutral protease (Dispase ™, Collaborative Research). Neurons were coated at a density of 5 x 10 4 cells / well (1.5 x 10 5 cells / square centimeter) on plates coated with poly-ornithine and laminin. The cells were cultured in serum free N2 medium containing 0.05 percent bovine serum albumin at 37 ° C in a humidified atmosphere with 5 percent C02 / 95 percent air. The activity of ChAT was evaluated 5 days after the coating, using the ChAT assay as described in Example III (A) (1).

B. Inhibition of Enzyme Activity The ability of indolocarbazole K-252a, for example, to inhibit the enzymatic activity of PKC is well known and well documented. The inhibition of PKC activity has been suggested as an approach to inhibit, mediate, reduce, and / or prevent a variety of disease states, including inflammatory diseases, allergy and cancerous conditions, as indicated in the following representative references; Patents of the United States of North America Nos. 4,877,776 and 4,923,986; Published European Patent Specification No. 558,962 (published September 8, 1993 in the name of E.R. Squibb &Sons, Inc.); Tadka, T. et al., 170 (3) Biochem. Biophys. Res. Comm. 1151, 1980). Tyrosine kinases, of which trk is a member, are enzymes that catalyze the transfer of ATP? -phosphate to the hydroxyl group of tyrosine in many key proteins. Activated tyrosine protein kinases have been identified as the products of about half of the known oncogens (see Chang, CJ &Geahlen, RL 55 (11) J. "Na t. Prods. 1529, 1992). inhibition, mediation, reduction, and / or prevention of a variety of cancerous conditions by means of the inhibition of protein kinases (see Chang, CJ, supra.) Due to the important association between protein kinase activity and certain diseases and disorders (for example, cancer), fused isoindolones are also found useful in research and therapeutic settings, for example, in a research environment, compounds can be used in the development of tests and models for further improvement of the understanding of the roles that inhibition of protein kinase (eg, PKC, tyrosine kinase trk) has in the mechanical aspects of disorders and associated diseases. In a therapeutic setting, compounds that inhibit these enzymatic activities can be used to inhibit the deleterious consequences of these enzymes with respect to disorders such as cancer. The data demonstrate the inhibition of the enzymatic activity using the fused isoindolones disclosed, as determined by the following assays: (1) inhibition assay of PKC activity; (2) inhibition assay of tyrosine kinase activity trk A.

Example III (B) (1): PKC Activity Inhibition Assay The fused isoindolones inhibited the activity of protein kinase C (Table VI). The protein kinase C assay has been reported (Murakata et al., U.S. Patent No. 4,923,986; Kikkawa et al., "Biol. Chem. 257: 13341-13348 (1982)). performed with several concentrations of fused isoindolones.The concentration at which protein kinase C (IC50) was inhibited at 50 percent was determined Table I: Inhibition of Protein Kinase C Example III (B) (2): Assay of Inhibition of Tyrosine Kinase Activity trfcA Fused isoindolones inhibited the activity of tyrosine kinase trkA, as determined by ELISA. TrkA is a high affinity receptor for neurotrophins. Fused isoindolones were added to 96-well microtiter plates, which were previously coated with a phosphorylation substrate (phospholipase C-? (PLC?) / PGEX fusion protein) (see Rotin et al., 11 EMBO J. 559, 1992) . These compounds were then tested for their ability to inhibit substrate phosphorylation by the tyrosine kinase trkA.

TABLE II: Inhibition of TrkA Tyrosine Kinase Activity Methods: 96-well ELISA plates were coated (Nunc) with 100 microliter / cavity phosphorylation substrate (40 micrograms / milliliter PLC? / PGEX fusion protein) in 20 mM Tris, pH 7.0, 137 mM NaCl, and 0.02% NaN3 overnight at 4 ° C. The plates were then washed three times with TBST (20 mM Tris, pH 7.6, 137 mM NaCl, 0.2 percent Tween 20), and subsequently blocked with 3 percent bovine serum albumin (BSA) in TBST for 1 hour. hour at 37 ° C. Plates were washed three times with TBST, followed by two washes with TBS (TBST without Tween 20). Then pyrrolocarbazoles fused at different concentrations were added to a reaction mixture (50 mM HEPES, pH 7.4, 5 mM MnCl 2, 5 mM MgCl 2, 140 mM NaCl, 16 μM ATP, and 15 nanograms of trkA in a total volume of 100 microliters ). As a negative control, 100 mM EDTA was included in the reaction solution. Then the plates were incubated at 37 ° C for 15 minutes. The detection antibody, anti-phosphotyrosine monoclonal antibody (UBI), was added at a 1: 2000 dilution in TBST, and incubated for 1 hour at 37 ° C. The plates were then washed three times with TBST, followed by a 1 hour incubation at 37 ° C with goat anti-mouse IgG labeled with alkaline phosphatase (1: 2000 in TBST (BioRad)). After washing three times with TBST, followed by two washes with TBS, a colored product was produced by the use of NADPH as substrate for alkaline phosphatase, and the coupled reactions of diaphorase and alcohol dehydrogenase (ELISA amplification system of GIBCO- BRL). The colored product was read at 490 nanometers in a microplate reader (Biotek).

IV. General Description of the Synthetic Processes The compounds of the invention are prepared by the general processes described below. The compounds wherein X = CH2, CH2, are illustrated in Figure 3. The 2-2 '-bi-indene (3, R1, R2, R3, R4, R5, R6, = H, Example IV (2)) was prepared by an improved method, by palladium catalyzed coupling of 2- (tributylstannyl) indene (2) with 2-bromoindene (1). 2-Bromoindene (1), prepared using the literature procedure (J. Org. Chem., 1982, 47, 705), was used to prepare 2- (tributylstannyl) indene (2) (Example IV (1)) (Figure 3). Aryl-substituted 2-bromoindennes can be prepared from indenos, or 1- or 2-indanones, by those skilled in the art of organic synthesis. The cycloaddition reaction of the compounds of the general formula 3 with maleimide (method 1), preferably at temperatures of 160 ° C to 200 ° C, forms the corresponding tetraisoindolyl-dione (R1, R2, R3, R4, R5, R6, = H; Example IV (3)). The cycloaddition reactions of 2- (2-indenyl) indenes have not been described previously. The cycloaddition reactions of dienes with maleimides are well known (see, for example, J \ Chem. Soc., Perkin Trans. 1, 1990, 2475). Example IV (3) is dehydrogenated according to conventional processes, for example, with 2,3-dichloro-5,6-dicyan-1,4-benzoquinone, Pd on activated charcoal, sulfur or sodium nitrite (US Pat. United States of America number 4,912,107, and references cited therein), to give the corresponding aromatized isoindolone-imide derivative (Example IV (4)) (Compound 1-1, R1, R2, R3, R4, R5 , R6, = H). The lactams of the general formula 6 (Example IV (5), Compound 1-2, R1, R2, R3, R4, R5, R6, = H); they can be prepared by reducing the imide 5 with reducing agents (eg, zinc amalgam, gaseous hydrogen chloride, zinc amalgam in acetic acid, zinc in glacial acetic acid, or hydride reducing agents, such as lithium hydride and aluminum). In cases where R2, R3, R4, R5, or R6 are different from H, lactam regioisomers are formed (general formulas 6 and 7). The lactam regioisomers can be separated by conventional processes, such as recrystallization or chromatography, for example, column chromatography or high performance liquid chromatography. The imides can be reduced in. hydroxylactams (8, Figure 3), wherein A1, A2, or B1, B2 = H, OH, by hydride reducing agents, such as borohydrides or aluminum hydrides (U.S. Patent Nos. 4,192,107 and 4,923,986, and the references of them). The resulting hydroxyl group is easily converted to alkoxy or thioalkyl groups (U.S. Patent No. 4,923,986). The derivatives wherein A1, A2, or B1, B2 together represent S or N, are prepared as described in European Patent Application No. 0,508,792 AI.

In Method II (Figure 15), the cycloaddition reaction of the appropriate diene with acetylene dicarboxylate (R = lower alkyl), gives the corresponding aromatic compounds of the general formula 39. The isobenzofurans (general formula 40) can be obtained by dealkylation of the ester with nucleosides (for example, Lil, NaCN, NaSCH3, NaSCN, etc.), followed by the formation of anhydride using acetic anhydride. The imides of the general formula 41 can be prepared by the reaction of isobenzofurans of formula 40 with 1, 1, 3, 3, 3-hexamethyldisilazane and methanol (Tetrahedron Lett, 1990, 31, 5201-5204). The lactams of the general formula 42 can be prepared by reducing the imide 41 with reducing agents (eg, zinc amalgam, gaseous hydrogen chloride, zinc amalgam in acetic acid, zinc in glacial acetic acid, or reducing agents of hydride, such as lithium aluminum hydride). In cases where R2, R3, R4, R5, or R6 are different from H, or the groups X are not equal, lactama regioisomers are formed (general structures 42 and 43). The lactam regioisomers can be separated by conventional processes, such as recrystallization or chromatography, for example, column chromatography or high performance liquid chromatography. The imides can be reduced in hydroxylactams (44, Figure 15) as described above. Specifically, the compounds wherein X = S are illustrated in Figure 13. The 2, 2'-Bi-benzothiaphene (25, R1, R2, R3, R4, R5, R6, = H, Example IV (6)), was prepared by the same method as described for compound 3. The cycloaddition reaction of the compounds of the general formula 25 with diethyl acetylenedicarboxylate, preferably at temperatures of 180 ° C to 200 ° C, forms the corresponding carboethoxydibenzothiaphene (26). , R1, R2, R3, R4, R5, R6, = H, Example IV (7)). Cycloadditions of 2, 2'-bisbenzothiaphenes have not been described previously. The carboethoxydibenzothiaphenes can be converted into the corresponding isobenzofurans (27, R1, R2, R3, R4, R5, R6, = H, Example IV (8)), by dealkylation of the ester with nucleophiles (for example, Lil, NaCN, NaSCH3, NaSCN, etc.), followed by formation of anhydride in acetic anhydride (Method II). The imides of the general formula 28 ((Compound 1-3), R1, R2, R3, R4, R5, R6, = H, Example IV (9)), can be prepared by the reaction of isobenzofuran 27 with 1.1. , 1,3,3, 3-hexamethyldisilazane and methanol, as described above (Method II). The lactams of the general formula 29 ((Compound 1-4), R1, R2, R3, R4, R5, R6, = H, Example IV (10)), can be prepared by reducing the imide 28 with reducing agents , as described in Method I. The imides can be reduced to hydroxylactams (30, Figure 13) as described above. The synthesis of the non-symmetric indenyl-benzothiaphene (XS, CH2) is illustrated in Figure 14. The 2- (2'-indeni-D-benzothiaphene (31, R1, R2, R3, R4, R5, R6, = H, Example IV (FIG. )), was prepared by the method described above for 3. The cycloaddition reaction of the compounds of the general formula 31 with diethylacetylene dicarboxylate, form the corresponding carboethoxydibenzothiaphene (32, R1, R2, R3, R4, R5, R6, = H, Example IV (12)) The carboethoxydibenzothiaphenes 32 were converted into the corresponding isobenzofurans (33, R1, R2, R3, R4, R5, R6, = H, Example IV (13)) by dealkylation of the ester with nucleophiles, followed by formation of the anhydride in acetic anhydride as described above The imides of the general formula 34 ((Compound 1-5), R1, R2, R3, R4, R5, R6, = H, Example IV (14)) are it can be prepared by the same methods as in Figure 13. The lactams of the general formula 35 ((Compound 1-6), R1, R2, R3, R4, R5, R6, = H; IV (10)) can be prepared by reducing imide 34 with reducing agents (eg, zinc amalgam, gaseous hydrogen chloride, zinc amalgam in acetic acid, zinc in glacial acetic acid, or hydride reducing agents, such as lithium aluminum hydride). In cases where R2, R3, R4, R5, or R6 are different from H, regioisomers of lactam are formed. The lactam regioisomers can be separated by conventional processes, such as recrystallization or chromatography, for example, column chromatography or high performance liquid chromatography. The imides can be reduced to hydroxylactams (37, Figure 14) as described above. Other isoindolone derivatives of the general formula II, wherein X = CH2CH2, or CH = CH, are prepared by the procedures described for 6 or 7 (Figure 3), except 2-bromoindene and / or 2- (tributylstannyl ) indene, which is replaced with a derivative of 2-bromo- or 2- (tributylstannyl) -3,4-dihydronafCylene (Figure 4). The 2-bromo-3,4-dihydronaphthylenes substituted by aryl can be prepared from 1- or 2-tetralone by those skilled in the art of organic synthesis. The replacement of the indene derivatives with a 2-benzocyclohexene derivative (J. Am. Chem. Soc. 13: 1344, (1991); J. Org. Chem. 44: 1342 (1979)), gives fused isoindolones of formula II, wherein X = CH2CH2CH2. Ketone derivatives wherein X is C = 0, can be prepared by oxidation of imide (5) or lactam (6 or 7), using conventional oxidizing reagents (for example, Se02, Cr03, Na2Cr07, or Mn02) (Figure 5). Alternatively, derivatives of X = (C = 0, H) (11) can be prepared starting with 2-bromoinden-l-one (9) (J ". Org. Chem., 1994, 59, 3453) which can be used to prepare 2- (tributylstannyl) inden-1-one (10) by the method described in Example IV (1) (Figure 6), in a similar manner, the X derivatives (C = 0, C = 0) (12) by the reaction of 2-bromoinden-1-one (9) with 2- (tributylstannyl) inden-1-one (Figure 7) Compounds with other X groups, such as X = S, can be prepared. 0, or C = 0 (Figure II), by the cycloaddition reaction with the appropriate diene and maleimide, as described in Method I (Figure 4), or by processes described for Method II (Figure 15). example, 2- (2-oxoindenyl)) indene (X = (C = 0), CH2), 2, 2 '- (1-oxo) bi-indene (X = (C = 0), (C = 0)), 2- (2-indenyl) benzothiophene (X = CH2, S), 2- (2-indenyl) benzofuran (X = CH2, 0), 2,2 '-bi-benzothiophene (X = S, S), 2- (2-benzothienyl) benzofuran (X = S, 0), each can be prepared by coupling the corresponding 2-tributylstannyl derivative with the appropriate 2-bromo-aryl or heteroaryl derivative. The preparation of the desired compounds can also be achieved by the treatment of, for example, 2- (2-benzothienyl) benzofuran (X = S, 0), or 2- (2-benzothienyl) benzothiophene (X = S, S ), with maleimide, in the presence of an acid catalyst, such as trifluoroacetic acid, or a Lewis acid (SnCl 4, Et 2 AlCl), which gives a compound of the general structure 13 (Figure 8). These compounds can be cyclized to form the corresponding fused isoindolone derivatives 14, by treatment with a catalyst, for example, Pd (0Ac) 2 in glacial acetic acid, or Pd (0Ac) 2, tetrachloro-1,4-benzoquinone in C2H4C12 (Figure 8). The palladium catalyzed cross coupling methodology, known to those skilled in the art of organic synthesis, is used to prepare other derivatives, for example, wherein X in Figure 8 is 1 to 3 carbon atoms (inclusive), by coupling the vinyl-3- (trifluoromethanesulfonate) derivative of the corresponding cyclic ketone, or a 2-triflate derivative of the appropriate aryl or heteroaryl moiety, with an appropriate tin derivative previously described. Derivatives wherein the nitrogen containing R1 is linked by hydrogen can be converted to a group R1 as described for formula I (U.S. Patent Number 4,923,986). Derivatives of the formula I wherein the substituents R3, R4, R5, or R6 are different from H, are prepared using previously described methods, starting with an appropriately substituted intermediate, or employing conventional methods known to those skilled in the art of organic chemistry for interconversions of functional groups. The derivatives with substitution R2, wherein the group X is a double-linked olefin (Formula II), can be formed from olefin-related reactions of Wittig on derivatives where X = (C = 0, C = 0, or C = 0, H) (Figure 9), by those skilled in the art of organic synthesis. The resulting alkenes (15) can be reduced to compounds of the general structure (16) (Figure 9). Derivatives wherein X = CH2, can be easily alkylated by reaction with a strong base, such as BuLi, NaNH2, or LiN (iPr) 2, followed by treatment with an appropriate electrophile (J. Med. Chem., 1992, 35, 3919; J. Org. Chem., 1991, 56, 4499) (Figure 10). The fused isoindolones of Formula I wherein the B and / or F rings can independently contain ring atoms of nitrogen, oxygen, or sulfur, as defined above for E1 and E2, can be prepared by similar processes employed for the preparation of carbocyclic analogues (Figure 11 and Figure 12). The preparation of the derivatives wherein ring B is a 6-membered nitrogen-containing heterocyclic ring (nitrogen in any of the six positions) is illustrated in Figure 11. The cycloaddition reactions of the compound of general structure 17 with maleimide, they would give compounds of the general structure 18. The dehydrogenation of intermediate 18 in a manner similar to the preparation of Example IV (4) (Figure 3), would give imide derivatives of the general structure 19 (Figure 11). The lactam isomers of the general structure 20 can be prepared by the reaction of the imide derivatives of the general structure 19, with reducing agents, such as zinc amalgam-HCl, zinc amalgam in acetic acid, or hydride reducing agents. , such as lithium aluminum hydride. The regioisomers can be separated by conventional processes, such as recrystallization or chromatography, for example, column chromatography or high performance liquid chromatography. The imides are reduced to hydroxylactams, wherein A1, A2, or B1, B2 = H, OH, by hydride reducing agents, such as borohydrides or aluminum hydrides. Compounds wherein ring B or F is a 5-membered ring containing oxygen or sulfur can be prepared starting with furyl-pyrroles or thieno-pyrroles, respectively, instead of the indenos, following the synthetic schemes illustrated in the Figures 3 and 4. Ring-fused furyl-pyrroles can be prepared using previously established literature procedures, or modifications thereof (Coll. Czech, Chem. Commun. 53: 1770 (1988); Can J. Chem. 56: 1429 (1978); CR Hebd. Seances Acad. Sci., Ser. C 281: 793 (1975)). Ring-fused thienyl pyrroles can be prepared using previously established literature procedures, or modifications thereof (Belgian patent specification No. BE 899925; Ind. J. Chem. 20B: 271 (1981); Can J. Chem. 1429 (1978); Bull. Soc. Chim. Fr. 11-12 pt2: 2511 (1975); C.R. Hebd. Seances Acad. Sci., Ser. C 277: 1149 (1973)). Alternatively, compounds wherein ring B or F contains nitrogen ring atoms can be prepared starting with pyridine derivatives fused with cycloalkanone (X = alkylene of 1 to 3 carbon atoms). The synthesis of the cycloalkanone-pyridine derivatives have been described in the literature (J. "Med. Chem. 36: 3381 (1993), Chem Ber., 1970, 103, 2403), and these compounds can be used directly to prepare intermediates of the general structure 21 or 22 (Figure 12) The ring-fused cycloalkyl- or cycloalkanone-pyridine derivatives can be converted into cyclic vinyl bromides by those skilled in the art of organic synthesis. of vinyl would be suitable substrates to go through the methodology of cross coupling with tin described in Figure 3 and Figure 1. Compounds wherein the F ring contains an oxygen atom, can be prepared starting with cycloalkanones or cycloalkenyl derivatives fused with furyl (X-alkylene of 1 to 3 carbon atoms) Compounds in which ring F contains sulfur ring atoms, can be prepared starting with cycloalkenyl-thiophenes fusi The thienyl and furyl derivatives fused with cycloalkyl ring can be prepared using the methods of the literature described above (Acta Chem. Scand. 25: 1287 (1971); J ". Am. Chem. Soc. 103: 2760 (1981)), or modifications thereof These intermediates can be converted to furyl- or thienyl-cyclopentanones, or furyl- or thienyl-cyclopentenes. starting materials can be converted into the corresponding cyclic vinyl bromides by those skilled in the art of organic synthesis.The vinyl bromide intermediates can be used to give the desired intermediates, using the methodology of tin cross-coupling described in Figure 3 and Figure 4. B and F rings can both be substituted by heteroatoms simultaneously as shown in Figure 12. Intermediate 23 can be formed from an intermediate of tin of ring B substituted by heteroatom 22, and a cyclic vinyl bromide substituted by heteroatom of the ring F 21 (or triflate of the corresponding cyclic ketone intermediate) .The imide and lactam derivatives containing n heteroatoms in rings B and F, can be prepared in the methods shown in Figure 3 and in Figure 4. Alternatively, the addition of. Michael, followed by closure of the palladium catalyzed ring, described in Figure 8, to prepare the imide derivatives of the general structure 20 (Figure 11) and of the general structure 24 (Figure 12). The reduction of the imides by the previously described methods would give lactam isomers.

Example IV (1): 2- (tributylstannyl) indene To a round bottom flask containing 2-bromoindene (1.64 grams, 8.4 millimoles) in 75 milliliters of Et3N, palladium (II) acetate (304 milligrams, 11.4 millimoles) was added. ), tetrakis (triphenylphosphine) palladium (0), (775 milligrams, 0.7 millimoles), and hexabutyl diestane (6.4 milliliters, 12.7 millimoles). The reaction was heated to reflux and monitored by thin layer chromatography (silica gel, EtAc: hexane, 1: 5). After 1 hour, the starting material was consumed. The reaction was allowed to cool to room temperature, diluted with CH2Cl2, and filtered through celite. The solvent was removed under reduced pressure, and the compound was purified through a column of silica gel (5 percent EtOAc-hexane), to give 4.7 grams of 2-tributylstanilindene as a clear oil (containing traces of hexabutyl diethylene). The compound was used as it was for the next step. 1 H NMR (300 MHz, CDC13): d_0.9 (m, 15H), 1.2 (m, 6H), 1.6 (m, 6H), 3.5 (s, 2H), 7.10 (s, 1H), 7.5-7.2 ( m, 4H).

Example IV (2): 2,2 '-bi-indene To a 100 milliliter round bottom flask, adapted with a reflux condenser, was added 1.2 grams (6.3 millimoles) of 2-bromoindene, 3.4 grams (8.4 millimoles) ) of 2-tributylstanilindene (Example IV (1)), and 70 milliliters of ethanol. To this mixture was added 442 milligrams (0.63 millimoles) of bis (triphenylphosphine) -palladium (II) chloride. The reaction was stirred at reflux for 16 hours. The reaction was allowed to cool to room temperature, diluted with diethyl ether (50 milliliters), then filtered through an alumina pad. The solvent was concentrated under reduced pressure, and the product was recrystallized from toluene to give 870 milligrams (60 percent) of 2,2'-di-indene. p.f. 238 ° C (p.f. lit. = 238 ° C; Chem. Ber., 1988, 121, 2195). 1 H NMR (300 MHz, CDC13): d 3.73 (s, 4H), 6.93 (s, 2H), 7.30 (m, 8H). MS (ES +) m / z = 231 (M + l).

Example IV (3): la, 3a, 4,7-tetrahydroindenyl [2, 3-c] indenyl [2, 3-e] isoindol-1,3-dione To a sealable borosilicate reaction tube was added 98 milligrams (0.4 millimoles) of 2, 2'-di-indene (Example (IV (2)), 43 milligrams (0.44 millimoles) of maleimide, 5 milligrams of BHT, and 1 milliliter of CH2Cl2 The tube was sealed and the reaction was heated at 130 ° C for 24 hours.The reaction was allowed to cool to room temperature, and the solvent was concentrated under reduced pressure.The crude solid was purified by column chromatography (silica gel, 10% EtOAc-hexane). -75 percent) to give 50 milligrams (38 percent) of a white solid, mp 244-247 ° C. 1H NMR (300 MHz, CDC13): d 3.68 (s, 4H), 3.80 (m, 2H), 4.00 (bs, 2H), 7.24 (m, 7H), 7.53 (d, J = 7 Hz, 2H) MS (ES +) m / z = 328 (M + l).

Example IV (4): lH-indenyl [2,3-c] -lH-indenyl [2,3-e] isoindol-1,3-dione (Compound 1-1) To a mixture of Example IV (3) (50 milligrams, 0.15 millimoles) in toluene (4 milliliters), solid 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (79 milligrams, 0.35 millimoles) was added in one portion. The reaction was heated under nitrogen at 65-70 ° C for 4 hours. The solution was cooled in an ice bath, and the solid material was collected by filtration. The crude precipitate was washed with cold methanol, leaving a pale yellow solid (28 milligrams, 63 percent), m.p. 244-247 ° C. X H NMR (300 MHz, CDC13): d 9.17 (d, 4 Hz, 2 H), 7.55 (m, 7 H), 4.15 (s, 4 H); MS (ES): m / z 346 (M + 1).

Example IV (5): lH-indenyl [2, 3-c] -lH-indenyl [2, 3-e] -3H-isoindol-1-one (Compound? -2) A zinc amalgam was prepared by suspending 122 milligrams (1.9 millimoles) of zinc powder in 1 milliliter of water, and adding 35 milligrams (0.08 millimoles) of HgCl2, followed by 4 drops of CHCl. This mixture was stirred for 10 minutes, and the aqueous layer was decanted. The amalgam was washed with water, and then repeatedly with EtOH. The above zinc amalgam was suspended in 5 milliliters of EtOH, and Compound 1-1 (Example IV (4)) (10 milligrams, 0.03 mmol) was added. A few drops of CHCl were added, and the reaction was heated to reflux for 3 hours. The yellow color disappeared during the first hour of heating. The reaction was allowed to cool to room temperature, and the solution was concentrated under reduced pressure. The residue was dissolved in 10 milliliters of THF-EtOAc (1: 1), and washed with saturated solutions of NaHCO 3 and NaCl, and then dried (MgSO 4). The drying agent was removed by filtration, and the solvent was concentrated under a reduced pressure to give 8 milligrams (88 percent) of the lactam as a white solid, m.p. 256 ° C. 1 H NMR (300 MHz, CDC13): d 9.20 (d, 8 Hz, 1H), 7.50 (m, 6H), 6.24 (s, 1H), 4.83 (s, 2H), 4.05 (s, 2H), 3.95 ( s, 2H); MS (ES): m / z 310 (M + 1).

Example IV (6): 2,2'-Bibenzothiafen A 3.3 gram (15.6 millimoles) of 2-bromobenzothiaphene, 7.3 grams (17 millimoles) of additive was added to a two-necked round bottom flask, adapted with a reflux condenser. 2- (tri-n-butyl normal-tin) benzothiafen, and 40 milliliters of toluene. To this mixture was added 360 milligrams (0.3 millimoles) of tetrakis (triphenylphosphine) palladium (o), and 5 milligrams of BHT. The reaction was heated to reflux for 16 hours. After cooling to room temperature, the solvent was removed in vacuo, the reaction was dissolved in dimethyl formamide, and filtered through celite. The solvent was removed in vacuo, and the solid was triturated with hexanes, to give 3.58 grams (13.4 millimoles, 85 percent yield) of 2,2 '-bibenzothiaphene as a silvery black solid. P.f. 260-262 ° C. X H NMR (300 MHz, DMSO d 6) d 7.98 (m, 2 H), 7.62 (S, 1 H), 7.36 (m, 2 H), 7.25 (s, 1 H).

Example IV (7): 3,4-Carboethoxybenzothienyl [1,2-a] dibenzothiafen In a sealable glass tube, 1.02 grams (3.8 millimoles) of 2, 20-bibenzothiaphene, 3.1 milliliters were placed (19 millimoles) of diethyl acetylenedicarboxylate, and 5 milligrams of BHT. The reaction vessel was sealed under N2, and heated to 190 ° C. The reaction was allowed to continue for 24 hours. After allowing the reaction vessel to cool, the contents were transferred to a round bottom flask using CHC13, and the solvent was removed in vacuo. The solid was recovered in diethyl ether, and filtered, yielding 468 milligrams (1.07 millimoles, 28 percent) of 3.4-. carboethoxybenzothienyl [1,2-a] dibenzothiaphene as a pale yellow solid, m.p. 206-207 ° C. A second crystallization provided 280 milligrams more material for a total yield of 45 percent. H NMR (300 MHz, DMSO 6) d 8.27 (d, 7.4 Hz, 2H), 8.05 (d, 7.9 Hz, 2H), 7.65 (m, 4H), 4.57 (q, 7.1 Hz, 4H), 1.38 (t , 7.1 Hz, 6H).

Example IV (8): Benzothienyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione A round bottom flask was charged with 500 milligrams (1.15 millimoles) of 3,4-carboethoxybenzothienyl [ 1, 2-a] dibenzothiafen and 50 milliliters of dimethyl formamide. To this mixture were added 124 milligrams (2.5 millimoles) of sodium cyanide and 476 milligrams (2.5 millimoles) of lithium iodide trihydrate in a solid form. The reaction was heated to 150 ° C, and was followed by thin layer chromatography. More NaCN / Lil was added as time progressed. A total of 4 equivalents of each of NaCN and Lil were added during a reaction time of 36 hours, at which time the starting material was completely consumed. The reaction mixture was cooled to room temperature, and poured into cold aqueous HCl (at 0 ° C). The mixture was filtered and washed with water. The resulting solid was dried in vacuo. The above crude solid was then placed in a round bottom flask, and 50 milliliters of acetic anhydride was added. The reaction mixture was then heated to reflux. After 4 hours at reflux, the reaction was completed by thin layer chromatography (new spot in RF 0.65 in 1: 1 EtOAc / hexane). The solvent was removed, and the crude oil was purified by flash chromatography to give a bright yellow-orange solid. This solid was triturated with diethyl ether to give 160 milligrams (0.44 millimole, 40 percent yield) of benzothienyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione as a bright yellow solid. , pf > 300 ° C. 1 H NMR (300 MHz, DMSO d 6) d 9.54 (dd, 5.2 Hz, 2H), 8.34 (dd, 4.0 Hz, 3.3 Hz, 2H), 7.73 (m, 4H).

Example IV (9): Benzothieno [2, 3-c] bßnzothieno [2, 3-e] isoindol-1,3-dione (Compound 1-3) Benzothieno [4,5-a] benzothienil [6,7] was dissolved -a] isobenzofuran-1,3-dione (75 milligrams, 0.2 mmol) in 3 milliliters of dimethyl formamide. To this mixture was added 4.4 milliliters (20.8 millimoles) of 1,1,1,3,3,3-hexamethyldisilazane, followed by 30 microliters (1 millimole) of methanol. The suspension became clear after approximately 15 minutes. Thin layer chromatography after 1 hour left an almost complete consumption of the starting material. The reaction was allowed to stir overnight, for a total reaction time of 18 hours. The solvent was removed to give 65 milligrams (0.18 mmol, 80 percent yield) debenzothiene [2, 3-c] benzothieno [2,3-e] isoindol-1,3-dione as a yellow solid, m.p. >300 ° C. X H NMR (300 MHz, DMSO d 6) d 9.8 (dd, 5.0 Hz, 4.1 Hz, 2H), 8.25 (dd, 4.9 Hz, 4.1 Hz, 2H), 7.70 (m, 4H).

Example IV (10): Benzothieno [] 2, 3-c] benzothieno [2, 3-e] isoindol-1-one (Compound 1-4) To a suspension in ethanol of 10 milliliters of Zn amalgam (3 equivalents) , 68 milligrams (0.18 millimoles) of the benzothieno [2, 3-c] benzothieno [2, 3-e] isoindol-l, 3-dione was added as a solution in 10 milliliters of acetic acid. The reaction was heated to reflux after the addition of 5 milliliters of concentrated HCl. After refluxing overnight, the reaction became clear and slightly tanned. The reaction was cooled and decanted from the mercury layer. After removing most of the solvent, the mixture was diluted with ethyl acetate, and washed twice with saturated NaHCO 3. The organic layer was dried over MgSO4, filtered, and the solvent was removed. The crude reaction mixture was purified by column chromatography to give 65 milligrams (0.18 mmol, 100 percent yield) of benzothieno [2,3-c] benzothieno [2,3-e] isoindol-1-one as a solid tanned, mp 225-226 ° C. 1 H NMR (300 MHz, DMSO d 6) d 10.17 (dd, 6.4 Hz, 2.7 Hz, 1 H), 8.22 (s, 1 H), 8.21 (dd, 4.1 Hz, 3.7 Hz, 2 H), 8.11 (dd, 6.5 Hz, 2.2 Hz, 1H), 7.63 (t, 3.7 Hz, 2H), 7.55 (t, 3.7 Hz, 2H), 5.19 (s, 2H).

Example IV (ll): 2- (2'-indenyl) benzothiafen A 2-necked round bottom flask, adapted with a reflux condenser, was added with 2 grams (13.3 millimoles) of 2-bromoindene, 5.1 grams (11.9 g). millimoles) of 2- (tributyl normal-tin) benzothiafen, and 50 milliliters of toluene. To this mixture was added 1 gram (1.5 millimoles) of bis (triphenylphosphine) palladium (II) dichloride, and 5 milligrams of BHT. The reaction was heated to reflux for 16 hours. After allowing to cool, the solvent was removed, the reaction was recovered in dimethyl formamide / tetrahydrofuran, and filtered through celite. The solvent was removed, and the solid was triturated with hexanes, to give 1.4 grams (5.6 mmol, 47 percent yield) of 2- (2'-indenyl) benzothiaphene as an orange solid. P.f. 260-265 ° C. X H NMR (DMSO d5) d 7.82 (m, 4 H), 7.61 (s, 1 H), 7.35 (m, 5 H), 3.97 (s, 2 H).

Example IV (12): 3,4-Carboethoxyindenyl [1,2-a] dibenzothiafen In a sealable glass tube, 480 milligrams (3.95 millimoles) of 2- (2'-indenyl) benzothiaphene, 3.2 milliliters (19 millimoles) were placed. ) of diethyl acetylenedicarboxylate, and 10 milligrams of BHT. The reaction vessel was sealed under N2, and heated to 190 ° C. The reaction was allowed to continue for 24 hours. After allowing the vessel to cool, the contents were transferred to a round bottom flask using CHC13, and the solvent was removed. The raw material was passed through a silica column, collecting the upper fractions. This solid was recovered in diethyl ether, and filtered, yielding 538 milligrams (1.29 millimoles, 23 percent) of 3,4-carboethoxyindenyl- [1,2-a] dibenzothiaphene as a pale orange solid, m.p. 186 ° C. 1 H NMR (300 MHz, DMSO d 6) d 8.15 (d, 7.4 Hz, 1 H), 7.95 (d, 7.4 Hz, 1 H), 7.71 (m, 2 H), 7.56 (m, 2 H), 7.41 (m, 2 H) , 4.50 (q, 7.0 Hz, 4H), 4.22 (ß, 2H), 1.33 (t, 7.0 Hz, 6H).

Example IV (13): Indenyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione A round bottom flask was charged with 250 milligrams (0.6 millimoles) of 3,4-carboethoxyindenyl [ 1, 2-a] dibenzothiafen and 10 milliliters of pyridine. To this mixture was added 677 milligrams (3.6 millimoles) of lithium iodide trihydrate. The reaction was heated to 115 ° C, and was followed by thin layer chromatography. More Lil was added as time progressed. A total of 5 Lil equivalents were added during a reaction time of 36 hours, at which time the starting material was completely consumed. The reaction mixture was cooled to room temperature, and poured into cold aqueous HCl (0 ° C). The mixture was filtered and washed with water. The resulting solid was dried in vacuo. Then the previous crude solid was placed in a round bottom flask, and 50 milliliters of acetic anhydride were added. The reaction mixture was then heated to reflux. After 4 hours at reflux, the reaction was completed by thin layer chromatography (fresh spot in Rf 0.6 in 1: 1 EtOAc / hexanes). The solvent was removed, and the crude oil was purified by flash chromatography, to give a bright yellow-orange solid. This solid was triturated with diethyl ether, to give 160 milligrams (0.44 millimole, 40 percent yield) of indenyl [4,5-a] benzothienyl [6,7-a] isobenzofuran-1,3-dione as a yellow solid bright, mp >300 ° C. 1 H NMR (300 MHz, DMSO d6) d_9.65 (d, J = 7.2 Hz, 1H), 8.76 (d, J = 7.6 Hz, 1H), 8.15 (s, J = 7.4 Hz, 1H), 7.78-7.38 (m, 5H), 4.97 (s, 2H).

Example IV (14): Indenyl [2, 3-c] benzothienyl [2, 3-e] isoindol-1,3-dione (Compound 1-5) Indenyl [4, 5-a] benzothienyl [6, 7- a] isobenzofuran-1,3-dione (120 milligrams, 0.35 millimole) was dissolved in 3 milliliters of dimethyl formamide. To this mixture were added 7.4 milliliters (35 millimoles) of 1,1,1,3,3,3-hexamethyldisilazane, followed by 50 microliters (1 millimole) of methanol. The suspension became clear after approximately 15 minutes. Thin layer chromatography after 1 hour showed almost complete consumption of the starting material. The reaction was allowed to stir overnight for a total reaction time of 18 hours. The solvent was removed to give 35 milligrams (0.18 millimoles, 30 percent yield) of indenyl [2, 3-c] benzothienyl [2,3-e] isoindol-1,3-dione as an orange solid. 1 H NMR (300 MHz, DMSO d6) d_12.72 (s, 1H), 9.84 (d, J = 8.3 Hz, 1H), 8.14 (d, J = 6.4 Hz, 1H), 8.07 (d, J = 7.5 Hz , 1 H), 7.82 - 7.28 (m, 5H), 5.03 (s, 2H), MS (APcI) 342 (M + H).

Example IV (15): Indenyl [2, 3-c] benzothienyl [2, 3-e] isoindol-1 and 3-one (Compound 1-6) To a suspension in ethanol of 2 milliliters of Zn amalgam (3 equivalents ), 10 milligrams (0.3 millimoles) of indenyl [2, 3-c] tianaphtene [2,3-e] isoindol-1,3-dione was added as a solution in 10 milliliters of acetic acid. The reaction was heated to reflux after the addition of 1 milliliter of concentrated HCl. After refluxing for 3 hours, the reaction became clear and slightly tanned. The reaction was cooled and decanted from the mercury layer. After removing most of the solvent, the mixture was diluted with ethyl acetate, and washed twice with saturated NaHCO 3. The organic layer was dried over MgSO4, filtered, and the solvent was removed to give the compound as a mixture of indenyl [2,3-c] tianaphtheno [2,3-e] isoindol-1-one as a tan solid, MS (APcI) 329 (M + H). Although the invention has been described in considerable detail, the invention disclosed herein should not be limited by the description presented, but should receive the full scope of any appended claims and all their equivalents.

Claims (18)

1. A compound whose chemical structure is: wherein: ring B and ring F are independently selected from the group consisting of: (a) a 6-membered carbocyclic aromatic ring; and (b) a 6-membered carbocyclic aromatic ring R1 is selected from the group consisting of H; alkyl of 1 to 4 carbon atoms; aril; Arylalkyl; heteroaryl; heteroarylalkyl; COR9, wherein R9 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, aryl, and heteroaryl; -OR10, wherein R10 is selected from the group consisting of H and alkyl of 1 to 4 carbon atoms; -CONH2, -NR7R8, - (CH2) nNR7R8, and -O (CH2) = nNR7R7, wherein n is from 1 to 4, and (a) R7 and R8 are independently selected from the group consisting of H and alkyl from 1 to 4 carbon atoms; or (b) R7 and R8 together form a linking group of the formula - (CH2) 2 -Xx- (CH2) 2-, wherein X1 is selected from the group consisting of -0-, -S-, and -CH2-; A1 and A2, in pairs, are selected from the group consisting of: H, H; H, -OR 11, wherein R 11 is H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, or heteroaryl; H, -SR11; H, -U (R11) 2; = 0; = S; y = NR1; L, wherein A1 and A2 can together represent a double-linked atom; B1 and B2, in pairs, are selected from the group consisting of: H, H; H, -OR11; H, -SR11; H, -N (R?: L) 2; = 0; = S; y = NR1: L, wherein B1 and B2 can together represent a double-bonded atom; with the proviso that at least one of the pairs A1 and A2, and B1 and B2, is = 0; X, in each position, is independently selected from the group consisting of: (a) an unsubstituted alkylene of 1 to 3 carbon atoms; (b) an alkylene of 1 to 3 carbon atoms substituted with R2, wherein R2 is selected from the group consisting of: OR10; -SR10; R15, wherein R15 is alkyl of 1 to 4 carbon atoms; phenyl; naphthyl; Arylalkyl of 7 to 14 carbon atoms; H; -S02R9; -C02R9; -COR9; alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms, wherein: (i) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is unsubstituted; or (ii) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is substituted with a substituent selected from the group consisting of 1 to 3 aryls of 6 to 10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; -N02; OH; -OR9; -O (CH2) nNR7R8, wherein n is from 1 to 4; -OCOR9; -OCONHR9; 0-tetrahydropyranyl; NR2; -NR7R8; NR10COR9; -NR10CO2R9; -NR10CONR7R8; -NHC (= NH) NH2; -NR10SO2R9; -S (0) VR1: L, where y is 1 OR 2; -SR11; -C02R9; -CONR7R8; -CHO; COR9; -CH2OR7; -CH = NNR1-LR12, wherein R12 is selected from the group consisting of H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, and heteroaryl; -CH = NOR1: L; -CH = NR9; -CH = NNHCH (N = NH) NH2; -S02NR12R13, wherein R13 is selected from the group consisting of H, alkyl of 1 to 4 carbon atoms, aryl of 6 to 10 carbon atoms, and heteroaryl, or R12 and R13 together form a linking group, which consists of - (CH2) 2-? l- (CH2) 2 ~ > wherein X1 is -O-, -S-, or -CH2-; -PO (OR11) 2, -OR14, wherein R14 is the residue of an amino acid after the hydroxyl group of the carboxyl group is removed; and (c) a functional group selected from the group consisting of -CH = CH-; -CHOH-CHOH-; -0-; -S-; -S (= 0) -; -S (S = 0) 2-; -C (R10) 2-; -C = C (R2) 2; -C (= 0) -; -C (= NOR11) -; -CÍOR11) (R11) -; -C (= 0) CH (R15) -; -CH (R15) C (= 0) -; -C (= N0R1: L) CH (R15) -; -CH (R15) C (= N0R1: L) -; CONR15; NR15C0; -CH2Z-; -ZCH2-; and -CH2ZCH2-, wherein Z is -CR11; -0-; -S-; -C (= 0) 0R1: L; -C (= N0R11); and -NR11; R3, R4, R5, and R6 are each independently selected from the group consisting of: H; aril; heteroaryl; F; Cl; Br; I; -CN; CF3; -N02; OH; -OR9; -0 (CH2) nNR7R8; -OCOR9; -0C0NHR9; NH2; -CH20H; -CH2OR14; -NR7R8; - NR10COR9; -NR10CONR7R8; -SR11; -S (0) and R13-, where y is 1 or 2; - C02R9; -COR9; -CONR7R8; -CHO; -CH = N0R1: L; -CH = NR9; -CH = NNR11R12; - (CH2) nSR9, wherein n is from 1 to 4; - (CH2) nS (0) and R9; -CH2SR15, wherein R15 is alkyl of 1 to 4 carbon atoms; -CH2S (O) and R1; - (CH2) nNR7R9; - (CH2) nNHR1; alkyl, alkenyl, alkynyl of 1 to 8 carbon atoms, wherein: (a) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is unsubstituted; or (b) each alkyl, alkenyl, or alkynyl of 1 to 8 carbon atoms is substituted with 1 to 3 aryl of 6 to 10 carbon atoms; heteroaryl; F; Cl; Br; I; -CN; -N02; OH; -OR9; -0 (CH2) nNR7R8; -OCOR9; -OCONHR9; O-tetrahydropyranyl; NH2; -NR7R8; -NR10COR9; -NR10CO2R9; -NR10CONR7R8; -NHC (= NH) NH2; -NR10SO2R9; -S (0) yRi: L, e y is 1 or 2; -SR11; -C02R9; -CONR7R8; -CHO; COR9; -CH2OR7; -CH- ^ NNR ^ R12; -CH = N0R1: L; -CH = NR9; -CH = NNHCH (N = NH) NH2; -S02NR12R13; -PO (OR?: L) 2; OR14; or a monosaccharide of 5 to 7 carbon atoms, wherein each hydroxyl group of the monosaccharide is independently unsubstituted, or is replaced by H, alkyl of 1 to 4 carbon atoms, alkylcarbonyloxy of 2 to 5 carbon atoms, or alkoxy of 1 to 4 carbon atoms. 2. The compound of claim 1, wherein the chemical structure is:
2. Rl
3. 3. The compound of claim 2, wherein A1 and A2 are selected in pairs from the group consisting of H, H; H, OH; y = 0; and B1 and B2 are selected in pairs from the group consisting of H; H; H, OH; y = 0; with the understanding that A1 and A2, or B1 and B2, are = 0.
4. 4. The compound of claim 2, wherein R1 is H. The compound of claim 2, wherein R1 is COR9, and R9 is selected from the group consisting of phenyl and naphthyl. 6. The compound of claim 2, wherein X, in any position, or both, is an unsubstituted alkylene of 1 to 3 carbon atoms. 7. The compound of claim 2, wherein X, at any position, or at both positions, is selected from the group consisting of -O- and -S-. 8. The compound of claim 2, wherein X has a substituent R2, and R2 is -OR10. 9. The compound of claim 2, wherein X has a substituent R2, and R2 is benzyl. The compound of claim 2, wherein X has a substituent R2, and R2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, and alkynyl of 1 to 4 carbon atoms. The compound of claim 2, wherein X has a substituent R2, and R2 is selected from the group consisting of substituted alkyl of 1 to 8 carbon atoms, substituted alkenyl of 1 to 8 carbon atoms, and alkynyl substituted from 1 to 8 carbon atoms, and R2 has a substituent selected from the group consisting of phenyl and naphthyl. The compound of claim 2, wherein X has a substituent R2, R2 is -S (O) R11, and is 1 or 2, and R11 is phenyl or naphthyl. The compound of claim 2, wherein X has a substituent R2, R2 has a substituent which is -CH = NNR11R12 or -S02NR12R13, and R12 or R13 is selected from the group consisting of phenyl and naphthyl. The compound of claim 2, wherein X has a substituent R2, and R12 and R13 together represent a linking group. 1
5. 5. The compound of claim 14, wherein the linking group is - (CH2) 2-X1- (CH2) 2-, wherein X1 is selected from the group consisting of -0-; -S-; Y -CH2- 1
6. 6. The compound of claim 2, wherein R3, R4, R5, and R6 are H. The compound of claim 2, wherein at least one of R3, R4, R5, and R6 is selected from the group consisting of phenyl and naphthyl, with the proviso of which R3 or R4 is H, and R5 or R6 is H. 18. The compound of claim 2, wherein at least one R3, R4, R5, and R6 is selected from the group consisting of alkyl of 1 to 4 carbon atoms, alkenyl of 1 to 4 carbon atoms, and alkynyl of 1 to 4 carbon atoms, with the condition of R3 or R4 is H, and R5 or R6 is H.