MXPA99003637A - Neurotrophin antagonist compositions - Google Patents

Abstract

A pharmaceutical composition comprising a compound of formula (I) wherein R1 is selected from, inter alia, alkyl, aryl-loweralkyl, heterocycle-loweralkyl, loweralkyl-carbonate;optionally substituted amino;benzimidaz-2-yl;optionally substituted phenyl;loweralkyl-(R5), (R6) wherein one of R5 and R6 is selected from H and loweralkyl and the other is selected from carboxy, carboxy-loweralkyl and loweralkoxycarbonyl;NHCH2CH2OX wherein X represents an in vivo hydrolyzable ester;and R2 and R3 are independently selected from H, NO2, halo, di(loweralkyl)amino, cyano, C(O)OH, phenyl-S-, loweralkyl, and Z(O)OR7 wherein Z is selected from C and S and R7 is selected from H, loweralkylamino and arylamino;or pharmaceutically acceptable salts or certain in vivo hydrolyzable esters or amides thereof, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable carrier, is described. The compositions are useful to inhibit undesirable neurotrophin-mediated activity such as the neurite outgrowth that occurs in some neurodegenerative disease states.

Description

ANTAGONIST COMPOSITIONS OF NEUROTROPHINS FIELD OF THE INVENTION The present invention relates to antagonists of neurotrophins. Specifically, the present invention relates to compositions consisting of an effective amount of a compound that inhibits or reduces the undesirable activity of neurotrophins and a pharmaceutically acceptable carrier.

BACKGROUND OF THE INVENTION There is a family of structurally and functionally related neurotrophic factors, collectively known as neurotrophins. The neurotrophin family includes nerve growth factor ("NGF"), brain derived neurotrophic factor ("BDNF"), neurotrophin 3 ("NT-3"), neurotrophin 4 ("NT-4"), neurotrophin 5 (" NT-5") and neurotrophin 6 (" NT-6"). Neurotrophins exhibit similar structural conformations, including three ß-hairpin surface loops, a β-strand, an inverted inner region and N and C ends. Regarding sequence similarities, neurotrophins share approximately 50% amino acid identity . Neurotrophins are also functionally similar, in the sense that they exhibit a low affinity binding to a receptor known as the "p75 nerve growth factor receptor" or p75 * Each neurotrophin also exhibits binding to a receptor of the p75 family. tyrosine kinases (trk), which is of higher affinity than binding to the p75 receptor. It is thought that the interaction is related to the survival of neurons, but is also involved in the differentiation of neurons, including the formation of processes. The receptor interaction of trk-neurotrophins has been found to be more selective than the interaction of neurotrophins with the p75 receptor. * Specifically, NGF binds only to a receptor known as the TrkA receptor, whereas BDNF, NT-4 and NT-5 exhibit exclusive union to a TrkB receiver. NT-3 is less selective and, although it binds primarily to a TrkC receptor, it also exhibits some binding to the TrkA and TrkB receptors (Ibáñez et al., EMBO J., 1993, 12: 2281). Neurotrophins function primarily by promoting the survival of certain classes of peripheral and central neurons, both during development and after neuronal injury. NGF, in particular, is involved in the development of neurons in the peripheral nervous system and contributes to the survival of neurons, also enhancing and maintaining the differentiated state of neurons. However, in some neurological states of disease, neurotrophins also collaborate with an inappropriate overgrowth of neurites, thus facilitating the progression of a morbid condition. For example, neurotrophins promote the undesirable appearance of "mossy fibers" of the hippocampus. This inappropriate appearance of mossy fibers is a common companion of epilepsy in humans. It is also postulated that the pain experienced by patients suffering from some chronic pain syndrome may be associated with the appearance of sensory fibers for pain that respond to NGF, particularly in the spinal cord. In other disease states, such as Alzheimer's disease, an aberrant growth of processes, known as dystrophic neurite formation, has a strong correlation with the severity of the disease.

Therefore, although neurotrophins are essential for the normal development and growth of neurons, they can be harmful in certain circumstances. In some cases, ligands capable of inhibiting or reducing selected activities mediated by neurotrophins to treat diseases and neurodegenerative conditions, including neuropathic pain, and to repair nervous system injury would be desirable from a therapeutic point of view.

OBJECTS OF THE INVENTION It is an object of the present invention to provide compositions capable of inhibiting, or at least reducing, the undesirable activity mediated by neurotrophins. In one aspect of the present invention, there is provided a composition consisting of a vehicle and an effective amount of a compound of Formula I: where R1 is selected from alkyl; arylalkyl lower; heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl, aryl, and lower hydroxyalkyl; benzimidaz-2-yl; where R 4 is phenyl optionally substituted or disubstituted with a substituent selected from lower alkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, lower alkoxy, hydroxy and lower alkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, halo, lower dialkylamino, cyano, C (0) 0H, phenyl-S-, lower alkyl and Z (0) 0R7, where Z is selected from C and S and R7 is selected between H, lower alkylamino and arylamino, and their pharmaceutically acceptable salts. In another aspect of the present invention, a method of inhibiting a neurotrophin-mediated activity is provided, consisting of the step of exposing the neurons to a composition as described above. In another aspect of the present invention there is provided a method of inhibiting neurotrophin-mediated activity in a mammal, consisting of the step of administering a composition as described to said mammal.

These and other aspects of the present invention will be described herein in greater detail below.

DETAILED DESCRIPTION OF THE INVENTION The term "alkyl", as used herein, means straight and branched chain alkyl radicals containing from one to eight carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl. and similar. The term "lower alkyl", as used herein, means straight and branched chain alkyl radicals containing from one to four carbon atoms and includes methyl, ethyl, propyl, isopropyl, tere-butyl and the like. The term "alkoxy", as used herein, means straight and branched chain alkoxy radicals containing from one to eight carbon atoms and includes methoxy, ethoxy, tere-butoxy and the like. The term "lower alkoxy", as used herein, means straight and branched chain alkoxy radicals containing from one to four carbon atoms and includes methoxy, ethoxy, tert-butoxy and the like. The term "aryl", as used herein, means a 5 or 6 membered aromatic or heteroaromatic ring containing 1, 2 or 3 heteroatoms independently selected from O, N and S and includes phenyl, pyridyl, thienyl, furanyl, pyrrolo , imidazolo and the like. The term "heterocycle", as used herein, means a non-aromatic five- or six-membered ring optionally containing one or more double bonds and one or two heteroatoms selected from 0, S and N and includes dihydropyran, tetrahydropyran, tetrahydrofuranyl, azacyclohexane, azacyclohexene, dihydrothiapyran, tetrahydrothiapyran, morpholino and the like.

The term "halo", as used herein, means halide and includes fluoro, chloro, bromo and iodo. As used herein, in vivo hydrolysable esters or amides are those easily hydrolysable esters or amides of compounds of Formula I, which are known and used in the pharmaceutical industry and include α-acyloxyalkyl and C3_20 fatty acid esters. As used herein, the term "neurotrophins" refers to neurotrophic factors that are structurally homologous to NGF, that is, include three surface β-hairpin loops, a β-strand, an inverted inner region, and N and C ends. and that promote at least one between neuronal survival and neuronal differentiation, as determined by the use of conventional design trials, such as the in vi tro assay exemplified here and described by Riopelle et al. in Can. J. of Phys. And Pharm., 1982, 60: 707. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3), neurotrophin 4 (NT-4), neurotrophin 5 (NT-5), and neurotrophin 6 (NT-6) of mammals are examples of neurotrophins. The "biological activity mediated by neurotrophins" is a biological activity that is normally promoted, either directly or indirectly, in the presence of a neurotrophin. Activities mediated by neurotrophins include, for example, the binding of neurotrophins to the p75NGFR receptor or the binding of neurotrophins to one of the trk receptors, the survival of neurons, the differentiation of neurons, including the formation of neuronal processes and overgrowth of neurites, and biochemical changes, such as enzyme induction. Reference is here made to a biological activity mediated by a particular neurotrophin, for example NGF, by reference to that neurotrophin, for example, NGF-mediated activity. To determine the ability of a compound to inhibit a neurotrophin-mediated activity, conventional in vitro and in vivo assays can be used. For example, a receptor binding assay, such as the assay described herein in Example 1, can be used to assess the extent to which a compound inhibits neurotrophin / receptor binding. The inhibition of survival and neurite overgrowth can be determined using the in vitro assay described by Riopelle et al. in the Can. J. of Phys. And Pharm., 1982, 60: 707, illustrated herein in Example 2. The present invention relates to compositions consisting of an effective amount of a compound of Formula I, or pharmaceutically acceptable salts or hydrolysable esters or amides. in vivo thereof (hereinafter referred to as a compound of Formula I), which inhibits neurotrophin-mediated activity, and a pharmaceutically acceptable carrier. In embodiments of the invention, the compounds of Formula I include those in which R1 is selected from alkyl; arylalkyl lower; heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl, aryl, and lower hydroxyalkyl; benzimidaz-2-yl; where R 4 is phenyl optionally substituted or disubstituted with a substituent selected from lower alkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, lower alkoxy, hydroxy and lower alkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, halo, lower dialkylamino, cyano, C (0) 0H, phenyl-S-, lower alkyl and Z (0) 0R7, where Z is selected from C and S and R7 is selected between H, lower alkylamino and arylamino, and their pharmaceutically acceptable salts. In another embodiment of the invention, the compounds of Formula I include those in which R1 is selected from arylalkyl; heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl and lower hydroxyalkyl; benzimidaz-2-yl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, lower dialkylamino and phenyl-S-, and their pharmaceutically acceptable salts. In another embodiment of the invention, the compounds of Formula I include those in which R1 is selected from amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl and hydroxy-lower alkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (Rd), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H and N02, and their pharmaceutically acceptable salts. In specific embodiments of the invention, the compounds of Formula I include: N-. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2-aminoethanol, N-dimethylamino-lS-dioxo-S-nitro-l ^ / S ^ -tetrahydrobenzo- [i] isoquinoline, N- (l, 3-dioxo-5-nitro-l, 2, 3, 4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-l, 3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-1,8-naphthalimide, 6- (N, N-dimethylamino) -2 - (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1,8-naphthalimide, 1,3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2, 3,4-tetrahydrobenzo [i] isoquinoline, 2-. { 2- (4-methylphenylsulfonamido) phenyl} -6- (N, N-dimethylamino) -naphthalimide, 1,3-dioxo-2 -. { 2- (4-methylphenylsulfonamido) phenyl} -1, 2, 3, 4 -tetrahydrobenzo [i] isoquinoline, N-octyl-5-nitronaphthalimide, 5-bromo-1,3-dioxo-N-methylpyrid-3-yl-l, 2,3,4-tetrahydrobenzo [i] isoquinoline, 1, 3-dioxo-5-nitro-N- (pyrid-2-ylethyl) -1, 2, 3, 4-tetrahydro [i] -isoquinoline, 6-nitro-2- (tetrahydrofuran-2 -ylmethyl) naphthalimide, N- (1,3-dioxo-1, 2,3,4-tetrahydrobenzo [i] isoquinoline) amino-ethanol, N-aminoimide of naphthalic acid, 2-. { 2- (4-methylbenzsulfonamido) -4,5-dichlorophenyl} naphthalimide, 3-nitro-l, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2- (2-aminophenyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 6-nitro-2- (pyrid-3-methyl) naphthalimide, 3-amino-7,4 -bis (ethyl-1,3-dioxo) -1,2,3,4-tetrahydrobenzo [i] -isoquinoline 2- (benzimidaz-2-yl) -1,3-dioxo-l, 2, 3, 4 -tetrahydrobenzo [i] -isoquinoline, 2- (2-aminophenyl) naphthalimide, 1,3-dioxo-2-. { 4, 5-dimethyl-2- (4-methylphenylsulfonamido) phenyl} -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 3-methyl-3- (1,3-dioxo-5-nitro- (1H) methyl ester, 3H) benz [des] isoquinolyl) butyric, 1,3-dioxo-N-methyltetrahydrofurfur-2-yl-5-nitro-l, 2,3,4-tetrahydro [i] isoquinoline, N- (4-ethoxyphenyl) -5-nitronaphthalimide, 6-nitro-2- (furfuryl) naphthalimide, 5-nitro-l, 3-dioxo-lH-benz [de] isoquinoline-2-3H-ethyl acetate, N, N'-diimide acid naphthalic acid, 2- (2-hydroxyphenyl) naphthalimide, 5-amino-N-butylaphthalimide, 1,3-dioxo-5-nitro-n-propylmorpholino-l, 2,3,4-tetrahydroben-zo [i] isoquinoline, -nitro-2- (pyrid-2-ylethyl) naphthalimide, N-methylnaphthalimide, N- (pyrid-2-ylmethyl) naphthalimide, N- (3,5-dimethylphenyl) -1,8-naphthalimide, 6-bromo-N -dimethylamino-1,3-dioxo-1, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (1, 3-dioxo-6-phenylmercapto-1,2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol and N-acrylin-1,8-naphthalimide. In a preferred embodiment of the invention, the compounds of Formula I include: N-. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (1, 3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-nitro) -1, 2,3, 4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-1,8-naphthalimide, 6- (N, N-dimethylamino) -2- (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1,8-naphthalimide, 1,3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 2- . { 2- (4-methylphenylsulfonamido) phenyl} -6- (N, N-dimethylamino) -naphthalimide, 1,3-dioxo-2-. { 2- (4-methylphenylsulfonamido) phenyl} -1,2, 3,4-tetrahydrobenzo [i] isoquinoline, N-octyl-5-nitronaphthalimide, 5-bromo-1,3-dioxo-N-methylpyrid-3-yl-l, 2,3,4-tetrahydrobenzo [i] isoquinoline, 1,3-dioxo-5-nitro-N- (pyrid-2-ylethyl) -1,2, 3,4-tetrahydro [i] -isoquinoline, 6-nitro-2- (tetrahydrofuran-2 -ylmethyl) naphthalimide, N- (1, 3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-aminoimide of naphthalic acid, 2-. { 2- (4-methylbenzsulfonamido) -4,5-dichlorophenyl} naphthalimide, 3-nitro-1, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2- (2-aminophenyl) -1,2,3, -tetrahydrobenzo [i] isoquinoline, 6-nitro-2- (pyrid-3-methyl) naphthalimide, 3-amino-7, 4-bis (ethyl-1,3-dioxo-1, 2,3,4-tetrahydrobenzo [i] -isoquinoline, 2- (benzimidaz-2-yl ) -1, 3-dioxo-l, 2, 3, 4-tetrahydrobenzo [i] -isoquinoline and 2- (2-aminophenyl) naphthalimide In a more preferred embodiment of the invention, the compounds of Formula I include: N- {.5-Nitro-lH-benz [des] isoquinoline-1,3 (2H) -dione.} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-l, 2,3 , 4-tetrahydrobenzo- [i] isoquinoline, N- (l, 3-dioxo-5-nitro-l, 2,3, 4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo- 1, 2,3, 4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-nitro-1, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-1, 8 -naphthalimide, 6- (N, N-dimethylamino) -2- (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1, 8-naphthalamide da and 1,3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline. In a more preferred embodiment of the invention, the compounds of Formula I include: N-. { 5-Nitro-lH-benz [de] isoquinoline-1, 3- (2H) -dione} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-1,2,4,4-tetrahydrobenzo- [i] isoquinoline, N- (1,3-dioxo-5-nitro-l, 2, 3, 4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo-1, 2,3, 4-tetrahydrobenzo [i] isoquinoline and N- (1,3-dioxo-5-nitro) -1, 2,3,4-tetrahydrobenzo [i] isoquinolone) aminoethanol. Another embodiment of the invention includes an in vivo hydrolysable ester or amide of a compound selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1, 3- (2H) -dione} -2-aminoethanol, N- (1, 3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) acetic acid, N- (1,3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N- (1, 3-dioxo-l, 2, 3, 4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-aminoimide of naphthalic acid, 3-nitro-1, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2 - (2-Aminophenyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 3-amino-7,4-bis (ethyl-1,3-dioxo) -1,2,3,4-tetrahydrobenzo [ i] -isoquinoline, 2- (2-aminophenyl) naphthalimide and 2- (2-hydroxyphenyl) naphthalimide. The compounds of the present invention can be prepared by techniques well known in the art. The compounds of formula I in which R1, R2 and R3 are as defined above can be prepared by reacting a 1,8-naphthalic anhydride of Formula A with a primary amine of Formula B in a suitable solvent, such as toluene, methanol, ethanol, propanol or acetone, and at temperatures in the range of 0 ° C to the boiling point of the solvent used. Both reagent A and reagent B are commercially available or can be prepared using methods known to those skilled in the art.

The acid addition salts of the compounds of Formula I are more suitably formed from pharmaceutically acceptable acids and include, for example, those formed with inorganic acids, such as hydrochloric, sulfuric or phosphoric acids, and with organic acids, such as succinic, maleic, acetic or fumaric acid. Other non-pharmaceutically acceptable salts, for example oxalates, can be used, for example, in the isolation of the compound of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt. The solvates and hydrates of the invention are also included in the scope of the invention. The conversion of a given salt of a compound into a desired salt of a compound is achieved by applying standard techniques, wherein an aqueous solution of the given salt is treated with a base solution, for example sodium carbonate or potassium hydroxide, for releasing the free base, which is then extracted in an appropriate solvent, such as ether. The free base is then separated from the aqueous portion, dried and treated with the necessary acid to obtain the desired salt. You can. forming the hydrolysable esters or amides in vivo of certain compounds of Formula I by treating those compounds having a hydroxy or free amino functionality with the acid chloride of the desired ester in the presence of a base, in an inert solvent such as methylene chloride or chloroform. Suitable bases include triethylamine or pyridine. In contrast, compounds of Formula I having a free carboxy group can be esterified using standard conditions, which may include activation followed by treatment with the desired alcohol in the presence of a suitable base. The compositions of the present invention are useful for inhibiting or reducing the undesirable activity of neurotrophins both in vi tro and in vivo. Thus, in one aspect of the invention, there is provided a composition consisting of an effective amount of a compound of Formula I and a suitable vehicle. By "suitable vehicle" is meant a vehicle that is mixed with the compound of Formula I to obtain a composition suitable for the application for which it is to be used. By "effective amount" is meant an amount of the compound sufficient to inhibit an undesired neurotrophin-mediated activity to a measurable degree, preferably by about 20%, more preferably by about 40%, more preferably by about 50%, according to it is determined by conventional design tests, such as those described herein in the specific examples. The present composition has use as a means supplement to avoid the undesirable neurotrophin-mediated activity of neuronal cells in vi tro. For example, primary sensory neurons require NGF to survive in cell culture; however, NGF also influences the differentiation of neurons, notably in the formation of processes and overgrowth, which are undesirable for the use of primary sensory neurons in cell culture. Therefore, to preserve the survival of the neurons in vi tro, while inhibiting cell differentiation, NGF is added to the cell culture medium together with the compound of Formula I. For the addition to the cell culture, the compound is firstly combined with a vehicle that does not adversely affect the growth of the cells in culture. Such vehicles will include, for example, physiologically acceptable fluids, such as water or any other fluid suitable for addition to the cell culture. Alternatively, the compound can be combined with suitable media for culturing neuronal cells before being added to the cell culture. To be effective in preventing the differentiation of neurons, the concentration of the compound in the cell culture will be in the range of about 1-500 μM and, preferably, of about 1-100 μM. The optimum concentration of compound for use in preventing the differentiation of neurons in cell culture will, of course, vary depending on the degree of inhibition desired, as well as the type of neuronal cells involved. Compositions for in vivo administration are also contemplated, for example for the treatment of neurological conditions such as epilepsy or Alzheimer's disease, or for the treatment of chronic pain. Said compositions consist of a therapeutically effective amount of the compound of Formula I together with a pharmaceutically acceptable carrier. In this context, the term "pharmaceutically acceptable" means acceptable for use in the pharmaceutical and veterinary techniques, ie, non-toxic and which does not adversely affect the activity of the compound. The term "therapeutically effective amount" means an amount of the compound sufficient to reduce the undesirable activity mediated by neurotrophins, as determined using conventionally designed assays, in an affected individual without causing adverse effects. Pharmaceutically acceptable carriers useful for preparing compositions for in vivo administration include conventional carriers used in the formulation of drugs, such as diluents, excipients and the like. Reference may be made to "Remington's Pharmaceutical Sciences," 17th Ed., Mack Publishing Company, Easton, Penn. , 1985, as a guide in drug formulations in general. As will be appreciated, the pharmaceutical vehicles used to prepare compositions according to the present invention will depend on the dosage form that is to be used to treat the affected individual. According to an embodiment of the invention, a compound of Formula I is formulated for administration intraventricularly by injection and, consequently, it is presented as an aqueous solution in a sterile and pyrogen-free form and optionally buffered or made isotonic. Therefore, the compound can be administered in distilled water or, more desirably, in saline or 5% dextrose solution. The water solubility of the compound of the invention can be increased, if desired, by incorporating a solubility enhancer, such as acetyltrimethylammonium bromide or chloride, into the composition. Lyoprotectants, such as mannitol, sucrose or lactose and buffer systems, such as acetate, citrate and phosphate, as well as bulking agents, such as serum albumin, may also be included in the formulation. For use in the treatment of individuals with a neurological condition, the precise dosage sizes of an appropriate pharmaceutical composition for treatment are established in appropriately controlled trials and will correspond to an amount of a compound of Formula I that reduces the undesirable activity mediated by neurotrophins. without causing intolerable side effects to the individual being treated. It is anticipated that an effective treatment regimen for patients will include intraventricular administration of dosages that reach a level of the compound in the spinal fluid of the individual in treatment of approximately 1-500 μM. It will be appreciated, of course, that the dosage sizes required to achieve this concentration in vivo will vary according to the route of administration, the frequency of administration, the individual under treatment and the neurological condition being treated.

Specific embodiments of the present invention are described in more detail in the following examples, which are not to be considered as limiting. Example 1 - Binding of f125IlNGF to PC12 cells in the presence and absence of BDNE The ability of the compounds of Formula I to antagonize the interaction of NGF with p75 and trkA receptors was determined as follows.

(A) Imagination of NGF NGF was labeled using the Lactoperoxidase labeling method (Sutter et al., J *. Biol. Chem., 1979) and labeled NGF was separated from the radiolabel and free iodide using a PD-10 Sephadex G-column. 25 (B) Cell culture and cell preparation PC12 cells were grown in RPMl with 10% heat-inactivated donor horse serum and 5% fetal calf serum. Cells were harvested for binding by washing the medium with calcium-magnesium-free balanced salt solution (Gey's solution) and were incubated in 5 ml of Gey's solution at 37 ° C for 15 minutes. The cells were pelleted by centrifugation and suspended in Hepes-Krebs Ringer buffer (HKR) (10 mM Hepes, pH 7.35, containing 125 mM NaCl, 4.8 mM KCl, 1.3 mM CaCl 2, MgSO 4). 1.2 mM, 1.2 mM KH2P04, 1 mg / ml BSA and 1.0 mg / ml glucose) at a concentration of 4xl06 / ml and kept on ice. (C) NGF binding The reaction was carried out in a 96-well plate. The suspended cells (150 μl, 10 cells) were added to 125 I-NGF (final concentration of 0.5 nM) and the competitive compound of Formula I in a final volume of 300 μl of HKR buffer. Plates were incubated with shaking for 2 h at 4 ° C. At the end of the incubation, 100 μl aliquots of the reaction sample were added to 400 μl microcentrifuge tubes containing 200 μl of 10% glycerol in HKR buffer. The tubes were centrifuged for 1 minute at -5,000 rpm and the tip containing the cell pellet was cut. The radioactivity bound to the cells was determined by measuring the 125I-NGF associated with each pellet in a gamma counter. The specific binding is calculated as the difference between the amount of 125 I-NGF bound in the absence (total) and in the presence (NSB) of unlabeled 50 nM NGF. TrkA binding is determined in a similar manner, except for the addition of 10 nM BDNF to all reactions. Table 1 summarizes the values obtained from this experiment for inhibiting the binding of NGF to P75 and TrkA by the compounds of Formula I.

TABLE 1 TABLE 1 (cont.) TABLE 1 (cont.) Example 2 - Inhibition of neurite overgrowth The N- capacity was determined. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2-aminoethanol (Compound A) to inhibit neuritic overgrowth using the following assay. Dorsal root ganglia ("DRG") of eight-day-old chicken embryos were released from the meninges and aseptically removed. The DRGs were maintained at 4 ° C at all times. The ganglia of six embryos (40-50 per embryo) were washed in Ca2 + and Mg2 + free Gey's balanced salt solution (Gibco) and exposed to 0.01% trypsin (Worthington) in the same solution for 10 min at 37 ° C. A half volume of phosphate-buffered Gey's balanced salt solution was added for a further 5 min at 37 ° C and the reaction was then terminated with one third volume of Ham's F12 medium (Gibco), containing 5% serum fetal calf (FCS, Gibco). The ganglia were then crushed using a 5 ml narrow tip pipette to obtain a single cell suspension. After filtering through a 37 mm nylon mesh (Small Parts Inc., Miami, FL) in a Millipore chamber to remove agglomerates, the cell suspension was washed through a 500 ml FCS recess (700 xg). for 5 min at 4 ° C) and resuspended in 4 ml of Ham's F12 medium plus 5% FCS. The cell suspension was then pre-plated in a 100 mm Flacon culture dish and incubated for 45-60 min at 37 ° C in a humidified atmosphere with 5% C02. The cells enriched in neurons were decanted for the bioassay, since the non-neuronal cells of the DRGs adhere preferentially to the substrate of the culture. The internal wells of 96-well Falcon microculture plates were coated with polylysine (0.1 mg / ml) (Sigma) for 4 h at 37 ° C (the external wells were filled with distilled water to provide moisture) and, after a washed with tissue culture medium, 100 ml of neuron-rich cell suspension was added to each well at 10 5 cells / ml. 90 ml of NGF solution (prepared in tissue culture medium) was then added to each well at a final concentration of 0.25 ng / ml of NGF per well. Then 10 ml of the test compound solution, ie, tissue culture medium mixed with a compound of Formula I, were added to the duplicate assay wells to obtain wells containing compound concentrations between 0 μM and 100 μM. . For the control assays, 10 ml of Ham's F12 medium was added to wells containing NGF in duplicate. The plates were then covered and incubated in the dark for 24-30 h at 37 ° C, in a humidified atmosphere containing 5% C02. The bioassays were read using a Leitz Diavert microscope with phase optics. To obtain a suitable optics, the meniscus effect of each well was eliminated by filling the well with a balanced salt solution until a flat interface filled with air was obtained in the upper part of the well. At least 100 neurons were counted per well and the assay was scored as the proportion of neurite-bearing cells larger than the diameter of a cell to total viable cells (bright phase). These results are summarized in Table 2.

ABLA 2 Example 3 - Animal models of neuropathic pain For pain related to nerve injury, compound N- was studied. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -di } -2-aminoethanol (Compound A) in rats with ligated nerves in terms of activity against tactile allodynia, thermal hyperalgesia and in the direct production of thermal antinociception. The nerve ligation model is commonly accepted as representing the aspects of neuropathic pain described by humans. Rats operated in sham served as appropriate controls for neuropathic experiments.

Injury by nerve ligation: The lesion was produced by nerve ligation according to the method described by Kim and Chung (Pain 50: 355-363, 1992). Rats were anesthetized with halothane and the vertebrae of the L4 to S2 region were exposed. The spinal nerves L5 and L6 were exposed, they were carefully isolated and a tight ligature was made with 4-0 silk suture distal to the DRG. After ensuring hemostatic stability, the wounds were sutured and the animals were allowed to recover in the cages. Simulated rats were prepared in an identical manner, except for the fact that the nerve roots L5 / L6 were not ligated.

Intrathecal catheter placement: The test compounds were injected through fixed intrathecal catheters. Under anesthesia, a PE-10 (8 cm) tube was inserted through an incision made in the atlanto-occipital membrane to the level of the lumbar spreading of the rat and secured. The drug injections were performed in a volume of 5 μl of 50% aqueous DMSO, followed by a wash with 9 μl of saline. Objectives: (A) Evaluation of tactile allodynia: Mechanical allodynia was determined in the manner described by Chaplan et al. (J. Neurosci, Meth. 53: 55-63, 1994). The paw withdrawal threshold was determined in response to probing with calibrated von Frey filaments. The rats were kept in suspended cages with grid floors and the von Frey filaments were applied perpendicularly to the plantar surface of the rat paw until it was slightly bent and held for 3-6 sec. A positive response was indicated by a sudden withdrawal of the leg. 50% of the paw withdrawal threshold was determined by the nonparametric method of Dixon (Ann.Rev.Pharmacol.Toxicol.20: 441-462, 1980). (B) Evaluation of thermal hyperalgesia: Thermal hyperalgesia was determined by directing a source of radiant heat to the plantar surface of the affected leg of rats with injured or sham-operated nerves. The latencies in the removal of the paw are determined by means of a photodetection device that stops the stimulus and the chronometer after a maximum interval of 40 sec to avoid injury of the tissues. The withdrawal latency of sham-operated rats was compared with that of the rats bound to measure the degree of hyperalgesia.

(O Evaluation of acute nociceptive responses: Acute nociception was determined using the nociceptive reflex of the blow of the tail with hot water.) This test was performed by placing the tail of rats with nerve injury or operated on simulation in a water bath heated to 55 ° C. Latency was determined until the tail was removed (fast blow) from the bath and compared between the treatments, a 15-second interval was used to avoid tissue injury, Compound A and morphine were studied in the lesion model by nerve ligation of neuropathic pain using 3 routes of administration: intraperitl (ip), intrathecal (i.t.) and intracerebroventricularly (i.c.v.). The compounds were evaluated for three objectives: tactile allodynia, thermal hyperalgesia and acute nociception. Compound A is not active when i.c.v. The results for the administration i.p. and i.t. they are shown in Table 3.

TABLE 3 Summary of the A50 doses with confidence limits (L.C.) of 95% for Compound A and morphine in rats with L5 / L6 nerve ligatures and operated on simulation in models of tactile allodynia, acute nociception and thermal hyperalgesia * nd = not available Example 4 - Preparation of N-. { 5-nitro-lH-benz Tdesl isoquinoline-1, 3 (2H) -dione} -2-aminoethanol (Compound A) 3-Nitro-1, 8-naph alic anhydride (1 equiv.) And 2-hydroxyethylhydrazine (1 equiv.) Are dissolved in toluene and heated to reflux. The reaction is monitored by thin layer chromatography and stopped when all the starting material has been consumed. The solvent is removed under reduced pressure and the product is purified, if necessary, by recrystallization or chromatography on silica gel. Other compounds of Formula I can be prepared in an analogous manner, or commercially available from Ryan Scintific Inc., Isle of Palms, South Carolina, USA.

Claims (13)

1. Claims 1. A pharmaceutical composition consisting of a compound of Formula I, where R1 is selected from alkyl; arylalkyl lower; heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl, aryl, and lower hydroxyalkyl; benzimidaz-2-yl; where R 4 is phenyl optionally substituted or disubstituted with a substituent selected from lower alkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, lower alkoxy, hydroxy and lower alkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, halo, lower dialkylamino, cyano, C (0) 0H, phenyl-S-, lower alkyl and Z (0) OR7, where R7 is selected from C and S and R7 is selected between H, lower alkylamino and arylamino, and their pharmaceutically acceptable salts, in an amount effective to inhibit neurotrophin-mediated activity, and a suitable vehicle.
2. 2. A pharmaceutical composition according to claim 1, wherein R1 is selected from alkyl; arylalkyl lower; heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl and lower hydroxyalkyl; benzimidaz-2-yl; where R 4 is phenyl optionally substituted or disubstituted with a substituent selected from lower alkyl and halo; phenyl optionally monosubstituted or disubstituted with a substituent selected from amino, lower alkoxy, hydroxy and lower alkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, halo, lower dialkylamino and phenyl-S-.
3. 3. A pharmaceutical composition according to the claim 2, wherein R1 is selected from arylalkyl lower; • heterocycle-lower alkyl; lower alkyl carbonate; amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl and lower hydroxyalkyl; benzimidaz-2-yl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and Rd is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02, lower dialkylamino and phenyl-S-.
4. 4. A pharmaceutical composition according to the claim 3, wherein R1 is selected from amino optionally monosubstituted or disubstituted with a substituent selected from lower alkyl and lower hydroxyalkyl; NHCH2CH2OX, where X represents a hydrolysable ester in vivo, and lower alkyl- (R5) (R6), wherein one of R5 and R6 is selected from H and lower alkyl and the other is selected from carboxy, lower carboxyalkyl and lower alkoxycarbonyl, and R2 and R3 are independently selected from H, N02.
5. 5. A pharmaceutical composition according to claim 1, wherein the compound of Formula I is selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2- to inert ethanol, N-dimethylamino-1,3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (l, 3-dioxo-5-nitro-l) , 2,3,4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo-1,2,3,4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-) nitro-1, 2,3, 4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-1,8-naphthalimide, 6- (N, N-dimethylamino) -2- (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1,8-naphthalimide, 1 3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 2-. { 2- (4-methylphenylsulfonamido) phenyl} -6- (N, N-dimethylamino) -naphthalimide, 1,3-dioxo-2-. { 2- (4-methylphenylsulfonamido) phenyl} -l, 2,3,4-tetrahydrobenzo [i] isoquinoline, N-octyl-5-nitronaphthalimide, 5-bromo-l, 3-dioxo-N-methylpyrid-3-yl-l, 2,3,4-tetrahydroben -zo [i] isoquinoline, 1,3-dioxo-5-nitro-N- (pyrid-2-ylethyl) -1,2,3, -tetrahydro [i] -isoquinoline, 6-nitro-2- (tetrahydrofuran- 2-ylmethyl) naphthalimide, N- (1,3-dioxo-1,2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-aminoimide of naphthalic acid, 2-. { 2- (4-methylbenzsulfonamido) -, 5-dichlorophenyl} naphthalimide, 3-nitro-1, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2- (2-aminophenyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 6-nitro-2 - (pyrid-3-methyl) naphthalimide, 3-amino-7,4-bis (ethyl-1,3-dioxo) -1,2,3,4-tetrahydrobenzo [i] -isoquinoline, 2- (benzimidaz-2) -yl) -1,3-dioxo-1, 2, 3, 4-tetrahydrobenzo [i] -isoquinoline, 2- (2-aminophenyl) naphthalimide, 1,3-dioxo-2-. { 4, 5-dimethyl-2- (4-methylphenylsulfonamido) phenyl} 1,2,3,4-tetrahydrobenzo [i] isoquinoline, 3-methyl-3- (1, 3-dioxo-5-nitro- (1H, 3H) benz [des] isoquinolyl) butyric acid methyl ester, 1 , 3-dioxo-N-methyltetrahydrofurfur-2-yl-5-nitro-l, 2,3,4-tetrahydro [i] isoquinoline, N- (4-ethoxyphenyl) -5-nitronaphthalimide, 6-nitro-2 - ( furfuryl) naphthalimide, 5-nitro-l, 3-dioxo-lH-benz [des] isoquinoline-2-3H-ethyl acetate, N, N'-diimide of naphthalic acid, 2- (2-hydroxyphenyl) naphthalimide, -amino-N-butylnaphthalimide, 1,3-dioxo-5-nitro-n-propylmorpholino-l, 2,3, 4-tetrahydroben-zo [i] isoquinoline, 6-nitro-2- (pyrid-2-ylethyl) naphthalimide, N-methylnaphthalimide, N- (pyrid-2-ylmethyl) -phthalimide, N- (3, 5-dimethylphenyl) -1,8-naphthalimide, 6-bromo-N-dimethylamino-1,3-dioxo-1, 2 , 3,4-tetrahydrobenzo- [i] isoquinoline, N- (1,3-dioxo-6-phenylmercapto-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol and N-anilino-1,8-naphthalimide .
6. 6. A pharmaceutical composition according to claim 2, wherein the compound of Formula I is selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-l, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (1, 3-dioxo-5-nitro-l, 2, 3, 4-tetrahydrobenzo [i] iso-quinoline) acetic acid, N-acetoxy-l, 3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-nitro-1,2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-l, 8-naphine, 6- (N, N-dimethylamino) - 2- (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1,8-naphthalimide, 1,3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2 , 3,4-tetrahydrobenzo [i] isoquinoline, 2-. { 2- (4-methylphenylsulfonamido) phenyl} -6- (N, N-dimethylamino) -naphthalimide, 1,3-dioxo-2-. { 2- (4-methylphenylsulfonamido) phenyl} -1,2, 3,4-tetrahydrobenzo [i] isoquinoline, N-octyl-5-nitronaphthalimide, 5-bromo-1,3-dioxo-N-methylpyrid-3-yl-l, 2, 3, 4-tetrahydroben -zo [i] isoquinoline, 1,3-dioxo-5-nitro-N- (pyrid-2-ylethyl) -1,2,3, 4-tetrahydro [i] -isoquinoline, 6-nitro-2- (tetrahydrofuran -2-methylmethyl) naphthalimide, N- (1, 3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-aminoimide of naphthalic acid, 2-. { 2- (4-methylbenzsulfonamido) -4,5-dichlorophenyl} naphthalimide, 3-nitro-l, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2- (2-aminophenyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 6-nitro-2- ( pyrid-3-methyl) naphthalimide, 3-amino-7,4-bis (ethyl-1,3-dioxo-1, 2,3,4-tetrahydrobenzo [i] -isoquinoline, 2- (benzimidaz-2-yl) -1, 3-dioxo-l, 2,3,4-tetrahydrobenzo [i] -isoquinoline and 2- (2-aminophenyl) naphthalimide.
7. 7. A pharmaceutical composition according to claim 3, wherein the compound of Formula I is selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1,3 (2H) -dione} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-1, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (1,3-dioxo-5-nitro-1, 2, 3, 4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo-1, 2,3,4-tetrahydrobenzo [i] isoquinoline, N- (1,3-dioxo-5-nitro) -1, 2,3, 4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-furfuryl-1,8-naphthalimide, 6- (N, N-dimethylamino) -2- (benzimidazol-2-yl) naphthalimide, N- (pyrid-2-ylethyl) -1,8-naphthalimide and 1,3-dioxo-6-phenylmercapto-N- (pyrid-2-ylethyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline.
8. 8. A pharmaceutical composition according to claim 4, wherein the compound of Formula I is selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1, 3- (2H) -dione} -2-aminoethanol, N-dimethylamino-1,3-dioxo-5-nitro-1, 2,3,4-tetrahydrobenzo- [i] isoquinoline, N- (1,3-dioxo-5-nitro-1, 2,3,4-tetrahydrobenzo [i] isoquinoline) acetic acid, N-acetoxy-1,3-dioxo-l, 2,3,4-tetrahydrobenzo [i] isoquinoline and N- (1,3-dioxo-5-nitro) -1,2, 3, -tetrahydrobenzo [i] isoquinoline) aminoethanol.
9. 9. A pharmaceutical composition as defined in claim 1, which inhibits the activity mediated by NGF.
10. 10. A method of inhibiting a neurotrophin-mediated activity consisting of the step of exposing the neuronal cells to an effective amount of a composition as defined in claim 1.
11. 11. A method of inhibiting a neurotrophin-mediated activity in a mammal consisting of the step of administering to said mammal a therapeutically effective amount of a composition as defined in claim 1.
12. 12. A method as defined in claim 11, wherein said composition is administered intraventricularly.
13. 13. An in vivo hydrolysable ester or amide of a compound selected from the group consisting of: N-. { 5-Nitro-lH-benz [de] isoquinoline-1, 3- (2H) -dione} -2-aminoethanol, N- (1,3-dioxo-5-nitro-1, 2,3,4-tetrahydrobenzo [i] iso-quinoline) acetic acid, N- (1,3-dioxo-5-nitro) 1, 2,3, 4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N- (1,3-dioxo-1,2,3,4-tetrahydrobenzo [i] isoquinoline) aminoethanol, N-aminoimide of naphthalic acid, 3 - Nitro-1, 8- (N-propioncarboxylate) succinamidonaphthalene, 1,3-dioxo-2- (2-aminophenyl) -1,2,3,4-tetrahydrobenzo [i] isoquinoline, 3-amino-7,4-bis (ethyl-1, 3-dioxo) -1,2,3, 4-tetrahydrobenzo [i] -isoquinoline, 2- (2-aminophenyl) naphthalimide and 2- (2-hydroxyphenyl) naphthalimide.