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Definitions

• the present invention is directed to novel fused aryl and heteroaryl bridged indenopyrrolocarbazoles, which are referred to herein as "bridged indenopyrrolocarbazoles.”
• the invention also is directed to methods for making and using the bridged indenopyrrolocarbazoles .
• K- 252a The microbial -derived material referred to as "K- 252a" is a unique compound which has gained significant attention over the past several years due to the variety of functional activities which it possesses.
• K-252a is an indolocarbazole alkaloid that was originally isolated from a Nocardiosis sp . culture (Kase, H et al . 39 J. Antibiotics 1059, 1986) .
• K-252a is an inhibitor of several enzymes, including protein kinase C (PKC) which plays a central role in regulating cell functions, and trk tyrosine kinase.
• PKC protein kinase C
• the reported functional activities of K-252a and its derivatives are numerous and diverse: tumor inhibition (See U.S. Patent Nos.
• the reported indolocarbazoles share several common attributes.
• Both K-252a and staurosporine have been extensively studied with respect to their utility as therapeutic agents.
• the indolocarbazoles are generally lypophilic which allows for their comparative ease in crossing biological membranes, and, unlike proteinaceous materials, they manifest a longer in vivo half life.
• K-252a is normally derived from culture media via a fermentation process, the total synthesis of the natural (+) isomer and the unnatural (-) isomer, in which the three chiral carbons of the sugar have the opposite configurations, has been achieved (See Wood et al . , J. Am.
• Fused isoindolones which are non-indole-containing molecules that can be chemically synthesized de novo are also known (See WIPO Publication WO 97/21677) .
• the present invention is directed to novel fused aryl and heteroaryl bridged indenopyrrolocarbazoles, which are referred to herein as "bridged indenopyrrolocarbazoles.
• bridged indenopyrrolocarbazoles Exemplary compounds of the invention have the general Formula I :
• the compounds are useful, inter alia, for enhancing trophic factor-induced activities of trophic factor responsive cells, e.g., cholinergic neurons, and may also function as survival-promoting agents for other neuronal cell types, e.g., dopaminergic and glutamatergic, and are thus beneficial pharmacological and therapeutic agents.
• the present compounds are also useful in the treatment of disorders associated with decreased ChAT activity or the death or injury to spinal cord motoneurons, and also have utility in diseases associated with apoptotic cell death of the central and peripheral nervous system, immune system, and in inflammatory diseases.
• the certain bridged indenopyrrolocarbazole compounds described herein may also find utility in the treatment of disease states involving malignant cell proliferation, such as cancer.
• compositions containing the subject compounds, and methods for using the subject compounds are disclosed. Methodologies for making the present bridged indenopyrrolocarbazoles are also disclosed. Other useful methodologies will be apparent to those skilled in the art, once armed with the present disclosure.
• Figure 1 is a schematic drawing showing a general preparation of bridged indenopyrrolocarbazoles.
• Figure 2 is a schematic drawing showing a general preparation of bridged indenopyrrolocarbazoles .
• Figure 3 is a schematic drawing showing a preparation of resin-bound indenopyrrolocarbazoles.
• Figure 4 is a schematic drawing showing the preparation of protected, soluble indenopyrrolocarbazoles.
• Figure 5 is a schematic drawing showing the preparation of intermediate V.
• Figure 6 is a schematic drawing showing the preparation of bridged indenopyrrolocarbazoles using method A.
• Figure 7 is a schematic drawing showing the preparation of bridged indenopyrrolocarbazoles using method B.
• Figure 8 is a schematic drawing showing the preparation of B ring-substituted bridged indenopyrrolocarbazoles .
• Figure 9 is a schematic drawing showing the derivatization of the E ring of bridged indenopyrrolocarbazoles .
• ring B and ring F independently, and each together with the carbon atoms to which they are attached, are selected from the group consisting of: a) an unsaturated 6 -membered carbocyclic aromatic ring in which from 1 to 3 carbon atoms may be replaced by nitrogen atoms; b) an unsaturated 5 -membered carbocyclic aromatic ring; and c) an unsaturated 5 -membered carbocyclic aromatic ring in which either
• one carbon atom is replaced with an oxygen, nitrogen, or sulfur atom; 2) two carbon atoms are replaced with a sulfur and a nitrogen atom, an oxygen and a nitrogen atom, or two nitrogen atoms; or
• R 11 and R 12 are each independently selected from the group consisting of H and alkyl having from 1 to 4 carbons; or 2) R 11 and R 12 together form a linking group of the formula
• R 3 , R , R 5 and R 6 are each independently selected from the group consisting of : a) H, aryl, heteroaryl, F, Cl, Br, I, -CN, CF 3 ,
• each alkyl, alkenyl, or alkynyl group is unsubstituted; or
• each alkyl, alkenyl, or alkynyl group is substituted with 1 to 3 groups selected from the group consisting of aryl having from 6 to 10 carbons, heteroaryl, arylalkoxy, heterocycloalkoxy, hydroxyalkoxy, alkyloxy-alkoxy, hydroxyalkylthio, alkoxy- alkylthio, F, Cl , Br, I, -CN, -N0 2 , -OH, -OR 9 ,
• X 2 is 0, S, or NR 10 ;
• Y is selected from the group consisting of -0- , -S-,
• R 17 is selected from the group consisting of H, alkyl, aryl, and heteroaryl;
• a 1 and A 2 are selected from the group consisting of H,
• the compounds of the invention includes all diasteriomers and enantiomers around the carbon atoms to which the substituents R 2 , R 7 , and R 8 are attached.
• Preferred bridged indenopyrrolocarbazoles are represented by the following formula:
• the compounds of Formula II have diastereomers of formula:
• the compounds of Formula II have enantiomers of the formula:
• R 1 is H. In further preferred embodiments,
• R is H, hydroxyl, or substituted or unsubstituted alkyl
• R 3 , R 4 , R 5 , and R 6 are independently H, substituted or unsubstituted alkyl, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted amino, or substituted or unsubstituted aryl.
• R 7 and R 8 are independently H, or substituted or unsubstituted alkyl.
• Y is O.
• Z is a bond, 0, S, or substituted or unsubstituted N.
• m and n are independently 1 or 2.
• Y is O, Z is a bond or 0, and m and n are independently 1 or 2.
• compounds of Formula II have the formula:
• Some especially preferred embodiments of the compounds of Formula II are compounds II-l, Il-lb, II-2, II-3, II-4a, II-4b, II-5, II-6, II-7a, II-7b, II-8, II-9, 11-10, 11-11, 11-12, 11-13, II-14a, II-14b, 11-15, II-16a, and II-16b, the structures of which are set forth in Table 8, infra .
• the present invention provides pharmaceutical compositions comprising a compound of Formula I or Formula II and a pharmaceutically acceptable carrier.
• the composition is for inhibiting one or more of trk kinase activity, VEGFR kinase activity, or PDGFR activity wherein the composition comprises a compound of Formula I and a pharmaceutically acceptable carrier.
• the composition is for enhancing tropic factor or spinal chord ChAT activity wherein the composition comprises a compound of Formula I and a pharmaceutically acceptable carrier.
• the composition is for treating or preventing prostate disorders such as prostate cancer or benign prostate hyperplasia.
• the composition is for treating or preventing angiogenic disorders such as cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, ocular disorders or macular degeneration.
• the composition is for treating or preventing neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.
• the composition is for treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or injuries of the brain or spinal chord.
• the present invention provides a method for inhibiting trk kinase activity comprising providing a compound of Formula I in an amount sufficient to result in effective inhibition.
• the compound of Formula I is provided to treat inflammation.
• the trk kinase receptor is trk A.
• the present invention provides a method for treating or preventing prostate disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I.
• the prostate disorder is prostate cancer or benign prostate hyperplasia .
• the present invention provides a method for treating or preventing angiogenic disorders where VEGFR kinase activity contributes to pathological conditions comprising providing a compound of Formula I in an amount sufficient to result in the vascular endothelial growth factor receptor being contacted with an effective inhibitory amount of the compound.
• the present invention provides a method for treating or preventing angiogenic disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I.
• the angiogenic disorder is cancer of solid tumors, ocular disorders, macular degeneration, endometriosis, diabetic retinopathy, psoriasis, or hemangioblastoma .
• the present invention provides a method for treating or preventing disorders where PDGFR activity contributes to pathological conditions comprising providing a compound of Formula I in an amount sufficient to result in the platelet derived growth factor receptor being contacted with an effective inhibitory amount of the compound.
• the present invention provides a method for treating or preventing pathological disorders which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I .
• the pathological disorder is neoplasia, rheumatoid arthritis, pulmonary fibrosis, myelofibrosis, abnormal wound healing, atherosclerosis, or restenosis.
• the present invention provides a method for treating disorders characterized by the aberrant activity of trophic factor responsive cells comprising providing a compound of Formula I in an amount sufficient to result in the trophic factor cell receptor being contacted with an effective activity inducing amount of the compound.
• the activity of the trophic factor responsive cells is ChAT activity.
• the present invention provides a method for treating or preventing Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, stroke, ischaemia, Huntington's disease, AIDS dementia, epilepsy, multiple sclerosis, peripheral neuropathy, or injuries of the brain or spinal chord which comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of a compound of Formula I.
• the compounds of the present invention include all diastereomers and enantiomers.
• Compounds of Formula (I) are also referred to herein as Compound (I), and the same applies to the compounds of other formula numbers.
• Carbocyclic refers to cyclic groups in which the ring portion is composed solely of carbon atoms.
• heterocyclo and heterocyclic refer to cyclic groups in which the ring portion includes at least one heteroatom such as O, N, or S .
• alkyl means a straight- chain, cyclic, or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, neopentyl, 1-ethylpropyl , hexyl , octyl , cyclopropyl, and cyclopentyl .
• alkyl moiety of alkyl -containing groups such as alkoxy, alkoxycarbonyl , and alkylaminocarbonyl groups, has the same meaning as alkyl defined above.
• Lower alkyl groups which are preferred, are alkyl groups as defined above which contain 1 to 4 carbons.
• alkenyl is intended to include straight -chain or branched hydrocarbon chains having at least one carbon-carbon double bond. Examples of alkenyl groups include ethenyl and propenyl groups.
• alkynyl is intended to include straight-chain or branched hydrocarbon chains having at least one carbon- carbon triple bond. Examples of alkynyl groups include ethynyl and propynyl groups .
• acyl moiety of acyl-containing groups such as acyloxy groups is intended to include a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butyryl, valeryl, pivaloyl or hexanoyl .
• aryl means a group having 6 to 12 carbon atoms such as phenyl , biphenyl and naphthyl . Preferred aryl groups include unsubstituted or substituted phenyl and naphthyl groups.
• heteroaryl denotes an aryl group in which one or more ring carbon atom is replaced by a hetero (i.e., non-carbon) atom such as O, N or S .
• Preferred heteroaryl groups include pyridyl, pyrimidyl, pyrrolyl, furyl , thienyl, imidazolyl, triazolyl, tetrazolyl, quinolyl, isoquinolyl, benzoimidazolyl, thiazolyl, pyrazolyl, and benzothiazolyl groups .
• aralkyl (or “arylalkyl”) is intended to denotes a group having from 7 to 15 carbons, consisting of an alkyl group that bears an aryl group.
• aralkyl groups include benzyl, phenethyl, benzhydryl and naphthylmethyl groups.
• Alkyl groups and alkyl moieties contained within substituent groups such as aralkyl, alkoxy, arylalkoxy, hydroxyalkoxy, alkoxy-alkoxy, hydroxy-alkylthio, alkoxy-alkylthio, alkylcarbonyloxy, hydroxyalkyl and acyloxy groups may be substituted or unsubstituted.
• a substituted alkyl group has 1 to 3 independently-selected substituents, preferably hydroxy, lower alkoxy, lower alkoxy-alkoxy, substituted or unsubstituted arylalkoxy-lower alkoxy, substituted or unsubstituted heteroarylalkoxy-lower alkoxy, substituted or unsubstituted arylalkoxy, substituted or unsubstituted heterocycloalkoxy, halogen, carboxyl, lower alkoxycarbonyl , nitro, amino, mono- or di-lower alkylamino, dioxolane, dioxane, dithiolane, dithione, furan, lactone, or lactam.
• Substituted aryl, substituted heteroaryl and substituted aralkyl groups each have 1 to 3 independently- selected substituents that are preferably lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, nitro, amino, mono- or di-lower alkylamino, and halogen.
• Heterocyclic groups formed with a nitrogen atom include pyrrolidinyl , piperidinyl, piperidino, morpholinyl, morpholino, thiomorpholino, N-methylpiperazinyl, indolyl, isoindolyl, imidazole, imidazoline, oxazoline, oxazole, triazole, thiazoline, thiazole, pyrazole, pyrazolone, and triazole groups.
• Heterocyclic groups formed with an oxygen atom includes furan, tetrahydrofuran, pyran, and tetrahydropyran groups.
• Haldroxyalkyl groups are alkyl groups that have a hydroxyl group appended thereto. Halogens include fluorine, chlorine, bromine and iodine.
• heteroarylalkyl means an arylaklyl group that contains a heteroatom.
• oxy denotes the presence of an oxygen atom.
• alkoxy are alkyl groups that are attached through an oxygen atom
• carbonyloxy are carbonyl groups that are attached through an oxygen atom.
• heterocycloalkoxy means an alkoxy group that has a heterocyclo group attached to the alkyl moiety thereof
• arylalkoxy means an alkoxy group that has an aryl group attached to the alkyl moiety thereof.
• alkyloxy-alkoxy denotes an alkoxy group that contains an alkyloxy substituent attached to its alkyl moiety.
• alkoxy-alkylthio means an alkylthio group (i.e., a group of formula -S-alkyl) that contains an alkoxy substituent attached to its alkyl moiety.
• hydroxy-alkylthio means an alkylthio group (i.e., a group of formula -S-alkyl) that contains a hydroxy substituent attached to its alkyl moiety.
• amino acid denotes a molecule containing both an amino group and a carboxyl group.
• amino acids include -amino acids; i.e., carboxylic acids of general formula HOOC-CH (NH 2 ) - (side chain) .
• Side chains of amino acids include naturally occurring and non-naturally occurring moieties.
• Non-naturally occurring (i.e., unnatural) amino acid side chains are moieties that are used in place of naturally occurring amino acid side chains in, for example, amino acid analogs. See, for example, Lehninger, Biochemistry, Second Edition, Worth
• Preferred ⁇ -amino acids include glycine, alanine, proline, glutamic acid, and lysine, having the D configuration, the L configuration, or as a racemate.
• Functional groups present on the compounds of Formula I may contain protecting groups.
• the amino acid sidechain substituents of the compounds of Formula I can be substituted with protecting groups such as benzyloxycarbonyl or t-butoxycarbonyl groups.
• protecting groups are known per se as chemical functional groups that can be selectively appended to and removed from functionalities, such as hydroxyl groups and carboxyl groups. These groups are present in a chemical compound to render such functionality inert to chemical reaction conditions to which the compound is exposed. Any of a variety of protecting groups may be employed with the present invention.
• One such protecting group is the benzyloxycarbonyl (Cbz; Z) group.
• Other preferred protecting groups according to the invention may be found in Greene, T.W. and Wuts, P.G.M., "Protective Groups in Organic
• effect when used to modify the terms "function” and “survival” means a positive or negative alteration or change.
• An effect which is positive can be referred to herein as an “enhancement” or “enhancing” and an effect which is negative can be referred to herein as “inhibition” or “inhibiting.”
• the terms “enhance” or “enhancing” when used to modify the terms “function” or “survival” means that the presence of a bridged indenopyrrolocarbazole compound has a positive effect on the function and/or survival of a trophic factor responsive cell compared with a cell in the absence of the compound.
• the compound would evidence enhancement of survival of a cholinergic neuronal population at risk of dying (due to, e.g., injury, a disease condition, a degenerative condition or natural progression) when compared to a cholinergic neuronal population not presented with such compound, if the treated population has a comparatively greater period of functionality than the non- treated population.
• inhibitor and “inhibition” mean that a specified response of a designated material (e.g., enzymatic activity) is comparatively decreased in the presence of a bridged indenopyrrolocarbazole compound.
• trk refers to the family of high affinity neurotrophin receptors presently comprising trk A, trk B, and trk C, and other membrane associated proteins to which a neurotrophin can bind.
• inhibition of VEGFR implies utility in, for example, diseases where angiogenesis plays important roles, such as cancer of solid tumors, endometriosis, diabetic retinopathy, psoriasis, hemangioblastoma, as well as other ocular diseases and cancers.
• Inhibition of trk implies utility in, for example, diseases of the prostate such as prostate cancer and benign prostate hyperplasia, and treatment of inflammatory pain.
• PDGFR Platelet Derived Growth Factor Receptor
• cancer and “cancerous” refer to any malignant proliferation of cells in a mammal.
• examples include prostate, benign prostate hyperplasia, ovarian, breast, brain, lung, pancreatic, colorectal, gastric, stomach, solid tumors, head and neck, neuroblastoma, renal cell carcinoma, lymphoma, leukemia, other recognized malignancies of the hematopoietic systems, and other recognized cancers.
• neuronal lineage and “neuronal cell” include, but are not limited to, a heterogeneous population of neuronal types having singular or multiple transmitters and/or singular or multiple functions; preferably, these are cholinergic and sensory neurons.
• cholinergic neuron means neurons of the Central Nervous System (CNS) and Peripheral Nervous System (PNS) whose neurotransmitter is acetylcholine; exemplary are basal forebrain, striatal, and spinal cord neurons.
• sensory neuron includes neurons responsive to environmental cues (e.g., temperature, movement) from, e.g., skin, muscle and joints; exemplary is a neuron from the dorsal root ganglion.
• a “trophic factor-responsive cell,” as defined herein, is a cell which includes a receptor to which a trophic factor can specifically bind; examples include neurons
• non-neuronal cells e.g., monocytes and neoplastic cells
• the bridged indenopyrrolocarbazole compounds described herein find utility in both research and therapeutic settings in, for example, inhibition of enzymatic activity.
• the compounds can be used in the development of assays and models for further enhancement of the understanding of the roles that inhibition of serine/threonine or tyrosine protein kinase (e.g., PKC, trk tyrosine kinase) play in the mechanistic aspects of the associated disorders and diseases.
• the compounds which inhibit these enzymatic activities can be used to inhibit the deleterious consequences of these enzymes with respect to disorders such as cancer.
• VEGFR Vascular Endothelial Growth Factor Receptor
• PKC Activity inhibition assay 4. PDGFR inhibition assay.
• the disclosed bridged indenopyrrolocarbazole compounds can be used to enhance the function and/or survival of cells of neuronal lineage in a mammal, e.g., a human.
• the compounds can be utilized individually or with other fused pyrrolocarbazoles and/or indolocarbazoles, or in combination with other beneficial molecules which also evidence the ability to effect the function and/or survival of a designated cell.
• a variety of neurological disorders are characterized by neuronal cells which are dying, injured, functionally compromised, undergoing axonal degeneration, at risk of dying, etc.. These disorders include, but are not limited to: Alzheimer's disease; motor neuron disorders (e.g. amyotrophic lateral sclerosis); Parkinson's disease; cerebrovascular disorders (e.g., stroke, ischaemia); Huntington's disease; AIDS dementia; epilepsy; multiple sclerosis; peripheral neuropathies (e.g., those affecting DRG neurons in chemotherapy-associated peripheral neuropathy) including diabetic neuropathy; disorders induced by excitatory amino acids; and disorders associated with concussive or penetrating injuries of the brain or spinal cord.
• motor neuron disorders e.g. amyotrophic lateral sclerosis
• Parkinson's disease cerebrovascular disorders (e.g., stroke, ischaemia); Huntington's disease
• AIDS dementia epilepsy
• peripheral neuropathies e.g., those affecting DRG neurons in chemotherapy-
• ChAT catalyzes the synthesis of the neurotransmitter acetylcholine, and it is considered an enzymatic marker for a functional cholinergic neuron.
• a functional neuron is also capable of survival. Neuron survival is assayed by quantitation of the specific uptake and enzymatic conversion of a dye (e.g., calcein AM) by living neurons.
• a dye e.g., calcein AM
• the bridged indenopyrrolocarbazole compounds disclosed herein find utility in a variety of settings.
• the compounds can be used in the development of in vi tro models of neuronal cell survival, function, identification, or for the screening of other synthetic compounds which have activities similar to that of the bridged indenopyrrolocarbazole compounds .
• the compounds can be utilized in a research environment to investigate, define and determine molecular targets associated with functional responses. For example, by radiolabelling a bridged indenopyrrolocarbazole compound associated with a specific cellular function (e.g., mitogenesis) , the target entity to which the derivative binds can be identified, isolated, and purified for characterization.
• a specific cellular function e.g., mitogenesis
• the compounds are useful, inter alia, not only for enhancing trophic factor-induced activities of trophic responsive cells, e.g., cholinergic neurons, but also may function as survival promoting agents for other neuronal cell types, e.g., dopaminergic or glutamatergic .
• Growth factor may regulate survival of neurons by signaling cascades downstream of the small GTP binding proteins ras, rac, and cdc42 (Denhardt, D.T., Biochem. J. , 1996, 318, 729) .
• ras small GTP binding proteins
• rac small GTP binding proteins
• cdc42 e.g., cdc42
• activation of ras leads to phosphorylation and activation of extracellular receptor- activated kinase (ERK) , which has been linked to biological growth and differentiation processes.
• ERK extracellular receptor- activated kinase
• Stimulation of rac/cdc42 leads to an increase in activation of JNK and p38, responses that are associated with stress, apoptosis, and inflammation.
• growth factor responses are primarily via the ERK pathway, affecting these latter processes may lead to alternative mechanisms of neuronal survival which may mimic growth factor enhancing survival properties (Xia et al . , Science, 1995, 270, 1326).
• the compounds may also function as survival promoting agents for neuronal and non-neuronal cells by mechanisms related to, but also distinct from, growth factor mediated survival, for example, inhibition of the JNK and p38 MAPK pathways which may lead to survival by inhibition of apoptotic cell death processes.
• the present compounds are useful in the treatment of disorders associated with decreased ChAT activity or the death, injury to spinal cord motoneurons, and also have utility in, for example, diseases associated with apoptotic cell death of the central and peripheral nervous system, immune system and in inflammatory diseases.
• bridged indenopyrrolocarbazole compounds described herein may also find utility in the treatment of disease states involving malignant cell proliferation, such as many cancers .
• the pharmaceutically acceptable salts of Compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, and amino acid addition salts.
• the acid addition salts are inorganic acid addition salts such as hydrochloride, sulfate and phosphate, and organic acid addition salts such as acetate, maleate, fumarate, tartrate, citrate and lactate;
• the metal salts are alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc salt;
• examples of the ammonium salts are ammonium salt and tetramethylammonium salt;
• examples of the organic amine addition salts are salts with morpholine and piperidine; and examples of the amino acid addition salts are salts with glycine, phenylalanine, glutamic acid and lysine.
• compositions can be formulated into pharmaceutical compositions by admixture with pharmaceutically acceptable nontoxic excipients and carriers.
• Such compositions can be prepared for use in parenteral administration, particularly in the form of liquid solutions or suspensions; or oral administration, particularly in the form of tablets or capsules; or intranasally, particularly in the form of powders, nasal drops, or aerosols; or dermally, via, for example, trans- dermal patches.
• the composition can be conveniently administered in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art, for example, as described in Remington ' s Pharmaceutical Sciences (Mack Pub.
• Formulations for parenteral administration may contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like.
• polyalkylene glycols such as polyethylene glycol, oils and vegetable origin, hydrogenated naphthalenes and the like.
• biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene-polyoxypropylene copolymers may be useful excipients to control the release of the active compounds.
• Other potentially useful parenteral delivery systems for these active compounds include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
• Formulations for inhalation administration contain as excipients, for example, lactose, or may be aqueous solutions containing, for example, polyoxyethylene- 9 -lauryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
• Formulations for parenteral administration may also include glycocholate for buccal administration, a salicylate for rectal administration, or citric acid for vaginal administration.
• Formulations for trans-dermal patches are preferably lipophilic emulsions.
• the compounds of this invention can be employed as the sole active agent in a pharmaceutical composition.
• Compound of Formula I and pharmaceutically acceptable salts thereof can be administered orally or non-orally, e.g., as an ointment or an injection.
• concentrations of the compounds of this invention in a therapeutic composition can vary. The concentration will depend upon factors such as the total dosage of the drug to be administered, the chemical characteristics (e.g., hydrophobicity) of the compounds employed, the route of administration, the age, body weight and symptoms of a patient, etc..
• the compounds of this invention typically are provided in an aqueous physiological buffer solution containing about 0.1 to 10% w/v compound for parenteral administration.
• Typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day; a preferred dose range is from about 0.01 mg/kg to 100 mg/kg of body weight per day, and preferably about 0.1 to 20 mg/kg once to four times per day.
• a preferred dosage of drug to be administered is likely to depend on variables such as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, and formulation of the compound excipient, and its route of administration.
• Compounds of Formula I and pharmaceutically acceptable salts thereof can be administered alone, or in the form of various pharmaceutical compositions, according to the pharmacological activity and the purpose of administration.
• compositions in accordance with the present invention can be prepared by uniformly mixing an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, as an active ingredient, with a pharmaceutically acceptable carrier.
• the carrier may take a wide range of forms according to the forms of composition suitable for administration. It is desired that such pharmaceutical compositions are prepared in a unit dose form suitable for oral or non-oral administration.
• the forms for non-oral administration include ointment and injection.
• Tablets can be prepared using excipients such as lactose, glucose, sucrose, mannitol and methyl cellulose, disintegrating agents such as starch, sodium alginate, calcium carboxymethyl cellulose and crystalline cellulose, lubricants such as magnesium stearate and talc, binders such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose and methyl cellulose, surfactants such as sucrose fatty acid ester and sorbitol fatty acid ester, and the like in a conventional manner. It is preferred that each tablet contains 15-300 mg of the active ingredient.
• disintegrating agents such as starch, sodium alginate, calcium carboxymethyl cellulose and crystalline cellulose
• lubricants such as magnesium stearate and talc
• binders such as gelatin, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl cellulose and methyl cellulose
• surfactants such as sucrose fatty
• Granules can be prepared using excipients such as lactose and sucrose, disintegrating agents such as starch, binders such as gelatin, and the like in a conventional manner. Powders can be prepared using excipients such as lactose and mannitol, and the like in a conventional manner.
• Capsules can be prepared using gelatin, water, sucrose, gum arabic, sorbitol, glycerin, crystalline cellulose, magnesium stearate, talc, and the like in a conventional manner. It is preferred that each capsule contains 15-300 mg of the active ingredient.
• Syrup preparations can be prepared using sugars such as sucrose, water, ethanol, and the like in a conventional manner .
• Ointment can be prepared using ointment bases such as vaseline, liquid paraffin, lanolin and macrogol, emulsifiers such as sodium lauryl lactate, benzalkonium chloride, sorbitan mono-fatty acid ester, sodium carboxymethyl cellulose and gum arabic, and the like in a conventional manner .
• ointment bases such as vaseline, liquid paraffin, lanolin and macrogol
• emulsifiers such as sodium lauryl lactate, benzalkonium chloride, sorbitan mono-fatty acid ester, sodium carboxymethyl cellulose and gum arabic, and the like in a conventional manner .
• Injectable preparations can be prepared using solvents such as water, physiological saline, vegetable oils (e.g., olive oil and peanut oil) , ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate and urethane, isotonicity agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoic ester and chlorobutanol , antioxidants such as ascorbic acid and sodium pyrosulfite, and the like in a conventional manner.
• solvents such as water, physiological saline, vegetable oils (e.g., olive oil and peanut oil) , ethyl oleate and propylene glycol, solubilizing agents such as sodium benzoate, sodium salicylate and urethane, isotonicity agents such as sodium chloride and glucose, preservatives such as phenol, cresol, p-hydroxybenzoic ester and chlorobutan
• NGF-stimulated phosphorylation of trk by selected bridged indenopyrrolocarbazole compounds was performed using a modified procedure, as described below, from that previously described (see US Patent No. 5,516,771) .
• NIH3T3 cells transfected with trkA were grown in 100 mm dishes. Subconfluent cells were serum-starved by replacing media with serum-free 0.05% BSA-DMEM containing compound (100 nM and 1 ⁇ M) or DMSO (added to controls) for one hour at 37°C. NGF (Harlan/Bioproducts for Science) was then added to the cells at a concentration of 10 ng/ml for 5 minutes.
• Cells were lysed in buffer containing detergent and protease inhibitors. Clarified cell lysates were normalized to protein using BCA method and immunoprecipitated with anti-trk antibody. Polyclonal anti- trk antibody was prepared against a peptide corresponding to the 14 amino acids at the carboxy terminus of trk (Martin- Zanca et al . , Mol . Cell . Biol . 9: 24-33, 1989). The immune complexes were collected on Protein A Sepharose beads (Sigma
• Bridged indenopyrrolocarbazole compounds were examined for their inhibitory effects on the kinase activity of baculovirus-expressed VEGF receptor (human flk-1, KDR, VEGFR2) kinase domain using the procedure described for the trkA kinase ELISA assay described above.
• the kinase reaction mixture consisting of 50 mM Hepes, pH 7.4, 40 ⁇ M ATP, 10 mM MnCl 2 , 0.1% BSA, 2% DMSO, and various concentrations of inhibitor, was transferred to PLC- ⁇ /GST- coated plates. VEGFR kinase was added and the reaction was allowed to proceed for 15 min. at 37°C.
• Detection of phosphorylated product was accomplished by addition of anti- phosphotyrosine antibody (UBI) .
• UBI anti- phosphotyrosine antibody
• a secondary enzyme- conjugated antibody was delivered to capture the antibody- phosphorylated PLC- ⁇ /GST complex.
• the activity of the bound enzyme was measured via an amplified detection system
• Assays were performed in 96-well Multiscreen-DP plates (Millipore) . Each 40-ml assay mixture contained 20 mM Hepes, pH 7.4 , 10 mM MgCl 2 , 2.5 mM EGTA, 2.5 mM CaCl 2 , 80 mg/ml phosphatidyl serine, 3.2 mg/ml diolein, 200 mg/ml histone H-1 (Fluka), 5 mM [ ⁇ - 32 P]ATP, 1.5 ng protein kinase C (UBI; mixed isozymes of a, b, g) , 0.1% BSA, 2% DMSO, and test bridged fused pyrrolocarbazole compound.
• UBI protein kinase C
• Activity Bridged indenopyrrolocarbazole compounds were examined for their inhibitory effects on the kinase activity of baculovirus-expresses PDGF ⁇ receptor kinase domain using the trkA kinase ELISA described above. Assays were performed in substrate (PLC- ⁇ /GST) -coated 96-well microtiter plates. Each 100- ⁇ l reaction mixture contained 50 mM HEPES, pH 7.4, 20 ⁇ M ATP, 10 mM MnCl 2 , 0.1% BSA, 2% DMSO, and various concentrations of inhibitor.
• the reaction was initiated by addition of prephosphorylated recombinant human enzyme (10 ng/ml PDGFR ⁇ ) and allowed to proceed for 15 minutes at 37°C.
• the prephosphorylated enzyme was prepared prior to use by incubation of the kinase in buffer containing 20 ⁇ M ATP and 10 mM MnCl 2 for 1 hour at 4°C.
• Detection of phosphorylated product was done by adding horseradish peroxidase (HRP) - conjugated anti-phosphotyrosine antibody (UBI) .
• HRP substrate solution containing 3, 3 '-5, 5 ' -tetramethylbenzidine and hydrogen peroxide was later added and the plates were incubated for 10 minutes at room temperature.
• ChAT is a specific biochemical marker for functional cholinergic neurons. Cholinergic neurons represent a major cholinergic input into the hippocampal formation, olfactory nucleus, interpeduncular nucleus, cortex, amygdala, and parts of the thalamus . In the spinal cord, the motor neurons are cholinergic neurons which contain ChAT (Phelps et al . , J. Comp . Neurol . 273:459- 472 (1988)) . ChAT activity has been used to study the effects of neurotrophins (e.g., 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 within cholinergic neurons. Bridged indenopyrrolocarbazole compounds increased
• ChAT activity in the dissociated rat embryonic spinal cord culture assay (Table 7) .
• a compound was directly added to a dissociated spinal cord culture.
• Compounds which increased ChAT activity at least 120% of the control activity were considered active. Results are summarized in Table 7.
• Fetal rat spinal cord cells were dissociated, and experiments were performed as described (Smith et al . , J. Cell Biology 101:1608-1621 (1985); Glicksman et al . , J " .
• Dissociated cells were prepared from spinal cords dissected from rats (embryonic day 14-15) by standard trypsin dissociation techniques (Smith et al . , supra . ) . Cells were plated at 6 x 10 5 cells/cm ⁇ on poly-1-ornithine coated plastic tissue culture wells in serum-free N2 medium supplemented with 0.05% bovine serum albumin (BSA) (Bottenstein et al . , PNAS USA 76:514-517
• BSA bovine serum albumin
• Figures 3 and 4 can be carried out by either an acid or a base-catalyzed process.
• the acid-catalyzed reaction can be carried out with a resin-bound reagent allowing immobilization of the indenopyrrolocarbazole (III) /(VIII) to a polymeric support, such as a polystyrene-based, Rink acid resin (XII) ( Figure 3), providing (XIII).
• the acid-catalyzed reaction can be carried out with a soluble reagent to yield a compound (XIV) ( Figure 4) .
• the silyl-protected compound (XV) is produced under base catalysis ( Figure 4) .
• Figure 5 describes several methods for preparing intermediate (V) .
• reduction of nitrile-acetal (XVI, D CN) with
• Reaction of compound (XXIV) with acetal/ketal (XVIII) gives (XXV) which is transformed to keto-acetal/ketal (XVII) by the methods described in Procedure (a) .
• R 3 , R , R 5 and R 6 can be carried out as described in US Patents Nos. 5,705,511 and 4,923,986, the disclosures of which are incorporated by reference in their entirety.
• An R 3 substituent can otherwise be introduced after the construction of the bridged indenopyrrolocarbazoles, as shown in Figure 8.
• the 3 position of the B ring is brominated with NBS providing compound (XXXI) .
• a carbon fragment is subsequently introduced by employing palladium-catalyzed Stille, Suzuki, Heck, Kumada or Castro-Stephens reactions to provide compounds of the type (XXXII), (XXXIII), etc.
• compound (XXXI) can provide access to compounds where the bromine group is displaced with a heteroatom, e.g. an amine- based group by utilization of Buchwald's palladium catalyzed amination chemistry.
• an oxygen linked group can be introduced at the indene carbon of the E ring, as shown in Figure 9, compound (XXXIV) .
• This chemistry also results in oxidation of the methylene group of the lactam (A ring) providing an imide derivative, as shown.
• Rink acid resin XII (10.00 g, 0.64 mmol/g)
• 1-methyl-2 -pyrolidinone 80 mL
• benzene 350 mL
• the resin was washed with THF (5 x 175 mL) and the filtrate set aside. The resin was then sequentially washed with DMSO (4 x 100 mL) , 2% aqueous NaHC0 3 (4 x 100 mL) , water (4 x 100 mL) , DMSO (2 x 200 mL) , THF (4 x 100 mL) and ethyl acetate (4 x 100 mL) . The resin was dried under vacuum (24 hours) to afford 11.70 (0.47 mmol/g) of resin bound VIII-A (XIII-A).
• the reaction was quenched with 10% aqueous NH 4 C1 (5 mL) and filtered.
• the resin was successively washed with 10% aqueous NH 4 C1 (3 x 10 mL) , water (3 x 10 mL) , THF (3 x 10 mL) , DMF (3 x 10 mL) , water (3 x 10 mL) , THF (3 x 10 mL) , and ether (3 x 10 mL) .
• the resin was dried under vacuum, taken up in methylene chloride (15 mL) , and treated with trifluoroacetic acid (0.15 mL) . After stirring for 1 hour, the reaction was filtered, and the filtrate was evaporated.
• a solution of Triton B in pyridine (0.45 M) was prepared by dissolving a 40% solution of Triton B in methanol (10 mL) in pyridine (10 mL) . Solvent was removed under reduced pressure (20 mm Hg) to a final volume of ⁇ 8 mL. The residue was diluted with pyridine to 50 mL, filtered and stored under nitrogen. A solution of XV (20.3 mg) in pyridine (2.0 mL) was flushed with argon and treated with 300 ⁇ L of Triton B (0.45 M in pyridine) and diethoxybutyraldehyde (50 ⁇ L) .
• the TBDPS-protected Il-la was dissolved in minimum amounts of (1:4, v/v) CHCl 3 : EtOH and 500 ⁇ L portions were injected on to a CHIRACEL OD column (1cm ID x 25 cm) and
• a 250 mL sealable tube was charged with the DMB protected 3-bromo compound (1.5 g, 2.4 mmol), bis (triphenylphosphinyl) palladium dichloride (100 mg, 0.14 mmol), anhydrous sodium acetate (3.9 g, 4.8 mmol), and methoxyethanol (50 mL) .
• the tube was alternately evacuated and filled with CO, leaving it under an atmosphere of CO. It was then lowered into an oil bath at 150°C. After 4 hours the tube was cooled to room temperature and recharged with CO. This was repeated once more with the reaction going a total of 10 hours.
• reaction mixture was cooled to room temperature, diluted with EtOAc (200 mL) , washed with saturated aqueous NaHC03 solution (4 x 100 mL) , water (4 x 100 mL) , and the organic layer was dried over anhydrous MgS04 , filtered and concentrated in-vacuo.

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