Hydrazone derivatives, their preparation and use

Abstract: A method of treatment with compounds having the formula wherein n is 0 or 1; R¹ is hydrogen, C₁₋₆-alkyl which may be branched, C₃₋₇-cycloalkyl, benzyl, phenyl which may be substituted, acyl, hydroxy, C₁₋₆-alkoxy, CH₂CO₂R' wherein R' is hydrogen or C₁₋₆-alkyl which may be branched, CH₂CN, CH₂CONR IV R V wherein R IV and R V independently are hydrogen or C₁₋₆-alkyl, or CH₂C(=NOH)NH₂; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵, R⁶, R⁷ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; or R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl, and R⁴ and R⁵ have the meanings set forth above; or R⁴ and R⁵ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl, and R⁶ and R⁷ have the meanings set forth above. Certain of the compounds are novel. The compounds and pharmaceutical compositions containing the compounds are useful in the treatment of central nervous system disorders and especially conditions sensitive to excitatory amino acids.

Description: The present invention relates to compounds having excitatory amino acid antagonizing properties, pharmaceutical compositions comprising such compounds, and to the preparation of such compounds. Object of the Invention It is an object of the present invention to provide novel isatine hydrazone compounds. Another object of the present invention is to provide novel pharmaceutical compositions for the treatment of disorders in mammals, including a human, responsive to the blockade of glutamic and aspartic acid receptors. Background of the Invention Excessive excitation by neurotransmitters can cause the degeneration and death of neurons. It is believed that this degeneration is in part mediated by the excitotoxic actions of the excitatory amino acids (EAA) glutamate and aspartate at the N-methyl-D-aspartate (NMDA), the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, and the kainate receptor. This excitotoxic action is responsible for the loss of neurons in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, a cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer's, and Huntington's diseases. The compounds of the present invention may also be useful in the treatment of schizophrenia, parkinsonism, epilepsy, anxiety, pain and drug addiction. S. Agarwal et al. (Indian Drugs, 22 , 633-639, 1985) describe that certain 1- substituted 3-(N-phenylsulphonyl-hydrazone)-5 substituted isatines are psychotropics (CNS depressant and stimulants). Some of the compounds were found to exhibit CVS and anti-inflammatory activity. S. Swarup et al. (Indian Drugs, 27 , 563-567,(1990) disclose that certain 1-hydrogen-3-hydrazone derivatives of isatines are useful as intermediates of other compounds having pharmacological properties, such as CNS, CVS, antiinflammatory, and MAO inhibitory activity. The intermediates have the general formula and the pharmacological active intermediates have the formula D. Popp (Journal of Heterocyclic Chemistry, 21 , 1641-1645 1984) discloses that compounds having the formula wherein R is phenyl, 2-pyridyl, 4-tolylsulphonyl, and 2-nitrophenyl respectively have very weak or no anticonvulsant activity. Summary of the Invention The invention then, inter alia , comprises the following, alone or in combination: The use of an indole-2,3-dione-3-hydrazone compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl, for the preparation of a medicament for the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic receptors, a pharmaceutical composition for use in the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors, comprising an effective glutamic or aspartic acid receptor blocking amount of a compound having the formula wherein n is 0 or 1; R¹ is hydrogen, R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring, a compound having the formula wherein n is 0 or 1; R¹ is hydrogen, R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring, a compound as above wherein the additional ring formed by R⁶ and R⁷ is substituted with halogen, NO₂, CF₃, CN or SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl, a compound as above, which is 5-nitro-1H-6,7,8,9-tetrahydrobenz[g]indole-2,3-dione-3-phenylsulphonylhydrazone, a compound as above, which is 5-nitro-1H-6,7,8,9-tetrahydrobenz[g]indole-2,3-dione-3-(2-pyridylhydrazone), a method of preparing a compound having the formula wherein n is 0 or 1; R¹ is hydrogen, R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring, comprising the step of reacting a compound of the formula wherein R¹, R⁴, R⁵, R⁶ and R⁷ have the meanings set forth above, with a compound having the formula H₂N-NH-(SO₂) n R², wherein R² and n have the meanings set forth above, a method of preparing a pharmaceutical preparation comprising mixing as active ingredient an effective amount of a compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together from an additional unsubstituted benzo ring. with at least one pharmaceutical acceptable carrier and/or diluent. Biological Activity The compounds of the invention exhibit valuable biological properties because of their strong excitatory amino acid (EAA) (glycine, glutamate, quisqualate, ATPA (α-amino-3-hydroxy-5-t-butylisoxazole-4-propionic acid), AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid), kainate, NMDA (N-methyl-D-aspartate)) antagonizing properties. Compounds of the invention show potent affinity for the glutamate subreceptor binding sites for kainate, NMDA, quisqualate and glycine. These properties make the compounds useful in the treatment of human malfunctions related to the excitatory amino acids (EAA). Compounds of the invention exhibit binding at the ³H-kainate, NMDA, ³H-AMPA and/or ³H-glycine binding sites with IC₅₀ in the range of 1-100 µM. Examples of such compounds are for example Z,E-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-phenylhydrazone, Z,E-1H-5-nitro-benz[g]indole-2,3-dione-3-phenylhydrazone, E-5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-(2-nitrophenylhydrazone), 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-phenylsulphonehydrazide. 5,9-dinitro-1H-benz[g]indole-2,3-dione-3-phenylsulphonehydrazide. The quisqualate binding assay was performed as described by T. Honoré et al., Neuroscience Letters 54 , 27-32 (1985). The kainate binding assay was performed as described by T. Honoré et al., Neuroscience Letters 65 , 47-52 (1986). The glycine binding assay was performed as described by W. Frost White et al., Journal of Neurochemistry 53(2) , 503-512 (1989). Pharmaceutical Compositions The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use. Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. Tablets containing ten (10) milligrams of active ingredients or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms. Method of Treating The compounds of this invention are extremely useful in the treatment of central nervous system disorders related to their biological activity. The compounds of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of an indication associated with the biological activity of the compounds. This includes especially excitatory amino acid dependent psychosis, excitatory amino acid dependent anoxia, excitatory amino acid dependent ischemia, excitatory amino acid dependent convulsions and excitatory amino acid dependent migraine. Suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge. Chemical Examples The compounds of the invention may be prepared according to chemical methods which are well known for a person skilled in the art. Example 1 a) 1H-benz[g]indole-2,3-dione , M.p. 242-245°C, and 1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione, M.p. 224-226°C were prepared according to known literature procedures. b) 1-methyl-5-nitro-7-trifluoromethyl-1H-indole-2,3-dione. To a stirred 10°C warm solution of KNO₃ (0.5 g) in 10 ml of conc. H₂SO₄ was dropwise added a solution of 1-methyl-7-trifluoromethyl-1H-indole-2,3-dione in 10 ml of conc. H₂SO₄. The addition was completed after 10 min, whereafter stirring was continued for 15 min at room temperature. The reaction mixture was poured on ice whereby the title compound precipitated as yellow crystals. The crystals were collected by filtration and washed with water. M.p. 168-169°C. In a similar manner to b), the following nitro compounds were prepared: 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione, M.p. 232-236°C. 5-nitro-1-methyl-1H-benz[g]indole-2,3-dione, M.p. 255-258°C. c) 5-dimethylsulfamoyl-1H-indole-2,3-dione. 10 g (68 mmol) isatin was added to 30 ml of chlorosulfonic acid at 30°C for 30 minutes and was thereafter poured dropwise onto ice. A crude material was obtained (14.5 g). 7 g of this crude material was added to dimethylamine in water and ethyl acetate. This reaction mixture was stirred at RT for 1 hour and the organic phase was evaporated to yield and oil which was stirred with 1N hydrochloric acid in hot ethyl acetate. This mixture was extracted with ethyl acetate, which was evaporated in vacuo . The residue was recrystallized from ethanol. Yield of the title compound 550 mg, M.p. 265-266°C. In a similar manner the following compounds were prepared: 5-sulfamoyl-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione, M.p. >350°C. Example 2 E-5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-(2-nitrophenylhydrazone) 0.5 g (2 mmol) of 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione, 0.34 g (2.2 mmol) 2-nitrophenylhydrazin and 2 drops of 1N HCl were dissolved in 15 ml of methanol and the mixture was stirred at room temperature for 30 minutes. The precipitate was isolated by filtration. The crude reaction product consisted of a mixture of the two isomers (Z and E forms) of the title compound. The title compound was obtained by washing the crude reaction product with tetrahydrofuran (THF) due to different solubility of the E and Z isomer in THF. Yield 350 mg of the title compound. M.p. >350°C. In similar way the following compounds were prepared from the appropriate isatine and hydrazine or sulphonehydrazide compounds. The Z and E isomers were obtained by utilizing their different solubility in THF. Furthermore an E isomer may be transformed into a Z isomer by heating in THF. Z,E-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-phenylhydrazone, M.p. 288-290°C. Z/E-5-nitro-1H-benz[g]indole-2,3-dione-3-phenylhydrazone, M.p. 294-295°C. 5,9-dinitro-1H-benz[g]indole-2,3-dione-3-phenylsulphonylhydrazone, M.p. 144-146°C. 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-phenylsulphonylhydrazone, M.p. 173-175°C. 5-nitro-1H-benz[g]indole-2,3-dione-3-phenylsulphonylhydrazone, M.p. 195-198°C. Example 3 The following compounds as E, Z or E/Z isomers are prepared according to the same procedure as given in example 2 by combinations of different isatine derivatives and hydrazines. 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-(2-pyridylhydrazone), 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2,3-dione-3-(4-fluorophenylhydrazone), It is thus seen that the present invention provides a new and convenient process for the production of indole-2,3-dione-3-hydrazone compounds, certain novel indole-2,3-dione-3-hydrazone compounds which are useful as excitatory amino acid antagonists, pharmaceutical-compositions useful as excitatory amino acid antagonists comprising certain indole-2,3-dione-3-hydrazone compounds, and a method of antagonizing the biological effects of excitatory amino acids in a subject in need thereof comprising the step of administering certain indole-2,3-dione-3-hydrazone compounds or a pharmaceutical composition comprising the same together with a pharmaceutically-acceptable diluent or carrier, all having the foregoing characteristics and advantages. It is to be understood that the invention is not to be limited to the exact details of operation, or to the exact methods, procedures, or embodiments shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the full scope of the appended claims.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, MC, NL, PT, SE A compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃. CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring. A compound of Claim 1, which is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulponylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3 -(2-pyridylhydrazone). A method of preparing a compound according to claim 1 comprising the step of reacting a compound of the formula wherein R¹, R⁴, R⁵, R⁶, and R⁷ have the meanings set forth in claim 1, with a compound having the formula H₂N-NH-(SO₂) n R², wherein R² and n have the meanings set forth in claim 1. A pharmaceutical composition for use in the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors, comprising an effective glutamic or aspartic acid receptor blocking amount of a compound according to claim 1 and at least one pharmaceutical acceptable carrier and/or diluent. A method of preparing a pharmaceutical composition comprising mixing as active ingredient an effective amount of a compound according to claim 1 with at least one pharmaceutical acceptable carrier and/or diluent. The use of an indole-2,3-dione-3-hydrazone compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₃, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂R¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; for the preparation of a medicament for the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors. The use according to claim 6 wherein the compound employed is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulphonylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3-2-pyridylhydrazone). Claims for the following Contracting State : ES A method of preparing a compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF 3. CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring comprising the step of reacting a compound of the formula wherein R¹, R⁴, R⁵, R⁶, and R⁷ have the meanings set forth above, with a compound having the formula H₂N-NH-(SO₂) n R², wherein R² and n have the meanings set forth above. The method of Claim 1, wherein the compound is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulphonylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3 -(2-pyridylhydrazone). A method of preparing a pharmaceutical composition comprising mixing as active ingredient an effective amount of a compound as prepared by the method according to claim 1 with at least one pharmaceutical acceptable carrier and/or diluent. The method of claim 3, wherein the pharmaceutical composition is for use in the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors. A method of preparing a medicament for the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors comprising mixing an indole-2,3-dione-3-hydrazone compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₃, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂R¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and at least one pharmaceutical acceptable carrier and/or diluent. The method according to claim 5 wherein the compound employed is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulphonylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3-2-pyridylhydrazone). Claims for the following Contracting State : GR A compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₂, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂NR¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF 3. CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R¹, R⁴ and R⁵ are not all hydrogen when R² is unsubstituted phenyl and R⁶ and R⁷ together form an additional unsubstituted benzo ring. A compound of Claim 1, which is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulphonylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3 -(2-pyridylhydrazone). A method of preparing a compound according to claim 1 comprising the step of reacting a compound of the formula wherein R¹, R⁴, R⁵, R⁶, and R⁷ have the meanings set forth in claim 1, with a compound having the formula H₂N-NH-(SO₂) n R², wherein R² and n have the meanings set forth in claim 1. A method of preparing a pharmaceutical composition comprising mixing as active ingredient an effective amount of a compound according to claim 1 with at least one pharmaceutical acceptable carrier and/or diluent. The method of claim 4, wherein the pharmaceutical composition is for use in the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors. The use of an indole-2,3-dione-3-hydrazone compound having the formula wherein n is 0 or 1; R¹ is hydrogen; R² is pyridyl or phenyl, both of which may be substituted one or more times preferably in the ortho and para positions with halogen, CF₃, NO₃, CN, phenyl, or SO₂NR''R''' wherein R'' and R''' independently are hydrogen, benzyl, or C₁₋₆-alkyl; R⁴, R⁵ independently are hydrogen, C₁₋₆-alkyl which may be branched, phenyl, halogen, C₁₋₆-alkoxy, NO₂, CN, CF₃, or SO₂R¹¹R¹² wherein R¹¹ and R¹² independently are hydrogen, benzyl, or C₁₋₆-alkyl; and R⁶ and R⁷ together form an additional 4 to 8 membered carbocyclic ring which may be aromatic or partial saturated and which may be substituted with halogen, NO₂, CF₃, CN, SO₂NR¹³R¹⁴ wherein R¹³ and R¹⁴ independently are hydrogen, benzyl, or C₁₋₆-alkyl; for the preparation of a medicament for the treatment of disorders of a mammal, including a human, responsive to the blockade of glutamic or aspartic acid receptors. The use according to claim 6 wherein the compound employed is 5-nitro-1H-6,7,8,9-tetrahydro-benz[g] indole-2,3-dione-3-phenylsulphonylhydrazone, or 5-nitro-1H-6,7,8,9-tetrahydro-benz[g]indole-2, 3-dione-3-2-pyridylhydrazone).

Inventors: DAHL BJARNE HUGO, WAETJEN FRANK, DAHL, BJARNE HUGO, WAETJEN, FRANK, Wätjen, Frank 
Applicants: NEUROSEARCH AS, NEUROSEARCH A/S
Application year: 1992
Main classification: C07D209
IPC codes: A61K31, A61P25, C07D209, C07D401, A61P9, A61P43