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WO1999057119A1 - Nouvelle hypoxanthine 9-substituee de type dopamine et methodes d'utilisation - Google Patents

Nouvelle hypoxanthine 9-substituee de type dopamine et methodes d'utilisation Download PDF

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Publication number
WO1999057119A1
WO1999057119A1 PCT/US1999/009743 US9909743W WO9957119A1 WO 1999057119 A1 WO1999057119 A1 WO 1999057119A1 US 9909743 W US9909743 W US 9909743W WO 9957119 A1 WO9957119 A1 WO 9957119A1
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Prior art keywords
oxohydropurin
ethyl
propanamide
dihydroxyphenyl
substituted hypoxanthine
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Alvin J. Glasky
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Spectrum Pharmaceuticals Inc
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Neotherapeutics Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine

Definitions

  • the present invention is broadly directed to purine based compounds. More particularly, the present invention is directed to a novel purine analog having activity mimicking dopamine in addition to other physiological activities and to associated methods of use.
  • the efficacy of many contemporary pharmaceutical compounds intended to treat neurological and physiological conditions is limited by their inability to cross the blood- brain barrier.
  • molecules that may have neurological activity cannot be administered orally or through injection into the bloodstream because the blood-brain barrier serves as a filter to keep these molecules from leaving the bloodstream and entering the brain and spinal cord.
  • the first is to introduce pharmaceutical compounds by direct injection into the brain through the skull. While such treatments have demonstrated some success, the possibility of infection coupled with the complexity and expense of such procedures have limited their practical usefulness. Additionally, there is resistance among many patients to the administration of such injections directly into the skull.
  • the second approach involves the utilization of chemical agents which temporarily break down the blood-brain barrier in order to allow molecules to enter the central nervous system.
  • this approach is in the very early stages of development and carries with it the potential for allowing molecules of all sizes (including undesirable compounds) to cross the blood-brain barrier.
  • This approach unless and until it can be refined to allow for greater selectivity in crossing the blood-brain barrier, carries with it serious risks.
  • the third approach pioneered by the present inventor, involves developing small molecules which can mimic the activities of bioactive molecules yet can pass 2 through the blood-brain barrier following oral administration or administration through injection into the bloodstream.
  • One embodiment of the present invention is a 9-substituted hypoxanthine derivative of formula (I)
  • Ri is selected from the group consisting of H, COOH, and COOWi, where Wi selected from the group consisting of lower alkyl, amino, and lower alkylamino
  • R 2 is selected from the group consisting of H and OH
  • R 3 is selected from the group consisting of H and OH.
  • n is 2.
  • This compound is designated as AIT-203.
  • Another aspect of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Yet another aspect of the present invention is a method of treating a disease or condition in a mammal treatable by inhibiting the activity of a monoamine oxidase comprising the step of administering an effective amount of a 9-substituted hypoxanthine derivative according to the present invention to the mammal.
  • Still another aspect of the present invention is a method of regulating calcium channel function in a mammal comprising administering an effective amount of a 9-substituted hypoxanthine derivative according to the present invention to the mammal.
  • the 9-substituted hypoxanthine derivative is N-(2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide.
  • Figure 1 is a diagram of a thin-layer chromatogram of the crude product from the synthesis of N-(2-(3,4-dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide of Example 2; chromatography was performed in 20% methanol in ethyl acetate, with visualization by ultraviolet light;
  • Figure 2 is a diagram of a thin-layer chromatogram of the purified product from the synthesis of N-(2-(3,4-dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide of Example 2; chromatography was performed in 30% methanol in ethyl acetate with visualization by ultraviolet light;
  • Figure 3 is a graph showing the effect of 150 ⁇ M of N-(2-(3,4- dihydroxyphenyl)ethyl)-3 -(6-oxohydropurin-9-yl)propanamide, N-(2-hydroxy-2-(3 ,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide, and N-( 1 -carboxyl-2-(3 ,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide, as well as, for comparison, a 9-substituted hypoxanthine derivative that is a serotonin analogue, N-(2-(5-hydroxyindol-3- 5 yl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, on the catalytic activity of monoamine oxidase A/B; the reaction mixture contained 150
  • Figure 4 is a graph showing the effects of increasing concentrations of the 9- substituted hypoxanthine derivatives tested in the experiment of Figure 3 on the activity of monoamine oxidase A/B; concentrations tested were 0 ⁇ M, 2 ⁇ M, 10 ⁇ M, 20 ⁇ M, and 100 ⁇ M; the reaction mixture contained 166 ⁇ M substrate (tyramine) and 0.24 mg/mL mitochondrial protein;
  • Figure 5 is a graph showing the effect of increasing concentrations of N-(2- (3 ,4-dihydroxyphenyl)ethyl)-3 -(6-oxohydropurin-9-yl)propanamide, N-(2-hydroxy-2-(3 ,4- dihydroxyphenyl))ethyl-3 -(6-oxohydropurin-9-yl)propanamide, and N-( 1 -carboxyl-2-(3 ,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide on the binding of labeled spiroperidol to D 2 dopamine receptors;
  • Figure 6 is a graph showing the effect of increasing concentrations of N-(2- (3,4-dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, N-(2-hydroxy-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide, and N-(l-carboxyl-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide on the binding of labeled SCH- 23390 to Di dopamine receptors; and
  • Figure 7 is a graph showing the effect of increasing concentrations of N-(2- (3 ,4-dihydroxyphenyl)ethyl)-3 -(6-oxohydropurin-9-yl)propanamide, N-(2-hydroxy-2-(3 ,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide, and N-(l-carboxyl-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide on the binding of labeled MK- 801 to NMDA receptors.
  • novel pharmaceutical composition and associated methods of the present invention which provide a novel 9-substituted hypoxanthine based composition which is able to cross the blood-brain barrier and which can impact a variety of physiological and psychological systems.
  • 9-substituted hypoxanthine-based compounds according to the present invention have the structure shown in Formula (I), where n is an integer from 1 to 6, Ri is selected from the group consisting of H, COOH, and COOWi, where Wi selected from the group consisting of lower alkyl, amino, and lower alkylamino, R 2 is selected from the group consisting of H and OH, and R 3 is selected from the group consisting of H and OH.
  • the present invention provides a novel purine analog, N-(2- (3,4-dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, which, in a broad aspect, can be viewed as analogous to hypoxanthine chemically linked to a dopamine analog.
  • this compound exhibits functional features of both hypoxanthine and dopamine. As a result, it is able to pass through the blood-brain barrier following oral administration or administration through injection into the bloodstream and, because of the structural similarity of a portion of this compound to dopamine, it exhibits physiological activity mimicking dopamine.
  • exemplary dosages in accordance with the teachings of the present invention range from 0.01 mg/kg to 60 mg/kg, though alternative dosages are contemplated as being within the scope of the present invention.
  • Suitable dosages can be chosen by the treating physician by taking into account such factors as the size, weight, age, and sex of the patient, the physiological state of the patient, the severity of the condition for which the compound is being administered, the response to treatment, the type and quantity of other medications being given to the patient that might interact with the compound, either potentiating it or inhibiting it, and other pharmacokinetic considerations such as liver and kidney function.
  • a pharmaceutical composition according to the present invention comprises:
  • the 9-substituted hypoxanthine-based compound is N-(2-(3,4- dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide.
  • the pharmaceutically acceptable carrier can be chosen from those generally known in the art, including, but not limited to, human serum albumin, ion exchangers, alumina, lecithin, buffered substances such as phosphate, glycine, sorbic acid, potassium sorbate, and salts or electrolytes such as protamine sulfate. Other carriers can be used.
  • Yet another aspect of the present invention is a method of treating a disease or condition in a mammal treatable by inhibiting the activity of a monoamine oxidase.
  • the method comprises the step of administering an effective amount of the 9-substituted hypoxanthine derivative of the present invention to the mammal.
  • the amount that is an effective amount can be determined from enzyme assays as an amount that produces a detectable inhibition of either monoamine oxidase A or monoamine oxidase B or both enzymes in the enzyme assay used in Example 4.
  • the most effective mode of administration and dosage regimen for the 9- substituted hypoxanthine derivatives as used in the methods in the present invention depend on the severity and course of the disease, the patient's health, the response to treatment, other drugs being administered and the response to them, pharmacokinetic considerations such as the condition of the patient's liver and/or kidneys that can affect the metabolism and/or excretion of the administered 9-substituted hypoxanthine derivatives, and the judgment of the treating physician. According, the dosages should be titrated to the individual patient.
  • monoamine oxidase inhibitors are clinically indicated are psychological and psychiatric conditions such as depression, panic disorders, and obsessive-compulsive disorder; chronic pain disorders such as diabetic and other peripheral neuropathic syndromes and fibromyalgia; peptic ulcer and irritable bowel syndrome; chronic fatigue; cataplexy; sleep apnea; migraine, and Parkinson's Disease.
  • Such monoamine oxidase inhibitors may also be useful for other conditions.
  • the mammal can be a human or another socially or economically important mammal such as a dog, a cat, a horse, a cow, a pig, or a sheep.
  • the method of the present invention is not limited to treatment of humans.
  • Yet another aspect of the invention is the use of compounds according to the present invention, particularly N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide, in regulating the activity of calcium channels in mammalian tissues.
  • Dysfunction of calcium channels has been implicated in a wide spectrum of human cardiovascular (e.g., hypertension, arrythmia), respiratory (e.g., asthma), and neurological diseases (e.g., stroke, amyotrophic lateral sclerosis (ALS or Lou Gehrig's Disease),
  • the compound N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6-oxohydropurin- 9-yl)propanamide exhibits both Ca 2+ agonistic and antagonistic effects.
  • the compound exhibits agonistic effects with vascular smooth muscle, and antagonistic effects with gastrointestinal smooth muscle.
  • the Ca 2+ agonistic effect is strongest in a small muscular artery and weakest in large elastic arteries.
  • this aspect of the invention comprises administering an effective amount of a compound according to the present invention, preferably N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide, to a mammal to regulate calcium channel function.
  • a compound according to the present invention preferably N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide
  • the dopamine analogue N-(2-(3,4-dihydroxyphenyl)ethyl)-3-(6- oxohydropurin-9-yl)propanamide was synthesized by reacting the reaction mixture resulting from Example 1 directly with tyramine hydrochloride to form the amide link.
  • a suspension of 14.9 g tyramine hydrochloride in 40 ml DMF was heated with 16.7 ml triethylamine with swirling and this mixture was added to the reaction mixture from Example 1.
  • the flask was washed with another 20 ml DMF and added to the reaction mixture. Stirring and heating at 90°C (oil bath) continued. Within 15-20 minutes the reaction mixture became homogeneous.
  • thin-layer chromatography (TLC) was performed in 20% methanol in ethyl acetate, with visualization by ultraviolet light. The results are shown in Figure 1.
  • the product was cooled to room temperature and then in an ice/water bath for 30 minutes.
  • the precipitated dicyclohexylurea was filtered off.
  • the filtrate was evaporated to dryness.
  • the residue was heated with methanol with magnetic stirring for 2 hours, filtered, and washed with methanol.
  • the residue was heated with heated with 300 ml saturated aqueous NaHCO 3 with magnetic stirring for 30 minutes to remove any unreacted acid.
  • the product was filtered, washed with water, and dried under vacuum at 60°C overnight.
  • a total of 20 g of the product was recrystallized from 300 ml DMF and 200 ml acetonitrile.
  • the recrystallization mixture was kept in the freezer overnight, filtered, washed with acetonitrile and dried at 60°C under high vacuum for 18 hours.
  • N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide was carried out as follows: A quantity (0.300 g; 0.9111 mmol) of 3-(l,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, 4-nitrophenyl ester and (R)-(-)- norepinephrine hydrochloride (0.190 g; 0.924 mmol) were placed into a 10-ml round bottom flask with 2 ml dimethylsulfoxide and a magnetic stirring bar.
  • Triethylamine (128 mg; 1.26 mmol) was added and the solution was stirred at room temperature for one hour. Chloroform (10 ml) was added and a copious yellow precipitate formed immediately. The solution was stirred for several minutes and was filtered by vacuum. The resulting solid was washed with chloroform and allowed to dry. After drying, 359 mg of a yellow solid, N-(2-hydroxy-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide, was obtained. The yield was about 110%.
  • mice mice were sacrificed by cervical dislocation.
  • the brains were isolated and placed immediately in 10 ml cold isolation medium (IM) (500 ⁇ M EDTA, 5 mM HEPES, 0.25 M sucrose, and 10 mg L bovine serum albumin (BSA)).
  • IM cold isolation medium
  • the brains were minced and rinsed twice with 10 mL IM.
  • the brains were then homogenized (5-6 strokes) in 10 mL IM.
  • a volume (20 mL) of IM was then added and the homogenized preparation was centrifuged 8-10 minutes at 600 x g at 4°C. The supernatant was transferred to a new tube.
  • the pellet was resuspended in 30 mL IM and centrifuged again for 8 minutes at 600 x g at 4°C. The supernatant was transferred to a new tube and the pellet discarded. Both supernatants were centrifuged for 10 min at 12,000 x g at 4°C. The supernatant was discarded, the pellet was dislodged with a glass rod, and both pellets were resuspended in 5 mL IM and combined. A volume of IM (20 mL) was added and the suspension centrifuged for 10 min at 12,000 x g at 4°C. The supernatants were discarded. The pellets were dislodged with a glass rod and resuspended in 2-4 mL IM and stored on wet ice during the course of the experiments.
  • the compounds tested were predissolved in dimethyl sulfoxide (DMSO) and further diluted with water as required.
  • DMSO dimethyl sulfoxide
  • Mitochondrial protein (0.22-0.24 mg/mL final concentration) was added, and the reaction mixtures were preincubated approximately 6 minutes with 16 ⁇ M pargyline (monoamine oxidase B inhibitor) and 166 ⁇ M clorgyline (monoamine oxidase A inhibitor) or 2-150 ⁇ M of the tested serotonin analogues or the corresponding volume of water containing 1-5% DMSO respectively at 37°C.
  • the reading was interrupted and 150-166 ⁇ M tyramine (monoamine oxidase A and monoamine oxidase B substrate) or the corresponding amount of water were added according to the plate layout. The reading was continued for approximately 30 minutes at 3-minute intervals. The rate of the fluorescence decrease during this time was used to determine the effect of the tested 13 compounds on the catalytic activity of both enzyme isoforms.
  • Each plate contained a positive control containing the inhibitors for monoamine oxidase A or B respectively as well as a negative control without enzyme substrate. All determinations were in duplicates on the plate.
  • N-(2-(3,4-dihydroxyphenyl)ethyl)-3-(6-oxohydropurin-9- yl)propanamide is designated as AIT-203
  • N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide is designated as AIT-297
  • N-(l-carboxyl-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide is designated as AIT-201.
  • a 9-substituted hypoxanthine derivative that is a serotonin analogue, N-(2-(5- hydroxyindol-3-yl)ethyl)-3-(6-oxohydropurin-9-yl)propanamide, designated AIT-203 is also included in the experiments of Figures 3 and 4.
  • the reaction mixture contained 150 ⁇ M substrate (tyramine) and 0.22 mg/mL mitochondrial protein.
  • the reaction mixture contained 166 ⁇ M substrate (tyramine) and 0.24 mg/mL mitochondrial protein.
  • the ICso is estimated at 6.0 ⁇ M for N-(2-(3,4-dihydroxyphenyl)ethyl)-3-(6- oxohydropurin-9-yl)propanamide, 6.0 ⁇ M for N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3- (6-oxohydropurin-9-yl)propanamide, and 8.0 ⁇ M for N-(l-carboxyl-2-(3,4- dihydroxyphenyl))ethyl-3-(6-oxohydropurin-9-yl)propanamide. Lyles et al. (J. Pharm. Pharmac.
  • Bovine Striatal Membrane Preparation Bovine striata were obtained from a local abbatoir, dissected, and stored at -80°C until use. The striata were homogenized at 0°C in 10 volumes homogenization buffer containing 0.25 M sucrose, 50 mM Tris, pH 7.4, 1 mM EDTA, and 0.1 mM phenylmethylsulfonylfluoride (PMSF), using a motor-driven Dounce homogenizer. The tissue was then centrifuged at 1 lOOxg at 4°C for 10 min. The resultant supernatant was collected and stored on ice.
  • homogenization buffer containing 0.25 M sucrose, 50 mM Tris, pH 7.4, 1 mM EDTA, and 0.1 mM phenylmethylsulfonylfluoride (PMSF)
  • the pellet was resuspended in 5 volumes of homogenization buffer and centrifuged at 1 lOOxg at 4°C for 10 min. The resulting supernatant was collected and pooled with the previous supernatant. The pooled supernatants were mixed and centrifuged at 35,OOOxg for 20 min at 4°C. The resultant pellet was collected nd resuspended in 5 volumes of storage buffer containing 50 mM Tris, pH 7.4, 1 mM EDTA, 5 mM MgCl 2 , and 0.1% ascorbic acid. The membrane suspension was centrifuged at
  • Dopamine D ⁇ Receptor Binding The method employed was substantially as previously described (S.K. Gupta & R.K. Mishra, "Desensitization of Di Dopamine Receptors Down-Regulates the G s ⁇ Subunit of G Protein in SK-N-MC Neuroblastoma Cells," J. Mol. Neurosci. 4: 117-123 (1993); S.K. Gupta & R.K. Mishra, "Up-Regulation ofDi Dopamine Receptors in SK-N-MC Cells After Chronic Treatment with SCH 23390," Neurosci. Res. Commun. 15: 157-166 (1994)).
  • Bovine striatal membranes (175 ⁇ g) were incubated in an 0.5 ml volume of assay buffer containing 50 mM Tris, 1 mM EDTA, 5 mM MgCl 2 , 0.1% ascorbic acid, and 0.8 nM [ 3 H]-SCH 23390 (84.0 Ci/mmol) for 90 minutes at 25°C. Non-specific binding was determined in the presence of 1 ⁇ M cis-flupenthixol. Dose-response curves were generated for the compounds being tested over a concentration range of 100 pM to 100 ⁇ M.
  • the assay was terminated by the addition of 4 ml ice-cold wash buffer (50 mM Tris, pH 7.4, and 5 mM MgCl 2 ), followed by rapid vacuum filtration through Whatman GF-B filter paper using a Brandell M24 cell harvester. Non-specific binding was removed by washing the filter paper four times with 4 ml of ice-cold wash buffer. Radioactivity was determined by counting the 3 H dpm in 5 ml scintillation fluid (BCL, Amersham) using a Beckman LS5000TA liquid scintillation counter.
  • 4 ice-cold wash buffer 50 mM Tris, pH 7.4, and 5 mM MgCl 2
  • Dopamine D 2 Receptor Binding The method employed was essentially as previously described (P.W. Baures et al., "Design, Synthesis, X-Ray Analysis, and Dopamine Receptor-Modulating Activity of Mimics of the 'C5' Hydrogen-Bonded Conformation in the Peptidomimetic 2-Oxo-3-(R)-[(2(S)-Pyrrolidinylcarbonyl)amino]- 1 -Pyrrolidineacetamide," 1 Med. Chem. 37: 3677-3683 (1994)).
  • Bovine striatal membranes (175 ⁇ g) were incubated in an 0.5 ml volume of assay buffer containing 50 mM Tris, 1 mM EDTA, 5 mM MgCl 2 , 0.1% ascorbic acid, 50 nM ketanserin and 0.5 nM [ 3 H]-spiroperidol (93.0 Ci mmol) for 60 minutes at 25°C. Non-specific binding was determined in the presence of 1 ⁇ M butaclamol. Dose- response curves were generated for the compounds being tested over a concentration range of 100 pM to 100 ⁇ M. The assay was terminated by the addition of 4 ml ice-cold wash buffer (50 mM Tris, pH 7.4, and 5 mM MgCl 2 ), followed by rapid vacuum filtration through 16
  • Non-spcific binding was determined in the presence of 30 ⁇ M MK-801. Dose-response curves were generated for the compounds being tested over a concentration range of 100 pM to 100 ⁇ M.
  • the assay was terminated by the addition of 4 ml ice-cold wash buffer (50 mM Tris, pH 7.4, and 5 mM MgCl 2 ), followed by rapid vacuum filtration through Whatman GF-B filter paper using a Brandell M24 cell harvester. Non-specific binding was removed by washing the filter paper four times with 4 ml of ice-cold wash buffer. Radioactivity was determined by counting the 3 H dpm in 5 ml scintillation fluid (BCL, Amersham) using a Beckman LS5000TA liquid scintillation counter.
  • 6-hydroxy-dopamine 6-OHDA
  • 6-OHDA 6-hydroxy-dopamine
  • the compounds were tested at a dose of 0.25 mg/kg; when these compounds were given in combination with apomorphine, they were given 15 minutes prior to the injection of apomorphine.
  • IC50 values for various 9-substituted hypoxanthine derivatives toward dopamine Di, dopamine D 2 , and NMDA receptors in bovine striatum were determined for various 9-substituted hypoxanthine derivatives toward dopamine Di, dopamine D 2 , and NMDA receptors in bovine striatum.
  • N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide has tissue selectivity in two respects.
  • the Ca 2+ agonistic effect of this compound was associated with vascular smooth muscle, while the Ca 2+ antagonistic effect was associated with gastrointestinal smooth muscle.
  • the Ca 2+ agonistic effect of this compound was strongest in dog mesenteric artery, a small muscular artery, and relatively low in dog carotid artery and rat aorta, the large elastic arteries.
  • N-(2-hydroxy-2-(3,4-dihydroxyphenyl))ethyl-3-(6- oxohydropurin-9-yl)propanamide exhibits selectivity by tissue type and size of artery.
  • the 9-substituted hypoxanthine derivatives of the present invention cross the blood-brain barrier efficiently and selectively and have unexpected activity as monoamine oxidase inhibitors. These derivatives therefore have use in treating conditions and diseases treatable with monoamine oxidase inhibitors.

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Abstract

L'invention concerne de nouveaux dérivés d'hypoxanthine 9-substitués ayant des effets physiologiques inattendus. Parmi ces composés on trouve N-(2-(3,4- dihydroxyphényl) éthyl-3- (6-oxohydropurin-9-yl) propanamide, N-(2-hydroxy-2- (3,4-dihydroxyphényl) éthyl-3-(6- oxohydropurin-9-yl) propanamide, et N-(1-carboxyl- 2-(3,4-dihydroxyphényl) éthyl-3-(6- oxohydropurin-9-yl) propanamide. L'invention concerne également des compositions pharmaceutiques et des méthodes d'utilisation de ces dérivés pour traiter des troubles ou des états pouvant être traités par une activité inhibitrice de la monoamine-oxydase et pour réguler la fonction du canal calcique.
PCT/US1999/009743 1998-05-04 1999-05-04 Nouvelle hypoxanthine 9-substituee de type dopamine et methodes d'utilisation Ceased WO1999057119A1 (fr)

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Cited By (18)

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WO2001036419A1 (fr) * 1999-11-16 2001-05-25 Neotherapeutics, Inc. Utilisation de derives d'hypoxanthine 9-substituee afin de stimuler la regeneration des tissus nerveux
US6407237B1 (en) 2001-02-21 2002-06-18 Neotherapeutics, Inc. Crystal forms of 9-substituted hypoxanthine derivatives
WO2002085904A1 (fr) * 2001-04-20 2002-10-31 Neotherapeutics, Inc. Synthese et procedes d'utilisation d'analogues et de derives de purine
US6630478B2 (en) 2000-07-07 2003-10-07 Neotherapeutics, Inc. Methods for treatment of drug-induced peripheral neuropathy
US6849735B1 (en) 2000-06-23 2005-02-01 Merck Eprova Ag Methods of synthesis for 9-substituted hypoxanthine derivatives
US6982269B2 (en) 2001-04-20 2006-01-03 Spectrum Pharmaceuticals, Inc. Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
EP3311842A1 (fr) * 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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US6288069B1 (en) 1999-11-16 2001-09-11 Neotherapeutics, Inc. Use of 9-substituted hypoxanthine derivatives to stimulate regeneration of nervous tissue
WO2001036419A1 (fr) * 1999-11-16 2001-05-25 Neotherapeutics, Inc. Utilisation de derives d'hypoxanthine 9-substituee afin de stimuler la regeneration des tissus nerveux
US6849735B1 (en) 2000-06-23 2005-02-01 Merck Eprova Ag Methods of synthesis for 9-substituted hypoxanthine derivatives
US6630478B2 (en) 2000-07-07 2003-10-07 Neotherapeutics, Inc. Methods for treatment of drug-induced peripheral neuropathy
US6630490B2 (en) 2000-07-07 2003-10-07 Neotherapeutics, Inc. Methods for treatment of disease-induced peripheral neuropathy and related conditions
US6407237B1 (en) 2001-02-21 2002-06-18 Neotherapeutics, Inc. Crystal forms of 9-substituted hypoxanthine derivatives
US7531670B2 (en) 2001-04-20 2009-05-12 Sprectrum Pharmaceuticals, Inc. Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
WO2002085904A1 (fr) * 2001-04-20 2002-10-31 Neotherapeutics, Inc. Synthese et procedes d'utilisation d'analogues et de derives de purine
US6982269B2 (en) 2001-04-20 2006-01-03 Spectrum Pharmaceuticals, Inc. Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
US8734818B2 (en) 2001-04-20 2014-05-27 Spectrum Pharmaceuticals, Inc. Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
US8377456B2 (en) 2001-04-20 2013-02-19 Spectrum Pharmaceuticals, Inc. Methods for treating cognitive/attention deficit disorders using tetrahydroindolone analogues and derivatives
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
US8809010B2 (en) 2003-05-05 2014-08-19 Probiodrug Ag Method for prophylactic treatment of alzheimer's disease using inhibitors of glutaminyl cyclase and glutamate cyclases
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
EP2481408A2 (fr) 2007-03-01 2012-08-01 Probiodrug AG Nouvelle utilisation d'inhibiteurs glutaminyle cyclase
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
EP3311842A1 (fr) * 2013-06-13 2018-04-25 VeroScience LLC Compositions et procédés de traitement des troubles métaboliques
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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