TWI230064B - Anticonvulsant derivatives useful in treating chronic neurodegenerative disorders - Google Patents

Abstract

Anticonvulsant derivatives useful in treating chronic neurodegenerative conditions are disclosed. A pharmaceutical composition for treating chronic neurodegenerative disorders, which comprises a therapeutically effective amount of a compound of the formula I, wherein X is CH2 or oxygen; R1 is hydrogen or C1-6alkyl; and R2, 3, R4 and R5 are independently hydrogen or C1-6alkyl and, when X is CH2, R4 and R5 be C4 alkene groups joined to form a benzene ring and, when X is oxygen, R2, and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II), wherein R6 and R7 are the same or different and are hydrogen, C1-6alkyl or are alkyl and are joined to form a cyclopentyl or cyclohexyl ring, as an active ingredient and a pharmaceutically acceptable carrier.

Description

1230064 A7 B7 V. Description of the invention (1) Background of the invention The compound of formula I: 1 win

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs is a novel structured antiepileptic compound that has been shown in animals to be a highly effective anticonvulsant (Maryanoff, BE, Nortey, SO ·, Gardocki, JF, Shank, Rp and Dodgson , SP J Med. Chem. 30, 880- 887, 1987; Maryanoff, BE ·, Costanzo, MJ ·, Shank, RP ·, Schupsky, JJ5 Ortegon, ME, and Vaught JL Bioorganic & Medicinal Chemistry Letters 3, 2653 -2656, 1993). There are three types of patents for these compounds, namely U.S. Patent No. 4,513,006, No. 5,242,942, and No. 5,3,84,327. One of these compounds is 2,3: 4,5-bisfluorenylethylene piperan fructosyl sulfamate (topiramate), which has been shown to be simple and complex in human epilepsy clinical trials Partial seizures and secondary generalized seizures can be effective as additional treatments or monotherapy (E. FAUGHT, BJ WILDER, RE · RAMSEY, RA REIFE, LD · KRAMER, GW PLEDGER, RM · KAR 丨M et. Al ·, Epilepsia 36 (S4) 33, 1995; SK · SACHDEO, RC SACHDEO, RA REIFE, P · LIM and G · PLEDGER, Epilepsia 36 (S4) 33, 1995), there are currently about twenty National governments (including the United States) have market requirements for the treatment of complex partial tumor onset of fgj early and with or without secondary general tumor onset, and several countries are applying for approval. (Please read the precautions on the back before filling this page) Loading -------- Order --- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 1230064 A7 __B7____ V. Description of the Invention (2) (Please read the notes on the back before filling out this page) The compound of formula I was originally found in mice's traditional Optimum Electric Shock Seizure (MES) test, which has anticonvulsant activity (SHANK, RP ·, GARDOCKI , JF ·, VAUGHT, JL ·, DAVIS, CB ·, SCHUPSKY, JJ ·, RAFFA, RB ·, DODGSON, SJ ·, NORTHY, SO ·, and MARYANOFF, Β · Ε ·, Epilepsia 3-5 450-460, 1994). Subsequent research also revealed that compounds of formula I have high potency in MES tests in mice. Recently, topiramate can be found in several rodent epilepsy models (J. NAKAMURA, S. TAMURA, T. KANDA, A. ISHII, K. ISHIHARA, T. SER) KAWA, J. YAMADA, andM · SASA, Eíπ \ J. Pharmacol. 254 83-89, 1994), and animal epilepsy epilepsy (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24 73-77, 1996) effectively prevent seizures. Recent preclinical studies have revealed the unknown pharmacological properties of topiramate, suggesting that topiramate should be effective in treating some other neurological disorders. These disorders are chronic neurodegenerative disorders such as: Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, diabetic neurodegenerative disease, retinopathy, head trauma or spinal cord injury Peripheral nerve injury and neurodegeneration of the brain and spinal cord. Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economics, the disclosure of the invention Therefore, this case found' the following compound of formula I:;

This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm)! 230064 Detailed description of the preferred specific embodiment The amino acid ester of the present invention is the following formula (I).

Α7 5. Description of the invention (3)

Where X is 〇 or CH2, Rf, r2, R can be used to treat chronic neurodegeneration; 4 and R5 are defined as follows: 'Parkinson's disease, Huntington's disease senile cancer dementia, degenerative disease, retinopathy, head Department of trauma: 4 hard dagger, diabetic nerve damage and neurological changes in the brain and spine: y #####

Crb--1. Υ-: where

1 ~ -J x is CH2 or oxygen;

Ri is hydrogen or alkynyl; and 2rR3 and RAR5 are independently hydrogen or academy. When X is ch2, and \ and ::, are hydrocarbon groups linked to form a benzene ring. When X is oxygen, R and Han 3 and / or R and R may be combined with 5 /, and the gate is formed as a methylene dioxy group of the following formula (II). Equipment -------- Order --------- (Please read first (Notes on the back, please fill out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Re c! 'Π / bark: of which x 297 mm) This paper size is ii ^^ _ (CNS) A4 size ⑵f 1230064 A7 -------___ 5. Description of the invention (4) Especially hydrogen or Alkyl groups of about 4 to 4 carbon atoms, such as: methyl, earth, and ', propyl. In the entire text of this specification, alkyl groups include linear and branched alkyl groups of 3, R4, R5, R6, and R7. The alkyl groups include about 1 to 3 stone anaerobic atoms, including: fluorenyl, ethyl, and ; Propyl and n-propyl. When X is CH2, 'A and & can be combined to form a fused stupid ring containing X fusion, that is, the definition of the heart and the heart is an alkyltriene group = C-CH = CH-CH =. In the specific group of compounds of the formula VII, X is oxygen, and 1 and R3, and 4 and h may together form a fluorenyldioxy group of formula (11). The center and 1 may be both hydrogen, and both are alkyl or Combine to form a spirocyclopentyl or cyclohexyl ring, especially when I and R7 are both alkyl (eg, fluorenyl). In the second group of compounds, X is CH2, and Han 4 and Rs are linked to form a benzene ring. In the third group of compounds of formula VII, R2 and R3 are hydrogen. Compounds of formula (I) can be synthesized by the following methods: (a) Examination of alcohols with a knife formula of rch2OH and gaseous amino acid esters of molecular formulas cls〇2NH2 or ClSC ^ NHRi (such as potassium α-butoxide or hydrogenation) Sodium) in the presence of a temperature of about -20 to 25t: in the presence of a solvent, such as toluene, TFIF or dimethylformamide, in which the rule is a group of the following formula (^): two ...

(b) Alcohols with a knife formula of rcH ^ OH and thioguanyl chloride with a molecular formula of 〇2ci2 in the presence of a base (such as triethylamine or pyridine) at a temperature of about -40 to 25 ° C and Reaction in a solvent (such as diethyl ether or methylene chloride) ____ _6_ Paper size applies to China National Standard (CNS) A4 (210 X 297 public love) ------ (Please read the precautions on the back before Fill in this page} Binding · -------- # Printed by the Employees ’Cooperative of the Ministry of Economic Affairs, the Smart Finance and Economics Bureau 1230064 A7 B7 V. Description of the invention (5) Produces chlorosulfate with molecular formula Rch2oso2ci. (Please read the back first (Please note that this page is to be completed on this page.) Then the chlorosulfate with molecular formula rch2oso2ci and the amine with molecular formula R〗 NH2 are reacted at a temperature of about -40 to 25 and in a solvent (for example: aerosol or ethyl guess) Thallium compounds. (B) The reaction conditions are also described in τ · Tsuchiya et al. In Tet · Letters, No. 36, ρ · 3365 to 3368 (1978) 〇 (O will gas sulfate RCH2〇s〇2C1 and metal The reaction of a nitride (such as sodium azide) in a solvent (such as chloromethylene or acetonitrile) results in a molecular formula of RCH2 Sodium azide sulfate of S2N3, described in M. Hedayatullah in Tet. Lett. Ρ 2455-2458 (1975). Azide sulfate is then catalyzed by hydrogenation (such as precious metals and rhenium 2 or with copper Metal heating), reduced in a solvent (such as methanol) to a compound of the formula i where Ri is hydrogen. The consumer cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed a starting material of molecular formula RCH2〇H which is commercially available or for this technology Known. For example, the molecular formula is RCH20, where R2, R3, and 4 are all the same, and the starting material whose molecular formula is (Η) can be used. RF Brady in Carbohydrate Reaearch, Vol. 1 4, p. 3 5 to 4〇 (1970) method to obtain or convert r6c〇R7 ketone or aldehyde and fructose of trimethylsilyl enol ether at a temperature of about 25t: in a halogen carbon solvent (such as air methylene), in the protonic acid (Such as hydrochloric acid or Lewis acid, such as zinc chloride). The reaction is described in GL "η⑽ et al in J. 〇rg. Cherrf. Volaa 38, No. 22 , ρ · 3935 (1973). Further, its molecules The carboxylic acids and aldehydes that are RC〇〇H and RCH〇 can be reduced to compounds with the molecular formula rch2oh by standard reduction techniques, such as inert solvents with lithium aluminum hydride, sodium borohydride or borane-THF complex. 7- Standards in time for Guan Jiaxian (CNS) A4 specifications (2i0x 297, public love 1230064, printed by A7, Consumer Finance Co., Ltd., Employees ’Cooperatives of the Ministry of Economic Affairs, V. 5. Description of the invention (6) M (Yaethylene glycol monomethyl ether, butyl HF or Jiaben) The reaction at a temperature of about 0 to 100 ° C is described, for example, in Η ··· House in " Modern Synthetic

Reactions ^, 2nd Ed. Pages 45 to 144 (1972) 〇 Formula 1 of the mouth can also be produced by the methods disclosed in U.S. Patent Nos. 4,5 13,006, 15,242,942, and No. 5,384,32, the full text here Incorporate references. Formula I & compounds include various individual isomers and their racemic acid salts, such as various α and / 5 are linked, that is, lower and higher than R2, R3, R4 & heart plot on the% flat. Preferably, the oxygen attached to the methylenedioxy group is located on the same side as the 6-pyrene. The ability of compounds of formula I to treat chronic neurodegenerative disorders is based on the discovery that topiramate can promote the axonal growth of nerve cells in culture and enhance the regeneration and recovery of nerve damage in vivo and in vivo. In in vitro studies, mouse hippocampal and cerebral cortical cultured cells were established from 18-day-old fetal mice. At various concentrations of birami (topiramateXO nanomolar concentration 100 micromolar concentration), or neurotrophic factor BDNF (brain-derived neurotrophic factor, 10 nanograms) and MSH (a- Cells were grown in culture wells (discs) for seven days in the presence of melanocyte-stimulating hormone, 50 nanomolar concentration), or a vehicle (isotonic saline). When the cells were implanted, each compound was added to the culture medium of one of the labeled culture wells, and then the culture medium was removed and replaced with fresh culture medium after four days. On the seventh day of culture, cells were treated with formalin (tissue fixative). Then the cells are labeled with luciferin specific anti-microtubule-related proteins _ ^ ----------------- (Please read the precautions on the back before filling this page)

1230064

2 (MAP-2) antibody treatment (selected to identify dendrites). The amount of luciferin-labeled antibody bound to MAP-2 (FITC signal) was determined in each well for analysis. This data was then used to calculate the relative extent of cell axon growth in each well. When compared with the growth of cells in the culture medium containing only the carrier, the FITC signal of the cells treated with topiramate was significantly higher, showing that topiramate can cause axons to grow outward. increase. In the hippocampal cells, the concentration ranged from 100 nanomolar to 100 micromolar (Figure D, the increase was significantly higher (P < 0.05), but no concentration-response effect was clearly observed. 10 A significant increase in cortical cells was observed at a concentration of 100 nanomolar (119% in the control group) and a significant increase in cells in the cortex was observed at a concentration of 10 micromolar (119% in the control group χρ < 0 · 05). There is no evidence of a dose-response relationship, but it can cause a moderate increase in axonal outward growth under the treatment of most research concentrations of topiramate (range = 106% of the control group to 15 119%) 〇 Printed in an in-vivo study by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs, the facial nerve compression of the peripheral nerve injury in rats was evaluated by topiramate. The mice were anesthetized and their resections were removed. The facial nerve was found on the skin and muscle. The forceps were used to pinch the nerve at the tip to make it known. The wound was sutured and the rats were healed before the compound was administered. The mice were divided into 202 groups: the vehicle-treated group and topiramate End of treatment group Kg) and a-MSHt treatment group (s.c., 1 mg / kg). The compound was administered twice daily for 14 days after surgery. Facial nerve compression can cause paralysis of the musculature at the injury site on the same side. Daily monitoring of tadpole exercise (comparison between injury and non-injury) for 14 days. As soon as possible after the operation, 10-9-89172A · The size of the paper is translated to the Family Standard (CNS) A4 specification (210 X 297 issued) 1230064 V. Description of the invention (8) 5 10 15 Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs The consumer cooperative printed 20 days to detect the spontaneous rehabilitation exercise and fully recover after 13 days. On days 11 and 12, rats in the topiramate treatment group had a significantly higher degree of motor rehabilitation than the vehicle-treated group (Rehabilitation U / 0; topiramate) = 60%. , Vehicle = 19%;? ≪ 0.001) (% recovery from the 12th; dopiramate (t0piramate) = 92%, vehicle = 68%, ρ < 〇 · οι). In comparison, at the nth and 12th days: the recovery rate of the treatment group 811 was smaller, and there was no statistically significant increase (Figure 3). In the treatment of chronic neurodegenerative symptoms, dopiramate or other compounds of formula (I) can be administered orally repeatedly at doses ranging from about i6 to 256 mg 'once a month or twice a day. In order to prepare the pharmaceutical composition of the present invention, one or more of the amino acid vinegar compounds of the formula (1) may be mixed with a pharmaceutical carrier according to common medical techniques; the technique is intimately mixed, and the carrier depends on the investment It can be prepared in various forms, for example, it can be prepared with a suitable dissolving agent. Iv. A unit dose contains from about 1 mg to about mg of active ingredient. Topiramate Oral tablets for topiramate contain 1 g, _mg, or 200 mg of active agent. The tablet contains the following: 1 Sexual ingredients: water-containing lactose 'pre-gelatinized tincture, microcrystalline, sodium glycolate starch, magnesium stearate, pure Huan β e IK, palm wax, hypromellose fiber Element, titanium dioxide, polyethylene dioxin 1 ^ ^, a known, synthetic iron oxide, # polyflower acid ester 80. ^ 10-This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 public copy) A7 1230064 B7 V. Description of the invention (9) Simple illustration of the figure Figure 1. Topiramate dose response, rat hippocampus (7 die) Axon outgrowth-MAP2-FITC assay Figure 2. For topiramate dose response, mouse brain cortex (7 5 die) axon outgrowth-MAP2-FITC assay Fig. 3 Printed for facial nerve squeezing mode after oral administration of topiramate and 0-MSH after consumption by the Intellectual Property Bureau Staff Consumer Cooperatives of the Ministry of Economic Affairs (210 X 297 mm)

Claims (1)

1230064 A8 B8 C8 D8 VI. Application for Patent Scope Patent Application No. 89106372 ROC Patent Appln. No. 89106372 Amended Claims in Chinese-EncL (ID (May 1993 (Submitted on May ζ, 2004) 1. A pharmaceutical composition for treating chronic neurodegenerative diseases, which comprises an effective therapeutic amount of a compound of formula I: Where X is CH2 or oxygen; Ri is nitrogen or Ci_6 alkyl, and R2, R3, R4, and R5 are independently hydrogen or C6 alkyl, and when X is CH2, R4 and R5 can be linked to form benzene The c4 olefinic hydrocarbon group of the ring, and when X is oxygen, R2 and R3 and / or R4 and R5 may together form a methylene dioxy group of the following formula (II): R6 1 Employee of the Intellectual Property Bureau of the Ministry of Economic Affairs C printed by consumer cooperatives, where 116 and 117 can be the same or different, are hydrogen, Cu alkyl or alkyl, and are linked to form a cyclopentyl or cyclohexyl ring, which is the active ingredient and a pharmaceutically acceptable carrier . -12-This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 89172B then 1230064 3 C8 _D8_ VI. Scope of patent application 2. For example, if you apply for a pharmaceutical composition under the scope of patent application 1, the compound of formula I is Topiramate. 3. The pharmaceutical composition of item 1 in the patent application scope, wherein the expected effective therapeutic amount is between about 32 to 512 mg. 4. The pharmaceutical composition according to item 1 of the patent application range, wherein the dosage for oral administration is between about 16 and 256 mg. Printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 3 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)