TW567069B - Anticonvulsant derivatives useful in lowering blood pressure - Google Patents

Abstract

Anticonvulsant derivatives useful in lowering blood pressure in overweight individuals. A pharmaceutical composition for lowering blood pressure in mammals, comprising a therapeutically effective amount of a compound of the formula I as an active ingredient. wherein X is oxygen; R1 is hydrogen; and R3 and/or R4 and R5 together may be a methylenedioxy group of the following formula (II): wherein R6 and R7 are C1-C4-alkyl.

Description

567069

A7 B7 V. Description of the invention (1) Background of the compound of the formula I: # is a novel 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, JJ ·, Ortegon, Μ · Ε ·, and Vaught JL Bioorganic & Medicinal Chemistry Letters 3, 2653-2656, 1993). The patent for such compounds is U.S. Patent: No. 4,513,006. One of these compounds is 2,3 ·· 4,5-bismethylethylene buxin fructosyl sulfamate vinegar (topiramate), which has been shown in clinical trials in humans to treat Simple and complex partial seizures and secondary generalized seizures can be effective as an additional treatment or a single therapeutic agent (E · Faught, BJ · Wilder, RE · RAMSEY, RA REIFE, L D. KRAMER, GW PLEDGER , RM KARjM et. Al. 5 Epilepsia 36 (S4) 33, 1995; SK · SACHDEO, RC SACHDEO, RA REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S4) 33, 1995), currently about twenty Many countries (including the United States) have market requirements for the treatment of complex partial seizures that are simple and with or without secondary generalized seizures, and several countries are applying for approval. The compound of formula I was originally found in rats with the most suitable electric shock seizures. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm). Read the note on the back and fill in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 567069 A7 B7 V. Description of Invention (2) (MES) test, it has anticonvulsant Activity (SHANK, RP ·, GARDOCKI, JF ·, VAUGHT, JL ·, DAVIS, CB ·, SCHUPSKY, JJ ·, RAFFA, RB ·, DODGSON, SJ ·, NORTHY, SO ·, and MARYANOFF, BE ·, 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. SERIKAWA, J. YAMADA, and Μ. SASA, Eur. J. Pharmacol. 254 83-89, 1994), and Animal Excitement 24 73-77, 1996) effectively prevent seizures. Tobi ram ate clinical study reveals its unknown pharmacological properties, showing that topiramate can be effectively used to reduce blood pressure (systolic and diastolic) in humans, especially overweight People. Disclosure of the Invention Therefore, the present case found the following compound of formula I:

Where X is 0 or CH2, R, R2, R3, R4 and R5 are defined as follows and can be used to maintain weight loss. The detailed description of the preferred embodiment is the following formula (I): _ _____ This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) "- ---------- Install ------- Order ·· ------- (Please read the notes on the back before filling this page) 567069 A7 V. Description of the invention (

fCH2OS02NHR1 where X is CH2 or oxygen;

Ri is hydrogen or alkyl; and R4 and R5 are independently hydrogen or alkyl. When X is CH2, I and I may be olefinic hydrocarbon groups linked to form a benzene ring.

And I and / or R4 and Rs may together form a methylene diyl group of the following formula (π):-L

Re c (please read the precautions on the back before filling in this page). 〇 Ordered. · H and I can be the same or different, hydrogen, lower carbon number alkyl or alkyl and linked to form cyclopentyl Or cyclohexyl ring. R1 is especially hydrogen or an alkyl group of about 1 to 4 carbon atoms, such as methyl, ethyl, and iso-propyl. Throughout this specification, alkyl includes both straight and branched alkyl groups. The alkyl group of R2, R3, R4, R5, R6 and R7 has about 1 to 3 stone antiatoms 'including: fluorenyl, ethyl, iso-propyl and n-propyl. When χ is CH2' R4 And it can be combined to form a benzene ring containing X fusion, that is, the meanings of feet 4 and R5 are alkanetriene groups = cch = chch =. # The Intellectual Property Bureau of the Ministry of Economic Affairs printed a special formula (I) In the compound group, X is oxygen, and & and & and & and R5 can be formed together as a methylenedioxy group of the formula (11), and RJR7

297 mm) 567069 A7 V. Description of the invention (4 may all be hydrogen, all are alkyl groups or combined to form JL ^ R ^ p ^ yipentyl or cyclohexyl ring, especially Hachida & and R7 are alkyl ( For example, A # X Ά ΓΗ ^ RU In a group of compounds, 2 4 and & are linked to form a benzene ring. In the third group of compounds, R2 and r3 are hydrogen. ) Compounds can be synthesized by the following methods: or = L alcohols of formula _2〇Η and chloroaminophenate of molecular formula clso with 2 HR | in the presence of a test (such as potassium ^ butoxide or listening) , The temperature is about -20 to 2 generations and the solvent, such as: methylbenzyl, TFIF or dimethylformamide, the groups in: 中 反应, # 中 R is with the following formula _ FV X,, specifically: Λ 丨: Stubble! Fb! Giant;

fV (b) Alcohols with molecular formula RCH2OH and thiophosphonium chloride with molecular formula 80022 in the presence of a base (such as triethylamine or pyridine) at a temperature of about -40 to 25 ° C The reaction in a solvent (for example, diethyl ether or a fluorenyl gas) generates a gas sulfate having a molecular formula of RCH20S02C1. Then, a gas sulfate having a molecular formula of rCH1 2SO2C1 and an amine having a molecular formula of hNH2 are reacted at a temperature of about -40 to 2 yc in a solvent (for example, aerosol or acetonitrile) to produce a compound of the formula (I). (B) The reaction conditions are also described in T · Tsuchiya et al · in " Tet · Letters, No · 36, ρ · 3365 to 3368 (1978) 〇 (c) gas sulfate rch20S02C1 and metal azide (such as & Chemicals) reaction in a solvent (such as gas methylene or acetonitrile) to produce a molecular formula of 1 ___ -υ- 2 This paper size applies to China National Standard (CNS) A4 (21〇X 297 mm) 567069 Ministry of Economic Affairs Printed by A7 of the Intellectual Property Bureau Consumer Cooperatives V. Invention Description (5) RCH2〇S〇2N3 azide sulfate, described in M Hedayatu Uah ratio

Tet Lett ρ 2455-245 8 (1975). The azide sulfate is then reduced to a compound of formula IX where R1 is hydrogen by catalytic hydrogenation (such as precious metals and% or heating with copper metal) in a solvent (such as methanol). The starting materials with molecular formula RCH20H are either commercially available or are known in the art. For example, the molecular formula is RCH2〇H where R2 and I and R4 and R5 are the same 'and the starting material with molecular formula (π) can be used as R · F · Brady in Carbohydrate Reaearch, Vol. 1, 4, ρ · 3 5 to 40 (1970) method to obtain or convert the trimethylsilyl enol ether R6COR7 ketone or aldehyde and fructose at a temperature of about 25 ° C in a halogen carbon solvent (such as airbornene), in the protonic acid (Such as hydrochloric acid or Lewis acid, such as zinc chloride) in the presence of reaction. The trimethylsilyl enol ether reaction is described in G. L. et al in J. Org. Chem. Volaa 38, No. 22, p. 3935 (1973). Further, carboxylic acids and aldehydes whose molecular formulas are RCOOH and RCHO can be reduced to compounds with a molecular formula of RCr20h by standard reduction techniques, such as with lithium aluminum hydride, sodium borohydride or borane-THF complex in an inert solvent (for example : Diethylene glycol dimethyl ether, THF, or toluene) at temperatures between about ⑴ and ιο ° C, as described in HO House in ,, Modem Synthetic Reactions '', 2nd Ed., Pages 45-144 (1972) . Compounds of formula I: can also be prepared by the method disclosed in 5,387,700, which is incorporated herein by reference in its entirety. The compounds of formula I include various individual isomers and their racemates, such as various α and yS linkages (ie, lower and higher than the drawing) of R2, R3, R4 and R5 on the 6-membered ring. Preferably, the oxygen of methylenedioxy (11) is attached to the same 6-membered ring ^ -------- ^ --------- '(Please read the precautions on the back first (Fill in this page again)

This paper size is in accordance with China National Standard (CNS) A4 (21 × 297 public love) 567069 A7 V. Description of the invention (7) Technical coating sugar coating or enteric coating. A suppository tincture can be prepared with oil as a carrier. When preparing parenteral preparations, two can be used, which can contain other ingredients to increase solubility. The body is usually sterilized water, prepared as an injection solution, which can be added with appropriate: ·, And clams. Currently commercially available round tablets of tolapine (t0P_ate) for oral administration contain 21 000 mg or 200 mg of active agent. Pills,., ^ &Amp; The following active ingredients: hydrated lactose, pre-gelatinized starch, microcrystalline fiber '^ ^, **, Beijing, powdered sodium glycolate, hard moon SiL lock, pure water, standard櫊 蠛, hydrazone 80 is synthesized by propylpropylglycanyl cellulose, titanium dioxide, polyethylene glycol, synthetic iron oxide, and ^. The pharmaceutical composition herein contains about 25 to about -1 per dosage unit (such as Le tablet, Mai Yi, injection powder, one teaspoon of medicament, suppository and mg of active ingredient.) ------- Installation -------- Order --------- (Please read the precautions on the back before filling in this page) Appropriate rule paper for the national standard of the standard country_this Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

Claims (1)

567069 A8 B8 C8 D8 Patent Application Range 1 Pain Charge Patent Application No. 89106370-ROC Patent Appln. No. 89106370 Amended Application Patent Fragmentation Text-Annex I,-Amended Claims in Chinese-Enel T 92. 1. 29 | (Submitted on January, 2003) (Submitted on January, 2003) A pharmaceutical composition for lowering blood pressure in mammals, which contains a therapeutically effective amount of a compound of formula I as an active ingredient: Where X is oxygen; Ri is hydrogen; and R2 and R3 and / or FU and R5 can together form a methyleneoxy group of the following formula (Π): Where R6 and R7 are CrC4 alkyl. 2. The pharmaceutical composition according to item 1 of the patent application scope, wherein the compound of formula I is topiramate. 3. The pharmaceutical composition according to item 1 of the patent application range, wherein the effective therapeutic amount is between 100 and 400 mg / day. 10-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 89170B-connected