TWI255182B - Pharmaceutical compositions for lowering lipids - Google Patents

Abstract

Pharmaceutical compositions useful in lowering lipids. A pharmaceutical composition for lowering lipids in overweight mammals, comprising a therapeutically effective amount of a compound of the formula I, wherein X is oxygen; R1 is hydrogen; and R2 and R3 together form a methylenedioxy group of formula (II), and R4 and R5 together form a methylenedioxy group of the following formula (II), wherein R6 and R7 are C1-6alkyl.

Description

!255182 Α7 B7 V. INSTRUCTIONS (1) BACKGROUND OF THE INVENTION Compounds of formula I:

R4 R3 x ch2oso2nhr1 (please read the note on the back and fill out this page) is a novel anti-epileptic compound that has been shown to be highly effective anticonvulsant in animal studies (Maryanoff; Β·Ε, Nortey, SO, Gardocki , JF, Shank, RP and Dodgson, SP J Med. Chem. 30, 880-887, 1987; Maryanoff, Β·Ε·, 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. 4,5 13,006. One of such compounds is 2,3:4,5-bis-indole-(diterpene ethylpyranose sulfonate (ie, topiramate), which has been shown in clinical trials for human epilepsy. Simple and complex partial seizures and secondary general seizures can be effective as an additional treatment or a single therapeutic agent (E·FAUGHT, BJ· WILDER, RE·RAMSEY, RA· REIFE, LD·KRAMER, Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed GW PLEDGER, RM KAR, M et. al.5 Epilepsia 36(S4)33,1995; SK SACHDEO, RC SACHDEO, RA REIFE, P. LIM and G. PLEDGER, Epilepsia 36 (S4 33, 1995), there are currently more than 20 countries (including the United States) in the treatment of simple and partial seizures with or without secondary general seizures have market demand, and several countries Applying for approval. The compound of formula I was originally found in the mouse's traditional optimal electric shock seizures. This paper scale is applicable to Ningguo Guozheng (CNS) A4 specification (21〇X 297 public love 1255182 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing A7 B7 V. Description of invention 2) (MES) test, it has anticonvulsant activity (SHANK, RP·, GARDOCK1, JR, VAUGHT, JL·, DAVIS, CB·, SCHUPSKY, JJ·, RAFFA, RB·, DODGSON, SJ·, NORTEY , SO·, and MARYANOFF, BE·, Epilepsia 3-5 450-460, 1994). Subsequent studies have also revealed that compounds of formula I are highly potent in MES testing in mice. Recently found to be topiramate Can be in several rodent epileptic patterns (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-induced epileptic patterns (A. WAUQUIER and S. ZHOU, Epilepsy Res. 24 73-77, 1996) effectively prevent seizures. Clinical studies of top iramate Uncovering its unknown pharmacological properties, it has been shown that topiramate can be effectively used to reduce human lipids, especially overweight individuals. DISCLOSURE OF THE INVENTION Therefore, the following compounds of formula I have been found in this case:

Where X is hydrazine or CH2, h, r2, r3, r4 and r5 are defined as follows and can be used to maintain weight loss. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT The sulfonate of the present invention is of the following formula (I): -4- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ----- ---I - ·1111111 — — —____ (Please read the note on the back and fill out this page) 1255182 A7 V. Invention Description (

-X r5- /CH2〇s〇2NHRi, r2 r4 r3 丨Bad person /’ where x is ch2 or oxygen;

Ri is hydrogen or alkyl; and ^4 and 1 are independently hydrogen or stimuli, when 4 is called,

4 and R5 may be an olefinic hydrocarbon group linked to form a benzene ring, and # χ = 3 and/or R4 and 5 may be formed into the following formula (ΙΙ) of methylene dihydrogen I R6

C 〇 order

Wherein 'J RJR7' may be the same or different and is hydrogen, lower alkyl or alkyl, and associate to form a cyclopentyl or cyclohexyl ring. R丨 is especially hydrogen or an alkyl group of about 1 to 4 carbon atoms, such as methyl, ethyl and iso-propyl. The alkyl groups throughout the specification include both linear and branched alkyl groups. The alkyl groups of R2, R3, R4, R5, R6 and R7 are from about 1 to 3 carbon atoms and include methyl, ethyl, iso-propyl and n-propyl groups. When X is CH2, R4 and can be combined to form a 6-membered benzene ring containing an X fusion, i.e., R4 and is defined as an alkylene group = C-CH di CH-CH=. In the group of compounds of the formula (I), the oxime is oxygen, && and & and I can be formed together to form the fluorene dioxy group of the formula (11), the center and the paper size of the paper are applicable to China. National Standard (CNS)^^2i〇χTear 5cm 蓦 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1255182

A7 V. Inventive Note (4) may be hydrogen, all of which are combined with m to form a spiro ring. When R6 and R are both Η丨美Η丨二Η丨己基基哀, X is CH, R ρ 1 soil σ methyl) Time. In the second group of compounds, horse LH2 R4 and R5 are linked to form 芏戸 ^ MR3 is hydrogen. The compound of the formula (I) in the compound of the formula (1) can be synthesized by the following method: · ========================================================================================== In the presence of potassium α-butoxide or sodium, at a temperature of about -20 to 25 t and in a solvent such as methyl t-butane or dimethylformamide, wherein the ruler has the following formula (111) ) %

Rz R; (3⁄4 (b) an alcohol of the formula rchwh and a molecular formula of s〇fi2 thiol chloride in the presence of a base (eg · triethylamine or acridine), 2 temperatures, -40 to 25 ° The reaction between C and a solvent (for example, diethyl ether or methylene chloride) produces a chlorosulfate having the formula RCH20S02C1. Then, the sulfate of the formula RCH2〇S〇2C1 and the amine of the formula hNH2 are at a temperature of about -4. 〇 to 25. The reaction between the day and the solvent (for example: chloromethane or acetonitrile) yields the compound of formula (1). The reaction conditions of (b) are also described in τ·Tsuchiya et al in, Tet. Letters, No 36, ρ· 3365 to 3368 (1978) 〇(C) reacting chlorosulfate RCH2〇S〇2Cl with a metal azide (eg, sodium hydride) in a solvent such as chloromethane or acetonitrile to give a molecular formula of 1255182 Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 Β7 V. Inventive Notes (5) RCH2〇S〇2Ni3 is based on m. Hedayatullah in Tet· Lett· ρ· 2455-2458 (1975). Catalytic nitriding of azido sulfates (eg precious metals and &am) p; or with copper metal heating), reduced to R in a solvent (such as sterol), a compound of formula (I) that is hydrogen. The starting material of formula RCH2〇H is commercially available or has been technically For example, the formula is rch2oh where r2 and r3 and R4 and I are the same, and the starting material of the formula (π) is available RF Brady in Carbohydrate Reaearch, Vol. 1 4, p. 3 5 to 40 (1970) A method for obtaining or adding a R6CQR7 ketone or an aldehyde of a trimethyl sulphonyl enol ether to a fructose at a temperature of about 25 t, a halogen carbon solvent (such as chloromethane), a protonic acid (such as hydrochloric acid or Lewis) The reaction is carried out in the presence of an acid such as a chlorinated hydrazine. The reaction of trimethyl decyl enol ether is described in GL Lars (10) et al m L Org Chem. Volaa 38, N. 22, ρ 3935 (1973). The carboxylic acid and aldehyde of the formula rC〇OH and rcHO can be reduced to a compound of the formula RCH2OH by standard reduction techniques, for example, with lithium aluminum hydride, sodium borohydride or a borane to THF complex in an inert solvent (for example: The temperature in diethylene glycol dimethyl ether, THF or toluene is about 0, to Inter-C reaction, as described, for example, in H 〇 H〇use in, M〇dem

Reactions' 2nd Ed·, pages 45 to 144 (1972). Compounds of formula i: can also be made by the methods disclosed in 5,387,7, which is incorporated herein by reference. The compounds of formula I include the various individual isomers and their racemates, for example, R2, R3 on the 61 ring, and various alpha and 10,000 linkages at 4 and R5 (i.e., below and above the surface). Preferably, the oxygen of methylene dioxyl (11) adheres to the Chinese National Standard (CNS) A4 specification (210 297 297 liters) on the paper scale of the staff. _ ------------装--------Book--- (Please read the notes on the back and fill out this page again) #· 1255182 The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, can clearly use the carrier on solid medicine. Two-in-one's 'its" skill _ clothing or intestinal coating. Preparation of suppositories: to =

This paper scale chat, _ fresh 297 mm) A7 B7 V. Invention description (6) $ on the same side of the garment. In the testers weighing more than 100 kg (n = 14), a 20.2% reduction in triglyceride content was observed. Among the test subjects with a higher level of the five-position triglyceride (> 1 43 mg/dl), the triglyceride reduction was between 24.8% and 54.8%. The average total cholesterol was reduced by 4.4% in all subjects with baseline cholesterol levels (n = 562). Among the testers weighing more than 1 kg (n = 52), the total cholesterol reduction was more pronounced, at 88%. When the monthly deduction is lowered, the dose per liter of the compound of the formula (I) is from about 1 mg to 400 mg, and the average adult usually gives two divided doses per day. The unit dose contains from about 15 to 200 mg of the active ingredient. In order to prepare the pharmaceutical composition of the present invention, one or more of the amino acid hydrochloride compounds of the formula (1) can be closely mixed with the medicinal carrier according to the common pharmaceutical compounding technique, and the carrier can be prepared according to the desired dosage form. In various forms, for example, in the form of oral, suppository, or parenteral. = Any general pharmaceutical " quality can be used when preparing a composition in an oral dosage form. Therefore, when preparing liquid oral preparations (for example, suspensions, ugly agents, and t liquids), appropriate carriers and additives may be added, including: water, ethyl alcohols, oils, alcohols, flavoring agents, 偌m& Μ, chromogens and the like; = body oral preparations (such as: powder, wins and tablets), additives, lubricants, binders, collapse; Easy to administer, so the most is u 柰 及 and glue. Aw R,--------^---------^9. (Please read the notes on the back and fill out this page. 1255182 A7 -—^_____ V. Invention description (7) _ ~ -----^ ΓΓ is the carrier. In the preparation of parenteral preparations, the carrier is usually sterile water, sputum, t private, 69 plus / combined solution or saved. Also

Prepare an injection bath, in which I can add I to the half a. There are currently more than 1 (10) mg or fan gram active agents in round tablets that are orally administered by t〇piramate. The tablets contain the following effective 1 points::=, the former gelatinized powder, microcrystalline cellulose, sodium acetazone: Hardy, Xiyi Town, pure water, standard «, propyl propyl methyl octane, two Oxidation, polyethylene glycol, synthetic iron oxide, and polyantimonic acid. The pharmaceutical composition of the present invention per dosage unit (for example: tablets, capsules, main shot powder, - teaspoon amount of medicament, test agent and: 200 mg of active ingredient. , , ) 25 to,,, spoon. Μ-- ------1--------- (Please read the notes on the back and then fill out this page) Appropriate ruler sheet in the country of the standard country _ The Intellectual Property Office of the Ministry of Economic Affairs system

Claims (1)

1255182 A8 B8 C8 D8 VI. Patent application scope less patent application No. 89106371 v ' ROC Patent Appln. No. 89106371 Amendment without a line, patent range replacement page - Annex (I) Amended Claims in Chinese - Encl/ D (Submitted on February 2005) (Submitted on February 2005) 1. A pharmaceutical composition for reducing lipids in overweight mammals, comprising a therapeutically effective amount of a compound of formula I: 10 15 wherein X is oxygen; Ri is nitrogen; and R2 and R3 together form a methylene group of the following formula (II) to form a methylenedioxy group of the following formula (II): oxy' and R4 and R5 20 Re CR? The R6 and R7 of the Intellectual Property Office of the Ministry of Economic Affairs printed the CI.6 base. 25 2. The pharmaceutical composition of claim 1, wherein the compound of formula I is a topiramate. 3. The pharmaceutical composition of claim 1 wherein the effective therapeutic amount is between about 100 and 400 mg/day. -10 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 89171B-connection 1