Method for treating manic-depressive bipolar disorder

MINISTRY OF EDUCATION SCIENCE OF UKRAINE

STATE DEPARTMENT OF INTELLECTUAL PROPERTY

UKRAINE

(13)

and

A (11I

59363 from) C2

(51) 7 А61К31 / 18,31 / 35, А61Р25 / 18,25 / 24

DESCRIPTION

TO THE INVENTORY PATENT

(54) METHOD OF TREATMENT OF MANIACAL-DEPRESSIVE BIPOLAR DISORDER

(21) 98126942

(22) 24 061 997

(24) 15 09 2003

(86) PCT / and397 / 10949, 24 June 1997

(31) 60 / 020,580

(32) 28 06 1996

(33) from

(46) 15 09 2003, Bull No. 9, 2003

(72) Shen Richard Π, IZZ

(73) ORTO-MAKNEIL PHARMACEUTICAL, INC, IZ

(56) SieujeIapb Sisses ZoygpaI and Messiisipes, 56, No. 8,1989-R 756-761

ReusNorNaptiasoIoDioViIeIip, th 29, No. 4, 1993 / -R 447-456

Eriyervu ReveağsN, the 24th, No. 2, 1996 - P 73-77

(57) 1 A method for treating a manic-depressive bipolar disorder, which comprises administering to a subject suffering from such an disorder therapeutically effective amount for the treatment of a given state of a compound of Formula I

where X is CH₂ or oxygen, R 1 is hydrogen or alkyl, and R is₂, Rz, Pd and Fe are, independently, hydrogen or lower alkyl,

when X is oxygen, P₂ and R6, and / or Pd and Ta together may be methypenduxes by a group of the formula II

x^{0 -}

with

to₇ at-

where Re and P7 are the same or different groups and are hydrogen, lower alkyl or alkyl and are combined to form a cyclopentyl or cyclohexyl ring

2 A method according to claim 1, characterized in that the formulation of formula I is topiramate

3 A method according to claim 1, characterized in that the therapeutically effective amount is from about 50 to 200 mg

4 A method according to claim 1, characterized in that said amount is from about 25 to 100

mg ^m

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Compounds of formula I

G ~ \

2 ~ -

^Sh Pas

are structurally new antiepileptic compounds that are highly effective anti-inflammatory agents in animal tests (Magoupoyi, V E, Yogiyev, OO, SagsIoski, ZB Zgiapp, P R and Oosidjeop, S. P. Mesi SN, 30, 880 -887,1987, Magoupoya, E E, Sieyapho, M, S, N, P, P, N, N, P, P, P, P, P, P, P, P, P, P, P, P, P, P, P, P, E, E, B, C, D, E, B, C, , VE, Ý Ogd SNet 1995) These compounds are covered by three

U.S. Patent Nos. 4,513,006, 5,384,327, and 5,498,629 One of these compounds, namely, Superfate-mat 2,3 4,5-buph-O- (1-methylethylidene) -p-Y-

Fructopiranosis, known as topiramate, was found in clinical trials for the treatment of epilepsy of Lyudin as effective as adjuvant or monster-cleavage for the treatment of simple and complex parcial attacks and secondary generalized attacks (E BABISNT, VZ M / IBOER, P, E, P REBE, BO CRAMER, O / R / RBEOSER, RMKARIM it ai, Ariyererea 36 (34) 33, 1995, FROM KSASNUEEO, R, SINUEO, R REBE, R BIM AND RBEOSER, Eriierzia 36 (34) 33, 1995) , and is now on sale as a means for the treatment of simple and precise partial epileptic seizures with secondary generalization vanymy attacks (or without them)

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Great Britain, Finland, the United States of America and Sweden, and in many countries expect authorization for its use

Initially, it was found that compounds of Formula I have prostatic activity in conventional tests for the maximum attack induced by an electroshock (MEN) performed on mice (3HNNC, R, Sakooski, Urs, Udient, B, OAUIZ, c The following investigations showed that the compounds of formula I were highly effective in the treatment of hypertension, MEN tests on rats Later it was found that topiramate effectively blocks attacks in several models of epilepsy in oestrus (0 NACCONTROL, FROM TAMBICA, T ΚΑΝ IA, AND IZNIIA, IN IZNINAKA, TEKHKAYAL / A, YYMMYATA M 5A5A, EIG B RNAGTAZOI 254 83-89, 1994), and the moles of excited epilepsy in animals (A / L / AiOiIEC and 5 ΖΗΟυ, Eriyervu Kev 24 73-77L996 in print)

Recent research on top-ramat has revealed its previously unknown pharma-macular properties that suggest that topiramate should be effective in the treatment of manic-depressive bipolar disorder (MDBR)

Accordingly, it has been found that the compounds of the formula I are

2 .......... ζ

"*" With

where X is O or CH₂, and Ki, K.₂, K.₃, RCA Kg as defined below, are useful in treating a maniacal-depressive bipolar disorder (MDBR)

Sulfamates of the present invention have the following formula (I)

IN,

.ΟΗϊΟ50 * ΝΗΑ,

%

where X is CH₂ or oxygen, C 1 is hydrogen or alkyl, and K is₂, Kz, K₄ and K.₃ are independently hydrogen or lower alkyl

when X is oxygen, K₂ and kz, and / or k₄and Кb together can be methylenedioxy group the following formula (II)

\ / ° ·

with

"/ \

ή

I? at·

where Ke and K7 are the same or different groups and are hydrogen, lower alkyl or alkyl and are combined with the formation of a cyclopentyl or cyclohexyl ring

Ci is, in particular, hydrogen or alkyl having from about 1 to 4 carbon atoms, such as methyl, ethyl, and isopropyl Alkyl in this specification includes straight chain and branched chain alkyl groups. The protecting groups labeled K₂, Kz, K₄, Кb, Ке and К7, contain from 1 to 3 carbonates and include methyl, ethyl, isopropyl and п-propyl

A particular group of compounds of formula (I) are those compounds in which X is oxygen and K₂ and Kz are both, and K₄ together, represent a methylenedioxy group of the formula (II), wherein Ke and K7 are both hydrogen, alkyl or are combined with the formation of a spiro-cyclopentyl or cyclohexyl ring, in particular where KB and K7 are both alkyl, such as methyl Second group compounds are those compounds wherein X is CH₂1 K₄ and K5 are combined with the formation of a benzene ring. The third group of compounds of formula (I) consists of those compounds wherein K₂ and Kz are both hydrogen

The compounds of formula (I) can be synthesized by the following methods

(a) The alcohol reaction of the formula of the KSN₂OH ischlorosulfamate of formula III₂NN₂ or fifth₂NNCI in the presence of a base such as a-bucoxide or sodium hydride at a temperature of about -20 ° to 25 ° C., and in such a solvent such as toluene, tetrahydrofuran or dimethoprop-copper, wherein K is an integral part of the following form (III)

(B) By the alcohol reaction of the formula of the KSN₂OH with isulfuryl chloride of formula 30₂SI₂ in the presence of such a base as triethylamine or pyridine at a temperature of from about -40 ° C. to 25 ° C., and in a solvent such as diethyl ether or methylene chloride, to form chlorosulphate of the formula BCH₂OZ₂SI

Chlorosulphate of the formula of the KSN₂OZ₂SI may in turn be reacted with an amine of the formula ClNN₂at a temperature of from about 40 ° to 25 ° C. in a solvent such as methylene chloride or acetonitrile, to form the compound of formula (I). The reaction conditions for (b) are also given in the work of T. Tiysiyuia et al., et. eeyege, No 36, p. 3365-3368 (1978)

(о) By reaction of chlorosulphate КСН₂OZ₂SI isazide of a metal, such as sodium azide, in a solvent such as methylene chloride or acetongrile, by forming an azide sulfate of formula

GSSN₂OZ₂G4z, as presented in the work of Melbourne Institute in Teye Bay, p. 2455-2458 (1975), is converted to a compound of formula (I), wherein Rc is hydrogen, by catalytic hydrogenation, for example, with a noble metal, and H₂, or by heating with metallic copper in a solvent such as methanol

Outputs of the formula of the KSN₂They can be obtained commercially or according to methods known in the art. For example, starting materials of the formula of the CSN₂OH, where as K.₂ and Kz, both and K5 are identical and correspond to the formula (II), can be restrained by the method of KP Vagabus in Carbon dioxide in Cetera, in those 14, p. 35-40 (1970), or by the reaction of trimethopropenopyrene ketone KsSOK? or aldehyde with fructose at a temperature of about 25 ° C. in a solvent such as halo-androglyhydrogen, for example, methylene chloride, in the presence of prestonic acid such as chloride or a Lewis acid such as chloride, a trimethylsilylene ether solution,

5

Glossy in the work of I. Lazzop et al. Yu Ogd SNet, v. 38, No. 22, p. 3935 (1973)

In addition, the carboxylic acid and aldehyde formulas of ROSS and FNAs can be recovered from compounds of the Formula FCH₂OH using standard methods, for example, by reaction with a Li-aluminum hydride, sodium borohydride, or borane-tetrahydrofuran complex in an inert solvent such as diglyme, tetrahydrofuranobotoluene, at a temperature of about 0 ° to about 0 ° to about 0 ° C, for example, as given by NOE Noveve in "MosiheppupnEiis ReasioPv", 2pcs! ΕΕ, ρ p 45-144 (1972)

The compounds of formula I may also be formulated in accordance with the process disclosed in US Pat. No. 4,513,006, which is described herein as an impregnation

Compounds of formula I include a variety of distinct isomers as well as their racemates, for example, different alpha and beta arrangement of groups P₂, P₃, K4 tana for a 6-membered ring, that is, below and above the surface of the picture. Preference will be given to such a dilution, when the oxygen methylenedioxy groups (II) are placed on ONE and on the same side of the 6-membered KI-LITZ

Manic-depressive bipolar disorder is associated with a progressive psychiatric illness of unknown etiology (P, SOSO, and KKAAmY50N, Mapis-Oerghetia, Iiiypeve, Οχίοτά ipyuezziou Rgeve, Wohk, 1990), prete, a hypothesis was put forward that the manic-depressive illnesses of the zuma-venlen Electrophysiological Excitement (RPO and Violin Physiological Excitement) (ROPOZNYNYNY and KP MYPHA, Mashs-OerghezvoueiIiPe55, Ochyotsya ipikhegeiou Phe55, Noni Uohk, pp. 405-407, 1990). In the work of A ΙΛ / ΑΝΟυΐΕΡ and 5 ΖΗΟυ, Ariereau Rev 24, 73-77, 1996 (in print) , the effectiveness of the topiramat was now in relation to the blocking

Excited attacks in rats

For the treatment of a manic-depressive bi-polar disorder, the compound of formula (I) may be treated as a daily dose in the range of from about 50 to about 200 mg, usually in the form of a half dose for an average adult. A single dose of about 25 to about 30 mg of active ingredient

For the preparation of the pharmaceutical compositions of the present invention, one or more sulfamate-

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The compounds of formula (I) are thoroughly mixed with the pharmaceutical carrier in accordance with the usual pharmaceutical methods, and the carrier may have a wide variety of forms, depending on the desired form of administration, for example, oral, as a suppository or parenteral. In the preparation of compositions in the form of oral dosages, any For example, for liquid oral products, such as, for example, suspensions, elixirs and solutions, suitable nose and additives include water, glycols, olives, alcohols, flavoring re such as, for example, powders, capsules and tablets, suitable nasal syrups and adjuvants include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, cleavage agents, etc. Due to ease of use, tablets and capsules are those spongy single forms that are given the most advantageous, and in this case, obviously, use the hard pharmaceutical noses. If desired, tablets can be coated in a standard way, for example, with sugar. In the manufacture of suppositories as a carrier can be used cocoa butter V preparations for parenteral The designation of the urea usually involves sterile water and may also contain other ingredients, for example, in order to enhance the solubility or for better preservation. May also be made penziyi for injections, that, in this case using reasonable ridkinosy, suspending agents, etc. Topiramate for ne-roralnoho destination is now a kruhlyhtabletok containing 25 mg, 200 mg or asset 10Omh tion agent tablets contain the following neaktyvniinhrediyenty aqueous lactose

Pharmaceutical compositions of the present invention can be used per unit dosage form, for example, a tablet-ku, a capsule, a powder injection, a teaspoon of a liquid, a suppository, etc., from 25 to 30 IU active ingredient

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Ministry of Education and Science of Ukraine

State Department of Intellectual Property, Lvivska square, 8, m Kyiv, SME, 04655, Ukraine

LLC "International Scientific Committee", Artema str, 77, Kyiv, 04050, Ukraine