TW200843785A - Methods for preventing and treating neurodegenerative disorders - Google Patents

Abstract

The present invention relates to a method for treating, preventing or slowing, delaying or reversing progression of one or more neurodegenerative disorders in a patient in need thereof characterized by administering a glucopyranosyloxy-pyrazole as defined in claim 1 to the patient in need thereof.

Description

200843785 IX. Description of the invention: [Technical field to which the invention belongs]

The present invention relates to a method for preventing and treating a medical disorder of a neurodegenerative compound in a patient in need thereof by administering a substance comprising the formula I.

Wherein the group is to R6 and is as defined below, and the compounds of the formula include tautomers, stereoisomers, mixtures thereof and salts thereof. Further, the present invention relates to the use of a compound of the formula (j) of the present invention for the preparation of a pharmaceutical composition for the prophylaxis and treatment of a neurodegenerative disease. [Prior Art] Pyrazole-indole-glucoside derivatives inhibit sodium-dependent glucose co-transport protein (SGLT), particularly SGLT2. The filtered glucose is resorbed across the renal epithelial cell line along the sodium gradient (1) via a sodium-dependent grape vine co-transporter (SGLT) located on the proximal tubule brush membrane. There are at least three SGLT isoforms with different phenotypes and different physical and chemical properties (2). 8 (31^丁2 is only expressed in the kidney (7). At normal glucose concentration, glucose is completely reabsorbed by SGLT in the kidney' and the resorption capacity of the kidney is saturated when the glucose concentration is above 1 mM. This results in glucoseuria (,, diabetes). This threshold concentration can be reduced by the inhibition of 127892.doc 200843785 ^GLT2. In addition to other mechanisms, renal filtration and reabsorption of glucose in particular cause a steady state of plasma glucose concentration and therefore It can be used as an anti-diabetic target. Therefore, σ-biazole-valvate glucoside derivative is recommended as an inducer of urinary excretion of g-sugar and as an agent for treating diabetes. ()ight, Ε, Μ, (2001) Am. J · Renal Physiol· 280, Fl〇^ F18; ()Wright, EM荨 (2004) Pflugers Arch. 447(5): 510-8; 0) You, G. et al. (1995) j Bi〇1 chem· 270 (49) 29365· • 29371. Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory, judgment, and understanding. Multiple cognitive deficits in sexual function remission Exhibitions, • Activities, sensations and language skills are also affected until a comprehensive impairment of multiple cognitive functions. These perceptions are gradually lost, but generally cause serious injury and eventually die between 4 and 12 years. Current treatment is not every All patients are effective. _ Therefore, there is still a medical need to treat or prevent neurodegenerative diseases (such as dementia, especially Alzheimer's type dementia) or to slow, delay or • reverse the progression of these diseases. The present invention is directed to a novel method for treating a neurodegenerative disease (especially dementia). Another object of the present invention is to prevent the prevention of neurodegenerative diseases ( A novel method for slowing, delaying or reversing its progression. Another object of the invention is to find novel therapeutic uses of glucopyranosyloxy-pyrazole derivatives. The aim is to provide novel pharmaceutical compositions suitable for the treatment of neurodegenerative diseases, in particular dementia. Other objects of the present invention will be apparent to those skilled in the art from the foregoing and the following description. In the first aspect, the present invention relates to a method for treating a patient or a neurodegenerative disease in need thereof, wherein the method Including the administration of the glucopyranyloxy-n ratio of the formula (I) to a patient in need thereof

R represents hydrogen, Cl.6.alkyl, C1-4-alkyl substituted with 1 to 3 fluorine atoms, C:24.alkyl' substituted with hydroxy or Cl.3. -Alkenyl C3t ¥ alkyl, C3-6-cycloalkyl-Ci.3-alkyl, c3_6-alkynyl, tetrahydrofuran-3, tetrahydropyran-3-yl, tetrahydrod-d-tetrahydrofuran a base-Cw alkyl group, or a tetrahydropyranyl group -Ci 3-alkyl group, and R2 represents a Cl-4-alkyl group, a C1-4-alkyl group substituted with 1 to 3 fluorine atoms, 127892.doc 200843785 or C3_6 a cycloalkyl group, and R represents nitrogen, fluorine, gas, desert, Cn alkyl, C2-6-thyl, C2.6-block, C3-6-cycloalkyl, Cw-cycloalkylene a group, a CK6-alkoxy group, a C3-6-i-pyringyl-oxy group, a C3_6·^-yl-Ci-3-alkoxy group, a methyl or methoxy group substituted with 1 to 3 fluorine atoms, 1 to 5 gas atoms substituted by 〇2·4-alkyl or C2_4_alkoxy, substituted by cyano c] 4_pyringyl, substituted by hydroxyl or C!·3-alkyloxy 2CN4 -alkyl, cyano, thiol, Cy alkoxycarbonyl, nitro, amine, c1-3_alkylamine-yl, bis-(C--3-alkyl)amine, tetrahydrofuran-3- Alkoxy group, tetrahydrogen 17 ratio. An alkoxy group, a tetrahydroanthracene alam-4-yloxy group, a tetrahydroanthranyl 3-alkoxy group, a tetrahydropyranylalkoxy group, and • R4 and R5 may be the same or different, and Represents hydrogen, fluorine, chlorine, bromine, Cl|alkyl, C!·3-alkoxy, methyl or decyloxy substituted with 1 to 3 fluorine atoms, and R6, R7a, R7b, R7e are independent of each other The ground has the meanings selected from the following: hydrogen, (Ci 8-alkanoyl)carbonyl, (Cw alkyl)oxycarbonyl, arylcarbonyl and aryl_(Ci)-Weiyl, The aryl group referred to in the definition of a group is intended to mean a phenyl group which may be mono- or disubstituted independently of each other by Rh, and the substituents may be the same or different and Rh represents fluorine, chlorine, bromine, iodine, c-[alkane] a base, a difluorodecyl group, a trifluoromethyl group, a q-3-alkoxy group, a difluoromethoxy group, a trifluoromethyl fluorenyl group or a cyano group, and unless otherwise specified, the above alkyl group may be straight or branched. Chain, 127892.doc -9- 200843785 A mixture of compounds of formula (I) or a tautomer thereof, a stereoisomer thereof, and a salt thereof. In a further aspect, the present invention relates to a method of preventing a degenerative disease or delaying, delaying or reversing the progression of a disease in a patient in need thereof, wherein the method comprises administering to a patient in need thereof And t-glucosyloxy κ, a tautomer, a stereoisomer, a mixture or a salt thereof of the formula (1) as defined above and below.

Another aspect of the invention relates to the use of glucopyranosyloxy-carbazole, tautomers, stereoisomers, mixtures or salts thereof of formula (1) as defined above and below, To manufacture an agent for treating one or more neurodegenerative diseases. Another aspect of the invention relates to the use of glucopyranosyloxypyrazole, its tautomers, stereoisomers, mixtures or salts of the formula (1) above and below, for the manufacture thereof An agent for preventing one or more neurodegenerative diseases or slowing, delaying or reversing the progression of such diseases. Another sorrow of the present invention relates to a pharmaceutical composition for treating one or more neurodegenerative diseases comprising a σ-pyranosyloxy-ti ratio tT of the general formula (I) as defined above and below. Sit, its tautomers, stereoisomers, mixtures or salts. Another aspect of the invention relates to a pharmaceutical composition for preventing or delaying, delaying or reversing the progression of such diseases comprising a formula (1) as defined above and below. °pyranosyloxy-carbazole, its tautomers, stereoisomers, mixtures or salts. [Embodiment] 127892.doc -10- 200843785 Unless otherwise stated, such groups, residues and substituents, especially R1 to R and R7a, R7b, r7c are as defined above and below. If a residue, substituent or group occurs several times in a compound, they may have the same or different meanings. The group R1 preferably represents hydrogen, C! 4·alkyl, alkyl substituted with i to 3 fluorine atoms, c3_6·cycloalkyl, C36•cycloalkyl-methyl, c-alkynyl, tetrahydrofuran 3-yl, tetradecano-3-yl, tetrahydropyran-yl, tetrahydrofuranyl-methyl, tetrahydropyridinyl-methyl. Even preferred meanings of the group R1 are H, methyl, ethyl, n-propyl, isopropyl, 2-propyne-fluorenyl, 2-butyne q-yl, tetrahydrofuranyl, tetrahydropyran-3 -yl, tetrahydropyran-4-yl, tetrahydrofuranylfluorenyl and tetrahydropyranylmethyl. According to the invention, the preferred meaning of the group R2 is fluorenyl and trifluoromethyl, especially methyl. Preferred meanings of the group R3 are hydrogen, fluorine, chlorine, methyl, ethyl, isopropyl, t-butyl, 2-cyano-2-propyl, difluoromethyl, trifluoromethyl, ring. Propyl, phosphonium butyl, cyclopentyl, methoxy, ethoxy, isopropoxy, difluoromethylindenyl, trifluoromethoxy, U, 252_tetrafluoroethoxy, cyclopropyl Oxyl, cyclobutyloxy, cyclopentyloxy, tetrahydrofuranyloxy, tetrahydropyran-3-yloxy, tetrahydropyran-4-yloxy, tetrahydrofuranylfluorenyl Oxyl, tetrahydrofuranyl-methyloxy, ethynyl. The most preferred meaning of the group R3 is fluorine, chlorine, methyl, ethyl, isopropyl, tert-butyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, Methoxy, ethoxy, |propoxy, difluoromethoxy, trifluoromethoxy 127892.doc • 11- 200843785 The preferred meaning of the group R4 is hydrogen and fluorine. The preferred meaning of the group R5 is hydrogen and fluorine. Preferably, R4 or R5 represents fluorine. According to the invention, the group r6 preferably denotes hydrogen, (Ci_8-alkyl)oxycarbonyl or oxime 8-alkylcarbonyl, especially η or (Cl·6-alkyl)oxycarbonyl, especially preferably Η , methoxycarbonyl or ethoxycarbonyl. The substituents R7a, R7b, and R7e independently of each other preferably represent hydrogen or ((polyalkyl)carbonyl, especially hydrogen or alkyl)carbonyl, and more preferably hydrogen, methylcarbonyl or ethylcarbonyl. Most preferably, R7a, R7b and R7e represent hydrogen. In the method, use and pharmaceutical composition of the invention, the compound of formula II to (138) is particularly preferred

Wherein the groups R1, R3, R4, R5 and R6 are defined in the following Table 1, wherein Me represents a fluorenyl group and Et represents an ethyl group. Table 1

Compound R6 R1 R3 R4 Rs (1) H- 2-propyne small base Η jv (2) MeO-CO- 2-propyne small ethyl hydrazine XT H (3) EtO-CO-2-propyne small ethyl Η AXH 127892.doc 12 200843785

(4) H- 2-Butry-1-ylethyl hydrazine 5 (5) MeO-CO- 2-butyne small ethyl hydrazine 6 (6) EtO-CO- 2-butan-1-ylethyl hydrazine Η (7) Η-tetrazinc π-pyran-4-ylethyl Η Η (8) MeO-CO- four spots ^ 0 -4- -4-ethyl Η Η (9) EtO-CO- tetrahydrofuran-4-yl Base Η (10) H-tetrahydropyran-4-ylmethoxy oxime (11) MeO-CO- tetrahydro σ-pyran-4-yl oxime Η Η (12) EtO-CO- Hydrogen σ 喃 -4 · · · · 曱 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 (13) MeO-CO- (S) South-3-ylethyl hydrazine 15 (15) EtO-CO- (S)·tetrahydrofuran-3-ylethyl hydrazine 16 (16) H-(S)-tetrahydrofuran-3-ylmethoxy oxime Η (17 MeO-CO- (S)-tetrazonia-β-ran-3-ylmethoxy oxime (18) EtO-CO- (S)-tetrahydrofuran-3. methoxy oxime 19 (19) H- ( R)-Tetraza-β-propan-3-ylethylΗ Η (20) MeO-CO- (R)-Tetrazazin-3-ylethylΗ Η (21) EtO-CO- (R) - Four rats σvran-3-ylethyl hydrazine 22 (22) H-(R)-tetrazaptidine-3-ylmethoxy oxime (23) MeO-CO- (R)-tetrazole喃-3-yl oxime oxime Η (24) EtO-CO- (R)-tetrazonitrile-3-ylmethoxy oxime (25) H-isopropylcyclopropyloxy oxime ( 26) MeO-CO-isopropyl propyl propyl hydrazine 27 (27) EtO-CO-isopropyl propyl propyl hydrazine 28 (28) H-isopropyl cyclobutyl oxy hydrazine 29 (29 MeO-CO-isopropylcyclobutyloxyindole 30 (30) EtO-CO-isopropylcyclobutyloxyindole 31 (31) H-isopropylcyclopentyloxy oxime Η (32) MeO-CO-isopropylcyclopentyloxy oxime (33) EtO-CO-isopropylcyclopentyloxy oxime 127 127892.doc -13- 200843785

(34) Η-Isopropyl tetrahydrofuran-3-yloxyindole 35 (35) MeO-CO- isopropyl tetraphobic ratio °N--3-yloxy oxime (36) EtO-CO - Isopropyltetrazolium pyran-3-yloxyindole 37 (37) Η-isopropyltetrazine. Ratio 11 Nan-4-yloxyanthracene (38) MeO-CO-isopropyltetrazolium 0 to ° Nan-4-yl lactyl hydrazine 39 (39) EtO-CO- isopropyl tetra-amp; ° ratio喃-4-yloxy 1 hydrazide 40 (40) H-isopropyl (R)-tetrazonitrile-3-yloxy oxime (41) MeO-CO-isopropyl (R)-tetrahydrofuran- 3-yloxyindole Η (42) EtO-CO-isopropyl(R)-tetrazonitrile-3-yloxyindole 43 (43) H-isopropyl (S)-tetrahydrofuran-3-yl Oxime Η (44) MeO-CO- isopropyl (S)-tetrahydrofuran-3-yloxyindole 45 (45) EtO-CO- isopropyl (S)-tetrahydrofuran-3-yloxy Η Η (46) H- 2-propyn-1-ylethyl F Η (47) MeO-CO- 2-propan-1-ylethyl F Η (48) EtO-CO- 2-propen-1- Ethyl Ethyl F Η (49) H- 2-Butry-1-ylethyl F Η (50) MeO-CO- 2· 快 -1--1-ylethyl F Η (51) EtO-CO- 2-快快_1•基ethyl F Η (52) H-tetrazopyranpyran-4-ylethyl F Η (53) MeO-CO- tetrahydropyridin-4-ylethyl F Η (54 EtO-CO-tetrahydropyran-4-ylethyl F Η (55) H-tetrahydropyran-4-pyryloxy F Η (56) MeO-CO-tetrahydro-pyran- 4-yloxyl F Η (57) EtO-CO- tetrahydropyran-4-pyrimidyl Base F Η (58) H- (S)-tetrazole 68 Nan-3-ylethyl F Η (59) MeO-CO- (S)·tetrazine ° ° Nan-3·ylethyl F Η (60) EtO-CO-(S)-tetrazonia-β-furan-3-ylethyl F Η (61) H-(S)-tetrazole^^^-ylmethoxy F Η (62) MeO-CO-(S)-tetrazine-trident-3-ylmethoxy F Η (63) EtO-CO- (S)-tetrazide-3 -ylmethoxy F Η 127892.doc -14 - 200843785

(64) Η-(R)-tetrazole -3-ylethyl F Η (65) MeO-CO- (R)-tetrazaptidine-3-ylethyl F Η (66) EtO-CO - (R)-Tetraza-β-propan-3-ylethyl F Η (67) Η-(R)-tetrazole. Nan-3-ylmethoxy F Η (68) MeO-CO- (R)-tetrazolfufen-3-yl fluorenyl F Η (69) EtO-CO- (R)- four mouse sig -3-3· methoxyl F Η (70) H-isopropylcyclopropyloxy F Η (71) MeO-CO-isopropylcyclopropyloxy F Η (72) EtO-CO- Propylcyclopropyloxy F Η (73) H-isopropylcyclobutyloxy F Η (74) MeO-CO-isopropylcyclobutyloxy F Η (75) EtO-CO-isopropyl Cyclobutyloxy F Η (76) H-isopropylcyclopentyloxy F Η (77) MeO-CO-isopropylcyclopentyloxy F Η (78) EtO-CO-isopropyl Cyclopentyloxy F Η (79) H-isopropyl tetraphobic pyran-3-yloxy F Η (80) MeO-CO- isopropyl tetraphobic pyran-3-yl lactyl F Η (81) EtO-CO-isopropyltetrazolium σ-pyran-3-yloxy F Η (82) H-isopropyl tetrahazinpyran-4-yloxy F Η (83) MeO- CO-Isopropyl four mouse ° ° ° -4 -based milk base F Η (84) EtO-CO- isopropyl tetra-miso-pyran-4-yloxy F Η (85) H-isopropyl (R)-tetrahydrofuran-3-yloxy F Η (86) MeO-CO-isopropyl (R)-tetrahydrofuran-3-yloxy F Η (87) EtO-CO-isopropyl (R)- Tetrahydrogen喃-3-yloxy F Η (88) H-isopropyl (S)-tetrachaine-3-yloxy F Η (89) MeO-CO-isopropyl (S)-tetrahydrofuran-3 -yloxy F Η (90) EtO-CO-isopropyl (S)-tetrahydrofuran-3-yloxy F Η (91) H- 2-propan-1-ylethyl hydrazine F (92) MeO -CO- 2-propan-1-ylethyl hydrazine F (93) EtO-CO- 2-propan-1-ylethyl hydrazine F 127892.doc •15- 200843785

(94) Η- 2-butyne small ethyl hydrazine F (95) MeO-CO- 2-butyn-1-ylethyl hydrazine F (96) EtO-CO- 2-butfast-1-ylethyl Base F (97) H-tetrazo σ-pyran-4-ylethyl hydrazine F (98) MeO-CO- four porphyrin -4--4-ylethyl hydrazine F (99) EtO-CO- four mice σ比鸣-4-ylethylΗ F (100) H- Four mouse σ-pyran-4-ylmethoxy oxime F (ιοί) MeO-CO- tetranitrogen ratio ° Nan-4-ylmethoxy Η F (102) EtO-CO- Four mouse 11-pyran-4-yl oxime oxime F (103) H-(S)-tetrahydrofuran-3-ylethyl Η F (104) MeO-CO- (S )-tetranitropyran-3-ylethylhydrazine F (105) EtO-CO- (S)-tetrazole. Nan-3-ylethyl hydrazine F (106) H-(S)-Four mice biting 南N--3-methoxy methoxy fluorene F (107) MeO-CO- (S)-tetrahydrocarbamate-3- Methoxy fluorene F (108) EtO-CO- (S)-tetrazonia-β-furan-3-ylmethoxy fluorene F (109) H- (R)-four-rat suffol-3-yl Base Η F (110) MeO-CO- (R)-tetrazonia-β-propan-3-ylethyl hydrazine F (111) EtO-CO- (R)- four-rat-n-yl-3-ylethyl fluorene F (112) H-(R)-Tetrazatriazin-3-ylmethoxyfluorene F (113) MeO-CO- (R)-Tetrazotriazine-3-ylmethoxyfluorene F (114) EtO -CO-(R)-tetrazosofran-3-ylmethoxy fluorene F (115) H-isopropyloxy fluorene F (116) MeO-CO-isopropyl fluorenyl fluorene F ( 117) EtO-CO-isopropyl fluorenyl hydrazine F (118) H-isopropylcyclopropyloxy fluorene F (119) MeO-CO-isopropylcyclopropyloxy fluorene F (120) EtO -CO-isopropylpropylpropyloxyfluorene F (121) H-isopropylcyclobutyloxyfluorene F (122) MeO-CO-isopropylcyclobutyloxyfluorene F (123) EtO- CO-isopropylcyclobutyloxyfluorene F 127892.doc -16- 200843785

(124) H-Isopropylcyclopentyloxyfluorene F (125) MeO-CO-isopropylcyclopentyloxyfluorene F (126) EtO-CO-isopropylcyclopentyloxyfluorene F ( 127) Η-isopropyltetrazolium ratio 喃-3·yloxyj Η F (128) MeO-CO- isopropyl tetranitrogen σ-pyran-3-yl aryl Η F (129) EtO-CO - Isopropyl tetranitrogen ～--3-based lactyl Η F (130) H-Isopropyl tetra-miso-4-pyrimidinyl fluorene F (131) MeO-CO- isopropyl four wind σ 喃 -4- -4-yl-based Η F (132) EtO-CO- isopropyl tetra- wind ratio ° South-4-based milk based Η F (133) H-isopropyl (R)- four mouse bites喃-3-yloxy oxime F 034) MeO-CO- isopropyl (R)-tetrazonia-β-ran-3-yloxy fluorene F (135) EtO-CO-isopropyl (R)-four Rat α-furan-3-yloxyindole F (136) H-isopropyl (S)-tetrahydrofuran-3-yloxyfluorene F (137) MeO-CO-isopropyl (S)-tetrahydrofuran-3 - hydroxy oxime F (138) EtO-CO- isopropyl (S) · tetrahydrofuran-3-yloxy fluorene F

Some of the terms used above and below to illustrate the compounds of the invention will now be more precisely defined. The term halogen means an atom selected from the group consisting of F, CM, Br and I, especially F, C1 and Br. The term Cm-alkyl (wherein n may have a value of from 2 to 8) denotes a saturated, branched or unbranched hydrocarbon group having from 1 to n C atoms. Examples of such groups include mercapto, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, n-pentyl, isopentyl, neopentyl , third amyl, n-hexyl, isohexyl and the like. The term Ck alkyl (where η can have a value from 2 to 8) denotes a saturated, branched or unbranched hydrocarbon bridge having from 1 to n C atoms. Examples of such groups include methylene (-CH2-), ethylidene (-CH2-CH2-), 1-methyl-extension 127892.doc -17- 200843785 (-ch(ch3).ch2_ ), 1, 丨_二f基_Extended ethyl (C(CH3)2_CH(1), n-propanyl1,3-) (-CH2-CH2-CH2-), 1-methylpropan-1,3_extension (-CH(CH3)-CH2-CH2-), 2-methylpropane.13_extension gCH2-CH(CH3)_CHy), and the like, and corresponding mirror-symmetric forms. The term C2_n-alkenyl (wherein n has a value from 3 to 6) means having 2 to. One. Branched or unbranched hydrocarbon groups of atoms and OC double bonds. Examples of such groups include ethenyl, K propylene, 2-propenyl, isopropenyl, propenbutyl, 2-butenyl, 3-butenyl, 2-methyl-hydrazine-propenyl, ^pentenyl, 2-pentenyl, 3-pentopentyl, 4-pentenyl, 3-methyl-2-butenyl, hexenyl, 2-hexenyl, 3-hexenyl , 4-hexenyl, hexenyl, and the like. The term C2-n-alkynyl (wherein n has a value from 3 to 6) denotes a branched or unbranched hydrocarbon group having 2 to n ε atoms and a CeC triple bond. Examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 丨-butynyl, 2-butynyl, 3-butynyl, 2-nonyl-fluorenyl-propynyl , pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, hexenyl, 5-hexyl Alkynyl and the like. The term Ck alkoxy or ^alkylalkyl refers to a Cin-alkyl-hydrazine group, wherein the Ck alkyl group is as defined above. Examples of such groups include decyloxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, second butoxy, tert-butoxy, n-pentyloxy Base, isopentyloxy, neopentyloxy, third pentyloxy, n-hexyloxy, isohexyloxy and the like. The term Ci_n-alkyl-based Weissyl represents a Ci-n-alkyl-C(=〇) group, wherein the q-alkyl group is as defined above. Examples of such groups include methyl-propenyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutyl 127892.doc -18- 200843785 carbonyl, second butylcarbonyl, Tributylcarbonyl 'n-pentylcarbonyl, isopentylcarbonyl, neopentylcarbonyl, third pentylcarbonyl, n-hexylcarbonyl, isohexylcarbonyl, and the like. The term (Ζ:3·η•cycloalkyl) denotes a saturated mono-, di-, tri- or spirocarbocyclic group having 3 to n C atoms. Examples of such groups include cyclopropyl, cyclobutyl, and ring. Pentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, bicyclo[3·2·1·]octyl, spiro[4.5]decyl, norbornyl, descending Decane

Base, original #烧基, 金刚烧基, etc. Preferably, the term 匸 3 ^cyclodecyl represents a saturated monocyclic group. The term <^.n-cycloalkenyl represents a monounsaturated mono, mono, di or spiro carbocyclic group having 5 to n c atoms. Examples of such groups include cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclodecenyl and the like. The term C3-n-cycloalkyloxy denotes a C3_n-cycloalkyl-fluorene group wherein the cycloalkyl group is as defined above. Examples of such groups include cyclopropyloxy, cyclobutyloxy, cyclo-siloxy, cyclohexyloxy, cycloheptyloxy, etc. The term Ch-cycloalkylcarbonyl represents cm-cycloalkyl. A c(=〇) group wherein the C3-n-cycloalkyl group is as defined above. Above = and the form used hereinafter (wherein the bond of the substituent in the phenyl group is shown toward the center of the fluorene %) unless otherwise stated, indicating that the substituent may be bonded to any free position bond of the benzene ring having a ruthenium atom. Knot. Synthetic methods are known to be obtained. Preferably, for example, WO 02/36602, WO WO 02/053573 > WO 02/the compounds of the invention are used in principle, as described in 02/088157, WO 01/16147, 127892.doc - Methods obtained in the documents cited in the documents cited in WO 02/068440, WO 02/098893, WO 05/021566, and the like. As described previously, the compound of the formula I of the present invention and a physiologically acceptable salt thereof have important pharmacological properties, and particularly have an inhibitory effect on the sodium-dependent glucose synergistic transfer protein SGLT (preferably SGLT2). Further, the compound of the present invention and a physiologically acceptable salt thereof have a therapeutic agent capable of treating and/or preventing a neurodegenerative disease (especially dementia). Dementia is characterized by a variety of cognitive deficits and memory impairments. Such cognitive deficits may include one or more aphasia, apraxia, agnosia, and executive function disturbance (see, for example, "Diagnostic and statistical manual of mental disorders", 4th edition, American Psychiatric

Association, 2000) 〇 The compounds of the present invention have potential value in treating one or more neurodegenerative diseases and preventing one or more neurodegenerative diseases or slowing, delaying or reversing the progression of such diseases in a patient in need thereof. A patient intended to treat or prevent a disease or condition according to the present invention is a mammal, especially a human. Preferably, the term patient comprises an individual diagnosed with a neurological neoplasia (especially dementia, in particular Alzheimer's type dementia). The term patient also encompasses individuals diagnosed with an increased risk of developing neurodegenerative diseases, particularly dementia, in particular Alzheimer's type dementia. In the context of this description, the term neurodegenerative disease refers especially to dementia. The term dementia includes Alzheimer's type dementia, vascular dementia, Parklnson dementia, and dementia caused by other common medical conditions 127892.doc -20- 200843785. Dementia caused by other medical conditions include Huntington's dementia, dystonia, degenerative ataxia, aids-related dementia, Cremzfeld_Jak〇b, s syndrome, bovine spongiform encephalopathy , prion-related infections, diseases involving mitochondrial dysfunction, Down syndrome (D〇wn, s syndr〇me), hepatic encephalopathy, amyotrophic lateral sclerosis, multiple sclerosis, olive-bridge brain-cerebellum Atrophy, postoperative cognitive deficits, weak cognitive impairment, hypoxia, ischemia caused by cardiac arrest, stroke, glioma and other tumors, attention deficit hyperactivity disorder, autism, convulsions, epilepsy, Coxaco Korsakoff syndrome, depression and schizophrenia. The course of A Hwang-type Dementia is characterized by gradual onset and continued sorrow. The compounds of the invention may improve cognitive ability and memory, especially in patients as defined above. Thus, administration of a compound to a patient in accordance with the present invention can attenuate, slow, delay, or even reverse cognitive decline or memory impairment. The effects of the compounds of the invention on cognitive ability, learning and memory can be tested by methods well known in the literature or familiar to those skilled in the art. Examples of such tests are set out below: Cognitive abilities, especially their cognitive abilities related to learning and memory, can be tested in the MoITis water maze. Merris Water Maze is a device used to study space learning and memory in rodents. It consists of a large circular pool filled with opaque water, where the small escape platform is submerged below the water surface. During extensive training trials, the animal learned to find the platform 127892.doc -21 - 200843785 and escaped from the pool using different labyrinth tips contained in the laboratory. Details by D’Hooge R. and De Deyn p p (2(m) "AppHcati_ 〇f plus

Morris water maze in the study of learning and memory.-, Brain Research Reviews 36, 6〇_9(). Another method of testing cognitive ability is based on scene-based fear conditioning. The classic fear of '13⁄4 conditioning is the reference task of studying fear memory. It is implemented in an operating room where the animal is properly moderately shocked. The % of laboratories and shocks were tested after 24 hours of sputum by returning the animals to a room for training (scene) and speculating on their freezing behavior, ie the animal's tendency to remain motionless and defensive. Details by Kim J.J. and Jung M w (2〇〇6) ”Neural

And mechanisms involved in Pavlovian fear conditioning: A critical review.", Neuroscience and Biobehavioral Reviews 30, 188-202. Another test for knowing the force is to identify new objects. The test is based on the difference between familiarity and new objects. In the first test (T1), the animal was faced with two identical objects (samples) and in the second experiment (Τ2), two different objects, one of which was a familiar object (the sample) and the other was a new one. object. The increase in the acquisition of new objects is a measure of memory recognition. This test is described by Prickaerts J. (2004) ''Phosphodiesterase type 5 inhibition improves early memory consolidation of object information'', Neurochemistry International 45, 915-928. Such cognitive ability tests described above can also be performed using an Alzheimer's disease animal model (e.g., using a transgenic mouse model such as Tg2576 mice). 127892.doc -22- 200843785 The dose required to achieve the corresponding activity for treatment or prevention depends on the nature and severity of the disease or condition and the method and frequency of administration. And decided by the patient's doctor. Conveniently, by intravenous route, the dose may be U 500 mg, preferably H 〇〇, and from 1 to 1000 mg, preferably from 1 〇 to 6 藉, by the oral route, in each Fees • % are administered 1 to 4 times per day. To achieve this, the compound of formula 1 according to the invention may optionally be formulated with other active substances, together with one or more inert conventional carriers and/or diluents, for example, with corn starch, lactose, glucose. , microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, sixteen Formulated with alkyl stearyl alcohol, carboxymethyl cellulose or fatty substances (for example, hard fat) or a suitable mixture thereof, thereby producing conventional herbs such as plain tablets or coated tablets, capsules, powders, suspensions or suppositories preparation. Formulation Examples The following examples of formulations which can be obtained in a manner similar to those well known in the art are used to more fully illustrate the present invention and are not to be construed as limited to the examples. The term "active substance" means the present invention has a ratio of salicylic acid to glucosinolate. 0: Example 1: an anhydrous ampoules containing 75 mg of active substance/10 ml: Active substance 75.0 mg Mannitol 50.0 mg Water for injection Add to 10.0 ml I27892.doc • 23- 200843785 Preparation: Dry solution Dissolve active substance and mannitol in water. Cool the liquid after packaging. To prepare a ready-to-use solution, the product is dissolved in water (4). Example 2: An anhydrous parental preparation containing 35 active substances / 2 ml. Composition:

Active substance Mannitol Water for injection Preparation: 35.0 mg 100.0 mg Add to 2.0 ml Freeze-dried. The active substance and mannitol are dissolved in water. After encapsulation, the solution. For the preparation of ready-to-use, the product is dissolved in water for injection. Example 3: Composition of tablet containing 5 mg of active substance · 50.0 mg 98.0 mg 50.0 mg 15.0 mg ^ 2.0 mg 215.0 mg (1) Active substance (2) Lactose (3 ) corn starch

(4) Polyvinyl ketone (5) Magnesium stearate _ Preparation: Mix (1), (2) and (3) together and granulate with an aqueous solution of (4). Add (7) to the dried granulated material. Tablets are compressed from the mixture, which are biplanar with facets on both sides and a split notch on one side. Key: agent diameter: 9 mm. 127892.doc -24- 200843785 Example 4: Preparation of tablets containing 350 mg of active substance: (1) Active substance 350.0 mg (2) Lactose 136.0 mg (3) Corn starch 80.0 mg (4) Polyvinylpyrrolidine Ketone 30.0 mg (5) Magnesium stearate 4.0 me 600.0 mg • Mix (1), (2) and (3) together and granulate with an aqueous solution of (4). (5) is added to the dried granulated material. Tablets are compressed from the mixture, which are biplanar with facets on both sides and a split notch on one side. Tablet diameter: 12 mm. Example 5: Capsule composition containing 5 mg of active substance: (1) Active substance (2) Dry corn starch (3) Powdered lactose (4) Magnesium stearate 50.0 mg 58.0 mg 50.0 mg 2.0 mg 160.0 mg By: (1) A powder was ground using (3). The ground powder was added to the mixture of (7) and (4) with vigorous stirring. The powder was mixed in a capsule filling machine and filled into a No. 3 hard gelatin capsule. Example 6: Capsules containing 35 mg of active substance I27892.doc -25- 200843785 Composition: 350.0 mg 46.0 mg 30.0 mg 4.0 mg (1) Active substance (2) Dry corn starch (3) Powdered lactose (4) Stearic acid Magnesium Magnesium 430.0 mg Preparation: (1) was ground into a powder using (3). The ground powder was added to the mixture of (2) and (4) with vigorous stirring. This powder mixture was placed in a No. 0 hard gelatin capsule in a capsule filling machine. Example 7: Composition of suppository containing 100 mg of active substance · Active substance 100.0 mg Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg Reference 2000.0 Mg 127892.doc •26-

Claims (1)

200843785 X. Patent application scope: L Use of a glucopyranosyloxy-pyrazole of the formula (I), a tautomer thereof, a stereoisomer thereof, a mixture of the compound of the formula (1) or a salt thereof, To manufacture an agent for treating one or more neurodegenerative diseases, R represents hydrogen, alkyl, Cw alkyl substituted by 1 to 3 fluorine atoms, C2|alkyl substituted by hydroxy or alkoxy, dilute, C3.6-cycloalkyl, c3.6. Cycloalkyl-Ci_3·alkyl, C3_6-alkyne four gas bite South-3-based, tetrahydrou-r-sigma·3-yl, tetrachloro-sigma-tetra-yl, tetrahydrofuranyl-Ci·3 An alkyl group, or a tetrahydropyranyl group -Ci 3-alkyl group, and R represents Cl.4.alkyl, substituted iCl_4-alkyl with 1 to 3 fluorine atoms, or c3e6-cycloalkyl, and R3 represents hydrogen, fluorine, chlorine, bromine, Ci6.alkyl, C26-alkenyl , C26_ alkynyl, c: 3·6-cycloalkyl, c: 3·6·cycloalkylenemethyl, Ci 6-alkoxy, ^3·6-cycloalkyl-oxy, cycloalkyl Alkoxy group, methyl or methoxy group substituted by 1 to 3 fluorine atoms, C2-4-alkyl group or c2-4_alkoxy group substituted by 1 to 5 fluorine atoms, substituted by cyano group Oral-4, alkyl group substituted by hydroxy or alkyloxy group 127892.doc 200843785, cyano, thiol, C!-3-alkoxycarbonyl, nitro, amine, alkyl Amino, bis-(Cu-alkyl)amino, tetrahydrofuran-3-yloxy, tetrahydropyran-3-yloxy, tetrahydro, pyran-4-yloxy, tetrahydrofuranyl-C! • alkoxy, tetrahydropyranylalkoxy, and R 4 and R 5 may be the same or different and represent hydrogen, fluorine, chlorine, bromine. Alkane-yl, Ci-3-alkoxy, methyl substituted by 1 to 3 fluorine atoms or .methoxy, and R6, R7a, R7b, r7. Independently of each other, has the meanings selected from the group consisting of hydrogen, (Cy alkyl)carbonyl, (Cn alkyl)oxycarbonyl, arylcarbonyl and aryl-(Cw alkyl)-weiki, simultaneously in the above groups The aryl group referred to in the definition is intended to mean a phenyl group which may be mono- or disubstituted independently of each other by Rh, and the substituents may be the same or different and Rh represents fluorine, gas, bromine, iodine, Cw alkyl, difluoro. Methyl, trifluoromethyl, C!·3·alkoxy, dimethoxyl trifluoromethoxy or cyano, and unless otherwise specified, the above alkyl group may be straight or branched. 0. 2. A use of a pyranoglucosyloxy group of the formula (I) as defined in claim 1 for the use of a tautomer, a tautomer, a stereoisomer, a mixture or a salt thereof An agent for preventing one or more neurodegenerative diseases or slowing, delaying or reversing the progression of such diseases. 3. The use of claim 1 or 2, wherein the neurodegenerative disease is dementia 0 127892.doc 200843785 4. The use of claim 1 or 2, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's type dementia, vascular dementia, Parkins〇n dementia, and dementia caused by other general medical conditions. 5. A medical team ^ « , mouth, /, for the treatment of one or more neurodegenerative diseases: ::::::: as defined in claim 1 - 6 - a pharmaceutical composition , for use in pre-diagnosing or slowing, delaying or reversing the progression of the general formula (1) as defined in claim 1 of the neurodegenerative disease claim 1, the composition comprising a glucosyloxy group 如Oxazole. 127892.doc 200843785 VII. Designation of Representative Representatives (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the representative figure: VIII. If there is a chemical formula in this case, please reveal the characteristics that best show the invention. Chemical formula: 127892.doc