TW442288B - Pharmaceutical composition for the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof - Google Patents

Abstract

A pharmaceutical composition for the treatment and/or prophylaxis of leptin resistance and/or conditions associated with leptin resistance and/or complications thereof, which composition comprises an effective, non-toxic and pharmaceutically acceptable amount of a leptin sensitiser or a pharmaceutically acceptable derivative thereof, wherein the leptin sensitiser is 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and a pharmaceutically acceptable carrier thereofor.

Description

442288 A7 B7 V. Description of the invention (/) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives The present invention is related to novel treatments and in particular to treat and / or prevent leptin resistance and / or with Conditions and / or complications associated with halide resistance. Zhang Zhang et al. (Nature, 372, 425-431, 1994) proposed that one of the key molecules that play a key role in energy balance regulation is the M protein. Zhang et al. Also published the selection and sequencing of mouse and human gene proteins or 'leptin'. British Patent Application, Publication No. 2292382 is particularly relevant to polypeptides, OB polypeptides or allelic variants or their analogs, and their use for regulating body weight. In particular, GB 2292382 discloses that OB polypeptides and their specific analogs, such as agonists, will be useful in the treatment of obesity. European Patent Application, Publication No. 0306228 discloses that the specifically disclosed tetrahydrothiazole dione derivative has blood glucose lowering and lipid lowering activity and is effective for treating specific dietary diseases. International patent application, Publication No. WO 95/25026 also discloses that the compounds of EP 0306228 are essentially used for problems related to under-eating, such as anorexia, or over-eating, such as obesity and mental health disorders. Appetite and food intake. EP0306228 The compound of Example 30 is 5 · (4- [2-N-methyl-N- (2-tonidyl) amino) ethoxy] benzyl) -2,4-tetrahydrothiazoledione ( Or TBRL49653 '). European Patent Application, Publication No. · 0306228, 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740: International Patent Application, Publication No.-3-Standard of this paper Applicable to China National Standard < CNS) A4 specification (210 X 297 mm) {Please read the precautions on the back before filling this page)

n IF. ^ 1 * 1 I »^ 1 1 H 1 i I t ^ in II II I Λ42288 A7 B7 V. Description of the invention (2> Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 92 / 185〇1, 93 / 〇2〇79 'Magic / 22445 and U.S. Patent Nos. 5104888 and 5478852 have also revealed that certain tetrahydropyrazole dibream derivatives have hypoglycemic and lipid-lowering activities. "• These compounds have also been identified as having insulin sensitizer activity. It is generally judged as another series of compounds having insulin sensitizer activity. These are the compounds disclosed as representative by international patent applications, Publication Nos. WO 93/21166 and W094 / 01420 t. This compound is referred to herein as Are examples of other acyclic insulin sensitizers, which are disclosed in US Patent No. 5232945 and International Patent Application, Publication Nos. WO92 / 03425 and WO91 / 19702. Other cyclic insulin sensitizers Examples are those disclosed in European Patent Application 'Publication No. 0533933, Japanese Patent Application Publication No. 05271204, and U.S. Patent No. 5264451 »Known via oxygen Xiao Zhao proliferator-live > (specific isoform of receptor (hereinafter referred to as ΑΡΙΙγ), a member of the nuclear receptor superfamily (including steroids, thyroid, and retinal hormone receptors) (Evans, Science 240, 889-895, (1988)). From Chawla and others also learned that PPARY has been expressed as early as during adipocyte differentiation (Endocrinology 135, 798-800, 1994) p from J. Biol. Chem., 270, 12963-12966 It is known that tetrahydrothiazole difluorene, such as BRL49653, is a PPAKγ agonist. In the recently published Proceedings of the National Academy of Science, Kallen and others declared that they The results show that BRL49653 and other anti-diabetic tetra-argon thiacillin ---------- 1--------- · I ------- (Please read the note on the back first Please fill in this page again for this matter) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 gt) Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs for consumer cooperation Du printed »442288 A7 B7 V. Description of the invention (3) Adjustment of ketone reduction The expression of the lutein gene has led to a decrease in plasma leptin concentration. Kallen et al. The effect of serotonin is related to the activity of PPAIII γ agonists of these tetrahydrothiazoles. In an independent series of experiments using vasoline-resistant rats, we found that BRL49653 has no effect on hordes in rat adipose tissue. Effect, and more importantly, 'circulating plasma leptin concentration is significantly reduced a most importantly' is due to lack of food intake and weight gain, the aforementioned reduction occurs, leading to the proposed BRL49653 and other similar compounds In response to leptin, stem cells must be sensitized. Therefore, it is concluded that BRL 49653 and similar compounds' will enhance hormones, their agonists, and other agents that enhance the response to the hormone cells, and their effects on anorexia and weight loss. The above is considered to be incomplete for the hormone signal The treatment of those individuals that are responding, that is, halogen-resistant individuals is particularly important. Therefore, the present invention provides a human or non-human mammal for treating and / or preventing halogen resistance and / or with halogen A method of resistance-related conditions and / or complications thereof, the method comprising administering an effective, non-toxic, and pharmaceutically acceptable amount of a leptin sensitizer or a pharmaceutically acceptable deduction to internal administration. In particular, this method involves the use of a selective leptin sensitizer. Suitably, the leptin sensitizer is co-administered with leptin and its analogs, such as agonists. In a beneficial aspect, therefore, the method includes co-administering an effective, non-toxic, and pharmaceutically acceptable amount of a leptin sensitizer and a leptin and / or avidin analogue, such as an agonist. Halogen resistance causes obesity and loss of food and energy control. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public love) -------- III 'I · ------- Order · -------- Line— < Please read the notes on the back before filling this page)

Λ4228 B A7 B7 Member of the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperative, India. V. Invention Description (4) Conditions and complications associated with leptin resistance, including cardiovascular disease, 1: atherosclerosis, damaged Glucose for Receptive and Non-Aidin-dependent Diabetes. ^ In a particular aspect, the present invention provides a method for treating and / or preventing obesity in a human or non-human mammal. The method comprises combining two effective, non-toxic and pharmaceutically acceptable amounts. A sensitizer or a pharmaceutically acceptable derivative thereof is administered internally. Preferably, the obesity is associated with or caused by halide resistance < This method is resistant to diarrhea resistance syndrome, including impaired pre-diabetes in this syndrome Sexual patients are particularly benefited. Prevention is particularly beneficial for the pre-diabetic 'impaired glucose tolerance phase of this syndrome. Suitable sensitizers are Congdao sensitizers, including tetra-argon B stopper, and acyclic insulin sensitizer β. Suitable sensitizers are PPAIIII agonists. In particular, the halogen sensitizers are active as insulin sensitizers and PPAIIII gamma agonists-suitable tetrahydro "thiazolides are tetrahydrothizone-2,4 · diodon derivatives, which have Compounds of the formula (A): Υ The paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) ------------- ^ -------- Order --------- line (please read the precautions on the back before filling this page) A7 B7 r 442288 V. Description of the invention (female) Suitable formulas including formula (A) include compounds of formula (I) :

, Its tautomeric form and / or its pharmaceutically acceptable salts and / or its alternately acceptable solvates, where T represents an aryl or heterocyclic group, as needed, via one or more alkanes Substituted with aryl, aralkyl or heterocycloalkyl, the alkyl, aryl, and heterocycloalkyl themselves may be substituted with β as appropriate, as appropriate, in Formula (I), marked with an asterisk (*) The carbon atom is asymmetric carbon = suitably, T is represented by (la), yang, (fc), (⑹, (Ie), (all '⑽, (Ih)', (Ij), ⑽, (11 ), Rhenium, osmium and coltan are selected from the list ...

R in —------ 11 ^-— —1 --— —Order --I ------ Line f Please read the notes on the back before filling out this page) Staff Consumption of Intellectual Property Bureau, Ministry of Economic Affairs Printed by the cooperative] — (CH2) n— ~ 〇

(la) where Al, A2 'Ri, and "are defined as follows and conform to the standard of EP030622S. This paper standard is applicable to the national standard of China (" CNS "A4 specification). Α7 _ Β7 V. Description of the invention (Handled) ( I) related; Cheng, 1

db) where Li and L2 are the same or different and each represent argon or a lower alkyl group, or L! and L2 are combined to form an alkylene group; L3 is an unsubstituted or substituted alkyl group, alkoxy group, or cycloalkyl group ' Phenyl 'phenyl, aromatic fluorenyl, 5- or 6-membered heterocyclyl, including 1 or 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or a formula

R 1 R > N- ------------ ^ -------- (Please read the notes on the back before filling out this page) The Intellectual Property Bureau of the Ministry of Economic Affairs is responsible for Λ Consumer Cooperatives The printed base map 'wherein Ri4 is the same or different and each is a low alkyl group' or R13 and Ri4 are directly or by interrupting a heteroatom from the group consisting of nitrogen 'oxygen or sulfur to combine with each other to Forms a 5 or 6 member ring; R2 is a bonded or lower elongation group or a pharmaceutically acceptable salt thereof (assuming that the compound is as defined in EPδ203); or -8 uses the Chinese national standard (CNS > A4 specification) (210 X 297 public gold 442288

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

And R2 are the same or different, and each represents an argon atom or, for example, R3 represents a hydrogen atom, Cl.6 lipid fine group, a wax ring, an aromatic chemotactic group, a heterocyclic group, a aromatic wax group, Linmei, and a truncated group; Lai Bao (such as Mao 氡 group) silk, or aryl Hyun oxygen R4 and R5 are the same or obtained and each represents a hydrogen atom such as Hyunyl or such as Hyunoxy, or R4 and r5 together represent Cm elongation dioxy, η is 1, 2 or 3; w "-CH2 ·, > 〇〇, or ch〇r6 · group (where Miao 'represents r3 = any of the-atoms or groups defined, and r3 can be the same or different) Y and Z is the same or different, and each represents an oxygen atom or an acid group: and a pharmaceutically acceptable group thereof (assuming that the compound of formula (VII) is as defined in EP 0B9421): or

This paper size is applicable to the national standard (CNS) A4 regulations' Ca x 297 Gongchu) ^ -------- Order --------- line (.Please read the precautions on the back before (Fill in this page) 442288 A7 B7

V. Description of the invention (?) TR! And r2aR3 are as defined in formula (1) in ep0032i2S: or

RA— / R 乂 — <CH2} 2 (Ie) or a pharmaceutically acceptable salt thereof, in which R is a cycloalkyl, naphthyl, thienyl, furyl, or phenyl group of 3 to 7 carbon atoms Or a substituted phenyl group, wherein the substituent is an alkyl group of 1 to 3 carbon atoms, an oxo group of 1 to 3 carbon atoms, a trifluoromethyl group, an amino group, or a bis (trifluoromethyl) group; R1 is an alkyl group of 1 to 3 carbon atoms; X is 0 or c = o; A is 0 or S; and B is N or CH; (assuming that the compound is as defined in formula (1) in EP04283I2) ,·or

(If)

Among them, A, B, R, and Rl are as described above for Cheng Yi and EP -ία-This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ----------- -Install -------- Order ------- line (please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

Δά2288 A7 B7 5. Definition of formula (II) in the description of the invention (f) 0428312; or

HO (Ig) wherein R1 is as defined in relation to formula (I) in EP0489663; or

R

OR CH——CH2——〇

(Ih) where R1, R2, R3 and η are as defined in formula (I) in EP0155845; or (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

R -CH2CH20

di) The dimensions of this paper are applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 442288 A7 B7 V. Description of the invention (M) Where R is CI-6 alkyl group, especially ethyl group, as described in As defined in EP0257781: or

Wherein Ar, Rl, R2, r3, r4, R5, n,] [; and the double system are as defined in Formula (I) in US Patent No. 5104888; or

(Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs When A, Rl, R2 and X are as defined in formula (I) in EP〇2〇S42〇: or

⑼ When R1, R2 'X, Z, m and η are as -12 in EP0177353-This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 4 42 28 8 A7 ________B7 V. Invention &Quot; Defined by formula (I); or

According to formula (I) of EP 03I9IS9; or X1

(Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, where A and B are each independently CH or N, but when A or ^ is \, the other is CH;- 'X is S, SO, S02' CH2, CHOH or C0; η is 0 or 1:

Yl is CHR20 or R2i, but η is 1 and Υ1 is NR21, Xl is S〇2 or CO; Z is CHR22, CH2CH2, CH = CH, OCH2, SCli2, SOCH2 or SO2CH2;

Rl9, and 20, R21, and ruler 22 are each independently argon or methyl; and X2fX3 are each independently hydrogen, methyl, trifluoromethyl, benzyl, benzyl, -11-This paper size applies to Chinese national standards (CNS ) A4 specifications &lt; 210 X 297 mm) 442288 7 A7 __B7 V. Description of the invention (y) meridian, methoxy, benzyloxy, benzyloxy, bromo, gas, or fluoro; or its medicine Acceptable cationic salts, or pharmaceutically acceptable acid addition salts thereof, wherein A or B is N (assuming the compound is as defined in formula (I) in EP0332331); or X ^ Y | ζΛψ ^ ~ ίαΗ2} π—w—— ζ1 (Ιο) where V is -CH = CH-, -N = CH-, -CH = N-, or s: D is CH2, CHOH, CO, C = NORn or CH = CH; X is S, O, NRI8, -CH = N or -N = CH; Y is CH or N; Z is hydrogen, (Ci-7) alkyl, (C! J?) Cycloalkyl, benzene Base, naphthyl, pyridyl, furyl '«synyl, (Ci_7) alkyl, trifluoromethyl' (Cl-3) alkyl, trifluoromethyl, bromo, or bromo Single or two-substituted phenyl in the base map; printed as hydrogen or (C 〖_3) by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Group;

Ri7 and Han18 are each independently qi or methyl, and η is 1, 2 or 3, or a pharmaceutically acceptable cationic charge thereof, or when the compound contains a basic nitrogen, the pharmaceutically acceptable acidity plus Salts, (assuming that the compound is as defined in formula (I) in EP0332332): and -14.- This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) 442288 Α7 Β7 X —CH2—α

5. Description of the invention (β

Q

Ν (Ip) where Q and X are as defined in relation to Formula ⑴ in International Application No. WO92 / 18501. Suitably, T represents part of the formulae (Ia), (Ic), (Ie), (if), (Ii) '(Ik), (Π)' (Im) or (Ιο) as defined above. In particular, T represents a part of the list consisting of ⑻, (b), (c), ⑷ '(e), (ί), (g), (h), and (i): (Please read the note on the back first (Fill in this page again)

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs

15.

(d) This paper size is in accordance with Chinese National Standard (CNS) A4 (210x297 mm) 442288 Α7 Β7 V. Description of invention (outside)

(g)

(f)

&gt; ja

(Please read the notes on the back before filling out this page> (0 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, especially the formula 0), (b), (c), (d), and (e) Some are also included in the treatment of the present invention are disclosed in European patent applications, bulletin numbers: 0008203, 0139421 '0032128' 0428312, 0489663, 0155845, 0257781, 0208420, 0Π7353, 03191S9, 0332331, 0332332, 0528734 and 050S740; International Patent applications, Bulletin Nos. 92/18501, 93/02079, 93/22445, and U.S. Patent Nos. 5104888 and 5478852 of tetrahydroxazolidine and / or PPAIIII gamma agonists. Specific examples of tetrahydrooxazolidine are those disclosed In EP 0306228 and WO94 / 05659. Another special example is the tetrahydrothiazole dimer disclosed in EP 0139421 and USP 5478852. The compounds of EP0306228 and WO94 / 05659 include compounds of formula (II): &quot; 16. · ^ Paper size applies Chinese national standard (CNS &gt; A4 specifications & 21〇X 297 public meal) 442288 A7 B7 V. Description of the invention (

A

ΐ f R3 —N— (CH2) n—〇- £ ^ 2Xch —q __ ^. ° VH O Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy (Π) or its tautomeric form and / or its substitute Accepted salts, and / or pharmaceutically acceptable solvates thereof, wherein: Ai represents a substituted or unsubstituted aromatic heterocyclic group: R1 represents a hydrogen atom, an alkyl group, a fluorenyl group, an aromatic alkyl group Where the aryl moiety may be substituted or unsubstituted, or substituted or unsubstituted aryl; R2 and R3 each represent hydrogen * or r2 and r3 together represent a bond; A2 represents a total of 5 substituents Benzene ring; and π represents an integer ranging from 2 to 6; for human or non-human mammals in need thereof. When it represents a 5-membered aromatic heterocyclic group, suitable values of 'a1 include thiazolyl and oxazolyl, especially oxazolyl. When it represents a 6-membered aromatic heterocyclic group, a suitable value of 'Al includes a pyridyl group and a spermidine group, especially a bitenyl group.' Preferably, A] represents the formula 0, (k) or a fluorene moiety:- 17. This paper size applies Chinese national standard (CMS &gt; A4 specification (210 X 297 mm) (. Guess read the notes on the back before filling in this page) --------- Order ----- ---- line 442288 A7 V. Description of the invention (Μ)

A

R

V η '·

R

ω

R (k) ⑴ where:, sub-time, then, and 7 and the% of 唆 atom to which they are attached, where each completed atom represented by R and R7 together is substituted or unsubstituted: and in the formula (part 〇 In the formula, χ1 represents oxygen or sulfur. Suitably, Al represents the part of the formula ① defined above. Suitably, A1 represents the part of the formula defined above). Suitably, A is a part of the formula ① defined above. The special form of part (I) is part (Γ):

R ------------ Raid ------- Order ί ------- Line (Please read the precautions on the back before filling out this page) Employees of the Intellectual Property Bureau of the Ministry of Economy Consumption Printed by a cooperative

R

(!) Where R6 and R7 are as defined for formula (1). In a more favorable situation, R6 and R7 together represent the formula (m) part 18. ^ The paper size is appropriate to use the Chinese national standard (⑽) A4 specifications ⑵ χ 公 公 442288 A7 B7 V. Description of the invention (π.) 8b

R R 8a

Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ⑽ Among them, R8a and R8b each independently represent 羞, 衣, 卤素, halogen, substituted or unsubstituted alkyl or alkoxy. Wood clogs suitably, R8a and R8b each independently represent nitrogen, sulfonium, sulfonyl or oxo. Suitably 'RSa stands for hydrogen. Suitably, R8b is preferably R1 and R8b both represent hydrogen. In another advantageous case, R6 and R7 are freely represented by R, _K each independently represents hydrogen, alkyl, or substituted or unsubstituted phenyl, and more suitably, Re and r7 independently represent hydrogen, alkyl, or Phenyl. Preferably, 'for the part of formula (j)', R6 and r7_ represent the part of formula ⑹. Preferably, for parts of formula (k), (1) or (1,), R6 and R7 both represent hydrogen. It was identified that A2 included three optional substituents among the five substituents. Suitable substituents of Part A include dentine, substituted or unsubstituted alkynyl or alkoxy, as appropriate. In addition, suitable, more favorable and better values for variables A2, R1, ore, jealousy and η, such as As defined in Ep0306228 and WO94 / 05659. A specific example of the compound of formula (II) is 5_ [4 ~ [2_ (N_methyl_N_ (2-pyridyl) amino) ethoxy] benzyl] tetrahydrothiazole-2,4-dione or Tautomeric forms and / or pharmaceutically acceptable salts thereof, including the salts disclosed in WO 94/0565 g, and most particularly their maleate salts, and / or Pharmaceutically acceptable solvates. -19- The size of this paper 剌 Chinese National Standard (CNS) A4 (210 X 297 g t) 8 6 3 4 1 f &lt;. Please read the notes on the back &gt; s before filling this page) II— ^ OJI . ^ 1 It tt · ^^^ 1 flf 1 '. 4 n _1 nnn If ti t— »44228 8 A7 ___B7 V. Description of Invention (β) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs as shown above. The compounds may exist in one of several tautomeric forms, all of which are included in the method of the invention. It has been identified that the present invention encompasses all isomeric forms of the compounds of formula (I) 'and their pharmaceutically acceptable salts, including whether they are administered as early monoisomers or as any stereoisomeric form of a mixture of isomers 》 ”In addition, the special tetrahydropyrazole dihydrazones are those disclosed in EP 0139421 and USP M78852, which have the formula ① as defined above (where the T part represents the (ic) part as defined above), especially (+)-5-[[4-[(3,4-Dihydrogenyl-2,5,7,8-tetramethyl-2H-1-benzypiperan-2-yl) methoxy ] Phenyl] methyl] -2,4-tetrahydrodiamine (or), 5- [4-[(1 · T cyclohexyl) methoxy] benzyl] tetrahydro "thiazolyldiamine (or ciglitazone), 5- [4- [2- (5-acetamidin-2-yl) ethoxy] benzyl] tetrahydropyrazole · 2,4 · dione (or Pioglitazone) or 5-[(2 -Fluorenyl-2,3-dihydrobenzocarbazepine 5-methyl) methyl] tetrahydroargument 2,4-diphenyl (or englitazone). Revealed in European Patent Applications, Publication Nos. 0306228, 0008203 &gt; 0139421 &gt; 0032128 '0428312' 0489663 &gt; 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734 and 0508740, International Patent Application 'Built No. 92 / 18501, 93/02079, 93/22445, and U.S. Pat. Nos. 5104888 and 5478852 are suitable, more advantageous, and better tetrahydrocarbazolidines, which are equivalent to the respective published patent cases, which are defined as "Benefiting Better Compounds" has been disclosed in international patent applications, Publication Nos. WO91 / 19702, WO92 / 03425, W093 / 21166 and W094 / 01420, and U.S. Patent-2α ----------------- ^ -------- ^ --------- line (Please read the notes on the back before filling in this I &gt; This paper size applies the national standard (CNS) A4 specification (210 X 297 (Mm) 1 442 28 8 A7 ___B7_____ V. A suitable, more favorable and better non-cyclic insulin sensitizer of invention description () No. 52329452 is equivalent to the respective published patent cases, which are defined as suitable and more favorable And better compounds. Advantageous and preferred insulin sensitizers are disclosed in European Patent Application, Publication No. 0533933, International Patent Application, Publication No. W093 / 02079, Japanese Patent Application Publication No. 05271204, and US Patent Nos. 52645515 and 5478852. And preferred compounds.-Those also specifically included in the method of the present invention are the specific implementations disclosed in the above-mentioned applied patents. Suitable pharmaceutically acceptable forms of halogens and / or their analogs, such as Agonists and / or agents that mimic or increase the effects of leptin medicine are as described in GB2292382. The disclosure of GB2292382 is incorporated herein as a reference. It is understood that the treatment of the present invention, when the treatment includes a separate compound agent Compounds of formula (II) as defined above, including 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] tetrathiathiazole-2, When 4-dione or its tautomeric form and / or its pharmaceutically acceptable salts are administered, it does not include the treatment of diseases related to overeating, such as obesity and bulimia caused by overeating. The use of the term & M Shou Sumin agent &quot;, related to one line increases' e.g. pharmacological response of target cells to the substance of the predetermined plasma leptin concentrations. "&quot; Selective sensitization of sensitizers" operates to be substantially immune to specific effects, such as a decrease in plasma hormonal concentrations or a reduction in hormonal expression or secretion, especially when these effects originate from effects in adipose tissue 21- This paper size ilffl Zhongguanjia Standard (CNS) A4 specification (⑽AX 4 7mm) ~ 'Γ Please read the unintentional matter on the back before filling in this page) Printed by the Consumer Cooperative of Intellectual Property Bureau of the Ministry of Economic Affairs nn n -'— w, a ^ in I n t_l I line! ------------------------ A7

44228 B _________B7___ V. Description of the invention (w) The term "痩 素 防 &" used in the text is related to a condition in which an individual has a lower than normal pharmacological response to leptin, such as attributed to a given plasma At leptin concentrations, the response to target cells is reduced. 'Leptin analogues' includes their agonists and analogues disclosed in GB2292382. The term &quot; PPAR τ agonist M, as used herein, is related to the oxidized bodies of a gamma subtype Proliferators ~ agonists of activated receptors, such as small molecular weight agonists, a member of the nuclear factor-activated ligand-activated transcription factor superfamily (including steroids, retinoids, and thyroid receptors). PPARr agonists The activity can be determined by using the method disclosed in Lehmann et al .: Journal of Biochemical Chem, 270, 12953-12956 (1995). The term "obesity" Treatment &quot; includes a soy or cosmetic treatment intended to cause weight loss. It is particularly important for obesity-related diabetes syndromes. The term "aryl" used in the text includes benzyl and tea base, and if necessary, up to five, preferably up to three are selected from the group consisting of dysprosin, academy, phenyl, alkoxy, iS, and iS. Substituted by radicals, amines, cans, slow radicals, oxygen-burning radicals, oxygen-burning radicals, silk-silk radicals, or base radicals. Suitable heterocyclic radicals are aromatic or non-aromatic heterocyclic radicals. Suitable non-aromatic heterocyclic groups, including heterocyclic groups containing a single or condensed ring group 'in each%' which contain up to 4 heteroatoms selected from oxygen, pyrene or gas, as required Condensed to one or more aryl groups. 22- This paper size is applicable to China National Standard (cns) A4 specification. -Order -------- Line — 1 {Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs f 442 28 8 A7 B7 5 V. Description of the invention (α 丨Suitable aromatic heterocyclic groups include substituted or non-excepted: Ring of the fragrant _ county, in each of its wealth, its bag of money from the four = = or sulfur or nitrogen heteroatoms. History in the oxygen, branch favorable aromatic Heterocyclyl, including substituted or unsubstituted rings Atom 'is preferably a mono-aromatic heterocyclic ring of 5 to 6 ring atoms. It is an aromatic heterocyclic group, which contains 1, 2 or 3 heteroatoms, especially 1 or 2 selected from oxygen. Heteroatoms of sulphur, nitrogen or nitrogen. — Suitable substituents for heterocycles, including up to 4 substituents selected from the group consisting of alkyl, alkoxy, aryl and halogen, or on adjacent carbon atoms Any two substituents together with the carbon atom to which they are attached form an aryl group, preferably a benzene ring, and the aryl carbon atom represented by the di-substituent itself may be substituted or unsubstituted. It is understood that the above The references to "aryl" and "heterocyclyl" and its substituents are different from the definitions of related special compounds disclosed in the above-mentioned published patents in that announcement. The term &quot; halogen &quot; means fluorine, gas, bromine, and iodine; preferably gas. The terms "alkyl" and "alkoxy," as used herein, are related to having up to 12 A straight or branched carbon chain group of carbon atoms. As used herein, the term "fluorenyl" includes alkylcarbonyl The suitable base is Cu alkyl, especially Ci-e 1 group, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl or tertiary — Ding Shao. Suitable substituents for any alkyl group, including the above-mentioned terms • 23- This paper size applies the Chinese National Standard (CNS) A4 specification &lt; 210 X 297 mm> ^ ------- -Order --------- Line r Jing first read the note on the back before filling in this page)

Printed by the Consumers 'Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs M 442288 Α7 Β7 5 Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Invention Description (22) "Fangji". Suitable pharmaceutically acceptable salts include carboxylates and acid addition salts. Suitable pharmaceutically acceptable carboxy salts include metal salts, such as ig 'metal test salts, such as calcium, sodium, or sodium, metal test salts such as calcium or magnesium, and ammonium or substituted ammonium Salts, such as alkylamines with a low carbon number, such as triethylamine, hydroxyalkylamines, such as 2-hydroxyethylamine, bis- (2-hydroxyethyl) -amine or tri- (2-hydroxyethyl) -Amines, cycloalkylamines, such as dicyclohexylamine, or dibenzylamine with procaine, N-fluorenyl-b-benzylethylamine, dehydropinosylamine, HN1-didehydropinosamine , Grapeline, N-methylgrapeline, or pyridine based on 4-pyridine 'Colin test, quinine or quine β Suitable acid addition salts, including pharmaceutically acceptable inorganic salts, such as Sulfates, nitrates, phosphates, borates, hydrogenates and hydrogen blues' and pharmaceutically acceptable organic salts such as acetate, tartrate, maleate, citrate, benzene Formate, ascorbate, methane-nanoate, a-fluorenyldiabirate and a-glyceryl phosphate, especially maleate, are suitable for medical use. Accepted solvates, including hydrates. The tetrahydrothiazole dione referred to herein can be conveniently prepared using, for example, the methods disclosed in the aforementioned published patents. The PPAIIII gamma agonist referred to herein: can be conveniently prepared according to the method disclosed in the above-mentioned published patent case: for example, a compound of formula (I), or a tautomeric form thereof, and / or Pharmaceutically acceptable salts and / or pharmaceutically acceptable solvates can be used as described in -34.- This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) ( Please read the precautions on the back before filling this page) J 442 28 8 A7. ^ B7 V. Description of the invention (23) EP 0306228 and W094 / 〇5659 are prepared according to the method "and for example (+)-5 · [ [4-[(3,4-Dihydro-6-Ethyl-2,5,7,8-tetramethyl-2H-I-benzopyran-2-yl) methoxylphenyl] methyl Tetra-2,4-tetrahydrocarcinoma is also a troglitazone, which can be prepared by the method described in EP0139421 or USP 5478852. Tetrahydrothiazole dione salts and / or solvates can be prepared according to, for example, the The method disclosed in the above-mentioned published patent cases is conveniently prepared and isolated. '' The invention also provides leptin sensitizers or pharmaceutically acceptable derivatives thereof for use in the treatment and / or prevention of conditions and / or complications associated with leptin resistance and / or halide resistance . The present invention also provides a leptin sensitizer or a pharmaceutically acceptable derivative thereof for use in the manufacture and treatment of and / or prevention of hafnium resistance and / or conditions and / or complications associated with hafnium resistance Pharmaceutical products. In the method described above, the leptin sensitizer may be peed, or preferably, it may also be used as a pharmaceutical composition comprising a pharmaceutically acceptable vehicle. In the treatment of the present invention, the rhenium sensitizer mentioned in the text can be formulated and administered according to the methods disclosed in the above-mentioned applied patents and patents. Therefore, the present invention also provides a pharmaceutical composition for the treatment and / or prevention of obesity, the composition comprising a halogen sensitizer, or a pharmaceutically acceptable derivative thereof, and therefore a pharmaceutically acceptable excipient . As shown above, when it is assumed that the tincture may also contain an effective, non-toxic, and pharmaceutically acceptable amount of tincture and / or its analogs, such as agonists, and / or agents that mimic or increase the effects of leptin tincture For the better "This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) f Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ^ 1 ^ 1 ^ 1 ^ 1 ϋ ϋ I t ^ I n ϋ ϋ nn I— xn tt ln I fi Λ42288 A7 _______B7 V. Description of the invention (蚪) The Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the term used in this term 'Medicine "Acceptable" includes compounds, compositions, and ingredients for both human and veterinary uses: for example, the term 'pharmaceutically acceptable salts' includes veterinary acceptable salts. If desired, this composition can be packaged with written or printed instructions. Although the composition is also envisaged for administration by other routes, such as by injection or transdermal absorption, the pharmaceutical composition of the present invention will generally be suitable for oral administration. A particularly suitable combination powder for oral administration is a unit dosage form such as Poor or capsule. Other fixed unit dosage forms, such as powders in sachets, can also be used. According to common medical practice, excipients may include diluents, fillers, disintegrating agents, wetting agents, lubricants, colorants, flavoring agents or other conventional adjuvants. Representative excipients include, for example, Crystal weaving vitamins, starch, starch by sodium acetic acid, k-bake this Luoyao 嗣, poly-HQ 《slightly burned tt, magnesium stearate, sodium lauryl sulfate or sucrose. Most suitably, this composition will be formulated in a unit dosage form. The unit dose normally includes the active ingredient in the range of 0.1 to 1000 mg, more usually, from 0.1 to 500 mg, and more particularly, from 0.1 to 250 mg, preferably from 0.5 to 1 〇mg. Conveniently, before being defined, this active ingredient is administered as a pharmaceutical composition to form a particular aspect of the invention. In the above method, the active compound is taken at a dose, such as the above -26.- — '' HIIIII — -------- Order (please read the precautions on the back before filling this page) The scale is applicable to the Chinese National Standard (CMS) A4 specification (2〗 〇X 297 mm) ί 44228 8 Α7 _ Β7 V. The method described in the description of the invention (&gt; r), for a 70 kg adult, the usual daily The total dose ranges from 0.1 to 6000 mg ', but more usually from about 1 to 1500 mg, and generally from about 0 to 5 to 10 mg, one to six times per day. That is, from 1.429x10-3 to 85,714 mg / kg / day *, which is usually about 1.429x10-2 to 21.429 mg / kg / day, and generally about 7.143x10-3 to 0.1429 mg / kg / day. In another aspect, 'the present invention provides novel leptin sensitizers, especially excluding any compounds disclosed in the above patents and patent applications', such as the leptin sensitizers of specific embodiments thereof. No unacceptable toxic effects are expected when the method is performed within the above-mentioned dosage range. The effectiveness of the active compounds in the present invention can be obtained by using conventional methodologies, such as the test procedures disclosed in European Patent No. 0223385 or GB 2292382. And confirmed. (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 27. This paper is inversely applicable to China National Standard (CNS) A4 (21〇χ 297 mm · 1 IIIIII · — — — — 1 —-'-------- ---- ------------. 442288 A7 ___B7 V. Description of the invention (尨) Pharmacological data Tetrahydro The effect of two-feed knee knee sensitizer, BRL49653, on gray leptin concentration and the expression of epithelial fat mRNA in mature Wistar rats from high fat silver food and high carbohydrate silver food It is known that when the atmosphere is eaten with 1¾ fatty foods, it will lead to resistance to auntrin (Storlein et al. 1991, Diabetes 40: 280-289). Given a prescribed diet for four weeks BRL49653 (10 μmol / kg / S) was administered orally on the last four days. When treated with BRL49653, the plasma halide concentration in high-fat-fed rats decreased from 2.34 to 0.19 to 1.42 to 0.09 nanograms. Per milliliter (p &lt; 0.001). Plasma hormones are not affected by BRL49653 in high carbohydrate-fed rats. There was no difference in o6 mRNA performance between the rats fed with high fat and those fed with high carbohydrates. BRL49653 has no effect on weight gain or food intake (Table)). BRL49653 reduces circulating carbohydrate However, observations of no effect on dietary or weight gain in phosphinolide-resistant rats show that this compound is enhancing the cellular response to leptin. ------------ "Strike- ------- Order ------- Line (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -2a-ΐ The paper size applies Chinese national standards ( CMS) A4 specification (210 X 297 mm) 44228 8 A7 B7 V. Description of the invention (7) Table 1 · Zhao Zhong of rats treated with HF or HC + diet soil and their intake of high fat and high carbohydrate control group BRL 49653 Control group BRL 49653 Weight (g) (Initiation of treatment) 378.3 +7.1 378.3 ± 6.6 353.1 ± 8.3 366.0 ± 6.5 Weight (g) (Jiedong treatment) 392.1 ± 5.8 390.3 ± 6.4 364'0 9.6 380.3 ± 5.8 During treatment Of food (g / animal / day) 17-66 ± 0,64 17.60 ± 0.33 25 .91 ± 1.41 24.88 ± 0.91 Dietary energy (calorie / animal / say) 78,39 ± 2.84 78.14 ± 1.45 83.18 ± 4.53 79.86 ± 2.93 Table 2: Silver eating plasma in rats treated with HF or HC diet soil Determination of high fat and high carbohydrate street photos group BRL 49653 control group BRL496S3

Leptin (nanograms / ml) 2.34 ± 0.19 *** 1'42 Soil 0,09 2-10 ± 0.11 Ι · 91 ± 0 09 I Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs n ϋ ί nn ϋ I, f— nd ^ OJk n tl I ϋ I (Please read the notes on the back before filling this page)

*** ρ &lt; 0.001 Treatment group treated with HP vs. street photo group treated with HF meal I

I \ 29 · · This paper size is in accordance with China National Standard (CNS) A4 (210 x 297 mm) 4 4 2 2 8 8 Α7 Β7 5. Description of the invention (2 to Table 3: 馄 HF or HC diet ± treatment The performance of the large-striped mRNA is high in fat and high in carbohydrate integration intensity. Control group BRL 496S3 Control group BRL 49653 ob 0.89 ± 0.27 1.11 ± 〇, 2S 1.00 ± 0.29 1.15 ± 0,22 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs Materials and Methods Animals: Mature male Wistar rats (175-200 g) from Charles River, Charles River, UK were allowed to use food and water freely and were placed at a controlled temperature of 21 ° C ± 2 ° C, relative humidity 55% ± 10%, in a room with 12 hours of lighting: 12 hours of darkness (lighting at 06: 00-18: 00). Diet: rats were divided into two groups, one Group 馁 was fed with HF diet for 4 weeks, and the other group was fed with high carbohydrate (HC) diet for 4 weeks. ItF diet contained (by weight) 30,7% casein, 7.5% weave, 7.2% polyunsaturated fat, 35.2 % Saturated fat and 10.4% corn starch. HC diet contains 21.2% casein, 3,3% weave, 5.0% polyunsaturated Fat and 61.8% corn starch. The metabolizable energy in the HF diet is 4440 kcal / kg, and the HC diet is 3210 kcal / kg. For the HF diet, 20% of the metabolizable energy comes from protein and 12%. "From carbohydrates and 68% from fat" and the corresponding values for HC are 20% from protein, 68% from carbohydrates and 12% from fat. I have not checked that after 3 weeks, I will be fed a large amount of HF diet The mouse is divided into two 耝 β will be -3α-------------- install if (please read the precautions on the back before filling this page) Order--line · This paper size applies + country Standard (CNS) A4 Regulations (210 X 297 mm) f Λ42288 A7 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs B7 V. Description of the invention (4). The control group was given daily pharmaceutical excipients (1. 〇 Ml / kg body weight) for 4 days, while the treatment group received an oral dose of antihyperglycemic tetrahydrothiazoledione BRL 49653 (10 μmol / kg) for 4 days. Similarly, the hc diet will be the largest Rats were divided into two groups. Rats continued to receive their respective diets during the four-day treatment period. Body weight and food and water recordings were recorded On the 5th day, rats were fasted for 6 hours from 08:00, and anesthetized with sodium pentobarbital at 14:00. Blood was collected from the aorta of the back, anticoagulated with EDTA, and plasma was stored Used for leptin measurement at -20 ° C. The rats were killed, and the adipose appendix was removed, immediately clamped on a cold bed and stored at -80 ° C. The gray emperor uses the recombinant murine lutein as a standard and performs immunoassay to determine the concentration of lutein (rabbit anti- 痩 IgG is initiated by recombinant murine leptin, biotinylated and reacted with streptavidin The protein was cultured together and subsequently detected by fluorescence). Total RP extraction and Kitamoto Li: extract the total RNA (17) and check the integrity of the RNA on a 1.1% agarose gel before performing the northern analysis. Twenty micrograms of the total RNA was loaded on a 1.1% denatured nail gel and separated by electrophoresis at 150 mA for 3 hours. The gel stored in 2 X SSC was washed twice at room temperature for 10 minutes. Print the legs by capillary transfer to a positively charged nylon membrane: all night. After RNA transfer, the sample was fixed to the membrane with UV-crosslinking. ^ Explore the $ tag: Digitalisin-U-UTP was incorporated into CDNA for ob and b-actin via PCR. b-actin is used for each sample-31-This paper size applies Yin National Standard (CNS) A4 specification (210 X 297 public dream) {Jing first read the urgent matters on the back before filling this page) -I »Ί ί ϋ n 5 5, I ϋ I ϋ Γ. &Lt; H ϋ ϋ nnn ϋ I nnn 1» 4 42 ^ 88 A7 B7 V. Description of the invention (RNA normalization in 30) Hybridization: at 42 ° Pre-hybridization buffer (DIG Easy Hyb, Boehringer Mannheim) under C. Perform pre-hybridization for one hour. Denaturing the cDNA probe by boiling for 5 minutes, cooling on ice, and adding to fresh hybridization. Buffer (DIG Easy Hyb, Boehringer Mamihdm). Immunodetection of DIG-labeled probes: After hybridization, the membrane is washed at room temperature (2 X SSC, 0.1% SDS) Two times for 10 minutes each, and washed twice at 48 ° C (0.1 X SSC, 0.1% SDS) for 10 minutes each. Then, follow the Boehringer Mannheim procedure for standard immunoassay. Subsequent blocking, washing, and detection stages: The wet film is sealed in a plastic bag and exposed to X-ray film at room temperature. Analysis was performed on a densitometer, and the content of o6 mRNA was expressed relative to the content of b-actin (integrated strength) present in all samples. ^ Data analysis: The results are expressed as the mean ± SEM, n = 9. Significant differences in the statistical averages caused by treatment or diet were determined using 2-way analysis of variance (ANOVA) and Student's t-test. ----- I- ----- • Equipment --- (Please read the precautions on the back before filling this page). --Line-Consumption Cooperation by Employees, Intellectual Property Bureau, Ministry of Economic Affairs, Du-printing -32-This paper size applies Chinese national standards ( CNS) A4 size (210 X 297 mm)

Claims (1)

# 、 Scope of patent application CQ8 8 8 ABCD 018 Ben se 611 ^ 1 sinclojocu case ^ Esas 3n s4cmitt (-JQ 87 pieces No. 3 101 attached | 8761--E g | / aer month tob Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A pharmaceutical composition for the treatment and / or prevention of halogen resistance and / or conditions and / or complications associated with halogen resistance, which includes an effective, non-toxic and pharmaceutically acceptable amount of Halogen sensitizer or its pharmaceutically acceptable derivative and pharmaceutically acceptable carrier, wherein the halogen sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridine Group) Amino group) Ethyl] amyl] tetrahydrooxazole-2,4-dione. 2. The composition according to item 1 of the scope of patent application, wherein the treatment is preventive treatment. 3. According to the scope of patent application The composition sensitizer of item 1 or item 2 is a selective leptin sensitizer. 4. The composition agent according to item 1 or item 2 of the patent application scope is administered in combination with leptin and / or its agonist 5_ According to the condition of the patent application scope item 1 or 2 the statin resistance is related to obesity. 6_ According to the Chinese Patent Application No. 5 composition, wherein the obesity is related to The hormone resistance is related to or caused by the hormone resistance. 7. According to f, please be full-time Mi or the composition of item 2, the condition related to leptin resistance in 1 is Tengdaosu sugar resistance exhibition Symptoms and symptoms. 8_ Radicals, please determine the composition of item 7, in which the condition associated with orydin resistance is the pre-disease stage and weakened glucose financial stage of the Tengdaosu resistant diabetes syndrome. Wherein the leptin and its leptin sensitization which should be related to 痩 -33 ------------ .Exhibition -------- Order --------- Line · (Please read the precautions on the back before filling this page) 9L J,} f Columns with more than 1,000 passengers are to be filled by this Office) Patent Application No. 86110187 ROC Patent Appln. No. 86110187 Full text of the Chinese manual: Attachment (1) Amended Chinesar Specification-End. ΓΠ (1989) Submitted on October 12) (Submitted on October 12, 2000) Collection · J Patent Specification 442288 Inventive New Name Invention Creation &gt; Chinese English Name Nationality Residence, Residence Name (Name) Used to Treat and / or Prevent Leptin Resistance Phannaceutical composition for the treatment and / or prophylaxis of leptin resistance and / or conditions associated with leptin resistance ^ nd / or complications thereof 1 .George Henry POSTE 1. Stephen Stephen Alistair SMITH 1-2 are all British. 1-2 are British business Smith Clemmy ’s Pharmaceutical Company SmithKline, Fifth Avenue South, Harlow, Essex, UK Beecham Pharmaceuticals, New Frontiers Science Park South, Third Avenue, Harlow, Essex CM 19 5AW, England, UK Pack Order by the Ministry of Economic Affairs ^ *. ^ 埘 4 _ ^: * £ Consumer Co-operative Printing Smith & Kline Beecham plc SmithKline Beecham plc UK Line Applicant Residence, Residence (Office) Representative Name Middlesbroughford, UK City Horizons Court New Horizons Court, Brentford, Middlesex TW8 9EP, England David Roberts This paper size applies to Chinese National Standards (CNS &gt; A4 size (210X297mm) #, scope of patent application CQ8 8 8 ABCD 018 Ben se 611 ^ 1 sinclojocu case ^ Esas 3n s4cmitt (-JQ 87 pieces No. 3 101 attached | 8761--E g | / aer month tob Printed by the Consumers ’Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A pharmaceutical composition for the treatment and / or prevention of halogen resistance and / or conditions and / or complications associated with halogen resistance, which includes an effective, non-toxic and pharmaceutically acceptable amount of Halogen sensitizer or its pharmaceutically acceptable derivative and pharmaceutically acceptable carrier, wherein the halogen sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridine Group) Amino group) Ethyl] amyl] tetrahydrooxazole-2,4-dione. 2. The composition according to item 1 of the scope of patent application, wherein the treatment is preventive treatment. 3. According to the scope of patent application The composition sensitizer of item 1 or item 2 is a selective leptin sensitizer. 4. The composition agent according to item 1 or item 2 of the patent application scope is administered in combination with leptin and / or its agonist 5_ According to the condition of the patent application scope item 1 or 2 the statin resistance is related to obesity. 6_ According to the Chinese Patent Application No. 5 composition, wherein the obesity is related to The hormone resistance is related to or caused by the hormone resistance. 7. According to f, please be full-time Mi or the composition of item 2, the condition related to leptin resistance in 1 is Tengdaosu sugar resistance exhibition Symptoms and symptoms. 8_ Radicals, please determine the composition of item 7, in which the condition associated with orydin resistance is the pre-disease stage and weakened glucose financial stage of the Tengdaosu resistant diabetes syndrome. Wherein the leptin and its leptin sensitization which should be related to 痩 -33 ------------ .Exhibition -------- Order --------- Line · (Please read the precautions on the back before filling this page)