TW200946114A - Use of substituted phenylimidazolidines for producing medicaments for treatment of metabolic syndrome - Google Patents

Abstract

Use of substituted phenylimidazolidines for producing medicaments for treatment of metabolic syndrome The invention relates to the use of the compounds of the formula I in which the radicals are each defined as specified for producing a medicament for treatment of metabolic syndrome.

Description

200946114 VI. Description of the Invention: [Technical Field] The present invention relates to substituted phenylimidazolium and physiologically compatible salts thereof for the manufacture of a medicament for treating metabolic syndrome, obesity, diabetes and CNS diseases 5 Use. [Prior Art #f] US 5,411,981 has disclosed compounds of this structure which exhibit anti-androgen action. It is an object of the present invention to provide compounds which are useful in the treatment of metabolic syndrome ίο. In addition, it must be as suitable as possible for the treatment of diabetes. In addition, it must be as suitable as possible for the treatment of obesity. SUMMARY OF THE INVENTION The present invention therefore relates to compounds of formula I

15 I where ^

Ri is -CN, -N02, halo; R2 is -cf3, halo; -A-B- is selected from the group consisting of 3 20 2〇〇946li4

x is 〇, s; hydrogen, (crc12)-alkyl, (c2-c12)-dilute and (CrCi2)-alkynyl, (C6_Ci2)_square, (Ci-C!)-stretching base- (C6-Ci2)_aryl, wherein at least (crc12)-alkyl, (c2-c12), yl, (CrCi2)-alkynyl and θ 12)-extension _(c6_c 12)-aryl, at least A carbon can be optionally substituted by an aeration, an atmosphere and a sulfur atom. 'The sulfur can be arbitrarily oxidized to a stony wind or 10 (CVC) 2)-aryl and (crc) 2)-stretching base _ (Q_Ci2 Aryl group -cf3. (Crc6)-^^ (c2-c6)^ group, (CrC6)-alkenyloxy group, (CrC6) fluorenyl group and (Crc6)i oxy group substituent substituted; and 15 wherein CrC12)-alkyl, (C2-C12)-dilute, (C2-C12)-alkynyl, (C6-C12)-aryl and (Crc 12)-alkylene-(c6_Ci-aryl) 〇H, halo, -SH, -CN, COO-(CrC12)-alkyl, [_0(〇0)_((:6-712)-aryl], COOH, carboxylate (COO-) , (crc12)-alkylene-COOH, NH2, NH-(CrCi2)-alkyl, N-[(C]-Ci2)-alkyl]2, CONH2, -(C=0)-NHKCrC12)-alkane Base, -(c=〇)_N-[(C"C12)-alkyl]2, fluorenyl, (CrC7)-decyloxy, (C6-C) 2)-aryl, _〇_(c6_c12) -aryl group, -0-(CrC)2)-stretching -(C6-C 12)-aryl, -S_(c6-C]2)-aryl, 4 20 200946114 -S(0)-(C6-C12)_aryl, -SOHQ-Cm, w-gan 6 also * Ap Gan 2) - square base, three (c wide cu) - burnt based sulfhydryl group, wherein the burnt group contains from 丨 to 6 carbon atoms; Y is 0, S, NH; ', ' and It is the use of the upper phase == _ chest therapy _ scaly heat. The father and the compound of formula I have the center -CN, -N02, halo; R2 is -cf3, halo; _A-B- Selected from 10

X is 0, S; ❹ 15 ft 3 is (cvy base, (CrC 〖 2) _ stretched base melon seven aryl, from: Γ, 中在(CrCl2)_烧基和(CrC 12)- Burning base AC ! 2) - aryl standing stone can be optionally substituted by atoms including oxygen, gas and sulfur, which can be followed by Wei Weicheng (four) or 砸; ', middle (C〗 C) 2) The alkyl-(Q-Ci2)-aryl group may be derived from a halo group, a -CF3, I 6) alkyl group, a _q decyloxy group, a (C2<:6) county, a dilute oxy group, (2_Q> alkynyl group and C2_Q> substituted by alkynyloxy group and έ_ among them (CrC alkyl group and (CrC A alkyl group _(Q_C ί2) aryl group, OH, dentate, fine, _CN, c〇a (c]_q2>silk, f 〇(c哪(Μ 20 200946114 I2)-aryl], COOH, acid retardation g (c〇〇_), (CiCi2) extension base _c〇〇H, _νη2 , νηκ: 12)-alkyl, Nwi2)-alkyl]2, c〇NH2, -(C=0)-NH-(CrC12)-alkyl, alkyl]2, fluorenyl, (CrC7)-醯Oxy, (C6-C12)-aryl, _〇<C6_Ci2)_aryl, _〇%( ,Ht^^(C6-C12)^^^ -S-(C6-Cl2)^^. S (〇KC, C12)-aryl, SCMCeC! 2)-aryl, alkyl sulphate substituted, wherein the yard contains from 1 to 6 carbon atoms; γ is 0, S; The use of a drug for treating metabolic syndrome. 10 and its physiologically compatible salts are produced; particularly preferably, the compound of formula I has a center of -CN, -N02, a halogen group; R2 is a -cf3, a dentate group; -B- is 15

x is 〇, S; r^c\cCrCl2H^^, at least one (fC 12> wire-(c A)-aryl group can be oxidized arbitrarily into: wind: wind includes oxygen, nitrogen and sulfur Atomic substitution, ^ 20 200946114 wherein (CrC! 2)-alkylene-(C6-C)2)-aryl group can be derived from halo, -CF3, (CrC6)-alkyl, (Cl_c6)·decyloxy , (C2_q) a dilute group, a (C2_q)-alkenyloxy group, a (C2_C6)-block group, and a (QQ)-alkynyloxy group substituent; and ❹ 10 15 ❹ wherein (CrC!2)-alkyl and CrC 12)-alkylene-(C6-C 12)-aryl group can be via -OH, halo, -SH, -CN, aXHCVCA alkyl, [-〇(〇〇)-(C6-C12)-aryl Base, COOH, decanoic acid (COO-), (CpCu)-alkylene_COOH, -NH2, NH-(C"C12)-alkyl, N-[(CrC12)-alkyl]2 CONH2, -(C=0)-NH-(CrC12)-alkyl, -(C=〇)-N-[(CrC]2)-alkyl]2, fluorenyl, (C1-C7)-brewed oxygen , (C6-Ci2)-aryl, -〇_(C6-Ci2)·aryl,-0-(CrC 12)-alkylene-(C6_C 】2)·aryl, -S-(C6- C12)-aryl, _S(0)-(C6-C12)-aryl, -S〇2-(C6-C12)-aryl, tri(crc12)-alkyl sulphide substituted, wherein the alkyl group contains From 1 to 6 carbon atoms; Y is 0; and its physiologically compatible The use of a salt for the manufacture of a medicament for the treatment of metabolic syndrome. It is also particularly preferred to be a compound of formula I

Ri is -CN, -N02, halo; R2 is -CF3; -Α_Β· is 20 7 200946114 X is ο; R3 is (CrCl2)_alkyl, (C!-C 12Η alkyl-(c6-c 12)-aryl, wherein in the (crc12>alkyl group and (Crc 12)-alkylene-(c6-c 12)-aryl group, at least one carbon may be optionally substituted by an atom including oxygen, nitrogen and sulfur. , wherein sulfur can be arbitrarily oxidized to sulfoxide or sulfone; wherein (CrC) 2)-alkylene-(c6-C12)-aryl can be derived from _ group, -CF3, (CrC6)-alkyl, alkoxy a group, a (crc6)alkenyl group, a (c2-c6)-alkenyloxy group, a (CrQ> fast group and a (C2-c6> alkynyloxy substituent substituted; and a (CrC)2)-alkyl group and Cl_C 12)·alkylene-(cvc 12)-aryl group can be via -OH, halo, _SH, _CN, c〇〇(Ci Ci2), [-0(C-0)-(C6-C12) )-aryl], C00H, carboxylic acid vine (c〇〇_c 2)_

Base, -CKCrc12)-alkylene aryl,

CJONH2, ·(ΟΟ^ΝΗ%·.)·丝,_(C=Q)_N[(C1CJ alkyl), brewing base, (CVC7)-decyloxy, (Q-ca aryl, _〇_ (C6-Cl2)_Fluorine-S-(C6-C)2)-aryl, bis(CpC)2)-alkylate and its physiologically compatible salts are manufactured for treatment

Xie syndrome, diabetes or obesity, the use of drugs for the treatment of metabolic syndrome. Compound treatment is preferably treated with a compound of formula I wherein -A-B- is 8 200946114

And X is oxygen. In a specific embodiment, it is preferred to use a compound of formula I for the treatment of metabolic syndrome, diabetes or obesity wherein -A-B- is

N-K.3 and X is sulfur. In a particular embodiment, it is preferred to treat the metabolic syndrome, diabetes or obesity using a compound of formula I, wherein R3 is hydrogen. In a particular embodiment, it is preferred to treat a metabolic syndrome, diabetes or obesity using a compound of formula I, wherein R3 is an alkyl group containing from 1 to 4 carbon atoms which is optionally substituted with an -OH or a decyloxy group. . In a particular embodiment, it is preferred to use a compound of formula I for the treatment of metabolic syndrome, diabetes or obesity, centered on -CN or a halo group. In a particular embodiment, it is preferred to use a compound of formula (I) wherein R! is -0^ and R2 is CF3 to treat metabolic syndrome, diabetes or obesity. In a specific embodiment, it is preferred to use a compound of formula I for the treatment of metabolic syndrome, diabetes or obesity, wherein -A-B- is 9 20 200946114 f3

And R3 is an alkyl or alkenyl group containing up to 6 carbon atoms which is substituted or unsubstituted or uninserted or oxygen-inserted or unoxidized or oxidized sulfur or unsubstituted or substituted aralkyl , mercapto or trialkylsulfonyl. In a specific embodiment, it is preferred to use a compound of the formula to treat metabolic syndrome, diabetes or obesity, wherein Rs is an alkyl group containing from about 6 to 6 carbon atoms, which is unsubstituted or at least one selected from the group consisting of _ a group substituted with a 10 -fluorenyl group, a carboxyl group, an alkyl-esterified carboxyl group, a heterocyclic group, a fluorene-alkyl group, and an unpurified or oxidized S_aryl group, wherein the aryl group is not It is substituted by a working group or by at least one group selected from the group consisting of a halogen group and an alkoxy group. It is better to use the compound of formula 1 to treat the progeny or to get fat. The R3 is from 2 to 4 carbon atoms and its t, :: one is selected from the group consisting of gas and ethoxy group. , a third butoxy A soil, a cyclopentyloxy group, an oxirane-free oxyalkyl group, a thiol group of Ml-milk, a ruthenium, a di-p-methoxy group, and a methylsulfonyloxy group The base of the base 15 was replaced by the 200946114 regiment. In a particular embodiment, it is preferred to treat the metabolic syndrome, diabetes or obesity using a compound of formula I, wherein R3 is sulfhydryl or benzhydryl or (1 decylethyl) dimethyl sulphur. 5 In a specific embodiment, it is preferred to use a group selected from the group consisting of 4-(5-keto•2-thio-3,4,4-trimethyloxazolidinyl)_2-(trifluoromethyl) nitrite. 4-(4,4-Dimethyl-5-keto-2-oxa-1,3-imidazolidinyl)_2-(trifluoromethyl)benzonitrile, 4-[4,4-didecyl- 3-(2-hydroxyethyl)-5-keto·2-thio-1-imidazolium]-2_(trifluoromethyl)benzonitrile, 3-(3,4-diphenyl)-2 -thio-1,5,5-trimethyl10-based "micidone, 1-(4-nitro-3-(trifluoromethyl)phenyl-3,4,4-trimethyl-2 , 5-imidazolidinone, 4-4,5-dihydro-4,4-dimercapto-5-one-2-(phenylmethyl)-thio-111-imidazol-1-yl 2-(Trifluoromethyl)benzonitrile, 4-4,4-dimercapto-3-(2-hydroxyethyl)-5-keto-2-thio-1-imidazolidinyl-2-(three Fluorinyl)benzonitrile, 4-(4,4-dimercapto-3-(4-hydroxybutyl)-5-one-2-thio-1-imidazolidinyl 15 yl)-2-(three Fluorinyl)benzonitrile, 3-(4-cyano-3-trifluoromethyl)-phenyl)-5,5-dimercapto-2,4-dione-1-pyrimidinium butyrate And 4-(4,4-dimercapto-2,5-dione-3-(4-hydroxybutyl)-1-imidazolidinyl)_2-trifluoromethylbenzonitrile, 4-(4, 4-Dimethyl-2,5-dione-3-(4-trifluorodecylbenzyl)_1-imidazole Benzyl-2-pyridylbenzonitrile, 4-(4,4-dimercapto-2,5-dione-3-(2-(4-fluorophenylthio)ethyl 20-yl)-1 _Imidazolidinyl-2-(trifluoromethyl)benzonitrile, 4-(4,4-dimercapto-2,5-dione-based 3-(2-(2-fluorophenyl)sulfinium) Ethyl)-1-imidazolidinyl-2-(trifluoromethyl)benzonitrile, 4-(4,4-dimercapto-2,5-dione-3-(4-fluorobenzyl) )-1-imidazolidinyl-2-trifluorodecylbenzonitrile, 4-(4,4-dimercapto-2,5-dione-3-(3-methoxyphenyl)indolyl -1 - Imidazolidinyl-2-(trifluoromethyl)benzonitrile compound treatment 11 11 15 20 200946114 Xie syndrome, diabetes or obesity. The following examples provide values of ^^ containing up to 12 carbon atoms Alkyl f is a straight chain or a branch, a group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a 'f, a second butyl group, a third butyl group, a pentyl group, an isopentyl group, a second pentyl group. , pentaerythritol, hexyl, isohexyl, second hexyl, third hexyl, :, earth, fluorenyl, undecyl and dodecyl. Preferably, the alkyl group contains from j carbon atoms. Especially methyl, ethyl, propyl and isopropyl, butyl, isobutyl, second butyl and branched or linear pentane And hexyl. Examples of alkenyl groups containing up to 12 carbon atoms are ethyl, propyl, propyl-propyl, T, Langji, and Jixian and preferably contain from 2 to * = atomic In particular, it is a vinyl, allyl or butenyl group. Examples of a block containing 12 carbon atoms are ethynyl, propyl, butyl, decynyl and hexyl, and more preferably a block having from 2 to 4 carbon atoms, such as acetylene. Base and propynyl. Examples of aryl groups are carbocyclic aryl groups such as phenyl and naphthyl. Examples of the aryl group include the above-mentioned stilbene of the above aryl group. Preferred extended alkyl groups are tris-methyl, ethyl and meridin. The example of the letter base is fluorine, chlorine, indifferent and hard, but it is more suitable for fluorine, gas and performance. Examples of the alkyl group substituted with at least one dentate group are fluoromethyl, chloromethyl, dimethylmethyl, iodonyl, difluoromethyl, dichloroindenyl, dibromomethyl and trifluoromethyl. Examples of the substituent of the aryl group and the aryl group are a phenyl group which is para-substituted with dimethyl, _cc3 or -cf3. The example of the brewing base preferably contains up to 7 carbon atoms, such as ethyl ketone, propyl sulfonyl, butyl sulfonyl and astringent broth, as well as broth, hexyl, propylene 12 200946114 sulfhydryl, crotonyl, amine Base or base. The decyloxy group can be derived from the same acid, especially the ethoxylated oxy group and the propyl fluorenyloxy group. Examples of the trialkyl-based calcining group are a trimethyl-calcyl group, a triethyl-stone group, and (i, i-diylethyl) decyl decyl group. 5 Preferred compounds of formula I include those wherein Y is oxygen, excluding such compounds, wherein -A-B- is

Ίο X is oxygen, R3 is hydrogen, Rule 2 is -CF3 or a halogen group and R1 is -N〇2 or a halogen group. More preferred compounds of formula I are those in which -A-B- is

N-BL3 15 X is sulfur and R 3 is according to the above definition, wherein R 3 is hydrogen or an alkyl group having from 1 to 4 carbon atoms, which is optionally substituted by -OH or a decyloxy group, wherein K Is a cyano or a halogen group, preferably chlorine, and among them -AB- is 13 200946114 sr3 or <>

N-R3, a mask or a dilute base and optionally oxidize a disc or optionally substituted aryl, alkenyl or trialkyldecyl. The pure grading material of the present invention has a towel R; * contains * at most S singular atoms which hinder the atom, and the system is followed by at least - (4) self-recording, free or acetylation, heterocyclic group, Q a group substituted with a aryl or s. aryl group is optionally substituted with at least one halo or alkoxy group.

And the sulfur atom is oxidized in the form of a sulfoxide or a sulfone, and very specifically wherein R3 is an alkyl group having from 2 to 4 carbon atoms, which is selected from the group consisting of chlorine, ethoxycarbonyl, a third butoxycarbonyl group, a cyclopentyloxycarbonyl group, a 4-fluorophenylthio group which is optionally oxidized to a sulfoxide or sulfone form, a ruthenium group, a phenylmethoxy group, a diphenylphosphonium group, and a methyl group. Substituted by a group of a sulfomethoxy group. Other preferred compounds of formula I are those in which the rule 3 is ethenyl or benzhydryl or (I,1-didecylethyl)didecylalkyl, wherein Ri is nitro and R3 is An alkyl or alkenyl group containing up to 4 carbon atoms which is optionally substituted by a thiol group which is converted to a salt or a free form by acetation, and the formula 14 15 200946114

The formulas of Ri, R2 and 尺3 according to the above are defined according to the above, except that the product wherein R ❹ is a nitro group, R 2 and a trifluoromethyl group R 3 is hydrogen. An example of a preferred compound of the formula I is 4-(5-keto-2-thieno-3,4,4-trimercaptoimididyl)_2-(trifluoromethyl)-thousand, 吣4, 4_Dimercapto-5-keto-2-thio-1-imidazolidinyl)_2_(trifluoromethyl)benzonitrile, 4_[4,4, dimethyl-3-(2-hydroxyethyl) )_5·keto-2-α-thio-1-imidazolidinyl]_2_(trifluoro 10 fluorenyl) ladenonitrile, Η3,4·dichlorophenyl)-2-thio-1,5,5-three Methyl-4-imidazolium, H4-decyl-3-(trifluoromethyl)phenyl-3,4,4.trimethyl-2,5-imidazolidinone, 4-[[4, 5-Dihydro-4,4-dimercapto-5-one-2-benzylthio]_1-imidazolium-l-yl]-2-(trifluoromethyl)octonitrile, 4_[4, 4-Dimethyl-3-(2-hydroxyethyl)toxin-2-thio-1-imidazolidinyl]_2-(trifluoromethyl)benzonitrile, 4_(4,4-dimethyl 15 Diketo-3-(4-butylbutyl)-1_i-pyridinyl)_2-(trifluoromethyl)-n-nitrile, 4-(4,4-dimethyl-3-(4- Benzyl)-5-indolyl-2-thio-1-imidyl)_2_(trifluoromethyl) nitrite and 3-(4-cyano-3-(trifluoromethyl) Phenyl)_5,5-dimercapto-2,4-didecyl-1-.°m. The process for the preparation of a compound of formula I according to the invention comprises the following formula:

II 200946114

Ri

Wherein R!, R2 and X are each according to the above definition, and a compound of the formula

反应 Reaction in the presence of a tertiary base wherein R'3 is as defined according to R3, wherein the reactive group is optionally protected, and when Ri is -N02 or halo, R2 is halo or -cf3 and X is Oxygen, r'3 is not hydrogen, so as to obtain compound 10 of the formula

Wherein Ri, R2, X and R'3 are each according to the above definition, and optionally subject the latter to one or more of the following reactions in any order: is a) reaction to eliminate the protecting group of R'3 16 200946114 b C=NH hydrolysis reaction to ketone functional group or convert C=S to c=o

c) C=0 conversion reaction becomes C=S d) and after hydrolysis of C=NH to ketone, the product of formula IV wherein R'3 5 is hydrogen is reacted with a compound of formula R"3-Hal, wherein Hal is halo And R"3 is R'3 but does not include hydrogen in order to obtain a compound of formula I wherein -AB- is hydrazine

^ and optionally reacting the latter to eliminate the protecting group of R"3, or reacting the above with an esterifying agent, a salt converting agent or a hydrazide, or a compound of the formula

II 17 200946114 wherein Rk I and X are each reacted according to the above formula, in the presence of a tertiary base,

ΙΠ -中R'3 is a burnt group according to the above definition to 6 carbon atoms, and Q is a metal such as sodium or a product extending from 1 to the following formula, *~R2 〇/ CH3 IVa -R'3 Ch3 10 wherein X, R!, R2 and R, 3 are each a stalk, and the above definition is carried out in any order, if a) reaction is required to eliminate R, 3 may carry 髻b) 々〇 conversion reaction becomes > : is c = 〇. L s, or if appropriate, > c = s becomes 15 0 such that the product of formula m wherein % is hydrogen reacts with the reagent of toe r,3, where R"3 false Further R'3 but excluding hydrogen and Hd is a halo group, in order to obtain the product of formula I wherein _eight_3_ is

1S 200946114

5

Wherein R"3 is as defined above and then, if desired, the action of the agent to eliminate the protective group which R"3 may carry on these products, or, if desired, an esterifying agent, a hydrazide or salt The action of a transforming agent, or the reaction of a reagent of the formula R'VHal as defined above with a compound of the formula

F3c

In order to obtain a compound of the formula

IV" 10 and optionally subject the latter to one or more of the following reactions: a) react to eliminate the protective group that R"3 may carry, and then react with an esterifying agent, a salt converting agent or a hydrazide, 15 b The reaction converts C=0 to C=S. 19 200946114 The reaction of the product of formula II with the product of formula III is preferably carried out in an organic solvent such as tetrahydrofuran or a gas or acetonitrile or isopropyl test. A tertiary test such as pyridine or methyl ethylpyridinium. The optionally reactive functional group of I, optionally protected in the formula IV, IVa*IV, compound 5, is -OH or an amine The base is protected by a conventional protecting group. Examples of such a protecting group for -NH2 are a third butyl group, a third pentyl group, a gas group, a gas ethyl group, a methyl group, and a benzophenone group. Examples of the hydroxy protecting group are a fluorenyl group, a gas oxime group, a tetrahydropyranyl group, a trimethyl fluorenyl group, and a tert-butyl fluorenyl decyl group. 10 The above list is not exhaustive, and any protecting group known, for example, in the chemistry may be used. Other known protecting groups are disclosed, for example, in the law. U.S. Patent No. 2,499,995, the disclosure of which is incorporated herein by reference in its entirety in its entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire entire all all all all all allally Or acidic hydrolysis of trifluoroacetic acid, preferably 15 is hydrochloric acid. C=NH becomes a random hydrolysis reaction of hydrazine is preferably carried out with an acid such as aqueous hydrochloric acid under reflux. When C=NH is hydrolyzed to c=0 When carried out with the same enthalpy of C=S, the latter can be converted to C=mercapto. The hydroxy group optionally present in R3 can be converted to _SH. 20 c=0 is converted to C=s using the following formula Lawesson reagent

20 200946114 It is a commercialized agent, such as *Fluka, and its system is revealed in

Bull. Soc. Chim. Belg., Vol. 87Να 3 (1 987), p. 229. When two oximes are converted to C-S, the reaction is carried out in an excess of Lawesson's reagent. This is also true when molecule 5 contains both c_s and C-0 and needs to convert c=0 to c=S. Conversely, when a part of the molecule contains two C=〇 and it needs to obtain a product of a cs, it is an under-utilized Lawess〇n reagent, so that a mixture of the three products is obtained, and the two products are in each In the case, one c=〇 and c==s and one product contains two C=S. These products can be isolated by known methods such as chromatography. The compound of formula IV, IVA or IV' is reacted with a compound of formula R,,3-Hal in a phase transfer reaction in the presence of a quaternary ammonium salt such as tributylammonium in the presence of a strong test such as sodium hydride or potassium hydride. The protecting group for R''3 may be those described above for R3. The reaction to remove the protecting group is based on the above description. For example, the 15th dibutylmethylsulfonate can be removed via hydrazine hydride according to the description of the examples below. The random acetification of a compound of formula I wherein R''3 is a free state -0H is carried out under conventional conditions, for example using an acid or a functional derivative thereof, such as an anhydride thereof, such as acetic anhydride, in the presence of, for example, pyridoxine. Go on. The random esterification or salt conversion of a compound of formula I wherein r,,3 20 is _CO〇H can be carried out by known methods. The random amide amination of a compound of formula I wherein R,3 is -C00H is carried out under conventional conditions using a primary or secondary amine using a functional derivative of -C00H such as its symmetric or mixed acid hydrazine. 21 200946114 Method for preparing a compound of the formula according to the present invention

R2" y ch3 where R", R"2 and each are defined according to Rl, R2 and -A-B-, except when 是

II • C—N_(R3w)· and R′”3 is hydrogen or an alkyl group having from 1 to 7 carbon atoms and Y is oxygen, and R”! ίο is -CN, including a compound of the formula

R2" wherein the scales '^ and R"2 are each according to the above definition and Hal is a halogen group, and the compound of the following formula 15 22 200946114

Hn/A,, b" VI

Y ch3 wherein Y and Y are each reacted in the presence of a catalyst and optionally a solvent according to the above definition. In the compound of the formula V, the halogen group is preferably chlorine, but it may be moth or bromine.

The role of the ® catalyst is evident by the removal of the hydrogen halide formed and the condensation of the compounds of formula V and VI to form the desired product. The catalyst is preferably a metal of its original form or an oxide or salt thereof, or it may be a base. When the catalyst is a metal, it is preferably copper or nickel, and the metal salt is preferably chloride 10 or acetate. When the catalyst is a base, it is preferably sodium hydroxide or potassium hydroxide, and disulfoxide may be added to the reaction medium. The catalyst of the process may be selected from the group consisting of copper (II) oxide, copper (I) oxide, copper metal or a base such as sodium hydroxide or potassium hydride, and more preferably copper (II) oxyhydroxide in powder form. The solvent to be used is preferably an ether having a high boiling point such as a benzene bond, a diethylene glycol dioxime ether, a triethylene glycol dioxime ether and a dimethylene base; however, a high boiling oil is also suitable, such as a stone butterfly or Vaseline. It is preferred to carry out the reaction in another solvent such as phenyl ether, diglyme, triethylene glycol dioxime or disulfoxide, most preferably in phenyl ether or triethylene glycol dioxime ether. The method can be carried out at atmospheric pressure or under pressure for more than 2 hours at a temperature of more than 100 ° C of 20 °, preferably above 150 ° C. The reaction is preferably carried out using copper (II) oxide in triethylene glycol dioxime ether at a temperature of 200 ° C or higher for more than 3 23 200946114 hours. Surprisingly, the compounds of formula I are cannabinoid 1 receptor (CB1R) modulators and are therefore suitable for use in humans and animals for the treatment or prevention of diseases which are disrupted by the inner cannabis system. 5 For example and without limitation, the compounds of formula I are valuable psychotropic agents, especially for the treatment of psychiatric disorders including anxiety, depression, mental disorders, insomnia, timidity, compulsive psychosis, general Psychiatric disorders, schizophrenia, hyperactive attention deficit hyperactivity disorder (ADHD), and disorders associated with the use of psychotropic substances, especially drug abuse and/or dependence on the drug, including alcohol dependence Nicotine dependence, as well as coca, amphetamine and heroin dependence (see, for example, Behavioural Pharmacology 2005, 16:275-296). A review of the medical interventions of CBR1 - intervening effects can be found, for example, in Ken Mackie: Annu. Rev.

Pharmacol. Toxicol. 46, 101-122 (2006), SC Black: Curr. Opin. 15 Investig. Drugs 5, 389-394 (2004), V. DiMarzio et al.: Nat. Rev. Drug Discov. 3, 771- 784 (2004), B. Le Foil et al.: J. Pharmacol. Exp. Ther. 312, 875-883 (2005) or L. Walter et al.: Br. J. Pharmacol. 141, 775-785 (2004) ). The compounds of the formula I according to the invention can be used as medicaments for the treatment of migraine, 20 stress, physical and mental disorders, pain episodes, epilepsy, disrupted movement, especially dyskinesia or Parkinson's disease, tremor and dysfunction disease. The compounds of the formula I according to the invention can also be used as medicaments for the treatment of memory disorders, psychological defects, in particular for the treatment of age-related dementia, and for the treatment of decreased alertness or sensibility. In addition, it is also possible to use a compound of formula I as a protective agent for the treatment of ischemia, head injuries and treatment of neurodegenerative disorders including chorea Huntington's disease, Tourette's syndrome. 5 ❺ 10 15 〇 20 The compound of the formula I of the present invention can also be used as a medicament for the treatment of pain, including neuralgia, acute peripheral pain, chronic pain of inflammation. The compounds of the formula I according to the invention may also be used as medicaments for the treatment of eating disorders (for example indulgent eating disorders, loss of appetite and appetite treatment of confectionery snacks, carbohydrates 'drugs, _ or other addictive substances) of the invention I The compounds are particularly suitable for the treatment of obesity or excessive appetite, and for the treatment of type 2 diabetes and for the treatment of dyslipidemia and metabolic syndrome. The compounds of the invention are therefore useful for the treatment of obesity and the risks associated with obesity, in particular It is a cardiovascular risk. Moreover, the compound of the present invention can be used as a medicament for the treatment of gastrointestinal pain, for treating diarrhea, ulcers of the stomach and intestines, vomiting, bladder problems and dysuria, endocrine disorders, cardiovascular problems, hypotension Hemorrhagic tg, hemorrhagic shock, chronic cirrhosis, hepatic sebaceous adenosis, nonalcoholic steatohepatitis, asthma, Raynaud's syndrome, glaucoma, production problems, abortion, premature labor, inflammatory symptoms, disorders of the immune system, especially Spontaneous immunity, and neuroinflammatory disorders, such as joint rheumatism inflammation, responsiveness Inflammation, disorders that cause damage to the myelin sheath, multiple sclerosis, infection disorders, and viral disorders, such as encephalitis, ischemic stroke, and chemical medicine used as a medicament for cancer, for the treatment of the Guillain-Barr†syndrome For the treatment of 25 200946114 osteoarthritis. The compounds of the formula I according to the invention are also found to be useful as medicaments for the treatment of polycystic ovarian syndrome (PCOS). According to the invention, the compounds of the formula I are especially useful for the treatment of mental complaints, 5疋 Schizophrenia, declining alertness and hyperactivity (ADHD) for the treatment of eating disorders and obesity, for the treatment of type η diabetes mellitus for the treatment of memory deficits and under-recognition for the treatment of alcohol addiction Nicotine addiction, that is, alcohol and tobacco withdrawal.

, CI The compounds of the formula I according to the invention are very useful for the treatment and prevention of diets - 10 disorders, appetite disorders, metabolic disorders, gastrointestinal disorders, inflammatory syndromes, immune system disorders, mental disorders, alcohol addiction and nicotine addiction. According to one aspect, the invention relates to the use of a compound of formula I, a pharmaceutically acceptable salt thereof, and solvates or hydrates thereof, for the treatment of the above disorders and diseases. 15 The compound of formula I can also be administered in combination with other active ingredients. Other suitable active ingredients for combination preparations are: All anti-diabetic agents mentioned in Chapter 12 of Rote Liste 2007; all weight loss/appetite inhibitors mentioned in Chapter 1 of 〇RoteListe 2007; All the diuretics mentioned in the morning of the coffee list Liste 2007; all the lipid-lowering agents mentioned in the R〇te Liste 2〇〇7 Chapter 2 chapter. These can be combined with the compounds of the formula I of the present invention in particular for synergistic improvement. The active ingredient combination can be administered by separating the active agent into the patient or in the form of a combination product wherein the plurality of activities are in the presence of a pharmaceutical preparation. If the active ingredients are administered separately, 73 they can be administered simultaneously or sequentially. Most of the active ingredients mentioned herein are disclosed in the USP Dictionary of USAN and International Drug Names, US Pharmacopeia, Rockville 2006. Antidiabetic agents include insulin and insulin derivatives such as Lantus® (see www.lantus.com) or HMR 1964 or Levemir® (detemir), Humalog® (Insulin Lispro), Humulin®, VIAjectTM, SuliXen® or The person disclosed in WO2005005477 (Novo Nordisk), fast acting insulin (see US 6,221,633), inhalable insulin such as Exubera®, NasulinTM, or oral insulin such as IN-105 (Nobex) or Oral-lynTM (Generex Biotechnology), Or Technosphere® Insulin (MannKind) or CobalaminTM Oral Insulin, or insulin disclosed in WO2007128815, WO2007128817, WO2008034881, WO2008049711, or insulin that can be administered transdermally; GLP-1 derivatives and GLP-1 agonists, such as Ace That peptide (either Qiu Zhanru) or its specific modulator, disclosed in, for example, WO2008061355, liraglutide, taspoglutide (R-1583), albiglutide, Cisineptide (lixisenatide) or Novo Nordisk A/S in WO 98/08871, WO2005027978, W02006037811, W02006037810, Zealand in WO 01/04156 or Bea ufour-Ipsen in WO 00/34331 jins revealer, pramintide acetate (Symlin; Amylin Pharmaceuticals), AVE-00I0, BIM_51077 (R-1583, ITM-077), PC-DAC: Acetate Exendin-4 (a type of exenatide acetate covalently bonded to recombined human serum albumin), CVX-73, CVX_98 and CVx-96 (GLP-1 homologues) The valency bond to the monoclonal antibody contains a specific binding site for the GUM peptide), CNTO_736 (a region of the GLrM homolog that binds to the Fc portion containing the antibody), pgc-glj^ (GUM-bonded to nai Mt. 27 200946114, discloses agonists in, for example, D. Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943, in WO2006124529, WO2007124461, W02008062457, W02008082274, W02008101017, W02008081418, WO2008112939 , WO0116112941, WO2008116601, WO2008116294, WO2008116648, WO2008119238, the peptides such as octopipide (TM-30338), rabbit amylin receptor agonist, disclosed in, for example, WO2007104789, a homologue of human GUM , revealed at W02007120899, W02 008022015, W02008056726, and oral active blood sugar lowering ingredients. Anti-diabetic agents also include agonists of glucose-dependent insulinotropic polypeptide (GIP) receptors, as disclosed, for example, in WO2006121860. Anti-diabetic agents also include glucose-dependent insulinotropic polypeptide (GIP), and similar compounds, disclosed, for example, in w〇2〇〇8〇21560. Antidiabetic agents also include homologs and derivatives of fibroblast growth factor 21 (FGF-21). Oral active blood glucose lowering components preferably include scutellariae, biguanides, meglitinides, oxadipine ketones, thiazolidinediones, PP AR and RXR regulators, glucosides Inhibitor, inhibitor of glycogen phosphorylase, 200946114 Glucagon receptor antagonist, glucokinase activator, inhibitor of fructose 1,6-bisphosphatase, regulation of glucose transporter 4 (GLUT4) Agent, 5 glutamine-fructose-6-acid hydrazide-transferase inhibitor, GLP-1 agonist, potassium channel opener, such as pinacidil, cromakalim, 0 diazoxide or in RD Carr et al., Diabetes 52, 2003, 2513.2518, in I B. Hansen et al, Current Medicinal Chemistry 11, i〇 in TM Tagmose et al., J. Med. Chem. 7, 2004, 3202-3211 or as disclosed in MJ Coghlan et al., J. Med. Chem. 44, 2 (9) 7, 1627-16535, or NovoNordisk A/S as disclosed in WO 97/26265 and WO 99/03861 The active ingredient of ATP-dependent unloading channel acting on ^ cells, 15 dipeptidyl peptidase IV (DPP-IV) Inhibitor, beta insulin sensitizer, inhibitor of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, regulator of glucose uptake, glucose transport and glucose reabsorption, sodium-dependent glucose transport 1 or 2 a regulator of (SGLT1, SGLT2), an inhibitor of 20 11-/5-base steroid dehydrogenase-1 (110,000-HSD1), an inhibitor of protein tyrosine acetylase IB (FTP-IB), As an acid-receptor agonist, an inhibitor of hormone-sensitive or endothelial lipase, an inhibitor of acetyl-CoA carboxylase (ACC1 and/or ACC2) bites 29 200946114 GSK-3 /9 inhibitor. Also included are metabolically modified compounds such as active hypolipidemic agents and active lipid lowering agents, HMGCoA reductase inhibitors, 5 farnesyl ester derivative X receptor (FXR) modulators, fibric acid derivatives, cholesterol re Absorption inhibitor, CETP inhibitor, bile acid reuptake inhibitor, 10 MTP inhibitor, agonist of estrogen receptor r (ERR T agonist), sigma-1 receptor antagonist, somatostatin 5 receptor Antagonists of (SST5 receptor), compounds that reduce food intake, and 15 compounds that increase thermal decomposition. In a particular embodiment of the invention, the compound of formula I is administered in combination with temsin. In a particular embodiment, the compound of formula I is administered in an active fraction of an ATP-dependent potassium channel that binds to a/5 cell, such as a sulfonylurea, such as tolbutamide, glibenclamide ( Glibenclamide), glipizide, gliclazide or glimepiride. In a particular embodiment, the compound of formula I is administered in combination with a tablet containing both a fast-release glimepiride and a longer-released diterpene bismuth (disclosed in, for example, US2007264331, WO2008050987, WO2008062273). 200946114 In a specific embodiment, the compound of formula i is administered in combination with a biguanide such as diterpene. In another embodiment, the compound of formula I is administered in combination with glinide, such as repaglinide, nateglinid or mitiglinide. In another embodiment, the compound of formula I is administered in combination with mitiglinide and glitazone, such as pioglitazone hydrochloride. ® In another embodiment, the compound of formula I is administered in combination with mitiglinide and an alpha-glycosidase inhibitor. In another embodiment, the compound of formula I is administered in combination with an anti-diabetic agent compound disclosed in WO2007095462, WO2007101060, WO2007105650. In another embodiment, the compound of formula I is administered in combination with an anti-hypolipide compound disclosed in WO2007137008, WO2008020607. In a particular embodiment, the compound of formula I is a combination of a thiazole ketone (e.g., troglitazone, ciglitazone, pioglitazone, rosiglitazone). Or the compound disclosed by Dr. Reddy's Research Foundation in WO 97/41097, especially 5-[[4-[(3,4-dihydro-3-methyl-4-keto-2-a) In the specific embodiment of the invention, the compound of formula I is a binding PPARr agonist such as rosiglitazone, piroxime, JTT- 501, G1 262570, R-483, CS-011 (rivoglitazone), DRL-17564, DRF-2593 (barglitazone Oalaglitazone), INT-131, T-2384, or disclosed in W02005086904 , 31 200946114 W02007060992, W02007100027, W02007103252, W02007122970, WO2007138485, W02008006319, W02008006969, W02008010238, W02008017398, W02008028188, W02008066356, W02008084303, 5 W02008089461-W02008089464, W02008093639, W02008096769, W02008096820, W02008096829, US2008194617, W02008099944, W0200810860 2. Compounds of W02008109334, WO2008126731, and WO2008126732 are administered. In a particular embodiment of the invention, the compound of formula I is administered in combination with a solid combination of pyridinium hydrochloride and dioxindole hydrochloride. In a particular embodiment of the invention, the compound of formula I is a TandemactTM administration in combination with a solid combination of pioglitazone and glimepiride. In another embodiment of the invention, the compound of formula I is administered in combination with a solid combination of pioglitazone hydrochloride and an angiotensin II agonist such as TAK_536. In a particular embodiment of the invention, the compound of formula I is a PPARa agonist or a mixed PPARa/PPAR5 agonist such as GW9578, GW-590735, K-ll, LY-674, KRP-101, DRF-10945 , LY-518674, CP-900691, BMS-687453, BMS-711939 or disclosed in WO2001040207, 20 W02002096894, W02005097076, W02007056771, W02007087448, W02007089667, W02007089557, W02007102515, W02007103252, JP2007246474, W02007118963, W02007118964, W02007126043, W02008006043, W02008006044, Compounds of W02008012470, 32 200946114 W02008035359, W02008087365, W02008087366, W02008087367, WO2008117982 are administered. 5 ❹ 10 15 ❹ 20 In a particular embodiment of the invention, the compound of formula I is a binding PPAR agonist such as GW-501516 or disclosed in WO2006059744, W02006084176, W02006029699, W02007039172-W02007039178, W02007071766, W02007101864, US2007244094, W02007119887, Compounds of WO2007141423, US2008004281, W02008016175, W02008066356, WO200807111, W02008084962, US2008176861 are administered. In a particular embodiment of the invention, the compound of formula I is administered in combination with pan-SPPARM (selective PPAR modulator a, r, occupies) such as GFT-505 or a compound disclosed in WO2008035359. In a specific embodiment, the compound of formula I is administered in combination with metaglidasen or in combination with MBX-2044 or other partial PPAR gamma agonist/antagonist. In a particular embodiment, the compound of formula I is bound to an alpha-glucosidase inhibitor such as miglitol or acrabose or disclosed in, for example, WO2007114532, WO2007140230, US2007287674, US2008103201, W02008065796, W02008082017. The compound is administered. In a particular embodiment, the compound of formula I is an inhibitor of a glycogen-storing enzyme such as PSN-3 57 or FR-258900 or a compound disclosed in WO2003084922, W02004007455, WO2005073229-31, WO2005067932, W02008062739, W02008099000, W02008113760. . In a specific embodiment, the compound of Formula I is a combination of a glucagon receptor 33 antagonist 46146114 inhibitor such as A-770077 or NNC-25-2504 or disclosed in WO2004100875, W02005065680, W02006086488, W02007047177, W02007106181, W020071 1 1864, Compounds of W02007120270, W02007120284, WO2007123581, WO2007136577, 5 W02008042223, W02008098244 are administered. In another embodiment, the compound of formula I is administered in combination with an antisense compound that inhibits the production of a glucagon receptor, such as ISIS-325568. In a particular embodiment, the compound of formula I is a binding glucokinase activator such as LY-2121260 (W02004063 179), PSN-105, PSN-110, GKA-50 or disclosed in WO2004072031, W02004072066, W02005080360, W02005044801, W02006016194, W02006058923, W02006112549, WO2006125972, W02007017549, W02007017649, W02007007910, W02007007040-42, 15 W02007006760-61, W02007006814, W02007007886, W02007028135, W02007031739, W02007041365, W02007041366, W02007037534, W02007043638, W02007053345, W02007051846, W02007051845, W02007053765, W02007051847, W02007061923 20 10 15 0 20 W02008050101, W02008059625, US2008146625, W02008078674, W02008079787, W02008084043, W02008084044, W02008084872, W02008089892, W02008091770, W02008075073, W Compounds of 02008084043, W02008084044, W02008084872, W02008084873, W02008089892, W02008091770, W02008116107, W02008118718, W02008120754 are administered. In a particular embodiment, the compound of formula I is administered in combination with an inhibitor of gluconeogenesis disclosed, for example, in FR-2256M, W02008053446. In a particular embodiment, the compound of formula I is an inhibitor of fructose 1,6-bisphosphatase (FBPase) such as MB-07729, CS-917 (ΜΒ-06322) or MB07803 or disclosed in WO2006023515, W020061 04030, W02007014619 The compounds of WO2007137962, W02008019309, W02008037628 are administered. In a particular embodiment, the compound of formula I is a modulator that binds to glucose transporter 4 (GLUT4), such as KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (1 2) 835 (2004)). In a particular embodiment, the compound of formula I is administered in combination with an inhibitor of glutamine-fructose-6-phosphate thiotransferase (GFAT) disclosed, for example, in WO2004101528. In a particular embodiment, the compound of formula I is an inhibitor of the binding of dipeptidyl peptidase IV (DPP-IV) such as vildagliptin (LAF-237), sitagliptin (MK- 0431), Sitamin citrate, Segler> '7*(saxagliptin) ((BMS-477118), GSK-823093, PSN-9301, SYR-322, SYR-619, 35 200946114 TA-6666 , TS-021, GRC-8200 (Melogliptin), GW-825964X, KRP-104, DP-893, ABT-341, ABT-279, another salt, S-40010, S-40755, PF-00734200, BI- 1356, PHX-1149 or disclosed in W02003074500, W02003106456, W02004037169, 5 W0200450658, W02005037828, W02005058901, W02005012312. W02005/012308. W02006039325x W02006058064, W02006015691, W02006015701, W02006015699, W02006015700, W02006018117,

O W02006099943, W02006099941, JP2006160733, io W02006071752, W02006065826, W02006078676, W02006073167, W02006068163, W02006085685, W02006090915, W02006104356, W02006127530, W02006111261, US2006890898, US2006803357, US2006303661, W02007015767 (LY-2463665). W02007024993, 15 W02007029086, W02007063928, W02007070434, W02007071738, W02007071576, W02007077508, 〇W02007087231, W02007097931, W02007099385, W02007100374, W02007112347, W02007112669, W02007113226, W02007113634, W02007115821, 20 W02007116092, US2007259900, EP1852108, US2007270492, WO2007126745, W02007136603, WO20(m42253, W02007148185, W02008017670, US2008051452, W02008027273 , W02008028662, W02008029217, JP2008031064, JP2008063256, W02008033851, W02008040974, 36 200946114 W02008040995, W02008060488, W02008064107, W02008066070, W02008077597, JP2008156318, 5 Ο 10 15 20 W02008087560, W02008089636, W02008093960, W02008096841, W02008101953, WO2008118848 W02008119005, W02008119208, W02008120813, W02008121506 compound is administered. In one particular embodiment, the compound of formula I is a combination of sitagliptin phosphate (sitagliptin phosphate) and dimethylamine hydrochloride of biguanide Yue Janumet ™ administration of a solid composition. In a particular embodiment, the compound of formula I is administered in combination with a Eucelas® solid composition of vildagliptin and diterpenoid hydrochloride. In another embodiment, the compound of formula I is administered in combination with a solid composition of alogliptin benzoate and sigma-grain. In a particular embodiment, the compound of formula I is administered in combination with a solid composition of a salt of sitagliptin and metformin hydrochloride. In a particular embodiment, the compound of formula I is administered in combination with a DPP-IV inhibitor and a composition disclosed, for example, in Sigma-3 fatty acid or Sigma-3 fatty acid ester of WO2007128801. In a particular embodiment, the compound of formula I is administered in combination with a solid composition of sitagliptin; a salt of butyl and metformin hydrochloride. In a particular embodiment, the compound of formula I is administered in combination with a substance that enhances insulin secretion, such as KCP-265 (W02003097064) or a compound disclosed in WO2007026761, WO2008045484, US2008194617. In a specific embodiment, the compound of Formula I is administered as an agonist that binds glucose dependent insulin 37 200946114 Release Peptide Receptor (GDIR), such as APD-668. In a specific embodiment, the compound of formula I is administered in combination with an ATP citrate lyase, such as SB-20499. In a particular embodiment, the compound of formula I is a modulator that binds sodium-dependent glucose transporting 5 or 1 (SGLT1, SGLT2), such as KGA-2727, T-1095, SGL-0010, AVE 2268, SAR 7226, SGL-5083, SGL_5085, SGL-5094, ISIS-388626, sergliflozinin or dapagliflozin, or disclosed in, for example, WO2004007517, WO200452903, ❹W0200452902, PCT/EP2005/005959, W02005085237, ίο. JP2004359630, W02005121161, W02006018150, W02006035796, W02006062224, W02006058597, W02006073197, W02006080577, W02006087997, W02006108842, W02007000445, W02007014895, W02007080170, W02007093610, W02007126117, 15 W02007128480, W02007129668, US2007275907, W02007136116, WO20071433 16, WO2007147478, W02008001864, W02008002824, W02008013277, W02008013280, W02008013321, W02008013322, W02008016132, W02008020011, JP2008031161, 20 W02008034859, W02008042688, W02008044762, W02008046497, W02008049923, W02008055870, W02008055940, W02008069327, W02008070609, W02008071288, W02008072726, W02008083200, W02008090209, W02008090210, W02008101586, 38 200946114 W02008101939, W02008116179, W02008116195, US2008242596 or A. L. Handlon discloses the administration of a compound in Expert Opin. Ther. Patents (2005) 15(11), 1531-154. 5 10 15

In a particular embodiment, the compound of formula I is an inhibitor of 11-yS-hydroxysteroid dehydrogenase-1 (11; S-HSD1) such as BVT-2733, JNJ-25918646, INCB-13739, INCB-20817 , DIO-92 ((-)-ketoconazole) or disclosed in, for example, WO200190090-94, WO200343999, WO2004112782, W0200344000, W0200344009, W02004112779, W020041133 10, W02004103980, WO2004112784, W02003065983, W02003104207, W02003104208, W02004106294, W02004011410 , W02004033427, W02004041264, W02004037251, W02004056744, W02004058730, W02004065351, W02004089367, W02004089380, W02004089470-71, W02004089896, W02005016877, W02006010546, W02006017542, W02006051662, W02006048331, W02006040329, W02006078006, W02006134481, W02006136502, W02006133926, US2007066584, W02005063247, W02005097759, W02006012227 , W02006012173, W02006034804, W02006040329, W02006048750, W02006049952, W02006050908, W02006024627, W02006066109, W02006074244, W02006106423, W02006132436, WO2006134 467, WO2006135795, W02006138508, WO2006138695, W02007003521, W02007007688, 39 200946114 W02007029021, W02007047625, W02007051811, W02007051810, W02007057768, W02007058346, W0200706166U W02007068330, W02007070506, W02007087150, W02007092435, W02007089683, 5 W02007101270, W02007105753, W02007107470, W02007107550, W02007111921, US2007207985, US2007208001, WO2007115935, W02007118185, W02007122411, W02007124329, W02007124337, W02007124254, W02007127688, W02007127693, ίο W02007127704, W02007127726, W02007127763, W02007127765, W02007127901, US2007270424, JP2007291075, W02007130898, WO2007135427, WO2007139992, WO2007144394, WO2007145834, WO2007145835, WO200714676U W02008000950. W0200800095U 15 W02008003611, W02008005910, W02008006702, W02008006703, W02008011453, W02008012532, W02008024497, W02008024892, W02008032164, W02008034032, W02008043544, W02008044656. W02008046758, W02008052638, W02008053194, 20 W02008071169, W The compounds of 02008074384, W02008076336, W02008076862, W02008078725, W02008087654, W02008088540, W02008099145, W02008101885, W02008101886, W02008101907, W02008101914, W02008106128, W02008110196, W02008119017, 40200946114 W02008120655, WO2008127924 are administered. In a specific embodiment, the compound of formula I is disclosed in, for example, W0200119830-3U W0200 117516. W02004506446, W020050 12295, W02005116003, W02005116003, W02006007959, DE 10 5 2004 060542.4, W02007009911, W02007028145, W02007067612-615, W02007081755, W02007115058, US2008004325, W02008033455, W02008033931, • W02008033932, W02008033934, W02008089581 are administered as inhibitors of the protein tyrosine citrate oxime (ΡΤΡ-ΙΒ). In one embodiment, the compound of formula I is an agonist _74A receptor agonist that binds GPRI09A; a NAR agonist (in an alkali acid receptor agonist)) such as nicotinic acid or "long-term release of niacin连合MK-0524A (laropiprant) or MK-0524 or disclosed in WO2004041274, W02006045565, W02006045564, W02006069242, W02006085108, 15 W02006085112, W02006085113, W02006124490, W020061 ❺ 13150, W02007017261, W02007017262, W02007017265, W020070 1 5744, Compounds in W02007027532, W02007092364, W02007120575, WO2007134986, W02007150025, W02007150026, W02008016968, W02008051403, 20 W02008086949, W02008091338, W02008097535, W02008099448, US2008234277, WO2008127591 In another embodiment of the invention, the compound of formula I is a combination A solid composition of nicotinic acid and simvastatin is administered. 41 200946114 In another embodiment of the invention, the compound of formula i is administered in combination with niacin or a "long-term release of niacin" conjugate mk_〇 524A (nicotinic acid). In another embodiment of the invention, the compound of formula I is a combination of nicotinic acid or "long-term release of niacin" conjugate ΜΚ-0524A (nicotinic acid) and simvastatin. In another embodiment of the invention, the compound of formula I is administered in combination with a niacin or another nicotinic acid receptor agonist and a prostaglandin DP receptor antagonist such as the compound disclosed in WO2008039882. d In another embodiment of the invention, the compound of formula I is administered in combination with an agonist of GPR116 as disclosed in Example 10, such as WO2006067531, WO2006067532. In a specific embodiment, the compound of formula I is disclosed in, for example, WO2007013689, WO2007033 002, WO2007106469, US2007265332, WO2007123225, WO2007131619, W02007131621, W02007131621, US2007265332, 15 W02007131622, W02007136572, W0200800193 1, W02008030520, W02008030618, W02008054674, W02008054675, W02008066097, US2008176912 GPR40 sputum administration. In a specific embodiment, the compound of formula I is a modulator of GPR119 (G-protein-2〇 coupled glucose-dependent insulin releasing peptide receptor) such as PSN-119-1, PSN-821, PSN-119- 2. MBX-2982 or disclosed in, for example, WO2004065380, W02005061489 (PSN-632408), W02006083491, W02007003960-62 and 64, W02007003964, W02007035355, W02007116229, W02007116230, W02008005569, 42200946114 W02008005576, W02008008887, W02008008895, W02008025798, WO2008025799, W02008025800, Compounds in W02008070692, W02008076243, W0200807692, W02008081204, W02008081205, W02008081206, 5 W02008081207, W02008081208, W02008083238, W02008085316, W02008109702 are administered. In another embodiment, the compound of formula I is administered as a modulator that binds to GPR120 as disclosed, for example, in EP 1688138, WO2008066131, WO2008066131, WO2008103500, W02008103501. In a particular embodiment, the compound of the formula I is administered in combination with an inhibitor of a hormone-sensitive lyase (HSL) and/or a phospholipase, such as disclosed in WO2005073199, WO2006074957, WO2006087309, W02006111321, W02007042178, WO2007119837, WO2008122352, WO2008122357. . In a particular embodiment, the compound of formula I is administered in combination with an inhibitor of endothelial lipase disclosed, for example, in _W02007110216. In a particular embodiment, the compound of formula I is administered in combination with a phospholipase A2 inhibitor such as darapladib or A-002 or a compound disclosed in W02008048866, W020080488867. 2〇 In a specific embodiment, the compound of formula I is administered in combination with a lipase inhibitor, myricetin (W02007119827). In a particular embodiment, the compound of formula I is disclosed in, for example, US2005222220, WO2005085230, WO2005111018, W02003078403, WO2004022544, W02003106410, 43200946114 W02005058908, US2005038023, W02005009997, US2005026984, W02005000836, W02004106343, EP1460075, W02004014910, W02003076442, W02005087727, W02004046117 , W02007073 117, W02007083978, 5 W02007120102, WO2007122634, W02007125109, W02007125110, US2007281949, W02008002244, W02008002245, W02008016123, W02008023239, W02008044700, W02008056266, W02008057940, W02008077138, EP1939191, EPI939192, W02008078196, 10 W02008094992, W02008112642, W02008112651, WO2008113469, W02008121063, Inhibitor of glycogen synthase kinase-3p (GSK-3p) of W02008121064 is administered. In a particular embodiment, the compound of formula I is administered in combination with, for example, a phosphoenolpyruvate carboxykinase (PEPCK) disclosed in WO2004074288. In a particular embodiment, the compound of formula I is administered in combination with an inhibitor of phospholipid 醯 inositol-3 kinase, such as disclosed in WO2008027584, WO2008070150, WO2008125833, WO2008125835, WO2008125839. In a particular embodiment, the compound of formula I is administered in combination with, for example, an inhibitor of a serum that regulates serum/adrenal glucocorticoids disclosed in WO2006072354, WO2007093264, WO2008009335, W02008086854. In a specific embodiment, the compound of formula I is a combination For example, the modulators of adrenal glucocorticoid receptors are disclosed in 200946114 W02008057855, W02008057856, W02008057857, W02008057859, W02008057862, W02008059867, W02008059866, W02008059865, W02008070507, 5 Ο 10 15 ❹ 20 W02008124665, W02008124745. In a particular embodiment, the compound of formula I is administered as a modulator of mineralocorticoid (MR), such as drospirenone or a compound disclosed in WO2008104306, WO2008119918. In a particular embodiment, the compound of formula I is administered as a compound that binds to a protein kinase Cp (PKCp), such as ruboxistaurin or a compound disclosed in WO2008096260, WO2008125945. In a particular embodiment, the compound of formula I is administered in combination with an inhibitor of protein kinase D such as doxazosin (W02008088006). In a particular embodiment, the compound of formula I is administered in combination with an activator such as AMP-activated protein kinase (AMPK) disclosed in WO2007062568, WO2008006432, WO2008016278, W02008016730, WO2008083124. In a particular embodiment, the compound of formula I is administered in combination with a ceramide kinase inhibitor such as disclosed in WO2007112914, WO2007149865. In another embodiment, the compound of formula I is administered in combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1 or 2) disclosed, for example, in W020071 04053, WO2007115822, W02008008547, \¥0200β075741. 45 200946114 In another embodiment, the compound of formula i is a combination, for example, disclosed in WO2001000610, WO2001030774, WO2004022057, W02004022553, WO2005097129, WO2005113544, US2007244140, W02008099072, W02008099073,

5 W02008099073, W02008099074, W02008099075 "I-kappaB kinase" inhibitor (IKK inhibitor) is administered. In another embodiment, the compound of formula I is administered as an inhibitor of NF-kappaB (NFKB) activation, e.g., bis-salicylate. In another embodiment, the compound of formula I is administered in combination with an inhibitor such as ASK-1 (apoptosis signal-regulated kinase 1) disclosed in ίο W020080 16131. In a particular embodiment of the invention, the compound of formula I is a binding to an HMG-CoA reductase inhibitor such as simvastatin; dibutyl, pravastatin, lovastatin, atorvastat; Intravastatin, cerivastatin, rosuvastatin, bitavastat; pitavastatin, L-659699, 15 BMS-644950 or compounds disclosed in US2007249583, WO2008083551. In a particular embodiment of the invention, the compound of formula I is a combination of a farnesoid derivative X receptor (FXR) modulator such as WAY-362450 or disclosed in W02003099821, WO2005056554, W02007052843, 20 W02007070796, W02007092751, JP2007230909, W02007095174, The compounds in W02007140174, W02007140183, W02008000643, W02008002573, W02008025539, W02008025540, JP2008214222 are administered. In a particular embodiment of the invention, the compound of formula I is administered in association with a ligand for the liver sputum receptor (LXR) disclosed in, for example, 46 200946114 W02007092965, WO2008041003, WO2008049047, W02008065754, WO2008073825, US2008242677. In a particular embodiment of the invention, the compound of the formula I is administered in combination with a fibric acid-derived compound such as fenofibrate, clofibrate, bezafibmte or a compound disclosed in WO2008093655. . In a particular embodiment of the invention, the compound of formula I is administered in combination with a fibric acid-derived protein such as fenofibrate choline salt (SLV-348). In a particular embodiment of the invention, the compound of formula I is administered in combination with a fibric acid derivative such as fenofibrate choline salt and an HMG-CoA reductase inhibitor such as rosuvastatin. In another embodiment of the invention, the compound of formula I is administered in combination with abbott and diflunisal. In another embodiment of the invention, the compound of formula I is a combination of fenofibrate 15 or a salt thereof with simvastat>, butyl, rosuvastatin, fluvastatin, valvastatin, A combination of statin, sevostatin, pivastatin, bitastatin or atorvastatin is administered. In another embodiment of the invention, the compound of formula I is administered by Synordia(R) in combination with a solid composition of fenofibrate and metformin. In another embodiment of the invention, the compound of formula I is a binding cholesterol reuptake inhibitor such as ezetimibe, tiqUeside, pamaqueside, FM-VP4 (bean) Sitostanol / campesterol ascorbyl phosphate; F〇rbes Medi_Tech, w〇2005〇42692, W02005005453) N MD-0727 (Microbia Inc., W02005021497, 47 200946114 W02005021495) or with the disclosure at W02002066464 a compound in W02005000353 (Kotobuki Pharmaceutical Co. Ltd.) or W02005044256 or W02005062824 (Merck & Co.) or W02005061451 and W02005061452 (As Shi aZeneca AB) and W02006017257 (Phenomix) 5 or W02005033100 (Lipideon Biotechnology AG) or disclosed in W02002050060, W02002050068, W02004000803, W02004000804, W02004000805, W02004087655, W02004097655, W02005047248, W02006086562, W020061 02674, W02006116499, W02006121861, WO2006122186, WO2006122216, WO2006127893, WO2006137794, W02006137796, W02006137782, WO2006137793, WO2006137797, WO2006137795, WO2006137792, The compounds of WO2006138163, WO2007059871, US2007232688, WO2007126358, W02008033431, W02008033465, 15w〇2〇〇8052658, W02008057336, W02008085300 are administered. In another embodiment of the invention, the compound of formula I is administered in combination with an NPC1L1 antagonist, such as disclosed in WO2008033464, WO2008033465. In another embodiment of the invention, the compound of formula I is administered by VytorinTM in combination with a solid composition of ezetimibe and simvastatin. In another embodiment of the invention, the compound of formula I is administered in combination with a solid composition of ezetimibe and acestatin. In another embodiment of the invention, the compound of formula I is administered in combination with a solid composition of ezetimibe and fenofibrate. 48 200946114 In another embodiment of the invention, the other active ingredient is a diphenylazetidin derivative disclosed in, for example, US 6,992,067 or US 7,205,290. In another embodiment of the invention, the other active ingredient is a diphenylazetidone derivative, such as simvastatin, fluvastatin, disclosed in, for example, US 6,992,067 or US 7,205,290. Pivastatin, Levastatin, Sevastatin, Atovastatin, Bitavastatin or Rosovastatin. In another embodiment of the invention, the formula is administered as a solid composition in combination with laPaquistat, a squalene synthetase inhibitor and atorvastatin. In another embodiment of the invention, the compound of formula I is a CETP inhibitor, such as torcerapib, anacetrapib or JTT-705 (dalcetrapib), or to reveal In WO2006002342, W02006010422, W02006012093, W02006073973, W02006072362, W02007088996, W02007088999, US2007185058, 15 US2007185113, US2007185154, US2007185182, W02006097169, W02007041494, W02007090752, W02007107243, 〇W02007120621, US2007265252, US2007265304, WO2007128568, W02007132906, W02008006257. W02008009435, W02008018529, The compounds of W02008058961, 20 W02008058967, WO2008059513, WO2008070496, WO2008115442, W02008111604 are administered. In a particular embodiment of the invention, the compound of formula I is a binding bile acid reuptake inhibitor (Intestinal Bile Acid Transfer Agent (IBAT)) (see, for example, US 6,245,744, US 6,221,897 or 100〇/61568). ^1741 or a compound disclosed in 0£10 2005 49 200946114 033099.1 and DE 10 2005 033100.9, DE 102006053635, DE 10 2006 053637, WO2007009655-56, W02008058628, W02008058629, W02008058630, W0200805863 1 . In a particular embodiment of the invention, the compound of formula I is a GPBAR1 (G-protein-coupled bile acid receptor) disclosed in, for example, US20060199795, WO2007110237, WO2007127505, W02008009407, WO2008067219, WO2008067222, FR2908310, W02008091540, W02008097976 -1; TGR5) agonist administration. In a particular embodiment of the invention, the compound of formula I is administered in combination with an inhibitor disclosed in the TRPM5 channel (TRP cation channel M5) disclosed, for example, in WO2008097504. In a particular embodiment of the invention, the compound of formula I is administered in combination with a polymeric bile acid adsorbent such as cholestyramine or colesevelam hydrochloride. In a particular embodiment of the invention, the compound of formula I is administered in combination with colesevel hydrochloride and diterpene or sulfonylurea or insulin. In a particular embodiment of the invention, the compound of formula I is administered in combination with a chewing gum containing plant sterol (ReductolTM). 2. In a particular embodiment of the invention, the compound of formula I is an inhibitor of a microsomal triglyceride transfer protein (MTP inhibitor) such as implitapide, BMS-201038, R-103757, AS- 1552133, SLx-4090, AEGR-733 or compounds disclosed in WO2005085226, WO2005121091, W02006010423, WO2006113910, WO2007143164, 50200946114 W02008049806, W02008049808, W02008090198, WO2008100423. In another embodiment of the invention, the compound of formula I is an inhibitor (MTP inhibitor) such as Yingpu, which binds to a cholesterol absorption inhibitor disclosed in WO2008030382 or WO2008079398, for example, a 5%-fold wheat cloth and a triglyceride transfer protein. Lida drugs. In a particular embodiment of the invention, the compound of formula I is administered in combination with an active anti-high triglyceride component disclosed, for example, in U W02008032980. In another embodiment of the invention, the compound of formula I is administered in combination with an antagonist agent such as the somatostatin 5 receptor (SST5 receptor) disclosed in WO2006094682. In another embodiment of the invention, the compound of formula I is administered in combination with an ACAT inhibitor such as avasimibe, SMP-797 or KY-382 or a compound disclosed in WO2008087029, WO2008087030, WO2008095189. p In another embodiment of the invention, the compound of formula I is a combination of the inhibition of broil palmetto transferase 1 (L-CPT1) disclosed in, for example, WO2007063012, WO2007096251 (ST-3473), W02008015081, US2008103182, W02008074692. Drug administration. 2 〇 In another embodiment of the invention, the compound of formula I is administered in combination with a modulator that reveals a serine palmitoyltransferase (SPT), such as WO2008031032, WO2008046071, WO2008083280, W02008084300. In another embodiment of the invention, the compound of formula I is a squalene synthetase inhibitor such as BMS-188494, TAK-475 (lapaquistat acetate) or disclosed in WO2005077907, JP2007022943 The compound in W02008003424 is administered. In a specific embodiment of the invention, the compound of formula I is administered in combination with an antisense oligonucleoside that regulates the apolipoprotein B gene, ISIS-301012 (mipomersen). In another embodiment of the invention, the compound of formula I is administered in combination with an LDL receptor elicitor (see US 6,342,512) such as HMR1H1, HMR1586 or a compound disclosed in WO2005097738, WO2008020607. In another embodiment of the invention, the compound of formula I is administered in combination with an agent that increases ίο HDL cholesterol, such as the compounds disclosed in WO2008040651, W02008099278. In a particular embodiment of the invention, the compound of formula I is administered in combination with an ABCA1 expression enhancer such as the compounds disclosed in WO2006072393, WO2008062830. In a particular embodiment of the invention, the compound of formula I is administered in combination with a lipoprotein lipase modulator such as ibrolipim (NO-1886). In a particular embodiment of the invention, the compound of formula I is administered in combination with an adiponectin antagonist such as gemcabene (C1 - 1027). In a particular embodiment of the invention, the compound of formula I is administered in combination with a lipase inhibitor such as orlistat or cetilistat (ATL-962). In a particular embodiment of the invention, the compound of formula I is administered in combination with an adenylate A1 receptor agonist (adenylate A1 R) disclosed in, for example, EP 1258247, EP 1375508, W02008028590, WO2008077050. 52 200946114 In a specific embodiment of the invention, the compound of formula I is administered in combination with an adenylate A2B receptor agonist (adenylate A2B R) such as ALT-801. In a particular embodiment of the invention, the compound of formula I is a modulator of adenosine A2A and/or adenylate A3 receptors disclosed in, for example, WO2007111954, WO2007121918, WO200712192, 5 10 15 ❹ 20 W02007121923, W0200807066. Dosing. In another embodiment of the invention, the compound of formula I is administered in combination with an agonist of the adenylate A1/A2B receptor disclosed in, for example, WO2008064788, WO2008064789. In another embodiment of the invention, the compound of formula I is administered in combination with an adenylate A2B receptor antagonist (adenosine A2B R) disclosed in, for example, US2007270433, WO2008027585, WO2008080461. In another embodiment of the invention, the compound of formula I is disclosed in, for example, W0199946262, WO200372197, WO200372197, W02005044814, W02005108370, JP2006131559, W02007011809, W02007011811, W02007013691, W02007095601-603, WO2007119833, W02008065508, W02008069500, W02008070609, W02008072850 , Ethyl-CoA-carboxylase (ACC1 and/or ACC2) administered by W02008079610, W02008088688, W02008088689, W02008088692, US2008171761, W02008090944, JP2008179621, US2008200461, W02008102749.W02008103382XW02008121592. In another embodiment of the invention, the compound of formula I is a modulator that binds to a microsomal thiol-CoA: glycerol-3-phosphate thiol transferase 3 (GPAT3, disclosed at 53 200946114 W02007100789) or with microparticles The brewing agent _CoA oleo-3-ester thiol transferase 4 modulator (GPAT4, disclosed in WO2007100833) was administered. In another embodiment of the invention, the compound of formula I is administered as a modulator in combination with xanthine oxidoreductase (XOR). In another embodiment of the invention, the compound of formula I is administered in combination with an inhibitor of soluble epoxide hydratase (SEH) which is disclosed, for example, in WO2008051873, WO2008051875, WO2008073623, W02008094869, W02008112022. In another embodiment of the invention, the compound of formula I is a CART-regulated transcript influences energy metabolism Λ anxiety and gastric emptying in mice" Asakawa, A. et al.: Hormone And Metabolic Research (2001), 33(9), 554-558); NP Y antagonists such as N-{4-[(4-aminooxazolin-2-ylamino)methyl]-cyclohexylhydrazine Naphthoquinone sulfonamide hydrochloride (CGP 71683A) or velneperit; 15 NPY-5 receptor antagonists such as L-152804 or from Banyu's compound "NPY-5-B Y' Or a compound disclosed in, for example, W02006001318, WO2007103295, WO2007125952, W02008026563, WO2008026564, WO2008052769, W02008092887, W02008092888, W02008092891; NPY-4 receptor antagonists disclosed in, for example, WO2007038942; 20 NPY-2 disclosed in, for example, WO2007038943 Receptor antagonist; peptide YY 3-36 (PYY3-36) or a similar compound, such as CJC-1682 (PYY3-36 binds to human serum protein via Cys34) or CJC-1643 (a derivative of PYY3-36, which is In vivo binding to serum proteins), or Compounds shown in WO2005080424, W02006095166, W02008003947; 54 200946114 Derivatives of obesity suppressin not disclosed in WO2006096847; CB1R (marijuana receptor 1) antagonists such as rim〇nabant, dembynaban (surinabant) (SRI47778), SLV-319 (ibipinabant), AVE-1625, (taranabant) (MK_0364) or its salt, 〇tenabant ( CP-945, 598), rosonabant, V-24343 or disclosed in, for example, EP0656354, WO00/15609, WO2001164632-64634, WO02/076949, WO2005080345, WO2005080328, WO2005080343, WO2005075450, WO2005080357, W0200170700, W02003026647-48 , W0200302776, 10 W02003040107, W02003007887, W02003027069, US6,509,367, WO200132663, W02003086288, W02003087037, W02004048317, W02004058145, W02003084930, W02003084943, W02004058744, W02004013120, W02004029204, W02004035566, W02004058249, 15 W02004058255, W02004058727, W02004069838, _US20040214837, US20040214855, US20040214856, W02004096209, W02004 096763, W02004096794, W02005000809, W02004099157, US20040266845, W02004110453, W02004108728, W02004000817, 2〇W02005000820, US20050009870, W0200500974, W02004111033-34, W0200411038-39, W02005016286, W02005007111, W02005007628, US20050054679, W02005027837, W02005028456, W02005063761-62, W02005061509, W02005077897, WO2006018662, 55 200946114 W02006047516, W02006060461, W02006067428, W02006067443, W02006087480, W02006087476, W02006100208, W02006106054, W02006111849, W02006113704, W02007009705, W02007017124, 5 W02007017126, W02007018459, W02007018460, W02007016460, W02007020502, W02007026215, W02007028849, W02007031720, W02007031721, W02007036945 , W02007038045, W02007039740, US20070015810, W02007046548, W02007047737, i〇W02007057687, WO2007062193, W02007064272, W02007079681, W02007084319, W02007084450, W02007086080, EP1816125, US2007213302, W02007095513, W02007096764, US2007254863, W02007119001, W0200712045 4. WO2007121687, WO2007123949, 15 US2007259934, WO2007131219, WO2007133820, WO2007136571, W02007136607, WO2007136571, US7297710, W02007138050, WO2007139464, W02007140385, W02007140439, WO2007146761, W02007148061, W02007148062, US2007293509, W02008004698, 20 W02008017381, US2008021031, W02008024284, W02008031734, W02008032164, W02008034032, W02008035356, W02008036021, W02008036022, W02008039023, WO2998043544, W0200804411, W02008048648, EP1921072-A1, W02008053341, 56 200946114 5 ❹ 10 15 ❹ 20 W02008056377, W02008059207, W02008059335, W02008062424, WO2008068423, W02008068424, W02008070305, W02008070306, W02008074816, W02008074982, W02008075012, W02008075013, W02008075019, W02008075118, W02008076754, W02008081009, W02008084057, EP1944295, US2008090809, US2008090810, W02008092816, W02008094473, W02008094476, W02008099076, W02008099139, W02008101995, US2008207704, W02008107179, W02008109027, WO2008112674, Compounds in W02008115705, W02008118414, WO2008119999, W0200812000, WO2008121257, WO2008127585; Cannabinoid receptor 1 / cannabinoid receptor 2 (CB1 /CB2) regulatory compounds such as delta-9-tetrahydrocannabinol, or disclosed in, for example, WO2007001939, W020070442 Compounds of WOAH (fatty acid guanamine hydratase) disclosed in, for example, W02007140005, WO2008019357, WO200821625, W02008023720, WO2008030532; disclosed in, for example, W02008057585, W02008059214, W02008075064, compounds in W02007047737, WO2007095513, WO2007096764, WO2007112399, WO200712402, WO2008122618; , an inhibitor of fatty acid synthase (FAS) in W02008075070, WO2008075077; an inhibitor of LCE (long-chain fatty acid chain elongase) disclosed in, for example, WO2008120653; 57 200946114, for example, in WO2007091948, WO2007129188, WO2007133637, W02008007780, W02008010061, W02008007211, 5 10 15 20 W02008010061, W02008015335, W02008018827, W02008024433, W02008024438, W02008032204, W02008050199, W02008059339, W02008059370, W02008066664, W0200 Vanilloic acid-1 receptor modulator (modulator of TRPV1) in 8075150, W02008090382, W02008090434, WO2008093024, WO2008107543, ΟW02008107544, WO2008110863; modulator, antagonist or inverse agonist of sputum receptor such as GSK-982 Or a compound disclosed in, for example, WO2007047397, WO200821849, WO200821851, W02008032156, WO2008059335; a modulator of "orphan opium (ORL-1) receptor" disclosed in, for example, US2008249122, WO2008089201; a modulator of prostaglandin receptors such as Baima Bimatoprost or a compound disclosed in WO2007111806; MC4 receptor agonist (melanocortin-4 receptor agonist, MC4R agonist, eg > 1-[2-(38-:^: yl-2) -mercapto-3-copperyl-2,3,3&,4,6,7-hexahydroindole-p-[4,3-(:]-pyridin-5-yl)-1-(4_gas Phenyl)-2-ketoethyl]-1-amino-1,2,3,4-tetrahydronaphthalen-2-indoleamine; (WO01191752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764 , CHIR-785, PT-141, MK-0493 or disclosed in W02005060985, W02005009950, W02004087159, W02004078717, W02004078716, W02004024720, US200501246 52, W02005051391, WO2004112793, 58 200946114 5 ❹ 10 15 ❹ 20 WOUS20050222014, US20050176728, US20050164914, US20050124636, US20050130988, US20040167201, W02004005324, W02004037797, W02005042516, W02005040109, W02005030797, US20040224901, W0200501921, W0200509184, W02005000339, EP1460069, W02005047253, W02005047251, W02005118573, EP1538159, W02004072076, W02004072077, W02006021655-57, W02007009894, W02007015162, W02007041061, W02007041052, JP2007131570, EP-1842846, W02007096186, W02007096763, WO2007141343, W02008007930, W02008017852, W02008039418, W02008087186, W02008087187, W02008087187, WO2008087186-W02008087190, W02008090357 a compound; an orexin receptor 1 antagonist (OX1R antagonist), an orexin receptor 2 antagonist (OX2R antagonist) or a mixed OX1R/OX2R antagonist (eg 1-(2-methylbenzoxazole)- 6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride (SB-334867-A) or disclosed in, for example, WO200196302, WO200185693, WO2004085403, WO2005075458, W02006067224 W02007085718, W02007088276, W02007116374, WO2007122591, WO2007126934, WO2007126935, W02008008517, W02008008518. W02008008551, W02008020405, WO2008026149, W02008038251, US2008132490, W02008065626, W02008078291, W02008087611, W02008081399, W02008108991, W02008107335, US2008249125); 59 200946114 Histamine H3 a body antagonist/inverse agonist (eg, 3-cyclohexyl-1 _(4,4-didecyl-1,4,6,7-W-5- (WO00/63208), or disclosed in W0200064884, W02005082893 , US2005171181 (for example, PF-00389027), W02006107661, 5 W02007003804. W020070 16496, W02007020213, W02007049798, W02007055418, W02007057329, W02007065820, W02007068620, W02007068641, W02007075629, W02007080140, W02007082840, W02007088450, W02007088462, W02007094962, 10 W02007099423, W02007100990, W02007105053, W02007106349, W02007110364, W02007115938, W02007131907, WO2007133561, US2007270440, W02007135111, WO2007137955, US2007281923, WO2007137968, WO2007138431, WO2007146122, 15 W0 2008005338, W02008012010, W02008015125, W02008045371, EP1757594, W02008068173, W02008068174, US20080171753, W02008072703, W02008072724, US2008188484, US2008188486, US2008188487, W02008109333, W02008109336); 20 histamine H1/histamine H3 modulator, such as betahistine (betahistine) or a dihydrochloride thereof; a modulator of a histamine H3 transporter or a histamine H3/serotonin transporter disclosed in, for example, WO2008002816, WO2008002817, WO2008002818, W02008002820; 200946114 discloses histamine Η4 in, for example, WO2007117399 a modulator; an antagonist such as [2-mercapto-9-(2,4,6-tridecylphenyl)-911-:1,3,9-triazaindole-4-yl] Propylamine (WOOO/66585) or a CRF1 antagonist disclosed in WO2007105113, WO2007133756, WO2008036541, WO2008036579, W02008083070); a CRF sputum antagonist (such as urocortin); a vasopressin agonist; Ο 10 15 ❹ 20 β-3-adrenergic modulators such as 1-(4-chloro-3-indolesulfonylnonylphenyl)-2-[2-(2,3-dimercapto-1Η-吲Indole-6-yloxy)ethylamino ] Ethanol hydrochloride (WO 01/83451) or selelabegron (GW-427353) or Ν-5984 (KRP-204) or disclosed in JP2006111553, W02002038543, W02002038544, W02007048840-843, W02008015558, EPI947103 Compound; MSH (hormone stimulating melanocyte) agonist; MCH (melamine-concentrating melamine) receptor antagonist (eg NBi_845, A-761, A-665798, A-798, ATC-0175, T-226296, T -71 (AMG-071, AMG-076), GW-856464, NGD-4715, ATC-0453, ATC-0759, GW-803430 or disclosed in WO2005085200, W02005019240, W02004011438, W02004012648, W02003015769, W02004072025, W02005070898, W02005070925, W02004039780, W02004092181, W02003033476, W02002006245, W02002089729, W02002002744, W02003004027, FR2868780, W02006010446, W02006038680, W02006044293, W02006044174, JP2006176443, 61200946114 W02006018280, W02006018279, W02006118320, W02006130075, W02007018248, W02007012661, W02007029847, W02007024004, W02007039462, W02007042660, W02007042668, W02007042669, 5 US2007093 508, US2007093509, W02007048802, JP2007091649, W02007092416; W02007093363-366, W02007114902, W02007114916, W02007141200, WO2007142217, US2007299062, WO2007146758, WO2007146759, W02008001160, W02008016811, W02008020799, ίο W02008022979, W02008038692, W02008041090, W02008044632, W02008047544, W02008061109, W02008065021, Compounds in W02008068265, W02008071646, W02008076562, JP2008088120, W02008086404, W02008086409) 15 匚(^-eight (0:(:1^1) antagonist/regulator (eg {2-[4_(4-gas-2,5) -dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylaminoindenyl]-5,7-diindenyl-1 -yl}acetic acid trifluoroacetate (WO 99/15525) or SR-146131 (WO 0244150) or 化合物 Revealing compounds in WO2005116034, WO2007120655, WO2007120688, W02007120718, WO2008091631); 20 serotonin reuptake inhibitors (eg, exfenfluramine) Or a compound disclosed in WO2007148341, W02008034142, W02008081477, W02008120761; mixed serotonin/dopamine reuptake inhibition a compound such as amphetamine (bUpr〇pi〇n) or a compound disclosed in WO2008063673, or a solid composition of amphetamine and naitrexone 62 200946114 or albendamine and zonisarnide; mixed reuptake Inhibitors such as DO V-21947; mixed jk clarin and norepinephrine compounds (eg w〇〇〇/71549); 5 Ο 10 15 ❹ 20 5-HT receptor agonists such as 1-(3-B Benzofuran-7-yl) hexahydropyrrolic acid oxalate (WO 01/09111); mixed dopamine/norepinephrine/acetylcholine reuptake inhibitor (eg tesofensine) or A compound disclosed in, for example, WO2006085118; a dopamine antagonist disclosed in, for example, WO2008079838, WO2008079839, WO2008079847, W02008079848, which discloses a norepinephrine reuptake inhibitor, for example, in US2008076724; a 5-HT2A receptor antagonist disclosed in, for example, WO2007138343 5 - HT2C receptor antagonist (eg lorcaserine hydrochloride) (APD-356) or BVT-933, or disclosed in W0200077010, W0200077001-02, W02005019180, W02003064423, W0200242304, W02005035533, W02005082859, W02006004937, US2006025601, W02006028961, W02006077025, W02006103511, W02007028132, W02007084622. US2007249709; WO200713284U W02007140213, W02008007661, W02008007664, W02008009125, W02008010073, W020081 08445); 5-HT6 receptor modulators such as E-6837, BVT- 74316 or PRX-07034 or disclosed in, for example, W02005058858, W02007054257, W02007107373, W02007108569, W02007108742-744, W02008003703, W02008027073, W02008034815, W02008054288, EP1947085, 63200946114 W02008084491, W02008084492, W02008092665, W02008092666, W02008101247, W02008110598, W02008116831, W02008116833 a compound; an estrogen receptor 5 agonist (ERR γ agonist) disclosed in, for example, WO2007131005, WO2008052709; an agonist of an estrogen receptor alpha (ERRα / ERR1 agonist) disclosed in, for example, WO2008109727; Sigma-1 receptor antagonists in, for example, WO2007098953, W02007098961, W02008015266, W02008055932, W02008055933; ίο disclosed in, for example, W0200711 0782, W02008041 a muscarinic 3 receptor (M3R) antagonist in 184; a bombesin receptor agonist (BRS-3 agonist) disclosed in, for example, WO2008051404, WO2008051405, WO2008051406, W02008073311; galanin receptor antagonist 15 growth hormone (such as human growth hormone or AOD-9604); release of growth hormone compound (6-benzyloxy-1-(2-diisopropylaminoethylamino)-3,4-di Hydrogen-1H-isoporphyrin-2-carboxylic acid tert-butyl ester (WO 01/85695)); growth hormone secretagogue receptor modulator (growth hormone releasing peptide modulator) such as 20 JM^2959, JMV-3002 , JMV-2810, JMV-2951 or a compound disclosed in WO2006012577 (eg YIL-781 or YIL-870), W02007079239, W02008092681; a TRH agonist (see for example EP 〇 462 884); a decoupled protein 2 or 3 modulator 64 200946114 Chemical decoupling agents (eg W02008059023, W02008059024, W02008059025, W02008059026); Leptin agonists (see eg Lee, Daniel W.; Leinung, Matthew C.; Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists As a 5 potential approach to the treatment of o Besity. Drugs of the Future (2001), 26(9), 873-881); DA agonists (bromocriptin, doprexin); _ lipase/amylase inhibitors (eg WO 00/40569, W02008107184); inhibitors of dimercaptoglycerol hydrazone-hydrazinotransferases (DGATs) such as BA ίο Y-74-4113 or disclosed in, for example, US 2004/0224997, WO2004094618, W0200058491, W02005044250, W02005072740, JP2005206492, W02005013907 , W02006004200, W02006019020, W02006064189, W02006082952, W02006120125, W02006113919, WO2006134317, W02007016538, 15 W02007060140, JP2007131584, WO2007071%6, p W02007126957, WO2007137103, WO2007137107,

W02007138304, W02007138311, W02007141502, W02007141517, WO2007141538, WO2007141545, WO2007144571% W02008011130x W0200801113U 20 W02008039007, W02008048991, W02008067257 W02008099221; a monomercaptoglyceryl thiol transferase (2_mercaptoglycerol 0-醯 disclosed in, for example, WO2008038768) Inhibitors of basal transferases; MGAT); inhibitors of fatty acid synthase (FAS) such as C75 or compounds disclosed in 65 200946114 W02004005277, WO2008006113; 5 10 15 20 disclosed in, for example, WO2007009236, WO2007044085, WO2007046867, W02007046868, W020070501124, W02007056846, W02007071023, W02007130075, WO2007134457, WO2007136746, WO2007143597, WO2007143823, WO2007143824, W02008003753, W02008017161, W02008024390, W02008029266, W02008036715, W02008043087, W02008044767, W02008046226, W02008056687, W02008062276, W02008064474, W02008074824, W02008074832, W02008074833, W02008074834, W02008074835, W02008089580, W02008096746, W020081 04524, W02008116898, US2008249100, W020 08120744, W02008120759, \\^02008123469, "02008127349, stearyl--(: inhibitor of serotonin (SCD1); 0 reveals fatty acid desaturase 1 in, for example, WO2008089310 Inhibitor of saturase; a hypoglycemic/high glycerol triacetate alpha π-lin compound disclosed in WO2008039087; an inhibitor of "protein aP2 binding to fatty cell fatty acids" such as BMS-309403; disclosed in, for example, WO2006082978, WO2008105533 An activator secreted by adiponectin; adiponectin secreting agent disclosed in, for example, WO2007125946, WO2008038712; 66 200946114 discloses a modified adiponectin in, for example, WO2008121009; gastric acid regulating peptide or a homolog thereof; An agonist or partial agonist (thyroid hormone receptor agonist) such as ΚΒ-2115 (eprotirome), QRX-431 (Su) So 罗 (sobetirome) or DITPA, or disclosed in W020058279, WO200172692, W0200194293, W02003084915, W02004018421, W02005092316, W02007003419, W02007009913, W a compound of 02007039125, WO2007110225, WO2007110226, WO2007128492, WO2007132475, WO2007134864, WO20_G1959, WO2G081G6213; or an agonist of the glandular hormone receptor y3 (TR-/3), such as MB-07811 or MB-07344, or is not disclosed in WO2008062469 Compound. In a particular embodiment of the invention, the compound of formula I is administered in combination with a combination of eptiturol and ezetimibe. In a particular embodiment of the invention, the compound of formula is administered as an inhibitor of a binding site protease (S1P), such as PF _429242. In another embodiment of the invention, the compound of the formula is administered in combination with a modulator that discloses "a trace amine bound to receptor 1" (TAAR1) as disclosed, for example, in US2008146523, WO2008092785. In a particular embodiment of the invention, the compound of formula I is administered in combination with an inhibitor of protein 2 (GRB2) linked to growth factor receptor, e.g., WO2008067270. In another embodiment of the invention, the compound of formula I is a RNAi (siRNA) medical agent that binds to 67 200946114 directly against PCSK9 (proprotein convertase subtilisin/kexin9). In a particular embodiment, the compound of formula I is administered in combination with 0macor® or LovazaTM (omega-3 fatty acid ester; highly concentrated ethyl eicosapentaenoic acid or ethyl hexahexosahexaenoic acid) . In a specific embodiment, the compound of formula I is administered in combination with lycopene. In a particular embodiment of the invention, the compound of formula I is a combination of an anti-oxidant such as OPC-14117, AGI-1067 (succinobucol), ίο普罗布克(Pr〇buc〇l), tocopherol (tocopherol), ascorbic acid, β_caurocin or selenium. In a particular embodiment of the invention, the compound of formula I is administered in combination with a vitamin such as vitamin Β6 or vitamin Β12. In a particular embodiment, the compound of formula I is administered in combination with more than one of the above 15 compounds, for example, in combination with sulfonyl urea and metformin, sulfonyl urea and acarbose, repaglinide and metformin (prandiMet ( ΤΜ)), _ Insulin and sulfhydryl urea, insulin and metformin, insulin and troglitazone, sputum insulin and levastatin. In another embodiment, the compound of formula I is administered in combination with an inhibitor of carbonic anhydrase type 2 disclosed in Example 2, such as W02007065948. In another embodiment, the compound of formula I is administered in combination with topiramat or a derivative thereof as disclosed in, for example, WO2008027557. In another specific embodiment, the compound of formula I is administered in a solid composition in combination with tolten and phen 68 200946114 phentermin (QnexaTM). In another specific embodiment, the compound of formula I is administered in combination with a reverse compound that inhibits the production of the adrenocortical glucocorticoid receptor, such as ISIS-377131. 5 Ο 10 15 ❹ 20 In another embodiment, the compound of formula I is a combination of an aldosterone synthase inhibitor and an adrenal glucocorticoid antagonist disclosed in, for example, EP 1886695, WO2008119744, cortisol synthesis Inhibitors and/or antagonists of corticotropin releasing factor are administered. In a specific embodiment, the compound of formula I is administered in combination with an agonist disclosed in the RUP3 receptor disclosed in WO2007035355, WO2008005576. In another specific embodiment, the compound of Formula I is administered as an activator of a gene that binds to a protein kinase encoding a vasoactive telangiectasia mutation (ATM), such as chloroquine. In a specific embodiment, the compound of formula I is administered in combination with a tau protein kinase 1 inhibitor (TPK1 inhibitor) disclosed in, for example, WO2007119463. In a specific embodiment, the compound of formula I is disclosed in, for example, WO2007125405, W02008028860, The "c-Jun Ν-terminal kinase" inhibitor (JNK inhibitor) in W02008118626 was administered. In a specific embodiment, the compound of formula I is administered in combination with an endothelin A receptor antagonist such as avasentan (SPP-301). In a particular embodiment, the compound of formula I is a compound that binds to a modulator of the adrenal glucocorticoid receptor (GR), such as KB_3305 or a compound disclosed in, for example, WO2005090336, WO2006071609, WO2006135826, WO2007105766, WO2008120661. 69 200946114 In one embodiment, the other active ingredient is varenicline Tartrate, a partial agonist of the α4-/32-nicotinoid choline receptor. In a specific embodiment, the other active ingredient is trodusquemine. In a specific embodiment, the other active ingredient is a modulator of the enzyme SIRT1 and/or SIRT3 (a NAD+-dependent protein deacetylase); the active ingredient can be, for example, a white alcohol produced in a suitable preparation. (resveratrol) 或 or reveal 10 compounds in W02007019416 (eg SRT-1720), W02008073451. In one embodiment of the invention, the other active ingredient is DM-71 (N-ethylidene-L-semi-deaminic acid and bethanechol). In a particular embodiment, the compound of formula I is administered in combination with an anti-hypercholesterolemic compound disclosed in, for example, WO2007107587, W020071 11994, WO2008106600, 15 WO2008113796. In another embodiment, the compound of formula I is administered in combination with a sputum formulation that reveals SREBP (a protein that binds to a sterol regulatory element) as disclosed in WO2008097835. In another embodiment, the compound of formula I is administered in combination with a cyclic peptide agonist disclosed in the VPAC2 receptor of Example 20, such as WO2007101146, WO2007133828. In another embodiment, the compound of formula I is administered in combination with an agonist disclosed to express an endothelin receptor, such as WO2007112069. In another embodiment, the compound of formula I is administered in combination with AKp_〇2〇 200946114 (associated vanadyloxymethane (ιν)). In another embodiment, the compound of formula I is administered in combination with a tissue selective androgen receptor modulator (S ARM) disclosed, for example, in W02007099200, WO2007137874. In another embodiment, the compound of formula I is administered in combination with an AGE (late glycation end product) inhibitor disclosed, for example, in JP2008024673. In a particular embodiment of the invention, the other active ingredient is a steroidal hormone; see, for example, "Perspectives in the therapeutic use of leptin"

Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, Expert ίο Opinion on Pharmacotherapy (2001), 2(10), 1615-1622. In another embodiment of the invention, the other active ingredient is Metric The metreleptin (recombined guanidine thiol- steroid) binds to pramlintide. In another embodiment of the invention, the other active ingredient is the tetra-15 peptide ISF-402.一个 In one embodiment, the other active ingredient is dextroamphetamine or amphetamine. In a particular embodiment, the other active ingredient is fenfluramine or dextroamphetamine. 2〇 In another embodiment, the other active ingredient is sibutramine or a compound that is at the end of WO2008034142. In a specific embodiment, the other active ingredient is mazindol or phentermin. In another embodiment, the other active ingredient is genipin acid 71 200946114 (geniposidic acid) (W020071 00104) Or a derivative thereof (jp20081 〇6〇〇8) 0 In one embodiment, the other active ingredient is a nasal dance channel blocker such as diltiazem or a compound disclosed in US 7,138,107. In a specific embodiment, the other active ingredient is an inhibitor of sodium-dance ion exchange, such as the compounds disclosed in W02008028958, WO2008085711. In another embodiment, the other active ingredient is a feed channel blocker such as CaV3.2 Oder CaV2.2 disclosed in W02008033431, W02008033447, W02008033356, 1〇W02008033460, W02008033464, W02008033465, W02008033468, W02008073461. In another embodiment, the other active ingredient is a calcium channel modulator, such as the compounds disclosed in WO2008073934, WO2008073936. In another embodiment, the other active ingredient is a "T-type calcium channel" blocker disclosed in, for example, WO2008033431, WO2008110008. In another embodiment, the other active ingredient is an inhibitor of KCNQ potassium channel 2 or 3 as disclosed in, for example, US2008027049, US2008027090. In a specific embodiment, the other active ingredient is an inhibitor of the potassium Kvl.3 ion channel disclosed in, for example, 20 W02008040057, W02008040058, W02008046065. In a specific embodiment, the other active ingredient is a modulator of MCP-1 lean body (monocyte chemoattractant protein_1 (MCP-1)) disclosed in, for example, WO2008014360, WO2008014381. 72 200946114 In a specific embodiment, the other active ingredient is a modulator of somatostatin receptor 5 (SSTR5) as disclosed in, for example, WO2008019967, US2008064697, US2008249101, WO2008000692. In a specific embodiment, the other active ingredient is a modulator of somatostatin receptor 2 (SSTR2) disclosed in, for example, 5 W02008051272. In a specific embodiment, the other active ingredient is an erythropoietin-mimetic peptide that acts as an erythropoietin (EPO) receptor agonist. This sub-sub is disclosed in, for example, W02008042800. In a particular embodiment, the other active ingredient is a compound that inhibits appetite/reduced jk sugars as disclosed, for example, in 10 W02008035305, WO2008035306, WO2008035686. In a particular embodiment, the other active ingredient is an elicitor of lipoic acid synthase as disclosed in, for example, WO2008036966, WO2008036967. In a specific embodiment, the other active ingredient is a modulator of endothelial nitric oxide synthase (eN〇S) disclosed in, for example, q W02008058641, WO2008074413. In another embodiment, the other active ingredient is a modulator of carbohydrate and/or fat metabolism disclosed in, for example, WO2008059023, WO2008059024, WO2008059025, 2〇W02008059026. In another embodiment, the other active ingredient is an angiotensin II receptor antagonist disclosed in, for example, WO2008062905, WO2008067378. In a specific embodiment, the other active ingredient is an agonist of the serotonin-μ 73 200946114 phosphate receptor (SIP) disclosed in, for example, W020080643 15, WO2008074820, WO2008074821. In a specific embodiment, the other active ingredient is an agent that prevents gastric emptiness such as 4-hydroxyisoleucine (W02008044770). In a particular embodiment, the other active ingredient is a muscle relaxant disclosed in, for example, WO2008090200. In another embodiment, the other active ingredient is an inhibitor of monoamine oxidase B (MAO-B) disclosed in, for example, WO2008092091. 10 15 20

In another embodiment, the other active ingredient is an inhibitor that binds cholesterol and/or triglyceride to SCP-2 protein (sterol carrier protein-2) as disclosed, for example, in US2008194658. In another embodiment, the other active ingredient is a lisofylline that prevents spontaneous immunity from damaging the cells from which the insulin is made. In a particular embodiment, the compound of formula I is administered in combination with bulking agents, preferably insoluble fillers (see, for example, Carob/Caromax® (Zunft HJ; et al., Carob pulp preparation for treatment of hypercholesterolemia). , ADVANCES IN THERAPY (2001 Sep-Oct), 18(5), 230-6). Caromax is a carob-containing product from Nutrinova, Nutrition Specialties & Food Ingredients GmbH, Industriepark Hijchst, 65926 FrankfbrtJMain)). Combination with Caromax® may be in a single formulation or via separate administration of a compound of formula I and Caromax®. In this regard, Caromax® can also be administered in the form of food products, such as in baked products or oatmeal sticks. Suitable combinations of the compounds of the invention with one or more of the above compounds and optionally one or more other pharmaceutically active substances are, of course, considered to be encompassed by the scope of the invention. 74 25 200946114

75 200946114

76 200946114

Η BMS-477118 77 200946114

78 10 200946114

79 200946114

80 10 200946114

Trodusquemine xHCI

xHCI lorcaserine hydrochloride

81 200946114

OH

H 3C v /Η 3

OH *Glu _Gly T hr —P he —T hr

O

Leu _Tyr —Se r —Ser—Val —Asp —Ser Glu —G ly —Gin —Ala Ala —L ys —G lu

L ys —Val —Leu —T rp —Ala O —lie —P he

0^0 >Λ

Arg -NH

H C CH TAK-536 BIM-51077 5

E-6837

x CF3COOH BVT-74316 ABT-341 82 200946114

ABT-279

10 AYE 1625 (proposed INN: drinabant) TAK-475 (lapaquistat acetate)

83 200946114

CKD-501 (lobeglitazone sulfate)

BMS-309403 PSN-119-1 84 200946114

LY-2463665

At o

O 10

PF-429242

Χγχτχ I

HO 乂 SLV-348

ο balaglitazone

“NPY-5-BY’ 85 200946114 ci

BMS-711939 BMS-687453

xHCI DOV-21947 again

"Y 丫丫 'OH3 L / ,cr SH l+ Cl

AEGR-733 DM-71

YIL-781 a

YIL-870 o

x HCI 丨N PRX-07034 86 200946114

❹ 10 Ο

〇

Α-002 87 200946114

DGAT-1 inhibitor from W02007137103

Dalcetrapib otenabant 88 200946114

MB-07229

Succinobucol MB-07803

F

BMS-644950 T-2384

Alogliptin benzoate nicotinic acid / laropiprant 89 10 200946114

Velneperit

GSK-982

Drospirenone

PSN-119-2

Lisofylline The following active ingredients are also suitable for combination preparations: All antiepileptic drugs listed in Chapter 15 of Rote Liste 2007; all antihypertensive drugs listed in Chapter 17 of Rote Liste 2007; listed in Chapter 19 of Rote Liste 2007 All hypotonic agents; 15 all anticoagulants listed in Chapter 20 of Rote Liste 2007; perfUsion point receptors, milk channel blockers and inhibitors of the renin-angiotensin system; 90 200946114 at Rote Liste 2007 All diuretics and perfusion-promoting agents listed in Chapters 36 and 37; all withdrawal medications listed in Chapter 39 of Rote Liste 2007/agents for the treatment of addiction disorders; 5 in Rote Liste 2007 Chapters 55 and 60 All coronary agents and gastrointestinal agents; all migraine agents, _ neuropathic agents, and Parkinson's disease agents listed in Chapters 61, 66, and 70 of Rote Liste 2007. A starting compound of the formula II, which is prepared by reacting phosgene with X, when X is oxygen, by reacting sulphur phosgene with X, when X is sulfur, with an amine of the formula

A nh2 A product of this form is disclosed in French Patent No. 2,329,276. The amine of the formula A is disclosed in EpPatent No. 0,002,892 and French Patent No. 2,142,804. The product of the formula in or in' is known or can be prepared from the corresponding sterol nitrile via the method of j Am. 〇1 咖.8 沈., 仰 1.75 (1953), 1). 4841. Wherein the compound of formula III wherein 3 is not hydrogen may be derived from the formula, and the compound of 3-Hal is reacted with 2-cyano-2-aminopropyl in the conditions described above for the reaction of the halide with the compound of formula IV. . An example is 2 〇 Jilek et al. Rev. in Collect. Czech Chem. Comm., vol. 54(8) (1 989), p. 2248. The product of Formula IV' is disclosed in French Patent No. 2,329,276. 91 200946114 The compounds of the formulae V and VI are known compounds which are commercially available and can be prepared by known methods. The preparation of the compound of formula VI is disclosed in the following publication: zur Preklad Khim., vol. 28 (1955), p. 969-75 (CA, vol. 50 (1956), p 4881a); 5 Tetrahedron, vol. 43 (1 987), p. 1753; J. Org. Chem., vol. 52 (1987), p. 2407; Zh. Org. Khim., vol. 21 (1985), p. 2006; J. fluorine. Chem Vol. 17 (1981), p. 345; German Patent No. 637, 318, European Patent No. 0,130, 875, and Japanese Patent No. 81-121, 525. The product of formula VI, which is a derivative of hydantoin, is frequently used and is known in the literature, for example, J. Pharm. Pharmacal., 67, vol. 19(4), (1967), ρ·209- 16; J. Chem. Soc” vol· 74(2) (1 972), p. 219-221; Khim. Farm. Zh_, vol. 67(1)(5), p.51-2; German Patent No. 2,217,914; European Patent No. 0,091,596 and J. Chem. Soc. Perkin. Trans. 1, vol. 74(2), p. 48 and 219-221. The novel intermediate of the present invention is a compound of the formula

R2 where R!, R2, and Y are each according to the above definition and _8 1_ugly _ is

92 20 200946114 wherein X is oxygen or sulfur and R3 is a protected reactive group of size 3 which comprises _〇H or -NH2 which is protected as described above for R3. The following examples illustrate several preferred embodiments for illustrating the invention. However, it is apparent that the invention is not limited to the specific embodiments. [Examples] Example 1 1_(4_Shishiyl-3-difluoromethylphenyl)_3,4,4-trimethyl-2,5- miso dandione 3.17 g of 1-(3-three Fluoromethyl_4_nitrophenyl)_4,4-dimethylimidazoline-2,5-dione (French Patent No. 2,329,276) and 32 ml of dimethylformamide at 23° C to add 492 mg of a 50% suspension of sodium hydride in oil and 3 ml of dimethylformamide. After stirring for 15 minutes, add 0.7 ml of methyl iodide in 2 ml of dimethyl decylamine. The solution. The mixture was stirred for 25 minutes from 24 ° C to 28 ° C and poured into 200 g of a 1-1 water-ice mixture. The mixture was extracted with diethyl ether. EtOAc (EtOAc m.). The analyzed sample was crystallized from isopropanol, thus giving 2.73 g of product which was spurred at ii 6 °C. Analysis: molecular weight = 331.25 % C % B % F % N Theoretical value: 47.14 3.65 17.20 12.68 Experimental value: 47.0 3.5 17.1 12.5 93 200946114 d: - c=o Aromatic N〇2 1780, 1727 Guild. 1 161^ 1596, 1497 cm _〗, 1545, 1357 cm · Example 2 5,5-Dimercapto-1 -ethyl-3-(4-nitro-3-trifluoromethylphenyl)_2,4-imidazolidinium Analysis: CmHmFsNsCV Molecular weight = 345.28% 〇, . ; % Η %N Theoretical value: 48.70 4.09 16.51 —----S 12.17 Experimental value: _ 48.6 16.8 12.1 IR spectrum (CHC13) Using the method of Example 1, 1 gram according to 1-(3-Trifluoromethyl-4-stone-cholylphenyl)-4,4-dimethylimidazolin-2,5-dione and 0.37 ml of methyl iodide prepared by French Patent No. 2,329,276 And 166 mg of a 50% suspension of sodium hydride in oil is reacted, thus obtaining 119 g of the desired product which is melted at 11 ° C to 111 C to crystallize from isopropanol, thus obtaining 934 mg of product. Melted at 110 ° C to 111 ° C. c=o 1777, 1724 cm N〇2 1545, 1356 cm 1 Aromatic 1614, 1596, 1497 cm -1 ίο Example 3 5,5_Dimercapto-3·(4·Nitro-3-trifluoromethyl) Base phenyl)-2,5-diphenyl with 94 200946114 0.35 ml of 1-iodopropane and 155 mg of a 50% suspension of sodium hydride in oil, using acetone-dichlorodecane on the tannin (1- 99) After the composition of the eluate was chromatographed, 3.087 g of a crude product was obtained which was melted at i 〇 2 ° C. The product was crystallized from isopropanol to give 945 mg of desired product which melted at 102 °. Analysis: Molecular weight = 359.31% C; %H %F %N 1 Theoretical value: 50.14 4.49 15.86 11.69 Experimental IR spectrum (chci3) c=o 1778, 1724 cm-1 no2 1544, 1358 cm-1 Aromatic 1615, 1596 , 1497 cm Example 4 0 5,5--mercapto-1-isopropyl-3-(4-stone-cholyl-3-trifluoromethylphenyl)-2,4-imidadione: Example 1 Method, 1 gram of 1-(3-trifluoroindolyl-4-nitrophenyl)- 4,4-diindenyl imidazolin-2,5-dione with 0.4 ml of 2-iodopropane and 166 A 50% suspension of milligrams of sodium hydride in oil was reacted at 50 ° C for 18 hours, using silica gel chromatography (eluent: 99-1 dichloromethane-acetone), thus giving 685 mg of the desired product. I3 (rc was melted to crystallize from isopropanol to give 661 mg of the desired product which was melted at i30 ° C. Analysis: C15H16F3N304; molecular weight = 359.31 95 200946114

..5^. c=o N〇2 Aromatic example 5 1779, 1771, 1723 cm.1 1615, 1596, 1497 cm " -----Π 5,5-dimercapto-3-(4-nitrogen Benzyl-3-trifluoromethylphenyl)-1-(2-propenyl)-2,4. imipenone II. Using the method of Example 1, 1 gram of 1-(3-trifluoromethyl)- 4-Nitro(phenyl)-4'4-dimercaptoindole-2,5-dione was reacted with 0.35 ml of allyl bromide and 166 mg of a 50% suspension of sodium hydride in oil using a silicone After chromatography (eluent: dichloromethane-acetone (99-1)), 1.10 g of product was obtained, which was crystallised from isopropanol to give 1 g of the desired product. °C melting. Analysis · CisHmFsNsCXj; Molecular 詈 = trait 7 29 % C 〇 / 〇 H % F %N Theoretical value: 50.42 3.95 15.95 ·____^" ···· __一· ....... State...,- 11.76 Experimental value: 50.4 r8 15.8 IR spectrum (CHC13) C=0 1779, 1724 cm-1 96 200946114

'Methyl-3-(3-trifluorodecyl-4-stone phenyl)-l-nuclear-2,4-indenyl quinone II. Using the method of Example 1, 2 g of 1- (3-Trifluoromethyl-4-nitrophenyl^)-4,4-dimercaptoimidazolium-2,5-dione with 0.71 ml of benzyl bromide and 332 mg of sodium hydride in oil 50 The % suspension was reacted and subjected to 99-1 methyl chloride-propanol elution chromatography on silica gel, thus obtaining 2.375 g of the desired product, which crystallised from < Melt at 99 ° C.

Theoretical value experimental value··°〇1: 10.31 10.2 %N —--- _ —_g 14.00 13.9 c=o Aromatic + N〇2 1799, 1723 cm _ 1608 cm image; 13⁄43⁄4 激. 探黑: Hong WS: <+K.i(4). 1594 cm 'm) 1545 cm·ι(τρ)ι^ι±^· 97 200946114 4-(4,4-Dimercapto-5-imino-2-keto-yl) _Myridine)_2_Trifluorodecylbenzonitrile n IR spectrum: -NC=0 2268 cm 1 -CN 2233 cm -1 6·6 g of 4-isocyano-2-trifluoroanthine A solution of riding in 10 ml of di-hexane was added to 2.63 g of 2-amino-2-cyanopropane and 36 g of 10 g of 4-cyano-3-trifluorodecyl aniline (disclosed in European Patent No. 0,002,892) in 30 ml of ethyl acetate in a solution from 〇 to 5. 〇 was added to 33.6 ml of a solution containing 1.93 M/liter of phosgene and the temperature was raised to 25 ° C after stirring for 30 minutes from 〇 to 5 °C. The mixture was diluted and fresh terpene was added to maintain it at a fixed height to compensate the steam transcript until the temperature reached approximately 110 c. The mixture was kept at reflux until the release of hydrogen chloride (4.5 hours) was stopped. The temperature was returned to room temperature, and the white solid was dried over sodium sulfate and washed three times with toluene. The organic layer was concentrated to dryness under reduced pressure, and then cooled to hexane over 1 hour after heating for 1 hour, thus yielding 11.6 g of 4-isocyano-2-trifluorodecylbenzonitrile. 15 ml of dichloroethane After stirring for 16 hours at room temperature, the mixture was concentrated to dryness. A solution of 7.7 g of the residue was chromatographed on a mixture of 85-15 dioxane-acetone. The elution gave 3,54 g of the desired product which was melted at 228 ° C. An analytical sample was prepared by crystallizing 300 mg from isopropanol, thus obtaining 267 mg of product which was melted at 228 ° C. Analysis: C13HnF3N4 〇; molecular weight = 296.25 98 200946114 %c %H %F %N Theoretical value: 52.71 3.74 19.24 18.91 Experimental value: 52.7 3.6 19.1 18.6 IR spectrum (nujol) NH/OH 3340, 3290 cm-1 CN 2240 cm - 1 c=o 1760 cm 4 C=N 1655 cm n Aromatic 1606, 1570, 1502 cm

Example 8 4-(4,4-Dimercapto-2,5-dione-1-pyrimidinyl)-2-trifluorodecylbenzonitrile 2.76 g of the product from Example 7 and 60 mL of 0.5N hydrogen The chloric acid solution was heated under reflux for 35 minutes and poured into 100 grams of water and ice. The mixture was extracted with ethyl acetate, and the organic layer was washed with water, dried and evaporated to dryness. An analytical sample was prepared by crystallizing 440 mg from isopropanol, thus obtaining 383 mg of product which melted at 210 ° C to 211 ° C. Analysis: C13H1()F3N302; molecular weight=297.24 %C %H %F %N Theoretical value: 52.53 3.39 19.17 14.14 Experimental value · 52.4 3.2 19.4 13.9 IR spectrum (CHC13) 99 200946114 CN c=o Aromatic 2245 cm-1 1788 , 1722 cm -1 1610, 1572, 1502 cm.1 NH(max)^example 9 3340 cm · 3-(4-cyano-3-trifluorodecylphenyl)_5,5-dimethyl-2, 4_diketo-_ι_imidazolium acetic acid 600 mg of the product from Example 8 in 6 ml of dimethyl decylamine was added to 21 〇 mg of sodium hydride in oil with stirring. A suspension of % suspension in 3 ml of dimethylformamide was allowed to stand for 15 minutes. After adding 290 mg of bromoacetic acid, the mixture was stirred at room temperature for 16 hours. After the addition of 105 mg of sodium hydride, 145 mg of bromoacetic acid was added to the mixture, which was stirred for 30 minutes and poured into a mixture of 5 ml of water and 5 ml of 2N hydrogen acid. The mixture was extracted with EtOAc (EtOAc)EtOAc. 122 g of the residue was chromatographed on silica gel eluted with 9 〇 〇 〇 〇 二 二 二 。 。 。 。 。 。 。 。 。 。 ~ ~ ~~~ CN 2238 cm -1 C=: 〇海因 &acid 1784, 1725, 1710 cm -1 Aromatic 1616, 1580, 1508 cm -1 : One £ =13300 ETOH-O.iNHCl max. 258 Nanometer 100 200946114

Inflex 277 nm ε = 5000

Inflex 285 nm ε = 2600 ETOH-Ol NNaOH max. 287 nm ε = 19100 max. 342 nm ε = 1900 Example 10 3-(4-Cyano-3-trifluoromethylphenyl)-5,5 -Dimethyl-2,4-dione-1-pyrazolidine ethyl acetate

5 10

600 mg of a solution of the product of Example 8 in 6 ml of decylguanamine was added to a suspension of 100 mg of a 50% suspension of sodium hydride in oil in 3 ml of dimethylformamide and After stirring for 15 minutes, 0.25 ml of ethyl bromoacetate was slowly added at less than 30 °C. The mixture was stirred for 30 minutes and poured into 50 g of a 1-1 ice-water mixture. A 0.5 g portion of the acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated to dryness to give EtOAc (1 g, EtOAc) Melt at 152 °C. An analytical sample was prepared by crystallization from isopropanol, thus obtaining 667 mg of product which melted at 152 °C. Analysis: C 17H16F3N304; molecular weight = =383.33 % c %H %F %N Theoretical value: 53.21 4.21 14.83 10.96 Experimental value: 53.3 4.0 14.9 10.8 IR spectrum (CHC13)_ CN 2225 cm ^ 101 200946114 Imidazopyridine 1786, 1729 cm _ 1 COOEt 1751 cm-1 Aromatic 1616, 1572, 1505 cm _ Example 11 4-(5-imino-2-thio-3,4,4-tridecyl-1-imidazolidinyl)-2- Trifluorodecylbenzonitrile 2.23 g of 1-trifluorodecyl-4-aminobenzonitrile (disclosed in European Patent No. 5, No. 2,892) was slowly added to 22 ml of distilled water and 1 ml of sulphur After stirring for 1 hour in the solution, the mixture was extracted with a gas pattern. The organic layer was washed with an aqueous solution of sodium chloride, dried and concentrated to dryness under reduced pressure to give 3 g of the isocyanate product. A mixture of 3 g of product, 1.33 ml of 2-decylamino-2-cyanopropane, 23 ml of tetrahydrofuran and 0.23 ml of triethylamine was heated under reflux for 40 min and concentrated to dryness. 3.07 g of the residue was chromatographed on silica gel eluting with 1:1 cyclohexane-ethyl acetate mixture and 95-5 dichloro decane-acetone mixture, thus obtaining 2.83 g of product from Isopropanol crystallized, thus giving 2.63 g of the desired product which melted from 173 °C to 174 °C. Analysis .C14H13F3N4S, %c Molecular Weight = 326.35% H %F %N %S Theoretical Value: 53.21 4.21 14.83 17.46 9.82 Experimental Value: 53.3 4.0 14.9 17.2 9.9 IR Spectrum: 102 200946114 ONH 3308, 1679 cm·] C=S+ Aromatic 1608, 1575, 1505, 1488 cm-1 CN 2230 cm _1 CF3 1185 cm -1 Example 12 4-(5-keto-2-thio-3,4,4-tridecyl-1-imidazolidinyl -2-trifluorodecylbenzonitrile

10

2.21 g of the product from Example 11 and 44 ml of a 0.5 N hydrochloric acid mixture were heated under reflux and stirred for 1 hour, and then poured into a mixture of 200 g of ice-water (1-1). The mixture was extracted with dichloromethane and the organic layer was washed with sat. The residue was chromatographed on EtOAc (EtOAc) elute elut elut elut elut elut elut elut elut elut elut The desired product which melted at 171 °C. Analysis: C14H12F3N3OS; molecular weight = 327.33% c %H %F %N %S Theoretical value: 51.37 3.69 12.84 17.41 9.79 Experimental value '· 51.4 3.5 12.7 17.6 10.79 IR spectrum (CHC13) :_ C=0 1761,1756 cm ^ Aroma Family 1610, 1578, 1505 cm -1

CN 103 200946114 CF3_1178 cm ^_ Example 13 4-(2,5-Dithio-3,4,4-tridecyl-1-imidazolidinyl)-2-trifluorodecylbenzonitrile 839 mg from the example A mixture of product 12, 518 mg of Lawesson's reagent and 4.7 ml of toluene was heated under reflux for 24 hours and then concentrated to dryness under reduced pressure. 1.36 g of the residue was chromatographed on silica gel eluting with a mixture of 99-1 dichloromethane-ethyl acetate and a mixture of 85-15 cyclohexane-ethyl acetate to give 783 mg of product. Crystallization from isopropanol gave 690 mg of the desired product which melted from 211 °C to 212 °C. Analysis: C 14H12F3N3S2, molecular weight = 343.40 % c %H %F %N %S Theoretical value: 48.97 3.52 16.60 12.24 18.67 Experimental value: 49.0 3.4 16.6 12.2 18.6 IR spectrum (CHC13): CN Aromatic + co-vehicle system 1612, 1582 , 1508 cm -1 cf3 1178 cm 4 Example 14 ίο 4-(4,4-Dimercapto-5-imino-2-thio-1-imidazolidinyl)-2-trifluoromethyl bromide Add 1 gram of 2-amino-2-acylpropyl propylate and 1 ml of four rat bites of alpha south to 2.54 g of the isocyanate product from Example 11 with stirring at room temperature, 20 ml 104 200946114 5

A mixture of tetrahydrofuran and 0.2 ml of triethylamine was then concentrated to dryness. 3.5 g of the residue was chromatographed on silica gel eluting with EtOAc EtOAc EtOAc EtOAc 300 g of crystals were crystallized from isopropanol, thus obtaining 263 mg of product which was melted at 296 °C. Analysis: C13HnF3N4S; molecular weight = 312.32% c %H %F %N %S Theoretical value: 50.00 3.55 18.25 17.94 10.27 Experimental value: 49.9 3.4 18.3 17.6 10.4 IR spectrum (nujol): _ OH/NH 3260 cm _1 CN 2230 cm _1 C=S 1764 cm-1 _ Aromatic + OC 1612, 1575, 1530, 1501 cm "❹ - A new preparation was carried out using 1,2-dichloroethane instead of tetrahydrofuran, thus obtaining 60% of the product. 15 4-(4,4-Dimercapto-5-fluorenyl-3-thioxo-1-^σ sitny base)-1-dimurine-based guanidine 10 will be 635 mg of the product from Example 14 and 14 ml The mixture was heated under reflux for 1 hour, and after cooling, 100 ml of water was added. The residue was separated on silica gel 105 200946114 chromatography and eluted with a mixture of 95-5 dichloromethane-acetone, thus yielding 590 mg of product which melted from 190 ° C to 191 ° C. Thus 490 mg of product was obtained which melted at 190 ° C to 191 ° C. Analysis: c 13H10F3N3OS; %c Molecular weight = %H 313.3 0 %F %N %S Theoretical value: 49.84 3.22 18.19 13.41 10.23 Experimental value: 49.6 3.1 18.4 13.2 10.0 IR spectrum (CHC13): =C-NH 3430 cm -1 CN 2230 cm-1 C=0 1766 cm-1 Aroma Family and Conjugation System 1612, 1578, 1505 cm -1_ Example 16 5 5,5-Dimercapto-3-(4-Shischyl-3-di-p-mentylphenyl)-1 -pentyl-2,4- The second miso was placed in the same manner as in Example 1, and 1 g of 1-(3-trifluoromethyl-4-nitrophenyl)-4,4-dimercaptoididine-2,5-dione was added. Reaction with 170 mg of sodium hydride and 0.47 ml of 1-bromopentane, chromatography on silica gel and elution with a mixture of 8-2 dichloromethane-cyclohexane, afforded 1.23 g of product from isopropanol Crystallization, thus obtaining 995 mg of the desired product, which was melted at 84 ° C. _ Analysis: C17H2 〇04F3N3; molecular weight = 387.35

%C %H %F %N 106 200946114 Theoretical value: 52.71 5.20 14.71 10.85 Experimental value: 52.8 5.1 14.8 10.7 IR spectrum (CHC13): c=o 1778, 1723 cm _1 no2 1544, 1360 cm -1 Example 17 5, 5-Dimercapto-3-(4-nitro-3-trifluorodecylphenyl)-1-indenyl-2,4-diimidazole sigma 5 Using the method of Example 1, 1 g of 1- (3-Trifluorodecyl-4-nitrophenyl)-4,4-dimethylimidazolidin-2,5-dione with a 50% suspension of 170 mg of sodium hydride in oil and 0.7 ml of 1- The bromodecane reaction, after chromatography on silica gel, gave 1.08 g of the desired product which melted at < Analysis: C21 H2804F3N3; molecular weight = 443.46% C %H %F %N Theoretical value: 56.87 6.36 12.85 9.48 Experimental value. 57.0 6.5 12.8 9.5 IR spectrum (CHC13): c=o N〇2 c=o no2 1778, 1723 cm _1 1544, 1359 cm -1 1778, 1723 cm 1544, 1360 cm

Example 17 107 200946114 5,5-Dimercapto-3-(4-nitro-3-trifluoromethylphenyl)-1-indenyl-2,4-diimidazopyridine Using the method of Example 1, will 1 gram of 1-(3-trifluoromethyl-4-nitrophenyl)-4,4-dimercaptoimidazole-2,5-di prepared from a 50% suspension of sodium hydride in oil The ketone was reacted with 0.7 ml of 1-bromodecane and chromatographed on silica gel to give 1.08 g of the desired product which melted at 63 °. Analysis: C21 H2804F3N3; %c Molecular weight = 443.46% H %F %N Theoretical value: 56.87 6.36 12.85 9.48 Experimental value: 57.0 6.5 12.8 9.5 IR spectrum (CHC13): 〇〇1778, 1723 cm _1 no2 1544, 1359 cm example 18 4-(3,4,4-Tridecyl-2,5-dione-1-pyrimidinyl)-2-trifluorodecylbenzonitrile using the method of Example 1, 300 mg from Example 8 The product was converted, 10 thus giving 275 mg of desired product which melted at 158. IR spectrum (CHC13): c=o 1780, 1727 cm _1 aromatic 1615, 1574, 1505 cm-1 CN 2238 cm -1 Example 19 4-(5-thio-2-keto-3,4,4- Tridecyl-1-imidazolidinyl)-2-trifluoromethylbenzyl 108 200946114 耷 (product A), 4-(5-indolyl-2-thio-3,4,4-dimethyl - lp m 0 sits π-fixed)-2-trifluorodecylbenzonitrile (product oxime) and 4-(2,5-dithio-3,4,4-trimethyl-1-imidazolidinyl)- 2-Trifluorodecylbenzonitrile (Product C) 230 mg of a suspension of the product from Example 18, 1.4 mL of toluene and 78 mg of 5 Lawesson reagent was heated under reflux for 9 hours, returned to room temperature and concentrated. dry. The residue of 3,300 mg was separated and chromatographed on silica gel and eluted with a mixture of 9 9 -1 dichloromethane-acetone, thus obtaining 46 mg of the following sequence eluted product C having a melting point of 210 ° C to 211 ° C. And Rf = 0.63 (same as the product from Example 13), 26 mg of product B having a melting point of 170 ° C to 171 ° C and 10 Rf = 0.49 (same as the product from Example 12) and 42 mg of product A. 194 ° C and Rf = 〇.34. Analytical IR spectrum of product A (CHC13): C=0 CN 2235 cm -1 Aromatic 1615, 1580, 1508 cm UV spectrum (ethanol): max. 228 nm £ = 19400 256 nm £=12100 298 nm =8600 390 nm £=70 Example 20 4-(4,5-Dihydro-4,4-dimercapto-2-indolyl-5-oneyl-1H-imidazolidin-1-109 200946114 base) -2-trifluoromethylbenzonitrile 5 10 626 mg of the solution from the product of Example 15 in 6 ml of dimethylformamide was added to a suspension of 1 〇 8 mg of sodium hydride in oil and [8 ml After the mixture was washed with 0.3 ml of dimethylformamide, the mixture was stirred for 10 minutes and then the hydrogen evolution was stopped. A mixture of 0.19 ml of methyl iodide in 1 ml of dimethylformamide was added dropwise, and after reacting for 45 minutes, the mixture was poured into a 50 g ice-water mixture containing 0.5 g of monosodium phosphate.

The mixture was extracted 4 times with diethyl ether. EtOAc (EtOAc)EtOAc. A residue of 668 mg was chromatographed on silica gel eluting with a mixture of 95-5 methylene chloride-ethyl acetate to afford 640 mg of desired product which was chromatographed on silica gel. It was eluted with a mixture of 7-3 cyclohexane-ethyl acetate, and dissolved in 507 mg of the desired product, which was melted at 62 ° C. 0 = 0 1747 cm -1 _1614, 1581, 1563, 1503 cm

4~(4,5-Dihydro-4,4-dimercapto-5-one-2-benzylthio-1H-imidazolyl-7-trifluoromethylbenzonitrile 110 200946114 will be mutated in 4_(4, 4_Dimethyl-5-yl-2-thiocarbazolyl): 2-gu 3, fluoro 1 f, a solution in 3 ml of dimethylformamide added to 53 gram in oil Sodium bismuth and bismuth. 5 ml of two f ❹, thank t10 minutes, add. 1 ml of jieji desert'. Mix the mixture = half 30 minutes and then pour into the ice containing 750 mg of single steel The compound was extracted with diethyl ether, and the surface layer (4) was washed with water, dried and concentrated to dryness. The mg of the material was separated by chromatography and eluted with 97.5-2.5 digastric-acetic acid mixture. And thus get the product of its training RF=0.38 Analysis: %c %H Theoretical value: 59.54 4.0 Experimental value: 59.6 4.0

〇/〇F %N 14.12 10.41 !4·1 10.2 IR spectrum: ❹ c=° 1746 cm·]

CN 2236 cm J aromatic and conjugated system 1614, 1580, 1570, 1503, 1499 cm. 1 Example 22 4 (4'4-indolyl-3-(2-alkylethyl)-5-imino -2-thio-1 -weiwa sigma)-2-trifluoromethylbenzonitrile 8 ml of ethanolamine was added dropwise at 20 ° C to 30 ° C to 12.3 ml of sterol nitrile in propylene After stirring for 18 hours, the mixture was distilled, thereby obtaining 2.3 g of a mixture of 2-(2-hydroxyethyl)amino-2-mercaptopropionitrile and 2,2-dimercaptopurine 111 15 200946114 oxazolidine. It is used in the next step accordingly. A mixture of 1.18 g of this mixture, 2.11 g of the isocyanate from Example 11 and 20 ml of tetrahydrofuran and 0.5 ml of triethylamine was heated under reflux for 30 minutes and then concentrated to dryness. The residue was chromatographed on silica gel eluting eluting with 95-5 dichloro-hexane-hexane mixture to give 1.26 g of desired product and 686 mg of N-(4-cyano-2-trifluoromethylphenyl) )-2,2-Dimercapto-3-oxazolidine thioguanamine. After 686 mg was dissolved in 10 ml of ethyl acetate and 30 ml of cyclohexane was added, the mixture was concentrated to 4 ml and vacuum filtered and dried to give 518 mg of product. The crude product was dissolved in 20 ml of isopropyl OH 3630 cm a = NH 3314, 1677 cm _1 CN 2230 cm" Aromatic 1611, 1576, 1504 cm Example 23 4-(4,4-Dimercapto-3_(2- Benzyl)-5-mercapto-2-thio-1-17 m 嗤 定 定 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇 醇Melting at 181 ° C. Analysis: %C %H %F %N %S Theoretical value: 50.55 4.24 16.00 15.72 9.00 Experimental value: 50.4 4.1 15.9 15.6 9.0 IR spectrum (CHC13): 112 200946114 base)-2-trifluoromethyl Benzonitrile (product A) and 4-(4,4-dimethyl-2,5-diketo-3-(2-mercaptoethyl)-1-imidazolidinyl)-2-trifluorodecyl benzyl Nitrile (Product B) 5 A mixture of 680 mg of the product from Example 22, 7 ml of water and 7 ml of chloroformic acid was heated under reflux for 10 minutes, and after cooling to room temperature, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium chloride solution, dried and concentrated to dry. The residue was chromatographed on silica gel eluting eluting with 1-1 hexane-ethyl acetate mixture to give 119 mg of product B with Rf = 0.35

And 569 mg of product A have Rf = 0.14 and the melting point is -130 〇C. Analysis: C 15H14F3N3O2S; %C Molecular Weight = %H: 357.36 %F %N %S Theoretical Value: 50.42 3.95 15.95 11.76 8.97 Product A Experimental Value: 50.7 4.0 15.7 11.5 9.1 Product B Experimental Value: 50.6 3.8 15.9 11.6 9.1 IR Spectrum ( CHC13): Product A:

OH 3626 cm M CN 2236 cm ^ c=o 1763 cm -1 Aromatic 1615, 1578, 1504 cm Product B: No OH 113 200946114 CN 2228 cm _1 C=0 1780, 1726 cm-1 Aromatic _1615, 1578 , 1505 cm -1 using 4-(4,4-dimercapto-2,5-dione-1-pyrimidinyl)-2-trifluorodecylbenzonitrile from Example 8 and suitable reactants, The following product was prepared.

Example 24 4-(4,4-Dimercapto-2,5-dione-3-ethyl-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, which melts at io ° ° to lore .

Analysis: c15h14f3n3o2; Molecular weight = 325.29 % c %H %F %N Theoretical value: 55.39 4.34 17.52 12.92 Experimental value: 55.7 4.3 17.6 12.8 IR spectrum (CHC13): CN 2238 cm -1 c=o 1777, 1724 cm _1 Aroma Family 1617, 1575, 1505 cm-1 Example 25 4-(4,4-Dimercapto-2,5-diamidino-3-(2-propylpropanyl)-1-flavored succinyl)-2- Dioxin-benzonitrile, which melts at 109 ° C to 110 ° C. Analysis: G6HMF3N302; Molecular weight = 337.35% c %H %F %N 114 200946114 Theoretical value: 56.97 4.18 16.90 12.46 Experimental value: 57.0 4.1 16.2 12.3 IR Spectrum (CHC13): CN 2238 cm _1 c=o 1728, 1725 cm stomach 1 hc=ch2 1645 cm _1 aromatic 1616, 1575, 1505 cm example 26 4-(4,4-dimercapto-2,5 -Diketo-3-benzyl-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, which melts at 98 ° C to 99 ° C. Analysis: C2QH16F3N302; molecular weight = 387.36

%C %H %F %N Theoretical value: 62.01 4.16 14.71 10.58 Experimental value: 62.0 4.1 14.7 10.8 IR spectrum (CHC13) : C-NH: 3430 cm-1_ CN 2238 cm_1 00 1779, 1724 cm -1 aromatic _1615, 1605, 1575, 1504, 1497 cm _ Example 27 5 4-(4,4-Dimercapto-2,5-dimercapto-3-(4- gas fluorenyl)-1-mouth m 11 sitting定定)-2-dipyrybenzonitrile, which melts at 101 ° C to 102 ° C. _ Analysis: C2〇H15F4N302;molecular weight=405.35 115 200946114 __%C_%H_%F_%N_ Theoretical value: 59.26 3.73 18.75 10.37 Experimental value: 59·1 3.5 18.9 10.3 IR spectrum (CHC13): CN 2238 cm _1 C= 0 1780, 1724 cm _1

Aromatic _1615, 1612, 1505 cm _ Example 28 4-(4,4-Dimercapto-2,5-dione-3-(4-methoxybenzyl)-1-imidazolidinyl)- 2-Trifluorodecylbenzonitrile which melts at 95 ° C to 96 ° C. Analysis: C21H18F3N303; molecular weight = 417.39

%C %H %F %N Theoretical value: 60.43 4.35 13.65 10.37 Experimental value: 59.1 3.5 18.9 10.3 IR spectrum (CHC13): CN 2238 cm -1 c=o 1778, 1723 cm _1 Aromatic 1615, 1584, 1514, 1505 cm-1 Example 29 4-(4,4-Dimercapto-2,5-dione-3-(4-trifluorodecylbenzyl)-1-imidazolidinyl)-2·trifluoroanthracene Benzyzonitrile, which melts at ~89 ° C to 90 ° C. Analysis: C21H15F6N3O2; molecular weight = 313.30 116 200946114

_%C_%H_%F_%N Theoretical value: 55.39 3.32 25.03 9.23 Experimental value: 55.2 3.2 25.3 9.2 IR spectrum (CHC13): CN 2238 cm" c=o 1615, 1505 cm aromatic 1615, 1505 cm" Example 30 4 -(4,4-Dimethyl-2,5-dione-3-(2-epoxyindolyl)-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, which is at 112 ° C Melting to 113 ° C. Analysis: C16H14F3N303; molecular weight = 353.30

%C %H %F %N Theoretical value: 54.39 3.99 16.13 11.89 Experimental value: 54.7 4.0 16.1 11.8 ❹ IR spectrum (CHC13): CN c=o Aromatic 2235 cm -1 1781,1725 cm 1615, 1576, 1505 cm 31 4-(4,4-Dimercapto-2,5-dione-3-propyl-1H-imidazolidinyl)-2-trifluorodecylbenzonitrile at 113 ° C to 114 ° C melt. Analysis: C16H16F3N302; molecular weight = 339.32 117 200946114 %c %H %F %N Theoretical value: 56.64 4.75 16.80 12.38 Experimental value: 56.7 4.7 16.7 12.2 IR spectrum (CHC13): 2236 cm -1 1778, 1725 cm _1 1616, 1505 Gong u

CN c=o Aromatic Example 32 4-(4,4-Dimercapto-2,5-diketo-3-isopropyl-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, Melt at 138 ° C to 139 ° C. _ Analysis: C16H16F3N302; molecular weight = 339.32

_%C_%H_%F_°/〇N Theoretical value: 56.64 4.75 16.80 12.38 Experimental value: 56.5 4.7 17.1 12.3 IR spectrum (CHC13): _ CN 2236 cm-1 0=0 1778, 1724 cm_1 Aromatic_1616 , 1575, 1505 cm -1_ using 4-(4,4-dimercapto-5-keto-2-thio-1-imidazolidinyl)-2-trifluorodecylbenzonitrile from Example 15 and suitable The following compounds were prepared: Example 33 200946114 4-(4,5-Dihydro-4,4-dimercapto-2-mercaptothio-5-one-1H-imidazol-1-yl) -2-trifluoromethyl octonitrile, Rf = 〇 _35 (97.5-2.5 dimethylacetate · ethyl acetate eluent). Example 34 5 ❹ 10 15 ❹ 20 4-(4,5-Dihydro-4,5-diamidino-2-0hydroxypropylthio)-5-oneyl-1H-amido-1-yl) -2-trifluoromethylbenzonitrile, Rf = 〇.n (8-2 dichloromethane-ethyl acetate eluent). Example 35 Cyano-3-trifluorodecylphenyl)-4,5-dihydro-4,4-dimethyl-5-keto-1H-imidazol-2-yl)thio]acetate, Rf = 〇.20 (65-35 cyclohexane-acetic acid ethyl acetate eluent). The following compounds were prepared using the isocyanate from Example 11 and the appropriate reactants. Example 36 4-(4,4-Dimercapto-3-ethyl-5-imino-2-thio-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, Rf = 0.16 (95 -5 dichlorodecane-acetone eluent). Example 37 4-(4,4-Dimercapto-5-imino-3-mercapto-2-thio-1-σm β-sodium)-2-dioxadecylbenzonitrile, Rf= 0.35 (8-2 ethyl acetate-cyclohexane eluent). 4-(4,4-Dimercapto-3-ethyl-5-imino-2-thio-1-imidazolidinyl)-2-trifluorodecylbenzonitrile from Example 36 was used and examples 4-(4,4-Dimethyl-5-imino-3-pentyl-2-thio-1-imidazolidinyl)-2-trifluorodecylbenzonitrile and 0.5 N hydrochloric acid The following compounds were prepared. Example 38 119 200946114 4_(4,4-Dimethyl-3-ethyl-5-keto-2-thio-1-isoxazinyl)-2-trifluorodecylbenzonitrile, Rf=0.38 ( M ethyl acetate-cyclohexane eluent). Example 39 4-(4,4-Dimethyl-5-keto-3-impentyl-2-sulfobutyrylpyridinyl)-2-trifluorodecylbenzonitrile with a melting point of 78. (: and Rf = 0.66 (8-2 ethyl acetate-cyclohexane eluent). Using 4-(4,5-dihydro-4,4-dimethyl-2·fluorenyl sulfide from Example 20) 5--5-keto-1H-imidazol-1-yl)_2-trifluorodecylbenzonitrile and 4-(4,5-dihydro-4,4-didecyl-5-one from Example 21 2-Benzylthio-1H-imidazol-1-yldifluoroindolyl nitrile and Lawesson's reagent to prepare the following compound. Example 40 4-(4,5-Dihydro-4,4-didecyl- 2-mercaptothio-5-thio-1H-imidazol-1-yl)-2-trifluorodecylbenzonitrile, Rf = 0.36 (97.5-2.5 di-methane-ethyl acetate eluent). Example 41 4-(4,5-Dihydro-4,4-dimercapto-2-benzylthio-5-thio-1H-imidazol-1-yl)-2-trifluorodecylbenzonitrile, Rf = 0.62 (98-2 di-methane-ethyl acetate washing). Example 42 3-(4-Cyano-3-trifluoromethylphenyl)_5,5-diindenyl-2,4 -Diketodecyl-N-isopropyl-1-imidylacetamide 0.1 ml of hydrazinocarb was added to 3-(4-cyano-3-trifluorodecylphenyl)-5 The suspension of 5-dimercapto-2,4-dione-1-acetic acid in 4 ml of dioxane was cooled to _10 ° C, and isopropyl chloroformate was added dropwise. 120 200946114 Stirring at -10 ° C 25 After the clock, 0.15 ml of N-methyl-N-isopropylamine was added, and the mixture was allowed to reach room temperature for another 40 minutes. After adding 5 ml of aqueous sodium hydrogencarbonate solution and stirring for 30 minutes, the mixture was extracted with dichloromethane. The organic layer was washed with water, dried and evaporated to drynessjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ___ IR spectrum (CHC13): CN 2236 cm" Hein c=o 1783, 1728 cm" Brewed amine c=〇1661 cm -1 1615, 1575, 1505 cm -1 Example 43 4-(4,4-dimethyl -2,5-diketo-3-(2-hydroxyethyl)-1-imidazolidinyl)-2-trifluoromethylbenzonitrile 10 Using the procedure from Example 9, 900 mg of the product from Example 8 And < gram of 2-bromoethyl tert-butyl fluorenyl decyl ether, which is chromatographed on silica gel and eluted with a mixture of cyclohexane-ethyl acetate to obtain 1 gram of alkaloid a derivative, which is ashamed to "it melts." 15 * Add 1 ml of 2N hydrochloric acid to 380 mg of decyloxy ether, 4 ml of methanol and 1 liter of dichloromethane. After stirring at room temperature for 4〇 compound 1 'mixture was poured into 15 ml water and extracted with dichloromethane Yue chloride. The organic layer was washed with water, dried and concentrated to dryness, and chromatographed over silica gel. This was eluted with a mixture of 7-3 dioxane acetate to give the desired product which crystallised from isopropanol at <RTI ID=0.0>> 121 200946114 Analysis · %c %H %F %N Theoretical value: 52.79 4.23 16.70 12.31 Experimental value: 52.5 4.2 16.7 12.1 Example 44 Using the method of Example 43, 2-bromopropyl tert-butyldidecyl oxime was used. The riddle reaction gives 4-(4,4-dimercapto-2,5-dimercapto-3-(3-propylpropyl)-1-imidazolidinyl)-2-trifluoromethylbenzonitrile It melts at 131 ° C to 132 ° C and Rf = 0.13 (3-1 dichlorodecane-ethyl acetate eluent). Example 45 4-[3-(2-Ethyloxyethyl)-4,4-dimercapto-2,5-dione-1-pyrazolidyl]-2-trifluorodecylbenzonitrile A mixture of 215 mg of the product from Example 43, 15 mg of 4-dihexylamine ί pyridine, 1 ml of pyridine and 0.5 ml of acetic anhydride was stirred at room temperature for 30 minutes and then poured into 20 ml of saturated sodium hydrogen carbonate solution. After stirring for 20 minutes, the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated to dryness, and pyridine and residual acetic acid were evaporated. The residue was chromatographed on silica gel and eluted with a mixture of 65-35 dioxane-ethyl acetate. The residue of 15 Rf = 〇.35 was dissolved in isopropanol, partially concentrated, iced and vacuumed.

Filtration and drying gave 210 mg of the desired product which melted from 99t to 100. Analysis: %C %H %F %N Theoretical value: 53.27 4.21 14.87 10.96 122 200946114 Experimental value: _53^_4J_1^2_10.9 Using the above procedure, the following product was prepared. Example 46 4-(4,4-Dimercapto-2,5-dione-3-(5-hydroxypentyl)-1-imidazolidinyl)-2-trifluorodecylbenzonitrile, which was 〇l ° C to l 〇 2 ° C melting. 5 Example 47 4-(4,4-Dimercapto-2,5-dione-3-(2-methoxyethyl)-1-imidazolidinyl)-2-trifluorodecylbenzonitrile It melts at 68 ° C to 69 ° C. Example 48 4-(4,4-Dimercapto-2,5-dione-3-cyanoindole-1-imidazolidinyl)-2-trifluoro ochylbenzonitrile, 186 ° C Melted to 187 ° C. Example 49 4-(4,4-Dimethyl-2,5-dione-3-[(1,3-dioxolan-2-yl)-methyl]-1-imidazolidinyl)- 2-Trifluoromethylbenzonitrile which melts at 135 ° C to 136 ° C. Example 50 15 4-(4,4-Dimethyl-2,5-dimercapto-3-(2-chloroethyl)-1-methoxyl 11-decyl)-2-difluoro-1-indenylbenzyl Nitrile, which melts at 120 ° C to 121 ° C. Example 51 1-(3,4-Dichlorophenyl)-5-imino-3,4,4-trimethyl-2-imidazolidinylthione 2.4 g of 3,4-dichlorophenol isocyanate A mixture of 1.3 ml of 2-nonylamine 20-yl-2-cyanopropane, 23 ml of tetrahydrofuran and 0.23 ml of triethylamine was heated under reflux for 16 hours and then concentrated to dryness under reduced pressure. The residue was chromatographed on silica gel eluting with EtOAc EtOAc EtOAc (EtOAc). 123 200946114 Example 52 3-(3,4-Dichlorophenyl)-2-thio-1,5,5-tridecyl-1-imidazolidone

1.88 g of the product from Example 51 was heated under reflux for 14 minutes in 14 ml of a suspension of hydrochloric acid at 6 ° C, and after further addition of 14 ml of 6N hydrochloric acid 5, the mixture was heated under reflux for 2 hours. After further adding 4 ml of 6N hydrochloric acid, the mixture was heated under reflux for 90 minutes and then returned to room temperature again. 100 grams of ice was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to dry. The residue was chromatographed on silica gel eluting with EtOAc EtOAc EtOAc EtOAc _ Analysis·· C12H12C12N20S; Molecular Weight=303.21

%C %H %F %N %S Theoretical value: 47.54 3.99 23.38 9.24 10.57 Experimental value: 47.5 3.8 23.2 9.3 10.5 IR spectrum (CHC13): _ CN 1753 cm-1 OS + aromatic _1595, 1570, 1496 cm _ The following product was prepared using the above procedure. Example 53 4-(3,4-Dichlorophenyl)-3,5-dihydro-5,5-diindenyl-2-methylthio-411-imidazol-4-one, which melts at 110 ° C . 15 Example 54 124 200946114 l-(3,4-Dichlorophenyl)-3,4,4-trimethyl-2,5-imidazolidinone, which melted at ~146 °C. Example 55 1-(4-Chloro-3-trifluoromethylphenyl)-4,4-dimercapto-2-thio-5-imidazolidinone, 5 which was melted at 176 °C. Example 56 1-(4-A-3-trifluoromethylphenyl)-4,4-dimercapto-5-imino-2-imidazopyridine sulfonic acid ketone at 173 ° C to 174 ° C melt. ◎ Example 57 10 3-(3,4-Dichlorophenyl)-3,5-dihydro-5,5-dimercapto-2-benzylthio-4H-imidazol-4-one IR spectrum (CHC13) :_ C=0 1736 cm-1 CN+aromatic_1578, 1496 cm-1_ Example 58 4-(4,4-Dimercapto-2,5-dione-3-(4-hydroxybutyl)- 1-Imidazolidinyl)-2-(trifluoromethyl)benzonitrile 15 a) Condensation 600 mg of 4-(4,4-dimercapto-2,5-dione-1) from Example 8. -imidazolidinyl)-2-(trifluoromethyl)benzonitrile in 5 ml of dimethyl decylamine, added to a suspension of 104 mg of sodium hydride in 0.8 ml of dimethyl decylamine, and the temperature Keep below 20 °C. After stirring for 10 minutes, 445 mg of 2 〇 4-chloro-t-butyldimethyl decyl ether and 300 mg of sodium iodide were added. The mixture was heated at 50 ° C for 16 hours and then cooled to ambient temperature. Add 87 mg of 125 200946114 of sodium hydride, then add _ gram of chlorinated bond, and add milligrams of sodium hydride. The aged product was reheated for a few hours, sewn to return it to room temperature again, and then poured into 6 ml of water containing _mg of disc acid single unloading. 2 (four) line extraction, and the organic layer is washed with water and dried, and the solvent strip is sent. The residue was subjected to cleavage-chromatography (eluent: methylene chloride-acetone (99-D) to give 526 mg yield, which was used for the step after dissociation. 将此 This product was taken in 5 ml of methanol Mix with 1.5 ml of 2N hydrochloric acid and mix the mixture at ambient temperature (4) for 4 G minutes. Mix _ into % ml of water and extract with two gas. The organic layer is washed with water and dried and the solvent is evaporated. Analysis (eluent: two gas _ acetone _ acetone (9 · ^)), the obtained part of Rf = 〇 15, after crystallization from the isopropyl bond, ^ ΐ ΐ 307 307 307 307 古 . . . . . w w w w w w w w w w 'Analysis: C17H18F3N3〇3; Molecular weight=369.35 %c %H %F 0/.ΛΤ Theoretical value: 55.28 4.91 15.43 /0丄N 11.38 Experimental value: 55.2 ' 4.9 15.3 11 1 ---------- -- AX · X IR spectrum (CHC13): —- OH 3628 cm ^ — .. C=N 2236 公 公 a 〇

126 200946114

5 10 15 ❿ 9/9 liters of 4-chloro-1-butanol and 24.3 grams of imidazole are scrambled in 50 ml of four i ^ and added dropwise at 20 ml α jU at temperatures below 2 ° C 2.82 g of tert-butyldimethylfluorenyl chloride in the middle. Will the mixture be in degrees? After mixing for 18 hours, it was separated, washed with tetrahydrofuran and the solvent was removed at minus . The residue was purified by chromatography on EtOAc ( eluting EtOAc <RTI ID=0.0>> Example 59 Alkyl difluoromethylphenyl)-5,5-dimercapto-2,4·dione imidazole bite acetic acid (U-dimethyl) ethyl vinegar 450 mg from the product of Example _ 4 ml of dimercaptocaramine in liter: liquid_ was added to a suspension of 78 mg of sodium hydride in 50 〇 / 〇 in oil and 0.5 mmol of ketone. Mix the mixture for 15 minutes, then slowly add the hour after the odor to give the acid third vinegar, no more than Qing. The mixture was stirred with 16 monopotassium and two grams of water-and ice mixture (1-1). Add 〇. 5 grams of citric acid with water for extraction. The organic layer was washed with water, dried and concentrated to dryness. 1.1 g of crude silk cut gel was separated by chromatography (washing: methylene chloride (99-1)) to obtain 425 g of the desired product, which was at 122 tM 23 and acetone (99-1). . IR spectrum (CHC13): _ — 1788~172^^Ξ^Ζ^1745 cm~4 ON Aromatic 2235 cm 1616-1505 cm 127 20 200946114 UV spectrum (EtOH) :_

Max. 258 nm 2 16100_

Infl. 277 nm = 6000

Infl. 285 nm = 3000_ Example 60 3-(4-Cyano-3-trifluoromethylphenyl)-5,5-diindenyl-2,4-dione-1-pyrazolidineacetate The ester was cooled from 355 mg of the product of Example 9, 49 mg of 4-diguanylidenepyridine, 5 130 mg of cyclopentanol and 6.5 ml of dioxane to -10 ° C, then added to 2 ml of dioxane. 226 mg of dicyclohexylcarbodiimide in the alkane. The mixture was again brought to ambient temperature, stirred for 25 minutes, heated under reflux for 2 hours, allowed to reach ambient temperature, filtered and evaporated. The residue was chromatographed on silica gel (eluent: dichloroindole-10-acetone (99-1)) to give 281 mg of expected product, Rf = 0.25 (eluent: di- methane - Acetone (99-1)). IR spectrum (CHC13): c=o 1786-1729 cm -1 hyin, 1748 cm 4 (ester) C=N 2235 cm -1 aromatic 1615-1602-1576-1505 cm-1 UV spectrum (EtOH): Max 258 nm = 16800 Infl. 276 nm = = 5800 Infl. 286 nm = : 3000 128 200946114 Example 61 3-(4-Cyano-3-(trifluoromethyl)phenyl)-5,5- Ethyl dimercapto-2,4-dione-1-pyrazolidine butyrate The desired product was obtained by reacting the product of Example 8 with ethyl 4-bromobutyrate using the method of Example 59. Melt at 66 ° C - 67 ° C, and Rf = 0.16 (eluent · dioxane - acetone (99-1)). IR spectrum (CHC13): c=o 1770-1726 cm _1 C=N 2235 cm aromatic 16166-1576-1505 cm _1 UV spectrum (EtOH): Max. 260 nm = 15500 Infl. 277 nm = 7000 Infl. 286 nm = 3600 ❹ Example 62 3-(4-Cyano-3-trifluoromethylphenyl)-5,5-dimethyl-2,4-dione-1-imidazole 10 pyridine The acid was stirred in an amount of 1 g of the product from Example 61 in the presence of 2N sodium hydroxide at ambient temperature for 3 hours, and the mixture was poured into 20 ml of water and acidified to pH with 7 ml of 6N hydrochloric acid. =l. The mixture was extracted with diethyl ether and the extract was washed with water and dried, and the solvent was removed under reduced pressure to give 863 mg of crude product which was melted at 179-180 ° C and separated by chromatography on silica gel. Extract: chlorinated sterol (92.7-7.5)). 129 200946114 Crystallization from isopropanol gives 614 mg of expected product which is melted at 184-185 and Rf = 0.25 (eluent: dichloromethane-methanol (92.7-7.5)). IR spectrum (nujol): c= o 1770-1753-1735-1712-1690-1645 cm _1 ΟΝ 2235 cm 4 aromatic 1613-1587-1533-1502 cm _1 Example 63 3-(4-cyano-3-trifluorodecylphenyl) -5,5-dimercapto-2,4-dione-1-pyrimidinium butyrate (1,1.-didecyl)ethyl ester

The product of Example 62 was esterified with a third butanol in the presence of dicyclohexylcarbodiimide and 4-dimethylamino D-bipyridine according to Example 60 to afford the desired product, which was at 96. 〇97. (: Melted and Rf = 0.32 (eluent: dichlorodecane-acetone (98-2)).

IR spectrum (CHgo: c=o 1779-1725 cm -1 C three N 2235 cm -1 aromatic 16166-1576-1505 cm -1 UV spectrum (EtOH): Max. 261 nm = :15600 Infl. 276亳= 7800 Infl. 286亳micron = 3700 Example 64 3·(4-Cyano-3-trifluorodecylphenyl)-5,5-dimercapto-2,4·dione-1-imidazole 130 200946114 The cyclopentanoic acid cyclopentyl ester was reacted with cyclopentanol using the procedure of Example 63 to give the desired product, which melted from 85 ° C to 86 ° C and Rf = 0.33 (eluent: dioxane-acetone (98) -2;)) IR spectrum (CHC13): 〇〇1779-1728 cm -1 ON 2236 cm -1 Aromatic 1616-1578-1505 cm-1 UV spectrum (EtOH): Max. 261 nm == 16000 Infl 277 nm = 7600 Infl. 286 nm = 3700 Example 65 4-(4,4-Dimethyl-2,5-dione-3-(2-(4-fluorophenylthio)ethyl) )-1-imidazole _ pyridine-2-(trifluoromethyl)benzonitrile a) Preparation of phenoxide 1 〇 0.16 ml of 4-fluorothiophenol in 1.6 ml of dimethyl decylamine at less than 28 Add to a suspension of 80 mg of sodium hydride in 0.5 ml of dimethylformamide at a temperature of ° C and stir the solution 10 b) Substituting 548 mg of 4-[4,4-dimercapto-2,5-dione-3-(2-chloroethyl15-yl)-1-imidazolidinyl]-2-(trifluoro) Indole) benzonitrile (Example 50) - in 4 ml of dimethyl decylamine - was added to solution a), and the mixture was stirred for 2 hours and then poured into 131 200946114 in 50 ml of water containing 0.5 g of monopotassium phosphate. The extraction was carried out with water, and the organic layer was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on silica gel (eluent: cyclohexane-acetic acid ethyl acetate (75-25)) to give 570 mg of expected product which melted from 93 ° C to 94 ° C and Rf = 〇29 (Eluent: 5 cyclohexane-ethyl acetate (75-25)). IR spectrum (CHC13): c=o 1780-1726 cm "ON 2238 cm _1 aromatic 1616- 579 579-1506 cm -1 (fluorophenyl) thio 1591-1492 cm 1 UV spectrum (EtOH): Max. 254 Nano = 18600 Infl. 277 nm = 7500 Infl. 286 nm = 4200 Example 66 4-(4,4-Dimercapto-2,5-dione-3-(2-(4-fluorophenyl) Sulfhydryl)ethyl)imidazolidine-2-(trifluoromethyl)benzonitrile. Distillate 1.21 g of meta-benzoic acid in 24 ml of methylene chloride at a temperature below 29 °C. 222 mg of the product from Example 65 was added to 4.4 ml of dichlorohydrazine. After 30 min of scramble, the mixture was poured into 3 ml of sodium thiosulfate (0.5 liter/liter). After a few minutes, it was decanted and extracted with a gas purge. The organic layer was washed with a saturated aqueous solution of hydrogen carbonate steel, then washed with water and dried, and the solvent was evaporated. The residue was chromatographed on a stone film 200946114 (washing) Extract: Cyclohexane-ethyl acetate gave 220 mg of product which crystallised from isopropanol to give 196 mg of expected product which melted from 155 ° C to 156 ° C and Rf = 0.22 (eluent: acetic acid Ester-cyclohexane (1-1)) IR spectrum (CHCI3): c=o 1783-1727 cm·] C=N 2236 cm -1 Aromatic 1615-1593-1505-1497 cm-1 S〇2 1314 -1150 cm·] UV spectrum (EtOH): Max. 258 nm = =16700 ❹

Infl. 286 nm Example 67 ❹ 4-(4,4-Dimethyl-2,5-dione-based_3_(2_((4-fluorophenyl)sulfinyl)ethyl)-1-imidazole Pyridyl (trifluoromethyl)benzonitrile ^ 222 mg of the product from Example 65 in 15 ml of decyl alcohol, in the presence of 5 liters of sodium periodate (〇1 M / liter), stirred at ambient temperature The core float was heated at 4 ° C for 1 hour, 1 ml of methanol and 5 ^ oxidizing solution were added. The sterol was evaporated and added with H) ml of sodium chloride saturated: 2:, ethyl acetate extraction. The organic layer was washed with brine and dried, and then evaporated. The residue was cut into pieces by chromatography (eluent: dichloride to obtain 18 (an ancient product (2 gram of 2 〇 5 mg of product, which was crystallized from isopropanol, the expected product of the house, which is at 1451- 146^^(^^030 133 15 200946114 (eluent: dichlorodecane-acetone (9-1)). IR spectrum (CHC13): c=o 1782-1727 cm _1 ON 2236 cm "aromatic 1615 -1592-1505-1493 cm _1 UV spectrum (EtOH): Max. 258 nm ε = 17600 Infl. 285 nm Using the method of the above example, from Example 8 4-(4,4-dimercapto-2 ,5-diketo-1 -imidazolidinyl)-2-(trifluoromethyl)benzonitrile and a suitable reagent gave the compound of the following example: Example 68 4-(4,4-didecyl-2 ,5-diketo-3-((3-decyloxyphenyl)indolyl)-1-imidazolidinyl-2-(trifluoromethyl)benzonitrile, which melts at 88 ° C to 89 ° C And Rf=〇.21 (eluent: cyclohexane-ethyl acetate (7-3)). IR spectrum (CHC13): c=o 1779-1727 cm _1 C=N 2238 cm 4 aromatic 1161- 1602-1588_1575-1504-1491 cm-1 UV spectrum (EtOH): Max. 258 nm ε = 16800 Infl. 210 nm ε = 28500 134 200946114

Infl. 280 nm _ ε - 8900_ Example 69 4-(4,4-Dimethyl-2,5-di-S-iso- 3-(2-(4-indolyl)-yl)ethyl)-1 - succinyl-2-(trifluoromethyl)benzonitrile, Rf = 0.20 (eluent: dichloromethane-acetone (70-30)). IR spectrum (CHC13) ·· c=o 1779-1725 cm - 1 C^N 2235 cm aromatic 16166-1576-1505 cm-1 福福σ林基1117 cm _1 UV spectrum (EtOH): Max. 261 nm 8 = 14000 InfL 277 nm ε= 6900 hifl. 280 nm ε = 3600 © Example 70 4-(4,4-Dimercapto-3-(2-lightylethyl)-5-imino-2-thio-I-11 m α Preparation of isothiocyanate 10 by sitting on the base of 2-(trifluoromethyl)benzonitrile a) 2.23 g of 1-trifluoromethyl-4-aminobenzonitrile (prepared according to EP 0002892) was slowly added to In a solution of 22 ml of distilled water and 1 ml of thiophosgene, the mixture was stirred for 1 hour and then extracted with chloroform. The extract was washed with brine, dried and concentrated to dryness under reduced pressure to give 3 g of product. 135 200946114 b) Obtaining an imine 5 g of isothiocyanate was mixed with 37 ml of tetrahydrofuran in the presence of 1.5 ml of triethylamine, and 2.8 g of 2-[(2-hydroxyethyl)amino group was added in one portion at a time. ]-2-mercaptopropionitrile (prepared in Example 22) - a solution in 10 ml of tetrahydrofuran 5. The temperature was automatically raised to 34 ° C and the residual mixture was allowed to reach ambient temperature and stirred for 1 hour. The solvent was evaporated and the residue was chromatographed eluted eluted eluted eluted eluted elution elution elution elution elution elution elution °C melts. Example 71 ίο 4-(4,4-Dimethyl-3-(2-carbylethyl)-5-propenyl-2-thio-1 - σm0-spotting)-2-(trifluoro) The fluorenyl)benzonitrile was heated under reflux of 4.6 g of the product of Example 70 in the presence of 10 ml of 2 hydr. The mixture was allowed to cool to ambient temperature and poured into 300 mL of ice cold water. Extraction with ethyl acetate, 15 and the organic layer was washed with brine and dried and evaporated. The residue was chromatographed on silica gel (ethyl acetate-cyclohexane (1-1)), and fractions of Rf = 0.14 were collected. After crystallization from dichloromethane and cyclohexane, 4.37 g of the desired product was obtained which melted at &lt Analysis: c15h 14F3N302S; molecular weight = %C %H : 357.36 %F %N %S Theoretical value: 50.42 3.95 15.95 11.76 8.97 Experimental value: 50.3 3.9 15.9 11.6 8.9 136 200946114 3626 cm 2236 cm · 1763 cm · 1615-1578-1504 Cent

IR spectrum (chci3): OH ON c=o aroma 1 Example 72 4-(4,4-Dimethyl-3-(2-hydroxyethyl)-5-imino 2 thio-indole-imidazole Pyridyl)-2-(trifluoromethyl)-5-3H-benzonitrile a) Preparation of gasified noisy 15 mg of 2-difluoromethyl-4-amino-5-bromobenzonitrile with 2 The aliquot of ethyl acetate was mixed with 6.5 microliters of triethylamine and 2 milligrams of palladium on activated carbon to add 'money plus gas (1.42 bar). After passing the reaction, it was washed with ethyl acetate and evaporated to dryness at ambient temperature to give a product of about 66.6 gq (l 8 ci). 1〇b) Preparation of gasified isothiocyanate a 15 Torr of 1 〇% solution in chloroform and thiophosgene were added to the above product in 15 Torr of water, and the mixture was stirred at ambient temperature. 45 minutes. Dilute with 0.5 ml of water and i ml of air, then extract with a chloroform extraction knife. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc to give the desired product of 7 15 GBq (mCI), which was stored at -8 (Tc. C) to prepare the vaporized imine under reduced pressure. After removing the toluene from the above mixture, U0 microliters of tetrahydrofuran containing 1% triethylamine was added, and 13 μl of 2-[(2-hydroxyethyl)amino]-2-mercaptopropionitrile was added (Example 22 ). Then, l30 μl of tetrahydrofuran containing 1% of 3 137 200946114 =amine was added again, and the mixture was stirred at room temperature for 30 knives, and the solvent was removed under reduced pressure. Preparation of 2-trifluorodecylamino-5-bromobenzonitrile 5 λ used in Example 72 2 -Trifluoromethyl 4-aminobenzonitrile (prepared according to 0002 0002892) (5 mol) at 25 The solution in the methanol was cooled to 〇°c and added to the desert (5.2 moles). Allow the mixture to reach the ambient temperature again and stir it for 3 hours, M*| ····

, a G amine test, and then added sodium thiosulfate aqueous solution. The solvent was removed and extracted with chloroform. The organic layer was washed with water and dried, and the solvent product was used, which was used in the next step. Nh2 ~~~----~~-_ 3612-3408 cm-1

1621-1556-1506 cm 夂(4,4-dimercapto_3_(2-hydroxyethyl)_5-keto-2_thioimidazolidinyl)-2-(trifluoromethyl)_5_3h benzonitrile The product from Example 72 in 180 microliters of water was heated to 丨(九)七❹ and 6 〇 microliters of 2N hydrogen acid was added. The mixture was stirred under reflux for about $5 and then about 600 mg of ice was added. The extraction was carried out with ethyl acetate and the mixture was washed with brine and dried to give 34.7 GBq (937 m. Chromatography on tannin extract (eluent: cyclohexane-ethyl acetate (6 〇^〇 yield π to 19 GBq (513 mil Ci) expected product. 'Example 74 4-(4,4-didecyl) -3-hydroxypropyl)-5-imino-2_thio-indole-imidazolidine 138 200946114 base)-2-(trifluoromethyl)-benzonitrile using the method from Example 22, 2 g from the example The product of 70 (a) is reacted with 1.2 g of the appropriate amino nitrile to give 1.70 g of the desired product Rf = 0.25 (dioxane-acetone (65-35)). IR spectrum (CHC13): OH 3630 cm 4 =NH 3314-1676 cm·! ON 2235 cm -1 Example 75 4·(4,4-Dimercapto-3-(light propyl)-5· Brewing I-based-2-thioxo-1-salt Tetyl)-2-(trifluoromethyl)-benzonitrile was reacted from the product of Example 74 using the procedure from Example 71 to yield 226 mg of expected product which was refinished at 149 ° C. 10 Rf=0.32 (dichlorodecane-acetone (75-25)) 〇IR spectrum (CHC13): 0H 3626 cm-1 C=0 1763 cm-1 ON 2236 cm aromatic 1615-1580-1504-1483 cm_ 1 Example 76 4-(4,4-Dimercapto-3-(4-hydroxybutyl)-5-imino-2-thio-1-imidazolidinyl)-2-(trifluoromethyl) -benzonitrile is used In a method of 22, 2 g of isothiocyanate was reacted with 1.38 g of 15 suitable amino nitrile to give 2.08 g of the desired product Rf = 0.25 (2 139 200946114 chlorodecane-acetone (65-35)). Spectrum (CHC13): OH 3630 cm -1 = NH 3314-1675 cm -1 ON 2235 cm -1 Aromatic 1611-14577-1504 cm-1 Example 77 4-(4,4-Dimercapto-3-(4 -Phenylbutyl)-5-mercapto-2-thio-1-[1]-[sodium sulphate]-2-(trifluoromethyl)-indigo-5 using the method from Example 71, 300 mg from Example 76 The product was reacted to give 236 mg of the desired product which eluted from <RTI ID=0.0># </RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; ε= 19500 Infl. 254 nm ε= 24000 Infl. 266 nm Example 78 IR spectrum (CHC13): 0H 3624 cm -1 C=0 1762 cm -1 C=N 2237 cm -1 Aromatic 1615-1580-1504 Dimensions _1 1〇4-(4,4-dimercapto-3-(2-decyloxyethyl)-5-imino-2-thio-1 - σm0 sitting bite 140 200946114 base) -2-(Trifluoromethyl)-benzonitrile was reacted from Example 22 using 2.5 g of isothiocyanate with 1.56 g of the appropriate amino nitrile. To which 2.36 g of the expected product Rf = 0.23 (methylene chloride Yue dioxane - acetone (92.5-7.5)). _ IR spectrum (CHC13): 3314 cm -1 2236 cm -1 1614-1578-1504 cm -1 1675 cm 4

=NH C=N ❿aromatic C=N_ 5 Example 79 4-(4,4-Dimercapto-3-(2-decyloxyethyl)-5-one-2-thio-1-imidazole Pyridyl)-2-(trifluoromethyl)-benzonitrile was reacted from the product of Example 78 using the method of Example 71 to give the desired product which melted from 98 ° C to 99 ° C and Rf = 0.32 ( Chlorodecane - 1 oxime acetone (99-1)). IR spectrum (CHC13): 〇〇1757 cm 4 ON 2236 cm ί Aromatic 1615-1580-1504 cm _1 UV spectrum (EtOH): Max. 232 nm ε = 18200 Infl. 254 nm ε = 22400 Infl. 265 Nano 141 200946114 Example 80 4-(4,4-Dimercapto-3-(1-indolylethyl)-5-imino-2-halo-l-1^嗤 基)-2- (Trifluoromethyl)-benzonitrile, using the procedure of Example 22, 2.5 g of isothiocyanate and 1.32 g of the appropriate amino nitrile afforded 880 mg of expected product Rf = 0.20 (dichloromethane - Acetone (96-4)). IR spectrum (CHC13): =NH 3310-1675 cm _1 C=N 2236 cm -1 aromatic 1614-1580-1504 cm _1 Example 81 4-(4,4-dimercapto-3-(1-曱) Base ethyl)-5-keto-2-thio-1-imidazolidinyl)-2-(trifluoromethyl)-benzonitrile ίο Using the method from Example 71, 880 mg of product from Example 80 and 35 The reaction was carried out with EtOAc (6 mL), EtOAc (EtOAc) (EtOAc) IR spectrum (CHC13): OH 3626 cm -1 C=0 1753 cm -1 C=N 2232 cm -1 Aromatic 1615-1580-1504 cm -1 UV spectrum (EtOH): 142 200946114

Max. 232 nm ε = 18900 Infl. 235 nm ε = 22500 Infl. 273 nm Example 82 3-(3,4-Dichlorophenyl-5,5-dimercapto-1-(3-hydroxypropane) ))-4-imino-2-imidazole thione. Using the method of Example 51, 2.4 g of 3,4-dichlorophenyl isocyanate was reacted with 1.6 g of the appropriate amino nitrile in silicone. After chromatography (eluent: dichloromethane-acetone (6-4)), 2.16 g of the desired product was obtained with Rf = 0.25. IR spectrum (CHC13): OH 3630 cm - 1 + related C = NH 3294 -1676 cm-aromatic 1595-1569-1482 cm-1 Example 83 3-(3,4-diazophenyl-5,5-dimercapto-1 -(3-propylpropyl)-2-sulfate Using a method from Example 52, 0.88 g of the product from Example 82 was reacted with 35 ml of 6 hydr. hydrochloric acid, and extracted with chloroform to give 0.79 g of the desired product at 202. C-203 ° C melting. IR spectrum (CHC13): c = o 1753 cm ON 2232 cm -1 Aromatic 1615-1580-1504 cm -1 143 200946114 UV spectrum (EtOH): Max. 232 亳 micron ε = 18900 Infl 235 nm ε = 22500 Infl. 273 nm Example 84 4-(4,4-dimethyl-3-(4-hydroxybutyl)-5 -imino-2-thio-1-imidazolidinyl)-2-(trifluoromethyl)-(5-3H)benzonitrile a) 4-amino-2-(trifluoromethyl)-( 5-3H) benzonitrile 5 The following was cooled to -180 ° C and mixed under inert pressure: 16 mg of 2-trifluoromethyl-4-amino-5-bromobenzonitrile, 2-mg on activated carbon Palladium, 200 microliters of ethyl acetate and 6.5 microliters of triethylamine. The mixture was then placed under helium pressure and raised to 20 ° C, then the pressure was 1.68 bar. The mixture was stirred until the absorption was completed (P = 0.42 bar). Then, it was cooled to -180 ° C. The remaining helium gas was returned to ίο, and the temperature was raised to 20 ° C and then filtered. The filtrate was washed with ethyl acetate and concentrated at 40 ° C under reduced pressure to give 68 GB. Expected product b) 4-Thioisocyanooxy-2-(trifluoromethyl)-(5-3H)benzonitrile The following is mixed under argon pressure: 34 GBq of the above deuterated amine derivative, 150 μm The ionized water and 150 microliters of a 10% sulfur light 15 gas solution in the gas sample were lifted. The mixture was stirred at 20 ° C for 45 minutes, decanted, and extracted with chloroform. The extract was dried over MgSO.sub.4, filtered and evaporated. The resulting isothiocyanate is used accordingly in the next step. c) 4-(4,4-dimethyl-3-(4-carbylbutyl)-5-imino-2-thio-1-hydroxyzolidine)-2-(trifluoroanthracene) Base)-(5-3H)benzonitrile 20 The following is mixed with the thioisocyanate from step b) under argon gas pressure: 144 200946114 350 μl of four gas chitosan and 2 〇 microliters containing 1% triethylamine Prepared according to the instructions of the surface. The mixture was placed at 2 Torr. _ 2 hours, followed by concentration at 20 C and reduced pressure. The imine is used accordingly in the next step. Preparing 2_(tetra)butylbutylamine peak methylpropionitrile 5 used in the step 将 Mixing 550 μl of acetone sterol nitrile and 5 μl of 4-amino-!-butanol with each other' and mixing the mixture at 2 When 1 M is migrated, the desired product is obtained, which is used in the next step. g Example 85 4 (4'4-methyl-3-(4-3⁄4ylbutyl)-5,yl-2-thioxoxanthene 10yl)_2·(trifluoromethyl nitrite, 200 μm 2 L of hydrochloric acid was added to the imine from Example 84, and the mixture was heated under reflux for 5 minutes, then allowed to reach the greasy again and diluted with 1 ml of water. Extract with ethyl acetate and use the extract with water. It was washed and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (eluent: cyclohexane-ethyl acetate (6-4)) to give 2.8 gq of expected product. 86 4-(4,4-Dimethyl-3-(4-hydroxybutyl)-5-imino-2_thioxo; u imidazolidinyl)-2-(trifluoromethyl)·benzene And (14c)nitrile 10 a) 4_Amino-2_(trifluoromethyl)-benzo(I4C)nitrile 377 mg of copper cyanide (9) (called) and 732 g of 4-bromo-3- (Trifluoromethyl)benzylamine was mixed in 8 ml of dimethylformamide under nitrogen pressure, and the mixture was heated under reflux for 4 hours, then cooled to 〇〇c and diluted with 20 ml of hexane. The insoluble fraction was removed by filtration and concentrated under reduced pressure at 145 200946114. The residue was dissolved in dichloromethane and filtered, and then filtered and evaporated. The benzonitrile (C) was purified by chromatography on silica gel (eluent: dichloromethane-cyclohexane (7 〇 _3 〇)) to give the desired product (6.72 gq). 5 b) 4-thioisocyanooxy-2-(trifluoromethyl)benzo (mc) nitrile was mixed under nitrogen pressure: 189 mg of benzonitrile (I4C) from step a), 2.7 ml of water and 85 microliters of sulfur phosgene. The mixture was vigorously mixed for 5 minutes, and after adding 30 μl of sulphur phosgene, stirring was continued at 20 ° C for 1 hour, then extraction was carried out with a gas sample, and the extract was washed with water, dried and concentrated under reduced pressure 〇 10 . The resulting thioisocyanate was used in the next step accordingly. c) 4-(4,4-Dimethyl-3-(4-carbylbutyl)-5-imino-2-thio-1-n-oxazolidinyl)-2-(trifluoromethyl) - Benzene (14 fluoronitrile) 2 ml of tetrahydrofuran, a solution of propionitrile prepared below in 1.5 ml of di-methane and 150 μl of triethylamine were added under nitrogen pressure to the thioisocyanate from step b)15. The mixture was heated under reflux for 30 minutes and concentrated under reduced pressure to give an imamine which was used in the next step. Preparation of 2-(4-hydroxybutylamino)-2-methylpropanenitrile from step c 220 μl of acetone sterol nitrile and 200 μl of 4-amino-1-butanol were stirred at 20 ° C After mixing for 16 hours with each other, it was diluted with 2 ml of di-methane, dried, dried and filtered, and the filtrate was concentrated under reduced pressure to give propionitrile, which was used in the next step. Example 87 4-(4,4-Dimercapto-3(4-hydroxybutyl)-5-one-2-thio-1-imidazolidinyl)-2-(trifluoromethyl)-benzo (14C) Nitrile 146 200946114 To a solution of the imine from Example 86 was added methanol and 16 mL of 2? hydrochloric acid. The mixture was heated under reflux for 45 minutes, cooled to 2 ° C and diluted with 10 mL of water. Extraction was carried out with dioxane, and the extract was washed with water and concentrated under reduced pressure. The crude product was purified by chromatography on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc Example 88 ❹ 10 15 Ο 20 4-(4,4-Dimethyl_3_(4-hydroxybutyl)_5-iminoamino-2-ketopyridinyl)_2-(difluoromethyl)-( 5-3 Η) benzonitrile a) 4-amino-2-(trifluoromethyl)-(5_3η)benzonitrile 2 Using the procedure from step 84 of Example 84, 16 mg of 4-amino-5-bromo Gas methyl nitrile, 2 mg palladium on activated carbon, 2 Torr microliters of acetonitrile acetate and 6.5 will be reacted with diethylamine to give 68 GBq of the desired product. b) = isocyanato-2-(trifluoromethyl)_(5_3H) benzonitrile toluene step 34GBq of deuterated amine derivative and 100 microliters of 光i phosgene mixed under argon pressure and When the mixture was at 80 ° C. Add 100 microliters of phosgene and mix the mixture at 80. (: Heating 1 small: This step is repeated _ times, and then concentrated at 2 (rc and reduced pressure to obtain /, succinic acid S is used according to the following steps.) 4 (4,4-di Base_3_(4-hydroxybutyl)_5-imino-2-phenothazolidine)-2-(trifluoromethyl)-(5-3H)benzonitrile: the surface is added under gas pressure to From the isocyanate 1 of step b): -^UU -XL - jsst and 2 〇 π - 虱 methane, 5 〇 microliters of the propionitrile-dichloro decane solution prepared below, the diethylamine is lifted, and The mixture was stirred for 3 minutes. Add 5〇147 200946114 microliters of propionitrile solution and continue to stir for 30 minutes, then concentrate at 2 (rc and reduced pressure. The imine is used accordingly in the next step. Prepare 2-(4-hydroxyl) from step c) Butylamino)-2-methylpropionitrile 220 μl of acetone sterol nitrile and 200 μl of 4-amino-indole-butanol were mixed with each other 5 and the mixture was at 20. (: Stir for 16 hours, then dilute with 3 ml of dichlorohydrazine and dry over magnesium sulfate. The decanted solution was used in the next two steps. Example 89 4- (4,4-Dimethyl-2,5 -Diketo-3-(4-hydroxybutyl H-isoxazolidine-10-yl)_2-(trifluoromethyl)-(5_3H)benzonitrile Add 200 μl of sterol and 50 μl of 2N hydrogen acid From the imine of the example (10), and heating the mixture under reflux for 45 minutes, then it was again brought to 20 ° C and diluted with 1 ml of water. Extraction was carried out with dichlorohydrazine, and the extract was washed with water and at 20 Concentrate under reduced pressure at ° C. The crude product was purified by chromatography on EtOAc (eluent: dichloro hexane-ethyl acetate (7-3 then 5 - 5:)). Example 90 ❹ 4-(4,4-Dimethyl-3-(4-carbylbutyl)-5-imino-2-mercapto-1-ester σ sitting π-decyl)-2- (Trifluoromethyl)-benzo(14C)nitrile 20 a) 4-amino-2-(trifluoromethyl)benzo (14-carbonitrile) using the method from Example 86, 377 mg of copper cyanide (n) -14C, 1.0732 g of 4-bromo-3-trifluorodecylbenzylamine and 8 ml of dimethylformamide gave 0.558 g (6.62 gq) of expected product. b) 4-Isocyanooxy-2-(trifluoromethyl)benzo[]4C)carbonitrile 148 2〇〇946ii4 182.4 mg of benzonitrile (14C) (0.97 mmol), 2 ml of two The alkane and 1 ml of 20% phosgene in toluene were mixed with each other under nitrogen pressure, and the solution was heated at 6 (TC for 22 hours, and then concentrated under reduced pressure at 60 ° C. The 5 isocyanate was used in the next step. c) 4-(4,4-Dimercapto-3-(4-hydroxybutyl)-5-imino-2-one-1-imidazolidinyl)-2-(trifluoromethyl) - benzo(?4〇carbonitrile) I.5 ml of dichloromethane (on Siliporit NK3〇), from Example 88 I in 1. 5 ml of dichloromethane, and 150 μl of triethylamine under nitrogen pressure It was added to the isocyanate from step b). The mixture was concentrated at 2 ° C for 1 hour and then concentrated under reduced pressure. The imine was used in the next step. Example 91 4-(4,4-dimethyl Benzyl-2,5-diketo-3-(4-carbylbutyl)-m-[i-trinyl)-2-(trifluoromethyl)-benzo (14 mM nitrile 5 ml of methanol and 1.2 ml 1N hydrochloric acid was added to the imine from Example 9〇15, and the mixture was heated under reflux for 40 minutes, then allowed to cool again to 20 ° C and used 10 mM. Diluted with liters of water, extracted with dichloromethane, and the extract was washed with water and concentrated under reduced pressure. The crude product was purified by chromatography on celite (eluent: diethyl ether-acetonitrile-cyclohexane (5 〇) _15_35/ gave 2 289 mg (1.26 GBq) of expected product. '20 Examples 92 4-(2,5-Diketo-4,4-dimethyl.3_(4-triphenylphosphonyloxybutyl)imidazole 0-yl)-2-(trifluoromethyl)节 370 370 mg from the product of Example 58, 3 〇 7 mg of trityl in 仞 mg 4-dimethylamino hydrazine, 0.25 ml of triethylamine and 4 ml of dimethyl 149 200946114 decylamine Stir at ambient temperature for 16 hours. The mixture was heated to 4 Torr. (: After 4 hours and poured into water, extract with diethyl ether. The extract was washed with water and dried, and the solvent was removed under reduced pressure. The residue was chromatographed on a gelatin (eluent: cyclohexane) Alkyl-ethyl acetate 75_25) gives 467 grams of the expected product Rf = 〇.25 -------- IR spectrum (CHC13):

Example 93 〇15 1779, 1725 cm 2235 cm 150 200946114 1615, 1580, 1505, 1497 cm example 94 4_[4,4-dimethyl-2,5·dione-3-yt-4-methoxybutyl Small oxazolidinyl]-2-(trifluoromethyl)benzonitrile. 50 mg of sodium hydride was added in portions to 370 g of the product from Example 58 in 3 ml of dimethylformamide. The mixture was disturbed for 2 minutes. 0.06 ml of methyl iodide was added and the mixture was stirred for 1 hour. Further, 50 mg of sodium hydride was added to the aromaticity, and after 20 minutes, 6 ml of methyl iodide was added. The reaction medium was poured into water and extracted with diethyl ether. The extract was washed with water and dried, and the solvent was evaporated. The residue was chromatographed on silica gel (eluent &lt;RTI ID=0.0&gt;&gt; IR spectrum (CHC13): c=o 1779, 1725 cm -1 ON 2234 cm One side 1616,1576,1505 cm - 0CH3 Example 95 Methyl high 1 phase 3 Use the method from Example 59, 600 Do not hesitate to /.士 Α » 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸 攸Shout _ the product, which is at 151 15 200946114 IR.....^iI(chci3). c=o ON Aromatic 1779, 1725 cm -1 2238 cm -1616, 1575, 1505 cm _ Example 96,5-two Keto group_ι 4 口~[4-[(methylsulfonyl)oxy]butyl]_4 4 dinonyl imidazolidinyl]_2_(trifluoromethyl)benzonitrile in Ο.1? Sulfur helium gas was added to a solution of 740 mg of the product of Example 58, 4 ml of pyridine and 24 mg of 4,2,2,2,2,2,2,2,2,2,2,1,1,1,1 The mixture was poured into ice-cold water and extracted with methylene chloride. The extract was washed with water and the residual ratio was removed by distillation. The residue was chromatographed on EtOAc (EtOAc:EtOAc:EtOAc: IR spectrum (CHCM : C = 0 1779, 1725 cm -1 ON 2235 cm ί Aromatic 1615, 1575, 1505 cm -1 〇II - os - It 1361, 1175 cm -1 It ο UV spectrum (EtOH): Max. 261 nm ε = 14900 Infl. 279-297 nm ❹ 152 200946114 Example 97 4-(3-Ethyl-4,4-diindenyl 2,5-dione-based oxime-imidazolidinyl)_2_ (Trifluoromethyl)benzonitrile Using the procedure of Example 59, 420 mg of the product from Example 8 and 5 batches of 0.1 liters of ethidium chloride were reacted and chromatographed on silica gel (eluent: dioxane) After decane-ethyl acetate 8_2), 334 mg of the desired product was obtained, which melted from 129 ° C to 130 ° C. IR spectrum (CHC13): ------------------ 〇〇1800, 1740, 1717 cm-1 ON 2240 cm-1 Aromatic 1616, 1505 cm 1 UV spectrum (EtOH): Max. 250 nm ε = 12000 Infl. 274-284 nm Example 98 ❹ 10 4-( 3-Benzylmercapto-4,4-dimercapto-2,5-dione-1-pyrimidinyl)-2-(trifluoromethyl)benzonitrile using the method of Example 59, 300 mg From the product of Example 8 and two batches of 0.12 liters of benzamidine chloride in 〇·5 ml of dimethylhydrazine Solution reaction in guanamine 'chromatography on tannin (eluent · cyclohexane - ethyl acetate 8_2) to the desired product of the bundle, which melts at 179 ° C - 180 ° C. IR spectrum (CHC13): ___ C=〇____1800, 1780, 1746, 1699 cm-1 153 200946114 ON 2235 cm" Aromatic _1617, 1600, 1580, 1504 cm-1 UV spectrum (EtOH): Max. 250 nm ε = 28500 Infl. 275 nm ε = 6500 Infl. 263 nm ε = 3850 Example 99 4-[3_[Dimercapto-(1,1-dimethylethyl) fluorenyl]-4,4-dimethyl-2 ,5-Dinosadin-1-pyrimidinyl]-2-(trifluoromethyl)benzonitrile Using the procedure from Example 59, 450 mg of the product from Example 8 and 300 mg The decyl chloride was reacted in 2 ml of decyl decylamine and chromatographed on celite (eluent: dioxane _acetone 994) to give 527 mg of expected product, i. °C melts. IR spectrum (CHC13): ON 2236 cm ^ 'aromatic 1615, 1579, 1505 cm · ❹ UV spectrum (EtOH) : ~

Max. 258 nm ε = 17000

Infl. 275-285 nm ____ In addition to the above products, the following products are available within the scope of the invention, specifically, the product of the formula: 154 200946114 ο

Where Υα is oxygen or sulfur and R3A has the following values: .(CH2)n5

I -(CH2)«so2

(CH2)«—oh · (CH2)n—COO-alk alkj alk2

—(CH2)”—CO—alk CH3

-(OH2)n-CH CH3 ch3

A (CHA-N ch3 155 200946114 alk, alkl and alk2 are each an alkyl group having from 1 to 4 carbon atoms and n is an integer from 1 to 4. Example 100 Manufactured with 100 mg of 4-(5-keto) Composition of 2-thio-3,4,4-tridecyl-1-imidazolidinyl)-2-trifluoromethylbenzonitrile and sufficient composition of lactose, starch, talc and magnesium stearate The final tablet weight is 300 mg tablets. Pharmacological data 10 15 20 According to the regulation of cannabinoid receptor 1 (CB1R) and the selectivity of cannabinoid receptor 2 (CB2R) modulation pharmacology: in vitro test : In vitro functional test of recombined cells: Functional-test test by FLIPR technology (&quot;Fluorometric Imaging Plate Readern, Molecular Devices Corp.). In this regard, determination of ligand-induced Ca2+ in reconstituted HEK293纟_^^

In the cell, the degree of change, which expresses both the cannabinoid receptor (CB1 or €82) and the G_protein Galphal6. For this study, cells were seeded into 96-well microtiter plates (60,000 cells/cells) and placed to grow overnight. The medium was removed and the cells were cultured in a buffer containing fluorescein = dye Flu 〇 4 . After attaching the dye, wash the cells and add the bath solution to the substance in the peak liquid towel. The hydrate is cultured for 20 minutes, and the X-axis is added to the __, and the change is made in the FLIPR early το cut 1 fine axis #. 156 200946114 The experiment did not test the substance but there was an excess of reference agonist) and was used to calculate the dose/effect curve and determine the IQo value. Results * The values of the functional tests compared to the cannabin 1 receptor can be obtained from Table 1 below, including the selectivity as compared to the cannabinoid receptor. Example No. hCBIRrFLIPR; IC5〇 [nM] hCB2R: FLIPR; IC5〇 [nM] 27 557 29 90 &gt;30000 65 85 67 233 68 754 Binding to the CB1 receptor:

10 ❹ 15 Test compound: The compound inhaled into a 96-well PP microtiter plate = compound diluted with 27 μl of 100% DMS hydrazine (dimethyl sulfoxide). From this = liquid start, in each case slightly increased by transfer 1 至 to the new pp micro drop = plate and add 2G microliters of (10)% DMS 〇 and then 3 times thinner

Micro 曰 ΐ ΐ I 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 胄 这些 这些 这些 这些 这些 这些 这些 这些 这些The final concentration ranged from a micromolar concentration to a concentration of 0.005 micromolar. The medium group will be dissolved in the test buffer group containing 1% dms◦. The most embarrassing, 'curve= added to the serial dilution of the microtiter plate as a control, the end is 1 micromolar concentration. 157 200946114 Blank control group: Test buffer containing 1% DMSO was added to the serially diluted microtiter plate as a blank control group. Summary of test parameters: Method volume 200 μl receptor CHO-K1/Cannabis CB1 protein 2 μg/well ligand [3HJ-SR141716A 0.5 nanomolar concentration _ · 0.0195 micro Ci/well ion Tris-HCl 50 millimoles Concentration, pH 7.4 MgCl2 5 millimolar concentration EDTA 2.5 millimoles **----- BSA (no fatty acids) 0.2% non-specific combination of AM 251 1 micromolar concentration of compound in 1% DMSO 10 micromoles Ear concentration to --- _ Analysis of the data: ------ Mohr concentration Ο Same as the control group: 3h with no added compound combined with low control group: 3H p in the presence of 1 micromolar concentration am 251 After the original data calculated each value: inhibition of ligand binding (%) = 1, (1_ soil · low control group), - - - - -------- ) (high control group - low control group The reported value is the repeated test average value 丄5〇 value is calculated from the measured value using Xlfit ❹ 158 200946114 formula 205. The Ki value is obtained from the IC50 and Kd values using the Cheng-Prusoff formula: (concentration of the radioactive ligand) 1 +—— 〇10 Literature: Cheng, Y.-C., and Prusoff, WH (1973) Biochem. Pharmacol 22 , 3099-3108 Results: Ki values of the example compounds; Table 2: Example number hCBIR; binding Ki "nMl 29 76 can be seen from the test data: [The compound acts as a c B1R modulator and = this is very synonymous with therapeutic metabolism Symptoms, type π diabetes, and fat: appropriate for the treatment of CNS disorders, such as Alzheimer's disease or fine 〇 15 [Simple description of the diagram] [Main component symbol description] 159 20

Claims (1)

200946114 VII. Patent application scope: 1. The use of a compound of formula I CHs wherein R] is -CN, -N02, halo; R2 is -cf3, halo; -A-B- is selected from the group consisting of f X is 0, S; r3 is hydrogen, (crc tertiary group, (C2-Ci2&gt; quinone aryl, (Cl-C 12)·alkylene group _(QrC 12&gt; aryl, ～cI2)- f (Cl-c12m group, (CrC 12)-alkenyl group, (c(4)2)_block group and (c) 'at least one carbon may be optionally substituted by an atom including oxygen and nitrogen two' Cheng Ya or Shi Feng; wherein (QC! 2)-aryl and (crC) 2), the alkyl group _(c6_c) 2) aryl group can be derived from the dentate group, -CF3, (CrQ)-throw group, Substituted by (Cl_c6)-alkoxy, (C2_C6)alkenyl, (CVC6)-alkenyloxy, (Q-C6)-blockyl and (qq)-alkynyloxy; and wherein (Α-.) - an alkyl group, ((VCi2)-alkenyl, (C2_Ci2)-alkynyl, (C6_Cy_aryl 160 15 200946114 and (CrC 12)-alkylene-(C6_Ci2)-aryl group may be -OH, halo group , -SH, -CN, COCHCrC^)·alkyl, [-〇(〇0)-(C6-C12)·aryl], C00H, carboxylic acid g (COO-), (CrC12)-alkylene -COOH, marriage 2, NH_(CrCi2)_alkyl, N-[(CrC]2)-alkyl]2, CONH2, alkyl-(OC^-N-IXCrCu)-Hyun·base]2, 醯Base, (CrC;)-brewed oxy, (c6_c i2)_aryl-0-(C6-Ci2)-3?1.. -〇-( CrC12)-^it^.t(C6-C-S-(C6-C]2&gt; aryl, -S(0)-(C6-C)2-aryl, -S〇2_(C6-C 〖2)-aryl, three (crc12)_院美石石烧基substituted, wherein the alkyl group contains from 1 to 6 carbon atoms; Y is 〇, s, NH; and its physiologically compatible salts It is a drug for the treatment of inversion syndrome. ', 2. The use of the compound of formula I according to the scope of claim 1 wherein Ri is -CN, -N02, _ group; 'Κ·2 is -CF3, halo ; -AB- is selected from included R3 is (cvcy-alkyl, (CrC i2H), y = y (4), thank you paper (4) side oxidation 161 20 200946114 where (Ci-C) 2) · aryl aryl can be obtained from halogen Base, _Cf3, (Ci_c6)·alkyl, (CrC6)-alkoxy, (crc6)alkenyl, (c2-c6)-alkenyloxy, (c2-c6)-alkynyl and (CrC6)-alkyneoxy Substituent substitution; and wherein (Ci-C) 2)-alkyl and (CpCi2)_alkylene-(C6_Ci2)-aryl may be via -OH, dentate 5, -SH, -CN, COO- (CrC12)-alkyl, [-0(C=0)-(C6_CI2)_aryl], COOH, carboxylate (COO-), (CrC12)-alkylene-COOH, -NH2, NH- (CrC12)-alkyl, N-[(CrC12)-alkyl]2, CONH2, -(C=〇)-NH-(CrC12)-alkyl, -(0=0)-Ν-[(〇ν (:12)-Alkyl]2, anthracenyl, (CrC7)-decyloxy, (c6-C12)-aryl, -〇-(C6-C12)-aryl,-0-(CrC)2 -❹ 10 alkyl-(C6-C12)-aryl, -S-(C6-C]2)-aryl, -S(〇MC6-C12)-aryl, _SOr(C6-C12)_芳a cyano, tri(Ci-Cu)-alkyl decyl group substituted wherein the alkyl group contains from 1 to 6 carbon atoms; Y is hydrazine, S; and a physiologically compatible salt thereof, which is used in the manufacture of a compound Metabolic syndrome Medicine 15 Substance 0 3. The use of a compound of formula I according to claim 1 of the scope of the patent, wherein Ri is -CN, -N02, halo; Ο is -CF3, halo; -A-B- is X is 0, S; R3 is (Crc) 2)-yl, (QC 12)-alkyl-(C6-C12)-aryl, 162 20 200946114 is in (1 12) alkyl and (Ci- In the C1; 2)-alkylene-(Q-Cn)-aryl group, at least one of the slaves may be substituted with an atom of oxygen, nitrogen and sulfur, and (4) may be optionally oxidized to an azulene or a stone wind; wherein (CVC) 2)· Stretching base _(CVCi2)_aryl group may be derived from halo, _Cf3, (Ci_C6)_ 5 , yl, (CrC6) _ alkoxy, (c2-c6) alkenyl, (c2-c6) Alkenyloxy, substituted by (crc-based and (CVQ)-alkynyloxy; and wherein(Ci-C!2)-alkyl and (Qc!2)-alkylene-(C6_Ci2)-aryl It can be extended by _〇H, N-methyl, -SH, _CN, CO〇-(Ci-C]2&gt;alkyl, aryl], C00H, finemang (c〇〇_), (Ci_Ci2) Alkyl_c〇〇H, 师, 0 cis%2)-alkyl, ΝΚΐ2)-alkyl]2, C0NH2, -(〇0)-NH-(CrCl2)-alkyl, _(c=〇 w(cvCi2&gt;alkyl), fluorenyl, (crc7)_decyloxy, (C6_Cl2)-aryl, _〇_((VCi2)_aryl, alkyl-(c6-c12)·fang a group, each (c6_Ci2> aryl, _s(〇Mc6^-scmc6-q2)-aryl, tri(Ci_c]2&gt; There are 15 to 1 to 6 carbon atoms; Y is 0; ❹ 2 is compatible with the _, which is adjacent to the manufacture of a drug for the treatment of metabolic syndrome. 4. 20 The use of the compound according to the formula i of the scope of the patent application R] is -CN, -Ν〇2, halo; ' /, R2 is -cf3; -AB- is 163 200946114 and \N-RJ. x is ο; R3 疋(Ci-Cl2)_alkyl, Ci_C 12)-alkylene-(C6-Ci2)-aryl, wherein at least one carbon may be in (Ci-Ci2)-alkyl and (Q-Ci2)-alkylene-(CVCi2)-aryl Optionally substituted with an atom comprising oxygen, nitrogen and sulfur, wherein the sulfur can be arbitrarily oxidized to a argon or stone wind, wherein (CVC 2)-alkyl-(c6-c12)-aryl can be Tooth group, -〇ρ3, (Cl_c6&gt; oxime, (CrC6)•alkoxy, (c2-C6)alkenyl, (C2-C6&gt;alkenyloxy, (c2-C6)-alkynyl and (C2) -C6)-substituent substituent of a fast oxy group; and wherein (Ci-Cl2)-alkyl and (Ci-C!2)-alkylene-(C6-Ci2)-aryl group may be via -OH, a functional group , -SH, -CN, C00-(CrCi2)-alkyl, [-0(C=0)-(C6-Ci2)_aryl], C00H, carboxylic acid vine (COO-), (CrC^) - Stretching base - C00H, -NH2, NH-(CrC12)-alkyl, N_[(CrC12 )_alkyl]2, C〇NH2, -PCO-NIHCVC!2)-alkyl, -(C=0)good[(CrC12)·alkyl]2, fluorenyl, (crc7)-decyloxy, (c6-c12)-aryl, -〇(C6-C12)_aryl, -CKCVCu)- Οalkyl-(C6_C)2)-aryl, -s-(c6-c)2-aryl a group, -s(〇hc6-c12)-aryl, -SOHCVCn)-aryl, tri(Crc12)-alkyl group, wherein the alkyl group contains from 1 to 6 carbon atoms; Y is 0; Its physiologically compatible salts are used in the manufacture of drugs for the treatment of metabolic syndrome. 5. A compound of formula I according to any one of claims 1 to 4 and its birth 164 200946114 ❺ 10 15 用途 Use of a medicament for the treatment of diabetes. A compound of formula 1 which is compatible with any one of items 1 to 4 and the use thereof for the manufacture of a medicament for the treatment of obesity. The use of a chemically compatible salt in the application of a patent for a weight-reducing drug in accordance with the application of patents (4) to 4, according to the scope of claims 1 to 4 - or a plurality of compounds of formula I The use of drugs to treat nicotine dependence. The use of a hydrazine compound for the manufacture of a medicament for the treatment of alcohol dependence, according to the formula 1 to 4 of the scope of the patent application. 10. Use of a compound according to one or more of the scope of the scope of the patent application, in the manufacture of a medicament for the treatment of a CNS disorder. η. Use of a compound of formula I according to one or more of claims 1 to 4 for the manufacture of a medicament for the treatment of schizophrenia. 12. Use of a compound of formula I according to one or more of claims 1 to 4 of the patent application for the manufacture of a medicament for the treatment of Alzheimer's disease. 13. Use of a guanidine compound for the manufacture of a medicament for the treatment of polycystic ovary syndrome (PCOS) according to one or more of the patent claims 1 to 4. 6. 8· 9. 165 200946114 In which the radicals are each defined as specified for producing a medicament for treatment of metabolic syndrome. Fourth, the designated representative map: (=) The representative representative map of this case is: the (none) map. (2) Brief description of the symbol of the representative figure: None Five The chemical handle is on the right, please reveal the chemical formula of the most expensive invention: Take 2 Y B 2