CN1930155A - Acylaminothiazole derivatives, preparation method thereof and use of same in therapeutics - Google Patents
Acylaminothiazole derivatives, preparation method thereof and use of same in therapeutics Download PDFInfo
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Abstract
The invention relates to a compound having general formula (I), wherein: R1 represents either an optionally-substituted C1-6 alkyl or a C3-7 cycloalkyl, a thiophene, a benzothiophene, a pyridinyl, a furanyl or a phenyl which is optionally substituted; R2 and R'2 represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxy, a C1-3 alkoxy, a C1-3 alkyl, a C3-7 cycloalkyl, a O-C(O)-C1-6 alkyl group, or R2 and R'2 together form an oxo group; R3 represents a hydrogen atom, a C1-6 alkyl which is optionally substituted by a hydroxy, a C1-6 cycloalkyl or a C1-3 alkoxy; either R4 or R5 represents a group (Z) and either R4 or R5 represents a -C(X)R6 group; G represents a single bond or a -CH2- group; Y represents a single bond, an oxygen atom, a sulphur atom, an optionally-substituted C1-4 alkylene group or -N(W)-; A and B represent, independently of each other, a hydrogen atom, a halogen atom, a hydroxy group, C1-3 alkyl, C1-3 alkoxy, trifluoromethyl, trifluoromethoxy or -O-CHF2; X represents O or S; R6 represents an optionally-substituted C1-6 alkoxy group, hydroxy or -NR7R8; and R7 and R8 represent, independently of each other, either a hydrogen atom, an optionally-substituted C1-6 alkyl group, an optionally-substituted C3-7 cycloalkyl group, C1-6 alkoxy or phenyl which is optionally substituted, or R7 and R8, together with the nitrogen atom bearing same, form an aziridine, azetidine, pyrrolidine, piperidine, morpholine or benzopiperidine ring. The inventive compound takes the form of a base, an acid addition salt or a hydrate. The invention also relates to the use of said compound in therapeutics.
Description
The objective of the invention is acylaminothiazole derivative, their preparation method and the purposes in treatment.
People have known the acylaminothiazole derivative compound of describing in file WO 03/014095A, WO 2004/009565A and WO2004/033439A, i.e. the formation inhibitor of the peptide of amyloid beta (β-A4).
All the time be necessary to seek and development beta-amyloid peptide formation inhibitor product (β-A4).These compounds of the present invention meet this purpose.
First purpose of the present invention is the compound that meets following general formula (I):
In the formula:
R
1Representative:
Perhaps C
1-6Alkyl, it is randomly by 1-3 substituting group replacement, C that is selected from halogen, trifluoromethyl, hydroxyl
1-6Alkoxyl group, C
1-6Alkylthio (thioalkyle), thienyl or phenyl; Perhaps C
3-7Cycloalkyl, thienyl, benzothienyl, pyridyl, furyl or phenyl; Described phenyl randomly is selected from halogen atom, C by 1-3
1-6Alkyl, C
1-6The substituting group of alkoxyl group, hydroxyl, methylene-dioxy, phenoxy group or benzyloxy or trifluoromethyl replaces;
R
2And R '
2Represent hydrogen atom, halogen atom, hydroxyl, C each other alone
1-3Alkoxyl group, C
1-3Alkyl, C
3-7Cycloalkyl, O-C (O)-C
1-6Alkyl, or R
2And R '
2Constitute oxo (oxo) group together;
R
3Represent hydrogen atom, C
1-6Alkyl, it is randomly by hydroxyl, C
1-6Cycloalkyl or C
1-3Alkoxyl group replaces;
R
4Or R
5In one or another represent following Z group:
And R
4Or R
5In one or another representative-C (X) R
6Group;
G represent singly-bound or-CH
2-group;
Y represents singly-bound, Sauerstoffatom, sulphur atom, C
1-4Alkylidene group or-N (W)-group, C
1-4Alkylidene group is randomly by hydroxyl or C
1-3Alkoxyl group replaces;
W representative or hydrogen atom, perhaps C
1-3Alkyl, it is randomly replaced by phenyl, perhaps phenyl;
A and B represent hydrogen atom, halogen atom, oh group, C each other by oneself
1-3Alkyl, C
1-3Alkoxyl group, trifluoromethyl, trifluoromethoxy or-O-CHF
2If its condition is if Y is that singly-bound or Sauerstoffatom are following types with the Z group:
And A is not a hydrogen atom;
X represention oxygen atom or sulphur atom;
R
6Represent C
1-6Alkoxyl group, hydroxyl or-NR
7R
8Group; C
1-6Alkoxyl group is randomly replaced by phenyl;
R
7And R
8Solely represent each other directly:
Perhaps hydrogen atom; Perhaps C
1-6Alkyl, it is randomly by C
3-7Cycloalkyl, C
3-7Cycloalkenyl group, C
1-3Alkoxyl group, phenyl, morpholinyl or pyridyl replace; Perhaps C
3-7Cycloalkyl, C
1-6Alkoxyl group or phenyl; Described C
3-7Cycloalkyl and phenyl randomly are selected from halogen atom, oh group, C by one or two
1-3Alkyl or C
1-3The group of alkoxyl group replaces; Or
R
7And R
8Nitrogen-atoms with their bands constitutes 1-azacyclopropane (aziridine), azetidine, tetramethyleneimine, piperidines, morpholine or benzo piperidine ring.
In general formula (I) compound, first group's compound is by R wherein
1Represent C
1-6These compounds of alkyl or the phenyl that randomly replaced by 1-3 halogen atom are formed.
In general formula (I) compound, second group's compound is by R wherein
2And R '
2Represent hydrogen atom, hydroxyl or R each other by oneself
2And R '
2Constitute together that these compounds of oxo group form.
In general formula (I) compound, the 3rd group's compound is by R wherein
3Represent C
1-6These compounds of alkyl are formed.
In general formula (I) compound, the 4th group's compound is by R wherein
4Or R
5In one or another represent these compounds of Z group to form:
And R
4Or R
5In one or another representative-C (X) R
6Group;
G represents singly-bound;
Y represents singly-bound, Sauerstoffatom, sulphur atom, C
1-4Alkylidene group, more particularly methylene radical;
A and B represent hydrogen atom, halogen atom, more particularly fluorine, trifluoromethyl, trifluoromethoxy each other by oneself; If its condition is if Y is that singly-bound or Sauerstoffatom are following types with the Z group:
And A is not a hydrogen atom;
X represention oxygen atom or sulphur atom;
R
6Represent C
1-6Alkoxyl group, more particularly methoxy or ethoxy.
A, B, W, X, Y, Z, R
1, R
2, R '
2, R
3, R
4, R
5, R
6, R
7And R
8Be to have constituted the 5th group simultaneously as these compounds that define in the above-mentioned compound group.
In the compound of general formula (I) and above-mentioned group, the 6th group's compound is made up of the compound of following radicals:
R
1Represent C
1-4Alkyl, the preferably sec.-propyl or the tertiary butyl, or the phenyl that replaces with two fluorine atoms; And/or
R
2Represent hydrogen atom or hydroxyl, and R '
2Represent hydrogen atom; And/or
R
3Represent C
1-4Alkyl, preferably methyl, ethyl or propyl group; And/or
The X represention oxygen atom.
Within the scope of the invention, be appreciated that
-C
T-z, wherein t and z can value 1-7, and containing carbochain can have t-z carbon atom, for example C
1-3Contain carbochain, it can have 1-3 carbon atom, C
3-6Contain carbochain, it can have 3-6 carbon atom etc.
-alkyl, straight or branched radical of saturated aliphatic group; C for example
1-6Alkyl represent has the straight or branched of 1-6 carbon atom to contain carbochain, more particularly methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the second month in a season-butyl, the tertiary butyl etc., preferably methyl, ethyl, propyl group or sec.-propyl;
-alkylidene group, the saturated divalent alkyl of straight or branched, for example C
1-3The representative of-alkylidene group has the straight or branched divalence of 1-3 carbon atom to contain carbochain, more particularly methylene radical, ethylidene, isopropylidene, propylidene;
-cycloalkyl, cyclic alkyl, for example C
3-7The cycloalkyl representative has the ring-type of 3-7 carbon atom to contain carbochain, more particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, preferably cyclopentyl or cyclohexyl;
-cycloalkenyl group, single-or many-unsaturated cycloalkyl, for example, C
3-7Cycloalkenyl group representative have the list of 3-7 carbon atom-or many-unsaturated ring contain carbochain, more particularly cyclopropenyl radical, cyclobutene base, cyclopentenyl, cyclohexenyl, cycloheptenyl, preferably cyclopentenyl or cyclohexenyl;
-alkylthio has the S-alkyl of straight or branched saturated aliphatic chain;
-alkoxyl group, have the straight or branched saturated aliphatic chain-the O-alkyl;
-halogen atom, fluorine, chlorine, bromine or iodine;
-" R
2And R '
2Constitute oxo group together ", this group for example:
With
-in the Z group, aromatic group
Be such, one of carbon atom of aromatic ring can be replaced by nitrogen-atoms in the position that does not have substituent A or B.
General formula (I) compound can contain one or more asymmetrical carbon atoms.Therefore, they can exist with enantiomer or diastereo-isomerism volume morphing.These enantiomers, diastereomer and their mixture comprising racemic mixture, all are parts of the present invention.Have R
2And R '
2Carbon and/or have R
3Carbon when being asymmetrical, preferred formula (I) compound wherein has R
2And R '
2Carbon be configuration (S) and/or have R
3Carbon be configuration (S).
Formula (I) compound can exist with alkali or with the additive salt form of acid.Some additive salt all are parts of the present invention like this.Advantageously, use at pharmaceutically acceptable these salt of acid preparation, but other the sour salt that for example uses when purifying or separate type (I) compound also is a part of the present invention.
General formula (I) compound can exist with hydrate or solvate form, promptly to associate or the existence of chemical combination (combinaisons) form with one or more water moleculess or with solvent.Some hydrates or solvate also are parts of the present invention like this.
Second purpose of the present invention is the preparation method of formula (I) compound.
Therefore, the method for process description can prepare these compounds below adopting, and the operational condition of these methods is common for those skilled in the art.
Blocking group should be appreciated that and be, can the prevention official in the time can carrying out chemical reaction can or the group of position reaction, and after dissociating according to method known to those skilled in the art, it can recover this molecule.Especially at " blocking group in the organic synthesis " (Protective groupsin Organic Synthesis), Greene and colleague thereof, second edition (John Wiley ﹠amp; Sons, Inc., New York) in provided blocking group example and protection and gone guard method.
A, B, W, X, Y, Z, R in formula (II)-(XVIII) compound below
1, R
2, R '
2, R
3, R
4, R
5, R
6, R
7And R
8Meaning such as the definition of cotype (I) compound, unless spell out other definition.
According to following flow process 1; according to condition known to those skilled in the art; for example in the presence of phosphofluoric acid benzotriazole-1-base oxygen base-three (tetramethyleneimine also) (PyBOP) or phosphofluoric acid benzotriazole-1-base oxygen base-three (dimethylamino) (BOP) and N-ethylmorpholine or N-methylmorpholine; at for example N; in the inert solvent of dinethylformamide, acetonitrile or methylene dichloride; can be 0 ℃ to room temperature in temperature; the peptide coupling of the acylamino acid of the thiazolamine of through type (III) and formula (II) can obtain formula (I) compound.
According to for example previously described method known to those skilled in the art, the peptide coupling (Pg represents blocking group in the formula, for example phenmethyl) of through type (IV) compound and formula V protection acid can obtain formula (II) compound.The compound that so obtains goes protection again.In this protection is under the situation of phenmethyl, charcoal drape over one's shoulders palladium in the presence of, in dehydrated alcohol, under hydrogen barometric point and room temperature, in advance this compound is carried out hydrogenation, obtain formula (II) compound.
Flow process 1
Perhaps can preparation formula (I) compound according to flow process 2.
According to following flow process 2, according to method known to those skilled in the art, for example as at hydroxy benzotriazole hydrate (HOBt) and 1-ethyl-3-(3-dimethylamino-propyl group) carbodiimide hydrochloride (EDAC, HCl) exist down, the peptide coupling of the amine of through type (IV) compound and formula (VI) can obtain formula (I) compound.
Flow process 2
According to method known to those skilled in the art as described previously; (Pg represents blocking group in the formula in the protection amine peptide coupling of the thiazolamine of through type (III) and formula (VII); uncle N--butoxy carbonyl (Boc) for example), can obtain formula (VI) compound.Make the compound that so obtains go protection then.In this protection is under the situation of Boc, in the presence of gaseous hydrochloric acid that is dissolved in anhydrous solvent or trifluoroacetic acid, goes protection by acid hydrolysis, obtains formula (VI) compound.
By oxidation-type (I) compound, R in the formula
2Or R '
2The representation hydroxy group can obtain formula (I) compound, R in the formula
2And R '
2Constitute oxo group together.According to condition known to those skilled in the art, for example use Dess Martin reagent, can carry out this reaction.According to condition known to those skilled in the art, allow formula (IV) ketone acid (R in the formula
2And R '
2Constitute oxo group together) and the direct coupling of formula (VI) amine, also can obtain these compounds.The preparation method of some ketone acids is known to those skilled in the art like this.
Can obtain formula (III) compound according to following flow process 3, in the formula: R
4=-C (O)-R
6, R
6Represent C
1-6Alkoxyl group.
Flow process 3
According to flow process 3, according to Takeda (" Bull.Chem.Soc.JP ", 1970, p.2997) improving one's methods of institute's described method allows the aldehyde of formula (VIII), R in the formula
5Define as the front, with the methyl dichloroacetate of formula (IX), R in the formula
6The C that representative is randomly replaced by phenyl
1-6Alkoxyl group, and for example sodium methylate or sodium ethylate react at 0 ℃, can obtain formula (III) compound.The product that obtains (X) and (XI) mixture in the presence of for example methyl alcohol or alcoholic acid, refluxed 4 or 8 hours, handle obtaining formula (III) compound with thiocarbamide.
According to condition known to those skilled in the art, above-claimed cpd, wherein R
6The C that representative is randomly replaced by phenyl
1-6Alkoxyl group can obtain formula (III) compound, R in the formula through hydrolysis
4=-C (O)-R
6, and R
6Representation hydroxy.
According to following flow process 4, can obtain formula (III) compound, R in the formula
5=-C (O)-R
6, and R
6Represent C
1-6Alkoxyl group.
Flow process 4
According to flow process 4, according to A.Barton and colleague thereof (" J.C.S Perkin I ", 1982, p.159) improving one's methods of institute's described method makes formula (XIII) β-ketone-ester bromination, R in the formula
6The C that representative is randomly replaced by phenyl
1-6Alkoxyl group obtains formula (XII) compound, then reacts with thiocarbamide, can obtain formula (III) compound like this.
According to L. Crombie and colleague thereof (" J.C.S Perkin Trans I ", 1987, p.323) improving one's methods of institute's described method, the dialkyl carbonate of the ketone of formula (XIV) and formula (XVI) reacts R in the formula
6The C that representative is randomly replaced by phenyl
1-6Alkoxyl group can obtain β-ketone-ester of formula (XIII).According to for example D.W.Brooks and colleague thereof (" Angew.Chem.Int.Ed. ", 1979, p.72) improving one's methods of institute's described method allows the malonic ester with carbonyl dimidazoles (CDI) activatory formula (XV) acid and formula (XVIa) react R in the formula
6The C that representative is randomly replaced by phenyl
1-6Alkoxyl group also can obtain β-ketone-ester of formula (XIII).
According to condition known to those skilled in the art, above-claimed cpd, R in the formula
6Represent C
1-6Alkoxyl group can obtain formula (III) compound, R in the formula through hydrolysis
5=-C (O)-R
6, and R
6Representation hydroxy.
Can obtain formula (III) compound, R in the formula according to flow process 5
4Or R
5Representative-C (O)-NR
7R
8Group.
Flow process 5
According to flow process 5, at HOBt for example with (EDAC HCl) exists down through type (XVII) compound, R in the formula
5Or R
4Representation carboxy and Pg represent blocking group, and for example Boc with the peptide coupling of formula (XVIII) compound, can obtain formula (III) compound.According to condition known to those skilled in the art, make the compound that so obtains go protection then.In anhydrous tetrahydro furan, in the presence of dimethyl aminopyridine, at room temperature pass through effect protection (III) compound of two carbonic acid, two-tert-butyl ester, R in the formula
4Or R
5Representative-C (O) R
6Group, and R
6Be the C that is randomly replaced by phenyl
1-6Alkoxyl group, then according to this carboxylicesters of condition hydrolysis known to those skilled in the art, for example in tetrahydrofuran (THF)/water mixture 7: 3 (v/v), under 60 ℃ of temperature, be hydrolyzed with lithium hydroxide, can obtain formula (XVII) compound like this, Pg represents Boc in the formula.
According to M.P.Cava and colleague thereof at " tetrahedron " (Tetrahedron), 1985, the similar approach described in is p.5061 used corresponding general formula (I) or (III) compound, R in the formula
4Or R
5Representative-C (X) R
6Group, and X=O for example adopts Lawesson reagent, and group C (O) is changed into group C (S), can prepare general formula (I) compound like this, R in the formula
4Or R
5Representative-C (X) R
6Group, and X=S.
In these flow processs 1-5, these initial compounds and reagent, particularly formula (III), (IV), (V), (VII), (VIII), (IX), (XIV), (XV), (XVI), (XVIa), (XVII) and (XVIII) compound, when not describing their preparation method, but all be obtain on the market or describe in the literature, maybe can adopt the method for wherein having described to prepare or known to those skilled in the art.
For example, according to D.A.Evans and colleague (" J.C.S., Chem.Comm. ", 1973, p.55) institute's described method improves one's methods, by the addition reaction of cyaniding trimethyl silyl and aldehyde, or according to I.Shinn and colleague thereof (" organic chemistry magazine " (J.Org.Chem.), 2000, p.7667) institute's described method improves one's methods, by the effect of Sodium Nitrite and alpha amino acid, can preparation formula (IV) compound, R in the formula
2Or R '
2Representation hydroxy.
For example, according to Sindel and colleague (" Collect.csech.chim.Tchecosl. ", 1982, p.72) or Atkison and colleague thereof (" J.Med.Chem. ", 1983, p.1353) institute's described method improves one's methods, can preparation formula (XV) compound, Y=O in the formula.
For example, for example according to Crow and colleague (" Austral.J.Chem. " thereof, 1981, p.1037) institute's described method improves one's methods, perhaps according to Chahen and colleague thereof (" Synlett ", 2003, p.1668) institute's described method improves one's methods, can preparation formula (XV) compound by Suzuki reaction, Y is-C in the formula
1-4Alkylidene group-class.
For example, according to Goldberg (" Chem.Ber. ", 1994, p.4526) described method can preparation formula (XV) compound, Y=S in the formula.
For example, according to Chane and colleague (" tetrahedron communication " (Tetrahedron Letters) thereof, 1998, p.2933) or Chamain (" tetrahedron communication ", 1998, p.4179) or Huwe and colleague's (" tetrahedron communication " thereof, 1999, p.683) described method can preparation formula (XV) compound, Y=N in the formula (W).
For example, according to condition known to those skilled in the art, for example (" synthesizing " (Synthesis) according to Deng and colleague thereof, 2003, p.337) or Meier and colleague (" synthesizing ", 2003, p.551) described method, can preparation formula (XV) compound by Suzuki reaction, Y is a singly-bound in the formula.
For example, according to condition known to those skilled in the art, can obtain formula (VIII) compound by reduction-type (XV) compound.
When a kind of functional group of compound is reactive, R for example
1When containing hydroxyl, before reaction, can protect in advance this functional group.Those skilled in the art should be able to be easy to determine the necessity of protection in advance.
Below these embodiment the preparation method of some compounds of the present invention has been described.These embodiment are not restrictive, and the present invention just is described.
The illustrative compound number listed numbering that sees the following form.Elemental microanalysis and NMR, IR or LC-MS (liquid chromatography and mass spectrometry) analyze the structure that confirms resultant compound.
Embodiment 1:
2-{2-(S)-[2-(3, the 5-difluorophenyl) acetylamino] pentanoyl } amino-5-[2-(4-fluorophenoxy) phenyl] thiazole 4-methyl-formiate (No. 13 compound)
Embodiment 1.1:2-(4-fluorophenoxy) phenylformic acid
At 200ml N, the mixture in the dinethylformamide slowly adds 100g salt of wormwood toward 120g 2-iodo-benzoic acid, 1g copper powder and 54.4g 4-fluoro phenol.At 160 ℃ of heating 4h, allow its cooling then, evaporate again.This residue is dissolved in the distilled water, carries out acidifying, use ethyl acetate extraction again with the 1N aqueous hydrochloric acid.This organic phase is washed with saturated nacl aqueous solution, uses anhydrous sodium sulfate drying, concentrates then.Desired product carries out crystallization in ether/pentane admixture.Obtain the 50g white solid.
LC/MS：MH
+＝233。
Embodiment 1.2:2-(4-fluorophenoxy)-O, the N-dimethyl benzamide
Toward at the resulting 50g 2-of step 1.1 (4-fluorophenoxy)-phenylformic acid at 450mlN, the solution in the dinethylformamide adds the 29.7g hydroxy benzotriazole hydrate, then add 37g (EDAC, HCl), (O, N-dimethyl hydroxyl amine is HCl) with the 19.4g N-methylmorpholine for 19g.At room temperature stir 16h.Evaporate, use acetic acid ethyl dissolution, use the saturated sodium-chloride water solution washed twice, with distilled water wash once, with the washing of 1M aqueous potassium hydrogen sulfate once, wash with saturated sodium-chloride water solution then.Use anhydrous sodium sulfate drying, concentrate then.Obtain the coloured oil of 49g, but its former state is used for subsequent step.
LC/MS：MH
+＝276
Embodiment 1.3:2-(4-fluorophenoxy) phenyl aldehyde
At 0 ℃,, drip 2-(4-fluorophenoxy)-O that 48.5g obtains in step 1.2, the mixture of N-dimethyl benzamide in the 300ml anhydrous tetrahydro furan toward the solution of 100ml 1M lithium aluminum hydride in tetrahydrofuran (THF).Stir 1h at 0 ℃, drip 40ml 1M aqueous potassium hydrogen sulfate then and be hydrolyzed.Evaporate, use acetic acid ethyl dissolution, use the 1M aqueous potassium hydrogen sulfate earlier, use the saturated sodium-chloride water solution washed twice again.Use anhydrous sodium sulfate drying, concentrate then.Obtain the coloured oil of 35g.
LC/MS：MH
+＝217
NMR?300MHz(CDCl
3)δppm：6.70-7.00(m，4H)；7.20-7.35(m，2H)；7.55(t，1H)；7.95(d，1H)；10.43(s，1H).
Embodiment 1.4:2-amino-5-[2-(4-fluorophenoxy) phenyl] thiazole 4-methyl-formiate
At the solution of 2-(4-fluorophenoxy) phenyl aldehyde in the 400ml ether that step 1.3 obtains, add the 30g methyl dichloroacetate toward 35g, drip the solution of 325ml sodium methylate (0.5M) in methyl alcohol then at 0 ℃.Behind 0 ℃ of following 1h, only boil off ether, and keep methyl alcohol, add 11g thiocarbamide, reheat backflow 6h.This reaction medium is evaporated to dried, uses acetic acid ethyl dissolution again, with the washing of 10% ammonium hydroxide aqueous solution, washs with saturated sodium-chloride water solution again.The organic phase anhydrous sodium sulfate drying concentrates then.This residue 100ml ether dissolution filters with fritted glass filter again.Obtain the 30g white solid.
LC/MS：MH
+～345
NMR 300MHz (CDCl3) δ ppm:3.70 (s, 3H); 5.55 (s is wide, 2H); 6.55-6.80 (m, 4H); 7.00 (d, 1H); 7.20 (t, 1H); 7.35-7.45 (m, 2H).
Embodiment 1.5:2-[2-(S)-pentanoyl amino] amino-5-[2-(4-fluorophenoxy)-phenyl] thiazole 4-methyl-formiate
2-amino-5-[2-(4-fluorophenoxy) phenyl that obtains in step 1.4 toward 8.6g] thiazole 4-methyl-formiate is at 200ml N, solution in the dinethylformamide, add 2.75g N-methylmorpholine, 14.30g PyBOP at 0 ℃, add 5.97g (S)-BocNorvaline again.Allow this reaction medium return room temperature, stir 16h then.After the evaporation, this residue acetic acid ethyl dissolution is used the saturated sodium bicarbonate aqueous solution washed twice, washes twice with water, with the washing of 1M aqueous potassium hydrogen sulfate once, washs with saturated sodium-chloride water solution again.The organic phase anhydrous sodium sulfate drying concentrates then.This residue separates with silica gel column chromatography, with ethyl acetate and 3: 7 (v/v) wash-outs of sherwood oil mixture.Obtain the 8.5g white solid.
LC/MS：MH
+＝544
NMR 300MHz (CDCl
3) δ ppm:0.88 (t, 3H); 1.38 (s, 9H); 1.39-1.55 (2m, 2H); 1.75 (m, 2H); 3.35 (s is wide, 1H); 3.68 (s, 3H); 4.28 (m, 1H); 5.65 (d, 1H); 6.80-6.90 (m, 5H); 7.10 (t, 1H); 7.20-7.32 (m, 2H).
6.5g the solution of the above-mentioned product that obtains in the 60ml trifluoroacetic acid at room temperature stirs 30min, evaporates then.This residue acetic acid ethyl dissolution is used the saturated aqueous sodium carbonate washed twice, washs with saturated sodium-chloride water solution again.The organic phase anhydrous sodium sulfate drying evaporates then, the 3.9g white solid.
LC/MS：MH
+＝444。
Embodiment 1.6:2-{2-(S)-[2-(3, the 5-difluorophenyl) acetylamino] pentanoyl } amino-5-[2-(4-fluorophenoxy) phenyl] thiazole 4-methyl-formiate
2-amino-2-[2-(the S)-pentanoyl amino that obtains at embodiment 1.5 toward 0.7g]-5-[2-(4-fluorophenoxy) phenyl] thiazole 4-methyl-formiate is at 30ml N; solution in the dinethylformamide; add 0.20g N-methylmorpholine, 0.99g PyBOP at 0 ℃; add 0.33g 3 again, the 5-difluorophenylacetic acid.Allow this reaction go back up to room temperature, and stir 18h.Evaporate this reaction medium.This residue acetic acid ethyl dissolution is used the saturated sodium bicarbonate aqueous solution washed twice, washes twice with water, with the washing of 1M aqueous potassium hydrogen sulfate once, washs with saturated sodium-chloride water solution then.The organic phase anhydrous sodium sulfate drying concentrates.This residue silica gel chromatography with 1: 1 (v/v) mixture of petrol ether/ethyl acetate wash-out, obtains the 0.56g white solid.
LC/MS：MH+＝558
The NMR that this tabular goes out (No. 13 compound)
Embodiment 2:
2-{2-(S)-[2-(S)-hydroxyl-(3, the 3-dimethyl) butyryl radicals amino] pentanoyl } amino-5-[2-(thiophenyl) 3-pyridyl] thiazole 4-methyl-formiate (No. 19 compound)
Embodiment 2.1:(2-thiophenyl)-and O, the N-dimethyl nicotinamide
According to obtaining (2-thiophenyl)-O, N-dimethyl nicotinamide with the described similar approach of the step 1.2 of embodiment 1.Use 20g 2-thiophenyl nicotinic acid, obtain the 21.9g water white oil, but its former state is used for subsequent step.
LC/MS：MH
+＝275
NMR 300MHz (CDCl
3) (s is wide, 3H) for δ ppm:3.35; 3.58 (s is wide, 3H); 7.35 (m, 3H); 7.50 (m, 2H); 7.60 (d, 2H); 8.40 (d, 1H)
Embodiment 2.2:(2-thiophenyl) cigarette aldehyde
According to obtaining (2-thiophenyl) cigarette aldehyde with the described similar approach of the step 1.3 of embodiment 1.(2-the thiophenyl)-O that uses 21.9g to obtain in step 2.1, N-dimethyl nicotinamide (Weinreb acid amides) and the solution of 48ml 1M lithium aluminum hydride in the 300ml tetrahydrofuran (THF) obtain the 16.6g white solid.
NMR?300MHz(CDCl
3)δppm：7.18(m，1H)；7.42(m，3H)；7.57(m，2H)；8.05(d，1H)；8.46(d，1H)；10.35(s，1H).
Embodiment 2.3:2-amino-5-[2-(thiophenyl)-3-pyridyl] thiazole 4-methyl-formiate
According to obtaining 2-amino-5-[2-(thiophenyl)-3-pyridyl with the described similar approach of the step 1.4 of embodiment 1] thiazole 4-methyl-formiate.(2-thiophenyl) the cigarette aldehyde that uses 16.5g to obtain in step 2.2,11.2g methyl dichloroacetate and the solution of 150ml 0.5M sodium methylate in the 300ml ether obtain the 19g faint yellow solid.
LC/MS：MH
+＝344
NMR 300MHz (DMSOd
6) (s is wide, 2H) for δ ppm:3.41; 3.60 (s, 3H); 7.20 (d is wide, 1H); 7.38-7.48 (m, 5H); 7.65 (d is wide, 1H); 8.30 (d is wide, 1H).
Embodiment 2.4:2-[2-(S)-pentanoyl amino] amino-5-[2-(thiophenyl) 3-pyridyl]-thiazole 4-methyl-formiate
According to obtaining 2-[2-(S)-pentanoyl amino with the described similar approach of the step 1.5 of embodiment 1] amino-5-[2-(thiophenyl) 3-pyridyl] thiazole 4-methyl-formiate.2-amino-5-[2-(the thiophenyl)-3-pyridyl that uses 5.14g to obtain at embodiment 2.3] thiazole 4-methyl-formiate, and 3.58g (S)-BocNorvaline, in the presence of 8.58g PyBOP and 1.66gN-methylmorpholine, at N, in the dinethylformamide and under 0 ℃, behind chromatogram purification, obtain the 3.5g faint yellow solid.
LC/MS：MH
+＝542
NMR?300MHz(DMSOd
6)δppm：0.87(t，3H)；1.45(s，9H)；1.70(m，2H)；197(m，2H)；3.72(s，3H)；4.45(m，1H)；5.23(m，1H)；7.10(m，1H)；7.30(m，3H)；7.42(m，2H)；7.50(d，1H)；8.39(d，1H).
The amine that 3.5g is obtained in front is dissolved in 150ml 4M hydrochloric acid 1, the solution in 4-dioxane and the 20ml methyl alcohol.At room temperature stir 1h30, evaporate then.Obtain the 3.2g faint yellow solid.
LC/MS：MH
+＝442
Embodiment 2.5:
2-{2-(S)-[2-(S)-hydroxyl-(3, the 3-dimethyl) butyryl radicals amino] pentanoyl } amino-5-[2-(thiophenyl) 3-pyridyl] thiazole 4-methyl-formiate
According to obtaining 2-{2-(S)-[2-(S)-hydroxyl-(3, the 3-dimethyl) butyryl radicals amino] pentanoyl with the described similar approach of the step 1.6 of embodiment 1 } amino-5-[2-(thiophenyl) 3-pyridyl] thiazole 4-methyl-formiate.2-[2-(the S)-pentanoyl amino that uses 0.9g to obtain in step 2.4] amino-5-[2-(thiophenyl) 3-pyridyl]-thiazole-4-methyl-formiate; and 0.25g (S)-2-hydroxyl-3; the 3-acid dimethyl; in the presence of 1g PyBOP and 0.59g N-methylmorpholine; at 90ml N, in the dinethylformamide, under 0 ℃; through silica gel chromatography, with 7: 3 (v: v) obtain the 0.5g white powder behind the wash-out of ethyl acetate/petroleum ether mixture.
LC/MS：MH
+＝557
The NMR that this tabular goes out (No. 19 compound)
Embodiment 3:
2-{2-(S)-[2-(3, the 5-difluorophenyl) acetylamino] pentanoyl } amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate (No. 5 compound)
Embodiment 3.1:2-amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4 methyl-formiates
According to the described similar approach of the step 1.2-1.4 of embodiment 1, use 26.6g 4-trifluoromethyl-2-biphenyl acid, can obtain 2-amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate.Use the lithium aluminum hydride Weinreb acid amides (28.2g) that this is sour to be reduced into aldehyde, obtain the 18.7g light yellow oil.In the presence of 144ml 0.5M sodium methylate, in the presence of the 4.7g thiocarbamide, in methyl alcohol, reflux then earlier, allow this aldehyde (18g) and 10.3g methyl dichloroacetate react.Obtain the 16g faint yellow solid.
LC/MS：MH
+＝379
Embodiment 3.2:
2-[2-(S)-pentanoyl amino] amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate
According to obtaining 2-[2-(S)-pentanoyl amino with the described similar approach of the step 1.5 of embodiment 1] amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate.2-amino-5-[2-that use 2.26g obtains at embodiment 3.1 (4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate, and 1.43g (S)-BocNorvaline, in the presence of 3.43g PyBOP and 0.66g N-methylmorpholine, at 120ml N, in the dinethylformamide and under 0 ℃, through silica gel chromatography, with 8: 2 (v: v) behind the wash-out, obtain the 2g faint yellow solid of petrol ether/ethyl acetate mixture.
LC/MS：MH
+＝578
NMR?300MHz(CDCl3)δppm：0.92(t，3H)；1.45(s，9H)；1.70(m，2H)；1.80(m，2H)；3.69(s，3H)；4.40(m，1H)；5.10(m，1H)；6.98(m，4H)；7.27(m，2H)；7.32(d，2H)。
Then, according to embodiment 1.5 described methods, use the 50ml trifluoroacetic acid to make the compound that obtains go protection.Obtain 1g white foam thing.
LC/MS：MH
+＝478
Embodiment 3.3:
2-{2 (S)-[2-(3, the 5-difluorophenyl) acetylamino] pentanoyl } amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate
According to the described similar approach of the step 1.6 of embodiment 1, can obtain 2-{2 (S)-[2-(3, the 5-difluorophenyl) acetylamino] pentanoyl } amino-5-[2-(4 '-trifluoromethyl) xenyl] thiazole 4-methyl-formiate.2-[2-(the S)-pentanoyl amino that uses 0.94g to obtain in step 3.2] amino-5-[2-(4 '-trifluoromethyl) xenyl]-thiazole 4-methyl-formiate; with 0.18g 3; the 5-difluorophenylacetic acid; in the presence of 0.55g PyBOP and 0.11g N-methylmorpholine; at 50ml N, in the dinethylformamide under 0 ℃, through silica gel chromatography; behind 7: 3 (v:v) wash-outs of ethyl acetate/petroleum ether mixture, obtain the 0.45g white powder.
LC/MS：MH
+＝632
The NMR that this tabular goes out (No. 5 compound)
Following table has illustrated the chemical structure and the physicals of several The compounds of this invention examples.
In this table:
-hurdle " R
3" and " R
2, R
2' " in (S) or (R) be illustrated in the formula (I) R arranged
3Or R
2The stereochemistry of asymmetric carbon.For R is arranged
2Carbon, indication (S) or (R) do not relate to wherein R
2And R
2' constitute the situation of oxo group together;
-MH+ is to adopt LC-MS to measure by the protonated compound quality value of hydrogen atom (this compound quality+1).
These compounds of the present invention are pharmacology test objects, and these tests show their meanings as therapeutic active substance.
Them have been tested especially to producing the beta-amyloid peptide (restraining effect of β-A4).
(β-A4) is a bigger precursor protein fragment that is referred to as APP (precursor protein of amyloid) to beta-amyloid peptide.Its latter produces in the different cells of animal or human body tissue and exists.Yet the enzyme with protease in cerebral tissue makes its cracking cause generating β-A4 peptide, and it accumulates with the amyloid sheet.Two kinds of proteolytic enzyme that are easy to produce amyloid peptide are referred to as β and gamma-secretase (secr é tases) (Wolfe MS, the Secretases target of alzheimer's disease: identify and treatment possibility, " J.Med.Chem. ", 2001,44 (13): 2039-60).
Yet prove that it is neurotoxic that this β-A4 peptide deposits gradually, also may play an important role in alzheimer's disease.
Therefore, compound of the present invention, (β-A4) produces inhibitor as beta-amyloid peptide by the restraining effect of gamma secretase, can be used for the treatment of disease, for example old stupid disease, alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid vascular disease and/or cerebrovascular disease, frontotemporal dementia and Pick's disease, post-traumatic dementia, disease, Huntington Chorea and the Korsakov syndromes relevant with neural inflammatory process.
These tests have been carried out according to the scheme that describes below.
For the test cell line of amyloid beta, the CT100 of coexpression APP and the clone CHO-K1 of PS1 M146L clone 30-12 have been used.The restraining effect of this clone aiming gamma secretase.Relevant (the Wolfe MS of this senilism with the activity of gamma secretase, Haass C., the effect (" J.Biol.Chem. " of senilism in the gamma secretase activity, 2001,276 (8): 5413-6), the albumen coexpression of it and amyloid or its N-terminal fragment cause peptide A1-42 (β-A4) secretion increases, and therefore produces a kind of pharmacy instrument, it can bounds evaluation (I) compound to producing the restraining effect of peptide β-A4.In 150 μ l developing mediums, 1 * 105 cell is arranged according to each hole, inoculate 96 well culture plates.At 5%CO
2Exist down, after 2-3 hour, have the serum of minimum percentage (1.3% is last) cell adhesion may occur on plastics 37 ℃ of cultivations.Tested these products (15 μ l) with last 1%10 μ M DMSO, these products are at 5%CO
2Exist down with 100% humidity, cultivated 24-25 hour at 37 ℃.After cultivating 24-25h like this, the supernatant liquor (100 μ l) that will contain cell is transferred in the elisa plate, with capture antibody 6E10 (6E10, epi-position: aa1-17, INTERCHIM/SENETEK 320-10) handles, so that determine the ratio of the amyloid peptide of these emiocytosises in the presence of The compounds of this invention.Handle with 5 and 10ng/ml synthetic certain limit control peptide " peptide 1-40 " simultaneously.These elisa plates are cultivated a night down at 4 ℃.
Corresponding to truncated peptide, detect fixedly peptide amount under the competitor of the peptide 1-28 that is connected with vitamin H exists indirectly, and vitamin H adopts the streptavidin that is connected with alkaline phosphatase to detect again.Substrate, p-nitrophenyl phosphoric acid ester (pNPP FAST p-nitrophenyl phosphoric acid ester, Sigma N2770) is given in the faint yellow soluble reaction product of 405nm.Use 0.1MEDTA solution to stop its reaction.For this reason, after amyloid peptide was fixed in elisa plate, the peptide 1-28 that 50 μ l is contained vitamin H added in the celliferous supernatant liquor of 100 μ l, at room temperature cultivates 30 minutes.These elisa plates wash three times again.And with after the thieving paper drying, 100 μ l streptavidin-alkaline phosphatases (Interchim/JacksonImmunoResearch Laboratories 016-050-084) are added in each hole, at room temperature cultivate 1 hour again.These plates wash again, then, according to every hole 100 μ l add alkaline phosphatase substrate (pNPP, 1mg/ml).After at room temperature cultivating 30 minutes, every hole is added 0.1M EDTA solution and is stopped its reaction, carries out reading at 405nm.
Formula (I) compound that activity of the present invention is the strongest shows that CE50 (50% effective concentration) is lower than 500nM, more particularly is lower than 100nM.For example this table No. 13 compound shows that CE50 is 6nM.
These biological tests are the result show, these compounds are beta-amyloid peptide (formation inhibitors of β-A4).
Therefore, these compounds can be used for the treatment of wherein beta-amyloid peptide (β-A4) the peptide formation inhibitor can be brought into play the disease of result of treatment.Especially, some diseases is old stupid disease, alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid vascular disease, cerebrovascular disease, frontotemporal dementia and Pick's disease, post-traumatic dementia like this, the disease relevant with neural inflammatory process, Huntington Chorea and Korsakov syndromes.
The purposes for preparing the The compounds of this invention of the medicine that is used for the treatment of above-mentioned disease is an integral part of the present invention.
A further object of the invention is a medicine, and they contain formula (I) compound, or this compound with at the additive salt of pharmaceutically acceptable acid or the hydrate or the solvate of formula (I) compound.These medicines have use in treatment, in the above-mentioned disease of treatment use is arranged especially.
According to it on the other hand, the present invention relates to pharmaceutical composition, they contain at least a compound of the present invention as active ingredient.These pharmaceutical compositions contain the compound of the present invention of effective dose, or described compound at pharmacy acceptable salt, hydrate or solvate, and randomly one or more at pharmaceutically acceptable vehicle.
According to the administering mode of pharmaceutical dosage form and expectation, described vehicle is selected from common vehicle known to those skilled in the art.
In mouth, hypogloeeis, subcutaneous, intramuscular, intravenously, outside, part, tracheae, in the nose, in the pharmaceutical composition of the present invention of skin or rectal administration, the active ingredient of above-mentioned formula (I), its optional salt, solvate or hydrate, with with common drug excipient blended administration unit dosage, animal and human's administration be can give, above-mentioned obstacle or disease are used to prevent or treat.
Suitable administration unit dosage comprises oral dosage form, for example tablet, soft or hard capsule, pulvis, granule, chewing gum and oral liquid or outstanding mixture, the hypogloeeis, contain in the clothes, tracheae, in the intraocular, nose, inhalation formulation, subcutaneous, intramuscular or intravenous administration formulation and rectum or vagina administration formulation.For partially coated, can use the The compounds of this invention of cream, ointment or lotion shape.
As an example, the tablet administration unit dosage of The compounds of this invention can contain following component:
The compounds of this invention 50.0mg
N.F,USP MANNITOL 223.75mg
Croscarmellose sodium 6.0mg
W-Gum 15.0mg
Hydroxypropyl-methylcellulose gum 2.25mg
Magnesium Stearate 3.0mg
In order to reach desirable prevention or result of treatment, active ingredient dosage can be every kg body weight 0.1-200mg every day.Although these dosage are examples of generalized case, the suitably high or lower particular case of dosage is arranged, some dosage also belong to the present invention like this.According to general practice, the suitable dose that the doctor determines described patient according to administering mode, described patient's body weight and reaction.
Each unitary dose can contain 0.1-1000mg, preferably the active ingredient of 0.1-500mg and one or more drug excipients combination.This unitary dose can the administration every day 1-5 time, so that a day dosage is 0.5-5000mg, preferably 0.5-2500mg.
According to others, point out the treatment of diseases method above the invention still further relates to, this method comprises compound of the present invention, described compound is in the administration of pharmacy acceptable salt or hydrate.
Claims (11)
1. the compound that meets following general formula (I):
In the formula:
R
1Representative:
Perhaps C
1-6Alkyl, it is randomly by 1-3 substituting group replacement, C that is selected from halogen, trifluoromethyl, hydroxyl
1-6Alkoxyl group, C
1-6Alkylthio, thienyl or phenyl; Perhaps C
3-7Cycloalkyl, thienyl, benzothienyl, pyridyl, furyl or phenyl; Described phenyl randomly is selected from halogen atom, C by 1-3
1-6Alkyl, C
1-6The substituting group of alkoxyl group, hydroxyl, methylene-dioxy, phenoxy group or benzyloxy or trifluoromethyl replaces;
R
2And R '
2Represent hydrogen atom, halogen atom, hydroxyl, C each other alone
1-3Alkoxyl group, C
1-3Alkyl, C
3-7Cycloalkyl, O-C (O)-C
1-6Alkyl, or R
2And R '
2Constitute oxo group together;
R
3Represent hydrogen atom, C
1-6Alkyl, it is randomly by hydroxyl, C
1-6Cycloalkyl or C
1-3Alkoxyl group replaces;
R
4Or R
5In one or another represent following Z group:
And R
4Or R
5In one or another representative-C (X) R
6Group;
G represent singly-bound or-CH
2-group;
Y represents singly-bound, Sauerstoffatom, sulphur atom, C
1-4Alkylidene group or-N (W)-group ,-C
1-4Alkylidene group is randomly by hydroxyl or C
1-3Alkoxyl group replaces;
W representative or hydrogen atom, perhaps C
1-3Alkyl, it is randomly replaced by phenyl, perhaps phenyl;
A and B represent hydrogen atom, halogen atom, oh group, C each other by oneself
1-3Alkyl, C
1-3Alkoxyl group, trifluoromethyl, trifluoromethoxy or-O-CHF
2If its condition is if Y is that singly-bound or Sauerstoffatom are following types with the Z group:
And A is not a hydrogen atom;
X represention oxygen atom or sulphur atom;
R
6Represent C
1-6Alkoxyl group, hydroxyl or-NR
7R
8Group; C
1-6Alkoxyl group is randomly replaced by phenyl;
R
7And R
8Solely represent each other directly:
Perhaps hydrogen atom; Perhaps C
1-6Alkyl, it is randomly by C
3-7Cycloalkyl, C
3-7Cycloalkenyl group, C
1-3Alkoxyl group, phenyl, morpholinyl or pyridyl replace; Perhaps C
3-7Cycloalkyl, C
1-6Alkoxyl group or phenyl; Described C
3-7Cycloalkyl and phenyl randomly are selected from halogen atom, oh group, C by one or two
1-3Alkyl or C
1-3The group of alkoxyl group replaces; Or
R
7And R
8Nitrogen-atoms with their bands constitutes 1-azacyclopropane, azetidine, tetramethyleneimine, piperidines, morpholine or benzo piperidine ring,
Above-claimed cpd be alkali, with acid additive salt, hydrate or solvation form.
2. compound according to claim 1 is characterized in that R
1Represent C
1-6Alkyl or randomly by 1-3 halogen atom substituted-phenyl; This compound be alkali, with acid additive salt, hydrate or solvation form.
3. formula according to claim 1 and 2 (I) compound is characterized in that R
2And R '
2Represent hydrogen atom, hydroxyl each other alone, or R
2And R '
2Constitute oxo group together; This compound be alkali, with acid additive salt, hydrate or solvation form.
4. according to the described formula of each claim (I) compound among the claim 1-3, it is characterized in that R
3Represent C
1-6Alkyl; This compound be alkali, with acid additive salt, hydrate or solvation form.
5. according to the described formula of each claim (I) compound among the claim 1-4, it is characterized in that R
4Or R
5In one or another represent the Z group:
And R
4Or R
5In one or another representative-C (X) R
6Group;
G represents singly-bound;
Y represents singly-bound, Sauerstoffatom, sulphur atom, C
1-4Alkylidene group;
A and B represent hydrogen atom, halogen atom, trifluoromethyl, trifluoromethoxy each other by oneself; If its condition is if Y is that singly-bound or Sauerstoffatom are following types with the Z group:
And A is not a hydrogen atom;
X represention oxygen atom or sulphur atom;
R
6Represent C
1-6Alkoxyl group;
Above-claimed cpd be alkali, with acid additive salt, hydrate or solvation form.
6. according to the preparation method of the described formula of each claim (I) compound among the claim 1-5, the method comprising the steps of is to allow the 2-amino-thiazolyl-of following formula (III):
Carry out the peptide coupling with following formula (II) acylamino acid:
R in the formula
1, R
2, R '
2, R
3, R
4, R
5Limit as the described formula of each claim (I) among the claim 1-5.
7. according to the preparation method of the described formula of each claim (I) compound among the claim 1-5, the method comprising the steps of is to allow following formula (IV) compound:
Carry out the peptide coupling with following formula (VI) amine:
R in the formula
1, R
2, R '
2, R
3, R
4, R
5Limit as the described formula of each claim (I) among the claim 1-5.
8. medicine is characterized in that it contains the described formula of each claim (I) compound among the with good grounds claim 1-5, and it is in pharmaceutically acceptable alkali, salt, hydrate or solvation form.
9. pharmaceutical composition, it contains at least a according to the described formula of each claim (I) compound among the claim 1-5, it is in pharmaceutically acceptable alkali, salt, hydrate or solvation form and chooses any one kind of them or multiple at pharmaceutically acceptable vehicle.
10. according to the described formula of each claim (I) compound among the claim 1-5, it is in pharmaceutically acceptable alkali, salt, hydrate or solvation form, be used for the treatment of purposes in the medicine of disease in preparation, wherein: beta amyloid protein peptide β-A4 formation inhibitor has result of treatment.
11. according to the described formula of each claim (I) compound among the claim 1-5, it is in pharmaceutically acceptable alkali, salt, hydrate or solvation form, is used for the treatment of purposes in the medicine of following disease in preparation: old stupid disease, alzheimer's disease, Down's syndrome, Parkinson's disease, amyloid vascular disease, cerebrovascular disease, frontotemporal dementia and Pick's disease, post-traumatic dementia, disease, Huntington Chorea and/or the Korsakov syndromes relevant with neural inflammatory process.
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| FR0408115A FR2873370B1 (en) | 2004-07-22 | 2004-07-22 | ACYLAMINOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| FR0408115 | 2004-07-22 | ||
| PCT/FR2005/000032 WO2005073226A1 (en) | 2004-01-16 | 2005-01-07 | Acylaminothiazole derivatives, preparation method thereof and use of same in therapeutics |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20000069075A (en) * | 1996-11-22 | 2000-11-25 | 진 엠. 듀발 | N-(Aryl/Heteroaryl/Alkylacethyl)Amino Acid Amides, Pharmaceutical Compositions Comprising Same, and Methods for Inhibiting Beta-Amyloid Peptide Release and/or its Synthesis by Use of Such Compounds |
| GB9818621D0 (en) * | 1998-08-26 | 1998-10-21 | Glaxo Group Ltd | Formamide compounds as therapeutic agents |
| WO2000024392A1 (en) * | 1998-10-26 | 2000-05-04 | Sumitomo Pharmaceuticals Company, Limited | β-AMYLOID FORMATION INHIBITORS |
| AR039059A1 (en) * | 2001-08-06 | 2005-02-09 | Sanofi Aventis | COMPOUND DERIVED FROM ACILAMINOTIAZOL, ITS USE, PROCEDURES TO PREPARE IT, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT, AND INTERMEDIARY COMPOUNDS |
| FR2842523A1 (en) * | 2002-07-17 | 2004-01-23 | Sanofi Synthelabo | ACYLAMINOTHIAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
| KR20050070046A (en) * | 2002-10-09 | 2005-07-05 | 화이자 프로덕츠 인크. | Thiazole compounds for the treatment of neurodegenerative disorders |
-
2004
- 2004-01-16 FR FR0400387A patent/FR2865206B1/en not_active Expired - Fee Related
-
2005
- 2005-01-07 ZA ZA200605824A patent/ZA200605824B/en unknown
- 2005-01-07 CN CN2005800050955A patent/CN1930155B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| FR2865206B1 (en) | 2009-02-06 |
| ZA200605824B (en) | 2008-05-28 |
| CN1930155B (en) | 2011-06-08 |
| FR2865206A1 (en) | 2005-07-22 |
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