CN100378075C - Aniline derivative using as phosphodiesterase 4 inhibitor - Google Patents

Aniline derivative using as phosphodiesterase 4 inhibitor Download PDF

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CN100378075C
CN100378075C CNB028070100A CN02807010A CN100378075C CN 100378075 C CN100378075 C CN 100378075C CN B028070100 A CNB028070100 A CN B028070100A CN 02807010 A CN02807010 A CN 02807010A CN 100378075 C CN100378075 C CN 100378075C
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CN1498211A (en
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艾伦·霍珀
理查德·A·舒马克
阿肖克·泰姆
迈克尔·德维沃
小威廉·弗雷德里克·布鲁贝克
刘瑞平
汉斯-于尔根·厄恩斯特·埃斯
阿谢尔·翁特贝克
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Memory Pharmaceuticals Corp
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Abstract

PDE4 inhibition is achieved by novel compounds, e.g., N-substituted aniline and diphenylamine analogs. The compounds of the present invention are of Formula I: wherein R<1>, R<2>, R<3 >and R<4 >are as defined herein.

Description

Anils as phosphodiesterase 4 inhibitors
The right of priority of the U.S. Provisional Application 60/262,651 that the application requires to submit to January 22 calendar year 2001, the U.S. Provisional Application 60/267,196 that submit to February 8 calendar year 2001 and the U.S. Provisional Application 60/306,140 submitted to July 14 calendar year 2001.
Technical field
Generally speaking, the present invention relates to phosphodiesterase 4 (PDE 4) enzyme and suppress the field.More particularly, the present invention relates to by new compound, the selectivity PDE 4 that aniline that replaces as N-and pentanoic analogue carry out suppresses, and is used to prepare the method for these compounds, contains these compound compositions, and their using method.
Background technology
Cyclic nucleotide specific phosphodiesterase enzyme (PDEs) is represented the enzyme of the hydrolysis of the various phosphoric acid nucleolus glycosides (comprising cAMP and cGMP) of a class catalysis.These cyclic nucleotides are brought into play second messenger's effect in cell, and carry the pulse of the cell surface receptor that combines various hormones and neurotransmitter of controlling oneself as the courier.PDEs passes through these monocycle Nucleotide of degraded, causes the courier who stops them to act on and the level of the interior cyclic nucleotide of performance adjusting cell and the effect of retaining ring Nucleotide stable state.
Can be according to they specificitys to the hydrolysis of cAMP or cGMP, the susceptibility that they are regulated calcium, calmodulin or cGMP, and their situations about being suppressed by all cpds selectivity can be divided into the PDE enzyme 11 classes.For example, PDE1 is subjected to Ca 2+/ calmodulin stimulates.PDE2 is that cGMP is dependent, and is found in heart and the suprarenal gland.PDE3 is that cGMP is dependent, and the inhibition of this enzyme produces positive variable force activity.PDE4 is that cAMP is specific, and its inhibition causes that air flue is loose, anti-inflammatory and antidepressant activity.As if PDE5 is important aspect the cGMP content in regulating vascular smooth muscle, thereby the PDE5 inhibitor may have cardiac vascular activity.Because PDEs has unique biochemical property, therefore may they experience multiple multi-form adjusting.
The difference of PDE 4 is various kinetic properties, comprises to the low Michaelis-Menton constant of cAMP with to the susceptibility of some drugs.The PDE4 enzyme is by four kinds of genomic constitutions, these four kinds of genes produce 4 kinds of isoforms of the PDE4 enzyme that is called PDE4A, PDE4B, PDE4C and PDE4D [referring to people such as Wang, Expression, Purification, andCharacterization of human cAMP-Specific Phosphodiesterase (PDE 4) Subtypes A, B, C, and D, Biochem.Biophys.Res.Comm., 234,320-324 (1997)].In addition, the various splice variants of each PDE4 isoform have obtained identifying.
The PDE4 isozyme is arranged in the cytosol of cell, and does not associate with any known membrane structure.The PDE4 isozyme is hydrolyzed into adenosine 5 '-a phosphoric acid (AMP) by catalysis cAMP and with its specifically inactivating.CAMP is active to be adjusted in many bioprocesss, comprises that in inflammation and the memory be important.PDE4 isozyme inhibitor such as rolipram, Piclamilast, CDP-840 and ariflo are strong antiphlogistons, thereby can be used for the treatment of disease such as asthma or the sacroiliitis that the inflammation problem is arranged.And rolipram improves the cognitive ability of rat and mouse in learning model.
The rolipram Piclamilast
Except these compounds as rolipram, xanthine derivative such as pentoxifylline, denbufylline and theophylline suppress PDE 4, and have caused suitable concern because of its cognitive raising effect recently.CAMP is to regulate the second messenger of cell to many different hormones and neurotransmitter reaction with cGMP.Therefore, PDE suppresses and consequent key cells, as is in the cell of cell at neural system and other position of body cAMP or cGMP and increases may cause vital role on therapeutics.
Rolipram as thymoleptic in the exploitation in the past optionally suppresses the PDE4 enzyme, and has become the standard reagent of PDE enzyme hypotype classification.The early stage work in PDE4 field concentrates on depression and inflammation, extended to the indication that comprises such as dementia subsequently [referring to " The PDE IV Family Of Calcium-Phosphodiesterases Enzymes ", JohnA.Lowe, people such as III, Drugs of the Future 1992,17 (9): 799-807, summary].Other clinical development of rolipram and other first-generation PDE 4 inhibitor are owing to the side effect of these compounds stops.Major side effects in primates is vomiting, and the major side effects in rodent is testis degranulation, vascular smooth muscle reduction, mentation, gastric acid secretion increasing and stomach erosion.
Summary of the invention
The present invention relates to new compound, as aniline and the bisaniline compounds that new N-replaces, described compound suppresses PDE 4 enzymes, particularly improves the side effect feature, does not for example relatively have emetic property (for example, comparing with prior art compound previously discussed).Preferably, this compound selective ground suppresses PDE 4 enzymes.Compound of the present invention enters cell, particularly neural cell simultaneously easily.
And, the invention provides and have this activity and the synthetic method of compound optionally, and treatment needs PDE to suppress, the patient that suppresses of PDE 4 particularly, Mammals for example, the illness that PDE 4 levels raise or the cAMP level reduces in the cell that relates to that comprises the people, for example relate to nervous syndrome, particularly with dysmnesia, the method (with the corresponding pharmaceutical compositions that is used for this treatment) of the relevant illness of long-term memory obstacle the most particularly, wherein this dysmnesia partly are to cause owing to PDE 4 enzymes cause the katabolism of cAMP level in the cell, and perhaps wherein this dysmnesia can be improved by effective inhibition PDE 4 enzymic activitys.
One preferred aspect, compound of the present invention improves these diseases by suppress PDE 4 enzymes under the dosage of not inducing vomiting.
The present invention includes compound and the pharmacologically acceptable salts thereof of formula I:
Wherein:
R 1For having the alkyl of 1～4 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many (as CH by halogen 3, CHF 2, CF 3Deng);
R 2For having 1～12, the alkyl of preferred 1～8 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, hydroxyl, cyano group, C 1～4-alkoxyl group, oxygen or their combination, and wherein choose one or more-CH wantonly 2CH 2-group in each case by-CH=CH-or-C ≡ C-replaces (as CH 3, CHF 2, CF 3, methoxy ethyl etc.),
Have 3～10, the cycloalkyl of preferred 3～8 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, hydroxyl, oxygen, cyano group, have 1～4 carbon atom alkyl, have the alkoxyl group of 1～4 carbon atom or their combination (as cyclopentyl)
Have 4～16, the cycloalkylalkyl of preferred 4～12 carbon atoms, it is not substituted or is replaced one or many at cycloalkyl moiety and/or moieties by following group: halogen, oxygen, cyano group, hydroxyl, C 1～4-alkyl, C 1～4-alkoxyl group, or their combination (as cyclopentyl-methyl, cyclopropyl methyl etc.),
Aryl with 6～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, CF 3, OCF 3, alkyl, hydroxyl, alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, cyano group, or their combination (as aminomethyl phenyl, p-methoxy-phenyl, chloro-phenyl-etc.),
Arylalkyl, wherein aryl moiety has 6～14 carbon atoms, and moieties is side chain or non-side chain, has 1～5 carbon atom, described arylalkyl is not substituted or is replaced one or many at aryl moiety by following group: halogen, CF 3, OCF 3, alkyl, hydroxyl, alkoxyl group, nitro, cyano group, methylene-dioxy, ethylenedioxy, or their combination, and wherein in moieties, one or more-CH 2CH 2The optional separately quilt-CH=CH-of-group or-C ≡ C-replacement, and one or more-CH 2The optional separately quilt-O-of-group or-the NH-replacement, and/or moieties is optional by halogen, oxygen, hydroxyl, cyano group, or their combination replaces (as styroyl, hydrocinnamyl, benzene butyl, anisole ethyl, anisole propyl group, chlorobenzene ethyl, chlorobenzene propyl group, styryl, benzene oxygen ethyl, benzene oxygen-butyl, chlorobenzene oxygen ethyl, chloro-phenyl-amino-ethyl etc.)
Part unsaturated carbon cyclic group with 5～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, alkyl, alkoxyl group, hydroxyl, nitro, cyano group, oxygen, or their combination (as cyclohexenyl, cyclohexadienyl, indanyl, naphthane methyne etc.)
Heterocyclic radical, it is saturated, fractional saturation or undersaturated, have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, it is not substituted or is replaced one or many by following group: halogen, hydroxyl, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, or their combination (as 3-thienyl, 3-tetrahydrofuran base, 3-pyrryl etc.), perhaps
Heterocyclylalkyl, wherein heterocyclic moiety is saturated, fractional saturation or undersaturated, and have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, and moieties is side chain or non-side chain, and having 1～5 carbon atom, described Heterocyclylalkyl is not substituted or is replaced one or many at heterocyclic moiety by following group: halogen, OCF 3, hydroxyl, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, or their combination, wherein in moieties, one or more-CH 2CH 2The optional separately quilt-CH=CH-of-group or-C ≡ C-replacement, and one or more-CH 2The optional separately quilt-O-of-group or-NH-replaces, and/or moieties is optional by halogen, oxygen, hydroxyl, cyano group, or their combination replacement (as pyridyl ethyl, pyridyl propyl group, methylpiperazine base ethyl etc.);
R 3Be H,
Have 1～8, the alkyl of preferred 1～4 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, cyano group, C 1～4-alkoxyl group, or their combination (as methyl, ethyl, propyl group etc.),
Part unsaturated carbon cycloalkyl, wherein isocyclic part has 5～14 carbon atoms, and moieties is side chain or non-side chain, has 1～5 carbon atom, and be not substituted or replaced one or many by following group: halogen, alkyl, alkoxyl group, nitro, cyano group, oxygen at isocyclic part, or their combination, and moieties is optional by halogen, C 1～4-alkoxyl group, cyano group, or their combination replaces (as the cyclohexenyl methyl etc.),
Arylalkyl with 7～19 carbon atoms, wherein aryl moiety has 6～14 carbon atoms, and moieties is side chain or non-side chain, has 1～5 carbon atom, and described arylalkyl is not substituted or is replaced one or many at aryl moiety by following group: halogen, trifluoromethyl, CF 3O, nitro, amino, alkyl, alkoxyl group, alkylamino, dialkyl amido, and/or at moieties by halogen, cyano group or methyl substituted (as benzyl, styroyl, hydrocinnamyl, methyl-benzyl, methoxy-benzyl, trifluoromethyl, benzyl, (methylenedioxy) benzyl etc.), perhaps
Heteroarylalkyl, wherein heteroaryl moieties can be partly or entirely saturated, and have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, moieties is side chain or non-side chain, have 1～5 carbon atom, described heteroarylalkyl is not substituted or is replaced one or many at heteroaryl moieties by following group: halogen, alkyl, alkoxyl group, cyano group, trifluoromethyl, CF 3O, nitro, oxygen, amino, alkylamino, dialkyl amido, or their combination, and/or at moieties by halogen, cyano group or methyl, or their combination replaces (as pyridylmethyl, pyridyl propyl group, picoline ylmethyl, chloropyridine ylmethyl, dichloropyridine ylmethyl, thienyl methyl, thiazolyl methyl, quinolyl methyl, isoquinolyl methyl, piperidino methyl, furyl methyl, imidazolyl methyl, Methylimidazole ylmethyl, pyrryl methyl etc.);
R 4Be H,
Aryl with 6～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, OCF 3, amino, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl (as methylol), hydroxamic acid, tetrazolium-5-base, 2 (heterocycle) tetrazolium-5-base (as 2-(2-THP trtrahydropyranyl) tetrazolium-5-yl), hydroxy alkoxy base, carboxyl, carbalkoxy (as tertbutyloxycarbonyl, ethoxycarbonyl), cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl, phenoxy group, trialkylsiloxy (as the t-butyldimethylsilyloxy base), R 5-L-, or their combination (as is substituted or unsubstituted phenyl, naphthyl and xenyl, as phenyl, aminomethyl phenyl, chloro-phenyl-, fluorophenyl, ethenylphenyl, cyano-phenyl, methylene dioxy phenyl group, ethylphenyl, dichlorophenyl, carboxyl phenyl, carbethoxy phenyl, 3,5-dimethylphenyl, hydroxymethyl phenyl, nitrophenyl, aminophenyl etc.), perhaps
Heteroaryl with 5～10 annular atomses; wherein at least one annular atoms is a heteroatoms, and it is not substituted or is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; the alkoxyl group alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; trifluoromethyl; amino; amino methyl; aminoalkyl group; aminoalkoxy; dialkyl amido; hydroxyalkyl (as methylol); hydroxamic acid; tetrazolium-5-base; the hydroxy alkoxy base; carboxyl; carbalkoxy is (as tertbutyloxycarbonyl; ethoxycarbonyl); cyano group; acyl group; alkylthio; the alkyl sulfinyl; alkyl sulphonyl; phenoxy group; trialkylsiloxy (as the t-butyldimethylsilyloxy base); R 5-L, or their combination (as pyridyl, thienyl, pyrazinyl, quinolyl, isoquinolyl, pyrimidyl, imidazolyl, thiazolyl etc.);
R 5Be H,
Have 1～8, the alkyl of preferred 1～4 carbon atom, it is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen, or their combination (as methyl, ethyl, propyl group etc.),
Alkylamino or dialkyl amido, wherein each moieties has 1～8 independently, preferred 1～4 carbon atom (as dimethylamino etc.),
Part unsaturated carbon cycloalkyl, wherein isocyclic part has 5～14 carbon atoms, and moieties has 1～5 carbon atom, it is not substituted or is preferably replaced one or many at isocyclic part by following group: halogen, alkyl, alkoxyl group, nitro, cyano group, oxygen, or their combination (as cyclohexenyl methyl etc.)
Have 3～10, the cycloalkyl of preferred 3～8 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, hydroxyl, oxygen, cyano group, alkoxyl group, have the alkyl of 1～4 carbon atom, or their combination (as cyclopentyl etc.),
Have 4～16, the cycloalkylalkyl of preferred 4～12 carbon atoms, it is not substituted or is replaced one or many at cycloalkyl moiety and/or moieties by following group: halogen, oxygen, cyano group, hydroxyl, alkyl, alkoxyl group, or their combination (as cyclopentyl-methyl, cyclopropyl methyl etc.)
Aryl with 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; the alkoxyl group alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; trifluoromethyl; amino; amino methyl; aminoalkyl group; aminoalkoxy; dialkyl amido; hydroxyalkyl (as methylol); hydroxamic acid; tetrazolium-5-base; the hydroxy alkoxy base; carboxyl; carbalkoxy is (as tert-butoxycarbonyl; ethoxy carbonyl); cyano group; acyl group; alkylthio; the alkyl sulfinyl; alkyl sulphonyl (as is substituted or unsubstituted phenyl and naphthyl; aminomethyl phenyl; chloro-phenyl-; fluorophenyl; ethenylphenyl; cyano-phenyl; methylene dioxy phenyl group; ethylphenyl; dichlorophenyl; carboxyl phenyl; carbethoxy phenyl; 3,5-dimethylphenyl; hydroxymethyl phenyl; nitrophenyl; aminophenyl etc.); arylalkyl with 7～19 carbon atoms; wherein aryl moiety has 6～14 carbon atoms; and moieties is side chain or non-side chain; have 1～5 carbon atom, described arylalkyl is not substituted or is replaced one or many at aryl moiety by following group: halogen; trifluoromethyl; CF 3O, nitro, amino, alkyl, alkoxyl group, amino, alkylamino, dialkyl amido, and/or at moieties by halogen, cyano group or methyl substituted (as benzyl, styroyl, hydrocinnamyl, methyl-benzyl, methoxy-benzyl, trifluoromethyl benzyl, (methylenedioxy) benzyl etc.)
Heterocyclic radical; it is saturated; fractional saturation or undersaturated; have 5～10 annular atomses; wherein at least one annular atoms is N; O or S atom; it is not substituted or is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; the alkoxyl group alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; trifluoromethyl; amino; amino methyl; aminoalkyl group; aminoalkoxy; dialkyl amido; hydroxyalkyl (as methylol); hydroxamic acid; tetrazolium-5-base; the hydroxy alkoxy base; carboxyl; carbalkoxy is (as tertbutyloxycarbonyl; ethoxycarbonyl); cyano group; acyl group; alkylthio; the alkyl sulfinyl; alkyl sulphonyl; phenoxy group; or their combination is (as pyridyl; thienyl; pyrazinyl; quinolyl; isoquinolyl; pyrimidyl; imidazolyl; thiazolyl etc.), perhaps
Heterocyclylalkyl, wherein heterocyclic moiety is saturated, fractional saturation or undersaturated, and have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, and moieties is side chain or non-side chain, and having 1～5 carbon atom, described Heterocyclylalkyl is not substituted or is replaced one or many at heterocyclic moiety by following group: halogen, alkyl, alkoxyl group, cyano group, trifluoromethyl, CF 3O, nitro, oxygen, amino, alkylamino, dialkyl amido, or their combination, and/or at moieties by halogen, cyano group or methyl, or their combination replaces (as pyridylmethyl, pyridyl propyl group, picoline ylmethyl etc.);
L is singly-bound or the divalent aliphatic base with 1～8 carbon atom, wherein one or more-CH 2-group is optional separately to be replaced by following group :-O-,-S-,-NR 6-,-SO 2NH-,-NHSO 2-,-CO-,-NR 6CO-,-CONR 6-,-NHCONH-,-OCONH ,-NHCOO-,-SCONH-,-SCSNH-or-NHCSNH-(as-O-, CH 2-,-CO-,-CO-O-,-O-CO-,-CO-NH-,-NH-CO-,-CH 2CH 2CH 2-NH-CO-,-CH 2-CH 2-O-,-SO 2-NH-CH 2CH 2-O-,-O-CH 2CH 2-O-,-CH 2-NH-CO-,-CO-NH-CH 2-,-SO 2-NH-,-CH 2-NH-SO 2-,-CH 2CH 2CH 2-SO 2-NH-etc.); And
R 6Be H, or
Have 1～8, the alkyl of preferred 1～4 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～ 4-alkoxyl group, oxygen, or their combination (as methyl, ethyl, propyl group etc.);
R wherein 3And R 4One of at least be not H.
The new compound of one class formula II and III is provided according to a further aspect in the invention:
Figure C0280701000271
R wherein 1, R 2, R 3And R 4As above definition.The compound of the subclass of this formula I not only has PDE 4 and suppresses active, can also be used as the intermediate of the compound of preparation formula I, wherein R 3And R 4Not H.
In addition, the compound of preferred formula I is the compound of formula IV:
Figure C0280701000272
R wherein 1, R 2And R 4Such as in formula I definition, and one of A, B and D be N, and all the other are C.Preferred B is N.And, R 4Be preferably pyridyl or phenyl, it is substituted or is not substituted in each case.
The present invention also comprises compound and the pharmacologically acceptable salts thereof of formula I ':
Figure C0280701000281
Wherein
R 1' be methoxyl group, F, Cl, CHF 2Or CF 3
R 2' be alkyl with 1～12 carbon atom,
Alkyl with 1～12 carbon atom, it is replaced one or many by following group: halogen, oxygen, cyano group, or their combination,
Alkenyl with 2～12 carbon atoms,
Alkenyl with 2～12 carbon atoms, it is replaced one or many by following group: halogen, oxygen, cyano group, or their combination,
Alkynyl with 2～12 carbon atoms,
Alkynyl with 2～12 carbon atoms, it is replaced one or many by following group: halogen, oxygen, cyano group, or their combination,
Cycloalkyl with 3～10 carbon atoms,
Cycloalkyl with 3～10 carbon atoms, it is replaced one or many by following group: halogen, oxygen, alkyl, or their combination,
Cycloalkylalkyl with 4～12 carbon atoms,
Cycloalkylalkyl with 4～12 carbon atoms, it is replaced one or many by following group:
Halogen, oxygen, alkyl, or their combination,
Part unsaturated carbon cyclic group with 5～14 carbon atoms,
Part unsaturated carbon cyclic group with 5～14 carbon atoms, it is replaced one or many by following group: halogen, alkyl, alkoxyl group, nitro, cyano group, oxygen, or their combination,
Arylalkyl with 7～26 carbon atoms,
Arylalkyl with 7～26 carbon atoms, it is replaced one or many by following group: halogen, alkyl, alkoxyl group, nitro, cyano group, oxygen, trifluoromethyl, or their combination,
Heteroarylalkyl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, perhaps
Substituted heteroarylalkyl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, and it is replaced one or many at heteroaryl moieties by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, amino, alkylamino, dialkyl amido, or their combination, and/or at moieties by halogen, oxygen, cyano group, or their combination replaces;
X is O or S;
R 3' be aryl with 6～14 carbon atoms,
Aryl with 6～14 carbon atoms; it is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; amino; alkylamino; dialkyl amido; hydroxyalkyl; the hydroxy alkoxy base; carboxyl; cyano group; acyl group; carbalkoxy; alkylthio; the alkyl sulfinyl; alkyl sulphonyl; phenoxy group; heteroaryl; described heteroaryl is not substituted or by halogen; alkyl or alkoxyl group; or their combination replaces; heteroaryl with 5～10 annular atomses; wherein at least one annular atoms is a heteroatoms, perhaps
Substituted heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, it is replaced one or many by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino, dialkyl amido, or their combination;
L is-NH-,-NR 4'-,-NHCH 2-,-NR 4' CH 2-or-CH 2NR 4'-; And
R 4' be alkyl with 1～12 carbon atom,
Alkyl with 1～12 carbon atom, it is replaced one or many by following group: halogen, oxygen, cyano group, or their combination,
Aryl with 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino, dialkyl amido, hydroxyalkyl, hydroxy alkoxy base, carboxyl, cyano group, acyl group, carbalkoxy, alkylthio, alkyl sulfinyl, alkyl sulphonyl, phenoxy group; or their combination
Heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms,
Substituted heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, it is replaced one or many by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino, dialkyl amido, or their combination
Arylalkyl with 7～16 carbon atoms,
Arylalkyl with 7～16 carbon atoms, it is replaced one or many by following group:
Halogen, alkyl, alkoxyl group, nitro, cyano group, oxygen, trifluoromethyl, or their combination have the heteroarylalkyl of 5～10 annular atomses, and wherein at least one annular atoms is a heteroatoms, perhaps
Substituted heteroarylalkyl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, and it is replaced one or many at heteroaryl moieties by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino, dialkyl amido, or their combination, and/or at moieties by halogen, oxygen, cyano group, or their combination replaces.
Compound of the present invention effectively suppresses or regulates animal, as Mammals, and PDE 4 activity of philtrum particularly.These compounds show neural activity, particularly when this activity influence cognition, when comprising long-term memory.These compounds also will effectively be treated and be related to the disease that the cAMP level reduces.This includes but not limited to inflammatory diseases.These compounds also may be used as antidepressive, perhaps are used for the treatment of schizoid cognition and ill symptoms.
Being used to measure PDE inhibition optionally assay method active and PDE 4 active selectivity of inhibition and inhibition PDE4 isozyme is well known in the art.For example, referring to US6,136,821, this paper quotes its disclosed content as a reference.
According to a further aspect in the invention, provide the compound that is used as the intermediate of producing PDE 4 inhibitor as herein described (suc as formula PDE 4 inhibitor of I) and/or is used for synthetic the application's radiolabeled PDE 4 inhibitor analogues.
Therefore, the invention provides midbody compound, wherein R corresponding to the compound of formula I 2, R 3And R 4Define about formula I as the front, but R 1For H, t-butyldimethylsilyl-, or suitable phenol protecting group.Suitable phenol protecting group is for example described in the following document: Greene, T.W. and Wuts, P.G.M., Protective Groups in OrganicSynthesis, 3 RdEdition, John Wiley﹠amp; Sons, 1999, pp246-293.For example by removing protecting group and making the wherein R of gained 1Be the compound and suitable radio-labeling reagent react of H, these intermediates can also be used for the compound of synthesizing radioactive mark, as R wherein 1For 3H 3C-, 14CH 3-or 11CH 3-.These radiolabeled compounds are used for measuring the tissue distribution of compound in animal at the PET imaging research, and be used in the body, external (exvivo) and external (in vitro) in conjunction with studying.
The present invention also provides the midbody compound corresponding to the compound of formula I, wherein R 1, R 3And R 4Define about formula I as the front, but R 2Be H, t-butyldimethylsilyloxy base-or suitable phenol protecting group.Suitable phenol protecting group is for example described in the following document: Greene, T.W. and Wuts, P.G.M., Protective Groups in OrganicSynthesis, 3 RdEdition, John Wiley﹠amp; Sons, 1999,246-293.For example, R wherein 2For the compound of H as skeleton parallel or that combinatorial chemistry is used.And these compounds are used to introduce radio-labeled, as 3H, 14C or 11C.
As described above, R wherein 1, R 2And R 4The compound of formula II is to be used to produce wherein R as the aforementioned 3It is not the useful intermediates of compound of the formula I of H.
And, as described above, R wherein 1, R 2And R 3The compound of formula III is to be used to produce wherein R as the aforementioned 4It is not the useful intermediates of compound of the formula I of H.
Herein, halogen refers to F, Cl, Br and I.Preferred halogen is F and Cl.
Alkyl, itself is as group or substituting group, perhaps as the part of group or substituting group (as alkylamino, trialkylsiloxy, aminoalkyl group, hydroxyalkyl), mean and have 1～12 carbon atom, the straight or branched aliphatic hydrocarbyl of preferred 1～8 carbon atom, particularly 1～4 carbon atom.Suitable alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl, the tertiary butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl and dodecyl.Other example of suitable alkyl comprises 1-, 2-or 3-methyl butyl, 1,1-, 1,2-or 2,2-dimethyl propyl, 1-ethyl propyl, 1-, 2-, 3-or 4-methyl amyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3-or 3,3-dimethylbutyl, 1-or 2-ethyl-butyl, ethyl-methyl propyl group, trimethylammonium propyl group, methyl hexyl, dimethyl amyl group, ethyl pentyl group, ethyl-methyl butyl, dimethylbutyl etc.
The alkyl that replaces is above-mentioned alkyl, and it is replaced by following group in one or more positions: halogen, oxygen, hydroxyl, C 1～4-alkoxyl group and/or cyano group.Halogen is a preferred substituted, particularly F and Cl.
Alkoxyl group means alkyl-O-group, and the alkoxyl group alkoxyl group means alkyl-O-alkyl-O-group, and wherein moieties is with aforementioned consistent.Suitable alkoxyl group and alkoxyl group alkoxyl group comprise methoxyl group, oxyethyl group, propoxy-, butoxy, pentyloxy, hexyloxy, heptan oxygen base, octyloxy, methoxymethoxy, oxyethyl group methoxy base, propoxy-methoxyl group and methoxy ethoxy.Preferred alkoxyl group is methoxyl group and oxyethyl group.Similarly, carbalkoxy means alkyl-O-CO-, and wherein moieties is with aforementioned consistent.Example comprises methoxycarbonyl, ethoxycarbonyl, third oxygen carbonyl and the tertbutyloxycarbonyl.
Cycloalkyl means has 3～10 carbon atoms, preferred 3～8 carbon atoms, the particularly monocycle of 3～6 carbon atoms, dicyclo or the non-aromatics saturated hydrocarbyl of three rings.Suitable cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group, norcamphyl, 1-naphthane, diamantane-1-base and diamantane-2-base.Other suitable cycloalkyl comprises spiral shell amyl group, two ring [2.1.0] amyl groups, two ring [3.1.0] hexyls, spiral shell [2.4] heptyl, spiral shell [2.5] octyl group, two ring [5.1.0] octyl groups, spiral shell [2.6] nonyl, two ring [2.2.0] hexyls, spiral shell [3.3] heptyl, two ring [4.2.0] octyl groups, and spiral shell [3.5] nonyl.Preferred cycloalkyl is cyclopropyl, cyclopentyl and cyclohexyl.Cycloalkyl can be substituted, and is for example replaced by halogen and/or alkyl.
Cycloalkylalkyl finger ring alkyl-alkyl, wherein cycloalkyl and moieties are with aforementioned consistent.Suitable example comprises cyclopropyl methyl and cyclopentyl-methyl.
Aryl, itself perhaps as a group or a substituent part, refers to contain 6～14 carbon atoms, preferred 6～12 carbon atoms, the particularly aromatic carbocyclyl groups of 6～10 carbon atoms as group or substituting group.Suitable aryl comprises phenyl, naphthyl and xenyl.The aryl that replaces comprises above-mentioned aryl, and it is replaced one or many by following group: for example halogen, alkyl, hydroxyl, alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino, dialkyl amido, hydroxyalkyl, hydroxy alkoxy base, carboxyl, cyano group, acyl group, carbalkoxy, alkylthio, alkyl sulfinyl, alkyl sulphonyl and phenoxy group.
Arylalkyl refers to aryl-alkyl, and wherein aryl and moieties are with aforementioned consistent.Suitable example comprises benzyl, 1-styroyl, 2-styroyl, hydrocinnamyl, benzene butyl, benzene amyl group and menaphthyl.
Heteroaryl refers to have one or two ring and aromatic heterocyclic group of 5～10 annular atoms numbers altogether, and wherein at least one annular atoms is a heteroatoms.Preferred heteroaryl contains 1～3, particularly 1 or 2 heterocyclic atom that is selected from N, O and S.Suitable heteroaryl comprises furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, triazolyl, tetrazyl, dithiane base (dithialyl), oxathiane base (oxathialyl), different  azoles base,  azoles base, thiazolyl, isothiazolyl, the  di azoly, the  triazolyl, two  azoles bases, the  thiazolyl, thiadiazolyl group, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl,  piperazine base, different  piperazine base, the  thiazinyl, the  diazine, benzofuryl, isobenzofuran-base, thianaphthenyl, the isothianaphthene base, indyl, pseudoindoyl, indazolyl, benzisoxa  azoles base, the benzoxazol base, benzothiazolyl, the benzisothiazole base, purine radicals, benzopyranyl, quinolyl, isoquinolyl, the cinnolines base, quinazolyl, naphthyridinyl and Benzoxazinyl, for example 2-thienyl, the 3-thienyl, 2-, 3-or 4-pyridyl, 2-, 3-, 4-, 5-, 6-, 7-or 8-quinolyl and 1-, 3-, 4-, 5-, 6-, 7-or 8-isoquinolyl.
Substituted heteroaryl refers to the above-mentioned heteroaryl that replaced by following group in one or more positions: for example halogen, aryl, alkyl, alkoxyl group, carboxyl, methylene radical, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino and dialkyl amido.
Heterocycle comprises above-mentioned heteroaryl and contains the non-aromatic cyclic group of at least one heterocyclic atom that is preferably selected from N, S and O, for example tetrahydrofuran base, piperidyl and pyrrolidyl.
Heterocyclylalkyl refers to heterocycle-alkyl, and wherein heterocycle and moieties are with aforementioned consistent.Suitable example is pyridylmethyl, thienyl methyl, Pyrimidylmethyl, pyrazinyl methyl and isoquinolyl methyl.
Part unsaturated carbon ring structure is for containing 5～14 carbon atoms, and the non-aromatic monocyclic of preferred 6～10 carbon atoms or twin nuclei, wherein one or more ring structures contain at least one C=C key.Suitable example is cyclopentenyl, cyclohexenyl, cyclohexadienyl, naphthane methyne and indane-2-base.
Alkenyl refers to contain the straight or branched aliphatic group of 2～12 carbon atoms, wherein one or more-CH 2-CH 2-structure is replaced by CH=CH-separately.Suitable alkenyl is vinyl, 1-propenyl, 2-methyl ethylene, 1-butylene, 2-butylene, 1-pentenyl and pentenyl.
Alkynyl refers to contain the straight or branched aliphatic group of 2～12 carbon atoms, wherein one or more-CH 2-CH 2-structure is replaced by-C ≡ C-separately.Suitable alkynyl is ethynyl, proyl, ethyl acetylene base and 2-butyne base.
Acyl group refers to have the alkyloyl of 1～13 carbon atom; wherein moieties can be replaced by halogen, alkyl, aryl and/or alkoxyl group; the aroyl that perhaps has 7～15 carbon atoms, wherein aryl moiety can by, for example halogen, alkyl and/or alkoxyl group replace.Suitable acyl group comprises formyl radical, ethanoyl, propionyl, butyryl radicals and benzoyl.
Substituted group preferably has 1～3 substituting group, particularly 1～2 substituting group.
In the compound of formula I, R 1For preferably having the alkyl of 1～4 carbon atom, it is optional by halogen, and preferred fluorine or chlorine replaces.Especially, R 1Be preferably methyl or difluoromethyl.
R 2Be preferably cycloalkyl, particularly cyclopentyl.
R 2Also be preferably aryl or arylalkyl, particularly be substituted or unsubstituted phenyl or phenylalkyl, as phenyl, aminomethyl phenyl, p-methoxy-phenyl, chloro-phenyl-, styroyl, hydrocinnamyl, benzene butyl, styryl, benzene oxygen ethyl, benzene oxygen propyl group, benzene oxygen-butyl, chlorobenzene ethyl, p-methoxy-phenyl ethyl, chloro-styrene base, chlorobenzene oxygen ethyl, chlorobenzene propyl group, anisole propyl group, anisole butyl, chlorobenzene butyl, oil of mirbane butyl, chloro-phenyl-amino-ethyl etc.
R 2Also be preferably part unsaturated carbon cyclic group, it is not substituted or is substituted, particularly cyclohexenyl, cyclohexadienyl, indane-2-base.
R 2Also be preferably and have 1～8 carbon atom, the particularly alkyl of 1～4 carbon atom, it is substituted or is not substituted, for example methyl, difluoromethyl, trifluoromethyl and methoxy ethyl.
R 2Also be preferably heterocycle or heterocycle-alkyl, particularly wherein heterocyclic radical has 5～6 annular atomses and 1～2 group that is selected from the heterocyclic atom of N, O and S, for example tetrahydrofuran base, pyrrolidyl, pyrryl, pyridylmethyl, pyridyl ethyl, pyridyl propyl group, piperazinyl methyl, piperazinyl ethyl, methylpiperazine base ethyl etc.
Preferred R 2Comprise cyclopentyl, tetrahydrofuran base, CHF 2, methoxy ethyl, cyclopropyl methyl, styroyl, hydrocinnamyl, styryl, benzene oxygen ethyl, benzene oxygen-butyl, phenyl amino ethyl, indane-2-base, pyridyl ethyl and pyridyl propyl group.
R 3Be preferably hydrogen, have alkyl (as methyl, ethyl, n-propyl or normal-butyl), the arylalkyl (as being substituted or unsubstituted benzyl, styroyl and hydrocinnamyl) of 1～4 carbon atom, or heteroarylalkyl (as being substituted or unsubstituted pyridylmethyl, furyl methyl, thienyl methyl, pyrryl methyl, Pyrimidylmethyl, thiazolyl methyl, isoquinolyl methyl and quinolyl methyl).R 3Aryl and the preferred substituted of heteroaryl moieties be F, Cl, CH 3, C 2H 5, OCH 3And CN.
R 4Be preferably aryl or heteroaryl, particularly phenyl, naphthyl, xenyl, furyl, pyrazinyl, pyrimidyl, pyridyl, quinolyl and isoquinolyl, it is not substituted or is substituted one or many under every look condition.Preferred substituted is OH, F, Cl, CF 3, alkyl (as methyl or ethyl), alkoxyl group (as methoxyl group and oxyethyl group), CN, vinyl, CH 2OHCONHOH, CONH 2, methylene-dioxy, COOH and their combination.
In addition, work as R 4Be aryl, particularly during phenyl, preferred substituted comprises R 5-L-, as R 5-, R 5-O-, R 5-CO-, R 5-NH-CO-, R 5-SO 2-NH-, R 5-SO 2-NH-alkylidene group-O-, NH 2-alkyl-NH-CO-, R 5-alkylidene group-NH-CO-, alkyl-CO-NH-alkyl-and methyl, ethyl, Cl, F, CN, OCH 3, CF 3, amino, nitro, HOCH 2And COOH.
Work as R 4For by R 5-SO 2During aryl that-NH-replaces, it is preferably substituted phenyl, and R 5Be preferably methyl, ethyl, propyl group or phenyl.
Work as R 4For by R 5-SO 2During aryl that-NH-alkylidene group-O-replaces, it is preferably substituted phenyl.In these cases, R 5Be preferably methyl, ethyl, propyl group or phenyl, and alkylidene group is preferably-CH 2-,-CH 2CH 2-or-CH 2CH 2CH 2-.
Work as R 4For by R 5During aryl that-L-replaces, it is preferably substituted phenyl.In these cases, preferred R 5Group comprises tetrazyl,  piperazine base, piperazinyl, methylpiperazine base, pyridyl, picolyl, pyrrolinyl, methylpyrroline base, piperidyl or methyl piperidine base, and L be preferably singly-bound ,-O-,-CO-,-CH 2-,-CH 2CH 2-,-CH 2CH 2CH 2-,-CH 2-O ,-CH 2CH 2-O-,-CH 2CH 2CH 2-O-,-CH 2-NH-CH 2CH 2-O-,-CO-NH-or-NH-CO-.
In addition, preferred PDE of the present invention 4 inhibitor are for corresponding to formula I but show the described compound of inferior formula Ia～Ih of following preferred group:
Ia R 1Be methyl or CHF 2
R 2Be alkyl, alkenyl, alkynyl, cycloalkyl, arylalkyl, Heterocyclylalkyl, cycloalkylalkyl, aryl or heterocycle, it is substituted or is not substituted in each case;
R 3Be H, alkyl, arylalkyl or heteroarylalkyl, it is substituted or is not substituted in each case; And
R 4Be aryl or heteroaryl, it is substituted or is not substituted in each case.
Ib R 3For being substituted or unsubstituted heteroarylalkyl.
Ic R 1Be methyl or CHF 2And
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base).
Id R 1Be methyl or CHF 2
R 2Be cyclopentyl;
R 3Be heteroarylalkyl, it is substituted or is not substituted in each case; And
R 4For being substituted or unsubstituted aryl or heteroaryl.
Ie R 1Be methyl;
R 2Be cyclopentyl; And
R 3For being substituted or unsubstituted heteroarylalkyl.
If R 1Be methyl;
R 2Be cyclopentyl;
R 3For being substituted or unsubstituted heteroarylalkyl; And
R 4For being substituted or unsubstituted phenyl.
Ig R 1Be methyl;
R 2Be cyclopentyl;
R 3Be pyridylmethyl, styroyl, benzyl, thienyl methyl, pyridyl propyl group, piperidino methyl or pyrazinyl methyl, it is substituted or is not substituted in each case, perhaps methyl, ethyl or propyl group; And
R 4For phenyl or by the phenyl of 1～3 substituting group replacement.
Ih R 1Be methyl;
R 2Be cyclopentyl;
R 3Be pyridylmethyl, styroyl, benzyl, thienyl methyl, pyridyl propyl group, piperidino methyl, pyrazinyl methyl, it is substituted or is not substituted in each case, perhaps methyl, ethyl or propyl group; And
R 4Be phenyl, naphthyl, xenyl, pyridyl, pyrimidyl, thiazolyl, pyrazinyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
In addition, preferred PDE of the present invention 4 inhibitor are for corresponding to formula II but show the described compound of inferior formula Iia～IId of following preferred group:
IIa R 1Be methyl or CHF 2
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base); And
R 4Be phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
IIb R 1Be methyl or CHF 2
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base); And
R 4Be the phenyl that is not substituted or is replaced by following group: methyl, ethyl, methoxyl group, Cl, F, CF 3, vinyl, cyano group, amino, carboxyl, methylol or ethyl sulfonamido, perhaps 3-pyridyl for not being substituted or being replaced by carboxyl or carbalkoxy.
IIc R 1Be methyl;
R 2Be cyclopentyl; And
R 4Be phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
IId R 1Be methyl;
R 2Be cyclopentyl; And
R 4Be the phenyl that is not substituted or is replaced by following group: methyl, ethyl, methoxyl group, Cl, F, CF 3, vinyl, cyano group, amino, carboxyl, methylol or ethyl sulfonamido, perhaps 3-pyridyl for not being substituted or being replaced by carboxyl or carbalkoxy.
In addition, preferred PDE of the present invention 4 inhibitor are for corresponding to formula III but show the described compound of inferior formula III a～IIId of following preferred group:
IIIa R 1Be methyl or CHF 2
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base); And R 3Be benzyl, styroyl, cyclohexenyl methyl, furyl methyl, thienyl methyl, pyridylmethyl, quinolyl methyl, isoquinolyl methyl, thiazolyl methyl or pyrryl methyl, it is substituted or is not substituted in each case.
IIIb R 1Be methyl or CHF 2
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base); And
R 3Be pyrazinyl methyl, Pyrimidylmethyl or pyridylmethyl, it is not substituted or is substituted in each case.
IIIc R 1Be methyl;
R 2Be cyclopentyl; And
R 3Be benzyl, styroyl, cyclohexenyl methyl, furyl methyl, thienyl methyl, pyrazinyl methyl, Pyrimidylmethyl, pyridylmethyl, quinolyl methyl, isoquinolyl methyl, different imidazolyl, thiazolyl methyl or pyrryl methyl, it is substituted or is not substituted in each case.
IIId R 1Be methyl;
R 2Be cyclopentyl; And
R 3Be pyrazinyl methyl or pyridylmethyl, it is not substituted or is substituted in each case.
In addition, preferred PDE of the present invention 4 inhibitor are for corresponding to formula IV but show the described compound of inferior formula Iva～IVp of following preferred group:
IVa R 1Be methyl or CHF 2
IVb R 1Be methyl or CHF 2, and
B is N.
IVc R 1Be methyl or CHF 2, and
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base).
IVd R 1Be methyl or CHF 2,
B is N, and
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base).
IVe R 1Be methyl or CHF 2, and
R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
IVfR 1Be methyl or CHF 2,
B is N, and
R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
IVg R 1Be methyl or CHF 2,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
IVh R 1Be methyl or CHF 2,
B is N,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
IVi R 1Be methyl or CHF 2, and
R 4For at the substituted phenyl of 3-or 4-position.
IVj R 1Be methyl or CHF 2,
B is N, and
R 4For at the substituted phenyl of 3-or 4-position.
IVk R 1Be methyl or CHF 2,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4For at the substituted phenyl of 3-or 4-position.
IVl R 1Be methyl or CHF 2,
B is N,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4For at the substituted phenyl of 3-or 4-position.
IVm R 1Be methyl or CHF 2, and
R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
IVn R 1Be methyl or CHF 2,
B is N, and
R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
IVo R 1Be methyl or CHF 2,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
IVp R 1Be methyl or CHF 2,
B is N,
R 2Be cyclopentyl, CHF 2, cyclopropyl methyl, pyridyl ethyl (particularly 2-pyridyl ethyl), or tetrahydrofuran base (particularly (3R)-tetrahydrofuran base), and
R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
Preferred aspect comprises and comprises compound of the present invention and pharmaceutically acceptable carrier, and the pharmaceutical composition of optional another kind of following active agent; The method that suppresses PDE 4 enzymes, particularly isozyme, described method are for example measured by conventional determining method or assay method as herein described in external or body (in animal, as in animal model, or in Mammals or in the people); The treatment nervous syndrome is as memory loss, particularly long-term memory loss, cognitive disorder or decline, the method for dysmnesia etc.; The treatment Mammals is as people's the disease by PDE 4 active mediations, the method for disease as described herein.
Compound of the present invention can conventional prepare.Operable some method as described below.All initial substances all are known or can be by the conventional preparations of known initial substance.
Route 1
Figure C0280701000431
The initial nitrophenols of Class1 is available commercially (as R1=CH 3) or by disclosed method preparation (as R1=CHF 2, perhaps R1 and R2 all=CHF 2, referring to Mueller, Klaus-Helmut.Eur.Pat.Appl. (1994), 8pp.CODEN:EPXXDW EP626361A1; Touma, Toshihiko; Asai, Tomoyuki.Jpn.Kokai TokkyoKoho (1999), 6pp.CODEN:JKXXAF JP 11071319A2; Platonov, Andrew; Seavakov, Andrew; Maiyorova, Helen; Chistokletov, Victor.Int.Symp.Wood.Pulping Chem., 1995,8th, 3,295-299; Christensen, Siegfried Benjamin; Dabbs, Steven; Karpinski, Joseph M.PCT Int.Appl. (1996), 12pp.CODEN:PIXXD2WO 9623754A119960808).Preparation aniline intermediate 3 in two steps; At first, addition reaction provides intermediate 2, then carries out the reduction of nitro.Intermediate nitro-compound 2 can be by multiple disclosed method preparation, as preparing by Mitsunobu reaction or standard alkylated reaction.Wherein R2 be aryl or heteroaryl compound can by under the Ullman condition with aryl or heteroaryl iodine carry out the catalytic reaction of copper or by at copper catalyst (as Cu (OAc) 2) and alkali such as TEA make under existing aryl-, vinyl-, or heteroaryl-boric acid and phenol 2 couplings and prepare.The phosphine that uses azo-2-carboxylic acid (as DEAD, DIAD) and suit is (as Ph 3P, Bu 3P) the Mitsunobu reaction between the nitrophenols of the suitable replacement of carrying out and uncle or the secondary alcohol provides alkylation nitrophenols 2.The Mitsunobu reaction is generally carried out in aprotic solvent such as methylene dichloride or THF.Perhaps, can pass through at polar aprotic solvent (as DMF or CH 3CN) at alkali (as K 2CO 3Or NaH) suits the nitrophenols that replaces and the reaction between the alkylogen under the existence and realize alkylation.
Then by the standard method in this area, as use suitable catalyzer (as be supported on the charcoal Pd) in polar aprotic solvent (as MeOH or EtOH), under nitrogen atmosphere, to carry out hydrogenation and Nitrocatechol 2 is reduced into corresponding aniline 3.Perhaps, can be by using hydride source (as NaBH 4) and transition-metal catalyst (as NiCl 2, be supported on the Pd on the charcoal) or by use metal (as Zn, Sn, Fe) in inorganic acid solution (as HCl) with Nitrocatechol 3 reduction, produce corresponding aniline.Usually in these reactions, use polar aprotic solvent such as ethanol or methyl alcohol.
By the standard method in this area, as synthesizing N-arylalkyl aniline 4 by reduction amination, alkylated reaction or the corresponding amide of passing through to reduce.For example, aryl or arylalkyl aldehyde and the suitable aniline that replaces are at borohydride reduction agent such as NaBH 4Or NaBH 3CN and acid catalyst such as acetate or pTsOH exist the reduction amination that carries out down that N-arylalkyl aniline is provided.These reactions are generally carried out in polar aprotic solvent such as methyl alcohol, ethanol, Virahol, n-propyl alcohol etc.
By the standard method in this area, comprise the coupling of Ullman linked reaction, metal catalytic, or nucleophilic aromatic substitution reaction and easily with N-arylalkyl aniline 4N-arylation.For example, use palladium catalyst (as Pd 2Dba 3), a large amount of electron rich phosphine part (as tributylphosphine), and suitable alkali (as NaOtBu) and the Phenhenzamine that carries out and the reaction of the metal catalytic between the aryl halide provide N-arylalkyl pentanoic.Also adopt nickel and copper catalyst.The solvent that is used for this reaction comprises apolar aprotic solvent such as toluene, benzene, dimethylbenzene, tetrahydrofuran (THF) and ether.When the compound of the synthetic wherein R4 type 5 that is the carbalkoxy phenyl, with amine 4 and 1.1 normal tertiary butyl 3-iodobenzene couplings and use 22mol% (tBu) 3P, 5.5mol%Pd 2(dba) 3With 1.3 normal tBuONa be favourable.
Route 2
Figure C0280701000451
Carboxylicesters intermediate 6 can hydrolysis under acidity or alkaline condition, obtains corresponding carboxylic acid 7.For example, can use the mixture of the aqueous solution of alkali (as NaOH, KOH) and solvent (as EtOH, THF) that can be miscible with ethyl ester (R5=Et) hydrolysis with water.And if desired, the aqueous solution that can use acid (as HCl, formic acid, TFA) can with the miscible organic solvent of water in the tert-butyl ester (the R5=tertiary butyl) hydrolysis.
Route 3
Figure C0280701000452
The Thiazolyl blue tetrazolium bromide of protection or phenyl-iodide (as 5-(3-iodophenyl)-2-(2-tetrahydropyrans) tetrazolium) produce the tetrazolium 8 of THP protection with anils 4 couplings that N-replaces.Can use aqueous acid, finish the hydrolysis of the tetrazolium 8 of THP protection as the HCl in water and mixable solvent such as THF or EtOH, so that tetrazolium 9 to be provided.And, can also use reagent such as CAN and DDQ in halogenated hydrocarbon solvent such as methylene dichloride, chloroform, ethylene dichloride etc. with THP tetrazolium oxicracking, obtain tetrazolium 9.
Perhaps, can be by in polar aprotic solvent such as DMF, using the trinitride ion (as KN 3, NaN 3Deng) and proton source (as NH 4Cl) handle corresponding nitrile and prepare tetrazolium analogue 9.Trinitride ion that can also be by in water and Lewis acid are (as ZnBR 2), then use if desired with the miscible solubility promoter of water such as Virahol to prepare them.Another kind of preparation method be by in aprotic organic solvent such as benzene, toluene, methylene dichloride, ethylene dichloride, ether, THF etc. with tin or silicon trinitride (as Me 3SiN 3, Bu 3SnN 3) handle.
Route 4
Figure C0280701000461
Can be by in the presence of alkali such as triethylamine and copper catalyst such as neutralized verdigris, with substituted aniline 3, as 3-cyclopentyloxy-4-anisidine and aryl boric acid aptly coupling and prepare pentanoic 10 (as people such as Chan, Tetrahedron Lett., 39,2933-2936 (1998) is described).Generally speaking, use halogenated solvent such as methylene dichloride, chloroform, ethylene dichloride etc. and apolar aprotic solvent such as benzene, toluene or dimethylbenzene.The aminating reaction that these pentanoic (as 10) can more preferably pass through metal catalytic synthesizes.For example, the suitable aniline that replaces 3 with aryl halide at alkali (as K 3PO 4, CsCO 3Or NaOtBu) and palladium or nickel catalyzator, for example Pd (dppf) Cl 2, there are reaction down in part (as dppf) and alkali (as NaOtBu) (JACS.1996,118,7217), or and Pd 2Dba 3, the phosphine such as the P (tBu) of a large amount of electron riches 3And alkali (as NaOtBu) (J.Org.Chem.1999,64,5575) reaction, the pentanoic 10 that obtains expecting.The solvent that the most generally uses in this type reaction comprises apolar aprotic solvent such as benzene, toluene, tetrahydrofuran (THF), ether etc.
Then can be with various alkylogens or arylalkyl halogen, such as but not limited to methyl iodide, monobromoethane, benzyl chloride, 3-(chloromethyl) pyridine, 4-(chloromethyl)-2,6-dichloropyridine and 4-(brooethyl) phenylformic acid or their salt, in the presence of non-nucleophilic base such as sodium hydride, hexamethyl dimethylamino silane potassium azide or diisopropylamide potassium,, provide N-the pentanoic 5 of replacement with pentanoic 10 alkylations.The solvent that is used for this reaction comprises aprotic solvent such as benzene, toluene, tetrahydrofuran (THF), ether, DMF etc.
Route 5
Figure C0280701000471
Can use the standard method in this area further to handle carboxylic acid 7 to form acid amides.For example, with suitable uncle or secondary amine, at suitable coupling agent such as BOP, pyBOP or DCC and alkali such as Et 3There are processing carboxylic acid down in N or DIEA, obtain acid amides.These reactions are generally carried out in apolar aprotic solvent such as methylene dichloride, chloroform or ethylene dichloride.
Can use the standard method in this area that carboxylicesters 6 or carboxylic acid 7 are reduced, obtain corresponding aldehyde or methylol analogue.For example, can in aprotic solvent such as ether or THF, handle aryl ethyl ester (as structure 6, the R5=ethyl), produce corresponding aldehyde or methylol analogue with suitable reductive agent (as LAH, DIBAL etc.).These aldehyde and alcohol can also further be derived by the standard method in this area.
Similarly, can use the standard method in this area that acid amides (as structure 11) and nitrile are reduced, corresponding substituted amine or amino methyl analogue are provided.For example, can in aprotic solvent (as benzene, toluene, ether, THF etc.), arylamide 11 be reduced, obtain corresponding substituted amino methyl analogue with suitable reductive agent (as LAH).And the reduction of aryl nitrile obtains corresponding primary amino methyl analogue.
Route 6
Figure C0280701000481
Can be by the standard method in this area, as use suitable catalyzer (as be supported on the charcoal Pd) in polar aprotic solvent (as EtOH, MeOH etc.), to carry out hydrogenation and nitrobenzene compound 12 is reduced into corresponding aniline 13.Can also use hydride source (as NaBH 4) and transition-metal catalyst (as NiCl 2, be supported on the Pd on the charcoal) in polar aprotic solvent such as EtOH with oil of mirbane 12 reduction, produce corresponding aniline 13.These aniline can further be replaced by the standard method in this area then.For example, aniline alkylating, acidylate or the sulfonylation of Class1 3 can be obtained corresponding N-alkyl amine, acid amides (as structure 15) or sulfanilamide (SN) (as structure 14) respectively.For example, can be by aniline and suitable sulfonic acid halide or sulphonic acid anhydride (as MeSO 2Cl, EtSO 2Cl, BnSO 2Cl, PhSO 2Cl etc.) at alkali (as Et 3N, pyridine, DIEA etc.) the following preparation of existence sulfanilamide (SN).The suitable solvent that is used for this reaction comprises apolar aprotic solvent such as methylene dichloride, chloroform, ether etc.
Route 7
Figure C0280701000491
Can be as the trialkylsilyl ethers of preparation Class1 6 as described in the route 1.By the various kinds of document method (referring to Greene, T.W. and Wuts, P.G.M., Protective Groups inOrganic Synthesis, 3 RdEdition, John Wiley﹠amp; Sons, 1999,273-276), use fluoride ion source (as Bu as passing through 4NF) in aprotic solvent such as ether or THF; Perhaps under acidic conditions (as KF, 48%HBr, DMF) easily with catechol intermediate 16 deprotections of t-butyldimethylsilyl protection.The phenol 17 of gained is very useful synthetic intermediate, can be subsequently by the standard method in this area with route 1 in the described similar fashion of alkylation of nitrophenols 2 with its alkylation.For example, by Mitsunobu reaction, by in the presence of alkali with the alkylogen reaction, pass through the aryl coupling of Ullman type or by with vinyl-, aryl-or heteroaryl boric acid in the presence of copper catalyst, react.
Route 8
Figure C0280701000492
Can be by reacting in the presence of alkali with the amine, alcohol or the mercaptan that replace and will providing analogue as 19 by halogenated alkoxy intermediate 18 alkylations of the corresponding phenol preparation of alkylation.For example, can use suitable uncle or secondary amine and alkali such as K 2CO 3At polar aprotic solvent such as THF, DMF or CH 3Among the CN with the alkylogen ammonification.
Many these synthetic methods are more intactly described in following embodiment.
Those skilled in the art will recognize that the compound of some formula (I) and (I ') can exist with different rotamerism forms.In addition, some compound of the present invention has one or more unsymmetrical carbons, thereby can exist with the form of optical isomer form and racemize or non-racemic mixture and diastereomer and non-enantiomer mixture thereof.All these compounds comprise the non-raceme mixture of cis-isomeride, trans-isomer(ide), non-enantiomer mixture, racemic modification, enantiomer and pure and mild basically pure enantiomer all within the scope of the invention.Basically pure enantiomer only contains the corresponding opposite enantiomer that is no more than 5%w/w, preferably is no more than 2%, is most preferably not exceeding 1%.
Can for example, perhaps form the covalency diastereomer by the racemic mixture of carrying out according to conventional methods, thereby obtain optical isomer by using optical activity acid or alkali to form diastereomeric salt.The example of suitable acid is tartrate, diacetyl tartaric acid, dibenzoyl tartaric acid, xyloyl tartrate and camphorsulfonic acid.Can be according to their physics and/or chemical difference, by method known to those skilled in the art, for example be separated into their independent diastereomer by chromatogram or fractional crystallization and with non-enantiomer mixture.From isolating diastereomeric salt, discharge optically active alkali or acid then.The different methods that is used for the separating optical isomeric body comprises use chiral chromatography (as chirality HPLC post), and described chiral chromatography carries out or do not carry out conventional derivatize, and optimal selection is so that the separation maximization of enantiomer.Suitable chirality HPLC post is made by Diacel, for example can the conventional Chiracel OD that selects and Chiracel OJ etc. many.It also is useful that the enzyme of derivatize or underivatized separates.The optically active compound of formula I and I ' can be undertaken that chirality is synthetic to be obtained by using the optical activity initial substance equally.
The invention still further relates to the useful form of compound disclosed herein, as the pharmacologically acceptable salts and the prodrug of all compounds of the present invention.Pharmacologically acceptable salts comprises by main compound and salt inorganic or that organic acid reaction formation salt obtains, for example salt of hydrochloric acid, sulfuric acid, phosphoric acid, methylsulfonic acid, camphorsulfonic acid, oxalic acid, toxilic acid, succsinic acid and citric acid as alkali.Pharmacologically acceptable salts also comprises such salt: wherein main compound is as acid, and with suitable alkali reaction, form for example sodium, potassium, calcium, magnesium, ammonium and choline salt.Those of skill in the art also will appreciate that the acid salt of claimed compounds can prepare via any many currently known methodss reactions by this compound and the inorganic or organic acid that suits.Perhaps, by making compound of the present invention and the alkali that suits prepare alkali and alkaline earth salt via multiple currently known methods reaction.
Below be can by with further the example inorganic or hydrochlorate that organic acid reaction obtains: acetate, adipate, alginate, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, digluconate, cyclopentane propionate, dodecyl sulfate, esilate, glucoheptose salt, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrobromate, hydriodate, 2-hydroxyl-esilate, lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectinic acid salt, persulphate, the 3-phenpropionate, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, tosylate, mesylate and undecylate.
The salt that is preferably formed is for being that pharmacy is acceptable for the Mammals administration.But the unacceptable salt of the pharmacy of this compound is suitable for example to be used for the compound of separated salt form as intermediate, then by handling with alkali reagent and the salt conversion being back to free alkali compound.If expectation can change into free alkali the acceptable acid salt of pharmacy subsequently.
Compound of the present invention can be separately or as the delivery of active ingredients of prescription.Therefore, the present invention also comprises the pharmaceutical composition of the compound of formula I or I ', and it contains for example one or more pharmaceutically acceptable carriers.
Existing many descriptions are used to prepare the Standard Reference Materials of the multiple formulations that gives compound of the present invention.For example, possible prescription and examples of formulations are included in the following document: theHandbook of Pharmaceutical Excipients, American PharmaceuticalAssociation (current version); Pharmaceutical Dosage Forms:Tablets (Lieberman, Lachman and Schwartz, editors) current version, Marcel Dekker, Inc. publish, and Remington ' s Pharmaceutical Sciences (Arthur Osol, editor), 1553-1593 (current version).
Because the height PDE 4 of compound of the present invention suppresses, they can be needed or expect that PDE 4 suppresses and/or improve anyone of cognition.Can carry out administration according to patient's needs, for example oral, intranasal, parenteral (in subcutaneous, intravenously, intramuscular, the breastbone and infusion), suction, rectum, vagina, part, location, through skin and ocular administration.
Various solid oral dosage forms can be used for the administration of compound of the present invention, comprise following solid dosage: tablet, gel cap (gelcap), capsule, capsule sheet, granule, lozenge and powder.Compound of the present invention can be separately or with various pharmaceutically acceptable carriers as known in the art, thinner (as sucrose, seminose, lactose, starch) and vehicle, include but not limited to that suspension agent, solubilizing agent, buffer reagent, tackiness agent, disintegrating agent, sanitas, tinting material, seasonings, lubricant etc. give together.Time-delay release capsule, tablet and gel also are useful in the administration of compound of the present invention.
Also various liquid oral dosage forms can be used for the administration of compound of the present invention, comprise the aqueous solution and non-aqueous solution, emulsion, suspension, syrup and elixir.These formulations can also contain suitable inert diluent as known in the art, as water, ethyl suitable vehicle as known in the art is as sanitas, wetting agent, sweeting agent, seasonings and be used for emulsification and/or the reagent of the compound of the present invention that suspends.For example, compound of the present invention can be to wait form intravenous injection of oozing sterile solution.Other preparation also is possible.
The suppository that is used for the rectal administration of compound of the present invention can prepare by this compound is mixed with the vehicle that suits such as theobroma oil, salicylate and polyoxyethylene glycol.The prescription that is used for vagina administration can be the form of the pessary, tampon, emulsifiable paste, gel, paste, foam or the sprays that contain activeconstituents and appropriate carrier as known in the art.
For topical, this pharmaceutical composition can be the form that emulsifiable paste, ointment, liniment, lotion, emulsion, suspensoid, gel, solution, paste, powder, sprays and being suitable for gives the drops of skin, eye, ear or nose.Topical can also comprise by device as the skin administration of passing through through skin medicine exchange premium.
Can also prepare the aerosol formulations that is suitable for by inhalation.For example, for the treatment of respiratory tract disease, can give compound of the present invention by sucking powder (as micronization) or atomized soln or form of suspension.Aerosol formulations can be placed the propellent that can pressurize.
This compound can also (give as bright (rivastigimine) of E2020, Li Fansi with glanthanamine) as being used for the treatment of cognitive disorder and/or antipsychotic other reagent such as other PDE 4 inhibitor, calcium channel blocker, cholinergic agent, Adenosine Receptors conditioning agent, amphakines NMDA-R conditioning agent, mGluR conditioning agent and anticholinesterase as independent promoting agent or with other pharmaceutical agents.In these combinations, every kind of activeconstituents can give according to their routine dose scope or the dosage that is lower than its routine dose scope.
The present invention also comprises the methods of treatment that relates to the inhibition of PDE 4 enzymes.Therefore, the present invention includes selectivity and suppress animal, as Mammals, the method for people's PDE 4 enzymes particularly, wherein this inhibition has therapeutic action, can alleviate the illness that relates to nervous syndrome as this inhibition, as memory, particularly long-term memory loss.These methods comprise the animal, particularly Mammals, the most particularly people that the compound disclosed herein of amount of suppression is needed it separately or as the part of prescription.
Amnemonic symptom shows as the ability obstacle of study fresh information and/or can not recall the information of study in the past.Dysmnesia are dull-witted cardinal symptoms, can also be the syndrome relevant with disease such as alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, HIV, cardiovascular disorder and head trauma and with the age relevant cognition descends.
Dementia is the disease that comprises the memory loss and be independent of other dysnoesia outside the memory.The present invention includes the amnemonic patient's who is used for the treatment of the dementia of suffering from form of ownership method.Dull-witted cause of disease classification according to them, and comprise: the neurodegeneration dementia is (as alzheimer's disease, Parkinson's disease, Huntington Chorea, Pick's disease), blood vessel is (as infraction, hemorrhage, heart trouble), blended blood vessel and alzheimer's disease, bacterial meningitis, creutzfeldt-jakob disease, multiple sclerosis, traumatic (as subdural hematoma or traumatic brain injury), infectious (as HIV), heredity (mongolism), toxic is (as heavy metal, alcohol, some drugs), metabolic (as vitamin B12 or folic acid deficiency), the CNS anoxic, hypercortisolism, psychosis (as depression and schizophrenia), and hydrocephalus.
The present invention includes and be used for the treatment of the memory loss that is independent of outside the dementia, comprise the method for mild cognitive impairment (MCI) and the cognition decline relevant with the age.The present invention includes and be used for the treatment of the amnemonic method that causes by disease.In Another Application, the present invention includes the memory loss that is used for the treatment of owing to using general anesthetic, chemotherapy, radiotherapy, post-surgical trauma and therapeutic intervention to cause.
Compound of the present invention can be used for the treatment of mental illness, comprises schizophrenia, two-phase or make an uproar mad property depression, severe depression, and drug habit and morphine dependency.These compounds can improve insomnia.PDE 4 inhibitor can be used to the cAMP level that raises, and prevent neurone generation apoptosis.Also known PDE 4 inhibitor are antiphlogiston.The combination of anti-apoptosis and antiinflammatory property makes these compounds be used for the treatment of the neurodegeneration that is caused by any i or I, (amylolaterosclerosi is ALS) with multisystem atrophy (MSA) to comprise apoplexy, Spinal injury, neural generation, alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis.
Therefore, according to embodiment preferred, the present invention includes to be used for the treatment of and suffer from: alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, depression, aging, head trauma, apoplexy, CNS anoxic, brain aging, multi infarct dementia and other nervous disorders because the amnemonic method that causes such as following disease, comprise acute neuropathy, and HIV and cardiovascular disorder, described method comprises compound or its pharmacologically acceptable salts of the formula (I) that gives significant quantity or (I ').
Compound of the present invention can also be used for the treatment of suffers from the disease that is characterized as the reduction of NMDA function, as schizoid patient's method.This compound can also be used for the treatment of the psychosis that is characterized as the rising of PDE 4 levels, for example various forms of depressions, as make an uproar mad property depression, severe depression, and the depression relevant with psychosis and neuropathy.
As described, compound of the present invention also shows anti-inflammatory activity.Therefore, compound of the present invention is used for the treatment of various allergy and inflammatory diseases, and particularly raising with ring AMP level reduction and/or phosphodiesterase 4 level is the illness of feature.Therefore, according to another embodiment of the present invention, provide the method for treatment allergy and inflammatory conditions, described method comprises compound or its pharmacologically acceptable salts of the formula (I) that gives significant quantity or (I ').These illnesss comprise: asthma, chronic bronchitis, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, rhinallergosis, allergic conjunctivitis, vernal conjunctivitis, acidophilia (esoniophilic) granuloma, psoriatic, inflammatory arthritis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, the reperfusion injury of cardiac muscle and brain, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, cystic fibrosis, arterial restenosis, atherosclerosis, seborrheic keratosis, rheumatoid spondylitis, osteoarthritis, pyresis, diabetes, pneumoconiosis, chronic osbtructive air way disease, chronic obstructive pulmonary disease, toxic and allergic contact eczema, atopic eczema, seborrheic eczema, simple property liver moss, sunburn, anus genital region itch, alopecia areata, hypertrophic cicatrix, discoid lupus erythematosus, systemic lupus erythematous, folliculus and big area pyoderma, endogenous and exogenous acne, rosacea, behcets disease, supersensitivity purpura nephritis, inflammatory bowel, leukemia, multiple sclerosis, gastrointestinal disorder, autoimmune disorders etc.
The PDE4 inhibitor that is used for the treatment of asthma, chronic bronchitis, psoriatic, rhinallergosis and other inflammatory diseases and is used to suppress tumour necrosis factor is well known in the art.For example, referring to WO 98/58901, JP11-18957, JP 10-072415, WO 93/25517, WO 94/14742, US 5,814,651 and US 5,935,9778.These bibliographys have also been described and have been used to measure the active assay method of PDE 4 inhibition, and the method that is used for synthetic these compounds.The full content that this paper quotes these documents as a reference.
The PDE4 inhibitor can be used for prevention or improve osteoporosis, as microbiotic, be used for treating cardiovascular disorder by the cholesterol of mobilizing atherosclerotic lesions, be used for the treatment of rheumatoid arthritis (RA), be used for long term inhibition and transplant back mesenchymal cell propagation, be used for the treatment of the urethral obstruction that is secondary to benign prostatic hyperplasia, the intrusion that is used to suppress chemotaxis and reduces colon cancer cell, be used for the treatment of B cell lymphocytic leukemia (B CLL), be used to suppress uterine contraction, be used to reduce lung blood vessel ischemical reperfusion injury (IRI), be used for the cornea hydration, be used to suppress IL-2R and express, thereby eliminate HIV-1DNA nuclear and enter memory T cell, be used to increase the insulin secretion of glucose induction, be used for preventing and treat colitis simultaneously, and be used to suppress mast cell degranulation.
Compound of the present invention can be used as independent promoting agent or (gives as bright (rivastigimine) of E2020, Li Fansi with glanthanamine) as being used for the treatment of cognitive disorder and/or antipsychotic other reagent such as other PDE4 inhibitor, calcium channel blocker, cholinergic agent, Adenosine Receptors conditioning agent, amphakines NMDA-R conditioning agent, mGluR conditioning agent and anticholinesterase with other pharmaceutical agents.In these combinations, every kind of activeconstituents can give according to their routine dose scope or the dosage that is lower than its routine dose scope.
The dosage of compound of the present invention depends on multiple factor, comprises that particular integration to be treated is levied, the existence of effectiveness, toxicity feature, pharmacokinetics feature and any harmful side effect of the frequency of the severity of symptom, route of administration, spacing of doses, used specific compound, compound etc.
Compound of the present invention is generally with PDE 4 inhibitor, gives Mammals as the routine dose level of above-mentioned known compound.For example, this compound can give with one or many dosage, and for example the oral dosage level is 0.01～100mg/kg/ days, and preferred 0.1～70mg/kg/ days, particularly 0.5～10mg/kg/ days.For example, unit dosage form can contain 0.1～50mg active compound.For intravenous administration, can give compound with one or many dosage, and dosage level for example is 0.001～50mg/kg/ days, preferred 0.001～10mg/kg/ days, particularly 0.01～1mg/kg/ days.For example, unit dosage form can contain 0.1～10mg active compound.
In the process of implementing method of the present invention, certainly can understand the specific buffers mentioned, medium, reagent, cell, culture condition etc. unexpectedly for restrictive, think useful or valuable related substances in the certain content of being discussed and be understood to include all those of ordinary skills.For example, can replace another kind of buffering system or substratum with a kind of buffering system or substratum usually, and still realize similarly (if not identical words) effect.Art technology philtrum person has fully understood these system and methods, thereby can make this substituting under the situation of not carrying out undo experimentation, thus the purpose of in using method disclosed herein and step, serving them best.
To further describe the present invention by following non-limiting example now.When implementing the content of these embodiment, should clearly realize that their beyond all doubt prompting those skilled in the art other and different embodiments about method disclosed according to the present invention.
In aforementioned and following embodiment, all temperature do not proofread degree centigrade being that unit provides; And unless otherwise noted, all parts and per-cent are all by weight.
More than and below the full content of all applications, patents and publications quoted all be incorporated herein by reference.
Embodiment 1A
1-cyclopentyloxy-2-methoxyl group-5-oil of mirbane
At N 2Protection down, to the 2-methoxyl group-5-nitrophenols in dimethyl formamide (1L) (525g, 3.104mol) and salt of wormwood (643.5g, add in suspension 4.66mol) cyclopentyl bromide (499.2mL, 4.66mol).Suspension is heated to 100 ℃, continues 6 hours.Add salt of wormwood (85.8g, 0.62mol) and cyclopentyl bromide (50mL, 0.46mol).Suspension is heated to 100 ℃, continues 4 hours.TLC shows and reacts completely (9: 1DCM: MeOH).Reaction mixture is cooled to room temperature and water (3L) and ether (3L) dilution.Separate each layer and use ether (2L) aqueous layer extracted again.Organic layer with 1N NaOH (2L), water (2L) and salt solution (2L) washing merging.Use the dried over sodium sulfate organic layer, filter and evaporation.(2 * 300mL) azeotropic obtain 736.7g (99.6% yield) yellow solid with the solid of gained and toluene.
Prepare following compound in mode similar to the above:
A) 1-cyclo propyl methoxy-2-methoxyl group-5-oil of mirbane
B) 1-cyclopentyloxy-2-difluoro-methoxy-5-oil of mirbane
C) 1-cyclo propyl methoxy-2-difluoro-methoxy-5-oil of mirbane
Embodiment 1B
2-methoxyl group-5-nitro-1-((3R)-tetrahydrofuran oxygen base) benzene
Stir down, to the 2-methoxyl group in anhydrous tetrahydro furan (40mL)-5-nitrophenols (1.69g, 10mmol), triphenylphosphine (5.24g, 20mmol) and 3-(R)-hydroxyl tetrahydrofuran (1.80g, drip diisopropyl azo-2-carboxylic acid (4.0mL in mixture 20mmol), 20mmol), and with mixture under room temperature, stirred 16 hours.With ether (150mL) diluted mixture thing, and with 2N NaOH (3 * 50mL) and salt solution (50mL), (MgSO 4) washing, and vacuum concentration.With the thick resistates of silica gel (Biotage Flash 40M) flash distillation column chromatography purifying, be used in 20% eluent ethyl acetate in the hexane, obtain the 1.05g product.
Prepare following compound in mode similar to the above:
A) 2-methoxyl group-5-nitro-1-(3-tetrahydrofuran oxygen base) benzene
B) 2-methoxyl group-5-nitro-1-((3S)-tetrahydrofuran oxygen base) benzene
C) 2-difluoro-methoxy-5-nitro-1-(3-tetrahydrofuran oxygen base) benzene
D) 2-difluoro-methoxy-5-nitro-1-((3R)-tetrahydrofuran oxygen base) benzene
E) 2-difluoro-methoxy-5-nitro-1-((3S)-tetrahydrofuran oxygen base) benzene
F) 2-methoxyl group-5-nitro-1-(3-benzene propoxy-) benzene
G) 1-(2-indane oxygen base)-4-methoxyl group-5-oil of mirbane
Embodiment 1C
1-(t-butyldimethylsilyl) oxygen-2-methoxyl group-5-oil of mirbane
Stir down, to the 2-methoxyl group-5-nitrophenols in dry DMF (40mL) (1.53g, 9.0mmol) and imidazoles (1.08g adds tert-butyldimethylsilyl chloride (2.05g in mixture 15.9mmol), 13.6mmol), and mixture stirred under room temperature 16 hours.Remove under the vacuum and desolvate, and resistates is dissolved in 50% ethyl acetate of 40mL in hexane, and by the 10g filtered through silica gel.With the 50% ethyl acetate washing silica gel of additional 200mL in hexane, merging filtrate and vacuum concentrate and obtain the 2.01g product, are brown crystalline solid. 1H?NMR(CDCl 3)δ7.89(dd，1H，J＝9.0Hz，2.8Hz)，7.69(d，1H，J＝2.8Hz)，6.88(d，1H，J＝9.0)，3.90(s，3H)，1.00(s，9H)，0.18(s，6H)。
Embodiment 2
3-cyclopentyloxy-4-anisidine
At N 2Under the protection, and adding 1-cyclopentyloxy-2-methoxyl group-5-oil of mirbane in the suspension that is supported on the 10%Pd on the gac (25g) in ethanol (4L) (250g, 1.054mol).Under the vacuum reaction mixture is outgased three times.With the reaction mixture vigorous stirring, make hydrogen stream cross reaction mixture simultaneously.After 4 hours, by TLC (5: 1hex: EA) show and react completely.By celite pad filter reaction mixture, and with additional alcohol flushing celite.Remove under the vacuum and desolvate, obtain 208.38g (95% yield) 3-cyclopentyloxy-4-anisidine, be red liquid. 1H?NMR(CDCl 3)δ6.85(d，J＝8.4Hz，1H)，6.29(s，1H)，6.19(dd，J＝2.8，8.4，1H)，4.69(p，J＝4.4Hz，1H)，3.75(s，3H)，3.44(bs，2H)，1.90-1.81(m，6H)，1.61-1.55(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-difluoro-methoxy-aniline
B) 3-cyclo propyl methoxy-2-anisidine
C) 3-cyclo propyl methoxy-4-difluoro-methoxy-aniline
D) 4-methoxyl group-3-((3R)-tetrahydrofuran oxygen base) aniline
E) 4-methoxyl group-3-(tetrahydrofuran oxygen base) aniline
F) 4-methoxyl group-3-((3S)-tetrahydrofuran oxygen base) aniline
G) 4-difluoro-methoxy-3-(3-tetrahydrofuran oxygen base) aniline
H) 4-difluoro-methoxy-3-((3R)-tetrahydrofuran oxygen base) aniline
I) 4-difluoro-methoxy-3-((3S)-tetrahydrofuran oxygen base) aniline
J) 3-(t-butyldimethylsilyl) oxygen-4-anisidine
K) 4-methoxyl group-3-(3-benzene propoxy-) aniline
L) 3-(2-indane oxygen base)-4-anisidine
Embodiment 3
3-cyclopentyl-4-methoxyl group-N-(3-pyridylmethyl) aniline
(106.55g, (208.38g is 1.005mol) with tosic acid monohydrate (200mg) to add 3-cyclopentyloxy-4-anisidine in mixture 0.995mol) to the 3-pyridylaldehyde in methyl alcohol (5L).Reaction mixture was stirred 4 hours.Flask is cooled to 0 ℃ then, and in 4 hours, add in batches sodium borohydride (37.64g, 2.3mol).Make reaction mixture be warmed to room temperature under in 16 hours, stirring.TLC shows and reacts completely (1: 3hex: EA).Evaporating solvent is until keeping about 0.5L slurry.Water (1L) reduction paste, and with ethyl acetate (2 * 2L) extraction.Organic layer with salt solution (500mL) washing merges with dried over sodium sulfate and concentrated, obtains 300g (100% yield) target product, is brown viscous liquid. 1H?NMR(CDCl 3)δ8.61～8.48(m，2H)，7.69-7.67(m，1H)，7.24-7.21(m，1H)，6.72(d，J＝8.4Hz，1H)，6.23(s，1H)，6.13(dd，J＝2.6，8.6，1H)，4.65(bs，1H)，4.27(s，2H)，4.0(bs，1H)，3.73(s，3H)，1.88-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-N-(3-thienyl methyl) aniline
B) 3-cyclopentyloxy-4-methoxyl group-N-(4-pyridylmethyl) aniline
C) 3-cyclopentyloxy-N-(2,6-two chloro-4-pyridylmethyls)-4-anisidine
D) 3-cyclopentyloxy-4-methoxyl group-N-(2-quinolyl methyl) aniline
E) 3-cyclopentyloxy-4-methoxyl group-N-(3-quinolyl methyl) aniline
F) 3-cyclopentyloxy-4-methoxyl group-N-(4-quinolyl methyl) aniline
G) 3-cyclopentyloxy-4-methoxyl group-N-(2-pyrazinyl methyl) aniline
H) 4-methoxyl group-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) aniline
I) 4-methoxyl group-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) aniline
J) 4-methoxyl group-N-(3-pyridylmethyl)-3-((3S)-tetrahydrofuran oxygen base) aniline
K) 3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl) aniline
L) 3-cyclopentyloxy-4-difluoro-methoxy-N-(3-pyridylmethyl) aniline
M) 4-difluoro-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) aniline
N) 4-difluoro-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) aniline
O) 3, two (difluoro-methoxy)-N-(3-pyridylmethyl) aniline of 4-
P) 3-t-butyldimethylsilyloxy base-4-methoxyl group-N-(3-pyridylmethyl) aniline
Q) 3-cyclopentyloxy-4-methoxyl group-N-(2-pyridylmethyl) aniline
R) 3-cyclopentyloxy-4-methoxyl group-N-[1-(2-styroyl)] aniline
S) N-benzyl-3-cyclopentyloxy-4-anisidine
T) methyl N-[(hexamethylene-1-alkene-1-yl)]-3-cyclopentyloxy-4-anisidine
U) 3-cyclopentyloxy-4-methoxyl group-N-(3,4,5-trimethoxy benzyl) aniline
V) N-[(hexamethylene-3-alkene-1-yl) methyl]-3-cyclopentyloxy-4-anisidine
W) 3-cyclopentyloxy-4-methoxyl group-N-(2,4, the 6-trimethyl benzyl) aniline
X) 3-cyclopentyloxy-4-methoxyl group-N-(2-methyl-benzyl) aniline
Y) 3-cyclopentyloxy-4-methoxyl group-N-(2-trifluoromethyl benzyl) aniline
Z) 3-cyclopentyloxy-4-methoxyl group-N-((3, the 4-methylene-dioxy) benzyl) aniline
Aa) 3-cyclopentyloxy-N-(2-hydroxyl-3-methoxy-benzyl)-4-anisidine
Bb) 3-cyclopentyloxy-N-(3-furyl methyl)-4-anisidine
Cc) 3-cyclopentyloxy-4-methoxyl group-N-(3-methyl-benzyl) aniline
Dd) 3-cyclopentyloxy-4-methoxyl group-N-(2-methoxy-benzyl) aniline
Ee) 3-cyclopentyloxy-4-methoxyl group-N-(3-benzyl chloride base) aniline
Ff) 3-cyclopentyloxy-4-methoxyl group-N-(3-methoxy-benzyl) aniline
Gg) 3-cyclopentyloxy-4-methoxyl group-N-(2-benzyl chloride base) aniline
Hh) 3-cyclopentyloxy-4-methoxyl group-N-(3-methyl-benzyl) aniline
Ii) 4-methoxyl group-3-(3-benzene propoxy-)-N-(4-pyridylmethyl) aniline
Jj) N-(2,6-two chloro-4-pyridylmethyls)-3-(2-indane oxygen base)-4-anisidine
Kk) 4-methoxyl group-3-(3-benzene propoxy-)-N-(2-pyridylmethyl) aniline
Ll) N-(2,6-two chloro-4-pyridylmethyls)-4-methoxyl group-3-(3-benzene propoxy-) aniline
Mm) 4-methoxyl group-3-(3-benzene propoxy-)-N-(3-pyridylmethyl) aniline
Nn) 3-cyclopentyloxy-4-methoxyl group-N-(2-thienyl methyl) aniline
Oo) 3-(2-indane oxygen base)-4-methoxyl group-N-(3-thienyl methyl) aniline
Pp) 4-methoxyl group-3-(3-benzene propoxy-)-N-(3-thienyl methyl) aniline
Qq) 3-(2-indane oxygen base)-4-methoxyl group-N-(2-pyridylmethyl) aniline
Rr) 3-(2-indane oxygen base)-4-methoxyl group-N-(3-pyridylmethyl) aniline
Ss) 3-(2-indane oxygen base)-4-methoxyl group-N-(4-pyridylmethyl) aniline
Tt) 3-cyclopentyloxy-4-methoxyl group-N-(3-piperidine methyl) aniline
Uu) 3-cyclopentyloxy-4-methoxyl group-N-(3-(1-tertbutyloxycarbonyl) piperidine methyl) aniline
Vv) 3-cyclopentyloxy-4-methoxyl group-N-(6-methyl-2-pyridylmethyl) aniline
Ww) N-(2-chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-anisidine
Xx) N-(2-chloro-5-pyridylmethyl)-3-cyclopentyloxy-4-anisidine
Yy) 3-cyclopentyloxy-4-methoxyl group-N-(2-thiazolyl methyl) aniline
Embodiment 4
3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
In 100mL flask oven dry, argon cleaning, add 0.59g (6.10mmol) NaOtBu, 360mg Pd in the following sequence 2Dba 3, 20mL toluene, 0.14mL P (tBu) 3Solution with 1.3g (4.36mmol) N-(3-the pyridylmethyl)-3-cyclopentyloxy-4-anisidine of 20mL in toluene.Stir down, drip 3.1g (15mmol) phenyl-iodide, and mixture was stirred 18 hours.Use the EtOAc diluted reaction mixture, use H 2The O washed twice, and extract with 3 * 15mL 3N HCl.Acid extraction thing with 15mL EtOAc washing merges is neutralized to pH greater than 12 with 6N NaOH then carefully.With 2 * 15mL EtOAc extraction basic solution, use 15mL H then 2The organic moiety that O and salt water washing merge, dry (MgSO 4) and concentrate.With silica gel (Biotage Flash 40M) residue purified by chromatography, be used in the 25%EtOAc wash-out in the hexane.Further use the hexane crystallization and this material of purifying obtains the 550mg white solid. 1H?NMR(CDCl 3)δ8.61(s，1H)，8.49(d，1H，J＝4.2Hz)，7.67(d，1H，7.9Hz)，7.30-7.10(m，3H)，6.90-6.80(m，4H)，6.80-6.60(m，2H)，4.94(s，2H)，4.64(p，1H，J＝4.1Hz)，3.84(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-2 '-methyl-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4-methoxyl group-3 '-methyl-N-(3-pyridylmethyl) pentanoic
C) 3-cyclopentyloxy-4-methoxyl group-4 '-methyl-N-(3-pyridylmethyl) pentanoic
D) 3-cyclopentyloxy-4 '-ethyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
E) 3 '-chloro-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
F) 4 '-chloro-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
G) 3-cyclopentyloxy-2 ', 4-dimethoxy-N-(3-pyridylmethyl) pentanoic
H) 3-cyclopentyloxy-3 ', 4-dimethoxy-N-(3-pyridylmethyl) pentanoic
I) 3-cyclopentyloxy-4,4 '-dimethoxy-N-(3-pyridylmethyl) pentanoic
J) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-3 '-trifluoromethyl pentanoic
K) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-trifluoromethyl pentanoic
L) 3-cyclopentyloxy-3 '-fluoro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
M) 3-cyclopentyloxy-4 '-fluoro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
N) 3-cyclopentyloxy-4-methoxyl group-3 '-phenyl-N-(3-pyridylmethyl) pentanoic
O) 3-cyclopentyloxy-4-methoxyl group-4 '-phenyl-N-(3-pyridylmethyl) pentanoic
P) 3 '-cyano group-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Q) 4 '-cyano group-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
R) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin
S) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-4-subcutin
T) 3-cyclopentyloxy-4-methoxyl group-3 '-nitro-N-(3-pyridylmethyl) pentanoic
U) 3-cyclopentyloxy-4-methoxyl group-4 '-nitro-N-(3-pyridylmethyl) pentanoic
V) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-naphthalidine
W) 3-cyclopentyloxy-2 ', 3 '-dimethyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
X) 3-cyclopentyloxy-2 ', 4 '-dimethyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Y) 3-cyclopentyloxy-2 ', 5 '-dimethyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Z) 3-cyclopentyloxy-3 ', 4 '-dimethyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Aa) 3-cyclopentyloxy-2 ', 3 '-two chloro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Bb) 3-cyclopentyloxy-3 ', 4 '-two chloro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Cc) 3-cyclopentyloxy-3 ', 5 '-two chloro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Dd) 3 '-chloro-3-cyclopentyloxy-4 '-fluoro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Ee) 4 '-chloro-3-cyclopentyloxy-3 '-fluoro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Ff) 4 '-chloro-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-3 '-trifluoromethyl pentanoic
Gg) 3-cyclopentyloxy-4-methoxyl group-N-(3-thienyl methyl) pentanoic
Hh) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-thienyl methyl)-naphthalidine
Ii) 3-cyclopentyloxy-2 ', 3 '-two chloro-4-methoxyl group-N-(3-thienyl methyl) pentanoic
Jj) 3-cyclopentyloxy-4-methoxyl group-4 '-methyl-N-(4-pyridylmethyl) pentanoic
Kk) 3-cyclopentyloxy-N-(2,6-two chloro-4-pyridylmethyls)-4-methoxyl group-3 '-methyldiphenylamine
Ll) 2 '-chloro-3-cyclopentyloxy-N-(2,6-two chloro-4-pyridylmethyls)-4-methoxy diphenylamine
Mm) 3-cyclopentyloxy-N-(2,6-two chloro-4-pyridylmethyls)-4-methoxy diphenylamine
Nn) 3-cyclopentyloxy-4-methoxyl group-N-(6-methyl-2-pyridylmethyl) pentanoic
Oo) 3-cyclopentyloxy-4-methoxyl group-N-(3-quinolyl methyl) pentanoic
Pp) 3-cyclopentyloxy-4-methoxyl group-N-(4-quinolyl methyl) pentanoic
Qq) 3-cyclopentyloxy-4-methoxyl group-N-(2-pyrazinyl methyl) pentanoic
Rr) 4-methoxyl group-3 '-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Ss) 4-methoxyl group-4 '-methyl-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Tt) 4,4 '-dimethoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Uu) 3 '-chloro-4-methoxyl group-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Vv) 4-methoxyl group-4 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Ww) 3 '-cyano group-4-methoxyl group-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Xx) 3 '-cyano group-4-methoxyl group-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Yy) 3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl) pentanoic
Zz) 3-cyclopentyloxy-4-difluoro-methoxy-N-(3-pyridylmethyl) pentanoic
Aaa) 4-difluoro-methoxy-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
Bbb) 3, two (difluoro-methoxy)-N-(3-pyridylmethyl) pentanoic of 4-
Ccc) 4-difluoro-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Ddd) 3 '-cyano group-4-difluoro-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Eee) 3 '-chloro-4-difluoro-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Fff) N-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-N-(3-pyridylmethyl)-3-subcutin
Ggg) 3-cyclopentyloxy-4-methoxyl group-3 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl) pentanoic
Hhh) 3-cyclopentyloxy-4-methoxyl group-4 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl) pentanoic
Iii) 3 '-t-butyldimethylsilyloxy base-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Jjj) 4 '-t-butyldimethylsilyloxy base-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Kkk) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-aminobenzoic tert-butyl acrylate
Lll) N-(3-cyclopentyloxy)-4-difluoro-methoxy phenyl)-N-(3-pyridylmethyl)-3-subcutin
Mmm) N-(4-difluoro-methoxy-3-(3-tetrahydrofuran oxygen base) phenyl)-N-(3-pyridylmethyl)-3-subcutin
Nnn) N-(3, two (difluoro-methoxy) phenyl of 4-)-N-(3-pyridylmethyl)-3-subcutin
Ooo) N-(4-methoxyl group-3-((3R)-tetrahydrofuran oxygen base) phenyl)-N-(3-pyridylmethyl)-3-subcutin
Ppp) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin
Qqq) 3-cyclopentyloxy-4-methoxyl group-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Rrr) 3-cyclopentyloxy-4-methoxyl group-3 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Sss) 4-methoxyl group-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Ttt) 3-cyclo propyl methoxy-4-methoxyl group-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Uuu) 4-difluoro-methoxy-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base) pentanoic
Vvv) 3-cyclo propyl methoxy-4-difluoro-methoxy-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Www) 3-cyclopentyloxy-4-difluoro-methoxy-4 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Xxx) 3-cyclo propyl methoxy-4-difluoro-methoxy-3 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Yyy) two-(3, the 4-difluoro-methoxy)-3 '-(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl)-N-(3-pyridylmethyl) pentanoic
Zzz) 3-t-butyldimethylsilyloxy base-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Aaaa) 3-t-butyldimethylsilyloxy base-3 '-chloro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Bbbb) N-(3-t-butyldimethylsilyloxy base-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin
Cccc) 3-cyclopentyloxy-2 '-chloro-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Dddd) 3-(2-indane oxygen base)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 5
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid
Handle the solution of 6.5g N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-the pyridylmethyl)-3-subcutin in 50mL EtOH with 10mL 6N NaOH.Mixture was left standstill 6 hours, concentrate and use 50mL H 2The O dilution.With 2 * 50mL extracted with diethyl ether aqueous mixture, be acidified to pH 3 with AcOH, and extract with 2 * 50mL EtOAc.Use 25mL H 2The EtOAc cut that O and the water washing of 25mL salt merge, dry (MgSO 4) and concentrate.Use SiO 2(35g RediSep  post) residue purified by chromatography, the EtOAc of use linear gradient and hexane after 12 hours, provide 4.8g yellow solid product 60 ℃ of following vacuum-dryings as eluent (50%EtOAc to 70%EtOAc in 20 minutes). 1H?NMR(CDCl 3)δ11.15(bs，1H)，8.70-8.55(m，2H)，7.77-6.71(m，9H)，4.99(s，2H)，4.65(p，J＝3.8Hz，1H)，3.84(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-4-benzaminic acid
B) N-(3-cyclopentyloxy-4-difluoro-methoxy phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid
C) N-[4-difluoro-methoxy-3-(3-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
D) N-3, two (difluoro-methoxy) phenyl of 4-)-N-(3-pyridylmethyl)-3-benzaminic acid
E) N-[4-methoxyl group-3-((3R)-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
F) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-4-benzaminic acid
G) N-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid
H) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3-benzaminic acid
I) N-[3-(4-chloro-phenyl-) third-1-base oxygen-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
J) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid
K) N-[3-(2-indane oxygen base)-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
L) N-[4-methoxyl group-3-(3-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
M) N-[4-methoxyl group-3-((3R)-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
N) N-[3-(2-methoxy ethoxy)-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
O) N-[4-methoxyl group-3-(2-(2-pyridyl) ethyl) oxygen phenyl]-N-(3-pyridylmethyl)-3-benzaminic acid
Embodiment 6
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-2-benzaminic acid
(60mg 0.13mmol), and heated 4 hours under 40 ℃ to handle N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-2-aminobenzoic tert-butyl acrylate in 2mL 98% formic acid.Remove formic acid removal under the vacuum, and resistates is loaded into silica gel, and (RediSep is 4.2g) on the post.In 15 minutes, be used in 40%EtOAc in the hexane, obtain the 16mg product, be brown solid to the linear gradient elution product of 60%EtOAc in hexane. 1H?NMR(CDCl 3)δ8.47(d，1H，J＝4.9)，8.43(s，1H)，8.10(d，1H，J＝7.8)，7.67(d，1H，J＝7.8Hz)，7.56(m，1H)，7.40-7.20(m，3H)，6.75(d，1H，J＝8.7)，6.57(d，1H，J＝8.7)，6.47(s，1H)，4.72(s，2H)，4.54(p，1H，J＝4.3)，3.77(s，3H)，1.80-1.60(m，6H)，1.60-1.40(m，2H)。
Prepare following compound in mode similar to the above:
A) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid
B) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-6-amino-nicotinic acid
Embodiment 7
3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
(1.5g 0.26mmol) is dissolved in THF (5mL), and adds 3mL 1N HCl with 3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl)-4 '-[2-(2 THP trtrahydropyranyl)-2H-tetrazolium-5-yl] pentanoic.After following 6 hours of the room temperature, mixture is neutralized to pH=5, and (3 * 50mL) extract with EtOAc with saturated sodium bicarbonate aqueous solution.Merge the EtOAc extract, with salt solution (50mL) washing, dry (MgSO 4) and vacuum concentration.Thick resistates is loaded into RediSep post (10g, silica gel), and in 20 minutes, is used in 0%MeOH among the EtOAc, obtain the 0.96g product, be white powder to the linear gradient elution product of the 5%MeOH in EtOAc. 1H?NMR(CD 3OD)δ8.55(s，1H)，8.43(d，1H，J＝4.9Hz)，7.65(d，1H，8.0Hz)，7.21(dd，1H，J＝4.9Hz，8.0Hz)，7.18(d，1H，J＝8.9Hz)，7.10-6.90(m，3H)，6.87(dd，1H，J＝8.6Hz，2.5Hz)，6.75(t，1H，J＝75.5Hz)，5.14(s，2H)，3.82(d，2H，J＝6.9Hz)，1.23(m，1H)，0.60(m，2H)，0.33(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
B) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-3 '-(2H-tetrazolium-5-yl) pentanoic
C) 4-methoxyl group-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base)-4 '-(2H-tetrazolium-5-yl) pentanoic
D) 3-cyclo propyl methoxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
E) 4-difluoro-methoxy-N-(3-pyridylmethyl)-3-((3R)-tetrahydrofuran oxygen base)-4 '-(2H-tetrazolium-5-yl) pentanoic
F) 3-cyclopentyloxy-4-difluoro-methoxy-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
G) 3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl)-3 '-(2H-tetrazolium-5-yl) pentanoic
H) two-3,4-difluoro-methoxy-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
Embodiment 8 (method A)
3-cyclopentyloxy-4-methoxy diphenylamine
Method A. (Ref.Chan, D.M.T.; Monaco, K.L.; Wang, R.P.; Winters, M.P., Tetrahedron Lett., 1998,39,2933-2936).Under the room temperature, with 207mg 4-methoxyl group-3-cyclopentyloxy aniline, 280mg phenyl-boron dihydroxide, 182mgCu (OAc) 2, 280 μ L Et 3N and 4.0mL CH 2Cl 2Slurry stirred 20 hours.Use the filtered through silica gel black mixture, use CH 2Cl 2Wash-out concentrates, and uses SiO 2Chromatogram purification uses EtOAc/ hexane (15/85) as eluent, obtains the 75mg target product. 1H?NMR(CDCl 3)δ7.26-7.20(m，2H)，6.94-6.63(m，6H)，5.50(s，1H)，4.71(m，1H)，3.82(s，3H)，1.89-1.54(m，8H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-3 ', 4-dimethoxy pentanoic
B) 3 '-chloro-3-cyclopentyloxy-4-methoxy diphenylamine
C) 3-cyclopentyloxy-4-methoxyl group-3 '-methyldiphenylamine
D) 3-cyclopentyloxy-4 '-fluoro-4-methoxy diphenylamine
E) 3-cyclopentyloxy-4-methoxyl group-4 '-vinyl pentanoic
F) 3 '-cyano group-3-cyclopentyloxy-4-methoxy diphenylamine
G) 4 '-chloro-3-cyclopentyloxy-4-methoxy diphenylamine
H) 3-cyclopentyloxy-4,4 '-dimethoxy pentanoic
I) 3-cyclopentyloxy-4-methoxyl group-2 '-methyldiphenylamine
J) 3-cyclopentyloxy-4-methoxyl group-4 '-methyldiphenylamine
K) 2 '-chloro-3-cyclopentyloxy-4-methoxy diphenylamine
L) 3-cyclopentyloxy-2 ', 4-dimethoxy pentanoic
M) 3-cyclopentyloxy-4-methoxyl group-3 '-trifluoromethyl pentanoic
N) 3-cyclopentyloxy-4-methoxyl group-4 '-trifluoromethyl pentanoic
O) 3-cyclopentyloxy-2 ', 5 '-dimethyl-4-methoxy diphenylamine
Embodiment 8 (method B)
3-cyclopentyloxy-4-methoxy diphenylamine
Method B (Angerw Chem.Int.Ed., 1995,34 (17), 1348-1351).Merge 207mg 3-cyclopentyloxy-4-anisidine, 204mg phenyl-iodide, 115mgNaOtBu, 9mg Pd 2(dba) 3, 12mg P (o-tol) 3With the mixture of 7mL toluene, and be heated with stirring to 100 ℃, continue 4 hours.Mixture is cooled to room temperature,, and uses 10mL H with the 25mLEtOAc dilution 2O, the water washing of 10mL salt, dry (MgSO 4) and concentrate.Use SiO 2Residue purified by chromatography uses EtOAc/ hexane (5/95) as eluent, obtains the 84mg target product.
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-2 ', 4 '-dimethyl pentanoic
B) 3-cyclopentyloxy-2 ', 5 '-dimethyl-4-methoxy diphenylamine
C) 3-cyclopentyloxy-2 ', 3 '-dimethyl-4-methoxy diphenylamine
D) 3-cyclopentyloxy-3 ', 4 '-dimethyl-4-methoxy diphenylamine
E) 3-cyclopentyloxy-3 ', 4 '-methylene-dioxy pentanoic
F) 4 '-tertiary butyl-3-cyclopentyloxy-4-methoxy diphenylamine
G) 3-cyclopentyloxy-3 ', 4 '-two chloro-4-methoxy diphenylamines
H) 3-cyclopentyloxy-2 ', 3 '-two chloro-4-methoxy diphenylamines
Embodiment 8 (method C)
3-cyclopentyloxy-2 ', 4,5 '-trimethoxy pentanoic
Method C. is to Pd (dppf) Cl 2(0.025mmol, 5mol%), dppf (0.075mmol, 3dppf/Pd) and NaOtBu (0.70mmol, 1.4 add 1-bromo-2 equivalent) and in the mixture of 1.0mL THF, 5-dimethoxy benzene (0.55mmol, 1.1 equivalent), add the solution of the 3-cyclopentyloxy-4-anisidine of 1.0mL 0.5M in THF then.With mixture heating up to 60 ℃, continue 3 hours, with the ether dilution, and use H 2O and salt water washing, dry (MgSO 4) and concentrate.With the thick resistates of silica gel (Biotage Flash 12) chromatogram purification, be used in the 15%EtOA wash-out in the hexane;
Prepare following compound in mode similar to the above:
A) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3-pyridine amine
B) 3-cyclopentyloxy-2 ', 4 ', 4-trimethoxy pentanoic
C) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-pyridine amine
D) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-8-quinolyl amine
E) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-naphthylamines
F) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-naphthalidine
G) 3-cyclopentyloxy-4 '-ethyl-4-methoxy diphenylamine
H) 3-cyclopentyloxy-2 '-fluoro-4-methoxyl group-5 '-methyldiphenylamine
I) 3-cyclopentyloxy-3 '-fluoro-4-methoxyl group-4 '-methyldiphenylamine
J) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-PYRIMITHAMINE
K) 3-cyclopentyloxy-3 ', 5 '-two chloro-4-methoxy diphenylamines
L) 3-cyclopentyloxy-2 '-ethyl-4-methoxy diphenylamine
M) 4 '-chloro-3-cyclopentyloxy-3 '-fluoro-4-methoxy diphenylamine
N) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-4-isoquinoline 99.9 amine
O) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-pyrazine amine
P) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-5-PYRIMITHAMINE
Q) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-1-isoquinoline 99.9 amine
R) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3-quinolyl amine
S) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-4-pyridine amine
T) N-(3-cyclopentyloxy-4-difluoro-methoxy phenyl)-3-pyridine amine
U) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-3-pyridine amine
V) N-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-3-pyridine amine
W) N-(4-methoxyl group-3-(3R)-tetrahydrofuran oxygen base phenyl)-3-pyridine amine
X) N-(4-difluoro-methoxy-3-(3R)-tetrahydrofuran oxygen base phenyl)-3-pyridyl amine
Y) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3-subcutin
Z) 3-cyclopentyloxy-4 '-(N, N-dimethylamino)-4-methoxy diphenylamine
Aa) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-3-(6-methoxypyridine base) amine
Bb) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-2-amino-nicotinic acid methyl esters
Cc) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-6-amino-nicotinic acid tert-butyl ester
Dd) 2 '-amino-3-cyclopentyloxy-4-methoxy diphenylamine
Ee) 3-cyclopentyloxy-4-methoxyl group-3 '-(1-phthalimido) pentanoic
Ff) 3-cyclopentyloxy-4-methoxyl group-3 '-[2-(2-THP trtrahydropyranyl)-2H-tetrazolium-5-yl] pentanoic
Embodiment 9 (method A)
3-cyclopentyloxy-4-methoxyl group-N-methyldiphenylamine
Under 0 ℃, (70mg adds the 0.5M KN (TMS) of 0.55mL in toluene in solution 0.25mmol) to the cyclopentyloxy of the 3-in 3mL THF-4-methoxy diphenylamine 2Solution was stirred 0.5 hour down in 0 ℃, add 2.0 equivalent methyl iodide, and reaction mixture is warmed to room temperature.When reacting completely, add 10mL EtOAc, use 3mL H by the TLC demonstration 2O, 3mL salt solution purging compound, dry (MgSO 4) and concentrate.With the thick resistates of column chromatography (Biotage flash12) purifying, the 5%EtOAc of use in hexane is as eluent.
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-N-ethyl-4-methoxy diphenylamine
B) 3-cyclopentyloxy-4-methoxyl group-N-(1-propyl group) pentanoic
C) 3-cyclopentyloxy-4-methoxyl group-N-[1-(3-hydrocinnamyl)] pentanoic
D) N-benzyl-3-cyclopentyloxy-4-methoxy diphenylamine
E) 3-cyclopentyloxy-4-methoxyl group-N-(4-pyridylmethyl) pentanoic
F) 3-cyclopentyloxy-4-methoxyl group-N-(2-pyridylmethyl) pentanoic
G) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
H) 3-cyclopentyloxy-4-methoxyl group-N-[3-(3-pyridyl)-1-propyl group] pentanoic
I) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-ethyl-4-isoquinoline 99.9 amine
J) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-benzyl-4-isoquinoline 99.9 amine
K) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-methyl-4-isoquinoline 99.9 amine
L) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-propyl group-4-isoquinoline 99.9 amine
M) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(4-isoquinolyl)-N-(4-pyridylmethyl) amine
N) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(4-isoquinolyl)-N-(3-pyridylmethyl) amine
O) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-N-(5-pyrimidyl) amine
P) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(2-pyrazinyl)-N-(3-pyridylmethyl) amine
Q) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(2-pyridyl)-N-(3-pyridylmethyl) amine
R) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
S) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(4-pyridyl)-N-(3-pyridylmethyl) amine
T) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-6-amino-nicotinic acid tert-butyl ester
U) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
V) N-(4-methoxyl group-3-(3R)-tetrahydrofuran oxygen base phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
W) N-(3-cyclopentyloxy-4-difluoro-methoxy phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
X) N-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
Y) N-(4-difluoro-methoxy-3-(3R)-tetrahydrofuran oxygen base phenyl)-N-(3-pyridyl)-N-(3-pyridylmethyl) amine
Z) N-(4-chloro-3-pyridylmethyl)-N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(2-pyridyl) amine
Aa) N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(4-methyl-3-pyridylmethyl)-N-(2-pyridyl) amine
Bb) 3-cyclopentyloxy-4-methoxyl group-N-(2-thiazolyl methyl) pentanoic
Cc) N-(2-chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxy diphenylamine
Dd) N-(6-chloro-3-pyridylmethyl)-3-cyclopentyloxy-4-methoxy diphenylamine
Embodiment 9 (method B)
N-4-chloro-3-pyridylmethyl)-N-(3-cyclopentyl-4-p-methoxy-phenyl)-N-(2-pyridyl) amine
With (3-cyclopentyloxy-4-p-methoxy-phenyl)-2-pyridyl amine (30mg, 0.10mmol) and 4-chloropyridine methyl chloride hydrochloride (50mg, 0.25mmol) solution be dissolved in DMF (1mL), and divide small portion add sodium hydride (50mg 60% mineral oil dispersion liquid, 1.3mmol).Stir after 1 hour, in mixture impouring 25mL frozen water under the room temperature.(2 * 15mL) extraction mixtures, and merging EtOAc extract wash dry (MgSO with salt solution (15mL) with EtOAc 4) and vacuum concentration.Thick resistates is loaded on the RediSep post (4.2g, silica gel), and is used in 15%EtOAc eluted product in the hexane, obtain the 20mg product, be the yellow crystal solid. 1H?NMR(CDCl 3)δ8.61(s，1H)，8.34(d，1H，J＝5.3Hz)，8.17(d，1H，5.0Hz)，7.33(m，1H)，7.25(m，1H)，6.83(d，IH，J＝8.5)，6.75(d，1H，J＝8.5)，6.71(s，1H)，6.62(m，1H)，6.42(d，1H，J＝8.6)，5.31(s，2H)，4.63(p，1H，J＝4.12Hz)，3.83(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3, two (the difluoro-methoxy)-N-(4-chloro-3-pyridylmethyl)-3 ' of 4--(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl) pentanoic
B) 3, two (the difluoro-methoxy)-N-(4-methyl-3-pyridylmethyl)-3 ' of 4--(2-(tetrahydropyrans-2-yl)-2H-tetrazolium-5-yl) pentanoic
Embodiment 10
3-cyclopentyloxy-4-anisole amido-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide
Under the room temperature, at CH 2Cl 2N-(2mL) (3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid (20mg, 0.05mmol) and pyBOP (40mg, add in solution 0.08mmol) diisopropyl ethyl amine (20L, 0.11mmol).Stir after 15 minutes, the adding 4-aminopyridine (15mg, 0.15mmol), and with mixture stirring 16 hours.With EtOAc (25mL) diluted mixture thing, and water (2 * 15mL) and salt solution (15mL) washing, dry (MgSO 4) and vacuum concentration.Thick resistates is loaded on the RediSep post (4.2g, silica gel), and in 15 minutes, is used in 40%EtOAc in the hexane, obtain the 22mg product to the linear gradient elution product of 60%EtOAc in hexane. 1HNMR(CDCl 3)δ8.70-8.40(m，3H)，8.24(s，1H)，7.72(d，1H，9.0Hz)，7.68-7.55(m，2H)，7.30-7.20(m，1H)，6.88(d，2H，J＝8.5)，6.80-6.65(m，3H)，4.98(s，2H)，4.66(p，1H，J＝4.1Hz)，3.86(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-(3-cyclopentyloxy-4-anisole amido)-N-(3-pyridylmethyl)-N-3-[3-(N, N-dimethylamino) third-1-yl] benzamide
B) 3-cyclopentyloxy-4-methoxyl group-3 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl) pentanoic
C) 3-cyclopentyloxy-4-difluoro-methoxy-4 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl) pentanoic
D) 3-cyclopentyloxy-4-methoxyl group-4 '-(4-methylpiperazine-1-base carbonyl)-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base)-pentanoic
Embodiment 11
To prepare following compound with embodiment 2 described similar modes:
A) 4 '-amino-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3 '-amino-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
C) 3 '-amino-3-cyclo propyl methoxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
D) 3 '-amino-4-methoxyl group-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuran oxygen base] pentanoic
Embodiment 12
3-cyclopentyloxy-4 '-methanesulfonamido-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Under the room temperature, at CH 2Cl 24 '-amino (2mL)-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic (47mg, 0.12mmol) solution in add pyridine (20 microlitres 0.24mmol), add methylsulfonyl chloride (15 microlitres then, 0.18mmol), and mixture left standstill under room temperature 16 hours.With ether (50mL) diluted mixture thing, and water (25mL) and salt solution (25mL) washing, dry (MgSO 4) and concentrate.With the thick resistates of flash distillation column chromatography (4.2gRediSep post, silica gel) purifying, be used in 45%EtOAc in the hexane in 20 minutes to the linear gradient elution of 60%EtOAc in hexane, obtain the 41mg product. 1HNMR(CDCl 3)δ8.51(s，1H)，8.41(d，1H，J＝4.8Hz)，7.56(d，1H，7.9Hz)，7.16(m，1H)，6.98(d，2H，J＝9.0Hz)，6.80-6.60(m，6H)，4.82(s，2H)，4.56(p，1H，J＝4.0Hz)，3.75(s，3H)，2.86(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-3 '-ethanesulfonamido-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4-methoxyl group-3 '-(1-third sulfonamido)-N-(3-pyridylmethyl) pentanoic
C) 3 '-(1-fourth sulfonamido)-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
D) 3 '-benzyl sulfonamido-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
E) 3 '-acetamido-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
F) 3-cyclopentyloxy-4 '-ethanesulfonamido-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
G) 3-cyclopentyloxy-4-methoxyl group-4 '-(1-third sulfonamido)-N-(3-pyridylmethyl) pentanoic
H) 3-cyclo propyl methoxy-3 '-ethanesulfonamido-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
I) 4-difluoro-methoxy-3 '-ethanesulfonamido-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuran oxygen base] pentanoic
Embodiment 13
3-cyclopentyloxy-4-methoxyl group-3 '-methylol-N-(3-pyridylmethyl) pentanoic
Under 0 ℃, to the N-in THF (5mL) (3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin (50mg, 0.11mmol) drip while stirring at toluene (0.4mL, 1.00mmol) the 2.5M diisobutylaluminium hydride in the solution.Under 0 ℃, mixture was stirred 1 hour, by 5 EtOAc being added the reaction that stops excessive diisobutylaluminium hydride in the mixture.Enriched mixture, and use CH 2Cl 2(50mL) and water (50mL) distribute resistates.Separate each layer, and use CH 2Cl 2(2 * 10mL) aqueous layer extracted.Merge organic extract, with salt solution (50mL) washing, dry (MgSO 4) and concentrate.With flash distillation column chromatography (4.2g RediSep post, silica gel) the thick resistates of purifying, with the 50%EtOAc wash-out of 300mL in hexane, use the 100%EtOAc wash-out then, obtain the 15mg product. 1H?NMR(CDCl 3)δ8.51(s，1H)，8.40(br，1H)，7.58(d，1H，7.9Hz)，7.25-7.05(m，3H)，6.80-6.60(m，5H)，4.85(s，2H)，4.56(p，1H，J＝4.1Hz)，4.50(s，2H)，3.76(s，3H)，1.86-1.70(m，7H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-4 '-methylol-N-(3-pyridylmethyl) pentanoic
Embodiment 14
3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic
To the N-in DMF (3mL) (3-cyclopentyloxy-4-p-methoxy-phenyl)-(100mg adds NaN in solution 0.25mmol) to N-(3-pyridylmethyl)-3-aminobenzonitrile 3(163mg, 2.5mmol) and NH 4(135mg 2.5mmol), and stirs mixture 6 hours under 120 ℃ Cl.Mixture is cooled to room temperature, and water (50mL) dilutes, and (2 * 25mL) extract with EtOAc.Merge the EtOAc extract, water (25mL) and salt solution (25mL) washing, dry (MgSO 4) and vacuum concentration.Resistates is loaded on the RediSep post (4.2g, silica gel), and is used in the linear gradient elution of 50%～75%EtOAc in the hexane, obtain the 12mg product. 1H?NMR(CDCl 3)δ12.50(br，1H)，8.64(s，1H)，8.54(br，1H)，7.86(d，2H，J＝8.8Hz)，7.75(d，1H，7.8Hz)，7.36(m，1H)，6.80-6.60(m，5H)，4.99(s，2H)，4.66(p，1H，J＝4.1Hz)，3.84(s，3H)，1.86-1.70(m，7H)，1.65-1.45(m，2H)。
Embodiment 15
3-cyclopentyloxy-4-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl methyl)-N-(3-pyridylmethyl) pentanoic
To the 3-cyclopentyloxy-4-methoxyl group-4 ' in THF (5mL)-(4-methylpiperazine-1-base carbonyl) pentanoic (100mg, carefully add while stirring in solution 0.20mmol) lithium aluminium hydride (50mg, 1.3mmol).Mixture was stirred 15 minutes, and carefully add several EtOAc to stop excessive hydride reaction.Add entry (50mL) and CH 2Cl 2(50mL), and by the Celite filtering mixt.Separation of C H 2Cl 2Layer, with salt solution (25mL) washing, dry (MgSO 4) and vacuum concentration.(4.2g, silica) the thick resistates of purifying are used in 5%MeOH among the EtOAc to the gradient elution of 15%MeOH in EtOAc, obtain the 60mg product, are light yellow oil with ISCO RediSep post. 1H?NMR(CDCl 3)δ8.59(s，1H)，8.47(d，1H，J＝4.8Hz)，7.65(d，1H，7.9Hz)，7.21(dd，1H，J＝4.8Hz，7.9Hz)，7.11(d，2H，J＝8.6Hz)，6.82-6.73(m，3H)，6.70-6.65(m，2H)，4.91(s，2H)，4.62(p，1H，J＝4.12Hz)，3.82(s，3H)，3.41(s，2H)，2.75-2.20(m，8H)，2.27(s，3H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-4-methoxyl group-3 '-(4-methyl isophthalic acid-piperazinyl methyl)-N-(3-pyridylmethyl) pentanoic
Embodiment 16
3 '-amino methyl-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Stir down, to the N-in THF (5mL) (3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-aminobenzonitrile (50mg, in solution 0.12mmol) careful add lithium aluminium hydride (20mg, 0.52mmol).Mixture was stirred 4 hours, and carefully add several dripping to stop excessive hydride reaction.Add entry (50mL) and CH 2Cl 2(50mL), and by the Celite filtering mixt.Separation of C H 2Cl 2Layer, with salt solution (25mL) washing, dry (MgSO 4) and vacuum concentration.With the thick resistates of ISCO RediSep post (4.2g, silica gel) purifying, be used in the 10%MeOH wash-out among the EtOAc, obtain the 20mg product. 1H?NMR(CDCl 3)δ8.60(s，1H)，8.47(br，1H)，7.65(d，1H，7.8Hz)，7.26-7.10(m，2H)，6.90-6.65(m，6H)，4.94(s，2H)，4.63(p，1H，J＝4.1Hz)，3.83(s，3H)，3.75(m，2H)，2.29(br，2H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Embodiment 17
3-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Under 0 ℃, (1.20g is added in THF (10mL, 10mmol) the 1.0M tertiary butyl Neutral ammonium fluoride in solution 2.85mmol) to the 3-in THF (40mL) (t-butyldimethylsilyloxy base)-N-(3-pyridylmethyl)-4-methoxy diphenylamine.Mixture was stirred 30 minutes down in 0 ℃.Add entry (50mL), and (3 * 25mL) extract mixtures with ether.Merge ethereal extract, and water (3 * 25mL) and salt solution (25mL) washing, drying (MgSO 4) and vacuum concentration.Resistates is ground with hexane, and collect, obtain the 0.85g product by vacuum filtration. 1H?NMR(CDCl 3)δ8.58(s，1H)，8.46(br，1H)，7.67(d，1H，7.8Hz)，7.26-7.10(m，3H)，6.90-6.65(m，5H)，6.64(dd，1H，J＝8.6Hz，2.6Hz)，6.53(br，1H)，4.92(s，2H)，3.86(s，3H)。
Prepare following compound in mode similar to the above:
A) 3 '-chloro-3-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) N-(3-hydroxyl-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin
Embodiment 18 (method B)
To prepare following compound with similar mode described in the embodiment 1B:
A) 3-[3-(4-chloro-phenyl-) third-1-base oxygen]-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-[2-(4-chloro-phenyl-) oxyethyl group]-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
C) 4-methoxyl group-3-(4-phenoxy group fourth-1-yl) oxygen-N-(3-pyridylmethyl) pentanoic
D) 4-methoxyl group-N-(3-pyridylmethyl)-3-(3-tetrahydrofuran oxygen base) pentanoic
E) 4-methoxyl group-3-[3-(4-p-methoxy-phenyl) third-1-yl] oxygen-N-(3-pyridylmethyl) pentanoic
F) 4-methoxyl group-3-[3-(4-pyridyl) third-1-yl] oxygen-N-(3-pyridylmethyl) pentanoic
G) 4-methoxyl group-3-[2-(4-p-methoxy-phenyl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
H) 4-methoxyl group-3-(4-phenyl fourth-1-yl) oxygen-N-(3-pyridylmethyl) pentanoic
I) 4-methoxyl group-3-[4-(4-p-methoxy-phenyl) fourth-1-yl] oxygen-N-(3-pyridylmethyl) pentanoic
J) 4-methoxyl group-3-[4-(4-nitrophenyl) fourth-1-yl] oxygen-N-(3-pyridylmethyl) pentanoic
K) 4-methoxyl group-3-[2-(2-pyridyl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
L) 4-methoxyl group-3-[2-(4-pyridyl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
M) 4-methoxyl group-3-[3-(2-pyridyl) third-1-yl] oxygen-N-(3-pyridylmethyl) pentanoic
N) 4-methoxyl group-3-(2-methoxy ethoxy)-N-(3-pyridylmethyl) pentanoic
O) 3-cyclo propyl methoxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
P) 4-methoxyl group-3-(1-methylpyrrolidin-3-yl) oxygen-N-(3-pyridylmethyl) pentanoic
Q) 4-methoxyl group-3-(1-methyl piperidine-4-yl) oxygen-N-(3-pyridylmethyl) pentanoic
R) 4-methoxyl group-N-(3-pyridylmethyl)-3-[(3S)-tetrahydrofuran oxygen base] pentanoic
S) 4-methoxyl group-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuran oxygen base] pentanoic
T) 3 '-chloro-4-methoxyl group-3-[2-(2-pyridyl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
U) 3 '-chloro-4-methoxyl group-3-[2-(4-pyridyl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
V) 3 '-chloro-4-methoxyl group-3-(2-methoxy ethoxy)-N-(3-pyridylmethyl) pentanoic
W) 3 '-chloro-4-methoxyl group-N-(3-pyridylmethyl)-3-[(3R)-tetrahydrofuran oxygen base] pentanoic
X) 3-cyclohexyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Y) 3-ring oxygen base in heptan-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Z) 3-(2-cyclopropyl oxyethyl group)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Aa) 3-cyclopentyl methoxyl group-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Bb) N-[3-(4-chloro-phenyl-) third-1-base oxygen-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-subcutin
Cc) N-(3-cyclo propyl methoxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-subcutin
Dd) N-(3-cyclo propyl methoxy-4-difluoro-methoxy phenyl)-N-(3-pyridylmethyl)-3-subcutin
Ee) N-[3-(2-indane oxygen base)-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-subcutin
Ff) N-[4-methoxyl group-3-(3-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-subcutin
Gg) N-[4-methoxyl group-3-((3R)-tetrahydrofuran oxygen base) phenyl]-N-(3-pyridylmethyl)-3-subcutin
Hh) N-[3-(2-methoxy ethoxy)-4-p-methoxy-phenyl]-N-(3-pyridylmethyl)-3-subcutin
Ii) N-[4-methoxyl group-3-(2-(2-pyridyl) ethyl) oxygen phenyl]-N-(3-pyridylmethyl)-3-subcutin
Embodiment 18 (method C)
With with the described similar mode of embodiment 8A, prepare following compound by the coupling of phenol and boric acid rather than the coupling of aniline and boric acid:
A) 4-methoxyl group-3-(4-methoxyl group phenoxy group)-N-(3-pyridylmethyl) pentanoic
B) 4-methoxyl group-3-phenoxy group-N-(3-pyridylmethyl) pentanoic
C) 4-methoxyl group-3-(4-methylphenoxy)-N-(3-pyridylmethyl) pentanoic
D) 3-(4-chlorophenoxy)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
E) 3-[2-(4-chloro-phenyl-) vinyloxy group]-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 19
To prepare following compound with embodiment 17 described similar modes:
A) 3-cyclopentyloxy-3 '-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4 '-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
C) 3-cyclo propyl methoxy-4 '-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 20 (method A)
To prepare following compound with the described similar mode of embodiment 1A:
A) 3 '-(2-bromine oxethyl)-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 20 (method B)
To prepare following compound with the described similar mode of embodiment 1B:
A) 3-cyclopentyloxy-4 '-(2-methoxy ethoxy)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4 '-(3-methyl isophthalic acid-butoxy)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
C) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-[(3S)-tetrahydrofuran oxygen base] pentanoic
D) 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-[(3R)-tetrahydrofuran oxygen base] pentanoic
E) 3-cyclopentyloxy-4 '-cyclo propyl methoxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
F) 4 '-cyclohexyl oxyethyl group-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
G) 4 '-cyclopentyl oxyethyl group-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
H) 3-cyclopentyloxy-4-methoxyl group-4 '-(1-methyl piperidine-4-base oxygen)-N-(3-pyridylmethyl) pentanoic
I) 3-cyclopentyloxy-4-methoxyl group-4 '-(1-methylpyrrolidin-3-base oxygen)-N-(3-pyridylmethyl) pentanoic
J) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(1-methylpyrrolidin-2-yl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
K) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(1-pyrrolidyl oxyethyl group)-N-(3-pyridylmethyl) pentanoic
L) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(6-picolyl) methoxyl group)-N-(3-pyridylmethyl) pentanoic
M) 3-cyclopentyloxy-4-methoxyl group-4 '-[3-(1-methyl piperidine base) methoxyl group]-N-(3-pyridylmethyl) pentanoic
N) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(1-methyl piperidine base) methoxyl group]-N-(3-pyridylmethyl) pentanoic
O) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(5-oxo-pyrrolidine base) methoxyl group]-N-(3-pyridylmethyl) pentanoic
P) 4 '-[1-(3-bromopropyl) oxygen]-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Q) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(N-phthalimido) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
Embodiment 21
3-cyclopentyloxy-4-methoxyl group-3 '-[2-(piperidino) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
To 3 '-(2-the bromine oxethyl)-3-cyclopentyloxy in acetonitrile (1mL)-4-methoxyl group-N-(3 pyridylmethyl) pentanoic (17mg, 0.03mmol) solution in add salt of wormwood (25mg, 0.18mmol) and piperidines (5 μ L, 0.05mmol), and under 60 ℃, mixture was stirred 4 hours.Water (50mL) and EtOAc (50mL) distribute mixture.Separate each layer and water (25mL) and salt solution (25mL) washing organic layer, dry (MgSO 4) and vacuum concentration.Resistates is loaded on the ISCO RediSep post (4.2g, silicon-dioxide), and is used in 5%MeOH among the EtOAc, obtain the 11mg product to this post of linear gradient elution of 15%MeOH in EtOAc. 1H?NMR(CDCl 3)δ8.59(s，1H)，8.48(d，1H，J＝4.7)，7.64(d，1H，8.2Hz)，7.26-7.20(m，1H)，7.06(t，1H，J＝8.6Hz)，6.81(d，1H，J＝9.2Hz)，6.75-6.68(m，2H)，6.45-6.35(m，3H)，4.91(s，2H)，4.64(p，1H，J＝4.1Hz)，4.00(t，2H，J＝6.2Hz)，3.84(s，3H)，2.71(t，2H，J＝6.2Hz)，2.47(m，4H)，1.90-1.70(m，6H)，1.86-1.70(m，6H)，1.65-1.45(m，2H)。
Prepare following compound in mode similar to the above:
A) 3-cyclopentyloxy-3 '-[2-(1-imidazolyl) oxyethyl group]-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4-methoxyl group-3 '-[2-(1-methylpiperazine-4-yl) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
C) 3-cyclopentyloxy-4-methoxyl group-4 '-[3-(2-methylpiperazine-4-yl) propoxy-]-N-(3-pyridylmethyl) pentanoic
D) 3-cyclopentyloxy-4-methoxyl group-4 '-[3-(1-methylpiperazine-4-yl) propoxy-]-N-(3-pyridylmethyl) pentanoic
E) 3-cyclopentyloxy-4-methoxyl group-4 '-[3-(2-morpholine-4-base ethylamino) propoxy-]-N-(3-pyridylmethyl) pentanoic
F) 4-methoxyl group-3-(2-phenoxy group oxyethyl group)-N-(3-pyridylmethyl) pentanoic
G) 3-[2-(4-chlorophenoxy) oxyethyl group)-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
H) 4-methoxyl group-3-(2-tetramethyleneimine-1-yl) oxyethyl group-N-(3-pyridylmethyl) pentanoic
I) 4-methoxyl group-3-(2-(4-methylpiperazine-1-yl) oxyethyl group)-N-(3-pyridylmethyl) pentanoic
J) 3-[2-(4-chloro-phenyl-amino) oxyethyl group]-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 22
4 '-amino ethoxy-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
To the N-in MeOH (5mL) (3-pyridylmethyl)-3 '-[2-(2-phthalimido) oxyethyl group]-3 cyclopentyloxies-4-methoxy diphenylamine (0.39g, add in solution 0.69mmol) hydrazine hydrate (1.0mL, 20mmol).After following 6 hours of the room temperature, add EtOAc (50mL), and leach precipitation.Water (25mL) and salt solution (25mL) wash filtrate, dry (MgSO 4) and vacuum concentration.Resistates is loaded on the ISCO RediSep post (10g, silicon-dioxide).Be used in this post of 10%MeOH wash-out among the EtOAc (200mL), and be used in the 50%MeOH eluted product among the EtOAc, obtain 0.21g. 1H?NMR(CDCl 3)δ8.55(s，1H)，8.42(d，1H，J＝3.8Hz)，7.62(d，1H，7.7Hz)，7.20-7.10(m，1H)，6.91(d，2H，J＝9.0Hz)，6.78(d，2H，J＝9.0Hz)，6.70(d，1H，J＝8.6Hz)，6.50-6.35(m，2H)，4.82(s，2H)，4.54(p，1H，J＝4.1Hz)，3.90(t，2H，J＝6.1Hz)，3.74(s，3H)，3.01(m，2H)，1.86-1.70(m，8H)，1.65-1.45(m，2H)。
Embodiment 23
To prepare following compound with embodiment 12 described similar modes:
A) 3-cyclopentyloxy-4 '-(2-methanesulfonamido) oxyethyl group-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
B) 3-cyclopentyloxy-4 '-(2-ethanesulfonamido) oxyethyl group-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
C) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(2-third sulfonamido) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
D) 3-cyclopentyloxy-4-methoxyl group-4 '-[2-(1-third sulfonamido) oxyethyl group]-N-(3-pyridylmethyl) pentanoic
E) 4 '-[2-(1-fourth sulfonamido) oxyethyl group]-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic
Embodiment 24
The external test of 4 type phosphodiesterase depressing activities
Obtain people PDE4 from the Sf9 cell of the baculovirus infection of express recombinant enzyme.With the coding hPDE-4D6 the cDNA subclone to baculovirus vector.With this baculovirus infection insect cell (Sf9), and culturing cell is until giving expression to albumen.With the cytolysis of baculovirus infection, and with lysate as hPDE-4D6 enzyme source.With DEAE ion-exchange chromatography partially purified enzyme.Can use other PDE-4 enzyme of cDNA coding to repeat this process.
Assay method:
4 type phosphodiesterases are converted into 5 '-adenylic acid (5 '-AMP) with 3'5'-AMP (cAMP).Phosphonuclease is converted into adenosine with 5 '-AMP.Therefore, the combined activity of PDE 4 and phosphonuclease is converted into adenosine with cAMP.Easily separate cAMP and adenosine by the neutral alumina post.Phosphodiesterase inhibitor is blocked in this assay method cAMP to the conversion of adenosine, thereby PDE 4 inhibitor cause adenosine to reduce.
The cell lysates (40 μ l) of expressing hPDE-4D6 is merged with 50 μ l analysis of mixtures and 10 μ l inhibitor, and at room temperature cultivated 12 minutes.The ultimate density of analyzing component is: 0.4 μ g enzyme, 10mM Tris-HCl (pH 7.5), 10mM MgCl 2, 3 μ M cAMP, 0.002U 5 '-phosphonuclease and 3 * 10 4Cpm[3H] cAMP.By adding the 5mNHCl termination reaction that 100 μ l boil.The aliquots containig of 75 μ l reaction mixtures is transferred to alumina column (Multiplate from every hole; Millipore) on.Adenosine by rotation 2 minutes under 2000rpm with mark is eluted among the OptiPlate; The scintillating liquid in 150 μ l/ holes is added among this OptiPlate.Flat board is airtight, vibrated about 30 minutes, and use Wallac Triflux  mensuration [ 3H] cpm of adenosine.
All test compounds being dissolved in 100%DMSO, and being diluted to analysis, is 0.1% thereby make the ultimate density of DMSO.The DMSO of this concentration does not influence enzymic activity.
The active inhibition of PDE is represented in the reduction of adenosine concentration.Measure pIC by the compound concentration that to screen 6～12 scopes be 0.1nM to 10000nM 50Value, it is right to draw drug level then 3The figure of H-adenosine concentration.Use non-linear regression software (Assay Explorer ) estimation pIC 50Value.
Embodiment 25 (method A)
The passive avoidance of rat is about the in vivo test of learning and memory
As mentioned previously (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J. and O ' Donnell, J.M., Neuropsychopharmacology, 2000,23,198-204.) test.(Allentown PA) is made up of chamber, two septal area instrument for Model E10-16SC, Coulboum Instruments, wherein illuminates the septal area and is connected with dark septal area by gate.The door of dark septal area is made up of stainless steel, provides the foot from the constant current source to shock by electricity by this bar.All experimental group a day before beginning to test at first adapts to this instrument.At training period, before 1 minute, (male Spraque-Dawley (Harlan) weighs 250～350g) right the illuminating in the compartment of gate forward surface that are placed on and close with rat at lift door.Record enters the waiting time of dark compartment.After rat enters dark compartment, close door and use 3 second 0.5mA electric shock.After 24 hours, (dosage is 0.1～2.5mg/kg, i.p.) before 30 minutes, gives rat 0.1mg/kg MK-801 or salt solution, and it is before beginning test 30 minutes at pump pickle or test compound.Once more rat is placed on open the illuminating in the compartment of gate.Record enters the 180 seconds at the most waiting time of dark septal area, at this moment termination test.
(ANOVA) analyzes all data by variance analysis, uses Kewman-Keuls check carrying out individuality relatively.Nude mice on average needs to be less than 30 seconds and passes the septal area that illuminates and enters dark septal area.But after 24 hours, major part no longer enters dark septal area with the pretreated rat of vehicle in the electric shock contact; Average latency increases to 175 seconds (p＜0.001).Compare with vehicle, significantly shorten waiting time (p＜0.001) with MK-801 (0.1mg/kg) pre-treatment.Actual test compound makes with the dose-dependently pattern on this amnesia generation statistics of MK-801 and reverses significantly (as 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic, effective dosage ranges=0.5～2.5mg/kg, i.p.; And N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid, effective dosage ranges=0.1～2.5mg/kg, ip).
Embodiment 25 (method B)
The radial arms labyrinth task of rat is about the in vivo test of learning and memory
As mentioned previously (Zhang, H.-T., Crissman, A.M., Dorairaj, N.R., Chandler, L.J., and O ' Donnell, J.M., Neuropsychopharmacology, 2000,23,198-204) test.After raising in cages at first 5 days, rat (weighing the male Spraque-Dawley (Harlan) of 250～350g) is placed on (high 60 * 10 * 12cm of every arm in the radial labyrinth of eight arms; The labyrinth is risen to top, ground 70cm) to tame two days.Then rat was placed 5 minutes at the center, labyrinth separately, and food lumps is placed on place near the food pond, be placed on the pond of arm end subsequently at second day; Carry out twice operation every day.Then, four arms selecting are at random respectively adorned a food lumps bait.Rat is limited on the central platform (diameter 26cm), continues 15 seconds, it is moved freely by the labyrinth, collect all food lumps or through 10 minutes, which at first took place which then adopts until it.Write down four parameters: 1) working memory mistake promptly enters the bait arm in the accessed mistake of identical duration of test; 2), promptly enter the arm of not putting bait with reference to paramnesia; 3) total arm inlet; With 4) duration of test runs (second), promptly collect the time that all food lumps spent in the labyrinth.If in 5 long run tests, the working memory mistake is zero, and on average with reference to paramnesia less than 1, then rat begins drug test.Injection MK-801 or salt solution, injection of vehicle or trial drug after 15 minutes begin test after 45 minutes.Experimentize in that illumination is indoor, several additional labyrinths visual cues is contained in this chamber.
(ANOVA) analyzes all data by variance analysis, uses Kewman-Keuls check carrying out individuality relatively.Compared with the control, MK-801 (0.1mg/kg, i.p.) increase work and with reference to the frequency (p＜0.01) of paramnesia.The administration of actual test compound makes MK-801 to reversing significantly on this amnesia generation statistics of working memory (as 3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic with the dose-dependently pattern, effective dose=2.5mg/kg, i.p.; P＜0.01).
Can come the embodiment of repetition front and obtain similar success by replace in the previous embodiment used reactant and/or working conditions with the reactant of general or specific description of the present invention and/or operational condition.
Though illustration specific compound of the present invention and production, obviously can under the situation that does not deviate from design of the present invention or scope, change and revise the present invention.

Claims (63)

1. the compound of formula I and pharmacologically acceptable salts thereof,
Figure C028070100002C1
Wherein:
R 1For having the alkyl of 1～4 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by halogen;
R 2For having the alkyl of 1～12 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, hydroxyl, cyano group, C 1～4-alkoxyl group, oxygen or their combination,
Cycloalkyl with 3～10 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, hydroxyl, oxygen, cyano group, alkyl, alkoxyl group or their combination with 1～4 carbon atom with 1～4 carbon atom, or
Cycloalkylalkyl with 4～16 carbon atoms, it is not substituted or is replaced one or many at cycloalkyl moiety and/or moieties by following group: halogen, oxygen, cyano group, hydroxyl, C 1～4-alkyl, C 1～4-alkoxyl group or their combination;
R 3Be heteroarylalkyl, wherein heteroaryl moieties has 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, moieties is side chain or non-side chain, have 1～5 carbon atom, described heteroarylalkyl is not substituted or is replaced one or many at heteroaryl moieties by following group: halogen, alkyl, alkoxyl group, cyano group, trifluoromethyl, CF 3O, nitro, oxygen, amino, alkylamino, dialkyl amido or their combination;
R 4For having the aryl of 6～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, OCF 3, amino, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, 2-(tetrahydropyrans)-tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, alkylthio, alkyl sulfinyl, alkyl sulphonyl, R 5-L-or their combination, perhaps
Heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, and it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, the alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, the hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, the alkyl sulfinyl, alkyl sulphonyl, phenoxy group, trialkylsiloxy or their combination;
R 5For having the alkyl of 1～8 carbon atom, it is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination have the cycloalkylalkyl of 4～16 carbon atoms, and it is not substituted or is replaced one or many at cycloalkyl moiety by following group: halogen, oxygen, cyano group, hydroxyl, alkyl, alkoxyl group or their combination,
Aryl with 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl or their combination, perhaps
Heterocyclic radical, it is saturated, fractional saturation or undersaturated, has 5～10 annular atomses,
Wherein at least one annular atoms is N, O or S atom, and it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl, phenoxy group or their combination;
L is singly-bound or the divalent aliphatic base with 1～8 carbon atom, wherein one or more-CH 2-group is optional separately to be replaced by following group :-O-,-S-,-NR 6-,-SO 2NH-,-NHSO 2-,-CO-,-NR 6CO-or-CONR 6-; And
R 6Be H, or
Alkyl with 1～8 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination.
2. according to the compound of claim 1, R wherein 1Be methyl or CHF 2
3. according to the compound of claim 1, R wherein 1Be methyl or CHF 2, and R 2Be cyclopentyl, CHF 2Or cyclopropyl methyl.
4. according to the compound of claim 1, R wherein 1Be methyl or CHF 2, and R 2Be cyclopentyl.
5. according to the compound of claim 1, R wherein 1Be methyl, R 2Be cyclopentyl, and R 4For being substituted or unsubstituted aryl.
6. according to the compound of claim 1, R wherein 1Be CHF 2, R 2Be methyl, ethyl or CHF 2, and R 3For being substituted or unsubstituted heteroarylalkyl.
7. according to the compound of claim 1, R wherein 1Be methyl, R 2Be cyclopentyl, and R 4For being substituted or unsubstituted phenyl.
8. according to the compound of claim 1, R wherein 1Be methyl, R 2Be cyclopentyl, R 3Be pyridylmethyl, Pyrimidylmethyl, thienyl methyl, pyridyl propyl group or pyrazinyl methyl, it is substituted or is not substituted in each case, and R 4For phenyl or by the phenyl of 1～3 substituting group replacement.
9. according to the compound of claim 1, R wherein 1Be methyl, R 2Be cyclopentyl, R 3Be pyridylmethyl, Pyrimidylmethyl, thienyl methyl, pyridyl propyl group or pyrazinyl methyl, it is substituted or is not substituted in each case, and R 4Be phenyl, naphthyl, xenyl, pyridyl, pyrimidyl, thiazolyl, pyrazinyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
10. according to the compound of claim 1, R wherein 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 4Be phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
11. according to the compound of claim 1, R 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 4Be the phenyl that is not substituted or is replaced by following group: methyl, ethyl, methoxyl group, Cl, F, CF 3, vinyl, cyano group, amino, carboxyl, methylol or ethyl sulfonamido, perhaps 3-pyridyl for not being substituted or being replaced by carboxyl or carbalkoxy.
12. according to the compound of claim 1, wherein R 1Be methyl, R 2Be cyclopentyl, and R 4Be phenyl, naphthyl, pyridyl, quinolyl or isoquinolyl, it is substituted or is not substituted in each case.
13. according to the compound of claim 1, wherein R 1Be methyl, R 2Be cyclopentyl, and R 4Be the phenyl that is not substituted or is replaced by following group: methyl, ethyl, methoxyl group, Cl, F, CF 3, vinyl, cyano group, amino, carboxyl, methylol or ethyl sulfonamido, perhaps 3-pyridyl for not being substituted or being replaced by carboxyl or carbalkoxy.
14. according to the compound of claim 1, R wherein 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 3Be furyl methyl, thienyl methyl, pyridylmethyl, quinolyl methyl, isoquinolyl methyl, thiazolyl methyl or pyrryl methyl, it is substituted or is not substituted in each case.
15. according to the compound of claim 1, wherein R 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 3Be pyrazinyl methyl, Pyrimidylmethyl or pyridylmethyl, it is not substituted or is substituted in each case.
16. according to the compound of claim 1, wherein R 1Be methyl, R 2Be cyclopentyl, and R 3Be furyl methyl, thienyl methyl, pyrazinyl methyl, Pyrimidylmethyl, pyridylmethyl, quinolyl methyl, isoquinolyl methyl, thiazolyl methyl or pyrryl methyl, it is substituted or is not substituted in each case.
17. according to the compound of claim 1, wherein R 1Be methyl, R 2Be cyclopentyl, and R 3Be pyrazinyl methyl or pyridylmethyl, it is not substituted or is substituted in each case.
18. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound has formula IV
Figure C028070100006C1
R wherein 1And R 2As defined in claim 1, at least one is N among A, B and the D, and all the other are CH, and R 4Be pyridyl or phenyl, it is substituted or is not substituted in each case.
19. according to the compound of claim 18, wherein R 1Be methyl or CHF 2
20. according to the compound of claim 19, wherein B is N.
21. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, and R 2Be cyclopentyl, CHF 2Or cyclopropyl methyl.
22. according to the compound of claim 21, wherein B is N.
23. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, and R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
24. according to the compound of claim 23, wherein B is N.
25. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 4Be 3-pyridyl or phenyl, it is substituted or is not substituted in each case.
26. according to the compound of claim 25, wherein B is N.
27. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, and R 4For at the substituted phenyl of 3-or 4-position.
28. according to the compound of claim 27, wherein B is N.
29. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 4For at the substituted phenyl of 3-or 4-position.
30. according to the compound of claim 29, wherein B is N.
31. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, and R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
32. according to the compound of claim 31, wherein B is N.
33. according to the compound of claim 18, wherein R 1Be methyl or CHF 2, R 2Be cyclopentyl, CHF 2Or the cyclopropyl methyl, and R 4Be 3-pyridyl, 3-COOH-phenyl, 3-Cl-phenyl, 3-cyano group-phenyl, 3-ethyl-sulfonamido-phenyl, 3-tetrazolium-5-base-phenyl, 3-methylol-phenyl, 3-nitro-phenyl, 4-pyridyl, 4-COOH-phenyl, 4-cyano group-phenyl, 4-ethyl-sulfonamido-phenyl, 4-tetrazolium-5-base-phenyl or 4-methylol-phenyl.
34. according to the compound of claim 33, wherein B is N.
35. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound is selected from:
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid,
3-cyclo propyl methoxy-4-difluoro-methoxy-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic.
36. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound is selected from:
3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic,
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid,
3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl)-4 '-(2H-tetrazolium-5-yl) pentanoic.
37. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound is selected from:
3-cyclopentyloxy-4 '-methanesulfonamido-4-methoxyl group-N-(3-pyridylmethyl) pentanoic,
3-cyclopentyloxy-4-methoxyl group-3 '-methylol-N-(3-pyridylmethyl) pentanoic,
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid.
38. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound is selected from:
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid.
39. the compound of formula I ' and pharmacologically acceptable salts thereof:
Figure C028070100009C1
Wherein
R 1' be methoxyl group;
R 2' be alkyl with 1～12 carbon atom,
Alkyl with 1～12 carbon atom, it is replaced one or many by following group: halogen, oxygen, cyano group or their combination,
Cycloalkyl with 3～10 carbon atoms,
Cycloalkyl with 3～10 carbon atoms, it is replaced one or many by following group: halogen, oxygen, alkyl or their combination,
Cycloalkylalkyl with 4～12 carbon atoms, perhaps
Cycloalkylalkyl with 4～12 carbon atoms, it is replaced one or many by following group:
Halogen, oxygen, alkyl or their combination;
X is O;
R 3' for having the heteroaryl of 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms,
Perhaps
Substituted heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, and it is replaced one or many by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino, dialkyl amido or their combination;
L is-NR 4' CH 2-; And
R 4' for having the aryl of 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, amino, alkylamino, dialkyl amido, hydroxyalkyl, hydroxy alkoxy base, carboxyl, cyano group, acyl group, carbalkoxy, alkylthio, alkyl sulfinyl, alkyl sulphonyl, phenoxy group or their combination
Heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, perhaps
Substituted heteroaryl with 5～10 annular atomses, wherein at least one annular atoms is a heteroatoms, and it is replaced one or many by following group: halogen, aryl, alkyl, alkoxyl group, cyano group, trifluoromethyl, nitro, oxygen, amino, alkylamino, dialkyl amido or their combination.
40. the purposes of the compound of claim 1 in drug manufacture, described medicine are used to improve the patient's of this raising of needs cognition.
41. according to the purposes of claim 40, wherein said patient behaves.
42. the purposes of the compound of claim 1 in drug manufacture, described medicine is used for the treatment of the patient who suffers from cognitive disorder or decline.
43. according to the purposes of claim 42, wherein said patient behaves.
44. according to the purposes of claim 43, wherein said patient suffers from dysmnesia.
45. according to the purposes of claim 43, wherein said patient suffers from the dysmnesia that alzheimer's disease, schizophrenia, Parkinson's disease, Huntington Chorea, Pick's disease, creutzfeldt-jakob disease, depression, aging, head trauma, apoplexy, CNS anoxic, brain aging, multi infarct dementia, HIV or cardiovascular disorder cause.
46. the purposes of the compound of claim 1 in drug manufacture, described medicine are used for the treatment of the patient who suffers from the disease that relates to the reduction of cAMP level.
47. the purposes of the compound of claim 1 in drug manufacture, described medicine are used to suppress patient's PDE 4 enzymic activitys.
48. comprise the compound of claim 1 and the pharmaceutical composition of pharmaceutically acceptable carrier.
49. according to the composition of claim 48, wherein unit dosage form contains the described compound of 0.1～50mg.
50. being used for the treatment of, the purposes of the compound of claim 1 in drug manufacture, described medicine suffer from the amnemonic patient that neurodegenerative disease causes.
51. being used for the treatment of, the purposes of the compound of claim 1 in drug manufacture, described medicine suffer from the amnemonic patient that the acute neurodegenerative disease causes.
52. the purposes of the compound of claim 1 in drug manufacture, described medicine is used for the treatment of the patient who suffers from allergy or inflammatory diseases.
53. the compound of following formula and pharmacologically acceptable salts thereof
Wherein:
R 1For H, 3H 3C-, 14CH 3-or 11CH 3-;
R 2For having the alkyl of 1～12 carbon atom, its for side chain or non-side chain and be not substituted or replaced one or many by following group: halogen, hydroxyl, cyano group, C 1～4-alkoxyl group, oxygen or their combination,
Cycloalkyl with 3～10 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, hydroxyl, oxygen, cyano group, alkyl, alkoxyl group or their combination with 1～4 carbon atom with 1～4 carbon atom,
Cycloalkylalkyl with 4～16 carbon atoms, it is not substituted or is replaced one or many at cycloalkyl moiety and/or moieties by following group: halogen, oxygen, cyano group, hydroxyl, C 1～4-alkyl, C 1～4-alkoxyl group or their combination;
R 3Be heteroarylalkyl, wherein heteroaryl moieties can be partly or entirely saturated, and have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, moieties is side chain or non-side chain, have 1～5 carbon atom, described heteroarylalkyl is not substituted or is replaced one or many at heteroaryl moieties by following group: halogen, alkyl, alkoxyl group, cyano group, trifluoromethyl, CF 3O, nitro, oxygen, amino, alkylamino, dialkyl amido or their combination;
R 4For having the aryl of 6～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, OCF 3, amino, aminoalkyl group, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, 2-(THP trtrahydropyranyl)-tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl, R 5-L-or their combination; the heteroaryl that perhaps has 5～10 annular atomses; wherein at least one annular atoms is a heteroatoms, and it is not substituted or is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; the alkoxyl group alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; trifluoromethyl; amino; amino methyl; aminoalkyl group; aminoalkoxy; dialkyl amido; hydroxyalkyl; hydroxamic acid; tetrazolium-5-base; the hydroxy alkoxy base; carboxyl; carbalkoxy; cyano group; acyl group; alkylthio; the alkyl sulfinyl; alkyl sulphonyl; phenoxy group; trialkylsiloxy R 5-L-, dialkyl amido-L-or their combination;
R 5Be H,
Alkyl with 1～8 carbon atom, it is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination have the cycloalkylalkyl of 4～16 carbon atoms, and it is not substituted or is replaced one or many at cycloalkyl moiety by following group: halogen, oxygen, cyano group, hydroxyl, alkyl, alkoxyl group or their combination,
Aryl with 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl or their combination, perhaps
Heterocyclic radical, it is saturated, fractional saturation or undersaturated, have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, the alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, the hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, the alkyl sulfinyl, alkyl sulphonyl, phenoxy group or their combination;
L is singly-bound or the divalent aliphatic base with 1～8 carbon atom, wherein one or more-CH 2The optional separately quilt-O-of-group ,-S-,-NR 6-,-SO 2NH-,-NHSO 2-,-CO-,-NR 6CO-,-CONR 6-replace; And
R 6Be H, perhaps
Alkyl with 1～8 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination.
54. the compound of following formula and pharmacologically acceptable salts thereof:
Figure C028070100014C1
Wherein:
R 1For having the alkyl of 1～4 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by halogen;
R 2Be H;
R 3Be heteroarylalkyl, wherein heteroaryl moieties can be partly or entirely saturated, and have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, moieties is side chain or non-side chain, has that 1～5 carbon atom, heteroarylalkyl are not substituted or is replaced one or many at heteroaryl moieties by following group: halogen, alkyl, alkoxyl group, cyano group, trifluoromethyl, CF 3O, nitro, oxygen, amino, alkylamino, dialkyl amido or their combination, and/or replaced by halogen, cyano group or methyl or their combination at moieties;
R 4For having the aryl of 6～14 carbon atoms, it is not substituted or is replaced one or many by following group: halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, OCF 3, amino, aminoalkyl group, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, 2-(THP trtrahydropyranyl)-tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl, R 5-L-or their combination; the heteroaryl that perhaps has 5～10 annular atomses; wherein at least one annular atoms is a heteroatoms, and it is not substituted or is replaced one or many by following group: halogen; alkyl; hydroxyl; alkoxyl group; the alkoxyl group alkoxyl group; nitro; methylene-dioxy; ethylenedioxy; trifluoromethyl; amino; amino methyl; aminoalkyl group; aminoalkoxy; dialkyl amido; hydroxyalkyl; hydroxamic acid; tetrazolium-5-base; the hydroxy alkoxy base; carboxyl; carbalkoxy; cyano group; acyl group; alkylthio; the alkyl sulfinyl; alkyl sulphonyl; phenoxy group; trialkylsiloxy R 5-L-, dialkyl amido-L-or their combination;
R 5For having the alkyl of 1～8 carbon atom, it is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination have the cycloalkylalkyl of 4～16 carbon atoms, and it is not substituted or is replaced one or many at cycloalkyl moiety by following group: halogen, oxygen, cyano group, hydroxyl, alkyl, alkoxyl group or their combination,
Aryl with 6～14 carbon atoms; it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, alkyl sulfinyl, alkyl sulphonyl or their combination, perhaps
Heterocyclic radical, it is saturated, fractional saturation or undersaturated, have 5～10 annular atomses, wherein at least one annular atoms is N, O or S atom, it is not substituted or is replaced one or many by following group: halogen, alkyl, hydroxyl, alkoxyl group, the alkoxyl group alkoxyl group, nitro, methylene-dioxy, ethylenedioxy, trifluoromethyl, amino, amino methyl, aminoalkyl group, aminoalkoxy, dialkyl amido, hydroxyalkyl, hydroxamic acid, tetrazolium-5-base, the hydroxy alkoxy base, carboxyl, carbalkoxy, cyano group, acyl group, alkylthio, the alkyl sulfinyl, alkyl sulphonyl, phenoxy group or their combination;
L is singly-bound or the divalent aliphatic base with 1～8 carbon atom, wherein one or more-CH 2The optional separately quilt-O-of-group ,-S-, NR 6-,-SO 2NH-,-NHSO 2-,-CO-,-NR 6CO-or-CONR 6-replace; And
R 6Be H, perhaps
Alkyl with 1～8 carbon atom, it is side chain or non-side chain, and is not substituted or is replaced one or many by following group: halogen, C 1～4-alkyl, C 1～4-alkoxyl group, oxygen or their combination.
55. be selected from following compound:
3-cyclopentyloxy-4-methoxy diphenylamine,
3-hydroxyl-4-methoxyl group-N-(3-pyridylmethyl) pentanoic and
3 '-(2-bromine oxethyl)-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic.
56. according to the compound of claim 1, wherein said compound is N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid or its pharmacologically acceptable salts.
57. according to the purposes of claim 41, wherein said compound is N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid or its pharmacologically acceptable salts.
58. according to the composition of claim 48, wherein said compound is N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-3-benzaminic acid or its pharmacologically acceptable salts.
59. according to the composition of claim 48, wherein said composition further comprises other pharmaceutical agents that is selected from calcium channel blocker, cholinergic agent, Adenosine Receptors conditioning agent, ampakines, NMDA-R conditioning agent, mGluR conditioning agent and anticholinesterase or their arbitrary combination.
60. according to the composition of claim 58, wherein said composition further comprises other pharmaceutical agents that is selected from calcium channel blocker, cholinergic agent, Adenosine Receptors conditioning agent, ampakines, NMDA-R conditioning agent, mGluR conditioning agent and anticholinesterase or their arbitrary combination.
61. according to the purposes of claim 52, wherein said medicine is used for the treatment of asthma.
62. according to the purposes of claim 52, wherein said medicine is used for the treatment of chronic obstructive pulmonary disease.
63. according to the compound and the pharmacologically acceptable salts thereof of claim 1, wherein said compound is selected from:
N-(3-cyclopentyloxy-4-p-methoxy-phenyl)-N-(3-pyridylmethyl)-2-benzaminic acid,
N-4-chloro-3-pyridylmethyl)-(3-cyclopentyl-4-p-methoxy-phenyl)-N-(2-pyridyl) amine,
3-cyclopentyloxy-4-anisole amido-N-(3-pyridylmethyl)-N-3-(4-pyridyl) benzamide,
3-cyclopentyloxy-4-methoxyl group-4 '-(4-methyl isophthalic acid-piperazinyl methyl)-N-(3-pyridylmethyl) pentanoic,
3 '-amino methyl-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic,
3-cyclopentyloxy-4-methoxyl group-3 '-[2-(piperidino) oxyethyl group]-N-(3-pyridylmethyl) pentanoic,
4 '-amino ethoxy-3-cyclopentyloxy-4-methoxyl group-N-(3-pyridylmethyl) pentanoic.
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