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CN1444573A - Carboxamide compounds and their use as antagonists of human 11CBY receptor - Google Patents

Carboxamide compounds and their use as antagonists of human 11CBY receptor Download PDF

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Publication number
CN1444573A
CN1444573A CN01813601A CN01813601A CN1444573A CN 1444573 A CN1444573 A CN 1444573A CN 01813601 A CN01813601 A CN 01813601A CN 01813601 A CN01813601 A CN 01813601A CN 1444573 A CN1444573 A CN 1444573A
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CN
China
Prior art keywords
phenyl
group
oxyethyl group
compound
benzamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN01813601A
Other languages
Chinese (zh)
Inventor
C·N·约翰逊
M·琼斯
C·A·奥托勒
G·斯特姆普
K·M·图利斯
D·维蒂
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0018758.3A external-priority patent/GB0018758D0/en
Priority claimed from GB0112544A external-priority patent/GB0112544D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of CN1444573A publication Critical patent/CN1444573A/en
Pending legal-status Critical Current

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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
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Abstract

Compounds of formula (I) in which: each A is independently hydrogen, C1-6alkyl optionally substituted by hydroxyl, C1-6alkoxy, C1-6alkenyl or C1-6acyl group or a halogen atom or hydroxyl, CN or CF3 group; R3 is hydrogen, methyl or ethyl; R4 is an optionally substituted aromatic carbocyclic or heterocyclic ring; Z is an O or S atom, or an NH or CH2 group, or a single bond, at the 3 or 4 position of R4 relative to the carbonyl group; R5 is an optionally substituted aromatic carbocyclic or heterocyclic ring, or an optionally substituted, saturated or unsaturated, carbocyclic or heterocyclic ring; and Q is (a) Where X, Y, R1 and R2 are as defined in claim 1; are antagonists of a human 11CBy receptor.

Description

Benzamide compound and as the purposes of people 11CBY receptor antagonist
The methods of treatment, a class that the present invention relates to end user 11CBy receptor antagonist has the novel therapeutic use of the benzamide compound of antagonism, the method that also relates to the new compound in the described compounds and prepare described compound to people 11CBy acceptor.
International application published WO 01/21577 (Takeda Chemical IndustriesLtd.) discloses certain bi-aromatic compounds that concentrates hormone antagonist as melanocyte.
WO 98/00401 (Merck ﹠amp; Co.Inc.) benzamide derivatives as the fibrinogen deceptor antagonists prodrug is disclosed.
European patent EP 0 358 118 (Boehringer Mannheim GmbH) discloses as the erythrocyte aggregation inhibitor and can be used for treating certain bi-aromatic compounds of heart and circulatory diseases.
European patent application EP 0 968 999 (Mitsui Chemical Inc.) discloses and can be used for treating ARR certain anilide derivative.
WO 99/01127 (SmithKline Beecham) discloses to have as active some the N-[(aminoalkoxy of CCR5 receptors ligand) phenyl] benzamide, comprise compound N-[two (1-methylethyl) amino of 4-[2-[] oxyethyl group]-2-fluoro phenyl]-[1,1 '-xenyl]-4-methane amide and two (1-methylethyl) amino of N-[4-[2-[]-oxyethyl group]-phenyl]-[1,1 '-xenyl]-the 4-methane amide.WO99/06146 (SmithKline Beecham) also discloses some the substituted anilide as the CCR5 receptor antagonist, comprises compound:
Xenyl-4-carboxylic acid [4-(2-dimethylamino-oxyethyl group)-phenyl]-acid amides,
Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
4-cyclohexyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-cyclohexyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides and 4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides.
The present invention is based on such discovery, promptly a class adopts above-mentioned benzamide and anilide eclipsed methane amide surprisingly to Nature, and 400, disclosed people 11CBy acceptor has antagonism among the 261-265 (1999).
Therefore these compounds are considered to have the effect of prevention, improvement or treatment dysfunction or disease, include but not limited to various infection such as infectation of bacteria, fungi infestation, protozoal infections and virus infection, particularly by HIV-1 or the caused infection of HIV-2; Pain; Cancer; Diabetes; Fat; Diet is unusual as anorexia and Bulimia nerovsa; Asthma; Parkinson's disease; Acute and congestive heart failure; Ypotension; Hypertension; Uroschesis; Osteoporosis; Stenocardia; Myocardial infarction; Ulcer; Allergy; Benign prostatauxe; Disease on psychosis and the neurological comprises anxiety, schizophrenia, manic depression of sex; Vain hope; Dull-witted or serious mental retardation; And dyskinesia such as Huntington Chorea or tourette's syndrome and other disease, hereinafter referred to as " described disease (the Disorders) ".
The invention provides a kind of method for the treatment of described disease, this method comprises formula (I) compound or its pharmacy acceptable salt or the solvate of the Mammals significant quantity of suffering from one or more described diseases, wherein:
Each A independently is hydrogen, the optional C that is replaced by hydroxyl 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkenyl or C 1-6Acyl group or halogen atom or hydroxyl, CN or CF 3Group;
R3 is hydrogen, methyl or ethyl.
Preferred R3 is a methyl.
R4 is optional substituted aromatic carbocyclic or heterocycle.
Z be positioned at R4 with respect to O or S atom or NH or CH on 3 or 4 of carbonyl 2Group or singly-bound.
Preferred Z is a key.
More preferably Z be positioned at R4 with respect to the key on 4 of carbonyl.
R5 is optional substituted aromatic carbocyclic or heterocycle or optional substituted saturated or unsaturated carbocyclic or heterocycle.
Preferred R5 is a phenyl ring.
And Q is
(a) wherein X is O or S atom, is preferably the O atom,
Y is linearity or branching C 2-4Alkylidene group is preferably C 3Alkylidene group optional is replaced by hydroxyl, perhaps is C 5-6Cycloalkylidene,
R1 and R2 independently are linearity or branching C 1-6Alkyl, preferred ethyl, phenyl C 1-6Alkyl; Perhaps
(b) wherein X is O or S atom,
Y is linearity or branching C 2-4Alkylidene group optional is replaced by hydroxyl,
R1 and R2 are connected to form 5,6 or 7 yuan of rings, are preferably 5 yuan of rings, optional other heteroatoms that comprises one or more O of being selected from, S or N, wherein N or C annular atoms optional by Ra ,-CO-Ra ,-CO-NH-Ra or CO-O-Ra replace, wherein Ra is linearity or branching C 1-6Alkyl or aryl, and described 5,6 or 7 yuan of optional condensing of ring become choose substituted phenyl ring, the annular atoms of perhaps described 5,6 or 7 yuan of rings is optional to pass through singly-bound or methylene radical links to each other with Y; Perhaps
(c) wherein X is O or S atom,
Y is C 2-4Alkylidene group, R1 are to link to each other with Y to form the C of 5 or 6 yuan of rings 2-4Alkylidene group, and R2 is linearity or branching C 1-6Alkyl; Perhaps
(d) wherein X is the N atom,
Y is C 2-4Alkylidene group, R1 are to link to each other with X to form the C of 5 or 6 yuan of rings 2-4Alkylidene group, and R2 is linearity or branching C 1-6Alkyl.
Groups such as alkyl (comprising the alkyl as the part of alkoxyl group), acyl group comprise 1-6 carbon atom usually, can be linearity or branching, as methyl, ethyl, sec.-propyl and the tertiary butyl, and optional are replaced by hydroxyl.Aryl is generally phenyl, but can comprise bicyclic radicals such as naphthyl.Cycloalkyl generally comprises 3-7 carbon atom.Heterocyclic group can be to comprise the first monocycle of maximum 3 heteroatomic 5-7, as pyridyl or imidazolyl, perhaps can be dicyclo, particularly with the phenyl ring condensed heterocycle, as benzoxazole or benzoglyoxaline.Aryl, cycloalkyl and heterocyclic group can be chosen wantonly by maximum three substituting groups and replace, described substituting group can suitably be selected from aryl, alkyl, alkoxyl group, halogen, hydroxyl and cyano group, is perhaps replaced by continuous substituting group such as titanium dioxide methylene radical (dioxymethylene).
Suitable aromatic ring as R4 comprises phenyl, pyridyl, thienyl, furyl and pyrazolyl.The suitable optional substituting group of R4 comprises halogen, CF 3, C 1-4Alkyl, C 1-4Alkoxyl group.R4 can have 2 or 3 substituting groups, but preferably has only 1 substituting group except that Z, does not perhaps more preferably have substituting group except that Z.The suitable especially substituting group of R4 comprises chlorine, fluorine, trifluoromethyl, methyl, methoxyl group.
R5 can be monocycle, for example thienyl, furyl, imidazolyl, oxadiazole base, phenyl, pyridyl, cyclohexyl, piperidyl, piperazinyl, pyrazinyl, pyrimidyl; Perhaps be condensed-bicyclic system, naphthyl, 3 for example, 4-titanium dioxide methylene radical phenyl, benzofuryl, indyl; The bicyclic ring system that perhaps has cyclic substituents Li such as oxadiazole base, benzyloxy for monocycle wherein.The suitable optional substituting group of R5 comprises halogen, CF 3, CF 3O, CHF 2O, CN, amino, one or two C 1-6Alkylamino, C 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group, C 1-6Alkyl-S-, C 1-6Alkyl-SO 2-, C 1-6Alkenyl, phenyl-C 1-6Alkyl, phenyl-C 1-6Alkoxyl group.R5 can have 2 or 3 substituting groups, but preferably has only 1 substituting group, particularly in the contraposition of Z.The suitable especially substituting group of R5 comprises chlorine, fluorine, trifluoromethyl, cyano group, amino, methyl, ethyl, the tertiary butyl, methoxyl group, ethanoyl, formyl radical, methylthio group, methylsulfonyl, vinyl, benzyl, benzyloxy, hydrogen.
For cyclic substituents A, all A substituting groups can be hydrogen, but situation is that to be no more than 3 substituting groups be hydrogen preferably.Suitable A substituting group comprises halogen, the optional C that is replaced by hydroxyl 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Acyl group and C 1-6Alkenyl.Particularly suitable A substituting group comprises C 1-2Alkoxyl group, C 1-2Alkyl, C 1-2Acyl group.Preferred A substituting group comprises chlorine, fluorine, methyl, ethyl, hydroxyethyl, methoxyl group, formyl radical, ethanoyl, vinyl and allyl group.Preferred A substituting group comprises methoxyl group.The A substituting group is adjacent with group Q to be suitable.
In the configuration (a) of system Q, the suitable especially substituting group of R1 and R2 comprises methyl, ethyl, sec.-propyl, benzyl, styroyl.Y can be in particular for-(CH 2) 2-,-(CH 2) 3-,-(CH 2) 4-,-CH 2-CH (CH 3)-CH 2-.When Y is replaced by hydroxyl, it can be for example-CH 2-CH (OH)-CH 2-.
In the configuration (b) of system Q, the ring that is connected to form by R1 and R2 can be pyrrolidyl, piperidyl, azepanyl or imidazolyl.Condensed ring comprises indolinyl, tetrahydro isoquinolyl, tetrahydric quinoline group and benzo-aza base.When having second heteroatoms, suitable ring comprises thiazinyl, oxazinyl and piperazinyl.Second N atom can be replaced by for example phenyl, methyl, ethyl, sec.-propyl or ethanoyl.Y is generally-(CH 2) 2-.This ring can link to each other with Y back and form quinuclidinyl.
In the configuration (c) of system Q, can be pyrrolidine ring or piperidine ring by the R1 ring that forms that links to each other with Y.With being connected of Y can be such, promptly form a ring that directly links to each other by the singly-bound on the ring carbon atom or link to each other via methylene radical or ethylidene linking group with X.R2 is generally methyl, thereby the N atom of ring is by methyl substituted.
In the configuration (d) of system Q, be suitably for 5 or 6 yuan of rings by the R1 ring that forms that links to each other with N, as diazine or piperazinyl.Y is generally-(CH 2) 2-.R2 is generally methyl, thereby second N atom (being different from X) of ring is by methyl substituted.
In formula (I) scope is the compound of a class general formula (II),
Figure A0181360100111
Wherein A is H and OMe, and R3 is H, and X is O, and Y is CH 2CH 2, Z is a key, and R4 is Ph, and R5 is position or para-orientation between on the R4, and R1, R2 are identical with the definition in the formula (I) with R5.
In formula (I) scope, be the compound of a class general formula (III) also,
Figure A0181360100112
Wherein A is H and OMe, and R3 is H, and X is O, and Y is CH 2-CH 2, Z is O, CH 2Or NH, and between on the R4 position or para-orientation, R4 is Ph, R5 is Ph, R1 is identical with the definition in the formula (I) with R2.
In formula (I) scope, be the compound of a class general formula (IV) also, Wherein A is H and OMe, and R1 and R2 are sec.-propyl, and R3 is H, and X is O, and Y is CH 2-CH 2, and R4 and R5 be substituted phenyl or heterocycle, suc as formula the definition in (I).
In formula (I) scope, be the compound of the logical formula V of a class also, Wherein R3 is H, and X is O, and Y is CH 2-CH 2, Z is O, CH 2, NH or key, R4 is Ph, R5 is Ph or cyclohexyl (Cy), Z position or para-orientation between on the R4, A (R6, R7) and R1, R2 are suc as formula the definition in (I).
In formula (I) scope, be the compound of a class general formula (VI) also,
Figure A0181360100122
Wherein X is O, and Y is CH 2-CH 2, R4 is a phenyl, and R5 is phenyl or cyclohexyl (Cy), and Z is O, CH 2Or key, A (R8, R9), R3 and R1, R2 are suc as formula the definition in (I).
In formula (I) scope, be the compound of a class general formula (VII) also,
Figure A0181360100123
Wherein A is H and OMe, and X is O, and R3 is H, and R4 is 3-pyridyl (with respect to a carbonyl), and R5 is a phenyl, and Z is the contraposition key, and R1, R2 are suc as formula the definition in (I).
In formula (I) scope, be the compound of a class general formula (VIII) also,
Figure A0181360100131
Wherein A is H and OMe, and R3 is H, and X is O, and R4 is a phenyl, and Z is O, CH 2Or key, R5 is Ph or cyclohexyl (Cy), and Y is for choosing the chain of 3 or 4 carbon atoms that replaced by hydroxyl wantonly, and R1, R2 are suc as formula the definition in (I).
In formula (I) scope, be the compound of a class general formula (IX) also,
Figure A0181360100132
Wherein A is H and OMe, and R3 is H, and X is N, and R4 is a phenyl, and Z is the para-orientation key, and R5 is Ph or cyclohexyl (Cy), and Y and R2 form a piperazine ring between X and N, and R1 is suc as formula the definition in (I).
The preferred compound of a group that is used for methods of treatment of the present invention is that wherein R3 is formula (I) compound of methyl.
In formula (I) is that wherein R3 is one group of new compound of methyl or ethyl.Described new compound or its salt or solvate form another aspect of the present invention.
One group of specific new compound is a compounds of general formula (VI).
Figure A0181360100141
Wherein R8 and R9 suc as formula in (I) to the definition of A, R1, R2 and R5 are suc as formula the definition in (I), R3 is methyl or ethyl.
R5 is suitably for optional phenyl or the cyclohexyl that is replaced by halogen, haloalkyl, alkyl or alkoxyl group, and Z is O, CH 2Or singly-bound, R8 and R9 independently are selected from hydrogen, halogen, alkyl and alkoxyl group, and R1 and R2 are alkyl or are joined together to form ring that R3 is ethyl or methyl.
Another aspect of the invention is a class new compound or its salt or solvate, they are formula (I) compounds except that following compounds:
N-[4-[2-[two (1-methylethyl) amino] oxyethyl group]-2-fluoro phenyl]-[1,1 '-xenyl]-the 4-methane amide,
N-[4-[2-[two (1-methylethyl) amino] oxyethyl group] phenyl]-[1,1 '-xenyl]-the 4-methane amide,
Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
4-cyclohexyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-cyclohexyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
With 4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides.
Another aspect of the present invention is those new compounds among this paper embodiment.
The compound or its salt or the solvate of formula (I) to (IX) are preferably pharmaceutically acceptable or pure basically form.Pharmaceutically acceptable form is meant the pharmaceutically acceptable purity level except that standard medicinal additive such as thinner and carrier especially, and being included in does not have material to be considered to deleterious under the standard dose level.
Suitable salt and solvate comprise pharmacy acceptable salt and pharmaceutically acceptable solvate.
Suitable pharmacy acceptable salt comprises for example aluminium of metal-salt; An alkali metal salt is lithium, sodium or potassium for example; Alkaline earth salt is calcium or magnesium for example; And ammonium or the substituted ammonium salt salt that forms of those and low-grade alkylamine such as triethylamine, hydroxyalkyl amine such as 2 hydroxy ethylamine, two-(2-hydroxyethyl)-amine or three-(2-hydroxyethyl)-amine, Cycloalkyl amine such as dicyclohexylamine for example, perhaps those and PROCAINE HCL, PHARMA GRADE, dibenzyl piperidines, N-benzyl-β-phenylethylamine, dehydroabietylamine, N, N '-two dehydroabietylamine, glycosamine, N-methylglucosamine or pyridine type alkali such as the formed salt of pyridine, collidine, quinine or quinoline.
Suitable pharmacy acceptable salt also comprises pharmaceutically-acceptable acid addition, as those and pharmaceutically acceptable mineral acid or the formed salt of organic acid.
Comprise vitriol, nitrate, phosphoric acid salt, borate, hydrochloride and hydrobromate and hydriodate with the formed pharmaceutically acceptable suitable acid salt of pharmaceutically acceptable mineral acid.
Comprise acetate, tartrate, maleate, fumarate, malonate, Citrate trianion, succinate, lactic acid salt, oxalate, benzoate, ascorbate salt, mesylate, alpha-ketoglutarate and α-glycerophosphate with the formed pharmaceutically acceptable suitable acid salt of pharmaceutically acceptable organic acid.
Suitable pharmaceutically acceptable solvate comprises hydrate.
Basically pure form comprises at least 50% (except the standard medicinal additive) usually, and is preferred 75%, and more preferably 90%, the also more preferably compound or its salt or the solvate of 95% formula (I) to (IX).
A kind of form of preferred pharmaceutical compositions is a crystal, is included in this form in the medicinal compositions.Under the situation of salt and solvate, ion that attaches and solvent part also must be nontoxic.
The example of the pharmacy acceptable salt of formula (I) to (IX) compound comprises and the conventional medicinal acid formed acid salt of toxilic acid, hydrochloric acid, Hydrogen bromide, phosphoric acid, acetate, fumaric acid, Whitfield's ointment, citric acid, lactic acid, amygdalic acid, tartrate, succsinic acid, phenylformic acid, xitix and methylsulfonic acid for example.
The compound of formula (I) to (IX) can exist and surpass a kind of stereoisomerism form, and the present invention prolongs and all these forms and their mixture, comprises racemic modification.
By method or its amended method that is exemplified in the following general reaction scheme, use compound or its salt or solvate that raw material, reagent and the conventional synthesis step be easy to obtain can preparation formula (I) to (IX).A kind of specific enantiomer of The compounds of this invention if desired, the reaction that then can be begun and not comprise the racemize processing by the enantiomer of desired raw material is synthesized, perhaps can synthesize and prepare by chirality, perhaps prepare by derivatization with chirality subsidiary, wherein the gained non-enantiomer mixture is separated, and auxiliary group splits so that pure required enantiomer to be provided.Perhaps, when molecule contained basic functionality such as amino or acidic functionality such as carboxyl, photolytic activity acid or alkali formation diastereoisomeric salt with suitable carried out the separation of diastereoisomeric salt then by fractional crystallization, reclaim pure enantiomer subsequently.
Aryl that the compound of formula (I) to (IX) can suitably be replaced by condensation or heteroaryl carboxylic acid and the aniline that is suitably replaced prepare, and described material is easy to buy or can uses currently known methods synthetic by commercially available raw material by method known to those skilled in the art.For example, under suitable temperature such as reflux temperature, handle aryl or the heteroaryl carboxylic acid that is suitably replaced with activator such as thionyl chloride, obtain aryl or heteroaryl carbonyl chloride, in the presence of suitable alkali such as diisopropylethylamine, in appropriate solvent such as methylene dichloride, make described aryl or heteroaryl carbonyl chloride and the aniline condensation that is suitably replaced, obtain the compound of formula (I).
Specifically, wherein R3 is that the preparation of some formula (I) methane amide of H is disclosed among above-mentioned WO 99/01127 and the WO 99/06146, and the present invention can use similar preparation method.Many other methods that carboxylic acid changed into acid amides are known, can find among the volume I-VI (Wiley-Interscience publication) at the canonical reference book as " Compendium of Organic Synthetic Methods ".
For example, the compound that the compound of formula (I) can be by making formula (X) and the compound of formula (XI) react and prepare,
R5-Z-R4-COL (X) wherein L is leavings group such as halogen, particularly chlorine or bromine
Figure A0181360100171
Wherein A, Z, R3, R4, R5 and Q are suc as formula the definition of (I).
In this process, the group that can change into R1, R2, R3, R4 and R5 can exist during coupling, and after coupling, change into R1, R2, R3, R4 and R5.After coupling, it also is suitable that R1, R2, R3, R4 and a R5 are changed into another R1, R2, R3, R4 and R5.Specifically, can after coupling, between radicals R 1, X, Y, R2, form ring or add the suitable cyclic group of specifically representing with R1, X, Y, R2.
Thereby, provide a kind of and be used to prepare wherein that R3 is formula (I) compound or its salt of methyl or ethyl or the method for solvate, this method comprises makes formula (X) compound and the reaction of formula (XI) compound as defined above, and wherein A and Q as above define, and R3 is methyl or ethyl.
Therefore, also provide a kind of method that is used for preparation formula (I) compound or its salt or solvate, condition is not comprise following compounds:
N-[4-[2-[two (1-methylethyl) amino] oxyethyl group]-2-fluoro phenyl]-[1,1 '-xenyl]-the 4-methane amide,
N-[4-[2-[two (1-methylethyl) amino] oxyethyl group] phenyl]-[1,1 '-xenyl]-the 4-methane amide,
Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
N-[4-(2-diethylamino-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
4-cyclohexyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-cyclohexyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
4-benzyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
With 4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides.
This method comprises formula (X) compound and the reaction of formula (XI) compound as defined above as defined above.
The compound of formula (XI) can for example when X is O or S, make the nitrobenzene compound and dialkyl amido alcohol or the mercaptan coupling that are suitably replaced by the preparation of many approach, in the presence of palladium catalyst (perhaps with iron(ic) chloride/ammonium chloride), by hydrogenation with NO 2Groups converted becomes NH 2Group, with the chloride of acid coupling, for example as described below then:
Steps A 51
The chloride of acid of formula (X) can by easily obtain or document in the respective acids preparation put down in writing, perhaps can be prepared by the method that is similar to institute's record method in the document.
Perhaps the acid of formula (X) can prepare through the Z combination by the part that will contain R5 and R4 respectively.
This also can realize with compound R 5-Z-L (or L-R4-CO-L and R5-Z) reaction then easily by at first with the compound of R4-CO-L and the compound coupling of formula (XI).For example, can make the amine of formula (XI) and the bromobenzene formyl chloride reaction that is suitably replaced, it can react with phenyl moiety with leavings group that is for example suitably replaced or cyclic amine then, as described in following diagram: BINAP=(S)-(+)-2,2 '-two (diphenyl phosphine)-1,1 '-dinaphthalene
The similar reaction of setting up formula (I) structure can be begun by formula (X) compound; and segmentation adds the formula (XI) of equivalent; shown in following diagram, wherein the N-protected group on the Q (being piperazine ring herein) can be removed after the coupling of formula (I) component, and can be replaced by the get substituting group that needs:
Figure A0181360100201
Before being used for coupling, set up formula (XI) compound, thereby in Y, introduce in another alternatives of a hydroxyl, the nitrophenols that will suitably be replaced is connected on the epoxy compounds, the reaction of gained compound and amine forms group Q then, it is-O-Y (OH)-NR1R2, with the R5-Z-R4-CO-L coupling, as follows afterwards: Nos=p-nitrophenyl alkylsulfonyl
Wherein amide nitrogen can be carried out with the chloride of acid coupling of formula (X) by the anilide alkylation with formula (XI) then by the preparation of alkylating new-type (I) compound (R3 is methyl or ethyl), for example by utilizing following reduction amination step to carry out:
Figure A0181360100211
Step e 1
By with suitable organic acid or inorganic acid reaction, formula (I) compound can be changed into their pharmacy acceptable salt.
The solvate of formula (I) compound can form by crystallization from appropriate solvent or recrystallization.For example, hydrate can form by crystallization or recrystallization from the aqueous solution of aqueous solution or organic solvent.
Formula (I) compound be not that pharmacy acceptable salt or solvate also can be used as intermediate in the preparation of pharmacy acceptable salt or solvate.Corresponding this class salt or solvate also form a part of the present invention.
Above-listed compound and pharmacy acceptable salt thereof particularly hydrochloride and pharmaceutically acceptable solvate particularly hydrate form preferred aspect of the present invention.
These compounds of Drawing upon are as the activity of people 11CBy receptor antagonist, and the effect that above-mentioned formula (I) compound is considered to have prevention, improves or cure the dysfunction disease includes but not limited to previous " described disease ".
Think that also the treatment of above-mentioned some disease being carried out by people 11CBy receptor antagonist is new.Therefore, the present invention also is provided for treating the method for the following disease of people or non-human mammal: diabetes, major depression, manic depression of sex, anxiety, schizophrenia and sleep disordered, this method comprise the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the method for the diabetes of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the method for the major depression of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the method for the manic depression of sex of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the method for the anxiety of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the schizoid method of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.Particularly, the invention provides the sleep disordered method of a kind of people of treatment or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.
Giving Mammals with these compounds can be by oral (comprising the hypogloeeis), parenterai administration, nose administration, rectal administration or percutaneous dosing.
The significant quantity for the treatment of above-mentioned disease depends on character and the seriousness and the mammiferous weight of institutional factor such as disease to be treated.But dosage unit contains 1-1000mg usually, and that suitable is 1-500mg, for example is 2-400mg as 2,5,10,20,30,40,50,100,200,300 and the active compound of 400mg amount.Gave the dosage unit one or many in common one day, for example one day 1,2,3,4,5 or 6 time, more frequent is one day 1-4 time, thereby total per daily dose normally is 1000mg with respect to the 70kg adult, 1-500mg for example, this scope promptly is about 0.01-15mg/kg/ day, more generally is 0.1-6mg/kg/ day, for example 1-6mg/kg/ day.
Very preferably formula (I) compound is carried out administration with the form of dosage unit composition such as dosage unit oral (comprising the hypogloeeis), intranasal, rectum, part or non-enteron aisle (especially intravenously) composition.
Prepare these compositions by blending, and suitably be prepared into the form that is suitable for oral or parenterai administration, as tablet, capsule, oral liquid formulations, pulvis, particle, lozenge, reconfigurable pulvis, injectable and pourable solution or suspension or suppository.The preferred oral administration composition is particularly made the composition for oral administration of definite shape, the common purposes because they are more convenient for.
The tablet and the capsule that are used for oral administration are present in dosage unit usually, and comprise conventional excipients such as tackiness agent, filler, thinner, tablet agent, lubricant, disintegrating agent, tinting material, seasonings and wetting agent.Described tablet can carry out dressing by methods known in the art.
The suitable filler of available comprises Mierocrystalline cellulose, mannitol, other similar agents of lactose.Suitable disintegrating agent comprises starch, polyvinylpyrrolidone and starch derivative such as sodium starch glycollate.Suitable lubricant comprises for example Magnesium Stearate.Suitable pharmaceutically acceptable wetting agent comprises Sodium Lauryl Sulphate BP/USP.
These solid oral compositions can be prepared by ordinary methods such as blending, filling, compressing tablets.Blending operation repeatedly can be used for promoting agent is distributed to the whole composition that uses mass filler.It is conventional that certain these operate in this area.
Oral liquid formulations can perhaps can be used as the dry labor thing that reconfigures with water or other suitable vehicle before using and exist for for example moisture or contain oil suspension, solution, emulsion, syrup or elixir.These liquid preparations can contain conventional additives such as suspension agent, for example sorbyl alcohol, syrup, methylcellulose gum, gelatin, Natvosol, carboxymethyl cellulose, aluminium stearate gel or hydrogenation edible fat; Emulsifying agent, for example Yelkin TTS, monooleate sorbitan ester or gum arabic; Aqueous excipient (can comprise edible oil) not, for example Prunus amygdalus oil, fractionated coconut oil, contain grease such as glycerine, propylene glycol or alcoholic acid ester; Sanitas, for example methyl p-hydroxybenzoate or propylparaben or Sorbic Acid; Can also contain conventional seasonings or tinting material if desired.
Oral preparations also comprises conventional sustained-release, as has enteric coated tablet or particle.
For parenterai administration, preparation contains the flow unit formulation of compound and aseptic vehicle.Compound can be suspended or be dissolved according to vehicle and concentration.Usually can by with compound dissolution in vehicle and filter sterilization, load suitable phial or ampoule subsequently and sealing prepares non-enteron aisle solution.It is comparatively favourable that adjuvant also is dissolved in the vehicle as local anesthetic, sanitas and buffer reagent.In order to improve stability, can will carry out freezing after composition is in loading phial and vacuum is removed and anhydrated.
Prepare non-enteron aisle suspension with substantially the same method, difference is to be suspended in compound in the vehicle rather than to be dissolved in the vehicle, and comes sterilization in the ethylene oxide by being exposed to before in being suspended in aseptic vehicle.Comprising tensio-active agent or wetting agent in composition is comparatively favourable with the uniform distribution that promotes The compounds of this invention.
Usually and composition together the explanation of writing or printing arranged, be used to instruct related pharmacological agent.
Compound of the present invention can use separately or unite use with other compound such as therapeutic compound.
When carrying out administration, wish that The compounds of this invention does not have disadvantageous toxic action according to the present invention.
Therefore, on the other hand, the invention provides a kind of medicinal compositions that is used for the treatment of and/or prevents one or more described diseases, said composition comprises The compounds of this invention or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.
The present invention also provides a kind of method that treats and/or prevents one or more described diseases, and this method comprises the patient who needs this to treat and/or prevent the The compounds of this invention of significant quantity or preventive dose or its pharmacy acceptable salt or solvate.
The The compounds of this invention or its pharmacy acceptable salt or solvate of providing on the one hand more of the present invention is used for the treatment of and/or prevents purposes in the medicine of one or more described diseases in manufacturing.
Also on the one hand, the invention provides new compound of the present invention or its pharmacy acceptable salt or solvate as therapeutical agent, especially for the purposes that treats and/or prevents one or more described diseases.
Be used for compound of the present invention and preparation thereof and exemplify below embodiment and form.
These embodiment for example understand conventional steps and the pharmaceutical chemicals source that is used for preparing the compound of its structure shown in table data behind the embodiment.In the situation of the embodiment that paired arrangement group according to each is prepared, the synthetic source of all starting ingredients of described arrangement all is illustrated among each embodiment.With the experimental procedure under the various situations of its detailed description, not as the method that will be used for each integral part of preparation experiment by the reference related embodiment is listed in table.The mass spectral characteristic of all embodiment all is given in the data form.Provide the representative embodiment that further feature is used to select to have whole experimental procedures.
Embodiment A 1[WO-00/06146]
Utilize the step of embodiment A 7, usefulness 4-xenyl carboxylic acid [Aldrich] replacement 2 '-methyl-4-xenyl carboxylic acid.
Embodiment A 2
Corresponding to embodiment A 7, usefulness 4-(the 5-methyl-[1,2,4] oxadiazole-3-yls)-phenylformic acid [J.Org.Chem.50; 8; 1985; 1182].
Embodiment A 3
Corresponding to embodiment A 7, with 4-pyrazol-1-yl-phenylformic acid [Can.J.Chem.; 41; 1963; 1540].
Embodiment A 4
Corresponding to embodiment A 7, with 3-xenyl carboxylic acid [Med.Chem.Res.; 6; 2; 1996].
Embodiment A 5
Corresponding to embodiment A 7, with 4-(2-pyridyl)-phenylformic acid [J.Chem.Soc.; 1940; 355,356].
Embodiment A 6
Corresponding to embodiment A 7, with 3 '-ethanoyl-xenyl-4-carboxylic acid [patent WO9743262].
Embodiment A 7
2-aminomethyl phenyl-4-phenyl carboxylic acid [3-methoxyl group-4-(2-two (2-methylethyl) amino) oxyethyl group)-phenyl amide
To acid (2 '-methyl-xenyl-4-carboxylic acid) [patent WO-9901127] (55mg, 0.26mmol) dimethyl formamide solution in add (1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride [Aldrich] (50mg, 0.26mmol) and 1-hydroxyl-7-azepine benzotriazole [Aldrich] (35mg, 0.26mmol), add diisopropylethylamine (0.04ml afterwards, 0.25mmol) and aniline (4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-aniline) (69mg, 0.22mmol) [utilize the method that forms 3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-aniline in the embodiment A 51 to be prepared, but replace 1-(2-hydroxyethyl)-tetramethyleneimine with the 2-diisopropylaminoethanol].Reaction mixture was at room temperature stirred 16 hours.Evaporating solvent is dissolved in resistates in the methylene dichloride (10ml), through SAX[Varian again] post (2g) filtration, (100mg 0.38mmol) stirs filtrate 16 hours to use PS-isocyanate resin [Argonaut Technologies] then.Filtering mixt, evaporation is purified resistates through flash chromatography on silica gel, make elutriant with methylene dichloride-ammoniacal liquor-methyl alcohol, obtains the buttery title compound.
1H NMR (CDCl 3): δ 1.04 (12H, d), 2.28 (3H, s), 2.90 (2H, t), 3.05 (2H, m), 3.91 (3H, s), 3.95 (2H, t), 6.88 (1H, d), 7.03 (1H, dd), 7.27-7.32 (4H, m), 7.44, (2H, d), 7.53 (1H, d), 7.94 (2H, d) and 8.01 (1H, bs); MS (AP+ve): m/z 461[M+H] +
Embodiment A 8
Utilize the step of embodiment A 7, usefulness cyclohexyl-4 benzoic acid [Aldrich] replacement (2 '-methyl-xenyl-4-carboxylic acid).
Embodiment A 9
Corresponding to embodiment A 7, with 4-(2-thienyl)-phenylformic acid [J.Chem.Soc.PerkinTrans.1; 17; 1992; 2203].
Embodiment A 10
Corresponding to embodiment A 7, with 4-(1-methyl isophthalic acid H-pyrazoles-4-yl)-phenylformic acid [patent: WO-9906409].
Embodiment A 11
Corresponding to embodiment A 7, with 4 '-(5-methyl-[1,2,4]-oxadiazoles-3-yl)-xenyl-4-carboxylic acid [patent: WO-9743262].
Embodiment A 12
Corresponding to embodiment A 7, with 4-benzyl-carboxylic acid [Apin].
Embodiment A 13
Corresponding to embodiment A 7, with 3 '-cyano group-xenyl-3-carboxylic acid [J.Chem.Soc.Perkin Trans.2; 1; 1984; 35-38].
Embodiment A 14
Corresponding to embodiment A 7, with 3 '-methylsulfonyl-xenyl-4-carboxylic acid [Izv.Sib.Otd.Akad.Nauk SSSR Ser.Khim.Nauk; 11; 1966; 62].
Embodiment A 15
Corresponding to embodiment A 7, with 3-thiophene-2-base-phenylformic acid [Tetrahedron Lett.; 39; 24; 1998; 4175].
Embodiment A 16
Corresponding to embodiment A 7, with 3-thiene-3-yl--phenylformic acid [J.Chem.Soc.B; 1970; 1595].
Embodiment A 17
Corresponding to embodiment A 7, with 4-ethanoyl-4-xenyl carboxylic acid [Aldrich].
Embodiment A 18
Corresponding to embodiment A 7, with 4 '-cyano group-3 '-methyl biphenyl-4-carboxylic acid [WO-9850358].
Embodiment A 19
Corresponding to embodiment A 7, with 4 '-(the 5-methyl-[1,3,4] oxadiazole-2-yls)-xenyl-4 carboxylic acid [patent: WO-9743262].
Embodiment A 20
Corresponding to embodiment A 7, with 4-thiene-3-yl--phenylformic acid [J.Chem.Soc.B; 1970; 1595].
Embodiment A 21
Corresponding to embodiment A 7, with 4-pyrazine-2-base-phenylformic acid [patent WO-9854164].
Embodiment A 22
Utilize the step of embodiment A 93, replace 4-aminomethyl phenyl boric acid, and utilize the step in the embodiment A 51, and replace 1-(2-hydroxyethyl)-tetramethyleneimine with 2-(diisopropylaminoethyl) ethanol with 2-anisole ylboronic acid [Aldrich].
Embodiment A 23
Utilize the step of embodiment A 22, replace 2-anisole ylboronic acid [Aldrich] with 4-trifluoromethyl phenyl boronic acid [Aldrich].
Embodiment A 24
Corresponding to embodiment A 23, with 3-aminophenyl boric acid [Aldrich].
Embodiment A 25
Corresponding to embodiment A 23, with 4-benzyloxy phenyl-boron dihydroxide [Lancaster].
Embodiment A 26
Corresponding to embodiment A 23, with 2-naphthyl boric acid [Lancaster].
Embodiment A 27
Corresponding to embodiment A 23, with 3-naphthyl boric acid [Lancaster].
Embodiment A 28
Corresponding to embodiment A 23, with 4-aminomethyl phenyl boric acid [Lancaster].
Embodiment A 29
Corresponding to embodiment A 23, with 4-methylthio phenyl ylboronic acid [Lancaster].
Embodiment A 30
Corresponding to embodiment A 23, with 3-trifluoromethyl phenyl boronic acid [Lancaster].
Embodiment A 31
Corresponding to embodiment A 23, with 4-carbonyl phenyl boric acid [Aldrich].
Embodiment A 32
Corresponding to embodiment A 23, with 3,4-(methylene radical dioxy base) phenyl-boron dihydroxide [Aldrich].
Embodiment A 33
Corresponding to embodiment A 23, with 4-vinyl benzene ylboronic acid [Aldrich].
Embodiment A 34
Corresponding to embodiment A 23, with 3-anisole ylboronic acid [Lancaster].
Embodiment A 35
Utilize the step of embodiment A 51, replace 1-(2-hydroxyethyl) tetramethyleneimine with 1-(2-hydroxyethyl) morpholine [Aldrich].
Embodiment A 36
Utilize the step of embodiment A 35, replace 4-xenyl carboxylic acid with 4-phenylcyclohexane formic acid [Aldrich].
Embodiment A 37
Utilize the step of embodiment A 51, replace 1-(2-hydroxyethyl) tetramethyleneimine with 2-dimethylaminoethanol [Aldricll].
Embodiment A 39
Corresponding to embodiment A 51, with (R-(+)-1-methyl-2-pyrrolidine carbinol (patent WO-9932480).
Embodiment A 41
Corresponding to embodiment A 51, with 3-hydroxyl-1-methyl piperidine [Aldrich].
Embodiment A 43
Corresponding to embodiment A 51, with 2-dimethylamino-1-propyl alcohol [ICN-RF].
Embodiment A 45
Corresponding to embodiment A 51, with 2-(diethylamino)-ethanol [Aldrich].
Embodiment A 47
Corresponding to embodiment A 51, with (S)-(-)-1-methyl-2-pyrrolidine carbinol [Aldrich].
Embodiment A 49
Corresponding to embodiment A 51, with N-benzyl-N-Mono Methyl Ethanol Amine [Aldrich].
Embodiment A 51
Xenyl-4-carboxylic acid [3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl amide
(1.87ml adds sodium hydride [60% dispersion in the oil, (544mg, 16mmol)] in batches in dimethyl formamide solution 16mmol) to oxyamine (1-(2-hydroxyethyl)-tetramethyleneimine) [Aldrich].After at room temperature stirring 10 minutes, drip halogenated nitrobenzene (1-chloro-2-methoxyl group-4-oil of mirbane) [Avocado] (3g, dimethyl formamide 16mmol) (10ml) solution.Reaction mixture was at room temperature stirred 16 hours, concentrate then.Resistates is dissolved in the ethyl acetate (200ml), and water (3 * 50ml) wash.Organic phase through dried over mgso, is evaporated, and resistates is purified through flash chromatography on silica gel, make elutriant, obtain brown buttery 1-[2-(2-methoxyl group-4-nitro-phenoxy group)-ethyl with methylene dichloride-ammoniacal liquor-methyl alcohol]-tetramethyleneimine.
1H NMR (CDCl 3): δ 1.82 (4H, m), 2.65 (4H, m), 3.01 (2H, t), 3.94 (3H, s), 4.24 (2H, t), 6.92 (1H, d), 7.74 (1H, d) and 7.89 (1H, dd);
MS(AP+ve)：m/z?267[M+H] +。
To amine, 1-[2-(2-methoxyl group-4-nitro-phenoxy group)-ethyl]-(2.3g adds 10%Pd/C (50mg) in ethanol 8.6mmol) (100ml) solution to tetramethyleneimine.This mixture was stirred 16 hours under room temperature, hydrogen atmosphere, normal atmosphere, then through diatomite filtration, concentrated filtrate, obtain corresponding aniline: 3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-aniline is brown solid.
1H NMR (CDCl 3): δ 1.80 (4H, m), 2.62 (4H, m), 2.89 (2H, t), 3.80 (3H, s), 4.06 (2h, t), 6.20 (1H, dd), 6.29 (1H, d) and 6.75 (1H, d);
MS(AP+ve)：nz/z237[M+H] +。
Carboxylic acid in being suspended in methylene dichloride (1ml), (4-xenyl carboxylic acid) [Aldrich] (47.5mg, 0.24mmol) (0.06ml 0.72mmol), adds a dimethyl formamide to middle adding oxalyl chloride [Aldrich] afterwards.Reaction mixture was at room temperature stirred 1 hour, concentrate, with methylene dichloride coevaporation 3 times, obtain 4-phenyl Benzoyl chloride then.It is dissolved in the methylene dichloride (1ml), and join contain amine, (3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-aniline) (47mg, 0.2mmol), (0.14ml is 1mmol) and in the solution of methylene dichloride (1ml) for triethylamine.This reaction mixture was at room temperature stirred 16 hours, concentrate, be dissolved in the methylene dichloride (10ml) again, (2g) filter through SAX post [Varian], (100mg 0.38mmol) stirred 16 hours with PS-isocyanate resin [Argonaut Technologies].Filtering mixt, evaporation is purified through flash chromatography on silica gel then, makes elutriant with methylene dichloride-ammoniacal liquor-methyl alcohol, obtains the buttery title compound.
1H NMR (CDCl 3): δ 1.88 (4H, m), 2.90 (4H, m), 3.08 (2H, t), 3.84 (3H, s), 4.21 (2H, t), 6.83 (1H, d), 7.03 (1H, dd), 7.27-7.70 (8H, m) and 8.01 (2H, d);
MS(AP+ve)：m/z?417[M+H] +。
Embodiment A 54
Utilize the step of embodiment A 51, replace 1-(2-hydroxyethyl)-tetramethyleneimine with 1-dimethylamino-2-propyl alcohol [Aldrich].
Embodiment A 56
Corresponding to embodiment A 51, with 1-(2-hydroxyethyl)-piperidines [Aldrich].
Embodiment A 58
Corresponding to embodiment A 51, with 2-(hexa-methylene amino)-ethanol [Lancaster].
Embodiment A 60
Utilize the step of embodiment A 93, replace 2-anisole ylboronic acid with 3-aminophenyl boric acid, and the step of utilizing embodiment 51,1-(2-hydroxyethyl) tetramethyleneimine replaced with the 2-dimethylaminoethanol.
Embodiment A 63
Utilize the step of embodiment A 60, replace 3-aminophenyl boric acid with 4-carboxyl phenyl boric acid [Aldrich].
Embodiment A 70
Corresponding to embodiment A 63, with (3,4-methylenedioxyphenyl base) boric acid [Aldrich].
Embodiment A 72
Utilize the step of embodiment 51, replace 1-(2-hydroxyethyl)-tetramethyleneimine with N-(2-phenyl)-ethyl-N-methyl-thanomin [J.Org.Chem.1985,50 (22), 4359].
Embodiment A 74
Corresponding to embodiment 51, with 2-dimethylamino hexalin [J.Chem.Soc.C (1969), (2), 248-52].
Embodiment A 76
Corresponding to embodiment 51, with 2-(1,2,4,5-tetrahydro benzo [d] azatropylidene-3-yl)-ethanol [patent US-394682].
Embodiment A 78
Corresponding to embodiment 51, with 2-(3,4-dihydro-1H-isoquinoline 99.9-2-yl)-ethanol [patent WO-9719926].
Embodiment A 80
Corresponding to embodiment 51, with 2-(4-phenyl-Piperazine-1-yl)-ethanol [J.Med.Chem.1994,37 (13), 1964].
Embodiment A 82
Corresponding to embodiment 51, with 1-methyl-3 tetramethyleneimine phenol (pyrrolidinol) [Aldrich].
Embodiment A 84
Utilize the step of embodiment A 93, replace 2-anisole ylboronic acid, utilize the step of embodiment A 51, replace 1-(2-hydroxyethyl) tetramethyleneimine with the 2-DEAE diethylaminoethanol with 4-methoxyl group-phenyl-boron dihydroxide [Aldrich].
Embodiment A 88
Utilize the step of embodiment A 84, replace 4-methoxyl group-phenyl-boron dihydroxide with 4-methoxyl group-3-pyridyl boric acid [patent WO-9924440].
Embodiment A 89
Corresponding to embodiment A 88, with 2-methoxyl group-3-pyridyl boric acid [patent WO9910331].
Embodiment A 90
Corresponding to embodiment A 88, with benzo-[b]-FURAN-2-BORONIC ACID [Aldrich].
Embodiment A 91
Corresponding to embodiment A 88, with thiophene-3-boric acid [Aldrich].
Embodiment A 92
Corresponding to embodiment A 88, with indoles-5-boric acid [Frontier].
Embodiment A 93
4 '-methyl-xenyl-4-carboxylic acid [3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-acid amides
With methylene dichloride (20ml) solution-treated 3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-aniline [embodiment A 51] (4.7mM 1.1g) of 4-bromobenzene formyl chloride [Aldrich] and the mixture of triethylamine (14mmol), and at room temperature kept 16 hours.With solvent evaporation, thick product through silica gel column chromatography, is made elutriant with methylene chloride-methanol-ammoniacal liquor, obtain 4-bromo-N-[3-methoxyl group-4 (2-tetramethyleneimine-1-base-oxyethyl group)-phenyl of white solid]-benzamide, yield 72%.
1H NMR (DMSO-d6): δ 7.91 (2H, dd), 7.73 (2H, dd), 7.50 (1H, d), 7.30 (1H, dd), 6.94 (1H, d), 4.02 (2H, t), 3.76 (3H, s), 2.77 (2H, t), 2.51 (4H, m is under the DMSO-d-5 signal) and 1.67 (4H, m);
MS：(ES+ve)m/z419，421[M+H] +
Four-(triphen phosphino-)-palladium [0] (5mg) in the presence of, under argon gas atmosphere, with acid amides, 4-bromo-N-[3-methoxyl group-4 (2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-benzamide (0.1mM 42mg) and 4-methyl-phenylo boric acid [Aldrich] (0.1mM 14mg) refluxed 16 hours in the mixture of benzene (8ml), ethanol (2ml) and 2M aqueous sodium carbonate (2ml).With this mixture cooling, decant the upper strata, and this solution is purified through silica gel column chromatography, use methylene dichloride earlier: methyl alcohol (10: 1) is made elutriant, uses acetonitrile afterwards: saturated ammoniacal liquor (25: 1) is made elutriant, obtains the white solid compound.
1H NMR (CDCl 3): δ 7.92 (2H, dd), 7.68 (2H, dd), 7.50 (2H, dd), 7.26 (3H, dddd), 6.96 (1H, dd), 6.88 (1H, d), 4.13 (1H, t), 3.87 (3H, s), 2.92 (2H, t), 2.60 (4H, m), 2.41 (3H, s) and 1.80 (4H, m);
MS：(AP-ve)m/z429[M-H] -；(AP+ve)m/z?431[M+H] +。
Embodiment A 100
Utilize the step of embodiment A 93, replace 4-methyl-phenylo boric acid with 4-(2,6-dimethoxypyridin base)-boric acid [Frontier].
Embodiment A 103
Corresponding to embodiment A 93, with furans-3-boric acid [Frontier].
Embodiment A 104
Corresponding to embodiment A 93, with base-boric acid [Frontier].
Embodiment A 105
Utilize the step of embodiment A 51, difference is to replace methylene dichloride as solvent and eluent with chloroform, and uses 3-rubane phenol (quinuclidinol) [Aldrich] to replace 1-(2-hydroxyethyl hydroxyethyl).
Embodiment A 107
Utilize the step of Embodiment B 37, but replace aniline with piperidines.
Embodiment B 1
Utilize the step of embodiment A 7, usefulness 3-phenoxy benzoic acid [Aldrich] replacement 2 '-methyl-xenyl-4-carboxylic acid.
Embodiment B 2
Corresponding to Embodiment B 1, use 4-benzylbenzoic acid [Apin].
Embodiment B 34
Corresponding to Embodiment B 1, use 3-benzylbenzoic acid [patent WO-9828268].
Embodiment B 35
Corresponding to Embodiment B 1, use 4-phenoxy benzoic acid [Aldrich].
Embodiment B 37
N-[-[3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-4-phenyl amino-benzamide
Under argon gas atmosphere, with the Carbon Dioxide caesium (0.15mM, 49mg), (S)-BINAP[Aldich] (0.015mM, 9mg) and acid chloride (0.0075mM is 2mg) anhydrous glycol dimethyl ether (15ml) sonication 40 minutes.With 4-bromo-N-[3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-phenyl]-benzamide [embodiment A 93] (0.1mM, 42mg) and aniline (0.11mM 10mg) handles this suspension, refluxes then 40 minutes.This suspension is filtered through hydrophobic film, concentrate, use acetonitrile then: water is purified through the C18R.P. silica, obtains the title compound of white solid.
1H NMR (MeOH-d 4): δ 7.96 (2H, dd) 7.92 (1H, d), 3.1 (2H, dd), 7.20 (1H, dd), 7.04 (1H, d), 4.28 (2H, t), 3.92 (3H, s), 3.78 (2H, m), 3.60 (2H, t), 3.58-3.13 (6H, m) and 2.26-1.47 (10H, m);
MS：(ES+ve)m/z?424[M+H] +
Embodiment C 1
Utilize the step of embodiment A 7, usefulness 2-methyl biphenyl-4-carboxylic acid [patent WO-9606079] replacement 2 '-methyl-xenyl-4-carboxylic acid.
Embodiment C 2
Corresponding to Embodiment C 1, utilize 3-methoxyl biphenyl base-4-carboxylic acid [patent WO-9534540].
Embodiment C 3
Corresponding to Embodiment C 1, utilize 3-methyl biphenyl-4-carboxylic acid [patent WO-9534540].
Embodiment C 4
Corresponding to Embodiment C 1, utilize 4-phenyl thiophene-2-carboxylic acid [Specs].
Embodiment C 5
Corresponding to Embodiment C 1, utilize 4-(3, the 5-dichlorophenoxy)-furans-2-carboxylic acid [Maybridge].
Embodiment C 6
Corresponding to Embodiment C 1, utilize 5-methyl isophthalic acid-phenylpyrazole-4-carboxylic acid [Maybridge].
Embodiment C 7
Corresponding to Embodiment C 1, utilize 6-phenyl-nicotinic acid [WO-0006085].
Embodiment C 8
Corresponding to Embodiment C 1, utilize 3-chloro-xenyl-4-carboxylic acid [patent JP-09221476].
Embodiment C 9
Corresponding to Embodiment C 1, utilize 5-(4-chloro-phenyl-)-2-trifluoromethyl-furans-3-carboxylic acid [Maybridge].
Embodiment C 10
Corresponding to Embodiment C 1, utilize 2-(4-chloro-phenyl-)-3-(trifluoromethyl)-pyrazoles-4-carboxylic acid [Maybridge].
Embodiment C 11
Corresponding to Embodiment C 1, utilize 5-(2-pyridyl)-thiophene-2-carboxylic acid [Maybridge].
Embodiment C 12
Corresponding to Embodiment C 1, utilize 5-(methyl-trifluoromethyl-2-H-pyrazole-3-yl) thiophene-2-carboxylic acid [Maybridge].
Embodiment D1
Utilize the step of embodiment D5, with 3,4-dichloronitrobenzene [Aldrich] replaces 2, the 4-dichloronitrobenzene.
Embodiment D5
Xenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides
In 10 minutes, to water (28ml) the solution blended iron powder (938mg that is equipped with ammonium chloride (28mmol), 16.8mmol) three-necked flask (condenser is housed, dropping funnel and thermometer) the middle method preparation that drips amine [2-(3-chloro-4-nitro-phenoxy group)-ethyl]-di-isopropyl-amine [by being used to form 1-[2-(2-methoxyl group-4-nitro-phenoxy group)-ethyl in the embodiment A 51]-tetramethyleneimine, difference is with 2,4-dichloronitrobenzene [Aldrich] replaces 4-chloro-3-methoxy nitrobenzene, and replaces 1-(2-hydroxyethyl)-tetramethyleneimine with the 2-diisopropylaminoethanol].Reaction mixture is leniently refluxed, till t.l.c. analyzes the no raw material of demonstration.This mixture of filtered while hot, and use the methanol wash inorganic residues.Make the filtrate after the merging (distribute dry organic phase (MgSO between 3 * 10ml) at water (5ml) and ethyl acetate 4), filter and evaporation.Handle water with saturated sodium bicarbonate aqueous solution (10ml), with ethyl acetate (3 * 10ml) extractions, dry (MgSO 4), and evaporation.The resistates of twice extraction gained is merged, and purify, make elutriant, obtain brown buttery 2-chloro-4-(2-diisopropylaminoethyl-oxyethyl group)-aniline with methylene chloride-methanol-ammoniacal liquor through flash chromatography on silica gel.
1H NMR (CDCl 3): δ 1.02 (12H, d), 2.77 (2H, t), 3.03 (2H, septets), 3.72 (2H, bs), 3.80 (2H, t), 6.68 (2H, m) and 6.85 (1H, m);
MS(AP+ve)：m/z271，273[M+H] +。
In the step of embodiment A 51, replace 3-methoxyl group-4-(2-tetramethyleneimine-1-base-oxyethyl group)-aniline with this raw material, obtain transparent buttery title compound.
1H NMR (CDCl 3): δ 1.26 (12H, d), 3.07 (2H, m), 3.35 (2H, m), 4.22 (2H, m), 6.89 (1H, dd), 7.01 (1H, m), 7.44 (3H, q), 7.62 (2H, d), 7.71 (2H, d), 7.97 (2H, d) and 8.34 (1H, d);
MS(AP+ve)：m/z?452，454[M+H] +。
Embodiment D9
Utilize the step of embodiment A 51, with 2,4-difluoro nitrobenzene [Aldrich] replaces 4-chloro-3-methoxy nitrobenzene.
Embodiment D12[WO-00/06146]
Utilize the step of embodiment A 51, with 3,4-difluoro nitrobenzene [Aldrich] replaces 4-chloro-3-methoxy nitrobenzene.
Embodiment D16
Utilize the step of embodiment A 51, replace 4-chloro-3-methoxy nitrobenzene with 2-methyl-4-fluoro oil of mirbane [Aldrich].
Embodiment D20
Utilize the step of embodiment A 51, replace 4-chloro-3-methoxy nitrobenzene with 3-methyl-4-fluoro oil of mirbane [Aldrich].
Embodiment D24
Utilize the step of embodiment A 51, replace 4-chloro-3-methoxy nitrobenzene with 3-ethanoyl-4-fluoro oil of mirbane [Aldrich].
Embodiment D25
Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-2-formyl radical-5-p-methoxy-phenyl]-acid amides
With oxoethanoic acid trihydrate (1ml), methylene dichloride (5ml) and methylsulfonic acid (0.5ml) handle xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-phenyl]-acid amides [patent WO-9901127] (223mg, 0.5mmol).With this mixture vigorous stirring 24 hours, use saturated sodium bicarbonate aqueous solution (30ml) to handle then, and with methylene dichloride (3 * 20ml) extractions.With the organic phase drying (MgSO after merging 4), filter and evaporation, obtain the title compound of acetate form then through flash chromatography on silica gel [chloroform-methanol-aqueous acetic acid], be white solid.
1H NMR (CDCl 3): δ 1.13 (12H, d), 2.04 (3H, s), 3.02 (2H, t), 3.20 (2H, septets), 4.05 (3H, s), 4.10 (2H, t), 5.0 (1H, bs), 7.22 (1H, s), 7.40 (1H, t), 7.48 (2H, d), 7.65 (2H, d), 7.76 (2H, d), 8.14 (2H, d), 8.72 (1H, s) and 9.34 (1H, s);
MS(AP+ve)：m/z?475[M+H +]。
Embodiment D26
Xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-3-(1-hydroxyl-ethyl)-phenyl]-acid amides
Xenyl-4-carboxylic acid [3-ethanoyl-4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides [embodiment D24] (20mg in being dissolved in tetrahydrofuran (THF)/alcoholic acid 1: 1 mixture (3ml); 0.05mmol) middle adding sodium borohydride [Aldrich] (6mg, 0.15mmol).Reaction mixture was at room temperature stirred 16 hours.Evaporating solvent, and resistates purified by flash chromatography on silica gel, as elutriant, obtain the title compound of white solid with methylene dichloride-ammoniacal liquor-methyl alcohol.
1H NMR (CDCl 3): δ 1.09 (6H, t), 1.49 (3H, d), 2.75 (4H, q), 2.95 (2H, t), 4.15 (2H, t), 5.01 (1H, q), 6.84 (1H, d), 7.45-7.67 (9H, m) and 7.95 (2H, d)
MS(AP+ve)：m/z433?[M+H +]。
Embodiment D27
Xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-3-ethyl-phenyl]-acid amides
To the xenyl that is dissolved in methylene dichloride (1.5ml)-4-carboxylic acid [3-ethanoyl-4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides [embodiment D24] (25mg, 0.06mmol) middle triethyl silicane (0.5ml) and the trifluoroacetic acid (0.25ml) of adding.The gained yellow solution was at room temperature stirred 120 hours.Evaporating solvent is purified resistates through flash chromatography on silica gel, make elutriant with methylene dichloride-ammoniacal liquor-methyl alcohol, obtains the title compound of white solid.
1H NMR (CDCl 3): δ 1.17 (6H, m), 2.64 (2H, q), 2.8 (4H, q), 3.06 (2H, t), 4.15 (2H, t), 6.82 (1H, d), 7.35-7.71 (9H, m) and 7.96 (2H, d)
MS(AP+ve)：m/z?417[M+H] +
Embodiment D28[WO9901127]
Utilize the step of embodiment A 51, replace 4-chloro-3-methoxy nitrobenzene, replace 1-(2-hydroxyethyl)-tetramethyleneimine with the 2-diisopropylaminoethanol with 4-fluoro oil of mirbane [Aldrich].
Embodiment D30[WO9901127]
Utilize the step of embodiment D28, replace the 2-diisopropylaminoethanol with 2-dimethylaminoethanol [Aldrich].
Embodiment D32[WO9901127]
Utilize the step of embodiment D28, replace the 2-diisopropylaminoethanol with 2-DEAE diethylaminoethanol [Aldrich].
Embodiment D38[WO9901127]
Utilize the step of embodiment A 22, replace 4-chloro-3-methoxy nitrobenzene, replace 4-anisole ylboronic acid with 4-ethylphenyl boric acid with 4-fluoro oil of mirbane [Aldich].
Embodiment D39[WO9901127]
Utilize the step of embodiment A 84, replace 4-chloro-3-methoxy nitrobenzene, replace 4-anisole ylboronic acid with 4-ethylphenyl boric acid with 4-fluoro oil of mirbane [Aldich].
Embodiment E 1
Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-phenyl]-methyl-acid amides
In 4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-aniline (1mmol) [embodiment A 7], add triethyl orthoformate (8ml) and trifluoroacetic acid (0.15ml).Gained solution is heated to 90 ℃ to be kept 4 hours.Evaporating solns, and then be dissolved in the ethanol, and be cooled to approximately-10 ℃.In 10 minutes, drip sodium borohydride (190mg, 5mmol).Then with this mixture heating up to room temperature.This solution was at room temperature stirred 16 hours, use the 2M hcl acidifying then to pH1.Mixture is concentrated into about 10ml, is allocated in then between ethyl acetate and the water.With the 2M aqueous sodium hydroxide solution water is adjusted to pH14, with dichloromethane extraction (* 3), dry (MgSO 4), filter and evaporation.Resistates is purified through flash chromatography on silica gel, make elutriant, obtain oily [4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-phenyl]-methyl-amine with methylene dichloride-ammoniacal liquor-methyl alcohol.
1H NMR (CDCl 3): δ 1.03 (12H, d), 2.80 (3H, s), 2.85 (2H, t), 3.02 (2H, q), 3.80 (3H, s), 3.86 (2H, t), 6.13 (1H, dd), 6.23 (1H, d) and 6.80 (1H, d);
MS(AP+ve)：m/z?281[M+H] +。
In the 4-Phenylbenzoic acid (0.2mmol) that is suspended in methylene dichloride, add oxalyl chloride (0.6mmol), add dimethyl formamide (1) then.This reaction mixture was stirred 1 hour, and evaporation with methylene dichloride coevaporation (* 3), and then is dissolved in the methylene dichloride (1ml).Add to be dissolved in and contain amine [4-(2-diisopropylaminoethyl-oxyethyl group)-3-methoxyl group-phenyl]-methyl-amine (0.2mmol) and triethylamine (140mg, solution 1mmol) in the methylene dichloride (1ml).This solution was at room temperature stirred 14 hours, and evaporation is dissolved in methylene dichloride (1ml) and also (150mg) handles with PS-isocyanate resin [Argonaut Technologies].After at room temperature vibrating 18 hours again, filter this mixture, make it pass through SAX post [Varian] (1g), evaporate, and resistates is purified by silica gel column chromatography, make elutriant, obtain the oily title compound with methylene dichloride-ammoniacal liquor-methyl alcohol.
1H NMR (CDCl 3): δ 1.21 (12H, bd), 2.88-3.24 (4H, m), 3.32 (3H, s), 3.87 (3H, s), 4.11 (2H, m), 6.82-6.91 (3H, m) and 7.26-7.56 (9H, m);
MS(AP+ve)：m/z?476[M+H] +。
Embodiment E 5
Utilize the step of embodiment E 1, replace triethyl orthoformate with triethly orthoacetate [Aldrich].
Embodiment E 12
Xenyl-4-carboxylic acid [2-chloro-4-(2-diisopropylaminoethyl-oxyethyl group)-5-methoxyl group-phenyl]-acid amides
With xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-3-methoxyl group-phenyl]-methyl-acid amides [embodiment E 9] (45mg, 0.1mmol) be dissolved in the chloroform (1ml), and with benzotriazole [Aldrich] (12mg, 0.1mmol) and N-chlorosuccinimide (13mg 0.11mmol) handles.This mixture was at room temperature stirred 16 hours, evaporation then, and, obtain the oily title compound through flash chromatography on silica gel (methylene chloride-methanol-ammoniacal liquor) purification.
1H NMR (CDCl 3): δ 1.06 (6H, t), 2.63 (4H, q), 2.90 (2H, t), 3.39 (3H, s), 3.67 (3H, s), 4.03 (2H, t), 6.57 (1H, s), 6.84 (1H, s) and 7.31-7.53 (9H, m);
MS(AP+ve)：m/z?467，469[M+H] +。
Embodiment E 13
Utilize the step of embodiment A 93, replace 4-(2-diethylamino-oxyethyl group)-3-anisidine with [4-(2-diethylamino-oxyethyl group)-3-methoxyl group-phenyl]-methyl-amine [embodiment E 9], replace 4-anisole ylboronic acid with 2-fluoro aminomethyl phenyl boric acid [Aldrich], and the step of utilizing embodiment 51, replace 1-(2-hydroxyethyl) tetramethyleneimine with (N-diethyl) thanomin.
Embodiment E 14
Utilize the step of embodiment E 13, replace the 4-chlorophenylboronic acid with 2-aminomethyl phenyl boric acid [Aldrich].
Embodiment E 16
Corresponding to embodiment E 14, with 2-chloromethylbenzene ylboronic acid [Aldrich].
Embodiment E 17
Corresponding to embodiment E 14, with 4-methyl fluoride phenyl-boron dihydroxide [Aldrich].
Embodiment E 21
Corresponding to embodiment E 14, with 4-chloromethylbenzene ylboronic acid [Aldrich].
Embodiment E 22
Corresponding to embodiment E 14, with 4-ethylphenyl boric acid [Aldich].
Embodiment E 23
Corresponding to embodiment E 14, with 4-tert.-butylbenzene ylboronic acid [Aldrich].
Embodiment E 24
With 4-xenyl carboxylic acid [4-(2-diethylamino-oxyethyl group)-3-methoxyl group-phenyl]-methyl-acid amides [embodiment E 9] (45mg, 0.1mmol) be dissolved in the acetonitrile (1ml), and with N-fluoro-N '-chloro methyl-triethylenediamine-two (a tetrafluoro borate) (43mg, 0.12mmol) handle, be heated to 80 ℃ and kept 6 hours.With this solvent evaporation, and resistates purified through flash chromatography on silica gel (methylene chloride-methanol-ammoniacal liquor), obtain the oily title compound.
MS(AP+ve)：m/z?451[M+H] +。
Embodiment E 25
Utilize the step of embodiment E 1, replace 4-(2-diisopropylaminoethyl-oxyethyl group)-3-anisidine, and replace triethyl orthoformate with triethly orthoacetate with 4-(2-diisopropylaminoethyl-oxyethyl group)-3-methyl-aniline [embodiment D20].
Embodiment F 1
Utilize the step of embodiment A 7, with 6-phenyl nicotinic acid (patent WO-0006085) replace 2 '-methyl-4-xenyl carboxylic acid, and with N-dimethylethanolamine replacement 2-(diisopropylaminoethyl) ethanol.
Embodiment G1
Xenyl-4-carboxylic acid [4-(R)-diethylamino-hydroxyl-propoxy-)-3-methoxyl group-phenyl]-acid amides
(845mg 5mmol) is dissolved among the DMF (25ml) and (60% oil dispersion 200mg) is handled with sodium hydride with 4-nitro-2-methoxyphenol [Aldrich].When effervesce stops, handling this mixture with (R)-p-nitrophenyl alkylsulfonyl Racemic glycidol [Aldrich], and under agitation be heated to 50 ℃.After 16 hours, make this mixture cooling, evaporation, and at water (20ml) and methylene dichloride (distribution between 3 * 25ml), dry (MgSO 4), filter and evaporation.Resistates is purified by flash chromatography on silica gel (hexane-ether), obtain light brown solid (R)-2-(2-methoxyl group-4-nitro-phenoxymethyl)-oxyethane, yield 80%.
1H NMR (CDCl 3): δ 2.79 (1H, dd), 2.95 (1H, dd), 3.41 (1H, dddd), 3.96 (3H, s), 4.06 (1H, dd), 4.43 (1H, dd), 6.98 (1H, d), 7.75 (1H, d) and 7.87 (1H, dd).
With (the R)-2-in the methylene dichloride (3ml) (2-methoxyl group-4-nitro-phenoxymethyl)-oxyethane (0.5mmol, 113mg) with amine (diethylamine) [Aldrich] (1.5mmol, 110mg) and titanium tetraisopropylate [Aldrich] (50 μ l) handle.This solution is at room temperature stirred 24 hours, and water (1ml) processing, acutely swayed 10 minutes.Make gained suspension by (5ml), obtain (R)-diethylamino-(2-methoxyl group-4-nitro-phenoxy group)-propan-2-ol of yellow oily with the hydromatrix post [Varian ChemElut] of methylene dichloride (10ml) wash-out.
1H NMR (CDCl 3): δ 1.07 (6H, t), 2.55-2.72 (7H, m), 3.94 (3H, s), 4.09-4.13 (3H, m), 6.97 (1H, d), 7.74 (1H, d) and 7.89 (1H, dd);
MS(AP+ve)：m/z?299[M+H +]。
This substance dissolves in ethanol (5ml), is handled with 0.1ml hydrogenchloride (2M is in the diethyl ether), used 10% palladium charcoal (20mg) to handle then, and hydrogenation under atmospheric pressure 24 hours.With this solution of purification for argon, then through diatomite filtration, evaporation obtains white crystalline solid (R)-(4-amino-2-methoxyl group-phenoxy group)-diethylamino-propan-2-ol hydrochloride.
1H NMR (CD 3OD): δ 1.19 (6H, t), 3.36-3.45 (6H, m), 3.88 (s, 3H), 4.02-4.11 (2H, m), 4.03 (1H, m), 6.95-7.03 (2H, m) and 7.13 (1H, d).
The solution of this material in methylene dichloride (2ml) is used triethylamine (2mmol, 280 μ l) and triethylsilyl triflate, and (1mmol 264mg) handles.After 30 minutes, (1mmol 217mg) introduces in this mixture and mixture was stirred 12 hours with 4-xenyl carboxylic acid chloride [embodiment 1].Evaporating solvent is dissolved in resistates in the methyl alcohol (100ml), and handles with salt of wormwood (2g).Stir after 6 hours, with the suspension evaporation, form slurry with methylene dichloride (20ml), filter, evaporated filtrate is purified resistates by flash chromatography (methylene chloride-methanol-ammoniacal liquor), obtain the title compound of white solid.
1H NMR (CDCl 3): δ 1.11 (6H, t), 2.61-2.78 (6H, m), 3.88 (3H, s), 3.5-4.5 (1H, vbs), 3.99-4.13 (3H, m), 6.92 (1H, d), 6.99 (1H, dd), 7.41-7.49 (3H, m), 7.56 (1H, d), 7.63 (2H, d), 7.69 (2H, d) and 7.97 (3H, d);
MS(AP+ve)：m/z?449[M+H +]。
Embodiment G5
Utilize the step of preparation (R)-diethylamino-(2-methoxyl group-4-nitro-phenoxy group)-propan-2-ol [embodiment G1], but with 1, the 2-ethylene dichloride replaces methylene dichloride, replaces diethylamine with Diisopropylamine.In addition, the mixture of amine and epoxide 80 ℃ of heating 12 hours, rather than was at room temperature kept 24 hours.
Embodiment G8
Utilize the step of embodiment G1, but replace (R)-p-nitrophenyl alkylsulfonyl-Racemic glycidol, and replace diethylamine with tetramethyleneimine with (S)-p-nitrophenyl alkylsulfonyl-Racemic glycidol.
Embodiment G22
Utilize the step of embodiment A 51, but replace 1-(2-hydroxyethyl)-tetramethyleneimine with 4-dimethylamino-1-butanols [ICN-RF].
Embodiment H1
4-cyclohexyl-N-[3-methoxyl group-4-(4-methyl-piperazine-1-yl)-phenyl]-benzamide
Under agitation condition, (10mmol 2.18g) handles 1-(2-methoxyl group-4-nitro-phenyl)-piperazine (patent WO-9906382) (10mmol, methylene dichloride 2.37g) (50ml) solution with tert-Butyl dicarbonate.Emit gas tempestuously, stop after 1 hour.Evaporate this solution then, obtain yellow solid 4-(2-methoxyl group-4-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
1H NMR (CDCl 3): δ 1.50 (9H, s), 3.16 (4H, t), 3.61 (4H, t), 3.96 (3H, s), 6.88 (1H, d), 7.72 (1H, d) and 7.86 (1H, dd).
This substance dissolves is also handled with 10% palladium on carbon (100mg) in ethanol (50ml).With the hydrogenation 2 hours under 1 normal atmosphere of this suspension, then through diatomite filtration, evaporation obtains brown buttery 4-(4-amino-2-methoxyl group-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
1H NMR (CDCl 3): δ 1.48 (9H, s), 2.86-2.91 (4H, t), 3.52-3.60 (4H, t), 3.81 (3H, s), 6.22-6.27 (2H, m) and 6.73 (1H, d).
With this aniline (0.2mmol, 61mg) be dissolved in the methylene dichloride (1ml) and use in order DIEA resin [Argonaut Technologies] (0.5g) and 4-phenylcyclohexane formyl chloride [embodiment A 36] handle.This mixture was gently swayed 12 hours, filter then, evaporation, and resistates purified with flash chromatography on silica gel (methylene chloride-methanol-ammoniacal liquor), obtain white crystalline solid 4-(4-{[1-(4-cyclohexyl-phenyl)-methanoyl]-amino-2-methoxyl group-phenyl)-piperazine-1-carboxylic acid tert-butyl ester.
1H NMR (CDCl 3): δ 1.25-1.47 (5H, m), 1.54 (9H, s), 1.75-1.88 (5H, m), 2.56 (1H, m), 2.98 (4H, t), 3.61 (4H, t), 3.91 (3H, s), 6.87 (1H, d), 6.93 (1H, dd), 7.32 (2H, d), 7.54 (1H, s), 7.77, (1H, s) and 7.78 (2H, d);
MS(AP+ve)：m/z?493[M+H +]。
This substance dissolves is also handled with phenylmethylether (1ml) and trifluoroacetic acid (5ml) in methylene dichloride (5ml).After 2 hours, evaporate this solution, then coevaporation 2 times from toluene.This resistates is dissolved in the methylene dichloride (10ml), and washs, dry (MgSO with saturated sodium bicarbonate (2ml) 4) organic phase, filter and evaporation, obtain brown buttery 4-cyclohexyl-N-(3-methoxyl group-4-piperazine-1-base-phenyl)-benzamide.
1H NMR (CDCl 3): δ 1.22-1.87 (10, m), 2.57 (1, m), 3.04-3.12 (8H, m), 3.91 (3H, s), 6.95 (2H, bs), 7.32 (2H, d), 7.54 (1H, m), 7.77 (1H, s) and 7.78 (2H, d); MS (AP+ve): m/z 394[M+H +].
With this amine (0.1mmol, 39mg) be dissolved in the ethanol (3ml) and with metaformaldehyde (100mg), macroporous resin cyano group borohydride resin [Novabiochem] (100mg) and acetate (50 μ l) handle.This mixture was at room temperature stirred 3 hours, filter then, evaporation, and resistates is passed through flash chromatography on silica gel (methylene chloride-methanol-ammoniacal liquor) purify, obtain light brown oily title compound.It is evaporated from dilution acetate, obtain the Monoacetate hydrate.
1H NMR (CDCl 3): δ 1.22-1.45 (5H, m), 1.76-1.87 (5H, m), 2.02 (6H, 2xs), 2.56 (1H, m), 3.22-3.23 (4H, t), 3.29-3.30 (4H, t), 3.88 (3H, s), 6.86 (1H, d), 6.94 (1H, dd), 7.30 (1H, d), 7.59 (1H, d), 7.79 (2H, d), 7.98 (1H, s) and 8.54 (4H, bs);
MS(AP+ve)：m/z?408[M+H +]。
Following form provides exemplary embodiment, is not to limit the invention by any way.
Table A
The compound that comprises general formula (II), it is the part of general formula (I), and wherein A is H and OMe, and R3 is H, and X is O, Y is CH 2CH 2, Z is a key, and R4 is Ph, and R5 is position or para-orientation between on the R4.
Figure A0181360100491
Figure A0181360100501
Figure A0181360100511
Figure A0181360100531
Figure A0181360100541
Figure A0181360100551
Table B
The compound that comprises general formula (III), it is the part of general formula (I), and wherein A is H and OMe, and R1 and R2 are Me 2, R3 is H, and X is O, and Y is CH 2-CH 2, Z is O, CH 2Or NH; R4 is Ph, and R5 is Ph, and Z is position or para-orientation between on the R4.
Figure A0181360100581
Figure A0181360100582
Figure A0181360100591
Table C
The compound that comprises general formula (IV), it is the part of general formula (I), and wherein A is H and OMe, and R1 and R2 are Me 2, R3 is H, and X is O, and Y is CH 2-CH 2R4 and R5 are substituted phenyl or heterocycle.
Table D
Comprise the compound of logical formula V, it is the part of general formula (I), and wherein R3 is H, and X is O, and Y is CH 2-CH 2, Z is O, CH 2, NH or key; R4 is Ph, and R5 is Ph or cyclohexyl (Cy), and Z is position or para-orientation between on the R4.
Figure A0181360100661
Table E
The compound that comprises general formula (VI), it is the part of general formula (I), and wherein A is H, Cl, F and OMe, and X is O, and Y is CH 2-CH 2R4 is a phenyl, and R5 is phenyl or cyclohexyl (Cy), and Z is O, CH 2Or key.
Table F
The compound that comprises general formula (VII), it is the part of general formula (I), and wherein A is H and OMe, and X is O, and R4 is the 3-pyridyl, R5 is a phenyl, Z contraposition key.
Figure A0181360100692
Table G
The compound that comprises general formula (VIII), it is the part of general formula (I), and wherein A is H and OMe, and R3 is H, and X is O; R4 is a phenyl, and Z is O, CH 2Or key, R5 is Ph or cyclohexyl (Cy), Y is for choosing the chain of 3 or 4 carbon atoms that replaced by hydroxyl wantonly.
Figure A0181360100701
Figure A0181360100702
Figure A0181360100711
Table H
The compound that comprises general formula (IX), it is the part of general formula (I), and wherein A is H and OMe, and R3 is H, and X is N; R4 is a phenyl, and Z is the key of para-orientation, and R5 is Ph or cyclohexyl (Cy), and Y and R2 form piperazine ring between X and N.
Figure A0181360100721
The embodiment numbering R5 R1 [M+N] + Method
H1 Cy Me ?408 ?H1
H2 Cy Et ?436 ?H1
H3 Cy iPr ?422 ?H1
The activity that is used for compound of the present invention can be by estimating the competitive binding experiment of 11CBy acceptor, and as described below: radioligand is in conjunction with research
HEK293 cell by stably express 11CBy acceptor on careful washed film carries out radioligand in conjunction with experiment.Film (5-15mg protein) and [125I]-melanocyte are concentrated hormone (0.22nM) (deriving from NEN) exist and do not exist under the situation of competitive trials compound, 37 ℃, contain in the damping fluid (pH7.4) of 50mM Tris and 0.2%BSA and hatched 45 minutes.Concentrate hormone (deriving from Bachem) definition non-specific binding with the 0.1mM melanocyte.In 10 enrichment steps, test compound is added with the concentration between 10 M-10pM.After hatching, by filtering the GF/B strainer reaction is stopped, and wash with the ice-cooled 50mM Tris damping fluid of 4 * 1ml.In strainer, add microscint 20 (Packard), and measure radioactivity with Packard TopCount.
Be expressed as function when not having test compound in conjunction with cpm when having test compound, and chart with respect to compound concentration in conjunction with cpm.Determine IC50 by it, calculate pKi by the IC50 value again.
The pKi value of compounds effective of the present invention is in the 7.1-7.8 scope, for example:
Embodiment The pKi scope
????A48 ????7.5-7.8
????B2 ????7.1-7.4
????C8 ????7.1-7.4
????D15 ????7.5-7.8
????E9 ????7.5-7.8
????F4 ????7.1-7.4
????G1 ????7.1-7.4
????H1 ????7.1-7.4

Claims (11)

  1. One kind the treatment described disease method, this method comprises formula (I) compound or its pharmacy acceptable salt or the solvate of the Mammals significant quantity of suffering from one or more described diseases, wherein:
    Each A independently is hydrogen, the optional C that is replaced by hydroxyl 1-6Alkyl, C 1-6Alkoxyl group, C 1-6Alkenyl or C 1-6Acyl group or halogen atom or hydroxyl, CN or CF 3Group;
    R3 is hydrogen, methyl or ethyl;
    R4 is optional substituted aromatic carbocyclic or heterocycle;
    Z be positioned at R4 with respect to O or S atom or NH or CH on 3 or 4 of carbonyl 2Group or singly-bound;
    R5 is optional substituted aromatic carbocyclic or heterocycle or optional substituted saturated or unsaturated carbocyclic or heterocycle;
    And Q is
    (a) wherein X is O or S atom;
    Y is linearity or branching C 2-4Alkylidene group optional is replaced by hydroxyl, perhaps is C 5-6Cycloalkylidene,
    R1 and R2 independently are linearity or branching C 1-6Alkyl, phenyl C 1-6Alkyl; Perhaps
    (b) wherein X is O or S atom;
    Y is linearity or branching C 2-4Alkylidene group optional is replaced by hydroxyl,
    R1 and R2 are connected to form 5,6 or 7 yuan of rings, optional other heteroatoms that comprises one or more O of being selected from, S or N, wherein N or C annular atoms optional by Ra ,-CO-Ra ,-CO-NH-Ra or CO-O-Ra replace, wherein Ra is linearity or branching C 1-6Alkyl or aryl, and the optional phenyl ring that becomes to be optionally substituted that condenses of described 5,6 or 7 yuan of rings, the annular atoms of perhaps described 5,6 or 7 yuan of rings is optional to link to each other with Y by singly-bound or methylene radical; Perhaps
    (c) wherein X is O or S atom,
    Y is C 2-4Alkylidene group, R1 are to link to each other with Y to form the C of 5 or 6 yuan of rings 2-4Alkylidene group, and R2 is linearity or branching C 1-6Alkyl; Perhaps
    (d) wherein X is the N atom,
    Y is C 2-4Alkylidene group, R1 are to link to each other with X to form the C of 5 or 6 yuan of rings 2-4Alkylidene group, and R2 is linearity or branching C 1-6Alkyl.
  2. 2. (I) compound or its salt of formula as defined in claim 1 or solvate, wherein R3 is methyl or ethyl.
  3. 3. the compound of claim 2, any compound of this compound for delivering among this paper table E.
  4. 4. (I) compound or its salt of formula as defined in claim 1 or solvate, but do not comprise following compounds:
    N-[4-[2-[two (1-methylethyl) amino] oxyethyl group]-2-fluoro phenyl]-[1,1 '-xenyl]-the 4-methane amide,
    N-[4-[2-[two (1-methylethyl) amino] oxyethyl group] phenyl]-[1,1 '-xenyl]-the 4-methane amide,
    Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
    N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
    N-[4-(2-diethylamino-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
    N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
    N-[4-(2-diethylamino-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
    4-cyclohexyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
    4-cyclohexyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
    4-benzyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
    4-benzyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
    4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
    With 4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides.
  5. 5. one kind prepares formula (I) compound or its salt of claim 2 or the method for solvate, and this method comprises the reaction of formula (X) compound and formula (XI) compound,
    R5-Z-R4-COL (X) is the definition of R5, Z and R4 such as claim 1 Chinese style (I) wherein, and L is a leavings group,
    Figure A0181360100041
    The wherein definition of Q and A such as claim 1 Chinese style (I), R3 is methyl or ethyl.
  6. One kind prepare as defined in claim 1 formula (I) compound or its salt or the method for solvate, this method comprises the reaction of formula (X) compound and formula (XI) compound, the definition of R5, Z and R4 such as claim 1 Chinese style (I) in the formula (X), definition in the formula (XI) in Q, A and R3 such as the claim 1, condition is that this method does not comprise the method for preparing following compounds:
    N-[4-[2-[two (1-methylethyl) amino] oxyethyl group]-2-fluoro phenyl]-[1,1 '-xenyl]-the 4-methane amide,
    N-[4-[2-[two (1-methylethyl) amino] oxyethyl group] phenyl]-[1,1 '-xenyl]-the 4-methane amide,
    Xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
    N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
    N-[4-(2-diethylamino-oxyethyl group)-phenyl]-4-phenoxy group-benzamide,
    N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
    N-[4-(2-diethylamino-oxyethyl group)-phenyl]-3-phenoxy group-benzamide,
    4-cyclohexyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
    4-cyclohexyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
    4-benzyl-N-[4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-benzamide,
    4-benzyl-N-[4-(2-diethylamino-oxyethyl group)-phenyl]-benzamide,
    4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diisopropylaminoethyl-oxyethyl group)-phenyl]-acid amides,
    With 4 '-ethyl-xenyl-4-carboxylic acid [4-(2-diethylamino-oxyethyl group)-phenyl]-acid amides.
  7. 7. medicinal compositions that is used for the treatment of and/or prevents one or more described diseases, said composition comprises compound of the present invention or its pharmacy acceptable salt or solvate and pharmaceutically acceptable carrier.
  8. 8. method that treats and/or prevents one or more described diseases, this method comprises needs described The compounds of this invention patient's significant quantity or preventive dose or its pharmacy acceptable salt or the solvate that treats and/or prevents.
  9. 9. The compounds of this invention or its pharmacy acceptable salt or solvate are used for the treatment of and/or prevent purposes in the medicine of one or more described diseases in manufacturing.
  10. 10. new compound of the present invention or its pharmacy acceptable salt or solvate are as therapeutical agent, especially for the purposes that treats and/or prevents one or more described diseases.
  11. 11. diabetes, major depression, manic depression of sex, anxiety, schizophrenia and a sleep disordered method for the treatment of people or non-human mammal, this method comprises the people 11CBy receptor antagonist for the treatment of significant quantity.
CN01813601A 2000-07-31 2001-07-26 Carboxamide compounds and their use as antagonists of human 11CBY receptor Pending CN1444573A (en)

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