CN101605542A - Pharmaceutical composition with and using method - Google Patents
Pharmaceutical composition with and using method Download PDFInfo
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- CN101605542A CN101605542A CNA200780051253XA CN200780051253A CN101605542A CN 101605542 A CN101605542 A CN 101605542A CN A200780051253X A CNA200780051253X A CN A200780051253XA CN 200780051253 A CN200780051253 A CN 200780051253A CN 101605542 A CN101605542 A CN 101605542A
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- pyridin
- oxadiazole
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Abstract
The present invention relates to comprise the compositions of neuronal nicotinic sample receptors ligand and α 4 β 2 positive allosteric modulators, the goods of the method for use said composition and relevant manufacturing.
Description
Background of invention
The cross reference of related application
The application requires the U.S. Patent Application Serial Number 60/874 of December in 2006 submission on the 12nd, 609, the U.S. Patent Application Serial Number of submitting on April 12nd, 2,007 60/999, the U.S. Patent Application Serial Number 11/953 of 761 and 2007 on Decembers submission in 10,, 625 priority, its each be incorporated herein by reference with its full content.
Technical field
The present invention relates to comprise the compositions of neuronal nicotinic sample (nicotinic) receptors ligand and α 4 β 2 other structure (allosteric) regulators, the goods of the method for use said composition and relevant manufacturing.
Description of related art
Neuronal nicotinic sample receptor, especially α 4 β 2 neuronal nicotinic sample acetylcholinergic receptors (nAChRs) have been used as the target of pain and various central nervous system disease.The antisense of α 4 subunits knocks out and is found analgesic effect (the Bitner RS that can reduce agonist, Nikkel AL, Curzon P, Donnelly-Roberts DL, Puttfarcken PS, Namovic M, Jacobs IC, Meyer MD, and Decker MW (2000) Brain Res.871:66-74).In α 4 gene knockout animals, also see reduction (Marubio LM to the anti-nociception reaction of nicotine, Arroyo-Jimenez MD, Cordero-Erausquin M, Lena C, Le Novere N, d ' Exaerde AD, Huchet M, Damaj MI, and Changeux JP (1999) Nature398:805-810).α 4 and β 2 nAChRs react on vertebra and nicotine sample analgesia (Decker all is responsible for regulating in the spinal cord position, MW, Rueter, LE and Bitner, RS (2004) Nicotinicacetylcholine receptor agonists:a potential new class of analgesics, CurrTop Med Chem., 4:369-384).Antinociceptive activity by α 4 β 2 nAChRs can transmit owing to stimulation brain stem monoamine usually, especially at chi chung (Cucchiaro G, Chaijale N, andCommons KG (2005) J Pharmacol Exp Ther.313:389-394).But gama-α 4 β 2 the stimulations gabaergic gama-and transmission of glycine energy inhibition also have contribution (Rashid MH, Furue H, Yoshimura M, and Ueda H (2006) Pain 125:125-135) in the spinal cord.
Central α 3
*NAChRs may promote nicotine sample analgesia (Khan IM, Wennerholm M, Singletary E, Polston K, Zhang L, Deerinck T, Yaksh TL, and Taylor P (2004) J Neurocytol.33:543-556), but α 3 β 4 parts are not too interesting, because perhaps be spontaneous side effect.Really, described purpose has to avoid α 3
*Neuronal nicotinic sample receptor (NNR) is because the limited emetic tendency of the dosage of non-selective compound is considered to contain the activation of the nAChRs of α 3.α 3
*NAChRs expresses in enteric nervous system and in periphery and central nervous system's the other parts.Area postrema and nucleus solitarius are the brain stem nuclear that is considered to relate to nausea and vomiting.α 3 in vagus nerve motor dorsal nucleus and nucleus solitarius
*NAChRs has related to the harmonization of the stomach blood pressure response (Ferreira M, Singh A, Dretchen KL, Kellar KJ, and Gillis RA (2000) J.Pharmacol.Exp.Ther.294:230-238) after the nicotine local infusion.
Find that α 4 β 2nAChRs are had in various degree optionally chemical compound with respect to other nicotine sample hypotype (contain α 3, α 7, α 1-) recent years.For example, ABT-594 (being called as compd A in this application) comprises in acute heat, the chemical origin cause of formation, nerve and the visceral pain it being effective (Decker MW at the rodent model of some nociceptions, Meyer MD, and SullivanJP (2001) Expert Opinion on Investigational Drugs 10:1819-1830).Obtainable data show that having optionally to α 4 β 2nAChRs with respect to α 3 β 4 effectiveness, part preferably has low adverse events distribution.In theory, it is active or (b) increase α 4 β 2 and render a service and do not increase α 3 β 4 activity to reduce α 3 β 4 by (a), can enlarge therapeutic index.The latter can combine with exogenous α 4 β2Ji Dongji by positive allosteric modulators (PAM) of α 4 β 2 selectivitys or PAM separately and realize.By improving the effect and/or the effectiveness of agonist, positive allosteric modulators can reinforced effects.Therefore, at preferred α 4 β 2nAChRs places, with respect to other nAChR hypotype, the positive allosteric modulators of α 4 β 2 selectivitys can optionally improve effect.
The positive allosteric modulators of initial known α 4 β 2nAChRs is nonselective and is not very effective.For example, it is reported that nefiracetam reinforcing alpha 4 β 2nAChR react (NarahashiT, Moriguchi S, Zhao X, Marszalec W, and Yeh JZ (2004) Biol.Pharm.Bull.27:1701-1706.).Recently, subtype-selective PAMs is disclosed.Chemical compound such as 3-(3-pyridin-3-yl-1 has now been described, 2,4-oxadiazole-5-yl) benzonitrile etc. has firm α 4 β 2PAM effects, and does not have anything to regulate active (for example open on November 2nd, 2006/114400,2006 referring to WO) to other hypotype such as α 3 β 4.
Pain is a kind of unsatisfied medical science needs, and the Therapeutic Method of these indications and probability are not enough.Though still in the use nAChR agonist treatment pain that keeps punching, though different on degree, the stable effect of pain may be limited by the scope of the side effect relevant with their purposes.Consider the importance and the limitation in their treatments of chronic pain, the new Therapeutic Method of determining these diseases will be useful, particularly to reduce the mode that disadvantageous neuroganglion effect (is for example vomitted) for example at the gastronintestinal system place.This with particularly advantageous be to determine chemical compound and compositions, it provides the chance of a kind of like this expansion treatment window of nicotine sample (nAChR) agonist in pain.Wish that also for example cognition and attention-deficient have the effectiveness of raising with other central nervous system disease of nAChR ligands for treating.
Summary of the invention
Summary of the invention
The invention provides compositions, it can be used for treatment disease or the obstacle relevant with nicotine-like acetylcholinergic receptor (nAChR), and has the effect of raising and side effect still less than independent nicotine sample reagent.To a certain extent, the present invention relates to a kind of compositions, wherein the effect of nicotine sample (nAChR) reagent is improved by the positive allosteric modulators (PAM) that gives nicotine sample part and nAChR hypotype α 4 β 2 jointly.The present invention relates to compositions, it is used for the treatment of the disease of suffering from nAChR-mediation or the individuality of obstacle, and especially for treatment pain or CNS disease, described compositions comprises the combination of nicotine sample part and α 4 β 2 positive allosteric modulators.The invention provides the synergistic combination of nicotine sample agonist or partial agonist and α 4 β 2 positive allosteric modulators.The present invention further provides at mammal particularly disease and obstacle, particularly pain and the central nervous system disease of treatment or prevention nAChR-mediation among the people.This combination has improved the effect of α 4 β 2 parts and can provide useful alternative mode to current treatment.
In one embodiment, the present invention relates to a kind of compositions, it comprises (i) nicotine-like acetylcholinergic receptor part; The (ii) positive allosteric modulators of nicotine-like acetylcholinergic receptor hypotype α 4 β 2 selectivitys, they mix mutually with at least a pharmaceutically acceptable excipient.Preferred nicotine-like acetylcholinergic receptor part is nicotine-like acetylcholinergic receptor hypotype α 4 β 2 parts.The benefit of maximum of the present invention is: (i) and (ii) quantity together is effective in treatment nAChR-disease states mediated such as pain.Other CNS disease that relates to α 4 β 2nAChRs, for example cognitive and attention disease also can be benefited.
In another embodiment, the present invention relates to a kind of method that is used for comprising neuropathic pain and cognitive disorder in patient treatment or prevent irritation, this method comprises: (i) give described patient a certain amount of nicotine-like acetylcholinergic receptor part; (ii) give a certain amount of nicotine-like acetylcholinergic receptor hypotype of described patient α 4 β 2 allosteric modulators; Wherein (i) and (ii) together quantity is more effective in treatment pain or cognitive disorder.Preferred nicotine-like acetylcholinergic receptor part is neuronal nicotinic sample receptor subtype α 4 β 2 parts.The invention still further relates to nicotine-like acetylcholinergic receptor hypotype α 4 β 2 allosteric modulators and be used for the treatment of the purposes of attention or cognitive dysfunction in conjunction with the pharmaceutically active agents that improves cholinergic function.The present invention has also described nicotine-like acetylcholinergic receptor hypotype α 4 β 2 allosteric modulators are used for the treatment of neural psychology (neuropsychological) malfunction in conjunction with used pharmaceutically active agents purposes.
Another embodiment of the present invention relates to a kind of goods of manufacturing, comprises: first pharmaceutical dosage form that (i) comprises at least a nicotine-like acetylcholinergic receptor part; (ii) comprise second pharmaceutical dosage form of at least a nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators, wherein these goods contain first and second pharmaceutical dosage forms.
Also described radiolabeled chemical compound in this article, it can be used for estimating the binding affinity of nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators.The present invention has also disclosed radiolabeled α 4 β 2 positive allosteric modulators.
How embodiment of the present invention prepare them and how to use them to describe further below.
Brief description of drawings
Figure 1A and 1B describe representational nicotine-like acetylcholinergic receptor part, 5-[(2R)-azetidine-2-ylmethoxy]-there are not and exist nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators in 2-chloropyridine (compd A), 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (PAM, chemical compound 1) under the situation, to people α 4 β 2 that in the HEK-293 cell, express or the reaction of α 3 β 4 nicotine-like acetylcholinergic receptor hypotypes.This digital proof is at α 4 β 2 rather than α 3 β 4, nAChRs place doing the trick (EC
50Value) moves to left.
Fig. 2 A and 2B describe another representational nicotine-like acetylcholinergic receptor part, (3R)-1-pyridin-3-yl pyrrolidine-3-amine (compd B), there are not and exist α 4 β 2 positive allosteric modulators, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) under the situation of benzonitrile (PAM, chemical compound 1), to people α 4 β 2 that in the HEK-293 cell, express or the reaction of α 3 β 4 nicotinic receptor hypotypes.In addition, this digital proof, the nAChR agonist is to α 4 β 2 rather than α 3 β 4nAChRs doing the trick (EC
50Value) moves to left.
The effect aspect the effect of enhancing nAChR partial agonist of Fig. 3 A and 3B graphic representation α 4 β 2 positive allosteric modulators, described nAChR partial agonist for example is that (Compound C also claims ABT-089 to 2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine; Reuter, L.E., Anderson, D.J., Briggs, C.A., Donnelly-Roberts et al., CNS Drug Rev., 10 (2), 167-182,2004).Compound C does not cause that separately calcium replys, but when and PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1)) during co-administered, α 4 β 2nAChRs (Fig. 3 A) is caused firm reaction, but α 3 β 4nAChRs (Fig. 3 B) but can not.Compound C is the representative of other nicotine sample partial agonist.
Fig. 4 A and 4B graphic representation α 4 β 2 positive allosteric modulators improve another kind of nAChR partial agonist (1S, 5S)-3-(3,6-diaza-bicyclo-[3.2.0] heptan-3-yl)-quinoline (Compound D; α 4 β 2[
3H] cytisine K
i=6nM)) in effect.Compound D does not cause separately replys, but works as and PAM 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) causes firm reaction (Fig. 4 A) to α 4 β 2nAChRs when using together, but can not cause firm reaction (Fig. 4 B) to α 3 β 4nAChRs.Compound D is the representative of other nicotine sample partial agonist.
Fig. 5 represents existed and do not had α 4 β 2PAM by various nicotine-like acetylcholinergic receptor parts, under the situation of 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) α 4 β 2nAChRs is activated the dependency of effectiveness.Usually, in the presence of α 4 β 2PAM (chemical compound 1), it is more effective that these nicotine sample parts are found in activation α 4 β 2nAChRs aspects.
Fig. 6 A graphic representation α 4 β 2PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) is strengthening 5-[(2R in the counter-rotating neuropathic pain)-azetidine-2-ylmethoxy]-effect of the effect of 2-chloropyridine (compd A).
Fig. 6 B graphic representation α 4 β 2PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) is strengthening 5-[(2R)-azetidine-2-ylmethoxy]-the dose dependent effect of the neuropathic pain effect of 2-chloropyridine (compd A).When with the α 4 β 2PAM (chemical compound 1) of various dosage when combining, the ineffective dose of compd A (1nmol/kg) is proved to be effective.
Fig. 7 A represents 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A) is independent, α 4 β 2PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) separately and the compd A of chemical compound 1 (3.5 μ mol/kg) and various dosage be combined in dose dependent effect in the neuropathic pain.It is unfruitful using α 4 β 2PAM (chemical compound 1) separately.But in the presence of chemical compound 1, in the Chung of neuropathic pain model, the dose response curve of compd A is moved to the left.
Fig. 7 B represents the influence to vomitting in the ferret.Represented independent 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A), independent α 4 β 2PAM, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) the bonded effect of benzonitrile (chemical compound 1) and chemical compound 1 (3.5 μ mol/kg) and the compd A of various dosage.In ferret vomiting model, independent α 4 β 2PAM (chemical compound 1) do not cause vomiting, and the dose response curve of mobile compd A not.
Fig. 8 A and 8B represent the blood plasma level analysis in neuropathic pain and the vomiting model.Shown in Fig. 8 A, the effect of compd A is shifted to the left side, but shown in Fig. 8 B, not mobile to the effect of vomiting.Can there be α 4 β 2PAM in the maximum effect of compd A in the neuropathic pain that vomiting do not occur, realize in 3-(3-(pyridin-3-yl)-1,2, the 4-oxadiazole-5-yl) benzonitrile (chemical compound 1).Data show that the treatment window of α 4 β 2nAChR agonist becomes wideer in the presence of α 4 β 2PAM.
Fig. 9 represents partial agonist, and Compound D exists and do not exist α 4 β 2PAM, the effect under 3-(3-(pyridin-3-yl)-1,2, the 4-oxadiazole-5-yl) benzonitrile (chemical compound 1).In an exemplary example, when giving Compound D separately, it is invalid in easing the pain.When with α 4 β 2PAM (chemical compound 1) co-administered, it is resultful that Compound D is proved to be, and data show that Compound D provides the neuropathic pain that significantly obviously alleviates in the rat.
Figure 10 be the acceptor site in the graphic representation people meninges specificity in conjunction with (the every mg albumen of fmoles) be radioligand [
3H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile ([
3H]-POB, nM) function of concentration.
Detailed description of the invention
The compound that is suitable for the goods of composition of the present invention, method and manufacturing can be identified Any compound with α 4 β 2 nicotinic receptor activity.
Although it has been generally acknowledged that, represent that with asterisk the accurate subunit composition of acceptor is uncertain, for example α 4 β 2*Expression contains the acceptor that α 4 and beta 2 subunit unit albumen are combined with other subunit.
Have now found that, surprisingly, by with nicotinic acetylcholine receptor ligands particularly α 4 beta 2 receptor parts (activator, partial agonist) and nicotine-like acetylcholinergic receptor α 4 beta 2 subunit types Selective positive allosteric modulators (PAM) combination can improve the effect of nicotinic receptor part. Compare with giving separately α 4 beta 2 receptor parts, for example treating pain and Other diseases indication In the cognitive process that lacks, these combinations can improve the effect of α 4 β 2 parts very effectively.
Nicotine sample acetylcholine subtype alpha 4 beta 2 receptor parts
Nicotine sample acetylcholine subtype alpha 4 beta 2 receptor parts come regulatory function by changing receptor active. Suitable compound can also be partial agonist, and its part retardance or part activate α 4 beta 2 receptors, The perhaps activator of activated receptor. Being suitable for nicotine-like acetylcholinergic receptor α 4 β 2 of the present invention is subjected to The body part can comprise whole activators or partial agonist. Regulate nicotine-like acetylcholinergic receptor The compound of α 4 beta 2 subunit type activity all is suitable for the present invention, and no matter mutually do between they and acceptor With mode.
A kind of mode that characterizes α 4 beta 2 receptor parts is by the combination test. The compounds of this invention [3H]-eulexine associated value (" KiCyt ") at about .001 nanomole to greater than 100 micromolar scopes In. Prove that for the preferred compound of said composition associated value is little the rubbing of about .001 nanomole to 10 You. Described [3H]-eulexine in conjunction with the test fully reported; Yet, carry out advancing of this test The details in one step can be at international publication number WO 99/32480; U.S. Patent number 5,948,793 Hes 5,914,328; WO 2004/018607; U.S. Patent number 6,809,105; WO 00/71534 and U.S. Obtain in state's patent No. 6,833,370.
Therefore, being suitable for α 4 beta 2 receptor parts of the present invention can be the chemical combination of various chemical types Thing. Especially, some example that is suitable for α 4 beta 2 receptor parts of the present invention comprises, but office not Be limited to the heterocyclic radical ether derivant, for example such as disclosed international publication number WO on July 1st, 1999 The U.S. Patent number 5,948,793 of also further announcing on September 7th, 1999 described in 99/32480 And on June 22nd, 1999 announce 5,914,328 in be described and protect; N-replaces The diazabicyclo derivative is for example such as disclosed international publication number WO on September 23rd, 2004 Described in 2004/0186107, and the U.S. Patent number of announcing on October 26th, 2004 Further describe in 6,809,105 with claimed; The aminoazaheterocycles class that heterocyclic radical replaces, for example Described on November 30th, 2000 disclosed international publication number WO 00/71534, and Further describe and require in the U.S. Patent number 6,833,370 that on December 21st, 2004 announced to protect Protect; All these lists of references are incorporated herein by reference with its full content. About this compound Further describe with the preparation method and be reported in patent, patent publications and the world of quoting In the patent publications.
Other example that is suitable for α 4 beta 2 receptor parts of the present invention includes, but are not limited to aryl-condensed azapolycy clic compounds, for example described in August 30 calendar year 2001 disclosed international publication number WO2001062736; The enamine compound of aryl-replacement is for example as described in December in 1999 disclosed international publication number WO 9965876 on the 23rd and December in 2000 the disclosed international publication number WO 00/75110 on the 14th; Pyrido pyrans and azepine
Derivant, for example as on March 25th, 2003 laid-open U.S. Patents numbers 6,538, described in 003; Benzal-and cinnamylidene-anabaseines is for example as described on March 4th, the 1999 disclosed international publication number WO 99/10338; And 3-pyrrole base (pyridoxy) the alkyl heterocycle ether compound of trembling, for example as described in December in 1996 the disclosed international publication number WO 96/040682 on the 19th; All these lists of references are incorporated herein by reference with its full content.Be reported in the patent of being quoted and international monopoly publication about further describing of this chemical compound with preparation method.
Other chemical compound as proof α 4 β 2 parts report includes, but are not limited to TC-1734 (ispronicline), GTS-21,4-hydroxyl-GTS-21, TC-5619, TC-2696, dianicline and varenicline, it all is described in the obtainable document of the public.
Instantiation for α 4 beta 2 receptor chemical compounds that part is considered includes, but are not limited to:
5-[(2R)-azetidine-2-ylmethoxy]-the 2-chloropyridine;
(3R)-1-pyridin-3-yl pyrrolidine-3-amine;
2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine;
3-(5,6-two chloro-pyridin-3-yls)-1S, 5S-3,6-diazabicyclo [3.2.0] heptane;
(R, R)-1-(pyridin-3-yl) octahydro-pyrrolo-[3,4-b] pyrroles;
6,10-methylene (methano)-6H-pyrazine is [2,3-h] [3] benzo-aza also
7,8,9, the 10-tetrahydrochysene-(2S, 4E)-N-methyl-5-(5-isopropoxy-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-5-(5-methoxyl group-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-5-(5-ethyoxyl-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-3-pyrimidine-4-amylene-2-amine;
(5aS, 8S, 10aR)-5a, and 6,9,10-tetrahydrochysene-7H, 11H-8,10a-methylene pyrido [2 ', 3 ': 5,6] pyrans [2,3-d] azepine also
3-[1-(2,4-dimethoxy-phenyl)-first-(E)-subunit (ylidene)]-3,4,5,6-tetrahydrochysene-[2,3 '] bipyridyl; With
3-[1-(2-methoxyl group-4-hydroxy phenyl)-first-(E)-subunit]-3,4,5,6-tetrahydrochysene-[2,3 '] bipyridyl;
Or its pharmaceutically acceptable salt.
The positive allosteric modulators of nicotine sample acetylcholine hypotype α 4 beta 2 receptors
Positive allosteric modulators is to strengthen receptor to the response of acetylcholine but itself can not cause receptor activation or desensitization, or can not cause receptor activation or the desensitization simultaneously chemical compound of (or either, of the receptor).
Characterize the active a kind of mode of α 4 β, 2 positive allosteric modulators and be by characterizing in people HEK cell, described people HEK cellular expression people nicotine-like acetylcholinergic receptor hypotype α 4 β 2 are particularly by using fluorescence imaging to read plate instrument technology.This test has been in the news and can have obtained the disclosed International Patent Publication No. WO 2006/114400 from November 2nd, 2006 about the further details of carrying out this test.Identifying and characterizing the active other method of allosteric modulators is by express alpha 4 beta 2 subunit unit in African Bufo siccus ovum or cell line, follows (Curtis L, Buisson B, Bertrand S and Bertrand, D., 2002 as previously mentioned; Molecular Pharmacology is 61:127-135) by measuring the influence of the current response that part is caused.
On behalf of gang, steroid hormone nAChRs is had the molecule of change regulating action and other member of LGIC superfamily.For example, the adjusting of anode allosteric (Curtis L, BuissonB, Bertrand S.and Bertrand D, 2002 of the people α 4 β 2nAChRs that in African Bufo siccus ovum or HEKC, express have been reported with 17 beta estradiols; Molecular Pharmacology, 61:127-135).As the example Shi oxadiazole derivant of the chemical compound of the positive allosteric modulators report of selectivity α 4 β 2, for example described in WO 2006/114400.
Another suitable α 4 β 2 positive allosteric modulators are 3,5-diphenyl isoxazole, and it is purchased the Aldrich from Sigma, St.Louis, Missouri, USA.
Other suitable example of α 4 β 2 positive allosteric modulators includes, but are not limited to ， oxadiazole derivant.Suitable De oxadiazole derivant can comprise 1,2,4-oxadiazole derivant and 1,3,4-oxadiazole derivant.1,3, the example of 4-oxadiazole derivant is described in the Application No. 61/000,295 of the common pending trial of submitting on April 12nd, 2007, and its disclosed preparation method is incorporated herein by reference.These chemical compounds have the structure of formula (I):
Or its pharmaceutically acceptable salt and prodrug, wherein
X is a key, O, NR
1, S or C
1-C
3Alkylidene;
Y represents monocyclic aryl, cycloalkyl, heterocycle or heteroaryl;
Ar
1Expression monocyclic aryl or heteroaryl; With
R
1Be hydrogen, alkyl, haloalkyl or aryl alkyl.
X is selected from a key, O, NR
1, S or C
1-C
3Alkylidene, wherein R
1Be selected from hydrogen, alkyl, haloalkyl and aryl alkyl.Preferably, X is a key.Preferably, R
1It is hydrogen or alkyl.
Y represents monocyclic aryl, cycloalkyl, heterocycle or heteroaryl, and it can be unsubstituted or be substituted the base replacement.The example of suitable heterocyclic group can include, but are not limited to pyrrolidine, piperidines etc.The example of suitable heteroaryl can include, but are not limited to thienyl, furyl, pyridine radicals, pyrazinyl etc.Preferred monocyclic aryl is to replace or unsubstituted phenyl.Suitable substituent group for monocyclic aryl, heterocycle or heteroaryl is, for example, and alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxyl, alkoxyl, halogenated alkoxy, nitro and cyano group.
Ar
1The expression monocyclic aryl for example replaces or unsubstituted phenyl, or heteroaryl.The example of suitable heteroaryl comprises, but be not limited to, thienyl, furyl, pyrrole radicals, pyrazolyl, thiazolyl, 1,3,4-thiadiazolyl group and pyridine radicals, its each can be unsubstituted or replaced by one, two or three substituent groups, and described substituent group is selected from alkyl, cycloalkyl, cycloalkyl-alkyl, halo, haloalkyl, hydroxyl, alkoxyl, halogenated alkoxy, nitro, cyano group and amino.
In one embodiment, suitable 2,5-two replaces-1,3, and 4-oxadiazole derivant can have the structure of formula (I), and wherein X is a key; Y is aryl, cycloalkyl, heterocycle or heteroaryl; And Ar
1Be monocyclic aryl or heteroaryl.
In another embodiment, suitable 2,5-two replaces-1,3, and 4-oxadiazole derivant can have the structure of formula (I), and wherein X is a key; Y is optional monocyclic cycloalkyl, phenyl, thienyl, furyl, pyridine radicals, pyrazinyl, pyrrolidinyl or the piperidyl that is replaced by one or more substituent groups that are selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxyl, halogenated alkoxy, nitro and cyano group; And Ar
1Be optional phenyl, thienyl, furyl, pyrrole radicals, pyrazolyl, the thiazolyl, 1 that is replaced by one or more substituent groups; 3; 4-thiadiazolyl group, pyrimidine radicals, pyrazinyl or pyridine radicals, described substituent group is selected from alkyl, alkyl-carbonyl, alkyl sulphonyl, alkylthio group, aryl alkyl, aryloxy group, alkoxy aryl, halogen, haloalkyl, hydroxyl, alkoxyl, halogenated alkoxy, nitro, cyano group and NZ
1Z
2, Z wherein
1And Z
2Be hydrogen, alkyl, alkyl-carbonyl, alkoxy carbonyl group, aryl, aryl alkyl and formoxyl.
In another embodiment, suitable 2,5-two replaces-1,3, and 4-oxadiazole derivant can have the structure of formula (I), and wherein X is a key; Y is a pyridine radicals; And Ar
1Be optional phenyl, pyrimidine radicals, pyrazinyl or the pyridine radicals that is replaced by one or more substituent groups, described substituent group is selected from alkyl, halogen, haloalkyl, hydroxyl, alkoxyl, halogenated alkoxy, nitro, cyano group and NZ
1Z
2, Z wherein
1And Z
2Be hydrogen, alkyl, alkyl-carbonyl, alkoxy carbonyl group, aryl, aryl alkyl and formoxyl.
Other suitable example with the chemical compound of the positive allosteric modulators report of α 4 β 2 is the oxadiazole derivant, for example as described on November 2nd, the 2006 disclosed WO 2006/114400.Other example of suitable oxadiazole chemical compound as α 4 β 2 positive allosteric modulators also provided among the disclosed WO 02/100826 at December in 2002 on the 19th.Other suitable example that also has of α 4 β 2 positive allosteric modulators includes, but are not limited to the chemical compound of formula (II):
Or its pharmaceutically acceptable salt, wherein
Ar
2Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are replaced by 1,2,3 or 4 substituent group, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
4-C
10Heterocycle, C
1-C
6Alkyl ,-(C
1-C
6Alkyl) NHC (O) O-(C
1-C
6Alkyl), C
1-C
6Hydroxyalkyl, C
1-C
6Alkyl-carbonyl, amino, hydroxyl, haloalkyl-C (O)-, haloalkyl-SO
2-, alkyl-SO
2-,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl)
2, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-C (O) NH
2,-C (O) O-(C
1-C
6Alkyl) and carboxyl; With
Ar
3Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, amino, hydroxyl, haloalkyl-SO
2-, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-N (C
1-C
6Alkyl)
2Replace with the substituent group of carboxyl.
In one embodiment, suitable 3,5-two replaces-1,2, and 4-oxadiazole derivant can have the structure of formula (I), wherein Ar
2Be monocyclic aryl or the bicyclic heteroaryl that replaces, it can be replacement or unsubstituted, and Ar
3Be to replace monocyclic aryl or heteroaryl, it can be replacement or unsubstituted.When for Ar
2Described aryl or heteroaryl when being substituted, described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
4-C
10Heterocycle, C
1-C
6Alkyl ,-(C
1-C
6Alkyl) NHC (O) O-(C
1-C
6Alkyl), C
1-C
6Hydroxyalkyl, C
1-C
6Alkyl-carbonyl, amino, hydroxyl, haloalkyl-C (O)-, haloalkyl-SO
2-, alkyl-SO
2-,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl)
2, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-C (O) NH
2,-C (O) O-(C
1-C
6Alkyl) and carboxyl.When for Ar
3Described aryl or heteroaryl when being substituted, described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, amino, hydroxyl, haloalkyl-SO
2-, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-N (C
1-C
6Alkyl)
2And carboxyl.Preferred bicyclic heteroaryl is pyridin-3-yl, pyridin-4-yl and pyridine-2 (1H)-ketone.
In another embodiment, suitable 3,5-two replaces-1,2, and 4-oxadiazole derivant can have the structure of formula (I), wherein Ar
2Be pyridine radicals, it can be replacement or unsubstituted, or substituted-phenyl; And Ar
3Be pyridine radicals, it can be replacement or unsubstituted, or substituted-phenyl.Described pyridine radicals when being substituted, is replaced by fluorine.Described phenyl is replaced by cyano group or halo.Preferably, for Ar
2Or Ar
3Pyridine radicals be pyridin-3-yl.Preferred phenyl is replaced by fluorine, sulfonamide or cyano group, is preferably replaced by cyano group.
The instantiation of α 4 β 2 positive allosteric modulators is, for example, 3,5-two replaces-1,2,4-oxadiazole derivant, for example:
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3,5-two (pyridin-3-yl)-1,2,4-oxadiazole;
3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
3-(5-(6-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
5-(5-bromopyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(pyridin-3-yl)-5-(3-(trifluoromethyl sulfonyl) phenyl)-1,2, the 4-oxadiazole;
3-(3-(6-picoline-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
5-(5-(pyrroles-1-yl) pyridin-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-3-alcohol;
5-(3, the 4-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 3-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(pyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,3, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(5-methylpyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
2,3,6-three fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3, the 4-Dichlorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
5-(2,3, the 6-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
2,2,2-three fluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone;
5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3, the 4-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 6-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
5-(2,4 difluorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,3, the 4-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-nitrobenzophenone)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-(methyl sulphonyl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(2-chloropyridine-4-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) Benzoylamide;
4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) t-butyl perbenzoate;
2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
N, N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2-amine;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzoic acid;
5-(3-(1H-tetrazolium-5-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
N, N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(3-(1H-tetrazolium-5-yl) phenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(6-chloropyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone;
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone;
N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) aniline;
(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine (methanamine);
5-(2-chloropyridine-4-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzylamino t-butyl formate;
5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) pyrrolidin-2-one;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) the phenylcarbamic acid tert-butyl ester;
N, N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine;
5-(3-(piperazine-1-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone;
3-(6-chloropyridine-3-yl)-5-(2, the 3-difluorophenyl)-1,2, the 4-oxadiazole;
3-(6-chloropyridine-3-yl)-5-(3, the 4-difluorophenyl)-1,2, the 4-oxadiazole;
(R)-and 3-(pyridin-3-yl)-5-(3-(pyrrolidine-2-yl) phenyl)-1,2, the 4-oxadiazole;
5-(3-(1H-pyrazole-3-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethanol;
3-(3-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(5-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
3-(5-(2-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile; With
3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
Or its pharmaceutically acceptable salt.
Other instantiation of α 4 β 2 positive allosteric modulators is, for example, 2,5-two replaces-1,3,4-oxadiazole derivant, for example:
2,5-two (pyridin-3-yl)-1,3,4-oxadiazole;
2-(5-bromopyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(4-(trifluoromethyl) phenyl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-o-tolyl-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-m-tolyl-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-p-tolyl-1,3, the 4-oxadiazole;
2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(3-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) benzonitrile;
4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) benzonitrile;
N, N-dimethyl-3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
N, N-dimethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
2-(pyridin-3-yl)-5-(3-(trifluoromethyl) phenyl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(3-(trifluoromethoxy) phenyl)-1,3, the 4-oxadiazole;
2-(4-Phenoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(benzyloxy) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 3-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(benzo [d] [1,3] dioxole-5-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole;
2-(3, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
5-methyl-2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-methyl-5-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(3-fluoro-2-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-fluoro-2-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluoro-4-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,4 difluorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
1-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenyl) ethyl ketone;
2-(4-isopropyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-methoxyl group-4-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-ethoxyl phenenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluoro-4-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(naphthalene-1-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(naphthalene-2-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
4-chloro-2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(4-tert-butyl-phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
N-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenyl) acetamide;
2-(4-propoxyl group phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-isopropyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-chloro-2-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-fluoronaphthalene-1-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
N, N-diethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
2-(4-butoxy phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-methoxyl group-4-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(methyl sulphonyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-5-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-fluoro-5-(trifluoromethyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-5-(trifluoromethyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-phenethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-bromo-5-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-bromo-2-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(pyrimidine-5-yl)-1,3, the 4-oxadiazole;
2-(5-methylpyrazine-2-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-6-picoline-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-methyl-6-(trifluoromethyl) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-(ethylmercapto group) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,6-dimethoxy-pyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-(methyl mercapto) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
5-chloro-3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) pyridine-2-alcohol;
2-(2,6-two chloro-5-fluorine pyridin-3-yls)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,5-dichloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,6-dichloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole; With
2-(pyridin-3-yl)-5-(quinoline-3-yl)-1,3, the 4-oxadiazole;
Or its pharmaceutically acceptable salt.
The chemical compound title is named by using Struct=name nominating algorithm, and it is
ULTRA is the part of package software v.9.0.7.
The definition of term
As using in the whole text in this specification and the appended claims like that, title (designation) Cx-Cy, wherein x and y are the integers of 1-10, the hydrocarbon that is meant the described group that it is modified partly in the scope of carbon atom, for example, title " C
1-C
6Haloalkyl " be meant at least a halogen, it is attached to parent molecular moiety by the alkyl with 1-6 carbon atom.Following term has following meanings:
Be meant-C (O) NHNH at this employed term " acyl group hydrazides "
2Group.
Be meant the straight or branched hydrocarbon that contains 2-10 carbon and contain at least one carbon-to-carbon double bond by removing two hydrogen evolution at this employed term " alkenyl ".The representative example of alkenyl includes, but are not limited to, vinyl, 2-acrylic, 2-methyl-2-acrylic, 3-cyclobutenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl isophthalic acid-heptenyl and 3-decene base.
Be meant alkyl as defined in this at this employed term " alkoxyl ", it is attached to parent molecular moiety by oxygen atom.The representative example of alkoxyl includes, but are not limited to, methoxyl group, ethyoxyl, propoxyl group, 2-propoxyl group, butoxy, tert-butoxy, amoxy and hexyloxy.
Be meant alkoxyl as defined in this at this employed term " alkoxyl alkoxyl ", it is by being attached to parent molecular moiety at this defined another alkoxyl.The representative example of alkoxyl alkoxyl includes, but are not limited to, tert-butoxy methoxyl group, 2-ethoxy ethoxy, 2-methoxy ethoxy and methoxymethoxy.
Be meant alkoxyl alkoxyl as defined in this at this employed term " alkoxy alkoxy alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkoxy alkoxy alkyl includes, but are not limited to, tert-butoxy methoxy, ethyoxyl methoxy ylmethyl, (2-methoxy ethoxy) methyl and 2-(2-methoxy ethoxy) ethyl.
Be meant alkoxyl as defined in this at this employed term " alkoxyalkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkoxyalkyl includes, but are not limited to, tert-butoxy methyl, 2-ethoxyethyl group, 2-methoxy ethyl and methoxy.
Be meant alkoxyl as defined in this at this employed term " alkoxy carbonyl group ", it is by being attached to parent molecular moiety at this defined carbonyl.The representative example of alkoxy carbonyl group includes, but are not limited to, methoxycarbonyl group, carbethoxyl group and tertbutyloxycarbonyl.
Be meant alkoxy carbonyl group as defined in this at this employed term " alkoxycarbonyl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkoxycarbonyl alkyl includes, but are not limited to, 3-methoxycarbonyl propyl group, 4-ethoxy carbonyl butyl and 2-tert-butoxycarbonyl ethyl.
Be meant alkoxyl as defined in this at this employed term " alkoxyl sulfonyl ", it is by being attached to parent molecular moiety at this defined sulfonyl.The representative example of alkoxyl sulfonyl includes, but are not limited to, methoxyl group sulfonyl, ethyoxyl sulfonyl and propoxyl group sulfonyl.
Be meant the straight or branched hydrocarbon that contains 1-10 carbon atom at this employed term " alkyl ".The representative example of alkyl comprises, but be not limited to, methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methyl hexyl, 2,2-pendimethalin base, 2,3-pendimethalin base, n-heptyl, n-octyl, n-nonyl and positive decyl.
Be meant alkyl as defined in this at this employed term " alkyl-carbonyl ", it is by being attached to parent molecular moiety at this defined carbonyl.The representative example of alkyl-carbonyl includes, but are not limited to, acetyl group, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxo butyl and 1-oxo amyl group.
Be meant alkyl-carbonyl as defined in this at this employed term " alkyl-carbonyl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkyl-carbonyl alkyl includes, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxo butyl and 3-oxo amyl group.
Be meant alkyl-carbonyl as defined in this at this employed term " alkyl-carbonyl oxygen base ", it is attached to parent molecular moiety by oxygen atom.The representative example of alkyl-carbonyl oxygen base includes, but are not limited to, acetoxyl group, ethyl ketonic oxygen base and tert-butyl group ketonic oxygen base.
Be meant alkyl-carbonyl oxygen base as defined in this at this employed term " alkyl-carbonyl oxygen base alkyl ", it is attached to parent molecular moiety by alkyl.
Be meant divalent group at this employed term " alkylidene " derived from the straight or branched hydrocarbon of 1-10 carbon atom.The representative example of alkylidene includes, but are not limited to ,-CH
2-,-CH (CH
3)-,-C (CH
3)
2-,-CH
2CH
2-,-CH
2CH
2CH
2-,-CH
2CH
2CH
2CH
2-and-CH
2CH (CH
3) CH
2-.
Be meant alkyl as defined in this at this employed term " alkyl sulphinyl ", it is by being attached to parent molecular moiety at this defined sulfinyl.The representative example of alkyl sulphinyl includes, but are not limited to, methylsulfinyl and ethyl sulfinyl.
Be meant alkyl sulphinyl as defined in this at this employed term " alkyl sulphinyl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkyl sulphinyl alkyl includes, but are not limited to, methylsulfinyl methyl and ethyl sulfinyl methyl.
Be meant alkyl as defined in this at this employed term " alkyl sulphonyl ", it is by being attached to parent molecular moiety at this defined sulfonyl.The representative example of alkyl sulphonyl includes, but are not limited to, methyl sulphonyl and ethylsulfonyl.
Be meant alkyl sulphonyl as defined in this at this employed term " alkyl sulphonyl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkyl sulphonyl alkyl includes, but are not limited to, sulfonyloxy methyl ylmethyl and ethylsulfonyl methyl.
Be meant alkyl as defined in this at this employed term " alkylthio group ", it is attached to parent molecular moiety by sulphur atom.The representative example of alkylthio group includes, but not limited to methyl mercapto, ethylmercapto group, uncle's butylthio and own sulfenyl.
Be meant alkylthio group as defined in this at this employed term " alkylthio alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of alkylthio alkyl includes, but not limited to methylthiomethyl and 2-(ethylmercapto group) ethyl.
Be meant the straight or branched alkyl that contains 2-10 carbon atom and contain at least one carbon-to-carbon triple bond at this employed term " alkynyl ".The representative example of alkynyl includes, but not limited to acetenyl, 1-propinyl, 2-propynyl, 3-butynyl, valerylene base and ethyl acetylene base.
Be meant-NH at this employed term " amino "
2Group.
Be meant phenyl, bicyclic aryl or three cyclophane bases at this employed term " aryl ".Described bicyclic aryl is a naphthyl, or with Cycloalkylfused phenyl, or with the condensed phenyl of cycloalkenyl group.The representative example of described bicyclic aryl includes, but are not limited to, dihydro indenyl, indenyl, naphthyl, dihydro naphthyl and tetralyl.Described three cyclophane bases are anthracene or phenanthrene, or with Cycloalkylfused bicyclic aryl, or with the condensed bicyclic aryl of cycloalkenyl group, or with the condensed bicyclic aryl of phenyl.The representative example of three cyclophane rings includes, but are not limited to, azulene base, dihydro anthryl, fluorenyl and tetrahydrochysene phenanthryl.
Aryl of the present invention can be by 1; 2; 3; 4 or 5 substituent groups replace, and described substituent group is independently selected from alkenyl; alkoxyl; the alkoxyl alkoxyl; alkoxy alkoxy alkyl; alkoxyalkyl; alkoxy carbonyl group; alkoxycarbonyl alkyl; alkyl; alkyl-carbonyl; the alkyl-carbonyl alkyl; the alkyl-carbonyl oxygen base; alkyl-carbonyl oxygen base alkyl; alkyl sulphinyl; the alkyl sulphinyl alkyl; alkyl sulphonyl; the alkyl sulphonyl alkyl; alkylthio group; alkylthio alkyl; alkynyl; aryl alkyl; alkoxy aryl; aryloxy group; carboxyl; carboxyalkyl; cyano group; the cyano group alkyl; formoxyl; the formoxyl alkyl; halogen; haloalkyl; halogenated alkoxy; hydroxyl; hydroxyalkyl; sulfydryl; nitro;-NZ
1Z
2(NZ
3Z
4) carbonyl.
Be meant aryl as defined in this at this employed term " alkoxy aryl ", it is by being attached to parent molecular moiety at this defined alkoxyl.The representative example of alkoxy aryl includes, but are not limited to, 2-phenyl ethoxy, 3-naphthalene-2-base propoxyl group and 5-phenylpentyl oxygen base.
Be meant aryl as defined in this at this employed term " aryl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of aryl alkyl includes, but are not limited to, benzyl, 2-phenylethyl, 3-phenyl propyl and 2-naphthalene-2-base ethyl.
Be meant aryl as defined in this at this employed term " aryloxy group ", it is attached to parent molecular moiety by oxygen atom.The representative example of aryloxy group includes, but are not limited to phenoxy group, naphthoxy, 3-bromine phenoxy group, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxy phenoxy group.
Be meant-C (O)-group at this employed term " carbonyl ".
Be meant-CO at this employed term " carboxyl "
2The H group.
Be meant carboxyl as defined in this at this employed term " carboxyalkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of carboxyalkyl includes, but are not limited to, carboxymethyl, 2-carboxy ethyl and 3-carboxyl propyl group.
Be meant-the CN group at this employed term " cyano group ".
Be meant cyano group as defined in this at this employed term " cyano group alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of cyano group alkyl includes, but are not limited to, cyano methyl, 2-cyano ethyl and 3-cyano group propyl group.
Be meant the cyclic hydrocarbon that contains 3-8 carbon and contain at least one carbon-to-carbon double bond by removing two hydrogen evolution at this employed term " cycloalkenyl group ".The representative example of cycloalkenyl group includes, but are not limited to, 2-cyclohexene-1-base, 3-cyclohexene-1-base, 2,4-cyclohexadiene-1-base and 3-cyclopentenes-1-base.
Be meant monocycle, dicyclo or three ring ring systems at this employed term " cycloalkyl ".The example of monocycle ring system is the saturated cyclic hydrocarbons group that contains 3-8 carbon atom.The example of monocycle ring system is cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring octyl group.The example of dicyclo ring system is the monocycle ring system of bridging, and wherein monocyclic two adjacent or non-adjacent carbon atoms are by connecting at the alkylidene bridge between and three other carbon atoms.The representative example of dicyclo ring system includes, but are not limited to, bicyclo-[3.1.1] heptane, bicyclo-[2.2.1] heptane, bicyclo-[2.2.2] octane, bicyclo-[3.2.2] nonane, bicyclo-[3.3.1] nonane and bicyclo-[4.2.1] nonane.The examples of three ring ring systems are dicyclo ring systems, and wherein two of dicyclo non-adjacent carbon atoms connect by a key or at the alkylidene bridge between and three carbon atoms.The representative example of three ring ring systems includes, but are not limited to, three ring [3.3.1.0
3,7] nonane and three ring [3.3.1.1
3,7] decane (diamantane (obsolete)).
Cycloalkyl of the present invention is optional to be replaced by 1,2,3,4 or 5 substituent group, described substituent group be selected from alkenyl, alkoxyl, alkoxyl alkoxyl, alkoxyalkyl, alkoxy carbonyl group, alkoxyl sulfonyl, alkyl, alkyl-carbonyl, alkyl-carbonyl oxygen base, alkyl sulphonyl, alkylthio group, alkylthio alkyl, alkynyl, carboxyl, cyano group, formoxyl, halogenated alkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfydryl, oxo ,-NZ
1Z
2(NZ
3Z
4) carbonyl.
Be meant cycloalkyl as defined in this at this employed term " cycloalkyl-alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of cycloalkyl-alkyl includes, but not limited to cyclopropyl methyl, 2-cyclobutyl ethyl, cyclopentyl-methyl, cyclohexyl methyl and 4-suberyl butyl.
Be meant at this employed term " formoxyl "-C (O) H group.
Be meant formoxyl as defined in this at this employed term " formoxyl alkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of formoxyl alkyl includes, but are not limited to, formoxyl methyl and 2-formoxyl ethyl.
Be meant at this employed term " halo " or " halogen "-Cl ,-Br ,-I or-F.
Be meant at least a as defined in this halogen at this employed term " halogenated alkoxy ", it is by being attached to parent molecular moiety at this defined alkoxyl.The representative example of halogenated alkoxy includes, but are not limited to, chlorine methoxyl group, 2-fluorine ethyoxyl, trifluoromethoxy and five fluorine ethyoxyls.
Be meant at least a as defined in this halogen at this employed term " haloalkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of haloalkyl includes, but are not limited to, chloromethyl, 2-fluoro ethyl, trifluoromethyl, pentafluoroethyl group and 2-chloro-3-fluorine amyl group.
Be meant bicyclic heteroaryl or bicyclic heteroaryl at this employed term " heteroaryl ".Described bicyclic heteroaryl is to contain heteroatomic 5 or 6 yuan of rings that at least one is selected from nitrogen, oxygen and sulfur.Described 5 yuan of rings contain two two keys and described 6 yuan of rings contain three two keys.Described 5 or 6 yuan of heteroaryls are connected with parent molecular moiety by any carbon atom or any commutable nitrogen-atoms that is included in this heteroaryl, and condition is the quantivalence that keeps suitable.The representative example of bicyclic heteroaryl comprises, but be not limited to furyl, imidazole radicals, isoxazolyl, isothiazolyl, oxadiazole Ji, oxazolyl, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, pyrazolyl, pyrrole radicals, tetrazole radical, thiadiazolyl group, thiazolyl, thienyl, triazolyl and triazine radical.Described bicyclic heteroaryl by with the condensed bicyclic heteroaryl of phenyl, or with Cycloalkylfused bicyclic heteroaryl, or with the condensed bicyclic heteroaryl of cycloalkenyl group, or form with the condensed bicyclic heteroaryl of bicyclic heteroaryl.Described bicyclic heteroaryl is connected with parent molecular moiety by any carbon atom or any commutable nitrogen-atoms that is included in this bicyclic heteroaryl, and condition is the quantivalence that keeps suitable.The representative example of bicyclic heteroaryl comprises, but be not limited to, azaindole base, benzimidazolyl, benzofuranyl, Ben Bing oxadiazole base, benzoisoxazole base, phenylpropyl alcohol isothiazolyl, benzoxazolyl, 1,3-benzothiazolyl, benzothienyl, cinnolines base, furo pyridine, indyl, indazolyl, isobenzofuran, isoindolyl, isoquinolyl, naphthyridinyl, oxazole and pyridine, quinolyl, quinoxalinyl and thienopyridine base.
Heteroaryl of the present invention is optional to be replaced by 1,2,3 or 4 substituent group, described substituent group be independently selected from alkenyl, alkoxyl, alkoxyl alkoxyl, alkoxyalkyl, alkoxy carbonyl group, alkoxycarbonyl alkyl, alkoxyl sulfonyl, alkyl, alkyl-carbonyl, alkyl-carbonyl alkyl, alkyl-carbonyl oxygen base, alkylthio group, alkylthio alkyl, alkynyl, carboxyl, carboxyalkyl, cyano group, cyano group alkyl, formoxyl, halogenated alkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, sulfydryl, nitro ,-NZ
1Z
2(NZ
3Z
4) carbonyl.The application's the heteroaryl that is replaced by hydroxyl can exist with the form of tautomer.Heteroaryl of the present invention comprises all tautomers, comprises the non-aromatic tautomer.
(heterocyclic) be meant monocyclic heterocycles, bicyclic heterocycle or tricyclic heterocyclic at this employed term " heterocycle " or " heterocyclic radical ".Described monocyclic heterocycles is to contain heteroatomic 3,4,5,6 or 7 yuan of rings that at least one is independently selected from O, N and S.Described 3 or 4 yuan of rings contain a hetero atom that is selected from O, N and S.Described 5 yuan of rings contain the two keys of zero or and one, two or three are selected from the hetero atom of O, N and S.Described 6 or 7 yuan of rings contain zero, one or two pair key and one, two or three are selected from the hetero atom of O, N and S.Described monocyclic heterocycles is connected with parent molecular moiety by any carbon atom in this monocyclic heterocycles or any nitrogen-atoms.The representative example of monocyclic heterocycles comprises, but be not limited to, azetidinyl, the azepan base, '-aziridino, the Diazesuberane base, 1, the 3-alkyl dioxin, 1, the 3-dioxolanyl, 1,3-dithiolane base (dithiolanyl), 1,3-dithiane base (dithianyl), imidazolinyl, imidazolidinyl, the isothiazoline base, isothiazole alkyl; isoxazoline-3-yl; isoxazole alkyl, morpholinyl oxadiazole quinoline base oxadiazole alkyl oxazolinyl oxazolidinyl, piperazinyl, piperidyl, pyranose, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuran base, tetrahydro-thienyl, the Thiadiazoline base, the thiadiazoles alkyl, thiazolinyl, thiazolidinyl, thio-morpholinyl, 1,1-two oxo bridges (oxido) thio-morpholinyl (thiomorpholine sulfone), sulfo-pyranose and trithiane base.Described bicyclic heterocycle is and the condensed 5 or 6 yuan of monocyclic heterocycles of phenyl, or with 5 or 6 yuan of Cycloalkylfused monocyclic heterocycles, or with the condensed 5 or 6 yuan of monocyclic heterocycles of cycloalkenyl group, or with the condensed 5 or 6 yuan of monocyclic heterocycles of monocyclic heterocycles.Described bicyclic heterocycle is connected with parent molecular moiety by any carbon atom or any nitrogen-atoms that is contained in this bicyclic heterocycle.The representative example of bicyclic heterocycle comprises, but be not limited to, 1,3-benzo dioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-dibenzo cyclohexenyl group (dioxinyl), benzo dioxolyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl, chromenyl and 1,2,3, the 4-tetrahydric quinoline group.Described tricyclic heterocyclic is and the condensed bicyclic heterocycle of phenyl, or with Cycloalkylfused bicyclic heterocycle, or with the condensed bicyclic heterocycle of cycloalkenyl group, or with the condensed bicyclic heterocycle of monocyclic heterocycles.Described tricyclic heterocyclic is connected with parent molecular moiety by any carbon atom or any nitrogen-atoms that is contained in this tricyclic heterocyclic.The representative example of tricyclic heterocyclic includes, but are not limited to, and 2,3,4,4a, 9,9a-six hydrogen-1H-carbazyl, 5a, 6,7,8,9,9a-six diphenyl hydrogens are [b, d] furyl and 5a also, and 6,7,8,9,9a-six diphenyl hydrogens are [b, d] thienyl also.
Heterocycle of the present invention is optional to be replaced by 1,2,3 or 4 substituent group, described substituent group be independently selected from alkenyl, alkoxyl, alkoxyl alkoxyl, alkoxyalkyl, alkoxy carbonyl group, alkoxycarbonyl alkyl, alkoxyl sulfonyl, alkyl, alkyl-carbonyl, alkyl-carbonyl alkyl, alkyl-carbonyl oxygen base, alkylthio group, alkylthio alkyl, alkynyl, carboxyl, carboxyalkyl, cyano group, cyano group alkyl, formoxyl, halogenated alkoxy, haloalkyl, halogen, hydroxyl, hydroxy alkyl, nitro, sulfydryl, oxo ,-NZ
1Z
2(NZ
3Z
4) carbonyl.
Be meant-the OH group at this employed term " hydroxyl ".
Be meant at least one hydroxyl as defined in this at this employed term " hydroxyalkyl ", it is by being attached to parent molecular moiety at this defined alkyl.The representative example of hydroxyalkyl includes, but are not limited to, methylol, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxy amyl group and 2-ethyl-4-hydroxyl heptyl.
Term " hydroxyl-protecting group " or " O-protecting group " are meant a kind of substituent group, and it protects hydroxyl that undesirable reaction does not take place during synthesis step.The example of hydroxyl-protecting group includes, but are not limited to, the methyl ether of replacement, for example, methoxy, benzyloxymethyl, 2-methoxy ethoxy methyl, 2-(trimethyl silyl)-ethoxyl methyl, benzyl and trityl; THP trtrahydropyranyl ether; The ethylether that replaces, for example, 2,2,2-three chloroethyls and the tert-butyl group; Silyl ether, for example, trimethyl silyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; Cyclic acetal and ketal, for example, methylene acetal, acetonide and benzal acetal; Cyclic ortho ester, for example, the methoxyl group methylene; Cyclic carbonate; With the ring-type borate.Normally used hydroxyl-protecting group is at T.W.Greene and P.G.M.Wuts, Protective Groups inOrganic Synthesis, 3
RdVersion, John Wiley﹠amp; Sons, open among the New York (1999).
At this employed term " low-grade alkenyl " is subclass at this defined alkenyl, and is meant the alkenyl that contains 2-4 carbon atom.The example of low-grade alkenyl is vinyl, acrylic and cyclobutenyl.
At this employed term " lower alkoxy " is subclass at this defined alkoxyl, and is meant at this defined low alkyl group, and it is by linking to each other with parent molecular moiety at this defined oxygen atom.The representative example of lower alkoxy includes, but are not limited to, methoxyl group, ethyoxyl, propoxyl group, 2-propoxyl group, butoxy and tert-butoxy.
At this employed term " low alkyl group " is subclass at this defined alkyl, and is meant the straight or branched alkyl that contains 1-4 carbon atom.The example of low alkyl group is methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, sec-butyl and the tert-butyl group.
At this employed term " elementary halogenated alkoxy " is subclass at this defined halogenated alkoxy, and is meant the straight or branched halogenated alkoxy that contains 1-4 carbon atom.The representative example of elementary halogenated alkoxy includes, but are not limited to, trifluoromethoxy, trichlorine methoxyl group, dichloro methoxyl group, fluorine methoxyl group and five fluorine ethyoxyls.
At this employed term " low-grade halogenated alkyl " is subclass at this defined haloalkyl, and is meant the straight or branched haloalkyl that contains 1-4 carbon atom.The representative example of low-grade halogenated alkyl includes, but are not limited to, trifluoromethyl, trichloromethyl, dichloromethyl, methyl fluoride and pentafluoroethyl group.
Be meant-OCH at this employed term " methylene dioxy base "
2The O-group, wherein the oxygen atom of this methylene dioxy base is attached to parent molecular moiety by two adjacent carbon atoms.
Be meant those groups at this employed term " nitrogen-protecting group ", it protects amino that undesirable reaction does not take place during synthesis step.Preferred nitrogen-protecting group is acetyl group, benzoyl, benzyl, benzyloxycarbonyl group (Cbz), formoxyl, benzenesulfonyl, tertbutyloxycarbonyl (Boc), tert-butyl group acetyl group, trifluoroacetyl group and trityl (triphenylmethyl).
Be meant-the SH group at this employed term " sulfydryl ".
Be meant-NO at this employed term " nitro "
2Group.
At this employed term " NZ
1Z
2" be meant two groups, Z
1And Z
2, it is attached to parent molecular moiety by nitrogen-atoms.Z
1And Z
2Each is independently selected from hydrogen, alkyl, alkyl-carbonyl, alkoxy carbonyl group, aryl, aryl alkyl and formoxyl.In some situation in the present invention, Z
1And Z
2The nitrogen-atoms that links to each other with them forms heterocycle.NZ
1Z
2Representative example include, but are not limited to amino, methylamino, acetylamino, acetyl group methylamino, phenyl amino, benzylamino, azetidinyl, pyrrolidinyl and piperidyl.
At this employed term " NZ
3Z
4" be meant two groups, Z
3And Z
4, it is attached to parent molecular moiety by nitrogen-atoms.Z
3And Z
4Each is independently selected from hydrogen, alkyl, aryl and aryl alkyl.NZ
3Z
4Representative example include, but are not limited to amino, methylamino, phenyl amino and benzylamino.
Be meant=the O part at this employed term " oxo ".
Be meant-S (O)-group at this employed term " sulfinyl ".
Be meant-SO at this employed term " sulfonyl "
2-group.
Be meant that at this employed term " tautomer " proton moves on another atom of this same compound from an atom of chemical compound, the different chemical compound of wherein two or more structures is among the balance each other.
Term " radiolabeled " is meant a kind of chemical compound, wherein at least one atom is radioactive atom or radiosiotope, wherein said radioactive atom or isotope are spontaneously launched gamma-rays or high energy particle, for example alpha particle or beta-particle or positron.The example of these radioactive atoms includes, but are not limited to,
3H (tritium),
14C,
11C,
15O,
18F,
35S,
123I and
125I.
The preparation of chemical compound
The preparation that is suitable for the chemical compound of the present composition can be understood by following synthetic schemes and embodiment, and it is used to illustrate a kind of method that can be prepared chemical compound by it.The nicotine-like acetylcholinergic receptor part that preparation is suitable and the method for nicotine sample acetylcholine hypotype α 4 β 2 allosteric modulators that suit easily obtain in the literature.Suitable compounds can prepare with the initial substance that obtains easily by the conventional method of chemosynthesis.Nicotine-like acetylcholinergic receptor part and nicotine sample acetylcholine hypotype α 4 β 2 allosteric modulators can also be commercially available.
Being suitable for present composition De oxadiazole derivant can prepare according to conventional methods.The preparation method that some of Zhe Xie oxadiazole derivant are suitable is provided in the following scheme and embodiment.Yet this further illustrating only is informative, rather than is used to by any way limit the scope of the invention.
Shown in scheme 1, the chemical compound of formula (II), wherein Ar
2And Ar
3, define in as above facial (II), can described in scheme 1, prepare.The aryl or the heteroaryl compound of general formula (1) can include, but are not limited to handle in the pyridine at solvent under heating with formula (2), obtain the chemical compound of general formula (II).
Shown in scheme 2, the chemical compound of formula (4) can with the chemical compound of formula (5) at POCl
3In 40-100 ℃ temperature range internal reaction 1-24 hour, obtain the chemical compound of formula (6); R wherein
3Be Ar
1And R
4Be Y, or R
3Be Y and R
4Be Ar
1Perhaps, the chemical compound of formula (4) can react in acetonitrile in the presence of triphenylphosphine (it can be chosen wantonly with polymer and combine) and Tritox with the chemical compound of formula (5).Gained mixture such as Wang, Y.; Sauer, D.R.; Djuric, S.W.Tetrahedron.Lett.2006,47,105-108 is described to be heated 5-30 minute down at 100-175 ℃ in microwave oven.Another optional mode comprises as Isobe T.; Ishikawa, T.J.Org.Chem.1999,64,6989-6992 described with formula (4) chemical compound and the chemical compound of formula (5) solvent for example in the dichloromethane at 2-chloro-1,3-methylimidazole chloride and alkali for example triethylamine existed down at 15-35 ℃ of following chemical combination 10-120 hour.
Scheme 3
Shown in scheme 3, as Sobol, E.; Bialer, M.; Yagen, B.J.Med.Chem.2004,47, described in the 4316-4326, the chemical compound of formula (1) can for example for example react 1-12 hour at 25-40 ℃ in the presence of the triethylamine at alkali in the dichloromethane at solvent with urea (7), obtained the chemical compound of formula (8).Perhaps, the chemical compound of formula (1) and (7) can obtain the chemical compound of formula (8) at 20-110 ℃ of following chemical combination 1-24 hour in pyridine.The chemical compound of formula (8) can be used POCl under 25-100 ℃
3Handled 1-24 hour, and obtained the chemical compound of formula (9).The chemical compound of formula (9) can with H-X-Y alkali for example in the presence of two (trimethyl silyl) lithium amide, two (trimethyl silyl) sodium amide, two (trimethyl silyl) amination potassium, potassium tert-butoxide, sodium hydride, potassium carbonate, sodium carbonate or the cesium carbonate solvent for example oxolane, 1-Methyl-2-Pyrrolidone, dimethyl sulfoxine or acetonitrile in the presence of reaction 1-48 hour under-20 ℃ to 150 ℃ temperature, obtain the chemical compound of formula (I).
Shown in scheme 4, the chemical compound of formula (II), wherein Ar
2And Ar
3, define in as above facial (II), can described in scheme 4, prepare.The aryl or the heteroaryl compound of general formula (10), can for example under heating, comprise in the presence of N-(3-methylamino propyl group)-N '-ethyl-carbodiimide hydrochloride and the I-hydroxybenzotriazole at coupling agent with the chemical compound of formula (2) at solvent, but be not limited to handle in the dimethyl formamide, obtain the chemical compound of general formula (II).
Chemical compound of the present invention and intermediate can separate and purify with the known method of the those of skill in the art in organic synthesis field.The example of the conventional method of separation and purification compound can include, but are not limited to, as Vogel ' s Textbook of Practical Organic Chemistry ", 5
ThVersion (1989), by Furniss, Hannaford, Smith, and Tatchell, pub.LongmanScientific﹠amp; Technical, Essex CM20 2JE, such described in the England, at solid carrier such as silica gel, aluminium oxide or with the chromatograph on the deutero-silicon dioxide of alkyl silane group, by carrying out recrystallization with active carbon under the optional pretreatment under the high or low temperature, thin layer chromatography distills under various pressure, distillation in a vacuum, and grind.
Chemical compound is understood by the following example better with the method that is suitable for preparing the chemical compound that is used for the present composition, and these embodiment only are exemplary, do not constitute limitation of the scope of the invention.
The specific embodiment
2,5-two replaces-1,3, the preparation of 4-oxadiazole derivant
Suitable 2,5-two replaces-1,3, and 4-oxadiazole derivant uses the initial substance that obtains easily to be prepared.For example, December in 2002 disclosed international publication number WO 02/100826 on the 19th has described the preparation of certain a little oxadiazole derivant.Yet the chemical compound of formula (I) also can be prepared according to following conventional method.
Method A: with carboxylic acid (0.5mmol) and acyl group hydrazides (0.5mmol) at POCl
3Chemical combination (2mL), and under 80-90 ℃, stirred 2-4 hour.Then, described reactant mixture is cooled to ambient temperature, is poured in the frozen water (10-20g) and and alkalizes to pH=8-9 with saturated aqueous sodium carbonate.With the gained sedimentation and filtration, dry and purify with silica gel chromatography, obtain accordingly 2,5-two replaces-1,3, the 4-oxadiazole.Then, this free alkali is dissolved among the EtOAc (5-10mL) and (Aldrich in the 4M Zai diox, 2-3eq.) handles 5-10 hour at ambient temperature with HCl.Leach precipitation and dry, obtain accordingly 2,5-two replaces-1,3,4-oxadiazole hydrochlorate.
Method B: the stirring rod of in Smith Process bottle (0.5-2ml), packing into.In this container, add carboxylic acid (0.1mmol), nicotine sample hydrazides (Aldrich, 13.7mg, 0.1mmol), PS-PPh
3(Fluka, 2.2mmol/g, 136mg, 0.3mmol) and MeCN (anhydrous, Aldrich 2mL), then adds CCl
3CN (Aldrich, 28.8mg, 0.20mmol).With reaction vessel sealing and use Emrys
TM(Personal Chemistry www.personalchemistry.com) is heated to 150 ℃ and reaches 15 minutes the Optimizer microwave oven.After the cooling, this reaction vessel is opened lid, then remove by filter resin.Described mixture preparation property HPLC purification [Waters, post: Nova-
HR C18 6 μ m
Prep-
(25mm * 100mm), solvent: MeCN/ water (v.1%TFA), 5/95 to 95/5, flow velocity 40mL/min.Collect fraction based on the UV signal threshold, use anode A PCI ionization on FinniganLCQ, to use 70 by the Flow Injection Analysis mass spectrum subsequently: 30MeOH: 10mM NH
4OH (aq) analyzes selected fraction with the flow velocity of 0.8mL/min.Some mixture is with alternative preparation HPLC method purify [Waters, post: Sunfire OBD C8 5 μ m (30mmx75mm); Solvent: MeCN/10mM ammonium acetate solution, 10/90 to 100/0; Flow velocity 50mL/min.Based target material signal threshold is collected fraction, the selected fraction of described methods analyst before using by the Flow Injection Analysis mass spectrum subsequently.
3,5-two replaces-1,2, the preparation of 4-oxadiazole derivant
The preparation of suitable oxadiazole derivant is to make us interested especially.For compositions, Xu Duo oxadiazole derivant is the nicotine sample acetylcholine hypotype α 4 β 2 positive allosteric modulators that suit.The preparation of oxadiazole derivant is described in the literature.For example, disclosed WO 2006/114400 disclosed and can easily make fully oxadiazole derivant on November 2nd, 2006.December in 2002 disclosed international publication number WO 02/100826 on the 19th has also described the preparation of its its oxadiazole derivant.
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
With 3-pyridine radicals amidoxime (amideoxime) (Aldrich, 5.5g 40mmol) are dissolved in the 60mL pyridine, then add the 3-cyano-benzoyl chloride (Aldrich, 6.6g, 40mmol).With reactant mixture reflux 4 hours, be cooled to room temperature then.Described solution is poured in the water (500mL), filters, then collect described solid and dry in a vacuum.
1H NMR (300MHz, methanol-d
4) δ ppm 7.87 (td, J=8.0,0.7Hz, 1H), 8.10 (dt, J=8.1,1.4Hz, 1H), 8.23 (ddd, J=8.1,5.6,0.8Hz, 1H), 8.56 (ddd, J=8.0,1.7,1.2Hz, 1H), 8.64 (td, J=1.7,0.7Hz, 1H), 9.04 (dd, J=5.4,1.0Hz, 1H), 9.23 (dt, J=8.1,1.7Hz, 1H), 9.57 (d, J=1.7Hz, 1H); MS (+ESI) m/z 249 (M+H)
+.
3,5-two (pyridin-3-yl)-1,2,4-oxadiazole
With 3-pyridine radicals amidoxime (5.5g 40mmol) is dissolved in the 60mL pyridine, then add the nicotinoyl chlorine hydrochlorate (7.2g, 40mmol).With reactant mixture reflux 4 hours, be cooled to room temperature then.Described solution is poured in the water (500mL), and alkalization is filtered, and then collects described solid and dry in a vacuum.
1H?NMR(300MHz，DMSO-d
6)δ7.75-7.65(m，2H)，8.49-8.45(m，1H)，8.60-8.57(m，1H)，8.84-8.82(dd，J＝1.7Hz，1H)，8.92-8.90(dd，J＝1.7Hz，1H)，9.28(m，1H)，9.37(m，1H)ppm；MS(DCI/NH
3)m/z?225(M+H)
+.
Embodiment 3
3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
Embodiment 3A
3-cyano group-N '-hydroxy benzo acid imide amide (benzimidamide)
Will be in the azanol in the ethanol (100mL) (Aldrich, 7.65g, 100mmol) usefulness 10N sodium hydroxide (10mL, 100mmol) processing.In this solution, be added in different phthalonitrile (isophthalonitrile) in the 100mL ethanol (Aldrich, 12.8g, 100mmol).With reactant mixture reflux 3 hours, be cooled to room temperature then.Remove in a vacuum and desolvate, residue carries out flash chromatography purifies (5% ethanol/methylene), obtains title compound.
1H?NMR(300MHz，DMSO-d
6)δ5.98(bs，2H)，7.59(t，J＝7.4Hz，1H)，8.06-8.0(m，2H)，9.89(s，1H)ppm；MS(DCI/NH
3)m/z?162(M+H)
+.
Embodiment 3B
3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
With 3-cyano group-N '-hydroxy benzo acid imide amide (0.322g 1mmol) is dissolved in the pyridine (10mL), then add nicotinoyl chlorine (Aldrich, 0.141g, 1mmol).With reactant mixture reflux 3 hours, be cooled to room temperature then.Cooled reactant mixture water (25mL) cancellation is then filtered.Described solid is further purified (5% ethanol/methylene) with flash chromatography, obtains title compound.
1H?NMR(300MHz，DMSO-d
6)δ7.75-7.71(dd，J＝5.7，4.1Hz，1H)，7.85(t，J＝7.8Hz，1H)，8.15-8.12(d，J＝7.8Hz，1H)8.44-8.42(m，1H)，8.50(m，1H)，8.60-8.56(m，1H)，8.93-8.91(dd，J＝1.7Hz，1H)，9.37-9.38(d，J＝1.7Hz，1H)ppm；MS(DCI/NH
3)m/z?249(M+H)
+.
3-(5-(6-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
Embodiment 4A
3-cyano group-N '-hydroxy benzo acid imide amide
Will be in the azanol in the ethanol (100mL) (Aldrich, 7.65g, 100mmol) usefulness 10NNaOH (10mL, 100mmol) processing.In this solution, be added in different phthalonitrile in the 100mL ethanol (Aldrich, 12.8g, 100mmol).With reactant mixture reflux 3 hours, be cooled to room temperature then.Remove in a vacuum and desolvate, residue carries out flash chromatography purifies (5% ethanol/methylene), obtains title product.
1H?NMR(300MHz，DMSO-d
6)δ5.98(bs，2H)，7.59(t，J＝7.4Hz，1H)，8.06-8.0(m，2H)，9.89(s，1H)ppm；MS(DCI/NH
3)m/z?162(M+H)
+.
Embodiment 4B
3-(5-(6-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
With 3-cyano group-N '-hydroxy benzo acid imide amide (0.322g 1mmol) is dissolved in the pyridine (10mL), then add 6-fluorine nicotinoyl chlorine (Frontier Scientific, 0.160g, 1mmol).With reactant mixture reflux 3 hours, be cooled to room temperature then.Cooled reactant mixture water (25mL) cancellation is then filtered.Described solid is further purified (5% ethanol/methylene) with flash chromatography, obtains title product.
1H?NMR(300MHz，DMSO-d
6)δ7.56-7.52(m，1H)，7.85(t，J＝7.9Hz，1H)，8.15-8.12(m，1H)，8.43-8.41(m，1H)，8.49(m，1H)，8.8-8.74(m，1H)，9.11-9.0(m，1H)ppm；MS(DCI/NH
3)m/z?267(M+H)
+.
5-(5-bromopyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (nicotinimidamide) (Aldrich) to be prepared with 5-bromine nicotinoyl chlorine (Alfa) according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ8.65-8.69(m，1H)，8.45-8.49(m，1H)，8.79(t，J＝1.7Hz，1H)，8.84(dd，J＝1.7，2.0Hz，1H)，9.07(d，J＝2Hz，1H)，9.28-9.29(m，1H)，9.34(d，J＝1.7Hz，1H)ppm；MS(DCI/NH
3)m/z303(M+H)
+.
3-(pyridin-3-yl)-5-(3-(trifluoromethyl sulfonyl) phenyl)-1,2, the 4-oxadiazole
Embodiment 6A
3-(trifluoromethyl sulfonyl) benzoic acid
(222mg, 1mmol) (Aldrich 2.0mmol) stirred 12 hours together at ambient temperature for solution in dichloromethane (10mL) and chromium oxide (VI) with 3-(trifluoromethyl sulfenyl) benzoic acid.By this reactant mixture directly being loaded on the silicagel column and, obtaining title compound with methylene chloride (9: 1) eluting.
1H?NMR(300MHz，DMSO-d
6)δ8.8(s，1H)，8.28(m，1H)，8.05(m，1H)，7.9(m，1H)ppm；MS(DCI/NH
3)m/z?255(M+H)
+.
Embodiment 6B
3-(trifluoromethyl sulfonyl) Benzenecarbonyl chloride.
With the product of embodiment 6A (198mg, 0.8mmol) solution in dichloromethane (10mL) and oxalyl dichloro (Aldrich, 2.0mmol) and 1 dimethyl formamide stirred at ambient temperature 2 hours.Remove in a vacuum and desolvate, obtain the title compound (250mg) of yellow oil form, then this chemical compound is directly used in next step.
Embodiment 6C
3-(pyridin-3-yl)-5-(3-(trifluoromethyl sulfonyl) phenyl)-1,2, the 4-oxadiazole
This title compound uses the chemical compound of N '-hydroxyl nicotine acid imide amide (Aldrich) and embodiment 6B to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ7.73(dd，J＝4，5.0Hz，1H)，7.85(t，J＝8Hz，1H)，8.13(m，1H)，8.43(m，1H)8.5(m，1H)，8.6(m，1H)，8.92(m，1H)，9.37(m，1H)ppm；MS(DCI/NH
3)m/z?356(M+H)
+.
3-(3-(6-picoline-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
Embodiment 7A
N '-hydroxyl-6-methyl nicotine acid imide amide
(Aldrich, 0.765g is 10mmol) with 6-methyl nicotine nitrile (nicotinonitrile) (Aldrich, 12.8g, 100mmol) solution-treated in ethanol (10mL) for azanol in ethanol (10mL).With reactant mixture reflux 3 hours, be cooled to room temperature then.Remove in a vacuum and desolvate, residue carries out flash chromatography purifies (5% ethanol/methylene), obtains title compound.
1H?NMR(300MHz，DMSO-d
6)δ2.2(s，3H)，6.02(bs，2H)，7.59(m，1H)，8.06-8.0(m，2H)，10.2(s，1H)ppm；MS(DCI/NH
3)m/z?152(M+H)
+.
Embodiment 7B
3-(3-(6-picoline-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
This title compound uses N '-hydroxyl nicotine acid imide amide (embodiment 7A) and 3-cyano-benzoyl chloride (Aldrich) to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ2.59(s，3H)，7.52(d，J＝8.1Hz，1H)，7.39(t，J＝8.5Hz，1H)，8.23-8.21(m，1H)，8.36-8.32(m，1H)，8.53-8.49(m，1H)，8.64(m，1H)，9.14(m，1H)，ppm；MS(DCI/NH
3)m/z?263(M+H)
+.
5-(5-(pyrroles-1-yl) pyridin-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
To 5-(1H-pyrroles-1-yl) nicotinic acid (Maybridge, 188mg, 1.00mmol) (anhydrous at dimethyl formamide, add N-(3-methylamino propyl group)-N '-ethyl-carbodiimide hydrochloride (EDC) (Aldrich in the solution 5mL), 192mg, 1.00mmol) and I-hydroxybenzotriazole (HOBT) hydrate (Fluka, 153mg, 1.00mmol).Described mixture was stirred 20 minutes at ambient temperature.(137mg 1.0mmol), then stirs this mixture 6-10 hour, is warmed to 140 ℃ then and reaches 2-4 hour to add N '-hydroxyl nicotine acid imide amide.This reaction is cooled to ambient temperature and water (10mL) development.Leach precipitation and dry in a vacuum, obtain title compound.
1H?NMR(300MHz，DMSO-d6)δ6.34-6.44(m，2H)，7.60-7.82(m，3H)，8.50(dt，J＝8.1，1.9Hz，1H)，8.71(dd，J＝2.5，1.9Hz，1H)，8.84(dd，J＝4.6，1.5Hz，1H)，9.21(d，J＝1.7Hz，1H)，9.26(d，J＝2.4Hz，1H)，9.31(d，J＝1.7Hz，1H)ppm；MS(DCI/NH3)m/z?290(M+H)
+.
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-3-alcohol
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 5-hydroxy niacin (Matrix Scientific) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，DMSO-d
6)δ7.66(ddd，J＝8.0，4.9，1.0Hz，1H)，7.86(dd，J＝2.7，2.0Hz，1H)，8.31-8.55(m，2H)，8.83(s，2H)，9.26(s，1H)ppm；MS(DCI/NH
3)m/z?241(M+H)
+.
5-(3, the 4-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3 according to the method for embodiment 8, and 4-difluoro-benzoic acid (Aldrich) is prepared.
1HNMR(300MHz，CD
3OD)δ7.52-7.67(m，2H)，8.12(ddd，J＝8.7，4.3，1.5Hz，1H)，8.19(ddd，J＝10.8，7.5，2.0Hz，1H)，8.55(dt，J＝8.1，1.9Hz，1H)，8.74(dd，J＝5.1，1.7Hz，1H)，9.29(dd，J＝2.0，0.7Hz，1H)ppm；MS(DCI/NH
3)m/z260(M+H)
+.
5-(2, the 3-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2 according to the method for embodiment 8, and 3-difluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.51-7.67(m，2H)，8.08-8.14(m，1H)，8.18(ddd，J＝10.7，7.5，2.0Hz，1H)，8.55(dt，J＝8.0，1.9Hz，1H)，8.74(dd，J＝5.2，1.6Hz，1H)，9.29(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
5-(pyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and pyrazine-2-formic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.66(ddd，J＝8.0，4.9，1.0Hz，1H)，8.60(dt，J＝8.0，1.9Hz，1H)，8.77(dd，J＝5.0，1.8Hz，1H)，8.86-8.89(m，1H)，8.89-8.91(m，1H)，9.34(dd，J＝2.4，0.8Hz，1H)，9.56(d，J＝1.6Hz，1H)ppm；MS(DCI/NH
3)m/z?226(M+H)
+.
Embodiment 13
5-(3, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3 according to the method for embodiment 8, and 5-difluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.37(tt，J＝9.0，2.3Hz，1H)，7.65(ddd，J＝7.9，5.0，1.0Hz，1H)，7.82-7.91(m，2H)，8.56(dt，J＝7.9，2.0Hz，1H)，8.75(dd，J＝4.8，1.6Hz，1H)，9.30(dd，J＝2.0，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
5-(2,3, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,3 according to the method for embodiment 8, and 5-trifluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.55-7.68(m，2H)，7.83-7.90(m，1H)，8.57(dt，J＝8.1，1.9Hz，1H)，8.75(dd，J＝5.1，1.7Hz，1H)，9.30(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?278(M+H)
+.
5-(2,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,4 according to the method for embodiment 8, and 5-trifluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.55(td，J＝10.3，6.4Hz，1H)，7.64(ddd，J＝8.1，5.0，0.8Hz，1H)，8.23(ddd，J＝10.3，8.6，6.4Hz，1H)，8.56(dt，J＝8.1，1.9Hz，1H)，8.75(dd，J＝5.1，1.7Hz，1H)，9.29(d，J＝1.4Hz，1H)ppm；MS(DCI/NH
3)m/z?278(M+H)
+.
5-(2, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2 according to the method for embodiment 8, and 5-difluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.41-7.56(m，2H)，7.65(ddd，J＝7.9，5.0，1.0Hz，1H)，7.98-8.04(m，1H)，8.57(dt，J＝8.0，1.9Hz，1H)，8.75(dd，J＝5.2，1.6Hz，1H)，9.31(dd，J＝2.0，0.8Hz，1H)；MS(DCI/NH
3)m/z260(M+H)
+.
Embodiment 17
5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-chloro-2 according to the method for embodiment 8, and 5-difluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.65(ddd，J＝8.0，4.9，1.0Hz，1H)，7.73(dd，J＝9.7，5.9Hz，1H)，8.18(dd，J＝8.8，6.1Hz，1H)，8.57(dt，J＝8.1，1.9Hz，1H)，8.75(dd，J＝4.7，1.7Hz，1H)，9.30(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?294(M+H)
+.
Embodiment 18
5-(5-methylpyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 5-methylpyrazine-2-formic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ2.71(s，3H)，7.66(ddd，J＝8.0，5.1，0.8Hz，1H)，8.59(dt，J＝7.9，1.8Hz，1H)，8.74-8.78(m，2H)，9.33(dd，J＝2.0，0.8Hz，1H)，9.40(d，J＝1.2Hz，1H)ppm；MS(DCI/NH
3)m/z?240(M+H)
+.
Embodiment 19
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-cyano-benzoyl chloride (Aldrich) to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，CD
3OD)δ7.65(ddd，J＝8.0，4.9，1.0Hz，1H)，8.02(d，J＝8.8Hz，2H)，8.42(d，J＝8.8Hz，2H)，8.57(dt，J＝8.1，1.9Hz，1H)，8.75(dd，J＝4.7，1.7Hz，1H)，9.31(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?249(M+H)
+.
2,3,6-three fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,4 according to the method for embodiment 8, and 5-three fluoro-3-hydroxy benzoic acids (Aldrich) are prepared.
1H?NMR(300MHz，CD
3OD)δ7.63-7.76(m，2H)，8.44(dt，J＝7.9，2.0Hz，1H)，8.83(dd，J＝4.8，1.6Hz，1H)，9.25(d，J＝1.6Hz，1H)ppm；MS(DCI/NH
3)m/z?294(M+H)
+.
Embodiment 21
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-fluoro-3-hydroxy benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，DMSO-d
6)δ7.45(dd，J＝11.1，8.7Hz，1H)，7.62-7.71(m，2H)，7.78(dd，J＝8.3，2.0Hz，1H)，8.43(dt，J＝7.9，1.8Hz，1H)，8.82(dd，J＝5.0，1.8Hz，1H)，9.24(d，J＝2.0Hz，1H)ppm；MS(DCI/NH
3)m/z?258(M+H)
+.
Embodiment 22
2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-fluoro-4-hydroxy benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.09(t，J＝8.7Hz，1H)，7.63(ddd，J＝7.9，5.2，0.8Hz，1H)，7.86-7.93(m，2H)，8.53(dt，J＝7.9，2.0Hz，1H)，8.72(dd，J＝4.8，1.6Hz，1H)，9.27(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?258(M+H)
+.
Embodiment 23
5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-chloro-4-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.54(t，J＝8.8Hz，1H)，7.64(ddd，J＝8.1，5.0，0.8Hz，1H)，8.24(ddd，J＝8.6，4.6，2.0Hz，1H)，8.39(dd，J＝7.0，2.2Hz，1H)，8.55(dt，J＝8.1，1.9Hz，1H)，8.74(dd，J＝4.9，1.5Hz，1H)，9.29(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?276(M+H)
+.
5-(3, the 4-Dichlorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3 according to the method for embodiment 8, and 4-dichlorobenzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.64(ddd，J＝8.0，5.1，0.8Hz，1H)，7.82(d，J＝8.3Hz，1H)，8.14-8.19(m，1H)，8.40(d，J＝2.0Hz，1H)，8.56(dt，J＝7.9，2.0Hz，1H)，8.75(dd，J＝5.2，1.6Hz，1H)，9.29(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?292(M+H)
+.
Embodiment 25
2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-hydroxyl-4-nitrobenzoic acid (Maybridge) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，DMSO-d
6)δ6.51(d，J＝9.1Hz，1H)，6.92-7.31(s(broad)，1H)，7.61(ddd，J＝7.9，4.8，0.8Hz，1H)，7.68(dd，J＝9.1，2.4Hz，1H)，8.40(dt，J＝7.9，2.0Hz，1H)，8.53(d，J＝2.4Hz，1H)，8.77(dd，J＝4.8，1.6Hz，1H)，9.20(d，J＝1.6Hz，1H)ppm；MS(DCI/NH
3)m/z285(M+H)
+.
Embodiment 26
5-(2,3, the 6-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,3 according to the method for embodiment 8, and 6-trifluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.26-7.35(m，J＝9.4，9.4，3.8，2.0Hz，1H)，7.62-7.77(m，2H)，8.57(dt，J＝8.0，1.9Hz，1H)，8.76(dd，J＝4.8，1.6Hz，1H)，9.30(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?278(M+H)
+.
Embodiment 27
2,2,2-three fluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone trifluoroacetate
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-(2,2, the 2-trifluoroacetyl group) benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.81(ddd，J＝7.9，5.2，0.8Hz，1H)，7.96(d，J＝8.3Hz，2H)，8.28(d，J＝8.7Hz，2H)，8.76(dt，J＝8.2，1.8Hz，1H)，8.82(dd，J＝5.2，1.6Hz，1H)，9.38(d，J＝1.6Hz，1H)ppm；MS(DCI/NH
3)m/z?320(M+H)
+.
Embodiment 28
5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.43-7.51(m，J＝8.5，8.5，2.6，1.0Hz，1H)，7.61-7.72(m，2H)，7.98(ddd，J＝9.1，2.6，1.4Hz，1H)，8.08(ddd，J＝8.0，1.3，1.0Hz，1H)，8.56(dt，J＝8.0，1.9Hz，1H)，8.74(dd，J＝5.2，1.6Hz，1H)，9.30(dd，J＝2.0，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?242(M+H)
+.
Embodiment 29
5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.39(t，J＝8.9Hz，2H)，7.64(ddd，J＝7.9，4.8，0.8Hz，1H)，8.27-8.35(m，2H)，8.55(ddd，J＝8.1，2.0，1.8Hz，1H)，8.74(dd，J＝5.0，1.8Hz，1H)，9.29(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?242(M+H)
+.
5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.38-7.49(m，2H)，7.64(ddd，J＝8.0，4.9，1.0Hz，1H)，7.70-7.79(m，1H)，8.28(td，J＝7.5，1.9Hz，1H)，8.57(dt，J＝8.1，1.9Hz，1H)，8.74(dd，J＝4.7，1.7Hz，1H)，9.31(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?242(M+H)
+.
Embodiment 31
3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-cyano group-5-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.65(ddd，J＝8.0，5.1，0.8Hz，1H)，7.95(ddd，J＝8.1，2.6，1.6Hz，1H)，8.32(ddd，J＝8.7，2.6，1.4Hz，1H)，8.46(t，J＝1.4Hz，1H)，8.58(ddd，J＝8.1，2.0，1.8Hz，1H)，8.76(dd，J＝5.2，1.6Hz，1H)，9.31(dd，J＝2.0，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z267(M+H)
+.
Embodiment 32
3-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
Embodiment 32A
3-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses 2 according to the method for embodiment 1, and 3-two fluoro-N '-hydroxy benzo acid imide amide (Tyger Scientific) and nicotinoyl chlorine hydrochlorate (Aldrich) are prepared.
1H?NMR(300MHz，DMSO-d
6)δ7.42-7.61(m，1H)，7.67-7.85(m，2H)，7.91-8.04(m，1H)，8.57(dt，J＝8.1，1.9Hz，1H)，8.92(dd，J＝4.8，1.6Hz，1H)，9.36(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
Embodiment 32B
3-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
(320mg, 1.23mmol) (Aldrich, in the 4M Zai diox, 0.5mL 2.0mmol) stirred 4 hours together at ambient temperature for solution in ethyl acetate (5mL) and hydrochloric acid with the product of embodiment 32A.Filter and collect title compound, dry in a vacuum then.
1H?NMR(300MHz，MeOH-d
4)δ7.35-7.46(m，1H)，7.49-7.63(m，1H)，7.93-8.07(m，1H)，8.24(dd，J＝8.1，5.8Hz，1H)，9.10(dd，J＝5.8，1.4Hz，1H)，9.23(dt，J＝8.0，1.8Hz，1H)，9.66(d，J＝2.0Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
3-(3, the 4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
Embodiment 33A
3-(3, the 4-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses 3 according to the method for embodiment 1, and 4-two fluoro-N '-hydroxy benzo acid imide amide (Tyger Scientific) and nicotinoyl chlorine hydrochlorate (Aldrich) are prepared.
1H?NMR(300MHz，DMSO-d
6)δ7.74(dd，J＝7.5，4.4Hz，1H)，8.60(dt，J＝7.8，2.1Hz，1H)，8.93(dd，J＝4.8，1.6Hz，1H)，9.38(dd，J＝2.2，1.0Hz，1H)，9.44-9.48(m，3H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
Embodiment 33B
3-(3, the 4-difluorophenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
(280mg, 1.08mmol) (Aldrich, in the 4M Zai diox, 0.5mL 2.0mmol) stirred 4 hours together at ambient temperature for solution in ethyl acetate (5mL) and hydrochloric acid with the product of embodiment 32A.Filter and collect title compound, dry in a vacuum then.
1H?NMR(300MHz，MeOH-d
4)δ7.52(td，J＝10.5，8.3Hz，1H)，8.00-8.17(m，2H)，8.26(ddd，J＝8.1，5.8，0.7Hz，1H)，9.08-9.14(m，1H)，9.22-9.30(m，1H)，9.66(d，J＝2.0Hz，1H)ppm；MS(DCI/N?H
3)m/z?260(M+H)
+.
Embodiment 34
5-(2, the 6-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2 according to the method for embodiment 8, and 6-difluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.29(t，J＝8.6Hz，2H)，7.65(ddd，J＝8.0，4.9，1.0Hz，1H)，7.77(tt，J＝8.6，6.1Hz，1H)，8.57(ddd，J＝8.3，1.9，1.7Hz，1H)，8.75(dd，J＝4.7，1.7Hz，1H)，9.30(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
Embodiment 35
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-sulfamoylbenzoic acid (Oakwood) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.65(ddd，J＝8.0，4.9，1.0Hz，1H)，7.83(t，J＝7.9Hz，1H)，8.21(ddd，J＝7.9，1.8，1.0Hz，1H)，8.45(dt，J＝7.9，1.4Hz，1H)，8.58(dt，J＝8.0，1.9Hz，1H)，8.73-8.77(m，2H)，9.31(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?303(M+H)
+.
Embodiment 36
5-(2,4 difluorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,4 difluorobenzene formic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.23-7.36(m，2H)，7.64(ddd，J＝8.1，5.0，0.8Hz，1H)，8.35(td，J＝8.5，6.4Hz，1H)，8.56(dt，J＝7.8，1.9Hz，1H)，8.74(dd，J＝5.1，1.7Hz，1H)，9.30(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?260(M+H)
+.
Embodiment 37
5-(2,3, the 4-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 2,3 according to the method for embodiment 8, and 4-trifluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.37-7.48(m，J＝9.3，9.3，7.1，2.4Hz，1H)，7.64(ddd，J＝7.9，5.0，1.0Hz，1H)，8.08-8.18(m，1H)，8.56(dt，J＝8.0，1.9Hz，1H)，8.75(dd，J＝5.0，1.8Hz，1H)，9.30(dd，J＝2.0，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?278(M+H)
+.
5-(3,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3,4 according to the method for embodiment 8, and 5-trifluoro-benzoic acid (Aldrich) is prepared.
1H?NMR(300MHz，CD
3OD)δ7.64(ddd，J＝8.0，4.9，1.0Hz，1H)，8.01-8.13(m，2H)，8.56(ddd，J＝8.1，1.8，1.6Hz，1H)，8.75(dd，J＝4.8，1.6Hz，1H)，9.29(dd，J＝2.0，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?278(M+H)
+.
Embodiment 39
5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 4-chloro-3-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ7.64(ddd，J＝7.9，5.0，1.0Hz，1H)，7.78(dd，J＝8.3，7.5Hz，1H)，8.07(ddd，J＝8.3，2.0，0.8Hz，1H)，8.12(dd，J＝9.5，2.0Hz，1H)，8.55(dt，J＝7.9，2.0Hz，1H)，8.74(dd，J＝5.0，1.8Hz，1H)，9.28-9.30(m，1H)ppm；MS(DCI/NH
3)m/z?276(M+H)
+.
5-(3-nitrobenzophenone)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-nitrobenzoyl chloride (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CDCl
3)δ7.44-7.55(m，1H)，7.82(t，J＝8.3Hz，1H)，8.43-8.60(m，3H)，8.80(dd，J＝4.7，1.7Hz，1H)，9.07-9.13(m，1H)，9.42(d，J＝2.0Hz，1H)ppm；MS(DCI/NH
3)m/z?269(M+H)
+.
5-(3-(methyl sulphonyl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-(methyl sulphonyl) benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ3.24(s，3H)，7.65(ddd，J＝8.0，4.9，1.0Hz，1H)，7.89-7.96(m，1H)，8.28(ddd，J＝8.0，1.9，1.0Hz，1H)，8.55-8.61(m，2H)，8.75(dd，J＝5.1，1.7Hz，1H)，8.78(t，J＝1.5Hz，1H)，9.32(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z302(M+H)
+.
Embodiment 42
3-(2-chloropyridine-4-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
Embodiment 42A
2-chloro-N '-hydroxyl nicotimine acid imide amide
2-chlorine nicotimine nitrile (nicotinonitrile) (Aldrich, 0.73g, 5.27mmol) and azanol (Aldrich, 50wt%, 0.348g, 5.27mmol) vlil in methanol (10mL) and stirring 1 hour.Under reduced pressure remove volatile matter, obtain title compound.
1H?NMR(300MHz，DMSO-d
6)δ6.09(s，2H)，7.67(dd，J＝5.4，1.4Hz，1H)，7.73(d，J＝2.0Hz，1H)，8.40(d，J＝5.2Hz，1H)，10.22(s，1H)ppm；MS(DCI/NH
3)m/z?172(M+H)
+，174(M+H)
+.
Embodiment 42B
3-(2-chloropyridine-4-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses product and the nicotinoyl chlorine hydrochlorate (Aldrich) of embodiment 42A to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ7.73(ddd，J＝8.0，4.9，1.0Hz，1H)，8.04-8.13(m，2H)，8.59(dt，J＝7.9，2.0Hz，1H)，8.71(d，J＝5.2Hz，1H)，8.92(dd，J＝5.0，1.8Hz，1H)，9.38(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/N?H
3)m/z?259(M+H)
+，261(M+H)
+.
Embodiment 43
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) Benzoylamide
(248mg, 1mmol) (257mg 2.000mmol) stirred 10 hours at 65 ℃ the product of embodiment 1 together for solution in THF (10ml) and trimethyl silane potassium alcoholate.Then, water (20mL) cancellation was also stirred 2 hours at ambient temperature.Leach precipitation and dry in a vacuum, obtain title compound.
1H?NMR(300MHz，DMSO-d
6)δ7.67(ddd，J＝7.9，4.8，0.8Hz，1H)，7.78(t，J＝7.7Hz，1H)，8.23(dt，J＝8.1，1.4，1.2Hz，1H)，8.30[s(broad，2H]，8.36(dt，J＝8.1，1.3Hz，1H)，8.48(dt，J＝7.9，2.0Hz，1H)，8.68-8.73(m，1H)，8.83(dd，J＝4.8，1.6Hz，1H)，9.28(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?267(M+H)
+.
Embodiment 44
4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone hydrochloric acid
The product of embodiment 42 (100mg, 0.39mmol) concentrated hydrochloric acid (Aldrich, 36.5%, 3.0mL) solution in is at Emry
TMBe heated to 150 ℃ with 300 watts in the Creator microwave oven and reach 60 minutes.Concentrate then.Described residue (v.1/1, stirred 1 hour in 5mL) at ambient temperature in ethanol/ethyl acetate.Filter and collect title compound, dry then.
1H?NMR(300MHz，DMSO-d
6)
6.75(dd，J＝6.7，1.6Hz，1H)，7.04(d，J＝1.6Hz，1H)，7.61(d，J＝5.9Hz，1H)，7.67-7.81(m，1H)，8.56(dt，J＝8.0，1.9Hz，1H)，8.91(dd，J＝5.0，1.8Hz，1H)，9.31-9.40(m，1H)ppm；MS(DCI/NH
3)m/z?241(M+H)
+.
Embodiment 45
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) t-butyl perbenzoate
(274mg 2.00mmol) carries out coupling with 3-(tertbutyloxycarbonyl) benzoic acid (Aldrich) according to embodiment 8 described steps to N '-hydroxyl nicotine acid imide amide.
1H?NMR(300MHz，CD
3OD)δ1.65(s，9H)，7.65(ddd，J＝7.9，4.8，0.8Hz，1H)，7.71-7.77(m，1H)，8.26(ddd，J＝7.7，1.8，1.6Hz，1H)，8.42-8.46(m，1H)，8.57(dt，J＝7.9，2.0Hz，1H)，8.73-8.78(m，2H)，9.31(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?324(M+H)
+.
Embodiment 46
2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol
With the product of embodiment 25 (284mg, 1mmol) solution in oxolane (10mL) and Raney nickel (
Nickel) (Aldrich 100mg) stirred in hydrogen 2 hours together at ambient temperature.Then, remove by filter catalyst, organic solution is concentrated, obtain title compound.
1H NMR (300MHz, DMSO-d
6) δ 5.67 (s, 2H), 6.74 (d, J=8.1Hz, 1H), 7.41-7.50 (m, 2H), 7.62 (dd, J=8.3,4.6Hz, 1H), 8.39 (dt, J=8.2,1.9,1.7Hz, 1H), 8.78 (dd, J=4.7,1.7Hz, 1H), 9.20 (d, J=1.7Hz, 1H), 9.74 (s (wide), 1H) ppm; MS (DCI/NH
3) m/z 255 (M+H)
+.
Embodiment 47
N, N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2-amine
With the product of embodiment 42 (100mg, 0.39mmol) sealing of the solution in dimethyl formamide (2.0mL) and ammonium hydroxide (0.5mL) and at Emry
TMBe heated to 150 ℃ with 300 watts in the Creator microwave oven and reach 60 minutes.Then, it is concentrated.Residue was stirred 1 hour in water (5mL) at ambient temperature.Filter and collect title compound, dry then.
1H?NMR(300MHz，DMSO-d
6)
3.12(s，6H)，7.18(dd，J＝5.2，1.2Hz，1H)，7.21(t，J＝1.2Hz，1H)，7.66-7.78(m，1H)，8.31(dd，J＝4.8，0.8Hz，1H)，8.57(ddd，J＝8.3，2.0，1.6Hz，1H)，8.91(dd，J＝5.0，1.8Hz，1H)，9.35(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?268(M+H)
+.
Embodiment 48
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzoic acid
(180mg, 0.56mmol) solution in dichloromethane (5mL) at room temperature stirred 4 hours with trifluoroacetic acid (1mL) product of embodiment 45.Then, it is concentrated, residue stirred 1 hour in water (15mL).Filter collecting precipitation and dry, obtain title compound.
1H?NMR(300MHz，DMSO-d
6)δ7.66(ddd，J＝7.9，4.8，0.8Hz，1H)，7.83(t，J＝7.5Hz，1H)，8.28(ddd，J＝8.0，1.5，1.2Hz，1H)，8.42-8.51(m，2H)，8.70(t，J＝1.6Hz，1H)，8.83(dd，J＝5.0，1.8Hz，1H)，9.28(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z?268(M+H)
+.
5-(3-(1H-tetrazolium-5-yl) phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
(248mg, 1.0mmol) (anhydrous, 10mL) (Aldrich, 498mg 1.50mmol) stirred 15 hours at 110 ℃ the product of embodiment 1 together for the solution in and azido tributyl stannane at toluene.Then, it is cooled to ambient temperature and stirred at ambient temperature 1 hour with 5mL sodium hydroxide (1N).Organic solution is separated, and aqueous mixture is acidified to pH=2-3 with hydrochloric acid (10wt.%) and stirred 2 hours.Filter collecting precipitation and dry, obtain title product.
1HNMR(300MHz，DMSO-d
6)δ7.70-7.76(m，1H)，7.86-7.98(m，1H)，8.23(ddd，J＝7.8，1.7，1.0Hz，0.2H)，8.38-8.46(m，1.6H)，8.49-8.53(m，0.2H)，8.56(ddd，J＝8.1，1.9Hz，0.8H)，8.65(ddd，J＝1.7，0.7Hz，0.2H)，8.83-8.92(m，2H)，9.30(dd，J＝2.2，0.8Hz，0.2H)，9.33(dd，J＝2.2，0.8Hz，0.8H)ppm；MS(DCI/NH
3)m/z?292(M+H)
+.
N, N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide
Embodiment 50A
3-(N, N-diethyl amino sulfonyl) benzoic acid
At 0 ℃, ((Aldrich, 2.0g is 9.1mmol) in the solution in anhydrous methylene chloride (20mL) 24mmol) to join 3-(chlorosulfonyl) benzoic acid for Aldrich, 2.5mL with diethylamine.Then, described mixture stirred 2 hours at 0 ℃.Under reduced pressure remove volatile matter.(1M 10mL) handles residue, uses ethyl acetate extraction (3x50mL) then with aqueous potassium hydrogen sulfate.The extract that merges is dry in magnesium sulfate, filters, and concentrates then, obtains title compound.
1H?NMR(300MHz，CD
3OD)δ1.13(t，J＝7.1Hz，6H)，3.22-3.30(m，4H)，7.69(t，J＝7.8Hz，1H)，8.03(ddd，J＝7.9，1.9，1.4Hz，1H)，8.25(dt，J＝7.8，1.4Hz，1H)，8.40(t，J＝1.7Hz，1H)ppm；MS(DCI/NH
3)m/z?275(M+NH
4)
+.
Embodiment 50B
N, N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide
This title compound uses the product of N '-hydroxyl nicotine acid imide amide (Aldrich) and embodiment 50A to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ1.17(t，J＝7.1Hz，6H)，3.29-3.37(m，4H)，7.65(ddd，J＝8.1，5.0，0.8Hz，1H)，7.86(t，J＝7.6Hz，1H)，8.14(ddd，J＝7.9，1.8，1.2Hz，1H)，8.48(dt，J＝7.9，1.5Hz，1H)，8.58(dt，J＝8.1，1.9Hz，1H)，8.62(t，J＝1.5Hz，1H)，8.75(dd，J＝5.1，1.7Hz，1H)，9.31(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?359(M+H)
+.
Embodiment 51
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-cyano group-4-fluobenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δppm?7.62-7.71(m，2H)，8.54-8.63(m，2H)，8.69(dd，J＝5.9，2.2Hz，1H)，8.75(dd，J＝4.9，1.5Hz，1H)，9.30(dd，J＝2.0，1.0Hz，1H)；MS(DCI/NH
3)m/z?267(M+H)
+.
Embodiment 52
3-(3-(1H-tetrazolium-5-yl) phenyl)-5-(pyridin-3-yl)-1,2,4-oxadiazole hydrochloric acid
This title compound uses product and the azido tributyl stannane (Aldrich) of embodiment 3 to be prepared according to the method for embodiment 49.
1H?NMR(300MHz，DMSO-d
6)δ7.74(dd，J＝7.3，5.4Hz，1H)，7.87(t，J＝7.7Hz，1H)，8.25-8.43(m，2H)，8.53-8.70(m，1H)，8.75-8.85(m，1H)，8.88-9.00(m，1H)，9.32-9.58(m，1H)ppm；MS(DCI/NH
3)m/z?292(M+H)
+.
Embodiment 53
3-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
Embodiment 53A
6-chloro-N '-hydroxyl nicotine acid imide amide
2-chlorine nicotimine nitrile (Aldrich, 5.0g, 36.1mmol) and azanol (Aldrich, 50wt%, 2.38g, 36.0mmol) vlil in methanol (100ml) and stirring 1 hour.Under reduced pressure remove volatile matter, obtain title compound.
1H?NMR(300MHz，DMSO-d
6)δ6.03(s，2H)，7.54(d，J＝8.7Hz，1H)，8.07(dd，J＝8.3，2.4Hz，1H)，8.67(d，J＝2.8Hz，1H)，9.94(s，1H)ppm；MS(DCI/NH
3)m/z?172(M+H)
+，189(M+H)
+.
Embodiment 53B
3-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses product and the nicotinoyl chlorine hydrochlorate (Aldrich) of embodiment 53A to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，MeOH-d
4)δ7.62-7.75(m，2H)，8.53(dd，J＝8.1，2.4Hz，1H)，8.60-8.67(m，1H)，8.85(dd，J＝5.1，1.7Hz，1H)，9.14(dd，J＝2.4，0.7Hz，1H)，9.39(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?259(M+H)
+，261(M+H)
+.
Embodiment 54
5-(6-chloropyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Tyger) and 6-chloronicotinoyl chloride (Aldrich) to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，CDCl
3)δ7.48(dd，J＝7.6，5.3Hz，1H)，7.57(d，J＝8.5Hz，1H)，8.40-8.48(m，2H)，8.80(dd，J＝4.7，1.7Hz，1H)，9.24(d，J＝2.4Hz，1H)，9.40(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?259(M+H)
+，261(M+H)
+.
Embodiment 55
5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone
(0.10g, 0.39mmol) solution in concentrated hydrochloric acid (1.0mL) is heated to 150 ℃ with 300 watts and reaches 60 minutes the product of embodiment 53B in microwave.Then, under reduced pressure concentrate, residue is with chromatograph purify [silica gel, CHCl
3/ methanol (containing 10%v/v ammonium hydroxide) v.90/10], obtains title compound.
1H?NMR(300MHz，DMSO-d
6)δ6.28-6.73(m，1H)，7.64-7.74(m，1H)，7.98(dd，J＝9.5，2.7Hz，1H)，8.14(d，J＝2.4Hz，1H)，8.49-8.56(m，1H)，8.89(dd，J＝4.7，1.7Hz，1H)，9.32(d，J＝1.4Hz，1H)，12.17(s，1H)ppm；MS(DCI/NH
3)m/z?241(M+H)
+，258(M+NH
4)
+.
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone
This title compound uses the product of embodiment 54 to be prepared according to the method for embodiment 55.
1H?NMR(300MHz，DMSO-d
6)δ6.55(d，J＝9.2Hz，1H)，7.63(dd，J＝7.6，5.3Hz，1H)，8.05(dd，J＝9.8，2.7Hz，1H)，8.31-8.47(m，2H)，8.80(d，J＝3.4Hz，1H)，9.22(s，1H)，12.41(s，1H)ppm；MS(DCI/NH
3)m/z?241(M+H)
+，258(M+NH
4)
+.
Embodiment 57
N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide
Embodiment 57A
3-(N-methyl sulfamoyl) benzoic acid
This title compound uses 3-(chlorosulfonyl) benzoic acid (Aldrich) and methylamine (Aldrich) to be prepared according to the method for embodiment 50A.
1H?NMR(300MHz，CD
3OD)δ2.54(s，3H)，7.70(t，J＝7.8Hz，1H)，8.02-8.07(m，1H)，8.23-8.28(m，1H)，8.45(t，J＝1.9Hz，1H)ppm；MS(DCI/NH
3)m/z?233(M+NH
4)
+.
Embodiment 57B
N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide
This title compound uses the product of N '-hydroxyl nicotine acid imide amide (Aldrich) and embodiment 57A to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CD
3OD)δ2.60(s，3H)，7.65(ddd，J＝8.1，5.0，0.8Hz，1H)，7.87(t，J＝8.1Hz，1H)，8.15(ddd，J＝8.0，1.9，1.0Hz，1H)，8.48(ddd，J＝7.8，1.7，1.0Hz，1H)，8.58(dt，J＝8.1，1.9Hz，1H)，8.67(t，J＝1.5Hz，1H)，8.75(dd，J＝4.7，1.7Hz，1H)，9.31(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?317(M+H)
+.
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) aniline dihydrochloride
Embodiment 58A
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) aniline
This title compound uses the product of embodiment 40 to be prepared according to the method for embodiment 46.
1H?NMR(300MHz，DMSO-d
6)δppm?5.60(s，2H)，6.84-6.93(m，1H)，7.24-7.33(m，2H)，7.41(d，J＝1.7Hz，1H)，7.60-7.67(m，1H)，8.38-8.45(m，1H)，8.81(dd，J＝5.1，1.7Hz，1H)，9.23(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?239(M+H)
+，256(M+NH
4)
+.
Embodiment 58B
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) aniline dihydrochloride
(60mg, 0.25mmol) (Aldrich, in the 4M Zai diox, 0.14mL 0.55mmol) stirred 4 hours together at ambient temperature for solution in ethyl acetate (2mL) and hydrochloric acid with the product of embodiment 58A.Filter and collect title compound, dry in a vacuum then.
1H?NMR(300MHz，DMSO-d
6)δ7.44(d，J＝7.9Hz，1H)，7.62(t，J＝7.9Hz，1H)，7.80(dd，J＝7.9，5.2Hz，1H)，7.85-7.96(m，2H)，8.60(d，J＝7.9Hz，1H)，8.90(d，J＝4.8Hz，1H)，9.31(s，1H)ppm；MS(DCI/NH
3)m/z?239(M+H)
+，256(M+NH
4)
+.
Embodiment 59
(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine two (hydrochloric acid)
(120mg, 0.34mmol) (Aldrich, in the 4M Zai diox, 0.5mL 2.0mmol) stirred 4 hours together at ambient temperature for solution in ethyl acetate (5mL) and hydrochloric acid with the product of embodiment 62.Filter collecting precipitation and dry in a vacuum, obtain title compound.
1HNMR(300MHz，DMSO-d
6)δ4.21(q，J＝5.9Hz，2H)，7.65-7.79(m，2H)，7.86(dt，J＝8.0，1.3Hz，1H)，8.24(dt，J＝7.7，1.4Hz，1H)，8.35-8.45(m，3H)，8.48(dt，J＝8.1，1.9Hz，1H)，8.85(dd，J＝4.9，1.2Hz，1H)，9.28(d，J＝1.4Hz，1H)ppm；MS(DCI/NH
3)m/z?253(M+H)
+.
5-(2-chloropyridine-4-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and the different nicotinoyl chlorine of 2-chlorine (Maybridge) to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ7.68(ddd，J＝7.9，4.8，0.8Hz，1H)，8.16(dd，J＝5.1，1.4Hz，1H)，8.23(dd，J＝1.5，0.8Hz，1H)，8.42-8.54(m，1H)，8.77(dd，J＝5.1，0.7Hz，1H)，8.84(dd，J＝4.7，1.7Hz，1H)，9.28(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z259(M+H)
+，261(M+H)
+.
Embodiment 61
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone hydrochloric acid
This title compound uses the product of embodiment 60 to be prepared according to the method for embodiment 44.
1H?NMR(300MHz，DMSO-d
6)δ6.81(dd，J＝6.6，1.9Hz，1H)，7.09-7.14(m，1H)，7.67-7.76(m，2H)，8.51(dt，J＝8.0，1.9，1.7Hz，1H)，8.86(dd，J＝4.9，1.5Hz，1H)，9.28(d，J＝1.4Hz，1H)ppm；MS(DCI/NH
3)m/z?241(M+H)
+.
Embodiment 62
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzylamino t-butyl formate
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-((tert-butoxycarbonyl amino) methyl) benzoic acid (Fluka) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，DMSO-d
6)δ1.42(s，9H)，4.27(d，J＝6.1Hz，2H)，7.51-7.72(m，4H)，8.01-8.17(m，2H)，8.45(dt，J＝8.1，1.9Hz，1H)，8.82(dd，J＝5.1，1.7Hz，1H)，9.26(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?353(M+H)
+.
5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-bromo-benzoyl chloride (Aldrich) to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，DMSO-d
6)δ7.60-7.71(m，2H)，7.98(ddd，J＝8.1，2.0，1.0Hz，1H)，8.22(ddd，J＝7.4，1.6，1.3Hz，1H)，8.35(t，J＝1.8Hz，1H)，8.46(dt，J＝7.9，2.0Hz，1H)，8.83(dd，J＝4.8，1.6Hz，1H)，9.27(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?302(M+H)
+，304(M+H)
+.
Embodiment 64
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) pyrrolidin-2-one
Product (the 200mg of embodiment 63,0.66mmol) and pyrrolidin-2-one (Aldrich, 85mg, 0.99mmol) solution in toluene (anhydrous 10mL) degassing and with nitrogen purging three times, add cesium carbonate (Aldrich, 324mg, 0.993mmol) and three (dibenzalacetones), two palladiums (0) (Aldrich, 12.1mg, 0.013mmol), 4,5-two (diphenylphosphino)-9,9-dimethyl xanthene (xanthene) (Aldrich, 23.0mg, 0.040mmol, xantphos), the then degassing and with nitrogen purging three times.Then, stirred 15 hours with described mixture heated to 100 ℃ and in nitrogen.Then, it is cooled to ambient temperature and uses ethyl acetate (50mL) dilution,, concentrate, with chromatograph purification (ethyl acetate/hexane=1/1, R with saline (2x5mL) washing
f=0.1), obtains title compound.
1H?NMR(300MHz，DMSO-d
6)δ2.04-2.19(m，2H)，2.57(t，J＝7.9Hz，2H)，3.95(t，J＝6.9Hz，2H)，7.60-7.75(m，2H)，7.84-8.10(m，2H)，8.46(dt，J＝7.9，2.0Hz，1H)，8.64(t，J＝2.0Hz，1H)，8.82(dd，J＝5.0，1.8Hz，1H)，9.26(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?307(M+H)
+.
Embodiment 65
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) the phenylcarbamic acid tert-butyl ester
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-(tert-butoxycarbonyl amino) benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，CDCl
3)δ1.56(s，9H)，6.71(s，1H)，7.39-7.58(m，2H)，7.68(d，J＝7.9Hz，1H)，7.89(d，J＝9.1Hz，1H)，8.24(s，1H)，8.45(d，J＝7.9Hz，1H)，8.77(d，J＝4.8Hz，1H)，9.40(s，1H)ppm；MS(DCI/NH
3)m/z?339(M+H)
+，356(M+NH
4)
+.
Embodiment 66
N, N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine, dihydrochloride
The free alkali of this title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-((dimethylamino) methyl) benzoic acid (Aldrich) to be prepared according to the method for embodiment 8.The solution of this free alkali in ethyl acetate (5mL) was handled 2 hours at ambient temperature with hydrochloric acid (Aldrich, 0.5mL is in the 4M Zai diox).Filter and collect title compound, dry in a vacuum then.
1H?NMR(300MHz，CD
3OD)δ2.93(s，6H)，4.51(s，2H)，7.82(t，J＝7.8Hz，1H)，7.90(dt，J＝7.8，1.5Hz，1H)，8.23(dd，J＝8.0，5.9Hz，1H)，8.42(dt，J＝7.7，1.4Hz，1H)，8.49(t，J＝1.5Hz，1H)，9.04(d，J＝5.1Hz，1H)，9.21(dt，J＝8.1，1.7Hz，1H)，9.56(s，1H)ppm；MS(DCI/NH
3)m/z?281(M+H)
+.
Embodiment 67
5-(3-(piperazine-1-yl) phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole two (hydrochloric acid)
Embodiment 67A
4-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) piperazine-1-t-butyl formate
Product (the 200mg of embodiment 63,0.66mmol) and piperazine-1-t-butyl formate (Aldrich, 123mg, 0.66mmol) solution in toluene (anhydrous 10mL) degassing and with nitrogen purging three times, add sodium tert-butoxide (Aldrich, 64mg, 0.66mmol) and three (dibenzalacetones), two palladiums (0) (Aldrich, 12.1mg, 0.013mmol), 4,5-two (diphenylphosphino)-9,9-dimethyl xanthene (xanthene) (Aldrich, 23.0mg, 0.040mmol, xantphos), the then degassing and with nitrogen purging three times.Then, stirred 15 hours with described mixture heated to 100 ℃ and in nitrogen.Then, it is cooled to ambient temperature and uses ethyl acetate (50mL) dilution,, concentrate, with chromatograph purification (v. ethyl acetate/hexane=1/1, R with saline (2x5mL) washing
f=0.6), obtains title compound.
1H?NMR(300MHz，MeOH-d
4)δ1.49(s，9H)，3.25-3.30(m，4H)，3.56-3.71(m，4H)，7.31(ddd，J＝8.4，2.6，0.8Hz，1H)，7.49(t，J＝8.0Hz，1H)，7.64(ddd，J＝8.0，4.9，0.7Hz，1H)，7.70(dt，J＝8.0，1.1Hz，1H)，7.79(dd，J＝2.4，1.7Hz，1H)，8.56(dt，J＝7.9，2.0Hz，1H)，8.74(dd，J＝4.9，1.5Hz，1H)，9.29(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?408(M+H)
+.
Embodiment 67B
5-(3-(piperazine-1-yl) phenyl)-3-(pyridin-3-yl)-1,2,4-oxadiazole two (hydrochloric acid)
This title compound uses the product of embodiment 67A to be prepared according to the method for embodiment 59.
1H?NMR(300MHz，MeOH-d
4)δ3.40-3.48(m，4H)，3.54-3.62(m，4H)，7.42(ddd，J＝8.3，2.8，0.8Hz，1H)，7.58(t，J＝8.1Hz，1H)，7.78-7.94(m，2H)，8.24-8.39(m，1H)，9.08(d，J＝5.9Hz，1H)，9.32(dt，J＝8.3，1.8Hz，1H)，9.59(d，J＝1.6Hz，1H)ppm；MS(DCI/NH
3)m/z?308(M+H)
+.
Embodiment 68
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-acetylbenzoic acid (Aldrich) to be prepared according to the method for embodiment 8.
1H?N?MR(300MHz，CD
3OD)δ2.72(s，3H)，7.66(ddd，J＝8.0，4.9，1.0Hz，1H)，7.80(t，J＝8.1Hz，1H)，8.31(ddd，J＝8.1，1.4，1.2Hz，1H)，8.47(ddd，J＝8.1，1.4，1.2Hz，1H)，8.59(ddd，J＝8.1，2.0，1.8Hz，1H)，8.75(dd，J＝5.2，1.6Hz，1H)，8.81(t，J＝1.4Hz，1H)，9.32(dd，J＝2.4，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?266(M+H)
+.
Embodiment 69
3-(6-chloropyridine-3-yl)-5-(2, the 3-difluorophenyl)-1,2, the 4-oxadiazole
This title compound is according to the product and 2 of the method use embodiment 53A of embodiment 1, and 3-difluoro benzoyl chloride (Aldrich) is prepared.
1H?NMR(300MHz，DMSO-d
6)δ7.41-7.59(m，1H)，7.76-7.93(m，2H)，8.05(dd，J＝7.8，6.1Hz，1H)，8.48(dd，J＝8.3，2.5Hz，1H)，9.08(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?294(M+H)
+，296(M+H)
+.
3-(6-chloropyridine-3-yl)-5-(3, the 4-difluorophenyl)-1,2, the 4-oxadiazole
Title compound is according to the product and 3 of the method use embodiment 53A of embodiment 1, and 4-difluoro benzoyl chloride (Aldrich) is prepared.
1H?NMR(300MHz，DMSO-d
6)δppm?7.70-7.83(m，2H)，8.03-8.15(m，1H)，8.22-8.36(m，1H)，8.48(dd，J＝8.1，2.4Hz，1H)，9.08(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?294(M+H)
+，296(M+H)
+.
Embodiment 71
(R)-and 3-(pyridin-3-yl)-5-(3-(pyrrolidine-2-yl) phenyl)-1,2,4-oxadiazole two (hydrochloric acid)
Embodiment 71A
(R)-2-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) pyrrolidine-1-formic acid tertiary butyl ester
In nitrogen, under-78 ℃, to pyrrolidine-1-t-butyl formate (Aldrich, 0.52g, 3.00mmol) and (-)-eulexine (Aldrich, 0.69g, 3.0mmol) t-butyl methyl ether (Aldrich, anhydrous, add s-butyl lithium (Aldrich in the solution 10mL), 1.4M in cyclohexane extraction, 2.2mL, 3.1mmol).After finishing, will be reflected at-78 ℃ and stir 3 hours.Slowly add zinc chloride (Aldrich then, 1M in ether, 2.0mL, 2.0mmol), with gained solution-78 ℃ of restir 30 minutes, be warmed to ambient temperature then, at room temperature stirred again 30 minutes, then add the product (0.30g of embodiment 63,1.0mmol) (anhydrous at oxolane, 5.0mL) in solution and two (three-tert-butyl group phosphine) palladium (0) (Strem, 10.2mg, 0.02mmol).This mixture stirred 15 hours at ambient temperature, then with ammonium hydroxide (5mL) cancellation.This mixture extracts with ethyl acetate (3x20mL).The extract that merges concentrated and with chromatograph purify (v. hexane/ethyl acetate=1/1, R
f=0.5), obtains title compound.
1H NMR (300MHz, MeOH-d
4) δ 1.19 (s (wide), 6H), 1.48 (s (wide), 3H), 1.83-2.00 (m, 2H), and 2.37-2.55 (m, J=8.1,8.1Hz, 1H), 3.57-3.72 (m, 2H), 4.90-5.14 (m, 1H), 7.47-7.73 (m, 3H), and 8.00-8.25 (m, 2H), 8.56 (dt, J=8.3,1.8Hz, 1H), 8.74 (dd, J=5.1,1.7Hz, 1H), 9.29 (dd, J=2.0,0.7Hz, 1H) ppm; MS (DCI/NH
3) m/z 393 (M+H)
+.
Embodiment 71B
(R)-and 3-(pyridin-3-yl)-5-(3-(pyrrolidine-2-yl) phenyl)-1,2,4-oxadiazole two (hydrochloric acid)
This title compound uses the product of embodiment 71A to be prepared according to the method for embodiment 59.
1H?NMR(300MHz，DMSO-d
6)δ1.98-2.27(m，3H)，2.39-2.50(m，1H)，3.22-3.51(m，2H)，4.55-4.81(m，1H)，7.71-7.82(m，2H)，7.96(d，J＝7.9Hz，1H)，8.26(dt，J＝7.8，1.2Hz，1H)，8.40(s，1H)，8.58(dt，J＝8.1，1.9Hz，1H)，8.89(dd，J＝5.2，1.6Hz，1H)，9.21-9.53(m，J＝1.6Hz，2H)ppm；MS(DCI/NH
3)m/z?293(M+H)
+.
Embodiment 72
5-(3-(1H-pyrazole-3-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole
This title compound uses N '-hydroxyl nicotine acid imide amide (Aldrich) and 3-(1H-pyrazole-3-yl) benzoic acid (Maybridge) to be prepared according to the method for embodiment 8.
1H?NMR(300MHz，DMSO-d
6)δ6.91(d，J＝2.4Hz，1H)，7.62-7.69(m，1H)，7.72(t，J＝7.8Hz，1H)，7.79-7.92(m，1H)，7.82-7.88(m，1H)，8.10-8.20(m，3H)，8.49(dt，J＝8.2，1.9，1.7Hz，1H)，8.64(s，1H)，8.83(dd，J＝4.7，1.7Hz，1H)，9.29(dd，J＝2.2，0.8Hz，1H)ppm；MS(DCI/NH
3)m/z?290(M+H)
+.
Embodiment 73
1-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethanol
(265mg, 1.0mmol) (Aldrich, 83mg 2.2mmol) at room temperature stirred 16 hours the product of embodiment 68 together for solution in ethanol (5mL) and sodium borohydride.This inoganic solids leaches with syringe filter, then liquid mixture usefulness preparation property HPLC is purified (Gilson, pillar,
5 μ m, 30x100mm. eluting solvent, acetonitrile/water (pH=10, NH
4HCO
3-NH
3H
2The O buffer), v.5/95 to 95/5 in 35 minutes, flow velocity, 40mL/ minute, uv, 234nm).The fraction of collecting required product also concentrates, and obtains required product.
1H?NMR(300MHz，CD
3OD)δ1.51(d，J＝6.7Hz，3H)，4.97(q，J＝6.6Hz，1H)，7.57-7.73(m，3H)，8.13(dt，J＝7.6，1.5Hz，1H)，8.28(t，J＝1.8Hz，1H)，8.57(dt，J＝7.9，1.8Hz，1H)，8.74(dd，J＝5.0，1.8Hz，1H)，9.30(dd，J＝2.2，1.0Hz，1H)ppm；MS(DCI/NH
3)m/z268(M+H)
+.
Embodiment 74
3-(3-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile
This title compound uses product and the 3-cyano-benzoyl chloride (Aldrich) of embodiment 53A to be prepared according to the method for embodiment 1.
1H?NMR(300MHz，CDCl
3)δ7.52(d，J＝7.8Hz，1H)，7.75(t，J＝8.0Hz，1H)，7.93(d，J＝7.8Hz，1H)，8.30-8.50(m，2H)，8.54(s，1H)，9.19(d，J＝2.4Hz，1H)ppm；MS(DCI/NH
3)m/z?283(M+H)
+，300(M+NH4)
+.
Embodiment 75
3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole
With 4-fluoro-N '-hydroxy benzo acid imide amide (0.154g 1mmol) is dissolved in the pyridine (10mL), then add nicotinoyl chlorine (Aldrich, 0.141g, 1mmol).With reactant mixture reflux 3 hours, be cooled to room temperature then.Cooled reactant mixture water (25mL) cancellation is then filtered.Described solid is further purified (5% ethanol/methylene) with flash column chromatography, obtains title product.
1H?NMR(300MHz，DMSO-d
6)δ7.47(t，J＝6.8Hz，2H)，7.74-7.70(m，1H)，8.20-8.15(m，2H)，8.58-8.54(m，1H)，8.91-8.89(dd，J＝1.7，1.7Hz，1H)，9.35(d，J＝1.4Hz，1H)ppm；MS(DCI/NH
3)m/z?242(M+H)+
.
Embodiment 76
3-(5-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
This title compound uses 3-cyano group-N '-hydroxy benzo acid imide amide (embodiment 4A) and 6-chloronicotinoyl chloride (Aldrich) to be prepared according to the method for embodiment 4B.
1H?NMR(300MHz，DMSO-d
6)δ7.87(m，2H)，8.17(m，1H)，8.4(m，1H)，8.43(d，J＝1.7Hz，1H)，8.6(m，1H)，9.25(d，J＝1.7Hz，1H)ppm；MS(DCI/NH
3)m/z?283(M+H)
+.
Embodiment 77
3-(5-(2-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
This title compound uses 3-cyano group-N '-hydroxy benzo acid imide amide (embodiment 4A) and 2-fluorine nicotinoyl chlorine (Aldrich) to be prepared according to the method for embodiment 4B.
1H?NMR(300MHz，DMSO-d
6)δ7.87(m，1H)，7.95(m，1H)，8.17(m，1H)，8.17(m，1H)，8.43(m，1H)，8.6(m，1H)，8.8(m，1H)ppm；MS(DCI/NH
3)m/z?267(M+H)
+.
Embodiment 78
3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
This title compound uses 3-cyano group-5-fluoro-N '-hydroxy benzo acid imide amide (using the step preparation described in the embodiment 4A by the different phthalonitrile of 5-fluorine) and nicotinoyl chlorine (Aldrich) to be prepared according to the method for embodiment 4B.
1H?NMR(300MHz，DMSO-d
6)δ7.77(m，1H)，8.2(m，2H)，8.4(m，1H)，8.6(m，1H)，8.9(m，1H)，9.4(m，1H)ppm；MS(DCI/NH
3)m/z?267(M+H)
+.
Except that particular compound, this area common those of skill in the art will readily appreciate that, various pharmaceutically acceptable salts, ester and the amide of parent compound also can be incorporated in the goods of compositions of the present invention, method or manufacturing.
Suitable pharmaceutically acceptable base addition salts comprises, but be not limited to, cation based on alkali metal or alkaline-earth metal, for example lithium, sodium, potassium, calcium, magnesium and aluminum salt etc., and nontoxic quaternary ammonium and amine cation comprise ammonium, tetramethylammonium, etamon, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethamine etc.Other the representational organic amine that can be used for forming base addition salts comprises ethylenediamine, ethanolamine, diethanolamine, piperidines, piperazine etc.
Other possible chemical compound comprises pharmaceutically acceptable amide and ester." pharmaceutically acceptable ester " is meant those esters, and when this ester linkage hydrolyzing, it keeps the biological effectiveness of this carboxylic acid and character and is not biologically or otherwise undesirable.For description as the pharmaceutically acceptable ester of prodrug forms, referring to Bundgaard, E., ed., (1985) Design of Prodrugs, ElsevierScience Publishers, Amsterdam, it is incorporated herein by reference.These esters are typically formed by corresponding carboxylic acid and alcohol.Usually, ester forms and can finish by conventional synthetic technology.(referring to, for example, March Advanced Organic Chemistry, 3
RdVersion, John Wiley﹠amp; Sons, New York p.1157 (1985) reach the list of references of wherein being quoted, and Mark etc., Encyclopedia of Chemical Technology, John Wiley﹠amp; Sons, NewYork (1980), wherein the both is incorporated herein this paper as a reference.The alkoxide component of this ester comprises (i) C usually
2-C
12Aliphatic alcohol, it may contain or may not contain one or more pairs of keys and may contain or may not contain branch carbon or (ii) C
7-C
12Aromatic series or heteroaromatic alcohol.The present invention also considers the purposes of those compositionss, and two all is an ester described herein, and still is its pharmaceutically acceptable salt simultaneously.
" pharmaceutically acceptable amide " is meant those amide, and when this amido link hydrolysis, it keeps the biological effectiveness of this carboxylic acid and character and is not biologically or otherwise undesirable.For description as the pharmaceutically acceptable amide of prodrug forms, referring to Bundgaard, H., Ed., (1985) Design of Prodrugs, Elsevier Science Publishers, Amsterdam.These amide are typically formed by corresponding carboxylic acid and amine.Usually, amide forms and can finish by conventional synthetic technology.(referring to, for example, March Advanced Organic Chemistry, 3rd Ed., John Wiley﹠amp; Sons, New York, Encyclopedia ofChemical Technology such as (1985) and Mark p.1152, John Wiley﹠amp; Sons, New York (1980), its both is incorporated herein this paper as a reference.The present invention also considers the purposes of those compositionss, and it all is an amide described herein, and is its pharmaceutically acceptable salt simultaneously.
Those skilled in the art are very clear, by giving prodrug, it is after administration, discharge medicine in vivo by chemistry or physiological process, can generate described chemical compound (for example bring under the physiology pH or, parent compound can be converted into required medicament forms) in vivo by the enzyme effect.
Administration
As mentioned above, have now found that,, can treat pain by this patient (for example mammal, for example people) α 4 β 2PAM and α 4 beta 2 receptor parts of needing are arranged simultaneously.This combination especially can be used for enlarging dosage range to obtain the useful effect of treatment.
As employed in this application, term " administration simultaneously " is meant in the suitable time and gives patient α 4 beta 2 receptor parts that this patient has given (or having consumed) at least a α 4 β 2PAM that prescribe, so that patient's symptom can weaken.This can be meant and give α 4 β 2PAM and α 4 beta 2 receptor parts simultaneously, or give medicine in the different but suitable time.Those skilled in the art for example treat the doctor of various pain statuses, can easily determine this suitable dosage.
The α 4 β 2PAM of administration simultaneously and the dosage range of α 4 beta 2 receptor parts can change in wide region.Concrete dosage will be selected from by patient's doctor, consider selected particular compound, the order of severity of patient disease, any other medical conditions or disease that this patient suffers, the other medicines that the patient took and they cause the potential probability of interaction or adverse events, the patient is in the past to the reaction of medicine, and other factors.The suitable dosage range of α 4 β 2PAM is the body weight that is about 0.0001mg/kg to 100mg/kg.The suitable dosage range of α 4 beta 2 receptor parts is the body weight of about 0.0001mg/kg to 100mg/kg.
The administration simultaneously of α 4 β 2PAM and α 4 beta 2 receptor parts, the quantity that is given is effective to treatment patient's pain, cognitive disorder or associated conditions.In way more generally,, will produce combination of the present invention by the dosage of selecting α 4 β 2PAM and α 4 beta 2 receptor parts according to the spirit of the top guide that provides.
The present invention can also be by giving α 4 β 2PAM with any way that the chemical compound of effect level is provided simultaneously in vivo and α 4 beta 2 receptor parts carry out.Typically, oral administration is passed through in this combination.
Yet the present invention is not limited to oral administration.The present invention should be understood to include any related medicine and route of administration of patient of being suitable for.For example, forgetful or dislike the patient of oral drugs for those, percutaneous dosing is very ideal.For the patient of its medicine of refusal, drug administration by injection may be fit to.In particular case, one of medicine can be by a kind of approach such as oral administration, and other medicines can percutaneous, transdermal, intravenous, intramuscular, intranasal or rectum administration.Described route of administration can change by any way, but limited easily with the person of looking after by the physical property of medicine and patient.
Based on the diversity of potential chronic pain mechanism (for example nociception pain or neuropathic pain, the degree of pain intensity, various etiology etc.), present obtainable pain medication is not all to be effective to all patients or in all antalgesics.Analgesic can be divided into non-opioid analgesic (acetaminophen and nonsteroidal anti-inflammatory drug (NSAIDs)) widely, opioid analgesic (morphine) and auxiliary analgesic or associating analgesic (antuepileptic and antidepressants).In simple classification, non-opioid analgesic mainly is to be used to slow down slightly to moderate nociception pain, auxiliary analgesic (gabapentin, pregabalin) is used for alleviating neuropathic pain, and the opioid analgesic is used for treating the serious pain in all sources, depends on the dosage of being prescribed.
The nicotine-like acetylcholinergic receptor part works with alleviating pain in a plurality of positions of running through pain pathways.The nicotine-like acetylcholinergic receptor part is found on the first order sensory neuron (periphery), cause nociception information there, in these neuronic cyton zones (being dorsal root neuroganglion or DRG), the back spinal cord that is positioned at of the first pain synapse wherein, in the neural brain stem cell space zone that descends that distributes of control, and the integrated and senior brain zone of discovering sensory information as thalamus and cortex in.By the present theory of supporting from the evidence in a plurality of sources (referring to Decker etc., Curr Topics Med Chem, 4:369,2004 summary) be that the antinociceptive activity of nAChR part reduces inhibition input spinal cord by activating the mediation of brain stem nuclear, following.In rest pain or neuropathic pain, additional approaches also can mediate the analgesic effect of nAChR agonist.
When combining with α 4 β 2PAM, another aspect of the present invention be potential enhancing other be used to treat the effect of the medicine of pain.As mentioned above, the example of the medicine that uses at present comprises opioid, gabapentin, pregabalin, duloxetine and other.New mechanism such as cannabinoid, Rhizoma et radix valerianae element (vanilloid) receptor antagonist, calcium channel blocker and sodium channel inhibitor also just are being developed and are being used for the treatment of pain.For many in these mechanism, the fact shows that powerful component may be to be driven by the activation of descending inhibition input.For example, the opioid analgesic can block the pain transmission, comes to regulate pain transmission (Pasternack, G.W., Clin Neuropaharmcol.16:1,1993 in spinal levels by increasing descending inhibition passage to a certain extent; Lauretti, G.T., Expert Reviews in Neurotherapeutics, 6:613-622.2006).Because these medicines are brought into play their effect by activating descending inhibition input, and these passages can be shared or common the activation by α 4 β 2nAChR parts, therefore can expect, activate by expanding strong descending inhibitory control spinal cord, take α 4 β 2 selectivity PAMs jointly and can cause the effect of other analgesic to strengthen.Therefore, have an opportunity to generate the analgesic with wideer or more excellent effect spectrum with α 4 β 2PAMs binding energy, it will improve the treatment of chronic pain.
The disease of other nAChR-mediation or obstacle also can be benefited the administration from such the time.α 4 β 2nAChR parts can be used for treating disease or the obstacle relevant with the cholinergic system of central nervous system, peripheral nervous system with the combination of α 4 β 2 selectivity PAMs, disease relevant or obstacle with smooth muscle contraction, endocrinopathy or obstacle, disease relevant or obstacle with neural degeneration, disease relevant or obstacle with inflammation, and stop caused withdrawal symptom, and pain by abuse chemical substance (for example nicotine).In a kind of specific embodiments, this combination is used for disease and the obstacle relevant with the attention-deficient obstacle, the superactivity disease (ADHD) of attention-deficient, Alzheimer (AD), schizophrenia, mild cognitive damage, the memory impairment relevant (AAMI) with the age, alzheimer disease, AIDS dementia, Pick disease is with the relevant dementia of Lay dimension body, the dementia relevant with mongolism, schizophrenia, smoking stops, drug dependence, amyotrophic lateral sclerosis, Huntington Chorea, the CNS function that weaken relevant with traumatic brain injury, acute pain, postoperative pain, chronic pain, inflammatory pain, neuropathic pain, infertility, circulation lacks, to the demand of the neovascularity growth relevant with wound healing, the more particularly circulation around the vascular occlusion, to the demand of the neovascularity growth relevant, ischemia, inflammation with dermatoplastic vascularization, sepsis, wound healing, and other and diabetes complications associated with arterial system, and general and nerve immunity adjusting activity.Especially, this method can be used for and it is characterized in that disease disease and the obstacle relevant with obstacle of neural psychology and cognitive dysfunction, for example Alzheimer, bipolar disorder, schizophrenia, schizoaffective disorder (schizoaffective disorder) and other associated disorders of it is characterized in that neural psychology and cognitive dysfunction.
For example, a kind of embodiment of the present invention relates to treats or prevents it is characterized in that the disease of attention or cognitive dysfunction or the method for obstacle, for example Alzheimer and ADHD and other disease and obstacle.This method comprises nicotine-like acetylcholinergic receptor hypotype α 4 β, 2 positive allosteric modulators and the step of improving the medicine of cholinergic function bonded with it that the experimenter that these needs are arranged treats effective dose.The example of these medicines is nicotine-like acetylcholinergic receptor part and acetylcholinesteraseinhibitors inhibitors.
Another using method relates to the disease or the obstacle for the treatment of or preventing it is characterized in that neural psychological function obstacle, schizophrenia for example, wherein said method comprises nicotine-like acetylcholinergic receptor hypotype α 4 β, 2 positive allosteric modulators and the psychosis bonded with it that the experimenter that these needs are arranged treats effective dose.
Biologic activity
Embodiment 1: α 4 β 2 positive allosteric modulators improve the effect of nicotine sample agonist.
Use the cell of expressing the nAChR hypotype to carry out the test of calcium current amount
Experimental procedure: human embryo kidney (HEK) (HEK) 293 cells of stably express people α 4 β 2 or α 3 β 4 combinations are at 162cm
2In the DMEM medium that is supplemented with 10%FBS and 25 μ g/ml zeocin and 200 μ g/ml HYGs, grow to fusion in the tissue culture flasks.IMR-32 neuroblast oncocyte (ATCC) is at 162cm
2In the minimal essential medium that is supplemented with 10%FBS and 1mM Sodium Pyruvate, 1% non-essential aminoacid and 1% antibiotics-antimycoin, grow to fusion in the tissue culture flasks.Then, use cell dissociation buffer dissociated cell, with the 3.5x10 in the every hole of 100-150 μ L
5Cell/ml cell suspension (～50,000-100,000 cells/well) tile in the 96 hole black plates with clear bottom (poly--D-lysine precoated shet) and in tissue culture's incubator under 37 ℃ at 5%CO
2: kept 24-48 hour in the atmosphere of 95% air.Express endogenous α 4
*Other cloned cell line or the primary cell culture of nicotinic receptor also can be used for this test.The calcium current amount use calcium-3 test kit (Molecular Devices, Sunnyvale, CA) or fluo-4 (Invitrogen) measure.The 150mM NMDG that will be dissolved in Hank ' s balanced salt solution buffer (HBSS) or contain 10mM HEPES by each bottle of sale person's supply, 20mMCaCl
2In, making the storing solution of this dyestuff, before the use, this storing solution uses identical buffer with dilution in 1: 20.From cell, remove growth medium.Cell loading in the every hole of 100 μ l dyestuffs and at room temperature HEK 293 clone's stable cell lines are cultivated and be up to 1 hour or the IMR-32 cell is cultivated 30min-45min at 37 ℃, is read from porose simultaneously by fluorescence imaging plate analysis instrument (FLIPR) in the transmitted wave strong point of the excitation wavelength of 480nm and 520nm and to carry out fluoremetry.At first 6 seconds establishment of base line fluorescence, join in cell plates with 50 μ l the regulator/test compounds of 3X concentration and cultivated 5 minutes this moment.In first minute, per second is caught fluorescence intensity once, then in other 4 minutes, catches fluorescence intensity once in per 5 seconds.After this step, add the agonist of 50 μ l 4X concentration, and reading is once during every as mentioned above 3-5 minute.With data normalization to peak response and as the function plotting of concentration.By nonlinear regression analysis (GraphPad Prism, San Diego, CA), to changing the concentration dependent match of fluorescence response, to obtain EC
50Value.
Positive allosteric modulators passes through 3-(3-pyridin-3-yl-1 to the influence of α 4 β 2nAChRs, 2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) and 3,5-two (pyridin-3-yl)-1,2,4-oxadiazole (chemical compound 2) is illustrated, and it can use the fluoremetry plate reader by measuring them the reinforced effects of change in fluorescence to be determined in cellular calcium.α 4 β 2 regulators can also illustrate by the concentration-response to α 4 β2Ji Dongji under the situation of the PAM that has fixed concentration the reinforced effects of α 4 beta 2 receptors, for example 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A) and (3R)-1-pyridin-3-yl pyrrolidine-3-amine (compd B).Shown in Figure 1A and 2A, at α 4 β 2PAM (for example, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1) is with 10 μ M) have down α 4 β2Ji Dongji, for example 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A) and (3R)-1-pyridin-3-yl pyrrolidine-3-amine (compd B), concentration-response typically be moved to the left 1-2log unit (10-100-doubly), obtain the more effective EC of agonist
50Value.Except that compd A and B, other known nicotine sample agonist can move to left under α 4 β 2PAM such as 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1, Fig. 2 C) existence.When these experiments use the cell of expressing other nAChR subunit such as α 3 β 4 to carry out (referring to Figure 1B and 2B), PAM can not influence the concentration-response to agonist.This shows that PAM optionally strengthens the effectiveness at the chemical compound of α 4 β 2, rather than other (for example α 3 β 4) hypotype.When ideal hypotype, that is, α 4 β 2, this can cause the preferred effect of this agonist, and does not have an effect in that other nicotinic receptor hypotype is next, has therefore strengthened selectivity in the body of agonist.
Table 1 has been listed the result of The compounds of this invention.Active (allosteric effect-enhancing fluorescence response) scope definition is as follows; The field of activity of " a " expression 200-400%, the field of activity of " b " expression 150-200%, the field of activity of the field of activity of " c " expression 120-150% and " d " expression 90-120%.
The example of selected α 4 β of table 1. 2 positive allosteric modulators
Embodiment 2: under low-down intrinsic agonist effect, α 4 β 2 positive allosteric modulators strengthen the effect of nicotine sample part.
Calcium current amount test: the HEK-293 cell of stably express people α 4 β 2 or α 3 β 4 is being supplemented with in the 162cm2 tissue culture flasks in the DMEM medium of 10%FBS and 25 μ g/ml zeocin and 200 μ g/ml HYGs and is merging.IMR-32 neuroblast oncocyte (ATCC) is at 162cm
2In the minimal essential medium that is supplemented with 10%FBS and 1mM Sodium Pyruvate, 1% non-essential aminoacid and 1% antibiotics-antimycoin, grow to fusion in the tissue culture flasks.Then, use cell dissociation buffer dissociated cell, with the 3.5x10 in the every hole of 100-150 μ L
5Cell/ml cell suspension (～50,000-100,000 cells/well) tile in the 96 hole black plates with clear bottom (poly--D-lysine precoated shet) and in tissue culture's incubator under 37 ℃ at 5%CO
2: kept 24-48 hour in the atmosphere of 95% air.In this test, also can use and express endogenous α 4
*Other cloned cell line of nicotinic receptor or dissociative constitutional cortical neuron.The calcium current amount use calcium-3 test kit (Molecular Devices, Sunnyvale, CA) or fluo-4 (Invitrogen) measure.The 150mM NMDG that will be dissolved in Hank ' s balanced salt solution buffer (HBSS) or contain 10mM HEPES by each bottle of sale person's supply, 20mMCaCl
2In, make the storing solution of this dyestuff.Before the use, this storing solution uses identical buffer with dilution in 1: 20.From cell, remove growth medium.Cell loaded with the every hole of 100 μ l dyestuffs and at room temperature HEK 293 clone's stable cell lines are cultivated and be up to 1 hour, or the IMR-32 cell is cultivated 30min-45min at 37 ℃.At the excitation wavelength of 480nm and the emission wavelength of 520nm, from institute is porose, read the fluorescence measurement value simultaneously by fluorescence imaging plate reader (FLIPR).At first 6 seconds establishment of base line fluorescence, join in cell plates with 50 μ l the regulator/test compounds of 3X concentration and cultivated 5 minutes this moment.In first minute, per second is caught fluorescence intensity once, then in other 4 minutes, catches fluorescence intensity once in per 5 seconds.After this step, add the agonist of 50 μ l 4X concentration, and reading is once during every as mentioned above 3-5 minute.With data normalization to peak response and as the function plotting of concentration.By nonlinear regression analysis (GraphPad Prism, San Diego, CA), to changing the concentration dependent match of fluorescence response, to obtain EC
50Value.
α 4 β 2PAM can also improve the effect (it has low intrinsic effect for chemical compound, its combination, but activate α 4 β 2nAChRs, cause otherwise calcium response can detectedly be acted on hardly) of partial agonist.For example, Fig. 3 is illustrated under the situation that has and do not exist PAM the response to 2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine (Compound C).The result shows, at α 4 β 2PAM (for example, 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (chemical compound 1)) exists down, use 2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine to significantly improve maximum fluorescence calcium signal (Fig. 3 A) to α 4 beta 2 receptors, but α 3 β 4 receptors are not but had such phenomenon (Fig. 3 B).Another example is provided by Compound D, (1S, 5S)-3-(3,6-diaza-bicyclo-[3.2.0] heptan-3-yl)-quinoline; Chemical compound and toluene-4-sulfonic acid, its also with α 4 β 2nAChR ([
3H] cyt K
i=6nM) combination, but do not show significant calcium response separately; Yet when uniting cultivation with α 4 β 2PAM, response significantly improves (Fig. 4 A) when α 4 β 2nAChR, but response does not significantly improve (Fig. 4 B) when α 3 β 4nAChRs.When chemical compound such as 2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine with (1S, 5S)-more effective when 3-(3,6-diaza-bicyclo-[3.2.0] heptan-3-yl)-quinoline and PAM administering drug combinations, these observations provide the machinery support to the above-mentioned fact.The effect in indication such as ADHD, cognitive shortage, Alzheimer and pain can have potential probability for optimization and enhancing to come reinforcing alpha 4 β 2 effects by PAM.
Fig. 5 represents the EC from calcium fluorescence (FLIPR) test
50The comparison of value uses some nicotine sample agonist of α 4 β 2nAChRs to comprise that varenicline and ispronicline exist and do not exist under the situation of positive allosteric modulators.There is the effectiveness (EC that has increased nicotine sample agonist under the situation of positive allosteric modulators
50Value).
Embodiment 3: in the body inner model of neuropathic pain, α 4 β 2PAM improve the effect of compd A.
Increase the anti-nociception reaction of agonist in whether can body in order to estimate α 4 β 2PAM, carry out following research.The material and the method that are used to finish this research are as follows.
Animal: (MA), the body weight during operation is the 120-150 gram for Charles River, Wilmington to use male sprague-Dawley rat.These animals are supported in the device of AAALAC approval with group form figure in the Abbott laboratory, and these animals are housed in the thermoregulator environment and are early giving illumination between 7 to late 8.Except that duration of test, quantity-unlimiting (ad libitum) supply food and water.Processing of all animals and experimental program all pass through Inst animal protection and use committee (institutional animal care and use committee) (IACUC) to ratify.All cycle period carries out by day in all experiments.
Chemical reagent: use 5-[(2R)-azetidine-2-ylmethoxy]-the 2-chloropyridine (compd A, 1-100nmol/kg) and 3-(3-pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile (α 4 β 2PAM chemical compounds 1,1-35 μ mol/kg, i.p.).Estimate preceding 30 minutes in behavior, compd A and D are injected with the form of solution in prepared in saline and with the volume of 2ml/kg body weight.Chemical compound 1,3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile, in 30% hydroxyl beta cyclodextrin, make and just before compd A with the form injection of the volume of 4ml/kg body weight with solution.For the research of carrying out with Compound D, the dosage of being tested is in the scope of 0.3-30 μ mol/kg i.p..
Experimental procedure:, the L5-L6 spinal nerves is carried out tight ligation in order to produce neuropathic pain.As described in detail (Kim SH and Chung JM (1992) Pain50:355), after the sterilization steps, cut the otch of 1.5cm from the dorsal part to the lumbosacral plexus by Kim and Chung before.Separate the other muscle (left side) of spinal column from spinous process, separate L5 and L6 spinal nerves, then with the tightly ligation of 3-0 silk thread.After the hemostasis, sew up wound also is coated with the antibiotics ointment.Allow described rat recovery from illness (recover), be placed on then in the cage that cushion arranged and reach 7-14 days, then carry out the performance testing of mechanical allodynia.
Tactile allodynia is used the (power of calibration; G) (Stoelting, WoodDale IL) measure von Frey filament.Briefly, rat is put into each lucite (plexiglass) container, before test, allow it adapt to 15-20 minute.By increase and minimizing stimulus object strength detection withdrawal threshold value, and use the test of Dixon nonparametric to estimate (Chaplan etc., 1994; ChaplanSR, Bach FW, Pogrel JW, Chung JM and Yaksh TL (1994) J NeurosciMethods 53:55-63).That the rat that only has a threshold value scoring≤4.5g is considered to allodynia and further using in the test.Calculate the percentage ratio (%M.P.E.) of the maximum possible effect of test compounds according to following formula: ([the back threshold value of taking medicine]-[baseline threshold])/([max-thresholds]-[baseline threshold]) x100%, wherein max-thresholds equals 15g.
Statistical analysis: user's difference analysis is carried out the analysis of data in the body.If suitable, the multiple comparison test of Bonferroni is used for afterwards (post-hoc) and analyzes.Significance level is made as p＜0.05.Data provide with the form of meansigma methods ± S.E.M.
The result: as shown in Figure 6A, tangible mechanical allodynia is induced in the tight ligation of L5-L6 spinal nerves, and wherein mechanicalness pawl withdrawal threshold value (PWT) is reduced to 2.6 ± 0.4g in the excipient group.Chemical compound 1, (PAM, 10mg/kg i.p.) do not produce the reverse (PWT:3.3 ± 0.4g, P＞0.05 pair excipient group) of the mechanical allodynia of remarkable nerve injury-induced to 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile.(0.03 μ mol/kg i.p.) produces mechanical allodynia (PWT:5.6 ± 0.3g, P＜0.001 pair excipient group) weak but that significantly reverse to compd A.When administering drug combinations, compd A+(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) (chemical compound 1 PAM) produces the significantly mechanical allodynia (PWT:12.1 ± 0.5g), promptly significantly be different from excipient (P＜0.001) of the nerve injury-induced of reverse to benzonitrile, and be different from independent compd A (P＜0.001) and independent 3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile, chemical compound 1 (P＜0.001).Originally studies show that the administering drug combinations of α 4 β, 2 positive allosteric modulators and α 4 β2Ji Dongji has strengthened the effect of the anti-allodynia of this agonist.Because the effect of α 4 β, 2 parts in neuropathic pain significantly improves existing under the PAM, can imagine, use integrated processes (agonist and α 4 β 2PAM associating) totally to be improved for treating treatment of pain window aspect.
Fig. 6 B represents that the effect of PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile, chemical compound 1) is dose-dependent.The ineffective dose of compd A (1nmol/kg), when with the PAM (3-(3-(pyridin-3-yl)-1 of various dosage, 2,4-oxadiazole-5-yl) benzonitrile, when chemical compound 1) uniting, to cause dosage-dependency of effect to increase, the approaching effect of gabapentin at least of this effect, described gabapentin is a kind of medicine that is used to treat neuropathic pain clinically.
Fig. 7 A represents 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A) is independent, α 4 β 2PAM (3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile, chemical compound 1) separately and the compd A of chemical compound 1 (3.5 μ mol/kg) and various dosage be combined in dose-dependent effects in the neuropathic pain.α 4 β 2PAM (chemical compound 1) are separately invalid, but can move to left the dose response curve of compd A in the Chung of neuropathic pain model.
Embodiment 4: chemical compound is to the analysis of ferret (ferrets) vomiting influence.
Body weight is that (Marshall BioResources, NorthRose NY) are used to measure emetic effect for 1.0 to 1.7kg the male ferret of fasting.At first give α 4 β 2PAM (chemical compound 1), after 30 minutes, give the compd A of various dosage.After the administration, observe vomiting of animal and nauseating behavior characteristics in during 90 minutes.Be recorded in the percentage ratio of the animal of experience vomiting under the given dose.
Fig. 7 B represents the influence to vomiting.Expression 5-[(2R)-azetidine-2-ylmethoxy]-2-chloropyridine (compd A) is independent, α 4 β 2PAM (chemical compound 1) are independent and the bonded effect of the compd A of chemical compound 1 (3.5 μ mol/kg) and various dosage.In ferret vomiting model, α 4 β 2PAM (chemical compound 1) do not cause vomiting separately, and the dose response curve of mobile compd A not.
Fig. 8 A and 8B represent the blood plasma level analysis in neuropathic pain and the vomiting model.Shown in Fig. 8 A, the effect of compd A is moved to the left side, but shown in Fig. 8 B, the effect of vomiting is not moved.In other words, in the presence of α 4 β 2PAM (chemical compound 1), in neuropathic pain, under the situation that vomiting does not take place, can realize the maximum effectiveness of compd A, widen the treatment window of α 4 β 2nAChR agonist thus.
Embodiment 5: in the presence of α 4 β 2 positive allosteric modulators, α 4 β 2 partial agonists can be effective in the counter-rotating neuropathic pain.
In order further to study the effect in neuropathic pain, in the Chung model, studied the effect of Compound D, another α 4 β, 2 parts (partial agonist) with low intrinsic effect.Independent Compound D is invalid in the counter-rotating neuropathic pain, but when uniting use with PAM (chemical compound 1), can realize obvious effect.Fig. 9 represents partial agonist, the effect of Compound D under the situation that has and do not exist α 4 β 2PAM (chemical compound 1).Compound D is invalid in alleviating pain when giving separately.When with α 4 β 2PAM (chemical compound 1) co-administered, Compound D is effectively now, and shows the neuropathic pain that can obviously slow down in the rat.As shown in before like that, PAM (chemical compound 1) is separately invalid (P+V).
The sign of nicotine-like acetylcholinergic receptor part
The positive allosteric modulators of described evaluation nicotine-like acetylcholinergic receptor is (based on the mensuration of fluorescence before removing, using African Bufo siccus ovum or cell line to carry out electrophysiology measures) test outside, positive allosteric modulators to the acceptor interaction of α 4 β 2nAChRs can also according to [
3H]-POB estimates its as described below carrying out in conjunction with test.
[[
3
H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile ([
3
H]-POB) combination
Be attached to α 4 β 2nAChR regulator positions [[
3H]-POB ([
3H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile) (film enriched fraction DE) is measured for ABS Inc., Wilmington from people's cortex in use.Piller is thawed at 4 ℃, wash and be resuspended in BSS-Tris buffer (120mM NaCl, 5mM KCl, the 2mM CaCl of 30 volumes with the Polytron that is set at 7
2, 2mM MgCl
2And 50mM Tris-Cl, 7.4,4 ℃ of pH) in.For saturated in conjunction with constant temperature line, with eight kinds of concentration [
3H]-POB (10-250nM) is quadruplicate and cultivated 75 minutes at 4 ℃ in the final volume of 500 μ l in containing the proteic even oar of 100-200 μ g.Non-specific binding is measured under the unlabelled 3-of 30 μ M (5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile exists.In from the film enriched fraction of people's volume cortex, measure under these conditions, [
3H]-the bonded saturable combination of POB (Figure 10).K
dAnd B
MaxValue is respectively 60 ± 16nM and 2900 ± 500fmol/mg albumen.Also can use in conjunction with test from other species (rat, mice, ferret) with from the membrane product of clone or cells transfected system (it expresses the α 4 β 2nAChRs from the clone of various species) at this.
In order to be used for concentration-inhibition test, will contain 100-200 μ g albumen and 50nM[
3H]-test compounds of seven log-diluted concentrations of POB (16.4Ci/mmol) in 500 μ l final volumes 4 ℃ of duplicate cultivations 75 minutes.There is mensuration non-specific binding down at 30 μ M 3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile.At Millipore with 0.3% polymine pre-preg
Collection plate FB goes up and uses the PerkinElmer cell harvestor to gather binding radioactivity, with the washing of 2.5mL ice-cold buffer, then uses PerkinElmer TopCount microplate β enumerator to measure radioactivity.(Graphpad Software, SanDiego CA) measure the dissociation constant (K of self-saturation in conjunction with experiment to use GraphPad Prism
d) and maximum combined (B
Max) value.
Measure IC by nonlinear regression among Excel or the Assay Explorer
50Value.K
iValue is by IC
50Calculate, use the Cheng-Prusoff equation, wherein K
i=IC
50/ (the 1+[part]/K
D]).
[
3H]-the general described preparation process acquisition in embodiment as follows 79 of POB basis.
Embodiment 79
[
3
H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
Embodiment 79A
3-(5-(5-bromopyridine-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile
This title compound uses 3-cyano group-N '-hydroxy benzo acid imide amide and 5-bromine nicotinoyl chlorine (Alfa) to be prepared according to the method for embodiment 4B.
1H?NMR(300MHz，DMSO-d
6)δ7.67(m，1H)，7.74(m，1H)，8.41(m，1H)，8.49(m，1H)，8.64(s，1H)，8.93(s，1H)，9.4(s，1H)ppm；MS(DCI/NH
3)m/z?327(M+H)
+.
Embodiment 79B
[
3
H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile ([
3
H]-POB)
The chemical compound of Jiang embodiment 79A is dissolved in the mixture of dichloromethane, triethylamine and 5% palladium/carbon.Then, this reaction solution is saturated with tritium gas (1.2Ci).Described reactant mixture at room temperature stirred 3.5 hours, removed by filter catalyst, and filtrate concentrates, and obtains thick tritiated product.This thick material is further purified with reversed-phase HPLC, used 40% isoconcentration (isocratic) acetonitrile operation 30 minutes (pillar LunaC18,254nm), obtain altogether 200mCi (1mL, MeOH).
[
3H]-radiochemical purity of POB find be 99% and specific activity (specific activity) be determined as 16.4Ci/mmol.
When with [
3H]-when POB test is tested, be suitable for nicotine-like acetylcholinergic receptor part of the present invention and show at the K of about 1 nanomole to about 10 micro-molar ranges
iValue, many have less than 5 micromolar K
iValue.The chemical compound of regulating α 4 β 2nAChRs functions by change receptor or signal activity (signaling) is suitable for described compositions.More particularly, be desired as the effect of allosteric modulators performance raising acetylcholine or nicotine sample agonist and/or the chemical compound of effectiveness function.Can have a plurality of binding sites for these chemical compounds at α 4 β 2nAChRs, wherein only have a position can by [
3H] POB is in conjunction with qualification.
What also consider is the chemical compound of following formula:
Or its pharmaceutically acceptable salt, wherein
Ar
2Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are replaced by 1,2,3 or 4 substituent group, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
4-C
10Heterocycle, C
1-C
6Alkyl ,-(C
1-C
6Alkyl) NHC (O) O-(C
1-C
6Alkyl), C
1-C
6Hydroxyalkyl, C
1-C
6Alkyl-carbonyl, amino, hydroxyl, haloalkyl-C (O)-, haloalkyl-SO
2-, alkyl-SO
2-,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl)
2, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-C (O) NH
2,-C (O) O-(C
1-C
6Alkyl) and carboxyl; With
Ar
3Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are substituted base and replace, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, amino, hydroxyl, haloalkyl-SO
2-, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-N (C
1-C
6Alkyl)
2And carboxyl;
Its Chinese style (II
*) at least one available atom replaces with radiosiotope in the chemical compound.Concrete radiolabeled formula (II
*) chemical compound be [
3H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile.These chemical compounds are applicable to the binding affinity of measuring nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators.
The embodiment that is appreciated that above-mentioned detailed description and follows only is illustrative, and the scope that is not intended to limit the invention, scope of the present invention are only limited by appending claims and their coordinate.The goods of described compositions, method and manufacturing are described according to various specific embodiments and technology.Yet, include but not limited to can on the basis that does not break away from spirit and scope of the invention, carry out various changes and modification about those of chemical compound, substituent group, synthetic and/or using method of the present invention.Embodiment described herein is used to illustrate, rather than is limited in the scope of the present invention defined in appending claims and the equivalent thereof.
Claims (24)
1. compositions, it comprises:
(i) the nicotine-like acetylcholinergic receptor part and
(ii) with the nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators of at least a pharmaceutically acceptable excipient fusion.
2. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor part is nicotine-like acetylcholinergic receptor hypotype α 4 β 2 parts, confirm its pass through [
3H]-K that cytisine is measured in conjunction with test (Ki Cyt)
iValue is that about 0.001 nanomole is to about 100 micromoles.
3. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor part is nicotine-like acetylcholinergic receptor hypotype α 4 β2Ji Dongji or partial agonist.
4. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor part are the amino nitrogen heterocyclic compounds that the diazabicyclo derivant that replaces of heterocyclic radical ether derivant, N-or heterocyclic radical replace.
5. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor part is a kind of chemical compound, it is selected from:
5-[(2R)-azetidine-2-ylmethoxy]-the 2-chloropyridine,
(3R)-1-pyridin-3-yl pyrrolidine-3-amine and
2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine;
3-(5,6-two chloro-pyridin-3-yls)-1 (S), 5 (S)-3,6-diazabicyclo [3.2.0] heptane; With
(R, R)-1-(pyridin-3-yl) octahydro-pyrrolo-[3,4-b] pyrroles;
Or its pharmaceutically acceptable salt.
6. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor part is selected from aryl-condensed azapolycy clic compounds, the enamine compound of aryl-replacement, pyrido pyrans and azepine
Derivant, benzal-and cinnamylidene-anabaseines and 3-pyrrole base (pyridoxyl) the alkyl heterocyclic ether compound of trembling.
7. the chemical compound of claim 6, wherein said nicotine-like acetylcholinergic receptor part is selected from:
5-[(2R)-azetidine-2-ylmethoxy]-the 2-chloropyridine;
(3R)-1-pyridin-3-yl pyrrolidine-3-amine;
2-methyl-3-(2-(S)-pyrrolidinyl methoxyl group) pyridine;
3-(5,6-two chloro-pyridin-3-yls)-1S, 5S-3,6-diazabicyclo [3.2.0] heptane;
(R, R)-1-(pyridin-3-yl) octahydro-pyrrolo-[3,4-b] pyrroles;
6,10-methylene-6H-pyrazine is [2,3-h] [3] benzo-aza also
7,8,9, the 10-tetrahydrochysene-(2S, 4E)-N-methyl-5-(5-isopropoxy-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-5-(5-methoxyl group-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-5-(5-ethyoxyl-3-pyridine radicals)-4-amylene-2-amine;
(2S, 4E)-N-methyl-3-pyrimidine-4-amylene-2-amine;
(5aS, 8S, 10aR)-5a, and 6,9,10-tetrahydrochysene-7H, 11H-8,10a-methylene pyrido [2 ', 3 ': 5,6] pyrans [2,3-d] azepine also
3-[1-(2,4-dimethoxy-phenyl)-first-(E)-subunit]-3,4,5,6-tetrahydrochysene-[2,3 '] bipyridyl; With
3-[1-(2-methoxyl group-4-hydroxy phenyl)-first-(E)-subunit]-3,4,5,6-tetrahydrochysene-[2,3 '] bipyridyl;
Or its pharmaceutically acceptable salt.
8. the compositions of claim 1, wherein said nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators have the following formula structure:
Or its pharmaceutically acceptable salt or prodrug, wherein
X is a key, O, NR
1, S or C
1-C
3Alkylidene;
Y represents monocyclic aryl, cycloalkyl, heterocycle or heteroaryl;
Ar
1Expression monocyclic aryl or heteroaryl; With
R
1Be hydrogen, alkyl, haloalkyl or aryl alkyl.
9. the compositions of claim 1, wherein nicotine sample hypotype α 4 β 2 positive allosteric modulators have the following formula structure:
Or its pharmaceutically acceptable salt, wherein
Ar
2Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are replaced by 1,2,3 or 4 substituent group, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
4-C
10Heterocycle, C
1-C
6Alkyl ,-(C
1-C
6Alkyl) NHC (O) O-(C
1-C
6Alkyl), C
1-C
6Hydroxyalkyl, C
1-C
6Alkyl-carbonyl, amino, hydroxyl, haloalkyl-C (O)-, haloalkyl-SO
2-, alkyl-SO
2-,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl)
2, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-C (O) NH
2,-C (O) O-(C
1-C
6Alkyl) and carboxyl; With
Ar
3Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are substituted base and replace, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, amino, hydroxyl, haloalkyl-SO
2-, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-N (C
1-C
6Alkyl)
2And carboxyl.
10. the compositions of claim 1, wherein said nicotine sample hypotype α 4 β 2 positive allosteric modulators are chemical compounds of following formula:
Or its pharmaceutically acceptable salt, wherein Ar
2Be pyridine radicals, unsubstituted pyridine base or the substituted-phenyl that replaces; And Ar
3Be substituted pyridinyl, unsubstituting biocides base or substituted-phenyl; Wherein said pyridine radicals when replacing, is replaced by fluorine and described phenyl is replaced by cyano group, sulfonamide or fluorine.
11. the compositions of claim 10, wherein Ar
2Be cyano-phenyl and Ar
3It is pyridin-3-yl.
12. the compositions of claim 1, wherein said nicotine sample hypotype α 4 β 2 positive allosteric modulators are selected from:
3,5-diphenyl isoxazole;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3,5-two (pyridin-3-yl)-1,2,4-oxadiazole;
3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
3-(5-(6-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
5-(5-bromopyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(pyridin-3-yl)-5-(3-(trifluoromethyl sulfonyl) phenyl)-1,2, the 4-oxadiazole;
3-(3-(6-picoline-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
5-(5-(pyrroles-1-yl) pyridin-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-3-alcohol;
5-(3, the 4-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 3-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(pyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,3, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-chloro-2,5-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(5-methylpyrazine-2-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
2,3,6-three fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
2-fluoro-4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
5-(3-chloro-4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3, the 4-Dichlorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
2-nitro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
5-(2,3, the 6-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
2,2,2-three fluoro-1-(4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone;
5-(3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3, the 4-difluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2, the 6-difluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
5-(2,4 difluorobenzene base)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(2,3, the 4-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3,4, the 5-trifluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(4-chloro-3-fluorophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-nitrobenzophenone)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(3-(methyl sulphonyl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(2-chloropyridine-4-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) Benzoylamide;
4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) t-butyl perbenzoate;
2-amino-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenol;
N, N-dimethyl-4-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2-amine;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzoic acid;
5-(3-(1H-tetrazolium-5-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
N, N-diethyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
2-fluoro-5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(3-(1H-tetrazolium-5-yl) phenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(6-chloropyridine-3-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) pyridine-2 (1H)-ketone;
5-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone;
N-methyl-3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzsulfamide;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) aniline;
(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine;
5-(2-chloropyridine-4-yl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
4-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) pyridine-2 (1H)-ketone;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) benzylamino t-butyl formate;
5-(3-bromophenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) pyrrolidin-2-one;
3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) the phenylcarbamic acid tert-butyl ester;
N, N-dimethyl-1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) methylamine;
5-(3-(piperazine-1-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethyl ketone;
3-(6-chloropyridine-3-yl)-5-(2, the 3-difluorophenyl)-1,2, the 4-oxadiazole;
3-(6-chloropyridine-3-yl)-5-(3, the 4-difluorophenyl)-1,2, the 4-oxadiazole;
(R)-and 3-(pyridin-3-yl)-5-(3-(pyrrolidine-2-yl) phenyl)-1,2, the 4-oxadiazole;
5-(3-(1H-pyrazole-3-yl) phenyl)-3-(pyridin-3-yl)-1,2, the 4-oxadiazole;
1-(3-(3-(pyridin-3-yl)-1,2,4-oxadiazole-5-yl) phenyl) ethanol;
3-(3-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-5-yl) benzonitrile;
3-(4-fluorophenyl)-5-(pyridin-3-yl)-1,2, the 4-oxadiazole;
3-(5-(6-chloropyridine-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
3-(5-(2-fluorine pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
3-fluoro-5-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile;
2,5-two (pyridin-3-yl)-1,3,4-oxadiazole;
2-(5-bromopyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(4-(trifluoromethyl) phenyl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-o-tolyl-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-m-tolyl-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-p-tolyl-1,3, the 4-oxadiazole;
2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(3-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-fluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-bromophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) benzonitrile;
4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) benzonitrile;
N, N-dimethyl-3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
N, N-dimethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
2-(pyridin-3-yl)-5-(3-(trifluoromethyl) phenyl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(3-(trifluoromethoxy) phenyl)-1,3, the 4-oxadiazole;
2-(4-Phenoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(benzyloxy) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-3,5-dimethylphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 3-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-Dimethoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(benzo [d] [1,3] dioxole-5-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(3,4, the 5-trimethoxyphenyl)-1,3, the 4-oxadiazole;
2-(3, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 4-Dichlorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
5-methyl-2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-methyl-5-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(3-fluoro-2-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-fluoro-2-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluoro-4-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 3-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,4 difluorobenzene base)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2, the 5-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3, the 5-difluorophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
1-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenyl) ethyl ketone;
2-(4-isopropyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-methoxyl group-4-aminomethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-ethoxyl phenenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-fluoro-4-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(naphthalene-1-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(naphthalene-2-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
4-chloro-2-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenol;
2-(4-tert-butyl-phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
N-(4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) phenyl) acetamide;
2-(4-propoxyl group phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-isopropyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-chloro-2-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-fluoronaphthalene-1-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
N, N-diethyl-4-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) aniline;
2-(4-butoxy phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-methoxyl group-4-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-(methyl sulphonyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-5-(methyl mercapto) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-fluoro-5-(trifluoromethyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-5-(trifluoromethyl) phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-phenethyl phenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-bromo-5-methoxyphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(5-bromo-2-chlorphenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(3-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(4-iodophenyl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(pyridin-3-yl)-5-(pyrimidine-5-yl)-1,3, the 4-oxadiazole;
2-(5-methylpyrazine-2-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloro-6-picoline-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-methyl-6-(trifluoromethyl) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-(ethylmercapto group) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,6-dimethoxy-pyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-(methyl mercapto) pyridin-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
5-chloro-3-(5-(pyridin-3-yl)-1,3,4-oxadiazole-2-yl) pyridine-2-alcohol;
2-(2,6-two chloro-5-fluorine pyridin-3-yls)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,5-dichloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(6-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2,6-dichloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole;
2-(2-chloropyridine-3-yl)-5-(pyridin-3-yl)-1,3, the 4-oxadiazole; With
2-(pyridin-3-yl)-5-(quinoline-3-yl)-1,3, the 4-oxadiazole;
Or its pharmaceutically acceptable salt.
13. the compositions of claim 1, wherein said nicotine sample hypotype α 4 β 2 positive allosteric modulators are 2, and 5-two replaces-1,3,4-oxadiazole derivant; 3,5-two replaces-1,2,4-oxadiazole derivant or 3,5-diphenyl isoxazole.
14. a method that is used in patient's treatment or prevent irritation, this method comprises:
(i) give a certain amount of nicotine sample of described patient hypotype α 4 β 2 positive allosteric modulators; With
(ii) give a kind of pain medication, described pain medication comprises the chemical compound that is selected from opioid, gabapentin, pregabalin, duloxetine, cannabinoid part, vaniolloid receptor antagonist, calcium channel blocker and sodium channel inhibitor, wherein reduce the adjusting approach and be activated, described adjusting approach is shared by α 4 β 2 nicotinic receptor mechanism or common the activation.
15. one kind is used for comprising the method for neuropathic pain and cognitive disorder in patient's treatment or prevent irritation, this method comprises:
(i) give described patient a certain amount of nicotine-like acetylcholinergic receptor part; With
(ii) give a certain amount of nicotine-like acetylcholinergic receptor hypotype of described patient α 4 β 2 positive allosteric modulators; Wherein (i) and (ii) together quantity in treatment pain or cognitive disorder, be more effective.
16. method that is used for the treatment of or prevents disease or disease, described disease or disease are selected from the attention-deficient obstacle, the superactivity disease (ADHD) of attention-deficient, Alzheimer (AD), drug dependence comprises alcohol abuse, bipolar disorder, the mild cognitive damage, the memory impairment relevant (AAMI) with the age, alzheimer disease, the AIDS dementia, Pick disease, with the relevant dementia of Lay dimension body, the dementia relevant with mongolism, schizophrenia, schizoaffective disorder, smoking stops, amyotrophic lateral sclerosis, Huntington Chorea, the CNS function that weaken relevant with traumatic brain injury, infertility, lack circulation, the neovascularity growth demand relevant with wound healing, ischemia, sepsis, inflammation and inflammatory diseases, this method comprises:
(i) give described patient a certain amount of nicotine-like acetylcholinergic receptor part; With
(ii) give a certain amount of nicotine-like acetylcholinergic receptor hypotype of described patient α 4 β 2 positive allosteric modulators; Wherein (i) and (ii) together quantity be more effective in treatment in the disease.
17. one kind is used for the treatment of or prevents it is characterized in that the disease of attention or cognitive dysfunction or the method for disease, this method comprise nicotine-like acetylcholinergic receptor hypotype α 4 β, 2 positive allosteric modulators and nicotine-like acetylcholinergic receptor part bonded with it or acetylcholinesteraseinhibitors inhibitors that the experimenter that these needs are arranged treats effective dose.
18. treat or prevent and it is characterized in that the disease of neural psychological function obstacle or the method for disease, this method comprise nicotine-like acetylcholinergic receptor hypotype α 4 β, 2 positive allosteric modulators and psychosis bonded with it that the experimenter that these needs are arranged treats effective dose for one kind.
19. the goods of a manufacturing, it comprises:
(i) comprise first pharmaceutical dosage form of at least a nicotine-like acetylcholinergic receptor part; With
(ii) comprise second pharmaceutical dosage form of nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators at least; Wherein said goods contain first and second pharmaceutical dosage forms.
20. the chemical compound of formula (II):
Or its salt, wherein Ar
2Be substituted pyridinyl, unsubstituting biocides base or substituted-phenyl; And Ar
3Be substituted pyridinyl, unsubstituting biocides base or substituted-phenyl; Wherein said pyridine radicals when replacing, is replaced by fluorine and described phenyl is replaced by cyano group, sulfonamide or fluorine.
21. the chemical compound of claim 17, wherein Ar
2Be cyano-phenyl and Ar
3It is pyridin-3-yl.
22. formula (II
*) chemical compound:
Or its salt, wherein
Ar
2Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are replaced by 1,2,3 or 4 substituent group, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
4-C
10Heterocycle, C
1-C
6Alkyl ,-(C
1-C
6Alkyl) NHC (O) O-(C
1-C
6Alkyl), C
1-C
6Hydroxyalkyl, C
1-C
6Alkyl-carbonyl, amino, hydroxyl, haloalkyl-C (O)-, haloalkyl-SO
2-, alkyl-SO
2-,-SO
2NH
2,-SO
2NH (C
1-C
6Alkyl) ,-SO
2N (C
1-C
6Alkyl)
2, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-C (O) NH
2,-C (O) O-(C
1-C
6Alkyl) and carboxyl; With
Ar
3Be monocyclic aryl or bicyclic heteroaryl, wherein said aryl or heteroaryl are replacements or unsubstituted, and when replacing, described aryl or heteroaryl are substituted base and replace, and described substituent group is selected from halo, C
1-C
6Haloalkyl, C
6-C
10Aryl, C
4-C
7Cycloalkyl, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
5-C
10Heteroaryl, C
1-C
6Alkyl, C
1-C
6Hydroxyalkyl, amino, hydroxyl, haloalkyl-SO
2-, cyano group, nitro, C
1-C
6Acyl amino, C
1-C
6Alkoxyl ,-N (C
1-C
6Alkyl)
2And carboxyl;
Its Chinese style (II
*) at least one can utilize atom to replace with radiosiotope in the chemical compound.
23. a chemical compound, its be [
3H]-3-(5-(pyridin-3-yl)-1,2,4-oxadiazole-3-yl) benzonitrile.
24. formula (II
*) the radioactive label form of chemical compound is used to measure the purposes of the binding affinity of nicotine-like acetylcholinergic receptor hypotype α 4 β 2 positive allosteric modulators.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US87460906P | 2006-12-12 | 2006-12-12 | |
| US60/874,609 | 2006-12-12 | ||
| US60/999,761 | 2007-04-12 | ||
| US11/953,625 | 2007-12-10 |
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| Publication Number | Publication Date |
|---|---|
| CN101605542A true CN101605542A (en) | 2009-12-16 |
Family
ID=41470933
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|---|---|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316885A (en) * | 2015-07-03 | 2017-01-11 | 上海适济生物科技有限公司 | Preparation method of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid |
-
2007
- 2007-12-12 CN CNA200780051253XA patent/CN101605542A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106316885A (en) * | 2015-07-03 | 2017-01-11 | 上海适济生物科技有限公司 | Preparation method of 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)benzoic acid |
| CN106316885B (en) * | 2015-07-03 | 2019-02-12 | 普济生物科技（台州）有限公司 | A kind of preparation method of 3- [5- (2- fluorophenyl) -1,2,4- oxadiazoles -3- base] benzoic acid |
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