CN103260703A - Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors - Google Patents

Piperidin-4-yl-zetidine diamides as monoacylglycerol lipase inhibitors Download PDF

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CN103260703A
CN103260703A CN201180061809XA CN201180061809A CN103260703A CN 103260703 A CN103260703 A CN 103260703A CN 201180061809X A CN201180061809X A CN 201180061809XA CN 201180061809 A CN201180061809 A CN 201180061809A CN 103260703 A CN103260703 A CN 103260703A
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base
chemical compound
phenyl
trifluoromethyl
thiazol
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P.J.康诺利
H.卞
X.李
L.刘
M.J.马切拉
M.E.麦克唐奈
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Janssen Pharmaceutica NV
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Abstract

Disclosed are compounds, compositions and methods for treating various diseases, syndromes, conditions and disorders, including pain. Such compounds, and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, are represented by Formula (I) as follows: Formula (I), wherein Y, Z, and R are defined herein.

Description

Piperidin-4-yl-azetidine diamides as the monoacylglycerol lipase inhibitor
CROSS-REFERENCE TO RELATED PATENT
Inapplicable.
About the research of federal funding or the statement of exploitation
Research of the present invention hereinafter described or exploitation are not federal fundings.
Background technology
Fructus Cannabis (Cannabis sativa) has been used for the treatment of pain for many years.Δ 9-tetrahydrocannabinol is the main active from Fructus Cannabis, and be cannabinoid receptor agonists (Pertwee, Brit J Pharmacol " Britain pharmacology magazine ", 2008,153,199-215).Two kinds of cannabinoid g protein coupled receptors have been cloned, i.e. 1 type Cannabined receptor (CB 1People such as Matsuda, Nature " nature ", 1990,346,561-4) with 2 type Cannabined receptor (CB 2People such as Munro, Nature " nature ", 1993,365,61-5).CB 1Be expressed in brain district such as hypothalamus and nucleus accumbens septi at maincenter, and be expressed in week outside liver, gastrointestinal tract, pancreas, fatty tissue and skeletal muscle (people such as Di Marzo, Curr Opin Lipidol " blood fat is learned and newly seen ", 2007,18,129-140).CB 2Main (people such as Pacher in immunocyte such as mononuclear cell, Amer J Physiol " U.S. physiology magazine ", 2008,294, H1133-H1134) express, and under certain conditions, also (people such as Benito, Brit J Pharmacol " Britain pharmacology magazine ", 2008 in brain, 153, (people such as Cavuoto, Biochem Biophys Res Commun " biochemistry and biophysical research communication ", 2007 277-285) and in skeletal muscle, 364,105-110) and in cardiac muscle (people such as Hajrasouliha, Eur J Pharmacol " European pharmacology's magazine ", 2008,579,246-252) the middle expression.Use a large amount of pharmacologys, anatomy and the electrophysiology data of synthetic agonist to show, pass through CB 1/ CB 2The cannabinoid signal of enhancing be sent in the acute injury impression test and promoted analgesia, and hyperpathia (people such as Cravatt, J Neurobiol " neurobiology ", 2004 in chronic neuropathic pain and inflammatory pain model, have been suppressed, 61,149-60; People such as Guindon, Brit J Pharmacol " Britain pharmacology magazine ", 2008,153,319-334).
There is lot of documents to prove the effect of synthetic cannabinoid receptor agonists.In addition, use the research of cannabinoid receptor antagonists and knock out mice to show that also the Endocannabinoids system is a kind of important nociception regulator.Cannabinoid (AEA) (people such as Devane, Science " science ", 1992,258,1946-9) and 2-Semen arachidis hypogaeae acylglycerol (2-AG) (people such as Mechoulam, Biochem Pharmacol " biochemistry pharmacology ", 1995,50,83-90; People such as Sugiura, Biochem Biophys Res Commun " biochemistry and biophysical research communication ", 1995,215,89-97) be two kinds of main Endocannabinoids.AEA is by fatty acid amide hydrolase (FAAH) hydrolysis, and 2-AG coverlet acyl glycerin fatty enzyme (MGL) hydrolysis (Piomelli, Nat Rev Neurosci, 2003,4,873-884).The gene delection of FAAH has improved endogenous AEA level and caused CB in the acute inflammation pain model 1The dependency analgesia (people such as Lichtman, Pain " pain ", 2004,109,319-27), thereby show the natural function with inhibition of pain of Endocannabinoids system (people such as Cravatt, J Neurobiol, 2004,61,149-60).The Endocannabinoids horizontal group that occurs when using the FAAH knock out mice become second nature improve different, uses concrete FAAH inhibitor temporarily to improve the AEA level and produce the interior anti-nociception of body (people such as Kathuria, Nat Med, 2003,9,76-81).The further evidence of the anti-nociception view of relevant Endocannabinoids mediation is by following proof: formed AEA (people such as Walker behind periphery generation noxious stimulation in periaqueductal gray matter, Proc Natl Acad Sci USA, 1999,96,12198-203), and antisense RNA mediation CB in spinal cord on the contrary, 1Brought out after the inhibition hyperpathia (people such as Dogrul, Pain " pain ", 2002,100,203-9).
With respect to 2-AG, measure (people such as Mechoulam at whipping, Biochem Pharmacol " biochemistry pharmacology ", 1995,50,83-90) and hot plate measure (people such as Lichtman, JPharmacol Exp Ther " U.S. pharmacology and experimental therapeutic magazine ", 2002,302,73-9) the middle intravenous that confirms is sent 2-AG and has been produced analgesia.On the contrary, proved that giving 2-AG separately in hot plate is measured can not produce analgesia, but with other 2-monoacylglycerol (namely, 2-glyceryl linoleate and 2-tripalmitin) when associating, obtained significant analgesia, this phenomenon is called " partner's effect (entourage effect) " (people such as Ben-Shabat, Eur J Pharmacol, 1998,353,23-31).These " partner " 2-monoacylglycerols are endogenous lipids, and they and 2-AG discharge altogether and strengthen the Endocannabinoids signal and send, and this part ground is by suppressing the 2-AG degraded, and most probable is realized by the avtive spot on the competition MGL.This shows that synthetic MGL inhibitor will have similar effect.Really, relatively Ruo synthetic MGL inhibitor URB602 in the acute inflammation mouse model, show anti-nociception effect (people such as Comelli, Brit J Pharmacol " Britain pharmacology magazine ", 2007,152,787-794).
Though use synthetic cannabinoid agonists prove that really the cannabinoid signal that strengthens sends generation analgesia and antiphlogistic effects, it still is difficult that the side effect that the effect that these are useful and these chemical compounds are not expected separates.A kind of alternative approach is the signal transmission that strengthens the Endocannabinoids system by the level that improves 2-AG (the most abundant Endocannabinoids) in central nervous system (CNS) and the gastrointestinal tract, and this can realize by suppressing MGL.Therefore, the MGL inhibitor can be used for treating pain, inflammation and CNS obstacle (people such as Di Marzo, Curr Pharm Des, 2000,6,1361-80 potentially; People such as Jhaveri, Brit J Pharmacol " Britain pharmacology magazine ", 2007,152,624-632; People such as McCarberg Bill, Amer J Ther, 2007,14,475-83), and glaucoma and the morbid state (Njie, the Ya Fatou that raise and to cause by intraocular pressure; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp.Eye Res. (research of experimental eye section), 2008,87 (2): 106-14).
Summary of the invention
The present invention relates to chemical compound and enantiomer, diastereomer, solvate and the officinal salt of a kind of formula (I)
Figure BDA00003384930000031
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group a) is
I) C 6-10Aryl, it is selected from fluorine, chlorine, C for unsubstituted or quilt 1-4Alkyl, C 1-4The substituent group of alkoxyl, cyano group and trifluoromethyl replaces; Or
Ii) be selected from the unsubstituted heteroaryl of thiazolyl, isothiazolyl and 1H-pyrrole radicals;
Group b) is
I) C 6-10Aryl;
Ii) be selected from benzo
Figure BDA00003384930000041
The heteroaryl of azoles base, benzothiazolyl, benzimidazolyl, benzothienyl, indazolyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl or fluorine; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is selected from bromine, chlorine, fluorine, iodine, C independently of one another 1-4Alkyl, C 1-4Alkoxyl and R bPrecondition is that to be no more than a substituent group be R bWith
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that each is independently selected from trifluoromethyl, methyl, chlorine, cyano group and fluorine in the described substituent group;
R is hydrogen or hydroxyl.
The present invention also provides a kind of pharmaceutical composition especially, and described pharmaceutical composition comprises following material, formed and/or be made up of following material basically by following material: the compound or pharmaceutically acceptable salt thereof form of pharmaceutically suitable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent and formula (I).
The present invention also provides the method for the preparation of pharmaceutical composition, said method comprising the steps of, is formed and/or be made up of following steps basically by following steps: the compound or pharmaceutically acceptable salt thereof form of hybrid (I) and pharmaceutically suitable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.
The present invention also provides the compound or pharmaceutically acceptable salt thereof form of therapy of use formula (I) especially or has improved the method for the obstacle of the MGL adjusting among person under inspection's (comprising people or other mammal), wherein disease, syndrome or disease are subjected to the influence that the MGL enzyme is regulated, as pain, the disease that causes this pain, inflammation and CNS obstacle.
The present invention also provides the method for the preparation of The compounds of this invention and pharmaceutical composition and medicament especially.
The specific embodiment
About substituent group, term " independently " refers to when the substituent group that may exist above, the situation that described substituent group can be same to each other or different to each other.
No matter term " alkyl " is to use separately or use as substituent part, all refers to have the straight chain of 1 to 8 carbon atom or the carbochain of branching.Therefore, the carbon number of appointment (C for example 1-8) refer to the carbon atom number in the moieties independently or refer to carbon atom number in the bigger substituent moieties that contains alkyl.In the substituent group with a plurality of alkyl as (C 1-6Alkyl) 2Amino-in, the C of this dialkyl amido 1-6Alkyl can be identical or different.
Term " alkoxyl " refers to-the O-alkyl that wherein term " alkyl " is as defined above.
Term " thiazolinyl " and " alkynyl " refer to have the straight chain of 2 to 8 carbon atoms and the carbochain of branching, and wherein alkenylene chain contains at least one two key, and the alkynyl chain contains at least one triple bond.
Term " cycloalkyl " refers to have saturated or fractional saturation, monocycle or the multi-ring hydrocarbon ring of 3 to 14 carbon atoms.The example of this type of ring comprises cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and adamantyl.
Term " benzo-fused cycloalkyl " refers to be fused to 5 yuan to 8 yuan monocyclic cycloalkyl rings of phenyl ring.The carboatomic ring member who forms cycloalkyl ring can be saturated fully or fractional saturation.
Term " heterocyclic radical " refers to have non-aromatic monocyclic system or two member ring systems of 3 to 10 ring memberses, and described ring members comprises at least 1 carbon atom and 1 to 4 hetero atom, and described hetero atom is independently selected from N, O and S.Comprise that (wherein 0,1 or 2 member is N for the non-aromatic cyclic rings (wherein 1 to 2 member is N) with 5 to 7 members or the non-aromatic cyclic rings with 5 to 7 members, and 2 members are O or S at the most, and at least one member is necessary for N, O or S) be included in the term heterocyclic radical; Wherein randomly, described ring contains 0 to 1 unsaturated bond, and randomly, when described ring had 6 or 7 members, it contained 2 unsaturated bonds at the most.The carboatomic ring member who forms heterocycle can be saturated fully or fractional saturation.Term " heterocyclic radical " also comprises bridging and forms two 5 yuan of monocyclic heterocycles alkyl of bicyclo-.It is Wholly aromatic that this type of group is not considered as, and does not claim that they are heteroaryl.When heterocycle is bicyclo-, two heterocycles be non-aromatic and ring at least one contain the heteroatomic ring member.The example of heterocyclic radical comprises and is not limited to pyrrolinyl (comprising 2H-pyrroles, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, morpholinyl, thio-morpholinyl and piperazinyl.Except as otherwise noted, otherwise heterocycle is attached to its side group at any hetero atom that causes rock-steady structure or carbon atom.
Term " benzo-fused heterocyclic radical " refers to be fused to 5 yuan to 7 yuan monocyclic heterocycles of phenyl ring.Described heteroaryl contain carbon atom and 1 to 4 hetero atom, described hetero atom is independently selected from N, O and S.The carboatomic ring member who forms described heterocycle can be saturated fully or fractional saturation.Except as otherwise noted, otherwise benzo-fused heterocycle is attached to its side group at carbon atoms on a benzene ring.
Term " aryl " refers to 6 to 10 carbon members' unsaturated aromatic monocyclic or bicyclo-.The example of aromatic ring comprises phenyl and naphthyl.
Term " heteroaryl " refers to have 5 to 10 ring memberses, and contains carbon atom and 1 to 4 heteroatomic monocyclic aromatic member ring systems or bicyclic aromatic member ring systems, and described hetero atom is independently selected from N, O and S.Aromatic ring (wherein said ring be made up of carbon atom and have at least one hetero atom member) with 5 or 6 members is included in the term heteroaryl.Suitable hetero atom comprises nitrogen, oxygen and sulfur.Under the situation of 5 yuan of rings, heteroaryl ring preferably contains a member in nitrogen, oxygen or the sulfur, contains 3 additional nitrogen at the most in addition.Under the situation of 6 yuan of rings, heteroaryl ring preferably contains 1 to 3 nitrogen-atoms.Have the situation of 3 nitrogen-atoms for 6 yuan of rings wherein, maximum 2 nitrogen-atoms are adjacent.The example of heteroaryl comprise furyl, thienyl, pyrrole radicals,
Figure BDA00003384930000061
Azoles base, thiazolyl, imidazole radicals, pyrazolyl, different Azoles base, isothiazolyl,
Figure BDA00003384930000063
Di azoly, triazolyl, thiadiazolyl group, pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, indyl, isoindolyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzo
Figure BDA00003384930000064
Azoles base, benzisoxa
Figure BDA00003384930000065
Azoles base, diazosulfide base, benzotriazole base, quinolyl, isoquinolyl and quinazolyl.Except as otherwise noted, otherwise heteroaryl is attached to its side group at any hetero atom that causes rock-steady structure or carbon atom.
Term " halogen " or " halogen " refer to fluorine, chlorine, bromine and iodine atom.
Term " formoxyl " refers to group-C (=O) H.
Term " oxo " refer to group (=O).
When term " alkyl " or " aryl " or any one its prefix root come across the substituent group title (as aralkyl, alkylamino), those restrictions that provide at " alkyl " and " aryl " above this title should be interpreted as comprising.The specifying number of carbon atom (C for example 1-C 6) refer to moieties, aryl moiety independently or than the carbon atom number in the moieties of large-substituent, described than large-substituent in alkyl occur with its prefix root.With regard to alkyl and alkoxy substituent, the carbon number of appointment is included in all independent members that comprise in the prescribed limit that provides.C for example 1-6Alkyl will comprise that respectively methyl, ethyl, propyl group, butyl, amyl group and hexyl and subgroup thereof close (C for example 1-2, C 1-3, C 1-4, C 1-5, C 2-6, C 3-6, C 4-6, C 5-6, C 2-5Deng).
In general, under the standardized denomination that uses in disclosure full content, specifying the terminal part of side chain at first to describe, is the adjacent functional group towards junction point subsequently.Therefore, " C for example 1-C 6Alkyl-carbonyl " substituent group refers to the group of following formula:
The term at stereocenter place " R " indicates this stereocenter and only has the R-configuration, such as in this area definition; Equally, term " S " means stereocenter and only has the S-configuration.As used herein, term " * R " or " * S " at the stereocenter place are pure but unknown configurations for indicating stereocenter.As used herein, term " RS " refers to the stereocenter that the mixture with R-and S-configuration exists.Similarly, term " * RS " or " * SR " refer to that mixture with R-and S-configuration exists and are the stereocenter of unknown configuration with respect to other stereocenter in the molecule.
The chemical compound that contains a stereocenter that does not draw with three-dimensional key label is the mixture of 2 kinds of enantiomer.The chemical compound that contains 2 stereocenters that all do not draw with three-dimensional key label is the mixture of 4 kinds of diastereomers.Having 2 all is labeled as the stereocenter of " RS " and is to have the stereochemical relatively 2-component mixture that draws with the chemical compound that three-dimensional key label draws.Have 2 and all be labeled as the stereocenter of " * RS " and be to have the stereochemical relatively 2-component mixture of the unknown with the chemical compound that three-dimensional key label draws.The unmarked stereocenter of not drawing three-dimensional key label is the mixture of R-and S-configuration.With regard to the unmarked stereocenter that draws with three-dimensional key label, absolute spatial chemistry be as draw.
Except as otherwise noted, otherwise to be intended to be that the definition of the definition of any substituent group of specific location in the molecule or variable and its other position in this molecule is irrelevant.Should understand, substituent group and substitute mode on the chemical compound of formula (I) can be selected by those of ordinary skill in the art, chemically stable to be provided and to be easy to by technology known in the art and the synthetic chemical compound of those methods as described herein.
Term " person under inspection " refers to it is treatment, observe or the animal of the object of experiment, preferably refers to mammal, most preferably refers to the people.
Term " treatment effective dose " refers to comprise the amount of reactive compound or the medicament of chemical compound of the present invention, this amount can cause the tissue system that researcher, veterinary, doctor or other healthcare givers pursue, animal or human's biology or medicinal response, and this comprises and alleviating or part alleviates the symptom of subject disease, syndrome, disease or obstacle.
Term " compositions " refers to comprise the product of the predetermined component for the treatment of effective dose, and directly or indirectly by any product of the combination results of the predetermined component of ormal weight.
Term " MGL inhibitor " thereby be intended to is contained with MGL and is interacted to reduce basically or eliminate the chemical compound that the MGL catalytic activity increases the MGL concentration of substrate.Term " MGL regulates " is used in reference to and is subjected to the disease that the MGL enzyme is regulated to be influenced, and comprises being subjected to the MGL enzyme to suppress the disease that influences, for example disease, inflammation and the CNS obstacle of pain and this type of pain of initiation.
Unless otherwise noted, as used herein, term " influence " or " affected " (when referring to be subjected to MGL to suppress disease, syndrome, disease or the obstacle that influences) comprise one or more symptoms or the frequency of clinical manifestation and/or the reduction of seriousness of described disease, syndrome, disease or obstacle; And/or comprise one or more symptoms or the development of performance or the development of described disease, syndrome, disease or obstacle that prevents described disease, syndrome, disease or obstacle.
The chemical compound of formula (I) is useful being used for the treatment of, improving and/or preventing to be subjected to MGL to suppress in the method for disease, syndrome, disease or the obstacle influence.These class methods may further comprise the steps, formed and/or be made up of following steps basically by following steps: chemical compound or its enantiomer, diastereomer, solvate or the officinal salt that will treat the formula (I) of effective dose are administered to the person under inspection, animal, mammal and the mankind that described person under inspection comprises to be needed this type for the treatment of, improve and/or prevent.Particularly, the chemical compound of formula (I), or its enantiomer, diastereomer, solvate or officinal salt are used for the treatment of, improvement and/or prevent irritation; This type of pain that disease, syndrome, disease or obstacle cause; Inflammation and/or CNS obstacle.More specifically, the chemical compound of formula (I), or its enantiomer, diastereomer, solvate or officinal salt be used for the treatment of, improve and/or prevent inflammatory pain, the super quick disease of inflammatory and/or neuropathic pain, comprises that chemical compound or its enantiomer, diastereomer, solvate or the officinal salt of formula as herein defined (I) that will the treatment effective dose is administered to the person under inspection who needs it.
The example of inflammatory pain comprises by disease, disease, syndrome, pain due to obstacle or the pain status, described disease, disease, syndrome, obstacle or pain status comprise inflammatory bowel, Encelialgia, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, backache, back pain, arthralgia, stomachache, chest pain, childbirth, musculoskeletal disease, dermatosis, toothache, heating (pyresis), burn, sunburn, venom, venom, spider bites, insect stings, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/super quick disease, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after the mastectomy, dysmenorrhea, endometriosis, by the pain due to the physical trauma, headache, the sinus frontalis headache, tension headache or arachnoiditis.
One type inflammatory pain is inflammatory hyperpathia/allergy.The hyperalgesic example of inflammatory comprises disease, syndrome, disease, obstacle or pain status, described disease, syndrome, disease, obstacle or pain status comprise inflammation, osteoarthritis, rheumatoid arthritis, backache, arthralgia, stomachache, musculoskeletal disease, dermatosis, postoperative pain, headache, toothache, burn, sunburn, insect stings, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive disease of lung, rhinitis, contact dermatitis/allergy and/or skin allergy, scratch where it itches, eczema, pharyngitis, enteritis, irritable bowel syndrome, the inflammatory bowel that comprises clone disease, ulcerative colitis, benign prostatauxe and nose allergy.
In one embodiment, the present invention relates to a kind of hyperalgesic method of the irritated inflammatory internal organs of internal organs that is used for the treatment of, improves and/or prevent wherein to exist increase, described method comprises that chemical compound, salt or the solvate that will treat the formula (I) of effective dose are administered to the person under inspection's who needs this type for the treatment of step, are formed and/or be made up of this step basically by this step.In another embodiment, the present invention relates to a kind of hyperalgesic method of inflammatory body that wherein exists heat, machinery and/or chemical stimulation allergy that is used for the treatment of, described method comprises that chemical compound or its enantiomer, diastereomer, solvate or the officinal salt with the formula (I) for the treatment of effective dose is administered to the mammal that needs this type for the treatment of.
An alternative embodiment of the invention relates to a kind of method that is used for the treatment of, improves and/or prevent neuropathic pain.The example of neuropathic pain comprises by disease, syndrome, disease, pain due to obstacle or the pain status, described disease, syndrome, disease, obstacle or pain status comprise cancer, neurological disorder, spinal nerves and operation on peripheral nerve, the cerebral tumor, traumatic brain injury (TBI), spinal cord injuries receptor, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, the bilateral peripheral neuropathy, diabetic neuropathy, central pain, the neuropathy that is associated with spinal cord injury, apoplexy, amyotrophic lateral sclerosis (ALS), parkinson, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom pain, fracture, MN pain, charcot's pains, I type and II type complexity zone pain syndrome (CRPSI/II), radiculopathy, guillain-Barre syndrome, Bernhards disease, a bright mouthful syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis, tribute Bo Shi neuritis, neuronitis, cervico-brachial neuralgia, cranium portion neuralgia, neuralgia facialis vera, glossopharyngeal neuralgia, migrainous neuralgia, idiopathic neuralgia, intercostal neuralgia, mammary neuralgia, morton's neuralgia, nasociliary neuralgia, occipital neuralgia, postherpetic neuralgia, causalgia, erythromelalgia, sluder's neuralgia, sphenopalatine neuralgia, supraorbital neuralgia, trigeminal neuralgia, vulvodynia or Vidian neuralgia.
One type neuropathic pain is the cold sexual abnormality pain of nerve, and its feature can be the allodynia state (wherein having the allergy to cold stimulation) that exists neuropathy to be associated.The example of the cold sexual abnormality pain of neuropathic comprises because disease, disease, syndrome, allodynia due to obstacle or the pain status, described disease, disease, syndrome, obstacle or pain status comprise neuropathic pain (neuralgia), by spinal nerves and operation on peripheral nerve or wound, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, apoplexy, peripheral neuritis, polyneuritis, the pain that I type and II type complexity zone pain syndrome (CRPS I/II) or radiculopathy cause.
In another embodiment, the present invention relates to a kind ofly be used for the treatment of, improve and/or prevent wherein to exist method to the unusual cold type of pain of nerve of cold stimulation allergy, said method comprising the steps of, formed and/or be made up of following steps basically by following steps: chemical compound or its enantiomer, diastereomer, solvate or the officinal salt that will treat the formula (I) of effective dose are administered to the person under inspection who needs this type for the treatment of.
In another embodiment, the present invention relates to a kind of method that is used for the treatment of, improves and/or prevent nerve CNS obstacle.The example of CNS obstacle comprises stress obstacle after anxiety neurosis such as social anxiety disorder, the wound, phobia, social phobia, special phobia, panic disorder, obsession, acute stress disorder, separation anxiety disorder and generalized anxiety disorder, and depression such as major depression, biphasic or bipolar type mental disorder, seasonal affective disorder, postpartum depression, manic depressive illness and biphasic or bipolar type depression.
Embodiments of the invention comprise chemical compound and enantiomer, diastereomer, solvate and the officinal salt of formula (I)
Figure BDA00003384930000111
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z); And
A) group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazolyl, isothiazolyl and 1H-pyrrole radicals a);
B) group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazolyl, 1H-pyrroles-2-base and 1H-pyrroles-3-base a);
C) group b) be
I) phenyl;
Ii) be selected from benzo The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, wherein the phenyl of phenyl methyl is unsubstituted or is replaced by trifluoromethyl or fluorine; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, each is independently selected from chlorine, fluorine, methyl and R in the described substituent group bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that each is independently selected from trifluoromethyl, methyl, chlorine and fluorine in the described substituent group;
D) group b) be
I) phenyl;
Ii) be selected from benzo
Figure BDA00003384930000113
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, wherein the phenyl of phenyl methyl is unsubstituted or is replaced by trifluoromethyl; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl randomly replaced by 1 to 2 trifluoromethyl, methyl, chlorine or fluoro substituents independently;
E) R is hydrogen;
And above embodiment a) to e) any combination, precondition is should be appreciated that, wherein the compound mode that identical substituent different embodiment are made up forecloses.
One embodiment of the present of invention comprise chemical compound and enantiomer, diastereomer, solvate and the officinal salt of formula (I)
Figure BDA00003384930000121
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazolyl, isothiazolyl and 1H-pyrrole radicals a);
Group b) is
I) phenyl;
Ii) be selected from benzo The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, wherein the phenyl of phenyl methyl is unsubstituted or is replaced by trifluoromethyl or fluorine; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen.
One embodiment of the present of invention comprise chemical compound and enantiomer, diastereomer, solvate and the officinal salt of formula (I)
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazolyl, isothiazolyl and 1H-pyrrole radicals a);
Group b) is
I) phenyl;
Ii) be selected from benzo
Figure BDA00003384930000132
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, wherein the phenyl of phenyl methyl is unsubstituted or is replaced by trifluoromethyl; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen or hydroxyl.
One embodiment of the present of invention comprise chemical compound and enantiomer, diastereomer, solvate and the officinal salt of formula (I)
Figure BDA00003384930000141
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazolyl, 1H-pyrroles-2-base and 1H-pyrroles-3-base a);
Group b) is
I) phenyl;
Ii) be selected from benzo
Figure BDA00003384930000142
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, wherein the phenyl of phenyl methyl is unsubstituted or is replaced by trifluoromethyl; Or
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen or hydroxyl.
One embodiment of the present of invention comprise chemical compound and the pharmaceutical acceptable salt thereof of formula (I)
Figure BDA00003384930000151
Formula (I)
It is selected from:
Wherein Y is thiazole-4-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is isothiazole-5-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-3-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is thiazole-5-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is phenyl, and Z is 5-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of OH;
Wherein Y is thiazole-4-base, and Z is 3-chloro-6-fluoro-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-chloro-6-fluoro-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 2-phenyl-benzo
Figure BDA00003384930000161
Azoles-6-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 2-phenyl-benzo Azoles-6-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-phenyl-benzo
Figure BDA00003384930000172
Azoles-6-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 2-fluoro-4-phenyl-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 2-fluoro-4-phenyl-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure BDA00003384930000181
Azoles-6-base, Z are thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure BDA00003384930000182
Azoles-6-base, Z are thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure BDA00003384930000191
Azoles-6-base, Z are 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(2,2,2-trifluoroethyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-phenyl-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(2,2,2-trifluoroethyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4,4-difluoro cyclohexyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(5-chloropyridine-2-yl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of OH;
Wherein Y is thiazol-2-yl, and Z is 1-(2-picoline-4-yl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-phenyl-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4,4-difluoro cyclohexyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H.
For the purposes in medical science, the salt of the chemical compound of formula (I) refers to nontoxic " officinal salt ".Yet other salt can be used for the compound or pharmaceutically acceptable salt thereof form of preparation formula (I).The suitable officinal salt of the chemical compound of formula (I) comprises acid-addition salts, and described acid-addition salts can for example mix with the solution of the pharmaceutically acceptable acid of all example hydrochloric acids, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid by the solution with described chemical compound and forms.In addition, when the chemical compound of formula (I) had acidic moiety, its suitable officinal salt can comprise alkali metal salt (as sodium salt or potassium salt); Alkali salt (as calcium salt or magnesium salt); And the salt (as quaternary ammonium salt) that forms with suitable organic ligand.Therefore, representational officinal salt comprises acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, the edetic acid calcium salt, camsilate, carbonate, chloride, Clavulanate, citrate, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, gluconate, glutamate, Glu, the glycollyl arsanilate, two phenates between hexyl benzene, Hai Baming salt, hydrobromate, hydrochlorate, Hydroxynaphthoate, iodide, different thiosulfate, lactate, Lactobionate, laruate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucate, naphthalene sulfonate, nitrate, N-methylglucosamine ammonium salt, oleate, embonate (pamoate), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, 1, teoclate, toluene fulfonate, triethyl group iodate thing and valerate.
The representational bronsted lowry acids and bases bronsted lowry that can be used for preparing officinal salt comprises following bronsted lowry acids and bases bronsted lowry, described acid comprises acetic acid, 2, the 2-dichloroacetic acid, acetylizad aminoacid, adipic acid, alginic acid, ascorbic acid, the L-aspartic acid, benzenesulfonic acid, benzoic acid, the 4-acetaminobenzoic acid, (+)-dextrocamphoric acid., camphorsulfonic acid, (+)-(1S)-Camphora-10-sulfonic acid, capric acid, caproic acid, sad, cinnamic acid, citric acid, cyclamic acid, lauryl sulphate acid, ethane-1, the 2-disulfonic acid, ethyl sulfonic acid, 2-hydroxyl-ethyl sulfonic acid, formic acid, fumaric acid, galactosaccharic acid, gentisic acid, glucoheptonic acid, the D-gluconic acid, the D-glucuronic acid, L-glutamic acid, alpha-oxo--1,3-propanedicarboxylic acid, glycolic, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L MALIC ACID, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, the 5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, Palmic acid, pounce on acid, phosphoric acid, the L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, decanedioic acid, stearic acid, succinic acid, sulphuric acid, tannin, (+)-L-tartaric acid, Hydrogen thiocyanate, p-methyl benzenesulfonic acid and 9-undecylenic acid; Described alkali comprises ammonia, L-arginine, benethamine, benzyl star, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glycosamine, Hai Baming, 1H-imidazoles, L-lysine, magnesium hydroxide, 4-(2-ethoxy)-morpholine, piperazine, potassium hydroxide, 1-(2-ethoxy)-pyrrolidine, sodium hydroxide, triethanolamine, tromethane and zinc hydroxide.
Embodiments of the invention comprise the prodrug of the chemical compound of formula (I).Usually, this prodrug will be the functional derivatives of chemical compound, and it can easily change into required chemical compound in vivo.Therefore, in the method for the treatment of of the present invention or prevention embodiment, term administering " contained treatment or prevention to specifically described chemical compound or the described multiple disease of not specifically described chemical compound, disease, syndrome and obstacle, but described not specifically described chemical compound changes into specified chemical compound in body after being applied to the patient.For example, the conventional program that is used for selecting and preparing suitable prodrug derivant has been described in " Design of Prodrugs " (H.Bundgaard (editor), Elsevier, 1985).
When having at least one chiral centre according to the chemical compound of the embodiment of the invention, therefore they can exist as enantiomer.If chemical compound has two or more chiral centres, then they can exist as diastereomer in addition.Should be appreciated that this all class isomer and composition thereof contains within the scope of the invention.In addition, some crystal form of chemical compound can be used as polymorph and exists, and therefore is intended to be included in the present invention.In addition, some chemical compound can form solvate (being hydrate) or form solvate with ordinary organic solvents with water, and this kind solvent chemical compound also is intended to contain within the scope of the invention.The technical staff will understand, and the term as used herein chemical compound is intended to comprise the chemical compound of the formula (I) of solvation.
When producing the mixture of stereoisomer for the preparation of the method according to the chemical compound of certain embodiments of the invention, these isomers can separate as preparation property chromatography by routine techniques.Chemical compound can prepare by racemic form, and perhaps independent enantiomer can synthesize or prepare by splitting by the enantiomer specificity.For example, can pass through standard technique, as to form diastereomer right by forming salt with optical activity acid (as (-)-two toluoyls-d-tartaric acid and/or (+)-two toluoyls-l-tartaric acid), fractional crystallization and the free alkali of regenerating subsequently split into chemical compound their component enantiomer.Also can carry out chromatographic isolation subsequently and remove chiral auxiliary splitting chemical compound by forming diastereomeric ester or amide.Select as another kind, available chirality HPLC post splits chemical compound.
One embodiment of the present of invention relate to a kind of compositions, comprise pharmaceutical composition, its comprise the chemical compound of formula (I) (+)-enantiomer, form and/or formed by it basically by it, wherein said compositions is substantially free of (-)-isomer of described chemical compound.In the context of the present invention, be substantially free of mean be less than about 25%, preferably be less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than (-)-isomer of about 1%, its following calculating:
Figure BDA00003384930000231
An alternative embodiment of the invention is a kind of compositions, comprise pharmaceutical composition, its comprise the chemical compound of formula (I) (-)-enantiomer, form and formed by it basically by it, wherein said compositions is substantially free of (+)-isomer of described chemical compound.In the context of the present invention, be substantially free of mean be less than about 25%, preferably be less than about 10%, more preferably less than about 5%, even more preferably less than about 2%, and even more preferably less than (+)-isomer of about 1%, its following calculating:
In any process for the preparation of the chemical compound of a plurality of embodiment of the present invention, may be necessary and/or expect to protect sensitivity or reactive group on related any molecule.This can realize by means of the GPF (General Protection False group, for example at Protective Groups in Organic Chemistry (" blocking group in the organic chemistry ", second edition, J.F.W.McOmie, Plenum Press, 1973); T.W.Greene﹠amp; P.G.M.Wuts, Protective Groups in Organic Synthesis (" blocking group in the organic synthesis ", John Wiley Sons, 1991) and T.W.Greene﹠amp; P.G.M.Wuts, Protective Groups in Organic Synthesis (" blocking group in the organic synthesis ", the third edition, John Wiley﹠amp; Sons, 1999) find in the document.Can use methods known in the art at the blocking group of follow-up phase removal easily.
Although the chemical compound of the embodiment of the invention (officinal salt and the acceptable solvent thing that comprise them) can be used separately, their general and pharmaceutically suitable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluents (according to route of administration and standard is medicinal or the veterinary put into practice select) mix and use.Therefore, specific embodiments of the invention relate to medicinal and veterinary composition, and it comprises chemical compound and at least a pharmaceutically suitable carrier, pharmaceutically acceptable excipient and/or the pharmaceutically acceptable diluent of formula (I).
Mode with example, in the pharmaceutical composition of the embodiment of the invention, can be with chemical compound and any one or more suitable binding agents, one or more lubricants, one or more suspending agents, one or more coating materials, one or more solubilizing agents and their combined hybrid of formula (I).
Depend on the circumstances, the solid oral dosage form (as tablet or capsule) that contains The compounds of this invention can once be used with at least a dosage form.Also may use this chemical compound with the extended release preparation form.
Other the oral form that wherein can use The compounds of this invention comprises elixir, solution, syrup and suspensoid; Every kind of dosage form randomly contains flavoring agent and coloring agent.
Select as another kind, the chemical compound of formula (I) can be used or use with suppository or vaginal suppository form by sucking (the interior or intranasal of trachea), perhaps they can lotion, the form local application of solution, cream, ointment or face powder.For example, they can be sneaked in the cream, described cream comprises the aqueous emulsion of Polyethylene Glycol or liquid paraffin, is formed and/or is made up of it basically by it.They also can described cream the concentration between about 1 weight % and about 10 weight % sneak in the ointment, described ointment comprises wax or soft rock cerul together with any stabilizing agent and antiseptic (might need), formed and/or be made up of it basically by it.The application process that substitutes comprises by using skin patch or transdermal patch to come transdermal administration.
Pharmaceutical composition of the present invention (and independent The compounds of this invention) also can be by the injection of non-intestinal, for example in the spongy body, intravenous, intramuscular, subcutaneous, Intradermal or intrathecal injection.In this case, said composition also will comprise at least a in suitable carriers, suitable excipient and the suitable diluent.
Use for non-intestinal, pharmaceutical composition of the present invention preferably uses with the aseptic aqueous solution form, and described aseptic aqueous solution can contain other material, for example the solution that oozes with preparation and blood etc. of enough salt and monosaccharide.
For buccal surface or sublingual administration, pharmaceutical composition of the present invention can tablet or lozenge form use, described tablet or lozenge can be prepared in a usual manner.
Mode with another example, at least a pharmaceutical composition as active component that contains in the chemical compound of formula (I) can be according to conventional medicine compounding technology, by one or more chemical compounds and pharmaceutically suitable carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable mixed with excipients are prepared.Carrier, excipient and diluent can adopt various forms, and this depends on required route of administration (for example oral, non-intestinal is used etc.).Therefore for the liquid oral medicine such as suspensoid, syrup, elixir and solution, suitable carriers, excipient and diluent comprise water, glycols, oil, alcohols, flavoring agent, antiseptic, stabilizing agent, coloring agent etc.; For the solid orally ingestible such as powder, capsule and tablet, suitable carriers, excipient and diluent comprise starch, sugar, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc.Solid orally ingestible is also optionally used the material coating such as sugar, or enteric coated, in order to regulate the main position of absorption and disintegrate.Use for non-intestinal, carrier, excipient and diluent generally include sterilized water, and can add other composition to increase dissolubility and the keeping quality of compositions.Injection suspensoid or solution also can use aqueous carrier to prepare together with proper additive (as solubilizing agent and antiseptic).
Every day about 1 of the people of average (70kg) to about 4 times dosage regimen, the chemical compound of the formula (I) for the treatment of effective dose or its pharmaceutical composition comprise that about 0.1mg is to about 3000mg, or wherein any concrete amount or scope, about 1mg is to about 1000mg particularly, or wherein any concrete amount or scope, or more specifically about 10mg to about 500mg, or the active component of the dosage range of any concrete amount wherein or scope; But, it will be apparent to one skilled in the art that the treatment effective dose of the chemical compound of formula (I) will change along with disease to be treated, syndrome, disease and obstacle.
For Orally administered, pharmaceutical composition preferably with contain have an appointment 1.0, about 10, about 50, about 100, about 150, about 200, about 250 and the tablet form of the chemical compound of about 500 milligrams of formulas (I) provide.
Advantageously, the chemical compound of formula (I) can be used by the single daily dose, perhaps every day accumulated dose can every day the divided dose of twice, three times and four times use.
The optimal dose of the chemical compound of formula to be administered (I) can easily be determined, and will change with the progress of employed particular compound, mode of administration, preparation intensity and disease, syndrome, disease or obstacle.In addition, the factor (comprising person under inspection's sex, age, body weight, diet and time of application) that is associated with concrete person under inspection to be treated will cause having needs to adjust dosage to realize appropriate therapeutic and required therapeutic effect.Thereby above-mentioned dosage is the example of ordinary circumstance.Certainly, may exist wherein higherly or be useful individual cases than the low dosage scope, and this class situation also within the scope of the invention.
The chemical compound of formula (I) can be used in any above-mentioned composition and dosage regimen, and perhaps those compositionss and the dosage regimen of having established by means of this area used, and the use of the chemical compound of a solemnity (I) is to need its person under inspection required.
As the MGL inhibitor, the chemical compound of formula (I) is useful being used for the treatment of and preventing in the method for disease, syndrome, disease and obstacle among the person under inspection, described person under inspection comprises animal, mammal and people, and wherein said disease, syndrome, disease and obstacle are received the influence of the adjusting (comprising inhibition) of MGL enzyme.This method may further comprise the steps, formed and/or be made up of following steps basically by following steps: chemical compound, salt or the solvate that will treat the formula (I) of effective dose are applied to the person under inspection, and described person under inspection comprises animal, mammal and the mankind that need this type for the treatment of or prevention.
General synthetic method
Representative compounds of the present invention can according to hereinafter described and after scheme and example in the general synthetic method that illustrates synthetic.Because described scheme is illustrative, so the present invention should not be understood that to be subjected to chemical reaction in the described scheme and the restriction of condition.Be used for described scheme and example the commercially available acquisition of different material or can be by being proficient in method preparation well-known to those having ordinary skill in the art.Variable is as described herein.
Be used for this description, as follows especially for being abbreviated as in described scheme and the example:
The AcCl chloroacetic chloride
The AcOH glacial acetic acid
Aq. aqueous solution
Bn or Bzl benzyl
The Boc tert-butoxycarbonyl
Conc. concentrate
The DBE glycol dibromide
DCC N, N '-dicyclohexyl-carbodiimide
DCE 1, the 2-dichloroethanes
The DCM dichloromethane
The DIPEA diisopropylethylamine
DMAP 4-(N, N-dimethylamino) pyridine
The DMA N,N-dimethylacetamide
DMF N, dinethylformamide
The DMSO dimethyl sulfoxide
The DPPA diphenyl phosphoryl azide
EDC N-(3-dimethyl aminopropyl)-N '-ethyl-carbodiimide hydrochloride
The ESI electrospray ionization
The EtOAc acetoacetic ester
EtOH alcohol
H hour
HATU O-(1H-7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate
HBTU O-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylurea hexafluorophosphate
The HEK human embryo kidney (HEK)
HEPES (4-(2-ethoxy)-1-piperazine ethyl sulfonic acid
The HMPA hexamethyl phosphoramide
The HPLC high performance liquid chromatography
The mCPBA metachloroperbenzoic acid
The MeCN acetonitrile
MeOH methanol
MeOTf trifluoromethanesulfonic acid ester methyl ester
The MHz megahertz
Min minute
The MS mass spectrography
The NMR nuclear magnetic resonance, NMR
PIPES piperazine-N, N '-two (2-ethanesulfonic acid)
PyBroP tripyrrole alkyl bromination
Figure BDA00003384930000271
Hexafluorophosphate
RP is anti-phase
R tRetention time
TEA or Et 3The N triethylamine
The TFA trifluoroacetic acid
The THF oxolane
The TLC thin layer chromatography
The TMS tetramethylsilane
Option A shows the route of the intermediate of synthetic chemical compound for the preparation of formula (I), and wherein R is hydrogen.
Option A
The chemical compound of formula A1 (wherein P is conventional amido protecting group) maybe can be by the preparation of the known method described in the scientific literature for commercially available acquisition.The chemical compound of formula A1 can be handled with the zinc metal in the presence of TMS-Cl in aprotic solvent, adds the chemical compound of formula A2 subsequently in the presence of palladium catalyst, so that the chemical compound of formula A3 to be provided.Handle the pyridinium bromide that formula A4 is provided with benzyl bromide a-bromotoluene
Figure BDA00003384930000281
The chemical compound of formula A4 can be reduced to the chemical compound of formula A5 in the presence of hydride source (as sodium borohydride) in organic alcohol solvent (as ethanol).The reduction of the removal of benzyl and two keys can realize by the hydrogenation of palladium catalysis, so that the required intermediate of formula A6 to be provided.
Option b shows the route of the chemical compound of preparation formula (I)-B, and wherein Y and Z be for as defined herein, and the R of formula (I) is hydrogen.
Option b
Figure BDA00003384930000282
The amido protecting group (P) of the chemical compound of formula A3 can be removed by conventional synthetic method, so that the secondary amine of formula B1 to be provided.Randomly in the presence of alkali (as DIPEA), in the presence of suitable coupling agent (as HATU, DCC, EDC, HBTU, PyBrOP etc.), amino can with the carboxylic acid coupling of formula B2 (wherein Q is hydroxyl), so that the amide of formula B3 to be provided.Similarly, can use the acyl chlorides (wherein Q is chlorine) of formula B2 with the acidylate of the chemical compound of realization formula B1.In this case, can add non-nucleophilic base (as pyridine) so that the amide of formula B3 to be provided.The reduction of the pyridine ring of the chemical compound of formula B3 can realize by the hydrogenation of palladium catalysis, so that the chemical compound of formula B4 to be provided.Use second acidylate of the acyl chlorides of carboxylic acid that suitable Y-replaces or formula B5 that the chemical compound of formula (I)-B is provided, the R of its Chinese style (I) is hydrogen.
Scheme C shows the alternative route of the chemical compound of preparation formula (I)-B, and wherein Y and Z be for as defined herein, and the R of formula (I) is hydrogen.
Scheme C
Figure BDA00003384930000291
The chemical compound of formula A6 can be according to passing through the described synthetic method acidylate of option b, so that the acylated compounds of formula C1 to be provided.Conventional amino removes to protect the amine that formula C2 is provided, and it can experience second acidylate as previously mentioned, so that the chemical compound of formula (I)-B to be provided.
Scheme D shows the route of the chemical compound of preparation formula (I)-D, and wherein Y and Z be for as defined herein, and the R of formula (I) is hydroxyl.
Scheme D
Figure BDA00003384930000301
The chemical compound of formula D1 and D2 is maybe can preparing by the known method described in the scientific literature of commercially available acquisition.The chemical compound of formula D1 can be handled with means of samarium iodide in the presence of HMPA in aprotic solvent, adds the ketone of formula D2 subsequently, so that the condensation product of formula D3 to be provided.The removal of benzhydryl can realize by the hydrogenation of palladium catalysis, so that the unhindered amina of formula D4 to be provided.The amine of formula D4 can be used the compound acylation of the Z-replacement of formula B2 by the previously described method of this paper, so that the chemical compound of formula (I)-D to be provided.
Scheme E shows the alternative route of preparation formula (I)-D chemical compound, and wherein Y and Z be for as defined herein, and the R of formula (I) is hydroxyl.
Scheme E
Figure BDA00003384930000302
The chemical compound of formula D1 can be in the presence of means of samarium iodide and HMPA and formula E1 compound condensation, so that the chemical compound of formula E2 to be provided.Use conventional synthetic method to remove the chemical compound that amido protecting group (P) provides formula E3.The compound acylation of use formula B5 provides the chemical compound of formula E4, and it provides the unhindered amina of formula E5 when benzhydryl is removed.Second acidylate of the carboxylic acid that the Z-that use suitably replaces replaces or the acyl chlorides of formula B2 provides the chemical compound of formula (I)-D.
Example 1
Figure BDA00003384930000311
A.3-(pyridin-4-yl) azetidine-1-carboxylic acid uncle-butyl ester, 1c.Thermocouple, magnetic stirring apparatus, condenser, heating jacket and N be equipped with 2Pack in 1 liter of 3 neck round-bottomed flask of inlet adapter the anhydrous dimethyl yl acetamide (DMA, 100mL) and zinc (42.94g, 650.2mmol).Under 20 ℃, stir the mixture, simultaneously in 30min with the speed that keeps temperature to be lower than 65 ℃ add glycol dibromide (DBE, 5.38mL, 62.34mmol) and trim,ethylchlorosilane (TMS-Cl, 7.54mL, mixture 59.28mmol).With the aging 15min of gained slurry.Azetidine-(122.78g, 420.69mmol) solution in DMA (201mL) stirs 30min with cream to 1-carboxylic acid tert-butyl ester 1a, slowly cools to 20 ℃ simultaneously to drip the 3-iodo with the speed that keeps temperature to be lower than 65 ℃ in 1h.
At N 2Thermocouple, mechanical agitator, condenser, heating jacket and N be equipped with down 2Pack [1 in 3 liter of 4 neck round-bottomed flask of another of inlet adapter, 1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) dichloromethane complex (4.73g, 5.74mmol), Hydro-Giene (Water Science). (2.19g, 11.47mmol) and 4-iodine pyridine 1b (80.0g, 382.44mmol) solution in DMA (255mL).The gained mixture is with replacing vacuum/N 2Purging outgases.Adding is as the zinc iodide reagent of the chemical compound 1a in DMA that as above makes of suspension.Mixture vacuum/N 2The degassing twice is heated to 80 ℃ then.(note: described reaction is heat release.) progress of reaction is by HPLC and LC-MS monitoring, and behind 2h, finish.Reactant mixture is cooled to 40 ℃; Add EtOAc (1.6L), and mixture is stirred 10min.By removing soluble material (excessive Zn and Cu complex/salt) through Celite pad, described Celite pad washs with EtOAc (200mL * 2).With filtrate and the 1NNH that merges 4Cl (0.8L) aqueous solution stirs 30min down at 20 ℃, and use 3N NaOH aqueous solution (～480mL) water layer (pH=5-6) is adjusted to pH=9-10, form the brown precipitate of significant quantity simultaneously.Filter the removal precipitation by paper, and wash with deionized water (100mL).The water that separates extracts with EtOAc (1L), the saturated NH of the organic facies of merging 4Cl (0.8L * 2) aqueous solution is handled, and stirs 15min (repeating again), uses 5%NaHSO 3(500mL) aqueous solution and saline (1L) washing, and use MgSO 4Dry.Organic solvent the cleaning vacuum (house vacuum) (～120mmHg) under, then under fine vacuum (12mmHg), concentrate down at 66 ℃, so that 80.1g (89% isolated yield) oily crude compound 1c to be provided (88% purity under 254nm, 86% purity under 230nm; HPLC area %.Retention time=2.39min), it uses in next step and need not to be further purified.
B.1-benzyl-4-(1-(uncle-butoxy carbonyl) azetidine-3-yl) pyridine-1-
Figure BDA00003384930000321
Bromide, 1e.Thermocouple, magnetic stirring apparatus, condenser and N be equipped with 2Pack in 2 liter of 4 neck round-bottomed flask of inlet adapter crude compound 1c (78.22g, 290.5mmol) and acetonitrile (503mL).Under 20 ℃, stir the mixture, and adding benzyl bromide a-bromotoluene 1d (36.41mL, 299.2mmol).Mixture is warming up to 80 ℃, and stirs 1h.Reaction is cooled to 20 ℃, and solvent concentrates down at 60 ℃ under vacuum cleaning/fine vacuum.The gained material washs (chased) once with MeOH (100mL), so that 128.9g to be provided (109% isolated yield; 80-84% purity; HPLC area %.The syrupy shape crude product 1e of HPLC retention time=3.61min), it uses in next step and need not to be further purified.
C.3-(1-benzyl-1,2,3,6-tetrahydropyridine-4-yl) azetidine-1-carboxylic acid uncle-butyl ester, 1f.Thermocouple, magnetic stirring apparatus, condenser and N be equipped with 2Pack in 3 liter of 4 neck round-bottomed flask of inlet adapter crude compound 1e (117.73g, 232.4mmol) and EtOH (1.04L).Solution under agitation is cooled to 0 ℃; (17.8g 464.7mmol), and with mixture stirring 10min under 0 ℃, is warming up to 20 ℃ then gradually, and stirs 1h to add sodium borohydride.Mixture is cooled to 0 ℃, uses half saturated NaHCO 3(100mL is by adding the saturated NaHCO of 50mL with the 50mL deionized water 3And prepare) cancellation.Organic solvent is concentrated into moistening solid under 60 ℃ under the cleaning vacuum, described moistening solid is dissolved among the EtOAc (1.5L), with half saturated NaHCO 3(1L) stir 10min together.After being separated, using 3N NaOH aqueous solution that emulsus water layer (pH=6-7) is adjusted to pH=10-11, and extract with EtOAc (500mL).The organic facies that merges is washed with saline (500mL), under vacuum cleaning/fine vacuum, concentrate down at 60 ℃ then, so that 98.7g syrupy shape crude product 1f to be provided, it uses flash column chromatography (silica gel, the purification of EtOAc/ heptane/MeOH20/80/0-50/50/3), so that 67.11g to be provided (91% isolated yield, 95% purity under 210nm; HPLC area %) yellow syrupy shape chemical compound 1f.
D.3-(piperidin-4-yl) azetidine-1-carboxylic acid tert-butyl ester, 1g.In 500-mL Parr pressure bottle, pack into chemical compound 1f (18.4g, 54.3mmol), EtOH (152mL) and Pd (OH) 2 (1.91g).Mixture N 2Purge 2 times, then under 20 ℃ at 50psi H 2Shake under the atmosphere.Behind the 40h, remove H 2, and with additional Pd (OH) 2(1.9g) add in the mixture of 1f, dihydro-1f and 1g, it uses N 2Purge 2 times, and under 20 ℃ at 50psi H 2Shake 56h under the atmosphere again.Remove catalyst by filtering through Celite pad, described Celite pad washs (50mL * 3) with MeOH.Fine vacuum (～provide 13.4g (103% isolated yield, 97% purity under 210nm, HPLC area %) faint yellow viscous crude shape pure compound 1g the concentrated of 50 ℃ of following filtrates under 10mmHg), it passes through 1H-NMR analyzes the EtOH residue that contains trace.
E.3-(1-(thiazole-2-carbonyl) piperidin-4-yl) azetidine-1-carboxylic acid uncle-butyl ester, 1i.To chemical compound 1g (14.3mmol, 3.44g) and thiazole-2-carboxylic acid 1h (15.7mmol is 2.03g) at 50mLCH 2Cl 2In agitating solution in add Et 3N (42.9mmol, 5.98mL).Behind 20 ℃ of following 20min, adding HATU (17.2mmol, 6.53g), and with mixture stirring 5h under 20 ℃.Water is added in the mixture, and separate organic layer, use MgSO 4Drying, and concentrate.Residue uses flash column chromatography (silica gel, 30-70%EtOAc/ heptane) purification, to obtain 3.8g (75% productive rate) chemical compound 1i.MS?m/z374.2(M+Na +)，296.1(M+H-C 4H 8)，252.1(M+H-C 5H 8O 2)。
F. (4-(azetidine-3-yl) piperidines-1-yl) (thiazol-2-yl) ketone, 1j.A part of TFA (20mL) is added chemical compound 1i, and (10.8mmol is 3.8g) at 100mL CH 2Cl 2In solution in.Solution is stirred 5h down at 20 ℃.Vacuum is removed solvent, at CH 2Cl 2And distribute residue between the 1N NaOH aqueous solution.Organic layer MgSO 4Dry and concentrate, obtaining 2.6g (85% productive rate) chemical compound 1j, it uses in next reaction and need not purification.MS?m/z252.1(M+H +)。
G.4-(1-{[3-chloro-6-(trifluoromethyl)-1-benzothiophene-2-yl] carbonyl } azetidine-3-yl)-1-(1,3-thiazoles-2-base carbonyl) piperidines, Cpd29.(1.59mmol, 0.40g) (1.75mmol is 0.49g) at 10mL CH with 3-chloro-6-(trifluoromethyl) benzo [b] thiophene-2-carboxylic acid 1k to chemical compound 1j 2Cl 2In agitating solution in add Et 3N (6.37mmol, 0.89mL).Behind 20 ℃ of following 20min, adding HATU (1.91mmol, 0.73g), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 210mg (26% productive rate) Cpd29. 1H?NMR(CD 3OD，400MHz)：δ＝8.40(s，1H)，8.08(d，J＝8.6Hz，1H)，7.93(br.s.，1H)，7.75-7.85(m，2H)，5.31(t，J＝10.8Hz，1H)，4.63(t，J＝11.0Hz，1H)，4.37(t，J＝8.2Hz，1H)，4.28(t，J＝9.3Hz，1H)，4.10(br.s.，1H)，4.00(br.s.，1H)，3.15-3.29(m，1H)，2.82-3.00(m，1H)，2.47-2.63(m，1H)，1.67-2.02(m，3H)，1.05-1.34(m，2H)。MS?m/z514.0(M+H +)。
According on regard to example 1 described operation, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000341
Figure BDA00003384930000351
Example 2
Figure BDA00003384930000352
A.3-chloro-6-fluorobenzene [b] thiophene-2-carbonyl chlorine also, 2b.With thionyl chloride (73.7mmol, 5.36mL) add 4-fluoro cinnamic acid 2a (21.1mmol, 3.5g) and pyridine (2.53mmol is in mixture 0.2mL).Mixture is heated 30min down at 135 ℃, be cooled to room temperature then.Crude mixture grinds with hot hexane, to remove solid pyridine hydrochloride by-product.Separating compound 2b from the hexane solution that merges.
B.4-{1-[(3-carbonyl chloro-6-fluoro-1-benzothiophene-2-yl)] azetidine-3-yl }-1-(1,3-thiazoles-2-base carbonyl) piperidines, Cpd8.(0.45mmol is 112mg) at 4mL CH with chemical compound 2b under 0 ℃ 2Cl 2In solution add chemical compound 1j list-tfa salt (0.41mmol be 150mg) at Et 3(2.46mmol is 0.34mL) in the solution in for N.The gained reactant mixture is stirred 3h down at 0 ℃.Crude product is by preparation reversed phase chromatography purification, so that 18mg (9% productive rate) to be provided Cpd8. 1H?NMR(CD 3OD，400MHz)：δ＝7.88-7.97(m，2H)，7.81(d，J＝2.9Hz，1H)，7.76(dd，J＝8.8，2.2Hz，1H)，7.36(td，J＝9.0，2.3Hz，1H)，5.22-5.37(m，1H)，4.55-4.70(m，1H)，4.32-4.44(m，1H)，4.23-4.32(m，1H)，4.11(br.s.，1H)，3.91-4.05(m，1H)，3.15-3.28(m，1H)，2.84-3.00(m，1H)，2.48-2.62(m，1H)，1.70-2.02(m，3H)，1.10-1.29(m，2H)。MS?m/z464.1(M+H +)。
According on regard to example 2 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000361
Example 3
Figure BDA00003384930000362
A.3-methyl-6-(trifluoromethyl) benzo [b] thiophene-2-carboxylic acid ester, 3c.(30.3mmol, (60% oil dispersion, 75.8mmol is 3.03g) in the suspension in 10mL THF and 50mL DMSO 2.76mL) to drop to NaH with methyl thioglycolate 3b under 20 ℃.Mixture is stirred 15min, and (24.3mmol is 5.0g) in the solution in 10mLDMSO to add 1-(2-fluoro-4-(trifluoromethyl) phenyl) ethyl ketone 3a.Reactant mixture is stirred 4h down at 20 ℃, and add water.Mixture extracts with EtOAc.Organic layer MgSO 4Dry and concentrated, to obtain white solid chemical compound 3c.
B.4-(1-{[3-methyl-6-(trifluoromethyl)-1-benzothiophene-2-yl] carbonyl } azetidine-3-yl)-1-(1,3-thiazoles-2-base carbonyl) piperidines, Cpd20.(0.27mmol, 100mg) (0.30mmol is 78mg) at 4mL CH with chemical compound 3c to chemical compound 1j list-tfa salt 2Cl 2In agitating solution in add Et 3N (1.09mmol, 0.15mL).Behind 20 ℃ of following 20min, adding HATU (0.33mmol, 125mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 34mg (25% productive rate) Cpd20. 1HNMR(CD 3OD，400MHz)：δ＝8.29(s，1H)，8.04(d，J＝8.6Hz，1H)，7.93(br.s.，1H)，7.81(d，J＝3.2Hz，1H)，7.71(d，J＝8.3Hz，1H)，5.31(br.s.，1H)，4.564.69(m，1H)，4.324.42(m，1H)，4.26(t，J＝9.2Hz，1H)，4.09(br.s.，1H)，3.98(br.s.，1H)，3.23(br.s.，1H)，2.92(br.s.，1H)，2.61(s，3H)，2.472.59(m，1H)，1.702.00(m，3H)，1.031.35(m，J＝9.3Hz，2H)。MS?m/z494.1(M+H+)。
According on regard to example 3 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000363
Figure BDA00003384930000371
Example 4
Figure BDA00003384930000372
A.3 '-(trifluoromethyl)-[1,1 '-xenyl]-the 4-carboxylic acid, 4c.With a part of Pd (dppf) Cl 2(1.49mmol, 1.09g) add 4-bromobenzoic acid 4a (14.9mmol, 3.0g), 3-trifluoromethyl boric acid 4b (17.9mmol, 3.4g) and Cs 2CO 3(37.3mmol is 12.2g) in the suspension in 30mL dioxane and 7.5mL EtOH.Mixture is stirred 2h down at 80 ℃.After the cooling, solid by filtration is collected and is washed with MeOH.Filtrate is concentrated, and between EtOAc and 1NHCl aqueous solution, distribute.MgSO is used in organic layer salt water washing 4Drying, and concentrate.With CH 2Cl 2Add in the residue, the gained solid by filtration is collected, and uses CH 2Cl 2Washing, and dry, and to obtain 3.58g (86% productive rate) chemical compound 4c, it uses in next step and need not to be further purified.
B.1-(1,3-thiazoles-2-base carbonyl)-4-(1-{[3 '-(trifluoromethyl) xenyl-4-yl] carbonyl } azetidine-3-yl) piperidines, Cpd16.(0.27mmol, 100mg) (0.30mmol is 80mg) at 4mL CH with chemical compound 4c to chemical compound 1j list-tfa salt 2Cl 2In agitating solution in add Et3N (1.09mmol, 0.15mL).Behind 20 ℃ of following 20min, adding HATU (0.33mmol, 125mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 57mg (42% productive rate) Cpd16. 1H?NMR(CD 3OD，400MHz)：δ＝7.93(br.s.，3H)，7.73-7.83(m，5H)，7.63-7.73(m，2H)，5.24-5.38(m，1H)，4.64(t，J＝10.8Hz，1H)，4.46(t，J＝8.2Hz，1H)，4.13-4.31(m，2H)，3.90-4.01(m，1H)，3.15-3.29(m，1H)，2.84-2.99(m，1H)，2.44-2.60(m，1H)，1.73-2.00(m，3H)，1.08-1.32(m，2H)。MS?m/z500.3(M+H +)。
According on regard to example 4 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000381
According on regard to example 4 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000391
Figure BDA00003384930000401
Example 5
A.4-(3-(trifluoromethyl) benzyl) essence of Niobe, 5b.With a part of Pd (dppf) Cl 2(0.87mmol, 0.64g) add 4-(bromomethyl) essence of Niobe 5a (8.73mmol, 2.0g), 3-trifluoromethyl boric acid 4b (10.5mmol, 1.99g) and Na 2CO 3(17.5mmol is 1.85g) in the suspension in 20mL dioxane and 5mL water.Mixture is stirred 3h down at 80 ℃.After the cooling, solid by filtration is collected, and washs with EtOAc.Filtrate is used MgSO with 1N HCl aqueous solution and salt water washing 4Drying, and concentrate.Crude product by flash column chromatography (silica gel, 0-10%EtOAc: purification heptane), to obtain 2.2g (85% productive rate) chemical compound 5b.MS?m/z295.2(M+H +)。
B.4-(3-(trifluoromethyl) benzyl) benzoic acid, 5c.(12.9mmol, (6.46mmol is 1.9g) in the suspension in 75mL EtOH 12.9mL) to add chemical compound 5b with 1N NaOH aqueous solution.Mixture is stirred 20h down at 20 ℃.Reactant mixture is concentrated, and residue 1N HCl acidified aqueous solution.The gained solid by filtration is collected and is dry, and so that 1.6g (87%) chemical compound 5c to be provided, it uses in next reaction and need not to be further purified.MS?m/z281.1(M+H +)。
C.1-(1,3-thiazoles-2-base carbonyl)-4-[1-(4-[3-(trifluoromethyl) benzyl] and phenyl } carbonyl) azetidine-3-yl] piperidines, Cpd19.(0.27mmol, 100mg) (0.30mmol is 84mg) at 4mL CH with chemical compound 5c to chemical compound 1j list-tfa salt 2Cl 2In agitating solution in add Et 3N (1.09mmol, 0.15mL).Behind 20 ℃ of following 20min, adding HATU (0.33mmol, 125mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 46mg (33% productive rate) Cpd19. 1H?NMR(CD 3OD，400MHz)：δ＝7.92(br.s.，1H)，7.79(d，J＝3.2Hz，1H)，7.57-7.64(m，J＝8.1Hz，2H)，7.43-7.53(m，4H)，7.28-7.36(m，J＝8.1Hz，2H)，5.29(t，J＝10.0Hz，1H)，4.61(t，J＝10.9Hz，1H)，4.38(t，J＝8.6Hz，1H)，4.20(t，J＝9.3Hz，1H)，4.10(s，2H)，4.07-4.15(m，1H)，3.85-3.96(m，1H)，3.10-3.27(m，1H)，2.78-2.96(m，1H)，2.36-2.53(m，1H)，1.66-1.93(m，3H)，1.03-1.29(m，2H)。MS?m/z514.2(M+H +)。
According on regard to example 5 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000411
According on regard to example 5 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000412
Figure BDA00003384930000421
Example 6
Figure BDA00003384930000431
A.2-phenyl benzo [d] Azoles-6-carboxylic acid, 6c.(29.9mmol is 5.0g) with benzaldehyde 6b (29.9mmol, 3.02mL) the solution stirring 3h in 150mLMeOH with 4-amino-3-hydroxy methyl formate 6a under 20 ℃.Vacuum is removed solvent, and residue and 150mL acetonitrile are mixed together.Disposable adding lead acetate (IV) (29.9mmol, 13.3g), mixture backflow 20min.After the cooling, precipitation is removed and is washed with acetonitrile by filtering.(120mmol 40mL) stirs 20h down at 50 ℃ together for filtrate and wash solution and 3N NaOH aqueous solution.After the cooling, acidify and filter reaction mixture are to obtain 6.0g (79%) chemical compound 6c.MSm/z240.0(M+H+)。
B.2-phenyl-6-({ 3-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] azetidine-1-yl } carbonyl)-1, the 3-benzo Azoles, Cpd 28.(0.40mmol, 100mg) (0.44mmol is 100mg) at 4mL CH with chemical compound 6c to chemical compound 1j 2Cl 2In agitating solution in add Et 3N (1.59mmol, 0.22mL).Behind 20 ℃ of following 20min, adding HATU (0.48mmol, 180mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 75mg (39% productive rate) Cpd28. 1H?NMR(CD 3OD，400MHz)：δ＝8.23-8.32(m，2H)，8.01(s，1H)，7.89-7.97(m，1H)，7.77-7.85(m，2H)，7.73(dd，J＝8.3，1.2Hz，1H)，7.54-7.68(m，3H)，5.30(t，J＝11.0Hz，1H)，4.64(t，J＝12.0Hz，1H)，4.43-4.54(m，1H)，4.18-4.34(m，2H)，3.92-4.05(m，1H)，3.16-3.29(m，1H)，2.84-2.99(m，1H)，2.47-2.60(m，1H)，1.72-2.02(m，3H)，1.10-1.34(m，2H)。MS?m/z473.1(M+H +)。
According on regard to example 6 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000434
Figure BDA00003384930000441
Example 7
Figure BDA00003384930000442
A.1-(4-fluorophenyl)-indole-5-carboxylic acid's methyl ester, 7c.With indole-5-carboxylic acid's methyl ester 7a (0.5g, 2.85mmol), 1-bromo-4-fluoro-benzene 7b (2mL, 18.21mmol), CuI (0.544g, 2.85mmol) and K 2CO 3(0.591g, mixture 4.28mmol) heat 2.5h in microwave reactor under 220 ℃.With reactant mixture CH 2Cl 2Dilution is also filtered.With solution concentration, and residue is by flash column chromatography (silica gel, 15%EtOAc/ heptane) purification, to obtain 0.58g chemical compound 7c.MS?m/z270.1(M+H +)。
B.1-(4-fluorophenyl)-indole-5-carboxylic acid, 7d.With 1-(4-fluorophenyl)-indole-5-carboxylic acid's methyl ester 7c (0.58g, 2.15mmol) and LiOHH 2(0.36g is 8.6mmol) at THF (15mL) and H for O 2Mixture among the O (10mL) at room temperature stirred 5 days.The 10%HCl aqueous solution is added in this reactant mixture to regulate pH=3～4.The gained mixture extracts with EtOAc (2x).Organic solution is washed with NaCl, uses Na 2SO 4Drying, and concentrate, to obtain 0.5g chemical compound 7d.MS?m/z256.2(M+H +)。
C.1-(4-fluorophenyl)-5-({ 3-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] azetidine-1-yl } carbonyl)-1H-indole, Cpd 30.(0.40mmol, 100mg) (0.44mmol is 110mg) at 4mL CH with chemical compound 7d to chemical compound 1j 2Cl 2In agitating solution in add Et 3N (1.59mmol, 0.22mL).Behind 20 ℃ of following 20min, adding HATU (0.48mmol, 180mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 165mg (85% productive rate) Cpd30. 1H?NMR(CD 3OD，400MHz)：δ＝7.99(s，1H)，7.92(br.s.，1H)，7.79(d，J＝3.2Hz，1H)，7.44-7.58(m，5H)，7.30(t，J＝8.7Hz，2H)，6.77(d，J＝3.4Hz，1H)，5.28(br.s.，1H)，4.53-4.69(m，1H)，4.39-4.51(m，1H)，4.10-4.29(m，2H)，3.95(br.s.，1H)，3.10-3.27(m，1H)，2.89(t，J＝10.5Hz，1H)，2.33-2.56(m，1H)，1.65-1.98(m，J＝10.8Hz，3H)，1.19(br.s.，2H)。MS?m/z489.1(M+H+)。
According on regard to example 7 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000451
According on regard to example 7 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000452
Figure BDA00003384930000461
Example 8
Figure BDA00003384930000471
A.1-(3,4-difluorophenyl)-indole-5-carboxylic acid's methyl ester, 8b.With indole-5-carboxylic acid's methyl ester 7a (2g, 11.4mmol), 1-iodo-3,4-two fluoro-benzene 8a (1.5mL, 12.5mmol), CuI (0.22g, 1.14mmol), trans-N, N '-dimethyl-1, the 2-cyclohexanediamine (0.54mL, 3.43mmol) and K 3PO 4(6.06g, 28.5mmol) mixture in toluene (12mL) heats 7h down at 110 ℃.With reactant mixture CH 2Cl 2Dilution is also filtered.With solution concentration, and residue is by flash column chromatography (silica gel, 20%EtOAc/ heptane) purification, to obtain 3.0g chemical compound 8b.MS?m/z288.1(M+H+)。
B.1-(3,4-difluorophenyl)-indole-5-carboxylic acid, 8c.With 1-(3,4-difluorophenyl)-indole-5-carboxylic acid's methyl ester 8b (3.0g, 10.4mmol) and LiOH (1.0g is 41.8mmol) at THF (120mL) and H 2Mixture among the O (60mL) at room temperature stirred 5 days.The 10%HCl aqueous solution is added in this reactant mixture to regulate pH=3～4.The gained mixture extracts with EtOAc (2x).Na is used in organic solution salt water washing 2SO 4Dry and concentrated, to obtain 2.85g chemical compound 8c.MS?m/z274.2(M+H +)。
C.1-(3,4-difluorophenyl)-5-({ 3-[4-(1,3-thiazoles-2-base carbonyl) piperazine-1-yl] azetidine-1-yl } carbonyl)-1H-indole, Cpd32.(0.40mmol, 100mg) (0.44mmol is 120mg) at 4mL CH with chemical compound 8c to chemical compound 1j 2Cl 2In agitating solution in add Et 3N (1.59mmol, 0.22mL).Behind 20 ℃ of following 20min, adding HATU (0.48mmol, 180mg), and with mixture stirring 20h under 20 ℃.Remove solvent, and rough residue is by preparation reversed phase chromatography purification, to obtain 118mg (58% productive rate) Cpd32. 1H?NMR(CD 3OD，400MHz)：δ＝8.00(s，1H)，7.93(br.s.，1H)，7.81(d，J＝2.9Hz，1H)，7.51-7.60(m，4H)，7.44-7.52(m，1H)，7.33-7.42(m，1H)，6.79(d，J＝3.2Hz，1H)，5.22-5.38(m，1H)，4.55-4.71(m，1H)，4.48(t，J＝8.8Hz，1H)，4.14-4.33(m，2H)，3.89-4.04(m，1H)，3.14-3.28(m，1H)，2.83-2.99(m，1H)，2.43-2.58(m，1H)，1.70-2.00(m，3H)，1.09-1.32(m，2H)。MS?m/z507.1(M+H +)。
According on regard to example 8 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000491
According on regard to example 8 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000492
Figure BDA00003384930000501
Example 9
Figure BDA00003384930000502
A.4-((4-fluorophenyl) amino)-3-nitrobenzoic acid methyl ester, 9c.With 4-fluoro-3-nitrobenzoic acid methyl ester 9a (1g, 5.02mmol), 4-fluoroaniline 9b (4.34mL, 5.02mmol) and DIPEA (1.04mL, 6.03mmol) mixture in DMF (10mL) at room temperature stirs 2h.Water is added in the mixture, and the gained solid by filtration is collected, wash with water, and dry.Crude compound 9c uses in next reaction and need not to be further purified.
B.3-amino-4-((4-fluorophenyl) amino) essence of Niobe, 9d.With chemical compound 9c (1.4g, 4.8mmol) and SnCl 2.2H 2(4.9g, 21.7mmol) mixture in EtOH (50mL) stirs down at 80 ℃ O.Behind the 4h, mixture is cooled to room temperature, and slowly adds saturated NaHCO 3In the aqueous solution.Solid by filtration is collected, and uses H 2The O washing.Solid grinds with EtOAc, and filtrate is concentrated.Crude compound 9d uses in next reaction and need not to be further purified.MS?m/z261.1(M+H +)。
C.1-(4-fluorophenyl)-1H-benzo [d] imidazole-5-carboxylic acid methyl ester, 9e.With chemical compound 9d (0.18g, 0.693mmol) and trimethyl orthoformate (0.7mL, 6.39mmol) the mixture backflow 5h in DMF (2mL) is cooled to room temperature then.Water is added in the mixture.The gained solid by filtration is collected, washes with water, and dry.Crude compound 9e uses in next reaction and need not to be further purified.MS?m/z271.1(M+H +)。
D.1-(4-fluorophenyl)-1H-benzo [d] imidazole-5-carboxylic acid, 9f.To chemical compound 9e (0.18g, 0.666mmol) add in the solution in EtOH (10mL) 1N NaOH aqueous solution (2.5mL, 2.5mmol).Mixture was at room temperature stirred 4 days.Evaporating solvent, and add 1N HCl aqueous solution, extract with EtOAc subsequently.Organic layer MgSO 4Dry and concentrated.Crude compound 9f is by preparation reversed phase chromatography purification.MS?m/z257.1(M+H +)。
E.1-(4-fluorophenyl)-5-({ 3-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] azetidine-1-yl } carbonyl)-1H-benzimidazole, Cpd 81.To chemical compound 1j (0.058g, 0.178mmol) and HATU (0.081g is 0.214mmol) at 3mL CH 2Cl 2In solution in add Et 3N (0.099mL, 0.713mmol).Mixture is stirred down 30min at 20 ℃, add then chemical compound 9f (0.050g, 0.196mmol).Reactant mixture is stirred 20h down at 20 ℃.Add water (6mL) and extract this mixture with EtOAc.Organic layer MgSO 4Dry and concentrated.Crude product is by preparation reversed phase chromatography purification, to obtain 46mg (47% productive rate) Cpd81. 1H?NMR(CD 3OD)δ＝8.14(s，1H)，7.93(br.s.，1H)，7.78-7.84(m，2H)，7.67-7.78(m，3H)，7.45(t，J＝8.7Hz，2H)，5.23-5.38(m，1H)，4.57-4.71(m，1H)，4.44-4.54(m，1H)，4.29(t，J＝9.7Hz，1H)，4.22(br.s.，1H)，4.00(br.s.，1H)，3.17-3.27(m，1H)，2.85-2.99(m，1H)，2.48-2.61(m，1H)，1.70-2.02(m，3H)，1.09-1.34(m，2H)MS?m/z490.2(M+H +)。
According on regard to example 9 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
According on regard to example 9 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Figure BDA00003384930000522
Example 10
Figure BDA00003384930000531
A.2-methyl isophthalic acid-(4-fluorophenyl)-1H-benzo [d] imidazole-5-carboxylic acid methyl ester, 10a.Method described in the use-case 9, and the trimethyl orthoformate among the step C replaced with trimethyl orthoacetate and prepare title compound 10a.Crude compound 10a uses in next reaction and need not to be further purified.MS?m/z285.1(M+H +)。
B.2-methyl isophthalic acid-(4-fluorophenyl)-1H-benzo [d] imidazole-5-carboxylic acid ester, 10b.Method described in the use-case 9, and the chemical compound 9e among the step D replaced with chemical compound 10a and prepare title compound 10b.Crude product 10b uses in next reaction and need not to be further purified.MS?m/z271.2(M+H +)。
C.1-(4-fluorophenyl)-2-methyl-5-({ 3-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] azetidine-1-yl } carbonyl)-1H-benzimidazole, Cpd87.Method described in the use-case 9, and the chemical compound 9f in the step e replaced with chemical compound 10b and prepare title compound Cpd87.Crude product is by preparation reversed phase chromatography purification, to obtain 23mg (50% productive rate) Cpd87. 1H?NMR(CD 3OD)δ8.08(s，1H)，7.93(br.s.，1H)，7.76-7.84(m，2H)，7.68(dd，J＝8.7，4.5Hz，2H)，7.50(t，J＝8.6Hz，2H)，7.43(d，J＝8.8Hz，1H)，5.31(br.s.，1H)，4.64(t，J＝13.0Hz，1H)，4.45(t，J＝8.4Hz，1H)，4.29(t，J＝9.7Hz，1H)，4.15-4.24(m，1H)，4.00(br.s.，1H)，3.17-3.27(m，1H)，2.83-2.99(m，1H)，2.71(s，3H)，2.55(q，J＝7.7Hz，1H)，1.74-2.00(m，3H)，1.15-1.31(m，2H)。MS?m/z504.0(M+H +)。
According on regard to example 10 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000541
, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention at example 10 described programs according to top:
Example 11
Figure BDA00003384930000551
A.1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-carboxylic acid methyl ester, 11a.With chemical compound 9d (0.20g, 0.826mmol) and 1,1 '-(0.535g, 3.3mmol) mixture in DMF (8mL) is at 90 ℃ of heating 2h down for carbonyl dimidazoles.Remove solvent and residue water (15mL) is ground.Filter and collect the gained precipitation, and wash with water for several times.Crude product 11a uses in next reaction and need not to be further purified.MS?m/z287.1(M+H +)。
B.1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-carboxylic acid ester, 11b.Method described in the use-case 9 replaces with the chemical compound 9e among the step D chemical compound 11a and prepares title compound 11b.Crude product 11b uses in next reaction and need not to be further purified.MS?m/z273.1(M+H +)。
C.1-(4-fluorophenyl)-5-({ 3-[1-(1,3-thiazoles-2-base carbonyl) piperidin-4-yl] azetidine-1-yl } carbonyl)-1,3-dihydro-2H-benzimidazolyl-2 radicals-ketone, Cpd97.Method described in the use-case 9 replaces with the chemical compound 9f in the step e chemical compound 11b and prepares title compound Cpd97.Crude product is by preparation reversed phase chromatography purification, to obtain 51mg (32% productive rate) Cpd97. 1H?NMR(CD 3OD)δ＝7.93(br.s.，1H)，7.81(d，J＝3.2Hz，1H)，7.51-7.59(m，2H)，7.45(s，1H)，7.41(dd，J＝8.3，1.2Hz，1H)，7.33(t，J＝8.7Hz，2H)，7.04(d，J＝8.1Hz，1H)，5.30(br.s.，1H)，4.56-4.69(m，1H)，4.40-4.51(m，1H)，4.21-4.29(m，1H)，4.18(br.s.，1H)，3.95(br.s.，1H)，3.1?5-3.27(m，1H)，2.83-2.99(m，1H)，2.43-2.58(m，1H)，1.71-2.00(m，3H)，1.22(br.s.，2H)。MS?m/z506.1(M+H +)。
According on regard to example 11 described operations, and replace suitable reagent, raw material and the following midbody compound of purification process well known by persons skilled in the art preparation:
Figure BDA00003384930000561
According on regard to example 11 described operations, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention:
Example 12
A.3-(pyridin-4-yl) azetidine, 12a.Chemical compound 1c is dissolved in the mixture of 3N HCl aqueous solution and THF and stirs, until chemical compound 1c full consumption.With the mixture concentrating under reduced pressure, and with the aqueous residue lyophilizing, to obtain the chemical compound 12a of dihydrochloride form, it uses in next step and need not to be further purified.
B.[1,1 '-xenyl]-4-base-(3-(pyridin-4-yl) azetidine-1-yl) ketone, 12c.With chemical compound 12a (4.5mmol, 928mg), [1,1 '-xenyl]-4-carboxylic acid 12b (4.95mmol, 980mg), HBTU (6.43mmol, 2.44g) and DIEA (20.2mmol 3.49mL) mixes in DMF, and stirs 20h down at 20 ℃.Crude reaction mixture is by preparation reversed-phase HPLC purification, to obtain chemical compound 12c. 1H?NMR(CD 3OD，400MHz)：δ＝8.68(d，J＝6.6Hz，2H)，7.92(d，J＝6.8Hz，2H)，7.68-7.77(m，2H)，7.60-7.68(m，2H)，7.57(dd，J＝8.3，1.2Hz，2H)，7.38(t，J＝7.5Hz，2H)，7.23-7.34(m，1H)，4.56-4.68(m，1H)，4.43-4.56(m，1H)，4.12-4.34(m，2H)。
C.[1,1 '-xenyl]-4-base-(3-(piperidin-4-yl) azetidine-1-yl) ketone, 12d.Chemical compound 12c and 10% carbon are carried palladium to be mixed in 1: 5 mixture of 1N HCl aqueous solution and ethanol in the Parr pressure bottle.Mixture N 2Purge, then under 20 ℃ at 55psi H 2Shake under the atmosphere.When reaction is finished, remove catalyst by filtering by Celite pad.Filtrate is concentrated, and lyophilizing provides the chemical compound 12d of hydrochloride form with quantitative yield.
D.4-[1-(xenyl-4-base carbonyl) azetidine-3-yl]-1-(1,3-thiazoles-2-base carbonyl) piperidines, Cpd2.With chemical compound 12d HCl salt (0.28mmol, 98mg), thiazole-2-carboxylic acid 1h (0.33mmol, 43mg) and HBTU (0.33mmol, 126mg) the solution stirring 10min in 2.5mL DMF.Adding DIEA (1.1mmol, 0.2mL), and with mixture stirring 20h under 20 ℃.Crude reaction mixture is by preparation reversed-phase HPLC purification, to obtain Cpd2. 1H?NMR(CD 3OD，400MHz)：δ＝7.84(br.s.，1H)，7.69-7.75(m，1H)，7.60-7.69(m，4H)，7.53-7.60(m，2H)，7.37(t，J＝7.5Hz，2H)，7.24-7.33(m，1H)，5.13-5.29(m，1H)，4.54(t，J＝11.6Hz，1H)，4.38(t，J＝8.7Hz，1H)，4.04-4.22(m，2H)，3.80-3.94(m，1H)，3.07-3.18(m，1H)，2.73-2.91(m，1H)，2.35-2.50(m，1H)，1.63-1.91(m，3H)，0.99-1.25(m，2H)。MS?m/z432.0(M+H +)。
, and replace suitable reagent, raw material and purification process well known by persons skilled in the art and prepare following chemical compound of the present invention at example 12 described programs according to top:
Figure BDA00003384930000581
Example 13
Figure BDA00003384930000591
A. (4-(1-dibenzo-p-methyl-aza-cyclobutane-3-yl)-4-hydroxy piperidine-1-yl) (phenyl) ketone, 13c.(1.4mmol, 490mg) solution in 5mL THF adds SmI with 1-benzhydryl-3-iodo azetidine 13a 2(0.1M THF solution, 3mmol is 30mL) and in the stirring the mixture of 1.7mL HMPA.Behind the 5min, add 1-benzoyl piperidin-4-one-13b (3.1mmol, 626mg) solution in 5mL THF.Reactant mixture is stirred 2h.Add saturated NH 4Cl aqueous solution (20mL) is with suspension filtration over celite pad.Solid washs with chloroform, and the salt water washing of the organic layer of merging is dry and concentrated.Rough residue is by preparation reversed phase chromatography purification, to obtain 400mg (55% productive rate) yellow oily chemical compound 13c (list-tfa salt).MS?m/z401.2(M+H +)。
B. (4-(azetidine-3-yl)-4-hydroxy piperidine-1-yl) (phenyl) ketone, 13d.(0.34mmol 180mg) carries palladium (40mg) with 10% carbon and mixes in 30mL ethanol in the Parr pressure bottle chemical compound 13c list-tfa salt.Mixture N 2Purge, then under 20 ℃ at 50psi H 2Shake 20h under the atmosphere.Remove catalyst by filtering through Celite pad, filtrate is concentrated.Add water, CH 2Cl 2With the HCl aqueous solution, with mixture freezes and lyophilizing, to obtain 82mg (81% productive rate) chemical compound 13d (list-HCl salt).MS?m/z261.1(M+H+)。
C.1-(phenylcarbonyl group)-4-(1-{[5-(trifluoromethyl)-1-benzothiophene-2-yl] carbonyl } azetidine-3-yl) piperidines-4-alcohol, Cpd6.With 5-(trifluoromethyl) benzo [b] thiophene-2-carboxylic acid 13e (0.30mmol, 75mg), DIEA (0.83mmol, 0.15mL) and HBTU (0.33mmol, 126mg) the solution stirring 10min in 2mL DMF.Adding chemical compound 13d (0.28mmol, HCl salt 82mg), and with mixture stirring 20h under 20 ℃.Use CH 3CN makes reactant mixture filter 3g silica gel carbonic ester and 3g aminopropyl silica gel as eluent.CH is removed in decompression 3CN, and residue is by preparation reversed-phase HPLC purification, to obtain 45mg (33% productive rate) Cpd6. 1H?NMR(CD 3OD，400MHz)：δ＝8.13-8.24(m，1H)，8.04(d，J＝8.6Hz，1H)，7.82-7.90(m，1H)，7.60(d，J＝8.6Hz，1H)，7.27-7.42(m，5H)，4.44-4.59(m，2H)，4.25-4.39(m，J＝15.0，2.8Hz，1H)，3.98-4.19(m，2H)，3.42-3.54(m，1H)，3.32-3.42(m，1H)，2.79(quin，J＝7.4Hz，1H)，1.57-1.69(m，1H)，1.31-1.56(m，3H)。MS?m/z489.1(M+H +)。
Example 14
Figure BDA00003384930000601
A.4-(1-dibenzo-p-methyl-aza-cyclobutane-3-yl)-4-hydroxy piperidine-1-carboxylic acid tert-butyl ester, 14b.(4.75mmol, 1.66g) solution in 10mL THF adds SmI with 1-benzhydryl-3-iodo azetidine 13a 2(0.1M THF solution, 9.98mmol is 99.8mL) and in the stirring the mixture of 5.6mL HMPA.Behind the 15min, add 4-oxo-piperidine-1-carboxylic acid tert-butyl ester 14a (4.75mmol, 0.95g) solution in 15mL THF.Reactant mixture is stirred 18h.Add saturated NH 4Cl aqueous solution (40mL) is with suspension filtration over celite pad.Solid washs with chloroform, and the salt water washing of the organic layer of merging is dry and concentrated.Rough residue is by preparation reversed phase chromatography purification, with the chemical compound 14b of 90% purity that obtains the transparent oily of 1.0g (45% productive rate).MS?m/z423.3(M+H +)。
B.4-(1-dibenzo-p-methyl-aza-cyclobutane-3-yl) piperidines-4-alcohol, 14c.According to the described operation of step F in the example 1, and replace chemical compound 1i and prepare chemical compound 14c with chemical compound 14b.
C. (4-(1-dibenzo-p-methyl-aza-cyclobutane-3-yl)-4-hydroxy piperidine-1-yl) (thiazol-2-yl) ketone, 14d.With thiazole-2-carboxylic acid 1h (1.79mmol, 232mg), DIEA (6.53mmol, 1.12mL) and HBTU (1.96mmol, 742mg) the solution stirring 10min in 11mL DMF.Adding chemical compound 14c (1.63mmol, 526mg), and with mixture stirring 20h under 20 ℃.Reactant mixture is by preparation reversed-phase HPLC purification, to obtain 298mg (33% productive rate) yellow powder powder chemical compound 14d.MS?m/z434.2(M+H +)。
D.4 (4-(azetidine-3-yl)-4-hydroxy piperidine-1-yl) (thiazol-2-yl) ketone, 14e.(7.06mmol 0.76mL) drops to chemical compound 14d at 20mL CH with 1-chloroethyl chloro-formate in ice-water bath 2Cl 2In solution.Behind the 30min, remove cooling bath, reactant mixture is stirred 2h down at 20 ℃.Evaporation CH 2Cl 2, add 20mL MeOH, gained solution backflow 2h.Evaporating solvent, residue is at CH 2Cl 2And distribute between the 0.2N HCl aqueous solution.With the water layer lyophilizing, to obtain chemical compound 14e, it carries out next step and need not purification.MS?m/z267.7(M+H +)。
E.1-(1,3-thiazoles-2-base carbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophene-2-yl] carbonyl } azetidine-3-yl) piperidines-4-alcohol, Cpd94.With 6-(trifluoromethyl) benzo [b] thiophene-2-carboxylic acid 14f (0.30mmol, 75mg), DIEA (0.98mmol, 0.17mL) and HBTU (0.30mmol, 112mg) the solution stirring 10min in 2mL DMF.Adding chemical compound 14e (0.25mmol, 66mg), and with mixture stirring 20h under 20 ℃.Reactant mixture is by preparation reversed-phase HPLC purification, to obtain 77mg (62% productive rate) white powder Cpd94. 1H?NMR(DMSO-d 6)：δ＝8.39(s，1H)，8.29(d，J＝8.6Hz，1H)，8.02-8.08(m，1H)，8.00(s，2H)，7.76(dd，J＝8.6，1.5Hz，1H)，4.99(d，J＝12.7Hz，1H)，4.46-4.56(m，2H)，4.25(d，J＝12.2Hz，1H)，4.06-4.15(m，1H)，3.97-4.06(m，1H)，3.17-3.27(m，2H)，2.74-2.86(m，J＝14.8，7.3，7.3Hz，1H)，1.36-1.66(m，4H)。MS?m/z496.1(M+H +)。
Biological example
In vitro method
Example 1
The MGL enzyme assay
All all carry out in cumulative volume is the black 384 hole polypropylene PCR microwell plates (Abgene) of 30 μ L based on the mensuration of ratio.With substrate butanoic acid 4-methyl umbelliferone (4MU-B; Sigma) and the wild type MGL (wt-MGLL 6H-11-313) of the saltant MGL of purification (mut-MGLL 11-313 L179S L186S) or purification be diluted to respectively in the 20mM PIPES buffer (pH=7.0), described buffer contains 150mM NaCl and 0.001%Tween 20.Adding 4MU-B (ultimate density of 1.2X solution to the 10 μ M of 25 μ L), add enzyme (the 6X solution of 5 μ L is to the ultimate density of 5nM) subsequently before, use Cartesian Hummingbird with the chemical compound predistribution (50nL) of formula (I) in assay plate with initiation reaction.Final compound concentration scope is 17 to 0.0003 μ M.Under 37 ℃, use respectively 335 and 440nm excite bandwidth (Safire with emission wavelength and 10nm 2, Tecan), monitoring is by the change in fluorescence 5min due to the 4MU-B cracking.
Use Excel, with formula and concentration-response curve match as the mark activity (fractional activity) of inhibitor concentration function, thereby determine the IC of the chemical compound of formula (I) 50Value.
Biological data table 1
Figure BDA00003384930000621
Figure BDA00003384930000631
Figure BDA00003384930000641
Example 2
2-AG accumulates mensuration
In order to measure by the 2-AG accumulation due to the MGL inhibition, (Brinkmann PT300) contains homogenize in the 20mM HEPES buffer (pH=7.4) of 125mM NaCl, 1mMEDTA, 5mM KCl and 20mM glucose with the 1g rat brain at 10mL to use the Polytron homogenizer.Chemical compound (10 μ M) and big rat brain tissue homogenate's thing (50mg) precincubation with formula (I).After 15 minutes, add CaCl at 37 ℃ of following incubations 2(final concentration=10mM), then with the cumulative volume of 5mL 37 ℃ of following incubations 15 minutes.Organic solvent extraction solution cessation reaction with 2: 1 chloroform/methanol of 6mL.According to following formula, measured the 2-AG that accumulates in the organic facies by the HPLC/MS method:
Solvent percentage ratio=(the 2-AG accumulation in the 2-AG accumulation/solvent when having chemical compound) * 100.
Biological data table 2
Figure BDA00003384930000661
Example 3
MGL
Figure BDA00003384930000662
Mensuration-saltant
ThermoFluor (TF) is determined as based on the combination of 384 orifice plates and measures, and can measure protein 1,2Heat stability.Use is available from (the Johnson﹠amp of pharmaceutical development company of Johnson ﹠ Johnson; Johnson Pharmaceutical Research﹠amp; Development, instrument LLC) is implemented this experiment.Used TF dyestuff is 1,8-ANS (Invitrogen:A-47) in all experiments.The final TF condition determination that is used for MGL research is saltant MGL, 100 μ MANS, 200mM NaCl, the 0.001%Tween-20 at 50mM PIPES (pH=7.0) 0.07mg/mL.
Screening comprises the chemical compound plate of the 100%DMSO compound solution of single concentration.For after concentration-response investigations, chemical compound is arranged in the preallocated plate (Greiner Bio-one:781280), wherein a series 11 the row in, with the chemical compound serial dilution in 100%DMSO.The 12nd and 24 row are as the DMSO object of reference, and inclusion compound not.For single and polyvoltine compound concentration-response experiment, all use the Hummingbird liquid processor with the directly automatic predistribution of chemical compound aliquot (46nL) to black 384 hole assay plate (Abgene:TF-0384/k).After chemical compound distributes, add protein and dye solution to obtain the final mensuration volume of 3 μ L.Cover described mensuration solution to avoid evaporating with 1 μ L silicone oil (Fluka, type DC 200:85411).
For all experiments, the assay plate that will compile bar code with automat is loaded on the hot piece of PCR-type of automatic temperature-control control, and the heating rate with 1 ℃/min is heated to 90 ℃ from 40 then.By using by using ultraviolet light (Hamamatsu LC6) Continuous irradiation to measure fluorescence, wherein ultraviolet light is provided by optical fiber and filters by band pass filter (380-400nm＞6OD ends).By use to filter detecting CCD camera (Sensys, the Roper Scientific) measured light intensity of 500+25nm, produce simultaneously and the reading in all 384 holes independently, detect the fluorescent emission of whole 384-orifice plate.Under every kind of temperature, collect the single image of 20 seconds time of exposure, and pixel intensity sum in the relative temperature record assay plate appointed area, and with the normalized form match with acquisition T M1
1.Pantoliano, M.W., Petrella, E.C., Kwasnoski, J.D., Lobanov, V.S., Myslik, J., Graf, E., Carver, T., Asel, E., Springer, B.A., Lane, P., and Salemme, F.R. (2001) J Biomol Screen6,429-40.
2.Matulis, D., Kranz, J.K., Salemme, F.R. and Todd, M.J. (2005) Biochemistry 44,5258-66.
By with formula with T mThe K of the chemical compound of formula (I) is determined in the concentration-response curve match of the mark activity that changes dValue.For some experiment, use quantitative NMR spectrographic method (qNMR) to measure the concentration of initial 100%DMSO compound solution, and use identical approximating method, determine qK dValue.
Biological data table 3
Figure BDA00003384930000681
Figure BDA00003384930000691
Figure BDA00003384930000701
Method in the body
Example 4
The claw radiant heat allergy that CFA induces
Every rat is placed test box on the warm glass surface, and make it adapt to about 10 minutes.Making radiant heat stimulate (light beam) to see through glass then focuses on the sole of the foot face of each rear solid end successively.When claw moves or arrive deadline (under about 5 amperes, radiation heating 20 seconds), close thermostimulation automatically by the photoelectricity condenser.At injection complete Freund's adjuvant (CFA) before, record each animal to initial (baseline) response incubation period of thermostimulation.In the sufficient sole of the foot injection CFA after 24 hours, then reevaluate animal to the response latency of heat stimulus, and itself and animal baseline response time compared.Only showing the rat that responds (being hyperpathia) the phase reduction at least 25% of hiding just is included in the further analysis.After CFA assesses incubation period, the test compounds of dosage forms for oral administration appointment immediately or solvent.With regular time at interval (be generally 30,60,120,180 and 300min) assessment back compound treatment shrink back incubation period.
Reverse percentage ratio (%R) by a kind of calculating hypersensitivity in following two kinds of different modes: the meansigma methods or 2 of 1) using group) use the individual animals value.More specifically:
Method 1: for all chemical compounds, according to following formula, use the meansigma methods of each time point animal group to calculate the %R of allergy:
% reverses=[(the CFA response of processing response-group of group)/(the CFA response of the baseline response-group of group)] * 100
The result who provides reverses at the observed maximum % in some place of any testing time for each chemical compound.
Method 2: for some chemical compounds, calculate the %R of the allergy of each animal respectively according to following formula:
% reverses=[(the CFA response of individual processing response-individuality)/(the CFA response of individual baseline response-individuality)] * 100.
The meansigma methods that the result who provides reverses for the maximum % that each individual zoometer is calculated.
Biological data table 4
Figure BDA00003384930000711
Example 5
The claw pressure allergy that CFA induces
Before test, can be in 2 day time every day make rat adapt to treatment process twice.Described test comprises: left back pawl is placed on the politef platform, and use tenderness the instrument ((Stoelting of Stoelting company in Chicago, Illinois, Chicago, IL) (be also referred to as the Randall-Selitto device), between the 3rd and the fourth metatarsal bone at the rear solid end back of rat, apply the linear mechanical force (constant speed is 12.5mmHg/s) that increases with dome base for post (radius is 0.7mm).When rear solid end is shunk back, terminal point can be reached, terminal point power (in gram) can be recorded.At injection complete Freund's adjuvant (CFA) before, can record each animal to initial (baseline) response lag of mechanical stimulus.The foot sole of the foot was penetrated behind the CFA 40 hours, and the animal of can reappraising is to the response lag of mechanical stimulus, and compared with the baseline response threshold value of animal.Response can be defined as that rear solid end is shunk back, rear solid end moves and is obstructed or shouts.The rat that only shows response lag (being hyperpathia) reduction at least 25% just can be included in the further analysis.After the CFA threshold value assessment of back, can use test compounds or the solvent of appointment immediately to rat.Can when 1h, assess the post processing threshold value of shrinking back.According to following formula, the threshold transition of claw can being shunk back is that the % of allergy reverses:
% reverses=[(handling back response-predose response)/(baseline response-predose response)] * 100.
Example 6
Neuropathic pain model-cold acetone that chronic constriction damage (CCI) is induced-allergy test
Can use male sprague-Dawley rat (225-450g) to assess the ability that selected chemical compound reverses the cold allergy that CCI-induces.The loose ligature of four 4-0 chromic catguts can be arranged on by surgical operation around the left sciatic nerve sucking under the anesthesia, (Bennett GJ, Xie YK.Pain 1988,33 (1): 87-107) as described in people such as Bennett.In CCI operation the last 14 to 35 days, the person under inspection can be placed in the rising inspection box that has the silk screen floor, and can use the multiple dose syringe that five times acetone application (0.05mL/ uses, about 5 minutes at interval) is sprayed on the sufficient sole of the foot surface of claw.Claw starts back or lifts and can be regarded as positive reaction.Can in five tests, record the positive reaction number of times of every rat.After determining that baseline is shunk back, can use the chemical compound of specifying in the solvent by formulation approach (referring to table 6).After the compound administration, can redefine and shrink back several 1 to 4h.The result can be expressed as the % that trembles and suppress, and it is to calculate with [1-(test compounds is shunk back before shrinking back/testing)] * 100 for each person under inspection, then number of processes is averaged.
Example 7
Spinal nerves ligation (SNL) model of neuropathic pain-tactile allodynia test
For the 5th waist (L5) spinal nerves ligation (SNL) research, can suck isoflurane and bring out and keeps anaesthetizing.Can clamp the fur on the pelvis area of back, and can be at L 4-S 2The skin incision that center line left side on the ridge joint back side cuts out 2cm separates paraspinal muscle then with spinous process.Can be with L 6Transverse process remove carefully, and can distinguish L 5Spinal nerves.Can be with the L in left side 5Spinal nerves is tightened with the 6-0 silk thread, can be with muscle with 4-0 little tall suture, and the closed skin of available suture clip.After operation, can use s.c. saline (5mL).
Can after ligation, carry out performance testing all around.After baseline von Frey measures with the alleged occurrence mechanical allodynia, can give L 5The SNL rat oral is used solvent or the medicine of appointment.After administration 30,60,100,180 and 300min, claw that can be by record and neural ligation place homonymy is because applying a series of von Frey filaments (0.4,0.6,1.0,2.0,4,6,8 and 15g through calibrating; (the Stoelting of Stoelting company of Illinois Wood Dell; Wood Dale, IL)) and the power when shrinking back quantizes tactile allodynia.By intermediate stiffness (2.0g) beginning, filament can be applied in the middle of the rear solid end vola about 5 seconds, to determine response lag, quick pawl is shunk back and is caused adopting lighter stimulation next time, causes and adopts stronger stimulation next time and lack the response of shrinking back.Can collect totally four secondary responses after the threshold test for the first time.50% threshold value of shrinking back can more than response lag drops on detection range or when following, can be specified separately value 15.0 or 0.25g by being inserted by the improved Dixon method of people such as Chaplan.The threshold data of von Frey filament test can be used as the threshold value of shrinking back (in gram) report.Can be with data normalization, and the result can be expressed as the medicine %MPE (maximum possible effectiveness) that calculates according to following formula:
Figure BDA00003384930000731
Although above-mentioned description has been instructed principle of the present invention, provide example to be exemplified as purpose, but should be appreciated that enforcement of the present invention contain fall into appended claim and their equivalents scope in all common variations, change form and/or modification.

Claims (16)

1. the chemical compound of a formula (I) and enantiomer, diastereomer and officinal salt
Figure 201180061809X100001DEST_PATH_IMAGE001
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group a) is
I) C 6-10Aryl, it is selected from fluorine, chlorine, C for unsubstituted or quilt 1-4Alkyl, C 1-4The substituent group of alkoxyl, cyano group and trifluoromethyl replaces; Or
Ii) be selected from the unsubstituted heteroaryl of thiazolyl, isothiazolyl and 1H-pyrrole radicals;
Group b) be selected from:
I) C 6-10Aryl;
Ii) be selected from benzo
Figure 926449DEST_PATH_IMAGE002
The heteroaryl of azoles base, benzothiazolyl, benzimidazolyl, benzothienyl, indazolyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl or fluorine; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from bromine, chlorine, fluorine, iodine, C 1-4Alkyl, C 1-4Alkoxyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine, cyano group and fluorine;
R is hydrogen or hydroxyl.
2. chemical compound according to claim 1 is wherein organized a) to unsubstituted phenyl or is selected from the unsubstituted heteroaryl of thiazolyl, isothiazolyl and 1H-pyrrole radicals.
3. chemical compound according to claim 1 is wherein organized a) to unsubstituted phenyl or is selected from the unsubstituted heteroaryl of thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazolyl, 1H-pyrroles-2-base and 1H-pyrroles-3-base.
4. chemical compound according to claim 1 is wherein organized b) be selected from:
I) phenyl;
Ii) be selected from benzo The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl or fluorine; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine.
5. chemical compound according to claim 1 is wherein organized b) be selected from:
I) phenyl;
Ii) be selected from benzo
Figure 561010DEST_PATH_IMAGE002
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine.
6. chemical compound according to claim 1, wherein R is hydrogen.
7. the chemical compound of a formula (I) and enantiomer, diastereomer and officinal salt
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazolyl, isothiazolyl and 1H-pyrrole radicals a);
Group b) be selected from:
I) phenyl;
Ii) be selected from benzo
Figure 708274DEST_PATH_IMAGE002
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl or fluorine; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoro propyl, 4,4-difluoro cyclohexyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen.
8. the chemical compound of a formula (I) and enantiomer, diastereomer and officinal salt
Figure 530737DEST_PATH_IMAGE001
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazolyl, isothiazolyl and 1H-pyrrole radicals a);
Group b) be selected from:
I) phenyl;
Ii) be selected from benzo
Figure 469874DEST_PATH_IMAGE002
The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen or hydroxyl.
9. the chemical compound of a formula (I) and enantiomer, diastereomer and officinal salt
Figure 668774DEST_PATH_IMAGE001
Formula (I)
Wherein
Y and Z are independently selected from group a) or group b), make that another person is group b in order to organize a) for one of Y and Z);
Group is unsubstituted phenyl or the unsubstituted heteroaryl that is selected from thiazol-2-yl, thiazole-4-base, thiazole-5-base, isothiazolyl, 1H-pyrroles-2-base and 1H-pyrroles-3-base a);
Group b) be selected from:
I) phenyl;
Ii) be selected from benzo The heteroaryl of azoles base, benzimidazolyl, benzothienyl and indyl;
Iii) phenyl methyl-phenyl, the phenyl of wherein said phenyl methyl are unsubstituted or are replaced by trifluoromethyl; With
Iv) 1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-Ji;
Wherein be not the group b of phenyl methyl-phenyl) for unsubstituted or replaced by one or two substituent group, described substituent group is independently selected from chlorine, fluorine, methyl and R bPrecondition is that to be no more than a substituent group be R bAnd
R bBe selected from trifluoromethyl, thienyl, pyridine radicals and phenyl; R wherein bDescribed thienyl, pyridine radicals and phenyl be unsubstituted or replaced by one or two substituent group that described substituent group is independently selected from trifluoromethyl, methyl, chlorine and fluorine;
R is hydrogen or hydroxyl.
10. chemical compound and the pharmaceutical acceptable salt thereof of a formula (I)
Figure 268700DEST_PATH_IMAGE001
Formula (I)
It is selected from:
Wherein Y is thiazole-4-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is isothiazole-5-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-3-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is thiazole-5-base, and Z is xenyl-4-base, and R is the chemical compound of H;
Wherein Y is phenyl, and Z is 5-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of OH;
Wherein Y is thiazole-4-base, and Z is 3-chloro-6-fluoro-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-chloro-6-fluoro-benzothiophene-2-base, and R is the chemical compound of H;
Y thiazole-4-base wherein, Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(3-trifluoromethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-(3-fluorophenyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(5-trifluoromethyl thiophene-2-yl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 2-phenyl-benzo
Figure 23029DEST_PATH_IMAGE002
Azoles-6-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 2-phenyl-benzo
Figure 527802DEST_PATH_IMAGE002
Azoles-6-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazole-4-base, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-phenyl-benzo
Figure 51187DEST_PATH_IMAGE002
Azoles-6-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(4-fluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(4-trifluoromethyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 1-(3,4-difluorophenyl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is 2-fluoro-4-phenyl-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 2-fluoro-4-phenyl-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1H-pyrroles-2-base, and Z is 2-fluoro-4-phenyl-phenyl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-(3-fluorophenyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(5-trifluoromethyl-thiophene-2-yl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(3-trifluoromethylbenzene ylmethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-methyl-6-trifluoromethyl-benzothiophene-2-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 4-(4-trifluoromethylbenzene ylmethyl)-phenyl, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure 481032DEST_PATH_IMAGE002
Azoles-6-base, Z are thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure 457078DEST_PATH_IMAGE002
Azoles-6-base, Z are thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 2-phenyl-benzo
Figure 732202DEST_PATH_IMAGE002
Azoles-6-base, Z are 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 3-chloro-6-trifluoromethyl-benzothiophene-2-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(4-fluorophenyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(4-trifluoromethyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is thiazol-2-yl, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is thiazole-4-base, and R is the chemical compound of H;
Wherein Y is 1-(3,4-difluorophenyl)-1H-indole-5-base, and Z is 1H-pyrroles-2-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(2,2,2-trifluoroethyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-1H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-phenyl-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(2,2,2-trifluoroethyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4,4-difluoro cyclohexyl)-2-methyl isophthalic acid H-benzimidazole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(5-chloropyridine-2-yl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 6-trifluoromethyl-benzothiophene-2-base, and R is the chemical compound of OH;
Wherein Y is thiazol-2-yl, and Z is 1-(2-picoline-4-yl)-1H-indole-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-phenyl-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-fluorophenyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,4-difluorophenyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4-trifluoromethyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(3,3,3-trifluoro propyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H;
Wherein Y is thiazol-2-yl, and Z is 1-(4,4-difluoro cyclohexyl)-1,3-dihydro-3H-benzimidazolyl-2 radicals-ketone-5-base, and R is the chemical compound of H.
11. a pharmaceutical composition comprises claim 1 or 10 described chemical compounds and the member who is selected from pharmaceutically suitable carrier, pharmaceutically acceptable excipient and pharmaceutically acceptable diluent.
12. pharmaceutical composition according to claim 11, wherein said compositions are solid oral dosage form.
13. pharmaceutical composition according to claim 11, wherein said compositions is selected from syrup, elixir and suspensoid.
14. the method for a treatment inflammatory pain in the person under inspection of needs treatment comprises and gives described person under inspection with claim 1 or the 10 described compound administration for the treatment of effective dose.
15. method according to claim 14, wherein said inflammatory pain are by due to following: inflammatory bowel, Encelialgia, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, backache, back pain, arthralgia, stomachache, chest pain, childbirth, the muscle skeleton disease, dermatosis, toothache, heating, burn, sunburn, venom, venom, spider bites, insect stings, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/allergy, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, pain syndrome after the mastectomy, dysmenorrhea, endometriosis, pain, by the pain due to the physical trauma, headache, sinus headache, tension headache or arachnoiditis.
16. a chemical compound, it is formula 1g
Figure 201180061809X100001DEST_PATH_IMAGE003
。
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