CN102458407A

CN102458407A - Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitors

Info

Publication number: CN102458407A
Application number: CN2010800287618A
Authority: CN
Inventors: C·M·弗罗尔斯; M·I·内伦; E·L·努尔顿; S·普罗蒂; M·托德; S-P·张
Original assignee: Janssen Pharmaceutica NV
Current assignee: Janssen Pharmaceutica NV
Priority date: 2009-04-22
Filing date: 2010-04-22
Publication date: 2012-05-16
Anticipated expiration: 2030-04-22
Also published as: JP2012524810A; AU2010238746A1; WO2010124122A1; AU2010238746B2; EP2421535A1; KR20120005517A; TW201103914A; IL215797A0; RU2011147201A; BRPI1014874A2; CN102458407B; CA2759706A1

Abstract

Disclosed are compounds, compositions and methods for treating diseases, syndromes, conditions and disorders that are affected by the inhibition of MGL, including pain. Such compounds are represented by Formula (I) as follows: wherein R1, W and (Ia): are defined herein.

Description

Heteroaromatic and aromatics piperazinyl azelidinyl amide as the monoacylglycerol lipase inhibitor

CROSS-REFERENCE TO RELATED PATENT

Present patent application requires the U.S. Provisional Application No.61/171 of submission on April 22nd, 2009,661 rights and interests, and this provisional application is incorporated this paper into way of reference in full.

Present patent application is 61/171,660 to be correlated with being filed in U.S. Provisional Patent Application serial number that April 22 in 2009, day, were called Heteroaromatic and Aromatic Piperazinyl Azetidinyl Amides as Monoacylglycerol Lipase Inhibitors (as heteroaromatic and the aromatics piperazinyl azelidinyl amide of monoacylglycerol lipase inhibitor).

Statement about the federal funding development project

Development project of the present invention does not hereinafter described receive federal funding.

Technical field

The present invention relates to the purposes of formula defined herein (I) chemical compound aspect treatment, alleviation and/or prevention experimenter's MGL disease, said experimenter comprises the mammal and/or the mankind that suffer from the disease, syndrome or the disease that influenced by MGL.

Background technology

Fructus Cannabis (Cannabis sativa) has been used to treat pain for many years.Δ ⁹-THC be derived from Fructus Cannabis main active and for cannabinoid receptor agonists (Pertwee, Brit J Pharmacol, 2008,153,199-215 (Pertwee, " and Britain pharmacology journal, 2008, the 153rd the volume, the 199-215 page or leaf)).Two cannabinoid g protein coupled receptors have been cloned, i.e. 1 type Cannabined receptor (CB ₁, Matsuda et al., Nature, 1990,346,561-4 (people such as Matsuda, " nature ", nineteen ninety, the 346th volume, 561-564 page or leaf)) and 2 type Cannabined receptor (CB ₂, Munro et al., Nature, 1993,365,61-5 (people such as Munro, " nature ",, the 365th volume, 61-65 page or leaf in 1993)).CB ₁Be expressed in the brain district such as hypothalamus and nucleus accumbens septi at maincenter, outer circumferential reaches in liver, gastrointestinal tract, pancreas, fatty tissue and skeletal muscle (Di Marzo et al., Curr Opin Lipidol; 2007,18,129-140 (people such as Di Marzo; " blood fat is learned and is newly seen "; 2007, the 18th volume, 129-140 page or leaf)).CB ₂Mainly be expressed in immunocyte, for example mononuclear cell (Pacher et al., Amer J Physiol, 2008,294; H1133-H1134 (people such as Pacher, " U.S. physiology journal,, the 294th volume, H1133-H1134 page or leaf in 2008)); And also be expressed in brain (Benito et al., Brit J Pharmacol, 2008,153,277-285 (people such as Benito in some cases; " Britain pharmacology journal, 2008, the 153rd the volume, the 277-285 page or leaf)), skeletal muscle (Cavuoto et al., Biochem Biophys Res Commun; 2007,364,105-110 (people such as Cavuoto, " biochemistry and biophysical research communication ", 2007 years; The 364th volume, the 105-110 page or leaf)) and cardiac muscle (Hajrasouliha et al., Eur J Pharmacol, 2008,579; 246-252 (people such as Hajrasouliha, " European pharmacology's journal,, the 579th volume, 246-252 page or leaf in 2008)).A large amount of pharmacologys, anatomy and the electrophysiology data of using synthetic agonist to draw show CB ₁/ CB ₂The enhanced cannabinoid signal conduction of participating in has promoted to ease pain in the reaction test of acute injury property and in chronic neuropathic pain and inflammatory pain model, has suppressed hyperpathia and/or allodynia (Cravatt et al., J Neurobiol, 2004; 61; 149-60 (people such as Cravatt, " neurobiology journal, 2004; The 61st volume, the 149-160 page or leaf); Guindon et al., Brit J Pharmacol, 2008,153,319-334 (people such as Guindon, " Britain pharmacology journal,, the 153rd volume, 319-334 page or leaf in 2008)).

The effect of synthetic cannabinoid receptor agonists is confirmed fully.In addition, adopt the research of cannabinoid receptor agonists and knock out mice to show, the Endocannabinoids system is the important regulator of nocuity reaction.Arachidonic acid ethanolamine (AEA) (Devane et al., Science, 1992,258,1946-9 (people such as Devane; " science ", 1992, the 258th volume, 1946-1949 page or leaf)) and 2-arachidonic acyl glycerol (2-AG) (Mechoulam et al.; Biochem Pharmacol, 1995,50,83-90 (people such as Mechoulam; " biochemical pharmacology ", nineteen ninety-five, the 50th volume, 83-90 page or leaf); Sugiura et al., Biochem Biophys Res Commun, 1995,215,89-97 (people such as Sugiura, " biochemistry and biophysical research communication ", nineteen ninety-five, the 215th volume, 89-97 page or leaf)) be two kinds of main Endocannabinoids.AEA is by FAAH (FAAH) hydrolysis, 2-AG coverlet acyl glycerin fatty enzyme (MGL) hydrolysis (Piomelli, Nat Rev Neurosci, 2003; 4,873-884 (Piomelli, " comment of nature-neurological "); 2003, the 4th volume, 873-884 page or leaf).The gene delection of FAAH has improved endogenous AEA level and in the acute inflammation pain model, has played CB ₁Dependency analgesia (Lichtman et al., Pain, 2004,109,319-27 (people such as Lichtman; " pain ", 2004, the 109th volume, 319-327 page or leaf)), this shows that the Endocannabinoids system itself has function (the Cravatt et al. that suppresses the nocuity reaction; J Neurobiol, 2004,61,149-60 (people such as Cravatt; " neurobiology journal,, the 61st volume, 149-160 page or leaf in 2004)).The Endocannabinoids horizontal group that occurs when using the FAAH knock out mice becomes second nature and improves differently, uses the specific FAAH inhibitor only can instantaneous raising AEA level and produce anti-shock reaction in the body (Kathuria et al., Nat Med; 2003,9,76-81 (people such as Kathuria; " nature-medical science "; 2003, the 9th volume, 76-81 page or leaf)).The anti-shock reaction view of relevant Endocannabinoids mediation is further confirmed through this: after periphery produces noxious stimulation, in periaqueductal gray matter (a known pain maincenter), formed AEA (Walker et al., Proc Natl Acad Sci USA, 1999; 96,12198-203 (people such as Walker, " institute of NAS periodical "; 1999; The 96th volume, the 12198-12203 page or leaf)) and on the contrary, in spinal cord, use CB ₁Brought out hyperpathia (Dogrul et al., Pain, 2002,100,203-9 (people such as Dogrul, " pain ",, the 100th volume, 203-209 page or leaf in 2002)) behind the antisense RNA.

For 2-AG, in whipping experiment (Mechoulam et al., Biochem Pharmacol, 1995,50; 83-90 (people such as Mechoulam, " biochemical pharmacology ", nineteen ninety-five, the 50th volume, 83-90 page or leaf)) tests (Lichtman et al. with hot plate; J Pharmacol Exp Ther, 2002,302,73-9 (people such as Lichtman; " pharmacology and experimental therapeutic journal,, the 302nd volume, 73-79 page or leaf in 2002)) in confirm that intravenous sends this material and produced analgesic activity.On the contrary, confirm that in hot plate experiment giving 2-AG separately can not play analgesic activity, but with other 2-monoacylglycerols (that is, 2-glyceryl linoleate and 2-tripalmitin) when giving jointly; Reached significant analgesic activity, this phenomenon is called " cooperative effect " (Ben-Shabat et al., Eur J Pharmacol, 1998; 353,23-31 (people such as Ben-Shabat, " European pharmacology's journal; 1998, the 353rd volume, 23-31 page or leaf)).The 2-monoacylglycerol of these " synergism " is the endogenous lipid, and they and 2-AG discharge jointly, has strengthened the signal conduction of Endocannabinoids, decomposes through suppressing 2-AG on the part, and most probable combines the avtive spot on the MGL to play this effect through competitiveness.This shows that synthetic MGL inhibitor will have similar effect.More weak synthetic MGL inhibitor URB602 shows effect (Comelli et al., Brit J Pharmacol, 2007 of anti-shock reaction really in the acute inflammation mouse model relatively; 152; 787-794 (people such as Comelli, " Britain pharmacology journal, 2007; The 152nd volume, the 787-794 page or leaf)).

Although use synthetic cannabinoid agonists to confirm that fatefully enhanced cannabinoid signal conduction has produced analgesia and antiinflammatory action, be difficult to the beneficial effect and the harmful side effect disengaging of these chemical compounds are come.A kind of alternative method is to come the signal conduction of augment endogenous property cannabinoid system through improving the 2-AG level; And the raising of 2-AG level can realize that wherein 2-AG is the most abundant Endocannabinoids in central nervous system (CNS) and the gastrointestinal tract through suppressing MGL.Therefore, the MGL inhibitor is at treatment pain, inflammation and central nervous system disorder (Di Marzo et al., Curr Pharm Des, 2000,6,1361-80 people such as (, " current drug design ",, the 6th volume, 1361-1380 page or leaf in 2000) Di Marzo; Jhaveri et al., Brit J Pharmacol, 2007,152,624-632 (people such as Jhaveri, " Britain pharmacology journal,, the 152nd volume, 624-632 page or leaf in 2007); McCarberg Bill et al., Amer J Ther, 2007,14; 475-83 (people such as McCarberg Bill, " U.S.'s therapeutics journal, 2007; And glaucoma and the morbid state (Njie, the Ya Fatou that raise and to cause by intraocular pressure the 14th volume, 475-483 page or leaf)); He, Fang; Qiao, Xhuanhong; Song, Zhoa-Hui, Exp.Eye Res., 87,2008 (2): 106-14 (Njie; Ya Fatou, He, Fang, Qiao, Xhuanhong, Song, Zhoa-Hui; " research of experimental eye section ", 2008, the 87th the 2nd phase of volume, 106-114 page or leaf)) aspect has potential use.

Summary of the invention

The present invention relates to treat, alleviate or prevent to receive the method for disease, syndrome, disease or obstacle (like pain, the disease that causes this type of pain, inflammation and central nervous system disorder) that MGL suppresses to influence, said method comprises the following steps, is formed and/or be made up of the following step basically by the following step: to formula (I) chemical compound of experimenter's administering therapeutic effective dose that needs are arranged

It is selected from:

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenoxymethyl, and R ³Be 2, the chemical compound of 2-dimethyl propyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for cyclohexyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be the 4-aminomethyl phenyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl methyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 4-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 4-methoxyphenyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be isobutyl group, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenoxymethyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl, and R ³Be 2, the chemical compound of 2-dimethyl propyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenoxymethyl, and R ³Chemical compound for cyclohexyl methyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be cyclopentyl-methyl, and R ³Chemical compound for methyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be cyclohexyl methyl, and R ³Chemical compound for hydrogen;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 2-methoxybenzene ylmethyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be n-pro-pyl, and R ³Chemical compound for methyl;

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl methyl, and R ³Chemical compound for cyclohexyl methyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the tert-butyl group;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 3-methoxyphenyl;

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl methyl, and R ³Chemical compound for isobutyl group;

Wherein W is CH, R ¹Be the 2-methoxyl group, For

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl, and R ³Be 2, the chemical compound of 2-dimethyl propyl;

Wherein W is CH, R ¹Be the 4-fluoro,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be the tert-butyl group, and R ³Be 2, the chemical compound of 2-dimethyl propyl;

Wherein W is N, R ¹Be H, For X-Y-Z is-NH-C (R ²)-C (R ³)-, R ²Be the 4-aminomethyl phenyl, and R ³Chemical compound for methoxyl group-methyl-carbonyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be n-pro-pyl, and R ³Chemical compound for cyclohexyl methyl;

And enantiomer, diastereomer, solvate and officinal salt.

The invention still further relates to the purposes of formula (I) chemical compound aspect preparation medicament or pharmaceutical composition of this paper definition, said medicament or pharmaceutical composition are used for experimenter's treatment of needs being arranged, alleviate or preventing to receive MGL to suppress disease, syndrome, disease or the obstacle that is influenced.

The specific embodiment

Generally speaking,, specify the end portion of side chain at first to be described, then describe adjacent functional group towards junction point according to running through the standard nomenclature principle that present disclosure uses.Therefore, for example, " C ₁-C ₆Alkyl-carbonyl " substituent group is meant the group that following formula is represented:

Except as otherwise noted, the definition of any substituent group or variable is intended to its definition in these other positions of intramolecularly irrelevant otherwise on the intramolecularly ad-hoc location.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, to provide chemically stable and can be by the easy synthetic chemical compound of those methods shown in technology known in the art and this paper.

Term used herein " experimenter " refers to become treatment, observe or the animal of the target of experiment, and preferred mammal is most preferably human.

As used herein; Term " treatment effective dose " refers to cause biology or the reactive compound of medical response or the amount of medicinal reagent at tissue system, animal or human's apoplexy due to endogenous wind; What it was a research worker, veterinary, doctor or other clinicists pursued, it comprises the symptom of alleviating or partly alleviating disease, syndrome, disease or the obstacle of being treated.

As used herein, term " compositions " is intended to contain the product that comprises the special component of treating effective dose, and the spawn that can directly or indirectly be obtained by the combination of the special component of specified quantitative.

As used herein; Except as otherwise noted; Otherwise term " treatment (verb) ", " treatment (noun) ", " alleviation " etc. should comprise from the purpose of resisting disease, disease or obstacle experimenter or patient's (preferred mammal; More preferably people) manage and nurse and comprise give chemical compound of the present invention with prevention symptom or complication outbreak, mitigation symptoms or complication or eliminate this disease, disease or obstacle.

As used herein, except as otherwise noted, otherwise term " prevention (verb) " and " prevention (noun) " should comprise that (a) reduces the frequency of one or more symptoms; (b) reduce the seriousness of one or more symptoms; (c) postpone or avoid the development of other symptom; And/or (d) postpone or avoid the development of this obstacle or disease.

Those skilled in the art will recognize that; The present invention relates to therein in the situation of prevention method; Have the experimenter (experimenter that promptly need prevent) who needs should comprise any experienced or show the experimenter or the patient (preferred mammal, more preferably people) of at least a symptom of obstacle, disease or the disease that will prevent.In addition; It can also be any symptom that does not show obstacle, disease or the disease that will prevent that the experimenter who needs is arranged; But thought that by internist, clinician or other medical professions the experimenter (preferred mammal, more preferably people) of the risk that develops said obstacle, disease or disease is arranged.For example; Because this experimenter's medical history; Include but not limited to family history, be prone to obstacle or disease (morbid state that has simultaneously), the heredity test of ill body constitution, coexistence etc., this experimenter can be considered to the risk (and therefore needing prevention or prophylactic treatment) of development obstacle, disease or disease.

Term " MGL inhibitor " thereby be intended to is contained and MGL interacts to reduce or to eliminate the chemical compound that the MGL catalytic activity increases the MGL concentration of substrate.Term " MGL regulates " is used for representing to receive the disease that the MGL enzyme is regulated to be influenced, and comprises receiving the MGL enzyme to suppress the disease that influences, for example pain and the disease and inflammation and the central nervous system disorder that cause this type of pain.

As used herein; Except as otherwise noted, otherwise term " influence " or " influenced " (when relating to the disease that receives MGL to suppress to be influenced, syndrome, disease or obstacle) should mean one or more symptoms of said disease, syndrome, disease or obstacle or the occurrence frequency and/or the order of severity of clinical manifestation descends; And/or the development that means one or more symptoms or the clinical manifestation of said disease, syndrome, disease or obstacle is prevented from or the development of disease, syndrome, disease or obstacle is prevented from.

Formula (I) chemical compound is useful in the method for the disease, syndrome, disease or the obstacle that are used for treating, alleviate and/or prevent to receive MGL to suppress to be influenced.These class methods comprise the following steps, are formed and/or be made up of the following step basically by the following step: give formula (I) chemical compound or its enantiomer, diastereomer, solvate or the pharmaceutically useful salt of experimenter's administering therapeutic effective dose, animal, mammal and the mankind that said experimenter comprises to be needed this type of treatment, alleviate and/or prevent.Specifically, formula (I) chemical compound can be used for treatment, alleviates and/or prevents pain; Cause disease, syndrome, disease or the obstacle of this pain; Inflammation and/or central nervous system disorder.More particularly, formula (I) chemical compound can be used for treatment, alleviates and/or prevention inflammatory pain, the ultra quick disease of inflammatory and/or neuropathic pain, comprises formula (I) chemical compound to this paper definition of experimenter's administering therapeutic effective dose that needs are arranged.

The example of inflammatory pain comprises because the pain due to disease, disease, syndrome, obstacle or the pain status, and said disease, syndrome, disease, obstacle or pain status comprise: inflammatory bowel, visceral pain, migraine, postoperative pain, osteoarthritis, rheumatoid arthritis, backache, back pain, arthralgia, stomachache, chest pain, childbirth, musculoskeletal disease, dermatosis, toothache, heating, burn, sunburn, Serpentis sting, poisonous snake stings, Aranea stings, pain syndrome behind the sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/anaphylaxis, pruritus, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, mastectomy, dysmenorrhea, endometriosis, the pain, headache, sinus frontalis headache, tension headache or the arachnoiditis that cause because of the health wound.

One type inflammatory pain is inflammatory hyperpathia/ultra quick.The hyperalgesic example of inflammatory comprises disease, syndrome, disease, obstacle or pain status, and it comprises inflammation, osteoarthritis, rheumatoid arthritis, backache, arthralgia, stomachache, musculoskeletal disease, dermatosis, postoperative pain, headache, toothache, burn, sunburn, sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive disease of lung, rhinitis, contact dermatitis/allergy, scratches where it itches, eczema, pharyngitis, enteritis, irritable bowel syndrome, the inflammatory bowel that comprises clone disease, ulcerative colitis, urinary incontinence, prostatic hyperplasia, cough, asthma, rhinitis, nose allergy, scabies, contact dermatitis and/or skin allergy and chronic obstructive disease of lung.

In one embodiment; The present invention relates to be used to treat, alleviate and/or prevent wherein to exist the irritated hyperalgesic method of inflammatory internal organs that increases of internal organs, this method comprises the following steps, is formed and/or be made up of the following step basically by the following step: chemical compound, salt or the solvate of giving the formula (I) of the experimenter's administering therapeutic effective dose that needs this treatment.In another embodiment; The present invention relates to be used to treat the hyperalgesic method of inflammatory body that wherein exists heat, machinery and/or chemical stimulation hypersensitivity, this method comprises chemical compound or its enantiomer, diastereomer, solvate or the officinal salt to the formula (I) of the administration treatment effective dose of this treatment of needs.

An alternative embodiment of the invention relates to the method that is used to treat, alleviate and/or prevent neuropathic pain.The example of neuropathic pain comprises because the pain due to disease, syndrome, disease, obstacle or the pain status, and said 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, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathy, apoplexy, amyotrophic lateral sclerosis (ALS), parkinson, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom pain, fracture, MN property pain, charcot's pains, I type and II type complexity zone pain syndrome (CRPSI/II), radiculopathy, guillain-Barre syndrome, Bernhards disease, a bright mouth 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 the Vidian neuralgia relevant with spinal cord injury.

One type neuropathic pain is the unusual cold type of pain of nerve, and it is characterized by the allodynia state (wherein having the allergy to cold stimulation) that exists neuropathy relevant.The example of the unusual cold type of pain of nerve comprises because the allodynia due to disease, disease, syndrome, obstacle or the pain status, and this disease, disease, syndrome, obstacle or pain status comprise neuropathic pain (neuralgia), are derived from the pain of 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, I type and II type complexity zone pain syndrome (CRPS I/II) or radiculopathy.

In another embodiment; The present invention relates to be used to treat, alleviate and/or prevent wherein to exist the method to the unusual cold type of pain of nerve of cold stimulation hypersensitivity, this method comprises the following steps, is formed and/or be made up of the following step basically by the following step: formula (I) chemical compound or its enantiomer, diastereomer, solvate or the officinal salt of giving this paper definition of the experimenter's administering therapeutic effective dose that needs this type of treatment.

In another embodiment, the present invention relates to treat, alleviate and/or prevent the method for central nervous system disorder.The example of central nervous system disorder comprises pressure obstacle after anxiety neurosis such as social anxiety disorder, the wound, phobia, social phobia, special object phobia, painful disease, obsession, acute pressure obstacle, separation anxiety disorder and the impatient disease of popularity, and depression such as serious symptom depression, bipolar disorder, seasonal affective disorder, postpartum depression, manic depressive illness and bipolar depression.

The present invention relates to treat, alleviate and/prevention receives the method for obstacle, syndrome, disease or disease that MGL suppresses to influence, said method comprising the steps of, is formed or be made up of following steps basically by following steps: to formula (I) chemical compound of experimenter's administering therapeutic effective dose that needs are arranged

It is selected from:

[1-(2,2-dimethyl-propyl group)-2-phenoxymethyl-1H-indole-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #1)

(2-cyclohexyl-benzo

azoles-6-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #2)

[2-(3-fluoro phenyl)-benzo

azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #3)

(1-isobutyl group-2-p-methylphenyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #4)

[1-isobutyl group-2-(4-methyl-benzyl)-1H-indole-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #5)

[2-(4-fluoro phenyl)-benzo

azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #6)

[2-(4-methoxyl group-phenyl)-benzo

azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #7)

(1,2-diisobutyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #8)

(1-isobutyl group-2-phenoxymethyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #9)

[1-(2,2-dimethyl-propyl group)-2-phenyl-1H-indole-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #10)

(1-cyclohexyl methyl-2-phenoxymethyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #11)

(2-cyclopentyl-methyl-1-Methyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #12)

(1-isobutyl group-2-phenyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #13)

(2-cyclohexyl methyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #14)

[2-(2-methoxyl group-benzyl)-benzo azoles-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #15)

(2-ethyl-1-Methyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #16)

(1-isobutyl group-2-phenoxymethyl-1H-indole-5-yl)-{ 3-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #17)

(2-benzyl-1-cyclohexyl methyl-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #18)

(the 2-tert-butyl group-benzo

azoles-6-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #19)

[2-(3-methoxyl group-phenyl)-benzo

azoles-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #20)

(2-benzyl-1-isobutyl group-1H-indole-5-yl)-{ 3-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #21)

[1-(2,2-dimethyl-propyl group)-2-phenoxymethyl-1H-indole-5-yl]-{ 3-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #22)

(2-benzyl-1-cyclohexyl methyl-1H-indole-5-yl)-{ 3-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #23)

[1-(2,2-dimethyl-propyl group)-2-phenyl-1H-indole-5-yl]-{ 3-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #24)

[1-(2,2-dimethyl-propyl group)-2-phenyl-1H-indole-5-yl]-{ 3-[4-(4-fluoro-phenyl)-piperazine-1-yl]-azetidin-1-yl }-ketone; (chemical compound #25)

[2-tert-butyl-1-(2,2-dimethyl-propyl group)-1H-indole-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #26)

2-methoxyl group-1-{5-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidine-1-carbonyl]-2-p-methylphenyl-1H-indol-3-yl }-ethyl ketone; (chemical compound #27)

(1-cyclohexyl methyl-2-propyl group-1H-indole-5-yl)-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #28)

And enantiomer, diastereomer, solvate and officinal salt.Preferably, disease, syndrome, disease or the obstacle that receives MGL to suppress to influence is selected from like pain defined herein, inflammatory pain, the irritated disease of inflammatory and neuropathic pain.

In one embodiment, the present invention relates to treat, alleviate or prevent to receive MGL to suppress disease, syndrome, disease or the obstacle that influences, comprise formula (Ia) chemical compound to experimenter's administering therapeutic effective dose that needs are arranged

Or its enantiomer, diastereomer, solvate or officinal salt, wherein R ¹, W and-X-Y-Z-such as defined herein.In another embodiment, the present invention relates to treat, alleviate or prevent to receive MGL to suppress disease, syndrome, disease or the obstacle that influences, comprise formula (Ib) chemical compound to experimenter's administering therapeutic effective dose that needs are arranged

Or its enantiomer, diastereomer, solvate or officinal salt, wherein R ¹, W and-X-Y-Z-such as defined herein.In another embodiment, the present invention relates to treat, alleviate or prevent to receive MGL to suppress disease, syndrome, disease or the obstacle that influences, comprise formula (Ic) chemical compound to experimenter's administering therapeutic effective dose that needs are arranged

Or its enantiomer, diastereomer, solvate or officinal salt, wherein R ¹, W and-X-Y-Z-such as defined herein.

In another embodiment, the present invention relates to treat, alleviate or prevent to receive MGL to suppress disease, syndrome, disease or the obstacle that influences, comprise the following chemical compound that is selected to experimenter's administering therapeutic effective dose that needs are arranged:

(2-cyclohexyl-benzo

[2-(3-fluoro phenyl)-benzo azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #3)

[2-(4-fluoro phenyl)-benzo

[2-(4-methoxyl group-phenyl)-benzo

[2-(2-methoxyl group-benzyl)-benzo

azoles-5-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #15)

And enantiomer, diastereomer, solvate and officinal salt.

In another embodiment, the present invention relates to be selected from the purposes of following chemical compound:

[2-(3-fluoro phenyl)-benzo

[2-(4-fluoro phenyl)-benzo azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #6)

[2-(4-methoxyl group-phenyl)-benzo azoles-7-yl]-[3-(4-pyridine-2-base-piperazine-1-yl)-azetidin-1-yl]-ketone; (chemical compound #7)

And enantiomer, diastereomer, solvate and officinal salt.

(2-cyclohexyl-benzo

[2-(3-fluoro phenyl)-benzo

[2-(4-methoxyl group-phenyl)-benzo

[2-(3-methoxyl group-phenyl)-benzo

And enantiomer, diastereomer, solvate and officinal salt.

(2-cyclohexyl-benzo

[2-(3-fluoro phenyl)-benzo

[2-(4-fluoro phenyl)-benzo

(the 2-tert-butyl group-benzo

And enantiomer, diastereomer, solvate and officinal salt.

In another embodiment, the present invention relates to be selected from the purposes of any unification compound or chemical compound set or its enantiomer, diastereomer, solvate or the pharmaceutically useful salt of listed chemical compound in the following table 1 to 3; For the experimenter's treatment that needs, disease, syndrome, disease or the obstacle alleviating or prevent to receive the MGL inhibition to influence are arranged.Formula of the present invention (I) chemical compound such as following table 1 to 3 are listed.

Table 1: formula (Ia) chemical compound

Table 2: formula (Ib) chemical compound

Table 3: formula (Ic) chemical compound

In one embodiment, the present invention relates to treat, alleviate or prevent to receive MGL to suppress disease, syndrome, disease or the obstacle that influences, the said disease, syndrome, disease or the obstacle that wherein receive MGL to suppress to influence are selected from inflammatory pain and neuropathic pain; Comprise formula (I) chemical compound to the experimenter that needs are arranged (comprising the mammal and/or the mankind) administering therapeutic effective dose

It is selected from like chemical compound defined herein; And enantiomer, diastereomer, solvate and officinal salt.

In one embodiment, the present invention relates to treatment, alleviation or prevention inflammatory pain; Comprise formula (I) chemical compound to the experimenter that needs are arranged (comprising the mammal and/or the mankind) administering therapeutic effective dose

It is selected from like chemical compound defined herein; And enantiomer, diastereomer, solvate and officinal salt.In another embodiment of the present invention, inflammatory pain is selected from Encelialgia and inflammatory hyperpathia, is preferably Encelialgia.

In one embodiment, the present invention relates to treatment, alleviation or prophylaxis inflammatory pain and feel irritated, comprise formula (I) chemical compound to the experimenter that needs are arranged (comprising the mammal and/or the mankind) administering therapeutic effective dose

It is selected from like chemical compound defined herein; And enantiomer, diastereomer, solvate and officinal salt.In another embodiment of the present invention, inflammatory hyperpathia is ulcerative colitis.

In one embodiment, the present invention relates to treatment, alleviate or the prevention neuropathic pain, comprise formula (I) chemical compound to the experimenter that needs are arranged (comprising the mammal and/or the mankind) administering therapeutic effective dose

It is selected from like chemical compound defined herein; And enantiomer, diastereomer, solvate and officinal salt.In another embodiment of the present invention, neuropathic pain is the unusual cold type of pain of nerve.

For the use in medical science, the salt of formula (I) chemical compound refers to atoxic " officinal salt ".Yet other salt can be used for preparation formula (I) chemical compound or their officinal salt.The suitable officinal salt of formula (I) chemical compound comprises acid-addition salts, and described acid-addition salts can (for example) forms through the solution of said chemical compound is mixed with the solution of pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.In addition, if formula (I) chemical compound has acidic moiety, then its suitable officinal salt can comprise alkali metal salt, like sodium salt or potassium salt; Alkali salt is like calcium salt or magnesium salt; And the salt that forms with suitable organic ligand, like quaternary ammonium salt.Thereby representational officinal salt comprises acetate, benzene sulfonate, benzoate, bicarbonate, disulfate, biatrate, borate, bromide, edetic acid calcium salt, d-camphorsulfonic acid salt, carbonate, chloride, Clavulanate, citrate, dihydrochloride, edetate, ethanedisulphonate, Estolate, esilate, fumarate, gluceptate, gluconate, glutamate, Glu, to α-hydroxyl acetylamino phenylarsonate, hexyl resorcin salt, Hai Baming, hydrobromate, hydrochlorate, hydroxynaphthoate, iodide, different thiosulfate, lactate, lactobionate, laruate, malate, maleate, mandelate, mesylate, MB, methyl nitrate, Methylsulfate, mucus hydrochlorate, naphthalene sulfonate, nitrate, N-NMG ammonium salt, oleate, embonate (pamoate), palmitate, pantothenate, phosphate/diphosphate, Polygalacturonate, Salicylate, stearate, sulfate, basic acetate, succinate, tannate, tartrate, teoclate, toluene fulfonate, triethyl group iodate thing and valerate.

The representative bronsted lowry acids and bases bronsted lowry that can be used for preparing pharmaceutically useful salt comprises following acid: like acetic acid, 2; 2-dichloroacetic acid, acetylizad aminoacid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 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; 2-disulfonic acid, ethyl sulfonic acid, 2-hydroxyl-ethyl sulfonic acid, formic acid, fumaric acid, glactaric acid, gentisic acid, glucoheptonic acid, maltonic acid, D-glucuronic acid, L-glutamic acid, KG, 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, are pounced on acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4-aminosallcylic acid, decanedioic acid, stearic acid, succinic acid, sulphuric acid, tannin, (+)-L-tartaric acid, Hydrogen thiocyanate, p-methyl benzenesulfonic acid and undecylenic acid at 5-disulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, Palmic acid; And following alkali: comprise ammonia, L-arginine, benethamine, benzyl star, calcium hydroxide, choline, dimethylethanolamine, diethanolamine, diethylamine, 2-(lignocaine) ethanol, ethanolamine, ethylenediamine, N-methyl glucoside amine, 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 formula (I) chemical compound.Usually, this type of prodrug will be the functional derivative of chemical compound, and it can easily change into required chemical compound in vivo.Therefore; In the method for treatment of the present invention or prevention embodiment; Term administering " contained with specifically described chemical compound or not specifically described compounds for treating or prevented described multiple disease, disease, syndrome and obstacle, but said not specifically described chemical compound can change into specified chemical compound in body after being applied to the patient.For example, at " Design of Prodrugs ", ed.H.Bundgaard, Elsevier has described the conventional program that is used to select and prepare suitable prodrug derivant in 1985 (" the prodrug designs ", H.Bundgaard edits, Elsevier, 1985).

When having at least one chiral centre according to the chemical compound of the embodiment of the invention, they can correspondingly exist as enantiomer.If chemical compound has two or more chiral centres, then they also can be used as the diastereomer existence.Should be appreciated that all this type isomers and composition thereof all contain within the scope of the invention.In addition, some crystal form of chemical compound can be used as polymorph and exists, and therefore also is intended to be included in the present invention.In addition, some chemical compound can form solvate (being hydrate) or form solvate with OOS with water, and this kind solvent chemical compound also is intended to be covered in the scope of the present invention.The technical staff will understand, and the term as used herein chemical compound is intended to comprise formula (I) chemical compound of solvation.

If be used to prepare the mixture that produces stereoisomer according to the technology of the chemical compound of certain embodiments of the invention, then can separate these isomers through the routine techniques such as preparative chromatography.Chemical compound can be prepared as racemic form, and perhaps independent enantiomer can synthesize or prepare through splitting through the enantiomer specificity.For example; Can pass through standard techniques; As to form diastereomer right through forming salt with optical activity acid (like (-)-two pair methyl benzoyl-d-tartaric acid and/or (+)-two pair methyl benzoyl-l-tartaric acid), fractional crystallization and regenerate free alkali and chemical compound split into their component enantiomer then.Also can be through forming non-enantiomer ester or amide, carry out chromatographic isolation then and remove chiral auxiliary and split chemical compound.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 formula (I) chemical compound (+)-enantiomer, form and/or form by it basically by it, wherein said compositions is substantially free of (-)-isomer of said chemical compound.In this article, be substantially free of and be meant and be less than approximately 25%, preferably be less than approximately 10%, more preferably be less than approximately 5%, more preferably be less than approximately 2%, and more preferably be less than (-)-isomer of about 1%, it can calculate as follows:

An alternative embodiment of the invention is a kind of compositions, comprises pharmaceutical composition, its comprise formula (I) chemical compound (-)-enantiomer, form and form by it basically by it, wherein said compositions is substantially free of (+)-isomer of said chemical compound.In this article, be substantially free of and be meant and be less than approximately 25%, preferably be less than approximately 10%, more preferably be less than approximately 5%, more preferably be less than approximately 2%, and more preferably be less than (+)-isomer of about 1%, it can calculate as follows:

In any technical process of the chemical compound that is used for preparing a plurality of embodiment of the present invention, have sensitivity or reactive group on any molecule that necessity and/or expectation protection paid close attention to.This can use the GPF (General Protection False group to realize, those that for example in following document, describe: Protective Groups in Organic Chemistry, Second Edition; J.F.W.McOmie, Plenum Press, 1973 (" blocking groups in the organic chemistry "; Second edition; J.F.W.McOmie, Plenum Press, 1973); T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons; 1991 (T.W.Greene and P.G.M.Wuts; " blocking group in the organic synthesis ", John Wiley & Sons, 1991); With T.W.Greene & P.G.M.Wuts, Protective Groups in Organic Synthesis, Third Edition; John Wiley & Sons; 1999 (T.W.Greene and P.G.M.Wuts, " blocking group in the organic synthesis ", the third editions; John Wiley & Sons, 1999).Can use methods known in the art to remove blocking group in follow-up phase easily.

Though 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 veterinary practice is selected) mixed applying.Therefore, specific embodiment of the present invention relates to medicinal and veterinary composition, and said compositions comprises formula (I) chemical compound and at least a pharmaceutically suitable carrier, pharmaceutically acceptable excipient and/or pharmaceutically acceptable diluent.

For instance, in the pharmaceutical composition of the embodiment of the invention, can be with formula (I) chemical compound and any suitable bonding, lubricant, suspending agent, coating materials, solubilizing agent and their combined hybrid.

Depend on the circumstances, the solid oral dosage form (like tablet or capsule) that contains The compounds of this invention can once be used with at least a dosage form.Also can use this chemical compound by the mode of extended release preparation.

The compounds of this invention can other peroral dosage forms of using comprise elixir, solution, syrup and suspensoid; Each dosage form randomly contains flavoring agent and coloring agent.

Select as another kind, formula (I) chemical compound can be used perhaps with suppository or vaginal suppository administered through sucking (in the trachea or intranasal), perhaps they can lotion, the form local application of solution, cream, ointment or face powder.For example, can they be mixed in the cream, said cream comprises the water-based emulsion of Polyethylene Glycol or liquid paraffin, is formed and/or is made up of it basically by it.In the weight of cream, they also can mix in the ointment to about 10% concentration by about 1%, and said ointment comprises white beeswax or paraffinum molle alba base material and any stabilizing agent and antiseptic (might needs), is formed and/or is made up of it basically by it.The alternate means of using comprise through 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 through the injection of non-intestinal, for example in the spongy body, intravenous, intramuscular, subcutaneous, Intradermal or intrathecal injection.In this case, compositions 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 it can contain other materials, and for example enough salt and monosaccharide are with preparation and the isoosmotic solution of blood.

For buccal surface or sublingual administration, pharmaceutical composition of the present invention can tablet or lozenge form use, said tablet or lozenge can be prepared in a usual manner.

As other examples, the pharmaceutical composition that contains at least a formula (I) chemical compound can be according to the medicinal hybrid technology of routine, through chemical compound and pharmaceutically suitable carrier, pharmaceutically acceptable diluent and/or pharmaceutically acceptable mixed with excipients are prepared.Carrier, excipient and diluent can be taked various forms, and this depends on required route of administration (for example oral, non-intestinal etc.).Therefore, for liquid oral medicine such as suspensoid, syrup, elixir and solution, suitable carriers, excipient and diluent comprise water, glycols, oils, alcohols, flavoring agent, antiseptic, stabilizing agent, coloring agent etc.; For solid orally ingestible such as powder, capsule and tablet, suitable carriers, excipient and diluent comprise starch, saccharide, diluent, granulating agent, lubricant, binding agent, disintegrating agent etc.Solid orally ingestible also can be randomly with material coatings such as sugar, or enteric coated, absorbs and the main position of disintegrate so that regulate.Use for non-intestinal, carrier, excipient and diluent generally include sterilized water, but and can add the dissolubility and keeping quality of other compositions to increase compositions.The also available aqueous carrier of injection suspensoid or solution prepares with proper additive such as solubilizing agent and antiseptic.

The treatment effective dose of formula (I) chemical compound or its pharmaceutical composition comprises: in every day about 1 to 4 time drug regimen; For the people of general (70kg); Dosage range is that about 0.1mg is to about 3000mg; Or wherein any amount or scope, particularly about 1mg is to about 1000mg or wherein any amount or scope, and more particularly about 10mg is to formula (I) chemical compound of about 500mg or any amount wherein or scope; But the treatment effective dose of the formula of it will be apparent to one skilled in the art that (I) chemical compound will change with the disease of being treated, syndrome, disease and obstacle to some extent.

For Orally administered, pharmaceutical composition preferably with contain have an appointment 0.01, about 10, about 50, about 100, about 150, about 200, about 250 and the tablet form of about 500 milligrams of formulas (I) chemical compound 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 formula to be used (I) chemical compound can be confirmed easily, and will change with the process of employed particular compound, mode of administration, preparation intensity and disease, syndrome, disease or obstacle.In addition, relevant with the concrete experimenter who receives treatment factor (comprising subject age, body weight, diet and time of application) will cause needs adjustment dosage to realize appropriate therapeutic and required curative effect.Thereby above-mentioned dosage is the example of ordinary circumstance.Certainly, may exist wherein higher or be useful individual cases, and this type situation also within the scope of the invention than the low dosage scope.

Those skilled in the art will recognize that, use the cell and/or the animal model of suitable, known and common acceptance, in vivo test and in vitro tests all can the prediction experiment compounds for treating or are prevented the ability of given disease.Those of skill in the art also will appreciate that, in healthy patients and/or the human clinical who suffers to carry out among the patient of given disease experiment (comprising that human body uses experiment, dosage to explore experiment and effect experiment first) can accomplish according to the method that clinical and medical domain are known.

Formula (I) chemical compound can be used in any above-mentioned composition and dosage regimen, and those compositionss and the dosage regimen of perhaps having established by means of this area are used, and the use of the chemical compound of a solemnity (I) is to need its experimenter desired.

General synthetic method

Representative compound of the present invention can according to hereinafter described and after scheme in the general synthetic method explained synthetic.Because scheme is an illustrative, so the present invention should not be construed as the concrete chemical reaction described in the scheme of receiving and the instance and the restriction of actual conditions.The commercially available acquisition of different initial substances that is used for scheme perhaps can be through being proficient in method preparation well-known to those having ordinary skill in the art.Variable in this paper definition and in being proficient in those skilled in the art's technical scope.

In this description, especially used abbreviation is following in " scheme " and " instance ":

Can prepare formula of the present invention (I) chemical compound according to the method described in the following scheme 1.

Scheme 1

Therefore; Under situation about existing like organic bases such as (preferably not being TEA) such as DIPEA, pyridine; With suitable substituted formula V chemical compound (compound known or the chemical compound for preparing through known method) and suitable substituted formula (VI) chemical compound (compound known or the chemical compound for preparing through known method, wherein PG ¹Be the nitrogen-protecting group of suitably selecting, as-CH (phenyl) ₂, benzyl, the tert-butyl group, methyl etc., be preferably-CH (phenyl) ₂) reaction in organic solvent (like acetonitrile, THF, DCM etc.) (preferably about 50 ℃ to about 90 ℃ of temperature ranges), obtain corresponding formula (VII) chemical compound.

According to known method formula (VII) chemical compound is gone protection, to produce corresponding formula (VIII) chemical compound.For example, PG wherein ¹For-CH (phenyl) ₂, formula (VII) chemical compound goes protection through reacting in organic solvent (like dichloromethane) with chloroformate-1-chloro-ethyl ester, in organic solvent (like methanol), refluxes then, obtains corresponding formula (VIII) chemical compound.

Under the situation that has the coupling agent of suitably selecting (like HATU, HBTU, DCC etc.), the organic base of suitably selecting (like DIPEA, TEA, pyridine etc.); With formula (VIII) chemical compound and suitable substituted formula (IX) chemical compound (compound known or the chemical compound for preparing through known method, wherein LG ¹Be selected from-C (O) Cl and C (O) OH, and LG wherein ¹The benzo that is connected formula (IX) chemical compound merges the required bonding position on the phenyl ring partly) reaction in organic solvent (like acetonitrile, DMF, DCM etc.), obtain corresponding formula (I) chemical compound.

Following instance provides in order to help to understand the present invention, is not intended to and should be interpreted as and limit listed the present invention in the instance following claim book by any way.

In the following example, some synthetic products of having separated have been listed as residue.It should be appreciated by those skilled in the art that " residue " do not limit the physical state of product when separated, and can comprise for example solid, grease, foam, jelly, slurry etc.

At room temperature to 4-amino-3-hydroxy-benzoic acid methyl ester (5g, 29.91mmol)/CH ₃OH (150mL) solution adding hexahydrobenzaldehyde (3.6mL, 29.91mmol).The mixture of gained is at room temperature stirred 2h.Through the evaporative removal solvent, with CH ₃CN (150mL) adds in the residue.At N ₂(13.26g 29.91mmol), refluxes the mixture of gained 10 minutes to add a part of lead acetate (IV) under the atmosphere.After the cooling, filter the solid of gained and use CH ₃The CN washing.Add 3N NaOH (40mL) to filtrating then.Mixture with gained under 50 ℃ stirred 18 hours.Through the evaporative removal solvent; Through on silica gel, carrying out the residue of flash column chromatography purification gained, obtain 2-cyclohexyl-benzo

azoles-6-carboxylic acid.MS?m/z(M+H ⁺)246.2。

To 2-cyclohexyl-benzo

azoles-6-carboxylic acid (0.47g; 1.9mmol) and HBTU (0.94g; 2.5mmol) DMF (10mL) solution add DIPEA (1.4mL, 7.6mmol).At room temperature the mixture with gained stirred 10 minutes, added aza-cyclobutane-3-alcohol (0.452g, hydrochlorate 4.7mmol) then.At room temperature the mixture with gained stirred 1 hour, used the reversed phase liquid chromatography purification then.Lyophilizing comprises the fraction of product, obtains (2-cyclohexyl-benzo

azoles-6-yl)-(3-hydroxyl-azetidin-1-yl)-ketone.MS?m/z(M+H ⁺)301。

Step C:2-cyclohexyl-6-{ [3-(4-pyridine-2-base piperazine-1-yl) azetidin-1-yl] carbonyl }-

-40 ℃ with nitrogen atmosphere under with methylsufonyl chloride (0.152mL; 1.9mmol) dropwise join (2-cyclohexyl-benzo azoles-6-yl)-(3-hydroxyl-azetidin-1-yl)-ketone (0.48g; 1.6mmol) and DIPEA (0.558mL is in DCM 3.2mmol) (20mL) solution.Remove cooling bath immediately after adding, let mixture slowly be warming up to room temperature.Use the mixture of water washing gained then, carry out drying, filter, and under reduced pressure remove solvent with magnesium sulfate.The residue of gained is dissolved in the acetonitrile (1mL).Add DIPEA (0.41mL, 2.4mmol) and N-(2-pyridine radicals) piperazine (1.6mmol).Then under 160 ℃ with the mixture microwave heating of gained 4 hours.DMF (3mL) is added in the mixture of gained, carry out purification with reversed phase liquid chromatography then.The fraction that comprises product with 1N HCl (5mL) dilution; Lyophilizing then; Obtain 2-cyclohexyl-6-{ [3-(4-pyridine-2-base piperazine-1-yl) azetidin-1-yl] carbonyl of its corresponding hydrochloride form }-1,3-benzo azoles.

¹H?NMR(400MHz，DMSO-d ₆)δ＝9.21(s，1H)，8.15(d，J＝5.1Hz，1H)，7.96(d，J＝8.3Hz，1H)，7.81(br.s.，1H)，7.16-7.22(m，1H)，7.06(d，J＝8.3Hz，1H)，6.88(s，1H)，4.54(br.s.，2H)，4.38(d，J＝6.6Hz，2H)，4.13(br.s.，1H)，3.73(br.s.，8H)，3.31-3.60(m，1H)，1.77(d，J＝13.7Hz，4H)，1.65(br.s.，1H)，1.32-1.44(m，2H)，1.15-1.32(m，2H)，1.06(t，J＝7.0Hz，1H)。MS?m/z(M+H ⁺)446。

Can come similarly to prepare chemical compound #2 to 28 through replacing the suitable selection of warp well known by persons skilled in the art and/or alternate reagent, raw material and purification process according to above instance 1 described step.

Instance 2: (vitro detection analysis): MGL enzyme assay

In the black 384-hole polypropylene PCR microwell plate (Abgene) of 30 μ L cumulative volumes, carry out all check and analysis based on rat.(4MU-B, Sigma) the saltant MGL enzyme (mut-MGLL 11-313 L179S L186S) with purification is diluted to respectively in the 20mM PIPES buffer agent (pH 7) that comprises 150mM NaCl and 0.001% polysorbas20 with substrate 4-methyl umbelliferone butyrate.With Cartisian Hummingbird pipettor (Genomic Solutions (Ann Arbor; MI)) with formula (I) chemical compound pre-dispersed (50nL) in analysis plates; Add 4MU-B (the 1.2X solution of 25 μ L then; Ultimate density is 10 μ M), then add enzyme (the 6X solution of 5 μ L, ultimate density are 5nM) with initiation reaction.Final compound concentration is in 17 to 0.0003 μ M scopes.Under 37 ℃ respectively with the exciting and emission wavelength of 335nm and 440nm, and the bandwidth (Safire of 10nm ², Tecan) monitor the change in fluorescence that takes place because of the 4MU-B cracking, the time is 5 minutes.

Use Excel, by to as the active concentration of the part of inhibitor concentration function-response diagram fitting formula, the IC of mensuration formula (I) chemical compound ₅₀Value.

ThermoFluor (TF) is determined as based on the combination of 384 orifice plates and measures, and it can measure proteinic heat stability (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.J Biomol Screen 2001,6,429-40 (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., " biomolecular screening journal, calendar year 2001, the 6th volume, 429-440 page or leaf); Matulis, D., Kranz, J.K., Salemme, F.R.; And Todd, M.J.Biochemistry 2005,44,5258-66 (Matulis, D., Kranz, J.K., Salemme; F.R. and Todd, M., " journal of biological chemistry ",, the 44th volume, 5258-5266 page or leaf in 2005)).Experiment is used and is derived from the Development from Johnson & Johnson Pharmaceutical Research &, and the instrument of LLC carries out.The TF dyestuff that uses in all experiments is 1,8-ANS (Invitrogen:A-47).The final TF condition determination that is used for MGL research is for being dissolved in 0.07mg/ml purified mutant type MGL (mut-MGLL 11-313 L179S L186S), 100 μ M ANS, 200mM NaCl, 0.001% tween 20 of 50mM PIPES (pH=7.0).

The SCREENED COMPOUND plate comprises the 100%DMSO compound solution of single concentration.With regard to follow-up concentration-response investigations, chemical compound is arranged in (Greiner Bio-one:781280) in the pre-dispersed plate, the chemical compound serial dilution in wherein going continuous 11 is in 100%DMSO.The 12nd and 24 row are as the DMSO object of reference, and inclusion compound not.For single and a plurality of compound concentrations-response experiment; All be that (Genomic Solutions (Ann Arbor, MI)) is automatically directly pre-dispersed to black 384 hole polypropylene PCR microwell plates (Abgene:TF-0384/k) with chemical compound aliquot (50nL) with Cartesian Hummingbird pipettor.After chemical compound disperses, add protein and dye solution, obtain the final mensuration volume of 3 μ L.At the silicone oil (Fluka, DC 200:85411 type) of measuring solution upper berth skim 1 μ L to avoid evaporating.

The analysis plates that to compile bar code with automat is loaded on the hot piece of thermostatically controlled PCR-type, and all then experiments all are heated to 90 ℃ with the gradient speed of 1 ℃/min from 40.Adopt ultraviolet light (Hamamatsu LC6) Continuous irradiation to measure fluorescence, wherein ultraviolet light is provided by optical fiber and filters through bandpass filter (380-400nm,＞6 OD cutoff).Through 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.Collect the single image of 20 seconds time of exposure at each temperature, and record analysis plate appointed area interior pixel intensity with respect to temperature add with, and with the normalized form match, obtain T _m(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., J Biomol Screen 2001,6; 429-40 (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., " the biomolecular screening journal, calendar year 2001, the 6th the volume, the 429-440 page or leaf)).

Instance 4:2-AG accumulates mensuration

With HeLa cell with Polytron homogenize in 10ml (about 400,000,000 cells) the HEPES buffer (HEPES 20mM, pH 7.4, NaCl 125mM, EDTA 1mM, KCl 5mM, glucose 20mM).The homogenate that will derive from 0.2 hundred million cells (0.5ml) was with MGL inhibitor incubation 15 minutes, and MGL is active with retardance, then with the HEPES buffer with calcium (10mM) incubation 20 minutes.Total reaction volume is 5ml.Through 6mL organic solvent extraction (2: 1 chloroform/methanol) cessation reaction.Methyl arachidonic base fluoro phosphonate ester (MAFP) is used as positive control.Under the situation that does not have MAFP, the 2-AG level is that about 3.4 skins rub/sample.Under the situation that has 100nM MAFP, the 2-AG level increases to 174 skins and rubs/sample.Measure the 2-AG:%MAFP=(chemical compound 2-AG/MAFP 2-AG) * 100 that accumulates in the organic facies according to following formula with the HPLC/MS method.

According to the representative compound of the program test formula (I) described in preceding text instance 2,3 and 4, the result lists in the table 4.

Table 4

Instance 5: oral formulations-imaginary instance

As a specific embodiment of Orally administered composition, the chemical compound #1 for preparing in the instance 1 of 100mg is prepared with the lactose of abundant pulverizing, fill O size hard capsule with the total amount that 580-590mg is provided.

Although above-mentioned specification teaches principle of the present invention; To be exemplified as purpose instance is provided, 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

1. a treatment or alleviate receives the method for disease, syndrome, disease or obstacle that MGL suppresses to influence, and said method comprises formula (I) chemical compound to experimenter's administering therapeutic effective dose that needs are arranged

It is selected from:

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for cyclohexyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 4-fluoro phenyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 4-methoxyphenyl;

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H, For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be cyclohexyl methyl, and R ³Chemical compound for hydrogen;

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be n-pro-pyl, and R ³Chemical compound for methyl;

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the tert-butyl group;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 3-methoxyphenyl;

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is CH, R ¹Be the 2-methoxyl group,

Wherein W is CH, R ¹Be the 4-fluoro,

For

Wherein W is N, R ¹Be H, For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be the tert-butyl group, and R ³Be 2, the chemical compound of 2-dimethyl propyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-NH-C (R ²)-C (R ³)-, R ²Be the 4-aminomethyl phenyl, and R ³Chemical compound for methoxyl group-methyl-carbonyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be n-pro-pyl, and R ³Chemical compound for cyclohexyl methyl;

And enantiomer, diastereomer and officinal salt.

2. method according to claim 1, the chemical compound of wherein said formula (I) is selected from:

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for cyclohexyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be the 4-aminomethyl phenyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 4-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 4-methoxyphenyl;

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenoxymethyl, and R ³Chemical compound for cyclohexyl methyl;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is N, R ¹Be H,

For

And enantiomer, diastereomer and officinal salt.

3. method according to claim 1, the chemical compound of wherein said formula (I) is selected from:

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H, For

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 4-fluoro phenyl;

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 4-methoxyphenyl;

Wherein W is N, R ¹Be H, For X-Y-Z is-CH-C (R ²)-N (R ³)-, R ²Be phenoxymethyl, and R ³Chemical compound for isobutyl group;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

And enantiomer, diastereomer and officinal salt.

4. method according to claim 1, the chemical compound of wherein said formula (I) is selected from:

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for cyclohexyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 4-methoxyphenyl;

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H,

For

Wherein W is N, R ¹Be H, For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the 3-methoxyphenyl;

Wherein W is CH, R ¹Be the 2-methoxyl group,

For

Wherein W is N, R ¹Be H,

For

X-Y-Z is-NH-C (R ²)-C (R ³)-, R ²Be the 4-aminomethyl phenyl, and R ³Chemical compound for methoxyl group-methyl-carbonyl;

Wherein W is N, R ¹Be H,

For

And enantiomer, diastereomer and officinal salt.

5. method according to claim 1, the chemical compound of wherein said formula (I) is selected from:

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for cyclohexyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 3-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for 4-fluoro phenyl;

Wherein W is N, R ¹Be H,

For

X-Y-Z is-O-C (R ²)=N-, and R ²Chemical compound for the tert-butyl group;

And enantiomer, diastereomer and officinal salt.

6. method according to claim 1, disease, syndrome, disease or the obstacle that the wherein said MGL of receiving suppresses to influence are selected from pain, inflammatory pain, the irritated disease of inflammatory and neuropathic pain.

7. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are pain.

8. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are inflammatory pain.

9. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are visceral pain.

10. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are ulcerative colitis.

11. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are neuropathic pain.

12. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are the unusual cold type of pain of nerve.

13. method according to claim 1, disease, syndrome, disease or obstacle that the wherein said MGL of receiving suppresses to influence are selected from inflammatory pain and neuropathic pain.

14. the purposes of chemical compound according to claim 1 is used to prepare medicament or pharmaceutical composition, the said MGL of receiving that said medicament or pharmaceutical composition are used to treat the experimenter of needs suppresses the disease, syndrome, disease or the obstacle that influence.

15. the purposes of chemical compound according to claim 1 is used to prepare medicament or pharmaceutical composition, said medicament or pharmaceutical composition are used to treat the experimenter's of needs inflammatory pain or neuropathic pain.