CN101626770A - Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release - Google Patents
Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release Download PDFInfo
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Abstract
The present invention is directed to methods of enhancing insulin release, GLP-1 release, and insulin sensitivity, methods of increasing insulin gene expression, methods of decreasing gastric secretion and emptying and glucagons secretion, and methods of inhibiting food intake, and methods of treating diabetes mellitus, insulin resistance syndrome, hyperglycemia, and obesity comprising administering to a subject an effective amount of a TRPM5 inhibitor.
Description
Background of invention
Technical field
The formula I chemical compound that the present invention relates to TRPM5 inhibitor such as this paper by the experimenter being given effective dose strengthens insulin to be discharged, strengthens GLP-1 and discharge, increase insulin sensitivity, increase insulin gene and express, reduce gastric secretion, reduce gastric emptying and reduce the method for glucagon secretion.The invention still further relates to the method for formula I compounds for treating diabetes, insulin resistance syndrome, hyperglycemia and the obesity of TRPM5 inhibitor such as this paper by the experimenter being given effective dose.The invention further relates to the method for using this TRPM5 inhibitor above-mentioned disease of treatment in the animal that needs, preferred people or other mammal are arranged and relate to the pharmaceutical composition that can be used for this method.Of the present invention these are further described in detail in this article with other aspect.
Background technology
Diabetes be with insulin generate unusual, urine discharge increase and blood sugar level to raise be the syndrome of feature.Based on the insulin level that generates by human pancreas's beta cell, can mention two kinds of main subclass.One class is insulin dependent diabetes mellitus (IDDM) (IDDM, or 1 type), is called as juvenile onset diabetes in the past because its in life early stage just obviously.In type 1 diabetes, generate insulin seldom or do not generate insulin, because the pancreas beta cell is destroyed by the immune system of health self.It is IDDM (American DiabetesAssociation that 5-10% is arranged in all diabetes.Diabetes?1996?Vital?Statistics.Rockville，Md.：American?Diabetes?Association，1996)。Another kind of is non-insulin-dependent diabetes mellitus (NIDDM, or 2 types), is commonly called maturity-onset diabetes.In type 2 diabetes mellitus, the pancreas beta cell generates insulin, but growing amount is not enough to keep healthy blood sugar level.Degeneration (for example insulin resistant and insulin the discharge not enough) institute of the branch clamp mechanism of the effectiveness that type 2 diabetes mellitus is worked by mediation insulin pair cell causes.It is NIDDM (Harris, M.I., Cowie, C.C., Stern, M.P. volume, Diabetes in America, 2nd.ed.National Institutes ofHealth that 90-95% is arranged in all diabetes.National?Institute?of?Diabetes?and?Digestive?andKidney?Diseases.NIH?Publication?No.95-1468，1995)。
Opposing to the insulin metabolism effect is one of key feature of non-insulin-dependent diabetes mellitus.Insulin resistant is characterised in that the picked-up of glucose in target organ such as the adipose cell of insulin sensitivity and skeletal muscle and utilizes impaired and be that the inhibition that hepatic glucose discharges is impaired.The plain inhibition failure not enough and that insulin is discharged hepatic glucose of functional islets causes hyperglycemia on an empty stomach.The pancreas beta cell increases the usually compensatory insulin resistant of islets of langerhans of level by secretion.Yet beta cell can not keep the height output of this insulin, and, final, by the insulin release decline of glucose induction, the development that causes glucose homeostasis to degenerate and cause overt diabetes subsequently.
Comprise insulin resistance syndrome (hereinafter being called " IRS ") with impaired other metabolic disorder relevant with insulin resistant of glucose utilization, it is meant that one group comprises the following form of expression: insulin resistant; Hyperinsulinemia; Non-insulin-dependent diabetes mellitus (NIDDM); Arterial hypertension; Central authorities' (visceroatonia type) obesity; With the dyslipidemias mass formed by blood stasis.
Thereby the main target of insulin resistant treatment and treating diabetes thus is blood sugar lowering level prophylaxis of acute and secular disease complication.For some,, regulate diet and increase and temper the treatment selection that may become success in order to realize controlling the target of glucose.When adjusting diet and increase exercise are unsuccessful, bring into use the pharmacotherapy of oral antidiabetic.
The control that insulin discharges is extremely important, because there is its pancreas of diabetics of many survivals correctly not work.In the diabetes of some types, total insulin level is lowered, and is lower than for keeping the required level of euglycemia level.In other type, increase the back in blood sugar level and produce desired insulin, but only after unwelcome delay, just produce.In other type, health has opposing to the insulin effect for a certain reason.If the control to diabetes is poor, it can cause diabetic complication.Diabetic complication is common in 2 type patients, about 50% suffers from one or more complication (Clark when diagnosis, C.M., Vinicor, F.Introduction:Risks and benefits of intensive management innon-insulin-dependent diabetes mellitus.The FifthRegensrief Conference.Ann Intern Med, 124 (1, pt 2), 81-85,1996).
Use the injection exogenous insulin to come control of diabetes clinically, but run into many problems.Insulin is a protein, therefore since digestion and degraded cause and can not must be injected by oral.Can not obtain good control by insulin administration to blood sugar level.Insulin resistant takes place often, requires the insulin of the dosage more much higher than normal dose.Another shortcoming of insulin is, although its may command hormone abnormality, it can complication prevention such as neuropathy, retinopathy, glomerulosclerosis and cardiovascular diseases's generation.Insulin is mainly by acting on two target tissues: liver and muscle are regulated glucose homeostasis.Liver is glucogenic unique position, and skeletal muscle is the main position by the glucose uptake of insulin-mediated.
Have following a few class medicine to can be used for treating type 2 diabetes mellitus: 1) insulin releasing agent, it directly stimulates insulin to discharge, and has the hypoglycemia risk; Insulin releasing agent when 2) eating, it is strengthened by the insulin release of glucose induction and must be given before every meal; 3) biguanides comprises metformin, and it weakens liver glyconeogenesis (it raises contradictoryly) in diabetes; 4) insulin sensitizer, for example thiazolidine diketone derivative rosiglitazone and pioglitazone, it improves replying around the insulin, but it has side effect, such as weight increase, edema and accidental hepatotoxicity; With 5) the injection of insulin agent, when islets of langerhans can not be brought into play function under secular superelevation stimulates, injection of insulin was normally necessary in later stage of type 2 diabetes mellitus.The effectiveness of oral antidiabetic treatment at present is restricted, in part because relatively poor or limited glycemic control, or because because patient's compliance that unwelcome side effect caused is poor.These side effect comprise edema, weight increase, hypoglycemia and even severe complications more.
The insulin secretagogue agent is the standard treatment that is used to have the type 2 diabetes mellitus of light to moderate empty stomach hyperglycemia.The insulin secretagogue agent comprises sulfonylurea (SFU) and non-sulfonylurea Nateglinide and repaglinide.Sulfonylurea is subdivided into two groups: first generation medicament, for example tolbutamide, chlorpropamide, tolazamide, acetohexamide and second filial generation medicament, for example glibenclamide (glyburide), glipizide and gliclazide.
The restriction that the insulin secretagogue agent has comprises may induce hypoglycemia, weight increase and high constitutional and Secondary cases mortality.About 10 to 20% fail to show notable therapeutic effect (constitutional treatment failure) among the patient who receives treatment at first.Secondary cases treatment failure is presented at treats after 6 months therapeutic effect with the insulin secretagogue agent and loses 20-30% in addition.Behind treatment 5-7, in 50% insulin secretagogue agent respondent, require to use insulin treatment people such as (, Diabetes Res.Clin.Pract.6:533 543,1989) Scheen.Nateglinide and repaglinide are fugitive medicines, and it needs every day and gives three times.They only are used to control GLPP, but not are used to control fasting glucose.
Use the risk (or insulin shock) that sulfonylurea is treated increases hypoglycemia, hypoglycemia drops to normal level in blood sugar level (UKPDS Group.UKProspective Diabetes Study 33:Intensive blood-glucosecontrol with sulphonylureas or insulin compared withconventional treatment and risk of complications in patientswith type 2 diabetes.Lancet takes place when following, 352,837-853 (1998).
Treating with the gastrointestinal tract proteohormone may be the method for another kind of treatment diabetes.The gastrointestinal tract proteohormone, include but not limited to, glucose-dependent-insulinotropic polypeptide (GIP) and glucagon-like-peptide-1 (GLP-1) stimulate insulin synthetic and from the secretion of the beta cell of Langerhans' islands cell after food intake, thus the blood sugar lowering level.In addition, the oral administration of long-term known glucose increases insulin secretion and surpasses intravenous glucose dosage, although have similar plasma glucose concentration.People such as Scow, Am J.Physiol., 179 (3): 435-438 (1954).This effect is called as incretin secretion effect, for the treatment of regulating glucose disposal and diabetes and relevant disease thereof provides the foundation.
The most powerful gastrointestinal tract proteohormone is GLP-1, and it is 37 amino acid whose peptides at first and is the product of proglucagon.Endogenous between the 6th and the 7th division subsequently produces GLP-1 (7-37) peptide with biologic activity.When taking in glucose, GLP-1 is secreted by the L type enteroendocrine cell in the splanchnic cavity surface.The cell surface receptor (GLP-1R) of GLP-1 by the G albumen coupling works and is subjected to the T1R taste receptors and flavor albumen (gustducin) is regulated.Referring to people such as Kokrashvili, AChemS XXIX Abstract, 246 (2007).Research shows, by the GLP-1 of sugar and sweeting agent stimulation from the secretion of L type enteroendocrine cell, α-flavor protein binding sweet receptor T1R3.Referring to people such as Jang, Proc.Natl.Acad.Sci.USA, 104 (38): 15069-15074; People such as Margolskee, Proc.Natl.Acad.Sci.USA 104 (38): 15075-15080 (2007).GLP-1 has several physiological functions; For example, 1) it stimulates insulin synthetic from islet cells in glucose dependency mode, thus the blood sugar lowering level; 2) it reduces the secretion of glucagon from pancreas; 3) it increases beta cell amount and insulin gene expression; 4) it suppresses gastric secretion and emptying; 5) its dose-dependent inhibition food intake by increasing satiety; With 6) its promotion loses weight.Several effects of GLP-1 are described in United States Patent (USP) 6,583,118; United States Patent (USP) 7,211,557; US patent application publication 2005/0244810; Deacon, Regulatory Peptides 128:117-124 (2005); With people such as Turton, Nature, 379, among the 69-72 (1996).
Summary of the invention
Therefore, by increasing that the GLP-1 secretion level can be used for directly stimulating insulin secretion or the antidiabetic drug of indirect stimulation insulin will be required for the treatment of diabetes and associated conditions thereof.
The present invention relates to the application that the TRPM5 inhibitor is used to strengthen insulin secretion.In addition, according to the present invention, the TRPM5 inhibitor can be used for treating that increase has the patient's condition of other patient's condition of actively replying such as diabetes with to insulin.
In one embodiment, method by the formula I compounds for treating diabetes that the experimenter given this paper is disclosed.
The method of treatment in mammal, prevention or control hyperglycemia and/or insulin resistant also is provided, has comprised the TRPM5 inhibitor that the experimenter that needs are arranged is given effective dose, all suc as formula the I chemical compound.
Aspect of this embodiment, diabetes are type 2 diabetes mellitus or youthful maturity-onset diabetes, and on the other hand, the TRPM5 inhibitor strengthens insulin and discharges, and discharge such as strengthening the insulin that is stimulated by glucose.In others, this chemical compound strengthens the insulin that is stimulated by excusing from death reason (supraphysiological) concentration of glucose and discharges, and the insulin that does not strengthen under the condition that the physiology concentration of glucose exists discharges.
The pharmaceutical composition that is used for the treatment of diabetes, insulin resistance syndrome and hyperglycemia also is provided, and it is all suc as formula the I chemical compound that it comprises the TRPM5 inhibitor.These and other aspect of the present invention is described in more detail at this paper.
The invention still further relates to enhancing GLP-1 from the method that cell discharges, comprise one or more TRPM5 inhibitor that make described cells contacting effective dose.In certain embodiments, the TRPM5 inhibitor is a formula I chemical compound.
The invention still further relates to the method that in mammal, reduces gastric secretion and emptying, the method that suppresses food intake, reduce the method for glucagon secretion, strengthen the method for insulin sensitivity, increase the method that insulin gene is expressed, with the method for treatment of obesity, comprise one or more TRPM5 inhibitor that the described mammal that needs are arranged given effective dose.In certain embodiments, the TRPM5 inhibitor is a formula I chemical compound.
Description of drawings
Figure 1A is illustrated in the stimulation of in β-TC6 cell insulin being synthesized and discharging under the different condition (A-H).(A-H) is as follows for described different condition: A) KRBB buffer; B) KRBB and DMSO (vehicle); C) KRBB, DMSO and LG compd A (100 μ M, the chemical compound of a kind of known enhancing TRPM5); D) KRBB, DMSO and embodiment 4 (100 μ M); E) KRBB and 2mM glucose; F) KRBB, 2mM glucose and DMSO; G) KRBB, DMSO, 2mM glucose and LG compd A (100 μ M); H) KRBB, DMSO, 2mM glucose and embodiment 4.Figure 1B represents to be used for the identical result that quilt that KRBB (buffer) replys deducts.
Fig. 2 provides in β-TC6 cell under the condition that glucose (2mM) exists the dosage-response curve of the insulin secretion that the chemical compound by embodiment 4 stimulates.
The influence that the insulin that Fig. 3 has compared concentration of glucose to be stimulated chemical compound and tolbutamide by embodiment 3 discharges.As shown in Figure 3, the chemical compound of embodiment 3 and tolbutamide increase insulin secretion in glucose dependency mode on the contrary, and tolbutamide is insensitive to glucose level.
Fig. 4 represents that chemical compound, tolbutamide and the diazoxide of embodiment 3 are the influence of the insulin secretion of TC6 to mice beta cell insulinoma.
Fig. 5 illustrates that some TRPM5 reinforcing agent is invalid and the chemical compound of explanation embodiment 3 increases insulin secretion in stimulating insulin secretion.
Fig. 6 illustrates embodiment 4 and the tolbutamide adduction effect to insulin secretion.
Fig. 7 represents that the chemical compound of embodiment 4 and tolbutamide increase insulin secretion in glucose dependency mode on the contrary.
Fig. 8 represents that glibenclamide is for the dosage of insulin secretion-reply.
Fig. 9 is illustrated in the dose response of all cpds under the condition that 100 μ M tolbutamides exist.
Figure 10 is illustrated in the dose response of all cpds under the condition that 300 μ M diazoxide exist.
Figure 11 provides the experimental result that is plotted figure, its be illustrated in the β TC-6 cell and the HEK cell with the TRPM5 clone in, the similarity between calcium-activated ion channel current.
Figure 12 illustrated in β TC-6 cell and according to people such as Talavera, and Nature438:1022-1025 (2005) is reported in the temperature dependent similarity between calcium-activated electric current in the TRPM5 passage.
Figure 13 provides the electric current-time graph of calcium-activated electric current in β TC6 cell and has shown that the electric current that pulsed dosage caused by the chemical compound of embodiment 4 suppresses.
Figure 14 provides a gel electrophoresis figure, and it has shown to be determined in the mice β TC-6 cell according to RT-PCR and has mTRPM5.
Figure 15 provides the isolating result of HPLC of the enantiomer of embodiment 4 chemical compounds.
Figure 16 is illustrated in the GLUTag cell, and TRPM5 inhibitor (chemical compound of embodiment 3) strengthens the GLP-1 secretion under the condition that the 10mM glucose exists, and in the GLUTag cell, the TRPM5 reinforcing agent reduces the GLP-1 secretion under the condition that the 10mM glucose exists.
The chemical compound that Figure 17 is illustrated in embodiment 3 and embodiment 23 in the GLUTag cell increases the GLP-1 secretion under the condition that the 12.5mM glucose exists.The chemical compound of embodiment 3 increases the excretory effectiveness of GLP-1, and the chemical compound of embodiment 23 is stronger than the effectiveness of the chemical compound of embodiment 3.In order relatively to have shown the standard curve of the glucose that is used for GLP-1 release.
Figure 18 is illustrated in the GLUTag cell, and the chemical compound of embodiment 3 and embodiment 23 increases GLP-1 and discharges under the condition of glucose (3.3mM) existence of medium high concentration.
The chemical compound that Figure 19 is illustrated in embodiment 3 and embodiment 23 in the GLUTag cell increases GLP-1 and discharges under the condition that LG (0.1mM) exists.The IC of these two embodiment
50Value (being respectively 600nM and 111nM) and the IC that in the test of FLIPR transmembrane potential, obtains
50Be worth similar.
Detailed Description Of The Invention
The invention provides the method and composition and the application thereof that can be used for increasing insulin release, GLP-1 release, insulin sensitivity and insulin gene expression. Other side of the present invention is described in detail in this article.
Using method
A first aspect of the present invention relates to the method that strengthens insulin secretion, comprises the compound as the TRPM5 inhibitor that gives effective dose. This compound can be administered to cell or whole organism, in order to obtain the insulin secretion of enhancing. In addition, the TRPM5 inhibitor can be given such as glucose individually or with the known medicament that causes that insulin secretion discharges. For example, the used TRPM5 of the present invention can be IC50Be 1 micromole or lower, preferred 100 nanomoles or lower TRPM5 inhibitor. In another embodiment, the used TRPM5 inhibitor of this method suppresses TRPM5 acceptor at least 75%, preferred 90% under 5 micromoles or lower concentration.
The TRPM5 inhibitor can adopt test disclosed herein and method to identify. In addition, disclosed test can be used for identifying compound as the TRPM5 inhibitor in the U.S. Patent application 11/592,180 (it is merged in this paper in full) of submitting on November 3rd, 2006. In addition, disclosed test can be used for identifying compound as the TRPM5 inhibitor in the US patent application publication 20050019830 that is merged in full this paper.
In certain embodiments, the TRPM5 inhibitor can be protein, peptide, little molecule or natural products. In preferable case, suppress the sense of taste with little molecule TRPM5 inhibitor in the methods of the invention. For example, the TRPM5 inhibitor can be the micromolecular compound that molecular weight is less than or equal to about 500 mass units. In another embodiment, to can be molecular weight be about 50 to the little molecules of about 500 mass units to the TRPM5 inhibitor. As an alternative, the TRPM5 inhibitor can be the little molecule that molecular weight is about 100,200,300 or 400 mass units. These compounds can be selected from any particular compound as herein described or group.
Can be used for TRPM5 inhibitor of the present invention and can comprise many chemical functional groups. In some embodiment of this method, preferred TRPM5 inhibitor comprises that one or more are selected from the functional group of following preferred group. For example, in preferable case, the used TRPM5 inhibitor of this method comprises about 5 or hydrogen bond donor still less (for example OH and NH yl). In other embodiments, the used TRPM5 inhibitor of this method will comprise about 10 or hydrogen bond receptor still less (for example N and O). These compounds can be selected from any particular compound as herein described or group. In preferred version, the used TRPM5 inhibitor of this method will comprise 1 to 5 hydrogen bond donor and 1 to 5 hydrogen bond receptor.
The TRPM5 inhibitor can comprise for example one or more following functional groups in its structure: pyridine radicals, high pyridine radicals, amino piperidine base mephenesin Carbamate, carbanilic acid ester, cyclohexyl, cyclopenta, piperidyl, piperazinyl, pyrrole radicals, furyl, thienyl, pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl ， oxazolyl isoxazolyl ， oxadiazolyl, triazolyl, tetrazole radical, pyridine radicals, pyrimidine radicals, benzimidazolyl, naphthyl, indyl, isoindolyl, benzofuranyl, isobenzofuran-base, benzo [b] thienyl, benzo [d] isoxazolyl, quinolyl, isoquinolyl, cinnolines base, quinazolyl and quinoxalinyl.
In another embodiment, the TRPM5 inhibitor can include but not limited to following functional group in its chemical constitution: pyridine radicals, high pyridine radicals, amino piperidine base mephenesin Carbamate, carbanilic acid ester, cyclohexyl, cyclopenta, piperidyl, piperazinyl, pyrrole radicals, furyl thienyl, pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl oxazolyl ， isoxazolyl ， oxadiazolyl, triazolyl, tetrazole radical, pyridine radicals, pyrimidine radicals, benzimidazolyl, naphthyl, indyl, isoindolyl, benzofuranyl, isobenzofuran-base, benzo [b] thienyl, benzo [d] isoxazolyl, quinolyl, isoquinolyl, cinnolines base, quinazolyl and quinoxalinyl, they are randomly replaced by benzene, halide, amine, hydroxyl and/or alkyl. These compounds can be selected from any particular compound as herein described or group.
In other embodiments, the partition coefficient (log P) that the used TRPM5 inhibitor of this method has is for about 0 to about 5, is preferably about 1 to about 5, or is about 2 to about 4.These chemical compounds can be selected from any particular compound as herein described or group.
In yet another embodiment, suitable TRPM5 inhibitor is that molecular weight is 100 to 500 mass units and comprises one or more in its chemical constitution, the TRPM5 inhibitor of preferred 1-3 following functional group: pyridine radicals, high pyridine radicals, amino piperidine base mephenesin Carbamate, N-carboxyaniline. ester, cyclohexyl, cyclopenta, piperidyl, piperazinyl, pyrrole radicals, furyl thienyl, pyrazolyl, imidazole radicals, thiazolyl, isothiazolyl oxazolyl ， isoxazolyl ， oxadiazole base, triazolyl, tetrazole radical, pyridine radicals, pyrimidine radicals, benzimidazolyl, naphthyl, indyl, isoindolyl, benzofuranyl, isobenzofuran-base, benzo [b] thienyl, benzo [d] isoxazolyl, quinolyl, isoquinolyl, cinnolines base, quinazolyl and quinoxalinyl, they are randomly by benzene, halogenide, amine, hydroxyl and/or alkyl replace.These chemical compounds can be selected from any particular compound as herein described or group.
In one embodiment, this method comprises needing experimenter's giving construction I chemical compound that insulin discharges to be increased:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, it randomly is substituted separately;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, it randomly is substituted separately, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, it randomly is substituted separately.
In one embodiment, R
1Be optional substituted C
6-10Aryl is such as phenyl or naphthyl.In another embodiment, R
1Be the first heteroaryl of optional substituted 5-10, or the first heteroaryl of preferred 5-7, such as, but not limited to pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.In other situation, heteroaryl is nitrogenous heteroaryl or oxygen containing heteroaryl.
In another embodiment, R
1Be optional substituted 10-14 unit heteroaryl, such as carbazyl 9-carbazyl for example, or quinolyl 2-quinolyl for example.
R
1Another subclass comprise that having 1-3 is independently selected from following substituent substituted aryl or heteroaryl: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.Suitable R
1Group comprises 4,8-dimethyl quinoline-2-base.
In another embodiment, R
1Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.In another embodiment, R
1Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.Suitable R
1Group includes but not limited to cyclopropyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group etc.Cycloalkyl also comprises bicyclic alkyl and multi-ring alkyl, preferably contains 7-10 carbon atom, such as bicyclo-also [4.1.0] heptane base and adamantyl.
R
1Another subclass comprise that having 1-3 is independently selected from following substituent substituted C
3-10Cycloalkyl or C
3-10Cycloalkenyl group: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1- 4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1Be optional substituted C
1-6Alkyl, such as methyl, ethyl and propyl group.R
1Can be the straight or branched alkyl.Suitable substituted alkyl comprises haloalkyl, hydroxy alkyl, aminoalkyl etc.
In another embodiment, R
2Be H.As an alternative, R
2Be C
1-6Alkyl, such as methyl, ethyl or propyl group.R
2Can be the straight or branched alkyl.In other embodiments, R
2Be C
6-10Aryl (C
1-6) alkyl, such as benzyl, phenethyl or phenyl propyl.Preferably, R
2Be C
6-10Aryl (C
1-4) alkyl.
In other embodiments, R
3Be H.As an alternative, R
3Be C
1-6Alkyl, such as methyl, ethyl or propyl group.R
3Can be the straight or branched alkyl.In another embodiment, R
3Be cyano group (CN).
In another embodiment, R
4Be optional substituted C
6-10Aryl is such as phenyl or naphthyl.In another embodiment, R
4Be the first heteroaryl of optional substituted 5-10, or the first heteroaryl of preferred 5-7, such as including but not limited to: pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.In other situation, heteroaryl is nitrogenous heteroaryl.In other situation, heteroaryl is oxygen containing heteroaryl.
R
4Another subclass comprise that having 1-3 is independently selected from following substituent substituted aryl or heteroaryl: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxy C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.Suitable R
4Group comprises 3, the 4-Dimethoxyphenyl.
In another embodiment, R
4Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.In another embodiment, R
4Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.Suitable R
4Group includes but not limited to: cyclopropyl, cyclopenta, cyclohexyl, cyclopentenyl, cyclohexenyl group etc.Cycloalkyl also comprises bicyclic alkyl, such as bicyclo-[4.1.0] heptane base also.
In another embodiment, R
4Be optional substituted C
1-6Alkyl, such as methyl, ethyl and propyl group.R
4Can be the straight or branched alkyl.Suitable substituted alkyl comprises haloalkyl, hydroxy alkyl, aminoalkyl etc.
In one embodiment, L
1Do not exist.Therefore, according to this embodiment, R
1Directly be connected in nitrogen-atoms by single key.
In another embodiment, L
1Be to comprise 1-10, preferred 1-7 carbon atom and/or heteroatomic connection base and its to choose wantonly and be substituted.Connecting base is with R
1The divalent moiety that is connected with nitrogen.Connecting base can be to comprise 1-10 carbon atom and/or heteroatomic any suitable divalent moiety.Suitable connection base for example comprises 1,2,3,4,5 or 6 carbon atom and/or hetero atom.
For example, connecting base can be that the dicovalent carbon that contains individual, preferred 1-7 the carbon atom of 1-10 connects base, such as, but not limited to: methylene (CH
2-), ethylidene (CH
2-CH
2-), propylidene (for example ,-CH
2-CH
2-CH
2-), butylidene etc.As an alternative, L
1Can be C
3-10Cycloalkylidene connects base, such as the methylene cyclopropylidene.Dicovalent carbon connects base and can be replaced by suitable substituent group as herein described.In another subclass, substituent preferred group comprises: amino, hydroxyl, halogen, cyano group, mercaptan, oxo, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, amino carbonyl and C
2-6Carboxyalkyl.
L
1Also can be and contain 2-10, preferably contain 2-6 carbon atom and heteroatomic divalent linker.Suitable connection base comprises for example following limiting examples: alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylenedioxy group.Other suitable example comprises-OCH
2-,-SCH
2-,-NHCH
2-,-OCH
2CH
2-,-NHCH
2CH
2-and-OCH
2CH
2CH
2-.Can understand, not only having comprised carbon atom but also having comprised heteroatomic preferred connection base is that wherein hetero atom is not directly connected in the connection base of the nitrogen-atoms of formula I.
Connect basic L1 and also can comprise 1-10 hetero atom, preferably comprise 1,2 or 3 hetero atom.Suitable hetero atom connects base and comprises :-O-,-S-,-NH-,-N=N-etc.
In other embodiments, connect basic L
1Be 1-6 unit alkylidene, alkenylene or alkynylene part.In other embodiments, connect basic L
1Be the assorted alkylidene of 1-6 unit, assorted alkenylene or assorted alkynylene part.
Connect basic L
1Can as described hereinly be substituted.In one embodiment, connect basic L
1Be to comprise 1-6 carbon atom and be selected from the divalent moiety that following substituent group replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, oxo, C by 1,2 or 3
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, L1 is selected from following connection base:
In another embodiment, L
1Be to be selected from following connection base :-(O) CCH
2S-.
In other embodiments, R
1And L
1Form together and be selected from following group:
In one embodiment, L
2Do not exist.Therefore, according to this embodiment, R
4Be directly connected in by on two keys and the carbon atom that nitrogen-atoms is connected.
L
2Also can be and contain 2-10, preferably contain 2-6 carbon atom and heteroatomic divalent linker.Suitable connection base comprises for example following limiting examples: alkylidene oxygen base, alkylidene amino, alkylidene sulfenyl, alkylenedioxy group.Other suitable example comprises-OCH
2-,-NHCH
2-,-OCH
2CH
2-,-NHCH
2CH
2-and-OCH
2CH
2CH
2-.Can understand, not only having comprised carbon atom but also having comprised heteroatomic preferred connection base is that wherein hetero atom is not directly connected in the connection base of the nitrogen-atoms of formula I.In some cases, L
2Do not comprise loop systems.
Connect basic L
2Also can be and contain 1-10 hetero atom, preferably contain 1,2 or 3 heteroatomic connection base.Suitable hetero atom connects base and comprises :-O-,-S-,-NH-,-N=N-etc.
In other embodiments, R
4And L
2-rise to form and to be selected from following group :-N=N-aryl and-the N=N-heteroaryl.The suitable example of-N=N-aryl include but not limited to wherein phenyl optional substituted-the N=N-phenyl and wherein naphthyl choose substituted-N=N-naphthyl wantonly.
In other embodiments, R
4And L
2Form together and be selected from following group:
In first group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1Be optional substituted C
6-10Aryl;
R
2Be H or C
1-6Alkyl, preferred C
1-4Alkyl;
R
3Be H or C
1-6Alkyl, preferred C
1-4Alkyl; With
R
4Be optional substituted C
6-10Aryl.
In an embodiment of this first group, R
1It is unsubstituted phenyl.In other situation, C
6-10Aryl such as phenyl, is independently selected from following group by 1,2 or 3 and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of aryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2- 6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In another embodiment of this first group, L
1Be to contain 1-6 carbon atom and/or heteroatomic connection base and its optional being substituted.
In another embodiment of this first group, L
2Be to contain 1-6 carbon atom and/or heteroatomic connection base and its optional being substituted.
In another embodiment, L
2Do not comprise loop systems.
In another embodiment of this first group, R
4Be optional: nitro, bromo, chloro, carboxyl, methoxycarbonyl by 1-3 phenyl that is selected from following substituent group replacement, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In second group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1It is the first heteroaryl of optional substituted 5-10;
R
2Be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl; With
R
4Be optional substituted C
6-10Aryl.
In an embodiment of this second group, R
1Be the first heteroaryl of unsubstituted 5-10, such as indyl, pyridine radicals, benzothiazolyl, benzimidazolyl or quinolyl.As an alternative, R
1Be independently selected from the 5-10 unit heteroaryls that following substituent group replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2- 6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of heteroaryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In another embodiment of this first group, L
1Be to contain 1-10, preferably contain 1-4 carbon atom and/or heteroatomic connection base and its and choose wantonly and be substituted.
In another embodiment of this first group, L
2Be to contain 1-10, preferably contain 1-4 carbon atom and/or heteroatomic connection base and its and choose wantonly and be substituted.In other embodiments, L
2Do not comprise loop systems.
In the 3rd group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1Be optional substituted C
6-10Aryl;
R
2Be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl; With
R
4It is the first heteroaryl of optional substituted 5-10.
In an embodiment of the 3rd group, R
1It is unsubstituted phenyl.In other situation, C
6-10Aryl such as phenyl, is independently selected from following group by 1,2 or 3 and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
1-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of aryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2- 6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In another embodiment of this first group, L
1Be to contain 1-10, preferably contain 1-4 carbon atom and/or heteroatomic connection base and its and choose wantonly and be substituted.
In another embodiment of this first group, L
2Be to contain 1-10, preferably contain 1-4 carbon atom and/or heteroatomic connection base and its and choose wantonly and be substituted.In other embodiments, L
2Do not comprise loop systems.
In an embodiment of the 3rd group, R
4Be the first heteroaryl of unsubstituted 5-10, such as indyl, pyridine radicals, benzothiazolyl, benzimidazolyl or quinolyl.As an alternative, R
1Be independently selected from the 5-10 unit heteroaryls that following substituent group replaces by one or more: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In the 4th group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1It is the first heteroaryl of optional substituted 5-10;
R
2Be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl; With
R
4It is the first heteroaryl of optional substituted 5-10.
In an embodiment of the 4th group, R
1Be the first heteroaryl of unsubstituted 5-10, such as indyl, pyridine radicals or quinolyl.As an alternative, R
1Be independently selected from the 5-10 unit heteroaryls that following substituent group replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of heteroaryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In an embodiment of the 4th group, R
4Be the first heteroaryl of unsubstituted 5-10, such as indyl, pyridine radicals, benzothiazolyl, benzimidazolyl or quinolyl.As an alternative, R
1Be independently selected from the 5-10 unit heteroaryls that following substituent group replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2- 6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of heteroaryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
4On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In the 5th group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1Be optional substituted C
6-10Aryl;
R
2Be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl; With
R
4Be optional substituted C
3-10Cycloalkyl.
In an embodiment of the 5th group, R
1It is unsubstituted phenyl.In other situation, C
6-10Aryl such as phenyl, is independently selected from following group by 1,2 or 3 and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
In other other situation, the substituent group of aryl is selected from: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2- 6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In the 6th group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1It is the first heteroaryl of optional substituted 5-10;
R
2Be H or C
1-6Alkyl;
R
3Be H or C
1-6Alkyl; With
R
4And L
2Formation-N=N-aryl together.
In an embodiment of the 6th group, R
1Be the first heteroaryl of unsubstituted 5-10, such as indyl, pyridine radicals or quinolyl.As an alternative, R
1Be independently selected from the 5-10 unit heteroaryls that following substituent group replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
1-6Haloalkyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxyl, C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.In another embodiment, R
1On substituent group be independently selected from: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In the 6th group, R
4And L
2Formation-N=N-aryl together, wherein aryl is optional substituted C
6-10Aryl is such as phenyl or naphthyl.Suitable substituent group on the aryl includes but not limited to: nitro, bromo, chloro, carboxyl, methoxycarbonyl, methoxyl group, diethylamino, hydroxymethyl, methyl, pi-allyl oxygen base, trifluoromethyl sulfenyl, hydroxyl, trifluoromethyl, morpholinyl and pyrrolidinyl.
In the 7th group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1Be the first heteroaryl of optional substituted 5-10, such as pyridine radicals, quinolyl, benzothiazolyl, benzimidazolyl and indyl;
R
4Be optional substituted C
6-10Aryl is such as phenyl and naphthyl; With
L
1And L
2Do not exist.
In the 8th group, the present invention relates to increases the method that insulin discharges, and described method comprises the chemical compound to experimenter's giving construction I, wherein
R
1Be C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, assorted thiazolinyl of 3-10 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl;
L
1Do not exist, or contain 1-10, preferably contain 1-6 carbon atom and/or heteroatomic connection base and its and choose wantonly and be substituted;
R
3, R
4And L
2Form with carbon atom and to be selected from following group: C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, the assorted thiazolinyl of 3-10 unit ring, it randomly is substituted separately.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is heteroaryl; R
2Be H; R
4It is heteroaryl; L
1Do not exist; And L
2Be N=N.
In other group, the present invention relates to increases the method that insulin discharges, and wherein said method comprises chemical compound, wherein R to experimenter's giving construction I
1It is optional substituted nitrogenous heteroaryl; And R
2It is optional substituted phenyl.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is bicyclic alkyl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Do not exist; And L
2Do not exist.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is aryl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is cycloalkenyl group; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is optional substituted aryl; R
2Be H; R
3Be H; R
4Be optional substituted aryl or optional substituted heteroaryl; L
1Be-(CH
2)
1-6-C (O)-; And L
2Do not exist.
In other group, the present invention relates to increases the method that insulin discharges, and described method comprises chemical compound, wherein R to experimenter's giving construction I
1It is optional substituted naphthyl; R
2Be H; R
3Be H; R
4It is optional substituted aryl; L
1Be-(CH
2)-C (O)-; And L
2Do not exist.
In other group, method of the present invention comprises giving construction I chemical compound, wherein R
1Be optional by one or more C
1-6The quinolyl that alkyl replaces; L
1Be that optional substituted C1-4 connects base; And R
2Be optional substituted phenyl, such as by one or more C
1-6Alkoxyl replaces.
In other group, method of the present invention comprises giving construction I chemical compound, wherein R
1It is optional substituted carbazyl; L
1Be to contain 1 sulphur atom and further optional substituted C
1-6Connect base; And R
2Be optional substituted phenyl, such as by one or more C
1-6Alkoxyl replaces.
The suitable examples for compounds that is used for the inventive method comprises:
4-((E)-((Z)-1-(2-(benzo [d] thiazol-2-yl) hydrazine fork base)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group)-acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl)-acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine (carbohydrazide);
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl ((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide (carbonohydrazonoyldicyanide);
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N ' (4-morpholino-3-Nitrobenzol methylene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
And the acceptable salt of physiology.
Suitable chemical compound in addition comprises:
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides;
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides;
And the acceptable salt of physiology.
Method of the present invention also comprises the application of the acceptable salt of physiology of formula I chemical compound.The acceptable salt of term physiology is meant the acid-addition salts and/or the base addition salts of formula I chemical compound.Acid-addition salts can form by suitable acid is joined in the formula I chemical compound.Base addition salts can form by suitable alkali is joined in the formula I chemical compound.Described acid or alkali do not make described formula I chemical compound that substantial degraded, decomposition or destruction are taken place.The example of the acceptable salt of physiology comprises hydrochlorate, hydrobromate, acetate, fumarate, maleate, oxalates and succinate.Other suitable salt comprises the salt of sodium, potassium, carbonate and amino butanetriol salt.
Also will be understood that, the present invention is considered to contain stereoisomer and optical isomer, the for example mixture of enantiomer and independent enantiomer and the application of diastereomer, these isomers exist owing to the structure in the chemical compound of selecteed series of the present invention is asymmetric.Will be understood that also the application of the tautomer of formula I chemical compound has been contained in the present invention.Tautomer is well known in the art and comprises the ketoenol tautomerization body.
Will be understood that also formula I chemical compound comprises the E and the Z isomer that exist with variable ratio of hydrazone.As known in the art, isomerization can take place in the hydrazone part between E isomer and Z isomer, shown in following diagram:
Although the particular compound of listing above can be represented the specific spatial chemistry of hydrazone part, i.e. E or Z, the present invention comprise clearly isomer the two.
Formula I chemical compound also can fuse, and comprises hydration.During hydration can occur in chemical compound or comprise this compound compositions and make, perhaps hydration can be owing to the water absorption of chemical compound along with the time takes place.
Some chemical compound in formula I scope can be the derivant that is called as " prodrug ".The derivant of the known direct onset medicament of term " prodrug " expression, wherein the therapeutic value that has of this derivant may be similar to, be greater than or less than the therapeutic value of this medicament.Usually, prodrug is converted into activating agent by enzymatic or chemical process when being delivered to experimenter, cell or test(ing) medium.In some cases, prodrug is the derivant of The compounds of this invention, and it has to become by the cracked group of metabolism and by solvolysis or under physiological condition and has the active The compounds of this invention of pharmacy in the body.For example, the ester derivant of The compounds of this invention has activity in vivo usually, and does not have external activity.Other derivant of The compounds of this invention all has activity in its acid and acid derivative form in the two, but the acid derivative form provides the advantage of dissolubility, histocompatibility or delay release in the mammal organism (referring to Bundgard usually, H., Design of Prodrugs, pp.7-9,21-24, Blsevier, Amsterdam 1985).Prodrug comprises and well known to a person skilled in the art acid derivative, such as, for example, by ester with parent acid and suitable pure prepared in reaction, the perhaps amide by parent acid chemical compound and amine prepared in reaction.The simple aliphatic (acid) ester or the aromatic ester that obtain from the side-chain acid group of The compounds of this invention are preferred prodrug.In some cases, wish the prodrug of preparation dibasic acid esters type, such as (acyloxy) Arrcostab or ((alkoxy carbonyl) oxygen base) Arrcostab.
When any variable occurred surpassing one time, the definition of its definition when at every turn occurring when other time occurs at all with it had nothing to do, unless otherwise stated in any formation or in formula I.In addition, the combination of substituent group and/or variable has only to be only when this combination results stable compound and is allowed to.
Term " alkyl " is used separately in this article or is used as the part of other group, unless its chain length is limited to some extent, otherwise be meant the straight chain and the branched group that contain maximum 10 carbon, such as methyl, ethyl, propyl group, isopropyl, butyl, the 1-methyl-propyl, 2-methyl-propyl, amyl group, the 1-methyl butyl, isobutyl group, amyl group, tertiary pentyl (CH
3CH
2(CH
3)
2C-), hexyl, isohesyl, heptyl, octyl group or decyl.
Term " thiazolinyl " is used separately herein or is used as the part of other group, unless its chain length is limited to some extent, otherwise be meant the straight or branched group that contains 2-10 carbon atom, include but not limited to: vinyl, 1-acrylic, 2-acrylic, 2-methyl isophthalic acid-acrylic, the 1-butylene base, crotyl, 3-cyclobutenyl, pentenyl, 1-hexenyl and 2-hexenyl.
Term " alkynyl " is used separately in this article or is used as the part of other group, unless its chain length is limited to some extent, otherwise be meant the straight or branched group that contains 2-10 carbon atom, wherein have at least one triple bond between two carbon atoms in chain, include but not limited to: acetenyl, the 1-propinyl, 2-propynyl, ethyl acetylene base, 2-butyne base, 1-methyl-2-butyne base, 1-methyl-3-butynyl, 2-methyl-3-pentynyl, hexin base and heptyne base.
Exist therein in the situation of alkenyl part or alkynyl part as substituted radical, preferred unsaturated bond is not directly connected in nitrogen, oxygen or sulfur part.
Term " cycloalkyl " is used separately in this article or is used as the part of other group, is meant to contain 3-14, preferably contain the cycloalkyl of 3-10 carbon atom.Representative instance is a cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.Cycloalkyl also comprises bicyclic alkyl, multi-ring alkyl and other bridged ring alkyl.
Term " cycloalkenyl group " is used separately in this article or is used as the part of other group, is meant the cycloalkenyl group that contains 3-10 carbon atom and 1-3 carbon-to-carbon double bond.Representative instance comprises cyclopropanyl, cyclobutane base, cyclopentenyl, cyclohexenyl group, cycloheptenyl and cyclohexadienyl.Cycloalkenyl group also comprises bicycloenyl, multi-ring thiazolinyl and other bridged ring thiazolinyl.
Term " ring assorted alkyl " is used separately in this article or is used as the part of other group, is meant group carbon atoms and 1,2,3 or 4 oxygen, nitrogen or sulfur heteroatom, that comprise 3 to 14 annular atomses.Representative instance includes but not limited to the 2-tetrahydrofuran base, 2-tetrahydro-thienyl, 2-pyrrolidinyl, 3-isoxazole alkyl, 3-isothiazole alkyl, 1,3,4-oxazolidine-2-base, 2,3-dihydro-thiophene-2-base, 4,5-isoxazoline-3-base, 3-piperidyl, 1,3-diox-5-base, 4-piperidyl, 2-THP trtrahydropyranyl, 4-THP trtrahydropyranyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl (pirazolidinyl), tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, piperazinyl, quininuclidinyl and morpholinyl.
Term " ring assorted thiazolinyl " is used separately in this article or is used as the part of other group, is meant carbon atoms and 1,2,3 or 4 oxygen, nitrogen or sulphur atom and 1,2 or 3 two group key, that comprise 3 to 14 annular atomses.Representative instance preferably includes as mentioned above and process is modified with the ring that comprises 1 or 2 two key assorted alkyl, particularly pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuran base, THP trtrahydropyranyl, piperidyl, piperazinyl, quininuclidinyl and morpholinyl.
Term " alkylidene ", be used separately in this article or be used as the part of other group, be meant unless otherwise stated otherwise contain 1-15 carbon atom, preferably contain 1-10 carbon atom, more preferably contain the bilvalent radical of the non-branched-chain saturated hydrocarbon chain of 1-6 carbon atom.The exemplary group of this term is: methylene (CH
2-), ethylidene (CH
2CH
2-), propylidene (CH
2CH
2CH
2-), butylidene etc.
Term " alkenylene ", be used separately in this article or be used as the part of other group, be meant unless otherwise stated otherwise contain 2-15 carbon atom, preferably contain 1-10 carbon atom, more preferably contain 1-6 carbon atom and have at least one vinyl degree of unsaturation, preferably have a bilvalent radical of the non-side chain aliphatic unsaturated hydrocarbon of 1-6 vinyl degree of unsaturation.The exemplary group of this term is: ethenylidene (CH=CH-), allylidene (CH
2CH=CH-,-CH=CHCH
2-) etc.
Term " alkynylene ", be used separately in this article or be used as the part of other group, be meant unless otherwise stated otherwise contain 2-15 carbon atom, preferably contain 1-10 carbon atom, more preferably contain 1-6 carbon atom and have at least one acetylene (triple bond) degree of unsaturation, preferably have a bilvalent radical of the non-side chain aliphatic unsaturated hydrocarbon of 1-6 acetylene (triple bond) degree of unsaturation.Example comprises such as ethynylene (C ≡ C-), inferior propargyl (CH
2-C ≡ C-) etc. alkynylene.
Term " assorted alkylidene " is used separately in this article or is used as the part of other group, is meant as mentioned above and 1-5 of carbon atom shown in it is selected from hetero atom (amino for example, oxygen base, sulfenyl, the aminomethylene (NHCH of N, O or S
2-), oxygen methylene (OCH
2-) etc.) alkylidene replaced.Example comprises alkylidene oxygen base, alkylidene amino and alkylidene sulfenyl.Preferably, wherein contained oxygen, nitrogen and sulphur atom not with other hetero atom Cheng Jian.Suitable group comprises ethyleneoxy group, propylidene oxygen base, butylene oxide base, pentylidene oxygen base, inferior heptyl oxygen base, ethyleneimino, propylidene amino, butylidene amino, pentylidene amino, hexylidene amino, the amino and octylene amino of inferior heptyl.Other example comprises-CH
2CH
2-S-CH
2CH
2-and-CH
2-S-CH
2CH
2-NH-CH
2-.In an embodiment of assorted alkylidene, hetero atom also can occupy in the chain end any but not two.
Term " assorted alkenylene " is used separately in this article or is used as the part of other group, is meant as mentioned above and 1-5 alkenylene that is selected from the hetero atom replacement of N, O or S of carbon atom shown in it.Example comprises alkenylene oxygen base, the amino and alkenylene sulfenyl of alkenylene.Preferably, wherein contained oxygen, nitrogen and sulphur atom not with other hetero atom Cheng Jian.Suitable group comprises ethenylidene oxygen base, allylidene oxygen base, butenylidene oxygen base, inferior pentenyl oxygen base, inferior hexenyl oxygen base, ethenylidene amino, allylidene amino, butenylidene amino, the amino and inferior hexenyl amino of inferior pentenyl.In an embodiment of assorted alkenylene, hetero atom also can occupy in the chain end any but not two.In addition, in another embodiment, hetero atom does not constitute the part of ethylenic linkage.
Term " assorted alkynylene " is used separately in this article or is used as the part of other group, is meant as mentioned above and 1-5 alkynylene that is selected from the hetero atom replacement of N, O or S of carbon atom shown in it.Example comprises alkynylene oxygen base, the amino and alkynylene sulfenyl of alkynylene.Preferably, wherein contained oxygen, nitrogen and sulphur atom not with other hetero atom Cheng Jian.In an embodiment of assorted alkynylene, hetero atom can occupy in the chain end any but not two.In addition, hetero atom does not constitute the part of ethylenic linkage.
Term " cycloalkylidene " is used separately in this article or is used as the part of other group, is meant to contain 3-15 carbon atom, preferably contain the alicyclic ring bivalent hydrocarbon radical of the non-fragrance of 3-10 carbon atom.The example of " cycloalkylidene " used herein includes but not limited to: cyclopropyl-1,1-two bases, cyclopropyl-1,2-two bases, cyclobutyl-1,2-two bases, cyclopenta-1,3-two bases, cyclohexyl-1,4-two bases etc.Other example comprises the bilvalent radical that also comprises alkylidene, such as the methylene cyclopropylidene (that is ,-CH
2-cyclopropylidene-), and the ethylidene cyclopropylidene (that is ,-CH
2CH
2-cyclopropylidene-) and the methylene cyclohexylidene (that is ,-CH
2-cyclohexylidene-).
Term " inferior cycloalkenyl group " is used separately in this article or is used as the part of other group, is meant to contain 3-15 carbon atom, preferably contain the substituted alicyclic ring bivalent hydrocarbon radical of 3-10 carbon atom and at least one carbon-to-carbon double bond.The example of " inferior cycloalkenyl group " used herein includes but not limited to: 4, and 5-cyclopentenes-1,3-two bases, 3,4-cyclohexene-1,1-two bases etc.Inferior cycloalkenyl group is meant the as above described and two displaced bivalent hydrocarbon radicals of key of at least one singly-bound about cycloalkylidene in addition.Two keys can be comprised in the ring structure.As an alternative, when possibility, two keys can be positioned on the non-loop section of inferior cycloalkenyl group.
Term " inferior ring assorted alkyl " is used separately in this article or is used as the part of other group, is meant as mentioned above and 1-5 cycloalkylidene that is selected from the hetero atom replacement of N, O or S of carbon atom shown in it.In one embodiment, wherein contained oxygen, nitrogen and sulphur atom not with other hetero atom Cheng Jian.Suitable example comprises the bilvalent radical of piperidines, piperazine, morpholine and pyrrolidine.Other suitable example comprises the methylenepiperidines base, ethylidene piperidyl, methylene piperazinyl, ethylidene piperazinyl and methylene morpholinyl.
Term " inferior ring assorted thiazolinyl " is used separately in this article or is used as the part of other group and is meant as mentioned above and 1-5 inferior cycloalkenyl group that is selected from the hetero atom replacement of N, O or S of carbon atom shown in it.In one embodiment, wherein contained oxygen, nitrogen and sulphur atom not with other hetero atom Cheng Jian.
Term " alkoxyl " is used separately in this article or is used as the part of other group, is meant any abovementioned alkyl that is connected with oxygen atom.Representative instance is a methoxyl group, ethyoxyl, and isopropyl oxygen base, the second month in a season-butyl oxygen base and tert-butyl oxygen base.
Term " thiazolinyl oxygen base " is used separately in this article or is used as the part of other group, is meant any above-mentioned thiazolinyl that is connected with oxygen atom.Representative instance comprises vinyl oxygen base, acrylic oxygen base, cyclobutenyl oxygen base, pentenyl oxygen base and hexenyl oxygen base.
Term " aryl " is used separately in this article or is used as the part of other group, is meant to contain 6-14 carbon in loop section, preferably contain the monocycle or the bicyclic aromatic group of 6-10 carbon in loop section.Representative instance comprises phenyl, naphthyl, anthryl or fluorenyl.
Term " aralkyl " or " aryl alkyl " are used separately in this article or are used as the part of other group, are meant as mentioned above and have the C of aryl substituent
1-6Alkyl, such as benzyl, phenylethyl or 2-naphthyl methyl.
Term " heteroaryl " is used separately in this article or is used as the part of other group, is meant to contain 5-14 annular atoms; In ring is arranged, share 6,10 or 14 pi-electrons and comprise carbon atom and the group of 1,2,3 or 4 oxygen, nitrogen or sulphur atom; The example of heteroaryl is: thienyl, benzo [b] thienyl, naphtho-[2,3-b] thienyl, thianthrene group, furyl, pyranose, isobenzofuran-base benzoxazolyl, benzopyranyl, xanthyl, phenoxthine base, the 2H-pyrrole radicals, pyrrole radicals, imidazole radicals, pyrazolyl, pyridine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, the indolizine base, isoindolyl, 3H-indyl, indyl, indazolyl, purine radicals, 4H-quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinazolyl, the cinnolines base, pteridine radicals, 4 α H-carbazyls, carbazyl, the B-carboline base, phenanthridinyl, acridinyl, naphthalene embedding diazine, the phenanthroline base, phenazinyl, isothiazolyl, phenothiazine base isoxazolyl, furazan base ， Fen oxazinyl and tetrazole radical.Other heteroaryl is described in A.R.Katritzky and C.W.Rees, compile, Comprehensive HeterocyclicChemistry:The Structure, Reactions, Synthesis and Use ofHeterocyclic Compounds, Vol.1-8, Pergamon Press is among the NY (1984).
Term " alkylenedioxy group " is used separately in this article or is used as the part of other group, relates to ring and is meant C especially
1-4Alkylenedioxy group.Alkylenedioxy group can be chosen wantonly by halogen (particularly fluorine) and replace.Representative instance comprises methylene dioxy base (OCH
2O-) or difluoro methylene dioxy base (OCF
2O-).
Term " halogen " or " halo " are used separately in this article or are used as the part of other group, are meant chlorine, bromine, fluorine or iodine.
Term " alkylamine " or " alkyl amino " are used separately in this article or are used as the part of other group, are meant the group NH that one of them hydrogen replaces with aforesaid alkyl
2
Term " dialkylamine " or " dialkyl amido " are used separately in this article or are used as the part of other group, are meant wherein two group NH that hydrogen is all replaced by aforesaid alkyl
2
Term " hydroxy alkyl " is used separately in this article or is used as the part of other group and is meant alkyl as mentioned above any and that its one or more hydrogen are replaced by one or more hydroxylic moieties.
Term used herein " acyl amino " is meant formula-NR
aC (O) R
bShown in part, wherein R
aAnd R
bBe hydrogen or aforesaid alkyl independently.
Term " haloalkyl " is used separately in this article or is used as the part of other group, is meant alkyl as mentioned above any and that its one or more hydrogen are partly replaced by one or more halos.Representative instance comprises methyl fluoride, trifluoromethyl, three chloroethyls and trifluoroethyl.
Term " haloalkenyl group " is used separately in this article or is used as the part of other group, is meant thiazolinyl as mentioned above any and that its one or more hydrogen are partly replaced by one or more halos.Representative instance comprises fluoride-based, difluoroethylene base and trichloro-vinyl.
Term " carboxyalkyl " is used separately in this article or is used as the part of other group, is meant alkyl as mentioned above any and that its one or more hydrogen are replaced by one or more carboxylic moiety.
Term used herein " hetero atom " is meant oxygen atom (" O "), sulphur atom (" S ") or nitrogen-atoms (" N ").Will be understood that when hetero atom was nitrogen, it can form NR
aR
bPart, wherein R
aAnd R
bBe hydrogen or alkyl independently of one another, perhaps form saturated or unsaturated 5,6 or 7 yuan of rings with the nitrogen that they connected.
Term " oxygen base " is meant oxygen (O) atom.
Term " sulfenyl " is meant sulfur (S) atom.
Usually and unless otherwise defined, term used herein " optional being substituted " is meant that one or more groups are optional and is independently selected from following substituent group and replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
2-6Alkynyl, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
6-10Aryl, 5-10 unit heteroaryl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl (C
2-6) thiazolinyl, C
6-10Aryl (C
1-6) alkoxyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxy C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, amino carbonyl, C
6-14Aryl (C
1-6) alkoxy carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
6-10Aryl sulfonyl, C
6-10Aryl (C
1-6) alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
6-10Aryl (C
1-6) alkylsulfonamido, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
When term " optional be substituted " relate to alkyl, when alkenyl or alkynyl is used, term herein " optional being substituted " is meant that described one or more group is optional and is independently selected from following substituent group and replaces by one or more: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
3-6Cycloalkyl, C
3-6Cycloalkenyl group, C
3-6The assorted alkyl of ring, C
3-6The assorted thiazolinyl of ring, C
6-10Aryl, 5-10 unit heteroaryl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6The alkyl sulfenyl, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
6-10Aryl (C
1-6) alkyl, C
6-10Aryl (C
2-6) thiazolinyl, C
6-10Aryl (C
1-6) alkoxyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, (a C
1-4) alkyl amino (C
2-6) alkoxyl, two (C
1-4) alkyl amino (C
2-6) alkoxy C
2-10One (carboxyalkyl) amino, two (C
2-10Carboxyalkyl) amino, C
6-14Aryl (C
1-6) alkoxy carbonyl, C
2-6The alkynyl carbonyl, C
1-6Alkyl sulphonyl, C
2-6The alkynyl sulfonyl, C
6-10Aryl sulfonyl, C
6-10Aryl (C
1-6) alkyl sulphonyl, C
1-6Alkyl sulphinyl, C
1-6Alkylsulfonamido, C
6-10Aryl-sulfonyl amino, C
6-10Aryl (C
1-6) alkylsulfonamido, C
1-6Alkyl imino amino, formoxyl imino group amino, C
2-6The carboxyl alkoxyl, C
2-6Carboxyalkyl and carboxyl (C
1-6) alkyl amino.
Although not for above each used term all provides specific definition, each term can be understood by those of ordinary skills.
As defined in top some embodiment, connect basic L
1And L
2Can be and contain 1-10 carbon atom and/or heteroatomic connection base and its optional being substituted.This can be understood to mean described connection base can comprise carbon atom and heteroatomic any combination, thereby makes carbon atom and heteroatomic sum, does not comprise any optional substituent group, equals the integer of 1-10.Therefore, according to the present invention, suitable connection base can be including but not necessarily limited to the connection base (CH for example that contains 1 carbon atom
2); Contain 1 heteroatomic connection base (for example O); Connection base (the CH for example that contains 5 carbon atoms
2CH
2CH
2CH
2CH
2); Contain 3 carbon atoms and 2 heteroatomic base (OCH for example that are connected
2CH
2NHCH
2); The connection base that contains 10 carbon atoms; Or contain the heteroatomic base that is connected of 9 carbon atoms and 1.
Term " inhibitor " is meant and partly changes or weaken the function of TRPM5 and/or the molecule of character." inhibitor " comprises peptide, protein or its fragment, peptide mimics, organic compound and antibody.In certain embodiments of the invention, this inhibitor can be blocked the function of TRPM5 fully.In other embodiments, the percent that this inhibitor can be certain (is for example used IC
50Value representation) activity of blocking-up or inhibition TRPM5.
Term " diabetes " is meant and wherein has the impaired a kind of metabolic disease of glucose utilization of inducing hyperglycemia.Can understand by those skilled in the art about the pathogeny of diabetes and morphology and late complication summary thereof, for example, referring to Robins ' Pathologic Basis ofDisease (5
ThEd.pp.910-922).
The TRPM5 inhibitor of term " effective dose " is meant and suppresses the TRPM5 receptor or give amount to the inhibition effect of TRPM5 receptor.This amount is enough to give its cell that is given individually or with other TRPM5 inhibitor combinedly or whole organism suppresses effect with TRPM5.In some embodiments, effective dose is not cause excessive toxicity, zest, anaphylaxis or other possible complication and the amount that matches with rational benefit/risk ratio.
Term " insulin resistance syndrome " (IRS) is meant that one group comprises the following form of expression: insulin resistant; Hyperinsulinemia; Non-insulin-dependent diabetes mellitus (NIDDM); Arterial hypertension; Central authorities' (visceroatonia type) obesity; With the dyslipidemias mass formed by blood stasis.Main late complication (diabetic angiopathy except NIDDM, atherosclerosis, diabetic nephropathy, diabetic neuropathy, form and glaucoma with diabetic ocular complication such as retinopathy, cataract) outside, many other patient's condition are also relevant with NIDDM, these patient's condition comprise the insulin resistant of dyslipidemias mass formed by blood stasis glucocorticoid inducible, dyslipidemias mass formed by blood stasis, polycystic ovarian syndrome, obesity, hyperglycemia, hyperlipemia, hypercholesterolemia, hypertriglyceridemia, hyperinsulinemia and hypertension.The concise and to the point definition of these patient's condition can be for example obtained among the Stedman ' s Medical Dictionary at any medical dictionary.
As mentioned above, above-claimed cpd can be used to stimulate insulin to discharge.This activity can be external activity or activity in vivo.The TRPM5 inhibitor that is used to stimulate insulin to discharge, all amounts suc as formula I chemical compound or any above-mentioned specific group, group or particular compound needn't be identical with external use amount when using in vivo.When increasing insulin release in vivo, the factor of particular compound such as pharmacokinetics and pharmacodynamics may require to use greater amount or TRPM5 inhibitor more in a small amount, all chemical compounds, or any above-mentioned specific group, group or particular compound suc as formula I.
Present invention resides in the method for treatment diabetes in the animal that needs, the preferred mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.This method also is included in the method for prevent diabetes in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given insulin secretion enhancing amount, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
The present invention also is included in the method for treatment insulin resistance syndrome in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.The present invention also is included in the method for the treatment of or preventing insulin resistant in the mammal, comprises the TRPM5 inhibitor that described mammal is given effective dose, and is all suc as formula I chemical compound or any specific group, group or the acceptable salt of its pharmacy.
Present invention resides in the method for treatment hyperglycemia in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.This method also is included in the method for prevention hyperglycemia in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given insulin secretion enhancing amount, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
The invention still further relates to enhancing GLP-1 from the method that cell discharges, comprise the TRPM5 inhibitor that gives effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.As discussed above, GLP-1 stimulates insulin synthetic and from the secretion of pancreatic after food intake, thus the blood sugar lowering level.GLP-1 is 37 amino acid whose peptides and is the product of proglucagon.Endogenous between the 6th and the 7th division subsequently produces GLP-1 (7-37) peptide with biologic activity.When taking in glucose, the L-type enteroendocrine cell of GLP-1 from the surface, chamber of internal organs secreted.GLP-1 also responds other stimulation and is released.GLP-1 works by the cell surface receptor of G albumen coupling, particularly GLP-1R, and is regulated by T1R taste receptors and flavor albumen.Referring to people such as Kokrashvili, AChemS XXIX Abstract, 246 (2007).Research shows, by the GLP-1 of sugar and sweeting agent stimulation from the secretion of L type enteroendocrine cell, α-flavor protein binding sweet receptor T1R3.Referring to people such as Jang, Proc.Natl.Acad.Sci.USA, 104 (38): 15069-15074 (2007).
GLP-1 has several physiological functions: 1) it stimulates insulin synthetic from islet cells in glucose dependency mode, thus the blood sugar lowering level; 2) it reduces the secretion of glucagon from pancreas; 3) it increases beta cell amount and insulin gene expression; 4) it suppresses gastric secretion and emptying; 5) its dose-dependent inhibition food intake by increasing satiety; With 6) its promotion loses weight.Several effects of GLP-1 are described in United States Patent (USP) 6,583, and 118, United States Patent (USP) 7,211,557; US patent application publication 2005/0244810; Deacon, RegulatoryPeptides 128:117-124 (2005); People Nature such as Turton, 379:69-72 (1996).
Some researchs have been carried out to identify the non-natural peptide and the micromolecule agonist of GLP-1 receptor.These chemical compounds can be used for treating type 2 diabetes mellitus and other application.The effect of these chemical compounds imitation GLP-1 is because their are strengthened by the release from islet cells of the insulin of glucose induction.For example Exenatide is the synthetic variant of exendin-4, and exendin-4 is an isolating native peptides from Heloderma suspectum saliva at first.Exenatide is used for auxiliary therapy by FDA approval at present, to improve the combination of taking in metformin, sulfonylurea or metformin and sulfonylurea but the type 2 diabetes mellitus patient's of enough glycemic control that is unrealized glycemic control.Developing the medicament of other possible imitation GLP-1 effect.For example, referring to, people such as Knudsen, Small-molecule agonists for the glucagon-like peptide1 receptor, Proc.Natl.Acad.Sci.USA 104 (3): 937-942 (2007).
Therefore, another aspect of the present invention is by giving the method that the TRPM5 inhibitor stimulates GLP-1 to discharge.Prior art does not hint the TRPM5 inhibitor, such as this paper example those, can be used to strengthen the release of GLP-1, thereby increases the beneficial effect of GLP-1.Therefore, in certain embodiments, the invention provides enhancing GLP-1 and also have the method for enhancing insulin subsequently from the effect of pancreatic cell release from the release of enterocyte such as small intestine cells.
The TRPM5 inhibitor allly can be given to cell or whole organism suc as formula I chemical compound or any specific embodiment, discharges to obtain enhanced GLP-1.In addition, the TRPM5 inhibitor can be individually or the medicament that discharges with the known GLP-1 of causing secretion be given such as glucose.For example, the used TRPM5 of the present invention can be IC
50Be about 1 micromole or lower, preferred about 100 nanomoles or lower TRPM5 inhibitor.In some embodiments, the used TRPM5 inhibitor of this method suppresses TRPM5 receptor at least 75%, preferred 90% under 5 micromoles or lower concentration.
" GLP-1 " used herein or glucagon-like-peptide-1 (GLP-1) are the gastrointestinal tract proteohormones, and it strengthens by giving the insulin secretion that nutrient such as glucose, carbohydrate, fat, protein or kilnitamin cause.The physiological action of GLP-1 and the various mechanism that are suggested that GLP-1 discharges behind the thing that absorbs nourishment for example are described in Lancet 2:1300-1304 (1987) and are described in RegulatoryPeptides 128:117-124 (2005) by Deacon by people such as Kreymann.Except as otherwise noted, otherwise " GLP-1 " is meant GLP-1 (7-37).According to the general knowledge of this area, the amino terminal of GLP-1 (7-37) is specified with numeral 7 and carboxyl terminal is specified with numeral 37.The aminoacid sequence of GLP-1 (7-37) is well known in the art, but following expression: NH
2-His-Als-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val-Lys-Gly-Arg-Gly-COOH.
In certain embodiments, the TRPM5 inhibitor makes GLP-1 discharge increase about 5% to about 50%, or about 10% to about 70%, or about 25% to about 100%.In other embodiments, the TRPM5 inhibitor makes the amount of the GLP-1 that discharges from enterocyte increase about 25%, 50%, 75% or 100%.
Preferably, the method that increases GLP-1 release is used to mammal, such as other primate of people.In other situation, the experimenter of described method can be a house pet, such as Canis familiaris L. or cat.
The detection that GLP-1 discharges can be carried out according to method known to a person of ordinary skill in the art (comprising those methods as herein described).For example, referring to, people such as F.Reinmann, Diabetes, 55 (Supp.2): S78-S-85 (2006).
The present invention also is included in the method that reduces gastric secretion and emptying in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
The present invention also is included in the method that suppresses food intake in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.Known GLP-1 plays remarkable effect in the physiologic response of regulating food intake.The absorption of GLP-1 response food obtains and is discharged into blood from the endocrine L-cell that mainly is arranged in small intestinal and colon tip from proglucagon is processed.GLP-1 works by the link coupled cell surface receptor of G protein (GLP-1R) and strengthens by the synthetic and release of the inductive insulin of nutrient institute.GLP-1 stimulates insulin secretion (pancreotropic hormone effect) and cAMP forms.GLP-1 (7-36) amide stimulates the insulin releasing agent to reduce glucagon secretion, and suppresses gastric secretion and emptying.These gastrointestinal tract effects of GLP-1 are not recorded in cutting off vagal experimenter, have shown the effect by the maincenter mediation.GLP-1 combines with separated rat fat cell with high affinity, activates cAMP and produces people such as (, 1993) Valverde and stimulate lipogenesis or steatolysis.Glycogen in the GLP-1 stimulation in rats skeletal muscle is synthetic, and glucose oxidase and lactic acid form.Therefore, based on the inventor's observed result, TRPM5 inhibitor as herein described can be used for suppressing food intake, because the TRPM5 inhibitor increases the release of GLP-1.
The present invention also is included in the method that reduces glucagon secretion in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
Glucagon is the hormone that is made of the straight-chain polypeptide with 29 amino acid residues, is extracted from the pancreas A cells.Its physiological action such as rising blood sugar concentration and activation liver phosphorylase, can be understood by those skilled in the art, and for example, referring to Stedman ' sMedical Dictionary, 26th Ed. (1990), the 729th page.
The present invention also is included in the method that strengthens insulin sensitivity in the animal that needs, preferred people or other mammal, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
The present invention also is included in the beta cell amount of increase islets of langerhans in the animal that needs, preferred people or other mammal and the method that insulin gene is expressed, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
Present invention resides in the method for treatment in the animal that needs, preferred people or other mammal or prevent obesity, comprise the TRPM5 inhibitor that the experimenter is given effective dose, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound or the acceptable salt of its pharmacy.
" obesity " used herein is meant the unusual increase of fat in subcutaneous connective tissue.Stedman ' s Medical Dictionary, 26
ThEd. (1990), the 1235th page.
In each embodiment of said method, the experimenter of method unless other is restricted, otherwise can be the animal of the particular treatment or the effect of any this method of needs.These animals include but not limited to: the insulin secretory cell of cattle, horse, sheep, pig, chicken, turkey, Carnis Coturnicis japonicae, cat, Canis familiaris L., mice, rat, rabbit, monkey or Cavia porcellus.In other embodiments, animal is a livestock animals, performing animal or pet animals.In specific embodiments, the experimenter of claimed method is the people.
Yet usually, suitable dosage is about 0.005 to about 100 mg/kg, for example be about 0.1 to about 75 mg/kg body weight/day, such as 0.03 to about 50 mg/kg receiver body weight/day, be preferably 0.06 to 90 mg/kg/day, most preferably be 0.15 to 60 mg/kg/day.In other embodiments, suitable dosage is that about 0.1 mg/day arrives about 2000 mg/day in a whole day, is given as single dose or multiple dose.
Chemical compound can be given with unit dosage forms easily; For example, the per unit dosage form comprises 0.05 to 1000 milligram, comprises 0.1 to 750 milligram, most convenient ground easily and comprise 0.5 to 500 milligram active component.
The TRPM5 inhibitor allly can typically be present in the dosage form to the amount of about 80 weight % to about 100 weight %, preferred about 1 weight % with about 0.1 weight % suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.The present invention also considered to account for formulation weight about 1% to about 50%, preferred about 5% to about 20%, about amount of 8%, 15% or 18%.
Ideally, the TRPM5 inhibitor, all suc as formula the I chemical compound, should be given with the peak serum concentration of realizing reactive compound is about 0.005 to about 75 μ M, preferred about 0.01 to 50 μ M most preferably from about 0.02 arrives about 30 μ M.This for example can by the intravenous injection active component randomly 0.0005 to 5% solution in saline realize that or orally give contains the pill realization of the active component of about 0.01-1 milligram.Required blood levels can by provide about 0.0001-5 mg/kg/hour continuous infusion or the active component by the about 0.004-15 mg/kg of intermittent infusion kept.
Thereby this method can be implemented and make insulin secretion, GLP-1 secretion or insulin sensitivity be strengthened at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% or about 60% to about 99% or about 20% to about 50% suc as formula the I chemical compound by the TRPM5 inhibitor is all.Therefore, in a more particular embodiment, this method comprises and comprises one or more TRPM5 inhibitor, all dosage forms suc as formula the I chemical compound, wherein one or more formulas I chemical compound exists with the amount that insulin secretion, GLP-1 secretion or insulin sensitivity are strengthened at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% or about 60% to about 99% or about 30% to about 70%.Certainly, in other embodiments, insulin secretion, GLP-1 secretion or insulin sensitivity can be enhanced in various degree.
Required dosage can exist with single dose or exist with the divided dose that is given in appropriate intervals easily, such as every day 2,3,4 times or sub-doses more frequently.Sub-doses self can be segmented again, for example, is divided into many administrations discrete, loose interval; Such as repeatedly being sucked or repeatedly splashed into the eye from insufflator.
In another embodiment, above-claimed cpd can be used to strengthen insulin or GLP-1 from emiocytosis or strengthen the insulin sensitivity of cell.These enhancings can be in external enhancing or the body and strengthen.Be used to strengthen the excretory TRPM5 inhibitor of insulin secretion, insulin sensitivity or GLP-1, all amounts suc as formula I chemical compound or any above-mentioned specific group, group or particular compound needn't be identical with external use amount when using in vivo.When acting on pancreatic cell in vivo, the factor of particular compound such as pharmacokinetics and pharmacodynamics may require to use greater amount or TRPM5 inhibitor more in a small amount, all chemical compounds, or any above-mentioned specific group, group or particular compound suc as formula I.Therefore, one aspect of the present invention be strengthen insulin from cell discharge and GLP-1 from the method for the insulin sensitivity of emiocytosis or enhancing cell, comprise making cells contacting TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.
In an embodiment of this respect of the present invention, this method comprises makes cell, preferred pancreatic cell contact TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound, wherein said emiocytosis insulin.
In an embodiment of this respect of the present invention, this method comprises makes cell, preferred L type enteroendocrine cell contact TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound, wherein said emiocytosis GLP-1.
The invention still further relates to enhancing insulin and GLP-1 method from the insulin sensitivity of cell release or enhancing cell, comprise and make described cells contacting TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group and particular compound, and insulin secretion, GLP-1 secretion or the insulin sensitivity of cell are strengthened at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95% or about 50% to about 99%.In another embodiment, this method comprises makes described cells contacting TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group and particular compound, and make insulin secretion, GLP-1 secretion or the insulin sensitivity of cell strengthen about 10% to about 50%.In another embodiment, the present invention relates to strengthen insulin from emiocytosis or strengthen GLP-1 from emiocytosis or strengthen the method for the insulin sensitivity of cell, comprise and make described cells contacting TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group and particular compound, and make insulin secretion, GLP-1 secretion or insulin sensitivity strengthen at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or 50% to about 99%/or about 10% to about 50%, and wherein said cell is naturally occurring cell.In another embodiment, the present invention relates to strengthen insulin from emiocytosis or strengthen GLP-1 from emiocytosis or strengthen the method for the insulin sensitivity of cell, comprise and make described cells contacting TRPM5 inhibitor, all suc as formula I chemical compound or any above-mentioned specific group and particular compound, and make insulin secretion, GLP-1 secretion or insulin sensitivity strengthen at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 95%, or 50% to about 99%, or about 10% to about 50%, and wherein said cell is naturally occurring insulin human secretory cell or GLP-1 secretory cell.
The TRPM5 inhibitor of the required enhancing degree of providing of any amount can be provided, all suc as formula the I chemical compound.For example, based on every day about 0.001 to 100 milligram of every kg body weight, preferred every day every kg body weight about 0.01 be suitable to about 25 milligrams of single doses that provided or 2-4 divided dose.The administration of described material preferred oral, but also can use parenteral route, such as subcutaneous, intramuscular, intravenous or intraperitoneal approach or any other suitable delivery system such as intranasal or transdermal route.
The increase of term used herein " enhancing " and grammatical variants amount of being meant or degree.For example, strengthening insulin discharges or strengthens GLP-1 from cell and discharge from cell and be meant that increase is by insulin that cell discharged or the amount of GLP-1.Similarly, the insulin sensitivity of enhancing cell is meant the degree of the insulin sensitivity that increases cell.Enhancing is including but not necessarily limited to adjusting, modification, activation etc.
Compositions
The invention still further relates to various can be used for treating diabetes, insulin resistance syndrome, hyperglycemia and obesity compositions, it comprises TRPM5, and is all suc as formula I chemical compound or the acceptable salt of its physiology.
The invention still further relates to the various compositionss that can be used for increasing beta cell amount and insulin gene expression, reduction gastric secretion and the emptying and the glucagon secretion of islets of langerhans and suppress food intake, it comprises the TRPM5 inhibitor, and is all suc as formula I chemical compound or the acceptable salt of its physiology.
In one aspect, the present invention relates to comprise the pharmaceutical composition of TRPM5 inhibitor and one or more pharmaceutically acceptable carriers, wherein the TRPM5 inhibitor is the formula I chemical compound such as above definition, comprises any above-mentioned particular, group or material.Preferred composition of the present invention is to comprise the chemical compound that is selected from above listed one or more embodiments and the pharmaceutical composition of the acceptable excipient of one or more pharmacy.
Pharmaceutical composition of the present invention can be any form that is suitable for realizing its predetermined purpose.Yet preferably, compositions is can be through cheek or peroral administration form.As an alternative, pharmaceutical composition can be mouth or nasal spray.
Pharmaceutical composition of the present invention can be any being suitable for can experiencing one or more TRPM5 inhibitor, the form of the animals administer of all beneficial effects suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.Preferred people in these animals is although the present invention is not limited in the people.Other suitable animal comprises Canis animals, felid, Canis familiaris L., cat, domestic animal, horse, cattle, sheep etc.Veterinary composition used herein is meant the pharmaceutical composition that is applicable to the non-human animal.These veterinary compositions are known in the art.
Pharmaceutical preparation of the present invention can be adopted known method manufacturing, for example by means of traditional mixing, pelletize, sugar coating, dissolving or freeze drying process manufacturing.Therefore, the pharmaceutical preparation that is used for oral application can be by mixing reactive compound, randomly grind the gained mixture and mixture being processed as granule with solid excipient, if desired or necessary, after adding proper assistant, obtain tablet or sugar-coat core and obtained.
Drug excipient is well known in the art.Appropriate excipients comprises that filler is such as saccharide, for example lactose or sucrose, mannitol or sorbitol, cellulose preparation and/or calcium phosphate, for example tricalcium phosphate or calcium hydrogen phosphate, and binding agent for example uses corn starch, wheaten starch, rice starch, potato starch, gelatin, Tragacanth, methylcellulose, HYDROXY PROPYL METHYLCELLULOSE, sodium carboxy methyl cellulose and/or polyvinyl pyrrolidone such as gelatinized corn starch.If desired, can add disintegrating agent, such as above-mentioned starch and carboxyl methyl starch, cross-linking polyethylene pyrrolidone, agar or alginic acid or its salt such as sodium alginate.At first, auxiliary agent is flowing regulator and lubricant, for example, is silicon dioxide, Talcum, stearic acid or its salt such as magnesium stearate or calcium stearate, and/or Polyethylene Glycol.The sugar-coat core is provided with suitable coating, if desired, and this coating resistant to gastric juice.For this purpose, can use dense sugar juice, it can be chosen wantonly and comprise Radix Acaciae senegalis, Talcum, polyvinyl pyrrolidone, Polyethylene Glycol and/or titanium dioxide, lacquer solution and suitable organic solvent or solvent mixture.In order to produce the coating of resistant to gastric juice, use the solution of all phthalic acid acetylcelluloses of suitable cellulose preparation or Monophalic acid ester of hydroxypropyl ester.Can in tablet or dragee coating, add dyestuff or pigment, for example, be used to distinguish or be used to characterize the combination of active compound doses.
The liquid dosage form that is used for oral administration comprises the acceptable Emulsion of pharmacy, solution, suspending agent, syrup and elixir.Except reactive compound, liquid dosage form also comprises this area inert diluent commonly used, such as, for example water or other solvent, solubilizing agent and emulsifying agent be such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Semen Maydis oil, germ oil, olive oil, Oleum Ricini and Oleum sesami), glycerol, tetrahydrofurfuryl alcohol, the fatty acid ester of Polyethylene Glycol and sorbitan, and composition thereof.
Except reactive compound, suspending agent can comprise suspending agent, such as, for example, the ethoxylation isooctadecanol, polyoxyethylene sorbitol and sorbitan ester, microcrystalline Cellulose, aluminium hydroxide (aluminum metahydroxide) partially, bentonite, agar and Tragacanth, and composition thereof.
In other embodiments, the present invention relates to comprise the chewable tablet of the TRPM5 inhibitor of medical effective dose such as one or more formulas I chemical compound and one or more biologic activity agent.Chewable tablet is known in the art.For example, referring to, United States Patent (USP) 4,684,534 and 6,060,078, it incorporates this paper into as a reference separately in full.
In another embodiment, the present invention relates to oral Orally disintegrating composition, wherein said oral Orally disintegrating composition comprises the TRPM5 inhibitor in addition, such as one or more above-mentioned formula I chemical compounds or any above-mentioned specific group, group or particular compound.Orally disintegrating tablet is known in the art.For example, referring to, United States Patent (USP) 6,368,625 and 6,316,029, it incorporates this paper into as a reference separately in full.
In another embodiment, the invention further relates to nasal composition, it comprises the TRPM5 inhibitor of medical science effective dose in addition, such as one or more above-mentioned formula I chemical compounds or any above-mentioned specific group, group or particular compound.Nasal spray is known in the art.For example, referring to, United States Patent (USP) 6,187,332.As limiting examples, nose spray composite of the present invention comprises water (such as 95-98 weight %), citrate (such as the 0.02M citrate anion to the 0.06M citrate anion), formula I chemical compound and optional phosphate (such as the phosphate of 0.03M to 0.09M phosphate).
In another embodiment, the present invention relates to solid dosage forms, it comprises by water and/or the activatory effervescent granule of saliva such as the granule with controlled effervescent speed and TRPM5 inhibitor all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.Effervescence pharmaceutical composition is known in the art.For example, referring to, United States Patent (USP) 6,649,186, it incorporates this paper into as a reference in full.
In another embodiment, the present invention relates to pharmaceutical composition film shaped or that thin slice is shaped, it comprises the TRPM5 inhibitor, and is all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound, and can disintegrate.These pharmaceutical compositions film shaped or that thin slice is shaped for example can be built as the form of medication of disintegrate rapidly, for example, the form of medication of disintegrate in 1 second to maximum 3 minutes periods, perhaps can be built as the form of medication of slow disintegrate, for example the form of medication of disintegrate in 3-15 minute period.
By using the substrate that for example has different disintegrates or stripping feature to form polymer, above-mentioned disintegration time can be set in the above-mentioned scope.Therefore, by mixing corresponding polymers compositions, can regulate disintegration time.In addition, known its of disintegrating agent " draws " water and causes that substrate advances to split internally from substrate.Therefore, certain embodiments of the present invention comprise these disintegrating agents that are used to regulate the disintegration time purpose.
The suitable polymer that is used for the pharmaceutical composition that film shaped or thin slice is shaped comprises cellulose derivative, polyvinyl alcohol (MOWIOL for example
TM), polyacrylate, polyvinyl pyrrolidone, cellulose ether, such as ethyl cellulose, and polyvinyl alcohol, polyurethane, polymethacrylates, the derivant of polymethyl methacrylate and above-mentioned polymer and co-polymer.
In certain embodiments, the gross thickness film shaped or pharmaceutical composition that thin slice is shaped of the present invention is preferably 5 microns to maximum 10 millimeters, and preferred 30 microns to 2 millimeters, preferred especially 0.1 millimeter to 1 millimeter.Pharmaceutical preparation can be circle, avette, oval, triangle, tetragon or polygon, but they also can have any circle.
In another embodiment, the present invention relates to compositions, it comprises the TRPM5 inhibitor of the pharmaceutical active amount in being comprised in the coating that surrounds base formulation, and is all suc as formula I chemical compound or above-mentioned any specific group, group or particular compound.Preferably, coating accounts at least 50% of entire product weight.When core was chewed, medicine or medicament were released into saliva.For example, United States Patent (USP) 6,773,716, it incorporates this paper into as a reference in full, discloses the suitable medicine or the medicament that are comprised in the coating that surrounds base formulation.The formula I chemical compound that one or more are above-mentioned or any specific group, group or particular compound can be used for preparing coating.Above-mentioned formula I chemical compound or any specific group, group or particular compound can be different amount have all according to appointment 30%, 50%, 75% or 90%.In another embodiment, formula I chemical compound exists to about 99% with about 30%.In other embodiments, formula I chemical compound exists to about 30% with about 1%.
In other embodiments, the present invention relates to be applicable to the pharmaceutical composition of aerosol drug delivery, its TRPM5 inhibitor that comprises the medical science effective dose is all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound and appropriate carriers.Aerosol combination is known in the art.For example, referring to, United States Patent (USP) 5,011,678, it incorporates this paper into as a reference in full.As limiting examples, aerosol combination of the present invention can comprise the TRPM5 inhibitor, such as one or more formulas I chemical compound or any above-mentioned specific group, group or particular compound and biocompatibility propellant, such as (hydrogen/fluorine) carbon propellant.
In other embodiments, the present invention relates to the transdermal drug delivery compositions, it comprises the TRPM5 inhibitor of medical science effective dose, and is all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.The transdermal drug delivery compositions, the medicine that is designed to the delivery treatments effective dose such as device passes patient's skin.Device known in the art comprises relating to controls the depot device and the device that relate to medicine dispersion in substrate of medicine to the film of the speed of skin release.The transdermal drug delivery compositions is known in the art such as transdermal patch.
In certain embodiments, pharmaceutical composition of the present invention comprises about 0.001 milligram and arrives about 1000 milligrams TRPM5 inhibitor, and is all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.In certain embodiments, pharmaceutical composition of the present invention comprises about 0.01 milligram and arrives about 10 milligrams TRPM5 inhibitor, and is all suc as formula I chemical compound or any above-mentioned specific group, group or particular compound.
The TRPM5 inhibitor, all activity suc as formula I chemical compound or any above-mentioned specific group, group or particular compound can be measured by adopting many methods known in the art to test described chemical compound.For example, can come assessing compound to strengthen the ability of insulin secretion, GLP-1 secretion or insulin sensitivity by using in vivo test.This in vivo test has been identified the amount of the insulin that is discharged by pancreatic cell or the amount of the GLP-1 that discharged by L type enteroendocrine cell under all conditions that exists suc as formula the I chemical compound of TRPM5 inhibitor.
The TRPM5 inhibitor, all activity suc as formula I chemical compound or any above-mentioned specific group, group or particular compound also can be by means of measuring in the test described in the embodiment 23.
The preparation method of chemical compound
The TRPM5 inhibitor can adopt test disclosed herein and method to identify.In addition, can be used for identifying chemical compound incorporating in full disclosed test in this paper US patent application publication 20050019830 as a reference into as the TRPM5 inhibitor.These chemical compounds can adopt technology well known by persons skilled in the art to prepare.
Formula I chemical compound can be synthesized according to method hereinafter described.Being used for chemical compound of the present invention can use process known in the art to be synthesized.
Below general reaction scheme the synthetic method that is used to prepare The compounds of this invention has been described.In a method, formula I chemical compound can prepare by the hydrazides of suitable acyl groupization and suitable ketone or aldehyde are carried out condensation in suitable organic solvent such as ethanol, 2-propanol, oxolane, toluene etc. and composition thereof, (R wherein shown in reaction scheme 1
1, R
2, R
3, R
4, L
1And L
2Definition the same).The existence of water quencher such as molecular sieve or dry potassium carbonate can be used in this method.Can use acid or base catalysis to promote condensation.Acid catalyst includes but not limited to p-methyl benzenesulfonic acid, methanesulfonic acid, phosphoric acid and sulphuric acid.Base catalyst includes but not limited to triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate and sodium carbonate.
In alternative method, R wherein
2Some the formula I chemical compound that is H can be produced (R wherein shown in reaction scheme 2
1, R
2, R
3, R
4, L
1And L
2Definition the same).According to this method, suitable carboxylic acid is handled with the hydrazone of suitable aldehydes or ketones, so that formula I to be provided chemical compound.Carbonyl dimidazoles and triethylamine can be used as condensing agent and are used in this reaction, although also can use other suitable condensing agent.
As another embodiment, wherein R
1And R
2Be aryl formula I chemical compound can by with the hydrazides (such as chemical compound 1) of acyl groupization and aldehyde (such as chemical compound 2) in suitable organic solvent such as ethanol, 2-propanol, oxolane, toluene etc. and composition thereof, and under the condition that water quencher such as molecular sieve or dry potassium carbonate exist, carry out condensation and be produced (reaction scheme 1).Can use acid or base catalysis to promote condensation.Acid catalyst includes but not limited to p-methyl benzenesulfonic acid, methanesulfonic acid, phosphoric acid and sulphuric acid.Base catalyst includes but not limited to triethylamine, diisopropyl ethyl amine, pyridine, N-methylmorpholine, sodium carbonate, potassium carbonate and sodium carbonate.An example of this method is shown in reaction scheme 3.
The variant of this method can comprise with the hydrazone of suitable aldehyde (such as chemical compound 4) handles suitable carboxylic acid (such as chemical compound 3) so that Compound I to be provided.Carbonyl dimidazoles and triethylamine are used as condensing agent in this reaction usually.An example of this method is shown in reaction scheme 4.
This reaction also can be carried out under the condition of non-impurity-doped (for example solvent-free).After reacting completely, come products of separated by crystallization from solvent such as ethanol, dichloromethane, ethyl acetate and toluene etc.
Similarly, other chemical compound of the present invention can obtain from commercially available source or can be prepared by those skilled in the art.Parent material is commercially available or they can prepare by those skilled in the art.For example, above-mentioned chemical compound 1 can followingly be produced: carboxylic acid (such as chemical compound 3) and protected hydrazine (such as chemical compound 5) are reacted so that protected hydrazides (such as chemical compound 6) to be provided under the condition that carbonyl dimidazoles/triethylamine exists.After reacting completely, can from hydrazides (such as chemical compound 6), remove protecting group down in standard conditions (such as acid condition, for example trifluoroacetic acid), to provide formula 1 chemical compound.An example of this method is shown in reaction scheme 5.
Other chemical compound of the present invention can be produced by the small variant of methods described herein.These methods and other method are described in the document, such as Wyrzykiewicz and Prukala, and Polish J.Chem.72:694-702 (1998); With Elderfield and Wood, J.Org.Chem.27:2463-2465 (1962), it incorporates this paper into as a reference separately in full.
Other formula I chemical compound (L wherein
2Be N=N) can be produced by making diazol and hydrazone reaction.The reaction condition that is used for this condensation be the organic synthesis those skilled in the art known (for example, referring to, Synthesis, 577-581 (1995); Chemical and PharmaceuticalBulletin 42 (11): 2363-2364 (1994); Tetrahedron 38 (12): 1793-1796 (1982)).Parent material can be commercially available source or can be produced by organic reaction condition commonly used.
L wherein
2Do not exist, R
3And R
4Be cyano group and R
2The other formula I chemical compound that is H can be by being produced Cyanoacetyl-Cyacetazid and diazol condensation.This reaction and condition are that the organic synthesis those skilled in the art are known.(for example, referring to, Archiv.der Pharmazie 337 (3): 140-147 (2004); Monatshefte fuer Chemie 130 (11): 1409-1418 (1999)).
L wherein
1-R
1It is the other formula I chemical compound of following formula
Can be produced (referring to Zhurnal Organischeskoi Khimii17 (3): 481-486 (1981)) by in alcohol solvent (for example methanol, ethanol, isopropyl alcohol) or other solvent, handling lactone A with hydrazine
So that the acyl group hydrazone that can as described hereinly be used B to be provided.
L wherein
1-R
1It is the other formula I chemical compound of following formula
Can be produced (referring to Org.Syn.Coll.Vol.9,530) from keto acid C.Keto acid C carries out esterification with Azimethylene., trimethyl silyl two azomethanes or other agent combination, and the ester that obtains reduces in methanol or ethanol with selective reduction agent such as sodium borohydride, so that intermediate D and/or its lactone to be provided.Intermediate D (or its lactone) handles in alcohol solvent (for example methanol, ethanol, isopropyl alcohol) or other solvent with excessive hydrazine, so that intermediate E to be provided.This intermediate can as described hereinly be used to preparation I compound.
L wherein
1Do not exist and R
1It is the other formula I chemical compound of following formula
Can be produced from intermediate G.1041-3 (1987)) etc. intermediate G is by (for example, referring to, Journal of Heterocyclic Chemistry 24 (4): the commercially available diazol F of reduction is produced with stannic chloride.
L wherein
1-R
1It is the other formula I chemical compound of following formula
Can be produced from intermediate K.Intermediate K is produced shown in following reaction scheme.Aniline (H) alkali such as potassium carbonate, another kind of carbonate bases or stronger alkali such as hexamethyl two silicon sodium nitrides (sodium hexamethyldisilazide) or sodium hydride; Handle with bromoacetate, so that J to be provided.Intermediate J handles in alcohol solvent or other solvent with excessive hydrazine, so that the K that is used as described herein to be provided.
L wherein
1Do not exist and R
1It is the other formula I chemical compound of following formula
Can be produced from intermediate M.Intermediate M can be as JCS Perkin 1, and 2216-2221 (1976) is described obtained with the commercially available halogenide L of pyrrolidine processing.
Certainly, can use other method known in the art and process to prepare some formula I chemical compound.
Following examples have illustrated method of the present invention, chemical compound and compositions without limitation.Below listed each chemical compound obtain from commercially available catalogue company, such as AldrichRarechemLib, Aldrich Sigma, AlsInEx, Biotech Corp., Brandon/Berlex, Calbiochem, ChemBridge, Comgenex West, FoksH, G.﹠amp; J.Research, IBS, ICN Biochemicals, Institute forChemotherapy, Kodak, Lederle Labs, Ligand-CGX, Maybridge PRI, Menai Organics, Menai/Neurocrine, MicroSource, MPA Chemists, Mybrgd/ONYX, PRI-Peakdale, RADIAN, Receptor Research, RGI, Rhone-Poulenc, SPECS/BioSPECS/SYNTHESIA, T.Glinka, TriposModern, VWR, Zaleska, Zelinksy/Berlex, Aeros and Chemica.Chemical compound uses traditional purge process such as HPLC to carry out purification.Chemical compound can use HPLC and mass spectrography to confirm.As known in the art and aforesaid, the hydrazone part can E or the existence of Z configuration.Therefore, although represent with concrete spatial chemistry, be appreciated that to the present invention includes all stereoisomers, particularly all E and Z isomer for particular compound as herein described.Usually that run into and be conspicuous to different condition with parameter is carried out other suitable change and modification is in the spirit and scope of the present invention for those skilled in the art.
Embodiment
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl) diazenyl) benzoic acid methyl ester
Molecular formula: C
19H
19N
5O
2S; Molecular weight: 381.5 (value of calculation).
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid
Molecular formula: C
18H
14BrN
3O
3Molecular weight: 400 (value of calculation).
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide
Molecular formula: C
21H
20N
2O
3Molecular weight: 348 (value of calculation), 348 (measured values).
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane formylhydrazine
Molecular formula: C
19H
20N
2O
3Molecular weight: 324 (value of calculation), 324 (measured values).
The enantiomer of embodiment 4 (R, R, R, S, S, S and S R) use 20% methanol (flow velocity is 5mL/min, 100 crust, 35 ℃) separated on 4.6 * 250mmDiacel ODH post by supercritical fluid chromatography.Isolating HPLC chromatograph as shown in figure 15.
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene) daminozide
Molecular formula: C
18H
24N
2O
3Molecular weight: 316.40 (value of calculation).
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine
Molecular formula: C
20H
30N
2O
4Molecular weight: 364.5 (value of calculation), 364 (measured values).
2-((Z)-2-(phenyl-((E)-phenyl diazenyl)-methylene) diazanyl) benzoic acid
Molecular formula: C
20H
16N
4O
2Molecular weight: 344.7 (value of calculation).
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide
Molecular formula: C
18H
20N
2O
4Molecular weight: 328 (value of calculation), 328 (measured values).
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl) acethydrazide
Molecular formula: C
20H
21BrN
2O
3S; Molecular weight: 449 (value of calculation), 447.9 (measured values).
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also
Molecular formula: C
18H
24N
2O; Molecular weight: 284 (value of calculation), 284 (measured values).
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base) ethylidene) indoline
Molecular formula: C
19H
20N
4O
2Molecular weight: 336 (value of calculation), 336 (measured values).
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine
Molecular formula: C
21H
25N
3O
2Molecular weight: 351 (value of calculation), 351 (measured values).
Embodiment 13
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide (carbonohydrazonoyldicyanide)
Molecular formula: C
10H
5F
3N
4S; Molecular weight: 270.24 (value of calculation).
Embodiment 14
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide
Molecular formula: C
26H
22N
4O
3Molecular weight: 438.5 (value of calculation).
Embodiment 15
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid
Molecular formula: C
20H
21N
3O
2Molecular weight: 335.4 (value of calculation).
Embodiment 16
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine
Molecular formula: C
19H
17N
3Molecular weight: 287 (value of calculation), 287.2 (measured values).
Embodiment 17
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine
Molecular formula: C
16H
21N
3O; Molecular weight: 271 (value of calculation).
Embodiment 18
(Z)-1-(2-(4-(ethyl-(2-hydroxyethyl)-amino) phenyl) hydrazine fork base) naphthalene-2 (1H)-ketone
Molecular formula: C
20H
21N
3O
2Molecular weight: 335 (value of calculation), 333.2 (measured values).
Embodiment 19
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl hydrazine fork base) methyl) benzene-1, the 3-diphenol
Molecular formula: C
14H
11ClF
3N
3O; Molecular weight: 345.7 (value of calculation), 344.9 (measured values).
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-Nitrobenzol methylene) acethydrazide
Molecular formula: C
21H
25N
5O
4Molecular weight: 411.4 (value of calculation), 411.3 (measured values).
Embodiment 21
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine
Molecular formula: C
17H
23N
5O
2Molecular weight: 329.4 (value of calculation).
Embodiment 22
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol
Molecular formula: C
18H
21N
5O; Molecular weight: 323.4 (value of calculation).
Embodiment 23
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides
Molecular formula: C
24H
23N
3O
3
Embodiment 24
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides
Molecular formula: C
22H
22N
3O
3
Be used to measure of the test of TRPM5 inhibitor to the reinforced effects of insulin release
As people such as Poitout, Diabetes, 44:306-313 (1995) is described, and β-TC-6 cell is the insulin secretory cell system that obtains from the antigenic transgenic mice of big T-of expressing simian virus 40 (SV40) the pancreas beta cell.This cell line is containing 5%CO from ATCC cell bank CAT#CRL-11506 acquisition and the DulbeccoShi modification Eagle's medium (DMEM) that contains 15% hyclone (FBS), 4mM glutamine, 4.5mM glucose, 1500mg/L sodium bicarbonate and 1X penicillin/streptomycin antibiotic cocktail
237 ℃ couveuse in grow.Culture divided twice with 1: 2 weekly under tryptic help by convention.
Testing the previous day, with 0.1 * 10
6Individual β-TC-6 cell is bed board in each hole of 96 orifice plates, and with cell overnight incubation in growth medium.
Second day, take out growth medium in the slave plate, with monolayer with phosphate buffered saline (PBS) (PBS) rinsing and at 37 ℃ by 118.5mM NaCl, 2.54mM CaCl
2, 1.19mMKH
2PO
4, 4.74mM KCl, 25mM NaHCO
3, 1.19mM MgSO
4, the pre-cultivation 30 minutes in the Krebs-Ringer bicarbonate buffer (KRBB) (pH 7.4) formed of 10mM HEPES buffer and 0.1% bovine serum albumin.This buffer is taken out and replaces with the same buffer of comprising of 100 μ L of various insulin release regulators: comprise the glucose of the various concentration that are up to 12mM, high chemical compound to 100 μ M.With the chemical compound stock solution for example 10-20mM in DMSO, dilute.Final DMSO concentration in cultivating buffer is 0.5% or lower.Comprised the vehicle contrast.Then 37 ℃ of static cultivations 2 hours.Cultivate the back whole volume of culture of collection at 2 hours and be used for the insulin test.
The ELISA rules are used for insulin assay.Use derives from Linco Research, the rat/mouse insulin ELISA test kit CAT# EZRMI-13K of Inc. and
Red hydrogen peroxide/peroxidase test kit CAT# A22188 and
Red reagent (10-acetyl group-3,7-dihydroxy Fen oxazine) CAT# A12222 uses following regulation implement ELISA.
All reagent were warming to room temperature in advance before experimentizing.
1. the 10X lavation buffer solution is diluted to the 1X lavation buffer solution.The 50mL+450mL deionized water.Pair cell culture supernatant (β-TC-6 cell culture) is carried out dilution in 1: 10.
2. use string (8 holes) hole to be used for standard sample and QC1 and QC2, typically 0 and the insulin of 5ng/mL.On some plates, the complete standard curve of acquisition insulin as follows.
3. cover the not hole of usefulness.1X lavation buffer solution with each 300 μ L washs (each washing step is 2 minutes on agitator) three times with each hole.The lavation buffer solution decant fallen and by board reversal being removed residual volume and carry out several times and acutely knock so that it is struck and absorb on the towel from institute being porose.Before carrying out next step, do not allow orifice drying.
4. 20 μ L test buffer is joined in the blank well, 10 μ L standard sample and sample are joined in those holes.
5. 10 μ L rat insulin standard sample and sample are joined in the suitable hole.
6. 80 μ L being detected antibody joins in whole holes.Plate is covered and at room temperature cultivated 2 hours.
7. tear off the plate covering and the slave plate decant falls solution.Rap to remove the residual solution in the hole.
8. the rare lavation buffer solution with each 300 μ L washs (each washing step is 2 minutes on agitator) 3 times with each hole.Rap as previously mentioned to remove residual solution.
9. 100 μ L enzymatic solution are joined in each hole.At room temperature cultivated 30 minutes under slightly shaking with the sealer overlay and on the microtitration plate agitator.
10. remove sealer, the slave plate decant falls solution and raps plate to remove residual fluid.
11. the rare lavation buffer solution with each 300 μ L washs every hole 6 times.After each washing, carry out decant and rap to remove remaining buffer.
12. prepare the 5mL working solution of 100 μ L Amolex Red reagent, it comprises 2.0mM H
2O
2, the H of the 20mM of the Amplex reagent of the 10mM of the 1x reaction buffer of 4.45mL+50 μ L+500 μ L
2O
2
13. in each hole, add Amplex Red reagent/H of 100 μ L
2O
2
14. reactant is cultivated.At room temperature cultivated keep in Dark Place (using foil paper parcel plate) 30 minutes.Then in Molecular Devices FlexStation at the fluorescence (excitation wavelength range be 530-560nm) of a plurality of point in time measurement at 590nm.
Said process or its minor variations are used to measure the enhancing of TRPM5 inhibitor to insulin secretion.
Embodiment 26
The electrophysiologic studies that the cell that comprises TRPM5 is carried out
Obtain the full cell record of TRP channel current from the HEK cell of acute trypsinized β TC-6 cell and expression TRPM5.Bathing solution is the HankShi balanced salt solution, consists of (mM): 1.2 CaCl
2, 0.5 MgCl
2-6H
2O, 0.4 MgS
4-7H
2O, 5.3 KCl, 0.4KH
2PO
4, 137.9 NaCl, 0.3 Na
2HPO
4-7H
2O and 5.5D-glucose contain 20mMHEPES (Invitrogen), pH 7.4 (NaOH).Inner pipet solution comprises (representing with mM): 135 glutamic acid, 8NaCl, 9CaCl
2, 10HEPES and 10EGTA, pH7.2 (CsOH) is (Sigma).The calculating concentration of free calcium is 1.5 μ M (http://www.stanford.edu/～cpatton/webmaxc/webmaxcS.htm) in internal solution.Use Flaming/Brown trace pipette drawbench (Sutter Instruments) to pull out the record pipet to about 2M Ω from the flame polish Pyrex.
MultiClamp 700B augmentor and Digidata 1322A transducer that use is gone up operation at Clampex 9.2 softwares (Axon Instruments) have obtained the voltage clamp record in full cell mode.Record at room temperature carries out.The record rules comprise from-80mV current potential and rising to+oblique line of 80mV current potential, step to then-80mV.At following three different voltage measurement peak currents :-80mV, rise at oblique line+80mV, turn back to then-80mV.After slope change (break-in), compensate series resistance immediately automatically, and the measurement capacitance that obtains is used for the calculating of electric current density.Image data and under 1kHz, filtering under 5kHz.
Compound is become the DMSO liquid storage.Testing the same day, and they had been dissolved in the bath solution reach 0.1% final DMSO concentration.Use multitube implement device (SF-72, Warner) realize solution exchange rapidly (～100ms).
Embodiment 27
The existence of mTRPM5 in mice β TC6 cell
The growth of β TC-6 cell is rotated then slow down, and use the mini test kit of RNeasy (Cat #:74104) that derives from Qiagen RNA to prepare prepared product.Use Invitrogen deoxyribonuclease I (Cat #:18068-015) to carry out the deoxyribonuclease processing for the second time this prepared product.Use is used for Invitrogen Superscript First-Strand Synthesis System (Cat #:12731-019) the preparation first chain cDNA synthetic of RT-PCR.RT (+) and RT (-) cDNA have been prepared to check the genome contamination of heavy.
Use derives from platinum Taq archaeal dna polymerase (Cat #:10966-018) and specific forward primer of mtrpM5 and the reverse primer of Invitrogen, makes RT (+) and RT (-) cDNA that polymerase chain reaction all take place.Observe RT (+) product that is fit to the size band and can find out do not have genome to pollute from the shortage of the band of RT (-) cDNA.The result as shown in figure 14.
The activity of selecteed chemical compound
Checked selecteed chemical compound of the present invention to increase the ability of insulin secretion.The result is as shown in the table.To concentration is that the chemical compound of 10 μ M is tested.Data show generates with respect to glucose dependency insulin, the enhancing percent of the insulin secretion that is caused by test compound.The activity of tolbutamide also is provided in following table, and tolbutamide is tested at 30 μ M.
| The embodiment numbering | The enhancing percent of insulin secretion (10 μ M) | ??IC 50TRPM5??(μM) |
| ??3 | ??250 | ??0.6 |
| ??4 | ??111 | ??0.6 |
| ??8 | ??39 | ??3 |
| ??23 | ??208 | ??0.5 |
| ??24 | ??207 | ??0.4 |
| Tolbutamide (30 μ M) | ??228 | ??-- |
Embodiment 29
Use of the test of GLUTag raji cell assay Raji TRPM5 inhibitor to the influence of GLP-1 release
Mice GLUTag cell is the system of enterocyte originally of expressing TRPM5.This cell line obtains from the Daniel J.Drucker doctor of the endocrine subject of the department of medial science of University of Toronto, and is containing 5%CO in containing the high glucose Invitrogen DulbeccoShi Eagle's medium (DMEM) (Cat #:11995) of 10% hyclone (FBS) and 1X penicillin/streptomycin antibiotic cocktail
237 ℃ of incubators in grow.Beginning before the experiment all reagent and culture medium to be warming to room temperature in advance.Before soon using, substrate dilution and photosensitive substrate are thawed.
The inoculation of cell plates
Use bed board culture medium ((Cat #:31985) the OPTI-modification Eagle's medium (MEM) of Invitrogen of 100 μ L, contain 10%FBS and 1X penicillin/streptomycin antibiotic cocktail) will contain the BD 96 hole Matrigel coating plate (Fisher of GLUTag cell, Cat #:08-774-166) carries out rehydrated processing, and containing 5%CO
237 ℃ of couveuses in cultivated 30 minutes.Then the GLUTag cell is carried out trypsinized and counting.Prepared that to have inoculum density be 7.5 * 10
5The cell dilution thing of the GLUTag cell of individual cells/ml.With the sucking-off from the Matrigel coating plate of rehydrated culture medium.With the cell dilution thing bed board of 100 μ L in each hole of plate.Then this plate is being contained 5%CO
237 ℃ of incubators in overnight incubation.
Following rules adopt Millipore GLP-1 enzyme-linked immunosorbent assay kits (Cat. #:EGLP-35K) to analyze under the condition that TRPM5 inhibitor/reinforcing agent and glucose exist GLP-1 from the secretion of GLUTag cell.
Enzyme-linked immunosorbent assay test first day
The stock solution plate and the dilution plate that have prepared TRPM5 inhibitor or reinforcing agent.Before be about to using, 1% bovine serum albumin (BSA) is joined in the Krebb ' s Ringer bicarbonate buffer (KRBB).KRBB forms: 118.5mM NaCl, 2.54mM CaCl
22H
2O, 1.19mM KH
2PO
4, 4.74mM KCl, 25mM NaHCO
3, 1.19mM MgSO47H
2O and 10mM HEPES buffer, pH 7.4.The KRBB of cell plates and 100 μ L was cultivated 30 minutes.Then with the sucking-off of KRBB buffer.This incubation step is repeated once.With the sucking-off of KRBB buffer and to replace with the TRPM5 inhibitor that comprises various concentration or reinforcing agent and glucose be the same buffer of 150 μ L of 12.5mM glucose and 1.5 μ M TRPM5 inhibitor.Also detected the KRBB buffer that does not contain TRPM5 inhibitor/reinforcing agent and glucose in triplicate.Containing 5%CO then
237 ℃ of incubators in treated cell was carried out static culture 2 hours.
During last 30 minutes of cultivation in 2 hours, be prepared as follows 96 hole enzyme-linked immunosorbent assay plates.Lavation buffer solution (1: 10 dilution of lavation buffer solution concentrate (the PBS buffer that contain polysorbas20 and Hydrazoic acid,sodium salt of the 10mM)) washing of GLP-1 (activity) the enzyme-linked immunosorbent assay plate of anti-GLP-1 monoclonal antibody with 300 μ L/ holes three times will be scribbled.Test buffer (PBS that comprises protease inhibitor of 0.05M (pH 6.8) contains polysorbas20,0.08% Hydrazoic acid,sodium salt and 1%BSA) with 200 μ L joins among the A10-A12 of non-specific binding hole then.To join in the GLP-1 gauge orifice with the test buffer of 100 μ L total amounts.The combination that to test buffer (98 μ L) and DPP IV (DPP-IV) inhibitor (Linco Cat# DPP4) (2 μ L) joins in all cell sample holes with 100 μ L.With 100 μ L the GLP-1 amidase linked immunosorbent assay standard sample of test in the buffer (GLP-1 (7-36 amide): 2,5,10,20,50 and 100pM) join in the suitable hole with incremental order in duplicate.Sample with 100 μ L joins in the residue hole of cell plates then.With enzyme-linked immunosorbent assay (ELISA) plate gently jolting be used for suitable mixing.
Use the seal thing with the covering of enzyme-linked immunosorbent assay plate and in 4 ℃ of overnight incubation (20-24 hour) then.
The wash rice that inclines from elisa plate then falls liquid, and by knocking excess fluid is struck on the absorption towel.Use the lavation buffer solution of 300 μ L that every hole of elisa plate is washed 5 times, when the 4th is washed, elisa plate was at room temperature cultivated in lavation buffer solution 5 minutes.After the 5th washing, excessive buffer is struck on the absorption towel by knocking.At once the detection conjugate (anti-GLP-1 alkali phosphate conjugate) of 200 μ L is joined in each hole then, at room temperature cultivated then 2 hours.To detect the conjugate wash rice that inclines then and fall, then with the lavation buffer solution of 300 μ L with each hole washing 3 times.By knocking excess fluid is struck on the napkin.Join the diluted substrate of 200 μ L in each hole and at room temperature cultivated at least 20 minutes in the dark.10mg photaesthesia substrate MUP (methyl umbelliferone phosphate (MethylUmbelliferyl Phosphate)) joined in the Millipore ' s GLP-1 enzyme-linked immunosorbent assay kit and before being about to use, in the 1mL deionized water, carry out hydration.In the substrate dilution, prepare 1: 200 dilution (for example the substrate of 100 μ L hydrations is in 20mL substrate dilution).Before being about to use, prepare fresh dilution each time.After 20 minutes, read plate at 355nm/460nm.When the maximal phase that has enough signal to noise ratios (being 2pM) and reading the plate device in the standard curve minimum point has the highest standard point (that is, in the time of 100pM), not require extra culture period in to fluorescent apparatus (RFU) reading.Otherwise, need other culture period.
When signal is abundant, the stop bath of 50 μ L according to being that identical order joins in each hole with the substrate addition sequence, is at room temperature cultivated 5 minutes then in the dark to obtain phosphatase activity.Read to use on the plate device emission wavelength of excitation wavelength/460nm of 355nm that ELI SA plate is carried out reading at fluorescence then.The result is shown in Figure 16-19.
Fully described the present invention at present, one skilled in the art will appreciate that under the condition of the scope that does not influence the present invention or its any embodiment, can the broad of condition, preparation and other parameter but carry out same enforcement in the scope of equal value.All patents and communique that this paper quotes are incorporated this paper into as a reference in full.
Claims (157)
1. strengthen insulin from the method that cell discharges, comprise one or more TRPM5 inhibitor that make described cells contacting effective dose.
2. the process of claim 1 wherein that described TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, it randomly is substituted separately.
3. the method for claim 2, wherein R
1Be optional substituted C
6-10Aryl.
4. the method for claim 2, wherein R
1It is the first heteroaryl of optional substituted 5-14.
5. the method for claim 2, wherein R
1Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.
6. the method for claim 2, wherein R
1Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.
7. the method for claim 2, wherein R
1Be optional substituted C
1-6Alkyl.
8. the method for claim 2, wherein R
2Be H.
9. the method for claim 2, wherein R
2Be C
1-6Alkyl.
10. the method for claim 2, wherein R
2Be C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl.
11. the method for claim 2, wherein R
3Be H.
12. the method for claim 2, wherein R
3Be C
1-6Alkyl.
13. the method for claim 2, wherein R
3Be C
6-10Aryl.
14. the method for claim 2, wherein R
3Be cyano group.
15. the method for claim 2, wherein R
4Be optional substituted C
1-6Alkyl.
16. the method for claim 2, wherein R
4Be optional substituted C
6-10Aryl.
17. the method for claim 2, wherein R
4It is the first heteroaryl of optional substituted 5-10.
18. the method for claim 2, wherein R
4Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.
19. the method for claim 2, wherein R
4Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.
20. the method for claim 2, wherein L
1Do not exist.
21. the method for claim 2, wherein L
1Be to contain 1-10 carbon atom and/or heteroatomic connection base and its optional being substituted.
22. the method for claim 2, wherein L
2Do not exist.
23. the method for claim 2, wherein L
2Be to contain 1-10 carbon atom and/or heteroatomic connection base and its optional being substituted.
24. the method for claim 2, wherein R
1It is unsubstituted phenyl.
25. the method for claim 2, wherein R
1Be phenyl or naphthyl, it is independently selected from following substituent group by 1,2 or 3 separately and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
26. the method for claim 2, wherein R
1It is nitrogenous heteroaryl.
27. the method for claim 2, wherein R
1Be selected from: pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.
28. the method for claim 2, wherein R
4It is unsubstituted phenyl.
29. the method for claim 2, wherein R
4Be phenyl or naphthyl, it is independently selected from following substituent group by 1,2 or 3 separately and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
30. the method for claim 2, wherein R
4It is nitrogenous heteroaryl.
31. the method for claim 2, wherein R
4Be selected from: pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.
32. the method for claim 2, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
6-10Aryl.
33. the method for claim 2, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
6-10Aryl.
34. the method for claim 2, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4It is the first heteroaryl of optional substituted 5-10.
35. the method for claim 2, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4It is the first heteroaryl of optional substituted 5-10.
36. the method for claim 2, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
3-10Cycloalkyl.
37. the method for claim 2, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4And L
2Formation-N=N-aryl together.
38. the method for claim 2, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
4Be optional substituted C
6-10Aryl is such as phenyl and naphthyl; And L
1And L
2Do not exist.
39. the method for claim 2, wherein R
1Be C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, assorted thiazolinyl of 3-10 unit ring or C
1-6Alkyl, its optional separately being substituted; R
2Be H, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl; L
1Do not exist, or contain 1-6 carbon atom and/or heteroatomic connection base and its optional being substituted; And R
3, R
4And L
2Form with carbon atom and to be selected from following group: C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, the assorted thiazolinyl of 3-10 unit ring, it randomly is substituted separately.
40. the method for claim 2, wherein R
1It is heteroaryl; R
2Be H; R
4It is heteroaryl; L
1Do not exist; And L
2Be N=N.
41. the method for claim 2, wherein R
1It is bicyclic alkyl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Do not exist; And L
2Do not exist.
42. the method for claim 2, wherein R
1It is aryl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
43. the method for claim 2, wherein R
1It is cycloalkenyl group; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
44. the method for claim 2, the chemical compound of wherein said formula I is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
45. the process of claim 1 wherein cell right and wrong human pancreas cell.
46. the method for claim 45, wherein inhuman pancreatic cell are the pancreatic cells of cattle, horse, sheep, pig, cat, Canis familiaris L., rabbit or monkey.
47. the process of claim 1 wherein that cell is human pancreas's cell.
48. the method for claim 2, its Chinese style I chemical compound is given as pharmaceutical composition.
49. the method for claim 2, its Chinese style I chemical compound is given as veterinary composition.
50. the method for claim 2, its Chinese style I compound-base is given with about 1% to about 10% concentration in percetage by weight.
51. the method for claim 2, its Chinese style I chemical compound is given to about 10 milligrams amount with about 0.01 milligram.
52. it is external to the process of claim 1 wherein that described cell is positioned at.
53. in mammal, strengthen the method that insulin discharges, comprise the described insulin of needs is discharged one or more TRPM5 inhibitor that enhanced experimenter gives effective dose.
54. claim 53 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough enhancing insulins discharge.
55. the method for claim 54, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
56. the method for claim 53, wherein said experimenter is the people.
57. the method for claim 54, wherein chemical compound is given to about 100 milligrams amount with about 0.01 milligram.
58. the method for claim 54, wherein chemical compound is given as the component of drug products.
59. the method for claim 54, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 0.01 weight %.
60. the method for treatment diabetes comprises the described insulin of needs is discharged one or more TRPM5 inhibitor that enhanced experimenter gives effective dose in mammal.
61. the method for claim 60, wherein said TRPM5 inhibitor are formula I chemical compounds:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough enhancing insulins discharge.
62. the method for claim 61, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(m-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
63. the method for claim 60, wherein said experimenter is the people.
64. the method for claim 61, wherein chemical compound is given to about 100 milligrams amount with about 0.01 milligram.
65. the method for claim 61, wherein chemical compound is given as the component of drug products.
66. the method for claim 61, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 0.01 weight %.
67. the method for treatment insulin resistance syndrome in mammal comprises giving one or more formulas I chemical compound to the experimenter that needs are arranged:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough enhancing insulins discharge.
68. the method for claim 67, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
69. the method for claim 67, wherein said experimenter is the people.
70. the method for claim 67, wherein chemical compound is given to about 100 milligrams amount with about 0.01 milligram.
71. the method for claim 67, wherein chemical compound is given as the component of drug products.
72. the method for claim 67, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 0.01 weight %.
73. the method for claim 67, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 1 weight %.
74. the method for treatment hyperglycemia comprises the described insulin of needs is discharged one or more TRPM5 inhibitor that enhanced experimenter gives effective dose in mammal.
75. the method for claim 74, wherein said TRPM5 inhibitor are formula I chemical compounds:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough enhancing insulins discharge.
76. the method for claim 75, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
77. the method for claim 74, wherein said experimenter is the people.
78. the method for claim 75, wherein chemical compound is given to about 195 milligrams amount with about 0.01 milligram.
79. the method for claim 75, wherein chemical compound is given as the component of drug products.
80. the method for claim 75, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 0.01 weight %.
81. the method for claim 75, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 1 weight %.
82. in mammal, strengthen the method that GLP-1 discharges, comprise that the experimenter that the described enhancing of needs GLP-1 is discharged gives one or more TRPM5 inhibitor of effective dose.
83. the method for claim 82, wherein said TRPM5 inhibitor are formula I chemical compounds:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3Unit that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
84. the method for claim 83, wherein R
1Be optional substituted C
6-10Aryl.
85. the method for claim 83, wherein R
1It is the first heteroaryl of optional substituted 5-14.
86. the method for claim 83, wherein R
1Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.
87. the method for claim 83, wherein R
1Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.
88. the method for claim 83, wherein R
1Be optional substituted C
1-6Alkyl.
89. the method for claim 83, wherein R
2Be H.
90. the method for claim 83, wherein R
2Be C
1-6Alkyl.
91. the method for claim 83, wherein R
2Be C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl.
92. the method for claim 83, wherein R
3Be H.
93. the method for claim 83, wherein R
3Be C
1-6Alkyl.
94. the method for claim 83, wherein R
3Be C
6-10Aryl.
95. the method for claim 83, wherein R
3Be cyano group.
96. the method for claim 83, wherein R
4Be optional substituted C
1-6Alkyl.
97. the method for claim 83, wherein R
4Be optional substituted C
6-10
98. the method for claim 83, wherein R
4It is the first heteroaryl of optional substituted 5-10.
99. the method for claim 83, wherein R
4Be optional substituted C
3-10Cycloalkyl or optional substituted C
3-10Cycloalkenyl group.
100. the method for claim 83, wherein R
4Be optional substituted 3-10 assorted alkyl of unit's ring or the assorted thiazolinyl of optional substituted 3-10 unit's ring.
101. the method for claim 83, wherein L
1Do not exist.
102. the method for claim 83, wherein L
1Be to contain 1-10 carbon atom and/or heteroatomic connection base and its optional being substituted.
103. the method for claim 83, wherein L
2Do not exist.
104. the method for claim 83, wherein L
2Be to contain 1-10 carbon atom and/or heteroatomic connection base and its optional being substituted.
105. the method for claim 83, wherein R
1It is unsubstituted phenyl.
106. the method for claim 83, wherein R
1Be phenyl or naphthyl, it is independently selected from following substituent group by 1,2 or 3 separately and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
107. the method for claim 83, wherein R
1It is nitrogenous heteroaryl.
108. the method for claim 83, wherein R
1Be selected from: pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.
109. the method for claim 83, wherein R
4It is unsubstituted phenyl.
110. the method for claim 83, wherein R
4Be phenyl or naphthyl, it is independently selected from following substituent group by 1,2 or 3 separately and replaces: amino, hydroxyl, nitro, halogen, cyano group, mercaptan, C
1-6Alkyl, C
2-6Thiazolinyl, C
1-6Haloalkyl, C
1-6Alkoxyl, C
3-6Thiazolinyl oxygen base, C
1-6Alkylenedioxy group, C
1-6Alkoxyl (C
1-6) alkyl, C
1-6Aminoalkyl, C
1-6Aminoalkoxy, C
1-6Hydroxy alkyl, C
2-6The hydroxy alkoxy base, (a C
1-4) alkyl amino, two (C
1-4) alkyl amino, C
2-6Alkyl-carbonyl-amino, C
2-6Alkoxycarbonyl amino, C
2-6Alkoxy carbonyl, carboxyl, (C
1-6) alkoxyl (C
2-6) alkoxyl, C
2-6Carboxyl alkoxyl and C
2-6Carboxyalkyl.
111. the method for claim 83, wherein R
4It is nitrogenous heteroaryl.
112. the method for claim 83, wherein R
4Be selected from: pyridine radicals, pyrimidine radicals, imidazole radicals, tetrazole radical, furyl, thienyl, indyl, azaindolyl, quinolyl, pyrrole radicals, benzimidazolyl and benzothiazolyl, it randomly is substituted separately.
113. the method for claim 83, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
6-10Aryl.
114. the method for claim 83, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
6- 10Aryl.
115. the method for claim 83, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4It is the first heteroaryl of optional substituted 5-10.
116. the method for claim 83, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4It is the first heteroaryl of optional substituted 5-10.
117. the method for claim 83, wherein R
1Be optional substituted C
6-10Aryl; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4Be optional substituted C
3-10Cycloalkyl.
118. the method for claim 83, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
2Be H or C
1-6Alkyl; R
3Be H or C
1-6Alkyl; And R
4And L
2Formation-N=N-aryl together.
119. the method for claim 83, wherein R
1It is the first heteroaryl of optional substituted 5-10; R
4Be optional substituted C
6-10Aryl is such as phenyl and naphthyl; And L
1And L
2Do not exist.
120. the method for claim 83, wherein R
1Be C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, assorted thiazolinyl of 3-10 unit ring or C
1-6Alkyl, its optional separately being substituted; R
2Be H, C
1-6Alkyl or C
6-10Aryl (C
1-6) alkyl; L
1Do not exist, or contain 1-6 carbon atom and/or heteroatomic connection base and its optional being substituted; And R
3, R
4And L
2Form with carbon atom and to be selected from following group: C
6-10Aryl, 5-10 unit heteroaryl, C
3-10Cycloalkyl, C
3-10Cycloalkenyl group, the assorted alkyl of 3-10 unit ring, the assorted thiazolinyl of 3-10 unit ring, it randomly is substituted separately.
121. the method for claim 83, wherein R
1It is heteroaryl; R
2Be H; R
4It is heteroaryl; L
1Do not exist; And L
2Be N=N.
122. the method for claim 83, wherein R
1It is bicyclic alkyl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Do not exist; And L
2Do not exist.
123. the method for claim 83, wherein R
1It is aryl; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
124. the method for claim 83, wherein R
1It is cycloalkenyl group; R
2Be H; R
3Be H; R
4Be aryl or heteroaryl; L
1Be the optional substituted 2-4 of a containing carbon atom or heteroatomic connection base; And L
2Do not exist.
125. the method for claim 83, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
126. the method for claim 82, wherein said experimenter is the people.
127. the method for claim 83, wherein chemical compound is given to about 100 milligrams amount with about 0.01 milligram.
128. the method for claim 83, wherein chemical compound is given as the component of drug products.
129. the method for claim 83, wherein chemical compound is present in the drug products to the amount of 50 weight % with about 0.01 weight %.
130. strengthen GLP-1 from the method that cell discharges, comprise one or more TRPM5 inhibitor that make described cells contacting effective dose.
131. the method for claim 130, wherein said TRPM5 inhibitor are formula I chemical compounds:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
132. the method for claim 131, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(m-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4 dimethoxy benzylidene) hydrazides.
133. the method for claim 130, wherein said cell are the inhuman enteroendocrine cells in the internal organs.
134. the method for claim 133, wherein inhuman enteroendocrine cell are the enteroendocrine cells of cattle, horse, sheep, pig, cat, Canis familiaris L., rabbit or monkey.
135. the method for claim 130, wherein cell is people's enteroendocrine cell.
136. the method for claim 131, its Chinese style I chemical compound is given as pharmaceutical composition or veterinary composition.
137. the method for claim 131, its Chinese style I compound-base is given with about 1% to about 10% concentration in percetage by weight.
138. the method for claim 131, its Chinese style I chemical compound is given to about 10 milligrams amount with about 0.01 milligram.
139. the method for claim 130, wherein said cell is positioned at external.
140. in mammal, reduce the method for gastric secretion and emptying, comprise that the experimenter that the described stomach function of needs is reduced gives one or more TRPM5 inhibitor of effective dose.
141. claim 140 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
142. the method for claim 141, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
143. in mammal, suppress the method for food intake, comprise that the experimenter to the described food intake inhibition of needs gives one or more TRPM5 inhibitor of effective dose.
144. claim 143 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
145. the method for claim 144, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
146. in mammal, reduce the method for glucagon secretion, comprise that the experimenter that the described glucagon secretion of needs is reduced gives one or more TRPM5 inhibitor of effective dose.
147. claim 146 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
148. the method for claim 147, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
149. in mammal, strengthen the method for insulin sensitivity, comprise to needing the enhanced experimenter of insulin sensitivity to give one or more TRPM5 inhibitor of effective dose.
150. claim 149 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
151. the method for claim 150, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
152. in mammal, increase the method that insulin gene is expressed, comprise the described insulin gene of needs is expressed one or more TRPM5 inhibitor that the experimenter who increases gives effective dose.
153. claim 152 is according to method, wherein said TRPM5 inhibitor is a formula I chemical compound:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
154. the method for claim 153, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
155. the method for treatment or prevent obesity comprises that the experimenter to the described bariatrician of needs gives one or more TRPM5 inhibitor of effective dose in the experimenter.
156. claim 155 method, wherein said TRPM5 inhibitor are formula I chemical compounds:
Or the acceptable salt of its physiology, wherein
R
1Be C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, assorted thiazolinyl of 3-14 unit ring and C
1-6Alkyl, its optional separately being substituted;
R
2Be H, C
1-6Alkyl, C
6-10Aryl or C
6-10Aryl (C
1-6) alkyl;
R
3Be H, C
1-6Alkyl, C
6-10Aryl or cyano group;
R
4Be C
1-6Alkyl, C
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, assorted alkyl of 3-14 unit ring or the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted, or cyano group;
L
1Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted;
L
2Do not exist, or contain 1-10 carbon atom and/or heteroatomic connection base and its and randomly be substituted; Or
R
3, R
4And L
2, with L
2And R
3The carbon atom that is connected forms and is selected from following group: C together
6-14Aryl, 5-14 unit heteroaryl, C
3-14Cycloalkyl, C
3-14Cycloalkenyl group, the assorted alkyl of 3-14 unit ring, the assorted thiazolinyl of 3-14 unit ring, its optional separately being substituted;
Wherein said chemical compound is given with the amount that enough strengthens GLP-1 release.
157. the method for claim 156, its Chinese style I chemical compound is selected from:
4-((E)-((Z)-1-(2-(benzo [d] thiazole-2-1) the hydrazine fork is basic)-2-methyl-propyl group) diazenyl) benzoic acid methyl ester;
(E)-2-(4-bromo-2-((2-(quinoline-8-yl) hydrazine fork base) methyl) phenoxy group) acetic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(naphthalene-1-yl) acethydrazide;
(E)-N '-(3,4-dimethoxy benzylidene)-2-benzyl ring propane-formylhydrazine;
(E)-3-cyclohexenyl group-4-hydroxy-n '-(4-methoxybenzene methylene)-daminozide;
(E)-N '-(3,4-dimethoxy benzylidene)-4-hydroxyl hexanoyl hydrazine;
2-((Z)-2-(phenyl-((E)-phenyl diazenyl) methylene) diazanyl) benzoic acid;
(E)-N '-(3,4-dimethoxy benzylidene)-2-(-tolyl oxygen base) acethydrazide;
(E)-N '-(4-(pi-allyl oxygen base)-3-methoxybenzene methylene)-2-(3-bromobenzyl sulfenyl)-acethydrazide;
(E)-N '-(4-cumene methylene) bicyclo-[4.1.0] heptane-7-formylhydrazine also;
(Z)-1,3,3-trimethyl-2-((E)-2-(2-(4-nitrobenzophenone) hydrazine fork base)-ethylidene) indoline;
(E)-N '-(4-(diethylamino)-2-phenol methylene)-2-benzyl ring propane formylhydrazine;
(4-(trifluoromethyl sulfenyl) phenyl) hydrazine is pitched basic carbon dicyanide;
N-((E)-3-((Z)-2-(1,5-dimethyl-2-oxoindoline-3-base subunit) diazanyl)-3-oxo-1-phenyl third-1-alkene-2-yl) Benzoylamide;
(Z)-2-(2-((1-butyl-1H-indol-3-yl) methylene) diazanyl) benzoic acid;
(E)-4-((2-benzyl-2-phenyl hydrazine fork base) methyl) pyridine;
(Z)-N '-((1H-pyrroles-2-yl) methylene) three ring [3.3.1.1 also
3,7] decane-3-formylhydrazine;
(Z)-1-(2-(4-(ethyl (2-hydroxyethyl) amino) phenyl) hydrazine fork base)-naphthalene-2-(1H)-ketone;
(E)-and 4-((2-(5-chloro-3-(trifluoromethyl) pyridine-2-yl)-2-2-methyl-hydrazine fork base) methyl) benzene-1, the 3-diphenol;
(E)-2-(3,4-3,5-dimethylphenyl amino)-N '-(4-morpholino-3-nitro-benzylidene) acethydrazide;
(Z)-and 3-(2-nitro-5-(pyrrolidine-1-yl) phenyl) hydrazine fork base) quinuclidine;
(E)-2-((2-(1H-benzo [d] imidazoles-2-yl) hydrazine fork base) methyl)-5-(diethylamino) phenol;
3-carbazole-9-base propanoic acid (3,4-dimethoxy benzylidene) hydrazides; With
(4,8-dimethyl quinoline-2-base sulfane base) acetic acid (3,4-dimethoxy benzylidene) hydrazides.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US88799607P | 2007-02-02 | 2007-02-02 | |
| US60/887,996 | 2007-02-02 | ||
| US61/016,394 | 2007-12-21 |
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| Publication Number | Publication Date |
|---|---|
| CN101626770A true CN101626770A (en) | 2010-01-13 |
Family
ID=41522286
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200880007617A Pending CN101626770A (en) | 2007-02-02 | 2008-02-04 | Use of a TRPM5 inhibitor to regulate insulin and GLP-1 release |
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| Country | Link |
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| CN (1) | CN101626770A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592120A (en) * | 2015-02-13 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | Cyclopropyl hydrazide and methoxybenzene-containing GPR119 agonist as well as preparation method and application thereof |
| CN105732476A (en) * | 2016-02-04 | 2016-07-06 | 吉首大学 | Carbazole-isatin type compound and preparation method and application thereof |
| CN110139672A (en) * | 2016-12-26 | 2019-08-16 | 花王株式会社 | Motor adjustment function enhancer |
-
2008
- 2008-02-04 CN CN200880007617A patent/CN101626770A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104592120A (en) * | 2015-02-13 | 2015-05-06 | 佛山市赛维斯医药科技有限公司 | Cyclopropyl hydrazide and methoxybenzene-containing GPR119 agonist as well as preparation method and application thereof |
| CN105732476A (en) * | 2016-02-04 | 2016-07-06 | 吉首大学 | Carbazole-isatin type compound and preparation method and application thereof |
| CN105732476B (en) * | 2016-02-04 | 2017-12-01 | 吉首大学 | A kind of carbazole isatin type compound and its preparation method and purposes |
| CN110139672A (en) * | 2016-12-26 | 2019-08-16 | 花王株式会社 | Motor adjustment function enhancer |
| US11319369B2 (en) | 2016-12-26 | 2022-05-03 | Kao Corporation | Motor control function improving agent |
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