CN105272963A - 2-oxo-4-thio-3,4-dihydropyrimidine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors - Google Patents
2-oxo-4-thio-3,4-dihydropyrimidine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors Download PDFInfo
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- 0 CN(C(C=C(N1CC(C2)=C(*)C=CC2I)Cl)=O)C1=O Chemical compound CN(C(C=C(N1CC(C2)=C(*)C=CC2I)Cl)=O)C1=O 0.000 description 4
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Abstract
The invention provides 2-oxo-4-thio-3,4-dihydropyrimidine derivatives represented by the general formula (I), and pharmaceutically acceptable salts, hydrates, solvates and stereoisomers thereof, and a preparation method of the compounds and pharmaceutical compositions containing the compounds. The compounds can inhibit dipeptidyl peptidase IV (DPP-IV) activity, and can be used for treatment of dipeptidyl peptidase IV related diseases.
Description
Technical field
The present invention relates to the compound that may be used for suppressing dipeptidyl peptidase, treat the application in the disease relevant to dipeptidylpeptidase activity separately or with other drug conbined usage with its preparation method and this compounds.
Background technology
Diabetes are a kind of because of a series of clinical syndromes that Regular Insulin in body is absolute or relative deficiency causes.Its sickness rate increases in the world year by year, and become the chronic comprehensive disease of the 3rd threat human health after cardiovascular disorder and tumour, wherein more than 90% is 2 type glycosurias.Treatment diabetes B medicine conventional clinically at present mainly contains Regular Insulin, biguanides, thiazolidinediones, alpha-glucosidase inhibitor, sulfonylurea and non-sulfonylurea euglycemic agent etc., but As time goes on their curative effect reduces gradually, effectively can not control the development of diabetes, and have untoward reaction in various degree.Many novel targets for the diabetes B cause of disease are constantly developed, and wherein dipeptidyl peptidase-4 (DPP-4) inhibitor is because its action target spot is unique, effectiveness and reliability is better, becomes one of study hotspot of Novel diabetes medicine.
Glucagon-like-peptide-1 (GLP-1) is a kind of incretin, and it is by stimulating and protecting beta Cell of islet, promotes synthesis and the secretion of Regular Insulin, reduces postprandial blood sugar.Dipeptidyl peptidase 4 (DPP-4) is a kind of high specific serine protease existed with dimeric forms, can the alanine residue of N-terminal the 2nd of specific recognition GLP-1, and excises dipeptides from here and make GLP-1 inactivation.Suppress DPP-4 can strengthen the activity of GLP-1, reduce the hyperglycemic symptoms of diabetes B patient.
At present, DPP-4 inhibitor has caused the concern of Ge great drugmaker of the world, and the DPP-4 inhibitor gone on the market has Xi Gelieting (sitagliptin), Vildagliptin (vildagliptin), BMS-477118 (saxagliptin), Egelieting (alogliptin), Li Gelieting (linagliptin) etc.
Summary of the invention
The object of the present invention is to provide class 4-sulfo--3, a 4-dihydropyrimidine-2-keto compounds, its pharmacy acceptable salt, hydrate, solvate or steric isomer as novel DPP-4 inhibitor.
Another object of the present invention is to provide the pharmaceutical composition of compound of the present invention, its pharmacy acceptable salt, hydrate, solvate or steric isomer.
Another object of the present invention is to provide the application of the compounds of this invention in the medicine preparing the disease relevant to DPP-4 enzymic activity.
Further aim of the present invention is to provide a kind of compound of the present invention, its pharmacy acceptable salt, hydrate, solvate or steric isomer, or its composition treats the method for the disease relevant to DPP-4 enzymic activity.
One aspect of the present invention provides a kind of formula compound that (I) represents, its pharmacy acceptable salt, hydrate, solvate or steric isomer:
Ar is substituted or unsubstituted aryl, heteroaryl;
R
1for H, to be substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, ring are mixed alkyl;
R
2for H, halogen, C
1-6alkyl, thiazolinyl, alkynyl;
R
3for amino, alkyl ,-NR
4r
5, ring mixes alkyl, arylalkyl, heteroarylalkyl, alkylsulfonyl C
1-4alkyl, carbonyl C
1-4alkyl, alkoxyl group, aryloxy, heteroaryloxy, respectively substituted or unsubstituted naturally;
L is-(CH
2)
n-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-NH-,-(CH
2)
n-CO-,-CO-, wherein n is 1,2; (CH
2)
nin any methylene carbon optionally by 1-2 independent selected from halo, hydroxyl, C
1-4alkyl, C
1-4the substituting group of alkoxyl group replaces;
R
4and R
5separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
In a kind of embodiment of the compounds of this invention, Ar is phenyl, 5-10 unit heteroaryl, and wherein said phenyl or heteroaryl can by 1-5 R
6replace;
Each R
6independently be selected from: hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, amido, imido grpup, carboxyl, sulfydryl, substituted or unsubstituted alkyl, acyl group, amide group, ester group, acyl group ester group, alkylsulfonyl, sulfinyl, cycloalkyl, ring are mixed alkyl, thiazolinyl, alkynyl, alkoxyl group, alkene oxygen base, alkyl amine group;
R
1for H, C
1-8alkyl, C
1-6thiazolinyl, C
1-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group; Wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be independently selected from halogen, oxo, trifluoromethyl, hydroxyl, amino, carboxyl, cyano group, C by 1-6
1-4alkyl, C
1-4alkoxyl group replaces;
R
2for H, F, C
1-4alkyl;
R
3for 1-5 is independently selected from hydrogen, amino ,-NR
4r
5, halogen, oxo, trifluoromethyl, hydroxyl, carboxyl, cyano group, C
1-4alkyl, C
1-4the ring of the replacement of alkoxyl group is mixed alkyl;
L is methylene radical, and can be selected from halogen, OH, C
1-4alkyl, C
1-4the substituting group of alkoxyl group replaces;
R
4and R
5separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
In the embodiment that a class is such, Ar is phenyl, 5-6 unit heteroaryl, and can be independently selected from halogen, cyano group, hydroxyl, C by 1-3
1-4the substituting group of alkyl, trifluoromethyl, trifluoromethoxy replaces;
In another kind of such embodiment, R
3for 3-amino-piperadine-1-base;
In another kind of such embodiment, L is methylene radical;
Typical compound of the present invention includes, but are not limited to:
The invention provides pharmaceutical composition, comprise compound described herein and pharmaceutically acceptable carrier.
The invention provides the method for the treatment of to the corresponding disease of DPP IV, comprise, to confirming that the patient needed gives at least one compound described herein and/or its at least one pharmacy acceptable salt of significant quantity.
The invention provides compound described herein for the preparation of need treatment in its Mammals be selected from insulin resistant, hyperglycemia, diabetes B disease medicine in purposes.
The present invention relates to all optical isomers of formula (I) compound and all steric isomers, comprise the racemic mixture of this compounds and other enantiomorph and diastereomer, and composition thereof, and contain or adopt their composition respectively.
The present invention includes isotope-labeled compound, they be equal to described by formula (I) those, but one or more atom be different from by atomic mass or total mass number the atom of the common atomic mass of nature or total mass number replace.The isotopic example can introduced in the compounds of this invention comprises hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, the isotropic substance of fluorine and chlorine, respectively such as
2h,
3h,
13c,
11c,
14c,
15n,
18o,
17o,
31p,
32p,
35s,
18f and
36cl.The pharmacy acceptable salt of other the isotopic the compounds of this invention containing above-mentioned isotropic substance and/or other atom, its prodrug and described compound or described prodrug all belongs to scope of the present invention.Some isotope-labeled the compounds of this invention, such as introduce radio isotope (as
3h and
14c) those can be used for medicine and/or substrate tissue measure of spread.Tritium, namely
3h and carbon-14, namely
14c isotropic substance is particularly preferred, because their easy preparation and determination methods.And then, replaced by heavier isotropic substance, such as deuterium, namely
2h, due to the higher benefit that can provide in treatment of metabolic stability, such as extending Half-life in vivo or reduce volume requirements, may be thus preferred in some cases.Isotope-labeled formula (I) compound and prerequisite medicine thereof generally can be prepared like this, when carrying out the technique disclosed in following flow process and/or embodiment and preparation example, replace nonisotopically labelled reagent with the facile isotope-labeled reagent of appearance.
Formula (I) compound can generate pharmaceutically acceptable preparation further, and salt, the solvate of contained (I) compound, salt includes but not limited to acid salt and/or alkali salt.
The present invention also provides pharmaceutical preparation, comprises treatment formula (I) compound of significant quantity or its therapeutically acceptable salt and its pharmaceutically acceptable carrier, thinner or vehicle.All these forms all belongs to the present invention.
Definition
Term " alkyl " refers to not containing heteroatomic alkyl.Therefore, this term comprises straight chained alkyl as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl etc.This term also comprises the branched chain isomer of branched-chain alkyl, includes but not limited to the group such as :-CH (CH
3)
2,-CH (CH
3) (CH
2cH
3) ,-CH (CH
2cH
3)
2,-C (CH
3)
3,-C (CH
2cH
3)
3,-CH
2cH (CH
3)
2,-CH
2cH (CH
3) (CH
2cH
3) ,-CH
2cH (CH
2cH
3)
2,-CH
2c (CH
3)
3,-CH
2c (CH
2cH
3)
3,-CH (CH
3)-CH (CH
3) (CH
2cH
3) ,-CH
2cH
2cH (CH
3)
2,-CH
2cH
2cH (CH
3) (CH
2cH
3) ,-CH
2cH
2cH (CH
2cH
3)
2,-CH
2cH
2c (CH
3)
3,-CH
2cH
2c (CH
2cH
3)
3,-CH (CH
3) CH
2cH (CH
3)
2,-CH (CH
3) CH (CH
3) CH (CH
3)
2,-CH (CH
2cH
3) CH (CH
3) CH (CH
3) (CH
2cH
3) etc.Therefore term alkyl comprises primary alkyl, secondary alkyl and tertiary alkyl.
Term " thiazolinyl " refers to wherein at least one unsaturated point, that is, wherein two adjacent carbonss connect alkyl as defined above by double bond.
Term " alkynyl " relates to the alkyl that wherein two adjacent carbonss are connected by triple bond.
Term " alkoxyl group " refers to-OR, and wherein R is alkyl.
Term " halogen " refers to fluorine, chlorine, bromine and iodine group.
Term " cycloalkyl " refers to the carbocyclic alkyl substituent of list-or many rings.Comprise cyclic alkyl, thiazolinyl and alkynyl.Cycloalkyl can make monocycle or many rings (such as containing condensing, bridging and/or spiro system), and wherein carbon atom is positioned at inside ring system or outside.Cycloalkyl can have 3-14 annular atoms (such as have 3-8 carbon atom with regard to monocyclic cycloalkyl, have 7-14 carbon atom with regard to polycyclic naphthene base) as a whole.The ring position suitable arbitrarily of cycloalkyl can be covalently bound with defined chemical structure.The example of cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatriene base, norcamphyl, norpinanyl, norcarane alkyl, adamantyl and spiral shell [4.5] decyl and homologue and isomer etc.
Term " ring mix alkyl " refers to the heteroatoms that has at least one to be selected from O, N and S and optional containing one or more double bond or triple bond non aromatic cycloalkyl.Ring alkyl of mixing can have 3-14 annular atoms and as a whole containing 1-5 heteroatoms (such as mix with regard to alkyl with regard to monocycle ring and have 3-6 annular atoms, mixing with regard to alkyl with regard to many rings ring has 7-14 annular atoms).Ring mixes alkyl can to produce the chemical structure with defined on any heteroatom of rock steady structure or carbon atom covalently bound.Ring one or more N or S atoms of mixing on alkyl can oxidized (such as morpholine N-Oxide, parathiazan S-oxide compound, parathiazan S, S-dioxide).Ring alkyl of mixing can also contain one or more oxo group, such as phthalimido group, piperidone base, oxazolidine ketone group, 2,4 (1H, 3H)-dioxo-pyrimidyl, pyridine-2 (1H)-one base etc.The mix example of alkyl of ring also comprises morpholinyl, parathiazan base, pyranyl, imidazolidyl, imidazolinyl, oxazolidinyl, pyrazolidyl, pyrazolinyl, pyrrolidyl, pyrrolinyl, tetrahydrofuran base, tetrahydro-thienyl, thiazolidine base, piperidyl, azetidine, piperazinyl etc.
Term " aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the right ring of adjacent carbons) group, has many rings (namely with the ring that adjacent carbons the is right) group of the π-electron system of conjugation.Aryl can on any carbon atom producing rock steady structure chemical structure with defined covalently bound.In some instances, aryl only can have aromatic carbocyclic, as phenyl, anthryl, phenanthryl etc.In other instances, aryl can be that wherein at least one aromatic carbocyclic and one or more ring are mixed many rings ring system that alkyl or cycloalkyl ring condenses, and nonrestrictive example comprises indanyl (i.e. the benzo derivative of pentamethylene), tetralyl (i.e. the benzo derivative of hexanaphthene), benzimidazoline base, chromenyl (i.e. the benzo derivative of pyrans), benzdioxan base, benzodioxole base, chromanyl, different chromanyl, indolinyl etc.
Term " heteroaryl " refers to and comprises 1 to 5 heteroatoms, and the heteroaromatic system of 5 to 14 annular atomses, wherein heteroatoms comprises O, S and N.In some instances, heteroaryl can comprise the bicyclic heteroaryl that alkyl of mixing with one or more aromatic carbocyclic, non-aromatic carbocycle or non-aromatic ring condenses.Heteroaryl can to produce the chemical structure with defined on any heteroatom of rock steady structure or carbon atom covalently bound.One or more N or S atoms in heteroaryl can oxidized (as pyridine N-oxides, thiophene S-oxide compound, thiophene S, S-dioxide).The example of this heteroaryl comprises furyl, pyrryl, pyridyl, thienyl, pyrimidyl, pyridazinyl, triazolyl, pyrazinyl, tetrazyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, thiadiazolyl group, oxazolyl, isoxazolyl, oxadiazoles base, indyl, pseudoindoyl, benzothienyl, benzofuryl, quinolyl, isoquinolyl, 2-toluquinoline base, quinazolyl, quinoxalinyl, benzotriazole base, benzothiazolyl, benzimidazolyl-, benzisothiazole base, benzisoxa oxazolyl, benzisoxa oxazolyl, benzo oxadiazoles base, cinnolines base, 1H-indyl, 2H-indyl, indolizine base, isobenzofuran-base, naphthyridinyl, phthalazinyl, pteridyl, purine radicals, oxazole pyridyl, thiazolopyridinyl, imidazopyridyl, furopyridyl, thienopyridine base, Pyridopyrimidine base, pyrido-pyrazine base, pyrido pyridazinyl, thieno-thiazolyl, thieno-oxazolyl, Thienoimidazole base, tetrahydric quinoline group, thionaphthene pyridyl, cumarone pyridyl, 4,5,6,7-tetrahydro indole base etc.
Embodiment
Flow process 1:
Formula (I) compound can be prepared according to flow process 1, wherein each substituting group as in summary of the invention define:
Intermediate II and intermediate III, in suitable solvent, such as methyl alcohol, tetrahydrofuran (THF), toluene, DMF or DMSO, react, provide intermediate compound IV.This reaction uses alkali such as sodium bicarbonate, salt of wormwood or cesium carbonate, generally carries out in a heated condition.Intermediate III can be salt, example hydrochloric acid salt, acetate or fluoroform hydrochlorate.Then intermediate compound IV and sulphur exchange reagent, as Lloyd's's reagent (Lawesson ' sreagent), Davy reagent, Japanese reagent, Belleau reagent, oxygen sulphur permutoid reaction is there is in suitable solvent is as toluene, dioxane, preparation I compound, this reaction is generally carried out in a heated condition.
Flow process 2:
Intermediate II can be prepared according to the scheme one in flow process 2 or scheme two, wherein each substituting group as in summary of the invention define, X
1and X
2for halogen.
Scheme one:
Intermediate V and intermediate VI in a suitable solvent, as methyl-sulphoxide, DMF, reacts and obtains intermediate II.This reaction generally uses alkali as salt of wormwood, cesium carbonate, and reaction is carried out usually in a heated condition.
Scheme two:
Intermediate VII and intermediate VI in a suitable solvent, as DMF/DMSO, dioxane, at alkali as under salt of wormwood, cesium carbonate existence, reacts and provides intermediate VIII.Then, intermediate VIII and intermediate compound I X in a suitable solvent, as acetone, tetrahydrofuran (THF), reacts and obtains intermediate II.This reaction generally uses alkali as salt of wormwood, cesium carbonate, generally carries out in a heated condition.
The following example intends to set forth specific invention embodiment, never the scope of plan restriction specification sheets or claims.Those skilled in the art are by accreditation, and raw material can be different, can adopt additional step to generate the compound contained by the present invention, prove as the following example.The following example only supplies purposes of illustration, neither intends, also should not be interpreted as restriction invention in any way.Those skilled in the art will recognize that, can carry out changing and revising, and without prejudice to the spirit or scope of the present invention.
Embodiment 1
Prepare compound 1:(R)-2-[6-(3-amino piperidine-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-4-fluorobenzonitrile
Step 1: synthesis 2-brooethyl-4-fluorobenzonitrile
To 2-methyl-4-fluorobenzonitrile (2g, 14.8mM, N-bromo-succinimide (2.64g is added in tetracol phenixin (24mL) solution 1.0equiv), 14.8mM, 1.0equiv), benzoyl peroxide (BPO, 179mg, 0.74mM, 0.05equiv), and be heated in nitrogen reflux 3h.React completely through TLC monitoring, be cooled to room temperature, filter, with tetracol phenixin washing, concentrating under reduced pressure solvent obtains crude product white solid.Non-purifying is directly used in next step reaction.
1HNMR(400MHz,CDCl
3)：δ＝7.71(dd,J＝8.6,5.4Hz,1H),7.30(dd,J＝8.8,2.3Hz,1H),7.15(td,J＝8.2,2.3Hz,1H),4.62(s,2H)。
Step 2: synthesis 2-(chloro-2,4-dioxo-3,4-dihydro-pyrimidin-1 (the 2H)-ylmethyls of 3-methyl-6-)-4-fluorobenzonitrile
By 3-methyl-6-chlorouracil (1.968g, 12.3mM, 1.0equiv), 2-brooethyl-4-fluorobenzonitrile (3.168g, 14.8mM, 1.2equiv) with salt of wormwood (1.782g, 12.915mM, 1.05equiv) mixture in dimethyl sulfoxide (DMSO) (30mL), at 60 DEG C, in nitrogen atmosphere, heat 3h.This mixture is cooled to room temperature, adds water, be extracted with ethyl acetate, merge organic layer, use water, normal saline flushing respectively.Organic layer, through anhydrous sodium sulfate drying, filters and concentrates.White solid compound (2.285g, yield 63.3%) is obtained after column chromatography (sherwood oil: ethyl acetate=5:1 ~ 2:1) process.
1HNMR(400MHz,CDCl
3)：δ＝7.75(dd,J＝8.6,5.3Hz,1H),7.16(td,J＝8.3,2.5Hz,1H),6.96(dd,J＝8.9,2.4Hz,1H),6.06(s,1H),5.51(s,2H),3.41(s,3H)。
Step 3: synthesis (R)-2-[6-(3-amino piperidine-1-base)-3-methyl-2,4-oxo-3,4-dihydro-1 (2H)-ylmethyl]-4-fluorobenzene first cyanogen
2-(3-methyl-6-chloro-2 is added successively in 100mL tube sealing, 4-dioxo-3,4-dihydro-pyrimidin-1 (2H)-ylmethyl)-4-fluorobenzonitrile (1.3g, 4.426mM, 1.0equiv), (R)-3-amino piperidine dihydrochloride (1.149g, 6.64mM, 1.5equiv), sodium bicarbonate (2g, 23.9mM, 5.4equiv), activation molecular sieve (1g
) and dry methyl alcohol (20mL), at 100 DEG C, heat 3h.This mixture is cooled to room temperature, by diatomite filtration, by methanol wash, concentrated filtrate.Column chromatography (methylene dichloride: methyl alcohol=20:1) process obtains white solid (490mg, yield 31%).
1HNMR(400MHz,CDCl
3)：δ＝7.71(dd,J＝8.6,5.3Hz,1H),7.11(td,J＝8.3,2.3Hz,1H),6.88(dd,J＝9.0,2.2Hz,1H),5.41(s,1H),5.31-5.29(m,2H),3.34(s,3H),3.06-3.03(m,1H),2.97-2.94(m,2H),2.66-2.60(m,1H),2.46-2.41(m,1H),1.99-1.95(m,1H),1.83-1.78(m,1H),1.68-1.59(m,1H),1.30-1.24(m,1H)。
Step 4:(R) synthesis of-2-[6-(3-amino piperidine-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-4-fluorobenzonitrile
By (R)-2-[6-(3-amino piperidine-1-base)-3-methyl-2,4-oxo-3,4-dihydro-1 (2H)-ylmethyl]-4-fluorobenzene first cyanogen (490mg, 1.37mM, 1.0equiv), Lloyd's's reagent (278mg, 0.685mM, 0.5equiv) mixture be suspended in dry toluene (11mL), at 120 DEG C, heat 2.5h under nitrogen atmosphere.Reaction mixture is cooled to room temperature.Add 5mL methylene dichloride, dry method loading silica gel column chromatography (methylene dichloride: methyl alcohol=40:1 ~ 20:1) process obtains orange/yellow solid (401mg, yield 78.4%).
1HNMR(400MHz,CDCl
3)：δ＝7.72(dd,J＝8.6,5.3Hz,1H),7.13(td,J＝8.3,2.4Hz,1H),6.91(dd,J＝8.9,2.1Hz,1H),6.41(s,1H),5.33-5.23(m,2H),3.77(s,3H),3.12-3.09(m,1H),3.01-2.98(m,2H),2.74-2.68(m,1H),2.56-2.51(m,1H),2.00-1.97(m,1H),1.86-1.80(m,1H),1.70-1.60(m,1H),1.33-1.27(m,1H)。ESI-MS:374.3(M+1)
+。
Embodiment 2
Prepare compound 2:(R)-2-[6-(3-amino piperidine-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-cyanobenzene
The synthetic method reference example 1 of the compounds of this invention 2, changes the 2-methyl-4-fluorobenzonitrile in embodiment 1 into 2-methyl benzonitrile, obtains orange/yellow solid (239mg, yield 67.2%).
1HNMR(400MHz,CDCl
3):δ＝7.70-7.69(m,1H),7.61-7.57(m,1H),7.42(t,J＝7.6Hz,1H),7.18(d,J＝7.9Hz,1H),6.38(s,1H),5.32-5.27(m,2H),3.75(s,3H),3.20-3.17(m,1H),3.06-2.96(m,2H),2.66-2.55(m,4H),2.01-1.97(m,1H),1.81-1.76(m,1H),1.65-1.54(m,1H),1.38-1.32(m,1H)。ESI-MS:356.3(M+1)
+。
Embodiment 3
Prepare compound 3:(R)-2-[6-(3-amino piperidine-1-base)-3-ethyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-cyanobenzene
The compounds of this invention presses the method synthesis of the scheme two of flow process 1 and flow process 2, obtains compound 3.ESI-MS:388.4(M+1)
+。
Embodiment 4
Prepare compound 4:(R)-2-[6-(3-amino piperidine-1-base)-3-sec.-propyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-cyanobenzene
The compounds of this invention synthesizes according to the method for flow process 1 and flow process 2 scheme two, obtains compound 4.ESI-MS:402.6(M+1)
+。
Embodiment 5
Prepare compound 5:(R)-2-[6-(3-amino piperidine-1-base)-3-cyclopentyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-ylmethyl]-cyanobenzene
The compounds of this invention synthesizes according to the method for flow process 1 and flow process 2 scheme two, obtains compound 5.ESI-MS:428.1(M+1)
+。
Embodiment 6
Prepare compound 6:(R)-3-[6-(3-amino piperidine-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji-fluoro-2-methyl-]-4-Cyano-pyridin
The synthetic method reference example 1 of the compounds of this invention, changes the 2-methyl-4-fluorobenzonitrile in embodiment 1 into 3-methyl different cigarette cyanogen, obtains compound 6.ESI-MS:357.7(M+1)
+。
Embodiment 7
Prepare compound 7:(R)-2-[6-(3-aminoazaheterocycles heptane-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji-fluoro-2-methyl-]-benzene first cyanogen
The synthetic method reference example 1 of the compounds of this invention, changes amino-six hydrogen-1H-azepans of (R)-3-into, obtains compound 7 by (the R)-3-amino piperidine dihydrochloride in embodiment 1.ESI-MS:388.2(M+1)
+。
Embodiment 8
Prepare compound 8:(R)-2-{6-[(2-amino-ethyl) is amino]-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji-fluoro-2-methyl-}-benzene first cyanogen
The synthetic method reference example 1 of the compounds of this invention, changes (the R)-3-amino piperidine dihydrochloride in embodiment 1 into quadrol, obtains compound 8.ESI-MS:334.4(M+1)
+。
Embodiment 9
Prepare compound 9:(R)-6-(3-amino piperidine-1-base)-1-(2,5-difluorophenyl)-3-methyl-4-sulfo--3,4-dihydro-pyrimidin-2 (1H)-one
The synthetic method reference example 1 of the compounds of this invention, changes the 2-methyl-4-fluorobenzonitrile in embodiment 1 into 2,5-difluoro toluene, obtains compound 9.ESI-MS:367.2(M+1)
+。
Embodiment 10
Prepare compound 10:(R)-2-{ [6-(3-amino piperidine-1-base)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-thiophene-3-cyanogen
The synthetic method reference example 1 of the compounds of this invention, changes the 2-brooethyl-4-fluorobenzonitrile in embodiment 1 into 2-(brooethyl) thiophene-3-cyanogen (preparation method is shown in OrgLett, 2011,13,1622-1625), obtains compound 10.ESI-MS:362.0(M+1)
+。
Embodiment 11
Prepare compound 11:(R)-6-(3-amino piperidine-1-base)-1-(the chloro-5-fluorophenyl of 2-)-3-methyl-4-sulfo--3,4-dihydro-pyrimidin-2 (1H)-one
The synthetic method reference example 1 of the compounds of this invention, changes the 2-methyl-4-fluorobenzonitrile in embodiment 1 into 2-chloro-5-difluoro toluene, obtains compound 11.ESI-MS:383.5(M+1)
+。
Embodiment 12
Prepare compound 12:(R)-2-{ [6-(3-amino piperidine-1-base) the fluoro-3-methyl of-5--2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-4-fluorobenzene first cyanogen
The synthetic method reference example 1 of the compounds of this invention, changes the 3-methyl-6-chlorouracil in embodiment 1 into the fluoro-3-methyl of 1--6-chlorouracil, obtains compound 12.ESI-MS:392.8(M+1)
+。
Embodiment 13
Prepare compound 13:(R)-2-{ [6-(3-amino piperidine-1-base)-3,5-dimethyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-4-fluorobenzene first cyanogen
The synthetic method reference example 1 of the compounds of this invention, changes the 3-methyl-6-chlorouracil in embodiment 1 into 1,3-dimethyl-6-chlorouracil, obtains compound 13.ESI-MS:388.1(M+1)
+。
Embodiment 14
Prepare compound 14:(R)-2-{ [6-(3-(dimethylamino) piperidin-1-yl)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-4-fluorobenzene first cyanogen
The compounds of this invention 14 is obtained by compound 1 and iodomethane reaction.ESI-MS:402.7(M+1)
+。
Embodiment 15
Prepare compound 15:(R)-2-{ [6-(3-(ethylamino) piperidin-1-yl)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-4-fluorobenzene first cyanogen
The compounds of this invention 15 is obtained by reacting by compound 1 and monobromethane.ESI-MS:402.2(M+1)
+。
Embodiment 16
Prepare compound 16:(R)-2-{ [6-(3-(cyclopropylamino) piperidin-1-yl)-3-methyl-2-oxo-4-sulfo--3,4-dihydro-pyrimidin-1 (2H)-Ji] methyl }-4-fluorobenzene first cyanogen
The compounds of this invention 16 is obtained by reacting by compound 1 and cyclopropane bromide.ESI-MS:414.4(M+1)
+。
Biological assessment
Embodiment 1:
The compounds of this invention is tested DPP-4 enzyme inhibition activity:
Sample box HEPES damping fluid (25mMHEPES, 140mMNaCl, 1%BSA, the 80mMMgCl of appropriate DPP-4 enzyme (SIGMA) and 3 times of concentration gradient dilutions is added in reaction system
2), and set up blank, negative control and positive control (positive compound is Alogliptin and SYR-472), room temperature reaction 10min, add substrate Gly-Pro-7-amido-4-methylcoumarin (SIGMA), room temperature lucifuge reaction 30min, detect fluorescence (excitation wavelength 355nm, emission wavelength 460nm).
Inhibiting rate is calculated, inhibiting rate=[1-(sample-blank)/(negative-blank)] * 100%, IC according to fluorescence measurement value
50the 4ParameteriLogisticModel of value in Xlfit software calculates.Experimental result is as shown in table 1.
Table 1: Compound D PP-4 external activity test result
| Sample | The active IC of DPP-4 50(nM) |
| Compound 1 | 0.7 |
| Compound 2 | 0.9 |
| Compound 3 | 1.1 |
| Compound 4 | 1.2 |
| Compound 5 | 0.8 |
| Compound 6 | 1.3 |
| Compound 7 | 0.9 |
| Compound 8 | 1.7 |
| Compound 9 | 1.5 |
| Compound 10 | 1.2 |
| Compound 11 | 1.3 |
| Compound 12 | 1.1 |
| Compound 13 | 1.2 |
| Alogliptin | 7.7 |
| SYR-472 | 6.1 |
Conclusion: the inhibit activities of part of compounds of the present invention to DPP-4 enzyme is significantly better than Alogliptin and SYR-472.
Claims (9)
1. the compound of structural formula I:
Or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein
Ar is substituted or unsubstituted aryl, heteroaryl;
R
1for H, to be substituted or unsubstituted alkyl, thiazolinyl, alkynyl, cycloalkyl, ring are mixed alkyl;
R
2for H, halogen, C
1-6alkyl, thiazolinyl, alkynyl;
R
3for amino, alkyl ,-NR
4r
5, ring mixes alkyl, arylalkyl, heteroarylalkyl, alkylsulfonyl C
1-4alkyl, carbonyl C
1-4alkyl, alkoxyl group, aryloxy, heteroaryloxy, respectively substituted or unsubstituted naturally;
L is-(CH
2)
n-,-(CH
2)
n-O-,-(CH
2)
n-S-,-(CH
2)
n-NH-,-(CH
2)
n-CO-,-CO-, wherein n is 1,2; (CH
2)
nin any methylene carbon optionally by 1-2 independent selected from halo, hydroxyl, C
1-4alkyl, C
1-4the substituting group of alkoxyl group replaces;
R
4and R
5separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
2. compound as claimed in claim 1, or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein
Ar is phenyl, 5-10 unit heteroaryl, and wherein said phenyl or heteroaryl can by 1-5 R
6replace;
Each R
6independently be selected from: hydrogen, halogen, cyano group, hydroxyl, nitro, nitroso-group, amido, imido grpup, carboxyl, sulfydryl, be substituted or unsubstituted alkyl, acyl group, amide group, ester group, acyl group ester group, alkylsulfonyl, sulfinyl, cycloalkyl, ring are mixed alkyl, thiazolinyl, alkynyl, alkoxyl group, alkene oxygen base, alkyl amine group;
R
1for H, C
1-8alkyl, C
1-6thiazolinyl, C
1-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group; Wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be independently selected from halogen, oxo, trifluoromethyl, hydroxyl, amino, carboxyl, cyano group, C by 1-6
1-4alkyl, C
1-4alkoxyl group replaces;
R
2for H, F, C
1-4alkyl;
R
3for 1-5 is independently selected from hydrogen, amino ,-NR
4r
5, halogen, oxo, trifluoromethyl, hydroxyl, carboxyl, cyano group, C
1-4alkyl, C
1-4the ring of the replacement of alkoxyl group is mixed alkyl;
L is methylene radical, and can be selected from halogen, OH, C
1-4alkyl, C
1-4the substituting group of alkoxyl group replaces;
R
4and R
5separately be selected from hydrogen, C
1-8alkyl, C
2-6thiazolinyl, C
2-6alkynyl, C
3-8cycloalkyl, 3-8 membered cycloheteroalkyl group, wherein alkyl, thiazolinyl, alkynyl, cycloalkyl and ring alkyl of mixing can be selected from C
1-4the substituting group of alkyl, hydroxyl, halogen, oxo replaces.
3. as compound according to claim 1 or claim 2, or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein, Ar is phenyl, 5-6 unit heteroaryl, and can be independently selected from halogen, cyano group, hydroxyl, C by 1-3
1-4the substituting group of alkyl, trifluoromethyl, trifluoromethoxy replaces.
4. as compound according to claim 1 or claim 2, or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein, R
3for 3-amino-piperadine-1-base.
5. as compound according to claim 1 or claim 2, or its pharmacy acceptable salt, hydrate, solvate, steric isomer; Wherein, L is methylene radical.
6. be selected from following compound:
7. pharmaceutical composition, comprises compound and the pharmaceutically acceptable carrier of claim 1-6.
8. the method for the treatment of to the corresponding disease of DPP IV, comprises, to confirming that the patient needed gives arbitrary at least one the described compound of claim 1-6 and/or its at least one pharmacy acceptable salt of significant quantity.
9. according to the compound of claim 1-6 for the preparation of need treatment in its Mammals be selected from insulin resistant, hyperglycemia, diabetes B disease medicine in purposes.
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|---|---|---|---|
| CN201410349078.4A CN105272963A (en) | 2014-07-22 | 2014-07-22 | 2-oxo-4-thio-3,4-dihydropyrimidine derivatives as dipeptidyl peptidase IV (DPP-IV) inhibitors |
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|---|---|---|---|
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106562969A (en) * | 2016-11-15 | 2017-04-19 | 河南大学 | Application of trelagliptin succinate in preparation of drugs for preventing and/or improving insulin resistance in fat cells |
| WO2017181924A1 (en) * | 2016-04-20 | 2017-10-26 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrimidinedione and pharmaceutical composition thereof |
-
2014
- 2014-07-22 CN CN201410349078.4A patent/CN105272963A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017181924A1 (en) * | 2016-04-20 | 2017-10-26 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrimidinedione and pharmaceutical composition thereof |
| CN108368085A (en) * | 2016-04-20 | 2018-08-03 | 深圳市塔吉瑞生物医药有限公司 | A kind of substituted hybar X compound and its pharmaceutical composition |
| CN108368085B (en) * | 2016-04-20 | 2021-05-04 | 深圳市塔吉瑞生物医药有限公司 | Substituted pyrimidinedione compound and pharmaceutical composition thereof |
| CN106562969A (en) * | 2016-11-15 | 2017-04-19 | 河南大学 | Application of trelagliptin succinate in preparation of drugs for preventing and/or improving insulin resistance in fat cells |
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