CN108218861A - A kind of drug for preventing and treating diabetes and preparation method thereof - Google Patents
A kind of drug for preventing and treating diabetes and preparation method thereof Download PDFInfo
- Publication number
- CN108218861A CN108218861A CN201810110219.5A CN201810110219A CN108218861A CN 108218861 A CN108218861 A CN 108218861A CN 201810110219 A CN201810110219 A CN 201810110219A CN 108218861 A CN108218861 A CN 108218861A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- alkyl
- officinal salt
- prodrug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 CC(C*)=CC(C(N(C(N=I)=O)C(c1c2*)=C)=Nc1c(*)nc2I)=NC* Chemical compound CC(C*)=CC(C(N(C(N=I)=O)C(c1c2*)=C)=Nc1c(*)nc2I)=NC* 0.000 description 8
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the drug with protein tyrosine phosphatase 1B (PTP1B) inhibitory activity and its applications.This kind of compound includes compound of formula I or its officinal salt, precursor：
Description
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to a kind of drug for preventing and treating diabetes, the present invention also relate to
And the preparation method and purposes of the drug.
Background technology
Diabetes be it is a kind of because internal insulin is absolute or relative deficiency caused by a series of Clinical syndromes,
Research shows that it not only has very close association with gene, but also also closely related with daily life custom.Glycosuria
The Major Clinical illness of disease shows as more drinks, diuresis more, eats more but weight but declines (" three-many-one-little ") and blood-sugar content
Containing glucose (glucose should not be contained in normal urine) etc., various clinical illness in high, urine.
Diabetes can cause multiple complications, if diabetes patient does not obtain the effective treatment, will cause
Acute complications, such as non-ketone hyperosmolar coma disease, hypoglycemia, ketoacidosis.If be in a bad way, will cause for a long time simultaneously
Send out disease such as：Chronic renal failure (i.e. diabetic nephropathy is the main reason for patient carries out haemodialysis), regards cardiovascular and cerebrovascular disease
Retinopathy (i.e. diabetic eye diseases are the principal diseases of non-aged adult's blindness), neuropathy and microangiopathies etc..Its
In, microangiopathies may cause patient wound to be difficult to heal, it is possible that can cause if foot has the wound for being difficult to heal
Gangrenous (" diabetes " that are commonly called as) cause patient must amputation.
Diabetes are generally divided into two classes, type-1 diabetes mellitus (insulin-dependent diabetes mellitus, IDDM) and II type glycosurias at present
Sick (Non-Insulin Dependent Diabetes Mellitus, NIDDM).More than 90% is type-2 diabetes mellitus in diabetes.WHO is, it is expected that due to population
Aging, fat, unsound diet and the life style for lacking movement, by 2025, the number of diabetic will be by
The 1.35 hundred million of nineteen ninety-five rise to 300,000,000.The characteristics of type-2 diabetes mellitus is insulin sensitive tissues such as skeletal muscle, liver, adipose tissue
Resistance to insulin action.Although its specific mechanism is unclear, decrease of the insulin signaling in its conduction path is very
Must be direct factor to blocking.Insulin by in the extracellular alpha subunit combination activated receptor intracellular β subunits of its receptor
Tyrosine kinase activity, lead to tyrosine residue autophosphorylation crucial in Regulatory domain, so as to activating pancreas islet completely
Plain receptor tyrosine kinase activity, insulin receptor tyrosine kinase are again handed on signal by phosphorylation its substrate.With
The intensification recognized invertibity tyrosine phosphorylation in insulin inside cells effect path, protein-tyrosine-phosphatase
(PTPases) effect in the access is balanced in GAP-associated protein GAP tyrosine phosphorylation level is increasingly taken seriously.PTPases
Multiple links in the access, such as insulin receptor (IR) dephosphorylation that autophosphorylation is activated may be acted on, so as to
Reduce kinase activation；It or will substrate 1 (IRS-1), insulin receptor substrate2 (IRS-2), Shc etc.
Protein-tyrosine residue pathological phosphorylation in the substrate of insulin receptor, so as to access after negative regulation insulin action receptor.It is special
The imbalance for determining enzymatic activity between tyrosine kinase in PTPases and insulin access may be that type-2 diabetes mellitus insulin is caused to support
The reason of anti-.Therefore, inhibit its activity by finding selectively acting inhibitor of PTPases in the access, strengthen and prolong
Long insulin signaling becomes the new way of more and more valued treatment type-2 diabetes mellitus.
PTPases includes big nation's cross-film (receptor type) and intracellular (non-receptor type) enzyme, participates in a series of important lifes
Life process.Although a variety of PTPases have expression, such as the CD45 and LAR-PTPase of cross-film in the tissue of insulin sensitivity；
SHPTP-1, SHPTP-2, PTP1B, PTP1C of intracellular etc., but only several PTPases may in insulin access receptor or
Receptor metasomite influences Normal insulin effect.Current research is concentrated mainly on LAR-PTPase, SHPTP-2, PTP1B.
PTP1B is the PTPase for being purified and determining earliest biological characteristics, and early stage research has shown that can in vitro effectively
By insulin receptor dephosphorylation, it is subsequently found PTP1B high expression in all insulin sensitive tissues；With the side of osmotic shock
After method gives PTP1B antibody, mouse KRC-7 liver cells significantly rise through DNA synthesis and PI3 kinase activity levels during insulin stimulating
Height, IR autophosphorylations are horizontal, IR kinase activity levels and IRS-1 tyrosine phosphorylation levels also significantly increase.It grinds recently
Study carefully and show that PTP1B directly interacts with the IR of state of activation；Highest selectivity is also shown to IRS-1 in testing in vitro
Activity；The method transfected with adenovirus mediated gene, in insulin target tissue skeletal muscle and the model cell L6 fleshes of hepatic tissue
High expression PTP1B in cell and Fao cells, hence it is evident that inhibit the tyrosine phosphorylation of insulin-induced IR and IRS-1, and thereby
Significantly inhibit the formation of IRS-1 and PI3 kinases P85 subunits compound and the phosphorylation level of Akt, MAPK, and pancreas islet
The Glycogen synthesis of element induction is also suppressed (" Protein-tyrosine Phosphatase-1B Negatively
Regulates Insulin Signaling in L6Myocytes and Fao Hepatoma Cells”,Katsuya
Egawa et al.,J.Biol.Chem.,2001,276(13)：10207-10211).The high expression of PTP1B to it is basic, in
Deng and glucose transport that maximum is insulin-induced without influence, to the EC of transhipment50Insulin concentration is without influence.These researchs
Prove that PTP1B negative regulation Insulin signaling pathway and can mainly act on insulin receptor.Prior experimental evidence
From PTP1B knock out mice.The reports such as Elchebly, the PTP1B gene knockouts generated with the method for homologous recombination
Mouse growth is normal, there is fecundity, and (" Increased insulin sensitivity are significantly increased to insulin sensitivity
and obesity resistance in mice lacking the protein tyrosine phosphatase-1B
gene”,Elchebly et al.,Science,1999,283:1544).It is surprising that the mouse of PTP1B gene knockouts
Also there is resistant function to food-induced weight gain and insulin resistance.Klaman etc. is generated with roughly the same method
The mouse of PTP1B gene knockouts also obtains same result (" Increased Energy Expenditure, Decreased
Adiposity,and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine
Phosphatase1B-Deficient Mice”,Klaman,L.D.et al.,Molecular and Cellular
Biology,2000,20,5479-5489).These experiments have more convincingly demonstrated PTP1B and have disappeared in insulin sensitivity, energy
Important function in terms of consumption and fatty storage, so as to which definitely it can be as a kind of novel type-2 diabetes mellitus medicine
And it plays an important role.
Therefore, the hypoglycemic medicine of novel PTP1B inhibitor is developed for prevention and treatment diabetes particularly II types glycosuria
Disease is of great significance.
Invention content
One aspect of the present invention provides a kind of compound of formula I or its officinal salt, prodrug：
Wherein：
R1、R2、R3Can be identical or different, be each independently hydrogen, halogen, cyano, hydroxyl, sulfydryl, amino, carboxyl,
C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy C 1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxies, C1-6 alkyl aminos,
Aryl, Heterocyclylalkyl；
R4Represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl；
Het represents heteroaryl or Heterocyclylalkyl, optionally by 1,2 or 3 selected from halogen, cyano, hydroxyl, sulfydryl, amino,
Carboxyl ,-L-C1-6 alkyl ,-L-C1-6 halogenated alkyls ,-L-C3-7 cycloalkyl ,-L-C1-6 alkyl-C3-7 cycloalkyl group institute
Substitution；Wherein L be not present or L for-O- ,-(C=O)-,-C (=O) O- ,-C (=O) N (R)-,-S- ,-S (O)-,-S (O)2,-
S(O)2N (R)-or-N (R)-；R represents hydrogen or C1-4 alkyl.
Second aspect of the present invention offer prepares the compound of formula I or the method for its officinal salt.
Third aspect present invention provides a kind of pharmaceutical composition, contains at least one compound of formula I or it can medicine
With salt, prodrug and one or more pharmaceutical acceptable carrier or excipient.
Fourth aspect present invention provides a kind of compound of formula I or its officinal salt, prodrug are preparing PTP1B inhibitor
In application.
Fifth aspect present invention provide a kind of compound of formula I or its officinal salt, prodrug in medicine preparation should
With.
The compounds of this invention shows significant inhibiting effect to protein tyrosine phosphatase 1B, in animal experiment
Rat blood sugar value can be significantly reduced, and compared with positive control Rosiglitazone, blood sugar reducing function is further promoted, therefore this hair
Bright compound has the function of significantly to control blood glucose in diabetic rats value, in the prevention and treatment that can be applied to diabetes.
Specific embodiment
Although the preferred embodiment of the invention has shown and described in this application, to those skilled in the art
Speech is it is evident that the embodiment only provides by way of example.Those skilled in the art will remember a large amount of change, transformation and
Displacement, these are within the scope of the present invention.It should be understood that in the practice of the present invention, described herein hair can be used
The various alternatives of bright embodiment.It is intended to appended claims to define the scope of the invention and thus cover at these
Method and structure and their equivalent form in right.
Unless otherwise defined, all technical and scientific terms used in this application have and fields technology people of the present invention
Member is generally understood identical meaning.All patents and publications that the application is referred to is incorporated herein by reference.
Compound
In some embodiments of the compounds of this invention, R1、R2、R3All it is hydrogen.
In some embodiments of the compounds of this invention, R4Represent hydrogen.
In some embodiments of the compounds of this invention, Het represents heteroaryl, and the heteroaryl is containing there are one, two
A, three or four be independently selected from oxygen, nitrogen and sulphur heteroatomic 5 to 10 yuan monocyclic or bicyclic heteroaryls.
In some embodiments of the compounds of this invention, Het represents Heterocyclylalkyl, and the Heterocyclylalkyl is contains one
A, two, three or four heteroatomic 4 to 10 unit monocycles or two ring filling heterocycles for being independently selected from oxygen, nitrogen and sulphur.
In some embodiments of the compounds of this invention, the compound is selected from：
Term " inhibitor " is the compound for referring to inhibit target protein biological function, either by inhibiting target protein
Activity is still by inhibiting the expression of target protein.
Term " officinal salt " refers to derived from various organic and inorganic counterion salt well known in the art, and works as
Molecule includes (only for example) sodium salt, sylvite, calcium salt, magnesium salts, ammonium salt, tetraalkylammonium salt etc. when containing acid functionality；With
When molecule contains basic functionality, the salt is organic acid or salt such as hydrochloride, hydrobromate, the tartaric acid of inorganic acid
Salt, mesylate (methane sulfonates), esilate, acetate, maleate, oxalates, phosphate etc..With more than one
In the compound of a basic moiety, the more than one in the basic moiety can convert salifie form, including but not limited to two-salt
Or three-salt.Selectively, the compound with more than one basic moiety can be only in a basic moiety forming salt.
" prodrug ", which is intended to mean that, to be converted to biology described herein in physiological conditions or by solvolysis
The compound of reactive compound.Therefore, term " prodrug " refers to the precursor of pharmaceutical bioactive compound.When be administered to by
During examination person, prodrug can be inactive, but for example be converted to reactive compound in vivo by hydrolysis.Prodrug compound leads to
Advantages below is often provided：Dissolubility, histocompatbility or sustained release in mammalian organism.Term " prodrug "
It is intended to include any covalently bound carrier, when by the prodrug administration mammalian subject, the prodrug discharges in vivo
Reactive compound.The prodrug of reactive compound described herein can be prepared as follows：Modification activities compound in the following manner
Present in functional group, the mode causes trim in routine operation or is cracked into parent active compound in vivo.
Prodrug includes such compound, and wherein hydroxyl, amino or sulfydryl combined with any group, when by the prodrug of reactive compound
When mammalian subject is administered, any group cracks to be respectively formed free hydroxyl, free amino or dissociate
Sulfydryl.The example of prodrug includes but not limited to the acetic acid esters of hydroxy functional group, formic acid esters and benzoic ether in reactive compound
The acetamide of derivative or amine functional group, formamide and heterocyclic carbamate derivatives etc..
The present invention all embodiments in, term " alkyl " including branch and straight chained alkyl or cyclic hydrocarbon group or they
Combination.Alkyl is fully saturated and may include two-and multivalence group, has the carbon atom specified number (that is, C1-C6
Refer to that there is 1,2,3,4,5 or 6 carbon).Common alkyl be methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl,
Isobutyl group, tertiary butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, iso-octyl, nonyl, decyl, undecyl, dodecyl,
Myristyl, cetyl, octadecyl, eicosyl etc..
Term " halogen " or refer to fluorine, chlorine, bromine or iodine.
Unless otherwise indicated, term " cycloalkyl " refers to can there is 3 to 10 carbon, such as the ring-shaped fat of 3 to 7 carbon
Race's ring structure, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl etc..
Term " aryl " refers to the aromatic group with preferably 6 to 10 annular atoms of 6 to 14 annular atoms, has at least
One carbocyclic ring (such as phenyl, fluorenyl and naphthalene) with conjugated pi electron system.When numberical range such as " 6 to 10 " is in the application
In when occurring, numberical range such as " 6 to 10 " refers to each integer in given range；For example, " 6 to 10 annular atoms " refers to
The aryl can be made of 6 annular atoms, be made of 7 annular atoms, highest and including being made of 10 annular atoms.The art
Language includes monocyclic groups or fused polycycle (ring for sharing adjacent cyclic atom pair) group.The example of aryl includes but not limited to
Phenyl, naphthalene.
Term " heteroaryl " refer to contain there are one, two, three or four be independently selected from heteroatomic the 5 of oxygen, nitrogen and sulphur
To 13 yuan, preferably 5 to 10 yuan of monocyclic or bicyclic heteroaryl.When such as " 5 to 13 " occur numberical range in this application, numerical value
Range such as " 5 to 13 " refers to each integer in given range；For example, " 5 to 13 yuan " refer to that the heteroaryl can be by 5
Annular atom forms, and is made of 6 annular atoms, highest and including being made of 13 annular atoms.The example of heteroaryl is included but not
Xian Yu oxazolyls, pyrrole radicals, phenazinyl, phenothiazinyl, phenoxazine groups, phthalazinyl, pteridyl, purine radicals, pyranose, pyrazoles
Base, pyrazolo [3,4-d] pyrimidine radicals, pyridyl group, pyrido [3,2-d] pyrimidine radicals, pyrido [3,4-d] pyrimidine radicals, pyrazinyl,
Pyrimidine radicals, pyridazinyl, pyrrole radicals, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, 5,6,7,8- tetra-
Hydrogen quinazolyl, thiazolyl, thiadiazolyl group, thiapyran base, triazolyl, tetrazole radical, triazine radical, thieno [2,3-d] pyrimidine radicals, thiophene
Fen simultaneously [3,2-d] pyrimidine radicals, thieno [2,3-c] pyridyl group etc..
Term " heterocycle " refer to contain there are one, two, three or four be independently selected from heteroatomic the 4 of oxygen, nitrogen and sulphur
To 10 unit monocycles or two ring filling heterocycles.The example of heterocycle includes but not limited to azelidinyl, oxetanylmethoxy, pyrroles
Alkyl, tetrahydrofuran base, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, piperidyl, homopiperidinyl, morpholinyl, thiomorpholine
Base, piperazinyl or homopiperazine base etc..
Compound of the present invention can contain one or more asymmetric centers simultaneously can therefore generate diastereoisomer and
Optical isomer.The present invention includes all such possible diastereoisomers and their racemic mixture, their bases
This pure enantiomter through fractionation, all possible geometric isomer and their officinal salt.Above shown
The spatial chemistry that compound of formula I is not determined in some positions.The present invention includes compound of formula I and its all of officinal salt stand
Body isomers.In addition, mixture and separated specific stereoisomer the invention also includes stereoisomer.For
It prepares the synthetic operation of the compound in the process or is using racemization or epimerism well known by persons skilled in the art
Change in operation, the product of the operation can be the mixture of stereoisomer.
The present invention includes the rotational isomer of all modes of the compounds of this invention and configuration constrained state.
Unless otherwise mentioned, herein described structure is also intended to including such compound, be the difference is that only and is deposited
In one or more isotope enrichment atoms.For example, with structure of the present invention but with deuterium either tritium replace hydrogen or be enriched with
The carbon of 13C or 14C replaces carbon compound also within the scope of the present invention.
The compounds of this invention can also contain unnatural proportions at one or more atom for forming the compound
Atom isotope.For example, the compound can use radioactive isotope such as tritium, iodine-125 or carbon-14 radioactive label.This
All isotopic variations of invention compound either have radioactivity again without radioactivity, are included in the scope of the invention.
Purposes
Formula Compound I inhibits the activity of phosphotyrosine phosphatase 1B (PTP1B) and therefore very applicable
In reduction blood glucose level.Therefore, it is especially suitable for treatment I types and type-2 diabetes mellitus, insulin resistant, dyslipidemia, metabolism
Syndrome/X syndrome, morbid oberity and weight and the obesity for the treatment of mammal for reducing mammal.
Because can inhibit PTP1B, the compound of Formulas I applies also for treatment Hyperglycerolemia, immune system function
Obstacle, autoimmune disease, allergic disease such as, for example, asthma, arthritis, osteoarthritis, osteoporosis, proliferative
Illness such as cancer and psoriasis, growth factor, inducing growth hormone release hormone or cell factor generation reduce or increase
Disease.
These compounds apply also for the illness for the treatment of nervous system such as, for example, Alzheimer's or multiple hard
Change.These compounds apply also for treating healthy disorderly and other psychiatry indications such as, for example, depression and anxiety state, coke
Consider neurosis, schizophrenia, the illness related with circadian rhythm, and can be additionally used in medicine abuse.
Pharmaceutical composition
Appropriate pharmaceutical acceptable carrier or excipient include such as processing aid and drug delivery modifying agent with increasing in the present invention
Strong agent, such as calcium phosphate, magnesium stearate, talcum powder, monosaccharide, disaccharides, starch, gelatin, cellulose, methylcellulose, carboxymethyl
Sodium cellulosate, glucose, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidone, low melt wax, ion exchange resin etc., further include
The two or more of combinations of any of which.Liquid and semisolid excipient may be selected from glycerine, propylene glycol, water, ethyl alcohol and various oil,
Include the oil of oil, animal oil, vegetable oil or synthesis source, such as peanut oil, soybean oil, mineral oil, sesame oil etc..At some
In embodiment, liquid-carrier (the especially liquid-carrier of Injectable solution) is including water, brine, glucose solution and glycol
Class.Other appropriate pharmaceutically acceptable excipients are described in " Remington ' s Pharmaceutical Sciences ", Mack
Pub.Co., New Jersey (1991).
The compound of preferred embodiment can by oral, parenteral, sublingual, aerosol or sucking spraying, rectum or
Part is administered in the form of taking the circumstances into consideration the unit dose formulations containing usual non-toxic pharmaceutical acceptable carrier, adjuvant and excipient.Part
Administration is further included using percutaneous dosing, such as transdermal skin patches or iontophoresis device.The term as used herein " parenteral " is including skin
Lower injection, intravenous, intrathecal, intramuscular, breastbone inner injection or infusion techn.
Injectable formulation (such as sterile injectable aqueous or oil-based suspension) can be according to known technology using appropriate point
Powder or wetting agent and suspending agent are prepared.Aseptic injection preparation can also be in nontoxic parenteral acceptable diluent or solvent
In aseptic injectable solution or suspension, such as in solution in 1,3-PD.The acceptable carrier that may be used and
Solvent is water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterile fixed oil is also commonly used as solvent or suspends to be situated between
Matter.For this purpose, any mild fixed oil all can be used, list-or two-glyceride including synthesis.In addition, aliphatic acid such as oleic acid
It can also be used for the preparation of injectable formulation.
Include capsule, tablet, pill, powder agent and granule for the solid dosage forms of oral medication.In such solid formulation
It, can (such as sucrose, lactose or starch a) mix at least one inert diluent by reactive compound in type.In general, such dosage form
It also may include other materials besides inert diluents, such as lubricant such as magnesium stearate.In the feelings of capsule, tablet and pill
Under condition, such dosage form also may include buffer.In addition, tablet and pill can be in addition enterically coated.
Liquid formulation for oral administration includes pharmaceutical emulsion, solution, suspension, syrup and elixir, they contain
There is the common inert diluent in this field such as water.Such composition also may include adjuvant, such as wetting agent, emulsifier and suspending
Agent, cyclodextrin and sweetener, flavoring agent and aromatic.
Preparation method
Formula Compound I or the preparation method of its officinal salt include the following steps：
Step 1：
The step includes Formula II compound is made to be reacted in atent solvent with formula IVization with formula III compound and alkali
Close object.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, isobutanol, tertiary fourth
Alcohol, isoamyl alcohol, octanol, cyclohexanol；Aromatic hydrocarbons, such as benzene, toluene or dimethylbenzene；Halogenated hydrocarbons, such as chloroform, dichloromethane.Solvent
Preferably aromatic hydrocarbons, more preferable toluene.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium；Bicarbonate, such as sodium bicarbonate, saleratus；Acetate, such as sodium acetate or potassium acetate.Alkali is preferably bicarbonate
Salt, more preferable saleratus.
The reaction temperature of the step is preferably 0 DEG C to 180 DEG C, more preferable 20 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 30 minutes to 24 hours, more preferable 1 hour to 6 hours.
Step 2：
The step includes formula IV compound is made to react to make in atent solvent with Formula V compound and palladium catalyst, alkali
Standby compound of formula I.
Solvent for the step can be alcohol, such as methanol, ethyl alcohol, isopropanol etc.；Aromatic hydrocarbons, such as benzene, toluene or diformazan
Benzene；Halogenated hydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride；Nitrile solvents, such as acetonitrile；Ether solvent, such as tetrahydrofuran, 1,
4- dioxane；Or their mixed solvent.Solvent is preferably 1,4- dioxane.
Alkali for the step can be hydroxide, such as sodium hydroxide, potassium hydroxide；Carbonate, such as sodium carbonate, carbon
Sour potassium, cesium carbonate；Bicarbonate, such as sodium bicarbonate, saleratus.Alkali is preferably carbonate, more preferable potassium carbonate.
Palladium catalyst for the step can be tetrakis triphenylphosphine palladium, preferably palladium, tetrakis triphenylphosphine palladium.
The reaction temperature of the step is preferably 0 DEG C to 160 DEG C, more preferable 30 DEG C of reflux temperatures to solvent.
The reaction time of the step is preferably 30 minutes to 24 hours, more preferable 1 hour to 10 hours.
And
Optional step three：
Compound of formula I is converted into its officinal salt in case of need.
In above-mentioned steps, R1、R2、R3、R4, Het as defined above, X represents halogen, preferably chlorine or bromine, particularly preferred bromine.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps
Other compounds of more present invention, and the other methods for being used to prepare the compound of the present invention are considered as the model in the present invention
Within enclosing.It for example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
It is completed by method of modifying, such as appropriate protection interference group, by using other known reagent in addition to described in the invention
Or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
Embodiment
Embodiment 1：2- (2- methyl -2H-1,2,3- triazole-4-yls) -3- (pyridine -2- formoxyls) pyridine [3,4-d] is phonetic
Pyridine -4 (3H) -one (compound 1)
Step 1：2- pyridine carboxylic acids 3.08g is added in the 500ml there-necked flasks with stirring and reflux
The mixed solution of (25.0mmol), toluene 100ml and DMF2ml, temperature rising reflux, dropwise addition 10ml thionyl chlorides and 50ml toluene, half
Hour adds, and is then refluxed for isothermal reaction 4 hours.Reaction finishes, static half an hour liquid separation, divides to fall reaction impurities, then depressurizes
Excessive thionyl chloride and toluene are steamed, obtains 2- pyridinecarboxylic chlorides, adds the dissolving of 50ml toluene, it is spare.With stirring and
In the 500ml there-necked flasks of reflux, 2- bromopyridines [3,4-d] (3H) -one 4.48g of pyrimidine -4 (20.0mmol), carbonic acid are added in
Hydrogen potassium 5.0g (50.0mmol), a small amount of water and 100ml toluene, stirring are warming up to reflux, the 2- pyridine first of aforementioned preparation are added dropwise
Acyl chlorides toluene solution is added dropwise for 30 minutes.Back flow reaction 5 hours.Reaction finishes, and is down to room temperature filtering, a small amount of first of filter cake
Alcohol is beaten, and drying obtains the bromo- 3- of 2- (pyridine -2- formoxyls) pyridine [3,4-d] pyrimidine -4 (3H) -one, content 5.59g, yield
85%, content 98.9%.ESI-MS：330.98[M+H]+。
Step 2：2- bromo- 3- (pyridine -2- bases) formylpyridine [3,4-d] is added in into dry Schlenk reaction tubes
Pyrimidine -4 (3H) -one (3.30g, 10.0mmol), 2- methyl -2H-1,2,3- triazole-4-yl boric acid (1.52g, 12.0mmol),
Tetrakis triphenylphosphine palladium (0.12g, 0.1mmol), K2CO3(2.74g, 20mmol) under nitrogen protection, adds in Isosorbide-5-Nitrae-dioxy six
Ring (50mL), water (5mL), 50 DEG C of reaction 4h.After reaction, solvent is removed under reduced pressure, residue is used after being dissolved with ethyl acetate
Silica gel column chromatography detaches, with petrol ether/ethyl acetate 10:1 elution, obtains the title compound 2.36g of white solid, yield
71%, content 98%.
ESI-MS：334.10[M+H]+
Elemental analysis：Theoretical value/measured value, C (57.66/57.51), H (3.33/3.41), N (29.24/29.27), O
(9.60/9.81)
1H NMR(400MHz,CDCl3)δ8.79(s,1H),7.83-8.26(m,7H),3.63(s,3H)。
Embodiment 2：2- (2- methyl -2H-1,2,3- triazole-4-yls) -3- (piperidines -3- formoxyls) -8- (trifluoromethyl)
Pyridine [3,4-d] pyrimidine -4 (3H) -one (compound 2)
According to the method for embodiment 1,2- pyridine carboxylic acids are replaced with piperidines -3- formic acid, with the bromo- 8- of 2- (trifluoromethyl)-pyrrole
Pyridine [3,4-d] pyrimidine -4 (3H) -one replaces 2- bromopyridines [3,4-d] pyrimidine -4 (3H) -one, obtains the title compound of white solid
Object, two step gross production rates 54%.
ESI-MS：408.13[M+H]+
Elemental analysis：Theoretical value/measured value, C (50.12/50.02), H (3.96/3.87), F (13.99/14.07), N
(24.07/24.12), O (7.86/9.92)
1H NMR(400MHz,CDCl3)δ8.89(d,1H),8.14(s,1H),7.69(d,1H),3.63(s,3H),3.12
(q,1H),2.86(q,1H),2.74(m,2H),2.47(s,1H),2.06(s,1H),1.86(m,1H),1.64(m,1H),1.56
(m,1H),1.42(m,1H)。
In a similar way, following compound is synthesized：
Embodiment 7：Protein tyrosine phosphatase 1B (PTP1B) inhibitory activity measures
Test sample solution：Final concentration is respectively 100.0 μM, 50.0 μM, 25.0 μM, 12.5 μM, 6.3 μM, 3.1 μM, 1.6
μM, 0.8 μM of compound 1-6 solution (after being dissolved in a small amount of DMSO, respective concentration is diluted to distilled water, controls that DMSO's is final
Volume fraction<0.1%).
The above test sample solution of 25 μ L various concentrations is taken, adds in 175 μ L phosphate buffer solutions (50mM, pH7.0)
And 25 μ L p-nitrophenol phosphate ester solutions (2mM；Solvent is includes 50mM citrates, 0.1M sodium chloride, 1mM ethylenediamines
The mixing buffer solution of tetraacethyl and 1mM dithiothreitol (DTT)s).Negative control：DMSO, positive control：Sodium vanadate.Mixed solution
Reaction temperature is 37 DEG C, reaction time 30min.Light absorption value is measured at wavelength 405nm after reaction, is counted as follows
Calculate the inhibiting rate to PTP1B activity of compound.Inhibiting rate=(experimental group light absorption value-negative control group light absorption value)/(control group
Light absorption value-negative control group extinction) × 100%.To experimental data statistical analysis, IC is used50Software calculates each test sample
IC50Value.The results are shown in Table 1.
The Activity determination result that 1 compound 1-6 of table inhibits PTP1B
| Compound | IC50(μM) |
| Compound 1 | 5.9 |
| Compound 2 | 8.4 |
| Compound 3 | 12.7 |
| Compound 4 | 7.3 |
| Compound 5 | 6.8 |
| Compound 6 | 14.5 |
Result of the test shows：The compounds of this invention 1-6 shows significantly to press down to protein tyrosine phosphatase 1B
It makes and uses, PTP1B inhibitor can be used as to be applied in anti-type-2 diabetes mellitus.
Embodiment 8：The hypoglycemic zoopery of target compound
Wistar male rats 90 are taken, adaptability is raised one week：18-25 DEG C of room temperature, humidity 50-60%, light and shade period
It 12/12 hour, freely ingests, drink water；Give standard rat chow.Then 2 groups are randomly divided by weight, including：Blank group：10
Wistar male rats, give common standard rat chow；Model group：It is high to give high sugar for 80 wistar male rats
Fat feed.After feeding 4 weeks, fasting 8 hours took rat tail vein blood to measure fasting blood-glucose in the 29th day, and is injected intravenously chain urea
Mycin 45mg/kg weight is fed 72 hours, fasting 8 hours after intravenous injection, and rat tail vein blood is taken to survey fasting blood-glucose.Knot
Fruit shows, after injecting streptozotocin, the fasting blood sugar of model group and experimental group rat is 16.75 ± 0.87mmol/L, significantly
Higher than 5.14 ± 0.79mmol/L (P ＜ 0.01) of blank group rat.And the situation of model group rats is not good enough, the more drinks of appearance,
The diabetic symptoms such as diuresis, more foods are bright, these results suggest that type-2 diabetes mellitus rat model modeling success.
Model group rats are randomly divided into 8 groups, including：Negative control group, positive controls, compound 1-6 groups, every group 10
Only build successful type-2 diabetes mellitus rat；Wherein negative control group gives 0.5%CMC-Na suspensions, and positive controls are given
The 0.5%CMC-Na suspensions of Rosiglitazone, compound 1-6 groups give the 0.5%CMC-Na suspensions of compound 1-6 respectively.
Blank control group is 10 normal wistar male rats, gives 0.5%CMC-Na suspensions.Each group rat is fed under the conditions of
Corresponding feed, and gastric infusion, once a day, the dosage of Rosiglitazone and compound 1-6 are 20mg/kg weight, even
Continuous administration one week takes the tail vein of each group rat to measure fasting blood-glucose.The results are shown in Table 2：
2 each group rat fasting blood-glucose value of table
Note：Compared with negative control group, * P<0.01；Compared with positive controls,#P<0.05
Result of the test shows：The compounds of this invention 1-6 can significantly reduce rat blood sugar value (P compared with negative control is given
<0.01), and compared with positive control Rosiglitazone, blood sugar reducing function further promotes (P<0.05) the compounds of this invention, is prompted
Have the function of significantly to control type-2 diabetes mellitus rat model blood glucose value, in the prevention and treatment that can be applied to diabetes.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the variation without departing from scope and spirit.
Claims (10)
1. a kind of compound of formula I or its officinal salt, prodrug：
Wherein：
R1、R2、R3Can be identical or different, it is each independently hydrogen, halogen, cyano, hydroxyl, sulfydryl, amino, carboxyl, C1-6 alkane
It is base, halogenated C1-6 alkyl, C1-6 alkoxy C 1-6 alkyl, C3-7 cycloalkyl, C1-6 alkoxies, C1-6 alkyl aminos, aryl, miscellaneous
Cycloalkyl；
R4Represent hydrogen, C1-6 alkyl, C3-7 cycloalkyl；
Het represents heteroaryl or Heterocyclylalkyl, optionally by 1,2 or 3 selected from halogen, cyano, hydroxyl, sulfydryl, amino, carboxylic
Base ,-L-C1-6 alkyl ,-L-C1-6 halogenated alkyls ,-L-C3-7 cycloalkyl ,-L-C1-6 alkyl-C3-7 cycloalkyl group taken
Generation；Wherein L be not present or L for-O- ,-(C=O)-,-C (=O) O- ,-C (=O) N (R)-,-S- ,-S (O)-,-S (O)2,-S
(O)2N (R)-or-N (R)-；R represents hydrogen or C1-4 alkyl.
2. compound according to claim 1, which is characterized in that the R1、R2、R3All it is hydrogen.
3. compound according to claim 1, which is characterized in that the R4Represent hydrogen.
4. compound according to claim 1, which is characterized in that the Het represents heteroaryl, the heteroaryl be containing
The monocyclic or bicyclic heteroaryl of one, two, three or four be independently selected from oxygen, nitrogen and sulphur heteroatomic 5 to 10 yuan.
5. compound according to claim 1, which is characterized in that the Het represents Heterocyclylalkyl, and the Heterocyclylalkyl is
Containing there are one, two, three or four heteroatomic 4 to 10 unit monocycles or two ring filling heterocycles for being independently selected from oxygen, nitrogen and sulphur
Base.
6. compound according to claim 1, is selected from：
7. a kind of prepare according to the compound of formula I or the method for its officinal salt described in claim 1, include the following steps：
Step 1：
The step includes Formula II compound is made to be reacted in atent solvent with formula IV chemical combination with formula III compound and alkali
Object；
Step 2：
The step includes formula IV compound is made to be reacted in atent solvent with formula I with Formula V compound and palladium catalyst, alkali
Compound；
And
Optional step three：
Compound of formula I is converted into its officinal salt in case of need；
In above-mentioned steps, R1、R2、R3、R4, Het as defined above, X represents halogen, preferably chlorine or bromine, particularly preferred bromine.
8. a kind of pharmaceutical composition, contain at least one compound of formula I according to claim 1 or its officinal salt,
Prodrug and one or more pharmaceutical acceptable carrier or excipient.
9. the application of compound of formula I according to claim 1 or its officinal salt, prodrug in PTP1B inhibitor is prepared.
10. the application of compound of formula I according to claim 1 or its officinal salt, prodrug in medicine preparation, the medicine
Object is used to treat diabetes, especially type-2 diabetes mellitus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810110219.5A CN108218861B (en) | 2018-02-05 | 2018-02-05 | A kind of drug and preparation method thereof preventing and treating diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810110219.5A CN108218861B (en) | 2018-02-05 | 2018-02-05 | A kind of drug and preparation method thereof preventing and treating diabetes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108218861A true CN108218861A (en) | 2018-06-29 |
| CN108218861B CN108218861B (en) | 2019-07-23 |
Family
ID=62670553
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810110219.5A Expired - Fee Related CN108218861B (en) | 2018-02-05 | 2018-02-05 | A kind of drug and preparation method thereof preventing and treating diabetes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108218861B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005115993A1 (en) * | 2004-05-31 | 2005-12-08 | Banyu Pharmaceutical Co., Ltd. | Quinazoline derivative |
| CN101001857A (en) * | 2002-01-22 | 2007-07-18 | 沃尼尔·朗伯有限责任公司 | 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones |
| WO2007134986A1 (en) * | 2006-05-23 | 2007-11-29 | F. Hoffmann-La Roche Ag | Pyridopyrimidinone derivatives |
| CN101641358A (en) * | 2007-03-23 | 2010-02-03 | 霍夫曼-拉罗奇有限公司 | Aza-pyridopyrimidinone derivatives |
-
2018
- 2018-02-05 CN CN201810110219.5A patent/CN108218861B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101001857A (en) * | 2002-01-22 | 2007-07-18 | 沃尼尔·朗伯有限责任公司 | 2-(pyridin-2-ylamino)-pyrido [2,3-d]pyrimidin-7-ones |
| WO2005115993A1 (en) * | 2004-05-31 | 2005-12-08 | Banyu Pharmaceutical Co., Ltd. | Quinazoline derivative |
| WO2007134986A1 (en) * | 2006-05-23 | 2007-11-29 | F. Hoffmann-La Roche Ag | Pyridopyrimidinone derivatives |
| CN101641358A (en) * | 2007-03-23 | 2010-02-03 | 霍夫曼-拉罗奇有限公司 | Aza-pyridopyrimidinone derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| CN108218861B (en) | 2019-07-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11254681B2 (en) | Optionally fused heterocyclyl-substituted derivatives of pyrimidine useful for the treatment of inflammatory, metabolic, oncologic and autoimmune diseases | |
| EP2909204B1 (en) | Gsk3 inhibitors and methods of use thereof | |
| EP3766882B1 (en) | Phthalazine isoxazole alkoxy derivatives, preparation method thereof, pharmaceutical composition and use thereof | |
| JP7352294B2 (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| EP3697781B1 (en) | Antagonists of the muscarinic acetylcholine receptor m4 | |
| AU2015330490B2 (en) | Hydroxyl purine compounds and applications thereof | |
| WO2020007322A1 (en) | Compound targeted to degrade bet protein and application thereof | |
| RU2440346C2 (en) | Method and composition for stimulating neurogenesis and inhibiting neuron degeneration | |
| JP2021503443A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| JP2020526557A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| EP3071578B1 (en) | Tricyclic piperidine compounds | |
| JP2020530451A (en) | Antagonist of muscarinic acetylcholine receptor M4 | |
| WO2016148232A1 (en) | Morphinan derivative | |
| US20150203498A1 (en) | Inhibitors of phosphodiesterase 10 enzyme | |
| WO2018232154A1 (en) | Methods of treating metabolic diseases with fused bicyclic pyrazoles | |
| CN105745211B (en) | It is used as the tricyclic imidazole compound of the inhibitor of tryptophan hydroxylase | |
| CN106687464A (en) | Macrocyclic RIP2 kinase inhibitors | |
| CN108218861B (en) | A kind of drug and preparation method thereof preventing and treating diabetes | |
| CN104418820A (en) | Carboxylic acid derivative as lysophosphatidic acid receptor antagonist | |
| CN106317043B (en) | A kind of 2 agonist of Cannabined receptor | |
| TWI840489B (en) | Dihydropyrazolopyrazinone derivative having mgat-2 inhibitory activity | |
| CN104788423B (en) | A kind of new cystic fibrosis transmembrane conductance regulator inhibitor | |
| CN106317059B (en) | A kind of 2 (CB2) agonist of Cannabined receptor | |
| CN112826821B (en) | Application of allopurinol derivative in preparation of medicine for preventing and/or treating diabetes | |
| US20030144345A1 (en) | Treatment of metabolic diseases with soraphen derivatives |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190723 Termination date: 20200205 |