CN106432026A - Compound with potential therapeutic activity on diabetes - Google Patents
Compound with potential therapeutic activity on diabetes Download PDFInfo
- Publication number
- CN106432026A CN106432026A CN201610818878.5A CN201610818878A CN106432026A CN 106432026 A CN106432026 A CN 106432026A CN 201610818878 A CN201610818878 A CN 201610818878A CN 106432026 A CN106432026 A CN 106432026A
- Authority
- CN
- China
- Prior art keywords
- group
- amino
- acyl
- obsolete
- diamantane
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a compound with the potential therapeutic activity on diabetes. The compound has a general formula (please see the formula in the description), wherein X can be groups such as hydrogen, an alkyl group, halogen, a hydroxyl group, a hydrocarbon oxygen group, an acyloxy group, an aldehyde group, an acyl group, a nitro group, an amino group, a hydrocarbon ammonia group, a carboxy group, an acyl halide group, an acyl-oxygen acyl group, an ester group, an acylamino group, a cyano group, a guanidine group, an amidine group, an azide group and an inorganic acid ester group, n is larger than or equal to 0, Y can be heteroatom or 1,2-vinylidene or methylene or free of atoms; Z can be substituted at the 2<th> position, the 3<th> position and the 4<th> position of an adamantane ring and can be common organic groups such as hydrogen, an alkyl group, halogen, a hydroxyl group, a hydrocarbon oxygen group, an acyloxy group, an aldehyde group, an acyl group, a nitro group, an amino group, a hydrocarbon ammonia group, a carboxy group, an acyl halide group, an acyl-oxygen acyl group, an ester group, an acylamino group and a cyano group.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeuticss field, and in particular to be used singly or in combination to treat and/or pre-
Anti- diabetes and diseases related.It is more particularly to a series of compound and preparation method thereof shown in following formulas and can pharmaceutically connects
The salt received or pharmaceutically acceptable solvate etc..
Background technology
Diabetes (Diabetes Mellitus) be a kind of by Different types of etiopathogenises cause based on chronic hyperglycemia out of control
Feature, and the metabolic disease with multiple complications is wanted, is lacked mainly due to hypoinsulinism and (or) action function
Fall into caused.Diabetes seriously threaten the life and health of the mankind, and the method that there is no radical cure diabetes at present, so patient of diabetes
Person can only be selected by sustained medication with stably internal blood sugar level, and this just brings to the family and society of patient
Heavy financial burden.
Diabetes can be divided mainly into type i diabetes, type ii diabetes, gestational diabetes and other kinds of glycosuria
Disease, wherein type ii diabetes patient account for more than 90%.Type ii diabetes are treated at present in addition to insulin injection, mainly by mouth
Take Drug therapy.Traditional oral hypoglycemic drug has：(1) euglycemic agent, such as pioglitazone；(2) sulfonylurea, such as lattice are arranged
U.S. urea；(3) biguanideses, such as metformin；(4) a- glucosidase inhibitor, such as acarbose；(5) blood sugar regulator used during user having meals,
As Repaglinide.As traditional hypoglycemic medicine side effect is more, wherein hypoglycemic reaction and body weight increase these two aspects are particularly bright
Aobvious, therefore limit patient's long-term prescription.People have developed better efficacy by lot of experiments, the less new drop of side effect
Sugared medicine-incretin synergist, comprising glucagon-like-peptide-1 (Glucagon-1ike peptide 1, GLP-1) class
Like thing and dipeptidyl peptidase-4 (Dipeptidyl peptidase IV, DPP-4) inhibitor.Incretin potentiation at present
Agent has become one of focus of global type ii diabetes medicine research and development.
The present invention in order to improve curative effect further, reduces side effect, seeks based on the basis of above-mentioned oral antidiabetic thing
More preferable medicine is looked for, proposes invention below.
Content of the invention
The purpose of the present invention be compound shown in following formula and preparation method thereof with diabetes and its diseases related side
The treatment use in face.
In above formula structure, wherein X can be：Hydrogen, alkyl, halogen, hydroxyl, oxyl, acyloxy, aldehyde radical, acyl group, nitre
Base, amino, hydrocarbon amino, carboxyl, acid halide group, acyl-oxygen acyl group, ester group, amide groups, cyano group, guanidine radicals, amidino groups, azido, mineral acid
The groups such as ester group (wherein n is more than or equal to 0).Y can be：Hetero atom, 1,2- ethenylidene, methylene or no atom etc..Z：Can
It is substituted on 2,3,4 of diamantane (obsolete) ring, Z can be hydrogen, alkyl, halogen, hydroxyl, oxyl, acyloxy, aldehyde radical, acyl group, nitre
The common organic groups such as base, amino, hydrocarbon amino, carboxyl, acid halide group, acyl-oxygen acyl group, ester group, amide groups, cyano group.
Further, X can be specifically halogen, hydroxyl, oxyl, acyloxy, acyl group, amino, hydrocarbon amino, carboxyl, ester group,
The groups such as amide groups, cyano group, azido, mineral acid ester group.Y can be specifically hetero atom, methylene etc..Z is may replace in Buddha's warrior attendant
On 3 of alkane ring, Z can be specifically halogen, hydroxyl, oxyl, acyloxy, acyl group, nitro, amino, hydrocarbon amino, carboxyl, ester
Base, amide groups, cyano group etc..
Further, the X more specifically group such as halogen, hydroxyl, amino, carboxyl, cyano group, azido, mineral acid ester group.Y
It can be specifically hetero atom etc..Z is may replace on 3 of diamantane (obsolete) ring, and Z can be specifically halogen, hydroxyl, nitro, amino, carboxylic
Base, cyano group etc..
Further, the X more specifically group such as halogen, azido.Y can be specifically oxygen, nitrogen-atoms etc..Z may replace
On 3 of diamantane (obsolete) ring, Z can be specifically hydroxyl, nitro, carboxyl etc..
One specific examples of compounds CMD-05-151013 can be described as, but be not limited to the example, wherein Z
It is substituted on 3 of diamantane (obsolete) ring, it is chlorine (wherein n is equal to 3) that Z is OH, X, and Y is methylene.
With regard to the preparation method of such compound, with amantadine as initiation material, with (S) -1- chloracetyl -2- cyano group
Pyrrolidine react, prepare the mono-substituted amantadine of amino, then diamantane (obsolete) ring is replaced and continues with corresponding acyl chlorides or
Acibenzolar reacts, and prepares target compound.And the Professional knowledge that has of those skilled in the art can complete its
Its corresponding alternative preparation method.Here a preparation method example is proposed, but is not limited to the example.
With amantadine hydrochloride as initiation material, it is reagent with nitration mixture and potassium hydroxide, 3 of amantadine ring is carried out
Hydroxylating, obtains diamantane (obsolete) ammonia alcohol；Diamantane (obsolete) ammonia alcohol is reacted with (S) -1- chloracetyl -2- Cyanopyrolidine again, is prepared
The mono-substituted diamantane (obsolete) ammonia alcohol of amino, is then proceeded to be reacted with 5-Chlorovaleryl Chloride, prepares target compound CMD-05-
151013.And other corresponding alternative preparation methoies.
Present invention research finds that above-claimed cpd can be used for the SD rat 2 of high fat diet joint STZ lumbar injection induction
The treatment of patients with type Ⅰ DM.
Mechanism of action may relate to multiple target spots, including 1. suppressing DPPIV enzymatic activity, reduces DPPIV enzyme and GLP-1 is divided
Solution, increases the concentration of blood plasma GLP-1；2. the release of GLP-1 is directly facilitated, increases the concentration of blood plasma GLP-1；3. by increasing
GLP-1 concentration, improves islet cellss form and function, promotes the release of insulin, so as to play the hypoglycemic effect of drop.
Present invention research shows that above-claimed cpd is tested in vitro：The In Cultured Rat pancreas of STZ induction can be significantly inhibited
The apoptosis of island cell strain INS-1, promotes the propagation of INS-1 cell, while the compound can effectively facilitate people's intestinal endocrine
The release of GLP-1 in cell strain NCI-H716.
Present invention research shows that above-claimed cpd in vivo test includes：1. pass through Oral Administration in Rats carbohydrate tolerance test, should
Compound can effectively reduce the area under curve after Oral Administration in Rats glucose, and oral 4.5mg/kg compound AUC reduces amplitude
For 51.35%, the corresponding vildagliptin dosage of same molar ratio is that to reduce amplitude be 47.59% for 3mg/kg, AUC, draws this
Compound is slightly better than vildagliptin (see Fig. 1).
2. by detecting rat limosis blood plasma, the DPPIV activity in glucose load blood plasma and casual plasma understands, the compound
DPPIV enzymatic activity in blood plasma, fasting plasma after oral 4.5mg/kg, glucose load blood plasma, the suppression in casual plasma can effectively be suppressed
Rate processed is respectively 50%, 70%, 55%, and the suppression ratio of the vildagliptin of corresponding 3mg/kg is respectively 65%, 75%, 60%,
Both compare not has significant difference (see Fig. 2).
3. by detecting rat limosis blood plasma, the GLP-1 concentration in glucose load blood plasma and casual plasma and insulin concentration
Understand, the compound can improve the concentration of the content of GLP-1 and insulin in blood plasma, and with statistical significance (see Fig. 3).
4. by detecting the saccharification hemoglobin content in rat casual plasma, the compound can reduce rat plasma
In saccharification hemoglobin content, 1.5%-2% can be reduced, vildagliptin can reduce 1%-2% (see Fig. 4).
5. by T-CHOL in detection rat plasma, triglyceride, low density lipoprotein, LDL content understands, the compound energy
Triglyceride effectively in reduction rat plasma, low density lipoprotein, LDL content, and with significant difference (see Fig. 5).
6. dyeed by HE, immunofluorescence dyeing, Tunnel dyeing observation, the compound can be obviously improved T2DM model mouse
Islets of langerhans destroy, repairing islet cells, reduce glucagon expression, reduce model group islet cellss apoptosis.
And, when toxicity test shows the activity inhibition rate of 293 cell strains for 10%, the concentration of CMD-05 is more than 1*10- 4M, the concentration of vildagliptin is more than 1*10-4M；When the activity inhibition rate of HT22 cell strain is 10%, the concentration of CMD-05 more than etc.
In 3*10-5M, the concentration of vildagliptin is more than 1*10-5M；When the activity inhibition rate of LO-2 cell strain is 10%, CMD-05's is dense
Degree is more than or equal to 1*10-4M, the concentration of vildagliptin is more than 1*10-5M.Result above points out the compound to have less cell
Toxicity, and compared to vildagliptin, cytotoxicity is less than vildagliptin.Giving the 2g/kg change of kunming mice single oral dose
After compound, mice no any untoward reaction, the no phenomena of mortality in 15 days.
Such compound that the above results explanation we have found that has significant antidiabetic effect, and toxicity is low.
The purpose of the present invention, is to provide a kind of medicine and combinations thereof characterized in that, above-mentionedization containing effective dose
Compound, and the various dosage forms made such as pharmaceutically acceptable carrier or excipient and its with the combining of other related drugs
Thing.
Description of the drawings
Fig. 1 was each group rat at the 1st day, the 19th day and the 29th day OGTT area under a curve figure
Fig. 2 is each group rat limosis, the suppression ratio figure of DPPIV in glucose load and casual plasma
Fig. 3 is each group rat limosis, level (B) figure of the content (A) of GLP-1 and insulin in glucose load and casual plasma
Fig. 4 is each group rat limosis, the saccharification hemoglobin content figure in glucose load and casual plasma
Fig. 5 is the T-CHOL (A) in each group rat casual plasma, triglyceride (B), low density lipoprotein, LDL content (C)
Figure
Specific embodiment
The present invention is further appreciated that by following specific embodiment, but they do not constitute the limit to present invention
System.The present invention above-mentioned under the premise of to the invention belongs to the Professional knowledge of those skilled in the art obtainable extend extension in
Holding should be all in the scope of protection of present invention.
Embodiment 1
The preparation of CMD-05-151013：
98% concentrated sulphuric acid of 38ml combination cooling under ice bath with 65% concentrated nitric acid of 4ml, is added by several times in the nitration mixture
3.75 grams of amantadine hydrochlorides, stirring reaction 3 hours under ice bath；60 grams of trash ice is added, is stirred 0.5 hour；Add appropriate hydrogen
Potassium oxide solid, adjusts pH value to 12-13, stirring reaction 2 hours under ice bath；Sucking filtration, filtrate adjusts pH value to 8- with concentrated hydrochloric acid
9, it is concentrated to dryness；Add 80ml dehydrated alcohol to flow back 1 hour, let cool, sucking filtration, filtrate is concentrated to dryness；Add 10ml mixed liquor
(acetone: ethyl acetate=3: 1) flow back 1 hour, place under ice bath, sucking filtration, obtain 3.2 grams of 3- aminoadamantan alcohol solid, fusing point
More than 256 DEG C.
3 grams of 3- aminoadamantan alcohol, 0.25 gram of potassium iodide, 10 grams of potassium carbonate are added to stirring in 30ml tetrahydrofuran and rise
Temperature is to 40 DEG C, and holding is slowly added dropwise 3 grams of (S) -1- chloracetyl -2- Cyanopyrolidines at this temperature and is dissolved in 30ml tetrahydrofuran
Solution, drip off within about 1.5 hours.Drop finishes, and after being incubated 40 DEG C of reactions 1 hour, is warming up to back flow reaction 2 hours.Backflow terminates, and takes advantage of
Heat filtering, filter cake is washed with a small amount of tetrahydrofuran, and merging filtrate is concentrated into grease.Grease adds appropriate butanone dissolving, puts
Crystallize is put, is filtered, dry 4 grams of the mono-substituted diamantane (obsolete) ammonia alcohol solid of amino, 147-149 DEG C of fusing point.HPLC normalization method is surveyed
Purity is determined for 98.1%, the satisfactory structure of the structural characterization such as IR, NMR.
In reaction bulb, add the mono-substituted diamantane (obsolete) ammonia alcohol of the above-mentioned amino of 5g, 0.2 gram of DMAP, 15g potassium carbonate to add
100ml anhydrous tetrahydro furan is stirred.5ml 5-Chlorovaleryl Chloride is dissolved under 50ml tetrahydrofuran, ice bath and is slowly dropped to reactant liquor
In, heating up after completion of dropping and be stirred at reflux, TLC monitors (developing solvent：Ethyl acetate: methanol=10: 1).After completion of the reaction while hot
Filter, filter cake is washed with appropriate tetrahydrofuran, merging filtrate obtains oily liquid after concentrating under reduced pressure, methanol is added in oily liquid
It is recrystallized to give CMD-05-151013 white solid.mp：158-161℃.HPLC normalization method determine purity be 95%, IR,
The satisfactory structure of the structural characterizations such as NMR.
Embodiment 2
The In vitro cell experiment of CMD-05-151013：1. the compound discharges the impact of GLP-1 to intestinal system L cell：Culture
People's intestinal system L cell strain NCI-716, a few days ago, cell is with 1*10 for experiment6Individual/ml is layered in coated 12 orifice plate of matrigel, is added
DMEM containing 10%FBS is cultivated.After 48h, cell supernatant is suctioned out, with the KRB buffer solution for cleaning containing 0.2%BSA
Afterwards, pastille KRB buffer (PH7.2) 1ml being added, 2h is incubated in 37 DEG C, resets and add the PMSF of 50ug/ml, be stored in -80 in absorption
℃.Concentration using GLP-1 in ELISA kit detection culture medium；2. proliferation function of the compound to Islet cells：
Inoculation Islet cells INS-1 are in 96 orifice plates, and plating density is 1*105Individual/ml, replaces culture medium after incubation 24h, adds
Final concentration of 3*10-4, 1*10-4, 3*10-5, 1*10-5, 3*10-6, 1*10-6, 3*10-7, 1*10-7, 3*10-8, 1*10-8Pastille
Culture medium continues incubation 24h, then adds CCK-810ul per hole, continues culture 2h, and horizontal shaker shakes 10s, at 450nm
Determine OD value；3. Anti-G value of the compound to STZ induced rat islet cellss：INS-1 cell is pressed 3*104Individual/ml
Being inoculated on 6 orifice plates final concentration of 10 is simultaneously introduced after culture 24h-5, 10-6, 10-7The STZ buffering of the compound of M and 3mM
Liquid, collects cell after continuing culture 36h, and PBS is resuspended, and stream type cell analyzer analyzes apoptosis.
Embodiment 3
The experiment in vivo of CMD-05-151013：1. the effect to normal rat：Choose 200g or so SD male rat 25
Only, 5 groups are randomly divided into：Vildagliptin group (3mg/kg), CMD-05 (4.5mg/kg), CMD-05 (1.5mg/kg), CMD-05
(0.5mg/kg), solvent control group.When doing oral glucose tolerance experiment, after surveying fasting glucose, gavage gives medicine, surveys blood after 30min
Sugared and gavage gives 25% D/W, and after gavage gives D/W, 30min, 60min, 120min survey blood
Sugar.When determining GLP-1, Insulin, the DPPIV in glucose load blood plasma, after gavage gives each group medicine 30min, gavage gives
25% D/W, takes blood by eyes venous plexuses after 30min, and 3000rpm is centrifuged 5min, and separated plasma, using ELISA
The content of GLP-1 and Insulin, fluorescence spectrometry DPPIV activity in test kit detection blood plasma.2. the effect to rat model：
100g or so male SD rat 70 is chosen, is randomly selected 6 and normal control is only used as, remaining 64 high-sugar-fat-diet feeds 30
Its pneumoretroperitoneum injection low dose STZ (35mg/kg), continues high lipid food and feeds 30 days, chooses continuous three days fasting glucose and is more than
The rat of 16.7mmol/L 30, is divided into five groups：Vildagliptin group (3mg/kg), CMD-05 (4.5mg/kg), CMD-05
(1.5mg/kg), CMD-05 (0.5mg/kg), solvent control group.Successive administration one month, administration the 1st day, the 19th day, the 29th day
Make oral glucose tolerance test (concrete steps are as previously mentioned), take 30 days or so rat limosis, glucose load, casual plasma, employing
ELISA detection insulin content, GLP-1 content, saccharification hemoglobin content, DPPIV activity, detects random blood using test kit
T-CHOL in slurry, low density lipoprotein, LDL, the content of triglyceride.After administration terminates, Isolation of pancreatic is organized, and is done HE dyeing, is seen
Pancreatic tissue form is examined, does immunofluorescence dyeing, observe pancreatic tissue insulin, the expression of glucagon, do Tunnel dye
Color, observes the apoptosis of islet tissue, does transmission electron microscope, observes the change of secretory granule in islets of langerhans micro structure.
Embodiment 4
The toxicity test of CMD-05-151013：1. cytotoxicity：Human embryonic kidney cell 293 is cultivated respectively, and normal person liver is thin
Born of the same parents LO-2, hippocampus neurons in mice HT22, treat that cell growth state is good, be inoculated in 96 orifice plates, it is 1*10 to plant plate density5
Individual/ml.After planting plate 4h, vildagliptin and the compound of variable concentrations are added so as to final concentration of 3*10-4, 1*10-4, 3*10-5, 1*10-5, 3*10-6, 1*10-6, 3*10-7, 1*10-7, 3*10-8, 1*10-8, MTT solution 20ul being added after culture 24h, continues
Culture 4h, suctions out culture medium, adds 150ulDMSO, shakes 5min on horizontal shaker, determines OD value, calculate cell at 450nm
Suppression ratio.2. animal toxicity：Kunming mice male 10 is randomly selected, female 10, fasting can't help water overnight, and gavage gives this
Compound 2g/kg, gavage volume be 0.4ml/10g, to observation post administration 15 days.
Claims (9)
1. a class is shown below compound and its prepare with which to diabetes and the therapeutic use of diseases related aspect；
Wherein X can be：Hydrogen, alkyl, halogen, hydroxyl, oxyl, acyloxy, aldehyde radical, acyl group, nitro, amino, hydrocarbon amino, carboxylic
(wherein n is big for the groups such as base, acid halide group, acyl-oxygen acyl group, ester group, amide groups, cyano group, guanidine radicals, amidino groups, azido, mineral acid ester group
In or be equal to 0)；Y can be：Hetero atom, 1,2- ethenylidene, methylene or no atom etc.；Z：May replace diamantane (obsolete) ring 2,
3rd, on 4, Z can be hydrogen, alkyl, halogen, hydroxyl, oxyl, acyloxy, aldehyde radical, acyl group, nitro, amino, hydrocarbon amino, carboxylic
The common organic groups such as base, acid halide group, acyl-oxygen acyl group, ester group, amide groups, cyano group.
2. X can be specifically halogen, hydroxyl, oxyl, acyloxy, acyl group, amino, hydrocarbon amino, carboxylic according to claim 1
The groups such as base, ester group, amide groups, cyano group, azido, mineral acid ester group；Y can be specifically hetero atom, methylene etc.；Z can use
Generation on 3 of diamantane (obsolete) ring, Z can be specifically halogen, hydroxyl, oxyl, acyloxy, acyl group, nitro, amino, hydrocarbon amino,
Carboxyl, ester group, amide groups, cyano group etc..
3. according to claim 1 or claim 2 further, X more specifically halogen, hydroxyl, amino, carboxyl, cyano group, azido, no
The groups such as machine perester radical；Y can be specifically hetero atom etc.；Z is may replace on 3 of diamantane (obsolete) ring, Z can be specifically halogen,
Hydroxyl, nitro, amino, carboxyl, cyano group etc..
4. according to claim 1,2 or 3 further, the X more specifically group such as halogen, azido；Y can be specifically oxygen,
Nitrogen-atoms etc.；Z is may replace on 3 of diamantane (obsolete) ring, and Z can be specifically hydroxyl, nitro, carboxyl etc..
5., according to claim 1,2,3 or 4, specific examples of compounds CMD-05-151013 can be described as, but simultaneously
The example is not confined to, wherein Z is substituted on 3 of diamantane (obsolete) ring, it is chlorine (wherein n is equal to 3) that Z is OH, X, and Y is methylene
Base.
6. the compound according to claim 1,2,3,4 or 5 has the treatment to diabetes and diseases related aspect and makees
With.
7., according to claim 1,2,3,4 or 5, it is to provide a kind of medicine and combinations thereof characterized in that, having
The above-claimed cpd of effect amount, and the various dosage forms made such as pharmaceutically acceptable carrier or excipient and its related drugs group
Compound.
8., with amantadine as initiation material, react with (S) -1- chloracetyl -2- Cyanopyrolidine, prepare amino list and take
The amantadine in generation, is then replaced and continues to be reacted with corresponding acyl chlorides or Acibenzolar to diamantane (obsolete) ring, prepare target chemical combination
Thing；And other corresponding alternative preparation methoies that the Professional knowledge that has of those skilled in the art can be completed.
9. according to claim 8, a specific compound CMD-05-151013 prepares example, but is not limited to
The example, with amantadine hydrochloride as initiation material, is reagent with nitration mixture and potassium hydroxide, and 3 of amantadine ring are carried out
Hydroxylating, obtains diamantane (obsolete) ammonia alcohol；Diamantane (obsolete) ammonia alcohol is reacted with (S) -1- chloracetyl -2- Cyanopyrolidine again, is prepared
The mono-substituted diamantane (obsolete) ammonia alcohol of amino, is then proceeded to be reacted with 5-Chlorovaleryl Chloride, prepares target compound CMD-05-
151013；And other corresponding alternative preparation methoies.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610818878.5A CN106432026A (en) | 2016-09-12 | 2016-09-12 | Compound with potential therapeutic activity on diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610818878.5A CN106432026A (en) | 2016-09-12 | 2016-09-12 | Compound with potential therapeutic activity on diabetes |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106432026A true CN106432026A (en) | 2017-02-22 |
Family
ID=58169329
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610818878.5A Pending CN106432026A (en) | 2016-09-12 | 2016-09-12 | Compound with potential therapeutic activity on diabetes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106432026A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN109115924A (en) * | 2018-09-07 | 2019-01-01 | 重庆医科大学 | The detection method of vildagliptin derivative in rat brain blood plasma and brain tissue |
Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277688A (en) * | 2005-09-29 | 2008-10-01 | 诺瓦提斯公司 | Formulation comprising metformin and vildagli ptin |
| CN101798270A (en) * | 2010-02-25 | 2010-08-11 | 东华大学 | Method for preparing 3-amino-1-adamantane alcohol |
| CN101870671A (en) * | 2010-06-11 | 2010-10-27 | 漆又毛 | Adamantly pyrrolidine derivative, and preparation and application thereof |
| WO2012004210A1 (en) * | 2010-07-06 | 2012-01-12 | Chemelectiva Srl | Process and intermediates for preparation of an active ingredient |
| CN103140475A (en) * | 2010-05-05 | 2013-06-05 | 亚细亚化学工业有限公司 | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
| US20130184265A1 (en) * | 2011-12-15 | 2013-07-18 | Alkermes Pharma Ireland Limited | Prodrugs of Secondary Amine Compounds |
| CN103922986A (en) * | 2013-01-16 | 2014-07-16 | 上海彩迩文生化科技有限公司 | Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application |
| WO2015128718A1 (en) * | 2014-02-28 | 2015-09-03 | Hikal Limited | Novel economic process for vildagliptin |
-
2016
- 2016-09-12 CN CN201610818878.5A patent/CN106432026A/en active Pending
Patent Citations (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101277688A (en) * | 2005-09-29 | 2008-10-01 | 诺瓦提斯公司 | Formulation comprising metformin and vildagli ptin |
| CN101798270A (en) * | 2010-02-25 | 2010-08-11 | 东华大学 | Method for preparing 3-amino-1-adamantane alcohol |
| CN103140475A (en) * | 2010-05-05 | 2013-06-05 | 亚细亚化学工业有限公司 | Saxagliptin intermediates, saxagliptin polymorphs, and processes for preparation thereof |
| CN101870671A (en) * | 2010-06-11 | 2010-10-27 | 漆又毛 | Adamantly pyrrolidine derivative, and preparation and application thereof |
| WO2012004210A1 (en) * | 2010-07-06 | 2012-01-12 | Chemelectiva Srl | Process and intermediates for preparation of an active ingredient |
| US20130184265A1 (en) * | 2011-12-15 | 2013-07-18 | Alkermes Pharma Ireland Limited | Prodrugs of Secondary Amine Compounds |
| CN103922986A (en) * | 2013-01-16 | 2014-07-16 | 上海彩迩文生化科技有限公司 | Vildagliptin, vildagliptin analogues and vildagliptin intermediate, and preparation methods of three and application |
| WO2015128718A1 (en) * | 2014-02-28 | 2015-09-03 | Hikal Limited | Novel economic process for vildagliptin |
Non-Patent Citations (3)
| Title |
|---|
| 周鸿睿: "维达列汀衍生物的合成研究及活性筛选", 《重庆医科大学硕士学位论文》 * |
| 甘润 等: "维格列汀主要相关物质的合成及其优化", 《国际药学研究杂志》 * |
| 陶铸 等: "维格列汀中间体(S) -1-(2-氯乙酰基)吡咯烷-2-甲腈的合成", 《化学研究与应用》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325010A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | The safe preparation method and device of a kind of adamantanol |
| CN109115924A (en) * | 2018-09-07 | 2019-01-01 | 重庆医科大学 | The detection method of vildagliptin derivative in rat brain blood plasma and brain tissue |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| RU2624021C2 (en) | COMPOUNDS OF THIENYL[3, 2-d]PYRIMIDINE-4-ON, METHOD FOR PRODUCTION, PHARMACEUTICAL COMPOSITIONS AND THEIR APPLICATION | |
| JP7383124B2 (en) | Combination products containing limonoid compounds and DPP-4 inhibitors | |
| CN109381471A (en) | Combination product comprising limonoid and biguanide compound | |
| CN102898400B (en) | GPR119 agonist and application thereof | |
| AU2017252015A1 (en) | Peptide-oligourea foldamer compounds and methods of their use | |
| CN106432026A (en) | Compound with potential therapeutic activity on diabetes | |
| CN103896923B (en) | A kind of Hypoglycemics, its preparation method, comprise its medical composition and its use | |
| WO2011160597A1 (en) | Furocoumarin compounds with antihypertensive activity and preparation methods thereof | |
| WO2009128360A1 (en) | Therapeutic agent for diabetes | |
| CN102603575B (en) | Rhein-arginine eutectic compound, and preparation method, purification method and application thereof in preparation of medicines for treating diabetic complications | |
| CN104557944B (en) | A kind of hypoglycemic medicine and preparation method thereof | |
| CN101899048A (en) | Salt of (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1- carboxylic acid methyl ester | |
| CN102267959A (en) | Repaglinide crystal, preparation method thereof, and solid oral preparation containing same | |
| JP2022551679A (en) | Combination product containing a limonoid compound and an α-glucosidase inhibitor | |
| CN102639128A (en) | Sulfonamides for the prevention of diabetes | |
| JPWO2010050422A1 (en) | Diabetes treatment | |
| US8685952B2 (en) | Method for the treatment of diabetes | |
| CN103626722A (en) | Hypoglycemic compound of nitric oxide donor type, preparation method and purpose thereof | |
| RU2704257C2 (en) | Pharmaceutical application of hexahydro-dibenzo[a,g]quinolizine compound | |
| CN115304604B (en) | Double-target sitagliptin derivative | |
| CN102895650B (en) | Application of cyclotides ingredients in zizyphus jujube roots | |
| CN115246816B (en) | Double-target alogliptin derivative | |
| CN108101788A (en) | Composition and its application containing salvianolic acid salt | |
| US20220296555A1 (en) | Acylated active agents and methods of their use for the treatment of metabolic disorders and nonalcoholic fatty liver disease | |
| CN101584699A (en) | Application of lactoflavin ester derivative for preparing medicine for treating diabetes mellitus and complication thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170222 |