CN107033122A - A kind of thiophene-carboxamides analog derivative of N aryl 2 and its production and use - Google Patents
A kind of thiophene-carboxamides analog derivative of N aryl 2 and its production and use Download PDFInfo
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- CN107033122A CN107033122A CN201710361230.4A CN201710361230A CN107033122A CN 107033122 A CN107033122 A CN 107033122A CN 201710361230 A CN201710361230 A CN 201710361230A CN 107033122 A CN107033122 A CN 107033122A
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- 0 *c1ccc(CC(*C2=CC=CC=I2C(c(cc2)ccc2N)=O)=*)[n]1 Chemical compound *c1ccc(CC(*C2=CC=CC=I2C(c(cc2)ccc2N)=O)=*)[n]1 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
A kind of thiophene-carboxamides analog derivative of N aryl 2 and its production and use, wherein specifically disclosing the salt of a kind of compound and its pharmaceutically acceptable receiving, its structure is shown in formula I.And the compound and its salt of pharmaceutically acceptable receiving described in disclosing resist in preparation treatment or prevention hyperglycemia, diabetes, glucose tolerance reduction, insulin.
Description
Technical field
The present invention relates to field of medicaments, and in particular to a kind of N- aryl -2- thiophene-carboxamides classes for being used to treat diabetes B
Derivative.
Background technology
Diabetes are a kind of chronic diseases of worldwide epidemics, the health of the serious threat mankind.The whole world has within 2015
4.15 hundred million diabetics, it is contemplated that be up to 6.42 hundred million people to the year two thousand forty, Diabetes Death number reaches 4,900,000, average every 7 seconds
Clock just has diabetic's death, and more than the preventing and treating that 612,000,000,000 U.S. dollars are used for diabetes, heavy warp is brought to the whole world
Ji burden.China is diabetes big country, and there are 1.14 hundred million diabetics in the whole nation, accounts for the 1/4 of global sum, this people to China
Mouth health and socio-economic development produce tremendous influence.Therefore, it is badly in need of the effective means of development treatment diabetes.
Diabetes B accounts for more than the 90% of diabetes total number of persons, though have a variety of conventional medicaments such as melbine, sulfonylureas and
What non-sulfonylureas Insulin secretagogues, thiazolidinediones, alpha-glucosidase restrainer, insulin and nearly more than ten years researched and developed
Treatment based on secretin, including glucagon-like-peptide-1 (GLP-1) activator and dipeptidyl peptidase-4 (DPP-4) suppression
Preparation etc. is available, but most of patients blood glucose is still below standard.Main cause is the progress with the course of disease, islet beta cell function
Decay, current treatment means still can not meet the demand of patient.In recent years the beta mediated inflammatory immune mistakes of NLRP3/IL-1 are found
Journey plays a crucial role in islet beta cell function decay, therefore the inflammatory immune medicine of directly improvement beta Cell of islet is expected to turn into
Treat the newtype drug of diabetes B.Exploitation can improve the medicine of β cell functions, become the new target of diabetes drug treatment
Point.The present invention synthesizes a kind of N- aryl -2- thiophene-carboxamides class compounds first, is named as compound Y1, tool increases significantly
Level of insulin secretion, reduces the effect of islet beta-cell apoptosis.Test result indicates that the compound is to develop new treatment
The lead compound of diabetes B, finds the treatment diabetes B medicine of new structure there is provided possible.
The content of the invention
It is an object of the invention to provide a kind of compound, N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- first
Acid amides, shown in formula I, referred to as compound Y1, the compound can increase the secretion of insulin, reduce islet beta-cell apoptosis,
So as to provide a kind of new means and approach for the treatment of diabetes, with important research and development value and development significance.
The invention provides application of the compound shown in Formulas I in the medicine for the treatment of diabetes B.
Compound Y1 of the present invention, can carry out structural modification as primer, obtain activity preferably compound, and
For treating diabetes B.
The invention provides compound Y1 preparation method, it comprises the following steps：
1) the bromo- 2-Thiophene Carboxylic Acids of 5- are dissolved in thionyl chloride, add pyridine as catalyst, be stirred and heated to back
Stream, after reaction completely, the reaction solution that is concentrated under reduced pressure with Rotary Evaporators obtains the required bromo- 2- thiophene chloride compounds of 5- to dry；
2) 2- amino -4 '-chlorobenzophenone is dissolved in dichloromethane, adds triethylamine and make acid binding agent, the bromo- 2- of 5- are added dropwise
The dichloromethane solution of thiophene acyl chlorides, after reaction completely, removal of solvent under reduced pressure, column chromatography is obtained Formulas I shownization after purification
Compound.
Structural formula of compound of the present invention is as follows
The improvement islet beta cell function of compound energy dose dependent shown in above-mentioned, improves level of insulin secretion.
Compound Y1 of the present invention can be used for the medicine that treatment diabetes are made.With reference to modern common drug preparation hand
Section, can be made injection, tablet, pulvis, granule, capsule by the compound, so that using eaily form of medication,
Wherein mass percentage content of the compounds of this invention in the medicine is 1~20%.
The medicine of above-mentioned various formulations can be prepared according to the conventional method of pharmaceutical field.
One aspect of the invention provides a kind of compound and its medicinal acceptable salt, and its structure is shown in formula I.
Another aspect of the invention provides compound of formula I and its preparation method of medicinal acceptable salt, and it is included such as
Lower step：
1) carboxyl in the activation bromo- 2-Thiophene Carboxylic Acids of 5-, obtains the bromo- 2-Thiophene Carboxylic Acids of 5- that carboxyl is activated；
2) the bromo- 2-Thiophene Carboxylic Acids of 5- that carboxyl is activated will be added in 2- amino -4 '-chlorobenzophenone, reaction is obtained completely
To compound shown in Formulas I.
In the inventive solutions, step 1) in in thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride
One or more are activated to carboxyl, using pyridine as catalyst, it is preferable that using thionyl chloride as activating reagent.
In the inventive solutions, step 1) in reaction condition to be heated to reflux.
In the inventive solutions, step 2) in be dissolved in 2- amino -4 '-chlorobenzophenone in organic solvent, and
Add after acid binding agent and add the bromo- 2-Thiophene Carboxylic Acids of 5- that carboxyl is activated, it is complete to reacting.
In the inventive solutions, acid binding agent is selected from triethylamine, one or more combinations of pyridine.
In the inventive solutions, also comprising step 3), step 3) it is purification step, it is preferable that the purifying step
Suddenly it is column chromatography purifying.
The compound and its medicinal acceptable salt that another aspect of the invention provides shown in Formulas I are treated or pre- in preparation
Anti- hyperglycemia, diabetes, glucose tolerance reduction, insulin resist, it is preferable that the diabetes are selected from 1 type or diabetes B
Medicine in purposes.
Brief description of the drawings
Fig. 1 Y1 are in the secretion of the promotion insulin of dependence on the glucose.
Fig. 2 Y1 are in the secretion of the promotion insulin of concentration gradient.
Embodiment
Content for a better understanding of the present invention, makees furtherly with reference to specific implementation method to present invention
Bright but of the invention protects content not limit to following examples.
Embodiment 1N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- formamides Y1 synthetic method
The bromo- 2-Thiophene Carboxylic Acids of 5- (1mmol, 206mg), thionyl chloride 3mL, pyridine 3 are added in 50mL round-bottomed flask
Drop, agitating and heating adds stream (80 DEG C), after 2 hours, stops reaction, and rotary evaporation removes solvent, obtains the bromo- 2- thiophene acyl chlorides of 5-, plus
The dichloromethane for entering 5mL dryings is standby.Added in 50mL round-bottomed flask 2- amino -4 '-chlorobenzophenone (1mmol,
232mg), dichloromethane 5mL, triethylamine 1mL, stirring and dissolving, ice-water bath is cooled to 0 DEG C.Under agitation, the bromo- 2- thiophenes of 5- are added dropwise
After the dichloromethane solution (being dripped off in 10 minutes) of fen acyl chlorides, completion of dropping, continue stirring reaction 2 hours.Stop reaction, rotation
Evaporation under reduced pressure removes solvent, and column chromatography for separation purification obtains product Y1, yield 85%.
Above-claimed cpd is characterized as below：mp:84-85℃；1H NMR(400MHz,DMSO-d6)δ11.81(s,1H),
8.79-8.77 (d, J=8.0Hz, 1H), 7.79-7.77 (d, J=8.0Hz, 3H), 7.62 (s, 1H), 7.53-7.49 (t, J=
8.0Hz, 1H), 7.40 (s, 2H), 7.25-7.23 (d, J=8.0Hz, 1H), 6.98 (s, 2H)；13C NMR(101MHz,DMSO-
d6)198.83,162.55,153.80,146.43,140.25,139.10,137.83,136.62,134.93,133.73,
131.61,131.28,128.73,123.00,121.79,121.06.
Embodiment 2N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- formamides Y1 insulin secretion accelerating activity
Detection
Insulin secretion accelerating activity is detected using rat insulin oncocyte INS-832/13 cells.INS-832/13
Cell culture is in containing 10% hyclone, 10mM hydroxyethyl piperazine second thiosulfonic acids, 2mM Pidolidone salt, 1mM Sodium Pyruvates,
In the RPMI1640 culture mediums of 0.05mM mercaptoethanols, it is placed in containing 5%CO2Cell culture incubator in cultivate.
INS-832/13 cells are with 105Individual/hole is laid in 24 orifice plates, 37 DEG C, 5%CO248 hours of middle culture.Treat cell
When growing fine, RPMI1640 culture mediums are suctioned out, cushioning liquid (115mM sodium chloride, 5mM potassium chloride, the 24mM carbon of sugar-free is added
Sour hydrogen sodium, 2.5mM calcium chloride, 1mM magnesium chlorides, 10mM hydroxyethyl piperazine second thiosulfonic acids, 0.1% bovine serum albumin(BSA), pH7.2)
It is incubated 2 hours, then changes the cushioning liquid containing 2.5mM and 16.7mM concentration of glucose and 10mM N- (2- (4- chlorobenzene first into
Acyl group) phenyl) it is incubated 2 hours in -5- bromothiophene -2- formamides Y1.Cell culture medium is then collected, 3000 leave the heart 5 minutes,
Supernatant enzyme-linked immunoassay method is taken to detect the insulin content in supernatant.
As shown in figure 1, Y1 (N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- formamides) can significantly increase Portugal
The level of insulin secretion that grape sugar is stimulated, in glucose (2.5mM) of low concentration, it can not dramatically increase the secretion of insulin
Level, and in glucose (16.7mM) of high concentration, it can remarkably promote the secretion of insulin.
As shown in table 1, Fig. 2, Y1 (N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- formamides) in concentration according to
Property is relied to promote the secretion of insulin, its median effective dose is 4.8 micromoles.
Table 1Y1 promotes insulin secretion multiple
| N- (2- (4- chlorobenzene formacyls) phenyl) -5- bromothiophene -2- concentration of forma | Insulin secretion accelerating increases multiple |
| 0.63 micro- rubs | 1.03 |
| 1.25 micro- rub | 1.06 |
| 2.5 micro- rub | 1.20 |
| 5 micro- rub | 1.51 |
| 10 micro- rub | 1.51 |
| 20 micro- rub | 1.94 |
The result shows that the compound has the insulin secretion accelerating effect of good dependence on the glucose, resists with good
Diabetes B potentiality to be exploited.
Claims (8)
1. a kind of compound and its medicinal acceptable salt, its structure is shown in formula I
2. the preparation method of the compound and its medicinal acceptable salt as shown in claim 1, it comprises the following steps：
1) carboxyl in the activation bromo- 2-Thiophene Carboxylic Acids of 5-, obtains the bromo- 2-Thiophene Carboxylic Acids of 5- that carboxyl is activated；
2) the bromo- 2-Thiophene Carboxylic Acids of 5- that carboxyl is activated will be added in 2- amino -4 '-chlorobenzophenone, reaction obtains Formulas I completely
Shown compound.
3. preparation method according to claim 2, wherein, step 1) in thionyl chloride, phosphorus trichloride, phosphorus pentachloride,
One or more in oxalyl chloride are activated to carboxyl, using pyridine as catalyst, it is preferable that tried by activation of thionyl chloride
Agent.
4. preparation method according to claim 2, wherein, step 1) in reaction condition to be heated to reflux.
5. preparation method according to claim 2, wherein, step 2) in be dissolved in 2- amino -4 '-chlorobenzophenone it is organic
In solvent, and the bromo- 2-Thiophene Carboxylic Acids of 5- that addition carboxyl is activated after acid binding agent are added, it is complete to reacting.
6. preparation method according to claim 5, wherein, acid binding agent is selected from triethylamine, one or more groups of pyridine
Close.
7. preparation method according to claim 2, wherein, also comprising step 3), step 3) it is purification step, it is preferable that
The purification step purifies for column chromatography.
8. compound according to claim 1 and its medicinal acceptable salt are preparing treatment or prevention hyperglycemia, sugar
Urine disease, glucose tolerance reduction, insulin resist, it is preferable that the use in medicine of the diabetes selected from 1 type or diabetes B
On the way.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308626A (en) * | 1998-05-12 | 2001-08-15 | 美国家用产品公司 | Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia |
| CN1308620A (en) * | 1998-05-12 | 2001-08-15 | 美国家用产品公司 | Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
-
2017
- 2017-05-19 CN CN201710361230.4A patent/CN107033122B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1308626A (en) * | 1998-05-12 | 2001-08-15 | 美国家用产品公司 | Benzothiophenes, benzofurans, and indoles useful in the treatment of insulin resistance and hyperglycemia |
| CN1308620A (en) * | 1998-05-12 | 2001-08-15 | 美国家用产品公司 | Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
Non-Patent Citations (2)
| Title |
|---|
| PANAYOTIS C THEODOROPOULOS ET AL.: "Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase", 《NATURE CHEMICAL BIOLOGY》 * |
| XIN-GANG YAO ET AL.: "BBT improves glucose homeostasis by ameliorating β-cell dysfunction in type 2 diabetic mice", 《JOURNAL OF ENDOCRINOLOGY》 * |
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Effective date of registration: 20220623 Address after: 510515 no.1023 Jingxi street, shatai Road, Baiyun District, Guangzhou City, Guangdong Province Patentee after: Guangzhou South Medical University Science Park Co.,Ltd. Address before: 510515 No. 1023-1063 Shatainan Road, Baiyun District, Guangzhou City, Guangdong Province Patentee before: SOUTHERN MEDICAL University |