CN107033122B - A kind of N- aryl -2- thiophene-carboxamides analog derivative and its preparation method and application - Google Patents
A kind of N- aryl -2- thiophene-carboxamides analog derivative and its preparation method and application Download PDFInfo
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- CN107033122B CN107033122B CN201710361230.4A CN201710361230A CN107033122B CN 107033122 B CN107033122 B CN 107033122B CN 201710361230 A CN201710361230 A CN 201710361230A CN 107033122 B CN107033122 B CN 107033122B
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- 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 N- aryl -2- thiophene-carboxamides analog derivative and its preparation method and application, wherein specifically disclosing the salt of a kind of compound and its pharmaceutically acceptable receiving, structure is shown in formula I.And the salt for disclosing the compound and its pharmaceutically acceptable receiving is anti-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 for treating the N- aryl -2- thiophene-carboxamides class of diabetes B
Derivative.
Background technique
Diabetes are a kind of chronic diseases of worldwide epidemics, seriously threaten the health of the 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, every 7 seconds average
Clock just has diabetic's death, more than the prevention and treatment that 612,000,000,000 U.S. dollars are used for diabetes, brings heavy warp 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 about the 1/4 of global sum, this people to China
Mouth health and socio-economic development generate tremendous influence.Therefore, it is badly in need of the effective means of development treatment diabetes.
Diabetes B accounts for 90% or more of diabetes total number of persons, though there are many conventional medicament 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) agonist 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
Decaying, treatment means are not still able to satisfy the demand of patient at present.In recent years discovery NLRP3/IL-1 beta mediated inflammatory immune mistake
Journey plays a crucial role in islet beta cell function decaying, therefore the inflammatory immune drug for directly improving beta Cell of islet is expected to become
The newtype drug for treating diabetes B.Exploitation can improve the drug of β cell function, become the new target of diabetes drug treatment
Point.The present invention synthesizes a kind of N- aryl -2- thiophene-carboxamides class compound for the first time, is named as compound Y1, tool increases significantly
Level of insulin secretion reduces the effect of islet beta-cell apoptosis.The experimental results showed that the compound is to develop novel treatment
The lead compound of diabetes B finds new structural treatment diabetes B drug and provides possibility.
Summary of the invention
The purpose of the present invention is to provide a kind of compound, N- (2- (4- chlorobenzene formacyl) phenyl) -5- bromothiophene -2- first
Amide, shown in formula I, referred to as compound Y1, the compound can increase the secretion of insulin, reduce islet beta-cell apoptosis,
To which the treatment for diabetes provides a kind of new means and approach, there is important research and development value and development significance.
The present invention provides application of the compound shown in Formulas I in the drug for the treatment of diabetes B.
Compound Y1 of the present invention can carry out structural modification as primer, obtain the better compound of activity, and
For treating diabetes B.
The present invention provides the preparation methods of compound Y1 comprising following steps:
1) the bromo- 2-Thiophene Carboxylic Acid of 5- is dissolved in thionyl chloride, pyridine is added as catalyst, is stirred and heated to back
Stream after fully reacting, is concentrated under reduced pressure reaction solution to doing with Rotary Evaporators, obtains the bromo- 2- thiophene chloride compounds of required 5-；
2) 2- amino -4 '-chlorobenzophenone is dissolved in methylene chloride, triethylamine is added and makees acid binding agent, the bromo- 2- of 5- is added dropwise
After fully reacting, solvent is removed under reduced pressure in the dichloromethane solution of thiophene acyl chlorides, and column chromatography is obtained Formulas I shownization after purification
Close object.
Structural formula of compound of the present invention is as follows
The dose-dependent improvement islet beta cell function of above-mentioned compound represented energy, improves level of insulin secretion.
Compound Y1 of the present invention can be used for being made the drug for the treatment of diabetes.In conjunction with modern common drug preparation hand
Section, can be made injection, tablet, pulvis, granule, capsule for the compound, thus using eaily form of medication,
Wherein mass percentage content of the compounds of this invention in the drug is 1~20%.
The drug of above-mentioned various dosage forms 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, structure are shown in formula I.
Another aspect of the invention provides the preparation method of compound of formula I and its medicinal acceptable salt comprising such as
Lower step:
1) carboxyl in the bromo- 2-Thiophene Carboxylic Acid of 5- is activated, the bromo- 2-Thiophene Carboxylic Acid of 5- that carboxyl is activated is obtained；
2) by the bromo- 2-Thiophene Carboxylic Acid of 5- that addition carboxyl is activated in 2- amino -4 '-chlorobenzophenone, fully reacting is obtained
To compound shown in Formulas I.
In the inventive solutions, in step 1) in thionyl chloride, phosphorus trichloride, phosphorus pentachloride, oxalyl chloride
One or more pairs of carboxyls activate, using pyridine as catalyst, it is preferable that using thionyl chloride as activating reagent.
In the inventive solutions, the reaction condition in step 1) is to be heated to reflux.
In the inventive solutions, it is dissolved in organic solvent in step 2) with 2- amino -4 '-chlorobenzophenone, and
The bromo- 2-Thiophene Carboxylic Acid of 5- that carboxyl is activated is added after acid binding agent is added, until fully reacting.
In the inventive solutions, acid binding agent is selected from triethylamine, one or more combinations of pyridine.
It in the inventive solutions, also include step 3), step 3) is purification step, it is preferable that the purifying step
It suddenly is column chromatographic purifying.
Another aspect of the invention provides Formulas I compound represented and its medicinal acceptable salt in preparation treatment or pre-
Anti- hyperglycemia, diabetes, glucose tolerance reduce, insulin is anti-, it is preferable that the diabetes are selected from 1 type or diabetes B
Drug in purposes.
Detailed description of the invention
Fig. 1 Y1 is in the secretion of the promotion insulin of dependence on the glucose.
Fig. 2 Y1 is in the secretion of the promotion insulin of concentration gradient.
Specific embodiment
In order to better understand the content of the present invention, the content of present invention is made furtherly below with reference to specific implementation method
Bright but of the invention protects content not limit to following embodiment.
The synthetic method of embodiment 1N- (2- (4- chlorobenzene formacyl) phenyl) -5- bromothiophene -2- formamide Y1
The bromo- 2-Thiophene Carboxylic Acid of 5- (1mmol, 206mg) is added in the round-bottomed flask of 50mL, thionyl chloride 3mL, pyridine 3
Drop, agitating and heating adds stream (80 DEG C), after 2 hours, stops reaction, rotary evaporation removes solvent, obtains the bromo- 2- thiophene acyl chlorides of 5-, add
It is spare to enter the dry methylene chloride of 5mL.In the round-bottomed flask of 50mL be added 2- amino -4 '-chlorobenzophenone (1mmol,
232mg), methylene chloride 5mL, triethylamine 1mL, stirring and dissolving, ice-water bath are cooled to 0 DEG C.Under stiring, the bromo- 2- thiophene of 5- is added dropwise
The dichloromethane solution (dripping off in 10 minutes) of pheno acyl chlorides after being added dropwise, continues to be stirred to react 2 hours.Stop reaction, rotation
Evaporation under reduced pressure removes solvent, and column chromatography for separation purification obtains product Y1, yield 85%.
Above compound is characterized as below: mp:84-85 DEG C；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.
The insulin secretion accelerating activity of embodiment 2N- (2- (4- chlorobenzene formacyl) phenyl) -5- bromothiophene -2- formamide Y1
Detection
Insulin secretion accelerating activity is detected using rat insulin oncocyte INS-832/13 cell.INS-832/13
Cell culture in contain 10% fetal calf serum, 10mM hydroxyethyl piperazine second thiosulfonic acid, 2mM Pidolidone salt, 1mM Sodium Pyruvate,
In the RPMI1640 culture medium of 0.05mM mercaptoethanol, it is placed in containing 5%CO2Cell incubator in cultivate.
INS-832/13 cell is with 105A/hole is laid in 24 orifice plates, and 37 DEG C, 5%CO248 hours of middle culture.To cell
When growing fine, RPMI1640 culture medium is sucked out, buffer solution (115mM sodium chloride, 5mM potassium chloride, the 24mM carbon of sugar-free is added
Sour hydrogen sodium, 2.5mM calcium chloride, 1mM magnesium chloride, 10mM hydroxyethyl piperazine second thiosulfonic acid, 0.1% bovine serum albumin(BSA), pH7.2)
It is incubated for 2 hours, then changes the buffer solution containing 2.5mM and 16.7mM concentration of glucose and N- (2- (the 4- chlorobenzene first of 10mM into
Acyl group) phenyl) it is incubated for 2 hours in -5- bromothiophene -2- formamide Y1.Cell culture medium is then collected, 3000 turns are centrifuged 5 minutes,
Take the insulin content in supernatant enzyme-linked immunoassay method detection supernatant.
As shown in Figure 1, Y1 (N- (2- (4- chlorobenzene formacyl) phenyl) -5- bromothiophene -2- formamide) can significantly increase Portugal
The level of insulin secretion of grape sugar stimulation cannot dramatically increase the secretion of insulin in glucose (2.5mM) of low concentration
Level, and at the glucose of high concentration (16.7mM), the secretion of insulin can be remarkably promoted.
As shown in table 1, Fig. 2, Y1 (N- (2- (4- chlorobenzene formacyl) phenyl) -5- bromothiophene -2- formamide) in concentration according to
Property is relied to promote the secretion of insulin, median effective dose is 4.8 micromoles.
Table 1Y1 promotes insulin secretion multiple
| N- (2- (4- chlorobenzene formacyl) 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 compound has the insulin secretion accelerating effect of good dependence on the glucose as the result is shown for this, has good anti-
Diabetes B potentiality to be exploited.
Claims (6)
1. a kind of compound and its medicinal acceptable salt, structure are shown in formula I
2. the preparation method of compound as shown in claim 1 and its medicinal acceptable salt comprising following steps:
1) carboxyl in the bromo- 2-Thiophene Carboxylic Acid of 5- is activated, the bromo- 2-Thiophene Carboxylic Acid of 5- that carboxyl is activated is obtained；
2) by the bromo- 2-Thiophene Carboxylic Acid of 5- that addition carboxyl is activated in 2- amino -4 '-chlorobenzophenone, fully reacting obtains Formulas I
Shown compound.
3. preparation method according to claim 2, wherein in step 1) with thionyl chloride, phosphorus trichloride, phosphorus pentachloride,
One of oxalyl chloride or a variety of pairs of carboxyls activate, using pyridine as catalyst.
4. preparation method according to claim 2, wherein be dissolved in step 2) with 2- amino -4 '-chlorobenzophenone organic
In solvent, and the bromo- 2-Thiophene Carboxylic Acid of 5- that carboxyl is activated is added after acid binding agent is added, until fully reacting, acid binding agent is selected from three
Ethamine, one or more combinations of pyridine.
5. compound according to claim 1 and its medicinal acceptable salt treat or prevent hyperglycemia, sugar in preparation
Purposes in urine disease, the drug that glucose tolerance reduces, insulin is anti-.
6. compound according to claim 5 and its medicinal acceptable salt treat or prevent hyperglycemia, sugar in preparation
Purposes in urine disease, the drug that glucose tolerance reduces, insulin is anti-, the diabetes are selected from 1 type or diabetes B.
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| CA2330599A1 (en) * | 1998-05-12 | 1999-11-18 | Michael Sotirios Malamas | Biphenyl sulfonyl aryl carboxylic acids useful in the treatment of insulin resistance and hyperglycemia |
| HUP0101792A3 (en) * | 1998-05-12 | 2003-01-28 | Wyeth Corp | Benzothiophenes, benzofurans, and indoles, their use for producing medicaments and this medicaments useful in the treatment of insulin resistance and hyperglycemia |
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