CN1301259A - & alpha, -(1-piperazinyl) ocetamido arenecarboxylic acid derivatives as antidiabetic agents - Google Patents
& alpha, -(1-piperazinyl) ocetamido arenecarboxylic acid derivatives as antidiabetic agents Download PDFInfo
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- CN1301259A CN1301259A CN98814107A CN98814107A CN1301259A CN 1301259 A CN1301259 A CN 1301259A CN 98814107 A CN98814107 A CN 98814107A CN 98814107 A CN98814107 A CN 98814107A CN 1301259 A CN1301259 A CN 1301259A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
- C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Abstract
The invention relates to compounds of general formula (I). These compounds are useful in the treatment of diabetes.
Description
The present invention relates to can be used for treating new α-(1-piperazinyl) kharophen aromatic carboxylic acid derivative of diabetes.
Therefore, theme of the present invention be logical formula I compound, its solvate with and pharmacologically acceptable salt:
Wherein:
Ar is selected from
-have a monocyclic, bicyclic or tricyclic aryl of 6-14 carbon atom,
-be selected from the heteroaryl of pyridyl, pyrimidyl, pyrryl, furyl, thienyl, quinolyl, indyl, benzothienyl, benzofuryl, benzopyranyl, benzo thiapyran base, dibenzofuran group, carbazyl and benzothiazine base,
This Ar can have 1-3 and be selected from following substituting group: C
1-C
8Alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkyl, C
1-C
8Alkoxyl group, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, C
6-C
14Aryl, C
6-C
14Heteroaryl, (C
6-C
14) heteroaryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryloxy, (C
6-C
14) aryloxy (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group, (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, nitro, amino, carboxyl, (C
1-C
6) alkoxy carbonyl, formamyl, (C
1-C
8) alkylthio, (C
1-C
8) alkyl sulphinyl, (C
1-C
8) alkyl sulphonyl, sulfonamido, (C
1-C
8) alkyl sulfonyl amino, sulfamyl or (C
1-C
8) alkyl-carbonyl-amino, perhaps two in these substituting groups form methylene-dioxy,
In the definition of Ar, get rid of the 4-carboxyl phenyl of 4-carboxyl phenyl and replacement,
R
1, R
2And R
3Be independently from each other:
-hydrogen atom,
-C
1-C
8Alkyl or (C
1-C
6) alkoxyl group (C
1-C
6) alkyl,
-contain the cycloalkyl, (C of 3-8 carbon atom
3-C
8) cycloalkyl (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl or (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl,
-C
6-C
14Aryl, C
6-C
14Heteroaryl, (C
6-C
14) heteroaryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl or (C
6-C
14) aryloxy (C
1-C
6) alkyl,
A, B, C and D be=CH-, and one or two in them also can be nitrogen-atoms,
R
4, R
5And R
6Be independently from each other:
-hydrogen atom,
-C
1-C
8Alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkyl, C
1-C
8Alkoxyl group, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, C
6-C
14Aryl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryloxy, (C
6-C
14) aryloxy (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group or (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, halogen or trifluoromethyl, trifluoromethoxy, cyano group, carboxyl, hydroxyl, nitro, amino, (C
1-C
6) alkoxy carbonyl, formamyl, (C
1-C
6) alkylthio, (C
1-C
8) alkyl sulphinyl, (C
1-C
8) alkyl sulphonyl, sulfonamido, (C
1-C
8) alkyl sulfonyl amino, sulfamyl or (C
1-C
8) alkyl-carbonyl-amino, two ring condensed phenyl that can form methylene-dioxy or be connected in these groups with them,
Each aryl self also can be selected from following substituting group by 1-3 and replace: C
1-C
8Alkyl or C
1-C
8Alkoxyl group, halogen or trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino.
The example of the aryl that can mention has phenyl, Alpha-Naphthyl, betanaphthyl and fluorenyl.
C
1-C
8Alkyl can be a straight or branched.The example that can mention has methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl and amyl group.
Similarly, C
1-C
8Alkoxyl group can be a straight or branched.The example that can mention has methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy and isobutoxy.
Halogen can be selected from fluorine, chlorine, bromine and iodine.
At R
1, R
2And R
3Definition in, heteroaryl can be defined as defined heteroaryl in the definition of Ar particularly.
The invention still further relates to tautomer, enantiomer, diastereomer and the epimer of logical formula I compound.
Logical formula I compound has carboxylic acid functional, but and salify, thereby exist with the base addition salt form.
The example of the base addition salt of logical formula I compound comprises pharmacologically acceptable salt, for example sodium salt, sylvite, calcium salt and other similar salt.
Also available amine makes logical formula I compound salify to form pharmacologically acceptable salt.For example, available glycosamine, N-methylglucosamine, N, N-dimethyl glycosamine, thanomin, morpholine, N-methylmorpholine or Methionin make logical formula I compound salify.
Logical formula I compound has nitrogen-atoms, thereby available mineral acid or organic acid make it form single salt or two salt.The example of the acid salt of logical formula I compound comprises pharmacologically acceptable salt, such as but not limited to hydrochloride, hydrobromate, vitriol, succinate, maleate, fumarate, malate or tartrate, and sulfonate for example mesylate, benzene sulfonate or tosylate.
The invention still further relates to the method for the logical formula I compound of preparation.The inventive method comprises, will lead to the formula II arylamine
Wherein A, B, C, D, R
1, R
4, R
5And R
6Define the same, and R
7Be hydrogen atom, C
1-C
6Alkyl or benzyl are with logical formula III halogen acyl halide reaction
R wherein
2And R
3Define the samely, Hal represents the chlorine or bromine atom, to generate logical formula IV compound:
Wherein A, B, C, D, R
1, R
2, R, R
4, R
5, R
6, R
7The same with the Hal definition, and, will lead to formula IV compound and the reaction of general formula (V) compound under for example triethylamine exists at alkaline reagents:
Wherein the Ar definition is the same, to generate logical formula VI compound:
Wherein Ar, A, B, C, D, R
1, R
2, R
3, R
4, R
5, R
6And R
7Define the same.
Work as R
7When being alkyl, can will lead to the formula VI compound hydrolysis, to generate logical formula I compound by conventional acidity or alkaline hydrolysis method.
Work as R
7When being benzyl, can be at catalyzer, for example palladium/charcoal will lead to formula VI compound hydrogenolysis under existing, to generate logical formula I compound.
Formula II and (V) compound are known compounds, perhaps can make according to currently known methods.
For example, " the organic preparation and the method world " (Organic Preparation andProcedures International) described the formula II compound in 13,189,1981.
Formula (V) compound can make by people's (Collection Czechoslov.Chem.Communications, 6,211,1934) such as people such as R.Ratouis (" pharmaceutical chemistry magazine " J.Med.Chem., 8,104,1965) or Prelog method.
For example, can be at alkaline reagents, for example the following wherein R7 of dilute sodium hydroxide existence is the formula VI compound hydrolysis of alkyl.
The enantiomer that can separate the formula I compound by following method: the salt that acid (I) and opticity alkali are formed is replaced as opticity acid with mineral acid or organic acid with this salt according to ordinary method then in solvent fractional recrystallization in acetone, ethyl acetate or the Virahol for example.
The compounds of this invention can be used for treating diabetes, non insulin dependent diabetes especially, and this is because The compounds of this invention has the lowering blood glucose effect and do not have toxicity under active dose.
Therefore, another theme of the present invention is the pharmaceutical composition that comprises the significant quantity The compounds of this invention.
Pharmaceutical composition of the present invention can be and be used for parenteral administration, oral administration, rectal administration, through the formulation of mucous membrane or percutaneous dosing.
Pharmaceutical composition of the present invention can be injection liquid or injection suspension or multi-dose container or not dressing or coated tablet, sweet tablet tablet, the capsule that comprises hard-gelatin capsules, pill, cachet, pulvis, suppository, rectal administration with capsule, the percutaneous dosing in polar solvent with or the solution or the suspension agent form of transmucosal administration.
For solid dosage, the vehicle that is applicable to described administration is Mierocrystalline cellulose or Microcrystalline Cellulose, alkaline earth metal carbonate, trimagnesium phosphate, starch, treated starch or lactose.
Cocoa butter or polyethylene glycol stearate are preferred rectal administration vehicle.
Water, the aqueous solution, physiological solution or isotonic solution are the most frequently used parenteral administration carriers.
According to the indication of being treated and route of administration and patient age and body weight, dosage can change in wide scope.
Following embodiment for example understands the preparation of formula I compound and formula II and (IV) intermediate.A-prepares the embodiment of formula II compound.Preparation 2-cyclohexyl methyl amino-5-methoxyl methyl benzoate
In 1 liter of hydrogenation apparatus, 17.6g 5-methoxyl group methyl o-aminobenzoate, 11.8g hexanaphthene formaldehyde and 2g 10% palladium/charcoal (50% water) are added in the 200ml methyl alcohol.
This device placed under the nitrogen atmosphere and stirring at room 3 hours.
Add the 300ml methylene dichloride, by removing by filter palladium/charcoal, with gained filtrate vacuum concentration.
Gained oily matter with ethanol (200ml) and water (50ml) crystalline mixture, has been obtained the 25.4g yellow solid, and its fusing point is 58-60 ℃.
IR:(KBr)1683cm
-1(C=O),1528cm
-1(C=O)
1H NMR:(CDCl
3, 200 MHz) and δ ppm:1.06-1.64 (11H, m, cyclohexyl), 2.93 (2H, t, CH
2), 3.68 (3H, s, OCH
3), 3.78 (3H, s, OCH
3), 6.56 (1H, d, phenyl protons), 6.96 (1H, dd, phenyl protons), 7.34 (2H, d+s, phenyl protons+NH)
The structural formula of formula II compound and feature are shown in the table I.The table I
The embodiment that B-prepares the formula IV compound prepares 4-chloro-2-(chloro acetylamino) phenylformic acid
Under agitation, the 25.5ml chloroacetyl chloride is added drop-wise in 50g 2-amino-4-chloro-benzoic acid in the 600ml dioxane, this reaction mixture is remained on 20 ℃.
Stirring at room 2 hours, add 1200ml water afterwards then.Be settled out required product, this mixture was stirred 1 hour, filtered then, washed the gained solid with water.
After the drying, obtained 60.7g 4-chloro-2-(chloro acetylamino) phenylformic acid, its fusing point is 194-196 ℃.
IR:1676cm
-1(C=O)
1H NMR:(d
6-DMSO.200 MHz) δ ppm:4,30 (2H, s, CH
2), 71 (1H, d, phenyl protons), 77 (1H, d, phenyl protons), 8.5 (1H, s, phenyl protons), 11.75 (1H, s, NH), 1390 (1H, wide s, COOH) structural formula of formula IV compound and feature as the table II shown in.The table II
Table II (continuing)
The embodiment that C-prepares the formula II compound prepares 4-chloro-2-{[4-(2-p-methoxy-phenyl)-1-piperazinyl] kharophen } phenylformic acid
In room temperature and under stirring, 15g 4-chloro-2-(chloro acetylamino) phenylformic acid is added in 11.6g 1-(2-p-methoxy-phenyl) piperazine and 17ml triethylamine in 120mlDMF.
This reaction mixture stirring at room 48 hours, is added 500ml water then.Extract with 3 * 300ml methylene dichloride.With solvent vacuum-evaporation, the gained solid is placed 300ml 2N aqueous sodium hydroxide solution again.Wash this solution with 3 * 200ml ether, then with acetate with aqueous phase as acidified.
After the filtration, obtain the 22.5g crude product, be solid crystal.Behind the dioxane recrystallization, obtained 21.1g 4-chloro-2-{4-(2-p-methoxy-phenyl)-1-piperazinyl] kharophen } phenylformic acid, be white solid, its fusing point is 218-220 ℃.IR:1699cm
-1(C=O), 1673cm
-1(C=O)
1H NMR:(CF
3COOD), δ ppm:4.25 (3H, s, OCH
3), 4.65 (8H, wide s, 4, CH
2), 4.95 (2H, s, CH
2), 7.5 (2H, m, phenyl protons), 7.6 (1H, d, phenyl protons), 7.90 (2H, m, phenyl protons), 8.50 (1H, d, phenyl protons), 8.75 (1H, s, phenyl protons) the D-another way for preparing the formula I compound prepares 2-{[4-(4-fluorophenyl)-1-piperazinyl] kharophen }-4,5-(methylene three oxygen bases) phenylformic acid
In room temperature and under stirring, with 15g 2-(chloro acetylamino)-4,5-(methylene-dioxy) phenylformic acid is added in 10.5g 1-(4-fluorophenyl) piperazine and 16.2ml triethylamine in 150ml DMF.
With this reaction mixture stirring at room 48 hours.
Add 3.5ml acetate, and add 150ml water lentamente.Acid crystal comes out, and dilutes with 300ml water.This mixture was stirred 30 minutes, filter, and the gained solid is washed with water.
Behind dioxane/DMF mixture recrystallization, obtained 14.9g 2-{[4-(4-fluorophenyl)-1-piperazinyl] kharophen }-4,5-(methylene-dioxy) phenylformic acid, this product fusing point is 254-256 ℃.
IR(KBr):1654cm
-1(C=O)
1H NMR:(CF
3COOD, 200 MHz) δ ppm:4.40 (8H, s, piperazinyl), 4.67 (2H, s, CH
2), 6.05 (2H, s, O-CH
2-O) 7.30 (2H, t, phenyl protons), 7.65 (3H, m, phenyl protons), 7.90 (1H, s, phenyl protons)
The structural formula of formula I compound and feature are shown in the table III.The table III
Hereinafter provide The pharmacological results.The research of the anti-diabetic activity in the NOSTZ rat
With the anti-diabetic activity of determining the formula I compound of oral administration by U-9889 inductive non insulin dependent diabetes experimental model in rat.
This non insulin dependent diabetes model obtains by giving neonate rat (the birth same day) injection U-9889.
Used diabetes rat is that 8 weeks are big or small.Temperature regulation be 21-22 ℃ and have fixing light () at the 7th o'clock to the 19th o'clock and dark (the 19th o'clock to the 7th o'clock) round-robin Animal House in, these animals were remained to from its birth the same day test that day.The mode of arbitrarily absorbing with animal capable provides by the raising of keeping diet, water and food composition, and just fasting (postabsorptive state) was carried out in the test when cancellation food the time in preceding 2 hours.
Test the same day to the oral test product of rat.Last administration product after 30 minutes, is gathered 300 μ l blood samples from tail end with Animal Anesthesia after 2 hours and with vetanarcol (Nembutal).
The main result of gained is shown in the table IV.These results have shown the validity of formula I compound lowering blood glucose in diabetic animal.
These results change per-cent and represent to compare blood sugar when D4 (treating the 4th day) with D0 (treatment before).
The table IV
| Compound | 20?mg/kg/d | ?200?mg/kg/d |
| At the % of D4 blood sugar | At the % of D4 blood sugar | |
| 35 | -12 | -16 |
| 38 | -6 | -27 |
| 39 | -15 | -14 |
| 45 | -9 | -18 |
| 47 | -16 | -32 |
| 48 | -20 | -31 |
| 50 | -17 | -7 |
| 52 | -14 | -21 |
Claims (10)
1. be selected from formula I compound, its solvate with and the compound of pharmacologically acceptable salt:
Wherein:
Ar is selected from
-have a monocyclic, bicyclic or tricyclic aryl of 6-14 carbon atom,
-be selected from the heteroaryl of pyridyl, pyrimidyl, pyrryl, furyl, thienyl, quinolyl, indyl, benzothienyl, benzofuryl, benzopyranyl, benzo thiapyran base, dibenzofuran group, carbazyl and benzothiazine base,
This Ar can have 1-3 and be selected from following substituting group: C
1-C
8Alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkyl, C
1-C
8Alkoxyl group, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, C
6-C
14Aryl, C
6-C
14Heteroaryl, (C
6-C
14) heteroaryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryloxy, (C
6-C
14) aryloxy (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group, (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano group, hydroxyl, nitro, amino, carboxyl, (C
1-C
6) alkoxy carbonyl, formamyl, (C
1-C
8) alkylthio, (C
1-C
8) alkyl sulphinyl, (C
1-C
8) alkyl sulphonyl, sulfonamido, (C
1-C
8) alkyl sulfonyl amino, sulfamyl and (C
1-C
8) alkyl-carbonyl-amino, perhaps two in these substituting groups form methylene-dioxy,
In the definition of Ar, get rid of the 4-carboxyl phenyl of 4-carboxyl phenyl and replacement,
R
1, R
2And R
3Be independently from each other:
-hydrogen atom,
-C
1-C
8Alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl,
-contain the cycloalkyl, (C of 3-8 carbon atom
3-C
8) cycloalkyl (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl and (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl,
-C
6-C
14Aryl, C
6-C
14Heteroaryl, (C
6-C
14) heteroaryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl and (C
6-C
14) aryloxy (C
1-C
6) alkyl,
A, B, C and D be=the CH-group, and one or two in them also can be nitrogen-atoms,
R
4, R
5And R
6Be independently from each other:
-hydrogen atom,
-C
1-C
8Alkyl, (C
3-C
8) cycloalkyl (C
1-C
6) alkyl, C
1-C
8Alkoxyl group, (C
3-C
8) cycloalkyloxy (C
1-C
6) alkyl, (C
3-C
8) cycloalkyloxy, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group, (C
3-C
8) cycloalkyl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, C
6-C
14Aryl, (C
6-C
14) aryl (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkyl (C
6-C
14) aryl, (C
6-C
14) aryloxy, (C
6-C
14) aryloxy (C
1-C
6) alkyl, (C
6-C
14) aryl (C
1-C
6) alkoxyl group, (C
6-C
14) aryl (C
1-C
6) alkoxyl group (C
1-C
6) alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano group, carboxyl, hydroxyl, nitro, amino, (C
1-C
6) alkoxy carbonyl, formamyl, (C
1-C
6) alkylthio, (C
1-C
8) alkyl sulphinyl, (C
1-C
8) alkyl sulphonyl, sulfonamido, (C
1-C
8) alkyl sulfonyl amino, sulfamyl and (C
1-C
8) alkyl-carbonyl-amino, two ring condensed benzyl rings that can form methylene-dioxy or be connected in these groups with them,
Each aryl self also can be selected from following substituting group by 1-3 and replace: C
1-C
8Alkyl, C
1-C
8Alkoxyl group, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino.
2. the compound of claim 1, the element of wherein said ring system
It is benzyl ring.
3. the compound of claim 2, wherein R
4, R
5And R
6In at least one is C
1-C
8Alkoxyl group, perhaps two in these groups form methylene-dioxy.
4. the method for the compound of preparation claim 1 comprises the formula II arylamine
Wherein A, B, C, D, R
1, R
4, R
5And R
6Define the same, and R
7Be selected from hydrogen atom,
C
1-C
6Alkyl and benzyl,
React with the formula III halogen acyl halide
R wherein
2And R
3Define the samely, Hal is selected from chlorine and bromine,
To generate the formula IV compound:
Wherein A, B, C, D, R
1, R
2, R
3, R
4, R
5, R
6, R
7It is the same with the Hal definition,
And in the presence of alkaline reagents, formula IV compound and formula (V) compound are reacted:
Wherein the Ar definition is the same,
To generate the formula VI compound:
Wherein Ar, A, B, C, D, R
1, R
2, R
3, R
4, R
5, R
6And R
7Define the same,
And, work as R
7When being alkyl, with this compound hydrolysis generating the formula I compound,
And work as R
7When being benzyl, with this compound hydrogenolysis to generate the formula I compound.
5. the pharmaceutical composition that comprises the compound of significant quantity claim 1.
6. the pharmaceutical composition that comprises the compound of significant quantity claim 2.
7. the pharmaceutical composition that comprises the compound of significant quantity claim 3.
8. the method for treatment diabetes comprises people's administration that the compound as claimed in claim 1 of significant quantity is treated needs.
9. the method for treatment diabetes comprises people's administration that the compound as claimed in claim 2 of significant quantity is treated needs.
10. the method for treatment diabetes comprises people's administration that the compound as claimed in claim 3 of significant quantity is treated needs.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9705849A FR2763334A1 (en) | 1997-05-13 | 1997-05-13 | Piperazino alkyl anthranilic acid amide |
| PCT/EP1998/003431 WO1999064407A1 (en) | 1997-05-13 | 1998-06-08 | α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1301259A true CN1301259A (en) | 2001-06-27 |
| CN1119338C CN1119338C (en) | 2003-08-27 |
Family
ID=26070316
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN98814107A Expired - Fee Related CN1119338C (en) | 1997-05-13 | 1998-06-08 | & alpha, -(1-piperazinyl) ocetamido arenecarboxylic acid derivatives as antidiabetic agents |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1119338C (en) |
| BR (1) | BR9816021A (en) |
| FR (1) | FR2763334A1 (en) |
| WO (1) | WO1999064407A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804362A (en) * | 2012-11-12 | 2014-05-21 | 韩文毅 | Compounds for treating diabetes and application thereof |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MXPA00011889A (en) | 1998-06-02 | 2003-04-25 | Osi Pharm Inc | PYRROLO[2,3d]PYRIMIDINE COMPOSITIONS AND THEIR USE. |
| US6680324B2 (en) | 2000-12-01 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
| JO2390B1 (en) | 2001-04-06 | 2007-06-17 | شركة جانسين فارماسوتيكا ان. في | Lipid lowering biphenulcarboxamides |
| EP1450811B1 (en) | 2001-11-30 | 2009-10-21 | OSI Pharmaceuticals, Inc. | Compounds specific to adenosine A1 and A3 receptors and uses thereof |
| CN1620294A (en) * | 2001-12-20 | 2005-05-25 | Osi药物公司 | Pyrimidine A2b selective antagonist compounds, their synthesis and use |
| AR042067A1 (en) * | 2002-11-27 | 2005-06-08 | Bayer Pharmaceuticals Corp | USEFUL ANILINOPIRAZOL DERIVATIVES IN THE TREATMENT OF DIABETES |
| CN100448869C (en) * | 2002-11-27 | 2009-01-07 | 拜尔药品公司 | Anilinopyrazole derivatives useful for the treatment of diabetes |
| GB0319124D0 (en) * | 2003-08-14 | 2003-09-17 | Smithkline Beecham Corp | Chemical compounds |
| JP2008530074A (en) * | 2005-02-14 | 2008-08-07 | スミスクライン・ビーチャム・コーポレイション | Anthranilic acid derivatives as HM74A receptor agonists |
| IL277071B1 (en) | 2018-03-08 | 2024-03-01 | Incyte Corp | AMINOPYRAZINE DIOL COMPOUNDS AS PI3K-y INHIBITORS |
| US11046658B2 (en) | 2018-07-02 | 2021-06-29 | Incyte Corporation | Aminopyrazine derivatives as PI3K-γ inhibitors |
| US11871772B2 (en) * | 2018-08-10 | 2024-01-16 | Firmenich Incorporated | Antagonists of T2R54 and compositions and uses thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2346011A1 (en) * | 1976-02-02 | 1977-10-28 | Orsymonde | (4)-Phenyl-(1)-dimethylacetanilido-piperazine and salts - esp. for treating cardiovascular circulatory disorders |
| FR2674522B1 (en) * | 1991-03-26 | 1993-07-16 | Lipha | NOVEL INDOLE DERIVATIVES, PREPARATION METHODS AND MEDICAMENTS CONTAINING THEM. |
| FR2693722B1 (en) * | 1992-07-16 | 1994-10-14 | Meram Lab | N-cycloalkylpiperazine derivatives, process for obtaining them and pharmaceutical compositions containing them. |
| FR2707984B1 (en) * | 1993-07-23 | 1995-09-01 | Adir | New substituted piperazines, process for their preparation and compositions containing them |
| WO1996026924A1 (en) * | 1995-02-28 | 1996-09-06 | Suntory Limited | Arylpiperidine and arylpiperazine derivatives and drugs containing the same |
| FR2757158B1 (en) * | 1996-12-18 | 1999-04-02 | Lipha | NOVEL 4- (1-PIPERAZINYL) BENZOIC ACID DERIVATIVES, PROCESS FOR THEIR PREPARATION AND THERAPEUTIC APPLICATIONS |
-
1997
- 1997-05-13 FR FR9705849A patent/FR2763334A1/en not_active Withdrawn
-
1998
- 1998-06-08 BR BR9816021-4A patent/BR9816021A/en not_active IP Right Cessation
- 1998-06-08 WO PCT/EP1998/003431 patent/WO1999064407A1/en not_active Application Discontinuation
- 1998-06-08 CN CN98814107A patent/CN1119338C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804362A (en) * | 2012-11-12 | 2014-05-21 | 韩文毅 | Compounds for treating diabetes and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9816021A (en) | 2001-05-15 |
| FR2763334A1 (en) | 1998-11-20 |
| CN1119338C (en) | 2003-08-27 |
| WO1999064407A1 (en) | 1999-12-16 |
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