HK1036626A - α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS - Google Patents
α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS Download PDFInfo
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The present invention relates to novel alpha- (1-piperazinyl) acetamidoarene carboxylic acid derivatives useful in the treatment of diabetes.
The subject of the present invention is therefore the compounds of general formula (i), their solvates and their pharmaceutically acceptable salts:
wherein:
ar is selected from
-a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms,
-a heteroaryl group selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, quinolinyl, indolyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, dibenzofuranyl, carbazolyl, and benzothiazinyl,
ar may carry 1 to 3 substituents selected from: c1-C8Alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl radical, C1-C8Alkoxy group, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, C6-C14Aryl radical, C6-C14Heteroaryl, (C)6-C14) Heteroaryl (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryloxy group, (C)6-C14) Aryloxy radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkoxy group, (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)1-C6) Alkoxycarbonyl, carbamoyl, (C)1-C8) Alkylthio group, (C)1-C8) Alkylsulfinyl (C)1-C8) Alkylsulfonyl, sulfonamido, (C)1-C8) An alkylsulfonylamino group, a sulfamoyl group, or (C)1-C8) Alkylcarbonylamino, or two of these substituents form methylenedioxy,
in the definition of Ar, 4-carboxyphenyl and substituted 4-carboxyphenyl groups are excluded,
R1、R2and R3Independently of one another, selected from:
-a hydrogen atom,
-C1-C8alkyl or (C)1-C6) Alkoxy (C)1-C6) An alkyl group, a carboxyl group,
-containsCycloalkyl having 3 to 8 carbon atoms, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl, or (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) An alkyl group, a carboxyl group,
-C6-C14aryl radical, C6-C14Heteroaryl, (C)6-C14) Heteroaryl (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, or (C)6-C14) Aryloxy radical (C)1-C6) An alkyl group, a carboxyl group,
A. b, C and D are = CH-, one or both of which may also be a nitrogen atom,
R4、R5and R6Independently of one another, selected from:
-a hydrogen atom,
-C1-C8alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl radical, C1-C8Alkoxy group, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy group, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, C6-C14Aryl group, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryloxy group, (C)6-C14) Aryloxy radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkoxy or (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, halogen or trifluoromethyl, trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino, (C)1-C6) Alkoxycarbonyl, carbamoyl, (C)1-C6) Alkylthio group, (C)1-C8) Alkylsulfinyl (C)1-C8) Alkylsulfonyl, sulfonamido, (C)1-C8) An alkylsulfonylamino group, a sulfamoyl group, or (C)1-C8) Alkylcarbonylamino, two of these radicals may form methylenedioxy or phenyl fused to the ring to which they are attached,
each aryl group may itself be substituted with 1 to 3 substituents selected from: c1-C8Alkyl or C1-C8Alkoxy, halogen or trifluoromethyl, trifluoromethoxy, hydroxy, nitro and amino.
Examples of aryl groups which may be mentioned are phenyl, alpha-naphthyl, beta-naphthyl and fluorenyl.
C1-C8The alkyl group may be straight or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl.
Similarly, C1-C8The alkoxy group may be straight or branched. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy and isobutoxy.
The halogen may be selected from fluorine, chlorine, bromine and iodine.
At R1、R2And R3In the definition of (a), heteroaryl may be specifically defined as heteroaryl as defined in the definition of Ar.
The invention also relates to tautomers, enantiomers, diastereomers and epimers of the compounds of formula (i).
The compounds of formula (I) have carboxylic acid functions and can form salts, thus existing in the form of base addition salts.
Examples of base addition salts of the compounds of formula (I) include pharmaceutically acceptable salts such as sodium, potassium, calcium and the like.
The compounds of formula (I) may also be salified with an amine to form a pharmaceutically acceptable salt. For example, glucosamine, N-methylglucamine, N-dimethylglucamine, ethanolamine, morpholine, N-methylmorpholine or lysine can be used to salify the compound of formula (I).
The compounds of formula (I) have a nitrogen atom and can thus be brought into the form of mono-or di-salts with inorganic or organic acids. Examples of acid addition salts of compounds of formula (i) include pharmaceutically acceptable salts such as, but not limited to, hydrochloride, hydrobromide, sulphate, succinate, maleate, fumarate, malate or tartrate, and sulphonates such as methanesulphonate, benzenesulphonate or toluenesulphonate.
The invention also relates to a method for producing the compounds of general formula (I). The process of the invention comprises reacting an aromatic amine of the general formula (II)A, B, C, D, R therein1、R4、R5And R6Is as defined above, and R7Is a hydrogen atom, C1-C6Alkyl or benzyl, with halogen halides of the general formula (III)Wherein R is2And R3Hal represents a chlorine or bromine atom, as defined above, to give a compound of general formula (IV):a, B, C, D, R therein1、R2、R、R4、R5、R6、R7And Hal are as defined above, and a compound of the formula (IV) is combined with a compound of the formula (V) in the presence of a basic reagent, for example triethylamineCarrying out reaction on the materials:wherein Ar is as defined above, to produce a compound of formula (VI):wherein Ar, A, B, C, D, R1、R2、R3、R4、R5、R6And R7The definition is the same as above.
When R is7In the case of alkyl, the compound of formula (VI) may be hydrolysed by conventional acidic or basic hydrolysis methods to produce the compound of formula (I).
When R is7In the case of benzyl, the compound of formula (VI) may be hydrogenolysed in the presence of a catalyst, for example palladium on charcoal, to give the compound of formula (I).
The compounds of the formulae (II) and (V) are known compounds or can be prepared according to known methods.
For example, compounds of formula (II) are described in Organic Preparation and methods International 13,189,1981.
The compounds of formula (v) may be prepared by the methods of r.ratouis et al (journal of pharmaceutical chemistry, j.med.chem.,8,104,1965) or Prelog et al (Collection czechosov.chem.communications, 6,211,1934).
For example, a compound of formula (VI) wherein R7 is alkyl may be hydrolyzed in the presence of a basic agent, such as dilute sodium hydroxide.
Enantiomers of compounds of formula (i) can be isolated by: the salt of the acid (I) with the optically active base is fractionally recrystallized in a solvent such as acetone, ethyl acetate or isopropanol, and then the salt is replaced with the optically active acid by an inorganic or organic acid according to a conventional method.
The compounds of the invention are useful in the treatment of diabetes, especially non-insulin dependent diabetes mellitus, because they have a hypoglycemic effect and are not toxic at the active dose.
Thus, another subject of the invention is a pharmaceutical composition comprising an effective amount of a compound of the invention.
The pharmaceutical compositions of the present invention may be in dosage forms for parenteral, oral, rectal, transmucosal or transdermal administration.
The pharmaceutical compositions of the present invention may be in the form of injectable solutions or suspensions for injection, or in multi-dose containers, or uncoated or coated tablets, sugar coated tablets, capsules including hard gelatin capsules, pills, cachets, powders, suppositories, capsules for rectal administration, solutions or suspensions for transdermal or transmucosal administration in polar solvents.
For solid dosage forms, excipients suitable for the administration are cellulose or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starch, modified starch or lactose.
Cocoa butter or polyethylene glycol stearate are preferred excipients for rectal administration.
Water, aqueous solutions, physiological solutions or isotonic solutions are the most commonly used carriers for parenteral administration.
The dosage may vary within wide limits depending on the indication to be treated and the route of administration and the age and weight of the patient.
The following examples illustrate the preparation of compounds of formula (I) and intermediates of formula (II) and (IV). A-examples for the preparation of compounds of formula (II). Preparation of methyl 2-cyclohexylmethylamino-5-methoxybenzoate
In a 1 l hydrogenation unit, 17.6g of methyl 5-methoxyanthranilate, 11.8g of cyclohexane carboxaldehyde and 2g of 10% palladium on charcoal (50% water) are added to 200ml of methanol.
The apparatus was placed under a hydrogen atmosphere and stirred at room temperature for 3 hours.
300ml of dichloromethane were added, the palladium/carbon was removed by filtration and the filtrate was concentrated in vacuo.
The resulting oil was crystallized from a mixture of ethanol (200ml) and water (50ml) to give 25.4g of a yellow solid with a melting point of 58-60 ℃.
IR:(KBr)1683cm-1(C=O),1528cm-1(C=O)
1H NMR:(CDCl3200 MHz) delta ppm 1.06-1.64(11H, m, cyclohexyl), 2.93(2H, t, CH)2),3.68(3H,s,OCH3),3.78(3H,s,OCH3) 6.56(1H, d, phenyl proton), 6.96(1H, dd, phenyl proton), 7.34(2H, d + s, phenyl proton + NH)
The structural formula and characteristics of the compound of formula (II) are shown in Table I. TABLE IB-preparation of Compounds of formula (IV) preparation of 4-chloro-2- (chloroacetamido) benzoic acid
25.5ml of chloroacetyl chloride are added dropwise with stirring to 50g of 2-amino-4-chlorobenzoic acid in 600ml of dioxane, and the reaction mixture is maintained at 20 ℃.
Then stirred at room temperature for 2 hours, after which 1200ml of water was added. The desired product precipitated, the mixture was stirred for 1 hour, then filtered, and the resulting solid was washed with water.
After drying, 60.7g of 4-chloro-2- (chloroacetamido) benzoic acid are obtained, having a melting point of 194-196 ℃.
IR:1676cm-1(C=O)
1H NMR:(d6-DMSO.200 MHz)δ ppm:4,30(2H,s,CH2) The structural formulae and features of 71(1H, d, phenyl proton), 77(1H, d, phenyl proton), 8.5(1H, s, phenyl proton), 11.75(1H, s, NH),1390(1H, width s, COOH) compounds of formula (IV) are shown in Table II. TABLE IITABLE II (continuation)C-preparation of the Compound of formula (II) example preparation of 4-chloro-2- { [4- (2-methoxyphenyl) -1-piperazinyl]Acetylamino benzoic acid
15g of 4-chloro-2- (chloroacetamido) benzoic acid are added to 11.6g of 1- (2-methoxyphenyl) piperazine and 17ml of triethylamine in 120ml of DMF with stirring at room temperature.
The reaction mixture was stirred at room temperature for 48 hours, then 500ml of water was added. Extraction was carried out with 3X 300ml of dichloromethane. The solvent was evaporated in vacuo and the resulting solid was replaced in 300ml of 2N aqueous sodium hydroxide solution. The solution was washed with 3X 200ml of diethyl ether and the aqueous phase was acidified with acetic acid.
After filtration, 22.5g of crude product was obtained as solid crystals. After recrystallization from dioxane, 21.1g of 4-chloro-2- {4- (2-methoxyphenyl) -1-piperazinyl is obtained]Acetamido } benzoic acid as a white solid with a melting point of 218-220 ℃. IR of 1699cm-1(C=O),1673cm-1(C=O)1H NMR:(CF3COOD),δ ppm:4.25(3H,s,OCH3) 4.65(8H, width s,4, CH)2),4.95(2H,s,CH2) 7.5(2H, m, phenyl proton), 7.6(1H, D, phenyl proton), 7.90(2H, m, phenyl proton), 8.50(1H, D, phenyl proton), 8.75(1H, s, phenyl proton) D-alternative preparation of Compounds of formula (I) 2- { [4- (4-fluorophenyl) -1-piperazinyl]Acetylamino } -4,5- (methylenedioxy) benzoic acid
15g of 2- (chloroacetamido) -4,5- (methylenedioxy) benzoic acid are added to 10.5g of 1- (4-fluorophenyl) piperazine and 16.2ml of triethylamine in 150ml of DMF with stirring at room temperature.
The reaction mixture was stirred at room temperature for 48 hours.
3.5ml of acetic acid were added and 150ml of water were slowly added. The acid crystallized out and was diluted with 300ml of water. The mixture was stirred for 30 minutes, filtered, and the resulting solid was washed with water.
After recrystallization from a dioxane/DMF mixture, 14.9g of 2- { [4- (4-fluorophenyl) -1-piperazinyl ] acetamido } -4,5- (methylenedioxy) benzoic acid were obtained, the melting point of which was 254-256 ℃.
IR(KBr):1654cm-1(C=O)
1H NMR:(CF3COOD,200 MHz) Δ ppm 4.40(8H, s, pyrazinyl), 4.67(2H, s, CH)2),6.05(2H,s,O-CH2-O)7.30(2H, t, phenyl proton), 7.65(3H, m, phenyl proton), 7.90(1H, s, phenyl proton)
The structural formula and characteristics of the compound of formula (I) are shown in Table III. TABLE III
The results of pharmacological experiments are given below. Study of antidiabetic Activity in NOSTZ rats
The anti-diabetic activity of orally administered compounds of formula (I) was determined using an experimental model of non-insulin dependent diabetes induced in rats by streptozotocin.
The non-insulin dependent diabetes model was obtained by injecting streptozotocin into neonatal rats (day of birth).
The diabetic rats used were 8 weeks in size. These animals were kept from the day of their birth until the day of the experiment in animal houses adjusted to 21-22 ℃ and having a fixed light (time 7 to time 19) and dark (time 19 to time 7) cycle. The feeding consisting of maintenance diet, water and food was provided in such a way that the animals could ingest it at will, except that fasting (postabsorption state) was performed 2 hours before the test when the food was cancelled.
The test product was administered orally to rats on the day of testing. After 2 hours of the last product administration and 30 minutes of anesthesia of the animals with sodium pentobarbital (Nembutal), 300. mu.l blood samples were taken from the tail ends.
The main results obtained are shown in Table IV. These results demonstrate the effectiveness of the compounds of formula (I) in lowering blood glucose in diabetic animals.
These results are expressed as the percentage change in blood glucose at D4 (day 4 of treatment) compared to D0 (before treatment).
TABLE IV
| Compound (I) | 20 mg/kg/d | 200 mg/kg/d |
| % blood glucose at D4 | % blood glucose at D4 | |
| 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. A compound selected from the group consisting of compounds of formula (I):
wherein:
ar is selected from
-a monocyclic, bicyclic or tricyclic aryl group having 6 to 14 carbon atoms,
-a heteroaryl group selected from pyridyl, pyrimidinyl, pyrrolyl, furanyl, thienyl, quinolinyl, indolyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, dibenzofuranyl, carbazolyl, and benzothiazinyl,
ar may carry 1 to 3 substituents selected from: c1-C8Alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl radical, C1-C8Alkoxy group, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy group, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, C6-C14Aryl radical, C6-C14Heteroaryl, (C)6-C14) Heteroaryl (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryloxy group, (C)6-C14) Aryloxy radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkoxy group, (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, amino, carboxy, (C)1-C6) Alkoxycarbonyl, carbamoyl, (C)1-C8) Alkylthio group, (C)1-C8) Alkylsulfinyl (C)1-C8) Alkylsulfonyl, sulfonamido, (C)1-C8) Alkylsulfonylamino, sulfamoyl, and (C)1-C8) Alkylcarbonylamino, or two of these substituents form methylenedioxy,
in the definition of Ar, 4-carboxyphenyl and substituted 4-carboxyphenyl groups are excluded,
R1、R2and R3Independently of one another, selected from:
-a hydrogen atom,
-C1-C8alkyl, (C)1-C6) Alkoxy (C)1-C6) An alkyl group, a carboxyl group,
cycloalkyl having 3 to 8 carbon atoms, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl and (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) An alkyl group, a carboxyl group,
-C6-C14aryl radical, C6-C14Heteroaryl, (C)6-C14) Heteroaryl (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl and (C)6-C14) Aryloxy radical (C)1-C6) An alkyl group, a carboxyl group,
A. b, C and D are = CH-groups, one or both of which may also be nitrogen atoms,
R4、R5and R6Independently of one another, selected from:
-a hydrogen atom,
-C1-C8alkyl, (C)3-C8) Cycloalkyl (C)1-C6) Alkyl radical, C1-C8Alkoxy group, (C)3-C8) Cycloalkoxy (C)1-C6) Alkyl, (C)3-C8) Cycloalkoxy, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy group, (C)3-C8) Cycloalkyl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)1-C6) Alkoxy (C)1-C6) Alkyl radical, C6-C14Aryl group, (C)6-C14) Aryl radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkyl radical (C)6-C14) Aryl group, (C)6-C14) Aryloxy group, (C)6-C14) Aryloxy radical (C)1-C6) Alkyl, (C)6-C14) Aryl radical (C)1-C6) Alkoxy group, (C)6-C14) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, halogen, trifluoromethyl, trifluoromethoxy, cyano, carboxy, hydroxy, nitro, amino, (C)1-C6) Alkoxycarbonyl, carbamoyl, (C)1-C6) Alkylthio group, (C)1-C8) Alkylsulfinyl (C)1-C8) Alkylsulfonyl, sulfonamido, (C)1-C8) Alkylsulfonylamino, sulfamoyl and (C)1-C8) Alkylcarbonylamino, two of these radicals may form methylenedioxy or a phenyl ring fused to the ring to which they are attached,
each aryl group may itself be substituted with 1 to 3 substituents selected from: c1-C8Alkyl radical, C1-C8Alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxy, nitro, and amino.
2. A compound according to claim 1, wherein the essential part of the ring systemIs a phenyl ring.
3. The compound of claim 2, wherein R4、R5And R6At least one of which is C1-C8Alkoxy, or two of these groups form methylenedioxy.
4. A process for preparing a compound of claim 1 comprising reacting an arylamine of formula (II)
A, B, C, D, R therein1、R4、R5And R6Is as defined above, and R7Selected from the group consisting of hydrogen atoms,
C1-C6An alkyl group and a benzyl group,
with halogen halides of the formula (III)
Wherein R is2And R3Hal is selected from chlorine and bromine, as defined above,
to produce a compound of formula (iv):
a, B, C, D, R therein1、R2、R3、R4、R5、R6、R7And Hal is defined as above,
and reacting a compound of formula (IV) with a compound of formula (V) in the presence of a basic reagent:
wherein Ar is as defined above, and wherein,
to produce a compound of formula (VI):
wherein Ar, A, B, C, D, R1、R2、R3、R4、R5、R6And R7The definition is the same as that of the above,
and when R is7When alkyl, hydrolyzing the compound to produce a compound of formula (I),
and when R is7When benzyl, the compound is hydrogenolysed to yield the compound of formula (I).
5. A pharmaceutical composition comprising an effective amount of a compound of claim 1.
6. A pharmaceutical composition comprising an effective amount of a compound of claim 2.
7. A pharmaceutical composition comprising an effective amount of a compound of claim 3.
8. A method of treating diabetes comprising administering to a human in need thereof an effective amount of a compound of claim 1.
9. A method of treating diabetes comprising administering to a human in need thereof an effective amount of a compound of claim 2.
10. A method of treating diabetes comprising administering to a human in need thereof an effective amount of a compound of claim 3.
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1036626A true HK1036626A (en) | 2002-01-11 |
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