WO1999064407A1 - α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS - Google Patents

α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS Download PDF

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Publication number
WO1999064407A1
WO1999064407A1 PCT/EP1998/003431 EP9803431W WO9964407A1 WO 1999064407 A1 WO1999064407 A1 WO 1999064407A1 EP 9803431 W EP9803431 W EP 9803431W WO 9964407 A1 WO9964407 A1 WO 9964407A1
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Prior art keywords
alkyl
aryl
compound
alkoxy
formula
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PCT/EP1998/003431
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French (fr)
Inventor
Gérard Moinet
Gérard Botton
Gérard Patereau
Liliane Doare
Micheline Kergoat
Didier Mesangeau
Donald D. Bierer
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Merck Patent Gmbh
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Priority to FR9705849A priority Critical patent/FR2763334A1/en
Priority to EP98939495A priority patent/EP1091947A1/en
Priority to AU87989/98A priority patent/AU748712B2/en
Priority to PL98344006A priority patent/PL344006A1/en
Priority to CA002334558A priority patent/CA2334558A1/en
Priority to BR9816021-4A priority patent/BR9816021A/en
Priority to HU0102006A priority patent/HUP0102006A3/en
Priority to CN98814107A priority patent/CN1119338C/en
Application filed by Merck Patent Gmbh filed Critical Merck Patent Gmbh
Priority to KR1020007013900A priority patent/KR20010052662A/en
Priority to PCT/EP1998/003431 priority patent/WO1999064407A1/en
Priority to SK1859-2000A priority patent/SK18592000A3/en
Priority to JP2000553416A priority patent/JP2002517489A/en
Priority to RU2001101171/04A priority patent/RU2198881C2/en
Priority to UA2001010132A priority patent/UA56324C2/en
Publication of WO1999064407A1 publication Critical patent/WO1999064407A1/en
Priority to NO20006214A priority patent/NO20006214L/en

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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

Definitions

  • the present invention relates to new ⁇ -(1-piperazinyl)acetamido arenecarboxylic acid derivatives which are useful in the treatment of diabetes.
  • Ar is selected from
  • - a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms, - a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from a C ⁇ -C 8 alkyl, (C 3 -C 8 )cycloalkyl(C ⁇ -C 6 )alkyl, d-C 8 alkoxy, (C 3 - C 8 )cycloalkyloxy(C 1 -C 6 )alkyl, (C3-C 8 )cycloalkyl(C ⁇ -C 6 )alkoxy(C ⁇ -C 6 )alkyl, (
  • R 4 , R 5 and R 6 are selected, independently of one another, from
  • the C ⁇ -C 8 alkyl groups can be linear or branched Mention may be ⁇ made, as examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and pentyl groups
  • the C ⁇ -C 8 alkoxy groups can likewise be linear or branched Mention may be made, as examples, of the methoxy ethoxy, propoxy isopropoxy, butoxy and isobutoxy groups 0
  • the halogens can be selected from fluorine, chlorine, bromine and iodine
  • heteroaryl groups in the definition of R ⁇ R 2 and R 3 may be defined in particular as defined for the heteroaromatic groups in the definition of Ar
  • the invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I)
  • the compounds of general formula (I) possess a carboxylic acid functional group and can be sa fied, then existing in the form of salts with bases o Examples of salts with bases of the compounds of general formula
  • (I) include the pharmacologically acceptable salts, such as the sodium salts potassium salts, calcium salts and other salts of the same type
  • the compounds of general formula (I) can also be sahfied with amines in order to form pharmaceutically acceptable salts
  • the compounds of general formula (I) could be sahfied with glucamine, N- methylglucamine, N,N-d ⁇ methylglucam ⁇ ne, ethanolamme, morpholine N-methylmorpholine or lysine
  • the compounds of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids )
  • salts with acids of the compounds of general formula (I) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochlonde, the hydrobromide, the sulphate, the succmate, maleate, fumarate malate or tartrate and the sulphonates, such as the methanesulphonate, the be ⁇ zenesulphonate or the toluenesulphonate.
  • the invention also relates to a process for the preparation of the compounds of general formula (I).
  • a preparation process according to the invention comprises the reaction of an aromatic amine of general formula (II):
  • R 7 is a hydrogen atom, a d-C 6 alkyl group or a benzyl group, with a haloacyl halide of general formula (III):
  • Hal represents a chlorine or bromine atom, in order to form a compound of general formula (IV):
  • R 7 is an alkyl group
  • the compound of general formula (VI) can be hydrolysed by conventional acidic or basic means in order to give the compound of general formula (I)
  • the compound of general formula (VI) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (I)
  • the compounds of formula (V) can be prepared as described by R Ratouis et al (J Med Chem , 8, 104, 1965) or by Prelog et al (Collection 0 Czechoslov Chem Communications, 6, 211 , 1934)
  • the compound (VI), in which R 7 is an alkyl group can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide
  • a basic agent such as dilute sodium hydroxide
  • the enantiomers of the compounds of formula (I) can be separated by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol and then displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method
  • the compounds according to the present invention can be used in the treatment of diabetes, in particular of non-insu n-dependent diabetes, because of their hypoglycaemic effect and of their absence of toxicity at the active doses
  • Another subject of the present invention is thus pharmaceutical compositions comprising an effective amount of a compound according to the invention
  • compositions according to the invention can be presented in forms intended for parenteral, oral rectal, permucosal or 5 percutaneous administration
  • excipients which are suitable for such administrations are derivatives of cellulose or microcrystalhne cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms Cocoa butter or polyethylene glycol stearates are the preferred excipients for rectal use
  • the dosage can vary within wide limits depending on the o therapeutic indication and the administration route, as well as the age and weight of the patient.
  • the following examples illustrate the preparation of the compounds of formula (I) and of the intermediates of formulae (II) and (IV).
  • the apparatus is placed under a hydrogen atmosphere and agitated at room temperature for 3 hours.
  • the anti-diabetic activity of the compounds of formula (I) by the oral route was determined with respect to an experimental model of non-insu n- dependent diabetes induced in the rat by streptozotocm
  • the non-insulm-dependent diabetes model is obtained in the rat by a neonatal (the day of birth) injection of streptozotocm
  • the diabetic rats used are 8 weeks old The animals are kept, from the day of their birth to the day of the experiment, in an animal house at a temperature regulated from 21 to 22°C and subject to a fixed cycle of light (from 7 h to 19 h) and of darkness (from 19 h to 7 h)
  • Their feeding consisted of a maintenance diet, water and food was supplied "ad libitum", except for fasting for 2 hours before the test when the food is withdrawn (post-absorptive state)
  • the rats are treated orally during the day with the test product Two hours after the final administration of the product and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal ), a 300 ⁇ l blood sample is taken from the end of the tail

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention relates to compounds of general formula (I). These compounds are useful in the treatment of diabetes.

Description

α-(l-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABEΗC AGENTS
The present invention relates to new α-(1-piperazinyl)acetamido arenecarboxylic acid derivatives which are useful in the treatment of diabetes.
The subject of the present invention is thus compounds of general formula (I):
Figure imgf000003_0001
in which:
Ar is selected from
- a mono-, bi- or tricyclic aryl group having from 6 to 14 carbon atoms, - a heteroaromatic group selected from the pyridyl, pyrimidinyl, pyrrolyl, furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, benzopyranyl, benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from a Cι-C8 alkyl, (C3-C8)cycloalkyl(Cι-C6)alkyl, d-C8 alkoxy, (C3- C8)cycloalkyloxy(C1-C6)alkyl, (C3-C8)cycloalkyl(Cι-C6)alkoxy(Cι-C6)alkyl, (C3- C8)cycloalkyloxy, (C3-C8)cycloalkyl(C1C6)alkoxy, (Cι-C6)alkoxy(C1-C6)alkyl, C6-C14 aryl, C6-d4 heteroaryl, (C6-Ci4)heteroaryl(C1-C6)alkyl, (C6-C14)aryl(C1-C6)alkyl, (C6-Cι4)aryl(Cι-C6)alkyl(C6-Cι4)aryl, (C6-C14)aryloxy, (C6-C14)aryloxy(C1-C6)alkyl, (C6-C14)aryl(C1-C6)aikyloxy or (C6-C14)aryl(Cι-C6)alkyloxy(Cι-C6)alkyl group, a halogen, a trifluoromethyl, trifluoromethoxy, cyano, hydroxyl, nitro, amino, carboxyl, (Cι-C6)alkoxycarbonyl, carbamoyl, (C1-C8)alkylthio, (C1- C8)alkylsulphinyl, (C1-C8)alkylsulphonyl, sulphoamino, (d-
SUBSTΠTJTE SHEET (Rule 26) C8)alkylsulphonylamιno, sulphamoyl or (Cι-C8)alkylcarbonylamιno group or two of these substituents forming a methylenedioxy group, the 4-carboxyphenyl and substituted 4-carboxyphenyl groups being excluded from the definition of Ar, Ri, R2 and R3 are selected, independently of one another, from
- a hydrogen atom,
- a Ci-Cs alkyl or (Cι-C6)alkoxy(Cι-C8)alkyl group,
- a cycloalkyl group containing from 3 to 8 carbon atoms a (C3- C8)cycloalkyl(Cι-C6)alkyl group or a (C3-C8)cycloalkyloxy(C1-C6)alkyl or (C3- o C8)cycloalkyl(Cι-C6)alkoxy(Cι-C6)alkyl group,
- a C6-C1 aryl, C6-Cι4 heteroaryl, (C6-Cι4)heteroaryl(Cι-C6)alkyl (C6-d4)aryl(d-C6)alkyl, (C6-Cι4)aryl(Cι-C6)alkyl(C6-d4)aryl, (C6-C14)aryl(Cι-C6)- alkoxy(d-C6)alkyl or (C6-Cι4)aryloxy(d-C6)alkyl group,
A, B, C and D are =CH- groups, it being possible for one or two of 5 them also to be a nitrogen atom,
R4, R5 and R6 are selected, independently of one another, from
- a hydrogen atom,
- a Cι-C8 alkyl, (C3-C8)cycloalkyl(Cι-C6)alkyl, d-C8 alkoxy, (C3- Cs)cycloalkyioxy(d-C8)alkyl, (C3-C8)cycloalkyloxy, (C3-C8)cycloalkyl(d- o C6)alkoxy (C3-C8)cycloalkyl(Cι-C6)alkoxy(d-C6)alkyl, (d-C6)alkoxy(d-C6)alkyl, C6-C14 aryl (C6-Cι4)aryl(d-C6)alkyl (C6-C14)aryl(d-C6)alkyl(C6-C14)aryl, (C6- Cι4)aryloxy, (C6-Cι )aryloxy(d-C6)alkyl, (C6-Ci4)aryl(d-C6)alkoxy or (C6- Cι4)aryl(Cι-C6)alkyloxy(C1-C6)alkyl group, a halogen or a trifluoromethyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, ammo, (d-C6)alkoxycarbonyl,
25 carbamoyl, (Cι-C6)alkylthιo, (d-C8)alkylsulphιnyl, (d-C8)alkylsulphonyl, sulphoammo, (Cι-C8)alkylsulphonylamιno, sulphamoyl or (Ci-
C8)alkylcarbonylamιno group, it being possible for two of these groups to form a methylenedioxy group or a phenyl ring condensed with the ring to which they are attached
"><> it being possible for the various aryl groups to be themselves substituted by 1 to 3 substituents selected from a d-C8 alkyl or d-C8 alkoxy group, a halogen or a trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and ammo group, their solvates and their pharmaceutically acceptable salts
Mention may be made, as an example of the aryl group, of the phenyl, α-naphthyl, β-naphthyl and fluorenyl groups
The Cι-C8 alkyl groups can be linear or branched Mention may be ^ made, as examples, of the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert- butyl and pentyl groups
The Cι-C8 alkoxy groups can likewise be linear or branched Mention may be made, as examples, of the methoxy ethoxy, propoxy isopropoxy, butoxy and isobutoxy groups 0 The halogens can be selected from fluorine, chlorine, bromine and iodine
The heteroaryl groups in the definition of R^ R2 and R3 may be defined in particular as defined for the heteroaromatic groups in the definition of Ar The invention also relates to the tautomeric forms and to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I)
The compounds of general formula (I) possess a carboxylic acid functional group and can be sa fied, then existing in the form of salts with bases o Examples of salts with bases of the compounds of general formula
(I) include the pharmacologically acceptable salts, such as the sodium salts potassium salts, calcium salts and other salts of the same type
The compounds of general formula (I) can also be sahfied with amines in order to form pharmaceutically acceptable salts By way of example 2^ the compounds of general formula (I) could be sahfied with glucamine, N- methylglucamine, N,N-dιmethylglucamιne, ethanolamme, morpholine N-methylmorpholine or lysine
The compounds of general formula (I) possess basic nitrogen atoms and can be monosalified or disalified with inorganic or organic acids ) Examples of salts with acids of the compounds of general formula (I) include the pharmaceutically acceptable salts, such as, and non-exhaustively, the hydrochlonde, the hydrobromide, the sulphate, the succmate, maleate, fumarate malate or tartrate and the sulphonates, such as the methanesulphonate, the beπzenesulphonate or the toluenesulphonate.
The invention also relates to a process for the preparation of the compounds of general formula (I). A preparation process according to the invention comprises the reaction of an aromatic amine of general formula (II):
Figure imgf000006_0001
in which A, B, C, D, R^ R4, R5 and R6 are as defined above and R7 is a hydrogen atom, a d-C6 alkyl group or a benzyl group, with a haloacyl halide of general formula (III):
Figure imgf000006_0002
in which R2 and R3 are as defined above, Hal represents a chlorine or bromine atom, in order to form a compound of general formula (IV):
Figure imgf000006_0003
in which A, B, C, D, R,, R2, R3, R4, R5, Re, R7 and Hal are as defined above, and the reaction of the compound of general formula (IV) with a compound of general formula (V):
Figure imgf000007_0001
in which Ar is as defined above, in the presence of a basic agent, such as tnethylamine, in order to form the compound of general formula (VI)
Figure imgf000007_0002
in which Ar, A, B, C, D, R1 : R2, R3, R4, R5, R6 and R- are as defined above
In the case where R7 is an alkyl group, the compound of general formula (VI) can be hydrolysed by conventional acidic or basic means in order to give the compound of general formula (I)
In the case where R7 is a benzyl group, the compound of general formula (VI) can be hydrogenolysed in the presence of a catalyst, such as palladium-on-charcoal, in order to give the compound of general formula (I)
The compounds of formulae (II) and (V) are known compounds or ^ can be prepared according to known processes
Thus, compounds of formula (II) are described in Organic Preparation and Procedures International, 13, 189, 1981
The compounds of formula (V) can be prepared as described by R Ratouis et al (J Med Chem , 8, 104, 1965) or by Prelog et al (Collection 0 Czechoslov Chem Communications, 6, 211 , 1934)
By way of example, the compound (VI), in which R7 is an alkyl group, can by hydrolysed in the presence of a basic agent, such as dilute sodium hydroxide The enantiomers of the compounds of formula (I) can be separated by successive recrystallization of the salt of the acid (I) with an optically active base in solvents such as acetone, ethyl acetate or isopropanol and then displacement from the salt into an optically active acid by an inorganic or organic acid, according to a conventional method
The compounds according to the present invention can be used in the treatment of diabetes, in particular of non-insu n-dependent diabetes, because of their hypoglycaemic effect and of their absence of toxicity at the active doses Another subject of the present invention is thus pharmaceutical compositions comprising an effective amount of a compound according to the invention
The pharmaceutical compositions according to the invention can be presented in forms intended for parenteral, oral rectal, permucosal or 5 percutaneous administration
They will thus be presented in the form of injectable solutions or suspensions, or multi-dose containers, in the form of uncoated or coated tablets, of sugar-coated tablets, of capsules, including hard gelatin capsules, of pills, of cachets, of powders, of suppositories or of rectal capsules, of solutions or of o suspensions, for percutaneous use in a polar solvent or for permucosal use
The excipients which are suitable for such administrations are derivatives of cellulose or microcrystalhne cellulose, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches or lactose for the solid forms Cocoa butter or polyethylene glycol stearates are the preferred excipients for rectal use
Water, aqueous solutions, physiological solution or isotonic solutions are the most conveniently used vehicles for parenteral use
The dosage can vary within wide limits depending on the o therapeutic indication and the administration route, as well as the age and weight of the patient The following examples illustrate the preparation of the compounds of formula (I) and of the intermediates of formulae (II) and (IV).
A - Example of the preparation of a compound of formula (II). Preparation of methyl 2-cvclohexylmethylamino-5-methoxybenzoate
17.6 g of methyl 5-methoxyanthranilate, 11.8 ml of cyclohexanecarboxaldehyde and 2 g of 10% palladium-on-charcoal (50% water) are charged to 200 ml of methanol in a 1 litre hydrogenation apparatus.
The apparatus is placed under a hydrogen atmosphere and agitated at room temperature for 3 hours.
300 ml of dichloromethane are added, the palladium-on-charcoal is separated off by filtration and the filtrate obtained is concentrated under vacuum. The oil obtained crystallizes from an ethanol (200 ml) and water (50 ml) mixture to give 25.4 g of a yellow solid which melts at 58-60°C. 5 IR: (KBr) 1683 cm"1 (C=O), 1528 cm"1 (C=O)
1H NMR: (CDCI3, 200 MHz) δ ppm: 1.06-1.64 (11 H, m, cyclohexyl), 2.93 (2H, t, CH2), 3.68 (3H, s, OCH3), 3.78 (3H, s, OCH3), 6.56 (1 H, d, phenyl proton), 6.96 (1 H, dd, phenyl proton), 7.34 (2H, d + s, phenyl proton + NH).
The formulae and characteristics of the compounds of formula (II) o have been combined in Table I.
TABLE
Figure imgf000010_0001
B - Example of the preparation of a compound of formula (IV). Preparation of 4-chloro-2-(chloroacetamido)benzoic acid
25 5 ml of chloroacetyl chloride are added dropwise with stirring to 50 g of 2-amιno-4-chlorobenzoιc acid in 600 ml of dioxane, the reaction mixture being maintained at 20°C
Stirring is then maintained for 2 hours at room temperature and then 1200 ml of water are added The desired product precipitates, the mixture is stirred for one hour and then filtered and the solid obtained is washed with water After drying, 60 7 g of 4-chloro-2-(chloroacetamιdo)benzoιc acid are obtained, the melting point of which is 194-196°C
IR 1676 cm"1 (C=0)
1H NMR (dβ-DMSO, 200 MHz) δ ppm 4 30 (2H, s, CH2), 7 1 (1 H d phenyl proton), 7 7 (1 H, d, phenyl proton), 8 5 (1 H, s, phenyl proton), 1 1 75 (1 H s, NH), 13 90 (1 H, broad s, COOH)
The formulae and characteristics of the compounds of formula (IV) have been combined in Table II
TABLE II
Figure imgf000011_0001
TABLE II (continuation)
Figure imgf000012_0001
TABLE II continuation
Figure imgf000013_0001
C - Example of the preparation of a compound of formula (II)
Preparation of 4-chloro-2-(r4-(2-methoxyphenyl)-1 -piperazinvπacetamido) benzoic acid
15 g of 4-chloro-2-(chloroacetamιdo)benzoιc acid are added, with stirring and at room temperature, to 11 6 g of 1 -(2-methoxyphenyl)pιperazιne and 17 ml of tnethylamine in 120 ml of DMF
The reaction mixture is kept stirring for 48 hours at room temperature and then 500 ml of water are added Extraction is carried out with 3 * 300 ml of dichloromethane The solvent is evaporated under vacuum and the solid thus obtained is taken up again in 300 ml of a 2N aqueous sodium hydroxide solution The solution is washed with 3 x 200 ml of diethyl ether and the aqueous phase is then acidified with acetic acid
A solid crystallizes to give, after filtration, 22 5 g of crude product After recrystallization from dioxane, 21 1 g of 4-chloro-2-{[4-(2-methoxyphenyl)- 1 -pιperazιnyl]acetamιdo}benzoιc acid are obtained in the form of a white solid which melts at 218-220°C
IR 1699 cm"1 (C=O), 1673 cm"1 (C=O)
1 H NMR (CF3COOD), δ ppm 4 25 (3H, s, OCH3), 4 65 (8H, broad * s, 4 CH2), 4 95 (2H, s, CH2), 7 5 (2H, m, phenyl protons), 7 6 (1 H, d, phenyl proton), 7 90 (2H, m, phenyl protons), 8 50 (1 H, d, phenyl proton), 8 75 (1 H, s, phenyl proton)
D - Alternative form of the preparation of a compound of formula (I) 0 Preparation of 2-{r4-(4-fluorophenyl)-1 -piperazinvn- acetamido)-4,5-(methylenedioxy)benzoic acid
1 5 g of 2-(chloroacetamιdo)-4,5-(methylenedιoxy)benzoιc acid are added with stirring and at room temperature, to 1 0 5 g of 1 -(4- fluorophenyl)pιperazιne and 16 2 ml of tnethylamine in 150 ml of DMF ^ The reaction mixture is kept stirring for 48 hours at room temperature
3 5 ml of acetic acid are added and 150 ml of water are slowly added The acid crystallizes and is diluted with 300 ml of water The mixture is stirred for 30 minutes and filtered and the solid obtained is washed with water 0 After recrystallization from a dioxane/DMF mixture, 14 9 g of 2-{[4-
(4-fluorophenyl)-1 -pιperazιnyl]acetamιdo}-4,5-(methylenedιoxy)benzoιc acid are obtained, which product melts at 254-256°C
IR (KBr) 1654 cm"1 (C=O)
1 H NMR (CF3COOD, 200 MHz) δ ppm 4 40 (8H, s, piperazmyl) ^ 4 67 (2H s, CH2), 6 05 (2H, s, O-CH2-O), 7 30 (2H, t, phenyl proton), 7 65 (3H m phenyl proton), 7 90 (1 H, s, phenyl proton)
The formulae and characteristics of compounds of formula (I) have been combined in Table III TABLE III
Figure imgf000015_0001
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
">->
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Results of the pharmacological studies will be given herembelow
Study of the anti-diabetic activity in the NOSTZ rat
The anti-diabetic activity of the compounds of formula (I) by the oral route was determined with respect to an experimental model of non-insu n- dependent diabetes induced in the rat by streptozotocm
The non-insulm-dependent diabetes model is obtained in the rat by a neonatal (the day of birth) injection of streptozotocm
The diabetic rats used are 8 weeks old The animals are kept, from the day of their birth to the day of the experiment, in an animal house at a temperature regulated from 21 to 22°C and subject to a fixed cycle of light (from 7 h to 19 h) and of darkness (from 19 h to 7 h) Their feeding consisted of a maintenance diet, water and food was supplied "ad libitum", except for fasting for 2 hours before the test when the food is withdrawn (post-absorptive state) The rats are treated orally during the day with the test product Two hours after the final administration of the product and 30 minutes after anaesthetizing the animals with sodium pentobarbital (Nembutal ), a 300 μl blood sample is taken from the end of the tail
The mam results obtained are combined in Table IV These results show the effectiveness of the compounds of formula (I) in decreasing glycaemia in the diabetic animals
These results are expressed as percentage of change in glycaemia at D4 (4 days of treatment) in comparison with DO (before treatment)
TABLE IV
Figure imgf000032_0001

Claims

A compound selected from the compounds of the formula (I)
Figure imgf000033_0001
^ in which
Ar is selected from
- mono-, bi- or tricyc c aryl having from 6 to 14 carbon atoms,
- a heteroaromatic group selected from the pyridyl, pyrimidinyl pyrrolyl furyl, thienyl, quinolyl, indolyl, benzothienyl, benzofuryl, beπzopyranyl o benzothiopyranyl, dibenzofuryl, carbazolyl and benzothiazinyl groups, it being possible for the Ar group to carry 1 to 3 substituents selected from d-C8 alkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, Cι-C8 alkoxy, (C3- C8)cycloalkyloxy(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkoxy(C1-Ce)alkyl, (C3- C8)cycloalkyloxy, (C3-C8)cycloalkyl(Cι-C6)alkoxy, (CrC6)alkoxy(Cι-C6)alkyl C6- ι C14 aryl, C6-Cι4 heteroaryl, (C6-C14)heteroaryl(Cι-C6)alkyl, (C6-Cι4)aryl(Cι- C6)alkyl (C6-C14)aryl(C1-C6)alkyl(C6-Cι4)aryl, (C6-Cι4)aryloxy, (C6-Cι4)aryloxy(C1- C6)alkyl (C6-C14)aryl(C1-C6)alkyloxy, (C6-C14)aryl(C1-C6)alkyloxy(C1-C6)alkyl halogen, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, nitro, ammo, carboxy (C1-C6)alkoxycarbonyl, carbamoyl, (C1-C6)alkylthιo, (Cι-C8)alkylsulphιnyl (Ci-
2o C8)alkylsulphonyl, sulphoammo, (C-╬╣-C8)alkyisulphonylam╬╣no, sulphamoyl and (C1-C8)alkylcarbonylam╬╣no, or two of these substituents forming methylenedioxy,
4-carboxyphenyl and substituted 4-carboxyphenyl being excluded from the definition of Ar,
R╬╣, R2 and R3 are selected, independently of one another, from
2 - hydrogen,
- Ci-C8 alkyl, (C╬╣-C6)alkoxy(C1-C6)alkyl group, - cycloalkyl containing from 3 to 8 carbon atoms, (C3- C8)cycloalkyl(Ci-C6)alkyl,(C3-C8)cycloalkyloxy- (C╬╣-C6)alkyl and (C3- C8)cycloalkyl(C╬╣-C6)alkoxy(C1-C6)- alkyl,
- C6-C╬╣4 aryl, C6-C╬╣4 heteroaryl, (C6-C╬╣4)heteroaryl(C╬╣-C6)alkyl, (C6- C14)aryl(C╬╣-C6)alkyl, (C6-Cl4)aryl(C1-C6)alkyl(C6-C14)aryl, (C6-C╬╣4)aryl(C╬╣-C6)- alkoxy(C╬╣-C6)alkyl and (C6-C14)aryloxy(C╬╣-C6)alkyl,
A, B, C and D are =CH- groups, it being possible for one or two of them also to be a nitrogen atom,
R4, R5 and R6 are selected, independently of one another, from: - hydrogen,
- C╬╣-C8 alkyl, (Cs-C^cycloalkyKd-C^alkyl, d-C8 alkoxy, (C3- C8)cycloalkyloxy(C╬╣-C6)alkyl, (C3-C8)cycloalkyloxy, (C3-C╬┤)cycloalkyl(d-
C6)alkoxy, (C3-C8)cycloalkyl(C1-C6)alkoxy(C╬╣-C6)alkyl, (C╬╣-C6)alkoxy(C1-C6)alkyl, C6-C14 aryl, (C6-C╬╣4)aryl(C1-C6)alkyl, (C6-C14)aryl(C1-C6)alkyl(C6-C14)aryl, (C6- C14)aryloxy, (C6-C╬╣4)aryloxy(C╬╣-C6)alkyl, (C6-C14)aryl(C╬╣-C6)alkoxy, (C6- C1 )aryl(C╬╣-C6)alkyloxy(C╬╣-C6)alkyl, halogen, trifluoro- methyl, trifluoromethoxy, cyano, carboxyl, hydroxyl, nitro, amino, (C╬╣-C6)alkoxycarbonyl, carbamoyl, (Ci- C6)alkylthio, (C╬╣-C8)alkylsulphinyl, (C1-C8)alkylsulphonyl, sulphoamino, (Ci- C8)alkylsulphonylamino, sulphamoyl and (C╬╣-C8)alkylcarbonylam╬╣no, it being possible for two of these groups to form methylenedioxy or phenyl ring condensed with the ring to which they are attached, it being possible for the various aryl groups to be themselves substituted by 1 to 3 sub'stituents selected from d-C8 alkyl, C╬╣-C8 alkoxy, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, nitro and amino, their solvates and their pharmaceutically acceptable salts
2. A compound as claimed in Claim 1 , in which the base component of the ring system
Figure imgf000035_0001
is a phenyl ring
3 A compound as claimed in Claim 2, in which at least one of the R4 R5 and R6 groups is C╬╣-C8 alkoxy or two of these groups form methylenedioxy
4 A process for the preparation of a compound according to Claim 1 comprising the reaction of an aromatic amine of the formula (II)
Figure imgf000035_0002
in which A, B, C, D, Ri, R , R5 and R6 are as defined above and R7 is selected from hydrogen, d-C6 alkyl and benzyl, with a haloacyl ha de of the formula
Figure imgf000035_0003
in which R2 and R3 are as defined above, Hal is selected from chlorine and bromine in order to form a compound of the formula (IV)
Figure imgf000035_0004
in which A. B, C, D, Ri, R2, R3, R4, R5, Re, R? and Hal are as defined above, and the reaction of the compound of the formula (IV) with a compound of the formula (V)
Figure imgf000036_0001
in which Ar is as defined above, in the presence of a basic agent, in order to form the compound of the formula (VI)
Figure imgf000036_0002
in which Ar, A, B, C, D, R1 t R2, R3, R4, R5, R8 and R7 are as defined above, and, in the case where R7 is alkyl, the hydrolysis of this compound in order to form a compound of formula (I), and, in the case where R7 is benzyl, the hydrogenolysis of this compound in order to form a compound of formula (I) 5 A pharmaceutical composition comprising an effective amount of a compound as claimed in Claim 1
6 A pharmaceutical composition comprising an effective amount of a compound as claimed in Claim 2
7 A pharmaceutical composition comprising an effective amount of a compound as claimed in Claim 3
8 A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 1 9 A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 2.
10 A method for the treatment of diabetes which comprises administering to a human in need thereof an effective amount of a compound as claimed in Claim 3.
PCT/EP1998/003431 1997-05-13 1998-06-08 α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS WO1999064407A1 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
FR9705849A FR2763334A1 (en) 1997-05-13 1997-05-13 Piperazino alkyl anthranilic acid amide
CN98814107A CN1119338C (en) 1997-05-13 1998-06-08 & alpha, -(1-piperazinyl) ocetamido arenecarboxylic acid derivatives as antidiabetic agents
PL98344006A PL344006A1 (en) 1998-06-08 1998-06-08 Α-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents
CA002334558A CA2334558A1 (en) 1998-06-08 1998-06-08 .alpha.-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents
KR1020007013900A KR20010052662A (en) 1998-06-08 1998-06-08 α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS
HU0102006A HUP0102006A3 (en) 1998-06-08 1998-06-08 Alpha-(1-piperazinyl)acetamido arenecarboxylic acid derivatives medicaments comprising them and their use
AU87989/98A AU748712B2 (en) 1998-06-08 1998-06-08 Alpha-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents
EP98939495A EP1091947A1 (en) 1998-06-08 1998-06-08 Alpha-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents
BR9816021-4A BR9816021A (en) 1997-05-13 1998-06-08 Alpha- (1-piperazinyl) acetamido arene carboxylic acid derivatives as antidiabetic agents
PCT/EP1998/003431 WO1999064407A1 (en) 1997-05-13 1998-06-08 α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS
SK1859-2000A SK18592000A3 (en) 1998-06-08 1998-06-08 Alpha-(1-piperazinyl)acetamido arenecarboxylic acid derivatives as antidiabetic agents
JP2000553416A JP2002517489A (en) 1998-06-08 1998-06-08 Α- (1-Piperazinyl) acetamide arene carboxylic acid derivatives as antidiabetic agents
RU2001101171/04A RU2198881C2 (en) 1998-06-08 1998-06-08 α-(1-PIPERAZINYL)-ACETAMIDO-DERIVATIVES OF ARENE CARBOXYLIC ACID, METHOD OF THEIR SYNTHESIS, PHARMACEUTICAL COMPOSITIONS, METHODS OF TREATMENT
UA2001010132A UA56324C2 (en) 1998-06-08 1998-08-06 DERIVATIVES OF a-(1-PIPERAZINYL)ACETAMIDOAREN CARBOXYLIC ACIDS, A PROCESS FOR PREPARING THEREOF AND A PHARMACEUTICAL COMPOSITION
NO20006214A NO20006214L (en) 1998-06-08 2000-12-07 <alpha> - (1-piperazinyl) acetamidoarenecarboxylic acid derivatives as antidiabetic agents

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PCT/EP1998/003431 WO1999064407A1 (en) 1997-05-13 1998-06-08 α-(1-PIPERAZINYL)ACETAMIDO ARENECARBOXYLIC ACID DERIVATIVES AS ANTIDIABETIC AGENTS

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WO2006085112A1 (en) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Anthranilic acid derivatives as hm74a receptor agonists
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WO2003053366A2 (en) * 2001-12-20 2003-07-03 Osi Pharmaceuticals, Inc. Pyrimidine a2b selective antagonist compounds, their synthesis and use
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CN100448869C (en) * 2002-11-27 2009-01-07 拜尔药品公司 Anilinopyrazole derivatives useful for the treatment of diabetes
WO2004050651A1 (en) * 2002-11-27 2004-06-17 Bayer Pharmaceuticals Corporation Anilinopyrazole derivatives useful for the treatment of diabetes
WO2004050650A1 (en) * 2002-11-27 2004-06-17 Bayer Pharmaceuticals Corporation Anilinopyrazole derivatives useful for the treatment of diabetes
US7265144B2 (en) 2002-11-27 2007-09-04 Bayer Pharmaceuticals Corporation Anilinopyrazole derivatives useful for the treatment of diabetes
WO2006085112A1 (en) * 2005-02-14 2006-08-17 Smithkline Beecham Corporation Anthranilic acid derivatives as hm74a receptor agonists
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
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