Indian Patents. 206594:((AMINOIMINOMETHYL) AMINO) ALKANECARBOXAMIDES AND THEIR APPLICATIONS IN THERAPY

Title of Invention	((AMINOIMINOMETHYL) AMINO) ALKANECARBOXAMIDES AND THEIR APPLICATIONS IN THERAPY
Abstract	This invention relates to a process for the preparation of compounds of general formula (1) comprising reacting a compound of formula ff with a compound of formula:

Full Text	( (Amonoiminomethyl)amino) alkanecarboxamides and their applications in therapy The present invention relates to the use of derivatives of the ({aminoiminomethl)amino} alkane-carboxamide type in the treatment of pathologies associated with insulin resistance syndrome. The present invention therefore provides pharmaceutical compositions comprising as active principle a compound of general formula (I) in which: R1 is selected from one of the following groups: - H; - (C1-C20) alkyi substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, .(C1-C5) alkyi, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl; R2 and R3 are selected independently from - H; - (C1-C5) cycloalkyl substituted cr unsubstituted by one or more of the following groups: aminc, hydroxyi, (C1-C5) alkyl, (C1-C5) aikoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl; - (C3-C8)heterocycloaikyl containing one or more heteroatoms' selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyi, (C1-C5) alkyi, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5)alkylamino, trif luoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) aikyl group; - (C6-C14)aryi substituted or unsubstituted by one or more of the following groups: - 2 - amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl, cyano; (C1-C13) heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstitutad by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C5-C5)alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted bv a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) alkyl group; (C6-C14 )aryl-(C1-C5) alkyl subsniruted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl, cyano; and.A is selected from the groups: -CH2-, -CH2-CH2-, -CHR4-, R4 being selected from: - H; - (C1-C20) alkyl substituted' or unsubstituted by one or more of the following groups: amino, hydroxyl, (Cl-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl; - (C3-C8)cycloalkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) aikylamino, trifluoromethyl; (C3-Ca) heterocycloalkyl containing one or more heteroatoms selected from N, 0 and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14) aryl, (C6-C14)acyl or (C1-C5) alkyl group; - 3 - and their solvates and pharmaceutically acceptable salts. The heteroaryl groups are selected in particular from pyridyl, pyrimidinyl, furyl, pyrrolyl, thienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl/ indolyl, benzofuryi and imidazolyl. The heterocycloalkyl groups are selected in particular from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl and tetrahydropyranyl. A preferred group of compounds of formula I is constituted in which R1 is H or (C1-C6) alkyl. A preferred group of compounds of formula I is constituted in which: R2 is selected from - (C3-C3) cycloalkyl substitued or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifiuoromethyl; - (C6-C14) aryl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C:-C5) alkylthio, (C1-C5) alkylamino, trif Iuoromethy, cyano; (C1-C13) heteroaryl containing one or more heceroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkyiamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) alkyl group. A particularly preferred group of compounds of formula I is constituted in which R2 is selected from a (C6-C14) aryl group possibly substituted as defined above. To the knowledge of the Applicant, the compounds of formula (I) are novel with the exception' - 4 - of a-guanidinoacetaniiide, which 13 described by Mazundar (Indian Drugs 1989, 27, 5, 292), i.e. the compound of formula I- in which R1 = H, R2 = phenyl and R3 = K. The invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I) . The compounds of general formula (I) have basic nitrogen atoms and can be monosalified or disalified by mineral or organic acids. The compounds of formula (I) can.be prepared by reacting a compound of formula: with a compound of formula: in which: R5 is selected from -SCH3, pyrazolyl or -SO3H, and T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group. The compounds of formula (II) can be prepared in accordance with a process in which: a) a compound of formula: in which R2 and R3 are as defined above is reacted with an acyl halide of general formula (VI) : in which: A is as defined above, L represents a chlorine or bromine atom or an activated ester form, Z represents a chlorine or bromine atom or a protected amino group, to form a compound of general formula (VII): in which R2, R3, A and Z are as defined above; b) the compound of general formula (VII) is reacted with potassium phthalimide and then with hydrazine monohydrate or else with a nitride followed by a reduction to form a compound of general formula (II) in which R1 = H. In the.case where Z is a protected amino group, it is appropriate to deprotect it at this stage to form a compound of general formula (II). The compounds of general formula (II) in which R1 is other than H can be obtained by reacting a compound of formula (VII) with an amine of general formula (VIII): R1NH2 (VIII). The compositions according to the present invention are useful in the treatment of pathologies associated with insulin resistance syndrome (syndrome X) . - 6 - Insulin resistance , is characterized by a reduction in the action of insulin (cf. Presse Medicale, 1997, 26 (No. 14), 671-677) and is involved in a large number of pathological states, such as diabetes and, more particularly, non-msulin-dependent diabetes (type II diabetes or NIDDM), dyslipidaemia, obesity, arterial hypertension, and certain microvascular and macrovascular complications such as atherosclerosis, retinopathies and neuropathies. In this context, reference may be made, for example, to Diabetes, Vol. 37, 1983, 1595-1507; Journal of Diabetes and its complications, 1998, 12, 110-119, or Horm. Res., 1992, 38, 28-32. In particular, the compositions of the invention exhibit a strong hypogiycaemic activity. The compositions according to the present invention can also be usec fcr treating the chronic complications due to the formation of "advanced glycosylation end products", written AGEs, which result from the glycoxidation reaction between glucose, its oxidation derivatives and the amino functions of proteins, including the so-called Maillard reactions of glycation of glyoxal for example. The pharmaceutical compositions according to the invention can be provided in forms which are intended for parenteral, oral, rectal, pemucous or percutaneous administration. They will therefore be provided in the form of solutions or suspensions fcr injection or multi-dose bottles, in the form of plain or coated tablets, film-coated tablets, wafer capsules, gelatin capsules, pills, cachets, powders, suppositories or rectal capsules, or solutions or suspensions for percutaneous use in a polar solvent or for permucous use. The excipients which are suitable for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starches, modified. starches, and lactose for the solid forms. - 7 - For rectal use, cocoa butter or polyethylene glycci stearates are the preferred excipients. For parenteral use, water, aqueous solutions, physiological saline and isotonic solutions are the vehicles used most judiciously. The dosage can vary within wide limits (from 0.5 mg to 1000 mg) depending on the therapeutic indication and the administration route, and also on the age and weight of the individual. The following examples illustrate the preparation of the compounds of formula (I) and of various intermediates. A - Preparation Example of compounds of formula (VII) Preparation of N-(2,6-dimethylphenyl)-3-chIoro-propanamide A 2 1 three-necked flask is charged with 121.8 g of 2, 6-dimethyianiline, 300 ml of isopropyl ether and 150 ml of water. 126.5 g of 3-chloropropanoyl chloride are added at a rate such that the internal temperature is between 5 and 10 °C. At the end of the addition, the reaction medium is stirred for 3 h. The precipitate formed is filtered off with suction, washed with isopropyl ether and then with water and finally dried. 126 g of white crystals are obtained. m.p, = 134-136°C lH NMR (DMSO-d6, 200 MHz): 2.18 (s,6H); 2.31 (t,2H); 3.38 (t,2H); 7.03 (d,3H); 9.40 (s,lH) The formulae and characteristics of compounds oof formula (VII) have been collated in Table 1. - 12 - B - Preparation Example of compounds of formula (II) Preparation of N-(2,6-dimethyiphenyI)-3-aminopropanamide A three-necked flask is charged with 400 ml of DMF, 100 g of N-(2,6-dimethylphenyl)-3-chloropropanamide and 95.7 g of potassium phthalimide. After 3 h of stirring at reflux, the reaction medium is cooled to room temperature and 600 mi of water are added. Stirring is continued for 1.5 h. The precipitate formed is filtered off with suction and washed with water. 140 g of white crystals (m.p. >260°C) are obtained. The crystals are charged to a three-necked flask with 800 mi of 95° ethanol and 23.7 g of hydrazine monohydrate..After 3 h of stirring at reflux, 39 ml of concentrated hydrochloric acid are added and stirring is continued for 1 h. The precipitate formed is filtered off, and washed with ethanol and the ethanolic phases are concentrated. The crude product obtained is taken up in water; the insoluble material remaining is filtered off and the aqueous phase is concentrated to give 108 g of a cream-white solid, m.p: = 239-241°C 1H NMR (DMSO-d6, 200 MHz): 2.22 (s,6H); 2.44 (t,2H); 2.8 8 (t,2H); 7.07 (s,3H); 9.50 (s,iH). The formulae and characteristics of compounds of formula (II) have been collated in Table 2. - 13 - - 14 - - 15 - - 16 -C - Preparation Example of compounds of formula (XI) Preparation of N- (2, 6-dimethylphenyl) -2-methyiamino- acetamide A closed stainless-steel reactor is charged with 80 g of N-(2,6-dimethyiphenyl)-2-chIoro-acetamide and 600 ml of a 40% aqueous methyiamine solution. The mixture is heated with stirring at 80°C for 4 h and then concentrated under vacuum. The crude product is taken up in water and washed with dichlorcmethane. The aqueous solution is basified using sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulphate are concentrated to give 60 g of a colourless oil. 1H NMR (DMSO-d6, 200 MHz): 2.15 (s,6H); 2.44 (s,3H); 3.50 (s,2H); 6.50 (S,1H); 7.70 (s,3H); 9.58 (s,iH) The formulae and characteristics of compounds have been collated in Table 3. Table 3 - 17 - D - Preparation Example of compounds of formula (I) Preparation of 2-aminoiminomethylamino-N- (cyclohexyl) - acetamide A round-bottomed flask is charged with 15 g of 2-amino-N-(cyclohexyl)-acetamide, 14,6 g 1-aminoiminomehtylpyrazole hydrochloride and 100 ml of dioxane. After 18 h stirring at reflux, the reaction medium is cooled to room temperature and precipitate which has formed is filtered off with suction. 16 g of a white solid are obtained. m.p. = 232-234°C lH NMR (DMSO-d6, 200 MHz): 1.19 (m, 5H) ; 1-62 (m,5H); 3.46 (m,1H); 3.78 (d,2H); 7.21 (s,4H); 7.68 The formulae and characteristics of compounds of formula (I) have been collated in Table 4. - 18 - - 19 - - 20 - - 21 - - 22 - The results of pharmacological studies will be given below. STUDY OF THE ANTIPIABETIC ACTIVITY IN THE NOSTZ RAT The antidiabetic activity of the compounds of formula (I) was determined orally on an experimental model of non-insulin-dependent diabetes induced in the rat using streptozotocin. The model of non-insulin-dependent diabetes is obtained in rats by neonatal injection (on the day of birth) of streptozotocin. 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 regulated temperature of from 21 to 22°C and are subjectec to a fixed cycle of light (from 7.00 am to 7.00 cm) and darkness (from 7.00 pm to 7.00 am) . Their diet consisted of a maintenance diet; water and food were provided ad libitum, except for the 2 hours' fasting prior to the tests in which food is withdrawn (post-absorptive state). The rats are treated orally for one (dl) or four (d4) days with the test product. Two hours after the final administration of the product and 30 minutes after anaesthesia of the animals with sodium pentobarbital (Nembutal®) , 300 ml of blood is sampled from the end of the tail. Results obtained are collated, by way of example, in Table 5. These results demonstrate the efficacy of the compounds of formula (I) in reducing giycaemia in diabetic animals. These results are expressed as a percentage change in giycaemia on dl and d4 (number of days of treatment) relative to dO (before treatment) . - 23 - - 24 -STUDY OF THE ANTXGLYCOXIDATION ACTIVITY The compounds (I} are also capab le of inhibiting the so-called Maillard reactions by means of a "scavenging", effect on a-dicarbonyl derivatives such as glyoxal- - this is the antiglycation effect. This inhibitory effect on the Maillard reaction by 'the compounds of formula (I) was studied in viczo by assaying the ketamines ("fructcamines") produced during the incubation of albumin with mechylgiycxal in the presence or absence of a compound of formula (I). A 6.6 mg/ml solution of bovine albumin in 0.2 M phosphate buffer pH 7.4 is incubated with 1 mM methyiglyoxal in the presence or absence of a compound according to the invention at a concentration of 1 mM. The incubation is carried out under sterile conditions at 37°C for 6 days. At the end of the incubation period, the amount of ketamines is measured with a commercially available fructoamine assay kit (kit "ERA", product reference: 0757055, Roche S.A. products) in " accordance with the manufacturer's instructions. Under these experimental conditions, the level of fructoamine ' following incubation of albumin with methyiglyoxal in the presence of a compound of formula (I) "is from 30 to 50% lower than that observed when albumin is incubated.with methyiglyoxal in the absence of 'the compound, of formula (I) . -25-WE CLAIM 1. A process for the preparation of compounds of general formula (1) in which: R1 is selected from one of the following groups: -H; - (C1-C20)alkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxyt (C1-C5)alkyithio, (C1-C5)alkylamino, trifluoromethyl; R2 is selected from - (C3-C8)cycloalkyl substrtued or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5) alkylthio, (C1-C5)alkylamino, trifluoromethyl; - (C6-C14)aryl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen", (C1-C5)alkyI, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano; - (C1-C13)heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14)acyl or (C1-C5)alkyl group; EP221100doc AMENDED SHEET -26- R3 is selected from -H; - (C3-C8)cycloalkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyi, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl; - (C3-C8)heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14) acyl or (C1-C5)alkyl group; - (C6-C14)aryl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5)aikyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano; - (C1-C13)heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy. (C1-C5)alkylthio, (C1-C5)alkyiamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14) acy! or (C6-C5)alkyl group; - (C6-C14)aryl-(C1C5)alkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano; and A is selected from the groups; -CH2-, EP221100doc AMENDED SHEET -27- -CH2-CH2-, -CHR4 -, R4 being selected from: -H; - (C1-C20)alkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl; - (C3-C8)cycloalkyl substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl; - (C3-C6)heterocycloalkyl containing one or more heteroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthto, (C1-C5)alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14)aryl (C6-C14) acyl or (C1-C5)alky! group; and solvates and pharmaceutically acceptable salts thereof, with the exception of the compound of formula (I) in which R1 = H, R2 = phenyiand R3= H , comprising reacting a compound of formula: in which- R5 is selected from -SCH3, pyrazoly! or -SO3H, and T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group. -28- 2. A process for the preparation of compounds of formula 1 as claimed in claim 1 in which R1 is selected from H and a (C1-C8) alkyl group. 3. A process for the preparation of compounds as claimed inclaim 1 in which R2is selected from a (C8-C14) aryl group possibly substituted as defined in claim 1. This invention relates to a process for the preparation of compounds of general formula (1) comprising reacting a compound of formula ff with a compound of formula:

Full Text

( (Amonoiminomethyl)amino) alkanecarboxamides and their applications in therapy
The present invention relates to the use of derivatives of the ({aminoiminomethl)amino} alkane-carboxamide type in the treatment of pathologies associated with insulin resistance syndrome.
The present invention therefore provides pharmaceutical compositions comprising as active principle a compound of general formula (I)

in which:
R1 is selected from one of the following groups:
- H;
- (C1-C20) alkyi substituted or unsubstituted by
one or more of the following groups:
amino, hydroxyl, .(C1-C5) alkyi, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl; R2 and R3 are selected independently from
- H;
- (C1-C5) cycloalkyl substituted cr unsubstituted
by one or more of the following groups:
aminc, hydroxyi, (C1-C5) alkyl, (C1-C5) aikoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl;
- (C3-C8)heterocycloaikyl containing one or more
heteroatoms' selected from N, O and S and substituted or
unsubstituted by one or more of the following groups:
amino, hydroxyi, (C1-C5) alkyi, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5)alkylamino, trif luoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) aikyl group;
- (C6-C14)aryi substituted or unsubstituted by
one or more of the following groups:

- 2 -
amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl, cyano;
(C1-C13) heteroaryl containing one or more heteroatoms selected from N, O and S and substituted or unsubstitutad by one or more of the following groups:
amino, hydroxyl, halogen, (C1-C5) alkyl, (C5-C5)alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl, cyano;
a nitrogen atom can additionally be substituted bv a (C6-C14)aryl, (C6-C14)acyl or (C1-C5) alkyl group;
(C6-C14 )aryl-(C1-C5) alkyl subsniruted or unsubstituted by one or more of the following groups:
amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl, cyano;
and.A is selected from the groups: -CH2-, -CH2-CH2-, -CHR4-, R4 being selected from:
- H;
- (C1-C20) alkyl substituted' or unsubstituted by
one or more of the following groups:
amino, hydroxyl, (Cl-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) aikylamino, trifluoromethyl;
- (C3-C8)cycloalkyl substituted or unsubstituted
by one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5)alkylthio, (C1-C5) aikylamino, trifluoromethyl;
(C3-Ca) heterocycloalkyl containing one or more heteroatoms selected from N, 0 and S and substituted or unsubstituted by one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifluoromethyl; a nitrogen atom can additionally be substituted by a (C6-C14) aryl, (C6-C14)acyl or (C1-C5) alkyl group;

- 3 -
and their solvates and pharmaceutically acceptable salts.
The heteroaryl groups are selected in particular from pyridyl, pyrimidinyl, furyl, pyrrolyl, thienyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl/ indolyl, benzofuryi and imidazolyl.
The heterocycloalkyl groups are selected in particular from piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydrothienyl, pyrrolidinyl and tetrahydropyranyl.
A preferred group of compounds of formula I is constituted in which R1 is H or (C1-C6) alkyl.
A preferred group of compounds of formula I is constituted in which:
R2 is selected from
- (C3-C3) cycloalkyl substitued or unsubstituted by
one or more of the following groups:
amino, hydroxyl, (C1-C5) alkyl, (C1-C5) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, trifiuoromethyl;
- (C6-C14) aryl substituted or unsubstituted by one
or more of the following groups:
amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C:-C5) alkylthio, (C1-C5) alkylamino, trif Iuoromethy, cyano;
(C1-C13) heteroaryl containing one or more heceroatoms selected from N, O and S and substituted or unsubstituted by one or more of the following groups: amino, hydroxyl, halogen, (C1-C5) alkyl, (C1-C5) alkoxy,
(C1-C5) alkylthio, (C1-C5) alkyiamino, trifluoromethyl,
cyano;
a nitrogen atom can additionally be substituted by a
(C6-C14)aryl, (C6-C14)acyl or (C1-C5) alkyl group.
A particularly preferred group of compounds of formula I is constituted in which R2 is selected from a (C6-C14) aryl group possibly substituted as defined above.
To the knowledge of the Applicant, the compounds of formula (I) are novel with the exception'

- 4 -
of a-guanidinoacetaniiide, which 13 described by Mazundar (Indian Drugs 1989, 27, 5, 292), i.e. the compound of formula I- in which R1 = H, R2 = phenyl and R3 = K.
The invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers and epimers of the compounds of general formula (I) .
The compounds of general formula (I) have basic nitrogen atoms and can be monosalified or disalified by mineral or organic acids.
The compounds of formula (I) can.be prepared by reacting a compound of formula:

with a compound of formula:

in which:
R5 is selected from -SCH3, pyrazolyl or -SO3H,
and
T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group.
The compounds of formula (II) can be prepared in accordance with a process in which:
a) a compound of formula:

in which R2 and R3 are as defined above is reacted with an acyl halide of general formula (VI) :

in which:
A is as defined above,
L represents a chlorine or bromine atom or an activated ester form,
Z represents a chlorine or bromine atom or a protected amino group, to form a compound of general formula (VII):

in which R2, R3, A and Z are as defined above;
b) the compound of general formula (VII) is reacted with potassium phthalimide and then with hydrazine monohydrate or else with a nitride followed by a reduction to form a compound of general formula (II) in which R1 = H.
In the.case where Z is a protected amino group, it is appropriate to deprotect it at this stage to form a compound of general formula (II).
The compounds of general formula (II) in which R1 is other than H can be obtained by reacting a compound of formula (VII) with an amine of general formula (VIII):
R1NH2 (VIII).
The compositions according to the present invention are useful in the treatment of pathologies associated with insulin resistance syndrome (syndrome X) .

- 6 -
Insulin resistance , is characterized by a
reduction in the action of insulin (cf. Presse
Medicale, 1997, 26 (No. 14), 671-677) and is involved
in a large number of pathological states, such as
diabetes and, more particularly, non-msulin-dependent
diabetes (type II diabetes or NIDDM), dyslipidaemia,
obesity, arterial hypertension, and certain
microvascular and macrovascular complications such as atherosclerosis, retinopathies and neuropathies.
In this context, reference may be made, for example, to Diabetes, Vol. 37, 1983, 1595-1507; Journal of Diabetes and its complications, 1998, 12, 110-119, or Horm. Res., 1992, 38, 28-32.
In particular, the compositions of the invention exhibit a strong hypogiycaemic activity.
The compositions according to the present invention can also be usec fcr treating the chronic complications due to the formation of "advanced glycosylation end products", written AGEs, which result from the glycoxidation reaction between glucose, its oxidation derivatives and the amino functions of proteins, including the so-called Maillard reactions of glycation of glyoxal for example.
The pharmaceutical compositions according to the invention can be provided in forms which are intended for parenteral, oral, rectal, pemucous or percutaneous administration.
They will therefore be provided in the form of solutions or suspensions fcr injection or multi-dose bottles, in the form of plain or coated tablets, film-coated tablets, wafer capsules, gelatin capsules, pills, cachets, powders, suppositories or rectal capsules, or solutions or suspensions for percutaneous use in a polar solvent or for permucous use.
The excipients which are suitable for such administrations are derivatives of cellulose or microcrystalline cellulose, alkaline earth metal carbonates, magnesium phosphate, starches, modified. starches, and lactose for the solid forms.

- 7 -
For rectal use, cocoa butter or polyethylene glycci stearates are the preferred excipients.
For parenteral use, water, aqueous solutions, physiological saline and isotonic solutions are the vehicles used most judiciously.
The dosage can vary within wide limits (from 0.5 mg to 1000 mg) depending on the therapeutic indication and the administration route, and also on the age and weight of the individual.
The following examples illustrate the preparation of the compounds of formula (I) and of various intermediates.
A - Preparation Example of compounds of formula (VII) Preparation of N-(2,6-dimethylphenyl)-3-chIoro-propanamide
A 2 1 three-necked flask is charged with 121.8 g of 2, 6-dimethyianiline, 300 ml of isopropyl ether and 150 ml of water. 126.5 g of 3-chloropropanoyl chloride are added at a rate such that the internal temperature is between 5 and 10 °C. At the end of the addition, the reaction medium is stirred for 3 h. The precipitate formed is filtered off with suction, washed with isopropyl ether and then with water and finally dried. 126 g of white crystals are obtained.
m.p, = 134-136°C
lH NMR (DMSO-d6, 200 MHz):
2.18 (s,6H); 2.31 (t,2H); 3.38 (t,2H); 7.03 (d,3H); 9.40 (s,lH)
The formulae and characteristics of compounds oof formula (VII) have been collated in Table 1.

- 12 -
B - Preparation Example of compounds of formula (II) Preparation of N-(2,6-dimethyiphenyI)-3-aminopropanamide
A three-necked flask is charged with 400 ml of DMF, 100 g of N-(2,6-dimethylphenyl)-3-chloropropanamide and 95.7 g of potassium phthalimide. After 3 h of stirring at reflux, the reaction medium is cooled to room temperature and 600 mi of water are added. Stirring is continued for 1.5 h. The precipitate formed is filtered off with suction and washed with water. 140 g of white crystals (m.p. >260°C) are obtained.
The crystals are charged to a three-necked flask with 800 mi of 95° ethanol and 23.7 g of hydrazine monohydrate..After 3 h of stirring at reflux, 39 ml of concentrated hydrochloric acid are added and stirring is continued for 1 h. The precipitate formed is filtered off, and washed with ethanol and the ethanolic phases are concentrated. The crude product obtained is taken up in water; the insoluble material remaining is filtered off and the aqueous phase is concentrated to give 108 g of a cream-white solid, m.p: = 239-241°C 1H NMR (DMSO-d6, 200 MHz):
2.22 (s,6H); 2.44 (t,2H); 2.8 8 (t,2H); 7.07 (s,3H); 9.50 (s,iH).
The formulae and characteristics of compounds of formula (II) have been collated in Table 2.

- 13 -

- 14 -

- 15 -

- 16 -C - Preparation Example of compounds of formula (XI)
Preparation of N- (2, 6-dimethylphenyl) -2-methyiamino-
acetamide
A closed stainless-steel reactor is charged
with 80 g of N-(2,6-dimethyiphenyl)-2-chIoro-acetamide and 600 ml of a 40% aqueous methyiamine solution. The mixture is heated with stirring at 80°C for 4 h and then concentrated under vacuum. The crude product is taken up in water and washed with dichlorcmethane. The aqueous solution is basified using sodium hydroxide solution and extracted with dichloromethane. The organic phase is dried over sodium sulphate are concentrated to give 60 g of a colourless oil. 1H NMR (DMSO-d6, 200 MHz):
2.15 (s,6H); 2.44 (s,3H); 3.50 (s,2H); 6.50 (S,1H); 7.70 (s,3H); 9.58 (s,iH)
The formulae and characteristics of compounds have been collated in Table 3.
Table 3

- 17 -
D - Preparation Example of compounds of formula (I)
Preparation of 2-aminoiminomethylamino-N- (cyclohexyl) - acetamide
A round-bottomed flask is charged with 15 g of 2-amino-N-(cyclohexyl)-acetamide, 14,6 g 1-aminoiminomehtylpyrazole hydrochloride and 100 ml of dioxane. After 18 h stirring at reflux, the reaction medium is cooled to room temperature and precipitate which has formed is filtered off with suction. 16 g of a white solid are obtained.
m.p. = 232-234°C
lH NMR (DMSO-d6, 200 MHz): 1.19 (m, 5H) ; 1-62 (m,5H); 3.46 (m,1H); 3.78 (d,2H); 7.21 (s,4H); 7.68
The formulae and characteristics of compounds of formula (I) have been collated in Table 4.

- 18 -

- 19 -

- 20 -

- 21 -

- 22 -
The results of pharmacological studies will be given below.
STUDY OF THE ANTIPIABETIC ACTIVITY IN THE NOSTZ RAT
The antidiabetic activity of the compounds of formula (I) was determined orally on an experimental model of non-insulin-dependent diabetes induced in the rat using streptozotocin.
The model of non-insulin-dependent diabetes is obtained in rats by neonatal injection (on the day of birth) of streptozotocin.
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 regulated temperature of from 21 to 22°C and are subjectec to a fixed cycle of light (from 7.00 am to 7.00 cm) and darkness (from 7.00 pm to 7.00 am) . Their diet consisted of a maintenance diet; water and food were provided ad libitum, except for the 2 hours' fasting prior to the tests in which food is withdrawn (post-absorptive state).
The rats are treated orally for one (dl) or four (d4) days with the test product. Two hours after the final administration of the product and 30 minutes after anaesthesia of the animals with sodium pentobarbital (Nembutal®) , 300 ml of blood is sampled from the end of the tail.
Results obtained are collated, by way of example, in Table 5. These results demonstrate the efficacy of the compounds of formula (I) in reducing giycaemia in diabetic animals. These results are expressed as a percentage change in giycaemia on dl and d4 (number of days of treatment) relative to dO (before treatment) .

- 23 -

- 24 -STUDY OF THE ANTXGLYCOXIDATION ACTIVITY
The compounds (I} are also capab le of inhibiting the so-called Maillard reactions by means of a "scavenging", effect on a-dicarbonyl derivatives such as glyoxal- - this is the antiglycation effect. This inhibitory effect on the Maillard reaction by 'the compounds of formula (I) was studied in viczo by assaying the ketamines ("fructcamines") produced during the incubation of albumin with mechylgiycxal in the presence or absence of a compound of formula (I).
A 6.6 mg/ml solution of bovine albumin in 0.2 M phosphate buffer pH 7.4 is incubated with 1 mM methyiglyoxal in the presence or absence of a compound according to the invention at a concentration of 1 mM. The incubation is carried out under sterile conditions at 37°C for 6 days. At the end of the incubation period, the amount of ketamines is measured with a commercially available fructoamine assay kit (kit "ERA", product reference: 0757055, Roche S.A. products) in " accordance with the manufacturer's instructions. Under these experimental conditions, the level of fructoamine ' following incubation of albumin with methyiglyoxal in the presence of a compound of formula (I) "is from 30 to 50% lower than that observed when albumin is incubated.with methyiglyoxal in the absence of 'the compound, of formula (I) .

-25-WE CLAIM
1. A process for the preparation of compounds of general formula (1)

in which:
R1 is selected from one of the following groups: -H;
- (C1-C20)alkyl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxyt (C1-C5)alkyithio, (C1-C5)alkylamino, trifluoromethyl; R2 is selected from
- (C3-C8)cycloalkyl substrtued or unsubstituted by one or more of the
following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5) alkylthio, (C1-C5)alkylamino, trifluoromethyl;
- (C6-C14)aryl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyl, halogen", (C1-C5)alkyI, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano;
- (C1-C13)heteroaryl containing one or more heteroatoms selected
from N, O and S and substituted or unsubstituted by one or more of
the following groups:
amino, hydroxyl, halogen, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano;
a nitrogen atom can additionally be substituted by a (C6-C14)aryl,
(C6-C14)acyl or (C1-C5)alkyl group;
EP221100doc
AMENDED SHEET

-26-
R3 is selected from -H;
- (C3-C8)cycloalkyl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyi, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
- (C3-C8)heterocycloalkyl containing one or more heteroatoms
selected from N, O and S and substituted or unsubstituted by one or
more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, trifluoromethyl;
a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14) acyl or (C1-C5)alkyl group;
- (C6-C14)aryl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyl, halogen, (C1-C5)aikyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl, cyano;
- (C1-C13)heteroaryl containing one or more heteroatoms selected
from N, O and S and substituted or unsubstituted by one or more of
the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy. (C1-C5)alkylthio,
(C1-C5)alkyiamino, trifluoromethyl, cyano; a nitrogen atom can additionally be substituted by a (C6-C14)aryl, (C6-C14) acy! or (C6-C5)alkyl group;
- (C6-C14)aryl-(C1C5)alkyl substituted or unsubstituted by one or
more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio,
(C1-C5)alkylamino, trifluoromethyl, cyano; and A is selected from the groups; -CH2-,
EP221100doc
AMENDED SHEET

-27-
-CH2-CH2-, -CHR4 -,
R4 being selected from: -H;
- (C1-C20)alkyl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyl, (C1-C5)alkyl (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
- (C3-C8)cycloalkyl substituted or unsubstituted by one or more of the
following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthio, (C1-C5)alkylamino, trifluoromethyl;
- (C3-C6)heterocycloalkyl containing one or more heteroatoms
selected from N, O and S and substituted or unsubstituted by one or
more of the following groups:
amino, hydroxyl, (C1-C5)alkyl, (C1-C5)alkoxy, (C1-C5)alkylthto, (C1-C5)alkylamino, trifluoromethyl;
a nitrogen atom can additionally be substituted by a (C6-C14)aryl (C6-C14) acyl or (C1-C5)alky! group;
and solvates and pharmaceutically acceptable salts thereof, with the exception of the compound of formula (I) in which R1 = H, R2 = phenyiand R3= H , comprising
reacting a compound of formula:

in which-
R5 is selected from -SCH3, pyrazoly! or -SO3H,
and
T is a tert-butyloxycarbonyl or benzyloxycarbonyl protective group.

-28-

2. A process for the preparation of compounds of formula 1 as claimed in
claim 1 in which R1 is selected from H and a (C1-C8) alkyl group.

3. A process for the preparation of compounds as claimed inclaim 1 in which
R2is selected from a (C8-C14) aryl group possibly substituted as defined in
claim 1.

This invention relates to a process for the preparation of compounds of general formula (1)
comprising reacting a compound of formula ff
with a compound of formula:

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Patent Number

206594

Indian Patent Application Number

IN/PCT/2001/00792/KOL

PG Journal Number

18/2007

Publication Date

04-May-2007

Grant Date

03-May-2007

Date of Filing

03-Jun-2001

Name of Patentee

MERCK PATENT GMBH

Applicant Address

FRANKFURTER STRASSE 250 D-64293 DARMSTADT,

Inventors:

#	Inventor's Name	Inventor's Address
1	MOINET, GERARD	15 RUE LAMARTINE, F-91400 ORSAY
2	CRAVO, DANIEL	123 AVENUE JULES FERRY F-78500 SARTROUVILLE
3	MESANGEAU, DIDIER	5, RUE AUGUSTE REOIR F-77380 COMBS LA VILLE
4	DOARE, LILIANE	33 AVENUE MARMONT, F-91440 BURES SUR YVETTE;
5	KERGOAT, MICHELINE	5,VILLA DES BOIS, F-91440 BURES SUR YVETTE; FRANCE

PCT International Classification Number

C07C 279/14

PCT International Application Number

PCT/EP99/10468

PCT International Filing date

1999-12-30

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	99/00194	1999-01-11	France