Title of Invention	"NOVEL NAPHTHO (1,2-D) OXAZOLE DERIVATIVES AS AGENT FOR TREATMENT OR PROPHYLAXIS OF NON- IN SULIN DEPENDENT DIABETES AND RELATED METABOLIC DISORDERS"
Abstract	The present invention relates to novel alkyl amino substituted naphtho [1, 2-d] oxazoles. More particularly the present invention is relates to the novel naphtha [1, 2-d] oxazole phenoxy-subsitutied alkyl amino derivaties, their preparation and use as anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS) The main objective of the present invention is to provide agents to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders.

Title of Invention

"NOVEL NAPHTHO (1,2-D) OXAZOLE DERIVATIVES AS AGENT FOR TREATMENT OR PROPHYLAXIS OF NON- IN SULIN DEPENDENT DIABETES AND RELATED METABOLIC DISORDERS"

Abstract

The present invention relates to novel alkyl amino substituted naphtho [1, 2-d] oxazoles. More particularly the present invention is relates to the novel naphtha [1, 2-d] oxazole phenoxy-subsitutied alkyl amino derivaties, their preparation and use as anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS) The main objective of the present invention is to provide agents to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders.

Full Text	LD OF THE PRESENT INVENTION This indention relates to novel alkyl amino substituted naphtho [1, 2-d] oxazoles. More particularly the present invention is relates to the novel naphtha [1, 2-d] oxazole phenoxy-subsitutied alkyl amino derivaties, their preparation and use as anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS) The main objective of the present invention is to provide agents to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders. BACKGROUND OF THE PRESENT INVENTION An analysis of the molecular structure of active PPARy-agonists mentioned above would suggest the presence of four distinct substructures unit. (A unit) the thiazolidine 2,4-dione (B unit) the intermediate alkyl chain (C unit) alkyl chain as linker and (d unit) the aryl/heteroaryl substituent. Since the thiazolidine 2,4-dione derivatives are associated with side effects such as liver toxicity etc, a molecular modification to eliminate such a unit was considered desirable. In the present invention the thiazolidine 2 4-dic-ie unit has been replaced by substituted amino residues which has resulted in novel compounds showing the desired anti-hyperglycemic activity along with lipid lowering activity which is an added desirable activity. (Figure Removed) Fig 1 : Preferred site of variation in Structure of PPARv agonists Approaches in designing of Anti-diabetic agents Approach D: The most preferred approach is variation at Site D (figl) and it leads to many active glitazones Such as pioglitazones, ciglitazone troglitazone. Approach C: Variation at site C in fig 1 gave some interesting compounds such as Englitazone, Darglitazone and CP-68,722 and oxazolylethyl (Figure Removed) Approach B: Although variation at site B was not explored much but some very interesting compounds were reported like AY 31,637 and spirosucccinamides.Spirosuccinamide Approach A (Ghtazars): Currently most favored approach and many variations have been perfered, which gave compound with very good antidiabetic activities. (Glitazars) (Figure Removed) PPARy-agonists which act as insulin sensitizers are showing promise in the treatment of NIDDM (Type II diabetes) which is a disease prevalent in developed as well as developing countries. A number of agents show PPARy agonist activity. Most of these compounds are (Glitazone) thiazolidine 2,4-dione derivatives. Some of the compounds belonging to this class which have entered in clinic are Pioglitazone (Momose, Y.;Takeda ,H.; Hatanaka.C.; Oi, S.;Sohda , T.Chem .Pharm. Bull.1991,39,1440-1445), Rosiglitazone (Cantello, B.C.C.; Cawthorne, M.A.; Haigh.D.; Hindley ,R.M.; Smith,S.A.; Thurlby.P.L Bioorg.Med.Chem.Lett.1994,4,1181-1184), Netoglitazone ( Viton.R.; Widdowson, P.S.; Ishii.S.; Tanaka,H.; Wikllain, G. British J. Pharmacolgy 1998, 125, 1708-14), Troglitazone ( Yoshida, T.; Fujita, T.; Kanai.T.; et al J.Med. Chem. 1989, 32, 421-428). The thiazolidinedione ring was later replaced with oxazolidinediones and these compounds are known as Glitazar. JTT -501 is the best compound and recently under clinical trials.(Shinkai,H nogi,S;Tanaka, M;Shibata, T;lwao,M;Wakitani,K;Uchid,IJ.Med.Chem 1998 ,41,1927-1933 and Shinkai, H Drugs future 1999,24,893-898) OBJECTIVES OF THE PRESENT INVENTION The main object of the present invention is to provide a novel alkyl amino substituted naphtho [1, 2-d] oxazoles. Another object of the present invention is to provide a process of preparation of novel akyl ar lino substituted naphtho [1, 2-d] oxazoles. 6ne more object of the present invention is to provide a novel alkyl amino substituted naphtho [1, 2-d] oxazoles to use as an anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS). Another object of the present invention is to provide an agent to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders. SUMMARY OF THE PRESENT INVENTION According the present invention provides a novel compound of formula (I) and salts (Figure Removed) Wherein value of R1, R2 is selected from a group consisting of individually H, a lower alkyl containing 1-6 carbon atoms is selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl is selected from a group consisting of isopropyl, isobutyl, t-butyl, a cyclic alkane is selected from a group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, Wherein value of R3, Rs are .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue such as substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom O,N,S is selected from a group consisting of piperazine, morpholine, oxazole, oxathinazole , oxathiazine etc Wherein R4 is iselected from a group consisting of H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower aikyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, value of n is 1 to 6, In another embodiment of the present invention the representative compounds of formula (I) and salts thereof comprising: 1. 4-Naphtho[1,2-d]oxazole-2-yl-phenol 2. Acetic acid-4-naphtho[1,2-d]oxazole-2-yl-phenyl ester 3. 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole 4. 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole 5. 2-[4-(2-Piperidine-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole 6. Dimethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 7. Diethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 8. Butyl-methyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-propyl]-amine 9. 4-Methoxy-phenyl)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propyl]-amine 10. -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-p-tolyl-amine 11. -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-octyl-amine 12. 2-[-4-(-Piperidin-1 -yl-propoxy)-phenyl]-naptho[1,2-d]oxazole In another embodiment of the present invention the representative compounds of formula (I) and salts thereof used as an anti-hyperglycemic agent. In another embodiment of the present invention the representative compounds of formula (I) and salts thereof used as the lipid lowering agent. In another embodiment of the present invention the effective dose of the compound is ranging between 50 mg/kg to 100mg/kg. In another embodiment of the present invention the compound is useful as anti-hyperglycemic agent and for the treatment and prevention of cardiovascular disorders particularly by lowering low density cholesterol without effecting high density cholesterol. In another embodiment of the present invention the compound shows significant lowering of glucose level ranging between 25 to 40% at a dose of about 100 mg/kg in STZ-S models. In another embodiment of the present invention the exhibiting antidiabetic (18- 28 %), lipid lowering (12-24%) and triglyceride lowering activity in db/db mice models. In another embodiment of the present invention the compound exhibiting lipid lowering up to about 20% at about 300 u mol/kg body weight. In another embodiment of the present invention the the salts of the compound of general formula is selected from a group consisting of hydrochlrides, citrates, oxalates, fumarate and malates . In another embodiment of the present invention the process for the preparation of compound of general formula 1, the said process comprising: a) reacting a substituted p-naphthol derivative of formula II wherein RI, and R2 with a substituted aromatic acid formula III wherein Xi is selected from methoxy , hydroxy or lower alkoxy groups and R4 are same as defined above neat or in an organic solvent with poly phosphoric acid or Lewis acids at an elevated temperature ranging between 60-80°C to furnish intermediate compound of formula IV, (Figure Removed) b) reacting the compound of formula IV with hydroxylamine hydrochloride in presence of sodium acetate in methanol or ethanol to give compound of formula V, which on reaction with acetic anhydride and pyridine afforded compound of formula VI, (Figure Removed) Wherein R1, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from a group consisting of isopropyl, isobutyl, t-butyl etc, a cyclic alkane selected from a group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue selected from a group consisting of substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom O,N,S selected from a group consisting of piperazine, morpholine, oxazole, oxathinazole , oxathiazine ., (Figure Removed) (v) reacting the compound of formula VI with a dihaloalkane of formula VII wherein X2 and Xa is same or different halogens in an organic solvent in presence of a base selected form alkali metal carbonate at an elevated temperature ranging between 60-80°C for a period ranging between 2 to 10 hr to furnish intermediate compound of formula VIII, Wherein R-i, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is selected from a group consisting of Br (Figure Removed) (vi) subsequently reacting the compound of formula VIII with an amine of formula IX, wherein R3 and R5 are as defined above, in neat in presence of alkali metal halides selected from Kl, Nal, or in an organic solvent in presence of base at an elevated temperature ranging between 60-135°C for a period ranging between 2 to 8 hr to provide the compound of general formula I. In another embodiment of the present invention the solvent used in step (i) is selected form dry xylene, benzene, pantane, and mixture thereof. In another embodiment of the present invention the lewis acid used in step (i) is selected from a group consiting of BFSetherate or AICI3. In another embodiment of the present invention the solvent in step (Hi) used is selected form a group consisting of dry acetone, ethanol, and methanol. Dimethyl sulphoxide(DMSO), dimethylformamide(DMF), acetonitrile. In another embodiment of the present invention the base used in step (iii) is selected form a group consisting of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate. In another embodiment of the present invention the solvent used in step (iv) is selected form group consisting of dry DMSO, DMF, acetonitrile Hexamethylphosphoric triamide ( HMPA),. In another embodiment of the present invention the acetic anhydride is used in basic medium. In another embodiment of the present invention the base used is selected form a group consisting of pyridine, triethylamine, pyridine with dimethylaminopyridine. In another embodiment of the present invention the dihaloalkane used is selected form a group consisting of -Chloro ethyl bromide, dibromoethane, Chloro propyl bromide. In another embodiment of the present invention the base used in step (iv) is selected form a group consisting of potassium carbonate, cesium carbonate. In another embodiment of the present invention the organic solvent used in the condensation of amine is dry DMF or DMSO. In another embodiment of the present invention the pharmaceutical composition comprising an effective amount of a compound of formula 1 and salts thereof and a pharmaceutically acceptable salt thereof along with a pharmaceutical acceptable carrier or diluents. DETAIEO DESCRIPTION OF THE PRESENT INVENTION The present invention concerns naphtho [1,2-d] oxazole phenoxy substituted alkyl amino derivatives of formula (I), a novel class of compounds as anti-diabetic agents. In this we have designed a non-carboxylic acid or without active hydrogen contanting compound as anti-diabetic agents, Wherein RI, R2 are individually H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, n is 1to 6, halogens, nitro, amino R3 R5 are .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue such as substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocylic ring such as pyrrolidine, piperidine, form a heterocylic ring with additional heteroatoms O,N,S such as piperazine, morpholine, oxazole, oxathinazole , oxathiazine etc. R4 are individually H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, n is 1to 6,holgens ,nitro, amino groups in process for the preparation of compounds of general formula I, which constitute reacting a substituted p-naphthol derivative of formula II wherein R1t and RZ are as defined above with a of substituted aromatic acid formula III wherein Xi is methoxy , hydroxy or lower alkoxy groups and R4 are same as defined above neat or in an organic solvent such as dry xylene .benzene etc with poly phosphoric acid or lewis acids such as BF3etherate , AICI3 etc at an elevated temperature( 60-80°C) to furnish intermediate compound of formula IV .which on reaction with hydroxylamine hydrochloride in presence of sodium acetate in methnol gave compound of formula V, which on reaction with acetic anhydride and pyridine afforded compound of formula VI, which on reaction with a dihaloalkane of formula VII wherein X2 and X3 may be same or different halogens in an organic solvent such as dry acetone , ethanol, methanol. Dimethyl sulphoxide(DMSO), dimethylformamide (DMF), acetonitrile etc in the presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate etc at an elevated temperature( 60-80°C) to furnish intermediate compound of formula VIII, which on subsequent reaction with an amine of formula IX, wherein R3 and R5 are as defined above, in neat, , presence of metal halides such as Kl, Nal or in an organic solvent such as dry DMSO.DMF, Hexamethylphosphoric Triamide ( HMPA), acetonitrile etc in presence of base such as of a base such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate etc at an elevated temperature( 60-135°C) afforded compound of formula I. BIOLOGICAL ACTIVITY A ANTIDIABETIC ACTIVITY ANIMALS: Adult male and female albino rats (Sprague Dawley) of body weight 160±20g, bred in CDRI animal house were used during the course of experiment; 6 animals were kept in one cage. All the animals were fed ad-lib standard pellet diet (Lipton, Bombay) and allowed unrestricted access to water. The following norms were followed for animal room environment. Temperature: 22 ± 1°C; Humidity: 50-50%; Light 300 Lux at floor level with regular 12 hours light cycle; noise level 50 decibels; ventilation 10-50 air changes per hour. The blood-glucose lowering effects of the test samples/standard drugs were examined in the following two experimental models. Sucrose-loaded rat model: Overnight fasted male Sprague Dawley rats were used for the sucrose-loaded experiment. Blood was collected at 'O'min from the tail vein of the animals. After the '0' min blood collection, samples/drugs were given to the test group consisting of 5 rats by oral gavage at a dose of 100 mg/kg. Half an hour post test sample treatment, a sucrose-load of 10.0 gm/kg body weight was given to each rat. The blood was collected at 30, 60, 90 & 120 min post sucrose-load. Streptozotocin-induced diabetic rat model: Single-dose effect; Sprague Dawley strain male albino rats of average body weight 160±20 g were selected for this study. A calculated amount of the fresh solution of STZ dissolved in 100 mM citrate buffer (ph 4.5) was injected to overnight fasted rats (60 mg/Kg) intraperitoneally. Blood was checked for glucose content 48 h later by glucometer & animals showing blood glucose profile above 250 mg/dl were selected and were divided into different groups. Blood-glucose levels were again tested at 1, 2, 3, 4, 5, 6, 7 and 24 h post test sample/drug administration. Food but not water was withdrawn from the cages during the experiment. Sucrose challenged Streptozotocin-induced diabetic rat model: Single-dose effect; Sprague Dawley strain male albino rats of average body weight 160±20 g were selected for this study. A calculated amount of the fresh solution of STZ dissolved in 100 mM citrate buffer (ph 4.5) was injected to overnight fasted rats (60 mg/Kg) intraperitoneally. Blood was checked for glucose content 48 h later by glucometer & animals showing blood glucose profile between 150-250 mg/dl were selected and were divided into different groups. Half an hour post test sample treatment, a sucrose-load of 2.5 g/kg body weight was given to each rat. Blood-glucose levels were again tested at 30, 60, 90, 120,180, 240, 300 min and 24 h post test sample/drug administration. Food but not water was withdrawn from the cages during the experiment. 1} Hypoglycaemic activity of Test Compounds (compound no.5, 6,10 and 12), Glybenclamide and Gliclazide in normal rats: The antidiabetic effect of test compounds (compound no 5, 6 and 10) and standard drug Glybenclamide, Gliclazide on OGTT of normal rats was determined. At 100-mg/kg doses level, test compounds 5,6,10,12 Glybenclamide and Gliclazide showed significant lowering 26.9%, 35.9%, 27.8 %, 33.6 %, 33.9% and 44.8% respectively, at 120 min post glucose load. 2) Hypoglycaemic activity of example 6, Glybenclamide and Gliclazide in STZ-induced diabetic rats: The effect of Test compound 2-[-4-(-Piperidin-1-yl-propoxy)-phenyl]-naptho[1,2-djoxazole (12) and standard antidiabetic drug Glybenclamide and gliclazide on blood glucose lowering in STZ-induced diabetic rats were determined. At 100 mg/kg dose level compound 12, Glybenclamide and gliclazide showed significant lowering on blood glucose. The lowering started from 1-hour that persisted up to 7-hours post drug administration. The lowering was of the order 26.0%, 32.8% and 27.7% respectively in case of test compound 6, Glybenclamide and gliclazide 3^ Hypoglycaemic activity of compound no. 5, 6 and compound no 12. (compounds 5,6 &12) in sucrose challenged STZ-induced diabetic rats: The effect of compound 5 and 6 on blood glucose lowering in sucrose challenged STZ-induced diabetic rats was determined. At 100 mg/kg dose level, compounds 5 and 6 did showed moderate lowering (16. 64% ,27.4 and 16.80 %respectively) and in blood glucose. B. Lipid lowering activity of compound no. 5 and compound no. 6 Lipid lowering activity of compound-5 & 6 was evaluated in two different models (a)Triton Model: compound 5 and 6 showed the lowering in chol (14,21%) Tg.(11,14%) at 100 mg/kg respectively. (b) Dyslipemic Hamster Model: Feeding with test compound no 5 reduced levels of plasma Tg, chol, glycerol, HDL by 18, 8,14,15 respectively. Similarly for compound no 6 reduced levels of plasma Tg, chol, glycerol, HDL by 14,11,12,17 at 300 umole/kg respectively. Anti-hyperglycemic Activity in db/db mice : The db/db mouse is a well-characterised model of type 2 diabetes. The background for the db/db mouse is the C57BL/Ks strain. The major deficiency of the C57BL/KsBom-db mouse (db/db) is lack of a functional leptin receptor. This leads to defective leptin signalling and a complete lack of feedback from leptin. Both hypothalamic NPY content and secretion are consequently elevated, and this result in hyperphagia and decreased energy expenditure, obesity, insulin-resistance, hyperinsulinemia, hyperglycaemia and dyslipidemia. The db/db mouse develops NIDDM from around week 10. The disease is stable until week 20, where destruction of pancreatic D-cells can be recognized clinically as decreasing levels of plasma insulin and very severe hyperglycaemia. The db/db mouse has a maximal life span of 9 -12 months. The male mice are more diabetic than, and will normally die earlier than the females. The advantage of using male mice for experimental purposes is that the fluctuations in plasma parameters are less than in the females where the oestrogen cycle affects the clinical diabetes. The optimal age of db/db mice used for experiments will be from week 12 to 18 when they have developed NIDDM with diabetic dyslipidemia but still have functional D-cells in the pancreas. C57BL/KsBom-db mice 12-18 weeks, 40 - 50 g bred in the animal house of CDRI, Lucknow. 10 mice (5 males and 5 females) were used in the experiments. The mice were housed in groups of 5 (same sex) in a room controlled for temperature (23 ± 2.0 °C) and 12/12 hours light/dark cycle (lights on at 6.00 am). Body weight was measured daily from day 1 to day 10. All animals had free access to fresh water and to normal chow except on the days of the postprandial protocol day 6 and during the overnight fast before the OGTT on day 10. The animals always had access to water during experimental periods. Blood glucose was checked every morning up till day 5. On day 6 postprandial protocol was employed, in this method blood glucose was checked at -0.5h and Oh Test drugs were given to the treatment group whereas vehicle received only gum acacia (1.0%); the blood glucose was again checked at 1, 2, 3, 4 and 6h post test drug treatment. On day 8, blood was collected for serum insulin measurements and finally on day 10 an oral glucose tolerance test (OGTT) was performed after an overnight fasting. Blood glucose was measured at -30.0 min and test drugs were administered. The blood glucose was again measured at 0.0 min post treatment and at this juncture glucose solution was given at a dose of 3 gm/kg to all the groups including vehicle. The blood glucose levels were checked at 30 min, 60 min, 90 min and 120 min post glucose administration. Compounds 5,6 and 12 showed ( 16,2land 18 %) blood glucose lowering effect on postprandial protocol on day 3 in db/db. (detail results are in Table 2) Table 1: In vivo antihyperglycemic activity profile of active compounds in SLM and STZ S models (Table Removed) Table 2: In vivo antihyperglycemic, lipid lowering and triglyceride lowering profile of active compounds db/db mice models (% efficacy, 3 days,100mg/kg) (Table Removed) Following examples are given by way of illustration of the present invention and therefore should not construe to limit the scope of the present invention. Example 1: 4-Naphtho [1, 2-d] oxazole-2-yl-phenol: Naphthophenone oxime (1gm) was dissolved in acetic anhydride (3.0 ml_) and stirred at room temperature for 30 mins. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried on sodium sulfate and evaporated under vacuum, which afforded naphthophenone oxime acetate as a solid. The solid is as such used for second step. The naphthophenone oxime acetate was again dissolved in (Dry) pyridine (10 ml_, dry) and heated at 120° C for 14 hour. Completion of reaction was checked by Tic. Reaction mixture was washed with water and extracted with ethylacetate to give compound of formula VI. (Dry) Yield (62%) ,m.p. 278°C, I.R.(KBr) Cm'1 3450, 1610, 1437,1 HNMR (DMSO-d6) :6 8.4(ArH,d,J=8.1,1H); 8.1(ArH,d,J=8.1,2H); 8.08 (ArH.d, J= 8.1,1H); 7.92 (ArH,m,2H); 7.68 (ArH,d,J=6.9,1H); 7.57 (ArH, d,J= 8.1,1H); 6.98 (ArH, d,J=8.7,2H); 13C NMR (DMSO-de): 162.37 160.70, 147.30, 130 .86.129.05; 128.79; 127.09; 125.46; 121.59; 117.54; 116.19; 111.10 ; Mass (FAB) 262[M+]Analysis ::C,78.12 ;H 4.25 ; N.5.36; (Obs) C.78.32 ;H 4.26 ; N.5.58. Example 2: Acetic acid-4-naphtho [1, 2-d] oxazole-2-yl-phenyl ester: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1gm) was dissolved in acetic anhydride (solvent) and in presence of catalytic amount of pyridine in cold The reaction mixture was stirred at room temperature for 30 min to afford the acetic acid -4-naphtho[1,2-d] oxazole-2- yl-phenyl ester. Yield (80 %) ,m.p. 185-87°C J.R.(KBr) CnT13416, 1748, 1605 1 HNMR (CDCI3) .6 8.51(ArH,d,J=8.1, 1H); 8.28 (ArH, 2H,m); 7.90 (ArH, d,J=8.06, 1H); 7.68 (ArH,m,4H); 7.22( ArH, m,2H); 2.27(CH3CO,s,3H) ;Mass (FAB) 304[M+1] ; Analysis : 0,78.0 4 ;H 4.6 2 ; N.4.82 ; (Obs.) 0,78.23 ;H 4.8 2 ; N.4.8 2 Example 3: 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole.: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 1.32 gm was taken in dry acetone and 1-bromo-3-chloropropane (1.5ml ) .potassium carbonate ( 13.8 gm) was added. The reaction mixture was refluxed for 8 hr .Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction was taken in (100 ml) ethyl acetate and washes with 150 ml water, dried over sodium sulphate and crystallized with ethyl acetate and hexane. Yield (87 %) ,m.p. 108-10°C , I.R.(KBr) Cm'1 1609,1495,705;1 HNMR (CDCI3) .5 8.59 ArH,d,J=8.0,1H); 8.25(ArH,d,J=8.8,2H,); 7.86 (ArH,d,J=8.2, 1H); 7.68 (ArH,m,4H); 7.04(ArH,d,J=8.7,2H); 4.2(OCH2,t, J=5.8,2H) ;Mass (FAB) 338 [M+1] Analysis : 0,71.11 ;H 4..77 ; N.4.15 ;. (Obs.) C, 71.33; H 4.89; N, 4.33. Example 4 : 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 520 mg was taken in in dry DMF (10 ml) and 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (632mg) , potassium carbonate (6.5gm) was added. The reaction mixture was stirred at 100°C for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethylacetate150ml and dried over sodium sulphate., Column was run using ethylacetate and hexane as a eluent on basic alumina. Yield (74%) ,m.p. 98-100°C, I.R.(KBr) Cm'1 3446 ,1607, ; 1 HNMR (CDCI3) .6 8.57 (ArH,d,J=8.2,1H); 8.25(ArH,d,J=8.8,2H,); 7.95 (ArH, d, J=8.2,1H);7.68 (ArH,m,4H);7.06(ArH,d,J=8.4,2H);4.2(OCH2,t,J= 5.9, 2H) ,2.95(NCH2,t,J=6Hz), 2.62(m, 4H,NCH2), 1.86 (CH2CH2,m 4H).; Mass (FAB) 359 [M+1] Analysis ::C,78.12 ;H 4.25 ; N.5.36; (Obs) 0,78.32 ;H 4.26 ; N.5.58. Example 5: 2-[4-(2-Piperidine-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry DMF and 1-(2-Chloro-ethyl)-piperdine hydrochloride (441 mg), potassium carbonate 6.5gm was added. The reaction mixture was stirred at 100°C for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml)and. Extracted with ethylacetate (150ml) and dried over sodium sulphate. Column was run using etylacetate and hexane as a eluent on basic alumina. Yield (74%) ,m.p. 118-20°C; I.R.(KBr) Cm'1 3436 ,1612, 12561; HNMR (CDCI3) .6 8.57(ArH,d,J=8.2,1H); 8.25 (ArH, d,J=8.8,2H,); 7.95 (ArH,d,J=8.2, 1H); 7.68 (ArH,m,4H);7.04(ArH,d,J=7.4,2H); 4.18 (OCH2 ,t, J=5.9,2H), 2.80 (NCH2,t, J= 5.8Hz) , 2.56(m, 4H,NCH2), 1.66,(CH2CH2 CH2,m 6H).Mass (FAB) 373 [M+1] ] Analysis ::C,78.18 ;H6.75; N,7.50;(Obs) C.78.32 ;H 6.26 ; N.7.63 1.66, (CH2CH2CH2,m 6H) Example 6: Dimethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry acetone and 1-(2-Chloro-ethyl)-dimethyl,hydrocholoride (340 mg ), potassium carbonate (6.5g) was added. The reaction mixture was refluxed for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction mixture was taken in 100 ml ethylacetate and wash with (150 ml) water and dried over sodium sulphate. Column was run using ethylacetate and hexane as a eluent on basic alumina. Yield (81%) ,m.p. 102-04°C ; I.R.(KBr) Cm'1 3417 ,1609, 1243; 1 HNMR (CDCI3) .6 8.26 (ArH,d,J=9.8,1H); 7.74(ArH,d,J=5.4,2H,); 7.76 (ArH.m 1H); 7.68 (ArH, m,4H); 7.07 (ArH,d,J=8.,2H); 4.16(OCH2,t, J=5.6,2H), 2.78 (m,2H, NCH2, t,J=5.6Hz),2.3(NCH3,s, 6H).;Mass (FAB) 333 [M+1] °C Analysis ::C,75.58;H 5.65 ; N.8.26; (Obs) C.75.88 ;H 6.06 ; N.8.43 Example 7: Diethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry acetone and 1-(2-Chloro-ethyl)-diethyl,hydrocholoride (412mg), potassium carbonate (6.5g) was added. The reaction mixture was refluxed for 8 hr Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction mixture was taken in (100 ml) ethyl acetate and washes with (150 ml) water, dried over sodium sulphate and purified through basic alumina column using ethyl acetate and hexane as eluting solvent. Yield (84%) ,m.p.98-100 °C; I.R.(KBr) Cm'1 3437 ,1608, 1246; 1 HNMR (CDCI3) .5 8.56,(ArH,d,J=8.2,1H); 8.25(ArH,d,J=8.8 2H,); 7.96 (ArH,d,J=8.2,1 H); 7.68 (ArH,m,4H); 7.04 (ArH,d,J=9.,2H); 4.13 (OCH2,t,J=6.4,2H), 2.91 (NCH2,t, J= 5.4Hz,2H) ,2.6 (NCH2,q, 4H) 1.06 (CH3,t,J=1.66;Mass (FAB) 361 [M+1] Analysis :C,76.58;H 6.85;N,8.26; (Obs) C,76.64;H 6.71 ; N.7.77; Example 8: Butyl-methyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-propyl]-amine 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776mg) was taken in dry DMF (15ml) and N-methyl-butylamine (0.25ml),potassium iodide(830mg)were added. The reaction mixture was stirred at 100°C for 4 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in waterlOOml and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using etylacetate and hexane as eluting solvents. Yield(84%),m.p. 115-18°C(HCI salt); 1 HNMR (CDCI3) 6 8.57, ArH,d,J=5.2,1H); 8.25(AiH,d,J=5.8 2H,); 7.94 (ArH,d,J=5.6,1 H); 7.68 (ArH,m,4H); 7.02 (ArH.d, J= 6,2H); 4.08(OCH2,t,J=2.6,2H), 2.53 (NCH2, ,J=4.6Hz,2H), 2.36 (NCH2,t,J= 5.2.2H). 2.24 (NCH3 ,S,3H) ,1.97 NCH2,t, =4.8,2H)1.35(CH2CH2>m,4H), 0.99 (CH3,t,J=5.4);Mass (FAB) 389 [M+1] Analysis ::C,77.29;H 7.26; N,7.28; (Obs) 0,77.54 H 7.37 N 7.43 Example 9: 4-Methoxy-phenyl)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propyl]-amine 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776mg) was taken in dry DMF (15ml) and p- anisidine (295mg),potassium iodide (830mg) were added. The reaction mixture was stirred at 100°C for 4 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (84%),m.p. 136-40°C 1 HNMR (CDCI3) 5 8.57,(ArH,d,J=5.2,1H); 8.25(ArH,d,J=5.8 2H,); 7.94 (ArH,d,J=5.6,1 H); 7.68 (ArH,m,4H); 7.02 (ArH,d,J=6,2H); 4.08 (OCH2,t,J=2.6,2H),. 3.7(s,OCH3 3H); 3.37(t, NCH2, 3H,J + 4.4); 2.15 (m,CH2 ,2H)2.24 (NCH3,s,3H), 1.97(NCH2,t,J=4.8,2H) 0.99 (CH3, t,J=5.4);Mass (FAB) 389 [M+1] Analysis ::C,76.89 H7.74; N.7.17 ; (Obs) C,76.64;H7.54 ; N.7.34 Example 10: -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-p-tolyl-amine 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (710mg) was taken in dry DMF (15ml) and toludine (920 mg ),potassium iodide (830mg) were added.The reaction mixture was stirred at 100°C for 4 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in waterlOOml and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (89%) ,m.p. 118-20°C).1 HNMR (CDCI3) 5 8.57,(ArH,d,J=5.2,1H); 8.25(ArH,m 2H,); 7.95 (ArH,d,J=5.4,1H); 7.68 (ArH,m,3H); 7.52 (ArH, m,,2H);6.99(ArH,t,J=6.0,4H);6.57(ArH,d,J=5.6)5.27(NH,s,1H);4.14 (OCH2, t,J=3.8,2H), 3.34(NCH2,t,J=4.4Hz,2H) ,2.36 (NCH2,t,J=5.2, 2H) .2.23(PhCH3,s,3H), 2.11(CH2,m,2H);Mass (FAB) 409M+1] Analysis ::C,79.39 H 5.92; N.6.86; (Obs) C,79.54;H 5.64 ; N.6.86 Example 11: -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-octyl-amine;- 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (760mg) was taken in dry DMF (15ml) and octylamine (0.2ml), potassium iodide (830mg) were added. The reaction mixture was stirred at 100°C for 6 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (76%) ,m.p. 67-69°C); 1 HNMR (CDCI3) .6 8.57,(ArH,d,J=8.2,1H); 8.25(ArH,d,J=6 2H,); 7.96 (ArH,d,J=4.2,1H);7.68(ArH,m,4H);7.04 (ArH,d,J=6.,2H); 4.13 (OCH2, t, J=6.4,2H),2.83(NCH2,t)J=5.4Hz>2H),2.63(NCH2J=4,2H).2.01 (CH2,m,2H); 1.52(CH2 rn,4H); 1.2(CH2 ,m,8H); 0.88(CH3,t,J=4; Mass (FAB) 431 [M+1] Analysis ::C,78.10; H 7.96 ; N,6.51; (Obs) C,78.44;H 7.53 ;N,673; Example 12: 2-[-4-(-Piperidin-1-yl-propoxy)-phenyl]-naptho[1,2-d]oxazole 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776 mg) was taken in dry DMF (15ml) and piperidine (0.2ml), potassium iodide (830mg) were added. The reaction mixture was stirred at 100°C for 6 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (89%) ,m.p. 119°C. I.R.(KBr) Cm"1 3432, 1604, 1250; 1HNMR (CDCI3) :5 8.57 (ArH,d,J=7.61H); 8.23 (ArH,d,J=7.2,2H); 7.95(ArH,d, J= 7.2,1 H); 7.722(ArH,m,4H); 7.02(ArH,d,J=6.9,2H);4.09(OCH2,t.J=6.2); 2.52(NCH2 ,m,4H,) 2.05(NCH2,m,2H) 1.70(CH2.m,4H); 1.65 (CH2.m,2H) Mass (FAB) 287 [M+1]; Analysis ::C,77.18 ;H6.75, N.7.50; (Obs) C.77.32 ;H 6.46 ; N,7.58. ADVANTAGES OF THE PRESENT INVENTION The compounds of the present invention exhibiting significant antidiabetic activity with good lipid and Triglyceride lowering activity, which has given these compounds an added advantage over other antidiabetic compound. We claim: 1. A compound of formula (I) and salts thereof, wherein R1, RZ are individually H, a lower alkyl containing 1-6 carbon atoms selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from isopropyl, isobutyl, t-butyl etc, a cyclic alkane selected from group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, R3 alkoxy in which the alkyl group is as mentioned above, n is lto 6, halogens, nitro, amino R3 Rs are ,individually H, a lower straight or branched chain alkyl containing 1-1 0 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue selected from substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue selected from group consisting of benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom O,N,S such as piperazine, morpholine, oxazole, oxathinazole , oxathiazine. R4 is selected from a group consisting of H, a lower alkyl containing 1-6 carbon atoms selected from group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from isopropyl, isobutyl, t-butyl, a cyclic alkane selected from group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, an alkoxy in which the alkyl group is as mentioned above, value of n is 1 to 6. 2. A compound as claimed in claim 1 wherein the representative compounds comprising: (i) 4-Naphtho[l,2-dloxazole-2-yl-phenol (ii) Acetic acid-4-naphtho[1,2-d]oxazole-2-yl-phenyle ster (iii) 2-[4-(3-chloro-propoxy)-phenyll-naphtho [I ,2-dl oxazole (iv) 2-[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenyll-naphtho [1,2-dl oxazole (v) 2-[4-(2-Piperidine- 1 -yl-ethoxy)-phenyll-naphtho [l,2-dl oxazole (vi) Dimethyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine (vii)Diethyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine (viii) Butyl-methyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-propyl]-amine (ix) 4-Methoxy-pheny1)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propy1]-amine (x) [3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyll-p-tolyl-a(mx i) [3-(4- naphtho[l,2-d Ioxazol-2-yl-phenoxy)-propyll-octyl-amin(ex ii) 2-[-4-(-Piperidin- 1 -ylpropoxy)- phenyll-naptho[l,2-dloxazole 3. A process for the preparation of compound of general formula 1, the said process comprising : (a) reacting a formula A wherein R1, and R2 with compound formula B wherein X is selected from methoxy , hydroxy or an lower alkoxy groups and & are same as defined above neat or in an organic solvent with poly phosphoric acid or Lewis acids at an elevated temperamre ranging between 60-80°C to furnish intermediate compound of formula C. (b) reacting the compound of formula C with hydroxylamine hydrochloride in presence of sodium acetate in methanol or ethanol to give compound of formula D, which on reaction with acetic anhydride and pyridine afforded compound of formula E, wherein R1, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from a group consisting of isopropyl, isobutyl, tbutyl etc, a cyclic alkane selected from a group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is .individually H, a lower straight or branched chain alkyl containing 1-1 0 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue selected from a group consisting of substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with ' additional heteroatom O,N,S selected from a group consisting of piperazine, morpholine, oxazole, oxathinazole , oxathiazine. (c) reacting the compound of formula E with a dihaloalkane of formula F wherein X2 and X3 is same or different halogens in an organic solvent in presence of a base selected form alkali metal carbonate at an elevated temperature ranging between 60-80°C for a period ranging between 2 to 10 hr to furnish intermediate compound of formula G, wherein Rl , R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from group consisting of isopropyl, isobutyl, t-butyl, a cyclic alkane selected from group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, an alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is selected from a group consisting of Br.CI and I. (d) subsequently reacting the compound of formula G with an mine of formula H, wherein R3 and R5 are as defined above, in neat in presence of alkali metal halides selected from K1, Nal, or in an organic solvent in presence of base at an elevated temperature ranging between 60-1 35°C for a period ranging between 2 to 8 hr to provide the compound of general formula I. 4. A process as claimed in claim 3 wherein the solvent used in step (a) is selected from a group consisting of dry xylene benzene, pantane, and mixture thereof. 5. A process as claimed in claim 3 wherein the lewis acid used in step (a) is selected from a group consisting of BF3 etherate or AIC13. 6. A process as claimed in claim 3 wherein the solvent in step (c) used is selected form a group consisting of dry acetone, ethanol, methanol. Dimethyl sulphoxide(DMSO), dimethylformamide(DMF), acetonitrile. 7. A process as claimed in claim 3 wherein the base used in step (c) is selected form a group consisting of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate. 8. A process as claimed in claim 3 wherein the solvent used in step (d) is selected form group consisting of dry DMSO, DMF, acetonitrile, Hexamethylphosphoric triamide (HMPA), 9. A process as claimed in claim 3 wherein basic medium used in step (c) & (d) is selected from the group consisting of pyridine, triethylamine, pyridine with dimethylaminopyridine, potassium carbonate, cesium carbonate 10. A process as claimed in claim 3 wherein the dihaloalkane used in step (c) is selected form a group consisting of Chloro ethyl bromide, dibromoethane, Chloro propyl bromide.

Full Text

LD OF THE PRESENT INVENTION
This indention relates to novel alkyl amino substituted naphtho [1, 2-d] oxazoles. More particularly the present invention is relates to the novel naphtha [1, 2-d] oxazole phenoxy-subsitutied alkyl amino derivaties, their preparation and use as anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS) The main objective of the present invention is to provide agents to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders.
BACKGROUND OF THE PRESENT INVENTION
An analysis of the molecular structure of active PPARy-agonists mentioned above would suggest the presence of four distinct substructures unit. (A unit) the thiazolidine 2,4-dione (B unit) the intermediate alkyl chain (C unit) alkyl chain as linker and (d unit) the aryl/heteroaryl substituent. Since the thiazolidine 2,4-dione derivatives are associated with side effects such as liver toxicity etc, a molecular modification to eliminate such a unit was considered desirable. In the present invention the thiazolidine 2 4-dic-ie unit has been replaced by substituted amino residues which has resulted in novel compounds showing the desired anti-hyperglycemic activity along with lipid lowering activity which is an added desirable activity.
(Figure Removed)
Fig 1 : Preferred site of variation in Structure of PPARv agonists
Approaches in designing of Anti-diabetic agents
Approach D: The most preferred approach is variation at Site D (figl) and it
leads to many active glitazones Such as pioglitazones, ciglitazone troglitazone.
Approach C: Variation at site C in fig 1 gave some interesting compounds such as Englitazone, Darglitazone and CP-68,722 and oxazolylethyl
(Figure Removed)
Approach B: Although variation at site B was not explored much but some very interesting compounds were reported like AY 31,637 and spirosucccinamides.Spirosuccinamide
Approach A (Ghtazars): Currently most favored approach and
many variations have been perfered, which gave compound with very good antidiabetic activities. (Glitazars)
(Figure Removed)

PPARy-agonists which act as insulin sensitizers are showing promise in the treatment
of NIDDM (Type II diabetes) which is a disease prevalent in developed as well as
developing countries. A number of agents show PPARy agonist activity. Most of these
compounds are (Glitazone) thiazolidine 2,4-dione derivatives. Some of the compounds
belonging to this class which have entered in clinic are Pioglitazone (Momose,
Y.;Takeda ,H.; Hatanaka.C.; Oi, S.;Sohda , T.Chem .Pharm. Bull.1991,39,1440-1445),
Rosiglitazone (Cantello, B.C.C.; Cawthorne, M.A.; Haigh.D.; Hindley ,R.M.; Smith,S.A.;
Thurlby.P.L Bioorg.Med.Chem.Lett.1994,4,1181-1184), Netoglitazone ( Viton.R.;
Widdowson, P.S.; Ishii.S.; Tanaka,H.; Wikllain, G. British J. Pharmacolgy 1998, 125,
1708-14), Troglitazone ( Yoshida, T.; Fujita, T.; Kanai.T.; et al J.Med. Chem. 1989, 32,
421-428). The thiazolidinedione ring was later replaced with oxazolidinediones and
these compounds are known as Glitazar. JTT -501 is the best compound and recently
under clinical trials.(Shinkai,H nogi,S;Tanaka, M;Shibata,
T;lwao,M;Wakitani,K;Uchid,IJ.Med.Chem 1998 ,41,1927-1933 and Shinkai, H Drugs future 1999,24,893-898)
OBJECTIVES OF THE PRESENT INVENTION
The main object of the present invention is to provide a novel alkyl amino substituted naphtho [1, 2-d] oxazoles.
Another object of the present invention is to provide a process of preparation of novel akyl ar lino substituted naphtho [1, 2-d] oxazoles.

6ne more object of the present invention is to provide a novel alkyl amino substituted naphtho [1, 2-d] oxazoles to use as an anti-hyperglycemic agents (Anti-diabetic) and for the treatment and prevention of cardiovascular disorders (CVS). Another object of the present invention is to provide an agent to act in non insulin dependent diabetes mellitus (NIDDM) with the added advantage of their effect in the treatment and prevention of CVS disorders.
SUMMARY OF THE PRESENT INVENTION
According the present invention provides a novel compound of formula (I) and salts
(Figure Removed)
Wherein value of R1, R2 is selected from a group consisting of individually H, a lower alkyl containing 1-6 carbon atoms is selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl is selected from a group consisting of isopropyl, isobutyl, t-butyl, a cyclic alkane is selected from a group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens,
Wherein value of R3, Rs are .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue such as substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom O,N,S is selected from a group consisting of piperazine, morpholine, oxazole, oxathinazole , oxathiazine etc
Wherein R4 is iselected from a group consisting of H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower aikyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, value of n is 1 to 6,
In another embodiment of the present invention the representative compounds of formula (I) and salts thereof comprising:
1. 4-Naphtho[1,2-d]oxazole-2-yl-phenol
2. Acetic acid-4-naphtho[1,2-d]oxazole-2-yl-phenyl ester
3. 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole
4. 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole
5. 2-[4-(2-Piperidine-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole
6. Dimethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine
7. Diethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine
8. Butyl-methyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-propyl]-amine
9. 4-Methoxy-phenyl)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propyl]-amine
10. -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-p-tolyl-amine

11. -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-octyl-amine
12. 2-[-4-(-Piperidin-1 -yl-propoxy)-phenyl]-naptho[1,2-d]oxazole
In another embodiment of the present invention the representative compounds of formula (I) and salts thereof used as an anti-hyperglycemic agent.
In another embodiment of the present invention the representative compounds of formula (I) and salts thereof used as the lipid lowering agent.
In another embodiment of the present invention the effective dose of the compound is ranging between 50 mg/kg to 100mg/kg.
In another embodiment of the present invention the compound is useful as anti-hyperglycemic agent and for the treatment and prevention of cardiovascular disorders particularly by lowering low density cholesterol without effecting high density cholesterol.
In another embodiment of the present invention the compound shows significant lowering of glucose level ranging between 25 to 40% at a dose of about 100 mg/kg in STZ-S models.
In another embodiment of the present invention the exhibiting antidiabetic (18- 28
%), lipid lowering (12-24%) and triglyceride lowering activity in db/db mice models. In another embodiment of the present invention the compound exhibiting lipid
lowering up to about 20% at about 300 u mol/kg body weight.
In another embodiment of the present invention the the salts of the compound of
general formula is selected from a group consisting of hydrochlrides, citrates,
oxalates, fumarate and malates .
In another embodiment of the present invention the process for the preparation of
compound of general formula 1, the said process comprising:
a) reacting a substituted p-naphthol derivative of formula II wherein RI, and R2 with a substituted aromatic acid formula III wherein Xi is selected from methoxy , hydroxy or lower alkoxy groups and R4 are same as defined above neat or in an organic solvent with poly phosphoric acid or Lewis acids at an elevated temperature ranging between 60-80°C to furnish intermediate compound of formula IV,
(Figure Removed)
b) reacting the compound of formula IV with hydroxylamine hydrochloride in presence of sodium acetate in methanol or ethanol to give compound of formula V, which on reaction with acetic anhydride and pyridine afforded compound of formula VI,
(Figure Removed)
Wherein R1, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl selected from a group consisting of isopropyl, isobutyl, t-butyl etc, a cyclic alkane selected from a group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens,
X is .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue selected from a group consisting of substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom O,N,S selected from a group consisting of piperazine, morpholine, oxazole, oxathinazole , oxathiazine .,
(Figure Removed)

(v) reacting the compound of formula VI with a dihaloalkane of formula VII wherein X2 and Xa is same or different halogens in an organic solvent in presence of a base selected form alkali metal carbonate at an elevated temperature ranging between 60-80°C for a period ranging between 2 to 10 hr to furnish intermediate compound of formula VIII, Wherein R-i, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is selected from a group consisting of Br
(Figure Removed)

(vi) subsequently reacting the compound of formula VIII with an amine of formula IX, wherein R3 and R5 are as defined above, in neat in presence of alkali metal halides selected from Kl, Nal, or in an organic solvent in presence of base at an elevated temperature ranging between 60-135°C
for a period ranging between 2 to 8 hr to provide the compound of general formula I.
In another embodiment of the present invention the solvent used in step (i) is selected form dry xylene, benzene, pantane, and mixture thereof.
In another embodiment of the present invention the lewis acid used in step (i) is selected from a group consiting of BFSetherate or AICI3.
In another embodiment of the present invention the solvent in step (Hi) used is selected form a group consisting of dry acetone, ethanol, and methanol. Dimethyl sulphoxide(DMSO), dimethylformamide(DMF), acetonitrile.
In another embodiment of the present invention the base used in step (iii) is selected form a group consisting of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate.
In another embodiment of the present invention the solvent used in step (iv) is selected form group consisting of dry DMSO, DMF, acetonitrile Hexamethylphosphoric triamide ( HMPA),.
In another embodiment of the present invention the acetic anhydride is used in basic medium.
In another embodiment of the present invention the base used is selected form a group consisting of pyridine, triethylamine, pyridine with dimethylaminopyridine.
In another embodiment of the present invention the dihaloalkane used is selected form a group consisting of -Chloro ethyl bromide, dibromoethane, Chloro propyl bromide.
In another embodiment of the present invention the base used in step (iv) is selected form a group consisting of potassium carbonate, cesium carbonate.
In another embodiment of the present invention the organic solvent used in the condensation of amine is dry DMF or DMSO.
In another embodiment of the present invention the pharmaceutical composition comprising an effective amount of a compound of formula 1 and salts thereof and a pharmaceutically acceptable salt thereof along with a pharmaceutical acceptable carrier or diluents.
DETAIEO DESCRIPTION OF THE PRESENT INVENTION
The present invention concerns naphtho [1,2-d] oxazole phenoxy substituted alkyl amino derivatives of formula (I), a novel class of compounds as anti-diabetic agents. In this we have designed a non-carboxylic acid or without active hydrogen contanting compound as anti-diabetic agents,
Wherein RI, R2 are individually H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, a lower alkoxy in which the alkyl group is as mentioned above, n is 1to 6, halogens, nitro, amino R3 R5 are .individually H, a lower straight or branched chain alkyl containing 1-10 carbon atoms as mentioned above, a cyclic alkane as defined above, an aryl residue such as substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form a part of a heterocylic ring such as pyrrolidine, piperidine, form a heterocylic ring with additional heteroatoms O,N,S such as piperazine, morpholine, oxazole, oxathinazole , oxathiazine etc.
R4 are individually H, a lower alkyl containing 1-6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower alkyl such as isopropyl, isobutyl, t-butyl etc, a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned above, n is 1to 6,holgens ,nitro, amino groups in process for the preparation of compounds of general formula I, which constitute reacting a substituted p-naphthol derivative of formula II wherein R1t and RZ are as defined above with a of substituted aromatic acid formula III wherein Xi is methoxy , hydroxy or lower alkoxy groups and R4 are same as defined above neat or in an organic solvent such as dry xylene .benzene etc with poly phosphoric acid or lewis acids such as BF3etherate , AICI3 etc at an elevated temperature( 60-80°C) to furnish intermediate compound of formula IV .which on reaction with hydroxylamine hydrochloride in presence of sodium acetate in methnol gave compound of formula V, which on reaction with acetic anhydride and pyridine afforded compound of formula VI, which on reaction with a dihaloalkane of formula VII wherein X2 and X3 may be same or different halogens in an organic solvent such as dry acetone , ethanol, methanol. Dimethyl sulphoxide(DMSO), dimethylformamide (DMF), acetonitrile etc in the
presence of a base such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate etc at an elevated temperature( 60-80°C) to furnish intermediate compound of formula VIII, which on subsequent reaction with an amine of formula IX, wherein R3 and R5 are as defined above, in neat, , presence of metal halides such as Kl, Nal or in an organic solvent such as dry DMSO.DMF, Hexamethylphosphoric Triamide ( HMPA), acetonitrile etc in presence of base such as of a base such as cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate etc at an elevated temperature( 60-135°C) afforded compound of formula I. BIOLOGICAL ACTIVITY
A ANTIDIABETIC ACTIVITY ANIMALS:
Adult male and female albino rats (Sprague Dawley) of body weight 160±20g, bred in CDRI animal house were used during the course of experiment; 6 animals were kept in one cage. All the animals were fed ad-lib standard pellet diet (Lipton, Bombay) and allowed unrestricted access to water. The following norms were followed for animal room environment. Temperature: 22 ± 1°C; Humidity: 50-50%; Light 300 Lux at floor level with regular 12 hours light cycle; noise level 50 decibels; ventilation 10-50 air changes per hour.
The blood-glucose lowering effects of the test samples/standard drugs were examined in the following two experimental models.
Sucrose-loaded rat model:
Overnight fasted male Sprague Dawley rats were used for the sucrose-loaded experiment. Blood was collected at 'O'min from the tail vein of the animals. After the '0' min blood collection, samples/drugs were given to the test group consisting of 5 rats by oral gavage at a dose of 100 mg/kg. Half an hour post test sample treatment, a sucrose-load of 10.0 gm/kg body weight was given to each rat. The blood was collected at 30, 60, 90 & 120 min post sucrose-load.
Streptozotocin-induced diabetic rat model:
Single-dose effect; Sprague Dawley strain male albino rats of average body weight 160±20 g were selected for this study. A calculated amount of the fresh solution of STZ dissolved in 100 mM citrate buffer (ph 4.5) was injected to overnight fasted rats (60 mg/Kg) intraperitoneally. Blood was checked for glucose content 48 h later by glucometer & animals showing blood glucose profile above 250 mg/dl were selected
and were divided into different groups. Blood-glucose levels were again tested at 1, 2, 3, 4, 5, 6, 7 and 24 h post test sample/drug administration. Food but not water was withdrawn from the cages during the experiment.
Sucrose challenged Streptozotocin-induced diabetic rat model:
Single-dose effect; Sprague Dawley strain male albino rats of average body weight 160±20 g were selected for this study. A calculated amount of the fresh solution of STZ dissolved in 100 mM citrate buffer (ph 4.5) was injected to overnight fasted rats (60 mg/Kg) intraperitoneally.
Blood was checked for glucose content 48 h later by glucometer & animals showing blood glucose profile between 150-250 mg/dl were selected and were divided into different groups. Half an hour post test sample treatment, a sucrose-load of 2.5 g/kg body weight was given to each rat. Blood-glucose levels were again tested at 30, 60, 90, 120,180, 240, 300 min and 24 h post test sample/drug administration. Food but not water was withdrawn from the cages during the experiment.
1} Hypoglycaemic activity of Test Compounds (compound no.5, 6,10 and 12), Glybenclamide and Gliclazide in normal rats:
The antidiabetic effect of test compounds (compound no 5, 6 and 10) and standard drug Glybenclamide, Gliclazide on OGTT of normal rats was determined. At 100-mg/kg doses level, test compounds 5,6,10,12 Glybenclamide and Gliclazide showed significant lowering 26.9%, 35.9%, 27.8 %, 33.6 %, 33.9% and 44.8% respectively, at 120 min post glucose load.
2) Hypoglycaemic activity of example 6, Glybenclamide and Gliclazide in STZ-induced diabetic rats:
The effect of Test compound 2-[-4-(-Piperidin-1-yl-propoxy)-phenyl]-naptho[1,2-djoxazole (12) and standard antidiabetic drug Glybenclamide and gliclazide on blood glucose lowering in STZ-induced diabetic rats were determined. At 100 mg/kg dose level compound 12, Glybenclamide and gliclazide showed significant lowering on blood glucose. The lowering started from 1-hour that persisted up to 7-hours post drug administration. The lowering was of the order 26.0%, 32.8% and 27.7% respectively in case of test compound 6, Glybenclamide and gliclazide
3^ Hypoglycaemic activity of compound no. 5, 6 and compound no 12. (compounds 5,6
&12) in sucrose challenged STZ-induced diabetic rats:
The effect of compound 5 and 6 on blood glucose lowering in sucrose challenged STZ-induced diabetic rats was determined. At 100 mg/kg dose level, compounds 5 and 6 did showed moderate lowering (16. 64% ,27.4 and 16.80 %respectively) and in blood glucose.
B. Lipid lowering activity of compound no. 5 and compound no. 6
Lipid lowering activity of compound-5 & 6 was evaluated in two different models (a)Triton Model: compound 5 and 6 showed the lowering in chol (14,21%) Tg.(11,14%) at 100 mg/kg respectively.
(b) Dyslipemic Hamster Model: Feeding with test compound no 5 reduced levels of plasma Tg, chol, glycerol, HDL by 18, 8,14,15 respectively. Similarly for compound no 6 reduced levels of plasma Tg, chol, glycerol, HDL by 14,11,12,17 at 300 umole/kg respectively.
Anti-hyperglycemic Activity in db/db mice :
The db/db mouse is a well-characterised model of type 2 diabetes. The background for the db/db mouse is the C57BL/Ks strain. The major deficiency of the C57BL/KsBom-db mouse (db/db) is lack of a functional leptin receptor. This leads to defective leptin signalling and a complete lack of feedback from leptin. Both hypothalamic NPY content and secretion are consequently elevated, and this result in hyperphagia and decreased energy expenditure, obesity, insulin-resistance, hyperinsulinemia, hyperglycaemia and dyslipidemia. The db/db mouse develops NIDDM from around week 10. The disease is stable until week 20, where destruction of pancreatic D-cells can be recognized clinically as decreasing levels of plasma insulin and very severe hyperglycaemia. The db/db mouse has a maximal life span of 9 -12 months. The male mice are more diabetic than, and will normally die earlier than the females. The advantage of using male mice for experimental purposes is that the fluctuations in plasma parameters are less than in the females where the oestrogen cycle affects the clinical diabetes. The optimal age of db/db mice used for experiments will be from week 12 to 18 when they have developed NIDDM with diabetic dyslipidemia but still have functional D-cells in the pancreas. C57BL/KsBom-db mice 12-18 weeks, 40 - 50 g bred in the animal house of CDRI,
Lucknow. 10 mice (5 males and 5 females) were used in the experiments. The mice were housed in groups of 5 (same sex) in a room controlled for temperature (23 ± 2.0 °C) and 12/12 hours light/dark cycle (lights on at 6.00 am). Body weight was measured daily from day 1 to day 10. All animals had free access to fresh water and to normal chow except on the days of the postprandial protocol day 6 and during the overnight fast before the OGTT on day 10. The animals always had access to water during experimental periods. Blood glucose was checked every morning up till day 5. On day 6 postprandial protocol was employed, in this method blood glucose was checked at -0.5h and Oh Test drugs were given to the treatment group whereas vehicle received only gum acacia (1.0%); the blood glucose was again checked at 1, 2, 3, 4 and 6h post test drug treatment. On day 8, blood was collected for serum insulin measurements and finally on day 10 an oral glucose tolerance test (OGTT) was performed after an overnight fasting. Blood glucose was measured at -30.0 min and test drugs were administered. The blood glucose was again measured at 0.0 min post treatment and at this juncture glucose solution was given at a dose of 3 gm/kg to all the groups including vehicle. The blood glucose levels were checked at 30 min, 60 min, 90 min and 120 min post glucose administration. Compounds 5,6 and 12 showed ( 16,2land 18 %) blood glucose lowering effect on postprandial protocol on day 3 in db/db. (detail results are in Table 2)
Table 1: In vivo antihyperglycemic activity profile of active compounds in SLM and STZ S models

(Table Removed)
Table 2: In vivo antihyperglycemic, lipid lowering and triglyceride lowering profile of active compounds db/db mice models (% efficacy, 3 days,100mg/kg)
(Table Removed)
Following examples are given by way of illustration of the present invention and therefore should not construe to limit the scope of the present invention.
Example 1: 4-Naphtho [1, 2-d] oxazole-2-yl-phenol:
Naphthophenone oxime (1gm) was dissolved in acetic anhydride (3.0 ml_) and stirred at room temperature for 30 mins. The reaction was quenched with ice water and extracted with ethyl acetate. The organic layer was dried on sodium sulfate and evaporated under vacuum, which afforded naphthophenone oxime acetate as a solid. The solid is as such used for second step. The naphthophenone oxime acetate was again dissolved in (Dry) pyridine (10 ml_, dry) and heated at 120° C for 14 hour. Completion of reaction was checked by Tic. Reaction mixture was washed with water and extracted with ethylacetate to give compound of formula VI. (Dry) Yield (62%) ,m.p. 278°C, I.R.(KBr) Cm'1 3450, 1610, 1437,1 HNMR (DMSO-d6) :6 8.4(ArH,d,J=8.1,1H); 8.1(ArH,d,J=8.1,2H); 8.08 (ArH.d, J= 8.1,1H); 7.92 (ArH,m,2H); 7.68 (ArH,d,J=6.9,1H); 7.57 (ArH, d,J= 8.1,1H); 6.98 (ArH, d,J=8.7,2H); 13C NMR (DMSO-de): 162.37 160.70, 147.30, 130 .86.129.05; 128.79; 127.09; 125.46; 121.59; 117.54; 116.19; 111.10 ; Mass (FAB) 262[M+]Analysis ::C,78.12 ;H 4.25 ; N.5.36; (Obs) C.78.32 ;H 4.26 ; N.5.58.
Example 2: Acetic acid-4-naphtho [1, 2-d] oxazole-2-yl-phenyl ester: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1gm) was dissolved in acetic anhydride (solvent) and in presence of catalytic amount of pyridine in cold The reaction mixture was stirred at room temperature for 30 min to afford the acetic acid -4-naphtho[1,2-d] oxazole-2-
yl-phenyl ester. Yield (80 %) ,m.p. 185-87°C J.R.(KBr) CnT13416, 1748, 1605 1 HNMR (CDCI3) .6 8.51(ArH,d,J=8.1, 1H); 8.28 (ArH, 2H,m); 7.90 (ArH, d,J=8.06, 1H); 7.68 (ArH,m,4H); 7.22( ArH, m,2H); 2.27(CH3CO,s,3H) ;Mass (FAB) 304[M+1] ; Analysis : 0,78.0 4 ;H 4.6 2 ; N.4.82 ; (Obs.) 0,78.23 ;H 4.8 2 ; N.4.8 2
Example 3: 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole.: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 1.32 gm was taken in dry acetone and 1-bromo-3-chloropropane (1.5ml ) .potassium carbonate ( 13.8 gm) was added. The reaction mixture was refluxed for 8 hr .Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction was taken in (100 ml) ethyl acetate and washes with 150 ml water, dried over sodium sulphate and crystallized with ethyl acetate and hexane. Yield (87 %) ,m.p. 108-10°C , I.R.(KBr) Cm'1 1609,1495,705;1 HNMR (CDCI3) .5 8.59 ArH,d,J=8.0,1H); 8.25(ArH,d,J=8.8,2H,); 7.86 (ArH,d,J=8.2, 1H); 7.68 (ArH,m,4H); 7.04(ArH,d,J=8.7,2H); 4.2(OCH2,t, J=5.8,2H) ;Mass (FAB) 338 [M+1] Analysis : 0,71.11 ;H 4..77 ; N.4.15 ;. (Obs.) C, 71.33; H 4.89; N, 4.33.
Example 4 : 2-[4-(2-Pyrrolidin-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 520 mg was taken in in dry DMF (10 ml) and 1-(2-Chloro-ethyl)-pyrrolidine hydrochloride (632mg) , potassium carbonate (6.5gm) was added. The reaction mixture was stirred at 100°C for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethylacetate150ml and dried over sodium sulphate., Column was run using ethylacetate and hexane as a eluent on basic alumina.
Yield (74%) ,m.p. 98-100°C, I.R.(KBr) Cm'1 3446 ,1607, ; 1 HNMR (CDCI3) .6 8.57 (ArH,d,J=8.2,1H); 8.25(ArH,d,J=8.8,2H,); 7.95 (ArH, d, J=8.2,1H);7.68 (ArH,m,4H);7.06(ArH,d,J=8.4,2H);4.2(OCH2,t,J= 5.9, 2H) ,2.95(NCH2,t,J=6Hz), 2.62(m, 4H,NCH2), 1.86 (CH2CH2,m 4H).; Mass (FAB) 359 [M+1] Analysis ::C,78.12 ;H 4.25 ; N.5.36; (Obs) 0,78.32 ;H 4.26 ; N.5.58.
Example 5: 2-[4-(2-Piperidine-1-yl-ethoxy)-phenyl]-naphtho [1,2-d] oxazole: 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry DMF and 1-(2-Chloro-ethyl)-piperdine hydrochloride (441 mg), potassium carbonate 6.5gm was
added. The reaction mixture was stirred at 100°C for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml)and. Extracted with ethylacetate (150ml) and dried over sodium sulphate. Column was run using etylacetate and hexane as a eluent on basic alumina.
Yield (74%) ,m.p. 118-20°C; I.R.(KBr) Cm'1 3436 ,1612, 12561; HNMR (CDCI3) .6 8.57(ArH,d,J=8.2,1H); 8.25 (ArH, d,J=8.8,2H,); 7.95 (ArH,d,J=8.2, 1H); 7.68 (ArH,m,4H);7.04(ArH,d,J=7.4,2H); 4.18 (OCH2 ,t, J=5.9,2H), 2.80 (NCH2,t, J= 5.8Hz) , 2.56(m, 4H,NCH2), 1.66,(CH2CH2 CH2,m 6H).Mass (FAB) 373 [M+1] ] Analysis ::C,78.18 ;H6.75; N,7.50;(Obs) C.78.32 ;H 6.26 ; N.7.63 1.66, (CH2CH2CH2,m 6H)
Example 6: Dimethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry acetone and 1-(2-Chloro-ethyl)-dimethyl,hydrocholoride (340 mg ), potassium carbonate (6.5g) was added. The reaction mixture was refluxed for 8 hr. Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction mixture was taken in 100 ml ethylacetate and wash with (150 ml) water and dried over sodium sulphate. Column was run using ethylacetate and hexane as a eluent on basic alumina.
Yield (81%) ,m.p. 102-04°C ; I.R.(KBr) Cm'1 3417 ,1609, 1243; 1 HNMR (CDCI3) .6 8.26 (ArH,d,J=9.8,1H); 7.74(ArH,d,J=5.4,2H,); 7.76 (ArH.m 1H); 7.68 (ArH, m,4H); 7.07 (ArH,d,J=8.,2H); 4.16(OCH2,t, J=5.6,2H), 2.78 (m,2H, NCH2, t,J=5.6Hz),2.3(NCH3,s, 6H).;Mass (FAB) 333 [M+1] °C Analysis ::C,75.58;H 5.65 ; N.8.26; (Obs) C.75.88 ;H 6.06 ; N.8.43
Example 7: Diethyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine 4-Naphtho[1,2-d]oxazole-2-yl-phenol (1) 524 mg was taken in dry acetone and 1-(2-Chloro-ethyl)-diethyl,hydrocholoride (412mg), potassium carbonate (6.5g) was added. The reaction mixture was refluxed for 8 hr Completion of reaction was checked by Tic monitoring. Reaction was filtered and concentrated to remove acetone. The reaction mixture was taken in (100 ml) ethyl acetate and washes with (150 ml) water, dried over sodium sulphate and purified through basic alumina column using ethyl acetate and hexane as eluting solvent.
Yield (84%) ,m.p.98-100 °C; I.R.(KBr) Cm'1 3437 ,1608, 1246; 1 HNMR (CDCI3) .5 8.56,(ArH,d,J=8.2,1H); 8.25(ArH,d,J=8.8 2H,); 7.96 (ArH,d,J=8.2,1 H); 7.68 (ArH,m,4H); 7.04 (ArH,d,J=9.,2H); 4.13 (OCH2,t,J=6.4,2H), 2.91 (NCH2,t, J= 5.4Hz,2H) ,2.6 (NCH2,q, 4H) 1.06 (CH3,t,J=1.66;Mass (FAB) 361 [M+1] Analysis :C,76.58;H 6.85;N,8.26; (Obs) C,76.64;H 6.71 ; N.7.77;
Example 8: Butyl-methyl-[2-(4-naphtho[1,2-d]oxazol-2-yl-phenoxy)-propyl]-amine 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776mg) was taken in dry DMF (15ml) and N-methyl-butylamine (0.25ml),potassium iodide(830mg)were added. The reaction mixture was stirred at 100°C for 4 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in waterlOOml and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using etylacetate and hexane as eluting solvents. Yield(84%),m.p. 115-18°C(HCI salt); 1 HNMR (CDCI3) 6 8.57, ArH,d,J=5.2,1H); 8.25(AiH,d,J=5.8 2H,); 7.94 (ArH,d,J=5.6,1 H); 7.68 (ArH,m,4H); 7.02 (ArH.d, J= 6,2H); 4.08(OCH2,t,J=2.6,2H), 2.53 (NCH2, ,J=4.6Hz,2H), 2.36 (NCH2,t,J= 5.2.2H). 2.24 (NCH3 ,S,3H) ,1.97 NCH2,t, =4.8,2H)1.35(CH2CH2>m,4H), 0.99 (CH3,t,J=5.4);Mass (FAB) 389 [M+1] Analysis ::C,77.29;H 7.26; N,7.28; (Obs) 0,77.54 H 7.37 N 7.43
Example 9: 4-Methoxy-phenyl)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propyl]-amine
2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776mg) was taken in dry DMF (15ml) and p- anisidine (295mg),potassium iodide (830mg) were added. The reaction mixture was stirred at 100°C for 4 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (84%),m.p. 136-40°C
1 HNMR (CDCI3) 5 8.57,(ArH,d,J=5.2,1H); 8.25(ArH,d,J=5.8 2H,); 7.94 (ArH,d,J=5.6,1 H); 7.68 (ArH,m,4H); 7.02 (ArH,d,J=6,2H); 4.08 (OCH2,t,J=2.6,2H),. 3.7(s,OCH3 3H); 3.37(t, NCH2, 3H,J + 4.4); 2.15 (m,CH2 ,2H)2.24 (NCH3,s,3H), 1.97(NCH2,t,J=4.8,2H) 0.99 (CH3, t,J=5.4);Mass (FAB) 389 [M+1] Analysis ::C,76.89 H7.74; N.7.17 ; (Obs) C,76.64;H7.54 ; N.7.34
Example 10: -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-p-tolyl-amine
2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (710mg) was taken in dry
DMF (15ml) and toludine (920 mg ),potassium iodide
(830mg) were added.The reaction mixture was stirred at 100°C for 4 hr. Completion of
reaction was checked by Tic monitoring. Reaction mixture was poured in waterlOOml
and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified
through basic alumina column chromatography using ethyl acetate and hexane as
eluting solvents.
Yield (89%) ,m.p. 118-20°C).1 HNMR (CDCI3) 5 8.57,(ArH,d,J=5.2,1H); 8.25(ArH,m
2H,); 7.95 (ArH,d,J=5.4,1H); 7.68 (ArH,m,3H); 7.52 (ArH,
m,,2H);6.99(ArH,t,J=6.0,4H);6.57(ArH,d,J=5.6)5.27(NH,s,1H);4.14 (OCH2, t,J=3.8,2H),
3.34(NCH2,t,J=4.4Hz,2H) ,2.36 (NCH2,t,J=5.2, 2H) .2.23(PhCH3,s,3H),
2.11(CH2,m,2H);Mass (FAB) 409M+1]
Analysis ::C,79.39 H 5.92; N.6.86; (Obs) C,79.54;H 5.64 ; N.6.86
Example 11: -[3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyl]-octyl-amine;-
2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (760mg) was taken in dry
DMF (15ml) and octylamine (0.2ml), potassium iodide (830mg) were added. The
reaction mixture was stirred at 100°C for 6 hr. Completion of reaction was checked by
Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl
acetate (150 ml), dried over sodium sulphate and purified through basic alumina
column chromatography using ethyl acetate and hexane as eluting solvents.
Yield (76%) ,m.p. 67-69°C);
1 HNMR (CDCI3) .6 8.57,(ArH,d,J=8.2,1H); 8.25(ArH,d,J=6 2H,); 7.96
(ArH,d,J=4.2,1H);7.68(ArH,m,4H);7.04 (ArH,d,J=6.,2H); 4.13 (OCH2, t,
J=6.4,2H),2.83(NCH2,t)J=5.4Hz>2H),2.63(NCH2J=4,2H).2.01 (CH2,m,2H); 1.52(CH2
rn,4H); 1.2(CH2 ,m,8H); 0.88(CH3,t,J=4;
Mass (FAB) 431 [M+1] Analysis ::C,78.10; H 7.96 ; N,6.51;
(Obs) C,78.44;H 7.53 ;N,673;
Example 12: 2-[-4-(-Piperidin-1-yl-propoxy)-phenyl]-naptho[1,2-d]oxazole 2-[4-(3-chloro-propoxy)-phenyl]-naphtho [1,2-d] oxazole (3) (776 mg) was taken in dry DMF (15ml) and piperidine (0.2ml), potassium iodide (830mg) were added. The reaction mixture was stirred at 100°C for 6 hr. Completion of reaction was checked by Tic monitoring. Reaction mixture was poured in water (100ml) and extracted with ethyl acetate (150 ml), dried over sodium sulphate and purified through basic alumina column chromatography using ethyl acetate and hexane as eluting solvents. Yield (89%) ,m.p. 119°C. I.R.(KBr) Cm"1 3432, 1604, 1250; 1HNMR (CDCI3) :5 8.57 (ArH,d,J=7.61H); 8.23 (ArH,d,J=7.2,2H); 7.95(ArH,d, J= 7.2,1 H); 7.722(ArH,m,4H); 7.02(ArH,d,J=6.9,2H);4.09(OCH2,t.J=6.2);
2.52(NCH2 ,m,4H,) 2.05(NCH2,m,2H) 1.70(CH2.m,4H); 1.65 (CH2.m,2H) Mass (FAB) 287 [M+1]; Analysis ::C,77.18 ;H6.75, N.7.50; (Obs) C.77.32 ;H 6.46 ; N,7.58.
ADVANTAGES OF THE PRESENT INVENTION
The compounds of the present invention exhibiting significant antidiabetic activity with good lipid and Triglyceride lowering activity, which has given these compounds an added advantage over other antidiabetic compound.

We claim:
1. A compound of formula (I) and salts thereof,
wherein R1, RZ are individually H, a lower alkyl containing 1-6 carbon atoms selected
from a group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain
lower alkyl selected from isopropyl, isobutyl, t-butyl etc, a cyclic alkane selected from
group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, R3 alkoxy in which
the alkyl group is as mentioned above, n is lto 6, halogens, nitro, amino R3 Rs are
,individually H, a lower straight or branched chain alkyl containing 1-1 0 carbon atoms as
mentioned above, a cyclic alkane as defined above, an aryl residue selected from
substituted phenyl phenyl, substituted phenyl, naphthyl, an arylalkyl residue selected
from group consisting of benzyl, substituted benzyl, form a part of a heterocyclic ring
such as pyrrolidine, piperidine, form a heterocyclic ring with additional heteroatom
O,N,S such as piperazine, morpholine, oxazole, oxathinazole , oxathiazine. R4 is selected
from a group consisting of H, a lower alkyl containing 1-6 carbon atoms selected from
group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain
lower alkyl selected from isopropyl, isobutyl, t-butyl, a cyclic alkane selected from group
consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, an alkoxy in which the
alkyl group is as mentioned above, value of n is 1 to 6.
2. A compound as claimed in claim 1 wherein the representative compounds
comprising:
(i) 4-Naphtho[l,2-dloxazole-2-yl-phenol
(ii) Acetic acid-4-naphtho[1,2-d]oxazole-2-yl-phenyle ster
(iii) 2-[4-(3-chloro-propoxy)-phenyll-naphtho [I ,2-dl oxazole
(iv) 2-[4-(2-Pyrrolidin-1 -yl-ethoxy)-phenyll-naphtho [1,2-dl oxazole
(v) 2-[4-(2-Piperidine- 1 -yl-ethoxy)-phenyll-naphtho [l,2-dl oxazole
(vi) Dimethyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine
(vii)Diethyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-ethyl]-amine
(viii) Butyl-methyl-[2-(4-naphtho[l,2-d]oxazol-2-yl-phenoxy)-propyl]-amine
(ix) 4-Methoxy-pheny1)-[3-(4-naphtho[1,2-dloxazol-2-yl-phenoxy)-propy1]-amine
(x) [3-(4-naphtho[1,2-d loxazol-2-yl-phenoxy)-propyll-p-tolyl-a(mx i) [3-(4-
naphtho[l,2-d Ioxazol-2-yl-phenoxy)-propyll-octyl-amin(ex ii) 2-[-4-(-Piperidin- 1 -ylpropoxy)-
phenyll-naptho[l,2-dloxazole
3. A process for the preparation of compound of general formula 1, the said
process comprising :
(a) reacting a formula A wherein R1, and R2 with compound formula B wherein X is
selected from methoxy , hydroxy or an lower alkoxy groups and & are same as defined
above neat or in an organic solvent with poly phosphoric acid or Lewis acids at an
elevated temperamre ranging between 60-80°C to furnish intermediate compound of
formula C.
(b) reacting the compound of formula C with hydroxylamine hydrochloride in presence
of sodium acetate in methanol or ethanol to give compound of formula D, which on
reaction with acetic anhydride and pyridine afforded compound of formula E,
wherein R1, R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms,
selected from a group consisting of as methyl, ethyl, propyl, butyl, pentyl, hexyl, a
branched chain lower alkyl selected from a group consisting of isopropyl, isobutyl, tbutyl
etc, a cyclic alkane selected from a group consisting of cyclopropyl, cyclobutyl,
cyclohexyl, cycloheptyl etc, a lower alkoxy in which the alkyl group is as mentioned
above, nitro, amino, halogens, X is .individually H, a lower straight or branched chain
alkyl containing 1-1 0 carbon atoms as mentioned above, a cyclic alkane as defined
above, an aryl residue selected from a group consisting of substituted phenyl phenyl,
substituted phenyl, naphthyl, an arylalkyl residue such as benzyl, substituted benzyl, form
a part of a heterocyclic ring such as pyrrolidine, piperidine, form a heterocyclic ring with
' additional heteroatom O,N,S selected from a group consisting of piperazine, morpholine,
oxazole, oxathinazole , oxathiazine.
(c) reacting the compound of formula E with a dihaloalkane of formula F wherein X2 and
X3 is same or different halogens in an organic solvent in presence of a base selected form
alkali metal carbonate at an elevated temperature ranging between 60-80°C for a period
ranging between 2 to 10 hr to furnish intermediate compound of formula G, wherein Rl ,
R2, R4 are individually H, a lower alkyl containing 1-6 carbon atoms, selected from a
group consisting of methyl, ethyl, propyl, butyl, pentyl, hexyl, a branched chain lower
alkyl selected from group consisting of isopropyl, isobutyl, t-butyl, a cyclic alkane
selected from group consisting of cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, an
alkoxy in which the alkyl group is as mentioned above, nitro, amino, halogens, X is
selected from a group consisting of Br.CI and I.
(d) subsequently reacting the compound of formula G with an mine of formula H,
wherein R3 and R5 are as defined above, in neat in presence of alkali metal halides
selected from K1, Nal, or in an organic solvent in presence of base at an elevated
temperature ranging between 60-1 35°C for a period ranging between 2 to 8 hr to provide
the compound of general formula I.
4. A process as claimed in claim 3 wherein the solvent used in step (a) is selected
from a group consisting of dry xylene benzene, pantane, and mixture thereof.
5. A process as claimed in claim 3 wherein the lewis acid used in step (a) is
selected from a group consisting of BF3 etherate or AIC13.
6. A process as claimed in claim 3 wherein the solvent in step (c) used is
selected form a group consisting of dry acetone, ethanol, methanol. Dimethyl
sulphoxide(DMSO), dimethylformamide(DMF), acetonitrile.
7. A process as claimed in claim 3 wherein the base used in step (c) is selected
form a group consisting of cesium carbonate, potassium carbonate, sodium
carbonate, lithium carbonate.
8. A process as claimed in claim 3 wherein the solvent used in step (d) is selected form
group consisting of dry DMSO, DMF, acetonitrile, Hexamethylphosphoric triamide
(HMPA),
9. A process as claimed in claim 3 wherein basic medium used in step (c) & (d) is
selected from the group consisting of pyridine, triethylamine, pyridine with
dimethylaminopyridine, potassium carbonate, cesium carbonate
10. A process as claimed in claim 3 wherein the dihaloalkane used in step (c) is selected
form a group consisting of Chloro ethyl bromide, dibromoethane, Chloro propyl
bromide.

Documents:

611-del-2006-abstract.pdf

611-del-2006-Claims-(12-03-2013).pdf

611-del-2006-claims.pdf

611-del-2006-Correspondence Others-(12-03-2013).pdf

611-del-2006-correspondence-others 1.pdf

611-del-2006-correspondence-others.pdf

611-del-2006-description (complete).pdf

611-del-2006-description (provisional).pdf

611-del-2006-form-1.pdf

611-del-2006-form-18.pdf

611-del-2006-form-2.pdf

611-del-2006-form-3.pdf

611-del-2006-form-5.pdf

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Patent Number

258216

Indian Patent Application Number

611/DEL/2006

PG Journal Number

51/2013

Publication Date

20-Dec-2013

Grant Date

18-Dec-2013

Date of Filing

08-Mar-2006

Name of Patentee

Council of Scientific and Industrial Research.

Applicant Address

Anusandhan Bhawan, Rafi Marg, New Delhi - 110 001, India.

Inventors:

#	Inventor's Name	Inventor's Address
1	TIWARI, PRITI	Central Drug Research Institute, Chattar Manzil Palace, Post Box No 173, Lucknow 226 001, India.
2	TRIPATHI, BRAJENDRA KUMAR	Central Drug Research Institute, Chattar Manzil Palace, Post Box No 173, Lucknow 226 001, India.
3	AHMAD, PERVEZ	Central Drug Research Institute, Chattar Manzil Palace, Post Box No 173, Lucknow 226 001, India.
4	SRIVASTAVA, ARVIND KUMAR	Central Drug Research Institute, Chattar Manzil Palace, Post Box No 173, Lucknow 226 001, India.
5	KUMAR, ATUL	Central Drug Research Institute, Chattar Manzil Palace, Post Box No 173, Lucknow 226 001, India.

PCT International Classification Number

A61K 31/41

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA