Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
  • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
  • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
  • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring

Definitions

• TECHNICAL FIELD This invention relates to novel t ⁇ -substituted-naphthyloxy-amino alkanes, their preparation and use as antihyperglycemic agents and for the treatment and prevention of cardiovascular disorders (CVS) such as lipid lowering effects.
• CVS cardiovascular disorders
• PPAR ⁇ -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.
• NIDDM Type II diabetes
• a number of agents show PPAR ⁇ agonist activity.
• Most of these compounds are 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.
• Yet another object of the present invention relates to the to a pharmaceutical composition for the treatment or prevention of cardiovascular disorders (CVS) and of hyperglycemic condition (diabetes) in mammals, including humans, said composition comprising of administering effective dosage of novel ⁇ -naphthyloxy amino alkane derivatives having structural Formula 1 optionally along with acceptable salt/s, carrier/s or dilutent/s.
• CVS cardiovascular disorders
• diabetes hyperglycemic condition
• Still another object of the present invention relates to a method for treatment or prevention of cardiovascular disorders and hyperglycemia (diabetes) by administering pharmaceutical effective dosage of ⁇ -naphthyloxy amino alkane derivatives having structural Formula 1.
• This invention relates to novel TO-substituted-naphthyloxy-amino alkanes, their preparation and use as antihyperglycemic agents and for the treatment and prevention of cardiovascular disorders (CVS) such as lipid lowering effects.
• CVS cardiovascular disorders
• the present invention therefore relates to novel ⁇ -naphthyloxy amino alkane derivatives having structural formula I,
• Ri and R 2 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 and alkyl chains thereof.; a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and cyclic alkanes thereof.; a lower alkoxy in which the alkyl group is as mentioned above, n is 1 to 6; R 3 and t are individually H, a lower straight or branched chain alkyl containing 1-15 carbon atoms as mentioned above; a cyclic alkane as defined above; an aryl residue selected from group comprising of phenyl, substituted phenyl, naphthyl; an arylalkyl residue selected from group comprising
• This invention relates to novel ⁇ i-substituted-naphthyloxy-amino alkanes, their preparation and use as antihyperglycemic agents and for the treatment and prevention of cardiovascular disorders (CVS) such as lipid lowering effects.
• the main objective ofthe present invention is to provide agents to act in NIDDM with the added advantage of their effect in lowering low density cholesterol (LDL) without affecting high density cholesterol (HDL) in the treatment and prevention of CVS disorders.
• LDL low density cholesterol
• HDL high density cholesterol
• the main embodiment of present invention relates to novel ⁇ - naphthyloxy amino alkane derivatives having structural formula I,
• Ri and R 2 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 and alkyl chains thereof; a cyclic alkane such as cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and cyclic alkanes thereof.; a lower alkoxy in which the alkyl group is as mentioned above, n is 1 to 6; R 3 and j are individually H, a lower straight or branched chain alkyl containing 1-15 carbon atoms as mentioned above; a cyclic alkane as defined above; an aryl residue selected from group comprising of phenyl, substituted phenyl, naphthyl; an arylalkyl residue selected from group comprising of
• Ri and R 2 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 1 to 6; R 3 and t are individually H, a lower straight or branched chain alkyl containing 1-15 carbon atoms as mentioned above; a cyclic alkane as defined above; an aryl residue such as phenyl, substituted phenyl, naphthyl; an arylalkyl residue such as benzyl, substituted benzyl, form a part of a hetero
• Ri and R 2 are defined as above and wherein X ⁇ and X may be same or different halogens, and (b) reacting compound of formula IV with an amine of fomiula V in presence of an acid binding agent optionally in an organic solvent to obtain compound of formula I, wherein X 2 is a halogen-and R 3 and t are defined as above.
• Another embodiment ofthe present invention relates to base in step (a) wherein the said base is selected from a group comprising of cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate or other bases.
• organic solvents in step (b) wherein the said organic solvents are selected from group comprising of dimethyl sulphoxide (DMSO), dimethylformamide (DMF), Hexamethylphosphoric triamide (HMPA) or acetonitrile.
• DMSO dimethyl sulphoxide
• DMF dimethylformamide
• HMPA Hexamethylphosphoric triamide
• Yet another embodiment ofthe present invention relates to temperature wherein the said temperature in step (a) is in range of about 50°C to 100°C, Yet another embodiment ofthe present invention relates to temperature wherein the said temperature is preferably in the range of about 60°C to 80°C.
• Still another embodiment of the present invention relates to temperature wherein the said temperature in step (b) in the range of about 120°C to 180°C.
• Still another embodiment of the present invention relates to temperature wherein the said temperature is preferably in the range of about 130°C to 150°C.
• Still another embodiment of the present invention relates to the reaction time in steps (a) and (b) wherein said reaction time is in range of about 4 hours to 13 hours.
• the present invention relates to the derivatives of formula (1) wherein the said derivatives have their melting points in the range of about 75°C to 270°C.
• the present invention relates to the purity of the derivatives of formula (1) wherein the purity of the said derivatives is in the range ofabout 80% to l00%.
• Another embodiment of the present invention relates to a pharmaceutical composition for the treatment or prevention of cardiovascular disorders (CVS) and of hyperglycemic condition (diabetes) in mammals, including humans, said composition comprising of administering effective dosage of novel ⁇ -naphthyloxy amino alkane derivatives having structural Formula 1,
• Ri and R 2 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 1 to 6; R 3 and R t are individually H, a lower straight or branched chain alkyl containing 1-15 carbon atoms as mentioned above; a cyclic alkane as defined above; an aryl residue such as phenyl, substituted phenyl, naphthyl; an arylalkyl residue such as benzyl, substituted benzyl, form a part of
• Ri and R 2 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 1 to 6; R 3 and t are individually H, a lower straight or branched chain alkyl containing 1-15 carbon atoms as mentioned above; a cyclic alkane as defined above; an aryl residue such as phenyl, substituted phenyl, naphthyl; an arylalkyl residue such as benzyl, substituted benzyl, form a part of a hetero
• R is a lower alkyl as defined above, optionally along with acceptable salt/s, carrier/s or dilutent/s.
• Another embodiment of the present invention relates to the salts/carriers/diluents selected from a group consisting of lactose, sodium chloride, potassium chloride, magnesium sulphate, magnesium chloride, potassium sulfate, sodium sulfate, lithium sulphate, sodium phosphate, potassium phosphate, magnesium succinate, sodium carbonate, sodium sulfate, potassium acid phosphate or calcium bicarbonate.
• Another embodiment of the present relates to derivatives wherein the said derivatives may be administered in form syrup, capsule, tablet, intravenous, liquid or suspension.
• One more embodiment of the present invention relates to derivatives wherein method of administration for said derivatives may be oral, nasal, rectoral, or parenteral.
• One more embodiment of the present invention relates to derivatives wherein said derivatives lower the concentration of cholesterol by about 30%.
• One more embodiment of the present invention relates to derivatives wherein said derivatives lower the concentration of cholesterol preferably by about 26%.
• Another embodiment of the present invention relates to derivatives wherein the said derivatives lower the concentration of phospholipid by about 35 %.
• Another embodiment of the present invention relates to derivatives wherein the said derivatives lower the concentration of triglyceride by about 50 %
• One more embodiment of the present invention relates to derivatives wherein said derivatives enhances the high-density lipoprotein (HDL) concentration by about 20%.
• HDL high-density lipoprotein
• Yet another embodiment ofthe present invention relates to derivatives wherein said derivatives enhances the high-density lipoprotein concentration preferably by about 14%. Still another embodiment of the present invention relates to derivatives where said derivatives lowers the glucose (GLU) concentration to about 35 %. Still another embodiment of the present invention relates to derivatives wherein said derivatives lowers the glucose concentration preferably to about 30%. Another embodiment of the present invention relates to derivatives wherein said derivatives lowers the glycerol (GLY) concentration by about 18 %.
• GLU glucose
• GLY glycerol
• Still another embodiment ofthe present invention relates to derivatives wherein the said derivatives lower the glucose concentration in about 1 hr to 7 hrs during post drug administration.
• the below given examples should not be construed to limit the scope of the invention.
• a mixture of ⁇ -naphthol (lgm, 0.006 mole), anhydrous K 2 CO 3 (10 gm, in excess) and 1-bromo 4-chlorobutane (0.8 ml, 0.006 mole) was refluxed in dry acetone (50ml) for 6 hours. Reaction mixture was filtered and filtrate was concentrated to get oily compound, which was crystallized with benzene-hexane to give the colorless crystals of pure desired compound, m.p. 112°C, (yield 1.6 gm, 98%).
• the method of preparation of compounds of formula I are given in these following examples.
• Example 7 N-(4-Methoxyphenyl)-[3-(naphthalen-2-yloxy) propyl] amino ⁇ acetic acid ethyl ester.
• R 3 CH 2 COOEt
• R t 4-methoxy phenyl
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and p-toluedine (0.36 gm,0.003 mole) was taken in dry DMSO(40 ml) .Now 3-(2-na ⁇ hthyloxy)l- chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140 °C for 7 hrs. and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get (4-methylphenyl)-[3- (naphthylen-2-yloxy) propyl] amine, m. ⁇ .l00°C, (yield 0.63 gm, 94.3 %).
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and p-toluedine (0.35 gm, 0.003 mole) was taken in dry DMSO(40 ml)-Now 4-(2-naphthyloxy)-l- chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150 °C for 8 hrs.
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and m-methoxy- benzyl amine (0.45 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 3-(2- naphthyloxy)-l-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150°C for 8 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and ⁇ concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3- methoxybenzyl)-[3-napthalen-2-yloxy)propyl]amine yellow, solid, m.p.97 °C, (yield 0.66 gm, 90.6 %).
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and m-methoxy benzyl amine (0.46 gm, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2- naphthyloxy)-l-chloropropane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150°C for 9 hrs and the reaction was completed as checked by TLC.
• a mixture of anhydrous potassium carbonate (10 gm, Jn excess) and 2-ethyl n- hexyl amine ( 0.37 ml,0.003 mole) was taken in dry DMSO(40 ml).Now 2-(2- naphthyloxy)-l -chloroethane (0.5 gm, 0.002 mole) was added in it.
• Reaction mixture was refluxed at 140°C for 7 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl- n- hexyl)-(2-(naphthalen-2-yloxy) ethyl] amine, solid, m.p.92 °C, (yield 0.62 gm, 83.6 %).
• Reaction mixture was refluxed at 140°C for 7 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-dodecyl)-(3- (naphthalen-2-yloxy)-propyl) amine, solid, m.p.126 °C, (yield 0.78 gm, 92.8 %).
• a mixture of anhydrous potassium carbonate (10 gm,-in excess) and n-dodecyl amine (0.48 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 4-(2- naphthyloxy)-l -chlorobutane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 150°C for 8 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-dodecyl)-(4- (naphthalen-2-yloxy)-butyl) amine, solid, m.p. 129 °C, (yield 0.78 gm, 95.5 %).
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and isoamyl amine (0.24 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 2-(2-naphthyloxy)-l- chloroethane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 140°C for 6 hrs and the reaction was completed as checked by TLC.
• 3-(2-naphthyloxy)-l-chloropropane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 150°C for 7 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(3- phenylpropyl)-(3-(naphthalen-2-yloxy) propyl) amine, solid, m.p. 109 °C, (yield 0.645 gm, 89.3 %).
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and n-octyl amine (0.35 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 3-(2-na ⁇ hthyloxy)-l- chloropropane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 140°C for 6 hrs and the reaction was completed as checked by TLC.
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propyl amine (0.26 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 4-(2- naphthyloxy)-l -chlorobutane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 140°C for 7 hrs and the reaction was completed as checked by TLC.
• Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(n-butyl)-(3-(naphthalen- 2-yloxy) propyl) amine, solid, m.p. 112 °C, (yield 0.55 gm, 94.5 %).
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and n-propyl amine (0.28 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 3-(2- naphthyloxy)-l-chloropropane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 145°C for 8 hrs and the reaction was completed as checked by TLC.
• a mixture of anhydrous potassium carbonate (10 gm, in excess) and piperidine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml).
• 3-(2-na ⁇ hthyloxy)-l- chloropropane 0.5 gm, 0.002 mole was added in it. Reaction mixture was refluxed at 150°C for 8 hrs. and the reaction was completed as checked by TLC.
• a mixture of 2,7-bis (3-chloropropyloxy)naphthalene ( 1 gm, 0.003 mole) and p- anisidine (1.17gm, 0.005 mole) were taken in 60 ml dry DMSO. It was refluxed at 140 °C for 12 hrs the completion ofthe reaction was checked by TLC.
• reaction mixture was poured into distilled water (80 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was further crystallized by benzene hexane to get the desired compound as solid, m.p. 127 °C, (yield 1.34 gm, 89 %).
• a mixture of 2,6-bis(3-chloropropyloxy)naphthalene(lgm, 0.003 mole) and p- anisidine (1.17gm, 0.005 mole) was taken in 60 ml dry DMSO . It was refluxed at 140 °C for 12 hrs. The completion ofthe reaction was checked by TLC.
• reaction mixture was poured into distilled water (80 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was further crystallized by benzene hexane to get the desired compound, m.p. 129 °C, (yield 1.4 gm, 91 %).
• 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 tailNein 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 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.
• test compounds Compound no. 1 and 4
• Glybenclamide and Gliclazide The antidiabetic effect of test compounds (compound no.l and 4) and standard drug Glybenclamide, Gliclazide on OGTT of normal rats was determined.
• test compounds 1, 4, Glybenclamide and Gliclazide showed significant lowering 33.6%, 37.6%, 33.9% and 44.8% respectively, at 120 min post glucose load.
• Table-1 Lipid lowering activity of test compound 1 (% lowering of plasma lipids)
• Dyslipemic Hamster Model Male golden Syrian hamster weighing 120-130 gm were divided into control, dyslipemic and dyslipemic plus drug treated group of 8 animals in each. Dyslipemia was produced by feeding with " fructose rich high fat diet(HFD).Dyslipemic hamsters had free acccess to HFD and water ad. Lib for 10 days(daylto daylO). Compound 1 was macerated in vehicle containing 0.2%CMC + 0.4% tween-80 in distilled water and fed orally at the dose of 300 mole/kg from day 4 to day 10 simultaneously with HFD feeding to hamster. Control animals received same amount of vehicle.
• HFD fructose rich high fat diet
• Tg triglyceride
• HDL high density lipoprotein
• FFA free fatty acids
• va ues are mean + s o an ma s

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