3-ARYL-α-AMINO PROPANOIC DERIVATIVES AND PROCESS FOR THEIR
PREPARATION
Field of the invention
The present invention relates to novel antidiabetic compounds, their derivatives, their analogs and pharmaceutically acceptable compositions containing them. More particularly, the present invention relates to novel 3- aryl propanoic acid of the general formula (I), their derivatives, their analogs and pharmaceutically acceptable compositions containing them
wherein R represents hydroxy or a protecting group such as (C]-C
8)alkoxy- CH
2-O-, mesylate, tosylate, triflate or halogen atom such as fluorine, chlorine, bromine or iodine.
The present invention also relates to a process for the preparation of compounds of formula (I). The present invention also relates to novel intermediates of formula
(IV) and (VI) and their use in the preparation of compounds of formula (I).
The compounds of formula (I) are useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL). The compounds of formula (I) are useful in reducing body weight, glucose intolerance and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
The compounds of formula (I) are useful as intermediates for the preparation of many pharmaceutically active compounds. Few representative examples of such compounds are
disclosed in WO 99/62870 and
disclosed in WO 99/16758. The compounds of formulae (Ila) and (lib) are shown to have potent blood glucose lowering, triglyceride lowering, cholesterol lowering and body weight reducing activities.
Background of invention
WO 96/01901 describes the streptogramines and method for preparing the same by muta synthesis, in which they have disclosed L-Tyrosine, O-(2- chloroethyl)-, hydrochloride.
WO 99/66870 and WO 99/66872 describes compounds of formula (lie)
where A is chiral auxiliary group, -OH or OR
p, wherein R
p is a protective group, example ethyl, Q is hydrogen, -CH
2-CH
2Ph-4-OSO
2CH
3 or R
q, wherein R
q is a protective group, example benzyl.
WO 00/59889 describes compounds of formula (lid) as an intermediate
wherein W
1 represents is alkylene, W
2 represents single bond or alkylene, and n
B represents O or S, R represents -hydrogen or the like, for preparing the compounds of formula (He)
The process for preparing compounds of formula (lid) comprises reacting the compound of formula (Ilf) with MsCl, NaN3 and then followed by reduction is shown in scheme 1 below :
Scheme-1
Objective of present invention
The main objective of the present invention is to provide novel compounds of the formula (I) for the treatment and / or prophylaxis of diabetes with high chiral purity, which can be used in the synthesis of pharmaceutically acceptable compounds, which will not have problems of racemization in subsequent steps, when used in the preparation of pharmaceutically acceptable compounds.
Another objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (I).
Detailed description of the invention
Accordingly, the present invention relates to novel 3-aryl propanoic acid derivatives of the formula (I)
wherein R represents hydroxy or a protecting group such as (CrC
8)alkoxy- CH
2-O-, mesylate, tosylate, triflate or halogen atom such as fluorine, chlorine, bromine or iodine.
Particularly useful compounds of the formula (I) according to the present invention, include :
(-) 2-Amino 3-[4-(2-chloroethoxy)phenyl]propanoic acid ; (-) 2-Amino 3-[4-(2-bromoethoxy)phenyl]propanoic acid ; (-) 2-Amino 3-[4-(2-methoxymethoxyethoxy)phenyl]propanoic acid ; (-) 2-Amino 3-[4-(2-ethoxymethoxyethoxy)phenyl]propanoic acid ; (-) 2-Amino 3-[4-[2-(4-methylphenyl sulfonyloxy)ethoxy]phenyl]propanoic acid ;
According to another embodiment of the present invention there is provided a process for the preparation of novel 3-aryl propanoic acid derivatives of the formula (I)
where R represents hydroxy or a protecting group such as (C C
8)alkoxy-CH
2- O-, mesylate, tosylate, triflate or halogen atom, which comprises : i). protecting L-tyrosine of the formula (III) with protecting groups such as copper acetate, acetone, benzaldehyde in the presence of a base to produce a compound of formula (IV) where X represents a protecting group such as copper, acetonide, benzylidine and the like,
ii). reacting the compound of formula (IV) with compound of formula (V) where R is as defined above and L
1 is a leaving group such as halogen, hydroxy, mesylate, tosylate and the like to produce a compound of formula
(VI) iii). deprotecting the compound of formula (VI) to yield pure compound of formula (I).
The process explained above is shown in scheme-2 below :
The reaction of compound of formula (III) with protecting group such as copper acetate, acetone, benzaldehyde to produce compound of formula (IV) may be carried in the presence of alkaline solutions such as sodium carbonate, potassium carbonate, NaH, NaOMe, potassium tertiary butoxide and the like. The reaction may be carried out at a temperature in the range of 40 C to 140 °C, for a period in the range of 2 h to 20 h.
The reaction of compound of the formula (IV) with mesylate of the formula (V) where R is as defined above may be carried out in the presence of bases such as potassium carbonate, sodium carbonate and the like. The reaction may also be carried out in the presence of solvents such as toluene, xylene, DMF, DMA and the like. The reaction may be carried out at
temperature in the range of 60 to 110 °C and the duration of the reaction may range from 2-40 h.
The deprotection of compound of formula (VI) to produce compound of the formula (I) where R is as defined above may be carried out in the presence of acids such as hydrochloric acid, sulfuric acid, acetic acid and the like. The reaction may be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropanol and the like. The reaction may be carried out at a temperature in the range of 60 to 110 °C and the duration of the reaction may range from 2-40 h.
According to another embodiment of the present invention there is provided a novel intermediate of formula (IV)
wherein X is a protecting group such as copper, acetonide, benzylidine and the like.
According to yet another embodiment of the present invention there is provided a novel intermediate of formula (VI)
wherein R represents hydroxy or a protecting group such as (Cj-C
8)alkoxy- CH
2-O-, mesylate, tosylate, triflate or halogen atom such as fluorine, chlorine, bromine or iodine; X is a protecting group such as copper, acetonide, benzylidine and the like.
The compounds of formula (I) are useful in the preparation of pharmaceutically important compounds such as
The process for preparing the compounds of formula (lib) starting from compound of formula (I) is as shown in scheme -3 :
(lib) (lie)
Scheme - 3
It is appreciated that in any 'of the above mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl dimethyl silylchloride, methoxymethyl chloride and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
Demonstration of Efficacy of Compounds Efficacy in genetic models
Mutation in colonies of laboratory animals and different sensitivities to dietary regimens have made the development of animal models with non- insulin dependent diabetes and ' hyperlipidemia associated with obesity and insulin resistance possible. Genetic models such as db/db and ob/ob (Diabetes, (1982) 31(1) : 1- 6) mice and zucker fa/fa rats have been developed by the various laboratories for understanding the pathophysiology of disease and testing the efficacy of new antidiabetic compounds (Diabetes, (1983) 32: 830-838 ; A nu. Rep. Sankyo Res. Lab. (1994). 46 : 1-57). The homozygous animals, C57 BL/KsJ-db/db mice developed by Jackson Laboratory, US, are obese, hyperglycemic, hyperinsulinemic and insulin resistant (J. Clin. Invest., (1990) 85 : 962-967), whereas heterozygous are lean and normoglycemic. In db/db model, mouse progressively develops insulinopenia with age, a feature commonly observed in late stages of human type II diabetes when blood sugar levels are insufficiently controlled. The state of pancreas and its course vary according to the models. Since this model resembles that of type II diabetes mellitus, the compounds of the present invention were tested for blood sugar and triglycerides lowering activities.
Male C57BL/KsJ-db/db mice of 8 to 14 weeks age, having body weight range of 35 to 60 grams, bred at Dr. Reddy's Research Foundation (DRF) animal house, were used in the experiment. The mice were provided with standard feed (National Institute of Nutrition (NTN), Hyderabad, India) and acidified water, ad libitum. The. animals having more than 350 mg / dl blood sugar were used for testing. The number of animals in each group was 4.
Test compounds were suspended on 0.25 % carboxymethyl cellulose and administered to test group at a dose of 0.1 mg to 30 mg / kg through oral gavage daily for 6 days. The control group received vehicle (dose 10 ml / kg). On 6th day the blood samples were collected one hour after administration of test compounds / vehicle for assessing the biological activity.
The random blood sugar and triglyceride levels were measured by collecting blood (100 μl) through orbital sinus, using heparinised capillary in tubes containing EDTA which was centrifuged to obtain plasma. The plasma glucose and triglyceride levels were measured spectrometrically, by glucose oxidase and glycerol-3-PO4 oxidase/peroxidase enzyme (Dr. Reddy's Lab. Diagnostic Division Kits, Hyderabad, India) methods respectively.
The blood sugar and triglycerides lowering activities of the test compound was calculated according to the formula.
Formulae for calculation :
Percent reduction in Blood sugar can be calculated according to the formula :
TT / OT
Percent reduction (%) = 1 - X 100
TC / OC
OC = Zero day control group value OT = Zero day treated group value TC = Test day control group value TT = Test day treated group value.