EP1171430A1 - Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them - Google Patents
Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- EP1171430A1 EP1171430A1 EP00917222A EP00917222A EP1171430A1 EP 1171430 A1 EP1171430 A1 EP 1171430A1 EP 00917222 A EP00917222 A EP 00917222A EP 00917222 A EP00917222 A EP 00917222A EP 1171430 A1 EP1171430 A1 EP 1171430A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phenoxazin
- ethoxy
- phenyl
- ethoxypropanoic acid
- arginine salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
- C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
- C07D265/38—[b, e]-condensed with two six-membered rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- This invention relates to novel polymorphic / pseudopolymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, preferably, L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula I shown below.
- the invention also relates to a , pharmaceutical composition comprising the novel polymorphic form or their mixture and a pharmaceutically acceptable carrier.
- polymorphic forms of the present invention are more active, as antidiabetic and hypolipidemic agent, than the novel 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
- the present invention also relates to a process for the preparation of novel polymorphic / pseudopolymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula (I).
- the polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of formula (I) defined above of the present invention lower total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
- TC total cholesterol
- HDL high density lipoprotein
- LDL low density lipoprotein
- novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) defined above of the present invention are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders.
- These novel polymorphic Forms compounds are useful for the treatment of familial hypercholesterolemia, hypertriglyceridemia, lowering of atherogenic lipoproteins, NLDL (very low density lipoprotein) and LDL.
- novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of formula (I) of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
- novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of formula (I) are also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes), leptin resistance, impaired glucose tolerance, dyslipidemia, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
- novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, of formula (I) may also be useful as aldose reductase inhibitors, for improving cognitive functions in dementia, treating diabetic complications, disorders related to endothelial cell activation, psoriasis, polycystic ovarian syndrome (PCOS), inflammatory bowel diseases, osteoporosis, myotonic dystrophy, pancreatitis, arteriosclerosis, retinopathy, xanthoma, inflammation and for the treatment of cancer.
- PCOS polycystic ovarian syndrome
- novel polymorphic Forms of arginine salt of 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of formula (I) of the present invention are useful in the treatment and/or prophylaxis of the above said diseases in combination/con-comittant with one or more HMG CoA reductase inhibitors, hypolipidemic/ hypolipoproteinemic agents such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
- HMG CoA reductase inhibitors hypolipidemic/ hypolipoproteinemic agents
- fibric acid derivatives such as fibric acid derivatives, nicotinic acid, cholestyramine, colestipol, probucol.
- Atherosclerosis and other peripheral vascular diseases are the major causes effecting the quality of life of millions of people. Therefore, considerable attention has been directed towards understanding the etiology of hypercholesterolemia and hyperlipidemia and development of effective therapeutic strategies.
- Hypercholesterolemia has been defined as plasma cholesterol level that exceeds arbitrarily defined value called “normal” level. Recently, it has been accepted that "ideal" plasma levels of cholesterol are much below the "normal” level of cholesterol in the general population and the risk of coronary artery disease (CAD) increases as cholesterol level rises above the "optimum” (or “ideal”) value. There is clearly a definite cause and effect-relationship between hypercholesterolemia and CAD, particularly for individuals with multiple risk factors. Most of the cholesterol is present in the esterified forms with various lipoproteins such as Low density lipoprotein (LDL), intermediate density lipoprotein (IDL), High density lipoprotein (HDL) and partially as Very low density lipoprotein (NLDL).
- LDL Low density lipoprotein
- IDL intermediate density lipoprotein
- HDL High density lipoprotein
- NLDL Very low density lipoprotein
- Obesity is a disease highly prevalent in affluent societies and in the developing world and is a major cause of morbidity and mortality. It is a state of excess body fat accumulation. The causes of obesity are unclear. It is believed to be of genetic origin or promoted by an interaction between the genotype and environment. Irrespective of the cause, the result is fat deposition due to imbalance between the energy intake versus energy expenditure. Dieting, exercise and appetite suppression have been a part of obesity treatment. There is a need for efficient therapy to fight this disease since it may lead to coronary heart disease, diabetes, stroke, hyperlipidemia, gout, osteoarthritis, reduced fertility and many other psychological and social problems.
- Diabetes and insulin resistance is yet another disease which severely effects the quality of a large population in the world. Insulin resistance is the diminished ability of insulin to exert its biological action across a broad range of concentrations. In insulin resistance, the body secretes abnormally high amounts of insulin to compensate for this defect; failing which, the plasma glucose concentration inevitably rises and develops into diabetes.
- diabetes mellitus is a common problem and is associated with a variety of abnormalities including obesity, hypertension, hyper- lipidemia (J. Clin. Invest., (1985) 75 : 809 - 817; N. Engl. J. Med. (1987) 317: 350-357; J. Clin. Endocrinol. Metab., (1988) 66 : 580 - 583; J.
- Hyperlipidemia is the primary cause for cardiovascular (CVD) and other peripheral vascular diseases.
- High risk of CVD is related to the higher LDL (Low Density Lipoprotein) and NLDL (Very Low Density Lipoprotein) seen in hyperlipidemia.
- LDL Low Density Lipoprotein
- NLDL Very Low Density Lipoprotein
- Patients having glucose intolerance/insulin resistance in addition to hyperlipidemia have higher risk of CVD.
- Numerous studies in the past have shown that lowering of plasma triglycerides and total cholesterol, in particular LDL and VLDL and increasing HDL cholesterol help in preventing cardiovascular diseases.
- Peroxisome proliferator activated receptors are members of the nuclear receptor super family.
- PPAR ⁇ The gamma ( ⁇ ) isoform of PPAR (PPAR ⁇ ) has been implicated in regulating differentiation of adipocytes (Endocrinology, (1994) 135: 798-800) and energy homeostasis (Cell, (1995) 83: 803-812), whereas the alpha ( ⁇ ) isoform of PPAR (PPAR ⁇ ) mediates fatty acid oxidation (Trend. Endocrin. Metab., (1993) 4: 291-296) thereby resulting in reduction of circulating free fatty acid in plasma (Current Biol.
- PPAR ⁇ agonists have been found useful for the treatment of obesity (WO 97/36579). It has been recently disclosed that there exists synergism for the molecules, which are agonists for both PPAR ⁇ and PPAR ⁇ and suggested to be useful for the treatment of syndrome X (WO 97/25042). Similar synergism between the insulin sensitizer (PPAR ⁇ agonist) and HMG CoA reductase inhibitor has been observed which may be useful for the treatment of atherosclerosis and xanthoma (EP 0 753 298). It is known that PPAR ⁇ plays an important role in adipocyte differentiation (Cell,
- PPAR ⁇ is consistently expressed in certain cells and activation of this nuclear receptor with PPAR ⁇ agonists would stimulate the terminal differentiation of adipocyte precursors and cause morphological and molecular changes characteristics of a more differentiated, less malignant state (Molecular Cell, (1998), 465-470; Carcinogenesis, (1998), 1949-53; Proc. Natl. Acad. Sci., (1997) 94, 237-241) and inhibition of expression of prostate cancer tissue (Cancer Research (1998) 58:3344-3352). This would be useful in the treatment of certain types of cancer, which express PPAR ⁇ and could lead to a quite nontoxic chemotherapy.
- Leptin resistance is a condition wherein the target cells are unable to respond to leptin signal. This may give rise to obesity due to excess food intake and reduced energy expenditure and cause impaired glucose tolerance, type 2 diabetes, cardiovascular diseases and such other interrelated complications.
- Kallen et al Proc. Natl. Acad. Sci. (1996) 93, 5793-5796) have reported that insulin sensitizers which perhaps due to the PPAR agonist expression and therefore lower plasma leptin concentrations.
- compounds having insulin sensitizing property also possess leptin sensitization activity. They lower the circulating plasma leptin concentrations by improving the target cell response to leptin (WO/98/02159).
- polymorphism we mean to include different physical forms, crystal forms, crystalline / liquid crystalline / non-crystalline (amorphous) forms. This has especially become very interesting after observing that many antibiotics, antibacterials, tranquilizers etc., exhibit polymorphism and some/one of the polymorphic forms of a given drug exhibit superior bio-availability and consequently show much higher activity compared to other polymorphs.
- Sertraline, Frentizole, Ranitidine, Sulfathiazole, Indomethacine etc. are some of the important examples of pharmaceuticals which exhibit polymorphism.
- Another objective of the present invention is to provide polymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, their stereoisomers, their pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures which may have agonist activity against PPAR ⁇ and/or PPAR ⁇ , and optionally inhibit HMG CoA reductase, in addition to having agonist activity against PPAR ⁇ and/or PPAR ⁇ .
- Another objective of the present invention is to provide novel polymorphic forms of arginine salt of 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, their stereoisomers, pharmaceutically acceptable solvates and pharmaceutical compositions containing them or their mixtures having enhanced activities, without toxic effect or with reduced toxic effect.
- the pharmaceutical salts of the compounds of the general formula (a) includes salts of the organic bases such as guanine, arginine, guanidine, diethylamine, choline, and the like. Particularly the compounds disclosed include 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
- the present invention relates to an observation that arginine salt of 3-[4-[2-(phenoxazin- 10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid exhibits polymorphism, which has not been reported till date.
- the polymorphic Forms I, II, III, IV and V are obtained from different solvents like isopropyl alcohol, acetone, 1,4-dioxane, dimethylsulphoxide, and dimethylformamide respectively.
- Form VI is obtained by dissolving any form (Form I- V) in water and freeze drying.
- Form VII is obtained by dissolving any form (Form I-V) in methanol and quick evaporation of the solvent under reduced pressure at 40-60 °C.
- Form VIII is obtained by refluxing Form-I in 1,4-dioxane.
- Form-IX is obtained by refluxing Form- VIII in isopropyl alcohol.
- Form X is prepared by heating Form I to 185 °C and cooling it to room temperature.
- Form XI is prepared by heating Form X to 175 °C and cooling it to room temperature.
- DSC of the polymorphic Form I shows melting endotherm at 181 °C.
- Form II displays endotherms at 131 °C, 166 °C, 178 °C, 214 °C and 276 °C and exotherms at 169 °C.
- Form III exhibits melting endotherm 182 °C in addition to an exotherm at 168 °C.
- Form IV exhibits endotherms at 149 °C, 164 °C and 185 °C and an exotherm at 171 °C.
- Form V exhibits endotherms at 119 °C, 164 °C, 172 °C and 185 °C in addition to a melting exotherm at 173 °C.
- Form VI exhibits exotherm at 157 °C and endotherms at 179 °C and 183 °C.
- Form VII exhibits exotherm at 132 °C and endotherms at 176 °C and 184 °C.
- Form VIII there was a similar exotherm of Form VI at 158 °C and the melting endotherm at 178 °C, whereas in Form IX there was only one sharp melting endotherm at 176 °C.
- Form X displays an exotherm at 163 °JC. and melting endotherm at 184 °C.
- Form XI exhibits a melting endotherm at 184 °C.
- X-ray powder diffraction pattern has been obtained on a Rigaku D/Max 2200 model diffractometer equiped with horizontal gonimometer in ⁇ /2 ⁇ geometry.
- Fig. 1 is a characteristic X-ray powder diffraction pattern of Form I.
- Fig. 2 is a characteristic X-ray powder diffraction pattern of Form II.
- Fig. 3 is a characteristic X-ray powder diffraction pattern of Form III.
- Fig. 4 is a characteristic X-ray powder diffraction pattern of Form IV.
- Fig. 5 is a characteristic X-ray powder diffraction pattern of Form V.
- Fig. 6 is a characteristic X-ray powder diffraction pattern of Form VI.
- Fig. 7 is a characteristic X-ray powder diffraction pattern of Form VII.
- Fig. 8 is a characteristic X-ray powder diffraction pattern of Form VIII.
- Fig. 9 is a characteristic X-ray powder diffraction pattern of Form IX.
- Fig. 10 is a characteristic X-ray powder diffraction pattern of Form X.
- Fig. 11 is a characteristic X-ray powder diffraction pattern of Form XL
- Fig. 12 is a characteristic X-ray powder diffraction pattern of polymorphic form mixture.
- Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using a Shimadzu TA-50 software. The samples weighed in aluminum cells were heated from room temperature to 220 °C at a heating rate of 5 °C /min. The empty aluminum cell was used as a reference. Dry nitrogen gas was purged through DSC cell continuously throughout the analysis at a flow of 30 ml/min.
- Fig. 13 is a characteristic differential scanning calorimetric thermogram of Form I.
- Fig. 14 is a characteristic differential scanning calorimetric thermogram of Form II.
- Fig. 15 is a characteristic differential scanning calorimetric thermogram of Form III.
- Fig. 16 is a characteristic differential scanning calorimetric thermogram of Form IV.
- Fig. 17 is a characteristic differential scanning calorimetric thermogram of Form V.
- Fig. 18 is a characteristic differential scanning calorimetric thermogram of Form VI.
- Fig. 19 is a characteristic differential scanning calorimetric thermogram of Form VII.
- Fig. 20 is a characteristic differential scanning calorimetric thermogram of Form VIII.
- Fig. 21 is a characteristic differential scanning calorimetric thermogram of Form IX.
- Fig. 22 is a characteristic differential scanning calorimetric thermogram of Form X.
- Fig. 23 is a characteristic differential scanning calorimetric thermogram of Form XI.
- Fig. 24 is a characteristic differential scanning calorimetric thermogram of polymorphic form mixture.
- Fig. 25 is a characteristic infrared absorption spectrum of Form I in KBr.
- Fig. 26 is a characteristic infrared absorption spectrum of Form II in KBr.
- Fig. 27 is a characteristic infrared absorption spectrum of Form III in KBr.
- Fig. 28 is a characteristic infrared absorption spectrum of Form IV in KBr.
- Fig. 29 is a characteristic infrared absorption spectrum of Form V in KBr.
- Fig. 30 is a characteristic infrared absorption spectrum of Form VI in KBr.
- Fig. 31 is a characteristic infrared absorption spectrum of Form VII in KBr.
- Fig. 32 is a characteristic infrared absorption spectrum of Form VIII in KBr.
- Fig. 33 is a characteristic infrared absorption spectrum of Form IX in KBr.
- Fig. 34 is a characteristic infrared absorption spectrum of Form X in KBr.
- Fig. 35 is a characteristic infrared absorption spectrum of Form XI in KBr.
- Fig. 36 is a characteristic infrared absorption spectrum of polymorphic form mixture in KBr.
- Infrared absorption bands (cm "1 ): 3061, 1710, 1588, 1510, 1491, 1379, 1273,
- a novel polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid having the formula I which is characterized by the following data : DSC: Endotherm at 185.95 °C, (onset at 178.09 °C) (Fig -17) Small endotherms at 119.81 °C, 164.69 °C, 172.44 °C Small exotherm at 173.82 °C
- Infrared absorption bands (cm "1 ): 3266, 3055, 1711, 1589, 1510, 1492, 1379, 1274, 1175, 1111, 1040, 918, 819, 730, 676, 544, (Fig -29)
- the temperature employed in the stirring step (iii) may be preferably 40-50 °C.
- step (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4-
- step (iv) filtering the white crystalline precipitate obtained in step (iii) above and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, (vi) heating the polymo ⁇ hic Form-I obtained in step (v) to 185 °C and cooling it to room temperature to yeild Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid and
- step (vii) heating the polymo ⁇ hic Form-X obtained in step (vi) to 175 °C and cooling it to room temperature to yield Form-XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
- step (iv) filtering the white crystalline powder obtained in step (iii) and (v) drying under vacuum at a temperature of 40-45 °C for a period in the range of 4- 16 h to yield mixture of polymo ⁇ hic Form of I and X of L-arginine salt of (2S) 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid.
- the organic solvents are selected from acetonitrile, ethanol, methanol and, isopropanol.
- the present invention also envisages a pharmaceutical composition
- a pharmaceutical composition comprising a polymo ⁇ hic Forms I to XI of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I) or the mixture of polymo ⁇ hic Form of I and X and a pharmaceutically acceptable carrier .
- the present invention also envisages a pharmaceutical composition
- a pharmaceutical composition comprising a mixture of any of polymo ⁇ hic Forms I to XI of L-arginine salt of (2S) 3-[4-[2- (phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, of the formula (I) and a pharmaceutically acceptable carrier .
- the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavourants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
- Such compositions typically contain from 1 to 25 %, preferably 1 to 15 % by weight of active ingredient, the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents.
- polymo ⁇ hic forms of the formula (I) as defined above are clinically administered to mammals, including man, via either oral, nasal, pulmonary, transdermal or parenteral, rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment.
- Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
- the patient cannot swallow the medication, or abso ⁇ tion following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally.
- the dosage is in the range of about 0.01 to about 100 mg / kg body weight of the subject per day or preferably about 0.01 to about 30 mg / kg body weight per day administered singly or as a divided dose.
- the optimum dosage for the individual subject being treated will be determined by the person responsible for treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage.
- Suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile aqueous or organic solutions.
- the active ingredient will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
- the polymo ⁇ hic form can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
- the pharmaceutical compositions may, if desired, contain additional components such as flavourants, sweeteners, excipients and the like.
- the polymo ⁇ hic form can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
- solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically- acceptable acid addition salts or salts with base of the compounds.
- Aqueous solutions with the active ingredient dissolved in polyhydroxylated castor oil may also be used for injectable solutions.
- the injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
- the preparation may contain the polymo ⁇ hic forms of the present invention dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
- a liquid carrier in particular an aqueous carrier
- the carrier may contain additives such as solubilizing agents, such as propylene glycol, surfactants, abso ⁇ tion enhancers such as lecithin (phosphatidylcholine) or cyclodextrin or preservatives such as parabenes.
- Tablets, dragees or capsules having talc and / or a carbohydrate carried binder or the like are particularly suitable for any oral application.
- carriers for tablets, dragees or capsules include lactose, corn starch and / or potato starch.
- a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
- the ingredients 1 to 3 are uniformly blended with water and granulated after drying under reduced pressure.
- the ingredient 4 and 5 are mixed well with the granules and compressed by a tabletting machine to prepare 1000 tablets each containing 30 mg of active ingredient.
- ingredients 1-4 are uniformly moistened with an aqueous solution of 5 and granulated after drying under reduced pressure.
- Ingredient 6 is added and granules are compressed by a tabletting machine to prepare 1000 tablets containing 30 mg of ingredient 1.
- Examples 1-4 illustrates the process for the preparation of the polymorphic Form-1 of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid,
- Example-1
- Example 6 Process for the preparation of the polymorphic Form-II of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 7 Process for the preparation of the polymorphic Form-Ill of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 8 Process for the preparation of the polymorphic Form-IV of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 9 Process for the preparation of the polymorphic Form-V of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 10 Process for the preparation of the polymorphic Form-VI of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 11 Process for the preparation of the polymorphic Form-VII of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 12 Process for the preparation of the polymorphic form- VIII of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, Polymo ⁇ hic Form-I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid (1 g), obtained by the process described in Example-2 above was refluxed in 1,4-dioxane (10 ml), filtered and dried under vacuum to yield Form- VIII of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]- 2-ethoxypropanoic acid which has the characteristics given earlier.
- Example 13 Process for the preparation of the polymorphic Form-IX of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 14 Process for the preparation of the polymorphic Form-X of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
- Example 15 Process for the preparation of the polymorphic Form-XI of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, Polymo ⁇ hic Form-X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10- yl)ethoxy]phenyl]-2-ethoxypropanoic acid obtained by the process described in Example 14 was heated to 175 °C and cooled it to room temperature to yield Form-XI of L- arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid which has the characteristics given earlier.
- Example 16 Process for the preparation of mixture of polymorphic Forms I and X of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2- ethoxypropanoic acid,
- Example 17 Process for the preparation of polymorphic Form I of L-arginine salt of (2S) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid,
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Steroid Compounds (AREA)
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IB1999/000681 WO2000063191A1 (en) | 1999-04-16 | 1999-04-16 | Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them |
WOPCT/IB99/00681 | 1999-04-16 | ||
IN436MA1999 | 1999-04-19 | ||
INMA043699 | 1999-04-19 | ||
PCT/IB2000/000470 WO2000063192A1 (en) | 1999-04-16 | 2000-04-17 | Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1171430A1 true EP1171430A1 (en) | 2002-01-16 |
Family
ID=26318745
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP00917222A Withdrawn EP1171430A1 (en) | 1999-04-16 | 2000-04-17 | Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them |
Country Status (17)
Country | Link |
---|---|
EP (1) | EP1171430A1 (bg) |
CN (1) | CN1351597A (bg) |
AU (1) | AU3831300A (bg) |
BG (1) | BG106022A (bg) |
BR (1) | BR0010683A (bg) |
CA (1) | CA2370401A1 (bg) |
CZ (1) | CZ20013711A3 (bg) |
EE (1) | EE200100529A (bg) |
HR (1) | HRP20010748A2 (bg) |
HU (1) | HUP0200758A3 (bg) |
IL (1) | IL145958A0 (bg) |
MX (1) | MXPA01010472A (bg) |
NO (1) | NO20015016L (bg) |
PL (1) | PL351492A1 (bg) |
RU (1) | RU2001130883A (bg) |
TR (1) | TR200103851T2 (bg) |
WO (1) | WO2000063192A1 (bg) |
Families Citing this family (36)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1263458B1 (en) | 2000-03-08 | 2005-11-16 | Novo Nordisk A/S | Lowering serum cholesterol |
US6897199B2 (en) * | 2001-02-05 | 2005-05-24 | Dr. Reddy's Laboratories Ltd. | Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds |
JP4563675B2 (ja) | 2001-10-12 | 2010-10-13 | ハイ・ポイント・ファーマスーティカルズ、エルエルシー | 置換ピペリジン類、およびヒスタミンh3受容体関連疾患の治療のためのその使用 |
RU2374236C2 (ru) | 2001-12-21 | 2009-11-27 | Ново Нордиск А/С | Амидные производные в качестве активаторов gk |
ATE347550T1 (de) * | 2002-04-19 | 2006-12-15 | Faes Farma Sa | Polymorph von 4-(2-(4-(1-(2-ethoxyethyl)-1h- benzimidazol-2-yl)-1-piperidinyl)ethyl)-alpha, alpha-dimethylbenzolessigsäure |
BR0312023A (pt) | 2002-06-27 | 2005-03-22 | Novo Nordisk As | Composto, composto ativador da glicose cinase, método para evitar a hipoglicemia, uso de um composto, e, composição farmacêutica |
WO2004101505A1 (en) | 2003-05-14 | 2004-11-25 | Novo Nordisk A/S | Novel compounds for treatment of obesity |
RU2381233C2 (ru) | 2003-09-30 | 2010-02-10 | Ново Нордиск А/С | Агонисты рецептора меланокортина |
JP4865565B2 (ja) | 2003-12-09 | 2012-02-01 | ノヴォ ノルディスク アー/エス | Glp−1アゴニストを用いた食物選択の制御 |
MXPA06007667A (es) | 2004-01-06 | 2006-09-01 | Novo Nordisk As | Heteroaril-ureas y su uso como activadores de glucocinasa. |
EP1758856A2 (en) | 2004-05-04 | 2007-03-07 | Novo Nordisk A/S | Indole derivatives for the treatment of obesity |
JP2008501765A (ja) | 2004-06-11 | 2008-01-24 | ノボ ノルディスク アクティーゼルスカブ | Glp−1アゴニストを用いた薬剤誘発性肥満の中和 |
US8263551B2 (en) | 2004-11-22 | 2012-09-11 | Novo Nordisk A/S | Soluble, stable insulin-containing formulations with a protamine salt |
US8148412B2 (en) | 2004-12-03 | 2012-04-03 | Novo Nordisk A/S | Heteroaromatic glucokinase activators |
ATE536344T1 (de) | 2005-07-04 | 2011-12-15 | High Point Pharmaceuticals Llc | Histamine h3 receptor antagonisten |
US7884210B2 (en) | 2005-07-14 | 2011-02-08 | Novo Nordisk A/S | Ureido-thiazole glucokinase activators |
EP1910317B1 (en) | 2005-07-20 | 2013-07-03 | Eli Lilly And Company | 1-amino linked compounds |
EP1951658B1 (en) | 2005-11-17 | 2012-09-26 | Eli Lilly & Company | Glucagon receptor antagonists, preparation and therapeutic uses |
JP2009531376A (ja) | 2006-03-28 | 2009-09-03 | ハイ ポイント ファーマシューティカルズ,リミティド ライアビリティ カンパニー | ヒスタミンh3受容体活性を有するベンゾチアゾール |
ES2375872T3 (es) | 2006-05-29 | 2012-03-07 | High Point Pharmaceuticals, Llc | 3-(1,3-benzodioxol-5-il)-6-(4-ciclopropilpiperacin-1-il)-piridacina, sus sales y solvatos, y su uso como antagonista del receptor h3 de la histamina. |
ATE538109T1 (de) | 2006-11-15 | 2012-01-15 | High Point Pharmaceuticals Llc | Neue für die behandlung von obesitas und diabetes geeignete 2-(2-hydroxyphenyl)benzothiadiazine |
WO2008059026A1 (en) | 2006-11-15 | 2008-05-22 | High Point Pharmaceuticals, Llc | Novel 2-(2-hydroxyphenyl)benzimidazoles useful for treating obesity and diabetes |
CA2675111C (en) | 2007-01-11 | 2016-04-05 | Novo Nordisk A\S | Urea glucokinase activators |
JP2010013472A (ja) * | 2009-09-09 | 2010-01-21 | Faes Farma Sa | 4−[2−[1−(2−エトキシエチル)−1H−ベンズイミダゾール−2−イル]−1−ピペリジニル]エチル]−α,α−ジメチルベンゼノ酢酸の多形体 |
BR112012021231A2 (pt) | 2010-02-26 | 2015-09-08 | Basf Plant Science Co Gmbh | método para acentuar o rendimento em plantas, planta, construto, uso de um construto, método para a produção de uma planta transgênica, partes coletáveis de uma planta, produtos derivados de uma planta, uso de um ácido nucleíco e método para a produção de um produto |
US20130012432A1 (en) | 2010-02-26 | 2013-01-10 | Novo Nordisk A/S | Peptides for Treatment of Obesity |
JP6026993B2 (ja) | 2010-03-26 | 2016-11-16 | ノヴォ ノルディスク アー/エス | 新規のグルカゴンアナログ |
WO2012104834A1 (en) | 2011-02-03 | 2012-08-09 | Pharmedica Ltd. | New oral dissolving films for insulin administration, for treating diabetes |
RU2013145013A (ru) | 2011-03-28 | 2015-05-10 | Ново Нордиск А/С | Новые аналоги глюкагона |
RU2610175C2 (ru) | 2011-09-23 | 2017-02-08 | Ново Нордиск А/С | Новые аналоги глюкагона |
US20150004144A1 (en) | 2011-12-02 | 2015-01-01 | The General Hospital Corporation | Differentiation into brown adipocytes |
WO2014170496A1 (en) | 2013-04-18 | 2014-10-23 | Novo Nordisk A/S | Stable, protracted glp-1/glucagon receptor co-agonists for medical use |
WO2015185640A1 (en) | 2014-06-04 | 2015-12-10 | Novo Nordisk A/S | Glp-1/glucagon receptor co-agonists for medical use |
US20200223889A1 (en) | 2017-03-15 | 2020-07-16 | Novo Nordisk A/S | Bicyclic Compounds Capable of Binding to Melanocortin 4 Receptor |
US20210221867A1 (en) | 2018-05-15 | 2021-07-22 | Novo Nordisk A/S | Compounds Capable of Binding to Melanocortin 4 Receptor |
WO2020053414A1 (en) | 2018-09-14 | 2020-03-19 | Novo Nordisk A/S | Bicyclic compounds capable of acting as melanocortin 4 receptor agonists |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5089514A (en) * | 1990-06-14 | 1992-02-18 | Pfizer Inc. | 3-coxazolyl [phenyl, chromanyl or benzofuranyl]-2-hydroxypropionic acid derivatives and analogs as hypoglycemic agents |
US5248699A (en) * | 1992-08-13 | 1993-09-28 | Pfizer Inc. | Sertraline polymorph |
WO1997027191A1 (en) * | 1996-06-19 | 1997-07-31 | Dr. Reddy's Research Foundation | Novel polymorphic forms of troglitazone having enhanced anti-diabetic activity and a process for their preparation |
IN182496B (bg) * | 1996-02-20 | 1999-04-17 | Reddy Research Foundation | |
GB9604242D0 (en) * | 1996-02-28 | 1996-05-01 | Glaxo Wellcome Inc | Chemical compounds |
FR2746099B1 (fr) * | 1996-03-13 | 1998-04-30 | Procede ameliore pour la preparation de derives de l'acide 3-(10-phenothiazyl)-propanoique ou 3-(10-phenoxazyl)-propanoique | |
WO1999019313A1 (en) * | 1997-10-27 | 1999-04-22 | Dr. Reddy's Research Foundation | Novel tricyclic compounds and their use in medicine; process for their preparation and pharmaceutical compositions containing them |
EP1051403A1 (en) * | 1998-01-29 | 2000-11-15 | Dr. Reddy's Research Foundation | Novel alkanoic acids and their use in medicine, process for their preparation and pharmaceutical compositions containing them |
EP1082313A1 (en) * | 1998-05-27 | 2001-03-14 | Dr. Reddy's Research Foundation | Bicyclic compounds, process for their preparation and pharmaceutical compositions containing them |
-
2000
- 2000-04-17 IL IL14595800A patent/IL145958A0/xx unknown
- 2000-04-17 CN CN00807705A patent/CN1351597A/zh active Pending
- 2000-04-17 AU AU38313/00A patent/AU3831300A/en not_active Abandoned
- 2000-04-17 TR TR2001/03851T patent/TR200103851T2/xx unknown
- 2000-04-17 HU HU0200758A patent/HUP0200758A3/hu unknown
- 2000-04-17 WO PCT/IB2000/000470 patent/WO2000063192A1/en active Search and Examination
- 2000-04-17 EE EEP200100529A patent/EE200100529A/xx unknown
- 2000-04-17 EP EP00917222A patent/EP1171430A1/en not_active Withdrawn
- 2000-04-17 CZ CZ20013711A patent/CZ20013711A3/cs unknown
- 2000-04-17 BR BR0010683-6A patent/BR0010683A/pt not_active IP Right Cessation
- 2000-04-17 CA CA002370401A patent/CA2370401A1/en not_active Abandoned
- 2000-04-17 MX MXPA01010472A patent/MXPA01010472A/es unknown
- 2000-04-17 PL PL00351492A patent/PL351492A1/xx not_active Application Discontinuation
- 2000-04-17 RU RU2001130883/04A patent/RU2001130883A/ru unknown
-
2001
- 2001-10-15 NO NO20015016A patent/NO20015016L/no not_active Application Discontinuation
- 2001-10-15 HR HR20010748A patent/HRP20010748A2/hr not_active Application Discontinuation
- 2001-10-16 BG BG106022A patent/BG106022A/bg unknown
Non-Patent Citations (1)
Title |
---|
See references of WO0063192A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUP0200758A2 (hu) | 2002-07-29 |
TR200103851T2 (tr) | 2002-04-22 |
NO20015016D0 (no) | 2001-10-15 |
MXPA01010472A (es) | 2002-05-06 |
BG106022A (bg) | 2002-04-30 |
CZ20013711A3 (cs) | 2002-07-17 |
NO20015016L (no) | 2001-12-11 |
CN1351597A (zh) | 2002-05-29 |
HRP20010748A2 (en) | 2003-02-28 |
AU3831300A (en) | 2000-11-02 |
HUP0200758A3 (en) | 2003-07-28 |
PL351492A1 (en) | 2003-04-22 |
CA2370401A1 (en) | 2000-10-26 |
WO2000063192A1 (en) | 2000-10-26 |
BR0010683A (pt) | 2003-07-01 |
IL145958A0 (en) | 2002-07-25 |
EE200100529A (et) | 2002-12-16 |
RU2001130883A (ru) | 2004-03-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2000063192A1 (en) | Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them | |
JP2003508348A (ja) | 新規多型形態の抗糖尿病薬剤:それらの製造方法およびそれらを含有する医薬組成物 | |
WO2000063193A1 (en) | Novel polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them | |
EP1322647A1 (en) | Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino]ethoxy]benzyl]thiazolidine-2,4-dione maleic acid salt and process for their preparation | |
US6528507B1 (en) | Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition containing them | |
US6897199B2 (en) | Pharmaceutically acceptable salts of phenoxazine and phenothiazine compounds | |
WO2002028857A1 (en) | Polymorphs of pioglitazone hydrochloride and their use as antidiabetics | |
US20040068116A1 (en) | Novel polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino[ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation | |
WO2002062798A2 (en) | Salts of pyrimidine derivatives for use against coronary heart disease and atherosclerose | |
US20020169175A1 (en) | Pharmaceutically acceptable salts of heterocyclic compounds | |
EP1623984A1 (en) | Polymorphic form I of 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2yl]methoxy]benzyl]thiazolidine-2,4-dione potassium salt | |
WO2002030914A1 (en) | Salts of benzothiazine and benzoxazine derivatives and pharmaceutical compositions containing them | |
AU2001291232A1 (en) | Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation | |
US20020142993A1 (en) | Pharmaceutically acceptable salts of bicyclic compounds | |
WO2003066612A1 (en) | Novel polymorphic forms of bicyclic antidiabetic agents: process for their preparation and pharmaceutical compositions containing them | |
AU2001291232B8 (en) | Novel polymorphic forms of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation | |
CN114377136A (zh) | 用于高脂血症治疗的联合用药物及其用途 | |
WO2003006022A1 (en) | Tetrahydroquinoline derivatives and their use in medicine, process for their preparation and pharmaceutical compositions containing them |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20011109 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE |
|
AX | Request for extension of the european patent |
Free format text: AL PAYMENT 20011109;LT PAYMENT 20011109;LV PAYMENT 20011109;MK PAYMENT 20011109;RO PAYMENT 20011109;SI PAYMENT 20011109 |
|
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: DR. REDDY'S LABORATORIES LTD. |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: LUGSTEIN, PETRA CHRISTINE Inventor name: EBDRUP, SOREN Inventor name: MAMILLAPALLI, RAMABHADRA, SARMA Inventor name: DHARMARAJA, SREENIVASA, RAO Inventor name: KRISHNAMURTHI, VYAS Inventor name: SIRISILLA, RAJU Inventor name: POTLAPALLY, RAJENDER, KUMAR Inventor name: GADDAM, OM, REDDY |
|
17Q | First examination report despatched |
Effective date: 20030711 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20031124 |