WO2000063192A1 - Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant - Google Patents

Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant Download PDF

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Publication number
WO2000063192A1
WO2000063192A1 PCT/IB2000/000470 IB0000470W WO0063192A1 WO 2000063192 A1 WO2000063192 A1 WO 2000063192A1 IB 0000470 W IB0000470 W IB 0000470W WO 0063192 A1 WO0063192 A1 WO 0063192A1
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Prior art keywords
phenoxazin
ethoxy
phenyl
ethoxypropanoic acid
arginine salt
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PCT/IB2000/000470
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English (en)
Inventor
Om Reddy Gaddam
Rajender Kumar Potlapally
Raju Sirisilla
Vyas Krishnamurthi
Sreenivasa Rao Dharmaraja
Ramabhadra Sarma Mamillapalli
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Dr. Reddy's Research Foundation
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Priority claimed from PCT/IB1999/000681 external-priority patent/WO2000063191A1/fr
Priority to CA002370401A priority Critical patent/CA2370401A1/fr
Priority to IL14595800A priority patent/IL145958A0/xx
Priority to BR0010683-6A priority patent/BR0010683A/pt
Priority to EP00917222A priority patent/EP1171430A1/fr
Priority to EEP200100529A priority patent/EE200100529A/xx
Application filed by Dr. Reddy's Research Foundation filed Critical Dr. Reddy's Research Foundation
Priority to JP2000612284A priority patent/JP2003508348A/ja
Priority to MXPA01010472A priority patent/MXPA01010472A/es
Priority to AU38313/00A priority patent/AU3831300A/en
Publication of WO2000063192A1 publication Critical patent/WO2000063192A1/fr
Priority to HR20010748A priority patent/HRP20010748A2/hr
Priority to NO20015016A priority patent/NO20015016L/no
Priority to BG106022A priority patent/BG106022A/bg

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    • 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,

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  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (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)

Abstract

L'invention concerne de nouvelles formes polymorphes/pseudompolymorphes d'un sel arginine d'acide 3-[4-[2-(phénoxazine-10-yl)éthoxy]phényl]-2-éthoxypropanoïque de formule (I). L'invention concerne aussi une composition pharmaceutique comprenant les nouvelles formes polymorphes ou leur mélange et un support pharmaceutiquement acceptable. Les formes polymorphes sont plus actives comme agent antidiabétique et hypolipidémique que le nouvel acide 3-[4-[2-(phénoxazin-10-yl)éthoxy]phényl]-2-éthoxypropanoïque.
PCT/IB2000/000470 1999-04-16 2000-04-17 Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant WO2000063192A1 (fr)

Priority Applications (11)

Application Number Priority Date Filing Date Title
AU38313/00A AU3831300A (en) 1999-04-16 2000-04-17 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
IL14595800A IL145958A0 (en) 1999-04-16 2000-04-17 Polymorphic form of arginine salt of (2s)-3-[4-[2-phenoxazin-10-yl)ethoxy] phenyl]2-ethoxypropanoic acid, processes for the preparation thereof and pharmaceutical compositions containing the same
BR0010683-6A BR0010683A (pt) 1999-04-16 2000-04-17 Formas polimórficas de um agente antidiabético: processo para seu preparo e composições farmacêuticas contendo o mesmo
EP00917222A EP1171430A1 (fr) 1999-04-16 2000-04-17 Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant
EEP200100529A EE200100529A (et) 1999-04-16 2000-04-17 Diabeedivastase agensi uudsed polümorfsed vormid:nende valmistamismeetod ja neid sisaldavad farmatseutilised kompositsioonid
CA002370401A CA2370401A1 (fr) 1999-04-16 2000-04-17 Nouvelles formes polymorphes d'un agent antidiabetique, leur procede de preparation et compositions pharmaceutiques les renfermant
JP2000612284A JP2003508348A (ja) 1999-04-16 2000-04-17 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
MXPA01010472A MXPA01010472A (es) 1999-04-16 2000-04-17 Formas polimorficas novedosas de un agente contra la diabetes; procedimiento para su preparacion y composiciones farmaceuticas que las contienen.
HR20010748A HRP20010748A2 (en) 1999-04-16 2001-10-15 Novel polymorphic forms of an antidiabetic agent: process for their preparation and pharmaceutical compositions containing them
NO20015016A NO20015016L (no) 1999-04-16 2001-10-15 Nye polymorfe former av et antidiabetisk middel; fremgangsmåte for deres fremstilling og farmasöytiskesammensetninger som inneholder dem
BG106022A BG106022A (bg) 1999-04-16 2001-10-16 Нови полиморфни форми на противодиабетично средство: метод за тяхното получаване и фармацевтични състави, които ги съдържат

Applications Claiming Priority (4)

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IBPCT/IB99/00681 1999-04-16
PCT/IB1999/000681 WO2000063191A1 (fr) 1999-04-16 1999-04-16 Nouvelles formes polymorphes d'un agent antidiabetique: procede de preparation et composition pharmaceutique contenant ces dernieres
IN436MA1999 1999-04-19
IN436/MAS/99 1999-04-19

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EP (1) EP1171430A1 (fr)
CN (1) CN1351597A (fr)
AU (1) AU3831300A (fr)
BG (1) BG106022A (fr)
BR (1) BR0010683A (fr)
CA (1) CA2370401A1 (fr)
CZ (1) CZ20013711A3 (fr)
EE (1) EE200100529A (fr)
HR (1) HRP20010748A2 (fr)
HU (1) HUP0200758A3 (fr)
IL (1) IL145958A0 (fr)
MX (1) MXPA01010472A (fr)
NO (1) NO20015016L (fr)
PL (1) PL351492A1 (fr)
RU (1) RU2001130883A (fr)
TR (1) TR200103851T2 (fr)
WO (1) WO2000063192A1 (fr)

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WO2002062772A1 (fr) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Derives de sels d'acide 3-4(4-(2-phenoxazin- ou phenothiazin-10-yl)alkoxy)phenyl)-2-alcoxypropanoique a activite ppar pour le traitement de l'hyperlipemie et du diabete de type ii
WO2003031432A1 (fr) 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
WO2004101505A1 (fr) 2003-05-14 2004-11-25 Novo Nordisk A/S Nouveaux composes pour le traitement de l'obesite
WO2005030797A2 (fr) 2003-09-30 2005-04-07 Novo Nordisk A/S Nouveaux agonistes du recepteur de la melanocortine
JP2005529120A (ja) * 2002-04-19 2005-09-29 ファエス・ファルマ・ソシエダッド・アノニマ 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
WO2005105785A2 (fr) 2004-05-04 2005-11-10 Novo Nordisk A/S Nouveaux derives d'indole
EP1634605A2 (fr) 2000-03-08 2006-03-15 Novo Nordisk A/S Traitement de la dyslipidémie chez un patient souffrant de diabète de type 2
WO2006053906A1 (fr) 2004-11-22 2006-05-26 Novo Nordisk A/S Formulations solubles stables contenant de l'insuline et un sel de protamine
WO2006058923A1 (fr) 2004-12-03 2006-06-08 Novo Nordisk A/S Composés hétéroaromatiques activants de glucokinase
WO2007006814A1 (fr) 2005-07-14 2007-01-18 Novo Nordisk A/S Activateurs de l'uree glucokinase
WO2007015805A1 (fr) 2005-07-20 2007-02-08 Eli Lilly And Company Composés joints en position 1-amino
WO2007110364A1 (fr) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles presentant une activité sur le récepteur h3 de l'histamine
WO2007123581A1 (fr) 2005-11-17 2007-11-01 Eli Lilly And Company Antagonistes des récepteurs du glucagon, leur préparation et leurs utilisations thérapeutiques
WO2007137968A1 (fr) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc Benzodioxolylcyclopropylpipérazinylpyridazines
WO2008059026A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouveaux 2-(2-hydroxyphényl)benzimidazoles utilisés pour traiter l'obésité et le diabète
WO2008059025A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouvelles 2-(2-hydroxyphényl) benzothiadiazines utilisées pour traiter l'obésité et le diabète
WO2008084044A1 (fr) 2007-01-11 2008-07-17 Novo Nordisk A/S Activateurs de l'urée glucokinase
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
EP2233470A1 (fr) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Antagonists du receptor histamine H3
EP2298337A2 (fr) 2003-12-09 2011-03-23 Novo Nordisk A/S Régulation des préférences alimentaires en utilisant des agonistes du GLP-1
EP2316446A1 (fr) 2004-06-11 2011-05-04 Novo Nordisk A/S Remède contre l'obésité induite par les médicaments au moyen d'agonistes GLP-1
WO2011104378A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides de traitement de l'obésité
WO2011104379A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides pour le traitement de l'obésité
WO2011117415A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
EP2444397A1 (fr) 2004-01-06 2012-04-25 Novo Nordisk A/S Hétéroaryl-urées et leur utilisation en tant qu'activateurs de glucokinase
WO2012130866A1 (fr) 2011-03-28 2012-10-04 Novo Nordisk A/S Nouveaux analogues de glucagon
WO2013082106A1 (fr) 2011-12-02 2013-06-06 The General Hospital Corporation Différenciation en adipocytes bruns
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (fr) 2017-03-15 2018-09-20 Novo Nordisk A/S Composés bicycliques aptes à se lier au récepteur de mélanocortine 4
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2019219714A1 (fr) 2018-05-15 2019-11-21 Novo Nordisk A/S Composés capables de se lier au récepteur de la mélanocortine 4
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2020053414A1 (fr) 2018-09-14 2020-03-19 Novo Nordisk A/S Composés bicycliques aptes à se lier aux agonistes du récepteur de la mélanocortine 4

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Cited By (45)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1634605A2 (fr) 2000-03-08 2006-03-15 Novo Nordisk A/S Traitement de la dyslipidémie chez un patient souffrant de diabète de type 2
WO2002062772A1 (fr) * 2001-02-05 2002-08-15 Dr. Reddy's Research Foundation Derives de sels d'acide 3-4(4-(2-phenoxazin- ou phenothiazin-10-yl)alkoxy)phenyl)-2-alcoxypropanoique a activite ppar pour le traitement de l'hyperlipemie et du diabete de type ii
EP2243776A1 (fr) 2001-10-12 2010-10-27 High Point Pharmaceuticals, LLC Piperidines substituées et leur utilisation dans le traitement de maladies liées au recepteur histaminique H3
WO2003031432A1 (fr) 2001-10-12 2003-04-17 Novo Nordisk A/S Nouvelles piperidines substituees
WO2003055482A1 (fr) 2001-12-21 2003-07-10 Novo Nordisk A/S Derives amide utiles en tant qu'activateurs de la glucokinase
EP2305648A1 (fr) 2001-12-21 2011-04-06 Novo Nordisk A/S Dérivés d'amide en tant qu'activateurs de la glucokinase
JP2005529120A (ja) * 2002-04-19 2005-09-29 ファエス・ファルマ・ソシエダッド・アノニマ 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
WO2004002481A1 (fr) 2002-06-27 2004-01-08 Novo Nordisk A/S Activateurs de la glycokinase
EP2471533A1 (fr) 2002-06-27 2012-07-04 Novo Nordisk A/S Dérivés d'aryle carbonyle en tant qu'agents thérapeutiques
WO2004101505A1 (fr) 2003-05-14 2004-11-25 Novo Nordisk A/S Nouveaux composes pour le traitement de l'obesite
WO2005030797A2 (fr) 2003-09-30 2005-04-07 Novo Nordisk A/S Nouveaux agonistes du recepteur de la melanocortine
EP2298337A2 (fr) 2003-12-09 2011-03-23 Novo Nordisk A/S Régulation des préférences alimentaires en utilisant des agonistes du GLP-1
EP2444397A1 (fr) 2004-01-06 2012-04-25 Novo Nordisk A/S Hétéroaryl-urées et leur utilisation en tant qu'activateurs de glucokinase
WO2005105785A2 (fr) 2004-05-04 2005-11-10 Novo Nordisk A/S Nouveaux derives d'indole
EP2316446A1 (fr) 2004-06-11 2011-05-04 Novo Nordisk A/S Remède contre l'obésité induite par les médicaments au moyen d'agonistes GLP-1
WO2006053906A1 (fr) 2004-11-22 2006-05-26 Novo Nordisk A/S Formulations solubles stables contenant de l'insuline et un sel de protamine
WO2006058923A1 (fr) 2004-12-03 2006-06-08 Novo Nordisk A/S Composés hétéroaromatiques activants de glucokinase
EP2386554A1 (fr) 2005-07-04 2011-11-16 High Point Pharmaceuticals, LLC Composés actives sur le recepteur histamine H3
EP2233470A1 (fr) 2005-07-04 2010-09-29 High Point Pharmaceuticals, LLC Antagonists du receptor histamine H3
EP2377856A1 (fr) 2005-07-14 2011-10-19 Novo Nordisk A/S Activateurs de la glucokinase d'urée
WO2007006814A1 (fr) 2005-07-14 2007-01-18 Novo Nordisk A/S Activateurs de l'uree glucokinase
WO2007015805A1 (fr) 2005-07-20 2007-02-08 Eli Lilly And Company Composés joints en position 1-amino
WO2007123581A1 (fr) 2005-11-17 2007-11-01 Eli Lilly And Company Antagonistes des récepteurs du glucagon, leur préparation et leurs utilisations thérapeutiques
WO2007110364A1 (fr) 2006-03-28 2007-10-04 High Point Pharmaceuticals, Llc Benzothiazoles presentant une activité sur le récepteur h3 de l'histamine
WO2007137968A1 (fr) 2006-05-29 2007-12-06 High Point Pharmaceuticals, Llc Benzodioxolylcyclopropylpipérazinylpyridazines
EP2402324A1 (fr) 2006-05-29 2012-01-04 High Point Pharmaceuticals, LLC Benzodioxolylcyclopropylpipérazinylpyridazines
WO2008059025A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouvelles 2-(2-hydroxyphényl) benzothiadiazines utilisées pour traiter l'obésité et le diabète
WO2008059026A1 (fr) 2006-11-15 2008-05-22 High Point Pharmaceuticals, Llc Nouveaux 2-(2-hydroxyphényl)benzimidazoles utilisés pour traiter l'obésité et le diabète
WO2008084044A1 (fr) 2007-01-11 2008-07-17 Novo Nordisk A/S Activateurs de l'urée glucokinase
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
WO2011104378A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides de traitement de l'obésité
WO2011104379A1 (fr) 2010-02-26 2011-09-01 Novo Nordisk A/S Peptides pour le traitement de l'obésité
WO2011117416A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
WO2011117415A1 (fr) 2010-03-26 2011-09-29 Novo Nordisk A/S Nouveaux analogues du glucagon
US10130684B2 (en) 2011-02-03 2018-11-20 Pharmedica Ltd. Oral dissolving films for insulin administration, for treating diabetes
WO2012130866A1 (fr) 2011-03-28 2012-10-04 Novo Nordisk A/S Nouveaux analogues de glucagon
US8541368B2 (en) 2011-09-23 2013-09-24 Novo Nordisk A/S Glucagon analogues
US9486505B2 (en) 2011-09-23 2016-11-08 Novo Nordisk A/S Glucagon analogues
WO2013082106A1 (fr) 2011-12-02 2013-06-06 The General Hospital Corporation Différenciation en adipocytes bruns
US9474790B2 (en) 2013-04-18 2016-10-25 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US9751927B2 (en) 2013-04-18 2017-09-05 Novo Nordisk A/S Stable, protracted GLP-1/glucagon receptor co-agonists for medical use
US10570184B2 (en) 2014-06-04 2020-02-25 Novo Nordisk A/S GLP-1/glucagon receptor co-agonists for medical use
WO2018167194A1 (fr) 2017-03-15 2018-09-20 Novo Nordisk A/S Composés bicycliques aptes à se lier au récepteur de mélanocortine 4
WO2019219714A1 (fr) 2018-05-15 2019-11-21 Novo Nordisk A/S Composés capables de se lier au récepteur de la mélanocortine 4
WO2020053414A1 (fr) 2018-09-14 2020-03-19 Novo Nordisk A/S Composés bicycliques aptes à se lier aux agonistes du récepteur de la mélanocortine 4

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PL351492A1 (en) 2003-04-22
HUP0200758A2 (hu) 2002-07-29
AU3831300A (en) 2000-11-02
CN1351597A (zh) 2002-05-29
IL145958A0 (en) 2002-07-25
TR200103851T2 (tr) 2002-04-22
NO20015016D0 (no) 2001-10-15
CZ20013711A3 (cs) 2002-07-17
MXPA01010472A (es) 2002-05-06
BR0010683A (pt) 2003-07-01
RU2001130883A (ru) 2004-03-20
BG106022A (bg) 2002-04-30
HUP0200758A3 (en) 2003-07-28
NO20015016L (no) 2001-12-11
EE200100529A (et) 2002-12-16
HRP20010748A2 (en) 2003-02-28
CA2370401A1 (fr) 2000-10-26
EP1171430A1 (fr) 2002-01-16

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