+

WO2003066612A1 - Nouvelles formes polymorphes d'agents bicycliques antidiabetiques, leur procede de preparation et compositions pharmaceutiques les contenant - Google Patents

Nouvelles formes polymorphes d'agents bicycliques antidiabetiques, leur procede de preparation et compositions pharmaceutiques les contenant Download PDF

Info

Publication number
WO2003066612A1
WO2003066612A1 PCT/IB2003/000408 IB0300408W WO03066612A1 WO 2003066612 A1 WO2003066612 A1 WO 2003066612A1 IB 0300408 W IB0300408 W IB 0300408W WO 03066612 A1 WO03066612 A1 WO 03066612A1
Authority
WO
WIPO (PCT)
Prior art keywords
ethoxy
benzothiazin
dihydro
phenyl
ethoxypropanoic acid
Prior art date
Application number
PCT/IB2003/000408
Other languages
English (en)
Inventor
Raju Srisilla
Rajender Kumar Potlapally
Ramabhadra Sarma Mamillapalli
Om Reddy Gaddam
Original Assignee
Dr. Reddy's Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Limited filed Critical Dr. Reddy's Laboratories Limited
Priority to AU2003244514A priority Critical patent/AU2003244514A1/en
Publication of WO2003066612A1 publication Critical patent/WO2003066612A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/16—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—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 sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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-(3,4-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid, preferably, L- arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4- benzothiazin-4-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 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-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 (2S) 3-[4-[2-(3,4-dihydro-l,4- benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, having the formula (I).
  • the polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4- benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the present invention lower plasma glucose, triglycerides, lower total cholesterol (TC) and increase high density lipoprotein (HDL) and decrease low density lipoprdte ⁇ (LDL), which have a beneficial effect on coronary heart disease and atherosclerosis.
  • TC total cholesterol
  • HDL high density lipoprotein
  • LDL low density lipoprdte ⁇
  • the polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4-benzothiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the present invention are useful in reducing body weight and for the treatment and/or prophylaxis of diseases such as atherosclerosis, stroke, peripheral vascular diseases and related disorders
  • the polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2- ethoxypropanoic acid are also useful for the treatment of hyperlipidemia, hyperglycemia, hypercholesterolemia, lowering of atherogenic lipoproteins, VLDL (very low density lipoprotein) and LDL.
  • polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4- dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl']-2-ethoxypropanoic acid of the present invention can be used for the treatment of certain renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis and nephropathy.
  • polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro- l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid of general formula (I) are also useful for the treatment and/or prophylaxis of leptin resistance, impaired glucose tolerance, disorders related to syndrome X such as hypertension, obesity, insulin resistance, coronary heart disease and other cardiovascular disorders.
  • the polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl] ⁇ 2-ethoxypropanoic acid 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, eating disorders, inflammation and for the treatment of cancer.
  • PCOS polycystic ovarian syndrome
  • polymorphic Forms of arginine salt of (2S) 3-[4-[2-(3,4-dihydro-l,4-benzothiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid of the present invention are also useful in the treatment and/or prophylaxis of the above said diseases in combination/concomitant with one or more HMG CoA reductase inhibitor; cholesterol absorption inhibitor; antiobesity drug; lipoprotein disorder treatment drug: fibrate; hypoglycemic agent: insulin; biguanide; sulfonylurea; thiazolidinedione; dual PPAR ⁇ and ⁇ agonist or a mixture thereof or their combination.
  • 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.
  • Another objective of the present invention is to provide polymorphic forms of arginine salt of (2S) 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-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 (2S) 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-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.
  • Yet another objective of the present invention to provide a process for the preparation of novel polymorphic forms of arginine salt of (2S) 3-[4-[2-(2,3-dihydro-l,4- benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid, their stereoisomers, pharmaceutically acceptable solvates.
  • Still another objective of the present invention is to provide pharmaceutical compositions containing novel polymorphic forms of arginine salt of (2S) 3-[4-[2-(2,3- dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoic acid, their stereoisomers, solvates or their mixtures in combination with suitable carriers, solvents, diluents and other media normally employed in preparing such compositions.
  • suitable carriers, solvents, diluents and other media normally employed in preparing such compositions in our PCT publication No. WO 99/20614 and 00/66572 we have described novel ⁇ -aryl ⁇ -oxy substituted alkyl carboxylic acids of the general formula (II),
  • the pharmaceutical salts of the compounds of the general formula (II) include salts of the organic bases such as guanine, arginine, guanidine, diethyl amine, choline and the like. Particularly the compounds disclosed include 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]- 2-ethoxy propanoic acid.
  • the present invention relates to an observation that arginine salt of (2S) 3-[4-[2- (3,4-dihydro-l ,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxypropanoic acid exhibits polymorphism, which has not been reported till date.
  • the polymo ⁇ hic Form I is obtained from solvents like isopropanol, methanol, ethanol, n-butanol, n-propanol, acetonitrile, MIBK, acetone, ethyl acetate, n-butyl acetate, diethyl ketone, diisopropyl ether, DMF/isopropanol.
  • Form II is obtained from 1,4-Dioxane, THF.
  • Form III is obtained from acetone. From powder X-ray diffraction studies Forms I and II were found to be crystalline in nature. Form III did not give any peaks in X- ray diffraction due to amo ⁇ hous nature.
  • DSC of the polymo ⁇ hic Form I shows melting endotherm at 182.23 °C.
  • Form II exhibits melting endotherm at 99.17 °C, 182.78 °C, exotherm at 167.61 °C.
  • Form III exhibits endotherm at 52.36, 220.23 °C.
  • 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.
  • Differential scanning calorimeter was performed on a Shimadzu DSC-50 equipped with a controller. The data was collected on to a Pentium PC using Shimadzu TA-50 software.
  • the samples weighed in aluminum cells were heated from room temperature to 300 °C at a heating rate of 10 °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. 4 is a characteristic differential scanning calorimetric thermogram of Form I.
  • Fig. 5 is a characteristic differential scanning calorimetric thermogram of Form II.
  • Fig. 6 is a characteristic differential scanning calorimetric thermogram of Form III.
  • Fig. 7 is a characteristic infrared abso ⁇ tion spectrum of Form I in KBr.
  • Fig. 8 is a characteristic infrared abso ⁇ tion spectrum of Form II in KBr.
  • Fig. 9 is a characteristic infrared abso ⁇ tion spectrum of Form III in KBr.
  • a novel polymo ⁇ hic Form-Ill of L-arginine salt of (2S) 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4- yl)ethoxy]phenyl]-2-ethoxypropanoic acid having the formula I which is characterized by the following data : DSC: Endotherms at 52.36 °C, 220.23 °C (Fig. 6)
  • the organic solvents are selected from n-propanol, isopropanol, n-butanol, ethanol, methyl isobutyl ketone (MIBK), ethyl acetate, n-butyl acetate, diethyl ketone, diisopropyl ether and acetone.
  • MIBK methyl isobutyl ketone
  • the organic solvent is selected from methanol or DMF.
  • the organic solvents are selected from methanol, n-propanol, isopropanol, ethanol and n-butanol.
  • the organic solvent is selected from acetonitrile or ethanol.
  • the organic solvent is selected from 1,4-dioxane or THF.
  • Examples 1-14 illustrates the process for the preparation of the polymorphic Form-1 of L-arginine salt of (2S) 3-[4 ⁇ [2-(2,3-dihydro-l,4-benzothiazin-4 ⁇ yl)ethoxy]phenyl]-2- ethoxypropanoic acid
  • (2S) 3-[4-[2-(2,3-Dihydro-l,4-benzothiazin-4-yl)ethoxy]phenyl]-2-ethoxy propanoic acid (2.5 g) was dissolved in ethanol (25 ml) and heated the reaction mass to 50-60 °C. A solution of L-arginine (1.12 g) dissolved in water (2.5 ml) was added with vigorous stirring. After complete addition, the reaction mass was stirred at room temperature for 12 h. The reaction mass became gummy, then decanted the solvent, added fresh ethanol (25 ml) and stirred at room temperature for 2-4 h.
  • Examples 15-16 illustrates the process for the preparation of the polymorphic Form- II of L-arginine salt of (2S) 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4- yl)ethoxy]phenyl]-2-ethoxy propanoic acid
  • Examples 17-18 illustrates the process for the preparation of the polymorphic Form- Ill of L-arginine salt of (2S) 3-[4-[2-(2,3-dihydro-l,4-benzothiazin-4- y ⁇ )ethoxy]phenyl]-2-ethoxy propanoic acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Obesity (AREA)
  • Hematology (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

L'invention se rapporte à de nouvelles formes polymorphes / pseudopolymorphes d'un sel d'arginine d'un acide 3-[4-[2-(3,4-dihydro-1,4-benzothiazine-4-yl)éthoxy]phényl]-2-éthoxypropanoïque, de préférence un sel de L- arginine d'un acide (2S) 3-[4-[2-(3,4-dihydro-1,4-benzothiazine-4-yl)éthoxy]phényl]-2-éthoxypropanoïque, de formule (I) illustrée ci-dessous. L'invention se rapporte également à une composition pharmaceutique contenant les nouvelles formes polymorphes et leur mélange et un support pharmaceutiquement acceptable. Les formes polymorphes de cette invention sont plus actives, comme agent antidiabétique et hypolipidémique que celles de l'acide 3-[4-[2-(2,3-dihydro-1,4-benzothiazin-4-yl)éthoxy]phényl]-2-éthoxypropanoïque.
PCT/IB2003/000408 2002-02-07 2003-02-07 Nouvelles formes polymorphes d'agents bicycliques antidiabetiques, leur procede de preparation et compositions pharmaceutiques les contenant WO2003066612A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2003244514A AU2003244514A1 (en) 2002-02-07 2003-02-07 Novel polymorphic forms of bicyclic antidiabetic agents: process for their preparation and pharmaceutical compositions containing them

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN95/MAS/2002 2002-02-07
IN95MA2002 2002-02-07

Publications (1)

Publication Number Publication Date
WO2003066612A1 true WO2003066612A1 (fr) 2003-08-14

Family

ID=27676883

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2003/000408 WO2003066612A1 (fr) 2002-02-07 2003-02-07 Nouvelles formes polymorphes d'agents bicycliques antidiabetiques, leur procede de preparation et compositions pharmaceutiques les contenant

Country Status (2)

Country Link
AU (1) AU2003244514A1 (fr)
WO (1) WO2003066612A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066572A1 (fr) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000066572A1 (fr) * 1999-04-28 2000-11-09 Dr. Reddy's Research Foundation Heterocycles bicycliques substitues, procede pour leur preparation et leur utilisation comme agents contre l'obesite et comme agents hypocholesterolemiques

Also Published As

Publication number Publication date
AU2003244514A1 (en) 2003-09-02

Similar Documents

Publication Publication Date Title
WO2000063191A1 (fr) Nouvelles formes polymorphes d'un agent antidiabetique: procede de preparation et composition pharmaceutique contenant ces dernieres
CZ20013711A3 (cs) Nové polymorfní formy antidiabetických činidel, způsob jejich přípravy a farmaceutické prostředky s jejich obsahem
SK3752003A3 (sk) Polymorfné formy 5-[4[2-[N-metyl-N-(2- pyridyl)aminol]etoxy]benzyl]tiazolidín-2,4-dión maleátu a spôsob ich prípravy
WO2000063193A1 (fr) Nouvelles formes polymorphes d'un agent antidiabetique: leur procede de preparation et composition pharmaceutique contenant lesdites formes
WO2002028857A1 (fr) Polymorphes de chlorhydrates de pioglitazone et leur utilisation en tant qu'antidiabetiques
CN1910161A (zh) 1型11－β－羟基甾醇脱氢酶抑制剂的新晶型
WO2003066612A1 (fr) Nouvelles formes polymorphes d'agents bicycliques antidiabetiques, leur procede de preparation et compositions pharmaceutiques les contenant
WO2017064635A2 (fr) Composé pyrrole, compositions et procédé de préparation associé
US7241895B2 (en) Polymorphic forms of 5-[4-[2-[n-methyl-n-(2-pyridyl)amino[ethoxy]benzyl] thiazolidine-2,4-dione maleate and process for their preparation
EP2160376B1 (fr) Nouvelles formes cristallines d'atovaquone
US8377950B2 (en) Crystalline form of 5-[4-[[3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl]methoxy]benzyl]thiazolidine-2,4-dione potassium salt
US6528507B1 (en) Polymorphic forms of an antidiabetic agent: process for their preparation and a pharmaceutical composition 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
JP2005523300A5 (fr)
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
SK3782003A3 (en) Sodium salts of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione
WO2003050116A1 (fr) Sel d'acide 10-camphorsulphonique de 5(-4-(2-(n-methyl-n-(2-pyridil)amino)ethoxy)benzyl)thiazolidine-2,4-dione et son utilisation contre le diabete sucre
KR20070116188A (ko) 5-[4-[2-[엔-메틸-엔-(2-피리딜)아미노]에톡시]벤질]티아졸리딘 4-디온 말레이트의 신규의 다형상 및 그제조방법
KR20070113328A (ko) 5-[4-[2-[엔-메틸-엔-(2-피리딜)아미노]에톡시]벤질]티아졸리딘 4-디온 말레이트의 신규의 다형상 및 그제조방법

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载