WO2005023766A1 - Salt of atorvastatin with metformin - Google Patents

Salt of atorvastatin with metformin Download PDF

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Publication number
WO2005023766A1
WO2005023766A1 PCT/IN2003/000307 IN0300307W WO2005023766A1 WO 2005023766 A1 WO2005023766 A1 WO 2005023766A1 IN 0300307 W IN0300307 W IN 0300307W WO 2005023766 A1 WO2005023766 A1 WO 2005023766A1
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WO
WIPO (PCT)
Prior art keywords
formula
atorvastatin
compound
metformin
salt
Prior art date
Application number
PCT/IN2003/000307
Other languages
French (fr)
Inventor
Sambasivam Ganesh
Goutam Das
Shankara Rao Arvind Atignal
Kiran Mazumdar-Shaw
Original Assignee
Biocon 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 Biocon Limited filed Critical Biocon Limited
Priority to PCT/IN2003/000307 priority Critical patent/WO2005023766A1/en
Priority to AU2003269484A priority patent/AU2003269484A1/en
Publication of WO2005023766A1 publication Critical patent/WO2005023766A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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 a novel compound of formula I, wherein the compound is prodrug and releases two pharmaceutically active moieties, which has independent pharmacological activity and are used for treating hyperlipidemia and diabetes.
  • Hyperlipidemia is generally accompanied by other disorders of heart, kidney, stomach or liver. Generally, hyperlipidemia in a patient is accompanied by diabetes. Hyperlipidemia is treated employing a widely known class of drug called statins. Atorvastatin is generally administered as a calcium salt so that active open acid form is made available. Antihyperglycemic agents are used for treatment of diabetes.
  • Metformin is used for treatment of Non- insulin dependent diabetes mellitus (NIDDM). Metformin is generally administered a HCI salt.
  • NIDDM Non- insulin dependent diabetes mellitus
  • the present inventions discloses a novel compound of formula I which can be used for simultaneous treatment of hyperlipidemia and diabetes.
  • SUMMARY OF THE INVENTION The present invention discloses a novel compound of formula: I. The compound is used for simultaneous treatment of hyperlipidemia and diabetes.
  • the compound of formula I is a prodrug. It is mutual salt of two drugs viz. atorvastatin and metformin. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a novel compound of formula I, which can be used for treating hyperlipidemia and diabetes simultaneously.
  • the important embodiment of the invention is that the compound of formula I, wherein the two drug molecules form a mutual salt which can be called 'metformin salt of atorvastatin'.
  • the invention discloses the compound of formula I, wherein the atorvastatin is an anticholesterolemic or antilipidemic drug and metformin is an antihyperglycemic drug.
  • the compound of formula I is formed when the two compounds are treated with each other under suitable conditions to form a non-covalent bond between the carboxylic group of atorvastatin and nitrogen of metformin.
  • the non- covalent bond thus formed is an ionic bond between atorvastatin and metformin.
  • the compound of formula I is a mutual salt of atorvastatin and metformin.
  • compound of formula I Like any metal salt of atorvastatin, compound of formula I retain the open chain active form of atorvastatin by preventing undesired inactive lactone formation. Compound of formula I also have the extra advantage of delivering the active open acid form of atorvastatin without employing any metal cation. Unlike prior art, compound of formula I deliver metformin free-base without employing any other acid salt like hydrochloride salt.
  • the following non-limiting examples illustrate the inventors' preferred method for preparing the compound of the invention. EXAMPLES Example 1 To a solution of atorvastatin free acid (10 g, 0.018 mol) in ethyl acetate (200 ml), metformin free base (2.3 g, 0.018 mol) was added and stirred.
  • Example 2 To a solution of atorvastatin free acid (10 g, 0.018 mol) in isobutyl acetate (200 ml), a solution of metformin free base (2.3 g, 0.018 mol), in ethanol (10 ml) was added and stirred. The reaction mixture was concentrated to about 25 ml and diisopropyl ether (25 ml) was " added to afford the mutual salt of atorvastatin and metformin.

Abstract

A novel compound of formula (I), a mutual salt of atorvastatin and metformin, is disclosed. The compound of formula (I) can be used for the treatment of hyperlipidemia and hyperglycemia.

Description

SALT OF ATORVASTATIN WITH METFORMIN FIELD OF THE INVENTION This invention relates to a novel compound of formula I, wherein the compound is prodrug and releases two pharmaceutically active moieties, which has independent pharmacological activity and are used for treating hyperlipidemia and diabetes. BACKGROUND OF THE INVENTION Hyperlipidemia is generally accompanied by other disorders of heart, kidney, stomach or liver. Generally, hyperlipidemia in a patient is accompanied by diabetes. Hyperlipidemia is treated employing a widely known class of drug called statins. Atorvastatin is generally administered as a calcium salt so that active open acid form is made available. Antihyperglycemic agents are used for treatment of diabetes. Metformin is used for treatment of Non- insulin dependent diabetes mellitus (NIDDM). Metformin is generally administered a HCI salt. The present inventions discloses a novel compound of formula I which can be used for simultaneous treatment of hyperlipidemia and diabetes. SUMMARY OF THE INVENTION The present invention discloses a novel compound of formula: I. The compound is used for simultaneous treatment of hyperlipidemia and diabetes.
Figure imgf000003_0001
FORMULA I The compound of formula I is a prodrug. It is mutual salt of two drugs viz. atorvastatin and metformin. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a novel compound of formula I, which can be used for treating hyperlipidemia and diabetes simultaneously.
Figure imgf000003_0002
FORMULA I The important embodiment of the invention is that the compound of formula I, wherein the two drug molecules form a mutual salt which can be called 'metformin salt of atorvastatin'. The invention discloses the compound of formula I, wherein the atorvastatin is an anticholesterolemic or antilipidemic drug and metformin is an antihyperglycemic drug. The compound of formula I is formed when the two compounds are treated with each other under suitable conditions to form a non-covalent bond between the carboxylic group of atorvastatin and nitrogen of metformin. Preferably, the non- covalent bond thus formed is an ionic bond between atorvastatin and metformin. The compound of formula I is a mutual salt of atorvastatin and metformin. Like any metal salt of atorvastatin, compound of formula I retain the open chain active form of atorvastatin by preventing undesired inactive lactone formation. Compound of formula I also have the extra advantage of delivering the active open acid form of atorvastatin without employing any metal cation. Unlike prior art, compound of formula I deliver metformin free-base without employing any other acid salt like hydrochloride salt. The following non-limiting examples illustrate the inventors' preferred method for preparing the compound of the invention. EXAMPLES Example 1 To a solution of atorvastatin free acid (10 g, 0.018 mol) in ethyl acetate (200 ml), metformin free base (2.3 g, 0.018 mol) was added and stirred. The reaction mixture was concentrated to about 25 ml and chilled to 10° C to afford the mutual salt of atorvastatin and metformin. Example 2 To a solution of atorvastatin free acid (10 g, 0.018 mol) in isobutyl acetate (200 ml), a solution of metformin free base (2.3 g, 0.018 mol), in ethanol (10 ml) was added and stirred. The reaction mixture was concentrated to about 25 ml and diisopropyl ether (25 ml) was"added to afford the mutual salt of atorvastatin and metformin.

Claims

We claim
1. A compound of formula I
Figure imgf000005_0001
FORMULA I
2. A compound of formula I as in claim 1, wherein the compound is a mutual salt of atorvastatin and metformin.
3. A process of preparing a compound of formula I comprising of OOstirring atorvastatin free acid with metformin free base
4. A pharmaceutical composition comprising the compound of formula I as in claim 1.
5. A method of treatment of hyperlipidemia and hyperglycemia comprising use of the compound of formula I as in claim 1.
PCT/IN2003/000307 2003-09-11 2003-09-11 Salt of atorvastatin with metformin WO2005023766A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000307 WO2005023766A1 (en) 2003-09-11 2003-09-11 Salt of atorvastatin with metformin
AU2003269484A AU2003269484A1 (en) 2003-09-11 2003-09-11 Salt of atorvastatin with metformin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2003/000307 WO2005023766A1 (en) 2003-09-11 2003-09-11 Salt of atorvastatin with metformin

Publications (1)

Publication Number Publication Date
WO2005023766A1 true WO2005023766A1 (en) 2005-03-17

Family

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2003/000307 WO2005023766A1 (en) 2003-09-11 2003-09-11 Salt of atorvastatin with metformin

Country Status (2)

Country Link
AU (1) AU2003269484A1 (en)
WO (1) WO2005023766A1 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011025271A3 (en) * 2009-08-25 2011-07-14 한올바이오파마주식회사 Metformin ascorbate, method for preparing same, pharmaceutical composition comprising same, and combined formulation comprising same
CN102906077A (en) * 2010-05-26 2013-01-30 转化技术制药公司 Use of metformin in combination with glucokinase activator and compositions comprising metformin and glucokinase activator
WO2014011926A1 (en) * 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US8796338B2 (en) 2011-01-07 2014-08-05 Elcelyx Therapeutics, Inc Biguanide compositions and methods of treating metabolic disorders
US9050292B2 (en) 2011-01-07 2015-06-09 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9211263B2 (en) 2012-01-06 2015-12-15 Elcelyx Therapeutics, Inc. Compositions and methods of treating metabolic disorders
US9480663B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US9572784B2 (en) 2011-01-07 2017-02-21 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US10004782B2 (en) 2012-05-17 2018-06-26 Vtv Therapeutics Llc Glucokinase activator compositions for the treatment of diabetes
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000045818A1 (en) * 1999-02-06 2000-08-10 Astrazeneca Ab Use of 3-hydroxy-3-methylglutaryl coenzym a reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy
WO2003075933A1 (en) * 2002-03-07 2003-09-18 Upsher-Smith Laboratories, Inc. Composition for reducing blood glucose and cholesterol

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000045818A1 (en) * 1999-02-06 2000-08-10 Astrazeneca Ab Use of 3-hydroxy-3-methylglutaryl coenzym a reductase inhibitors for the manufacture of a medicament for the treatment of diabetic neuropathy
WO2003075933A1 (en) * 2002-03-07 2003-09-18 Upsher-Smith Laboratories, Inc. Composition for reducing blood glucose and cholesterol

Cited By (35)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101211227B1 (en) 2009-08-25 2012-12-11 한올바이오파마주식회사 Metformin ascorbic acid salt, preparation thereof, pharmaceutical composition comprising the same and combined formulation comprising the same
WO2011025271A3 (en) * 2009-08-25 2011-07-14 한올바이오파마주식회사 Metformin ascorbate, method for preparing same, pharmaceutical composition comprising same, and combined formulation comprising same
US9359313B2 (en) 2010-05-26 2016-06-07 Vtv Therapeutics Llc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
CN102906077A (en) * 2010-05-26 2013-01-30 转化技术制药公司 Use of metformin in combination with glucokinase activator and compositions comprising metformin and glucokinase activator
EP2576524A1 (en) * 2010-05-26 2013-04-10 TransTech Pharma, Inc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
US10363244B2 (en) 2010-05-26 2019-07-30 Vtv Therapeutics Llc Compositions comprising metformin and a glucokinase activator
EP2576524A4 (en) * 2010-05-26 2014-03-05 Transtech Pharma Inc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
US10064846B2 (en) 2010-05-26 2018-09-04 Vtv Therapeutics Llc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
CN102906077B (en) * 2010-05-26 2015-03-04 转化技术制药有限责任公司 Use of metformin in combination with glucokinase activator and compositions comprising metformin and glucokinase activator
US9855251B2 (en) 2010-05-26 2018-01-02 Vtv Therapeutics Llc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
TWI508723B (en) * 2010-05-26 2015-11-21 Vtv Therapeutice Llc Use of metformin in combination with a glucokinase activator and compositions comprising metformin and a glucokinase activator
US9572784B2 (en) 2011-01-07 2017-02-21 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US9050292B2 (en) 2011-01-07 2015-06-09 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9463170B2 (en) 2011-01-07 2016-10-11 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US9480663B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US9481642B2 (en) 2011-01-07 2016-11-01 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US11759441B2 (en) 2011-01-07 2023-09-19 Anji Pharmaceuticals Inc. Biguanide compositions and methods of treating metabolic disorders
US11065215B2 (en) 2011-01-07 2021-07-20 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10201511B2 (en) 2011-01-07 2019-02-12 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US9962344B2 (en) 2011-01-07 2018-05-08 Elcelyx Therapeutics, Inc. Chemosensory receptor ligand-based therapies
US10668031B2 (en) 2011-01-07 2020-06-02 Anji Pharma (Us) Llc Biguanide compositions and methods of treating metabolic disorders
US10610500B2 (en) 2011-01-07 2020-04-07 Anji Pharma (Us) Llc Chemosensory receptor ligand-based therapies
US10028923B2 (en) 2011-01-07 2018-07-24 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US8796338B2 (en) 2011-01-07 2014-08-05 Elcelyx Therapeutics, Inc Biguanide compositions and methods of treating metabolic disorders
US10154972B2 (en) 2011-01-07 2018-12-18 Elcelyx Therapeutics, Inc. Biguanide compositions and methods of treating metabolic disorders
US10159658B2 (en) 2011-01-07 2018-12-25 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
US9770422B2 (en) 2012-01-06 2017-09-26 Elcelyx Therapeutics, Inc. Compositions and methods for treating metabolic disorders
US10603291B2 (en) 2012-01-06 2020-03-31 Anji Pharma (Us) Llc Compositions and methods for treating metabolic disorders
US9211263B2 (en) 2012-01-06 2015-12-15 Elcelyx Therapeutics, Inc. Compositions and methods of treating metabolic disorders
US10588943B2 (en) 2012-05-17 2020-03-17 Vtv Therapeutics Llc Glucokinase activator compositions for the treatment of diabetes
US10004782B2 (en) 2012-05-17 2018-06-26 Vtv Therapeutics Llc Glucokinase activator compositions for the treatment of diabetes
WO2014011926A1 (en) * 2012-07-11 2014-01-16 Elcelyx Therapeutics, Inc. Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
JP2018087214A (en) * 2012-07-11 2018-06-07 エルセリクス セラピューティクス インコーポレイテッド Compositions comprising statins, biguanides and further agents for reducing cardiometabolic risk
JP2015522080A (en) * 2012-07-11 2015-08-03 エルセリクス セラピューティクス インコーポレイテッド Compositions for reducing cardiovascular metabolic risk comprising statins, biguanides, and additional agents
US11833136B2 (en) 2018-06-12 2023-12-05 Vtv Therapeutics Llc Therapeutic uses of glucokinase activators in combination with insulin or insulin analogs

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