WO2005033067A1 - SALT OF 1,2,6,7,8,8A-HEXAHYDRO-β,δ,6-TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-1-OXOBUTOXY]-, (βR,δ R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE - Google Patents

SALT OF 1,2,6,7,8,8A-HEXAHYDRO-β,δ,6-TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-1-OXOBUTOXY]-, (βR,δ R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE Download PDF

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Publication number
WO2005033067A1
WO2005033067A1 PCT/IN2003/000330 IN0300330W WO2005033067A1 WO 2005033067 A1 WO2005033067 A1 WO 2005033067A1 IN 0300330 W IN0300330 W IN 0300330W WO 2005033067 A1 WO2005033067 A1 WO 2005033067A1
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Prior art keywords
methyl
oxobutoxy
trihydroxy
hexahydro
dimethyl
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PCT/IN2003/000330
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French (fr)
Inventor
Sambasivam Ganesh
Goutam Das
Shankara Rao Arvind Atignal
Kiran Mazumdar-Shaw
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Biocon Limited
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Priority to PCT/IN2003/000330 priority Critical patent/WO2005033067A1/en
Priority to AU2003272084A priority patent/AU2003272084A1/en
Publication of WO2005033067A1 publication Critical patent/WO2005033067A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • 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

  • Hyperlipidemia is generally accompanied by other disorders of heart, kidney, stomach or liver. Hyperlipidemia is treated employing l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8- [(2s)-2-methyl-l-oxobutoxy]-, ( ⁇ R, ⁇ ,lS,2S,6S,8S,8aR)- 1- naphthaleneheptanoic acid, sodium salt so that active, open acid form is made available.
  • Antihyperglycemic agents are used for treatment of diabetes. N,N -dimethyl- imidodicarbonimidic diamide is used for treatment of Non-insulin dependent diabetes mellitus (NIDDM).
  • N,N-dimethyl- imidodicarbonimidic diamide is generally administered as HCI salt.
  • the present invention discloses a novel compound of formula I, which is a salt of l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2- methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid with N,N-dimethyl- imidodicarbonimidic diamide and can be used for simultaneous treatment of hyperlipidemia and diabetes.
  • SUMMARY OF THE INVENTION discloses a novel compound of formula I. The compound can be used for treating hyperlipidemia and hyperglycemia.
  • FORMULA I It is mutual salt of two drugs viz. l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide.
  • the present invention discloses a novel compound (FORMULA I) which is a salt of l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2- methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid with N,N-dimethyl- imidodicarbonimidic diamide.
  • Compound of formula I can be used for treating hyperlipidemia and hyperglycemia.
  • FORMULA I The important embodiment of the present invention is that the compound of formula I, wherein the mutual salt which can be called x N,N-dimethyl- imidodicarbonimidic diamide salt of l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid.
  • the mutual salt which can be called x N,N-dimethyl- imidodicarbonimidic diamide salt of l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid.
  • the invention discloses the compound of formula I, wherein the l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-[(2s)-2- methy I- 1-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1- naphthaleneheptanoic acid is an anticholesterolemic or antilipidemic drug and N,N-dimethyl- imidodicarbonimidic diamide is an antihyperglycemic drug.
  • compound of formula I is a mutual salt of l,2,6,7,8,8a-hexahydro- ⁇ , ⁇ ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, ( ⁇ R, ⁇ R,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide.
  • compound of formula I deliver N,N-dimethyl- imidodicarbonimidic diamide free-base without employing any other acid salt like hydrochloride salt. ' Formation of a mutual salt enhances solubility of both the

Abstract

A novel compound of formula (I), a mutual salt of 1,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-1-oxobutoxy]-, (βR,δ R,1S,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N-dimethyl- imidodicarbonimidic diamide, is disclosed. The compound of formula (I) can be used for the treatment of hyperlipidemia and hyperglycemia.

Description

TITLE OF THE INVENTION SALT OF l,2,6,7,8,8A-HEXAHYDRO-β,δ,6- TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-l- OXOBUTOXY]-, (βR,δR,lS,2S,6S,8S,8AR)- 1- NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL- IMIDODICARBONIMIDIC DIAMIDE FIELD OF THE INVENTION This invention relates to a novel compound of formula I, wherein the compound is used for treating hyperlipidemia and hyperglycemia. BACKGROUND OF THE INVENTION Hyperlipidemia is generally accompanied by other disorders of heart, kidney, stomach or liver. Hyperlipidemia is treated employing l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8- [(2s)-2-methyl-l-oxobutoxy]-, (βR,δ ,lS,2S,6S,8S,8aR)- 1- naphthaleneheptanoic acid, sodium salt so that active, open acid form is made available. Antihyperglycemic agents are used for treatment of diabetes. N,N -dimethyl- imidodicarbonimidic diamide is used for treatment of Non-insulin dependent diabetes mellitus (NIDDM). N,N-dimethyl- imidodicarbonimidic diamide is generally administered as HCI salt. The present invention discloses a novel compound of formula I, which is a salt of l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2- methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid with N,N-dimethyl- imidodicarbonimidic diamide and 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 can be used for treating hyperlipidemia and hyperglycemia.
Figure imgf000003_0001
FORMULA I It is mutual salt of two drugs viz. l,2,6,7,8,8a-hexahydro- β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a novel compound (FORMULA I) which is a salt of l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2- methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid with N,N-dimethyl- imidodicarbonimidic diamide. Compound of formula I can be used for treating hyperlipidemia and hyperglycemia.
Figure imgf000004_0001
FORMULA I The important embodiment of the present invention is that the compound of formula I, wherein the mutual salt which can be called xN,N-dimethyl- imidodicarbonimidic diamide salt of l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid. The invention discloses the compound of formula I, wherein the l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-[(2s)-2- methy I- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1- naphthaleneheptanoic acid is an anticholesterolemic or antilipidemic drug and N,N-dimethyl- imidodicarbonimidic diamide is an antihyperglycemic drug. The compound of formula I is formed when a non-covalent bond between the carboxylic group of l,2,6,7,8,8a-hexahydro- β.δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and 5 nitrogen of N,N-dimethyl- imidodicarbonimidic diamide. Preferably, the non-covalent bond thus formed is an ionic bond between l,2,6/7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N-dimethyl- imidodicarbonimidic diamide. The
10 compound of formula I is a mutual salt of l,2,6,7,8,8a-hexahydro- β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide. Like any metal salt of l,2,6,7,8,8a-hexahydro-β,δ,6- i5 trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid, compound of formula I retain the open chain active form of 1,2,6,7,8,8a- hexahydro-β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l- oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic
20 acid and prevent formation of undesired inactive lactone derivative. Compound of formula I also have the extra advantage of delivering the active open acid form of l,2,6,7,8,8a-hexahydro- β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid without
25 employing any metal cation. Unlike prior art, compound of formula I deliver N,N-dimethyl- imidodicarbonimidic diamide free-base without employing any other acid salt like hydrochloride salt. ' Formation of a mutual salt enhances solubility of both the
3o drugs in water and aqueous media without the aid of any further derivatisation. 5 The following non-limiting examples illustrate the inventors' preferred method for preparing the compound of the invention. EXAMPLES Example 1 To a solution of l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2- ιo methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid (5 g, 0.012 mol) in ethyl acetate (75 ml), N,N-dimethyl- imidodicarbonimidic diamide free base (1.5 g, 0.012 mol) was added and stirred. The reaction mixture was chilled (10-15° C) to afford the mutual salt.of l,2,6,7,8,8a-hexahydro- i5 β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR7lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide. Example 2 To a solution of l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-
20 methyl-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid (10 g, 0.024 mol) in isobutyl acetate (200 ml), N,N-dimethyl- imidodicarbonimidic diamide free base (3 g, 0.024 mol) was added and stirred. The reaction mixture chilled (10-15° C) to afford the mutual salt of l,2,6,7,8,8a-hexahydro-
25 β,δ,6-trihydroxy-2-methyl-8-[(2s)-2-methyl- 1-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N- dimethyl- imidodicarbonimidic diamide.

Claims

We claim 1. A compound of formula I
Figure imgf000007_0001
FORMULA I 2. A compound of formula I as in claim 1, wherein the compound is a mutual salt of l,2,6,7,8,8a-hexahydro-β,δ,6- trihydroxy-2-methyI-8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1-naphthaleneheptanoic acid and N,N-dimethyl- imidodicarbonimidic diamide. 3. A process of preparing a compound of formula I comprising of treating l,2,6,7,8,8a-hexahydro-β,δ,6-trihydroxy-2-methyl- 8-[(2s)-2-methyl-l-oxobutoxy]-, (βR,δR,lS,2S,6S,8S,8aR)- 1- naphthaleneheptanoic acid with N,N-dimethyl- imidodicarbonimidic diamide 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/IN2003/000330 2003-10-07 2003-10-07 SALT OF 1,2,6,7,8,8A-HEXAHYDRO-β,δ,6-TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-1-OXOBUTOXY]-, (βR,δ R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE WO2005033067A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/IN2003/000330 WO2005033067A1 (en) 2003-10-07 2003-10-07 SALT OF 1,2,6,7,8,8A-HEXAHYDRO-β,δ,6-TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-1-OXOBUTOXY]-, (βR,δ R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE
AU2003272084A AU2003272084A1 (en) 2003-10-07 2003-10-07 SALT OF 1,2,6,7,8,8A-HEXAHYDRO-Beta,Delta,6-TRIHYDROXY-2-METHYL-8-((2S)-2-METHYL-1-OXOBUTOXY)-, (BetaR,Delta R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE

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PCT/IN2003/000330 WO2005033067A1 (en) 2003-10-07 2003-10-07 SALT OF 1,2,6,7,8,8A-HEXAHYDRO-β,δ,6-TRIHYDROXY-2-METHYL-8-[(2S)-2-METHYL-1-OXOBUTOXY]-, (βR,δ R,1S,2S,6S,8S,8AR)- 1-NAPHTHALENEHEPTANOIC ACID WITH N,N-DIMETHYL-IMIDODICARBONIMIDIC DIAMIDE

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009068556A1 (en) * 2007-11-29 2009-06-04 Dsm Ip Assets B.V. Purification of pravastatin
WO2010146604A2 (en) 2009-06-18 2010-12-23 Exemed Pharmaceuticals Processes for preparing metformin hydrochloride
US8076377B2 (en) 2007-09-21 2011-12-13 Hanall Pharmaceutical Company, Ltd. N,N-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same
US20160272582A1 (en) * 2015-03-21 2016-09-22 Mohan Murali Alapati Compositions and methods for the treatment of hyperglycemia and metabolic syndrome

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 (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8076377B2 (en) 2007-09-21 2011-12-13 Hanall Pharmaceutical Company, Ltd. N,N-dimethyl imidodicarbonimidic diamide dicarboxylate, method for producing the same and pharmaceutical compositions comprising the same
WO2009068556A1 (en) * 2007-11-29 2009-06-04 Dsm Ip Assets B.V. Purification of pravastatin
WO2010146604A2 (en) 2009-06-18 2010-12-23 Exemed Pharmaceuticals Processes for preparing metformin hydrochloride
US20160272582A1 (en) * 2015-03-21 2016-09-22 Mohan Murali Alapati Compositions and methods for the treatment of hyperglycemia and metabolic syndrome
US9604920B2 (en) * 2015-03-21 2017-03-28 Mohan Murali Alapati Compositions and methods for the treatment of hyperglycemia and metabolic syndrome

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