WO2005033089A1 - Salt of 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid with n, n-dimethyl-imidodicarbonimidic diamide - Google Patents

Salt of 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid with n, n-dimethyl-imidodicarbonimidic diamide Download PDF

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Publication number
WO2005033089A1
WO2005033089A1 PCT/IN2003/000329 IN0300329W WO2005033089A1 WO 2005033089 A1 WO2005033089 A1 WO 2005033089A1 IN 0300329 W IN0300329 W IN 0300329W WO 2005033089 A1 WO2005033089 A1 WO 2005033089A1
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Prior art keywords
methyl
isobenzofuranyl
dihydro
oxo
methoxy
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PCT/IN2003/000329
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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 AU2003272083A priority Critical patent/AU2003272083A1/en
Priority to PCT/IN2003/000329 priority patent/WO2005033089A1/en
Publication of WO2005033089A1 publication Critical patent/WO2005033089A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/87—Benzo [c] furans; Hydrogenated benzo [c] furans
    • C07D307/88—Benzo [c] furans; Hydrogenated benzo [c] furans with one oxygen atom directly attached in position 1 or 3
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • 6-(l,3 ⁇ dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid, sodium salt or its 2-ethyl morphoiino derivative is used as immunosuppressants.
  • 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid is generally administered as a sodium salt or 2-ethyl morphoiino derivative so that active free acid is made available for absorption.
  • 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 a HCI salt.
  • the present inventions discloses a novel compound of formula I which can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy.
  • SUMMARY OF THE INVENTION The present invention discloses a novel compound of formula I. The compound can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy.
  • 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 X N, N-dimethyl- imidodicarbonimidic diamide salt of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid.
  • the invention discloses the compound of formula I, wherein the 6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid is an immunosuppressive drug and N, N-dimethyl- imidodicarbonimidic diamide 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 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid and nitrogen of N, N- dimethyl- imidodicarbonimidic diamide.
  • the non- covalent bond thus formed is an ionic bond between 6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide.
  • the compound of formula I is a mutual salt of 6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide.
  • compound of formula I retain the free acid form of 6-(l,3-dihydro- 4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl- 4-hexenoic acid.
  • Compound of formula I have the extra advantage of delivering the free acid form of 6-( ⁇ ,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid without employing any metal cation. Unlike prior art, compound of formula I delivers N, N- dimethyl- imidodicarbonimidic diamide 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.
  • reaction mixture was chilled (10-15° C) and filtered to afford the mutual salt of 6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic5 acid and N, N-dimethyl- imidodicarbonimidic diamide.
  • Example 2 To a solution of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (10 g, 0.03 mol) in isobutyl acetate (75 ml), N, N-dimethyl-o imidodicarbonimidic diamide free base (4.0 g, 0.03 mol) was added and stirred.
  • reaction mixture was chilled (10-15° C) and filtered o afford the mutual salt of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide.

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  • Health & Medical Sciences (AREA)
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  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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Abstract

A novel compound of formula (I), a mutual salt of 6-(1,3­-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)­-4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide, is disclosed. The compound of formula (I) can be simultaneously used as an immunosuppressant and anti hyperglycemic agent for the treatment of diabetic nephropathy.

Description

TITLE OF THE INVENTION SALT OF 6-(l,3-DIHYDRO-4-HYDROXY-6-METHOXY- 7-METHYL-3-OXO-5-ISOBENZOFURANYL)-4-METHYL-4- HEXENOIC ACID WITH N, N-DIMETHYL- IMIDODICARBONIMIDIC DIAMIDE FIELD OF THE INVENTION This invention relates to a novel compound of formula I, which can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy. BACKGROUND OF THE INVENTION Drugs like 6-(l,3~dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid, sodium salt or its 2-ethyl morphoiino derivative is used as immunosuppressants. 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid is generally administered as a sodium salt or 2-ethyl morphoiino derivative so that active free acid is made available for absorption. 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 a HCI salt. The present inventions discloses a novel compound of formula I which can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy. SUMMARY OF THE INVENTION The present invention discloses a novel compound of formula I. The compound can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy. FORMULA I
Figure imgf000003_0001
It is mutual salt of two drugs viz. 6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide. DETAILED DESCRIPTION OF THE INVENTION The present invention discloses a novel compound of formula I, which can be simultaneously used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy.
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 XN, N-dimethyl- imidodicarbonimidic diamide salt of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid. The invention discloses the compound of formula I, wherein the 6-(l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid is an immunosuppressive drug and N, N-dimethyl- imidodicarbonimidic diamide 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 6- (l,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5- isobenzofuranyl)-4-methyl-4-hexenoic acid and nitrogen of N, N- dimethyl- imidodicarbonimidic diamide. Preferably, the non- covalent bond thus formed is an ionic bond between 6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide. The compound of formula I is a mutual salt of 6-(l,3- dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)- 4-methyl-4-hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide. Like any metal salt of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid, compound of formula I retain the free acid form of 6-(l,3-dihydro- 4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl- 4-hexenoic acid. Compound of formula I have the extra advantage of delivering the free acid form of 6-(ϊ,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid without employing any metal cation. Unlike prior art, compound of formula I delivers N, N- dimethyl- imidodicarbonimidic diamide 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 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (5 g, 0.015 mol) in ethyl acetate (75 ml), N, N-dimethyl- imidodicarbonimidic diamide free base (2.0 g, 0.015 mol) was added and stirred. The reaction mixture was chilled (10-15° C) and filtered to afford the mutual salt of 6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic5 acid and N, N-dimethyl- imidodicarbonimidic diamide. Example 2 To a solution of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid (10 g, 0.03 mol) in isobutyl acetate (75 ml), N, N-dimethyl-o imidodicarbonimidic diamide free base (4.0 g, 0.03 mol) was added and stirred. The reaction mixture was chilled (10-15° C) and filtered o afford the mutual salt of 6-(l,3-dihydro-4-hydroxy-6-methoxy-7- methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic 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 6-(l,3-dihydro-4-hydroxy-6- methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4- hexenoic acid and N, N-dimethyl- imidodicarbonimidic diamide. 3. A process of preparing a compound of formula I comprising of stirring 6-(l,
3-dihydro-4-hydroxy-6-methoxy-7-methyl-3- oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid free 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, which can be simultaneously, used as an immunosuppressant and antihyperglycemic agent for the treatment of diabetic nephropathy comprising use of the compound of formula I as in claim 1.
6. A compound of formula I in claim 1, used for the treatment of diabetic nephropathy.
PCT/IN2003/000329 2003-10-07 2003-10-07 Salt of 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid with n, n-dimethyl-imidodicarbonimidic diamide WO2005033089A1 (en)

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AU2003272083A AU2003272083A1 (en) 2003-10-07 2003-10-07 Salt of 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid with n, n-dimethyl-imidodicarbonimidic diamide
PCT/IN2003/000329 WO2005033089A1 (en) 2003-10-07 2003-10-07 Salt of 6-(1, 3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl)-4-methyl-4-hexenoic acid with n, n-dimethyl-imidodicarbonimidic diamide

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008003637A2 (en) * 2006-07-05 2008-01-10 Dsm Ip Assets B.V. Isolation and use of amine salts of mycophenolic acid
US7683188B2 (en) 2004-04-26 2010-03-23 TEVA Gyógyszergyár Zártkōrūen Mūkōdō Részvénytársaság Process for preparation of mycophenolic acid and ester derivatives thereof
WO2010146604A2 (en) 2009-06-18 2010-12-23 Exemed Pharmaceuticals Processes for preparing metformin hydrochloride

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
WO2003011273A1 (en) * 2001-07-31 2003-02-13 The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Metformin in the treatment of hyperglycemic conditions

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4948793A (en) * 1987-01-30 1990-08-14 Syntex (U.S.A.) Inc. Treatment of autoimmune diseases with the morpholinoethyl ester of mycophenolic acid, and derivatives thereof
WO2003011273A1 (en) * 2001-07-31 2003-02-13 The Governement Of The United States Of America, As Represented By The Secretary Of The Department Of Health And Human Services Metformin in the treatment of hyperglycemic conditions

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7683188B2 (en) 2004-04-26 2010-03-23 TEVA Gyógyszergyár Zártkōrūen Mūkōdō Részvénytársaság Process for preparation of mycophenolic acid and ester derivatives thereof
WO2008003637A2 (en) * 2006-07-05 2008-01-10 Dsm Ip Assets B.V. Isolation and use of amine salts of mycophenolic acid
WO2008003637A3 (en) * 2006-07-05 2008-05-08 Dsm Ip Assets Bv Isolation and use of amine salts of mycophenolic acid
WO2010146604A2 (en) 2009-06-18 2010-12-23 Exemed Pharmaceuticals Processes for preparing metformin hydrochloride

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