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WO2011004200A1 - Nouveaux dérivés de pyrrole - Google Patents

Nouveaux dérivés de pyrrole Download PDF

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Publication number
WO2011004200A1
WO2011004200A1 PCT/GB2010/051134 GB2010051134W WO2011004200A1 WO 2011004200 A1 WO2011004200 A1 WO 2011004200A1 GB 2010051134 W GB2010051134 W GB 2010051134W WO 2011004200 A1 WO2011004200 A1 WO 2011004200A1
Authority
WO
WIPO (PCT)
Prior art keywords
acid
sunitinib
process according
addition salt
pyrrole
Prior art date
Application number
PCT/GB2010/051134
Other languages
English (en)
Inventor
Vinayak Govind Gore
Laxmikant Patkar
Mahesh Gorakhnath Hublikar
Hemant Mande
Kiran Shivaji Pokharkar
Prakash Bansode
Original Assignee
Generics [Uk] Limited
Mylan India Private 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 Generics [Uk] Limited, Mylan India Private Limited filed Critical Generics [Uk] Limited
Publication of WO2011004200A1 publication Critical patent/WO2011004200A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

Definitions

  • the inventors have found that when an acid addition salt form of the pyrrole derivative (I) is used as opposed to the base 1 used in the prior art (see schemes 1 and 2), the resulting sunitinib salt had surprisingly high purity and high quantitative yield. It was also surprisingly found that the use of the salt form of the pyrrole derivative (I) meant subsequent purification was reduced or not needed at all.
  • a sunitinib salt could be prepared directly from the combination of the corresponding salt form of the pyrrole derivative (I) and a 5-fluoro-2-oxindole (III) without the need for first preparing the base (II) and then subsequently converting the base (II) to the desired salt as is the case in the prior art preparation of sunitinib salts.
  • the process of the invention utilizing acid addition salts of pyrrole derivatives (I) resulted in a more simple and cost effective process for the - A - preparation of sunitinib salts. Accordingly there is provided in a first aspect of the invention a process for the preparation of an acid addition salt of a pyrrole substituted indolinone, comprising:
  • R 1 and R 2 are independently any atom or group
  • R 1 and R 2 are independently halo, R 3 , COR 3 , CO 2 R 3 or CON(R 3 ) 2 , wherein R 3 is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • the preparation of the (L) malic acid salt of sunitinib (II) is particularly preferred. Accordingly, a particularly preferred embodiment of the present invention provides a process for the preparation of sunitinib malate (Ua)
  • a fifth aspect of the invention provides sunitinib (II) or an acid addition salt of sunitinib (II) such as sunitinib malate (Ha), prepared according to the first aspect of the invention, preferably having a purity of at least 97% as measured by HPLC, preferably at least 99%, most preferably having a purity of at least 99.8%.
  • n O, 1, 2, 3 or 4,
  • R 1 and R 2 are independently halo, R 3 , COR 3 , CO 2 R 3 or CON(R 3 ) 2 , wherein R 3 is independently hydrogen or an alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, alkylaryl, alkenylaryl or alkynylaryl group, each of which may optionally be substituted, and each of which may optionally include one or more heteroatoms N, O or S in its carbon skeleton.
  • R 1 is independently alkyl or CONHR 3 , more preferably R 1 is independently methyl or CO-NH-CH 2 CH 2 NEt 2 .
  • R 2 is independently halo, more preferably R 2 is fiuoro.
  • m is 3.
  • n is i.
  • R 8 or R 8 a is a formyl group and the other is H.
  • the processes of the first aspect of the invention also require a base to be added to the reaction mixture.
  • a base may be utilized.
  • the base may be an organic base.
  • the base is pyrrolidine, but most preferably the base is l,8-diazabicyclo[5.4.0]undec-7-ene (DBU).
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • the molar ratio of the base added with respect to the pyrrole derivative (I) is between 0.1 to 1.2.
  • the temperature of the reaction is kept at between about 0-85 0 C or in alternative embodiments between 0 0 C and the reflux temperature of the solvent system employed in the reaction.
  • the inventors have found that a reaction temperature around standard room temperature provides excellent reaction conditions without increasing the complexity and the cost of the process according to the invention. Accordingly in particularly preferred embodiments, the reaction is kept between about 20- 30 0 C.
  • the acid addition salt of the pyrrole derivative is prepared in situ and not isolated before reaction with the 2-oxindole derivative (such as the 5-fluoro-2-oxindole (HI)).
  • the acid addition salt of the pyrrole derivative is isolated before reaction with the 2-oxindole derivative (such as the 5-fluoro-2-oxindole (IH)). It is always advantageous to prepare a polymorphic form of sunitinib malate that has good bioavailability and processability.
  • the resulting sunitinib malate has crystalline form I having an XRP diffractogram according to Figure 1.
  • sunitinib malate (Ha) by using the (L) malic acid salt of the pyrrole derivative (I)
  • other sunitinib salts may be prepared simply by using the corresponding pyrrole derivative salts and still remain within the scope and spirit of the invention.
  • the corresponding acid may be any organic or inorganic acid.
  • organic acids like carboxylic acids, sulfonic acids, phosphorous derived acids and boron derived acids can be used.
  • carboxylic acids can be employed.
  • a more specific process for conversion of the pyrrole derivative acid addition salt to the corresponding sunitinib salt comprises the following steps:
  • R 8 is either a formyl group or hydrogen.
  • carboxylic acids can be employed, preferably acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • acetic acid oxalic acid
  • D oxalic acid
  • L malic acid
  • maleic acid methanesulfonic acid
  • salicylic acid tartaric acid
  • citric acid citric acid
  • succinic acid or malonic acid succinic acid or malonic acid
  • salts refers to those salts, which retain the biological effectiveness and properties of the parent compound.
  • Such salts include acid addition salts which are obtained by reaction of the free base of the parent compound with inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, sulfuric acid, perchloric acid and the like, or with organic acids such as acetic acid, oxalic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, salicylic acid, tartaric acid, citric acid, succinic acid, malonic acid and the like, preferably hydrochloric acid or (L) malic acid, more preferably (L) malic acid.
  • a particularly preferred pharmaceutically acceptable salt is the (L) malate salt of the pyrrole derivative (I).
  • a salt form comprising the (L) malic acid salt of the pyrrole derivative (I)
  • the solvent system comprises ketones (preferably acetone, MEK), esters (preferably ethyl acetate, isopropyl acetate), acetonitrile, C 1 -C 10 alcohols, DCM, dimethylformamide, dimethylacetamide, dimethyl sulfoxide or a combination thereof.
  • step (b) removing the DCM from the mixture in step (a);
  • the mixture from step (a) is stirred at between about 0-100 0 C, preferably for about 15 minutes.
  • the stirring is effected to ensure complete mixing of the reaction mixture and the components therein and thus the timing can be varied within the scope of the appended claims.
  • the temperature of the reaction can also be varied. The inventors found that 20-35 0 C was most advantageous.
  • the dichloromethane was decanted and fresh dichloromethane (30 ml) added to the sticky mass, followed by stirring and decantation of the dichloromethane. Methanol (20 ml) was added until the sticky mass completely dissolved. The DCM and methanol solvents were removed by rotary evaporation to obtain a brown coloured sticky mass, which was characterized as the malate salt by NMR.
  • Acetonitrile methanol (1.5:1, 300 ml), malate salt of N-[2-(diethylamino)ethyl]-5-formyl- 2,4-dimethyl-lH-pyrrole-3-carboxamide (15 g, 1 equivalent) and 5-fiuoro-2-oxindole (5.67 g, 1 equivalent) were added at 25-30 0 C to obtain a clear solution within 5 minutes. Pyrrolidine (2.62 g, 1 equivalent) was then added to the reaction mass. After 12 hours stirring at 25-30 0 C, a yellow solid progressively precipitated out of the solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention porte sur de nouveaux sels de dérivés de pyrrole, sur leur préparation et sur leur utilisation dans la préparation de sels de sunitinib, en particulier de malate de sunitinib (IIa), et de sunitinib base. L'invention porte également sur des compositions comprenant des sels de sunitinib ou du sunitinib base et sur l'utilisation de ces compositions dans le traitement d'un cancer.
PCT/GB2010/051134 2009-07-10 2010-07-09 Nouveaux dérivés de pyrrole WO2011004200A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN962KO2009 2009-07-10
IN962/KOL/2009 2009-07-10

Publications (1)

Publication Number Publication Date
WO2011004200A1 true WO2011004200A1 (fr) 2011-01-13

Family

ID=42582602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2010/051134 WO2011004200A1 (fr) 2009-07-10 2010-07-09 Nouveaux dérivés de pyrrole

Country Status (1)

Country Link
WO (1) WO2011004200A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003016305A1 (fr) 2001-08-15 2003-02-27 Pharmacia & Upjohn Company Cristaux comprenant un sel d'acide malique de n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide, procedes de preparation associes et compositions correspondantes
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2009150523A1 (fr) * 2008-06-13 2009-12-17 Medichem, S.A. Procédé de préparation d’un sel 2-indolinone malate à substitution 3‑pyrrole

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6573293B2 (en) 2000-02-15 2003-06-03 Sugen, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
US7125905B2 (en) 2000-02-15 2006-10-24 Agouron Pharmaceuticals, Inc. Pyrrole substituted 2-indolinone protein kinase inhibitors
WO2003016305A1 (fr) 2001-08-15 2003-02-27 Pharmacia & Upjohn Company Cristaux comprenant un sel d'acide malique de n-[2-(diethylamino)ethyl]-5-[(5-fluoro-1,2-dihydro-2-oxo-3h-indol-3-ylidene)methyl]-2,4-dimethyl-1h-pyrrole-3-carboxamide, procedes de preparation associes et compositions correspondantes
US7435832B2 (en) 2001-08-15 2008-10-14 Pharmacia & Upjohn Company Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
WO2003070725A2 (fr) 2002-02-15 2003-08-28 Pharmacia & Upjohn Company Procede de preparation de derives de l'indolinone
US7119209B2 (en) 2002-02-15 2006-10-10 Pharmacia & Upjohn Company Process for preparing indolinone derivatives
US20060009510A1 (en) 2004-07-09 2006-01-12 Pharmacia & Upjohn Company Llc Method of synthesizing indolinone compounds
WO2009150523A1 (fr) * 2008-06-13 2009-12-17 Medichem, S.A. Procédé de préparation d’un sel 2-indolinone malate à substitution 3‑pyrrole

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"SUNITINIB MALATE - ONCOLYTIC DRUG MULTITARGETED TYROSINE KINASE INHIBITOR", DRUGS OF THE FUTURE, PROUS SCIENCE, ES LNKD- DOI:10.1358/DOF.2005.030.08.928476, vol. 30, no. 8, 1 August 2005 (2005-08-01), pages 785 - 792, XP009070152, ISSN: 0377-8282 *
J. ORG. CHEM., vol. 68, no. 16, 2003, pages 6447 - 6450

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015031604A1 (fr) 2013-08-28 2015-03-05 Crown Bioscience, Inc. Signatures d'expression génique permettant de prédire la réponse d'un sujet à un inhibiteur multikinase et leurs procédés d'utilisation

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