Monday 27 February 2017

Trying to understand Gleevec India patent case

Image result for gleevec india patent case
Novartis v. Union of India & Others is a landmark decision by a two-judge bench of the Indian Supreme Court on the issue of whether Novartis could patent Gleevec in India, and was the culmination of a seven-year-long litigation fought by Novartis. The Supreme Court upheld the Indian patent office's rejection of the patent application.
Image result for gleevec india patent case
Image result for gleevec india patent case
The patent application at the center of the case was filed by Novartis in India in 1998, after India had agreed to enter the World Trade Organization and to abide by worldwide intellectual property standards under the TRIPS agreement. As part of this agreement, India made changes to its patent law; the biggest of which was that prior to these changes, patents on products were not allowed, while afterwards they were, albeit with restrictions. These changes came into effect in 2005, so Novartis' patent application waited in a "mailbox" with others until then, under procedures that India instituted to manage the transition. India also passed certain amendments to its patent law in 2005, just before the laws came into effect, which played a key role in the rejection of the patent application.
Image result for gleevec india patent case
The patent application claimed the final form of Gleevec (the beta crystalline form of imatinib mesylate). In 1993, during the time India did not allow patents on products, Novartis had patented imatinib, with salts vaguely specified, in many countries but could not patent it in India. The key differences between the two patent applications, were that the 1998 patent application specified the counterion (Gleevec is a specific salt - imatinib mesylate) while the 1993 patent application did not claim any specific salts nor did it mention mesylate, and the 1998 patent application specified the solid form of Gleevec - the way the individual molecules are packed together into a solid when the drug itself is manufactured (this is separate from processes by which the drug itself is formulated into pills or capsules) - while the 1993 patent application did not. The solid form of imatinib mesylate in Gleevec is beta crystalline.
As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR were granted in November 2003. Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India. Novartis set the price of Gleevec at USD 2666 per patient per month; generic companies were selling their versions at USD 177 to 266 per patient per month. Novartis also initiated a program to assist patients who could not afford its version of the drug, concurrent with its product launch.
Image result for gleevec india patent case
When examination of Novartis' patent application began in 2005, it came under immediate attack from oppositions initiated by generic companies that were already selling Gleevec in India and by advocacy groups. The application was rejected by the patent office and by an appeal board. The key basis for the rejection was the part of Indian patent law that was created by amendment in 2005, describing the patentability of new uses for known drugs and modifications of known drugs. That section, Paragraph 3d, specified that such inventions are patentable only if "they differ significantly in properties with regard to efficacy." At one point, Novartis went to court to try to invalidate Paragraph 3d; it argued that the provision was unconstitutionally vague and that it violated TRIPS. Novartis lost that case and did not appeal. Novartis did appeal the rejection by the patent office to India's Supreme Court, which took the case.
The Supreme Court case hinged on the interpretation of Paragraph 3d. The Supreme Court decided that the substance that Novartis sought to patent was indeed a modification of a known drug (the raw form of imatinib, which was publicly disclosed in the 1993 patent application and in scientific articles), that Novartis did not present evidence of a difference in therapeutic efficacy between the final form of Gleevec and the raw form of imatinib, and that therefore the patent application was properly rejected by the patent office and lower courts.
Image result for gleevec india patent case
Although the court ruled narrowly, and took care to note that the subject application was filed during a time of transition in Indian patent law, the decision generated widespread global news coverage and reignited debates on balancing public good with monopolistic pricing and innovation with affordability. Had Novartis won and gotten its patent issued, it could not have prevented generics companies in India from continuing to sell generic Gleevec, but it could have obligated them to pay a reasonable royalty under a grandfather clause included in India's patent law.
Image result for gleevec india patent case

Background

History of Patent laws and pharma industry in India

As part of the Commonwealth, India inherited its intellectual property laws from Great Britain. However, after gaining independence in 1947, there was a growing consensus that to boost manufacturing restrictive product patents must be temporarily removed.[2] In 1970, amendments to the Indian Patents Act abolished product patents but retained process patents with a reduced span of protection.
During the absence of any product patent regime, the Indian pharmaceutical industry grew at a remarkable pace, ultimately becoming a net exporter, the world's third-largest by volume, and fourteenth-largest by value.[3]
However, in the 1990s, during the Uruguay Round negotiations of the World Trade Organisation (WTO), India pledged to bring its patent legislation in tune with the TRIPS mandate in a phased manner.[4] Consequently, in 1999 India allowed for transitional filing of product patent applications, with retrospective effect from 1995. Full product and process patent protection was re-introduced beginning in 2005 when all transitional regulations ended.[5]
India's patent law also contained a "grandfather clause" in section 11A, subsection (7),[6] that created "a special regime for generic versions of medicines if the initial patent application was made between the 1st of January 1995 and the 31st of December 2004 and if these medicines were already on the Indian market before the 1st of January 2005.... Generics that enter into this category can stay on the Indian market even if their pharmaceutical substance is patented. However, the Indian law requires that the producers of those generics then pay a “reasonable royalty” to the patent holder."[7][8]
The case hinged on a section of the new Indian patent law dealing with whether incremental inventions would be patentable, namely Section 3d.
The initial version read as follows: "The mere discovery of any new property or new use of a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant."[9]
This was amended twice, the last time in 2005. The final version reads as follows (amendments in italics): "The mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation: For the purposes of this clause, salts,esters, ethers, polymorphs, metabolites, pureform, particle size isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy."[9]
As discussed below, Novartis filed its initial patent application on imatinib (the raw material in Gleevec) in 1993, and at that time India did not confer product patents.[10] As mentioned above, in 1995 India joined the World Trade Organization and signed onto TRIPS; Switzerland joined the WTO later that same year.[11][12] Novartis filed its initial patent applications on Gleevec itself in 1997, after both India and Switzerland had joined the WTO but while both were still in transition.
Image result for gleevec india patent case
Image result for gleevec india patent case

Initial patent filings and product launches

In the early 1990s a number of derivatives of N-phenyl-2-pyrimidineamine were synthesized by scientists at Ciba-Geigy (now part of Novartis), one compound of which was CGP 57148 in free base form (later given the International Nonproprietary Name ‘imatinib’ by the World Health Organisation (WHO)). A Swiss patent application was filed on April 3, 1992, which was then filed in the EU, the US, and other countries in March and April 1993[13][14] and in 1996 United States and European patent offices granted a patent to Novartis claiming imatinib and its derivatives, including salts thereof (but not mentioning mesylate). The patent does not specify any crystal forms of the compounds or discuss their relative advantages and disadvantages.[15][16]
On July 18, 1997, Novartis filed a new patent application in Switzerland on the beta crystalline form of imatinib mesylate (the mesylate salt of imatinib).
Image result for gleevec india patent case
The "beta crystalline form" of the molecule is a specific polymorph of imatinib mesylate; a specific way that the individual molecules pack together to form a solid. This is the actual form of the drug sold as Gleevec/Glivec; a salt (imatinib mesylate) as opposed to a free base, and the beta crystalline form as opposed to the alpha or other form.[17]:3 On July 16, 1998, Novartis filed this patent application in India, which was given application number No.1602/MAS/1998, and on July 16, 1998, it filed a PCT, each of which claimed priority to the 1997 Swiss application.[18][19] The application showed that compared to the alpha form, the beta form had (i) more beneficial flow properties, (ii) better thermodynamic stability, (iii) lower hygroscopicity.[19] Novartis did not however provide any data showing improved efficacy (showing that this form of the drug actually worked better in treating cancer than the amorphous form of the drug they had earlier patented) - that part of Indian patent law was created in 2005, years after Novartis' initial filing. Later, during the course of prosecution, appeals, and the litigation that ensued in India, Novartis undertook studies to compare the properties of the beta crystalline form of imatinib mesylate (described in its new patent application), with the freebase form of imatinib (described in the older patent), and submitted them in affidavits. The studies showed that the beta crystalline form of the drug had increased bioavailability in rats.[20] A United States patent was granted in 2005.[21]
In 2001 the United States Food and Drug Administration (FDA) approved imatinib mesylate in its beta crystalline form, sold by Novartis as Gleevec (U.S.)[22] or Glivec (Europe/Australia/Latin America). TIME magazine hailed Gleevec in 2001 as the "magic bullet" to cure cancer.[23][24] Both Novartis patents - on the freebase form of imatinib, and on the beta crystalline form of imatinib mesylate - are listed by Novartis in the FDA's Orange Book entry for Gleevec.[25]
As provided under the TRIPS agreement, Novartis applied for Exclusive Marketing Rights (EMR) for Gleevec from the Indian Patent Office and the EMR was granted in November 2003.[26] Novartis made use of the EMR to obtain orders against some generic manufacturers who had already launched Gleevec in India. Novartis set the price of Gleevec at USD 2666 per patient per month; generic companies were selling their versions at USD 177 to 266 per patient per month.[27] Novartis also initiated a program to assist patients who could not afford its version of the drug, concurrent with its product launch.[28]
Image result for gleevec india patent case

Initial patent prosecution and litigation

As mentioned above, Novartis' patent application on the beta crystalline form of imatinib mesylate was filed in India in 1998 and put in a "mail-box" as per the TRIPS agreement.[29] The application was processed in 2005 once the law in India allowed for product patents.[30] The Assistant Controller of Patents and Designs rejected the application on 25 January 2006 as failing to satisfy requirements for novelty and non-obviousness. As the appellate board was not yet convened, Novartis filed several appeals before the Madras High Court in 2006.
 
The free base form of anti-cancer agent imatinib. Imatinib mesylate is a salt formed by a 1:1 reaction of imatinib and methanesulfonic acid.
Before the High Court could decide on the issue of patentability, the Intellectual Property Appellate Board (IPAB) was formed and in 2007 the case was transferred before the IPAB in line with section 117G of the Indian Patent Act. The IPAB on 26 June 2009 modified the decision of the Assistant Controller of Patents and Designs stating that ingredients for grant of patent novelty and non obviousness to person skilled in the art were present in the application but rejected the application on the ground that the drug is not a new substance but an amended version of a known compound and that Novartis was unable to show any significant increase in the efficacy of the drug and it, therefore, failed the test laid down by section 3(d) of the Indian Patents Act.[31][32]
Novartis mounted a separate and concurrent litigation before the Madras High Court arguing that section 3(d) of the Indian Patents Act is violated Article 14 of the Indian constitution because the definition of "enhanced efficacy" was too vague and left too much power in the hands of the patent examiner, and was in violation of India's obligations under the TRIPs agreement because it rendered inventions that should be patentable, unpatentable, and argued that the Court was the proper venue for hearing the claim concerning violation of TRIPS. Counsel for the Indian government argued that any violation of TRIPS belonged before the Dispute Settlement Board established by TRIPS, not before the Court, and that in any case, TRIPS allowed national laws to address the needs of its citizens; with respect to the claim that the amended law was arbitrary, counsel argued that "enhanced efficacy" is well understood in the pharmaceutical arts. In 2007 the High Court decided, agreeing with Novartis that it had the right to hear the case, and agreeing with counsel for the Indian government that the law was not vague, and that the law complied with TRIPS, and observed that section 3(d) aims to prevent evergreening and to provide easy access for Indian citizens to life saving drugs.[9] Novartis did not further challenge this order.
After IPAB rejected the patent application in 2009, Novartis appealed directly before the Supreme Court through a Special Leave Petition (SLP) under Article 136 of the Indian Constitution;[33] under normal circumstances, an appeal from IPAB should have been before one of the High Courts before it could proceed to the Supreme Court. However the patent if granted on appeal would expire by 2018 and thus any further appeal at that stage would be pointless. Considering this urgency and the need for an authoritative decision on section 3(d) (other cases on this issue were pending before various High courts), the Supreme Court granted special leave to bypass the High Court appeals process and come directly before it.

Arguments before the Supreme Court

Novartis

The legal team of Novartis was led by ex-Solicitor General of India Gopal Subramaniam and senior advocate T. R. Andhyarujina.[34] Novartis had attempted to patent imatinib mesylate in beta crystalline form (rather than imatinib or imatinib mesylate), thus they sought to prevent extant literature on imatinib or imatininb mesylate from being considered as prior art. The thrust of the arguments by Novartis' legal team was two-fold: firstly, that the Zimmerman patents and the journal articles published by Zimmerman et al. do not constitute prior art for the beta crystalline form as it is only one polymorph of imatinib mesylate, thereby providing the required novelty and inventive step; and secondly, that imatinib mesylate in beta crystalline form has enhanced efficacy over imatinib or imatinib mesylate to pass the test of section 3(d).
To prove novelty and inventive step it was argued that the Zimmermann patent did not teach or suggest to a person skilled in the art to select the beta crystalline form in preference to other compounds of which examples were given in the Zimmermann patent. Further, even if the beta crystalline form was selected, the Zimmermann patent did not teach a person to how to prepare that particular polymorph of the salt. Having arrived at the beta crystal form of methanesulfonic acid addition salt (mesylate salt) of imatinib, Novartis contended that the inventors had to further research to be able to ensure that particular salt form of imatinib was suitable for administration in a solid oral dosage form. Hence, the coming into being of the beta crystalline form of imatinib mesylate from the free base of imatinib was the result of an invention that involved technical advance as compared to the existing knowledge and brought into existence a new substance. Research was required to define and optimise the process parameters to selectively prepare the beta crystalline form of imatinib mesylate. As the Zimmermann patent contains no mention of polymorphism or crystalline structure, the relevant crystalline form that was synthesized needed to be invented. There was no way of predicting that the beta crystalline form of imatinib mesylate would possess the characteristics that would make it orally administrable to humans without going through the inventive steps.[35]
To prove that the beta crystalline form enhanced efficacy over other polymorphs, it was stated that beta crystalline form has (i) more beneficial flow properties, (ii) better thermodynamic stability, (iii) lower hygroscopicity, and (iv) increased bioavailability.[20]

Respondents

There were seven named respondents who were represented before the court along with two Intervenor/Amicus. The respondents were led by Additional Solicitor General of India Paras Kuhad.[34]
Various arguments were brought before the court but primarily focussed on proving imatinib mesylate in beta crystalline form is neither novel nor is it non-obvious due to publications about imatinib mesylate in Cancer Research and Nature in 1996, disclosures in Zimmerman patents, disclosures to FDA and finally that efficacy as referred to in section 3(d) should be interpreted as therapeutic efficacy and not merely a physical efficacy.[36]
The respondents quoted extensively from Doha Declaration, excerpts from parliamentary debates, petitions from NGOs, WHO, etc. to highlight the public policy dimension of arguments in regards to easy affordability and availability of life saving drugs.

Supreme Court decision

Supreme Court decided the matter de novo looking into matters of both fact and law.
The court first analysed the question of prior art by looking into Zimmerman patent and the related academic publications. It was clear from the Zimmerman patent that imatinib mesylate itself was not new and did not qualify the test of invention as laid down in section 2(1)(j) and section 2(1)(ja) of the Patents Act, 1970.[37] The court then examined the beta crystalline form of imatinib mesylate and wrote that it, "for the sake of argument, may be accepted to be new, in the sense that it is not known from the Zimmermann patent. (Whether or not it involves an “inventive step” is another matter, and there is no need to go into that aspect of the matter now). Now, the beta crystalline form of Imatinib Mesylate being a pharmaceutical substance and moreover a polymorph of Imatinib Mesylate, it directly runs into section 3(d) of the Act with the explanation appended to the provision".[38]
In applying 3(d) of the Act, the Court decided to interpret "efficacy" as "therapeutic efficacy" because the subject matter of the patent is a compound of medicinal value. Court acknowledged that physical efficacy of imatinib mesylate in beta crystalline form is enhanced in comparison to other forms and that the beta crystalline form of imatinib mesylate has 30 per cent increased bioavailability as compared to imatinib in free base form.[39] However, as no material had been offered to indicate that the beta crystalline form of imatinib mesylate will produce an enhanced or superior efficacy (therapeutic) on molecular basis than what could be achieved with imatinib free base in vivo animal model, the court opined that the beta crystalline form of imatinib mesylate, does not qualify the test of Section 3(d).[40][41]
Thus in effect, Indian Supreme Court upheld the view that under Indian Patent Act for grant of pharmaceutical patents apart from proving the traditional tests of novelty, inventive step and application, there is a new test of enhanced therapeutic efficacy for claims that cover incremental changes to existing drugs.[42]
The Court took pains to point out that the subject patent application was filed during a time of transition in Indian patent law, especially with regard to striking Section 5, which had barred product patents and adding section 3(d), for which there was no case law yet.[43] The Court also took care to state the decision was intended to be narrow: "We have held that the subject product, the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act but that is not to say that Section 3(d) bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent regime by deletion of section 5 from the Parent Act. That is not said in this judgment."[44]

Reception

The decision received extensive coverage from Indian and international media.[28][45][46][47][48]
It reignited debates on balancing public good with monopolistic pricing and innovation with affordability.[49][50][51]
Several commenters, including Novartis, noted that a decision either way would not have affected the ability of generics companies in India to continue selling generic Gleevec. The new patent law India adopted in 2005 contains a grandfather clause that allows generic copies of drugs launched before 2005, which includes Gleevec, to continue to be sold, albeit with payment of a reasonable royalty to Novartis.[8][52] Other commenters noted that the case was unique with respect to its timing and the importance of the drug, and that large generalizations should not be taken from it. "As a case study, Glivec is peculiar and unlikely to be representative going forward. Had it been invented a few years later (or TRIPS implemented a few years earlier), Glivec likely would be patented in India, even under 3(d) standards. Newly discovered compounds are likely to receive basic patents and to be less vulnerable to 3(d) rejections."[53] Prashant Reddy, author of the Spicy IP blog and postgraduate student at Stanford University Law School, was quoted in Nature Drug Discovery as saying: “It was a very limited ruling in most aspects and very fact-specific. Although the Court has interpreted efficacy to mean only therapeutic efficacy, it has left the exact scope of therapeutic efficacy to be defined in future cases....Most importantly, the Court made the nuanced distinction between the rent-seeking practice of evergreening and the beneficial practice of incremental innovation, and has clarified that Indian patent law forbids only the former."[54][55]
There were however strong negative and positive reactions.

Support

The judgement garnered widespread support from international organisations and advocacy groups like Médecins Sans Frontières,[56] WHO, etc. who welcomed the decision against evergreening of pharmaceutical patents.
Most news item contrasted the huge price difference between patented Gleevec of Novartis and the generic versions of Cipla and other generic companies.[57][58] Some commentators have stated that this strict patent requirement would actually enhance innovation as the pharmaceutical companies would have to invest more in R&D to come up with new cures rather than repackage known compounds.[59] Others have suggested that exclusions under section 3(d) present the hard cases that lie at the margins of the patent system due to the eternally unsettled nature of the definition of the term 'invention'.[60] Several patent law experts have also pointed out that stringent conditions for patentability are followed in many jurisdictions around the world, and there is no reason India should not follow the same standards, given the extent of poverty and lack of availability of affordable medicines in the country.[61]

Opposition

Ranjit Shahani, vice-chairman and managing director of Novartis India Ltd is quoted as saying "This ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options."[62] He also said that companies like Novartis would invest less money in research in India as a result of the ruling.[46] Novartis also emphasized that it continues to be committed to access to its drugs; according to Novartis, by 2013, "95% of patients in India—roughly 16,000 people—receive Glivec free of charge... and it has provided more than $1.7 billion worth of Glivec to Indian patients in its support program since it was started...."[28] The New York Times quoted Chip Davis, the executive vice president of advocacy at the Pharmaceutical Research and Manufacturers of America, the industry trade group: “It really is in our view another example of what I would characterize as a deteriorating innovation environment in India. The Indian government and the Indian courts have come down on the side that doesn’t recognize the value of innovation and the value of strong intellectual property, which we believe is essential.”[46]
Image result for gleevec india patent case

References

  1. Jump up^ "Novartis v. Union Of India & Ors on 1 April 2013".
  2. Jump up^ "Patenting Landscape in India 2009".
  3. Jump up^ "Pharma to topple IT as big paymaster"The Economic Times. 8 June 2010. Retrieved 8 Jun 2010.
  4. Jump up^ "History of Patent Law in India".
  5. Jump up^ "Product v. Process Patent in India".
  6. Jump up^ Controller General of Patents Designs and Trade Marks, Department of Industrial Policy and Promotion, Ministry of Commerce and Industry The Patents Act 1970 (incorporating all amendments till 26-01-2013)
  7. Jump up^ Erklärung von Bern. May 8, 2007 Short questions and answers about the court case initiated by Novartis in India
  8. Jump up to:a b Kevin Grogan for PharmaTimes. February 27, 2012 Novartis explains stance over India patent law challenge
  9. Jump up to:a b c W.P. No.24759 of 2006
  10. Jump up^ Finally, the patients prevail, Sarah Hiddlestone, The Hindu, 7 April 2013
  11. Jump up^ Switzerland page at WTO
  12. Jump up^ Note: Further complicating matters, India's 1993 notification to the WTO indicating that it would join, included a list of countries whose priorities dates it would recognize for patenting, and Switzerland was not on the list as it was not a member of the WTO at that time.(Sudhir Ahuja, D P Ahuja & Co, Calcutta, India. India Decides to Join the Paris Convention and Ratify the Patent Cooperation Treaty. So What? Patent World Issue #106, October 1998). Additionally the EPO was not mentioned in the notification from India; it was not until 2003 that EPO became officially recognized by India, fully normalizing patent reciprocity between India and Europe. (G 0002/02 (Priorities from India/ASTRAZENECA) of 26.4.2004)
  13. Jump up^ US Patent Application No. 08/042,322). This application was abandoned and another continuation-in-part application was then filed on April 28, 1994 which matured into (US Patent 5,521,184).
  14. Jump up^ See here for worldwide filings]
  15. Jump up^ US Patent 5,521,184
  16. Jump up^ EP0564409
  17. Jump up^ Staff, European Medicines Agency, 2004. EMEA Scientific Discussion of Glivec
  18. Jump up^ Note: The Indian patent application does not appear to be publicly available. However according to the decision of the IPAB on 26 June 2009 (page 27) discussed below, "The Appellant’s application under the PCT was substantially on the same invention as had been made in India."
  19. Jump up to:a b Published PCT application WO1999003854
  20. Jump up to:a b Novartis v UoI, para 168
  21. Jump up^ US Patent 6,894,051
  22. Jump up^ Investigational New Drug Application (IND # 55,666) for Gleevec was filed on 9 April 1998 and on February 27, 2001, the original New Drug Application (FDA Drug Approval Package for Gleevec NDA # 21-335) was filed before the US Food and Drug Administration for imatinib mesylate for the treatment of patients with Chronic Myeloid Leukemia
  23. Jump up^ Closing In On Cancer by Alice Park, TIME Magazine, 21 May 2001
  24. Jump up^ Novartis' Gleevec Cancer "Magic Bullet" Extends Life In GIST Patients, 6 June 2011
  25. Jump up^ FDA Orange Book; Patent and Exclusivity Search Results from query on Appl No 021588 Product 001 in the OB_Rx list.
  26. Jump up^ Novartis v UoI, para 8-9
  27. Jump up^ Staff, LawyersCollective. September 6, 2011 Novartis case: background and update – Supreme Court of India to recommence hearing
  28. Jump up to:a b c R. Jai Krishna and Jeanne Whalen for the Wall Street Journal. April 1, 2013 Novartis Loses Glivec Patent Battle in India
  29. Jump up^ Application No.1602/MAS/1998
  30. Jump up^ The patent application attracted five pre-grant oppositions by M/s. Cancer Patients Aid Association, NATCO Pharma Ltd., CIPLA Ltd., Ranbaxy Laboratories Ltd. and Hetro Drugs Ltd. The Assistant Controller of Patents and Designs heard all the parties on December 15, 2005, as provided under rule 55 of the Patent Rules, 2003.
  31. Jump up^ Intellectual Property Appellate Board decision dated 26 June 2009, p 149
  32. Jump up^ Shamnad Basheer for Spicy IP March 11, 2006 First Mailbox Opposition (Gleevec) Decided in India
  33. Jump up^ Article 136 of the Indian Constitution
  34. Jump up to:a b "Supreme Court rejects Novartis patent plea for cancer drug Glivec".
  35. Jump up^ Novartis v UoI, para 105-108
  36. Jump up^ The Novartis Patent Intervention by Prof. Shamnad Basheer
  37. Jump up^ Novartis v UoI, Para 157
  38. Jump up^ Novartis v UoI, Para 158
  39. Jump up^ Novartis v UoI, Para 187, 188
  40. Jump up^ Novartis v UoI, Para 189, 191
  41. Jump up^ Novartis A.G. v. UOI & Ors. – Hon’ble Justice Aftab Alam’s Swansong, Rudrajyoti Nath Ray, RDA, 8 April 2013
  42. Jump up^ Novartis and Health - An analysis, Rajeev Dhavan, 11 April 2013
  43. Jump up^ Novartis v UoI, Para 24-25
  44. Jump up^ Novartis v UoI, Para 191
  45. Jump up^ Rama Lakshmi for the Washington Post April 1, 2013 India rejects Novartis drug patent
  46. Jump up to:a b c Gardiner Harris and Katie Thomas for the New York Times. April 1, 2013 Published: April 1, 2013 Top court in India rejects Novartis drug patent
  47. Jump up^ Sarah Boseley for The Guardian, April 1, 2013 Novartis patent ruling a victory in battle for affordable medicines
  48. Jump up^ Staff, BBC. April 2, 2013 Novartis case: Media hail 'key victory' for India
  49. Jump up^ "How the Indian judgment will reverberate across the world".
  50. Jump up^ "Patented drugs must be priced smartly".
  51. Jump up^ Patent with a purpose, Prof. Shamnad Basheer, Indian Express, 3 April 2013
  52. Jump up^ M Allirajan, TNN April 4, 2013 SC decision on Glivec is negative credit for branded drug firms: Moody’s
  53. Jump up^ Sampat BN et al. Challenges to India's Pharmaceutical Patent Laws Science 27 July 2012: Vol. 337 no. 6093 pp. 414-415
  54. Jump up^ Charlotte Harrison Patent watch Nature Reviews Drug Discovery 12, 336–337 (2013)
  55. Jump up^ "Supreme Court rejects bid by Novartis to patent Glivec".
  56. Jump up^ Major victory on affordable drugs
  57. Jump up^ Salve on cheaper medicine Patent blow to Big Pharma, The Telegraph
  58. Jump up^ "Drug price cut signal after court victory".
  59. Jump up^ Why Novartis case will help innovation, Achal Prabhala and Sudhir Krishnaswamy, The Hindu, 15 April 2013
  60. Jump up^ A New Template for Pharma Research, Yogesh Pai, The Hindu Business Line, 11 April 2013
  61. Jump up^ Nothing wrong with setting high standards of patentability, Srividhya Ragavan and Aju John, myLaw.net, 10 May 2013
  62. Jump up^ Shift in Novartis Strategy, The Telegraph

External links to text of judicial opinions

Novartis AG v. Union of India
Emblem of the Supreme Court of India.svg
CourtSupreme Court of India
Full case name'Novartis AG v. Union of India (UOI) and Ors.; Natco Pharma Ltd. v. UoI & Ors.; M/S Cancer Patients Aid Association v. UoI & Ors.
Decided1 April 2013
Citation(s)Civil Appeal No. 2706-2716 of 2013
Case history
Prior action(s)Application for patent by appellant denied by Assistant Controller of Patents and Designs on 25 January 2006; Intellectual Property Appellate Board (IPAB) partially reversed the decision by the Assistant Controller but still denied patent on 26 June 2009.
Holding
Upheld the rejection of the patent application (1602/MAS/1998) filed by Novartis AG for Glivec in 1998 before the Indian Patent Office.
Case opinions
MajorityMr. Justice Aftab Alam [1], joined by Ms. Justice Ranjana Prakash Desai
Laws applied
Sections 2(1)(j), 2(1)(ja) and 3(d) of Indian Patent Act, 1970 (as amended in 2005)
//////////

Tuesday 7 February 2017

New Patent, (S)-pregabalin, WO 2017019791, Teva

Image result for teva pharmaceuticals
Synthesis of (S)-pregabalin, Teva
TEVA PHARMACEUTICALS INTERNATIONAL GMBH [CH/CH]; Schusselstrasse 12 8645 Jona (CH) (For All Designated States Except US).
JANAGANI, Satyanarayana [US/US]; (US) (US only)
Improved process for preparing (S)-pregabalin, useful for treating pain, seizures, convulsions and anxiety. Also claims novel intermediates of (S)-pregabalin and their preparation method.
Pregabalin, a GABA alpha-2-delta subunit agonist, had been developed and launched by Pfizer.
Teva received a FDA approval for its generic pregabalin capsules (25, 50, 75, 100, 150, 200, 225 and 300 mg).
S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,
str1
is also known as pregabalin, γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the name LYRICA®, has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
Several processes for the synthesis of (S)-Pregabalin are known. For example, U.S. Patent No. 5,599,973 ("'973 patent") discloses the preparation of (S)-Pregabalin using a stoichiometric amount of (4R,5S)-(+) 4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. See, e.g., '973 patent, col. 14, 1. 29 to col. 18, 1. 23 (example 1). In general, however, the route disclosed in the '973 patent is of limited use on an industrial scale, principally due to the low temperature required for the reaction (e.g., -78°C), the use of pyrophoric reagent (e.g., butyl lithium), and a low overall yield (e.g. , 59%, 65%).
U.S. Publication No. 2003/0212290 ("'290 publication") discloses the synthesis of (S)-Pregabalin by an asymmetric hydrogenation of a cyano-substituted olefin of formula 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid of formula 8, which i btain (S)-Pregabalin, as described in the following scheme.
[(R,R)-MeD PHOS]Rh(COD)+BF4-
However, the disclosed method requires the use of carbon monoxide under high pressure, raising serious problems in adapting this process for production scale.
Another process is disclosed by G.M. Sammis, et al, J. Am. Chem. Soc , 125(15): 4442-43 (2003), in which an aluminum salen catalyst is used in the conjugate addition of hydrogen cyanide to a, β-unsaturated imides.
str1
Pregabalin
This process is also not practical for large scale production due to the use of highly poisonous reagents. In addition, the last reduction step requires high hydrogen pressure, which only adds to the difficulties required for adapting this process for use on an industrial scale.
International Publication WO 2006/110783 reports several processes for preparing (S)-Pregabalin via the following intermediate and its analogues.
R^OC "COOR2
wherein Ri and R2 are independently H, a straight or branched Ci-10 alkyl, C6-10 aryl, or C3-6 allyl.
U.S. Publication Nos. 2007/0191636 and 2007/0197827 also disclose processes for preparing (S)-Pregabalin.
Thus, there is a need in the art for additional process for the preparation of (S)-Pregabalin that provide (S)-Pregabalin in high quality and high yield, and that can be adapted to large (industrial) scale production.
EXAMPLES
Example 1: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid (III, wherein Ar = phenyl and R = methyl) with recycling of compound (Ilia)
A. 3-isobutylglutaric acid (700g) and acetic anhydride (420g) were heated to 130-140°C and maintained for about 3 hrs. At the end of the reaction, the reaction mixture was cooled to 70-80°C and acetic acid and acetic anhydride were distilled off under vacuum. Toluene (700 mL) was added to the reaction mixture and further evaporated=for 1.5-2 hrs at 90-95°C. Another 700mL of toluene were added and the resulting 4-isobutylglutaric anhydride (IBG anhydride) solution was cooled to 25-30°C.
B. A different reactor was charged with toluene (4L), S-phenylethylamine (1.05 mol equivalent) and 4-dimethylaminopyridine (DMAP) (4.5g) and the mixture was cooled to
-25 to -15°C. The IBG anhydride solution was added and stirred at -25 to -15°C for 2-3 hrs. The mixture was heated to 25-30°C, 180 mL of aq. HC1 (30%) and water (180 mL) were added and the mixture was heated to 70-75°C. The phases were separated and the organic phase was cooled to 15-30°C and stirred for 2-2.5 hrs. The mixture was filtered and washed twice with toluene (2 vol.).
C. The toluene mother liquor, contained 226 g of the compound of formula Ilia (Ar = phenyl and R = methyl) (ee 76.7 %). The toluene was distilled off to 3 vol and 136 g acetylchloride were added. The mixture was heated to 78-82°C and stirred for 5-6 hrs. At the end of the reaction time, 1130 mL water was added at 50-60°C and the phases were separated. 47.39 g NaOH in 474 mL of water were added to the organic phase and the reaction mixture was heated to 78-82°C and stirred for 8-10 hrs. Then, the reaction mixture was cooled to 25-30°C and the pH was adjusted to 1-3 with 30% HC1. Toluene (8 vol.) was added to the mixture and the phases were separated at 80°C. The organic phase was cooled to 25-30°C and filtered. The filtrate was washed with toluene (2 vol.) and re-crystallized from toluene. Yield 44.94%, purity 97.5%, ee 99.88%.
Example 2: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (400 ml), (S)-(-)-phenylethylamine (142.35 g,1.1764 mole), and 4-dimethylaminopyridine (0.7176 g, 0.0059 mole). The mixture was cooled to a temperature of -10°C to -15°C, followed by addition of a solution of 3- isobutyl glutaric anhydride (100 g, 0.59 mole) [e.g. obtained in accordance with the process disclosed Drugs of the Future, 24 (8), 862-870 (1999) or according to Example 1 step (A) above] in toluene (100 ml), over a period of 45-60 minutes, and stirring for additional 1.5-2 hours, at a temperature of -10°C to -15°C. The mixture was then extracted with 10% aqueous solution of NaOH (500 ml), and the aqueous phase was washed with toluene (1x250 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution of hydrochloric acid (1-12N). The aqueous phase was further extracted with toluene (lx 800 ml) at a temperature of 70-80°C. The toluene layer was washed with 10% sodium chloride solution {700ml) at a temperature of 70-80°C followed by crystallization to get 125 g (73.0% yield) of a white solid of (3S)-5-methyl-3-(2-oxo-2-{[(l S)-l-phenylethyl]amino}ethyl) hexanoic acid with an optical purity of 99.75 %, as measured by chiral HPLC.
The toluene mother liquor obtained from the crystallization, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).
Example 3; Preparation of (3S)-5-methyl-3-(2-oxo-2{[(l S)-l-phenylethyllamino} ethyl) hexanoic acid
Desired major
To a cooled (0 °C) solution of 4-Isobutylglutaric anhydride (0.1 moles) in toluene is added (lS)-l-phenylethanamine (0.1 moles) slowly during 30 minutes and the mixture is warmed to 70 °C, washed with dilute HC1 followed by brine and cooled to ambient temperature during several hours. The precipitate is filtered, washed with toluene and vacuum dried until constant weight to yield (3S)-5-methyl-3-[2-oxo-2-[[(lS)-l-phenylethyl] amino] ethyl]hexanoic acid. Diastereomeric purity by HPLC = 99.5%.
The toluene mother liquor obtained from the precipitation, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).
Example 4: Preparation of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)-methyllpentvUcarbamic acid methyl ester
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (25 ml), (3S)-5-methyl-3-(2-oxo-2{[(l S)-l-phenylethyl]amino} ethyl) hexanoic acid (5 g, 0.0172 mole), and with
triethylamine (2.17g, 0.0215 mole), and cooled to -10° to -20°C followed by addition of solution of ethyl chloroformate (2.05 g, 0.0189 mole in 5 ml acetone). The mixture was stirred for 1 hour at a temperature of -10° to -20°C, followed by addition of solution of sodium azide (2.8g, 0.0429 mole in water). The resulted slurry was maintained for 1 hour at -10° to -20°C, quenched over ice water followed by extracting the mass with sufficient amount of toluene. The toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol, followed by stirring for 2 to 4 hours. The stripping off the solvent results in 4.95 g (89.7% yield) of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)-methyl]pentylcarbamic acid methyl ester (120) with a purity of 97.4% area, as measured by HPLC.
Example 5: Preparation of (S)-Pregabalin
A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Β¾Ν was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Example 6: Preparation of (S)-Pregabalin
A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain
pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). B¾N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.
Example 7: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 14 of International Publication No. WO 2007/035890
A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S) Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Compound 26 has the following chemical structure:
str2
wherein Ar is a C6-1o aromatic group, and R is a straight or branched C1-4 alkyl, ester or carboxylic acid.
Example 8: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 16 of International Publication No. WO 2007/035890
A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). Bu3N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.
/////////////// (S)-pregabalin, WO 2017019791

Monday 6 February 2017

New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

str1
New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410
Preparation method for antitumor drug AP26113
Suzhou MiracPharma Technology Co Ltd
SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1,Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN)
XU, Xuenong; (CN)
Improved process for preparing brigatinib, useful for treating cancer eg non-small cell lung cancer (NSCLC). The present filing represents the first PCT patenting to be seen from Suzhou MiracPharma that focuses on brigatinib;  In February 2017, brigatinib was reported to be in pre-registration phase.
Disclosed is a preparation method for an antitumor drug AP26113 (I). The method comprises the following preparation steps: cyclizing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and N,N-dimethylamino acrylate, condensing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and 4-(dimethyl phosphitylate)aniline, and chlorinating N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine by means of a chlorinating agent, sequentially, so as to prepare AP26113 (I). The preparation method adopts easily-obtained raw materials, causes few side reactions, and is economical, environmentally-friendly, and suitable for industrial production.
front page image
AP26113 is an experimental drug developed by Ariad Pharmaceuticals to target small molecule tyrosine kinase inhibitors for the treatment of anaplastic lymphoma kinase-positive (ALK) metastases resistant to crizotinib Non-small cell lung cancer (NSCLC) patients. The drug was approved by the US Food and Drug Administration in August 2014 for breakthrough drug treatment. The current clinical data show that AP26113 on ALK-positive non-small cell lung cancer patients, including patients with brain metastases, have a sustained anti-tumor activity. And the inhibitory activity against ALK is about 10 times that of zolotriptan, which can inhibit all 9 kinds of identified mutations of kotatinib resistant ALK.
 
The chemical name of AP26113 is 5-chloro-N- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phosphono) phenyl] -2,4-pyrimidinediamine (I) having the structural formula:
 
 
Methods for the preparation of AP26113 have been reported. AP26113 and its starting materials A and B are prepared by PCT Patent WO2009143389 of Ariad and U.S. Patent No. 20130225527, US20130225528 and US20140066406 of Ariad. The target compound AP26113 is prepared by substituting 2,4,5-trichloropyrimidine with the pyrimidine ring of starting materials A and B in turn.
 
 
Although the synthetic procedure is simple, the nucleophilic activity of the three chlorine atoms on 2,4,5-trichloropyrimidine is limited. When the same or similar aniline group is faced, its position Selectivity will inevitably produce interference, resulting in unnecessary side effects, thus affecting the quality of the product. At the same time, the reaction process for the use of precious metal palladium reagent also increased the cost of production is not conducive to the realization of its industrialization.
 
Therefore, how to use modern synthesis technology, the use of readily available raw materials, design and development of simple and quick, economical and environmentally friendly and easy to industrialization of the new synthesis route, especially customer service location on the pyrimidine ring side effects of selectivity, for the drug Economic and technological development is of great significance
 
The synthesis step comprises the following steps: N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) and N, N-dimethylaminoacrylates Amino-4 (1H) -pyrimidinone (III) in the presence of a base such as N, N-dimethylformamide, N, N-dimethylformamide, (III) was reacted with 4- (dimethyl (dimethylamino) -1-piperidinyl) -2-methoxyphenyl] (A) is condensed under the action of a condensing agent and a base accelerator to obtain N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxybenzene (IV); the N2- [4- [4- (dimethylamino) -l- (4-fluorophenyl) (IV) with a chlorinating agent in the presence of a base such as sodium hydride, sodium hydride, sodium hydride, potassium hydride, AP26113 (I).
 
Example 1:
 
A solution of 2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline (24.9 g, 0.1 mol) and 250 mL of methanol was added to the reaction flask and the temperature was lowered to 0C (15 mL, 0.15 mol) and a 50% solution of cyanamide (10 mL, 0.15 mol) were added successively. The reaction was stirred for 12 to 14 hours and the reaction was complete by TLC. After cooling to 0-5 ° C, 250 mL of methyl tert-butyl ether was added to the reaction mixture. A solid precipitated and was filtered, washed successively with water and cold acetonitrile, and dried to give N- [2-methoxy- 16.3 g, yield 56.0%, FAB-MS m / z: 292 [M + H] + . [4- (Dimethylamino) piperidin-1-yl] aniline] guanidine (II)
 
Example 2:
 
A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, Methyl methacrylate (1.8 g, 13.7 mmol) and toluene (50 mL). The mixture was heated to reflux and stirred for 24-26 hours. The reaction was complete by TLC. After cooling to room temperature, a solid precipitated. The filter cake was washed with cold methanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III), yield 77.3%, FAB-MS m / z: 344 [M + H] + .
 
Example 3:
 
A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, (2.0 g, 14.0 mmol) and N, N-dimethylformamide (30 mL) was added and the temperature was raised to 115-125 ° C. The reaction was stirred for 22-24 hours and the reaction was complete by TLC. The mixture was concentrated under reduced pressure, and 50 mL of ethanol was added to the resulting residue. The mixture was cooled to room temperature while stirring to precipitate a solid. The filter cake was washed with cold ethanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III) in 79.6% yield, FAB-MS m / z: 344 [M + H] + .
 
Example 4:
 
A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone III) (3.43 g, 10 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (6.63 g, 15 mmol) and acetonitrile 100 mL. Diazabicyclo [5.4.0] -undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was evaporated under reduced pressure, 100 mL of ethyl acetate was dissolved, and the mixture was washed with 20 mL of 2M sodium hydroxide and 20 mL of water. The organic layer was dried over anhydrous sodium sulfate, and 50 mL of tetrahydrofuran-dissolved 4- (dimethylphosphoranylidene) A) (2.2 g, 13 mmol) and sodium hydride (0.31 g, 13 mmol) was added and the temperature was raised to 50-55 ° C. The reaction was stirred for 6-8 hours and monitored by TLC. The reaction was quenched with saturated brine, the organic phase was separated, dried and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidine Yl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) phenyl] -2,4-pyrimidinediamine (IV) in a yield of 83.2%. FAB-MS m / z: 495 [M + H] + .
 
Example 5:
 
A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone (Dimethylamino) phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol), 4- (dimethylsulfamoyl) phosphonium hexafluorophosphate Phosphoryl) aniline (A) (2.2 g, 13 mmol) and N, N-dimethylformamide. Diazabicyclo [5.4.0] undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise and reacted at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, 100 mL of ethyl acetate was added to dissolve, and the mixture was washed with 2 M sodium hydroxide 20 mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phenylidene] -2,4-pyrimidinediamine (IV) was obtained in a yield of 48.6%. FAB-MS m / z: 495 [M + H] + .
 
Example 6:
 
A solution of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) Phenyl] -2,4-pyrimidinediamine (IV) (4.9 g, 10 mmol) and 100 mL of acetonitrile were added and stirred at room temperature. N-Chlorosuccinimide (1.6 g, 12 mmol) was added in three portions, The reaction was allowed to proceed at room temperature for 4-6 hours, and the reaction was terminated by TLC. The reaction solution was poured into 50 mL of water to quench the reaction. Dichloromethane, and the combined organic layers were washed successively with saturated sodium bicarbonate solution, saturated brine and water. Dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was recrystallized from ethyl acetate / n-hexane to give 3.5 g of a white solid AP26113 (I) in 66.3% yield, FAB-MS m / z: 529 [M + the H] + , 1 the H NMR (CDCl 3 ) 1.67 (m, 2H), 1.81 (S, 3H), 1.85 (S, 3H), 1.93 (m, 2H), 1.96 (m, 2H), 2.10 (m, 2H), 3.86 (s, 3H), 6.50 (m, 1H), 6.57 (m, 1H), 7.12 (m, 1H) ), 7.31 (m, 1H), 7.50 (m, 1H), 8.13 (m, 2H), 8.64 (m, 1H).
 
////////////New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

Tuesday 3 January 2017

WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc


Image result for Acetylon Pharmaceuticals Inc
WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc
citarinostat
Acetylon Pharmaceuticals Inc
(WO2016200930) METHODS OF MAKING PROTEIN DEACETYLASE INHIBITORS
(I)
Compound (I) is disclosed in U.S. Patent No. 8,148,526 as an HDAC inhibitor.
Example 2 of U.S. Patent Application Publication No. 2015/0099744 discloses a synthesis of compound (I). As detailed herein in Example 3, this synthesis procedure resulted in the formation of significant amounts of de-chlorination and chlorine-migration side products. These impurities have solubilities that are similar to the solubilities of the desired
intermediates. Removal of the impurities is very challenging, requiring lengthy work-ups, involving numerous washes, triturations and crystallizations. Triturations, in particular, are known to be inefficient and unscalable processes. When compound (I) was prepared according to Example 2, the necessary purification steps resulted in a significant loss of desired intermdiates, led to a modest overall yield, and rendered further industrial scale up of the synthesis route unpractical. There remains a need for new methods for the synthesis of compound (I), and related compounds, that minimize the formation of impurities, and that are amenable to industrial scale-up.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts a generic synthesis of compound (I) according to the improved method described herein.
Figure 2 depicts a specific synthesis of compound (I) according to the improved method described herein.
Figure 6 depicts 1HNMR data for compound (I).
str1 str2 str3
Image result for Acetylon Pharmaceuticals Inc
Acetylon president and CEO Walter Ogier
Example 1: Comparative Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl) pyrimidine-5-carboxamide
Reaction Scheme
Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), compound 1 (7.5 g, 40 mmol), and K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to r.t. and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml χ 3). The organic layers were separated and dried over Na2S04, evaporated to dryness and purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).
Synthesis of Intermediate 3: A mixture of compound 2 (6.2 g, 25 mmol), iodobenzene (6.12 g, 30 mmol), Cul (955 mg, 5.0 mmol), Cs2C03 (16.3 g, 50 mmol) in TEOS (200 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 14 hrs.
After cooling to r.t., the residue was diluted with EtOAc (200 ml). 95% EtOH (200 ml) and H4F-H20 on silica gel [50g, pre-prepared by the addition of H4F (lOOg) in water (1500 ml) to silica gel (500g, 100-200 mesh)] was added, and the resulting mixture was kept at r.t. for 2 hrs. The solidified materials were filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give a yellow solid (3 g, 38%).
Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 χ 200 ml), and the organic layers were separated, washed with water (2 χ 100 ml), brine (2 χ 100 ml), and dried over Na2S04. Removal of the solvent gave a brown solid (2.5 g, 92 %).
Synthesis of Intermediate 6: A mixture of compound 4 (2.5 g, 8.58 mmol), compound 5 (2.52 g, 12.87 mmol), HATU (3.91 g, 10.30 mmol), and DIPEA (4.43 g, 34.32 mmol) was stirred at r.t. overnight. After the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 2/1) to give a brown solid (2 g, 54 %).
Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50%) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48%).
Example 2: Comparative Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7- (hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide - Compound (I)
Reaction Scheme
Step (1)
Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), ethyl 2-chloropyrimidine-5-carboxylate 1 (7.5 g, 40 mmol), K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to rt and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml x 3). The organic layer was separated and dried over Na2S04, evaporated to dryness and purified by silica gel
chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).
Step (2)
Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), l-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2C03 (42.04 g, 2 equiv.), K2C03 (39.32 g, 1 equiv.), Cu (1 equiv. 45 μπι) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 36 hours. Work-up of the reaction gave compound 3 at 93 % yield.
Step (3)
Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of the compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 x 200 ml), and the organic layer was separated, washed with water (2 x 100 ml), brine (2 x 100 ml), and dried over Na2S04. Removal of solvent gave a brown solid (2.5 g, 92 %).
Step (4)
Synthesis of Intermediate 5: A procedure analogous to the Synthesis of Intermediate 6 in Example 1 was used.
Step (5)
Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A procedure analogous to the Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide in Example 1 was used.
Exam le 3: Process development for Steps 2-3 of Example 2
Table 2. Reactants and reagents
(13.8, leq)
(22.2g, 2eq) Cu
5 24.3g (l.Oeq) 47.7g (2.0eq) 240mL 140 °C
K2C03 (1.0 ε¾45μπι)
(19.65, leq)
(42.04g, 2eq) Cu
6 69.2g (l.Oeq) 135.7g (2.0eq) 690mL 140 °C
K2C03 (1.0 ε¾45μπι)
(39.32g, leq)
Table 3. Results
Table 4. Purification of Compound 4 by extraction and slurry
MTBE/Heptane (lOvol/lOvol) 2.83% 2.67% 92.57%
MEK/Heptane (3vol/6vol) 4.42% 3.16% 90.00%
93.48%
EtoAc 3.87% 1.43%
iProAc 3.91% 2.81% 90.91%
Example 4: Improved synthesis of Compound (I)
Reaction Scheme
4 5 (I)
Step (1)
Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 7.0 Kgs), ethanol (60 Kgs), 2-Chloroaniline (9.5 Kgs, 2 eq) and acetic acid (3.7 Kgs, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis (method TM-113.1016). When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and N,N-Diisopropylethylamine (DIPEA) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 6 Kgs) and heptane (24 Kgs). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 8.4 Kgs compound 11 (81% yield and 99.9% purity (method TM-113.1016)). See 1HNMR data in Figure 3.
Step (2)
Synthesis of Compound 3: Copper powder (0.68 Kgs, 1 eq, <75 micron), potassium carbonate (4.3 Kgs, 3.0 eq), and dimethyl sulfoxide (DMSO, 12.3 Kgs) were added to a reactor (vessel A). The resulting solution was heated to 120 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (2.9 Kgs) and iodobenzene (4.3 Kgs, 2 eq) in DMSO (5.6 Kgs) was
heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 120 ± 5°C for 8-24 hours, until HPLC analysis (method TM-113.942) determined that < 1% compound 11 was remaining.
Step (3)
Synthesis of Compound 4: The mixture of Step (2) was cooled to 90-100 °C and purified water (59 Kgs) was added. The reaction mixture was stirred at 90-100 °C for 2-8 hours until HPLC (method TM-113.942-see step 2) showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with methyl t-butyl ether twice (2 x 12.8 Kgs). The aqueous layer was cooled to 0-5 °C, then acidified with 6N hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 2.2 kg (65% yield) compound 4 in 90.3% AUC purity (method TM-113.942-see step 2). No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed. See 1HNMR data in Figure 4.
Step (4)
Synthesis of Compound 5: Dichloromethane (40.3 Kgs), DMF (33g, 0.04 eq) and compound 4 (2.3 Kg) were charged to a reaction flask. The solution was filtered through a 0.2 μπι filter and was returned to the flask. Oxalyl chloride (0.9 Kgs, 1 eq) was added via addition funnel over 30-120 minutes at < 30 °C. The batch was then stirred at < 30°C until reaction completion (compound 4 <3 %) was confirmed by HPLC (method TM-113.946). Next, the dichloromethane solution was concentrated and residual oxalyl chloride was removed under reduced pressure at < 40 °C. When HPLC analysis (method TM-113.946) indicated that < 0.10%) oxalyl chloride was remaining, the concentrate was dissolved in fresh
dichloromethane (24 Kgs) and transferred back to the reaction vessel (Vessel A).
A second vessel (Vessel B) was charged with Methyl 7-aminoheptanoate
hydrochloride (Compound Al, 1.5 Kgs, 1.09 eq), DIPEA (2.5 Kgs, 2.7 eq), 4
(Dimethylamino)pyridine (DMAP, 42g, 0.05 eq), and DCM (47.6 Kgs). The mixture was cooled to 0-10 °C and the acid chloride solution in Vessel A was transferred to Vessel B while maintaining the temperature at 5 °C to 10 °C. The reaction is stirred at 5-10 °C for 3 to 24 hours at which point HPLC analysis indicated reaction completion (method TM-113.946, compound 4 <5%). The mixture was then extracted with a 1M HC1 solution (20 Kgs), purified water (20 Kgs), 7% sodium bicarbonate (20 Kgs), purified water (20 Kgs), and 25% sodium chloride solution (20 Kgs). The dichloromethane was then vacuumdistilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% DCM was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (6.4 Kgs). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 2.2 Kgs (77% yield) was isolated in 95.9% AUC purity (method TM-113.953) and 99.9 wt %. See 1HNMR data in Figure 5.
Step (5)
Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 5 < 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D.
The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IP A, 27.1 Kg). The slurry was heated to 75±5 °C to dissolve the solids. The solution was seeded with crystals of Compund (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55°C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form I/Pattern A) in 85% yield and 99.5% purity. See 1HNMR data in Figure 6.
Example 5: Alternative synthesis of Compound (I)
Reaction Scheme
(I)
Step (1)
Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 250g), ethanol (2179 g), 2-Chloroaniline (339.3 g, 2 eq) and acetic acid (132.1 g, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis. When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and Ν,Ν-Diisopropylethylamine (DIPEA, 553.6 g, 3.2 eq) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 401 g) and heptane (2 x 428 g). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 307. lg compound 11 (82.5% yield and 99.7% purity.
Step (2)
Synthesis of Compound 3: Cuprous iodide (17.5g, 8 eq), potassium carbonate (373.8 g, 3 eq), L-Prolin (11.4 g, 0.11 eq.) and dimethyl sulfoxide (DMSO, and 1180 g ) were added to a reactor (vessel A). The resulting solution was heated to 90 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (250g) and iodobenzene (1469.5 g, 8 eq) in DMSO (402.5 g) was heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 90 ± 5°C for 8-24 hours, until HPLC analysis determined that < 1%) compound 11 was remaining.
Step (3)
Synthesis of Compound 4: The mixture of Step (2) was cooled to 40-50 °C and water (500g) and potassium hydroxide solution 10% (700.0 g, 2.8 eq) were added. The reaction mixture was stirred at 40-50 °C for 2-8 hours until HPLC showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with toluene (3 x 150g). The aqueous layer was cooled to 0-5 °C, then acidified with hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 291 g (81% yield) compound 4 in 98% AUC purity. No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed.
Step (4)
Synthesis of Compound 5 :
Compound 4 (250.0 g), A-l (159.2 g, 1.06 eq) and Methy-THF (5113 g) were charged to the reactor. DIPEA (283.7 g, 2.85 eq), hydroxybenzotriazole (HOBt, 12.5 g, 0.11 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HC1, 216.3 g, 1.47 eq) were added. The reaction solution was stirred at ambient temperature for 6-24 hours, at which point HPLC analysis indicated reaction completion (compound 4 <3%). The mixture was then extracted with a 1M HC1 solution (2270 g), purified water (2270 g), 7% sodium bicarbonate (2270 g), purified water (2270 g), and 25% sodium chloride solution (2270 g). The Methyl-THF was then vacuumdi stilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% methyl-THF was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (700g). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 294g (82% yield) was isolated in 99.6% AUC purity and 99.4 wt %.
Step (5)
Synthesis of Compound (I): Hydroxylamine hydrochloride (330g, 10 eq) and methanol (960g) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (1120 g, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once
the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 210 g). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (220 g) was added. The reaction was stirred until the reaction was complete (compound 5 < 2%). The mixture was filtered and water (280 g) and ethyl acetate (890 g) were added to the filtrate. The pH was adjusted to 8 -9 using HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (2570 g), then dried under reduced pressure to constant weight to yield 980 g crude solid in 83% yield. The crude solid compound (I) was determined to be Form IV/ Pattern D.
The crude solid (980 g) was suspended in 1-propanol (400 g) and purified water (220 g). The suspension was heated to 40°C. The batch was then cooled to 38°C over 30 minutes. The solution was seeded with crystals of Compund (I) (Form I/Pattern A, 2-5 wt %). The batch was kept at 37-38°C for 2-4 hours, then was gradually cooled to 20±2°C. Water (950 g) was charged over 3 -5 hours. The batch was cooled to 12°C and was stirred for 2 hrs at this temperature. The batch was filtered and washed with cold 1-propanol/water, then dried at 50±5°C to constant weight to yield 910 g purified compound (I) in 93% yield and 99.8% AUC purity.
“DRUG APPROVALS INT” CATERS TO EDUCATION GLOBALLY, No commercial exploits are done or advertisements added by me. This article is a compilation for educational purposes only.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent