TRIPS Agreement

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Jan 232015

WTO members (where the TRIPS agreement applies)

Parties to the Agreement where also the membership of the European Union applies

“TRIPS” redirects here. For the microprocessor, see TRIPS architecture. For the German racing driver, see Wolfgang von Trips. For other uses, see Trip.

TRIPS Agreement
Annex 1C to the Agreement establishing the World Trade Organization
Agreement on Trade-Related Aspects of Intellectual Property Rights
WTO members (where the TRIPS agreement applies) Parties to the Agreement where also the membership of the European Union applies
Type	Annex to the Agreement establishing the World Trade Organization
Effective	1 January 1996
Parties	158 (All WTO members)^[1]
Languages	English, French and Spanish
Agreement on Trade-Related Aspects of Intellectual Property Rights at Wikisource

The Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) is an international agreement administered by the World Trade Organization (WTO) that sets down minimum standards for many forms of intellectual property (IP) regulation as applied to nationals of other WTO Members.^[2] It was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994.

The TRIPS agreement introduced intellectual property law into the international trading system for the first time and remains the most comprehensive international agreement on intellectual property to date. In 2001, developing countries, concerned that developed countries were insisting on an overly narrow reading of TRIPS, initiated a round of talks that resulted in the Doha Declaration. The Doha declaration is a WTO statement that clarifies the scope of TRIPS, stating for example that TRIPS can and should be interpreted in light of the goal “to promote access to medicines for all.”

Specifically, TRIPS requires WTO members to provide copyright rights, covering content producers including performers, producers of sound recordings and broadcasting organizations; geographical indications, including appellations of origin; industrial designs;integrated circuit layout-designs; patents; new plant varieties; trademarks; trade dress; and undisclosed or confidential information. TRIPS also specifies enforcement procedures, remedies, and dispute resolution procedures. Protection and enforcement of all intellectual property rights shall meet the objectives to contribute to the promotion of technological innovation and to the transfer and dissemination of technology, to the mutual advantage of producers and users of technological knowledge and in a manner conducive to social and economic welfare, and to a balance of rights and obligations.

Background and history

TRIPS was negotiated at the end of the Uruguay Round of the General Agreement on Tariffs and Trade (GATT) in 1994. Its inclusion was the culmination of a program of intenselobbying by the United States, supported by the European Union, Japan and other developed nations. Campaigns of unilateral economic encouragement under the Generalized System of Preferences and coercion under Section 301 of the Trade Act played an important role in defeating competing policy positions that were favored by developing countries, most notably Korea and Brazil, but also including Thailand, India and Caribbean Basin states. In turn, the United States strategy of linking trade policy to intellectual property standards can be traced back to the entrepreneurship of senior management at Pfizer in the early 1980s, who mobilized corporations in the United States and made maximizing intellectual property privileges the number one priority of trade policy in the United States (Braithwaite and Drahos, 2000, Chapter 7).

After the Uruguay round, the GATT became the basis for the establishment of the World Trade Organization. Because ratification of TRIPS is a compulsory requirement of World Trade Organization membership, any country seeking to obtain easy access to the numerous international markets opened by the World Trade Organization must enact the strict intellectual property laws mandated by TRIPS. For this reason, TRIPS is the most important multilateral instrument for the globalization of intellectual property laws. States like Russia and China ^[3] that were very unlikely to join the Berne Convention have found the prospect of WTO membership a powerful enticement.

Furthermore, unlike other agreements on intellectual property, TRIPS has a powerful enforcement mechanism. States can be disciplined through the WTO’s dispute settlementmechanism.

The requirements of TRIPS

TRIPS requires member states to provide strong protection for intellectual property rights. For example, under TRIPS:

Copyright terms must extend at least 20 years, unless based on the life of the author. (Art. 12 and 14)^[4]^{[not in citation given]}
Copyright must be granted automatically, and not based upon any “formality,” such as registrations, as specified in the Berne Convention. (Art. 9)
Computer programs must be regarded as “literary works” under copyright law and receive the same terms of protection.
National exceptions to copyright (such as “fair use” in the United States) are constrained by the Berne three-step test
Patents must be granted for “inventions” in all “fields of technology” provided they meet all other patentability requirements (although exceptions for certain public interests are allowed (Art. 27.2 and 27.3)^[5] and must be enforceable for at least 20 years (Art 33).
Exceptions to exclusive rights must be limited, provided that a normal exploitation of the work (Art. 13) and normal exploitation of the patent (Art 30) is not in conflict.
No unreasonable prejudice to the legitimate interests of the right holders of computer programs and patents is allowed.
Legitimate interests of third parties have to be taken into account by patent rights (Art 30).
In each state, intellectual property laws may not offer any benefits to local citizens which are not available to citizens of other TRIPS signatories under the principle of national treatment (with certain limited exceptions, Art. 3 and 5).^[6] TRIPS also has a most favored nation clause.

Many of the TRIPS provisions on copyright were copied from the Berne Convention for the Protection of Literary and Artistic Works and many of its trademark and patent provisions were modeled on the Paris Convention for the Protection of Industrial Property.

Access to essential medicines[

The most visible conflict has been over AIDS drugs in Africa. Despite the role that patents have played in maintaining higher drug costs for public health programs across Africa, this controversy has not led to a revision of TRIPs. Instead, an interpretive statement, the Doha Declaration, was issued in November 2001, which indicated that TRIPs should not prevent states from dealing with public health crises. After Doha, PhRMA, the United States and to a lesser extent other developed nations began working to minimize the effect of the declaration.^[7]

A 2003 agreement loosened the domestic market requirement, and allows developing countries to export to other countries where there is a national health problem as long as drugs exported are not part of a commercial or industrial policy.^[8] Drugs exported under such a regime may be packaged or colored differently in order to prevent them from prejudicing markets in the developed world.

In 2003, the Bush administration also changed its position, concluding that generic treatments might in fact be a component of an effective strategy to combat HIV. Bush created the PEPFAR program, which received $15 billion from 2003–2007, and was reauthorized in 2008 for $48 billion over the next five years. Despite wavering on the issue ofcompulsory licensing, PEPFAR began to distribute generic drugs in 2004-5.

Software and business method patents

Main article: Software patents under TRIPs Agreement

Another controversy has been over the TRIPS Article 27 requirements for patentability “in all fields of technology”, and whether or not this necessitates the granting of softwareand business method patents.

Implementation in developing countries

The obligations under TRIPS apply equally to all member states, however developing countries were allowed extra time to implement the applicable changes to their national laws, in two tiers of transition according to their level of development. The transition period for developing countries expired in 2005. The transition period for least developed countries to implement TRIPS was extended to 2013, and until 1 January 2016 for pharmaceutical patents, with the possibility of further extension.^[9]

It has therefore been argued that the TRIPS standard of requiring all countries to create strict intellectual property systems will be detrimental to poorer countries’ development.^[10] Many argue^[who?] that it is, prima facie, in the strategic interest of most if not all underdeveloped nations to use the flexibility available in TRIPS to legislate the weakest IP laws possible.^[11]

This has not happened in most cases. A 2005 report by the WHO found that many developing countries have not incorporated TRIPS flexibilities (compulsory licensing, parallel importation, limits on data protection, use of broad research and other exceptions to patentability, etc.) into their legislation to the extent authorized under Doha.^[12]

This is likely caused by the lack of legal and technical expertise needed to draft legislation that implements flexibilities, which has often led to developing countries directly copying developed country IP legislation,^[13] or relying on technical assistance from the World Intellectual Property Organization (WIPO), which, according to critics such as Cory Doctorow, encourages them to implement stronger intellectual property monopolies.

Banerjee and Nayak^[14] shows that TRIPS has a positive effect on R&D expenditure of Indian pharmaceutical firms.

Post-TRIPS expansion

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In addition to the baseline intellectual property standards created by the TRIPS agreement, many nations have engaged in bilateral agreements to adopt a higher standard of protection. These collection of standards, known as TRIPS+ or TRIPS-Plus, can take many forms.^[15] General objectives of these agreements include:

The creation of anti-circumvention laws to protect Digital Rights Management systems. This was achieved through the 1996 World Intellectual Property Organization Copyright Treaty (WIPO Treaty) and the WIPO Performances and Phonograms Treaty.
More stringent restrictions on compulsory licenses for patents.
More aggressive patent enforcement. This effort has been observed more broadly in proposals for WIPO and European Union rules on intellectual property enforcement. The 2001 EU Copyright Directive was to implement the 1996 WIPO Copyright Treaty.
The campaign for the creation of a WIPO Broadcasting Treaty that would give broadcasters (and possibly webcasters) exclusive rights over the copies of works they have distributed.

Panel reports

According to WTO 10th Anniversary, Highlights of the first decade, Annual Report 2005 page 142,^[16] in the first ten years, 25 complaints have been lodged leading to the panel reports and appellate body reports on TRIPS listed below.

The WTO website has a gateway to all TRIPS disputes (including those that did not lead to panel reports) here [1].

2005 Panel Report:^[17]
- European Communities – Protection of Trademarks and Geographical Indications for Agricultural Products and Foodstuffs.
2000 Panel Report:^[18] Part 2^[19] and 2000 Appellate Body Report^[20]
- Canada – Term of Patent Protection.
2000 Panel Report, Part 1:^[21] and Part 2^[22]
- United States – Section 110(5) of the US Copyright Act.
2000 Panel Report:^[23]
- Canada – Patent Protection of Pharmaceutical Products.
2001 Panel Report:^[24] and 2002 Appellate Body Report^[25]
- United States – Section 211 Omnibus Appropriations Act of 1998.
1998 Panel Report:^[26]
- India – Patent Protection for Pharmaceutical and Agricultural Chemical Products.
1998 Panel Report:^[27]
- Indonesia – Certain Measures Affecting the Automobile Industry.

Criticism

Since TRIPS came into force it has received a growing level of criticism from developing countries, academics, and non-governmental organizations. Some of this criticism is against the WTO as a whole, but many advocates of trade liberalization also regard TRIPS as bad policy. TRIPS’s wealth concentration effects (moving money from people in developing countries to copyright and patent owners in developed countries) and its imposition of artificial scarcity on the citizens of countries that would otherwise have had weaker intellectual property laws, are common bases for such criticisms.

Peter Drahos writes that “It was an accepted part of international commercial morality that states would design domestic intellectual property law to suit their own economic circumstances. States made sure that existing international intellectual property agreements gave them plenty of latitude to do so.”^[28]

Daniele Archibugi and Andrea Filippetti^[29] argue that the importance of TRIPS in the process of generation and diffusion of knowledge and innovation has been overestimated by both their supporters and their detractors. Claude Henry and Joseph E. Stiglitz^[30] argue that the current intellectual property global regime may impede both innovation and dissemination, and suggest reforms to foster the global dissemination of innovation and sustainable development.

References

Jump up^ “WTO TRIPS implementation”. International Intellectual Property Alliance. Retrieved22 May 2012.
Jump up^ See TRIPS Art. 1(3).
Jump up^ Farah, Paolo Davide & Cima, Elena (2010) ‘SSRN.com China’s Participation in the World Trade Organization: Trade in Goods, Services, Intellectual Property Rights and Transparency Issues” in Aurelio Lopez-Tarruella Martinez (ed.), El comercio con China. Oportunidades empresariales, incertidumbres jurídicas, Tirant lo Blanch, Valencia (Spain) 2010, pp. 85–121. ISBN 978-84-8456-981-7.
Jump up^ “intellectual property (TRIPS) – agreement text – standards”. WTO. 1994-04-15. Retrieved 2012-04-16.
Jump up^ World Trade Organization, “Part II — Standards concerning the availability, scope and use of Intellectual Property Rights; Sections 5 and 6”, Agreement on Trade-Related Aspects of Intellectual Property Rights
Jump up^ World Trade Organization, “Part I — General Provisions and Basic Principles”,Agreement on Trade-Related Aspects of Intellectual Property Rights
Jump up^ cf. Timmermann, Cristian, and Henk van den Belt. 2013. Intellectual property and global health: from corporate social responsibility to the access to knowledge movement. Liverpool Law Review 34 (1):47-73. also available at http://edepot.wur.nl/252885
Jump up^ World Trade Organization (1 September 2003), Implementation of paragraph 6 of the Doha Declaration on the TRIPS Agreement and public health
Jump up^ World Trade Organisation, IP – http://www.wto.org/english/tratop_e/trips_e/tripfq_e.htm
Jump up^ IP Justice policy paper for the WIPO development agenda, IP Justice
Jump up^ Trade and Health. McGill-Queen’s University Press. 2007. p. 33. |first1= missing|last1= in Authors list (help)
Jump up^ Musungu, Sisule F.; Oh, Cecilia (August 2005), The use of flexibilities in TRIPS by developing countries: can they promote access to medicines?, Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH)
Jump up^ Finger, J. Michael (2000). “The WTO’s special burden on less developed countries”(PDF). Cato Journal 19 (3).
Jump up^ Banerjee and Nayak, Effects of Trade Related Intellectual Property Rights on the R&D Expenditure of Indian Pharmaceutical Industry,2014 ‘Journal of Pharmaceutical Health Services Research.
Jump up^http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195390124.001.0001/acprof-9780195390124-chapter-8
Jump up^ World Trade Organization (2005). “Annual Report 2005”.
Jump up^ “2005 News items – Panel reports out on geographical indications disputes”. WTO. 2005-03-15. Retrieved 2012-04-16.
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391da.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/1391db.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/170abr_e.pdf
Jump up^ http://www.wto.org/english/news_e/news00_e/1234da.pdf
Jump up^ http://www.wto.org/english/news_e/news00_e/1234db.pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/canada-pharmaceuticals(panel)(full).pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176r_e.pdf
Jump up^ http://www.wto.org/english/tratop_e/dispu_e/176abr_e.pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/india-patents(panel)(ec)(full).pdf
Jump up^ http://www.worldtradelaw.net/reports/wtopanelsfull/indonesia-autos(panel)(full).pdf
Jump up^ Drahos with Braithwaite, Information Feudalism, New Press 2002, p38
Jump up^ Archibugi, D. and Filippetti, A. (2010) ‘The globalization of intellectual property rights: Four learned lessons and four thesis‘, Journal of Global Policy, 1: 137-49.
Jump up^ Henry, C. and Stiglitz, J. (2010) ‘Intellectual Property, Dissemination of Innovation and Sustainable Development‘, Journal of Global Policy, 1: 237-51.

Source

Braithwaite and Drahos, Global Business Regulation, Cambridge University Press, 2000
Westkamp, ‘TRIPS Principles, Reciprocity and the Creation of Sui-Generis-Type Intellectual Property Rights for New Forms of Technology’ [2003] 6(6) The Journal of World Intellectual Property 827-859, ISSN: 1422-2213
Banerjee and Nayak, ‘Effects of trade related intellectual property rights on the research and development expenditure of Indian pharmaceutical industry’ [2014] 5 Journal of Pharmaceutical Health Services Research 89-94.

External links

TRIPS agreement (PDF version)
Agreement on Trade-Related Aspects of Intellectual Property Rights (html version)
World Trade Organization links
- World Trade Organization – Official Text
- World Trade Organization – TRIPs gateway
Audio presentation by Professor Susan Sell, George Washington University, on intellectual property rights in the global context.
WTO TRIPS Agreement profile on database of Market Governance Mechanisms

Overview of the Patent System in Korea

PATENTS, Uncategorized Comments Off

Jan 212015

South Korea

http://www.kipo.go.kr/kpo/user.tdf?a=user.english.main.BoardApp&c=1001

The Korean Intellectual Property Office (KIPO) is the patent office and intellectual property office of South Korea. In 2000, the name of the office was changed from “Korean Industrial Property Office” to “Korean Intellectual Property Office”.^[1] It is located in Daejeon Metropolitan City.^[2]

References

KIPO web site, KIPO’s history. Consulted on January 20, 2008.
KIPO web site, Contact Us. Consulted on January 20, 2008.

External links

Korean Intellectual Property Office, in English
Korea Intellectual Property Rights Information Service (KIPRIS), in English
- Patent search database in KIPRIS, in English
- K2E-PAT Interface in KIPRIS (wherein “K2E-PAT” stands for “Korean to English Automatic Machine Translation”, see European Patent Office, “Lost in translation? Get the right type of Korean patent translation for your needs”, Patent Information News, Issue 1, 2010, p. 4)
Information about patent law in South Korea on the European Patent Office web site

Overview of the Patent System in Korea

History of the Korean patent system

What is a patent?

Purpose of the patent system

Requirements for acquiring patent rights

Effects and term of a patent right

Information on patent applications

First-to-file rule and first-to-invent rule

Inventions and devices

Patent examination system

Accelerated examination system

Deferred examination system

Divisional application

Converted application

Priority claim under treaty

Claim for domestic priority

Ex officio amendment

Request for reexamination (reexamination before a trial)

Pendency period

Korean Intellectual Property Office

http://www.kipris.or.kr/enghome/main.jsp

Patent

Patent Search Websites; IP Related Organizations in Korea …

http://engpat.kipris.or.kr/engpat/searchLogina.do?next=MainSearch

Searching in databases – Korea

Tips & tricks for searching in databases

Easy, step-by-step instructions on how to use official Korean databases. Click on the links below to download the respective search guides.

Saudi Patent Office AND GULF ( GCC Patent office)

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Jan 212015

http://www.gccpo.org/DefaultEn.aspx

The Patent Office of the Cooperation Council for the Arab States of the Gulf is delighted to announce launching the electronic filing system for patent applications “Protection” in its trial version, starting from the second of August of 2014, through the office’s official website on the internet www.gccpo.org.
The “Protection” system launch comes within the frame of the office’s comprehensi…More

The GCC Patent Office (GCCPO) is a regional patent office based in Riyadh, Saudi Arabia, within the Secretariat General of the Gulf Cooperation Council (GCC). It was established in 1992 and began operations in 1998. The GCC Patent Office grants patents valid in all GCC member states. The first GCC patent was granted in 2002. As of 2013, it employed about 30 patent examiners.^[1]

References

Mizael Al-Harbi, Hussam Al-Muqhim (18 April 2013). “Gulf countries: introduction to the GCC patent system”. East meets West 2013. Austria.

External links

(Arabic) Official website
(English) Official website

The Gulf Cooperation Council Patent Office (GCC Patent Office) is a unified patent office that serves as a convention patent office for the states of the Gulf namely, Saudi Arabia, Bahrain, Kuwait, Oman, Qatar and United Arab Emirates. The GCC Patent Office became operational in 1998. Saudi Arabia is a member of the Gulf Cooperation Council. A patent issued by the GCC Patent Office is valid and enforceable in all GCC States.

Under GCC Patent Law, it is possible to claim priority from an earlier foreign application. As compared with the Saudi Patent Office the examination process is much faster in the GCC Patent Office. Moreover, the GCC Patent Office has the following advantages:

Filing a GCC Patent application will be more cost-effective than filing six separate national applications.. Therefore, by filing one application at the GCC Patent Office, protection is granted in all GCC States at a reduced cost.
A Patent granted by the GCC Patent Office is valid and enforceable in all GCC States (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and U.A.E)
The term of protection under GCC Patent Law is 20 years counted from the date of filing the patent application with the GCC Patent Office as opposed to 15 years as far as the other national patent laws are concerned.
Duplication of registration is possible. It is possible to file a patent application in one or more of the GCC States and at the same time seek convention protection by filing at the GCC Patent Office.
Compulsory Licensing under GCC Patent Law is now subjected to detailed conditions in conformity with the provision of the Trips Agreement.
Importation of a patented product into GCC States will be considered as full exploitation of the invention.
The GCC is taking the necessary steps to join Paris and PCT treaties in the near future.
The Examination of applications is carried out by an Austrian and Australian Patent Offices.

The requirements for filing a new GCC patent application are as follows:

Documents that must be filed along with the application:
Specifications, Claims, Drawings (if any) and Abstract of the invention in English and Arabic.
Documents that may be filed belatedly within 90 days from the filing date:
1. A Power of Attorney from the applicant.
2. An Extract from the Commercial Register or a certified copy of the Certificate of Incorporation of the applicant if the applicant is a corporate body.
3. A Deed of Assignment, if the applicant is not the inventor.
4. A Certified copy of the Priority document, if the applicant is claiming priority on the basis of a foreign application. Item Nos. 1,2 & 3 should be legalized up to any one of the GCC States Consulates.

Image result for saudi arabia

Industrial property is one of the branches of intellectual property. It refers to the protection of rights related to the creations of the mind applied in industrial, commercial, and agricultural fields. It covers:

• Inventions
• Industrial Designs
• Plant Varieties
• Layout Designs of integrated circuits
• Trademarks
• Geographical indications of source

King Abdulaziz City for Science and Technology (KACST) grants protection documents for inventions, layout designs of integrated circuits, plant varieties and industrial designs.

History of Industrial Property in Saudi Arabia.

In 1982, KACST was notified of the Royal Decree approving the accession of Saudi Arabia to the World Intellectual Property Organization (WIPO). Accordingly, patents has been assigned to KACST since intellectual property is essentially about patents and technology transfer and KACST is the scientific body qualified for this mission.

The first Law of Patents was issued by the Royal Decree No. (M / 38) dated 10/6/1409 H (18/1/1989 AD). The Law aimed to provide protection for inventions in Saudi Arabia, and it was modified in 19 / 7 / 1425 H (4/9/2004 AD).

The modified Law of Patents, Layout Designs of Integrated Circuits, Plant Varieties, and Industrial Designs was issued by the Royal Decree No. (M/27) dated 17/7/2004 and was published in the Official Gazette (Om Alqura) in 7/8/2004, and became effective as of 5/9/2004.

Kingdom of Saudi Arabia

المملكة العربية السعودية
Al-Mamlakah al-Arabiyah as-Sa’ūdiyah

King Abdullah of Saudi Arabia (left) and Salman bin Abdulaziz Al Saud, the Crown Prince of Saudi Arabia on the right.

Patent Application Flowchart

Desgin Application Flowchart

Saudi Arabia has ratified the Berne Convention for the Protection of Literary and Artistic Works of 1886, revised in Paris on 24th July 1971 and the Paris Convention for the Protection of Industrial Property of 1883, both with effect from 11th March 2004. Three government authorities have authority to protect and enforce intellectual property rights: the Ministry of Commerce and Industry for trademarks, the Ministry of Culture and Information for copyright, and King Abdulaziz City for Science and Technology for patents.

Trademarks:
Trademarks are governed by the Trademarks Regulation, Royal Decree No. M/21 of 28th Jumada Awal 1423 Hejra corresponding to 8th August 2002 Gregorian, and its Implementing Rules of the same year. Applications for registration must be made to the Trademarks Office of the Ministry of Commerce and Industry which applies the ‘Nice Classification’ in accordance with the Agreement Concerning the International Classification of Goods and Services for the Purposes of the Registration of Marks of 1957.

Deera Square, central Riyadh. Known locally as “Chop-chop square”, it is the location of public beheadings.^[142]

Applications must contain the following particulars:
01. A copy of the trademark required to be registered.
02. Name, title, address, nationality and trade name of the applicant (if any). If the applicant is a juristic person, the name, address of the head office and nationality must be stated.
03. Where the application is submitted by an attorney, his name, title and address must be stated.
04. Description of the trademark required to be registered.
05. The products or services in respect of which the trademark is required to be registered, and the classification thereof.
06. Signature of the applicant or the attorney thereof.
07. Ten representations of the trademark identical to the trademark sample shown in the application for registration.
08. A copy of the power of attorney together with the original for verifying purposes must be attached where the application was submitted by an attorney of the person concerned.
09. Evidence of payment of application fees as stipulated in the Trademarks Regulation.

It is not permitted to register in Saudi Arabia, by other than its rightful owner, a trademark that is similar to an internationally known mark. Registration of a trademark allows holders protection for ten years from the date of application, renewable for similar periods. Any renewal must be specifically applied for before the end of the last year of expiry of the registration, and the procedure for renewal is the same as the one for the initial registration of the trademark. Service marks are included in the definition of trademarks. A trademark is deemed owned by the person who effects the registration. Once the registration is effected in the trademarks register, the party who has registered the trademark shall be considered the owner thereof to the exclusion of others.

A trademark can be licensed, pledged or transferred by the rightful owner. The trademark may be deleted or cancelled if it is not used for five consecutive years. Penalties for infringement of a valid trademark include imprisonment for a period of not more than one year and a fine of not less than SR50,000 and not more than SR1,000,000. Any civil or criminal disputes arising from the infringement are settled by the Board of Grievances.

The Nejd landscape: desert and the Tuwaiq Escarpment near Riyadh

Patents:
There are at present two overlapping patents systems in Saudi Arabia. The GCC Patents of Inventions Regulation of 2001, which is an amendment of an earlier statute of 1992, was approved in Saudi Arabia by Royal Decree No. M/28 of 2001. This permits the registration of patents with effect throughout the GCC countries. The GCC Patent Office is based in Riyadh.

Under Saudi Arabian law, patents are governed by the Layout Designs of Integrated Circuits, Plant Varieties, and Industrial Models Regulation, Royal Decree No. M/27 of 20th Jumada Awal 1425 Hejra corresponding to 17th July 2005 Gregorian, which gives effect to the Paris Convention for the Protection of Industrial Property under Saudi Arabian domestic law.

A protection document is granted by the General Directorate of Patents at King Abdulaziz City for Science and Technology, which gives full protection within the Kingdom to an invention, a layout design of an integrated circuit, a plant variety, or an industrial design. The protection document grants the owner the right to commercially exploit the subject matter of protection.

Applications for a protection document must be filed at the Directorate in the Arabic language, and must include:
01. Names and addresses of the applicant(s) and inventor(s);
02. Name and address of the local agent and the authorization, if the applicant resides outside the Kingdom;
03. A brief title of the subject matter of the application, an original copy and certified copies of the complete specification and certified copies of other relevant details thereof like examination and research reports;
04. Priority and disclosure information including previous filings; and
05. Evidence of payment of the filing fee at a designated bank, stipulated by the Directorate.
The protection document is the personal right of the owner and he may transfer or assign it or grant a contractual licence to others to commercially exploit the subject matter of protection. Protection is granted to the owner for a duration of 20 years for an invention, 10 years for an industrial design and a layout design of an integrated circuit, and 20 to 25 years for a new plant variety. The above periods are renewable, for an annual fee.

Provinces of Saudi Arabia

Copyright
The Copyright Regulation, Royal Decree No. M/41 of 2nd Rajab 1424 Hejra corresponding to 30th August 2003 Gregorian and its Implementing Rules, Resolution of the Minister of Commerce and Industry No. M/W/1788/1 of 10th Rabi Thani 1425 Hejra corresponding to 30th May 2004 Gregorian, define copyright protection to include architectural designs, speeches, theatrical, musical, photographic and cinematographic works, as well as works for radio and television, maps, video tapes and computer software. Copyright protection is not subject to any registration or renewal. The Regulation gives the author financial and moral rights, to print or publish the work, to make amendments or to delete his work, to withdraw it from circulation, and to assign it as he wishes.

In general the duration of protection afforded to different types of Copyright works is as follows:
01. The period of protection of copyright for the author of a work shall be for the duration of his life and for a period of fifty years following his death.
02. The period of protection for works where the author is a corporate entity, or if the author’s name is unknown, shall be fifty years from the date of the first publication of the work.
03. The protection period for sound works, audio-visual works, films, collective works and computer programs is fifty years from the date of the first show or publication of the work, regardless of republication.
04. The protection period for applied art (handcrafted or manufactured) and photographs shall be twenty-five years from the date of publication.
05. The protection period for broadcasting organizations shall be twenty years from the date of the first transmission of program or broadcast materials.

Office of Saudi Aramco, world’s most valuable company and main source of revenue for the state.

A special Copyright Violations Committee under the authority of the Ministry of Culture and Information presides over copyright infringement issues and it has broad powers to punish the infringer of a valid copyright including a fine of up to SR250,000 in the case of first time offenders, and this can be raised to SR500,000 if there is repeated infringement. The Committee may issue injunctions in certain cases and also order imprisonment of an offender. Any decision of the Violations Committee can be appealed by filing a claim with the Board of Grievances.

kacst

Saudi Arabia is the largest and richest of the Gulf States. Its wealth derives mainly from its vast reserves of oil and natural gas, which places the country as the largest exporter of petroleum and give it a leading role in the Organization of the Petroleum Exporting Countries. It possesses about one-fifth of the world’s proven petroleum reserves. The Intellectual Property framework of Saudi Arabia has evolved to protect the different intellectual properly rights and to cope with the rapid globalization and technological change. Both globalization and technological advancement have presented significant economic opportunities and challenges to the IP system. As a result, IP rights have become increasingly important in the country, but many of the challenges facing the IP system have yet to be addressed.

The Patent Office in Saudi Arabia is located at the King Abdulaziz City for Science & Technology, an independent scientific organization of the Saudi Arabian Government established back in the year 1977. The Patent Office’s main activities and objectives are to:
(1) Apply the patent law and its implementing regulations: Law of Patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(2) Grant Saudi patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(3) Establish a Registry for the collection of local and foreign Layout Designs of Integrated Circuits, Plant Varieties and Industrial Designs
(4) Publish the Patents Gazette
(5) Encourage the inventiveness of Saudi nationals.
The Office has taken a number of measures during the past years to hire and train examiners and translators in order to adequately handle patent applications.

Legislation
Law no. 159 on the Protection of Patents, Layout Designs of Integrated Circuits, Plant Varieties and Industrial Models.

Types of Patents
– Patents of Invention
– Divisional Patents

Priority Claim
Saudi Arabia is a member of the Paris Convention. Applicants can benefit from a right of priority of 12 months to file a corresponding Saudi patent application.

Patent Cooperation Treaty
Saudi Arabia has joined the PCT but still the entry of national phase of PCT application is not possible as the relevant regulations and laws have not been issued, we expect the implementation of PCT within next 6-12 months.

The Mosque of the Prophet in Medina containing the tomb of Muhammad.

Definition of an Invention
An invention must be novel, involves an inventive step and capable of industrial application. The invention may be a product, an industrial process or relates to either (Article 43).

Types of Claims
Product and process claims are acceptable. When a patent is granted for a process, any product made directly by such a process is also protected (Article 47(b)).

Exception to Protection
An invention is not patentable if it is: a discovery; a scientific theory or mathematical method; an aesthetic creation such as a literary, dramatic, or artistic work; a scheme or method for performing a mental act, games or business methods; the presentation of information; or a computer program.

Examination
– Novelty: the invention must never have been made public in any way, anywhere in the world, before the filing date or the priority date.
– Inventiveness: an invention involves an inventive step if, when compared with what is already known, it would not be obvious to someone skilled in the relevant field.
– Industrial applicability: an invention must be capable of being made or used in some kind of industry.

Laboratory buildings at KAUST

Novelty
Absolute novelty is required. Any act that makes an invention available to the public before the filing date or priority date has the effect of barring the invention from being patented in Saudi Arabia (Absolute Novelty). Examples of acts that can make an invention available to the public are publications, sales, public oral disclosures and public demonstrations or use, etc. However, the patent application can still be filed if disclosure was very limited and can not be cited by the examiner. Also, a one year grace period is available if the disclosure of the invention was proven to be made without the knowledge or consent of the inventor (Article 44). Wrong statement article 44 if disclosed within the priority period, but the exception is under article 30 of Implementing Regulations where the grace period is 6 months if the disclosure occurred because of abusive action.

Application Workflow
A formal examination is conducted first. If application fails to meet all the set requirements, the applicant will be notified and will be given a period of 90 days to complete the application. Once completed, the application will proceed to substantive examination. The examiner will assess the application for patentability (novelty and industrial applicability). If the claimed invention is not patentable, the applicant will be requested to present counter-arguments within 90 days from notification date. If the claimed invention is patentable, the applicant will be requested to settle the grant and publication fees. Accordingly, the letters patent will be issued and the decisions to grant the patent will be published in the Patent Official Gazette for opposition purposes.

Opposition
Oppositions may be filed within 90 days from publication date before the Board of Grievances.

Protection Term
The term of protection is 20 years from filing date.

Annuities
A maintenance fee is due annually on patents and is payable the first 3 months of each calendar year following the year the patent application was filed. There is a 3-month grace period for late payment with a surcharge.

Compulsory Licensing
A patent has to be worked. If the patent is not being fully exploited by the patentee within 4 years from the date of filing or 3 years from the date of grant, the patent will be subject to compulsory licensing under the provisions of the law.
Naming of the Inventor on the Letters Patent
Compulsory

Ibn Saud, the first king of Saudi Arabia

Employer and Employee’s Rights
Employer’s Rights
The employer shall be the patentee
(1) if the invention is made in execution of a contract or a commitment for the execution of inventive efforts, unless the work contract stipulates otherwise, or
(2) if the employee would not have developed the subject matter of the protection had he not used facilities, means or data made available through his employment
Employee’s Rights
The employee has the right to receive a remuneration to be agreed upon with the consent of both parties or assessed in light of the various circumstances of the contract of employment and the economic importance of the subject matter of the protection. Any special agreement depriving the employee of this right shall be null and void.
General Provisions
A patent application filed by the employee within two years from the date of termination of employment will be considered as if submitted during employment.
All previous provisions will apply to government employees.

Patent Linkage
Requests for marketing approval of generic drugs must include details on the corresponding patent if available (filing no., filing date, and country of grant). The SFDA will then contact the Saudi Patent Office to confirm whether a patent is involved before giving marketing approval. The GCC Patent Office is not usually contacted.

Filing Requirements
1. Power of attorney, legalized up to the Saudi Consulate
2. 2 copies of the specifications in English with Arabic translation
3. 2 sets of drawings in Arabic and one in English.
4. Deed of assignment from the inventor(s), legalized up to the Saudi Consulate
5. Copy of priority document, if priority is claimed, certified.
Item 3 must be submitted at the time of filing. Document 5 must be submitted within 12 months from priority date.
Documents 1 and 4 may be submitted within 1 month from filing date.

Verses from the Quran. The Quran is the official constitution of the country and a primary source of law. Saudi Arabia is unique in enshrining a religious text as a political document^[130]

GCC Protection
Patent protection in Saudi Arabia can also be obtained through the Gulf Cooperation Council unified patent registration system (GCC patent law of 1999).

2011 Figures
Saudi Arabia ranked first among the Arab countries in the number of patents granted for the year 2011 which amounted to 147, based on WIPO sources. It also ranked first in the number of patents filed in the same year which amounted to 78.

http://www.epo.org/searching/asian/faq.html

FAQ – Saudi Arabia (SA)

For more specific legal questions relating to the Saudi Arabian patent system, please contact International_legal_affairs@epo.org.

Questions

General information about IP in Saudi Arabia

From filing to grant

After grant

Sources of information

Supplicating pilgrim at Masjid Al Haram, Mecca

Answers

General information about IP in Saudi Arabia

How to protect an invention in Saudi Arabia

There are two options for protecting an invention on Saudi Arabian territory:

The first option is to file a patent application with the Saudi Arabian Patent Office. If a patent is granted, the invention will be protected only in Saudi Arabia.
The second option is to file a patent application with the Gulf Cooperation Council (GCC) Patent Office. The GCC is a regional organisation comprising six Arab countries: the Kingdom of Saudi Arabia, Qatar, Kuwait, the United Arab Emirates, the Sultanate of Oman, and Bahrain. The GCC Patent Office is a regional office that registers patents in the member states of the GCC. Patents granted by the GCC Patent Office are valid in all GCC member states.

GCC Patent Office website

All the information presented below relates to the first option, protection via the Saudi Arabian Patent Office.

What types of industrial property rights exist in Saudi Arabia?

Saudi Arabia has patents, plant varieties, industrial designs, layout designs of integrated circuits and trade marks, but not utility models. Patents and designs can be registered at the Saudi Arabian Patent Office (official name: General Directorate of Patents at King Abdulaziz City of Science and Technology (KACST)). Trade marks can be registered at the Ministry of Commerce and Industry.

How long are the terms of protection of Saudi Arabian intellectual property rights?

The terms of protection for the different types of intellectual property are as follows:

patents: 20 years from the date of filing
plant varieties: 20 years
industrial designs: 10 years
layout designs of integrated circuits: 10 years

riyadh

When may a patent not be granted?

Article 4 of the Saudi Arabian Patent Law states the following:

“(a) The protection document shall not be granted if its commercial exploitation violates the Shari’ah (Islamic law).

(b) The protection document shall not be granted if its commercial exploitation is harmful to life, to human, animal or plant health, or is substantially harmful to the environment.”

Riyadh

What inventions cannot be patented in Saudi Arabia?

Article 45 of the Saudi Arabian Patent Law states the following:

“In the application of provisions of this Law, the following shall not be regarded as inventions:

(a) Discoveries, scientific theories and mathematical methods.

(b) Schemes, rules and methods of conducting commercial activities, exercising pure mental activities or playing a game.

(c) Plants, animals and processes – which are mostly biological – used for the production of plants or animals, with the exception of micro-organisms, non-biological and microbiology processes.

(d) Methods of surgical or therapeutic treatment of human or animal body and methods of diagnosis applied to human or animal bodies, with the exception of products used in any of these methods.”

The exclusion also applies to computer programs and any other copyright work.

Laws & Regulations

Jeddah

Can computer software be patented in Saudi Arabia?

Computer programs as such are not patentable, but may be protected by copyright. Computer-related inventions may be patentable in Saudi Arabia if the requirements for patentability are met.

Laws & Regulations

Is Saudi Arabia a member of the Patent Cooperation Treaty (PCT)?

As of 3 August 2013, Saudi Arabia will be bound by the PCT. From that date onwards, nationals and residents of Saudi Arabia will be entitled to file international applications under the PCT.

Medina

From filing to grant

As a foreign applicant, do I need to appoint a professional representative in Saudi Arabia?

All non-residents wishing to apply for a patent require an authorised Saudi Arabian representative. Applicants have to file a power of attorney which has been duly notarised and legalised by the consulate of Saudi Arabia.

More information:

Professional representative

What language must I use for a patent application in Saudi Arabia?

Documents submitted under the Saudi Arabian Law of Patents must be in Arabic.

Mecca

Can I claim priority for an application filed in Saudi Arabia?

Yes, the priority term is 12 months from the earliest claimed priority, as stipulated in the Paris Convention. Saudi Arabia has been a member of the Paris Convention since 2004.

What do I need to do to get an early filing date in Saudi Arabia?

Does Saudi Arabia allow divisional applications?

Yes. Where an application contains two or more inventions, applicants may submit a divisional application on their own initiative any time before the decision to grant or reject the application.

Stoning of the Devil in Mina

Do I have to file a request for examination (“deferred examination”) in Saudi Arabia?

You do not need to file a request for examination. Applications are examined automatically, on the basis of the filing date. It is possible to withdraw applications.

Can I withdraw my application before it is published in Saudi Arabia?

Yes, you can withdraw an application before it is published.

Can I request that my application in Saudi Arabia be published earlier than 18 months from the filing (or earliest priority) date?

No, it is not possible to request early publication of an application.

Can I submit third-party observations on a Saudi Arabian patent application?

No, it is not possible to submit third-party observations.

King Abdullah Economic City

What is the time limit for responding to official actions in Saudi Arabia?

Responses to official actions should be submitted within 90 days from the date of the action.

After grant

When do I have to pay annual fees in Saudi Arabia?

Annual fees are due at the beginning of each year (1 January until 30 March), starting from the year following the filing date.

Is there a grace period for paying annual fees in Saudi Arabia?

Applicants or patent holders who fail to pay within a maximum period of three months from the due date are liable to pay double the amount of the fee. If they fail to pay after being warned during the three months following the expiration of the first three months, the patent will cease to be valid and this will be recorded in the Register and published in the Gazette.

Can a lapsed patent be restored in Saudi Arabia?

In case of force majeure it is possible to have a lapsed patent restored at the Saudi Arabian Patent Office.

Makkah in Saudi Arabia

Can I request an extension of the patent term in Saudi Arabia?

No. In Saudi Arabia the 20-year term for patents cannot be extended. The Saudi Arabian Patent Law does not include any provisions on patent term extensions or supplementary protection certificates (SPCs).

How can I challenge a granted patent in Saudi Arabia?

Within 90 days from publication of the decision to grant, any interested party may apply for partial or total revocation of the patent.

Invalidation is possible for a third party at any time after grant and must be raised before a separate governmental body (Appeals Committee).

Sources of information

Where can I search Saudi Arabian patent information in English?

The Saudi Arabian Patent Office has an English-language database known as “IP search”. On this platform you can perform searches according to dates, numbers or applicant/inventor names.

IP Search

If you require a more detailed answer, please send us your question using the contact form.

Where can I find English abstracts of Saudi Arabian patent documents?

In general, the Saudi Arabian Patent Office does not produce any English abstracts for its patent documents. Where a non-Saudi Arabian applicant files an application, the abstract may also be in English (and in Arabic), while the rest of the patent has to be in Arabic only. Therefore, English abstracts are also available in certain circumstances.

Where can I get an English machine translation of a Saudi Arabian patent?

There are no machine translations of Saudi Arabian patents available yet.

Where can I find legal-status information on Saudi Arabian patents in English?

In general, legal-status information for Saudi Arabian patents is not yet available, but a brief “application status” can be found together with the bibliographic information in the “IP search” database.

Where can I find official information about fees in Saudi Arabia?

Information about fees is currently available in Arabic only.

Schedule of fees

Where can I find information about patent agents in Saudi Arabia?

The KACST website gives detailed information about the role of patent attorneys and the services they provide. It is available in Arabic only.

Professional representative

If you require a more detailed answer, please send us your question using the contact form.

Methohexital

Uncategorized Comments Off

Jan 182015

Methohexital or methohexitone, (marketed under the brand name Brevital) is a drug which is a barbiturate derivative. It is classified as short-acting, and has a rapid onset of action. It is similar in its effects to sodium thiopental, a drug with which it competed in the market for anaesthetics.

Pharmacology

Methohexital binds to a distinct site which is associated with Cl⁻ ionophores at GABA_A receptors.^[1] This increases the length of time which the Cl⁻ ionopores are open, thus causing an inhibitory effect.

Metabolism of methohexital is primarily hepatic (i.e., taking place in the liver) via demethylation and oxidation.Side-chain oxidation is the primary means of metabolism involved in the termination of the drug’s biological activity.

Protein binding is approximately 73% for methohexital.

Indications

Methohexital is primarily used to induce anesthesia, and is generally provided as a sodium salt (i.e. methohexital sodium). It is only used in hospital or similar settings, under strict supervision.^{[citation needed]} It has been commonly used to induce deep sedation or general anesthesia for surgery and dental procedures. Unlike many other barbiturates, Methohexital actually lowers the seizure threshold, a property that make it particularly useful when anesthesia is provided for a electroconvulsive therapy (ECT). And rapid recovery rate with consciousness being gained within three to seven minutes after induction and full recovery within 30 minuntes is a major advantage over other ECT barbiturates (Schulgasser and Borowitz 1963).

Synthesis

Methohexital, 5-allyl-1-methyl-5-(1-methyl-2-pentinyl barbituric acid, is synthesized in the classic manner of making barbituric acid derivatives, in particular by the reaction of malonic ester derivatives with derivatives of urea.

Methohexital synthesis: W.J. Doran, U.S. Patent 2,872,448 (1959).

The resulting allyl-(1-methyl-2-pentynyl) malonic ester is synthesized by subsequent alkylation of the malonic ester itself, beginning with 2-bromo-3-hexyne, which gives (1-methyl-2-pentynyl)malonic ester, and then by allylbromide. In the final step, reaction of the disubstituted malonic ester with N-methylurea gives desired methohexital.

Methohexital
Systematic (IUPAC) name


5-hex-3-yn-2-yl-1- methyl-5-prop-2-enyl-1, 3-diazinane-2,4,6-trione
Clinical data
AHFS/Drugs.com	Consumer Drug Information
Pregnancy category	B (USA)
Legal status	AU: Prescription Only (S4) Schedule IV
Routes	Intravenous, rectal
Pharmacokinetic data
Bioavailability	I.V. ~100% Rectal ~17%
Metabolism	Hepatic
Half-life	5.6 ± 2.7 minutes
Excretion	?
Identifiers
CAS number	151-83-7
ATC code	N01 AF01 N05 CA15
PubChem	CID 9034
DrugBank	DB00474
ChemSpider	8683
UNII	E5B8ND5IPE
KEGG	D04985
ChEBI	CHEBI:102216
ChEMBL	CHEMBL7413
Chemical data
Formula	C₁₄H₁₈N₂O₃
Molecular mass	262.304

References

Katzung, Bertram G., Basic and Clinical Pharmacology, 10th ed., p. 406-407

^[1]

External links

Scaling from Milligrams to 1-2Kg

PROCESS Comments Off

Jan 142015

Dr John Knight

Scaling from Milligrams to 1-2Kg

see at…………..http://news.scientificupdate.co.uk/index.php?action=social&chash=1c1d4df596d01da60385f0bb17a4a9e0.1201

2 – 3 March 2015
Sheraton Fisherman’s Wharf Hotel – San Francisco

Fisherman's Wharf, San Francisco

The aim of this professional development course is to provide a good basis to work from when involved in taking development candidates to the first in human trials and with a view on some longer-term requirements. The course content will focus on the necessary early phases of chemical development, as would typically be required to support production of up to about 2kg.

The course will introduce and discuss the following:

Requirements in order to move from small (less than 1g) supplies to the first 100g or so for preclinical work
Further scaling to 1-2kg non-cGMP
Requirements to make material for use in clinical trial – an introduction to cGMP coupled with the scaling issues
An overview of the requirements to move processes to fixed vessels, assuming cGMP is required – what operations can readily be transferred and those that should ideally be developed out
The phases of development and indicative timelines with quality requirements
The importance of physical form selection, understanding and control
Impurities and their control, with specific discussion on genotoxic impurities and developing the specification for the API as it moves from preclinical batch preparation to cGMP batches for clinical trials

Your Course Tutor
Dr John Knight

Register 2 attendees and automatically SAVE 5% plus register 3 people and SAVE 15% on our standard booking fees!

sciupnew logo-master

Who should attend…

Project managers and those involved in technical outsourcing
Project leaders and bench chemists involved in preparation of material
New starters to the area
Medicinal Chemistry support teams involved in making the first batches for toxicological evaluation

What will you take away from this course…

How long it takes to get from milligrams to 1-2kgs suitable for human clinical trials
What are the main hurdles
What can be left out and what must be included
What are the key project management considerations

View the course brochure

The lectures are interspersed with interactive problem sessions.

see http://news.scientificupdate.co.uk/index.php?action=social&chash=1c1d4df596d01da60385f0bb17a4a9e0.1201

Scientific Update LLP, Maycroft Place, Stone Cross, Mayfield, East Sussex TN20 6EW, UK
T: +44 (0)1435 873062 F: +44 (0)1435 872734 E. info@scientificupdate.co.uk

OPRD network

Tipifarnib

Uncategorized Comments Off

Jan 082015

Tipifarnib

6-[(R)-Amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone;

(R)-(+)-R 115777; Zarnestra; 192185-68-5

zarnestra, 192185-72-1, R115777, R-115777, IND 58359, UNII-MAT637500A

192185-72-1, 192185-68-5

Molecular Formula: C27H22Cl2N4O

Molecular Weight: 489.39578 g/mol

cas

192185-72-1, 192185-68-5 (racemate), 192185-70-9 (racemic; diHCl), 192185-69-6 (racemic; fumarate)

R115777 is a substance that is being studied in the treatment of acute myeloid leukemia (AML) and other types of cancer. It belongs to the family of drugs called farnesyltransferase inhibitors. It is also called tipifarnib and Zarnestra.

Tipifarnib (trade name Zarnestra) is a farnesyltransferase inhibitor that is being investigated in patients 65 years of age and older with newly diagnosed acute myeloid leukemia (AML). It inhibits the Ras kinase in a post translational modification step before the kinase pathway becomes hyperactive. It inhibits prenylation of the CxxX tail motif, which allows Ras to bind to the membrane where it is active. Without this step the protein cannot function.

It is also being tested in clinical trials in patients in certain stages of breast cancer.^[1]

For treatment of progressive plexiform neurofibromas associated with Neurofibromatosis type I, it successfully passed phase one clinical trials but was suspended (NCT00029354) in phase two.^[2]^[3] The compound was discovered by and is under investigation byJohnson & Johnson Pharmaceutical Research & Development, L.L.C, with registration number R115777.

Approval process

Tipifarnib was submitted to the FDA by Johnson & Johnson for the treatment of AML in patients aged 65 and over with a New Drug Application (NDA) to the Food and Drug Administration (FDA) on January 24, 2005.

In June 2005, the FDA issued a “not approvable” letter for tipifarnib.^[4]

Farnesyltransferase inhibitors block the main post-translational modification of the Ras protein, thus interfering with its localization to the inner surface of the plasma membrane and subsequent activation of the downstream effectors. Although initially developed as a strategy to target Ras in cancer, farnesyltransferase inhibitors have subsequently been acknowledged as acting by additional and more complex mechanisms that may extend beyond Ras involving GTP-binding proteins, kinases, centromere-binding proteins and probably other farnesylated proteins.

A particular farnesyltransferase inhibitor is described in WO 97/21701, namely (R)-(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone. The absolute stereochemical configuration of the compound was not determined in the experiments described in the above-mentioned patent specification, but the compound was identified by the prefix “(B)” to indicate that it was the second compound isolated from column chromatography. The compound thus obtained has been found to have the (R)-(+)-configuration. This compound will be referred to below by its published code number R115777 and has the following formula (V).

R115777 (Tipifarnib) is a potent, orally active inhibitor of farnesylprotein transferase. It is one of the most advanced of the farnesylprotein transferase inhibitors currently reported to be in clinical development, being one of the agents that have progressed to phase III studies.

R115777 has been found to have very potent activity against neoplastic diseases. Antineoplastic activity in solid tumors, such as breast cancer, as well as in haematological malignancies, such as leukemia, have been observed. Also combination studies have been carried out demonstrating that R115777 can be safely combined with several highly active anticancer drugs.

In WO 01/53289, the racemates (±) (4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-(4-methoxy-benzylamino)-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 1) and (±) 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-[(4-methoxy-benzylidene)-amino]-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (racemate 2) are prepared.

After chiral molecule separation using column chromatography, either the benzylamino or the benzilidine moiety of the resulting (+) and/or (−) enantiomers are converted to an amino group under acidic conditions.

In WO 97/21701, it is described (on page 9, line 7-14) that intermediates of formula (XIII), can be prepared by reacting an intermediate of formula (XIV), wherein W is an appropriate leaving group, such as, for example, halo, with an intermediate ketone of formula (XV). In WO 97/21701, it is described that this reaction can be performed by converting the intermediate of formula (XV) into an organometallic compound, by stirring it with a strong base such as butyl lithium and subsequently adding the intermediate ketone of formula (XV). It is further indicated that although this reaction gives at first instance a hydroxy derivative (i.e. R⁸is hydroxy), said hydroxy derivative can be converted into other intermediates wherein R⁸has another definition by performing art-known (functional group) transformations. The drawings of the compounds of formula (XIII), (XV) and (XIV) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.

In WO 97/21701, it is also described (from page 7 line 32, to page 8 line 6) that the compounds of formula (XVI), wherein R is C_1-6alkyl, R^{(2-8, 16-19)}can be a substituent chosen from lists as defined in WO 97/21701 and R¹has a meaning as defined in WO 97/21701 apart from hydrogen, may be prepared by hydrolysing an intermediate ether of formula (XIII), according to art-known methods, such as stirring the intermediate of formula (XIII) in an aqueous acid solution. An appropriate acid can be for instance hydrochloric acid. Subsequently the resulting quinolinone, wherein R¹is hydrogen, may be transformed into a quinolinone of formula (XVI) by art-known N-alkylation. The drawings of the compounds of formula (XIII) and (XVI) have been taken over from WO 97/21701 and the substituents in these drawings are as defined in WO 97/21701.

The synthesis of R115777 as originally described in WO 97/21701, is presented in scheme 1.

Herein, in step 1, the intermediate 1-methyl imidazole in tetrahydrofuran, is mixed with a solution of n-butyllithium in a hexane solvent to which is added chlorotriethylsilane (triethylsilyl chloride), followed by a further addition of n-butyllithium in hexane, the resulting mixture being cooled to −78° C. before the addition of a solution of a compound of formula (I), i.e. 6-(4-chlorobenzoyl)-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone in tetrahydrofuran. The reaction mixture is subsequently brought to room temperature, and then hydrolysed, extracted with ethyl acetate and the organic layer worked up to obtain a compound of formula (II), i.e. (±)-6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 2, the hydroxy compound of formula (II) is chlorinated with thionylchloride to form a compound of formula (III), i.e. (±)-6-[chloro(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 3, the chloro compound of formula (III) is treated, with NH₄OH in tetrahydrofuran to form the amino compound of formula (IV), i.e. (±)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

In step 4, the amino compound of formula (IV) is separated into its enantiomers by chiral column chromatography over Chiracel OD (25 cm; eluent: 100% ethanol; flow: 0.5 ml/min; wavelength: 220 nm). The pure (B)-fractions are collected and recrystallised from 2-propanol resulting in R115777, the compound of formula (V).

However, the procedure described in WO97/21701 has a number of disadvantages. For example, during the first step, the procedure results in the undesired formation of a corresponding compound of formula (XI), i.e. 6-[hydroxy(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone), in which the imidazole ring is attached to the remainder of the molecule at the 2-position of the ring, instead of the desired 5-position. At the end of the procedure, this results in the formation of a compound of formula (XII), i.e. 6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-2-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone.

Furthermore, the purification of compound (V) using chiral chromatography is expensive and disadvantageous in view of the large amounts of solvent needed and the specialised equipment required to perform a large scale chiral chromatography.

Another process for the synthesis of R115777 as described in WO 02/072574, is presented in scheme 2.

Herein, in step 1, 1-methyl imidazole in tetrahydrofuran is mixed with a solution of n-hexyllithium in a hexane solvent to which is added tri-iso-butylsilyl chloride, followed by a further addition of n-hexyllithium in hexane. The compound of formula (I) in tetrahydrofuran is then added to the reaction mixture, keeping the temperature between −5° C. and 0° C. The resulting product of formula (II) is isolated by salt formation.

In step 2, the chlorination reaction is effected by treatment of the compound of formula (II) with thionyl chloride in 1,3-dimethyl-2-imidazolidinone.

In step 3, the chloro compound of formula (III) is treated with a solution of ammonia in methanol. After the addition of water, the compound of formula (IV), precipitates and can be isolated.

In step 4, the compound of formula (IV) can be reacted with L-(−)-dibenzoyl tartaric acid (DBTA) to form the diastereomeric tartrate salt with formula (VI) i.e. R-(−)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone [R—(R*,R*)]-2,3-bis(benzoyloxy)butanedioate (2:3).

Finally, in step 5, the compound of formula (VI) is treated with aqueous ammonium hydroxide, to form the crude compound of formula (V) which is then purified by recrystallisation from ethanol to the pure compound (V).

PatentSubmittedGrantedNOVEL IV FORMULATION OF TIPIFARNIB [US2009042935]2009-02-12

Novel IV formulation of tipifarnib [US2007093449]2007-04-26

Medical devices to treat or inhibit restenosis [US2005154451]2005-07-14

FARNESYL PROTEIN TRANSFERASE INHIBITORS WITH IN VIVO RADIOSENSITIZING PROPERTIES [WO0001411]2000-01-13

Patent	Submitted	Granted
Process for the preparation of imidazole compounds [US6844439]	2004-07-15	2005-01-18
TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR [US2010331363]	2010-12-30
TREATMENT OF MITOCHONDRIAL DISORDERS USING A FARNESYL TRANSFERASE INHIBITOR [US2011060005]	2011-03-10
Diastereoselective Synthesis Process with 6-Bromo-4-(3-Chlorophenyl)-2-Methoxy-Quinoline [US7572916]	2007-12-20	2009-08-11
Anti-cancer phosphonate analogs [US7452901]	2006-04-13	2008-11-18
Diastereoselective Synthesis Process for the Preparation of Imidazole Compounds [US7456287]	2007-10-11	2008-11-25
Diastereoselective Addition of Lithiated N-Methylimidazole on Sulfinimines [US7524961]	2007-12-20	2009-04-28
Therapeutic phosphonate compounds [US7645747]	2006-11-23	2010-01-12
TREATMENT OF PROTEINOPATHIES USING A FARNESYL TRANSFERASE INHIBITOR [US2010160372]	2010-06-24
ANTI-CANCER PHOSPHONATE ANALOGS [US2010022467]	2010-01-28

…………………………….

http://www.google.co.in/patents/US7572916

EXAMPLE A.1 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(R)] (Compound 25)

Ti(OEt)₄(0.0162 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0032 mol) and (R)-(+)-2-methyl-2-propane-sulfinamide (0.0032 mol) in DCE (7 ml). The mixture was stirred and refluxed for 6 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO₄), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH₄OH 97/3/0.5), yielding 0.475 g of compound 25 (46%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-2-methyl-2-propanesulfinamide [(S(S)] can be obtained in an analogous way.

b) Preparation of N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(R)] (Compound 26)

n-Butyllithium (0.00081 mol) in hexane, was added dropwise at −78° C. to a mixture of 6-bromo-4-(3-chlorophenyl)-2-methoxy-quinoline (0.00081 mol) in THF (3 ml) under nitrogen flow. The mixture was stirred at −78° C. for 30 minutes. A solution of compound 25 (0.00065 mol) in THF (0.6 ml) was added. The mixture was stirred at −78° C. for 1 hour and 30 minutes, poured out into ice water and extracted with EtOAc. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm)(eluent: DCM/MeOH/NH₄OH 97/3/0.1). The pure fractions were collected and the solvent was evaporated, yielding 0.138 g (36%) of compound 26, melting point 153° C.

The compound N-[(4-chlorophenyl)((4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl)(1-methyl-1H-imidazole-5-yl)methyl]-2-methyl-2-propanesulfinamide [S(S)] can be obtained in an analogous way

c) Preparation of (S)-1-(4-chlorophenyl)-1-[4-(3-chlorophenyl)-2-methoxy-quinoline-6-yl]-1-(1-methyl-1H-imidazole-5-yl)-methylamine (Compound 27)

Hydrochloric acid in isopropanol was added to a solution of compound 26 (0.000018 mol) in methanol (4.2 ml). The mixture was stirred at room temperature for 30 minutes. The mixture was added to potassium carbonate (10%) on ice and extracted with ethyl acetate. The organic layer was separated, washed with a solution of saturated sodium chloride, dried (MgSO₄), filtered, and evaporated giving 0.086 g (100%) of compound 27, melting point 96° C., enantiomeric excess 88%.

d) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1H)-quinolin-2-one (Compound 28)

Compound 27 (0.00038 mol) in hydrochloric acid 3N (9.25 ml) and THF (9.25 ml), was stirred at 60° C. for 24 hours and evaporated, giving 0.18 g (100%) of compound 28, melting point 210° C.

EXAMPLE A.2 a) Preparation of N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(S)](Compound 29)

Ti(OEt)₄(0.0419 mol) was added to a mixture of (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (0.0084 mol) and (S)-(+)-p-toluenesulfinamide (0.0084 mol) in DCE (18 ml). The mixture was stirred and refluxed for 7 days, then cooled to room temperature. Ice water was added. The mixture was filtered over celite. Celite was washed with DCM. The organic layer was extracted with saturated sodium chloride. The organic layer was separated, dried (MgSO4), filtered, and the solvent was evaporated. This fraction was purified by column chromatography over silica gel (40 μm) (eluent: DCM/MeOH/NH₄OH 97/3/0.5), yielding 1.15 g of compound 29 (38%).

The compound N-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methylene)]-p-toluenesulfinamide [(S(R)] can be obtained in an analogues way.

B. Preparation of Final Compounds

EXAMPLE B.1 a) Preparation of (S)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone (Compound 30)

Compound 28 (0.00038 mol) was added to a solution of THF (1.8 ml) and NaOH 10N (1.8 ml). BTEAC (0.0019 mol) and methyliodide (0.00076 mol) were added and the mixture was stirred for 2 hours at room temperature. EtOAc was added. The organic layer was separated, dried (MgSO₄), filtered, and evaporated giving 0.149 g (83%) of compound 30, enantiomeric excess 86%.

……………………………..

Cyclization of 3- (3-chlorophenyl) -N-phenyl-2-propenamide (I) by means of polyphosphoric acid (PPA) at 100 C gives 4- (3-chlorophenyl) -1,2,3,4-tetrahydroquinolin- 2-one (II), which is condensed with 4-chlorobenzoic acid (III) by means of PPA at 140 C to yield 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1,2,3,4 -tetrahydroquinolin-2-one (IV). The dehydrogenation of (IV) by means of Br2 in bromobenzene at 160 C affords 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) quinolin-2 (1H) -one ( V), which is methylated with iodomethane and NaOH / benzyltrimethylammonium chloride in THF to provide 6- (4-chlorobenzoyl) -4- (3-chlorophenyl) -1-methylquinolin-2 (1H) -one (VI). Condensation of compound (VI) with 1-methylimidazole (VII) by means of butyllithium in THF gives the triaryl carbinol (VIII), which is finally treated with ammonia in THF to afford R-115777.

………………………………

paper

Org. Lett., Article ASAP

DOI: 10.1021/ol503292p

http://pubs.acs.org/doi/full/10.1021/ol503292p

Quinolinone derivatives were constructed via a Pd-catalyzed C–H bond activation/C–C bond formation/cyclization cascade process with simple anilines as the substrates. This finding provides a practical procedure for the synthesis of quinolinone-containing alkaloids and drug molecules. The utility of this method was demonstrated by a formal synthesis of Tipifarnib.

synthesis

http://pubs.acs.org/doi/suppl/10.1021/ol503292p/suppl_file/ol503292p_si_001.pdf

References

Angibaud, P.; Venet, M.; Filliers, W.; Broeckx, R.; Ligny, Y.; Muller, P.;Poncelet, V.; End, D. Eur. J. Org. Chem. 2004, 479.

see………….http://onlinelibrary.wiley.com/doi/10.1002/ejoc.200300538/abstract

(b) Filliers, W.; Broeckx, R.;Angibaud, P. U.S. patent, US7572916, 2009.

A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

SYNTHESIS Comments Off

Jan 082015

Graphical Abstract

http://pubs.rsc.org/en/Content/ArticleLanding/2015/OB/C4OB02376E#!divAbstract

A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions

Maria Victoria Rojo,*^a Lucie Guetzoyan^a and Ian. R. Baxendale^a^b

*Corresponding authors

^aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK

E-mail: mavirm@hotmail.com

^bDepartment of Chemistry, University of Durham, South Road, Durham, UK

Org. Biomol. Chem., 2015, Advance Article

DOI: 10.1039/C4OB02376E

An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.

info…………….

Insights into the iridium-catalyzed water oxidation mechanism from a DFT study

Dr. David Balcells, Prof. Odile Eisenstein, Prof. Robert H Crabtree, Agusti Lledos Departament de Quimica, Universitat Autonoma de Barcelona, Bellaterra, Spain; Institut Charles Gerhardt, Universite Montpellier 2, Montpellier, France; Department of Chemistry, Yale University, New Haven, United States

The development of a new energy model is a major challenge in modern chemistry. The climate change and the raise of oil prices prompt the development of clean and cheap energy resources. In this field, artificial photosynthesis is one of the most promising solutions.¹ The catalytic oxidation of water to dioxygen is a fundamental part of this process. The mononuclear iridium complex Cp*Ir(ppy)(Cl) (ppy = phenylpyridine) is one of the most efficient catalysts reported for this reaction (Figure).² DFT calculations support the oxo complex Cp*IrO(ppy) as the active species. The electronic structure of this complex is characterized by having the antibonding p*(Ir=O) orbitals half-occupied. The calculations suggest that the reaction mechanism consists of an intermolecular attack of water to the oxo ligand. This reaction involves the formation of the O-O bond and a proton transfer, which is assisted by the molecules of water solvating the catalyst.

Figure. Iridium-catalyzed water oxidation.

References
(1) Hammarström, L.; Hammes-Schiffer, S. Acc. Chem. Res. 2009, 42, 1859-1860.
(2) Hull, J. F.; Balcells, D.; Blakemore, J. D.; Incarvito, C. D.; Eisenstein, O.; Brudvig, G. W.; Crabtree, R. H. J. Am. Chem. Soc.2009, 131, 8730-8731.

more info………….

The water-soluble iridium complex {Cp*Ir[6,6′-(OH)₂bpy](H₂O)}[OTf]₂(Cp*=η⁵-pentamethylcyclopentadienyl, bpy=2,2′-bipyridine) was found to be a general and highly efficient catalyst for the N-alkylation of the poor nucleophilic sulfonamides with alcohols as alkylating agents in water. The presence of OH units in the bpy ligand is crucially important for the catalytic activity of the iridium complex. Mechanistic investigations revealed that the catalytically active species is a ligand-metal bifunctional iridium complex bearing an N,N′-chelated 2,2′-bipyridinated ligand and an aqua ligand. Notably, the present catalytic system and the proposed mechanism provide a new horizon and scope for the development of “hydrogen autotransfer (or hydrogen-borrowing) processes”.

The N-Alkylation of Sulfonamides with Alcohols in Water Catalyzed by the Water-Soluble Iridium Complex {Cp*Ir[6,6′-(OH)₂bpy](H₂O)}[OTf]₂

Panpan Qu,
Chunlou Sun,
Juan Ma and
Feng Li^*

Article first published online: 13 JAN 2014

DOI: 10.1002/adsc.201300711

http://onlinelibrary.wiley.com/doi/10.1002/adsc.201300711/abstract

http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-9-110

Functionalized carbenes

http://www.itqb.unl.pt/news/generating-new-catalysts

Diastereoselective [2+2] Photocycloaddition of a Chiral Cyclohexenone with Ethylene in a Continuous Flow Microcapillary Reactor

SYNTHESIS Comments Off

Jan 082015

The diastereoselective [2+2] photocycloaddition of ethylene to a chiral cyclohexenone was studied in a continuous flow microcapillary reactor. In all cases examined, the microcapillary reactor gave higher conversions and selectivity than the batch system, even after shorter irradiation times. These findings were explained by the superior temperature control, favorable light penetration, and generation of a gas–liquid slug flow with improved mass transfer in the microreactor.

Diastereoselective [2+2] Photocycloaddition of a Chiral Cyclohexenone with Ethylene in a Continuous Flow Microcapillary Reactor

http://www.akademiai.com/content/03163u0p80225v14/?p=bb18d4ec7c044f5c80013806493e8850&pi=2

Journal of Flow Chemistry
Publisher	Akadémiai Kiadó
ISSN	2062-249X (Print) 2063-0212 (Online)
Subject	Flow Chemistry
Issue	Volume 2, Number 3/September 2012
Pages	73-76
DOI	10.1556/JFC-D-12-00005

Authors

Kimitada Terao¹, Yasuhiro Nishiyama¹, Hiroki Tanimoto¹, Tsumoru Morimoto¹, Michael Oelgemöller², Kiyomi Kakiuchi¹

^{kakiuchi@ms.naist.jp, http://mswebs.naist.jp/LABs/kakiuchi/member/staff/CV_kakiuchi.pdf}

¹Nara Institute of Science and Technology (NAIST) Graduate School of Materials Science 8916-5 Takayama-cho, Ikoma Nara 630-0192 Japan
²James Cook University School of Pharmacy and Molecular Sciences Townsville QLD 4811 Australia

more………..

http://mswebs.naist.jp/LABs/kakiuchi/achevement/paper.htm

“Novel Enhancement of Diastereoselectivity of [2+2] Photocycloaddition of
Chiral Cyclohexenones to Ethylene by Adding Naphthalenes”
Ken Tsutsumi, Hiroaki Nakano, Akinori Furutani, Katsunori Endou, Abdurshit Merpuge
Takuya Shintani, Tsumoru Morimoto, Kiyomi Kakiuchi
J. Org. Chem. 2004, 69, 3, 785-789.

“Diastereoselective [2+2] Photocycloaddition of Polymer-Supported
Cyclic Chiral Enone with Ethylene”
Takuya Shintani, Kazunori Kusabiraki, Atsuko Hattori, Akinori Furutani, Ken Tsutsumi,
Tsumoru Morimoto, Kiyomi Kakiuchi
Tetrahedron Lett. 2004, 45, 9, 1849-1851.

“Diastereoselective [2+2] Photocycloaddition of Cyclohexenone Derivative with Olefines in Supercritical Carbon Dioxide”
Yasuhiro Nishiyama, Kazuya Nakatani, Hiroki Tanimoto, Tsumoru Morimoto, Kiyomi Kakiuchi
J. Org. Chem. 2013, 78, 7186-7193.

Highlighted in
ChemInform 2013, 44(44)

“Diastereoselective [2+2] Photocycloaddition of Chiral Cyclic Enones with Olefins in Aqueous Media Using Surfactants”
Yasuhiro Nishiyama, Mikiko Shibata, Takuya Ishii, Tsumoru Morimoto, Hiroki Tanimoto,
Ken Tsutsumi, Kiyomi Kakiuchi
Molecules, 2013, 18, 1626-1637.

“Highly diastereodifferentiating and regioselective [2+2]-photoreactions using methoxyaromatic menthyl cyclohexenone carboxylates”
Inga Inhulsen, Naoya Akiyama, Ken Tsutsumi, Yasuhiro Nishiyama, Kiyomi Kakiuchi
Tetrahedron 2013, 69, 782-790.

“Diastereodifferentiating [2+2] Photocycloaddition of Chiral Cyclohexenone Carboxylates with Cyclopentene by a Microreactor”
Kimitada Terao, Yasuhiro Nishiyama, Shin Aida, Hiroki Tanimoto, Tsumoru Morimoto,
Kiyomi Kakiuchi
J. Photochem. Photobiol. A: Chem. 2012, 242, 13-19.

Oleocanthal for treating pain

Uncategorized Comments Off

Jan 062015

“Oleocanthal” is specifically deacetoxydialdehydic ligstroside aglycone, which exists as a single isomer (enantiomer). The (-)-enantiomer is the natural product and has the following chemical formula:

http://www.google.com/patents/EP2583676A1?cl=en

The Trustees of The University of Pennsylvania,

Monell Chemical Senses Center,

Russell S. J. Keast, Qiang Han, Amos B. Smith Iii, Gary K. Beauchamp, Paul A. S. Breslin, Jianming Lin,

In 1993, Montedoro and co-workers reported the isolation of a new class of phenolic compounds (1-4), including the dialdehydic and aldehydic forms of ligstroside (5) and oleuropeine (6) from virgin olive oils (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234) (See Figure 1 for structures). These phenolic compounds comprise important minor constituents of virgin olive oils that have been implicated in the organoleptic characteristics including bitterness, pungency, and astringency (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420 ).
In addition, these agents have been suggested to contribute to the oxidative stability of virgin olive oil and as such are associated with health benefits of olive oils, specifically their antioxidant/anticancer activities (Owen, R.W. et al. (2000) Food Chem. Toxicology 38:647-659; Owen, R.W. et al. (2000) Eur. J. Cancer 36(10):1235-1247; Baldioli, M. et al. (1996) J. Am. Oil Chem. Soc. 73(11):1589-1593; Manna, C. et al. (2002) J. Agric. Food Chem. 50(22):6521-6526).
Similar structural features have been reported in the constituents of the Jasminum (Somanadhan, B. et al. (1998) Planta Medica 64:246-50; Takenaka, Y. et al. (2002) Chem. & Pharm. Bull 50(3):384-389) and related plant species (Takenaka, Y. et al. (2002) Phytochemistry 59(7):779-787). It has been shown that both ibuprofen and a Mediterranean diet (i.e., high in olive oil) both decrease the risk/incidence for breast and lung cancer.
In 2003, Busch and co-workers at Unilever Research and Development Vlaardingen (The Netherlands) identified deacetoxydialdehydic ligstroside aglycone as a principal contributor to the potent pungent (burning) sensation at the back of throat associated with high quality virgin olive oils (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420). Studies at Firmenich, Inc., reached the same conclusion (Firmenich, Inc. study). The structure of 1 was assigned,

employing a series of 1 and 2D NMR experiments (Andrewes, P. et al. (2003) J. Agric. Food Chem. 57:1415-1420), in conjunction with comparison to literature data (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234). The absolute stereochemistry remained undetermined. That 1 was responsible for the strong pungent (burning) sensation at the back of the throat was based on an extensive series of HPLC fraction analysis, omission analysis and correlation, and hydrolysis studies, in conjunction with human sensory studies. Andrewes et al., however, acknowledged that “a coelution compound causing the burning sensation” could not be eliminated without completing a synthesis of 1, which they stated to be “extremely challenging.”

EXAMPLES

Example 1: Isolation of deacetoxydialdehydic ligstroside aglycone “Oleocanthal”A. Synthesis of Oleocanthal

Retrosynthetically, we envisioned both enantiomers of (1) to derive from the enantiomeric forms of cyclopentanediols (7) via oxidative cleavage of the diol moiety (Scheme 1). The requisite cyclopentanediols (7) in turn would be prepared from cyclopentanones (+)- and (-)-(10), via alkylation to introduce stereoselectively the side chain from the convex face, followed by stereoselective Wittig ethylnation and removal of the acetonide moiety (Scheme 1).

(5) Initially (+)- and (-)-cyclopentanones (10) were prepared via the sulfoximine and/or enzymatic protocols introduced and developed by Johnson (Johnson, C.R. and T. Penning (1988) J. Am. Chem. Soc. 110:4726-4735; Johnson, C.R. (1998) Acc. Chem. Res. 31:333-341). Although effective on modest scale (10-100mg), the requirement for gram quantities of the oleocanthals demanded that we secure for more scalable routes to (10). Towards this end, we optimized a hybrid of synthetic approaches (Moon, H. et al. (2002) Tetrahedron: Asym. 13(11):1189-1193; Jin, Y. et al. (2003) J. Org. Chem. 68(23):9012-9018; Yang, M. (2004) J. Org. Chem. 69(11):3993-3996; Palmer, A. et al. (2001) Eur. J. Org. Chem. 66(7):1293-1308; Paquette, L. and S. Bailey (1995) J. Org. Chem. 60:7849-7856) as outlined in Scheme 2. Importantly, both enantiomers of (10) could be prepared in multi-gram quantities in 7 steps, with an overall efficiency of 40% from inexpensive D-(-)-ribose. Key elements of both sequences entailed vinyl Grignard addition to the enantiomers of aldehyde (12), followed in turn by ring closing metathesis (RCM), PCC oxidation and hydrogenation (Scheme 2).
Alkylation of (+)- and (-)- cyclopentanone (10) with methyl bromoacetate was then anticipated to proceed from the less hindered convex face of the bicyclic skeleton to install the side chain in a stereoselective fashion. Initial attempts however to alkylate (-)-(8) with methyl bromoacetate employing LDA in the presence of HMPA furnished only a complex mixture containing only trace amounts of (-)-(16). Neither addition of Cu(I) (Johnson, C.R. and T. Penning (1988) J. Am. Chem. Soc. 110:4726-4735) reportedly to suppress side reactions, nor the use of the corresponding tin enolate [generated by treatment of (-)-(10) in THF with LDA, followed by HMPA and tributyltin chloride (Suzuki, M. et al. (1985) J. Am. Chem. Soc. 107:3348; Nishiyama, H. et al. (1984) Tetrahedron Lett. 25:223)] improved the situation. Alkylation of the zinc enolate of (-)-(10) [generated by treatment of (-)-(10) in THF with 1.1 eq. LHMDS, followed in turn by HMPA (3.0 eq.) and dimethyl zinc (Morita, Y. et al. (1989) J. Org. Chem. 54:1787-1788) (1.0 eq.)] with methyl bromoacetate, however consistently furnished (-)-(16) in 55-60% yield as a single diastereomer (this reaction was fairly clean except some baseline materials. Using t-butyl bromoacetate instead of methyl bromoacetate did not improve the yield) (Scheme 3).
Wittig ethylnation of (-)-(16) was next achieved with ethyltriphenylphosphine bromide. Best results were obtained employing LDA as the base at -45°C. Although excellent stereoselectivity (ca., 10:1 E:Z) favoring the E-isomer (-)-(17) was achieved, the yield was only modest (42%), presumably due to the ease of enolization of (-)-(16) (Edmunds, M. “The Wittig Reaction” In MODERN CARBONYL OLEFINATION, Takeda, Ed., John Wiley & Sons, New Jersey, 2004). Interestingly, the stereoselectivity varied dramatically with reaction temperature. At 0°C, the E:Z selectivity was 3.3:1, while at room temperature the selectivity was 1.6:1. Assignment of the E geometry of the olefin was based on NMR NOE analysis (Scheme 4).
Hydrolysis of ester (-)-(17) (LiOH/THF/H₂O) next afforded acid (-)-(18), which was subjected to Mitsunobu esterification (Mitsunobu, O. (1981) Synthesis 1-28) with 4-hydroxyphenethyl alcohol to furnish phenol (-)-(19) in 92% yield. As expected, the Mitsunobu reaction proceeded with complete chemoselectivety at the primary hydroxyl (Appendino, G. et al. (2002) Org. Lett. 4:3839-3841). Completion of the synthesis of (-)-oleocanthal (1) was then achieved via liberation of the vicinal diol moiety (4N HCl/acetonitrile), followed by oxidative cleavage (NaIO₄); (-)-oleocanthal (1) was identical in all respects (e.g., ¹H and ¹³C NMR, IR and HRMS) with an authentic sample isolated from virgin olive oil, the latter possessing spectral data identical to that reported in the literature (Montedoro, G. et al. (1993) J. Agric. Food Chem. 41:2228-2234). The structural assignment of (1) was also confirmed by COSY NMR analysis. Synthetic (-)-(1) displayed a small negative optical rotation ([α]²⁵D -0.78, c = 0.9, CHCl₃) identical to that obtained from a sample isolated from virgin olive oil ([α]²⁵ _D -0.9, c = 2.0, CHCl₃). Thus the stereochemistry of (-)-oleocanthal (1) is 3S, 4E. The enantiomer of the natural product (+)-(1) was prepared via a similar reaction sequence beginning with (+)-(10) to furnish (+)-1 ([a]²⁵ _D +0.73, c = 0.55, CHCl₃) (Scheme 5).
In summary, an effective, scalable synthesis of both enantiomers of oleocanthal (1) has been achieved, each in 13 steps (7 % overall yield) from inexpensive (D)-(-)-ribose, requiring only 6 chromatographic separations. The structural similarity of oleocanthal to a number of related natural products (Somanadhan, B. et al. (1998) Planta Medica 64:246-50; Takenaka, Y. et al. (2002) Chem. & Pharm. Bull. 50(3):384-389; Takenaka, Y. et al. (2002) Phytochemistry 59(7):779-787) suggests that the synthetic approach presented here should also be applicable to their construction.

Figure 3 shows the synthetic scheme of (-)-oleocanthal.

Figure 4 shows the synthetic scheme of (+)-oleocanthal.

Synthesis of Methoxyisopropyl (MIP)-Protected (R)-Mandelonitrile and Derivatives in a Flow Reactor

SYNTHESIS Comments Off

Jan 042015

Cyanohydrins are synthetically versatile chiral building blocks in organic synthesis. They can be conveniently synthesized in enantiomerically pure form via chemoenzymatic hydrogen cyanide addition onto the corresponding aldehyde using hydroxynitrile lyase.

Recently, we reported that such transformations can be efficiently carried out in a continuous flow manner using microreactors. Since racemization of enantiopure cyanohydrins occurs readily under slightly basic conditions, they should be protected before the follow-up reactions, preferably under acidic conditions.

In this contribution, we demonstrate that the methoxyisopropyl protection of mandelonitrile can be conveniently optimized in an automated microscale continuous flow system and subsequently scaled up under the same conditions by applying a larger flow reactor.

Synthesis of Methoxyisopropyl (MIP)-Protected (R)-Mandelonitrile and Derivatives in a Flow Reactor

http://www.akademiai.com/content/9488206462627n38/?p=6ed413d7b9fb47fe9fe7e1262c37694f&pi=2

Journal of Flow Chemistry
Publisher	Akadémiai Kiadó
ISSN	2062-249X (Print) 2063-0212 (Online)
Subject	Flow Chemistry
Issue	Volume 2, Number 4/December 2012
Pages	124-128
DOI	10.1556/JFC-D-12-00008

Authors

Mariëlle M.E. Delville, Jasper J.F. Gool, Ivo M. Wijk, Jan C.M. Hest, Floris P.J.T. Rutjes¹ ^{f.rutjes@science.ru.nl}

¹Institute for Molecules and Materials Radboud University Nijmegen Heyendaalseweg 135 6525 AJ Nijmegen the Netherlands

Floris P.J.T. Rutjes

Groepsfoto IMM 2014 klein-1

The IMM-office is located on the 3rd floor of the Huygens building, which is at walking distance (about 5 min.) from the railway station Nijmegen Heyendaal.